CN101420991A - Polymer compositions and methods for their use - Google Patents

Abstract

A combination including an anti-fibrosis agent and/or a polymer composition can be used in various medical applications including preventing surgical operation synechia, treating inflammatory arthritis, treating scar and keloid, treating blood vessel disease, and preventing cartilage damage.

Description

Polymer composition and using method thereof

Background of invention

Invention field

Generality of the present invention relates to the polymer composition that comprises therapeutic agent (for example fibre modification inhibitor or anti-infective) and relates to the method for preparing and use this based composition.

The description of association area

Polymer composition, particularly those comprise that synthetic polymer or synthetic combination of polymers compositionss with naturally occurring polymer have been applied to medical applications, such as prevention of surgical surgical adhesions, tissue engineered and be used as the bioadhesive material.United States Patent (USP) 5,162 has been described in 430 by making collagen protein and synthesis hydrophilic polymer, such as the application of the collagen protein-synthetic polymer conjugate of various polyethyleneglycol derivative covalent bond preparations.In relevant patent, United States Patent (USP) 5,328 has been described the various activated form and the various junctional complex of Polyethylene Glycol in 955, and they can be used to produce the collagen protein-synthetic polymer conjugate with certain limit physics and chemical characteristic.United States Patent (USP) 5,324 also described synthetic hydrophilic polyglycol conjugate in 775, but these conjugates comprises naturally occurring polymer, such as polysaccharide.Disclosed the crosslinked biomaterials compositions of the mixture preparation of using hydrophobic crosslinking agent or hydrophilic and hydrophobic crosslinking agent among EP 0 732 109 A1.United States Patent (USP) 5,614 has been described the biological adhesive that comprises the collagen protein that uses multifunctional activatory synthesis hydrophilic crosslinked polymer in 587.The U.S. Patent application serial number US 08/403 that submit to March 14 nineteen ninety-five, disclosed the compositions that is used for the prevention of surgical surgical adhesions in 360, it comprises host material and anti binding agent, and wherein host material comprises that collagen protein and binding agent can comprise at least one tissue reactive functional group and at least one substrate reaction functional group.The U.S. Patent application serial number US 08/476 that submit to June 7 nineteen ninety-five, disclose the collagen protein that uses multifunctional activatory synthesis hydrophilic crosslinked polymer in 825 and used this based composition to influence adhesion between first kind of surface and the second kind of surface, wherein at least aly in first kind and the second kind of surface can be the natural tissues surface.United States Patent (USP) 5,874 has been described in 500 and has been comprised a kind of composition and another kind of crosslinking polymer composition that has the composition of a plurality of electrophilic groups that has a plurality of nucleophilic groups.The covalent bond of nucleophilic group and electrophilic group forms three dimensional matrix, and it has various medical applications, comprises the tissue adhesion, is used for the pan coating of synthetic implant and passs medicine.More recent research and development comprise adds the third composition have nucleophilic group or electrophilic group, described in the United States Patent (USP) 6,458,889 of Trollsas etc.US 5,874, and 500, disclosed in-situ cross-linked or crosslinked polymer among US 6,051,648 and the US 6,312,725, particularly poly-(ethylene glycol) based polyalcohol, they are used to produce cross-linked composition.West and Hubbell (Biomaterials) have disclosed Polyethylene Glycol-common-polypropylene glycol hydrogel POLOXAMER 407 (the BASF Corporation that use photopolymerisable Polyethylene Glycol-common-lactic acid diacrylate hydrogel and physical crosslinking among (1995) 16:1153-1156 at " biomaterial ", Mount Olive, NJ) prevention of postoperative adhesion.Polymerisable cyanoacrylate has also been described as the application of tissue adhesive (Ellis, etc., " department of otorhinolaryngology magazine " be 19:68-72 (1990) (J.Otolaryngol.)).Described two-partial synthesis polymer composition, when being mixed with each other, they form covalent bond (PCTWO 97/22371, is equivalent to U. S. application serial number US 08/769,806 United States Patent (USP) 5,874,500) each other and with the tissue surface that contacts.

Summary of the invention

Briefly, provide a kind of compositions among the present invention in one aspect, it contains fibrosis agent and polymer or prepolymer, promptly forms the chemical compound of polymer.In one embodiment, these compositionss form when its precursor is delivered to position on position in the body or the implant in position.For example, compositions of the present invention comprises the cross-linking reaction product, and the two kind chemical compounds (multifunctional many nucleophilic compounds and multifunctional many electrophilic compound) of this product in the presence of the fibrosis agent is arranged form when being delivered in host's (in other words being the patient) body the position.Yet compositions of the present invention also comprises fibrosis agent and mixture of polymers, wherein said composition can be delivered to position in patient's body so that obtain beneficial effect, for example, and beneficial effect as herein described.

In some cases, described polymer self is used for the whole bag of tricks, comprises the prevention of surgical surgical adhesions.

The present invention provides in one aspect of the method and has been used for the treatment of and/or the method for prevention of surgical surgical adhesions.For example, described surgical operation adhesion can be the result of spinal column or neurosurgery operation, gynecilogical operation operation, abdominal operation operation, cardiac surgery procedure, orthopaedic surgery operation, reconstruction operations operation and cosmetic surgery operation.

The present invention provides in one aspect of the method and has been used for the treatment of or prevents inflammatory arthritis, such as the method for osteoarthritis and rheumatoid arthritis.This method comprises sends the fibrosis agent to the patient that these needs are arranged, and randomly sends with polymer.

The present invention provides in one aspect of the method and has been used for for example method of contingent cartilage loss (cartilage loss) after joint injury of prevention.This method comprises sends the fibrosis agent to the patient's that these needs are arranged joint, randomly sends with polymer.

The present invention provides the method that is used for the treatment of hypertrophic cicatrix and keloid (keloids) in one aspect of the method.This method comprises sends the fibrosis agent to the patient's that these needs are arranged cicatrix or keloid, randomly sends with polymer.

The present invention provides in one aspect of the method and has been used for the treatment of angiopathy, for example narrow, restenosis or atherosclerotic method.This method comprises sending the fibrosis agent around the blood vessel.

The method that is used to implant medical apparatus is provided among the present invention in one aspect, has comprised: (a) soaked into implanted or implanted the host tissue of described medical apparatus: i) fibrosis agent with following composition; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host.

The present invention randomly provides in aspect independently: be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus with the fibrosis agent; (b) each described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus with anti-infective; (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus with polymer; (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus with the compositions that comprises fibrosis agent and polymer; (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus with the compositions that comprises anti-infective and polymer; (b) described medical apparatus is implanted described host; Method with being used to implant medical apparatus comprises: (a) soak into implanted or implanted the host tissue of described medical apparatus with the compositions that comprises fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host.

These and other aspect of the present invention is apparent with reference to hereinafter the detailed description and the accompanying drawings the time.In addition, this paper has listed the various lists of references of more detailed description operating procedure and/or compositions, and thus their full content is incorporated herein by reference.

The accompanying drawing summary

Accompanying drawing 1 be the expression cell cycle inhibitor how biology by way of in one or more steps on the sketch map that works.

Accompanying drawing 2 is that expression is used to estimate the chart of mitoxantrone to the screening test result of the effect of the NO production of THP-1 macrophage.

Accompanying drawing 3 is that expression is used to estimate the chart of Bay 11-7082 to the screening test result of the effect of the TNF-α generation of THP-1 macrophage.

Accompanying drawing 4 is that expression is used to estimate the chart of rapamycin concentrations to the screening test result of the effect of the TNF α generation of THP-1 macrophage.

Accompanying drawing 5 is that expression is used to estimate the chart of rapamycin to the screening test result of the effect of human fibroblasts propagation.

Accompanying drawing 6 is that expression is used to estimate the chart of mitoxantrone to the screening test result of the effect of human fibroblasts propagation.

Accompanying drawing 7 is that expression is used to estimate the chart of paclitaxel to the screening test result of the effect of human fibroblasts propagation.

Accompanying drawing 8 is expression not impaired carotid photos from rat air bag damage model.

Accompanying drawing 9 is expression impaired carotid photos from rat air bag damage model.

Accompanying drawing 10 is carotid photos that paclitaxel/mesh is handled in the expression rat air bag damage model.

Accompanying drawing 11A has described the transcriptional regulatory of matrix metalloproteinase with diagram.

Accompanying drawing 11B is the trace that expression IL-1 stimulates the AP-1 transcriptional activity.

Accompanying drawing 11C is the expression inductive chart in conjunction with active reduction of IL-1 in the lysate of the pretreated chondrocyte of paclitaxel of use by oneself.

Accompanying drawing 11D is that expression IL-1 induces collagenase and the molten stromatin enzyme on the rna level in the increase chondrocyte, and this inducing can be because of the trace that is suppressed with the paclitaxel pretreatment.

Accompanying drawing 12A-H is the trace of the effect of the various anti-microtubule agent of expression in suppressing collagenase expression.

Accompanying drawing 13 is that expression is used to estimate the chart of paclitaxel to the screening test result of the effect of smooth muscle cell migration.

Accompanying drawing 14 is that expression is used to estimate the chart of geldanamycin to the screening test result of the effect of the IL-1 β generation of THP-1 macrophage.

Accompanying drawing 15 is that expression is used to estimate the chart of geldanamycin to the screening test result of the effect of the IL-8 generation of THP-1 macrophage.

Accompanying drawing 16 is that expression is used to estimate the chart of geldanamycin to the screening test result of the effect of the MCP-1 generation of THP-1 macrophage.

Accompanying drawing 17 is that expression is used to estimate the chart of paclitaxel to the screening test result of the effect of smooth muscle cell proliferation.

Accompanying drawing 18 is that expression is used to estimate the chart of paclitaxel to the screening test result of the effect of Mus RAW 264.7 macrophage systems propagation.

Accompanying drawing 19 is expression charts with the Hartley Cavia porcellus knee joint joint scoring average rank with ACL infringement of paclitaxel treatment.Scoring descends and represents that the cartilage scoring improves.Dose response trend has significance,statistical (p＜0.02).

Accompanying drawing 20A-C is the example of Hartley Cavia porcellus knee joint cross section of the animal of reference substance and paclitaxel treatment.Accompanying drawing 20A. represents the check sample of cartilage to bone erosion.Accompanying drawing 20B. represents the abrasive dose of paclitaxel 1 of cartilage (low dosage).Accompanying drawing 20C. represents the less damaged dose of paclitaxel 2 of cartilage (median dose).

Accompanying drawing 21A-F is for from natural (health) knee joint (accompanying drawing 21A and 21D) with have by giving the wave carrier piece of organizing of the painted representational synovial tissue of arthritic knee joint safranine-O that albumin (accompanying drawing 21B and 21C) in Freund's complete adjuvant or chondrus ocellatus Holmes polysaccharide (carageenan) (accompanying drawing 21E and 21F) bring out.The arthritis knee joint is accepted the microsphere (accompanying drawing 21C and 21F) of reference substance (accompanying drawing 21B and 21E) or 20% paclitaxel-load.Data declaration proteoglycan red colouring in the arthritis knee joint of reference substance framboid treatment reduces and to the proteoglycan protection feature of the preparation of paclitaxel-load.

Detailed Description Of The Invention

Definition

Before setting forth the present invention, the definition of at first illustrating some term used herein may be helpful for understanding the present invention.

" fibre modification " or " formation of scar scar " or " fibre modification reaction " refer to damage or medical science intervention are reacted and formation fibroid (scar) tissue. The therapeutic agent that suppresses fibre modification or the formation of scar scar is referred to herein as " fibre modification inhibitor ", " fibrillatable inhibitor ", " anti-scar scar forming agent " etc., wherein these activating agents suppress fibre modification by one or more mechanism, and described mechanism comprises: suppress inflammation or acute inflammatory reaction; The migration or the propagation that suppress phoirocyte (as fibroblast, smooth muscle cell, VSMC); Suppress Angiogenesis; Reducing extracellular matrix (ECM) produces or promotes ECM to decompose; And/or inhibition tissue remodeling. In narrow space after cicatrization occurs in operation or instrumentation (comprise implant medical device or implant) (such as in chamber) and make health passage (such as blood vessel, intestines and stomach, respiratory tract, the urinary tract, women or male sex's genital tract, Europe Stuckey pipe difficult to understand (eustacian) etc.) while partially or completely by cicatricial tissue, being blocked, this situation is called " narrow " (narrowing down). After the health passage of opening by operation (such as placing medical device or implant) success was at first blocked again, this situation was called " ISR ".

Synonym uses " host ", " people ", " experimenter ", " patient " etc. to represent wherein to implant the biology of apparatus of the present invention or implant.

" implantation " referred to that wholly or in part apparatus for placing or implant are in the host. When a part of installing reached or extend to the host outside, device was partly implanted.

Synonym uses " inhibition fibre modification ", " minimizing fibre modification ", " inhibition cicatrization " etc. to represent the effect of activating agent or composition, they cause fibrose formation to have the statistically minimizing of conspicuousness, are lacking the formation of estimating to occur described fibrose under described activating agent or composition.

" anti-infective " refers to pre-preventing microorganism growth and/or slows down microorganism growth rate and/or at activating agent or near the activating agent position, directly microorganism is produced activating agent or the composition of toxic action. Can estimate that these processes are being positioned at or near described activating agent or composition place compare to have significance,statistical with the effect under there is no described activating agent or composition level, are occurring.

" suppress infect " refers to activating agent or composition and prevents that microorganism is in the ability that is positioned at or accumulates and/or breed near described activating agent place. Can estimate that these processes are being positioned at or near described activating agent or composition place compare to have significance,statistical with the effect under there is no described activating agent or composition level, are occurring.

" inhibitor " refers to prevent the biological process generation or slows down the speed of biological process generation or the activating agent of degree. Described process can be that general process such as scar scar form or refer to specific biological agent, as the molecular process that for example causes cell factor to discharge.

" antagonist " refers to prevent the biological process generation or slows down the speed of biological process generation or the activating agent of degree. Although this process can be general process, general this refers to drug Mechanism, and its Chinese traditional medicine and molecule are competed the bioactive molecule site or prevented molecule and the molecular locus interaction. In these cases, effect is that molecular process is suppressed.

" agonist " is meant stimulating organism process or the speed of biological process generation or the activating agent of degree.Described process can be general process such as the formation of scar scar or refer to specific biological agent, as for example causing the molecular process of release of cytokines.

" anti-microtubule agent " should be understood to comprise any protein, peptide, chemicals or other molecule of infringement microtubule function, for example by preventing polymerization or stable polymerization.The stabilize microtubules polymeric compounds is referred to herein as " microtubule stabilizer ".Various methods can be used to measure the anti-microtubule activity of specific compound, comprise for example (" cancer communication " (Cancer Lett) 79 (2): 213-219 such as Smith, 1994) and the test described of Mooberry etc. (" cancer communication " (Cancer Lett) 96 (2): 261-266,1995).

Synonym uses " medical apparatus ", " implant ", " device ", " medical treatment device ", " medical implant ", " implant/device " to be waited and represents for one or more treatments or prevent purpose and be placed into the intravital any object of patient partial or completely, as be used to recover physiological function, alleviate symptom, delivering therapeutic agents and/or reparation or replacement or enhancing organ equivalent damage or ill and tissue with disease association.Although usually by allogenic biocompatibility synthetic material (for example, other rustless steel of medical grade, titanium and other metal; Polymer is such as polyurethane, silicon, PLA, PLGA and other material) form, but some medical apparatus and implant comprise and derive from animal (for example, " xenograft " is such as whole animal organ; Animal tissue is such as cardiac valve; Natural existence or chemical modification molecule are such as collagen protein, hyaluronic acid, protein, carbohydrate etc.), (for example, " alloplast " is such as complete organ for people's donor; Tissue is such as bone graft, skin graft etc.) or derive from the material of patient (for example, " autograft " is such as saphenous vein graft, skin graft, tendon/ligament/muscle graft) itself.The concrete representational example of using medical apparatus in the present invention includes, but are not limited to: the blood vessel stent; The gastrointestinal stent; Trachea/bronchus stent; Reproduction-urinary system stent; The ENT stent; The intraarticular implant; Intraocular lens; The implant that is used for hypertrophic cicatrix and keloid; Blood vessel graft; Connecting device coincide; Implantable sensor; Implantable pump; Soft tissue implant (implant of for example improving looks and the implant that is used for reconstructive surgery); Implantable electric installation is such as implantable nerve stimulator and implantable electric conductance connection; The adhesion barrier that surgery is used; The glaucoma drainage system; Surgical operation thin film or mesh; Prosthetic heart valve; The tympanostomy pipe; Penile implant; Endotracheal tube and tracheostoma intubate; Peritoneal dialysis catheters; The intracranial pressure monitor; IVCF; Central vein conduit (CVCs); Ventricular assist device (for example, LVAD); Spinal prostheses; Catheter (foley's catheter); The artificial urinary bladder sphincter; Rectificating surgery implant; With the gastrointestinal drainage tube.

" cartilage protection " refers to and prevents the cartilage loss.Cartilage is formed by chondrocyte, and cartilage protection is that the protection chondrocyte is not so that they can be dead.

" release of activating agent " is meant activating agent or its subcomponent and/or its (or interior) maintenance activity on described device/implant surface that has broken away from from implant/device existing on the significance,statistical.

" biodegradable " is meant the material that degradation process is mediated and/or carried out therein by biosystem to small part." degraded " is meant that polymer chain is cracked into oligomer and monomeric chain breaking process.Chain rupture can take place by different mechanisms, comprises, for example chemical reaction (for example hydrolysis) or by heat or photolysis process.Depolymerization for example can use gel permeation chromatography (GPC) to characterize, the variation of polymer molecular weight in gel permeation chromatography monitoring erosion and the drug release process.Biodegradable also the finger, can be by the material of erosion process degraded, and this erosion process is mediated by biosystem and/or carries out in biosystem." erosion " is meant that wherein material is from the process of body disengaging.In the situation of polymer system, material can be the part of monomer, oligomer, main polymer chain or the part of polymer body.Erosion comprises (i) surface erosion, wherein corrodes only to act on stromal surface but not inside; (ii) body corrodes, wherein whole system cracking in whole substrate by fast hydrating and polymer chain.The type that depends on polymer, corrode usually and (for example take place by three kinds of fundamental mechanisms, referring to Heller, J., " the crucial summary of the CRC in the medicine carrier system " (CRC Critical Reviewin Therapeutic Drug Carrier Systems) (1984), 1 (1), 39-90); Siepmann, J. etc., " senior medicament research and development summary " (Adv.Drug Del.Rev.) (2001), and 48,229-247): (1) is by covalent cross-linking dissolving and as the water-soluble polymer of crosslinked or main chain solubilising experience hydrolytic rupture not; (2) make initial water-insoluble polymer solubilising by hydrolysis, ionizing or protonated side group; (3) by the main chain cracking hydrophobic polymer is converted into soluble small molecular.Characterize erosive technology and comprise heat analysis (for example DSC), X-ray diffraction, scanning electron microscopy (SEM) (SEM), ESR spectrum method (EPR), NMR imaging and recording quality loss in the erosion experiment process.For framboid, can use photon correlation spectroscopy (PCS) and other grain diameter measurement technology and monitor the size differentiation in time of erodible device.

As used herein, " analog " be meant structurally be similar to parent compound, but the chemical compound of slightly different on forming (for example atom or functional group's difference, increase or remove).Analog can have or can not have chemistry or the physical property different with original chemical compound, and can or can not have the biology and/or the chemism of improvement.For example, compare with parent compound, analog can be more hydrophilic or it can have the reactivity of change.Analog can be simulated the chemistry and/or the biologic activity (that is, it can have similar or identical activity) of parent compound, perhaps in some cases, can have activity increase or that reduce.Analog can be (for example reorganization) variant that the natural or non-natural of original chemical compound exists.The example of analog have mutein (promptly wherein at least one aminoacid lacked, added or by the protein analogue of another aminoacid replacement).The analog of other type comprises the chirality variant of other type of isomer (enantiomer, diastereomer etc.) and chemical compound, and constitutional isomer.Analog can be the side chain or the ring-type variant of straight chain compound.For example, straight chain compound can have side chain, otherwise is exactly to be substituted and to give the analog of some ideal performance (for example hydrophilic of Gai Shaning or bioavailability).

As used herein, " derivant " is meant the form that the chemistry of chemical compound or biology modify, and its similar is derived from this parent compound in parent compound and (in fact or in theory)." derivant " is that with the difference of " analog " parent compound can be the raw material that produces " derivant ", and parent compound not necessarily produces " analog " as raw material.Derivant can or can not have chemistry different with parent compound or physical property.For example, compare with parent compound, derivant can be more hydrophilic or it can have the reactivity of change.Derivatization (promptly modifying) can comprise the intramolecular one or more parts of replacement (for example functional group changes).For example, hydrogen atom can be replaced as fluorine or chlorine by halogen, and perhaps hydroxyl (OH) can (COOH) be replaced by carboxylic moiety.Term " derivant " also comprises the conjugate and the prodrug (promptly can be converted into the derivant of the chemical modification of original chemical compound under physiological condition) of parent compound.For example, prodrug can be the inactive form of activating agent.Under physiological condition, prodrug can be converted into the activity form of chemical compound.For example, can form prodrug by with one or two hydrogen atom on acyl group (acyl group prodrug) or carbamate groups (carbamate prodrugs) substituted nitrogen atom.Relevant with prodrug more specifically information is for example seen Fleisher etc., " the senior medicine summary of passing " (Advanced Drug DeliveryReviews) 19 (1996) 115; " drug design " (Design of Prodrugs), H.Bundgaard (ed.), Elsevier, 1985; Or H.Bundgaard, " future drugs " (Drugs ofthe Future) 16 (1991) 443.Term " derivant " also is used to describe all solvates of parent compound, for example hydrate or the adduct adduct of alcohols (for example with), active metabolite and salt.The type of the salt that can prepare depends on the character of chemical compound interior section.For example, acidic-group, for example hydroxy-acid group for example can form alkali metal salt or alkali salt (for example sodium salt, potassium salt, magnesium salt and calcium salt, the salt that also has the quaternary ammonium ion that can tolerate with physiology, with the acid-addition salts of the organic amine that can tolerate with ammonia and physiology, the organic amine that described physiology can tolerate is as for example triethylamine, ethanolamine or three-(2-ethoxy) amine).Basic group can be for example forms acid-addition salts with mineral acid or organic carboxyl acid and sulfonic acid, described mineral acid example hydrochloric acid, sulphuric acid or phosphoric acid, described organic carboxyl acid and sulfonic acid such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-methyl benzenesulfonic acid.The chemical compound that contains basic group and acidic-group simultaneously for example also contains carboxyl except basic nitrogen atom, can be used as amphion and exist.Can obtain salt by conventional method well known by persons skilled in the art, for example by chemical compound and inorganic or organic acid or alkali are merged in solvent or diluent, perhaps by cation exchange or anion exchange from other salt.

" hyaluronic acid " used herein or " HA " refer to the hyaluronic acid of described herein or the form of ownership that relates to, comprise that those are through the hyaluronic acid of processing or chemistry or physical modification and the hyaluronic acid of crosslinked (for example by covalency, ion, heat or physics mode).The glycosaminoglycans that HA is made up of the straight chain of about 2500 repetition disaccharide unit.Each disaccharide unit is made up of the N-acetyl-glucosamine residue that is connected with glucuronic acid.Hyaluronic acid is the natural materials of finding in the extracellular matrix of many tissues, comprises vitreous body, cartilage, blood vessel, skin and the umbilical cord of Synovial joint liquid, eye.From rooster comb and other animal origin, extract and have the hyaluronic commercial form of about 1200-1,500 ten thousand dalton (Da) molecular weight.Other source of HA comprises that separation is from cell culture/sweat.Low-molecular-weight HA goods are also originated available from extensive stock.This molecule has length variable (being the repetition disaccharide unit of varying number and the pattern of different chain branchings) and can be on several position be modified (by adding or replacing different merit functional groups), but can not break away from the scope of fuzzy.

Term " react to each other " refer to form covalent bond, non-covalent bond or they both.This term with comprise thus crosslinked, this crosslinked intermolecular cross-linking and intramolecular crosslinking that also randomly causes of comprising because of the formation covalent bond.Covalent bond between two reactive groups can be directly, and in this case, the atom on the reactive group directly combines with atom on another reactive group, or it can be by connecting the indirect combination of base.Non-covalent bond comprises that ion (static) key, hydrogen bond or hydrophobic molecule segment that can be identical or different associate.Except that covalent bond, crosslinked substrate also comprises between this quasi-molecule and/or the intramolecularly non-covalent bond.

When relating to polymer, generally with term " hydrophilic " and " hydrophobicity is defined as HLB value, i.e. hydrophile-lipophile balance value.High HLB value representation hydrophilic compounds, and low HLB value is characterised in that hydrophobic compound.The HLB value is well-known in the art and generally in 1-18 scope.Preferred polyfunctional compound's parent nucleus is hydrophilic, contains at least one hydrophilic parts generally but condition is the polyfunctional compound, can also have crosslinkable hydrophobic parts.

Term " synthetic " is in order to refer to " chemosynthesis " polymer, chemical compound and other this class material.For example, the synthetic materials/substances in the present composition can have the molecular structure identical with natural occuring article matter, but as introduce in the present composition this material itself in laboratory or with industrialized mode by chemosynthesis." synthetic " material also comprises semisynthetic material, promptly available from natural origin according to certain way by the naturally occurring material of chemical modification.Yet in general, the synthetic of this paper is pure synthetic, and promptly they neither have identical structure with naturally occurring material neither semisynthetic.

Term " effective dose " refers to the amount that obtains the required compositions of required effect.For example, the amount of tissue growth " promote " of compositions refers to tissue growth being stimulated to can the required amount of detected degree, and in the context of this article, tissue comprises connective tissue, bone, cartilage, epidermis and corium, blood and other tissue.The actual amount that is determined as effective dose can be determined by executing the person of protecting according to changing and be easier to such as patient's size, situation, sex and age different.

Term used herein " original position " refers on medicine-feeding part.Therefore, compositions of the present invention can be injected at, otherwise be exactly to be coated on the intravital specific part of patient, for example need the position expanded, and make it crosslinked at the place, injection site.Suitable position be generally expansion corium holder intradermal or subcutaneous area, be used for the bone reparation fracture site, be used in the sphincter tissue of sphincter control in (for example be used to control recovery), wound or the suture site, so that promote tissue regeneration; With in the vascular anastomosis or adjacent with it, so that promote revascularization.

Term " aqueous medium " comprises the solution that contains water, suspension, dispersion liquid, colloid etc.Term " aqueous environments " refers to the environment that contains aqueous medium.Similarly, term " dry environment " refers to the not environment of property of water-bearing medium.

With regard to the name that relates to molecular structure, use following definition:

Term used herein " alkyl " refers to generally, but the side chain or the non-branched saturated hydrocarbon group that not necessarily contain 1-24 carbon atoms, such as: methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, octyl group, decyl etc., and cycloalkyl, such as cyclopenta, cyclohexyl etc.The alkyl of this paper is general, but not necessarily contains 1-about 12 carbon atoms.Term " low alkyl group " refers to 1-6 carbon atoms, the alkyl of preferred 1-4 carbon atoms." alkyl that replaces " refers to the alkyl that is replaced by one or more substituent groups." alkylidene ", " low-grade alkylidene " and " alkylidene that replaces " refer to the alkyl of divalent alkyl, low alkyl group and replacement respectively.

Used herein and except as otherwise noted, term " aryl " refer to contain single aromatic ring (monocycle) or a plurality of condense by covalent manner each other or with the aromatic substituent of the aromatic ring that is connected such as methylene or this class of ethylidene part group commonly used.Connection base commonly used can also be for as the carbonyl in the benzophenone, as the oxygen atom in the diphenyl ether or as the nitrogen-atoms in the diphenylamines.Preferred aryl groups contains aromatic ring or two aromatic rings that condense or connect, for example phenyl, naphthyl, xenyl, diphenyl ether, diphenylamines, benzophenone etc." aryl that replaces " refers to the aryl moiety that is replaced by one or more substituent groups and term " contains heteroatomic aryl " and " heteroaryl " refers to the aryl that at least one carbon atom is replaced by hetero atom.Term " arlydene " and " arlydene that replaces " refer to divalent aryl and substituted as mentioned above aryl.

" contain hetero atom " as the term in " containing heteroatomic alkyl " and refer to molecule or molecular fragment, wherein one or more carbon atoms are replaced by the atom of non-carbon, for example nitrogen, oxygen, sulfur, phosphorus or silicon.

" alkyl " refers to and contains 1-about 30 carbon atoms, preferred 1-about 24 carbon atoms, and the univalence hydrocarbyl of 1-about 12 carbon atoms most preferably comprises the saturated or undersaturated kind of side chain or non-side chain, such as alkyl, alkenyl, aryl etc.Term " lower alkyl " refers to 1-6 carbon atoms, the alkyl of preferred 1-4 carbon atoms.Term " alkylene " refers to and contains 1-about 30 carbon atoms, and most preferably the bivalent hydrocarbon radical part of 1-about 12 carbon atoms comprises the saturated or undersaturated kind of side chain or non-side chain etc.Term " rudimentary alkylene " refers to 1-6 carbon atoms, the alkylene of preferred 1-4 carbon atoms." alkyl that replaces " refers to the alkyl that is replaced by one or more substituent groups and term " contains heteroatomic alkyl " and " assorted alkyl " refers to the alkyl that at least one carbon atom is replaced by hetero atom.Similarly, " replace alkylene " refer to the alkylene that is replaced by one or more substituent groups and term " contains heteroatomic alkylene " and " assorted alkylene " refers to the alkylene that at least one carbon atom is replaced by hetero atom.As do not have an other explanation, and the alkyl that " alkyl " expression is not substituted and replaces, " containing heteroatomic alkyl " expression contains the heteroatomic alkyl that is not substituted and replaces etc.

Be meant in alkyl, alkyl or other parts during in relating to above-mentioned definition some such as so-called " replacement " in waiting as " alkyl that replaces ", " alkyl that replaces ", on at least one and the bonded hydrogen atom of carbon atom, replaced by one or more substituent groups, these substituent groups are the functional group, such as alkoxyl, hydroxyl, halogen, nitro etc.Except as otherwise noted, should understand concrete molecule segment can be replaced by one or more substituent groups of not damaging the chemical compound application.For example, " succinimido " succinimido in order to comprise that unsubstituted succinimido and sulfosuccinimide base and other are replaced by for example alkoxy substituent, polyethers substituent group etc. on ring carbon atom.

Except as otherwise noted, any concentration range as herein described, percentage range or ratio range should be interpreted as concentration, percentage ratio or the ratio of arbitrary integer that is included in its scope and the part, such as one of 1/10th and percentage of integer.In addition, except as otherwise noted, should relate to any physical features, be interpreted as the arbitrary integer that comprises in the described scope such as any number scope of polymer subunit, size or thickness with described herein.Term used herein " pact " refers to ± 15% any described structure, value or scope.

Shown in " a kind of (A) " and " a kind of (an) " refers in the project one or more.For example, " a kind of " polymer refers to a kind of polymer or comprises two or more mixture of polymers; " a kind of polyfunctional compound " not only refers to single polyfunctional compound, and refers among the identical or different polyfunctional compound two or more combination; " a kind of reactive group " refers to the combination of reactive group and refers to single reaction base etc.

As mentioned above, the invention provides polymer composition, said composition significantly increased be suppressed at or implant surface on or the formation of the reactive scar tissue around it or on therapentic part.This paper has described number of polymers compositions and therapeutic agent.

The invention provides the combination of the compositions (for example polymer) that comprises following one or more therapeutic agents.The preparation and the using method of this based composition have hereinafter also more specifically been described.

A. therapeutic agent

Disclosed the pharmaceutically active agents of the one or more aspects that suppress the generation of excessive fibroid (cicatrix) tissue among the present invention in one aspect.Based on such as (animal) model in those the external and body that in embodiment 20-33, provides, can easily measure suitable inhibition fibre modification or suppress narrow-activating agent.Can identify by the body inner model and suppress fibrotic activating agent, be included in and suppress neointimal hyperplasia generation (embodiment 25 and 33) in rat air bag (balloon) carotid artery model.Can be used for measuring the cell proliferation whether activating agent can be suppressed to fibrocyte and/or smooth muscle cell in the test described in embodiment 24 and 32.In one aspect of the invention, activating agent has about 10 for suppressing cell proliferation ^-6To about 10 ^-10The IC of M ₅₀Can be used to measure the migration whether activating agent can be suppressed to fibrocyte and/or smooth muscle cell in the test described in the embodiment 28.In one aspect of the invention, activating agent has about 10 for suppressing cell migration ^-6To about 10 ^-9The IC of M ₅₀Whether test as herein described can be used to measure activating agent can suppress inflammatory process, comprises that nitric oxide in the macrophage produces (embodiment 20) and/or macrophage produces TNF-α (embodiment 21) and/or macrophage produces IL-1 β (embodiment 31) and/or macrophage produces IL-8 (embodiment 30) and/or suppresses MCP-1 (embodiment 31) by macrophage.In one aspect of the invention, activating agent has about 10 for any one the inhibition in these inflammatory processes ^-6To about 10 ^-10The IC of M ₅₀Can be used to measure activating agent in the test described in the embodiment 26 and whether can suppress the MMP generation.In one aspect of the invention, activating agent has about 10 for the inhibition that MMP produces ^-4To about 10 ^-8The IC of M ₅₀Test described in the embodiment 27 (being also referred to as the CAM test) can be used to measure activating agent and whether can suppress angiogenesis.In one aspect of the invention, activating agent has about 10 for the inhibition of angiogenesis ^-6To about 10 ^-10The IC of M ₅₀Can pass through the body inner model, comprise that the evaluation of rabbit surgical operation adhesion model (embodiment 23,42 and 43) and rat caecum sidewall model (embodiment 22) reduces the activating agent that the surgical operation adhesion forms.These pharmaceutically active agents (following) can be delivered to group separately or by carrier (described herein) with suitable dosage then, so that treat clinical problem as herein described.

Identified and can suppress fibrotic treatment chemical compound in a large number, they have application of the present invention, comprising:

1) Angiogenesis inhibitor

In one embodiment; suppress fibrotic active constituents of medicine and be angiogenesis inhibitor (2-ME (NSC-659853) for example; PI-88 (D-mannose; O-6-O-phosphono-α-D-mannopyranose base-(1-3)-O-α-D-mannopyranose base-(1-3)-O-α-D-mannopyranose base-(1-3)-O-α-D-mannopyranose base-(1-2)-the hydrosulphuric acid ester); Thalidomide (1H-iso-indoles-1; 3 (2H)-diketone; 2-(2; 6-dioxo-3-piperidyl)-); CDC-394; CC-5079; ENMD-0995 (S-3-amino-2-benzo [c] furanone glutarimide); AVE-8062A; Vatalanib; SH-268; halofuginone hydrobromide; maleic acid hydrogen Atiprimod (2-azaspiro [4.5] decane-2-propylamine; N; N-diethyl-8; the 8-dipropyl; dimaleate); ATN-224; CHIR-258; combretastatin A-4 (phenol; 2-methoxyl group-5-[2-(3; 4; the 5-trimethoxyphenyl) vinyl]-, (Z)-); GCS-100LE or its analog or derivant).

2) 5-lipoxygenase inhibitor and antagonist

In another embodiment; (for example suppress fibrotic active constituents of medicine and be 5-lipoxygenase inhibitor or antagonist; Wy-50295 (2-naphthalene acetic acid); Alpha-Methyl-6-(2-quinolyl methoxyl group)-; (S)-); ONO-LP-269 (2; 11; 14-20 carbon triolefin amide; N-(4-hydroxyl-2-(1H-tetrazolium-5-yl)-8-quinolyl)-; (E; Z; Z)-); licofelone (1H-pyrrolizine-5-acetic acid; 6-(4-chlorphenyl)-2; 3-dihydro-2; 2-dimethyl-7-phenyl-); CMI-568 (urea; N-butyl-N-hydroxy-n '-(((tetrahydrochysene-5-(3 for 3-(mesyl)-2-propoxyl group-5-for 4-; 4; the 5-trimethoxyphenyl)-and the 2-furyl) phenoxy group) butyl)-; trans-); IP-751 ((3R; 4R)-(δ 6)-THC-DMH-11-acid); PF-5901 (benzyl alcohol; α-amyl group-3-(2-quinolyl methoxyl group)-); LY-293111 (benzoic acid; 2-(3-(3-[(5-ethyl-4 '-fluoro-2-hydroxyl [1; 1 '-biphenyl]-the 4-yl) the oxygen base] propoxyl group)-2-propyl group phenoxy group)-); RG-5901-A (benzyl alcohol; α-amyl group-3-(2-quinolyl methoxyl group)-; hydrochlorate); rilopirox (2 (1H)-pyridones; 6-((4-(4-chlorophenoxy) phenoxy group) methyl)-1-hydroxy-4-methyl-); L-674636 (acetic acid; ((4-(4-chlorphenyl)-1-(4-(2-quinolyl methoxyl group) phenyl) butyl) sulfenyl)-AS)); 7-((3-(4-methoxyl group-tetrahydrochysene-2H-pyrans-4-yl) phenyl) methoxyl group)-4-phenyl naphtho-[2; 3-c] furan-1 (3H)-ketone; MK-886 (1H-indole-2-propanoic acid; 1-((4-chlorphenyl) methyl)-3-[(1; the 1-dimethyl ethyl) sulfenyl]-α; alpha-alpha-dimethyl-5-(1-Methylethyl)-); quiflapon (1H-indole-2-propanoic acid; 1-((4-chlorphenyl) methyl)-3-((1; the 1-dimethyl ethyl) sulfo-)-α; alpha-alpha-dimethyl-5-(2-quinolyl methoxyl group)-); quiflapon (1H-indole-2-propanoic acid; 1-((4-chlorphenyl) methyl)-3-((1; the 1-dimethyl ethyl) sulfenyl)-α; alpha-alpha-dimethyl-5-(2-quinolyl methoxyl group)-); docebenone (2; 5-cyclohexadiene-1; the 4-diketone; 2-(12-hydroxyl-5; 10-12 carbon diynyls)-3; 5; the 6-trimethyl-); zileuton (urea, N-(1-benzo (b) thiophene-2-base ethyl)-N-hydroxyl-) or its analog or derivant).

3) Chemokine receptor anagonists CCR (1,3 and 5)

In another enforcement side. in the case, suppress fibrotic active constituents of medicine for suppressing one or more CCR (1,3, with 5) chemokine receptor anagonists of hypotype is (for example, ONO-4128 (1,4,9-thriazaspiro (5.5) hendecane-2, the 5-diketone, 1-butyl-3-(cyclohexyl methyl)-9-((2,3-dihydro-1,4-Ben Bing dioxine-6-yl) methyl-), L-381, CT-112 (L-arginine, L-threonyl-L-threonyl-L-seryl-L-glutaminate acyl-L-valyl-L-arginyl-L-prolyl-), AS-900004, SCH-C, ZK-811752, PD-172084, UK-427857, SB-380732, vMIP II, SB-265610, DPC-168, TAK-779 (N, N-dimethyl-N-(4-(2-(4-aminomethyl phenyl)-6,7-dihydro-5H-benzocyclohepta alkene-8-base amide groups) phenyl) tetrahydrochysene-2H-pyrans-4-ammonium chloride), TAK-220, KRH-1120), GSK766994, SSR-150106 or its analog or derivant).The example of other chemokine receptor anagonists comprises: immune factor (Immunokine)-NNS03, BX-471, CCX-282, Sch-350634; Sch-351125; Sch-417690; SCH-C; And analog and derivant.

4) Cell cycle inhibitor

In another embodiment, suppressing fibrotic active constituents of medicine is cell cycle inhibitor.The representational example of this class activating agent comprise taxanes (for example, paclitaxel (below in more detail discuss) and docetaxel) (Schiff etc., " nature " be 277:665-667 (Nature), 1979; Long and Fairchid, " cancer research " (Cancer Research) 54:4355-4361,1994; Ringel and Horwitz, and " National Cancer Institute's magazine " (J.Nat ' l cancer Inst.) 83 (4): 288-291,1991; Pazdur etc., " treatment of cancer summary " (Cancer Treat.Rev.) 19 (40): 351-386,1993), etanidazole, nimorazole (B.A.Chabner and D.L.Longo. " cancer chemotherapy and biotherapy-mechanism with put into practice " (Cancer Chemotherapy andBiotherapy-Principles and Practice.) Lippincott-Raven Publishers, New York, 1996, the 554th page), perfluorochemical with hyperbaric oxygen, blood transfusion (transfusion), erythropoietin, BW12C, nicotiamide, hydralazine, BSO, WR-2721, ludR, DudR, etanidazole, WR-2721, BSO, mono-substituted keto-aldehyde chemical compound (L.G. Egyud. " ketone-aldehyde-amine addition compound product and preparation method thereof " (Keto-aldehyde-amine addition products and method ofmaking same.) U.S. Patent number 4,066,650, on January 3rd, 1978), nitre imidazoles (K.C.AgraWal and M.Sakaguchi. " the nitroimidazole radiosensitizer and the compositions thereof that are used for hypoxic tumor cells " (Nitroimidazole radiosensitizers for Hypoxic tumor cells andcompositions thereof.) U.S. Patent number 4,462,992, on July 31st, 1984), 5-replaces-4-nitre imidazoles (Adams etc., " international radiobiology correlational study and physical chemistry medicine magazine " (Int.J.Radiat.Biol.Relat.Stud.Phys.Chem.Med.) 40 (2): 153-61,1981), SR-2508 (Brown etc., " international radiation oncology and biophysics's magazine " (Int.J.Radiat.Oncol., Biol.Phys.) 7 (6): 695-703,1981), 2H-isoindoledione class (J.A.Myers, " 2H-isoindoledione class; its synthetic and as the application of radiosensitizer " (2H-lsoindolediones, their synthesis and use as radiosensitizers.) patent No. No.4,494,547, on January 22nd, 1985), chirality (((2-bromoethyl)-amino) methyl)-nitro-1H-imidazoles-1-ethanol (V.G.Beylin etc., (Process for preparingchiral (((2-bromoethyl)-amino) the methyl)-nitro-1H-imidazole-1-ethanol and relatedcompounds.) U.S. Patent number 5 that " is used to prepare chirality (((2-bromoethyl)-amino) methyl)-nitro-alcoholic acid method of 1H-imidazoles-1-and related compound ", 543, on August 6th, 527,1996; U.S. Patent number 4,797,397; On January 10th, 1989; U.S. Patent number 5,342,959, on August 30th, 1994), nitroaniline derivant (W.A.Denny, Deng " nitroaniline derivant and as the application of antineoplastic agent " (Nitroaniline derivatives and their use as anti-tumor agents.) U.S. Patent number 5,571,845, on November 5th, 1996), DNA-affinity (affinic) hypoxia-selective cytotoxin (M.V.Papadopoulou-Rosenzweig. " DNA-affinity (affinic) hypoxia-selective cytotoxin " (DNA-affinic hypoxia selective cytotoxins.) U.S. Patent number 5,602,142, on February 11st, 1997), halogenated DNA part (R.F.Martin. " the halogenation DNA part radiosensitizer that is used for cancer therapy " (Halogenated DNA ligand radiosensitizers for cancertherapy.) U.S. Patent number 5,641,764, on June 24th, 1997), 1,2, the 4-benzotriazine oxides (W.W.Lee etc. " as 1 of radiosensitizer and selecting cell toxic agents; 2; the 4-benzotriazine oxides " (1,2,4-benzotriazine oxides as radiosensitizers and selective cytotoxicagents.) U.S. Patent number 5,616, on April 1st, 584,1997; U.S. Patent number 5,624, on April 29th, 925,1997; (the Process forPreparing 1 that " is used to prepare 1; 2; method of 4-benzotriazine oxides ", 2,4 Benzotriazine oxides.) U.S. Patent number 5,175,287, on December 29th, 1992), nitric oxide (J.B.Mitchell etc., (the Use of Nitric oxide releasing compounds as hypoxiccell radiation sensitizers.) U.S. Patent number 5 that " discharges of the application of nitric oxide production chemical compound " as the hypoxic cell radiosensitizer, 650,442, on July 22nd, 1997), 2-nitre imdazole derivatives (M.J.Sut etc. " with the 2-nitre imdazole derivatives of the radiosensitizer that acts on hypoxic tumor cells " (2-Nitroimidazole derivatives useful as radiosensitizers forhypoxic tumor cells.) U.S. Patent number 4,797, on January 10th, 397,1989; T.Suzuki. " 2-nitre imdazole derivatives, its production method and contain its radiosensitizer " (2-Nitroimidazole derivative as active component, production thereof, and radiosensitizercontaining the same as active ingredient.) U.S. Patent number 5,270, on December 14th, 330,1993; T.Suzuki etc. " 2-nitre imdazole derivatives, its production method and contain its radiosensitizer " (2-Nitroimidazole derivative as active component, production thereof, andradiosensitizer containing the same as active ingredient.) U.S. Patent number 5,270, on December 14th, 330,1993; T.Suzuki. " 2-nitre imdazole derivatives; its production method and contain its radiosensitizer as active component " (2-Nitroimidazole derivative, production thereof and radiosensitizer containing the same as activeingredient) patent No. EP 0 513 351 B1, on January 24th, 1991), fluorine-containing nitro-pyrrole derivant (T.Kagiya. " fluorine-containing nitro-pyrrole derivant and the radiosensitizer that comprises them " (Fluorine-containing nitroazole derivatives and radiosensitizer comprisingthe same.) U.S. Patent number 4,927,941, May 22 nineteen ninety), copper (M.J.Abrams. " copper radiosensitizer " (Copper Radiosensitizers.) U.S. Patent number 5,100,885, on May 31st, 1992), cancer therapy (the D.H.Picker etc. of associated form, " cancer therapy of associated form " (Combination modality cancer therapy.) U.S. Patent number 4,681, on July 21st, 091,1987).5-CldC or (d) H ₄U or 5-halo-2 '-halo-2 '-deoxidation-cytidine or-uridine derivatives (S.B.Greer. " to the method and the material of tumor tissues radiation sensitization " (Method andMaterials for sensitizing neoplastic tissue to radiation.) U.S. Patent number 4,894, on January 16th, 3641990), platinum complexes (K.A.Skov. " with a kind of platinum complexes of radiosensitivity part " (Platinum Complexes with one radiosensitizing ligand.) U.S. Patent number 4, on May 1st, 921,963.1990; K.A.Skov. " with a kind of platinum complexes of radiosensitivity part " (Platinum Complexes with one radiosensitizing ligand.) patent No. EP 0,287 317 A3), fluorine-containing nitro-pyrrole (T.Kagiya, fluorine-containing nitro-pyrrole derivant and the radiosensitizer that comprises them " (Fluorine-containing nitroazole derivatives andradiosensitizer comprising the same.) U.S. Patent number 4; 927; on May 22nd, 941.1990); Benzoylamide (W.W.Lee. " the Benzoylamide radiosensitizer of replacement " (SubstitutedBenzamide Radiosensitizers.) U.S. Patent number 5; 032; 617, on July 16th, 1991), autobiotic (L.G.Egyud. " Bai Shengsu and the application in non-self cell in eliminating body thereof " (Autobiotics and their use in eliminating nonself cells in vivo.) U.S. Patent number 5,147,652.1992 on JIUYUE 15), Benzoylamide and nicotiamide (W.W.Lee etc. " Benzoylamide and nicotiamide radiosensitizer " (Benzamide and Nictoinamide Radiosensitizers.) U.S. Patent number 5,215,738, on June 1st, 1993), acridine-intercalator (M.Papadopoulou-Rosenzweig. " based on the hypoxia-selective cytotoxin of acridine-intercalator " (Acridine Intercalator based hypoxia selective cytotoxins.) U.S. Patent number 5,294,715, on March 15th, 1994), fluorine-containing nitroimidazole (T.Kagiya etc. " fluorine-containing nitroimidazole compound " (Fluorine containing nitroimidazole compounds.) U.S. Patent number 5,304,654, on April 19th, 1994), hydroxylating texaphyrins (J.L.Sessler etc. " hydroxylating texaphyrins " (Hydroxylated texaphrins.) U.S. Patent number 5,457,183, October 10 nineteen ninety-five), the derivant of hydroxylated compounds (T.Suzuki etc. " the heterocyclic compound derivant; its production method and contain radiosensitizer and the antiviral agents of described derivant as active component " (Heterocyclic compound derivative, production thereof and radiosensitizerand antiviral agent containing said derivative as active ingredient.) publication number 011106775 A (Japan), on October 22nd, 1987; T.Suzuki etc. " heterocyclic compound derivant, its production method and contain radiosensitizer, antiviral agents and the anticarcinogen of described derivant " (Heterocyclic compound derivative as active component, production thereof andradiosensitizer, antiviral agent and anti cancer agent containing said derivativeas active ingredient.) publication number 01139596 A (Japan), on November 25th, 1987; S.Sakaguchi etc. " heterocyclic compound derivant, its production method and contain the radiosensitizer of described derivant " (Heterocyclic compound derivative, its productionand radiosensitizer containing said derivative as active ingredient) as active component; Publication number 63170375 A (Japan), on January 7th, 1987), fluorine-containing 3-nitro-1,2, the 4-triazole (T.Kagitani etc. " new fluorine-containing 3-nitro-1; 2; 4-triazole and the radiosensitizer that contains described chemical compound " (Novel fluorine-containing 3-nitro-1,2,4-triazole and radiosensitizercontaining same compound.) publication number 02076861 A (Japan), on March 31st, 1988), 5-sulfo-terazole derivatives or its salt (E.Kano etc. " radiosensitizer that is used for hypoxic cell " (Radiosensitizer for Hypoxic cell.) publication number 61010511 A (Japan), on June 26th, 1984), nitrothiazole (T.Kagitani etc. " radiation-sensitizing agent " be publication number 61167616 A (Japan) on January 22nd, 1985 (Radiation-sensitizingagent.)), imdazole derivatives (S.Inayma etc. " imdazole derivatives " (Imidazole derivative.) publication number 6203767 A (Japan) on August 1st, 1985; Publication number 62030768 A (Japan) on August 1st, 1985; Publication number 62030777A (Japan) on August 1st, 1985), 4-nitro-1,2, the 3-triazole (T.Kagitani etc. " radiosensitizer " be publication number 62039525 A (Japan) (Radiosensitizer.), on August 15th, 1985), 3-nitro-1,2, the 4-triazole (T.Kagitani etc. " radiosensitizer " be publication number 62138427 A (Japan) (Radiosensitizer.), on December 12nd, 1985), system cancer effect regulator (H.Amagase. " system cancer effect regulator " (Carcinostatic action regulator.) publication number 63099017 A (Japan), on November 21st, 1986), 4,5-dinitro imdazole derivatives (S.Inayama. " 4; 5-dinitro imdazole derivatives " (4,5-Dinitroimidazole derivative.) publication number 63310873 A (Japan) on June 9th, 1987), nitro-triazole chemical compound (T.Kagitanr " nitro-triazole chemical compound " (NitrotriazoleCompound.) publication number 07149737 A (Japan) on June 22nd, 1993), cisplatin, doxorubicin (doxorubin), misonidazole, mitomycin, tiripazamine, nitroso ureas, mercaptopurine, methotrexate, fluorouracil, bleomycin, vincristine, carboplatin, epirubicin, doxorubicin, cyclophosphamide, vindesine, etoposide (I.F.Tannock. survey article: use radiation and Drug therapy cancer (Review Article:Treatment of Cancer with Radiation and Drugs.)-" Journal of Clinical Oncology " (Joumal of Clinical Oncology) 14 (12): 3156-3174,1996), camptothecine (Ewend M.G. etc. " survival that the local delivery of chemotherapy and the external beam radiotherapy carried out has simultaneously prolonged the metastatic brain tumor model " (Local delivery of chemotherapy andconcurrent extemal beam radiotherapy prolongs survival in metastatic braintumor models.)-" cancer research " (Cancer Research) 56 (22): 5217-5223,1996) and paclitaxel (Tishler R.B. etc. " taxol: new radiosensitizer " (Taxol:a novel radiationsensitizer.)-" international radiation oncology and biophysics's magazine " (Intemational Joumalof Radiation Oncology and Biological Physics) 22 (3): 613-617,1992).

Many above-mentioned cell cycle inhibitors also have extensively multiple analog and derivant, include, but are not limited to cisplatin, cyclophosphamide, misonidazole, tiripazamine, nitroso ureas, mercaptopurine, methotrexate, fluorouracil, epirubicin, doxorubicin, vindesine and etoposide.

In a preferred embodiment of the invention, described cell cycle inhibitor is a paclitaxel, and is promptly a kind of by form chemical compound or its analog or the derivant that anomomitotic spindle destroys mitosis (M-phase) in conjunction with tubulin.In brief, paclitaxel is the deutero-diterpene-kind compound (Wani etc. of a kind of height, " Journal of the American Chemical Society " be 93:2325 (J.Am.Chem.Soc.), 1971), it is available from (Stierle etc. on the endogenetic fungus of yewtree (Taxus brevifolia) (Pacific yew (PacificYew)) and Taxomyces Andreanae results and exsiccant bark and Pacific yew, " science " be 60:214-216 (Science), and 1993)." paclitaxel " (it is construed as at this paper and comprises preparation, prodrug, analog and derivant, such as, TAXOL (Bristol-Myers Squibb company for example, New York, NY), TAXOTERE (AventisPharmaceuticals, France), docetaxel, the 10-deacetylate analog of paclitaxel and 3 ' N-of paclitaxel take off benzoyl-3 ' uncle N--butoxy carbonyl analog) technology that is easy to use those skilled in the art to be familiar with (for example is prepared, referring to Schiff etc., " nature " be 277:665-667 (Nature), and 1979; Long and Fairchild, " cancer research " (Cancer Research) 54:4355-4361,1994; Ringel and Horwitz, " National Cancer Institute's magazine " (J.Natl.CancerInst.) 83 (4): 288-291,1991; Pazdur etc., " treatment of cancer summary " (Cancer Treat.Rev.) 19 (4): 351-386,1993; WO 94/07882; WO 94/07881; WO 94/07880; WO94/07876; WO 93/23555; WO 93/10076; WO 94/00156; WO 93/24476; EP 590267; WO 94/20089; U.S. Patent number 5,294,637; 5,283,253; 5,279,949; 5,274,137; 5,202,448; 5,200,534; 5,229,529; 5,254,580; 5,412,092; 5,395,850; 5,380,751; 5,350,866; 4,857,653; 5,272,171; 5,411,984; 5,248,796; 5,248,796; 5,422,364; 5,300,638; 5,294,637; 5,362,831; 5,440,056; 4,814,470; 5,278,324; 5,352,805; 5,411,984; 5,059,699; 4,942,184; " tetrahedron communication " (Tetrahedron Letters) 35 (52): 9709-9712,1994; " pharmaceutical chemistry magazine " be 35:4230-4237 (J.Med.Chem.), and 1992; " pharmaceutical chemistry magazine " be 34:992-998 (J.Med.Chem.), and 1991; " natural product magazine " (J.Natural Prod.) 57 (10): 1404-1410,1994; " natural product magazine " (J.Natural Prod.) 57 (11): 1580-1583,1994; " Journal of the American Chemical Society " be 110:6558-6560 (J.Am.Chem.Soc.), and 1988); Or from many commercial source acquisitions, described commercial source for example comprises, Sigma Chemical Co., St.Louis, Missouri (T7402-is from yewtree).

The representational example of paclitaxel derivant or analog comprises 7-deoxidation-docetaxel (docetaxol); 7; 8-cyclopropataxanes; the 2-azetidones that N-replaces; 6; 7-epoxy paclitaxel; 6; the paclitaxel that 7-modifies; 10-removes the acetoxyl group paclitaxel; 10-deacetylate paclitaxel (from 10-deacetylate Baccatine III); the phosphonato of paclitaxel and carbonic acid ester derivative; paclitaxel 2 '; 7-two (1; 2-benzene dicarboxylic acid sodium; 10-removes acetoxyl group-11; 12-dihydro paclitaxel-10; 12 (18)-diene derivatives; 10-removes the acetoxyl group paclitaxel; Protaxol (2 '-and/or the 7-O-ester derivant); (2 '-and/or the 7-O-carbonic acid ester derivative); the asymmetric synthesis of paclitaxel lateral chain; the fluorine paclitaxel; 9-deoxidation taxanes; (13-acetyl group-9-deoxy baccatine III III; the 9-deoxy taxol; 7-deoxidation-9-deoxy taxol; 10-removes acetoxyl group-7-deoxidation-9-deoxy taxol; the derivant of hydrogeneous or Acetyl Groups and hydroxyl and uncle-butoxy carbonyl amino; sulfonated 2 '-acryloyl paclitaxel and sulfonated 2 '-O-acyl acid taxol derivant; the succinyl paclitaxel; 2 '-gamma-amino bytyry paclitaxel formic acid esters; 2 '-acetyl group paclitaxel; 7-acetyl group paclitaxel; 7-glycine carbamate paclitaxel; 2 '-OH-7-PEG (5000) carbamate paclitaxel; 2 '-benzoyl and 2 '; 7-dibenzoyl paclitaxel derivant; other prodrug (2 '-acetyl group paclitaxel; 2 '; 7-diacetyl paclitaxel; 2 ' succinyl paclitaxel; 2 '-(β-alanyl)-paclitaxel); 2 ' gamma-amino bytyry paclitaxel formic acid esters; the ethylene glycol derivative of 2 '-succinyl paclitaxel; 2 '-glutaryl paclitaxel; 2 '-(N; N-dimethyl glycyl) paclitaxel; 2 '-(2-(N; the N-dimethylamino) paclitaxel propiono); 2 ' ortho position carboxylbenzoyl paclitaxel; 2 ' aliphatic carboxylic acid derivates of paclitaxel; prodrug { 2 ' (N; N-lignocaine propiono) paclitaxel; 2 ' (N; N-dimethyl glycyl) paclitaxel; 7 (N; N-dimethyl glycyl) paclitaxel; 2 '; 7-two (N; N-dimethyl glycyl) paclitaxel; 7 (N; N-lignocaine propiono) paclitaxel; 2 '; 7-two (N; N-lignocaine propiono) paclitaxel; 2 '-(L-glycyl) paclitaxel; 7-(L-glycyl) paclitaxel; 2 '; 7-two (L-glycyl) paclitaxel; 2 '-(L-alanyl) paclitaxel; 7-(L-alanyl) paclitaxel; 2 '; 7-two (L-alanyl) paclitaxel; 2-' (L-leucyl) paclitaxel; 7-(L-leucyl) paclitaxel; 2 '; 7-two (L-leucyl) paclitaxel; 2 '-(L-isoleucyl-) paclitaxel; 7-(L-isoleucyl-) paclitaxel; 2 '; 7-two (L-isoleucyl-) paclitaxel; 2 ' (L-valyl) paclitaxel; 7-(L-valyl) paclitaxel; 2 '; 7-two (L-valyl) paclitaxel; 2 ' (L-phenylalanyl) paclitaxel; 7-(L-phenylalanyl) paclitaxel; 2 '; 7-two (L-phenylalanyl) paclitaxel; 2 '-(L-prolyl) paclitaxel; 7-(L-prolyl) paclitaxel; 2 '; 7-two (L-prolyl) paclitaxel; 2 '-(L-lysyl) paclitaxel; 7-(L-lysyl) paclitaxel; 2 '; 7-two (L-lysyl) paclitaxel; 2 '-(L-glutamy) paclitaxel; 7-(L-glutamy) paclitaxel; 2 '; 7-two (L-glutamy) paclitaxel; 2 ' (L-arginyl) paclitaxel; 7-(L-arginyl) paclitaxel; 2 '; 7-two (L-arginyl) paclitaxel }; paclitaxel analogs with phenylisoserine side chain of modification; taxotere; (N-removes benzoyl-N-uncle-(butoxy carbonyl)-10-deacetylate paclitaxel and taxanes (Baccatine III for example; Cephalomannine (cephalomannine); 10-deacetylate Baccatine III; short leaf Lignum Sappan alcohol (brevifoliol); yunantaxusin and taxusin) and other 10-deacetyltaxol and derivant; comprise that 14-beta-hydroxy-10 removes the acetyl Baccatine III; go benzoyl-2-acyl taxol derivant; the benzoate paclitaxel derivant; phosphonato and carbonic ester paclitaxel derivant; sulfonated 2 '-acryloyl paclitaxel; sulfonated 2 '-O-acyl acid taxol derivant; the paclitaxel derivant of 18-position-replacement; chlorating paclitaxel analogs; C4 methoxy-ether paclitaxel derivant; the sulfenamide Taxane derivative; the paclitaxel analogs of bromination; the Girard Taxane derivative; the nitrobenzophenone paclitaxel; the paclitaxel derivant of the replacement of 10-deacetylateization; 14-beta-hydroxy-10 deacetylate Baccatine III Taxane derivative; the C7 Taxane derivative; the C10 Taxane derivative; 2-removes benzoyl-2-acyl group Taxane derivative; 2-go benzoyl and-2-acyl taxol derivant; carry the taxane and the Baccatine III analog of new C2 and C4 functional group; n-acyl taxol analog; 10-deacetylate Baccatine III and from 10-deacetylate paclitaxel A; the 7-protection of 10-deacetylate paclitaxel B and 10-deacetylate paclitaxel-10-deacetylate Baccatine III; the benzoate derivatives of paclitaxel; 2-aroyl-4-acyl taxol analog; the ortho esters paclitaxel analogs; 2-aroyl-4-acyl taxol analog and 1-deoxy taxol and 1-deoxy taxol analogs.

In one aspect, described cell cycle inhibitor is the taxane with formula (C1):

Wherein the part that Lycoperdon polymorphum Vitt is outstanding can be substituted, and not outstanding part is a taxane nuclear.It is desirable to exist side chain (labelling " A " in the drawings) so that chemical compound has the excellent activity as cell cycle inhibitor.Examples for compounds with this structure comprises that paclitaxel (Merck index entry 7117), docetaxel (taxotere, Merck index entry 3458) and 3 '-Tuo phenyl-3 '-(4-nitrobenzophenone)-N-take off benzoyl-N-(tertbutyloxycarbonyl)-10-and remove the acetyl paclitaxel.

In one aspect, suitable taxanes, at U.S. Patent number 5,440, open in 056, it has structure (C2) such as paclitaxel and analog thereof and derivant:

Wherein X can be oxygen (paclitaxel), hydrogen (9-deoxidation derivative), sulfo-acyl group or dihydroxy precursor; R ₁Be selected from the alkanoyl of paclitaxel or taxotere side chain or formula (C3)

R wherein ₇Be selected from hydrogen, alkyl, phenyl, alkoxyl, amino, phenoxy group (replace or do not replace); R ₈Be selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, phenyl (replace or do not replace), α or betanaphthyl; And R ₉Be selected from the alkanoyl and the aminoalkanoyl radical of hydrogen, alkanoyl, replacement; Wherein substituent group is meant hydroxyl, sulfydryl, allalkoxyl, carboxyl, halogen, thio alkoxy, N, N-dimethylamino, alkylamino, dialkylamino, nitro and-OSO ₃H, and/or can be meant and contain these substituent groups; R ₂Be selected from hydrogen or oxy radical, such as hydrogen, hydroxyl, alkoyl, alkanoyl oxygen base, aminoalkanoyl radical oxygen base and peptidyl alkanoyl oxygen base; R ₃Being selected from hydrogen or oxy radical, such as hydrogen, hydroxyl, alkoyl, alkanoyl oxygen base, aminoalkanoyl radical oxygen base and peptidyl alkanoyl oxygen base, and can be group or the sulfur-containing group that contains silicyl in addition; R ₄Be selected from acyl group, alkyl, alkanoyl, aminoalkanoyl radical, peptidyl alkanoyl and aroyl; R ₅Be selected from acyl group, alkyl, alkanoyl, aminoalkanoyl radical, peptidyl alkanoyl and aroyl; R ₆Be selected from hydrogen or oxy radical, such as hydrogen, hydroxyl alkoyl, alkanoyl oxygen base, aminoalkanoyl radical oxygen base and peptidyl alkanoyl oxygen base.

In one aspect, open in pct international patent application WO 93/10076 as effective paclitaxel analogs of cell cycle inhibitor and derivant.As disclosed in the disclosure document, described analog or derivant should have at C ₁₃The side chain that the place is connected with taxane nuclear is shown in following structure (formula C4), so that give anti-tumor activity to taxane.

Disclose except the methyl that exists among the WO 93/10076, taxane is endorsed to be substituted on any position.Substituent group can comprise: for example hydrogen, alkanoyl oxygen base, alkenoyl oxygen base, aroyl oxygen base.In addition, oxo group can be connected with the carbon of labelling 2,4,9 and/or 10.Equally, the oxetanes ring can be connected on 4 and 5 carbon atoms.In addition, oxirane can be connected on the carbon of labelling 4.

In individual one side, be used for the cell cycle inhibitor based on taxane of the present invention at United States Patent (USP) 5,440, open in 056, disclosed 9-deoxidation taxanes in the document.These are chemical compounds that the carbon place of labelling 9 lacks oxo group in the taxane structure (formula C4) shown in above.Taxane-ring can be at the carbon place (independently) of labelling 1,7 and 10 by H, OH, O-R, or O-CO-R replaces, and wherein R is alkyl or aminoalkyl.In addition, it can be replaced by aryol, alkanoyl, aminoalkanoyl radical or alkyl at the carbon place (independently) of labelling 2 and 4.The side chain of formula (C3) can be at R ₇And R ₈Place's (independently) is replaced by the phenyl ring of phenyl ring, replacement, linear paraffin/alkene and the group that contains H, O or N.R ₉Can be replaced by alkanoyl H or replacement or unsubstituted.

Usually taxanes, particularly paclitaxel are considered to by as anti-microtubule agent with more specifically work as stabilizing agent and play the effect of cell cycle inhibitor.These chemical compounds have shown in the treatment of cell proliferation disorders that effectively described cell proliferation disorders comprises: non-small cell (NSC) pulmonary carcinoma; Small cell lung cancer; Breast carcinoma; Carcinoma of prostate; Cervical cancer; Carcinoma of endometrium; Head and neck cancer.

In one aspect of the method; anti-microtubule agent (microtubule inhibitor) is an albendazole (carbamic acid; [5-(rosickyite base)-1H-benzimidazolyl-2 radicals-yl]-; methyl ester); LY-355703 (1; 4-two oxa-s-8,11-diazacyclo 16 carbon-13-alkene-2,5; 9; the 12-tetraketone, 10-[(3-chloro-4-methoxyphenyl) methyl]-6,6-dimethyl-3-(2-methyl-propyl)-16-[(1S)-1-[(2S; 3R)-and 3-phenyl ethylene oxide base] ethyl]-; (3S, 10R, 13E; 16S)-); vindesine (vinblastine, 3-(amino carbonyl)-O4-deacetylation-3-go (methoxycarbonyl)-) or WAY-174286.

In one aspect of the method, described cell cycle inhibitor is a vinca alkaloids.Vinca alkaloids has following general structure.They are indole-indoline dimers.

As United States Patent (USP) 4,841,045 and 5,030,620 is disclosed, R ₁Can be formoxyl or methyl or H alternatively.R ₁Can also be the alkyl that replaces of alkyl or aldehyde (CH for example ₂CHO).R ₂CH typically ₃Or NH ₂Group.Yet the ester that it can alternatively be replaced by lower alkyl esters or be connected with indoline nuclear can be NH by R wherein ₂C (O)-R, amino-acid ester or peptide ester replace.R ₃C (O) CH typically ₃, CH ₃Or H.Alternatively, can connect protein fragments by double functional group such as maleoyl-aminoacid.R ₃Can also be substituted the Arrcostab that formation can further be replaced.R ₄Can be-CH ₂-or singly-bound.R ₅And R ₆Can be H, OH or low alkyl group, typically-CH ₂CH ₃R alternatively ₆And R ₇Can form the oxetanes ring together.R ₇Alternatively can be H.Replacement in addition comprises molecule, and wherein methyl is replaced by other alkyl, and unsaturated thus ring can be by adding side group, such as alkyl, thiazolinyl, alkynyl, halogen, ester group, amide groups or amino being derived.

Typical vinca alkaloids is vinblastine, vincristine, leucocristine sulfate, vindesine and vinorelbine, and it has following array structure:

R ₁ R ₂ R ₃ R ₄ R ₅

Vinblastine: CH ₃CH ₃C (O) CH ₃OH CH ₂

Vincristine: CH ₂OC H ₃C (O) CH ₃OH CH2

Vindesine: CH ₃NH ₂H OH CH ₂

Vinorelbine: CH ₃CH ₃CH ₃The H singly-bound

Analog typically requires side group (shadow region) so that have activity.These chemical compounds are considered to by playing an anti-microtubule agent, more specifically suppress polymerization and work as cell cycle inhibitor.These chemical compounds have shown in the treatment of cell proliferation disorders that effectively described cell proliferation disorders comprises: NSC pulmonary carcinoma; Small cell lung cancer; Breast carcinoma; Carcinoma of prostate; The brain cancer; Head and neck cancer; Retinoblastoma; Bladder cancer; And carcinoma of penis; And soft tissue sarcoma.

In one aspect of the method, described cell cycle inhibitor is camptothecine or its analog or derivant.Camptothecin has following general structure.

In this structure, X typically is O, but can be other group, for example is NH in the situation of 21-lactam derivatives.R ₁Typically be H or OH, but can be other group, for example the C of terminal hydroxylization _1-3Alkane.R ₂H or contain amino group typically is such as (CH ₃) ₂NHCH ₂, but can be other group, for example NO ₂, NH ₂, halogen (as open at United States Patent (USP) 5,552,156 for example) or contain the short chain alkane of these groups.R ₃H or short-chain alkyl typically are such as C ₂H ₅R ₄Typically be H.But can be other group, for example with R ₁Methylene-dioxy.

Typical Comptothecin compounds comprises hycamtin, Irinotecan (CPT-11), 9-aminocamptothecin, 21-lactams-20 (S)-camptothecine, 10,11-methylene-dioxy camptothecine, SN-38,9-nitrocamptothecin, 10-hydroxycamptothecine.Typical compound has following array structure:

R ₁ R ₂ R ₃

Camptothecine: H H H

Hycamtin: OH (CH ₃) ₂NHCH ₂H

SN-38： OH H C ₂H ₅

X: for most of analog is O, is NH for the 21-lactams

Camptothecine has five rings that show herein.For the ring of maximum activity and minimum toxicity labelling E must be complete (lactone rather than carboxylate form).These chemical compounds are useful as cell cycle inhibitor, and they can play topoisomerase I inhibitor and/or dna cleavage agent thus.They have shown and have been effective to treat proliferative disease, comprising: for example, and NSC pulmonary carcinoma, small cell lung cancer, and cervical cancer.

In other one side, described cell cycle inhibitor is podophyllotoxin or derivatives thereof or analog.The chemical compound of typical the type is etoposide or teniposide, and it has following array structure:

These chemical compounds are considered to by playing cell cycle inhibitor as the topoisomerase II inhibitor and/or by the dna cleavage agent.They have shown effective conduct for example small cell lung cancer, carcinoma of prostate and the brain cancer and retinoblastoma antiproliferative.

Another example of DNA topoisomerase enzyme inhibitor is two hydrochloric acid lurtotecan (11H-1, the 4-dioxin also [2,3-g] pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] and quinoline-9,12 (8H, 14H)-diketone, 8-ethyl-2,3-dihydro-8-hydroxyl-15-[(4-methyl isophthalic acid-piperazinyl) methyl]-, dihydrochloride, (S)-).

In one aspect of the method, described cell cycle inhibitor is an anthracycline.Anthracycline has following general structure, and wherein the R group can be multiple organic group:

According to United States Patent (USP) 5,594,158, suitable R group is: R ₁Be CH ₃Or CH ₂OH; R ₂Be daunosamine or H; R ₃And R ₄Be OH, NO independently ₂, NH ₂, F, Cl, Br, I, CN, H or be derived from one of these group; R _5-7Be H or R ₅And R ₆Be H and R ₇And R ₈Be alkyl or halogen, or opposite: R ₇And R ₈Be H and R ₅And R ₆Be alkyl or halogen.

According to United States Patent (USP) 5,843,903, R ₂It can be conjugated peptide.According to United States Patent (USP) 4,215,062 and 4,296,105, R ₅It can be the alkyl that OH or ether connect.R ₁Can also by except the group of C (O) as having the alkyl or the branched alkyl of C (O) coupling part at its end, as-CH ₂CH (CH ₂-X) C (O)-R ₁Be connected with the anthracycline ring, wherein X is H or alkyl (referring to for example United States Patent (USP) 4,215,062).R ₂Can alternatively pass through the group that functional group=N-NHC (O)-Y connects, wherein Y is the group such as the phenyl ring of phenyl or replacement.R alternatively ₃Can have following array structure:

R wherein ₉Be in the plane of a loop or outer OH, or second sugar moieties such as R ₃R ₁₀Can be H or and group, form secondary amine (referring to United States Patent (USP) 5,843,903) such as aromatic group, the saturated or fractional saturation 5 that contains at least one nuclear nitrogen or 6 yuan of heterocycles.Alternatively, R ₁₀Can be derived from aminoacid, it has structure-C (O) CH (NHR ₁₁) (R ₁₂), R wherein ₁₁Be H, or and R ₁₂Form C _3-4Unit's alkylidene.R ₁₂Can be H, alkyl, aminoalkyl, amino, hydroxyl, sulfydryl, phenyl, benzyl or methyl mercapto (referring to United States Patent (USP) 4,296,105).

Typical anthracyclines is doxorubicin, daunorubicin, darubicin, epirubicin, pirarubicin, zorubicin and carubicin.Suitable chemical compound has following array structure:

R ₁ R ₂ R ₃

Doxorubicin: OCH ₃CH ₂OH OH is outside plane of a loop

Epirubicin: OCH ₃CH ₂OH OH is in plane of a loop

(4 ' epimer of doxorubicin)

Daunorubicin: OCH ₃CH ₃OH is outside plane of a loop

Darubicin: H CH ₃OH is outside plane of a loop

Pirarubicin OCH ₃OH A

Zorubicin OCH ₃=N-NHC (O) C ₆H ₅B

Carubicin OH CH ₃B

Other suitable anthracyclines is anthracycline, mitoxantrone, menogaril, nogalamycin, Aclacnomycin A, Olivomycin A, chromomycin A ₃And plicamycin, it has following array structure:

Think that these chemical compounds are by playing cell cycle inhibitor as topoisomerase enzyme inhibitor and/or by the dna cleavage agent.These chemical compounds have shown in the treatment of cell proliferation disorders that effectively described cell proliferation disorders comprises: small cell lung cancer; Breast carcinoma; Carcinoma of endometrium; Head and neck cancer; Retinoblastoma; Hepatocarcinoma; Cancer of biliary duct; Islet-cell carcinoma; And bladder cancer; And soft tissue sarcoma.

In one aspect of the method, cell cycle inhibitor is a platinum compounds.In general, platinum complex can be Pt (II) or Pt (IV), and has following this basic structure:

Wherein X and Y are the anion leaving groups, such as sulfate radical, phosphate radical, carboxylate radical and halogen; R ₁And R ₂Be alkyl, amine, aminoalkyl, and can be further replaced, and be essentially inertia or bridging group.For Pt (II) complex Z ₁And Z ₂Do not exist.For Pt (IV) Z ₁And Z ₂Can be anionic group such as halogen, hydroxyl, carboxylate radical, ester, sulfate radical or phosphate radical.For example, referring to United States Patent (USP) 4,588,831 and 4,250,189.

Suitable platinum complex can comprise a plurality of Pt atoms.For example, referring to United States Patent (USP) 5,409,915 and 5,380,897.For example two platinum of the type and three platinum complexs:

Typical platinum compounds is cisplatin, carboplatin, oxaliplatin and rice platinum, and it has following array structure:

The cisplatin carboplatin

These chemical compounds are considered to by combining with DNA, for example work as the alkylating agent of DNA and play cell cycle inhibitor.These chemical compounds have shown in the treatment of cell proliferation disorders that effectively described cell proliferation disorders comprises: for example, and NSC pulmonary carcinoma; Small cell lung cancer; Breast carcinoma; Cervical cancer; The brain cancer; Head and neck cancer; Esophageal carcinoma; Retinoblastoma; Hepatocarcinoma; Cancer of biliary duct; Bladder cancer; Carcinoma of penis; And carcinoma vulvae; And soft tissue sarcoma.

In one aspect of the method, described cell cycle inhibitor is a nitroso ureas.Nitroso ureas has following general structure (C5), and wherein the typical R group is as follows.

The R group:

Other suitable R group comprises group, saccharide, aryl and heteroaryl, phosphono and the sulfonyl that naphthenic, alkanes, halogen replace.As United States Patent (USP) 4,367,239 is disclosed, and R can suitably be CH ₂-C (X) is (Z) (Y), and wherein X and Y can be identical or different following groups members: phenyl, cyclohexyl or quilt are such as halogen, low alkyl group (C _1-4), trifluoromethyl, cyano group, phenyl, cyclohexyl, lower alkoxy (C _1-4) phenyl or the cyclohexyl that replace.Z has following array structure :-alkylidene-N-R ₁R ₂, R wherein ₁And R ₂Can be identical or different following groups member: low alkyl group (C _1-4) and benzyl, perhaps R ₁And R ₂Can form 5 or 6 yuan of saturated heterocycles together, such as pyrrolidine, piperidines, morfoline, sulfo-morfoline, N-low alkyl group piperazine, wherein said heterocycle can randomly be replaced by low alkyl group.

As United States Patent (USP) 6,096,923 is disclosed, and the R and the R ' of formula (C5) can be identical or different, wherein can be replacement or the unsubstituted hydrocarbon that contains 1-10 carbon atom separately.Substituent group can comprise alkyl, halogen, ester, amide, carboxylic acid, ether, thioether and alcohol groups.Such as United States Patent (USP) 4; 472; 379 is disclosed, and the R of formula (C5) can be amido link and pyranose structure (for example amino-the 2 '-deoxidation of methyl 2 '-(N-(N-(2-chloroethyl)-N-nitroso-group-carbamoyl)-glycyl)-α-D-glycopyranoside).As United States Patent (USP) 4,150,146 is disclosed, and the R of formula (C5) can be the alkyl of 2-6 carbon atom and can be replaced by ester, sulfonyl or hydroxyl.It can also be by carboxylic acid or CONH ₂Group replaces.

Typical nitroso ureas is BCNU (carmustine), Semustine (semustine), CCNU (lomustine), Ranimustine, nimustine, chlorozotocin, fotemustine and streptozocin, and it has following array structure:

These nitroso-urea compounds are considered to by combining with DNA, i.e. effect by the cell cycle inhibitor that worked as the DNA alkylating agent.These cell cycle inhibitors have shown and have been effective to treat cell proliferation disorders, and described cell proliferation disorders is as for example, islet-cell carcinoma; Small cell lung cancer; Melanoma; And the brain cancer.

In one aspect of the method, cell cycle inhibitor is the nitre imidazoles, and wherein typical nitre imidazoles is metronidazole, benznidazole, etanidazole and misonidazole, and it has following array structure:

R R R

R ₁ R ₂ R ₃

Metronidazole OH CH ₃NO ₂

Benznidazole C (O) NHCH ₂-benzyl NO ₂H

Etanidazole CONHCH ₂CH ₂OH NO ₂H

Suitable nitre imidazolium compounds is for example disclosing in the United States Patent (USP) 4,371,540 and 4,462,992.

In one aspect of the method, described cell cycle inhibitor is an antifol, as methotrexate or derivatives thereof or analog, comprises edatrexate, trimetrexate, Raltitrexed, piritrexim, 9,10-dimethylpteroylglutamic acid, Tomudex, and Pteropterin.The methotrexate analog has following general structure:

The identity of R group can be selected from organic group, particularly at United States Patent (USP) 5,166, and 149 and 5,382, those groups described in 582.For example, R ₁Can be N, R ₂Can be N or C (CH ₃), R ₃And R ₃' can be H or alkyl, for example CH ₃, R ₄Can be singly-bound or NR, wherein R be H or alkyl.R _5,6,8Can be H, OCH ₃, or alternatively they can be halogen or hydrogen base.R7 is the side chain of following general structure:

Wherein for methotrexate n=1, for Pteropterin n=3.Can be with carboxyl esterification in the side chain or salify, such as Zn ²⁺Salt.R ₉And R ₁₀Can be NH ₂Maybe can be that alkyl replaces.

Typical folic acid antagonist immunomodulator compounds has following array structure:

R ₀ R ₁ R ₂ R ₃ R ₄ R ₅ R ₆ R ₇ R ₈

Methotrexate NH ₂N N H N (CH ₃) H H A (n=1) H

Edatrexate NH ₂N N H N (CH ₂CH ₃) H H A (n=1) N

Trimetrexate NH ₂N C (CH ₃) H NH H OCH ₃OCH ₃OCH ₃

Pteropterin NH ₂N N H N (CH ₃) H H A (n=3) H

9,10-dimethylpteroylglutamic acid OH N N CH ₃N (CH ₃) H H A (n=1) H

Piritrexim NH ₂N C (CH ₃) H single OCH ₃H H OCH ₃H

bonld

Tomudex

These chemical compounds are considered to play cell cycle inhibitor by the antimetabolite as folic acid.They have shown and have been effective to treat cell proliferation disorders that described cell proliferation disorders for example comprises, soft tissue sarcoma, small cell lung cancer; Breast carcinoma; The brain cancer; Head and neck cancer; Bladder cancer; And carcinoma of penis.

In one aspect of the method, described cell cycle inhibitor is a cytidine analog, such as cytosine arabinoside or derivatives thereof or analog, comprise enocitabine, FMdC ((E (2 '-deoxidation-2 '-(fluorine methylene) cytidine), gemcitabine, 5-azacitidine, ancitabine and 6-azauridine.Exemplary compounds has following array structure:

R ₁ R ₂ R ₃ R ₄

Cytosine arabinoside H OH H CH

Enocitabine e C (O) (CH ₂) ₂0CH ₃OH H CH

Gemcitabine e H F F CH

Azacitidine H H OHN

FMdC H CH ₂F H CH

Ancitabine 6-azauridine

Think that these chemical compounds play cell cycle inhibitor as the antimetabolite of pyrimidine.These chemical compounds have shown and have been effective to treat cell proliferation disorders that described cell proliferation disorders comprises: for example, and cancer of pancreas, breast carcinoma, cervical cancer, NSC pulmonary carcinoma and cancer of biliary duct.

In one aspect of the method, described cell cycle inhibitor is a pyrimidine analogue.In individual one side, pyrimidine analogue has following general structure:

Wherein 2 ', 3 ' and 5 ' on the sugar ring (is respectively R ₂, R ₃And R ₄) can be H, hydroxyl, phosphoryl (for example) or ester (for example, referring to United States Patent (USP) 3,894,000) referring to United States Patent (USP) 4,086,417.Ester can be alkyl, cycloalkyl, aryl or heterocyclic radical/aryl type.2 ' carbon can be at R ₂Or R ₂' locate by hydroxylating, another group is H.Alternatively, 2 ' carbon can be replaced by halogen such as fluorine or difluoro cytidine such as gemcitabine.Alternatively, sugar can or connect alkane such as C (O) NH (CH for another heterocyclic group such as furyl or alkane, alkyl ether ₂) ₅CH ₃Amide replace.2 ° of aliphatic acyl (R that amine can be connected with amide ₁) (for example, referring to United States Patent (USP) 3,991,045) or the replacement of urethane (for example, referring to United States Patent (USP) 3,894,000) key.It can also further be substituted the formation quaternary ammonium salt.R in the pyrimidine ring ₅Can be N or CR, wherein R be H, halogen-containing group or alkyl (for example, referring to United States Patent (USP) 4,086,417).R ₆And R ₇Can form oxo group or R together ₆=-NH-R ₁And R ₇=H.R ₈Be H or R ₇And R ₈Can form two keys or R together ₈Can be X, wherein X be:

Concrete pyrimidine analogue is at United States Patent (USP) 3,894, discloses (for example, referring to 2 '-O-palmityl-arabinose (ara)-cytidine, 3 '-O-benzoyl-arabinose-cytidine with more than other example of 10) in 000; United States Patent (USP) 3,991,045 (for example, referring to N4-acyl group-1-β-D-arabinofuranosyl adenin cytosine and the multiple acyl derivative wherein listed, as the palmityl derivant).

In one aspect of the method, described cell cycle inhibitor is a fluoropyrimidine analogue.As 5-fluorouracil or its analog or derivant, comprise carmofur, doxifluridine, emitefur, ftorafur and floxuridine.Exemplary compounds has following array structure:

R ₁ R ₂

5-fluorouracil H H

Carmofur C (O) NH (CH ₂) ₅CH ₃H

Doxifluridine A ₁H

Floxuridine A ₂H

Emitefur CH ₂OCH ₂CH ₃B

Ftorafur C H

Other suitable fluoropyrimidine analogue comprises 5-FudR (5-fluoro-BrdU) or its analog or derivant, comprises idoxuridine (5-IudR), 5-bromouracil deoxyribose (5-BudR), triphosphoric acid floxuridine (5-FUTP) and a phosphoric acid fluorodeoxyuridine (5-dFUMP).Exemplary compounds has following array structure:

5-fluoro-2 '-BrdU: R=F

5-bromo-2 '-BrdU: R=Br

5-iodo-2 '-BrdU: R=I

These chemical compounds are considered to play cell cycle inhibitor by the antimetabolite as pyrimidine.These chemical compounds have shown and have been effective to treat cell proliferation disorders, described cell proliferation disorders such as cervical cancer, non-melanoma skin cancer, head and neck cancer, esophageal carcinoma, cancer of biliary duct, cancer of pancreas, islet-cell carcinoma, carcinoma of penis and carcinoma vulvae.

In one aspect of the method, described cell cycle inhibitor is a purine analogue.Purine analogue has following general structure:

Wherein X typically is carbon; R ₁It is the phenyl of H, halogen, amine or replacement; R ₂Be H, primary, the second month in a season or tertiary amine, sulfur-containing group, typically be-SH, alkane, cycloalkanes, heterocycle or sugar; R ₃Sugar or ring-type or heterocycle alkane or aryl for H, sugar (typically furanose or pyranose structure), replacement.For the chemical compound of the type for example referring to United States Patent (USP) 5,602,140.

In the situation of pentostatin, X-R2 is-CH ₂CH (OH)-.Second carbon atom is inserted between the X and adjacent nitrogen atom in the ring in this case.The two keys of X-N become singly-bound.

United States Patent (USP) 5,446, disclosed in 139 as shown in the formula shown in the suitable purine analogue of the type:

Wherein N represents that nitrogen and V, W, X, Z can be carbon or nitrogen under following condition.Ring A can contain 0-3 nitrogen-atoms in its structure.If in ring A, have two nitrogen, so one must be in the W position.If only there is one, it must be in the Q position so.V and Q can not be nitrogen simultaneously.Z and Q can not be nitrogen simultaneously.If Z is a nitrogen, so R ₃Do not exist.In addition, R _1-3Be H, halogen, C independently _1-7Alkyl, C _1-7Alkenyl, hydroxyl, sulfydryl, C _1-7Alkylthio group, C _1-7Alkoxyl, C _2-7Alkenyloxy, aryloxy, nitro, contain primary, one of the group of the second month in a season or tertiary amine.R _5-8For H or nearly two positions can comprise one of amino of OH, halogen, cyano group, azido, replacement, R independently ₅And R ₇Can form two keys together.Y is H, C _1-7Alkyl-carbonyl or one, two or triguaiacyl phosphate.

Typical suitable purine analogue comprises 6-mercaptopurine, thiguanosine, ITG, cladribine, fludarabine, tubercidin, puromycin, pentoxifylline; Wherein these chemical compounds can be randomly by phosphorylation.Exemplary compounds has following structure:

Pentoxifylline

These chemical compounds are thought and are played cell cycle inhibitor by the antimetabolite as purine.

In one aspect of the method, described cell cycle inhibitor is a chlormethine.Many suitable chlormethine are known and are suitable as cell cycle inhibitor among the present invention.Suitable chlormethine is also referred to as cyclophosphamide.

Preferred chlormethine has following general structure:

Wherein A is:

Or-CH ₃Or other alkane, or chlorating alkane, typically be CH ₂CH (CH ₃) Cl, or multi-ring group, such as B, or the phenyl such as C or the heterocyclic radical that replace, such as D.

The example of suitable chlormethine is at United States Patent (USP) 3,808, discloses in 297, and wherein A is:

R _1-2Be H or CH ₂CH ₂Cl; R ₃Be H or oxy radical, such as hydroperoxy; R ₄Can be alkyl, aryl, heterocyclic radical.

Loop section need not complete.For example, referring to United States Patent (USP) 5,472,956,4,908,356,4,841,085, it describes the structure of following type:

R wherein ₁Be H or CH ₂CH ₂Cl, R _2-6Be various substituent groups.

Typical chlormethine comprises methyl chloride ethamine and analog or derivant, comprises methyl chloride amine oxides hydrochlorate, novoembichin and mannomustine (halogen-sugar).Exemplary compounds has following array structure:

Methyl chloride ethamine CH ₃Methyl chloride amine oxides HCl

Novoembichin CH ₂CH (CH ₃) Cl

Chlormethine can be cyclophosphamide, ifosfamide, perfosfamide or Torofosfamide, and wherein these chemical compounds have following array structure:

R ₁ R ₂ R ₃

Cyclophosphamide H CH ₂CH ₂Cl H

Ifosfamide CH ₂CH ₂Cl H H

Perfosfamide CH ₂CH ₂Cl H OOH

Torofosfamide CH ₂CH ₂Cl CH ₂CH ₂Cl H

Chlormethine can be estramustine or its analog or derivant, comprises phenesterin, prednimustine and estramustine PO ₄Therefore, the cell cycle inhibitor of the suitable chlormethine type of the present invention has following structure:

R

Estramustine OH

Phenesterin C (CH ₃) (CH ₂) ₃CH (CH ₃) ₂

Chlormethine can be chlorambucil or its analog or derivant, comprises melphalan and Chlormaphazine.Therefore the cell cycle inhibitor of the suitable chlormethine type of the present invention has following structure:

R ₁ R ₂ R ₃

Chlorambucil CH ₂COOH H H

Melphalan COOH NH ₂H

Chlormaphazin H

Form phenyl ring together

Chlormethine can be a uracil mustard, and it has following array structure:

Chlormethine is considered to play cell cycle inhibitor by the alkylating agent as DNA.Chlormethine has shown in the treatment of cell proliferation disorders that effectively described cell proliferation disorders comprises: for example small cell lung cancer, breast carcinoma, cervical cancer, head and neck cancer, carcinoma of prostate, retinoblastoma and soft tissue sarcoma.

Cell cycle inhibitor of the present invention can be a hydroxyurea.The hydroxyl ureas has following general structure:

Suitable hydroxyl ureas is for example at United States Patent (USP) 6,080, discloses in 874, wherein R ₁Be:

And R ₂Be the alkyl that contains 1-4 carbon atom, and R ₃Be one of H, acyl group, methyl, ethyl and composition thereof, as methyl ether.

Other suitable hydroxyl ureas is for example at United States Patent (USP) 5,665, discloses in 768, wherein R ₁Be cycloalkenyl group, N-(3-(5-(4-fluorobenzene sulfenyl)-furyl)-2-ring penta-1-yl) N-hydroxyurea for example; R ₂Be H or alkyl and the R that contains 1-4 carbon ₃Be H; X is H or cation.

Other suitable hydroxyl ureas is for example at United States Patent (USP) 4,299, discloses in 778, wherein R ₁The phenyl that is replaced by one or more fluorine atoms; R ₂It is cyclopropyl; R ₃With X be H.

Other suitable hydroxyl ureas is for example at United States Patent (USP) 5,066, discloses in 658, wherein R ₂And R ₃Form with adjacent nitrogen:

Wherein m is 1 or 2, and n is that 0-2 and Y are alkyl.

In one aspect, the hydroxyl urea has following array structure:

The hydroxyl urea

The hydroxyl ureas is considered to by being used to suppress the effect that DNA has synthesized cell cycle inhibitor.

In one aspect of the method, cell cycle inhibitor is mitomycin (mytomicin), such as ametycin, or its analog or derivant, such as porphyromycin.Suitable chemical compound has following array structure:

R

Ametycin H

Porphyromycin CH ₃

(N-methylmitomycin C)

These chemical compounds are considered to by playing cell cycle inhibitor as the DNA alkylating agent.Mitomycin has been presented in the treatment cell proliferation disorders effectively, described cell proliferation disorders such as for example esophageal carcinoma, hepatocarcinoma, bladder cancer and breast carcinoma.

In one aspect of the method, described cell cycle inhibitor is an alkylsulfonate, as busulfan, or its analog or derivant, as treosulfan, impromidine, piposulfan, and pipobroman.Exemplary compounds has following array structure:

Pipobroman

These chemical compounds are considered to by playing cell cycle inhibitor as the DNA alkylating agent.

In one aspect of the method, described cell cycle inhibitor is a Benzoylamide.In one aspect of the method, described cell cycle inhibitor is a nicotiamide.These chemical compounds have following basic structure:

Wherein X is O or S; A is NH normally ₂Perhaps it can be OH or alkoxyl; B is N or C-R ₄, R wherein ₄Be the hydroxylated alkane that H or ether connect, such as OCH ₂CH ₂OH, described alkane can be straight or branched and can contain one or more hydroxyls.Alternatively, B can be N-R ₅, relate in this case that two keys are singly-bounds in the ring of B.R ₅Can be H and alkyl or aryl (for example, referring to United States Patent (USP) 4,258,052); R ₂Be H, OR ₆, SR ₆Or NHR ₆, R wherein ₆It is alkyl; And R ₃Be the low alkyl group that H, low alkyl group, ether connect, such as-O-Me or-O-ethyl (for example, referring to United States Patent (USP) 5,215,738).

Suitable benzamide compounds has following structure:

Benzoylamide

X=O or S

Y=H, OR, CH ₃, acetoxyl group

Z＝H，OR，SR，NHR

The R=alkyl

Wherein additional compounds is at United States Patent (USP) 5,215, discloses (enumerating about 32 kinds of chemical compounds) in 738.

Suitable nicotiamide chemical compound has following array structure:

Nicotiamide

X=O or S

Z＝H，OR，SR，NHR

The R=alkyl

Wherein additional compounds is at United States Patent (USP) 5,215, disclose in 738,

In one aspect of the method, described cell cycle inhibitor is halogenated sugar, such as mitolactol, or its analog or derivant, comprise mitobronitol and mannomustine.Exemplary chemical compound has following structure:

Mitolactol mitobronitol mannomustine

In one aspect of the method, described cell cycle inhibitor is a diazonium compound, such as azaserine, or its analog or derivant, comprise 6-diazonium-5-oxo-L-nor-leucine and 5-diazouracil (also being pyrimidine analogue).Typical compound has following structure:

R ₁ R ₂

Azaserine O singly-bound

6-diazonium-5-oxo-L-nor-leucine singly-bound CH ₂

Can be as other chemical compound of cell cycle inhibitor of the present invention: pazelliptine; Wortmannin; Metoclopramide; RSU; Buthionine sulfoxime; Rhizoma Curcumae Longae; Curcumin; AG337, promptly a kind of thymidylate synthase inhibitor; Levamisole; Lentinan, promptly a kind of polysaccharide; Razoxane, promptly a kind of EDTA analog; Indomethacin; Chlorpromazine; α and interferon-; MnBOPP; Gadolinium texaphrin; 4-amino-1,8-naphthalene imines (naphthalimide); The staurosporine derivatives of CGP; And SR-2508.

Therefore, in one aspect in, described cell cycle inhibitor is the DNA alkylating agent.In one aspect of the method, described cell cycle inhibitor is anti-microtubule agent.In one aspect of the method, described cell cycle inhibitor is a topoisomerase enzyme inhibitor.In one aspect of the method, described cell cycle inhibitor is the dna cleavage agent.In one aspect of the method, described cell cycle inhibitor is a kind of antimetabolite.In one aspect of the method, described cell cycle inhibitor is by suppressing adenosine deaminase performance function (for example, as purine analogue).In one aspect of the method, described cell cycle inhibitor synthesizes by the inhibition purine ring and/or brings into play function (for example, as purine analogue, such as purinethol) as nucleotide interconversion inhibitor.In one aspect of the method, described cell cycle inhibitor is by suppressing dihydrofolate reduction and/or bringing into play function (for example, methotrexate) as the thymidine monophosphate blocker.In one aspect of the method, described cell cycle inhibitor is brought into play function (for example, bleomycin) by causing DNA damage.In one aspect of the method, described cell cycle inhibitor by bring into play as the synthetic inhibitory action of DNA intercalating agent and/or RNA function (for example doxorubicin, aklavine or detorubicin (acetic acid, diethoxy-, 2-[4-[(3-amino-2,3,6-three deoxies-α-L-lysol-own pyrans glycosyl) the oxygen base]-1,2,3,4,6,11-six hydrogen-2,5,12-trihydroxy-7-methoxyl group-6,11-dioxo-2-naphthacenyl]-2-oxo ethyl ester, (2S-cis)-)).In one aspect of the method, described cell cycle inhibitor synthesizes and brings into play function (for example, N-phosphono acetyl group-L-aspartate (ester)) by suppressing pyrimidine.In one aspect of the method, described cell cycle inhibitor is brought into play function (for example, hydroxyurea) by suppressing ribonucleotide.In one aspect of the method, described cell cycle inhibitor is brought into play function (for example, 5-fluorouracil) by suppressing thymidine monophosphate.In one aspect of the method, described cell cycle inhibitor synthesizes and brings into play function (for example, cytosine arabinoside) by suppressing DNA.In one aspect of the method, described cell cycle inhibitor is brought into play function (for example, platinum compounds) by the formation that causes dna adduct.In one aspect of the method, described cell cycle inhibitor synthesizes by Profilin matter and brings into play function (for example, altheine enzyme).In one aspect of the method, described cell cycle inhibitor is brought into play function (for example, taxanes) by suppressing the microtubule function.In one aspect of the method, the one or more steps of described cell cycle inhibitor in the biological pathway that accompanying drawing 1 shows work.

Useful in the present invention other cell cycle inhibitor and to the discussion of their mechanism of action, can see Hardman J.G, Limbird L.E.Molinoff R.B., Ruddon R.W., Gilman A.G edits, " chemotherapy of neoplastic disease " of Goodman and Gilman (Chemotherapy of Neoplastic Diseases)-" pharmacological basis of therapeutic agent " (ThePharmacological Basis of Therapeutics) the 9th edition, McGraW-Hill HealthProfessions Division, New York, 1996, the 1225-1287 pages or leaves.Also see U.S. Patent number 3,387,001; 3,808,297; 3,894,000; 3,991,045; 4,012,390; 4,057,548; 4,086,417; 4,144,237; 4,150,146; 4,210,584; 4,215,062; 4,250,189; 4,258,052; 4,259,242; 4,296,105; 4,299,778; 4,367,239; 4,374,414; 4,375,432; 4,472,379; 4,588,831; 4,639,456; 4,767,855; 4,828,831; 4,841,045; 4,841,085; 4,908,356; 4,923,876; 5,030,620; 5,034,320; 5,047,528; 5,066,658; 5,166,149; 5,190,929; 5,215,738; 5,292,731; 5,380,897; 5,382,582; 5,409,915; 5,440,056; 5,446,139; 5,472,956; 5,527,905; 5,552,156; 5,594,158; 5,602,140; 5,665,768; 5,843,903; 6,080,874; 6,096,923; And RE030561.

In another embodiment, described cell cycle inhibitor is camptothecine, mitoxantrone, etoposide, 5-fluorouracil, doxorubicin, methotrexate, peloruside A, ametycin, or CDK-2 inhibitor or listed other any member's of compounds analog or derivant.

In another embodiment, described cell cycle inhibitor is HTI-286, plicamycin or mithramycin or its analog or derivant.

The example of other cell cycle inhibitor also comprises: for example; 7-caproyl paclitaxel (QP-2); CA; 1antrunculin D; actinomycin D; Ro-31-7453 (3-(6-nitro-1-methyl-3-indyl)-4-(1-methyl-3-indyl) pyrroles-2; the 5-diketone); PNU-151807; brostallicin; the C2-ceramide; cytosine arabinoside ocfosfate (2 (1H)-pyrimidones; 4-amino-1-(5-O-(hydroxyl (octadecyl oxygen base) phosphinyl)-β-D-arabinofuranosyl adenin glycosyl)-; one sodium salt); paclitaxel (5 β; 20-epoxy-1; 2-α; 4; 7 β; 10 β; 13 α-hexahydroxy Ramulus et folium taxi cuspidatae-11-alkene-9-ketone-4; 10-diacetate esters-2-benzoate-13-(α-phenyl hippurate)); doxorubicin (5; 12-aphthacene diketone; 10-((3-amino-2; 3; 6-three deoxies-α-L-lysol-hexose pyrans glycosyl) oxygen base)-7; 8; 9; 10-tetrahydrochysene-6; 8; 11-trihydroxy-8-(ethoxy)-1-methoxyl group-; (8S)-suitable-); daunorubicin (5; 12-aphthacene diketone, 8-acetyl group-10-((3-amino-2,3; 6-three deoxies-α-L-lysol-hexose pyrans glycosyl) oxygen base)-7; 8,9,10-tetrahydrochysene-6; 8; 11-trihydroxy-1-methoxyl group-, (8S-is suitable)-); gemcitabine hydrochloride (cytidine, 2 '-deoxidation-2 '; 2 '-two fluoro-; one hydrochlorate); nitacrine (1,3-propane diamine, N; N-dimethyl-N '-(1-nitro-9-acridinyl)-); carboplatin (platinum; diamidogen (1, the 1-cyclobutane dicarboxylic acid radical closes (2-))-, (SP-4-2)-); altretamine (1; 3; 5-triazine-2,4, the 6-triamine; N; N, N ', N '; N "; N "-hexamethyl-); teniposide (fluorine (3 ', 4 ': 6,7) naphtho-(2; 3-d)-1; 3-dioxane pentadiene-6 (5aH)-ketone, 5,8; 8a; 9-tetrahydrochysene-5-(4-hydroxyl-3,5-Dimethoxyphenyl)-9-((4,6-O-(2-thienyl methene)-β-D-glycopyranosyl) oxygen base)-; (5R-(5 α; 5a β, 8aA, 9 β (R ^*)))-); eptaplatin (platinum; ((4R; 5R)-2-(1-Methylethyl)-1; 3-dioxolanes-4; 5-dimethylamine-κ N4; κ N5) (malonate closes (2-)-κ O1; κ O3)-; (SP-4-2)-); Amrubicin Hydrochloride (5; 12-aphthacene diketone; 9-acetyl group-9-amino-7-((2-deoxidation-β-D-red-pyranopentose base) oxygen base)-7; 8; 9; 10-tetrahydrochysene-6; the 11-dihydroxy-; hydrochlorate; (7S-is suitable)-); ifosfamide (2H-1; 3; 2-oxygen azepine phosphinylidyne-2-amine; N; 3-two (2-chloroethyl) tetrahydrochysene-; the 2-oxide); cladribine (adenosine; 2-chloro-2 '-deoxidation-); mitobronitol (D-mannitol; 1; 6-two bromo-1; 6-dideoxy base-); fludarabine phosphate (fludaribine) (9H-purine-6-amine; 2-fluoro-9-(5-O-phosphono-β-D-arabinofuranosyl adenin glycosyl)-); enocitabine (22 phosphoamides; N-(1-β-D-arabinofuranosyl adenin glycosyl-1; 2-dihydro-2-oxo--4-pyrimidine radicals)-); vindesine (vinblastine; 3-(amino carboxyl)-O4-deacetylation-3-take off (methoxycarbonyl)-); idarubicin (5; 12-aphthacene diketone; 9-acetyl group-7-((3-amino-2; 3; 6-three deoxies-α-L-lysol-hexose pyranose) oxygen base)-7; 8; 9; 10-tetrahydrochysene-6; 9; the 11-trihydroxy-; (7S-is suitable)-); zinostatin (neocarzinostain NCS); vincristine (vinblastine; the 22-oxo-); ftorafur (2; 4 (1H; 3H)-hybar X; 5-fluoro-1-(tetrahydrochysene-2-furyl)-); razoxane (2,6-piperazinedione, 4; 4 '-(1-methyl isophthalic acid; 2-second two bases) two-); methotrexate (L-glutamic acid, N-(4-(((2,4-diaminourea-6-pteridyl) methyl) methylamino) benzoyl)-); Raltitrexed (L-glutamic acid; ((5-(((1 for N-; 4-dihydro-2-methyl-4-oxo-6-quinazolyl) methylamino methyl))-and the 2-thienyl) carbonyl)-); oxaliplatin (platinum, (and 1,2-cyclohexanediamine-N; N ') (two of second are closed (2-)-O; O ')-, (SP-4-2-(1R-is anti-))-); doxifluridine (uridnine, 5 '-deoxidation-5-fluoro-); mitolactol (dulcitol; 1; 6-two bromo-1, the 6-dideoxy-); pirarubicin (piraubicin) (5,12-aphthacene diketone; 10-((3-amino-2; 3,6-three deoxidations-4-O-(tetrahydrochysene-2H-pyrans-2-yl)-α-L-lysol-hexose pyranose) the oxygen base)-7,8; 9; 10-tetrahydrochysene-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxyl group-; (8S-(8 α, 10 α (S ^*)))-); docetaxel ((2R; 3S)-N-carboxyl-3-phenylisoserine; the N-tert-butyl ester; with 5 β; 20-epoxy-1; 2 α; 4; 7 β; 10 β; 13 α-hexahydroxy Ramulus et folium taxi cuspidatae-11-alkene-9-ketone 4-acetas 2-benzoate-13-ester); capecitabine (cytidine; 5-deoxidation-5-fluoro-N-((amoxy) carbonyl)-); cytosine arabinoside (2 (1H)-pyrimidones; 4-amino-1-β-D-arabinofuranosyl adenin glycosyl-); valrubicin (valeric acid; 2-(1,2,3; 4; 6,11-six hydrogen-2,5; 12-trihydroxy-7-methoxyl group-6; 11-dioxo-4-((2,3,6-three deoxidations-3-((trifluoroacetyl group) amino)-α-L-lysol-hexose pyranose) oxygen base)-2-naphthacenyl)-2-oxo ethyl ester (2S-cis)-); trofosfamide (3-2-(chloroethyl)-2-(two (2-chloroethyl) amino) tetrahydrochysene-2H-1; 3; the 2-oxazaphosphorin-2-oxide); prednimustine (pregnant-1,4-diene-3,20-diketone; 21-(4-(4-(two (2-chloroethyl) amino) phenyl)-1-oxo butoxy)-11; the 17-dihydroxy-, (11 β)-); lomustine (urea, N-(2-chloroethyl)-N '-cyclohexyl-N-nitroso-group-); epirubicin (5; 12-aphthacene diketone; 10-((3-amino-2,3,6-three deoxidations-α-L-arabinose-hexose pyranose) oxygen base)-7; 8; 9,10-tetrahydrochysene-6,8; 11-trihydroxy-8-(hydroxyacetyl)-1-methoxyl group-, (8S-is suitable)-) or its analog or derivant).

5) The inhibitors of kinases of cyclin dependent

In another embodiment, the inhibitors of kinases that suppresses fibrotic pharmaceutical active compounds and be cyclin dependent (for example, R-roscovitine, CYC-101, CYC-103, CYC-400, MX-7065, alvocidib (4H-1-.alpha.-5:6-benzopyran-4-ketone 2-(2-chlorphenyl)-5,7-dihydroxy-8-(3-hydroxyl-1-methyl-4-piperidyl)-, cis-(-)-), SU-9516, AG-12275, PD-0166285, CGP-79807, fascaplysin, GW-8510 (benzsulfamide, 4-(((Z)-(6,7-dihydro-7-oxo-8H-pyrroles [2,3-g] benzothiazole-8-thiazolinyl) methyl] amino)-N-(3-hydroxyl-2,2-dimethyl propyl)-), GW-491619, indirubin 3 ' monoxime (monoxime), GW8510) or its analog or derivant).

6) EGF (epidermal growth factor) receptor kinase inhibitor

In another embodiment, (for example suppress fibrotic pharmaceutical active compounds and be EGF (epidermal growth factor) inhibitors of kinases, erlotinib (4-quinazoline amine, N-(3-ethynyl phenyl)-6,7-two (2-methoxy ethoxy)-, one hydrochlorate), erbstatin, BIBX-1382, gefitinib (4-quinazoline amine, N-(3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-(4-morpholinyl) propoxyl group))) or its analog or derivant).

7) Elastatinal

In another embodiment; (for example suppress fibrotic pharmaceutical active compounds and be elastatinal; ONO-6818; hydration sivelestat sodium (glycine; ((((4-(2 for 2-for N-; 2-dimethyl-1-oxopropoxy) benzoyl amino sulfonyl phenyl))))-); erdosteine (acetic acid; ((2-oxo-2-((tetrahydrochysene-2-oxo-3-thienyl) amino) ethyl) sulfenyl)-); MDL-100948A; MDL-104238 (N-(4-(4-morpholinyl carbonyl) benzoyl)-L-valyl-N '-(3; 3; 4; 4; 4-five fluoro-1-(1-Methylethyl)-2-oxo butyl)-L-2-azetamide); MDL-27324 (L-prolineamide (Prolinamide); N-((5-(dimethylamino)-1-naphthyl) sulfonyl)-L-alanyl-L-alanyl-N-[3; 3; 3-three fluoro-1-(1-Methylethyl)-2-oxopropyl]-; (S)-); SR-26831 (thieno [3; 2-c] pyridine; 5-((2-chlorphenyl) methyl)-2-(2; 2-dimethyl-1-oxopropoxy)-4; 5; 6; 7-tetrahydrochysene-5-hydroxyl-); Win-68794; Win-63110; SSR-69071 (2-(9 (2-piperidino ethyoxyl)-4-oxo-4H-pyridos (1; 2-a) pyrimidine-2-yloxy methyl)-4-(1-Methylethyl)-6-methoxyl group-1; 2-benzisothiazole-3 (2H)-ketone-1; the 1-dioxide); (N (α)-(1-adamantyl sulfonyl) N (ε)-succinyl group-L-lysyl-L-prolyl-L-valinal); Ro-31-3537 (N α-(1-diamantane (obsolete) sulfonyl)-N-(4-carboxylbenzoyl)-L-lysyl-alanyl-L-valinal); R-665; FCE-28204; ((6R; 7R)-2-(benzyloxy)-7-methoxyl group-3-methyl-4-pivaloyl-3-cephalosporin (cephem) 1; the 1-dioxide); 1; 2-benzisothiazole-3 (2H)-ketone; 2-(2; the 4-dinitrophenyl)-; 1; the 1-dioxide; L-658758 (L-proline; 1-((3-((acetoxyl group) methyl)-7-methoxyl group-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-yl) carbonyl)-; S; the S-dioxide; (6R-cis)-); L-659286 (nafoxidine; 1-((7-methoxyl group-8-oxo-3-(((1; 2; 5; 6-tetrahydrochysene-2-methyl-5; 6-dioxo-1; 2; 4-triazine-3-yl) methyl sulfo-))-and 5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-yl) carbonyl)-; S; the S-dioxide; (6R-cis)-); L-680833 (phenylacetic acid; 4-((3; 3-diethyl-1-(((1-(4-aminomethyl phenyl) butyl) amino) carbonyl)-4-oxo-2-azetidinyl) oxygen)-, (S-(R ^*, S ^*))-), FK-706 (L-prolineamide, N-[4-[[(carboxymethyl) amino] carbonyl] benzoyl]-L-is valyl-N-[3,3,3-three fluoro-1-(1-Methylethyl)-2-oxopropyl]-, a sodium salt), Roche R-665 or its analog or derivant.

8) Factor Xa inhibitor

In another embodiment, (for example suppress fibrotic pharmaceutical active compounds and be factor Xa inhibitor, CY-222, fondaparinux sodium (α-D-glycopyranoside, methyl O-2-deoxidation-6-O-sulfo group-2-(sulfo group amino)-α-D-glycopyranosyl-(1-4)-O-β-D-glucopyranuronosyl-(1-4)-O-2-deoxidation-3,6-two-O-sulfo group-2-(sulfo group amino)-α-D-glycopyranosyl-(1-4)-O-2-O-sulfo group-α-L-idopyranuronosyl-(1-4)-2-deoxidation-2-(sulfo group amino)-, 6-(disulfate)), Danaparoid sodium or its analog or derivant.

9) Farnesyl transferase inhibitor

In another embodiment; suppressing fibrotic pharmaceutical active compounds is that farnesyl transferase inhibitor is (for example from ARGLABIN-Paracure; Inc. (Virginia Beach; VA) dichlorobenzoprim (2; (4-(3 for 4-diaminourea-5-; 4-dichloro benzyl amino)-the 3-nitrobenzophenone)-the 6-ethyl-pyrimidine); B-581; B-956 (N-(8 (R)-amino-2 (S)-benzyl-5 (S)-isopropyls-9-sulfane base-3 (Z); 6 (E)-nonadiene acyl groups (nonadienoyl))-the L-methionine); OSI-754; perillyl alcohol (1-cyclohexene-1-methanol; 4-(1-methyl ethylene)-; RPR-114334; lonafarnib (1-piperidine formamide; 4-(2-(4-((11R)-3; 10-two bromos-8-chloro-6; 11-dihydro-5H-benzo (5; 6) ring heptan also (1; 2-b) pyridine-11-yl)-piperidino)-the 2-oxoethyl)-); Sch-48755; Sch-226374; (7; 8-two chloro-5H-dibenzo (b; e) (1; 4) diaza-11-yl)-the pyridin-3-yl methyl amine; J-104126; L-639749; L-731734 (pentane amide; 2-((2-((2-amino-3-sulfydryl propyl group) amino)-3-methyl amyl) amino)-3-methyl-N-(tetrahydrochysene-2-oxo-3-furyl)-, (3S-(3R ^*(2R ^*(2R ^*(S ^*), 3S ^*), 3R ^*)))-), L-744832 (butanoic acid, 2-((2-((2-((2-amino-3-sulfydryl propyl group) amino)-3-methyl amyl) oxygen base)-1-oxo-3-phenyl propyl) amino)-4-(methyl sulphonyl)-, 1-Methylethyl ester, (2S-(1 (R ^*(R ^*)), 2R ^*(S ^*), 3R ^*))-); L-745631 (1-piperazine propanethiol; beta-amino-2-(2-methoxy ethyl)-4-(1-naphthyl carbonyl)-; ((β R; 2S)-); amino-3 (the S)-dimethylpentylamines of N-acetyl group-N-naphthyl methyl-2 (S)-((1-(4-cyano group benzyl)-1H-imidazoles-5-yl) acetyl group); (2 α)-2-hydroxyl-24; 25-dihydroxylanost-8-alkene-3-ketone; BMS-316810; UCF-1-C (2; 4-decadinene amide; N-(5-hydroxyl-5-(7-((2-hydroxyl-5-oxo-1-cyclopentenes-1-yl) amino-oxo-1; 3; 5-heptantriene base)-and 2-oxo-7-oxabicyclo (4.1.0) heptan-3-alkene-3-yl) 2; 4; the 6-trimethyl; (1S-(1 α; 3 (2E; 4E, 6S ^*), 5 α, 5 (1E, 3E, 5E), 6 α))-, (the 3H-oxireme is (oxireno) [8,8a] azulenes [4,5-b] furan-8 (4aH)-ketone also also for UCF-116-B, ARGLABIN, 5,6,6a, 7,9a, 9b-six hydrogen-1,4a-dimethyl-7-methylene-, (3aR, 4aS, 6aS, 9aS, 9bR)-) or its analog or derivant).

10) The fibrinogen antagonist

In another embodiment; suppress fibrotic pharmaceutical active compounds and be fibrinogen antagonist (2 (S)-((p-toluenesulfonyl) amino)-3-(((5 for example; 6; 7; 8-tetrahydrochysene-4-oxo-5-(2-(piperidin-4-yl) ethyl-4H-pyrazolo-(1; 5-a) (1; 4) carbonyl two azepines-2-yl))-and amino) propanoic acid; streptokinase (kinases (activation-enzyme); strepto--); urokinase (kinases (activation-enzyme); urea-); activator of plasminogen; pamiteplase; Monteplase; heberkinase; anistreplase; alteplase; before-urokinase; G-137 (1; the 3-benzenedicarboxamide; 4-methoxyl group-N, N '-two (3-pyridylmethyl)-) or its analog or derivant).

11) The guanylate cyclase stimulus object

In another embodiment, suppress fibrotic pharmaceutical active compounds and be the guanylate cyclase stimulus object (for example isosorbide-5-mononitrate (the D-sorbitol, 1,4:3, the two dehydrations of 6--, the 5-nitrate) or its analog or derivant)).

12) Heatshock protein 90 antagonisies

In another embodiment, suppress fibrotic pharmaceutical active compounds be heatshock protein 90 antagonisies (for example: geldanamycin; NSC-33050 (17-allyl amino geldanamycin mycin); Rifabutin (rifamycin XIV, 1 ', 4-two dehydrogenations-1-deoxidation-1,4-dihydro-5 '-(2-methyl-propyl)-1-oxo-), 17AAG) or its analog or derivant).

13) The HMGCoA reductase inhibitor

In another embodiment, (for example: BCP-671, BB-476, fluvastatin (6-heptenoic acid suppress fibrotic pharmaceutical active compounds and be the HMGCoA reductase inhibitor, 7-(3-(4-fluorophenyl)-1-(1-Methylethyl)-1H-indole-2-yl)-3, the 5-dihydroxy-, one sodium salt, (R ^*, S ^*-(E))-(±)-), dalvastatin (2H-pyran-2-one, 6-2-(2-(2-(4-fluoro-3-aminomethyl phenyl)-4,4,6,6-tetramethyl-1-cyclohexene-1-yl) tetrahydrochysene vinyl))-the 4-hydroxyl-, (4 α, 6 β (E))-(+/-)-), glenvastatin (2H-pyran-2-one, 6-(2-(4-(4-fluorophenyl)-2-(1-Methylethyl)-6-phenyl-3-pyridine radicals) vinyl) tetrahydrochysene-4-hydroxyl-, (4R-(4 α, 6 β (E)))-), S-2468, N-(1-oxo dodecyl)-4 α, 10-dimethyl-8-azepine-trans-naphthalane-3 β-alcohol, Atorvastatin calcium (1H-pyrroles-1-enanthic acid, 2-(4-fluorophenyl)-β, δ-dihydroxy-5-(1-Methylethyl)-3-phenyl-4-((phenyl amino) carbonyl)-, calcium salt (R-(R ^*, R ^*))-), CP-83101 (6, the 8-nonadienoic acid, 3,5-dihydroxy-9, the 9-diphenyl-, methyl ester, (R ^*, S ^*-(E))-(+/-)-), pravastatin (1-naphthalene enanthic acid, 1,2,6,7,8,8a-six hydrogen-β, δ, 6-trihydroxy-2-methyl-8-(2-methyl isophthalic acid-oxo butoxy)-, a sodium salt, (1S-(1 α (β S ^*, δ S ^*), 2 α, 6 α, 8 β (R ^*), 8a α))-), U-20685, Pitavastatin (the 6-heptenoic acid, 7-(2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl)-3,5 dihydroxy-, calcium salt (2:1), (S-(R ^*, S ^*-(E)))-), N-((1-methyl-propyl) carbonyl)-8-[2-(tetrahydrochysene-4-hydroxyl-6-oxo-2H-pyrans-2-yl) ethyl]-cross hydrogen-isoquinolin, dihydro lovastatin (butanoic acid, the 2-methyl-, 1,2,3,4,4a, 7,8,8a-octahydro-3,7-dimethyl-8-(2-(tetrahydrochysene-4-hydroxyl-6-oxo-2H-pyrans-2-yl) ethyl)-1-naphthyl ester (1 α (R ^*), 3 α, 4a α, 7 β, 8 β (2S ^*, 4S ^*), 8 α β))-), HBS-107, dihydro lovastatin (butanoic acid, the 2-methyl-, 1,2,3,4,4a, 7,8,8a-octahydro-3,7-dimethyl-8-(2-(tetrahydrochysene-4-hydroxyl-6-oxo-2H-pyrans-2-yl) ethyl)-1-naphthyl ester (1 α (R ^*), 3 α, 4a α, 7 β, 8 β (2S ^*, 4S ^*), 8a β))-), L-669262 (butanoic acid, 2, the 2-dimethyl-, 1,2,6,7,8,8a-six hydrogen-3,7-dimethyl-6-oxo-8-(, 2-(, tetrahydrochysene-4-hydroxyl-6-oxo-2H-pyrans-2-yl) ethyl)-1-naphthyl (1S-(1 α, 7 β, 8 β (2S ^*, 4S ^*), 8 α β))-), simvastatin (butanoic acid, 2, the 2-dimethyl-, 1,2,3,7,8,8a-six hydrogen-3,7-dimethyl-8-(2-(tetrahydrochysene-4-hydroxyl-6-oxo-2H-pyrans-2-yl) ethyl)-1-naphthyl ester, (1S-(1 α, 3 α, 7 β, 8 β (2S ^*, 4S ^*), 8 α β))-), rosuvastatin calcium (6-heptenoic acid, 7-(4-(4-fluorophenyl)-6-(1-Methylethyl)-2-(methyl (methyl sulphonyl) amino)-5-pyrimidine radicals)-3,5-dihydroxy-calcium salt (2:1) (S-(R ^*, S ^*-(E)))), meglutol (2-hydroxy-2-methyl-1,3-propane dicarboxylic acid), lovastatin (butanoic acid, the 2-methyl-, 1,2,3,7,8,8a-six hydrogen-3,7-dimethyl-8-(2-(tetrahydrochysene-4-hydroxyl-6-oxo-2H-pyrans-2-yl) ethyl)-1-naphthyl ester, (1S-(1. α. (R ^*), 3 α, 7 β, 8 β (2S ^*, 4S ^*), 8 α β))-) or its analog or derivant).

14) The hydroorotic acid dehydrogenase inhibitor

In another embodiment, (for example: leflunomide (4-Isoxazolecarboxamidederivatives suppress fibrotic pharmaceutical active compounds and be the hydroorotic acid dehydrogenase inhibitor, 5-methyl-N-4-(trifluoromethyl) phenyl)-), laflunimus (2-acrylamide, 2-cyano group-3-cyclopropyl-3-hydroxy-n-(3-methyl-4 (trifluoromethyl) phenyl)-, (Z)-)) or atovaquone (1,4-naphthalenedione, 2-[4-(4-chlorphenyl) cyclohexyl]-the 3-hydroxyl-, trans-, or its analog or derivant).

15) The IKK2 inhibitor

In another embodiment, suppressing fibrotic pharmaceutical active compounds is IKK2 inhibitor (for example MLN-120B, SPC-839) or its analog or derivant).

16) IL-1, ICE and IRAK antagonist

In another embodiment; (for example: E-5090 (2-propanoic acid suppress fibrotic pharmaceutical active compounds and be IL-1, ICE or IRAK antagonist; 3-(5-ethyl-4-hydroxyl-3-methoxyl group-1-naphthyl)-2-methyl-; (Z)-), CH-164, CH-172, CH-490, AMG-719, iguratimod (N-(3-(formoxyl amino)-4-oxo-6-phenoxy group-4H-chromene-7-yl) Methanesulfomide), AV94-88, pralnacasan (6H-pyridazine also (1; 2-a) (1,2) diaza

-1-Methanamide; N-((2R; 3S)-and 2-ethyoxyl tetrahydrochysene-5-oxo-3-furyl) octahydro-9-((1-isoquinolyl carbonyl) amino)-6; the 10-dioxo-; (1S; 9S)-), (2S-cis)-5-(benzyloxycarbonyl amino-1,2,4; 5; 6,7-six hydrogen-4-(oxo azepine also (3,2; 1-hi) indole-2-carbonyl)-amino)-4-ketobutyric acid, AVE-9488, esonarimod (benzenebutanoic acid; α-((acetyl group sulfo-) methyl)-4-methyl-γ-oxo-), pralnacasan (the 6H-pyridazine also (1,2-a) (1,2) diaza

-1-Methanamide; N-((2R; 3S)-and 2-ethyoxyl tetrahydrochysene-5-oxo-3-furyl) octahydro-9-((1-isoquinolyl carbonyl) amino)-6; the 10-dioxo-; (1S; 9S)-; tranexamic acid (cyclohexane-carboxylic acid; 4-(amino methyl)-; trans-); Win-72052; romazarit (Ro-31-3948) (propanoic acid; 2-((2-(4-chlorphenyl)-4-methyl-5-oxazolyl) methoxyl group)-2-methyl-); PD-163594; SDZ-224-015 (L-aminopropanamide N-((phenyl methoxyl group) carbonyl)-L-valyl-N-((1S)-3-((2; 6-dichloro-benzoyl base) oxygen base)-1-(2-ethyoxyl-2-oxoethyl)-2-oxopropyl)-); L-709049 (L-aminopropanamide; N-acetyl group-L-tyrosyl-L-valyl-N-(2-carboxyl-1-formyl ethyl)-; (; S)-); TA-383 (1H-imidazoles); 2-(4-chlorphenyl)-4; 5-dihydro-4; the 5-diphenyl-; monohydrochloride; cis-); EI-1507-1 (6a; 12a-epoxy benzene (a) anthracene)-1; 12 (2H; 7H)-diketone; 3; 4-dihydro-3,7-dihydroxy-8-methoxyl group-3-methyl-); 4-(3, the 4-Dimethoxyphenyl)-6; 7-dimethoxy-2-(1; 2,4-triazol-1-yl methyl) quinoline-3-Ethyl formate; EI-1941-1; TJ-114; Antril (Synergen) (interleukin 1 receptor antagonist (x is reductive for people's isoform); the N2-L-methionyl-)); IX-207-887 (acetic acid, (10-methoxyl group-4H-benzo [4; 5] ring [1,2-b] inferior thiophene in heptan-4-yl)-); K-832 or its analog or derivant).

17) The IL-4 agonist

In another embodiment, suppress fibrotic pharmaceutical active compounds and be IL-4 agonist (acetic acid glatiramer (glatiramir) (L-glutamic acid for example, with the L-alanine, the polymer of L-lysine and L-tyrosine, acetas (salt)) or its analog or derivant).

18) Immunomodulator

In another embodiment; suppress fibrotic pharmaceutical active compounds and be immunomodulator (biolimus for example; ABT-578; methylamino sulfonic acid 3-(2-methoxyl group phenoxy group)-2-(((methylamino) sulfonyl) oxygen base) propyl diester; sirolimus (being also referred to as rapamycin or RAPAMUNE) (American Home Products; Inc.; Madison, NJ), CCI-779 (rapamycin 42-(3-hydroxyl-2-(hydroxymethyl)-2 Methylpropionic acid ester)); LF-15-0195; NPCI5669 (the L-leucine, N-(((2,7-dimethyl-9H-fluorenes-9-yl) methoxyl group) carbonyl)-); NPC-15670 (L-leucine; N-(((4,5-dimethyl-9H-fluorenes-9-yl) methoxyl group) carbonyl)-), NPC-16570 (4-(2-(fluorenes-9-yl) ethyoxyl-carbonyl) amino benzoic Acid); sufosfamide (ethanol; 2-((3-(2-chloroethyl) tetrahydrochysene-2H-1,3,2-oxazaphosphorin-2-yl) amino)-; mesylate (ester); the P-oxide), tresperimus (2-(N-(4-(3-amino propyl amino) butyl) carbamoyl oxygen base)-N-(6-guanidine radicals hexyl) acetamide), 4-(2-fluorenes-9-yl) ethoxy carbonyl amino)-benzo-hydroxamic acid; iaquinimod; PBI-1411, azathioprine (6-((1-methyl-4-nitro-1H-imidazoles-5-yl) sulfo-)-1H-purine), PBI0032; beclometasone; MDL-28842 (9H-purine-6-amine, 9-(5-deoxidation-5-fluoro-beta-D--penta-4-of Soviet Union alkene furyl)-, (Z)-); FK-788; AVE-1726, ZK-90695, ZK-90695; Ro-54864; didemnin-B, lllinois (didemnin A, N-(1-(2-hydroxyl-1-oxopropyl)-L-prolyl); (S)-); SDZ-62-826 (ethanaminium, 2-((hydroxyl ((1-((eight last of the ten Heavenly stems oxygen base) carbonyl)-3-piperidyl) methoxyl group) phosphinyl) oxygen oneself)-N, N; the N-trimethyl-; inner salt), argyrinB ((4S, 7S; 13R; 22R)-and 13-ethyl-4-(1H-indol-3-yl methyl)-7-(4-methoxyl group-1H-indol-3-yl methyl) 18,22-dimethyl-16-methyl-alkene-24-thiophene (thia)-3,6; 9; 12,15,18; 21; 26-eight azabicyclos (21.2.1)-26-1 (25), 23 (26)-diolefins-2,5; 8; 11,14,17; the 20-heptanone); everolimus (rapamycin, 42-O-(2-hydroxyethyl)-), SAR-943; L-687795; 6-((4-chlorphenyl sulfinyl)-2,3-dihydro-2-(4-methoxyl group-phenyl)-5-methyl-3-oxo-4-pyridazine nitrile, 91Y78 (1H-imidazo (4; 5-c) pyridine-4-amine; 1-β-D-ribofuranosyl-), auranofin (gold, (1-sulfo--β-D-Glucopyranose. 2; 3; 4,6-tetrem acid group closes-S) (triethyl phosphine)-), the 27-O-demethyl rapamycin; tipredane (androsta-1; 4-diene-3-ketone, 17-(ethylmercapto group)-9-fluoro-11-hydroxyl-17-(methyl mercapto)-, (11 β; 17 α)-); AI-402, and LY-178002 (the 4-thiazolidone, 5-((3; 5-two (1; the 1-dimethyl ethyl)-and the 4-hydroxy phenyl) methylene)-), SM-8849 (abadol, 4-(1-(2-fluorine (1; 1 '-xenyl)-and the 4-yl) ethyl)-the N-methyl-); piceatannol, resveratrol (resveratrol), triamcinolone acetonide (pregnant-1; 4-diene-3; the 20-diketone, 9-fluoro-11,21-dihydroxy-16; 17-((1-methyl ethylidene) two (oxygen))-; (11 β, 16 α)-, ciclosporin (ciclosporin A-); tacrolimus (15; 19-epoxy-3H-pyrido (2,1-c) (1,4) oxo aza ring tricosine-1; 7; 20,21 (4H, 23H)-tetraketone; 5; 6,8,11; 12; 13,14,15; 16; 17,18,19; 24; 25,26,26a-16 hydrogen-5; 19-dihydroxy-3-(2-(4-hydroxyl-3-methoxyl group cyclohexyl)-1-methyl ethylene)-14; the 16-dimethoxy-4 ', 10,12; 18-tetramethyl-8-(2-acrylic)-, (3S-(3R ^*(E (1S ^*, 3S ^*, 4S ^*)), 4S ^*, 5R ^*, 8S ^*, 9E, 12R ^*, 14R ^*, 15S ^*, 16R ^*, 18S ^*, 19S ^*, 26aR ^*))-); gusperimus (2-heptamide; 7-((amino imino methyl) amino)-N-(2-((4-((3-aminopropyl) amino) butyl) amino)-1-hydroxyl-2-oxoethyl)-; (+/-)-); it is (pregnant-4-alkene-3 that tixocortol cuts down ester; the 20-diketone; 21-((2; 2-dimethyl-1-oxopropyl) sulfo-)-11; the 17-dihydroxy-; (11 β)-; (1-92LFA-3 (antigen) (people) has the fusion rotein of immune globulin mortar G1 (people's hinge-CH2-CH3 γ 1-chain) to alefacept; dimer); halobetasol propionate (pregnant-1; 4-diene-3; the 20-diketone; 21-chloro-6,9-two fluoro-11-hydroxyl-16-methyl-17s-(1-oxopropoxy)-, (6 α; 11 β; 16 β)-), iloprost trometamol (valeric acid, 5-(six hydrogen-5-hydroxyl-4-(3-hydroxy-4-methyl-1-octene-6-alkynyl)-2 (1H)-pentalenylidene)-); Beraprost (1H-cyclopenta (b) benzofuran-5-butanoic acid); 2,3,3a; 8b-tetrahydrochysene-2-hydroxyl-1-(3-hydroxy-4-methyl-1-octene-6-alkynyl)-); rimexolone (androsta-1,4-diene-3-ketone, 11-hydroxyl-16; 17-dimethyl-17-(1-oxopropyl)-; (11 β, 16 α, 17 β)-); dexamethasone (pregnant-1; 4-diene-3,20-diketone, 9-fluoro-11; 17; 21-trihydroxy-16-methyl-, (11 β, 16 α)-); sulindac (cis-5-fluoro-2-methyl isophthalic acid-((p-methyl sulfinyl) benzal) indeno-3-acetic acid); proglumetacin (the 1H-indole-3-acetic acid, 1-(4-chlorobenzene formacyl)-5-methoxyl group-2-methyl-, 2-(4-(3-((4-(benzoyl-amido)-5-(dipropyl amino)-1; 5-dioxo amyl group) propyl group oxygen base))-and the 1-piperazinyl) ethyl ester; (+/-)-), alclometasone diproionate (pregnant-1,4-diene-3; the 20-diketone; 7-chloro-11-hydroxyl-16-methyl-17,21-two (1-oxopropoxy)-, (7 α; 11 β; 16 α)-), pimecrolimus (15,19-epoxy-3H-pyrido (2; 1-c) (1; 4) oxaazacyclotricosine-1,7,20; 21 (4H; 23H)-and tetraketone, 3-(2-(4-chloro-3-methoxyl group cyclohexyl)-1-methyl ethylene)-8-ethyl-5,6; 8; 11,12,13; 14; 15,16,17; 18; 19,24,25; 26; 26a-16 hydrogen-5,19-dihydroxy-14,16-dimethoxy-4 '; 10; 12, the 18-tetramethyl-, (3S-(3R ^*(E (1S ^*, 3S ^*, 4R ^*)), 4S ^*, 5R ^*, 8S ^*, 9E, 12R ^*, 14R ^*, 15S ^*, 16R*, 18S ^*, 19S ^*, 26aR ^*))-); hydrocortisone-17-butyrate (salt) is (pregnant-4-alkene-3; the 20-diketone; 11; 21-dihydroxy-17-(1-oxo butoxy)-; (11 β)-); mitoxantrone (9; the 10-amerantrone; 1; 4-dihydroxy-5; 8-two ((2-((2-hydroxyethyl) amino) ethyl) amino)-); mizoribine (1H-imidazoles-4-Methanamide; 5-hydroxyl-1-β-D-ribofuranosyl-); prednicarbate (pregnant-1; 4-diene-3; the 20-diketone; 17-((ethoxy carbonyl) oxygen base)-11-hydroxyl-21-(1-oxopropoxy)-; (11 β)-); lobenzarit (benzoic acid, 2-((2-carboxyl phenyl) amino)-4-chloro-), glucametacin (D-glucose; 2-(((1-(4-chlorobenzene formacyl)-5-methoxyl group-2-Methyl-1H-indole-3-yl) acetyl group) amino)-2-deoxidation-); ((6 α)-fluoro-16 Alpha-Methyls are pregnant-1,4-diene 11 β, 21-glycol-3 for the fluocortolone monohydrate; the 20-diketone); but the chlorine butyl ester (pregnant-1,4-diene-21-acid, 6-fluoro-11-hydroxyl-16-methyl-3; the 20-dioxo-; butyl ester, (6 α, 11 β; 16 α)-); difluprednate (pregnant-1,4-diene-3,20-diketone; 21-(acetoxyl group)-6; 9-two fluoro-11-hydroxyl-17-(1-oxo butoxy)-, (6 α, 11 β)-); diflorasone diacetate (pregnant-1; 4-diene-3,20-diketone, 17; the 21-diacetoxy)-6; 9-two fluoro-11-hydroxyl-16-methyl-, (6 α, 11 β; 16 β)-); the valeric acid dexamethasone (pregnant-1,4-diene-3,20-diketone; 9-fluoro-11; 21-dihydroxy-16-methyl-17-((1-oxo amyl group) oxygen base)-, (11 β, 16 α)-); methylprednisolone; the propanoic acid deprodone (pregnant-1,4-diene-3,20-diketone; 11-hydroxyl-17-(1-oxopropoxy)-; (11. β .)-), bucillamine (the L-cysteine, N-(2-sulfydryl-2-methyl isophthalic acid-oxopropyl)-); amcinonide (phenylacetic acid; 2-amino-3-benzoyl-, a sodium salt, monohydrate); acemetacin (1H-indole-3-acetic acid; 1-(4-chlorobenzene formacyl)-5-methoxyl group-2-methyl-, carboxymethyl ester)), or its analog or derivant).

In addition, the analog of rapamycin comprises tacrolimus and derivant (for example, EP0184162B1 and U.S. Patent number 6,258,823), everolimus and derivant (for example, U.S. Patent number 5,665,772) thereof.The representational example of other of the analog of sirolimus and derivant can see following PCT publication number: WO9710502, WO9641807, WO9635423, WO9603430, WO9600282, WO9516691, WO9515328, WO9507468, WO9504738, WO9504060, WO9425022, WO9421644, WO9418207, WO9410843, WO9409010, WO9404540, WO9402485, WO9402137, WO9402136, WO9325533, WO 9318043, WO9313663, WO9311130, WO9310122, WO9304680, WO9214737 and WO9205179.Representational United States Patent (USP) comprises: U.S. Patent number 6,342,507; 5,985,890; 5,604,234; 5,597,715; 5,583,139; 5,563,172; 5,561,228; 5,561,137; 5,541,193; 5,541,189; 5,534,632; 5,527,907; 5,484,799; 5,457,194; 5,457,182; 5,362,735; 5,324,644; 5,318,895; 5,310,903; 5,310,901; 5,258,389; 5,252,732; 5,247,076; 5,225,403; 5,221,625; 5,210,030; 5,208,241; 5,200,411; 5,198,421; 5,147,877; 5,140,018; 5,116,756; 5,109,112; 5,093,338; With 5,091,389.

The structure of sirolimus, everolimus, tacrolimus is provided below:

Title	The coding title	Company	Structure
				Everolimus	SAR-943	Novartis	As follows
Sirolimus RAPAMUNE rapamycin	AY-22989 NSC-226080	Wyeth	As follows
				Tacrolimus	FK506	Fujusawa	As follows

Everolimus

Tacrolimus

Sirolimus

The analog of other sirolimus and derivant comprise tacrolimus and derivant (for example, EP0184162B1 and U.S. Patent number 6,258,823), everolimus and its derivant (for example, U.S. Patent number 5,665,772).The other representative example of the analog of sirolimus and derivant comprises ABT-578, and other can see following PCT publication number: WO 97/10502, WO 96/41807, WO 96/35423, WO 96/03430, WO 96/00282, WO 95/16691, WO 95/15328, WO 95/07468, WO 95/04738, WO 95/04060, WO 94/25022, WO 94/21644, WO 94/18207, WO 94/10843, WO 94/09010, WO 94/04540, WO 94/02485, WO 94/02137, WO 94/02136, WO 93/25533, WO 93/18043, WO 93/13663, WO 93/11130, WO 93/10122, WO 93/04680, WO 92/14737 and WO 92/05179.Representational United States Patent (USP) comprises U.S. Patent number 6,342,507; 5,985,890; 5,604,234; 5,597,715; 5,583,139; 5,563,172; 5,561,228; 5,561,137; 5,541,193; 5,541,189; 5,534,632; 5,527,907; 5,484,799; 5,457,194; 5,457,182; 5,362,735; 5,324,644; 5,318,895; 5,310,903; 5,310,901; 5,258,389; 5,252,732; 5,247,076; 5,225,403; 5,221,625; 5,210,030; 5,208,241; 5,200,411; 5,198,421; 5,147,877; 5,140,018; 5,116,756; 5,109,112; 5,093,338; With 5,091,389.

In one aspect, described fibre modification inhibitor can be for example rapamycin (sirolimus), everolimus, biolimus, tresperimus, auranofin, 27-O-demethyl rapamycin, tacrolimus, gusperimus, pimecrolimus or ABT-578.

19. Inosine monophosphate dehydrogenase inhibitor

In another embodiment, (for example suppress fibrotic pharmaceutical active compounds and be inosine monophosphate dehydrogenase (IMPDH) inhibitor, Mycophenolic Acid, mycophenolate mofetil (4-hexenoic acid, 6-(1,3-dihydro-4-hydroxyl-6-methoxyl group-7-methyl-3-oxo-5-isobenzofuran-base)-the 4-methyl-, 2-(4-morpholinyl) ethyl ester, (E)-), ribavirin (1H-1,2,4-triazole-3-Methanamide, 1-β-D-ribofuranosyl-), tiazofurine (the 4-thiazole carboxamides, 2-β-D-ribofuranosyl-), viramidine, amino thiadiazoles, thiophenfurin, the thiophene furan is held up woods) or its analog or derivant.Representational example in addition is included in the following document: U.S. Patent number 5,536,747; 5,807,876; 5,932,600; 6,054,472,6,128,582; 6,344,465; 6,395,763; 6,399,773; 6,420,403; 6,479,628; 6,498,178; 6,514,979; 6,518291; 6,541496; 6,596,747; 6,617,323; 6,624,184; Patent application publication number 2002/0040022A1,2002/0052513A1,2002/0055483A1,2002/0068346A1,2002/0111378A1,2002/0111495A1,2002/0123520A1,2002/0143176A1,2002/0147160A1,2002/0161038A1,2002/0173491A1,2002/0183315A1,2002/0193612A1,2003/0027845A1,2003/0068302A1,2003/0105073A1,2003/0130254A1,2003/0143197A1,2003/0144300A1,2003/0166201A1,2003/0181497A1,2003/0186974A1,2003/0186989A1 and 2003/0195202A1; With PCT publication number WO 00/24725A1, WO 00/25780A1, WO 00/26197A1, WO 00/51615A1, WO 0056331A1, WO 00/73288A1, WO 01/00622A1, WO 01/66706A1, WO 01/79246A2, WO 01/81340A2, WO 01/85952A2, WO 02/16382A1, WO 02/18369A2, WO 02/51814A1, WO 02/57287A2, WO 02/57425A2, WO 02/60875A1, WO 02/60896A1, WO 02/60898A1, WO 02/68058A2, WO 03/20298A1, WO 03/37349A1, WO 03/39548A1, WO 03/45901A2, WO 03/47512A2, WO 03/53958A1, WO 03/55447A2, WO 03/59269A2, WO 03/63573A2, WO 03/87071A1, WO 90/01545A1, WO 97/40028A1, WO 97/41211A1, WO 98/40381A1 and WO 99/55663A1.

20). Leukotriene inhibitors

In another embodiment; (for example suppress fibrotic pharmaceutical active compounds and be leukotriene inhibitors; ONO-4057 (benzenpropanoic acid; 2-(4-carboxyl butoxy)-6-((6-(4-methoxyphenyl)-5-hexenyl) oxygen base)-; (E)-); ONO-LB-448; pirodomast 1; 8-1; 5-benzodiazine-2 (1H)-ketone; 4-hydroxyl-1-phenyl-3-(1-pyrrolidinyl)-; Sch-40120 (benzo (b) (1; 8)) 1; 5-benzodiazine-5 (7H)-ketone; 10-(3-chlorphenyl)-6; 8; 9; the 10-tetrahydrochysene-); L-656224 (4-benzofuran alcohol; 7-chloro-2-((4-methoxyphenyl) methyl)-3-methyl-5-propyl group-); MAFP (methyl arachidonylfluorophosphonate); ontazolast (2-benzoxazole amine; N-(2-cyclohexyl-1-(2-pyridine radicals) ethyl)-5-methyl-; (S)-); amelubant (carbamic acid; ((4-((3-((4-(1-(4-hydroxy phenyl)-1-Methylethyl) phenoxy group) methyl) phenyl) methoxyl group) phenyl) iminomethyl)-ethyl ester); SB-201993 (benzoic acid; 3-((((6-((1E)-2-carboxy vinyl)-5-((8-(4-methoxyphenyl) octyl group) oxygen base)-2-pyridine radicals) methyl) sulfo-) methyl)-); LY-203647 (ethyl ketone; 1-(2-hydroxyl-3-propyl group-4-(4-(2-(4-(1H-tetrazolium-5-yl) butyl)-2H-tetrazolium-5-yl) butoxy) phenyl)-); LY-210073; LY-223982 (benzenpropanoic acid; 5-(3-carboxylbenzoyl)-2-((6-(4-methoxyphenyl)-5-hexenyl) oxygen base)-; (E)-); LY-293111 (benzoic acid; 2-(3-(3-((5-ethyl-4 '-fluoro-2-hydroxyl (1; 1 '-xenyl)-and the 4-yl) the oxygen base) propoxyl group)-2-propyl group phenoxy group)-); SM-9064 (pyrrolidine, and 1-(4,11-dihydroxy-13-(4-methoxyphenyl)-1-oxo-5; 7; 9-tridecatriene base)-, (E, E; E)-); T-0757 (2,6-octadiene amide, N-(4-hydroxyl-3; the 5-3,5-dimethylphenyl)-3; the 7-dimethyl-, (2E)-)), or its analog or derivant).

21) The MCP-1 antagonist

In another embodiment, (for example suppress fibrotic pharmaceutical active compounds and be the MCP-1 antagonist, nitro naproxen (2-naphthalene alkene acetic acid, 6-methoxyl group-Alpha-Methyl 4-(nitrooxy) butyl ester (α S)-), bindarit (2-(1-benzyl indazole-3-ylmethoxy)-2 Methylpropionic acid), 1-α-25 dihydroxyvitamin D ₃Or its analog or derivant).

22) The MMP inhibitor

In another embodiment; (for example suppress fibrotic pharmaceutical active compounds and be matrix metalloproteinase (MMP) inhibitor; D-9120; doxycycline (2-aphthacene Methanamide; 4-(dimethylamino)-1; 4; 4a, 5,5a; 6; 11,12a-octahydro-3,5; 10; 12,12a-penta hydroxy group-6-methyl isophthalic acid, 11-dioxo-(4S-(4 α; 4a α; 5 α, 5a α, 6 α; 12a α))-); BB-2827; BB-1101 (2S-pi-allyl-N1-hydroxyl-3R-isobutyl group-N4-(1S-methylamino formoxyl-2-phenylethyl)-succinamide); BB-2983; solimastat (N '-(2; 2-dimethyl-1 (S)-(N-(2-pyridine radicals) carbamoyl) propyl group)-N4-hydroxyl-2 (R)-isobutyl group-3 (S)-methoxyl group succinamide); batimastat (succinamide, N4-hydroxy-n 1-(2-(methylamino)-2-oxo-1-(phenyl methyl) ethyl)-2-(2-methyl-propyl)-3-((2-thiophene thio) methyl)-, (2R-(1 (S ^*), 2R ^*, 3S ^*))-); CH-138; CH-5902; D-1927; D-5410; EF-13 (gamma-Linolenic acid lithium salts); CMT-3 (2-aphthacene Methanamide; 1; 4; 4a; 5; 5a; 6; 11; 12a-octahydro-3; 10; 12; 12a-tetrahydroxy-1; the 11-dioxo-; (4aS; 5aR; 12aS)-); (N-(2 for Marimastat; 2-dimethyl-1 (S)-(N-methylamino formoxyl) propyl group)-N; 3 (S)-dihydroxy-2 (R)-isobutyl group succinamides); TIMP ' S; ONO-4817; rebimastat (L-valine amide; N-((2S)-2-sulfydryl-1-oxo-4-(3; 4; 4-trimethyl-2; 5-oxo-1-imidazolidinyl) butyl)-L-leucyl-N; the 3-dimethyl-); PS-508; CH-715; nimesulide (first sulfonamides; N-(4-nitro-2-Phenoxyphenyl)-); six hydrogen-2-(2 (R)-(1 (RS)-(hydroxyl amino formoxyl)-4-phenyl butyl) pelargonyl group)-N-(2; 2; 6; 6-tetramethyl-4-piperidyl-3 (S)-pyridazine carboxamides; Rs-113-080; Ro-1130830; cipemastat (1-piperidines butyramide; β-(cyclopentyl-methyl)-N-hydroxyl-γ-oxo-α-((3; 4; 4-trimethyl-2; 5-dioxo-1-imidazolidinyl) methyl)-; (α R; β R)-); 5-(4 '-diphenyl)-5-(N-(4-Nitrobenzol) piperazinyl barbituric acid; 6-methoxyl group-1; 2; 3; 4-tetrahydrochysene-norhaman-1-carboxylic acid; Ro-31-4724 (L-alanine; N-(2-(2-(hydroxyl amino)-2-oxoethyl)-4-methyl isophthalic acid-oxo amyl group)-L-leucyl-; ethyl ester); prinomastat's (3-thiomorpholine Methanamide; N-hydroxyl-2; 2-dimethyl-4-((4-(4-piperidyl oxygen base) phenyl) sulfonyl)-(3R)-); AG-3433 (1H-pyrroles-3-propanoic acid); 1-(4 '-cyano group (1; 1 '-diphenyl)-the 4-yl)-b-((((3S)-tetrahydrochysene-4; 4-dimethyl-2-oxo-3-furyl) carbonyl amino))-; the phenyl methyl ester; (bS)-); PNU-142769 (2H-iso-indoles-2-butyramide; 1; 3-dihydro-N-hydroxyl-α-((3S)-3-(2-methyl-propyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidinyl)-1; the 3-dioxo-; (α R)-); (S)-(2-((((4 for 1-; 5-dihydro-5-sulfo--1; 3; 4-thiadiazoles-2-yl) amino)-and carbonyl) amino)-1-oxo-3-(pentafluorophenyl group) propyl group)-4-(2-pyridine radicals) piperazine; SU-5402 (1H-pyrroles-3-propanoic acid; 2-((1; 2-dihydro-2-oxo--3H-indole-3-thiazolinyl) methyl)-the 4-methyl-); SC-77964; PNU-171829; CGS-27023A; N-hydroxyl-2 (R)-((4-methoxybenzene-sulfonyl) (4-picolyl) amino)-2-(2-tetrahydrofuran base)-acetamide; L-758354 ((1; 1 ' diphenyl)-the 4-caproic acid; α-butyl-γ-(((2; 2-dimethyl-1-((methylamino) carbonyl) propyl group)-4 '-fluoro-carbonyl amino)), (α S-(α R ^*, γ S ^*(R ^*)))-), GI-155704A, CPA-926, TMI-005, XL-784 or its analog or derivant).Representational example in addition is included in the following document: U.S. Patent number 5,665,777; 5,985,911; 6,288,261; 5,952,320; 6,441,189; 6,235,786; 6,294,573; 6,294,539; 6,563,002; 6,071,903; 6,358,980; 5,852,213; 6,124,502; 6,160,132; 6,197,791; 6,172,057; 6,288,086; 6,342,508; 6,228,869; 5,977,408; 5,929,097; 6,498,167; 6,534,491; 6,548,524; 5,962,481; 6,197,795; 6,162,814; 6,441,023; 6,444,704; 6,462,073; 6,162,821; 6,444,639; 6,262,080; 6,486,193; 6,329,550; 6,544,980; 6,352,976; 5,968,795; 5,789,434; 5,932,763; 6,500,847; 5,925,637; 6,225,314; 5,804,581; 5,863,915; 5,859,047; 5,861,428; 5,886,043; 6,288,063; 5,939,583; 6,166,082; 5,874,473; 5,886,022; 5,932,577; 5,854,277; 5,886,024; 6,495,565; 6,642,255; 6,495,548; 6,479,502; 5,696,082; 5,700,838; 6,444,639; 6,262,080; 6,486,193; 6,329,550; 6,544,980; 6,352,976; 5,968,795; 5,789,434; 5,932,763; 6,500,847; 5,925,637; 6,225,314; 5,804,581; 5,863,915; 5,859,047; 5,861,428; 5,886,043; 6,288,063; 5,939,583; 6,166,082; 5,874,473; 5,886,022; 5,932,577; 5,854,277; 5,886,024; 6,495,565; 6,642,255; 6,495,548; 6,479,502; 5,696,082; 5,700,838; 5,861,436; 5,691,382; 5,763,621; 5,866,717; 5,902,791; 5,962,529; 6,017,889; 6,022,873; 6,022,898; 6,103,739; 6,127,427; 6,258,851; 6,310,084; 6,358,987; 5,872,152; 5,917,090; 6,124,329; 6,329,373; 6,344,457; 5,698,706; 5,872,146; 5,853,623; 6,624,144; 6,462,042; 5,981,491; 5,955,435; 6,090,840; 6,114,372; 6,566,384; 5,994,293; 6,063,786; 6,469,020; 6,118,001; 6,187,924; 6,310,088; 5,994,312; 6,180,611; 6,110,896; 6,380,253; 5,455,262; 5,470,834; 6,147,114; 6,333,324; 6,489,324; 6,362,183; 6,372,758; 6,448,250; 6,492,367; 6,380,258; 6,583,299; 5,239,078; 5,892,112; 5,773,438; 5,696,147; 6,066,662; 6,600,057; 5,990,158; 5,731,293; 6,277,876; 6,521,606; 6,168,807; 6,506,414; 6,620,813; 5,684,152; 6,451,791; 6,476,027; 6,013,649; 6,503,892; 6,420,427; 6,300,514; 6,403,644; 6,177,466; 6,569,899; 5,594,006; 6,417,229; 5,861,510; 6,156,798; 6,387,931; 6,350,907; 6,090,852; 6,458,822; 6,509,337; 6,147,061; 6,114,568; 6,118,016; 5,804,593; 5,847,153; 5,859,061; 6,194,451; 6,482,827; 6,638,952; 5,677,282; 6,365,630; 6,130,254; 6,455,569; 6,057,369; 6,576,628; 6,110,924; 6,472,396; 6,548,667; 5,618,844; 6,495,578; 6,627,411; 5,514,716; 5,256,657; 5,773,428; 6,037,472; 6,579,890; 5,932,595; 6,013,792; 6,420,415; 5,532,265; 5,691,381; 5,639,746; 5,672,598; 5,830,915; 6,630,516; 5,324,634; 6,277,061; 6,140,099; 6,455,570; 5,595,885; 6,093,398; 6,379,667; 5,641,636; 5,698,404; 6,448,058; 6,008,220; 6,265,432; 6,169,103; 6,133,304; 6,541,521; 6,624,196; 6,307,089; 6,239,288; 5,756,545; 6,020,366; 6,117,869; 6,294,674; 6,037,361; 6,399,612; 6,495,568; 6,624,177; 5,948,780; 6,620,835; 6,284,513; 5,977,141; 6,153,612; 6,297,247; 6,559,142; 6,555,535; 6,350,885; 5,627,206; 5,665,764; 5,958,972; 6,420,408; 6,492,422; 6,340,709; 6,022,948; 6,274,703; 6,294,694; 6,531,499; 6,465,508; 6,437,177; 6,376,665; 5,268,384; 5,183,900; 5,189,178; 6,511,993; 6,617,354; 6,331,563; 5,962,466; 5,861,427; 5,830,869; With 6,087,359.

23) The NF kB inhibitor

In another embodiment, (for example suppress fibrotic pharmaceutical active compounds and be NF κ B (NFKB) inhibitor, AVE-0545, Oxi-104 (Benzoylamide, 4-amino-3-chloro-N-2-(diethylamino) ethyl)-), dexlipotam, R-flurbiprofen ((1,1 '-xenyl)-4-acetic acid, 2-fluoro-Alpha-Methyl), SP100030 (2-chloro-N-(3,5-two (trifluoromethyl) phenyl)-and 4-(trifluoromethyl) pyrimidine-5-Methanamide), AVE-0545, Viatris, AVE-0547, Bay 11-7082, Bay 11-7085,15 deoxidations-prostaylandin J2, bortezomib (boric acid, ((1R)-3-methyl isophthalic acid-(((2S)-1-oxo-3-phenyl-2-((pyrazinyl carbonyl) amino) propyl group) amino) butyl)-), suppress Benzoylamide and the nicotinamide derivates of NF-κ B, as at U.S. Patent number 5,561, those that describe in 161 and 5,340,565 (OxiGene), PG490-88Na, or its analog or derivant).

24) The NO agonist

In another embodiment; suppress fibrotic pharmaceutical active compounds and be NO antagonist (NCX-4016 (benzoic acid, 2-(acetyl group oxygen base)-3-((nitrooxy methyl) phenylester), NCX-2216, L-arginine or its analog or derivant) for example.

25) The P38 map kinase inhibitor

In another embodiment; suppress fibrotic pharmaceutical active compounds and be P38 map kinase inhibitor (GW-2286 for example; CGP-52411; BIRB-798; SB220025; RO-320-1195; RWJ-67657; RWJ-68354; SCIO-469; SCIO-323; AMG-548; CMC-146; SD-31145; CC-8866; Ro-320-1195; PD-98059 (4H-1-.alpha.-5:6-benzopyran-4-ketone; 2-(2-amino-3-methoxyphenyl)-); CGH-2466; doramapimod; SB-203580 (pyridine; 4-(5-(4-fluorophenyl)-2-(4-(methylsulfinyl) phenyl)-1H-imidazol-4 yl)-); SB-220025 ((5-(2-amino-4-pyrimidine radicals)-4-(4-fluorophenyl)-1-(4-piperidyl) imidazoles)); SB-281832; PD169316, SB202190; GSK-681323; EO-1606; GSK-681323 or its analog or derivant).Representational example in addition is included in the following document: U.S. Patent number 6,300,347; 6,316,464; 6,316,466; 6,376,527; 6,444,696; 6,479,507; 6,509,361; 6,579,874; With 6,630,485, U.S. Patent Application Publication No. 2001/0044538A1; 2002/0013354A1; 2002/0049220A1; 2002/0103245A1; 2002/0151491A1; 2002/0156114A1; 2003/0018051A1; 2003/0073832A1; 2003/0130257A1; 2003/0130273A1; 2003/0130319A1; 2003/0139388A1; 2003/0139462A1; 2003/0149031 A1; 2003/0166647A1 and 2003/0181411A1; With PCT publication number WO 00/63204A2, WO 01/21591A1, WO 01/35959A1, WO 01/74811A2, WO 02/18379A2, WO 02/064594A2, WO 02/083622A2, WO 02/094842A2, WO 02/096426A1, WO 02/101015A2, WO 02/103000A2, WO03/008413A1, WO 03/016248A2, WO 03/020715A1, WO 03/024899A2, WO 03/031431A1, WO 03/040103A1, WO 03/053940A1, WO03/053941A2, WO 03/063799A2, WO 03/079986A2, WO 03/080024A2, WO 03/082287A1, WO 97/44467A1 is among WO 99/01449A1 and the WO 99/58523A1.

26) Phosphodiesterase inhibitor

In another embodiment; suppress fibrotic pharmaceutical active compounds and be phosphodiesterase inhibitor (CDP-840 (pyridine for example; 4 ((2R)-2 (3-(cyclopentyloxy)-4-methoxyphenyl)-2-phenylethyls)-); CH-3697; CT-2820; D-22888 (imidazo (1; 5-a) pyrido (3; 2-e) pyrazine-6 (5H)-ketone; 9-ethyl-2-methoxyl group-7-methyl-5-propyl group-); D-4418 (8-methoxy quinoline-5-(N-(2,5-dichloropyridine-3-yl)) Methanamide); 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(2,6-two chloro-4-pyridine radicals) ethyl ketone oxime; D-4396; ONO-6126; CDC-998; CDC-801; V-11294A (3-(3-(cyclopentyloxy)-4-methoxy-benzyl)-6-(ethylamino)-8-isopropyl-3H-purine hydrochloride); S; S '-methylene-two (2-(8-cyclopropyl-3-propyl group-6-(4-pyridylmethyl amino)-2-sulfo--3H-purine)) four hydrochlorates; rolipram (2-Pyrrolidone; 4-(3-(cyclopentyloxy)-4-methoxyphenyl)-); CP-293121; CP-353164 (5-(3-cyclopentyloxy-4-methoxyphenyl) pyridine-2-carboxamide); oxagrelate (6-2,3-benzodiazine carboxylic acid, 3; 4-dihydro-1-(methylol)-5; 7-dimethyl-4-oxo-, ethyl ester); PD-168787; ibudilast (1-acetone, 2-methyl isophthalic acid-(2-(1-Methylethyl) pyrazolo (1; 5-a) pyridin-3-yl)-); oxagrelate (6-2; 3-benzodiazine carboxylic acid, 3,4-dihydro-1-(hydroxymethyl)-5; 7-dimethyl-4-oxo-; ethyl ester); the acid of ash chain bacterium (α-L-talo-suffering-4-alkene furanose aldehydic acid, 1-(6-amino-9H-purine-9-yl)-3,6-dehydration-6-C-carboxyl-1; the 5-dideoxy-); KW-4490; KS-506; T-440; roflumilast (Benzoylamide, 3-(cyclo propyl methoxy)-N-(3,5-two chloro-4-pyridine radicals)-4-(difluoro-methoxy)-); rolipram; Mi Nong; triflusinal (benzoic acid; 2-(acetyl group oxygen base)-4-(trifluoromethyl)-); Anagrelide Hydrochloride (imidazoles (2; 1-b) quinazoline-2 (3H)-ketone, 6,7-two chloro-1; the 5-dihydro-; monohydrochloride); cilostazol (2 (1H)-quinolinones; 6-(4-(1-cyclohexyl-1H-tetrazolium-5-yl) butoxy)-3, the 4-dihydro-); propentofylline (1H-purine-2,6-diketone; 3; 7-dihydro-3-methyl isophthalic acid-(5-oxo-hexyl)-7-propyl group-); sildenafil citrate (piperazine, 1-((3-(4,7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo (4; 3-d) pyrimidine-5-yl)-and the 4-ethoxyl phenenyl) sulfonyl)-the 4-methyl; 2-hydroxyl-1,2,3-tricarballylic acid ester-(1:1)); tadalafil (pyrazine also (1 '; 2 ': 1; 6) (3,4-b) indole 1, the 4-diketone for pyrido; 6-(1; 3-benzo dioxole-5-yl)-2,3,6; 7; 12,12a-six hydrogen-2-methyl-, (6R-is trans)); Vardenafil (piperazine; (3-(1 for 1-; 4-dihydro-5-methyl (4-oxo-7-propyl imidazole (5,1-f) (1,2; 4)-triazine-2-yl)-the 4-ethoxyl phenenyl) sulfonyl)-the 4-ethyl-); milrinone ((3; 4 '-two pyridines)-and the 5-nitrile, 1,6-dihydro-2-methyl-6-oxo-); enoximone (2H-imidazoles-2-ketone; 1; 3-dihydro-4-methyl-5-(4-(methyl mercapto) benzoyl)-); theophylline (1H-purine-2,6-diketone, 3; 7-dihydro-1; the 3-dimethyl-); ibudilast (1-acetone, the 2-methyl isophthalic acid-(2-(1-Methylethyl) pyrazolo (1,5-a) pyridin-3-yl)-; aminophylline (1H-purine-2; the 6-diketone; 3,7-dihydro-1, the 3-dimethyl-; have 1; 2-ethylenediamine (2:1)-chemical compound); acebrophylline (7H-purine-7-acetic acid, 1,2; 3; 6-tetrahydrochysene-1,3-dimethyl-2,6-dioxo; has trans-4-(((2-amino-3; the 5-dibromo phenyl) chemical compound of Hexalin (1:1) amino methyl))); sprinkle appropriate bright (propionic acid amide., 2-(4-chlorophenoxy)-2-methyl-N-(((4-morpholinyl) methyl) amino) carbonyl)-); hydrochloric acid is coughed up Pu Linong (3-pyridine nitrile, 1; 2-dihydro-5-imidazoles (1; 2-a) pyridine-6-base-6-methyl-2-oxo-,-hydrochlorate-); fosfosal (benzoic acid, 2-(phosphonato)-); amrinone ((3; 4 ' two pyridines)-6 (1H)-ketone, 5-amino-, or its analog or derivant).

The example of other phosphodiesterase inhibitor comprises denbufylline (1H-purine-2, the 6-diketone, 1,3-dibutyl-3,7-dihydro-7-(2-oxopropyl)-), propentofylline (1H-purine-2,6-diketone, 3,7-dihydro-3-methyl isophthalic acid-(5-oxo-hexyl)-7-propyl group-) and pelrinone (5-pyrimidine nitrile, 1,4-dihydro-2-methyl-4-oxo-6-[(3-pyridylmethyl) amino]-).

The example of other phosphodiesterase iii inhibitor comprises enoximone (2H-imidazoles-2-ketone; 1; 3-dihydro-4-methyl-5-(4-(methyl mercapto) benzoyl)-) and Saterinone (3-pyridine nitrile; 1,2-dihydro-5-(4-(2-hydroxyl-3-(4-(2-methoxyphenyl)-1-piperazinyl] propoxyl group] phenyl)-6-methyl-2-oxo-).

The example of other phosphodiesterase IV inhibitors comprises AWD-12-281,3-auinolinecarboxylic acid, 1-ethyl-6-fluoro-1,4-dihydro-7-(4-methyl isophthalic acid-piperazinyl)-4-oxo-), tadalafil (pyrazine also (1 ', 2 ': 1,6) pyrido (3,4-b) indole 1, the 4-diketone, and 6-(1,3-benzo dioxole-5-yl)-2,3,6,7,12,12a-six hydrogen-2-methyl-, (6R-is anti-)) and filaminast (ethyl ketone, 1-(3-(cyclopentyloxy)-4-methoxyphenyl)-, O-(amino carbonyl) oxime, (1E)-).

The example of another Phosphodiesterase V inhibitors is Vardenafil (piperazine, 1-(3-(1,4-dihydro-5-methyl (4-oxo-7-propyl imidazole is (5,1-f) (1,2,4)-triazine-2-yl)-4-ethoxyl phenenyl also) sulfonyl)-4-ethyl-).

27) The TGF beta inhibitor

In another embodiment, (for example suppress fibrotic pharmaceutical active compounds and be the TGF beta inhibitor, Man-6-P, LF-984, tamoxifen (acetamide, (4-(1 for 2-, 2-xenyl-1-butylene base) phenoxy group)-and N, the N-dimethyl-, (Z)-), tranilast, or its analog or derivant).

28) The TXA2. antagonist

In another embodiment; (for example suppress fibrotic pharmaceutical active compounds and be the TXA2. antagonist; CGS-22652 (3-pyridine enanthic acid; γ-4 ((((4-chlorphenyl) sulfonyl) amino) butyl)-; (.+-.)-; ozagrel (2-acrylic acid; 3-(4-(1H-imidazoles-1-ylmethyl) phenyl)-; (E)-, argatroban (2 piperidine carboxylic acid, 1-(5-((amino imino methyl) amino)-1-oxo-2-(((1; 2; 3,4-tetrahydrochysene-3-methyl-quinolyl) sulfonyl) amino) amyl group)-the 4-methyl-), Leimaquban (9H-carbazole-9-propanoic acid; 3-(((4-fluorophenyl) sulfonyl) amino)-1; 2,3, the 4-tetrahydrochysene-; (R)-); torasemide (3-pyridine sulfonamides, N-(((1-Methylethyl) amino) carbonyl)-4-((3-aminomethyl phenyl) amino)-), gamma linoleic acid ((Z; Z; Z)-6,9,12-jeceric acid); seratrodast (benzene enanthic acid); ζ-(2,4,5-) trimethyl-3; 6-dioxo-1; 4-cyclohexadiene-1-yl)-, (+/-)-, or its analog or derivant).

29) TNF alpha-2 antagonists and tace inhibitor

In another embodiment; (for example suppress fibrotic pharmaceutical active compounds and be TNF alpha-2 antagonists or tace inhibitor; E-5531 (2-deoxidation-6-O-(2-deoxidation-3-O-(3 (R)-(5 (Z)-laurylene acyloxy) decyl-)-6-O-methyl-2-(3-oxo myristoyl amido)-4-O-phosphono-β-D-glucopyranosyl)-3-O-(3 (R)-hydroxyl decyl)-2-(3-oxo myristoyl amido)-α-D-Glucopyranose .-1-O-phosphate ester); AZD-4717; glycophosphopeptical; UR-12715 (benzoic acid; 2-hydroxyl-5-((4-(3-(4-(2-methyl isophthalic acid H-imidazoles (4; 5-c) pyridine-1-yl) methyl)-piperidino)-3-oxo-1-phenyl-1-acrylic) phenyl) azo) (Z)); PMS-601; AM-87; wood adenosine (xyloadenosine) (9H-purine-6-amine; 9-β-D-wood furyl glycosyl-); RDP-58; RDP-59; BB2275; benzydamine; E-3330 (hendecanoic acid; 2-((4; 5-dimethoxy-2-methyl-3; 6-dioxo-1; 4-cyclohexadiene-1-yl) methylene)-; (E)-); N-(D; L-2-(hydroxyl amino carbonyl) methyl-4-methylpent acyl group)-L-3-(2 '-naphthyl) alanyl-L-alanine; 2-amino-ethyl amide; CP-564959; MLN-608; SPC-839; ENMD-0997; ((2-(10 for Sch-23863; 11-dihydro-5-ethyoxyl-5H-dibenzo (a; d) cycloheptene-S-yl)-N; N-dimethyl-ethamine); SH-636; PKF-241-466; PKF-242-484; TNF-484A; cilomilast (cis-4-cyano group-4-(3-(cyclopentyloxy)-4-methoxyphenyl) cyclohexane extraction-1-carboxylic acid); GW-3333; GW-4459; BMS-561392; AM-87; cloricromen (acetic acid; ((8-chloro-3-(2-(diethylamino) ethyl)-4-methyl-2-oxo-2H-1-.alpha.-5:6-benzopyran-7-yl) oxygen base)-; ethyl ester); Thalidomide (1H-iso-indoles-1; 3 (2H)-diketone; 2-(2; 6-dioxo-3-piperidyl)-); vesnarinone (piperazine; 1-(3; 4-dimethoxy benzoyl)-4-(1; 2; 3; 4-tetrahydrochysene-2-oxo-6-quinolyl)-); infliximab; lentinan; Embrel (with 1-235-Tumor Necrosis Factor Receptors (people) fusion rotein of 236-467-immunoglobulin G 1 (people γ 1-chain Fc fragment)); diacerein (2-anthracene carboxylic acid; 4; two (acetoxyl group)-9 of 5-; 10-dihydro-9; the 10-dioxo-, or its analog or derivant).

30) Tyrosine kinase inhibitor

In another embodiment, (for example suppress fibrotic pharmaceutical active compounds and be tyrosine kinase inhibitor, SKI-606, ER-068224, SD-208, N-(6-benzothiazolyl)-4-(2-(1-piperazinyl) pyridine-5-yl)-2-pyrimidinamine, celastrol (24,25,26-Trinoroleana-1 (10), 3,5,7-tetraene-29-acid, 3-hydroxyl-9,13-dimethyl-2-oxo-, (9 β., 13 α, 14 β, 20 α)-), CP-127374 (geldanamycin, 17-de-methoxy-17-(2-acrylic amino)-), CP-564959, PD-171026, CGP-52411 (1H-iso-indoles-1,3 (2H)-diketone, 4,5-two (phenyl amino)-), CGP-53716 (Benzoylamide, N-(4-methyl-3-((4-(3-pyridine radicals)-2-pyrimidine radicals) amino) phenyl)-), imatinib (4-((methyl isophthalic acid-piperazinyl) methyl)-N-(4-methyl-3-((4-(3-pyridine radicals)-2-pyrimidine radicals) amino)-phenyl) Benzoylamide mesylate (ester)), NVP-AAK980-NX, KF-250706 (13-chlorine, 5 (R), 6 (S)-epoxy-14s, 16-dihydroxy-11-(hydroxyl (hydroy) imino group)-3 (R)-methyl-3,4,5,6,11,12-six hydrogen-1H-2-benzene oxa-ring 14 alkynes (benzoxacyclotetradecin)-1-ketone), 5-(3-(3-methoxyl group-4-(2-((E)-2-phenyl vinyl)-4-oxazolyl methoxyl group) phenyl) propyl group)-3-(2-((E)-2-phenyl vinyl)-4-oxazolyl methyl)-2, the 4-oxazolidinedione, genistein, NV-06, or its analog or derivant).

31) Vitronectin inhibitor

In another embodiment; (for example suppress fibrotic pharmaceutical active compounds and be vitronectin inhibitor; O-(9,10-dimethoxy-1,2; 3; 4,5,6-six hydrogen-4-((1; 4; 5,6-tetrahydrochysene-2-pyrimidine radicals) hydrazono-)-8-phenyl (e) Flos Chrysanthemi cyclic group)-N-((phenyl methoxyl group) carbonyl)-DL-homoserine 2,3-dihydroxypropyl ester; (2S)-(((4S)-(3-(4 for 2-for benzoyl carbonylamino-3-; 5-dihydro-1H-imidazoles-2-base is amino)-propyl group)-2,5-dioxo-imidazolidine-1-yl)-acetyl-amino)-propionate (ester), Sch-221153; S-836; SC-68448 (β-((2-2-(((3-((amino imino methyl) amino)-phenyl) carbonyl) amino) acetyl group) amino)-3,5-dichloro-benzenes propanoic acid), SD-7784; S-247, or its analog or derivant).

32) Fibroblast growth factor inhibitor

In another embodiment, (for example suppress fibrotic pharmaceutical active compounds and be fibroblast growth factor inhibitor, CT-052923 (((2H-benzo (d) 1,3-dioxolanes-5-methyl) amino) (4-(6,7-dimethoxyquinazoline-4-yl) methane-1-thioketone piperazinyl)), or its analog or derivant).

33) Kinases inhibitor

In another embodiment, suppressing fibrotic pharmaceutical active compounds is kinases inhibitor (for example, KP-0201448, NPC15437 (caproamide, 2,6-diamino-N-((1-(oxo tridecyl)-2-piperidyl) methyl)-), fasudil (1H-1,4-diaza

Six hydrogen-1-(5-isoquinolinesulfonylcompounds)-), and midostaurin (Benzoylamide, N-(2,3; 10,11,12,13-six hydrogen-10-methoxyl group-9-methyl isophthalic acid-oxo-9; 13-epoxy-1H, and 9H-two indole (1,2,3-gh:3 '; 2 ', 1 '-Im) pyrrolo-(3,4-j) (1,7) benzo two azonines-11-yl)-N-methyl-; (9 α, 10 β, 11 β; 13 α)-), fasudil (1H-1,4-diaza , six hydrogen-1-(5-isoquinolyl sulfonyl)-), dexniguldipine (3, the 5-dipicolinic acid, 1,4-dihydro-2,6-dimethyl-4-(3-nitrobenzophenone)-, 3-(4,4-xenyl-piperidino) propyl group methyl ester, one hydrochlorate, (R)-), LY-317615 (1H-pyrroles-2, the 5-diketone, 3-(1-Methyl-1H-indole-3-yl)-4-[1-[1-(2-pyridylmethyl)-4-piperidyl]-the 1H-indol-3-yl]-, a hydrochlorate), perifosine (piperidines, 4-[[hydroxyl (octadecyl oxygen base) phosphinyl] the oxygen base]-1, the 1-dimethyl-, inner salt), LY-333531 (9H, 18H-5,21:12, and 17-dimethylene dibenzo (e, k) pyrroles (3,4-h) (1,4,13) oxa-diazacyclo hexadecine-18,20 (19H)-diketone, 9-((dimethylamino) methyl)-6,7,10, the 11-tetrahydrochysene-, (S)-), Kynac; SPC-100270 (1,3-octadecyl glycol, 2-amino-, [S-(R ^*, R ^*)]-), Kynacyte, or its analog or derivant).

34) Pdgf receptor kinase inhibitor

In another embodiment, suppressing fibrotic pharmaceutical active compounds is pdgf receptor kinase inhibitor (for example, RPR-127963E, or its analog or derivant).

35) Endothelial growth factor receptor kinase inhibitor

In another embodiment, (for example suppress fibrotic pharmaceutical active compounds and be endothelial growth factor receptor kinase inhibitor, CEP-7055, SU-0879 ((E)-3-(3,5-two-tert-butyl-4-hydroxy phenyl)-2-(amino thiocarbonyl) acrylonitrile), BIBF-1000, AG-013736 (CP-868596), AMG-706, AVE-0005, NM-3 (3-(2-methyl carboxymethyl)-6-methoxyl group-8-hydroxyl-isocoumarin), Bay-43-9006, SU-011248, or its analog or derivant).

36) RAR antagonists

In another embodiment, suppressing fibrotic pharmaceutical active compounds is RAR antagonists (for example, etarotene (Ro-15-1570) (naphthalene; 6-(2-(4-(ethylsulfonyl) phenyl)-1-methyl ethylene)-1,2,3; 4-tetrahydrochysene-1,1,4; the 4-tetramethyl-, (E)-), (2E; 4E)-3-methyl-5-(2-((E)-2-(2,6,6-trimethyl-1-cyclohexene-1-yl) vinyl)-1-cyclohexene-1-yl)-2; the 4-pentadienoic acid; tocoretinate (tretinoin, 3,4-dihydro-2; 5; 7,8-tetramethyl-2-(4,8; 12-trimethyl alkyl)-and 2H-1-.alpha.-5:6-benzopyran-6-base ester, (2R ^*(4R ^*, 8R ^*))-(±)-), aliretinoin (tretinoin, cis-9, anti-form-1 3-), bexarotene (benzoic acid, (1-(5,6,7 for 4-, 8-tetrahydrochysene-3,5,5,8,8-pentamethyl-2-naphthyl) vinyl)-), tocoretinate (tretinoin, 3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyl tridecyl)-2H-1-.alpha.-5:6-benzopyran-6-base ester, [2R ^*(4R ^*, 8R ^*)]-(±)-, or its analog or derivant).

37) Platelet-derived growth factor receptor kinase inhibitor

In another embodiment, (for example suppress fibrotic pharmaceutical active compounds and be platelet-derived growth factor receptor kinase inhibitor, leflunomide (the 4-Isoxazolecarboxamidederivatives, 5-methyl-N-(4-(trifluoromethyl) phenyl)-, or its analog or derivant).

38) The Fibronogin antagonist

In another embodiment, suppress fibrotic pharmaceutical active compounds and be the fibronogin antagonist (for example, G-137 (1, the 3-benzenedicarboxamide, 4-methoxyl group-N, N '-two (3-pyridylmethyl)-, or its analog or derivant).

39) Antifungal

In another embodiment, (for example suppress fibrotic pharmaceutical active compounds and be antifungal, miconazole, sulconazole (sulconizole), parthenolide, rosconitine, nystatin, isoconazole, fluconazol, ketoconazole (ketoconasole), imidazoles, itraconazole, terpinafine, elonazole, bifonazole, clotrimazole, conazole, terconazole (triaconazole) (piperazine, (((2-(2 for 4-for 1-, the 4-Dichlorobenzene base)-2-(1H-1,2,4-triazol-1-yl methyl)-1,3-dioxolanes-4-yl) phenyl methoxyl group))-4-(1-Methylethyl)-, cis-), isoconazole (1-(2-(2-6-dichloro-benzyloxy)-2-(2-, the 4-Dichlorobenzene base) griseofulvin (spiral shell (benzofuran-2 (3H), 1 '-(2) cyclohexane extraction)-3 ethyl)),, 4 '-diketone, 7-chloro-2 ', 4,6-trimethoxy-6 ' methyl, (1 ' S-is trans)-), bifonazole (the 1H-imidazoles, 1-((1,1 '-xenyl)-4-base phenyl methyl)-), econazole nitrate (1-(2-((4-chlorphenyl) methoxyl group)-2-(2, the 4-Dichlorobenzene base) ethyl)-and 1H-nitric acid imidazoles), croconazole (1H-imidazoles, 1-(1-(2-((3-chlorphenyl) methoxyl group) phenyl) vinyl-), Sertaconazole (1H-imidazoles, 1-(2-((the 7-chlorobenzene is (b) thiene-3-yl-also) methoxyl group)-2-(2, the 4-Dichlorobenzene base) ethyl)-), omoconazole (1H-imidazoles, 1-(2-(2-(4-chlorophenoxy) ethyoxyl)-2-(2, the 4-Dichlorobenzene base)-the 1-methyl ethylene)-, (Z)-), flutrimazole (1H-imidazoles, 1-((2-fluorophenyl) (4-fluorophenyl) phenyl methyl)-), fluconazol (1H-1,2,4-triazole-1-ethanol, α-(2, the 4-difluorophenyl)-α-(1H-1,2,4-triazol-1-yl methyl)-), neticonazole (1H-imidazoles, 1-(2-(methyl mercapto)-1-(2-(amoxy) phenyl) vinyl)-, monohydrochloride, (E)-), butoconazole (1H-imidazoles, 1-(4-(4-chlorphenyl)-2-((2, the 6-Dichlorobenzene base) sulfo-) butyl)-, (+/-)-), clotrimazole (1-((2-chlorphenyl) xenyl methyl)-1H-imidazoles, or its analog or derivant).

40) Diphosphate

In another embodiment, suppressing fibrotic pharmaceutical active compounds is diphosphate (for example, clodronate, fosamax (alendronate), pamldronate (pamidronate), zoledronic acid salt (zoledronate), or its analog or derivant).

41) The E.C. 3.1.1.32 inhibitor

In another embodiment, (for example suppress fibrotic pharmaceutical active compounds and be the E.C. 3.1.1.32 inhibitor, loteprednol etabonate (androsta-1,4-diene-17-carboxylic acid, 17-((ethoxy carbonyl) oxygen base)-11-hydroxyl-3-oxo-, chloromethyl ester, (11 β, 17 α)-, or its analog or derivant).

42) Histamine H 1/H2/H3 receptor antagonist

In another embodiment; (for example suppress fibrotic pharmaceutical active compounds and be histamine H 1/H2/H3 receptor antagonist; ranitidine (1; the 1-ethylenediamine; N-(2-(((5-((dimethylamino) methyl)-2-furyl) methyl) sulfo-) ethyl)-N '-methyl-2-nitro-); niperotidine (N-(2-((5-((dimethylamino) methyl) furfuryl group) sulfo-) ethyl)-2-nitro-N '-piperonyl-1; the 1-ethylenediamine); famotidine (Propanimidamide; 3-(((2-(((amino imino methyl) amino)-4-thiazolyl) methyl) sulfo-)-N-(amino-sulfonyl)-); roxitadine acetate HCl (acetamide; 2-(acetoxyl group)-N-(3-(3-(piperidino methyl) phenoxy group) propyl group)-; monohydrochloride); lafutidine (acetamide; 2-((2-furyl methyl) sulfinyl)-N-(4-((4-(piperidino methyl)-2-pyridine radicals) oxygen base)-crotyl)-; (Z)-); nizatidine (1; the 1-ethylenediamine; N-(2-(((2-((dimethylamino) methyl)-4-thiazolyl) methyl) sulfo-) ethyl)-N '-methyl-2-nitro-); ebrotidine (benzsulfamide; N-(((2-(((2-((amino imino methyl) amino)-4-thiazolyl) methyl) sulfo-) ethyl) amino) methylene)-4-bromo-); rupatadine (5H-benzo (5; 6) ring heptan also (1; 2-b) pyridine; 8-chloro-6; 11-dihydro-11-(1-((5-methyl-3-pyridine radicals) methyl)-4-piperidines thiazolinyl)-; three hydrochloric acid-); fexofenadine HCl (phenylacetic acid; 4-(1-hydroxyl-4-(4 (xenol ylmethyl)-piperidino) butyl)-α; alpha-alpha-dimethyl-; hydrochloric acid, or its analog or derivant).

43) Macrolide antibiotics

In another embodiment; (for example suppress fibrotic pharmaceutical active compounds and be macrolide antibiotic; dirithromycin (erythromycin; 9-deoxidation-11-deoxidation-9; 11-(imino group (2-(2-methoxy ethoxy) vinyl) oxygen base)-; (9S (R))-); flurithromycin ethyl succinate (erythromycin; 8-fluoro-list (ethyl succinic acid ester) (ester)-); erythromycin stinoprate (erythromycin; 2 '-propionic ester; chemical compound with N-acetyl group-L-cysteine (1:1)); clarithromycin (erythromycin; the 6-O-methyl-); azithromycin (9-deoxidation-9a-azepine-9a-methyl-9a-homotype Erythromycin A); (3-goes ((2 to Ketek; 6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribose-own pyrans glycosyl (hexopyranosyl)) oxygen base)-11; 12-dideoxy-6-O-methyl-3-oxo-12; 11-(oxo carbonyl ((4-(4-(3-pyridine radicals)-1H-imidazoles-1-yl) butyl) imino group))-); Roxithromycin (erythromycin; 9-(O-((2-methoxy ethoxy) methyl) oxime)); rokitamycin (albomycin V, 4B-butyrate (ester) 3B-propionic ester), RV-11 (erythromycin one propanoic acid mercapto succinic acid ester); midecamycin acetate (albomycin V; 3B, 9-diacetin (ester) 3,4B-dipropionate); midecamycin (albomycin V; 3, the 4B-dipropionate), josamycin (albomycin V; 3-acetate (ester) 4B-(3 Methylbutanoic acid salt (ester)), or its analog or derivant).

44) GPIIb IIIa receptor antagonist

In another embodiment; (for example suppress fibrotic pharmaceutical active compounds and be GPIIb IIIa receptor antagonist; tirofiban hydrochloride (L-tyrosine; N-(butyl sulfonyl)-O-(4-(4-piperidyl) butyl)-; one hydrochloric acid-); eptifibatide (L-cysteinyl amine; N6-(amino imino methyl)-N2-(3-sulfydryl-1-oxopropyl)-L-lysyl glycyl-L-α-aspartoyl-L-tryptophanyl-L-prolyl-; cyclic (1-〉6)-disulphide); xemilofiban hydrochloride, or its analog or derivant).

45) Endothelin-receptor antagonists

In another embodiment, (for example suppress fibrotic pharmaceutical active compounds and be endothelin-receptor antagonists, bosentan (benzsulfamide, 4-(1, the 1-dimethyl ethyl)-N-(6-(2-hydroxyl-oxethyl)-5-(2-methoxyl group phenoxy group) (2,2 '-two pyrimidines)-the 4-yl)-, or its analog or derivant).

46) Peroxisome Proliferators activated receptor agonist

In another embodiment; (for example suppress fibrotic pharmaceutical active compounds and be peroxisome Proliferators activated receptor agonist; gemfibrozil (valeric acid; 5-(2; the 5-dimethyl phenoxy)-2; the 2-dimethyl-); fenofibrate (propanoic acid; 2-(4-(4-chlorobenzene formacyl) phenoxy group)-2-methyl-; 1-Methylethyl ester); ciprofibrate (propanoic acid; (4-(2 for 2-; 2-dichloro cyclopropyl) phenoxy group)-the 2-methyl-); rosiglitazone maleate (2; the 4-thiazolidinedione, 5-((4-(2-(methyl-2-pyridinylamino) ethyoxyl) phenyl) methyl)-, (Z)-2-butylene two acid esters (1:1)); pioglitazone hydrochloride (2; the 4-thiazolidinedione, 5-((4-(2-(5-ethyl-2-pyridine radicals) ethyoxyl) phenyl) methyl)-, monohydrochloride (+/-)-); etofylline clofibrate (propanoic acid; 2-(4-chlorophenoxy)-2-methyl-, 2-(1,2; 3; 6-tetrahydrochysene-1,3-dimethyl-2,6-dioxo-7H-purine-7-yl) ethyl ester); etofibrate (3-picolinic acid; 2-(2-(4-chlorophenoxy)-2-methyl isophthalic acid-oxopropoxy) ethyl ester), clinofibrate (butanoic acid, 2; 2 '-(cyclohexylidene two (4; the inferior phenoxy group of 1-)) two (2-methyl-)), bezafibrate (propanoic acid, 2-(4-(2-((4-chlorobenzene formacyl) amino) ethyl) phenoxy group)-2-methyl-); binifibrate (3-picolinic acid; 2-(2-(4-chlorophenoxy)-2-methyl isophthalic acid-oxopropoxy)-1,3-glyceryl, or its analog or derivant).

In one aspect, described pharmaceutically active compound is a peroxisome Proliferators activated receptor alfa agonists, GW-590735 for example, GSK-677954, GSK501516, pioglitazonehydrochloride (2, the 4-thiazolidinedione, 5-[[4-[2-(5-ethyl-2-pyridine radicals) ethyoxyl] phenyl] methyl]-, a hydrochlorate (+/-)-, or its analog or derivant).

47) The estrogen receptor activity agent

In another embodiment, suppressing fibrotic pharmaceutical active compounds is estrogen receptor reagent (for example, estradiol, 17-, or its analog or derivant).

48) Somatostatin analogs

In another embodiment, suppressing fibrotic pharmaceutical active compounds is somatostatin or somatostatin analogs (for example, angiopeptin (angiopeptin), or its analog or derivant).

49) Neurokinin 1 antagonist

In another embodiment; (for example suppress fibrotic pharmaceutical active compounds and be neurokinin 1 antagonist; GW-597599; lanepitant ((1; 4 '-two piperidines)-1 '-acetamide; N-(2-(acetyl group ((2-methoxyphenyl) methyl) amino)-1-(1H-indol-3-yl methyl) ethyl)-(R)-); a chlorination promise smooth ammonium (1-nitrogen bicyclo-[2.2.2] octane; 1-[2-[3-(3; the 4-Dichlorobenzene base)-and 1-((3-(1-methyl ethoxy) phenyl) acetyl group)-3-piperidyl] ethyl]-the 4-phenyl-; chloride, (S)-), or saredutant (Benzoylamide; N-(4-(4-(acetyl-amino)-4-phenyl-piperidino)-2-(3; the 4-Dichlorobenzene base) butyl)-the N-methyl-, (S)-), or vofopitant (3-piperidinamine; N-((2-methoxyl group-5-(5-(trifluoromethyl)-1H-tetrazolium-1-yl) phenyl) methyl)-2-phenyl-; (2S, 3S)-, or its analog or derivant).

50) Neurokinin 3 antagonisies

In another embodiment, suppress fibrotic pharmaceutical active compounds and be neurokinin 3 antagonisies (for example, talnetant (4-quinoline formyl amine, 3-hydroxyl-2-phenyl-N-[(1S)-1-phenyl propyl]-, or its analog or derivant).

51) Neurokinin

In another embodiment, (for example suppress fibrotic pharmaceutical active compounds and be neurokinin, GSK-679769, GSK-823296, SR-489686 (Benzoylamide, N-(4-(4-(acetyl-amino)-4-phenyl-piperidino)-2-(3, the 4-Dichlorobenzene base) butyl)-N-methyl-, (S)-), SB-223412; SB-235375 (4-quinoline formyl amine, 3-hydroxyl-2-phenyl-N-((1S)-1-phenyl propyl)-), UK-226471, or its analog or derivant).

52) The VLA-4 antagonist

In another embodiment, suppressing fibrotic pharmaceutical active compounds is VLA-4 antagonist (for example GSK683699 or its analog or derivant).

53) The osteoclast inhibitor

In another embodiment, suppress fibrotic pharmaceutical active compounds and be osteoclast inhibitor (for example, ibandronic acid (phosphonic acids, (1-hydroxyl-3-(methyl amyl amino) propylidene) two-), Alendronate sodium, or its analog or derivant).

54) DNA topoisomerase ATP hydrolysis inhibitor

In another embodiment; (for example suppress fibrotic pharmaceutical active compounds and be DNA topoisomerase ATP hydrolysis inhibitor; enoxacin (1; 8-benzodiazine-3-carboxylic acid; 1-ethyl-6-fluoro-1; 4-dihydro-4-oxo-7-(1-piperazinyl)-); levofloxacin (7H-pyrido [1; 2; 3-de]-1; 4-benzoxazinyl-6-carboxylic acid, 9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-; (S)-); ofloxacin (7H-pyrido [1,2,3-de]-1; 4-benzoxazinyl-6-carboxylic acid; 9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-, (+/-)-); pefloxacin (3-quinoline carboxylic acid; 1-ethyl-6-fluoro-1,4-dihydro-7-(4-methyl isophthalic acid-piperazinyl)-4-oxo-), pipemidic acid (pyrido [2; 3-d] pyrimidine-6-carboxylic acid; 8-ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl)-), pirarubicin (5; 12-aphthacene diketone; 10-[[3-amino-2,3,6-three deoxidations-4-O-(tetrahydrochysene-2H-pyrans-2-yl)-α-L-lysol-hexose pyrans glycosyl] the oxygen base]-7; 8; 9,10-tetrahydrochysene-6,8; 11-trihydroxy-8-(hydroxyacetyl)-1-methoxyl group-; [8S-(8 α, 10 α (S*))]-), Sparfloxacin (3-quinoline carboxylic acid; 5-amino-1-cyclopropyl-7-(3; 5-dimethyl-1-piperazinyl)-6,8-two fluoro-1,4 dihydro-4-oxo-; suitable-); AVE-6971, cinoxacin ([1,3] dioxole also [4; 5-g] cinnolines-3-carboxylic acid; 1-ethyl-1,4-dihydro-4-oxo-), or its analog or derivant).

55) Hypertensin I conversion enzyme inhibitor

In another embodiment, (for example suppress fibrotic pharmaceutical active compounds and be hypertensin I conversion enzyme inhibitor, ramipril (ring penta [b] pyrroles-2-carboxylic acid, 1-[2-[[1-(ethoxy carbonyl)-3-phenyl propyl] amino]-the 1-oxopropyl] octahydro-, [2S-[1[R ^*(R ^*)], 2 α, 3a β, 6a β]]-), trandolapril (1H-indole-2-carboxylic acid, 1-[2-[(1-carboxyl-3-phenyl propyl) amino]-the 1-oxopropyl] octahydro-, [2S-[1[R ^*(R ^*)], 2 α, 3a α, 7a β]]-); fasidotril (the L-alanine, N-[(2S)-3-(acetyl group sulfo-)-2-(1,3-benzo dioxole-5-ylmethyl)-1-oxopropyl]-, the phenyl propyl ester); (the 6H-pyridazine is [1,2-a] [1,2] diaza also for cilazapril

-1-carboxylic acid, 9-[[1-(ethoxy carbonyl)-3-phenyl propyl] amino] octahydro-10-oxo-, [1S-[1 α, 9 α (R ^*)]]-), ramipril (ring penta [b] pyrroles-2-carboxylic acid, 1-[2-[[1-(ethoxy carbonyl)-3-phenyl propyl] amino]-the 1-oxopropyl] octahydro-, [2S-[1[R ^*(R ^*)], 2 α, 3a β, 6a β]]-), or its analog or derivant).

56) Angiotension II antagonists

In another embodiment; (for example suppress fibrotic pharmaceutical active compounds and be angiotension II antagonists; HR-720 (1H-imidazole-5-carboxylic acid; 2-butyl-4-(methyl mercapto)-1-[[2 '-[[[(third amino) carbonyl] amino] sulfonyl] [1; 1 '-xenyl]-the 4-yl] methyl]-; di-potassium, or its analog or derivant).

57) The enkephalin enzyme inhibitor

In another embodiment, suppressing fibrotic pharmaceutical active compounds is enkephalin enzyme inhibitor (for example, Aventis 100240 (pyrido [2; 1-a] [2] benzo-aza-4-carboxylic acid, 7-[[2-(acetyl group sulfo-)-1-oxo-3-phenyl propyl] amino]-1,2; 3; 4,6,7; 8; 12b-octahydro-6-oxo-, [4S-[4 α, 7 α (R ^*), 12b β]]-), AVE-7688, or its analog or derivant).

58) Peroxisome Proliferators activated receptor gamma agonist insulin sensitizer

In another embodiment, (for example suppress fibrotic pharmaceutical active compounds and be peroxisome Proliferators activated receptor gamma agonist insulin sensitizer, maleic acid rosiglitazone (2, the 4-thiazolidinedione, 5-((4-(2-(methyl-2-pyridinylamino) ethyoxyl) phenyl) methyl)-, (Z)-two of 2-butylene close (1:1), farglitazar (GI-262570, GW-2570, GW-3995, GW-5393, GW-9765), LY-929, LY-519818, Y-674, or LSN-862), or its analog or derivant).

59) Inhibitors of protein kinase C

In another embodiment, suppressing fibrotic pharmaceutical active compounds is inhibitors of protein kinase C, as ruboxistaurin mesylate (ester) (9H, 18H-5,21:12, and 17-dimethylene (dimetheno) dibenzo (e, k) pyrrolo-(3,4-h) (1,4,13) oxa-diazacyclo hexadecine-18,20 (19H)-diketone, 9-((dimethylamino) methyl)-6,7,10, the 11-tetrahydrochysene-, (S)-), Safingol (1, the 3-octacosanol, 2-amino-, [S-(R ^*, R ^*)]-), or hydrochloric acid enzastaurin (1H-pyrroles-2,5-diketone, 3-(1-Methyl-1H-indole-3-yl)-4-[1-[1-(2-picolyl)-4-piperidyl]-the 1H-indol-3-yl]-, a hydrochlorate), or its analog or derivant.

60) ROCK (the related kinases of rho-) inhibitor

In another embodiment, suppressing fibrotic pharmaceutical active compounds is ROCK (the related kinases of rho-) inhibitor, as Y-27632, and HA-1077, H-1152 and 4-1-(aminoalkyl)-N-(4-pyridine radicals) cyclohexane carboxamide, or its analog or derivant.

61) The CXCR3 inhibitor

In another embodiment, suppressing fibrotic pharmaceutical active compounds is the CXCR3 inhibitor, as T-487, and T0906487 or its analog or derivant.

62) The Itk inhibitor

In another embodiment, suppressing fibrotic pharmaceutical active compounds is the Itk inhibitor, such as BMS-509744 or its analog or derivant.

63) CPLA2 A2-alpha inhibitor

In another embodiment, suppressing fibrotic pharmaceutical active compounds is cPLA2 A ₂-alpha inhibitor is such as efipladib (PLA-902) or its analog or derivant.

64) The PPAR agonist

In another embodiment, suppress fibrotic pharmaceutical active compounds and be PPAR antagonist (Metabolex ((-)-phenylacetic acid for example, 4-chloro-α-[3-(trifluoromethyl)-phenoxy group]-, 2-(acetylamino) ethyl ester), balaglitazone (5-(4-(3-methyl-4-oxo-3,4-dihydro-chinazoline-2-base-methoxyl group)-benzyl)-thiazolidine-2, the 4-diketone), ciglitazone (2, the 4-thiazolidinedione, the 5-[[4-[(1-methylcyclohexyl) methoxyl group] phenyl] methyl]-), DRF-10945, farglitazar, GSK-677954, GW-409544, GW-501516, GW-590735, GW-590735, K-111, KRP-101, LSN-862, LY-519818, LY-674, LY-929, muraglitazar; BMS-298585 (glycine, N-[(4-methoxyl group phenoxy group) carbonyl]-N-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl) ethyoxyl] phenyl] methyl]-), netoglitazone; Isaglitazone (2,4-thiazolidinedione, 5-[[6-[(2-fluorophenyl) methoxyl group]-the 2-naphthyl] methyl]-), Actos AD-4833; U-72107A (2,4-thiazolidinedione, 5-[[4-[2-(5-ethyl-2-pyridine radicals) ethyoxyl] phenyl] methyl]-, a hydrochlorate (+/-)-), JTT-501; PNU-182716 (3,5-isooxazolidinedione, 4-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl) ethyoxyl] phenyl] methyl]-), AVANDIA (from SB Pharmco Puerto Rico, Inc. (Puerto Rico); BRL-48482; BRL-49653; BRL-49653c; NYRACTA and Venvia are (from (SmithKline Beecham (Britain)); Tesaglitazar ((2S)-2-ethyoxyl-3-[4-[2-[4-[(methyl sulphonyl) oxygen base] phenyl] ethyoxyl] phenyl] propanoic acid); troglitazone (2; the 4-thiazolidinedione; 5-[[4-[(3; 4-dihydro-6-hydroxyl-2; 5,7,8-tetramethyl-2H-1-.alpha.-5:6-benzopyran-2-yl) methoxyl group] phenyl] methyl]-) and analog or derivant).

65) Immunosuppressant

In another embodiment, suppressing fibrotic pharmaceutical active compounds is immunosuppressant (for example, batebulast (cyclohexane-carboxylic acid, 4-[[(amino imino methyl) amino] methyl]-, 4-(1, the 1-dimethyl ethyl) phenylester, anti--), cyclomunine, exalamide (Benzoylamide, 2-(hexyloxy)-), LYN-001, CCI-779 (rapamycin 42-(3-hydroxyl-2-(hydroxymethyl)-2 Methylpropionic acid ester)), 1726; 1726-D; AVE-1726, or its analog or derivant).

66) The Erb inhibitor

In another embodiment, (for example suppress fibrotic pharmaceutical active compounds and be the Erb inhibitor, the canertinib dihydrochloride (N-[4-(3-(chloro-4 fluoro-phenyl aminos)-7-(3-morpholine-4-base-propoxyl group)-quinazoline-6-yl)-acrylamide dihydrochloride], CP-724714, or its analog or derivant).

67) The programmed cell death agonist

In another embodiment, suppressing fibrotic pharmaceutical active compounds is that (for example, CEFLATONIN (CGX-635) is (from ChemgenexTherapeutics for the programmed cell death agonist, Inc., Menlo Park, CA), CHML, LBH-589, metoclopramide (Benzoylamide, 4-amino-5-chloro-N-[2-(diethylamino) ethyl]-the 2-methoxyl group-), patupilone (4,17-two oxa-dicyclo (14.1.0) heptadecanes-5, the 9-diketone, 7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-(1-methyl-2-(2-methyl-4-thiazolyl) vinyl, (1R, 3S, 7S, 10R, 11S, 12S, 16R)), AN-9; Pivanex (butanoic acid, (2,2-dimethyl-1-oxopropoxy) methyl ester), SL-100; SL-102; SL-11093; SL-11098; SL-11099; SL-93; SL-98; SL-99, or its analog or derivant).

68) The lipocortin agonist

In another embodiment, (for example suppress fibrotic pharmaceutical active compounds and be the lipocortin agonist, CGP-13774 (9 α-chloro-6 α-fluoro-11 β, 17 alpha-dihydroxy-s-16 Alpha-Methyls-3-oxo-1,4-androstane diene-17 β-carboxylic acid-methyl ester-17-propionic ester), or its analog or derivant).

69) The VCAM-1 antagonist

In another embodiment, suppressing fibrotic pharmaceutical active compounds is VCAM-1 antagonist (for example DW-908e or its analog or derivant).

70) Collagen antagonist

In another embodiment, (for example suppress fibrotic pharmaceutical active compounds and be collagen antagonist, E-5050 (hydrocinnamamide, 4-(2,6-dimethyl heptyl)-N-(2-hydroxyethyl)-Beta-methyl-), lufironil (2,4-pyridine diformamide, N, N '-two (2-methoxy ethyl)-), or its analog or derivant).

71) α 2 integrin antagonisies

In another embodiment, suppressing fibrotic pharmaceutical active compounds is α 2 integrin antagonisies (for example E-7820 or its analog or derivants).

72) The TNF alpha inhibitor

In another embodiment, suppressing fibrotic pharmaceutical active compounds is TNF alpha inhibitor (for example, ethyl pyruvate, Genz-29155, lentinan (Ajinomoto Co., Inc. (Japan)), linomide (3-quinoline formyl amine, 1,2-dihydro-4-hydroxy-n, 1-dimethyl-2-oxo-N-phenyl-), UR-1505, or its analog or derivant).

73) Nitric oxide inhibitor

In another embodiment, suppressing fibrotic pharmaceutical active compounds is nitric oxide inhibitor (for example guanidine (guanidio) ethyl disulphide or its analog or derivant).

74) Cathepsin inhibitors

In another embodiment, suppressing fibrotic pharmaceutical active compounds is cathepsin inhibitors (for example SB-462795 or its analog or derivant).

Anti-infective

The present invention also provides the combination of polymer composition with the activating agent that reduces the probability of implanting said composition or medical apparatus postoperative infection.

Infection is to implant foreign body, such as the common complication of medical apparatus and implant.Foreign body provides ideal position for microorganic adhesion and residence.Also infer and have the damage of host the defence infected in the microenvironment around the foreign body.These factors make medical implant responsive especially to infecting, and in most of situation, make that eradicating this class infects the difficulty that becomes, even be not impossible.In many cases, must implant or the device that infect be taken out so that eradicate (irradicate) infection in body by surgical operation.

The invention provides the activating agent (for example chemotherapeutics) that can from compositions, discharge and under very low dose, have effective antibacterial activity.Various anti-infectives can be used for and compositions coupling of the present invention.Be easy to based on embodiment 34) in the test that provides determine suitable anti-infective.What hereinafter more specifically discuss is several representational examples that can be used as anti-infective, such as: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyurea; (G) platinum complexes (for example cisplatin).

A. Anthracyclines

In one aspect, the anti-infective of treatment usefulness is an anthracycline.Anthracycline has following general structure, and wherein the R group can be different organic groups:

According to U.S. Pat 5,594,158, the suitable R group is as follows: R ₁Be CH ₃Or CH ₂OH; R ₂Be daunosamine or H; R ₃And R ₄Be OH, NO independently ₂, NH ₂, F, Cl, Br, I, CN, H or derive from one of their group; R ₅Be hydrogen, hydroxyl or methoxyl group; And R _6-8Be hydrogen.Perhaps, R ₅And R ₆Be hydrogen and R ₇And R ₈Be alkyl or halogen, or vice versa.

According to United States Patent (USP) 5,843,903, R ₁Can be the peptide of puting together.According to United States Patent (USP) 4,296,105, R ₅Can be the alkyl group of ether connection.According to United States Patent (USP) 4,215,062, R ₅Can be the alkyl of OH or ether connection.R ₁Can also be connected with the ring of anthracycline by the group by non-C (O), the group of described non-C (O) is such as being alkyl or the branched alkyl that contains C (O) coupling part endways, such as-CH ₂CH (CH ₂-X) C (O)-R ₁, wherein X is H or alkyl group (see, for example, United States Patent (USP) 4,215,062).R ₂Alternative group for connecting by functional group=N-NHC (O)-Y, wherein Y is this class group of phenyl ring such as phenyl or replacement.Alternatively, R ₃Be following array structure:

R wherein ₉For in the plane of a loop or outer OH or be second sugar moieties, such as R ₃R ₁₀Can for H or with form secondary amine (referring to United States Patent (USP) 5,843,903) such as aromatic group, heterocyclic these class groups of 5 or 6 yuan of saturated or fractional saturation of containing at least one ring nitrogen.Perhaps, R ₁₀Can derive from and contain-C (O) CH (NHR ₁₁) (R ₁₂) aminoacid of structure, wherein R ₁₁Be H; Or R ₁₀Can with R ₁₂Form C _3-4Unit's alkylidene.R ₁₂Can be H, alkyl, aminoalkyl, amino, hydroxyl, sulfydryl, phenyl, benzyl or methyl mercapto (referring to United States Patent (USP) 4,296,105).

Typical anthracyclines is doxorubicin, daunorubicin, idarubicin, epirubicin, pirarubicin, zorubicin and carubicin.Suitable compound has following structure:

Other suitable anthracycline is antramycin, mitoxantrone, menogaril, nogalamycin, Aclacnomycin A, Olivomycin A, the chromomycin A with following structure ₃And plicamycin:

Other representational anthracycline comprises FCE 23762, doxorubicin derivant (J.Liq.Chromato such as Quaglia, 17 (18): 3911-3923,1994), annamycin (Zou etc., J.Pharm.Sci.82 (11): 1151-1154,1993), ruboxyl (Rapoport etc., J.Controlled Release 58 (2): 153-162,1999), anthracycline disaccharide doxorubicin analog (Pratesi etc., Clin.CancerRes4 (11): 2833-2839,1998), N-(trifluoroacetyl group) doxorubicin and 4 '-O-acetyl group-N-(trifluoroacetyl group) doxorubicin (Berube ﹠amp; Lepage, Synth.Commun.28 (6): 1109-1116,1998), 2-pyrrolin and doxorubicin (Proc.Nat ' l Acad.Sci.U.S.A.95 (4): 1794-1799 such as Nagy, 1998), disaccharide doxorubicin analog (Arcamone etc., J.Nat ' lCancer Inst.89 (16): 1217-1223,1997), 4-demethoxylation-7-O-[2, two deoxidation-the 4-O-(2 of 6-, 3,6-three deoxidations-3-amino-α-L-lysol-hexose pyrans glycosyl)-and α-L-lysol-hexose pyrans glycosyl] adriamicinone doxorubicin disaccharide analog (Monteagudo etc., Carbohydr.Res.300 (1): 11-16,1997), 2-pyrrolin and doxorubicin (Proc.Nat ' l Acad.Sci.U.S.A.94 (2): 652-656 such as Nagy, 1997), morpholinyl doxorubicin analog (Duran etc., CancerChemother.Pharmacol.38 (3): 210-216,1996), enamino malonyl-Beta-alanine doxorubicin derivant (Seitz etc., Tetrahedron Lett.36 (9): 1413-16,1995), cephalosporin doxorubicin derivant (Vrudhula etc., J.Med. Chem.38 (8): 1380-5,1995), hydroxyrubicin (Solary etc., Int.J.Cancer 58 (1): 85-94,1994), methoxyl group morpholinyl doxorubicin derivant (Kuhl etc., Cancer Chemother.Pharmacol.33 (1): 10-16,1993), (6-maleoyl-imino group caproyl) hydrazone doxorubicin derivant (Bioconjugate Chem.4 (6): 521-7 such as Willner, 1993), N-(5,5-diacetoxy penta-1-yl) doxorubicin (Cherif﹠amp; Farquhar, J, Med.Chem.35 (17): 3208-14,1992), FCE 23762 methoxyl group morpholinyl doxorubicin derivant (Ripamonti etc., Br.J.Cancer 65 (5): 703-7,1992), N-hydroxy-succinamide ester doxorubicin derivant (Demant etc., Biochim.Biophys.Acta1118 (1): 83-90,1991), poly deoxynucleosides doxorubicin derivant (Ruggiero etc., " biochemistry and biophysics's journal " (Biochim.Biophys.Acta) 1129 (3): 294-302,1991), morpholinyl doxorubicin derivant (EPA 434960), mitoxantrone doxorubicin analog (Krapcho etc., " pharmaceutical chemistry magazine " (J.Med.Chem.) 34 (8): 2373-80.1991), AD198 doxorubicin analog (Traganos etc., " cancer research " (Cancer Res.) 51 (14): 3682-9,1991), 4-demethoxylation-3 '-N-TFA base doxorubicin (Drug Des.Delivery 6 (2): 123-9 such as Horton, 1990), 4 '-epidoxorubicin (Drzewoski etc., " Polish pharmacology and materia medica magazine " (Pol.J.Pharmacol.Pharm.) 40 (2): 159-65,1988; Weenen etc., " European cancer Journal of Clinical Oncology " (Eur.J.Cancer Clin.Oncol.) 20 (7): 919-26,1984), alkylation cyano group morpholinyl doxorubicin derivant (Scudder etc., " National Cancer Institute's magazine " (J.Nat ' l Cancer Inst.) 80 (16): 1294-8,1988), deoxidation dihydro iodooxorubicin (EPA275966), amycin (Kalishevskaya etc., Vestn.Mosk.Univ., 16 (Biol.1): 21-7,1988), 4 '-(Schoelzel etc. " leukocyte research " (Leuk.Res.) 10 (12): 1455-9 for the deoxidation doxorubicin, 1986), 4-demethoxylation-4 '-o-methyl doxorubicin (Giuliani etc., Proc.Int.Congr.Chemother16:285-70-285-77,1983), 3 '-deaminizating-3 '-(Horton etc. " antibiotic magazine " (J.Antibiot.) 37 (8): 853-8 for the hydroxyl doxorubicin, 1984), 4-demethoxylation doxorubicin analog (Barieri etc., " clinical drug experimentation " (Drugs Exp.Clin.Res.) 10 (2): 85-90,1984), N-L-leucyl doxorubicin derivant (Trouet etc., anthracyclines (Anthracyclines)-Proc.Int.Symp.Tumor Pharmacother., 179-81,1983), 3 '-deaminizating-3 '-(4-methoxyl group-piperidino) doxorubicin derivant (U.S.4,314,054), 3 '-deaminizating-3 '-(4-morpholinyl) doxorubicin derivant (U.S.4,301,277), 4 '-deoxidation doxorubicin and 4 '-o-methyl doxorubicin (Giuliani etc., " international journal of cancer " (Int.J.Cancer) 27 (1): 5-13,1981), aglycone doxorubicin derivant (Chan ﹠amp; Watson, " pharmaceutical science magazine " (J.Pharm.Sci.) 67 (12): 1748-52,1978), SM 5887 (" Japanese pharmacy " (Pharma Japan) 1468:20,1995), MX-2 (" Japanese pharmacy " (Pharma Japan) 1420:19,1994), 4 '-deoxidation-13 (S)-dihydro-4 '-iodine doxorubicin (EP 275966), morpholinyl doxorubicin derivant (EPA 434960), 3 '-deaminizating-3 '-(4-methoxyl group-piperidino) doxorubicin derivant (U.S.4,314,054), doxorubicin-14-valerate, morpholinyl doxorubicin (U.S.5,004,606), 3 '-deaminizating-3 '-(3 " cyano group-4 "-morpholinyl doxorubicins, 3 '-deaminizating-3 '-(3 " cyano group-4 "-morpholinyl)-13-dihydro doxorubicin, (3 '-deaminizating-3 '-(3 " cyano group-4 "-morpholinyl) daunorubicin, 3 '-deaminizating-3 '-(3 " cyano group-4 "-morpholinyl)-3-dihydrodaunomycin; With 3 '-deaminizating-3 '-(4 " morpholinyl-5-imino group doxorubicin and derivant (U.S.4; 585; 859), 3 '-deaminizating-3 '-(4-methoxyl group-piperidino) doxorubicin derivant (U.S.4; 314; 054) and 3-deaminizating-3-(4-morpholinyl) doxorubicin derivant (U.S.4; 301,277).

B. Fluoropyrimidine analogue

In one aspect of the method, described therapeutic agent is a fluoropyrimidine analogue, such as 5-fluorouracil or its analog or derivant, comprises carmofur, doxifluridine, emitefur, florafur and floxuridine.Exemplary compounds has following structure:

Other suitable fluoropyrimidine analogue comprises 5-FudR (5-fluoro-BrdU) or its analog or derivant, comprises idoxuridine (5-IudR), 5-bromouracil deoxyribose (5-BudR), fluorouridine triphosphate (5-FUTP) and fluorodeoxyuridine one phosphoric acid (5-dFUMP).Exemplary compounds has following structure:

5-fluoro-2 '-BrdU: R=F

5-bromo-2 '-BrdU: R=Br

5-iodo-2 '-BrdU: R=I

Other representative example of fluoropyrimidine analogue comprises the N3-alkylation analog (Kozai etc. of 5-fluorouracil, J.Chem.Soc., Perkin Trans.1 (19): 3145-3146,1998), contain 1, (Gomez etc. " tetrahedron " (Tetrahdron) 54 (43): 13295-13312 for the 5-fluorouracil derivant of 4-oxa-loop section in heptan, 1998), 5-fluorouracil and nucleoside analog (Li, " anticancer research " (Anticancer Res.) 17 (1A): 21-27,1997), cis-and trans-5-fluoro-5,6-dihydro-6-alkoxyl uracil (Van der Wilt etc., " Britain's cancer magazine " (Br.J.Cancer) 68 (4): 702-7,1993), Pentamethylene. 5-fluorouracil analog (Hronowski ﹠amp; Szarek, " Canadian Journal of Chemistry " (Can.J.Chem.) 70 (4): 1162-9,1992), A-OT-fluorouracil (Zhang etc., " Chinese Journal of Pharmaceuticals " (Zongguo Yiyao Gongye Zazhi) 20 (11): 513-15,1989), N4-trimethoxy benzoyl-5 '-deoxidation-5-fluorine cytidine and 5 '-(Miwa etc. " chemicals bulletin " (Chem.Pharm.Bull.) 38 (4): 998-1003 for '-Deoxy-5-fluorouridine, 1990), 1-hexyl carbamoyl-5-fluorouracil (Hoshi etc., J.Pharmacobio-Dun.3 (9): 478-81,1980; Maehara etc., " chemotherapy " be (Basel) 34 (6) (Chemotherapy): 484-9,1988), B-3839 (Prajda etc., " in the body " (In Vivo) 2 (2): 151-4,1988), (Anai etc. " oncology " (Oncology) 45 (3): 144-7 for uracil-1-(2-tetrahydrofuran base)-5-fluorouracil, 1988), 1-(2 '-deoxidation-2 '-fluoro-beta-D-arabinofuranosyl adenin base)-5-fluorouracil (Suzuko etc., " molecular pharmacology " (Mol.Pharmacol.) 31 (3): 301-6,1987), doxifluridine (Matuura etc., Oyo Yakuri 29 (5): 803-31,1985), 5 '-'-Deoxy-5-fluorouridine (Bollag ﹠amp; Hartmann; " European cancer magazine " (Eur.J.Cancer) 16 (4): 427-32; 1980), 1-acetyl group-3-O-toluyl groups-5-fluorouracil (Okada; Hiroshhima J.Med.Sci.28 (1): 49-66,1979), 5-fluorouracil-m-formoxyl benzene sulfonate (JP55059173), N '-(2-furan alkyls)-5-fluorouracil (JP 53149985) and 1-(2-tetrahydrofuran base)-5-fluorouracil (JP 52089680).

Think that these chemical compounds play therapeutic agent by the antimetabolite as pyrimidine.

C. Antifol

In one aspect of the method, therapeutic agent is an antifol, such as methotrexate or derivatives thereof or analog, comprises edatrexate, trimetrexate, Raltitrexed, piritrexim, 9,10-dimethylpteroylglutamic acid, Tomudex and Pteropterin.The methotrexate analog has following general structure:

Symbol R group can be selected from organic group, and particularly United States Patent (USP) 5,166, and 149 and 5,382, those groups described in 582.For example, R ₁Can be N, R ₂Can be N or C (CH ₃), R ₃And R ₃' can be H or alkyl, for example CH ₃, R ₄Can be singly-bound or NR, wherein R is H or alkyl.R _5,6,8Can be H, OCH ₃Or they optional are halogen or hydrogen group.R ₇Side chain for following general structure:

Wherein with regard to methotrexate, n=1, with regard to Pteropterin, n=3.Carboxyl on the side chain can esterified or salify, such as Zn ²⁺Salt.R ₉And R ₁₀Can be NH ₂Maybe can replace for alkyl.Typical folic acid antagonist immunomodulator compounds has following structure:

Tomudex

Other representative examples include 6-S-amino-mercaptopurine acyloxymethyl derivative (Harada Et al, "chemicals Briefing" (Chem.Pharm.Bull,) 43 (10) :793-6, 1995), 6 - mercapto purine Purine (6-MP) (Kashida et al, "Presentation biopharmaceuticals" (Biol.Pharm.Bull.) 18 (11) :1492-7, 1995), 7,8 - polymethylene-imidazo 3,2 - diaza-phospha-nonyl Rings (diazaphosphorines) (Nilov, etc., Mendeleev Commun.2: 67,1995), azathioprine (Chifotides other "inorganic Journal of Biological Chemistry "(J.Inorg.Biochem.) 56 (4) :249-64, 1994), methyl-D-gluco Glucosidase mercaptopurine derivatives (Da Silva et al, "European Journal of Medicinal Chemistry" (Eur.J, Med. Chem.) 29 (2) :149-52, 1994) and s-alkynyl mercaptopurine derivatives (Ratsino etc., Khim.-Farm. Zh.15 (8) :65-7, 1981), containing the indoline ring and a modified ornithine or glutamic acid methotrexate Methotrexate derivatives (Matsuoka and other "chemical drugs Briefing" (Chem.Pharm.Bull.) 45 (7): 1146-1150,1997), containing an alkyl-substituted benzene derivatives, methotrexate C (Matsuoka, etc. "Chemicals Briefing" (Chem.Pharm.Bull.) 44 (12) :2287-2293, 1996), comprising The benzoxazine or benzothiazine derivatives portion methotrexate (Matsuoka other "Journal of Medicinal Chemistry" (J.Med.Chem.) 40 (1) :105-111, 1997), 10 - deaza analogs aminopterin (DeGraw Other "Journal of Medicinal Chemistry" (J.Med.Chem.) 40 (3) :370-376, 1997), 5 - amino butterfly deaza Methotrexate and 5,10 - double-deaza aminopterin methotrexate analogues (Piper and other "Journal of Medicinal Chemistry" (J. Med.Chem.) 40 (3) :377-384, 1997), containing a portion of the indoline derivatives of methotrexate (Matsuoka et al, "chemical drugs Briefing" (Chem.Ph-m.Bull.) 44 (7) :1332-1337, 1996), lipophilic methotrexate amide derivative (Pignatello and other "drugs and biologic drug technology world World Conference "(World Meet.Pharm., Biopharm.Pharm.Technol.) 563-4,1995), Containing L-threo - (2S, 4S) -4 - fluoro-glutamic acid and DL-3, 3 - difluoro-glutamic acid analogs methotrexate (Hart and other "Journal of Medicinal Chemistry" (J.Med. Chem.) 39 (1) :56-65, 1996), methotrexate Tetrahydro-quinazolinyl analogues (Gangjee, et al, "Journal of Heterocyclic Chemistry" (J.Heterocycl.Chem.) 32 (1) :243-8, 1995), N-(α-amino acid) methotrexate derivatives (Cheung other "pteridine" (Pteridines) 3 (1-2) :101-2, 1992), biotin methotrexate derivatives (Fan and other "pteridine Class "(Pteridines) 3 (1-2) :131-2, 1992), D-glutamic acid or D-erythrou, threo -4 - fluoro- Glutamic acid methotrexate analogues (McGuire and other "Biochemistry and Pharmacology" (Biochem. Pharmacol.) 42 (12) :2400-3, 1991), β, γ-methylene methotrexate analogues (Rosowsky Et al, "pteridine" (Pteridines) 2 (3) :133-9, 1991), 10 - deaza aminopterin (10-EDAM) Analogues (Braakhuis et al, "pteridine Biochemistry - pteridine derivative of folic International Symposium Journal "(Chem.Biol.Pteridines, Proc.Int.Symp.Pteridines Follic Acid Deriv.), 1027-30,1989), γ-tetrazole methotrexate analogues (Kalman and other "pteridine Biochemistry - Butterfly International Symposium pyridine class of folic acid derivatives "(Chem.Biol.Pteridines, Proc.Int.Symp. Pteridines Folic Acid Deviv) ,1154-7, 1989), N-(L-α-amino acid) derivative methotrexate Biology (Cheung et al, "heterocyclic" (Heterocycles) 28 (2) :751-8, 1989), aminopterin of Meta-and ortho-isomers (Rosowsky et al, "Journal of Medicinal Chemistry" (J.Med.Chem.) 32 (12): 2582,1989), hydroxymethyl methotrexate (DE 267495), γ-fluoro methotrexate (McGuire et al, "Cancer Diseases "(Cancer Res.) 49 (16) :4517-25, 1989), poly-glutamyl methotrexate derivatives Materials (Kumar and other "Cancer Research" (Cancer Res.) 46 (10) :5020-3, 1986), KAI - diphosphonic Methotrexate ester analogues (WO 88/06158), α-and γ-substituted analogs methotrexate (Tsushima other "Tetrahedron" (Tetrahedron) 44 (17) :5375-87, 1988), 5 - methyl-5 - Deaza methotrexate analogues (4,725,687), N δ-acyl-Nα-(4 - amino-4 - deoxy folic Yl)-L-ornithine derivative (Rosowsky other "Journal of Medicinal Chemistry" (J.Med.Chem.) 31 (7): 1332-7,1988) 8 - deaza methotrexate analogues (Kuehl and other "Cancer Research" (Cancer Res.) 48 (6) :1481-8, 1988), acivicin methotrexate analogue (Rosowsky other "drugs Journal of Chemistry "(j.Med.Chem.) 30 (8) :1463-9, 1987), methotrexate, cisplatin derivative polymer Substance (Carraher other "Polymer Science and Technology" (Polym.Sci.Technol.) (Plenum), 35 (Adv. Biomed.Polym.) :311-24, 1987), methotrexate-γ-dimyristoyl phosphatidyl ethanolamine (Kinsky et al, "Journal of Biochemistry and Biophysics" (Biochim.Biophys.Acta) 917 (2) :211-18, 1987), methotrexate polyglutamate analogues (Rosowsky, etc., Chem. Biol.Pteridines, Pteridines Folic Acid Deriv., Proc.Int.Symp.Pteridines Folic Acid Deriv.: Chem., Biol.Clin.Aspects :985-8, 1986), poly-γ-glutamyl methotrexate Purine derivatives (Kisliuk other Chem.Biol.Pteridines, Pteridines Folic Acid Deriv., Proc.Int.Symp.Pteridines Folic Acid Deriv.: Chem., Biol.Clin.Aspects: 989-92,1986), deoxy-uridine monophosphate methotrexate derivatives (Webber, etc., Chem.Biol. Pteridines, Pteridines Folic Acid Deriv., Proc.Int.Symp.Pteridines Folic Acid Deriv.: Chem., Biol.Clin.Aspects :659-62, 1986), iodoacetyl lysine methotrexate Purine analogs (Delcamp, etc., Chem.Biol.Pteridines, Pteridines Folic Acid Deriv., Proc.Int.Symp.Pteridines Folic Acid Deriv.: Chem., Biol.Clin.Aspects :: 807-9,1986) containing 2ω-diamino-alkanoic acid (alkanoid acid) analogues Methotrexate (McGuire and other "Biochemistry and Pharmacology" (Biochem.Pharmacol.) 35 (15) :2607-13, 1986), methotrexate polyglutamate analogues (Kamen & Winick, "Methods in Enzymology" (Methods Enzymol.) 122 (Vitam.Coenzymes, Pt.G) :339-46, 1986), 5 - methyl-5 - Deaza analogs (Piper and other "Journal of Medicinal Chemistry" (J.Med.Chem.) 29 (6) :1080-7, 1986), quinazoline methotrexate analogue (Mastropaolo etc., J.Med.Chem.29 (1) :155-8, 1986), pyrazine methotrexate analogue (Lever & Vestal, "Journal of Heterocyclic Chemistry" (J.Keterocycl. Chem.) 22 (1) :5-6, 1985), cysteic acid and high-cysteic acid analogs methotrexate (4,490,529), γ-tert-butyl esters of methotrexate (Rosowsky other "Journal of Medicinal Chemistry" (F, Med. Chem.) 28 (5) :660-7, 1985), fluorinated methotrexate analogues (Tsushima et al, "heterocycle" (Heterocycles) 23 (1) :45-9, 1985), folate methotrexate analogues (Trombe, "fine Journal of bacteria "(J.Bacteriol.) 160 (3) :849-53, 1984), phosphono acid analogues (Sturtz & Guillamot, "European Journal of Medicinal Chemistry - chemotherapy" (Eur.J.Med.Chem. - Chim. Ther.) 19 (3) :267-73, 1984), poly (L-lysine) methotrexate conjugates (Rosowsky other "drugs Journal of chemical "(J, Med.Chem.) 27 (7) :888-93, 1984), and tri-lysine methyl dilysine Aminopterin derivative (Forsch & Rosowsky, "Journal of Organic Chemistry" (J.Org.Chem.) 49 (7) :1305-9, 1984), 7 - hydroxy methotrexate (Fabre other "Cancer Research" (Cancer Res.) 43 (10) :4648-52, 1983), poly-γ-glutamyl methotrexate analogues (Piper & Montgomery, "Advances in Experimental Biology Drugs" (Adv.Exp.Med.Biol.,) 163 (Folyl Antifolyl Polyglutamates) :95-100, 1983), 3 ', 5'-dichloro-methotrexate (Rosowsky & Yu, "medicine Journal of chemical "(J.Med.Chem.) 26 (10) :1448-52, 1983), diazo ketone and chloromethyl ketone Methotrexate analogues (Gangjee other "Journal of Pharmaceutical Sciences" (J.Pharm.Sci.) 71 (6) :717-19, 1982) 10 - propargyl aminopterin and alkyl methotrexate homologs (Piper and other "Journal of Medicinal Chemistry" (J.Med. Chem.) 25 (7) :877-80, 1982), lectin derivatives of methotrexate (Lin so JNCI 66 (3) :523-8, 1981), methotrexate polyglutamate derivatives (Galivan, "Molecular Pharmacology" (Mol.Pharmacol.) 17 (1) :105-10, 1980), methotrexate halogenated derivatives (Fox, JNCI 58 (4): J955-8, 1977), 8 - alkyl -7,8 - dihydro analogues (Chaykovsky et al, "Pharmaceutical Chemistry Journal "(J.Med.Chem.) 20 (10): J1323-7, 1977), 7 - methyl methotrexate derivatives and II Chlorine methotrexate (Rosowsky & Chen, "Journal of Medicinal Chemistry" (J.Med. Chem.) 17 (12): J1308-11, 1974), lipophilic methotrexate derivatives and 3 ', 5'-dichloro-methotrexate (Rosowsky, "Journal of Medicinal Chemistry" (L.Med. Chem.) 16 (10): J1190-3, 1973), nitrogen Miscellaneous methotrexate analogues (Montgomery and other "New York Academy Yearbook" (Ann.NYAcad. Sci.) 186: J227-34, 1971), MX068 ("Japan Drugs" (Pharma Japan), 1658: 18,1999) and cysteic acid and high-cysteic acid methotrexate analogues (EPA 0142220); ...

Think that these chemical compounds play the antimetabolite of folic acid.

D. Podophyllotoxin

In one aspect of the method, therapeutic agent is podophyllotoxin or derivatives thereof or analog.Such typical compound is etoposide or teniposide, and they have following structure:

The representational example of other of podophyllotoxin comprises Cu (II)-VP-16 (etoposide) complex, and (Tawa etc. " bioorganic pesticide thing chemistry " (Bioorg.Med.Chem.) 6 (7): 1003-1008,1998), etoposide analog (the Ji etc. that contain pyrroles's amidino, " bioorganic chemistry communication " (Bioorg.Med.Chem.Lett.) 7 (5): 607-612,1997), 4 beta-amino etoposide analog (Hu, University of North Carolina Dissertation, 1992), (Zhou etc. " pharmaceutical chemistry magazine " (J.Med.Chem.) 37 (2): 287-92 for the fragrant amino etoposide analog of gamma lactone ring-modification, 1994), N-glucityl etoposide analog (Allevi etc., " tetrahedron communication " (Tetrahedron Lett.) 34 (45): 7313-16,1993), etoposide A-ring analogues (Kadow etc., " bioorganic pesticide thing chemistry communication " (Bioorg.Med.Chem.Lett.) 2 (1): 17-22,1992), 4 '-dehydroxylation-4 '-methyl etoposide (Saulnier etc., " bioorganic pesticide thing chemistry communication " (Bioorg.Med.Chem.Lett.) 2 (10): 1213-18,1992), (Sinha etc. " European cancer magazine " (Eur.J.Cancer) 26 (5): 590-3 for pendular ring (pendulum ring) etoposide analog, 1990) and E-ring deoxidation etoposide analog (Saulnier etc. " pharmaceutical chemistry magazine " (J.Med.Chem.) 32 (7): 1418-20,1989).

Think that these chemical compounds play topoisomerase II inhibitor and/or dna cleavage agent.

(E). Camptothecine

In one aspect of the method, therapeutic agent is camptothecine or its analog or derivant.Camptothecine has following general structure.

In this structure, X typically is O, but can be other group, for example, and the NH on the 21-lactam derivatives in the situation.R ₁Typically be H or OH, but can be other group, for example C of terminal hydroxylization _1-3Alkane.R ₂Typically be H or contain amino group, such as (CH ₃) ₂NHCH ₂, but can be other group, for example NO ₂, NH ₂, halogen (for example United States Patent (USP) 5,552,156 in disclosed) or contain the short alkane of these groups.R ₃Typically be H or short alkyl, such as C ₂H ₅R ₄Typically be H, but can be other group, for example have R ₁Methylene-dioxy.

Typical Comptothecin compounds comprises hycamtin, irinotecan (CPT-11), 9-aminocamptothecin, 21-lactams-20 (S)-camptothecine, 10,11-methylene-dioxy camptothecine, SN-38,9-nitrocamptothecin, 10-hydroxycamptothecine.Exemplary compounds has following structure:

R ₁ R ₂ R ₃

Camptothecine H H H

Hycamtin OH (CH ₃) ₂NHCH ₂H

SN-38 OH H C ₂H ₅

X: with regard to most of analog, be O, with regard to the 21-lactam analogs, be NH

Camptothecine has 5 rings shown in this article.The ring that is labeled as E must be complete (lactone but not carboxylate form) so that maximum activity and minimum toxicity are arranged.

Think that camptothecine plays topoisomerase I inhibitor and/or dna cleavage agent.

(F). The hydroxyl ureas

Therapeutic agent of the present invention can be hydroxyurea.The hydroxyl ureas has following general structure:

Suitable hydroxyl ureas for example is disclosed in United States Patent (USP) 6,080, in 874, and R wherein ₁For:

And R ₂For containing the alkyl of 1-4 carbon, and R ₃For one of H, acyl group, methyl, ethyl and composition thereof, such as methyl ether.

Other suitable hydroxyl ureas for example is disclosed in United States Patent (USP) 5,665,768, in, R wherein ₁Be cycloalkenyl, for example N-[3-[5-(4-fluorobenzene sulfenyl)-furyl]-2-cyclopentenes-1-yl] the N-hydroxyurea; R ₂For H or contain the alkyl and the R of 1-4 carbon ₃Be H; X is H or cation.

Other suitable hydroxyl ureas is disclosed in, and for example United States Patent (USP) 4,299, in 778, and R wherein ₁Be the phenyl that is replaced by one or more fluorine atoms; R ₂Be cyclopropyl; And R ₃With X be H.

Other suitable hydroxyl ureas is disclosed in, and for example United States Patent (USP) 5,066, in 658, and R wherein ₂And R ₃Form with adjacent nitrogen:

Wherein m is 1 or 2, and n is that 0-2 and Y are alkyl.

In one aspect, described hydroxyurea has following structure:

Hydroxyurea

Think that these chemical compounds work by inhibition DNA is synthetic.

(G) Platinum complexes

In one aspect of the method, therapeutic agent is a platinum compounds.In general, suitable platinum complexes can be the complex of Pt (II) or Pt (IV), and contains following this basic structure:

Wherein X and Y are the anion leaving group, such as sulfate, phosphate, carboxylate and halogen; R ₁And R ₂For can further arbitrarily substituted alkyl, amine, aminoalkyl, and be essentially the group of inertia or bridging.With regard to Pt (II) complex, Z ₁And Z ₂All do not exist.With regard to Pt (IV), Z ₁And Z ₂Can be anionic group, such as halogen, hydroxyl, carboxylate, ester, sulfate or phosphate.For example, referring to United States Patent (USP) 4,588,831 and 4,250,189.

Suitable platinum complexes can contain a plurality of Pt atoms.For example, referring to United States Patent (USP) 5,409,915 and 5,380,897.For example two platinum of following type and three platinum complexes:

Typical platinum compounds is cisplatin, carboplatin, oxaliplatin and the miboplatin with following structure:

The cisplatin carboplatin

The oxaliplatin miboplatin

Other representational platinum compounds comprises (CPA) ₂Pt[DOLYM] and (DACH) Pt[DOLYM] cisplatin (Choi etc. " drug research archives " (Arch.Pharmacal Res.) 22 (2): 151-156,1999), cis-[PtCl ₂(4,7-H-5-methyl-7-oxo) 1,2,4-[triazol [1,5-a] pyrimidine] ₂] (Navarro etc. " pharmaceutical chemistry magazine " (J.Med. Chem.) 41 (3): 332-338,1998), [Pt (cis-1,4-DACH) (trans-Cl ₂) (CBDCA)] (Shamsuddin etc. " inorganic chemistry " (Inorg.Chem.) 36 (25): 5969-5971 for the 1/2MeOH cisplatin, 1997), 4-Pvridoxic Acid ester diamidogen hydroxyl platinum (pyridoxate diammine hydroxy platinum) (Tokunaga etc. " pharmaceutical science " (Pharm.Sci.) 3 (7): 353-356,1997), Pt (II) ... Pt (II) (Pt ₂[NHCHN (C (CH ₂) (CH ₃))] ₄) (Navarro etc. " inorganic chemistry " (Inorg.Chem.) 35 (26): 7829-7835,1996), 254-S cisplatin analog (Koga etc. " neurological's research " (Neurol.Res.) 18 (3): 244-247,1996), contain cisplatin analog (the Koeckerbauer ﹠amp of o-phenylenediamine part; Bednarski, " inorganic biochemistry magazine " (J.Inorg.Biochem.) 62 (4): 281-298,1996), trans, cis-[Pt (OAc) ₂I ₂(alkene)] (Kratochwil etc. " pharmaceutical chemistry magazine " (J.Med.Chem.) 39 (13): 2499-2507,1996), contain estrogen 1, (Bednarski " inorganic biochemistry magazine " (J.Inorg.Biochem.) 62 (1): 75 for the cisplatin analog of 2-diaryl ethylenediamine part (aminoacid and the glutathion that have sulfur-bearing), 1996), cis-1,4-diamino-cyclohexane cisplatin analog (Shamsuddin etc. " inorganic biochemistry magazine " (J.Inorg.Biochem.) 61 (4): 291-301,1996), cis-[Pt (NH ₃) (4-amino TEMP-O) { d (GpG) }] and 5 ' orientation isomer (Dunham ﹠amp; Lippard " Journal of the American Chemical Society " (J.Am.Chem.Soc.) 117 (43): 10702-12,1995), contain cisplatin analog (the Koeckerbauer ﹠amp of chelating diamidogen; Bednarski, " pharmaceutical science magazine " (J.Pharm.Sci.) 84 (7): 819-23,1995), contain 1, the cisplatin analog of 2-diaryl ethylenediamine part (Otto etc. " cancer research and Journal of Clinical Oncology " (J.CancerRes.Clin.Oncol.121 (1): 31-8,1995), (ethylenediamine) platinum (II) complex (Pasini etc., J.Chem.Soc., Daalton Trans.4:579-85,1995), (Yang etc. " international oncology's magazine " (Int.J.Oncol.) 5 (3): 597-602 for CI-973 cisplatin analog, 1994), cis-diaminedichloroplatinum (II) and analog cis-1 thereof, 1-Cyclobutylcarboxylic acid (2R)-2-methyl isophthalic acid, 4-butanediamine platinum (II) and cis-diamidogen (glycolic acid) platinum (Claycamp ﹠amp; Zimbrick " inorganic biochemistry magazine " (J.Inorg.Biochem.) 26 (4): 257-67,1986; Fan etc. " cancer research " (Cancer Res.) 48 (11): 3135-9,1988; Heiger-Bernays etc., " biochemistry " (Biochemistry) 29 (36): 8461-6,1990; Kikkawa etc., " clinical experiment cancer research magazine " (J.Exp.Clin.CancerRes.) 12 (4): 233-40,1993; Murray etc., " biochemistry " (Biochemistry) 31 (47): 11812-17,1992; Takahashi etc.; " cancer chemotherapy pharmacology " (Cancer Chemother.Pharmacol.) 33 (1): 31-5; 1993); (Yoshida etc. " biochemistry pharmacology " (Biochem.Pharmacol.) 48 (4): 793-9 for cis-amine-cyclohexylamine-dichloro platinum (II); 1994); together with-bisphosphonates cisplatin analog (FR 2683529); (meso-1; 2-two (2; 6-two chloro-4-hydroxy phenyls) dichloro platinum (II) (Bednarski etc. ethylenediamine); " pharmaceutical chemistry magazine " (J.Med.Chem.) 35 (23): 4479-85; 1992); (Hartwig etc. " Journal of the American Chemical Society " (J.Am.Chem.Soc.) 114 (21): 8292-3 to contain the cisplatin analog of (tethered) dansyl base of constraint; 1992); platinum (II) polyamines class (Siegmann etc.; Inorg.Met.-Containing Polym.Mater; (Proc.Am.Chem.Soc.Int.Symp.); 335-61; 1990); dichloro (ethylenediamine) platinum (the II) (Eastman of cis-(3H); " biochemistry yearbook " (Anal.Biochem.) 197 (2): 311-15,1991); trans-diaminedichloroplatinum (II) and cis-(Pt (NH ₃) ₂(N ₃-cytosine) (Bellon ﹠amp Cl); Lippard, " biophysics and chemistry " be 35 (2-3): 179-88 (Biophys.Chem.), 1990), 3H-cis-1,2-diamino-cyclohexane dichloro platinum (II) and 3H-cis-1,2-diamino-cyclohexane-malonic acid platinum (II) (Oswald etc., " chemistry, pathology and pharmaceutical research communication " (Res.Commun.Chem.Pathol.Pharmacol.) 64 (1): 41-58,1989), diamino monocarboxylic acid platinum (EPA 296321), contain trans-(D, 1)-1, platinum analogs (the Wyrick ﹠amp of 2-diamino-cyclohexane carrier ligand; Chaney, " labelled compound and with radiopharmaceutical magazine " (J.Labelled Compd.Radiopharm.) 25 (4): 349-57,1988), amino alkylamino anthraquinone-deutero-cisplatin analog (Kitov etc., " European pharmaceutical chemistry magazine " (Eur.J.Med.Chem.) 23 (4): 381-3,1988), spiroplatin, carboplatin, iproplatin and JM40 platinum analogs (Schroyen etc. " European clinical cancer oncology magazine " (Eur.J.Cancer Clin.Oncol.) 24 (8): 1309-12,1988), the cis-platinum derivative (Orbell etc. " Chinese Journal of Inorganic Chemistry " (Inorg.Chim.Acta) 152 (2): 125-34,1988) that contains the bidentate tertiary diamine, platinum (II), platinum (IV) (Liu ﹠amp; Wang, " Shandong Medical University's journal " (Shandong Yike Daxue Xuebao) 24 (1): 35-41,1986), cis-diamidogen (1, the 1-cyclobutane dicarboxylic acid-) platinum (II) (carboplatin, JM8) and (JM40) (Begg etc. of ethylenediamine-malonic acid platinum (II), " tumor radiotherapy " (Radiother.Oncol.) 9 (2): 157-65,1987), JM8 and JM9 cisplatin analog (Harstrick etc., Int.J.Androl.10 (1); 139-45,1987), (NPr4) 2 ((PtCL4). cis-(PtC12-(NH2Me) 2)) (Brammer etc., " chemical association and chemical communication magazine " (J.Chem.Soc., Chem.Commun.) 6:443-5,1987), aliphatic tricarboxylic acids platinum complexes (EPA 185225) and cis-dichloro (aminoacid) (tert-butylamine) platinum (II) complex (Pasini﹠amp; Bersanetti, " Chinese Journal of Inorganic Chemistry " (Inorg.Chim.Acta) 107 (4): 259-67,1985).Think that these chemical compounds by working in conjunction with DNA, promptly play the alkylating agent of DNA.

The dosage of anti-infective

The present invention be used for preventing or suppress to infect depend on various factors from present composition administered agents dosage, comprise the type of preparation, the position of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in this area.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.With from generally be used for single anti-infective whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, in can be according to the time of immersing the tissue adjacent with described device definite time bar, described anti-infective discharges from described polymer composition with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to the administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Different polymer compositions discharges described anti-infective with different speed, above-mentioned administration parameter should with the rate of release coupling of medicine from compositions, make the least concentration of described activating agent on tissue surface maintained about 10 ^-8M-10 ^-7M; Or about 10 ^-7M-10 ^-6M; About 10 ^-6M-10 ^-5M; Or about 10 ^-5M-10 ^-4M.

(a) Anthracyclines.The anthracycline doxorubicin is used as example, no matter be as the polymer coating coating, mix the component that constitutes implant polymer, or do not use the carrier polymer coating, the accumulated dose that is coated on the doxorubicin on described device or the implant should not surpass 25mg (in the scope of 0.1 μ g-25mg).In particularly preferred embodiments, the coated drug total amount should be in 1 μ g-5mg scope.Dosage on the per unit area (medication amount of the function of the surface area of the implant part that promptly is coated with and/or mixes as medicine) should be at 0.01 μ g-100 μ g/mm ²The scope of surface area.In particularly preferred embodiments, should be with 0.1 μ g/mm ²-10 μ g/mm ²Dosage doxorubicin is coated on implant surface.Because different polymer and non-polymer coatings discharges doxorubicin with different rates, thus above-mentioned administration parameter should be used in combination with the rate of release of medicine from implant surface, so that keep 10 on described surface ^-7-10 ^-4The doxorubicin least concentration of M.Must guarantee that surface drug concentration surpasses the known concentration of multiple bacterioid and the lethal doxorubicin of fungus that makes and (promptly surpasses 10 ^-4M; But, with regard in some embodiment, lower concentration is just enough).In preferred embodiments, doxorubicin discharges so that anti-infection activity is kept several hours time limits to some months from implant surface.In particularly preferred embodiments, medicine discharges with valid density in month time limit in 1 week-6.Obviously be easy to find out that based on discussion provided herein analog and derivant (as mentioned above) with the active doxorubicin of identity function can be used for purpose of the present invention; The relative potency of comparing with parent compound according to analog or derivant is adjusted above-mentioned administration parameter (for example give the chemical compound that effect doubles doxorubicin with half of above-mentioned parameter, to give effect be half chemical compound etc. of doxorubicin to double above-mentioned parameter) then.

With mitoxantrone another example as anthracycline, no matter be as the polymer coating coating, mix the polymer that constitutes described device or implant, or do not use the carrier polymer coating, the accumulated dose of the mitoxantrone of coating should not surpass 5mg (in the scope of 0.01 μ g-5mg).In particularly preferred embodiments, the coated drug total amount should be in 0.1 μ g-1mg scope.Dosage on the per unit area (medication amount of the function of the surface area of the implant part that promptly is coated with and/or mixes as medicine) should be at 0.0 μ g-20 μ g/mm ²The scope of surface area.In particularly preferred embodiments, should be with 0.05 μ g/mm ²-3 μ g/mm ²Dosage mitoxantrone is coated on implant surface.When different polymer and non-polymer coating discharge mitoxantrone with different rates, above-mentioned administration parameter should be used in combination with the rate of release of medicine from implant surface, so that keep 10 ^-5-10 ^-6The mitoxantrone least concentration of M.Must guarantee that the drug level on the implant surface surpasses known multiple bacterioid and the lethal mitoxantrone concentration of fungus of making (promptly above 10 ^-5M; But, with regard in some embodiment, lower concentration is just enough).In preferred embodiments, mitoxantrone discharges so that anti-infection activity is kept several hours time limits to some months from implant surface.In particularly preferred embodiments, medicine discharges with valid density in month time limit in 1 week-6.Obviously be easy to find out that based on discussion provided herein analog and derivant (as mentioned above) with the active mitoxantrone of identity function can be used for purpose of the present invention; The relative potency of comparing with parent compound according to analog or derivant is adjusted above-mentioned administration parameter (for example give the chemical compound that effect doubles mitoxantrone with half of above-mentioned parameter, to give effect be half chemical compound etc. of mitoxantrone to double above-mentioned parameter) then.

(b) The fluorine pyrimidine. the 5-fluorouracil in the fluorine pyrimidine is used as example, no matter be as the polymer coating coating, mix the component that constitutes described device or implant polymer, or do not use the carrier polymer coating, the accumulated dose of the 5-fluorouracil of coating should not surpass 250mg (in the scope of 1.0 μ g-250mg).In particularly preferred embodiments, the coated drug total amount should be in 10 μ g-25mg scope.The dosage of per unit area (medication amount of the function of the surface area of the implant part that promptly is coated with and/or mixes as medicine) should be at 0.1 μ g-1mg/mm ²The scope of surface area.In particularly preferred embodiments, should be with 1.0 μ g/mm ²-50 μ g/mm ²Dosage 5-fluorouracil is coated on implant surface.Because different polymer and non-polymer coating discharge 5-fluorouracil with different rates, thus above-mentioned administration parameter should be used in combination with the rate of release of medicine from implant surface, so that keep 10 ^-4-10 ^-7The least concentration of the 5-fluorouracil of M.Must guarantee that lip-deep drug level surpasses known multiple bacterioid and the lethal 5-fluorouracil concentration of fungus of making and (promptly surpasses 10 ^-4M; But, with regard in some embodiment, lower concentration is just enough).In preferred embodiments, 5-fluorouracil discharges so that anti-infection activity is kept several hours time limits to some months from implant surface.In particularly preferred embodiments, medicine discharges with valid density in month time limit in 1 week-6.Obviously be easy to find out that based on discussion provided herein analog and derivant (as mentioned above) with the active 5-fluorouracil of identity function can be used for purpose of the present invention; The relative potency of comparing with parent compound according to analog or derivant is adjusted above-mentioned administration parameter (for example give the chemical compound that effect doubles 5-fluorouracil with half of above-mentioned parameter, to give effect be half chemical compound etc. of 5-fluorouracil to double above-mentioned parameter) then.

(c) Podophyllotoxin.The podophyllotoxin etoposide is used as example, no matter be as the polymer coating coating, mix the polymer that constitutes described device or heart implant, or do not use the carrier polymer coating, the accumulated dose of the etoposide of coating should not surpass 25mg (in the scope of 0.1 μ g-25mg).In particularly preferred embodiments, the coated drug total amount should be in 1 μ g-5mg scope.Dosage on the per unit area (medication amount of the function of the surface area of the implant part that promptly is coated with and/or mixes as medicine) should be at 0.01 μ g-100 μ g/mm ²The scope of surface area.In particularly preferred embodiments, should be with 0.1 μ g/mm ²-10 μ g/mm ²Dosage etoposide is coated on implant surface.Because different polymer and non-polymer coatings discharges etoposide with different rates, thus above-mentioned administration parameter should be used in combination with the rate of release of medicine from implant surface, so that keep 10 ^-5-10 ^-6The etoposide least concentration of M.Must guarantee that surface drug concentration surpasses known multiple bacterioid and the lethal etoposide concentration of fungus of making and (promptly surpasses 10 ^-5M; But, with regard in some embodiment, lower concentration is just enough).In preferred embodiments, etoposide discharges so that anti-infection activity is kept several hours time limits to some months from implant surface.In particularly preferred embodiments, medicine discharges with valid density in month time limit in 1 week-6.Obviously be easy to find out that based on discussion provided herein analog and derivant (as mentioned above) with the active etoposide of identity function can be used for purpose of the present invention; The relative potency of comparing with parent compound according to analog or derivant is adjusted above-mentioned administration parameter (for example give the chemical compound that effect doubles etoposide with half of above-mentioned parameter, to give effect be half chemical compound etc. of etoposide to double above-mentioned parameter) then.

Obviously should be easy to find out that based on discussion provided herein the combination of anthracyclines (for example doxorubicin or mitoxantrone), fluorine miazines (for example 5-fluorouracil), antifol (for example methotrexate) and/or podophyllotoxin (for example etoposide) can be used to improve the antibacterial activity of compositions.

Obviously should be easy to find out that based on discussion provided herein the combination of anthracyclines (for example doxorubicin or mitoxantrone), fluorine miazines (for example 5-fluorouracil), antifol (for example methotrexate) and/or podophyllotoxin (for example etoposide) can be used to improve the antibacterial activity of compositions.

Conjoint therapy

Except that mixing above-mentioned therapeutic agent (being anti-infective or fibre modification inhibitor), one or more pharmaceutically active agents can also be mixed compositions of the present invention to improve or to improve effect.In one aspect, described compositions may further include in the therapentic part or its around pathological process play inhibiting chemical compound.The representational example of other therapeutic activity agent comprises, as an example, but be not limited to: antithrombotic agent, antiproliferative, anti-inflammatory agent, tumor medicine, enzyme, receptor antagonist or agonist, hormone, antibiotic, antibacterial, antibody, cytokine inhibitor, IMPDH (inosine monophosphate dehydrogenase) inhibitor, tyrosine kinase inhibitor, MMP inhibitor, p38 map kinase inhibitor, immunosuppressant, programmed cell death antagonist, aspartic acid specific cysteine proteinase inhibitors and jnk inhibitor.

Described polymer composition may further include antithrombotic agent and/or anti-platelet agents and/or thrombolytic agent, and they can reduce the probability that thrombosis takes place separately when implanting medical implant.The representational example of antithrombotic agent and/or anti-platelet agents and/or thrombolytic agent comprises: heparin; Heparin fragment; The organic salt of heparin; Heparin complex (for example benzalkonium heparinate, three (dodecyl) ammonium heparinate); Glucosan; Sulfonated carbohydrate is such as dextran sulfate, warfarin, coumarin, Hirudoid Cream/gel; Danaparoid; Argatroban chitosan sulfuric ester; Chondroitin sulfate; Danaparoid; Lepirudin; Hirudin; AMP; Adenosine; 2-chlorine adenosine; Aspirin; Phenylbutazone; Indomethacin; Meclofenamate; Hydrochloroquine; Dipyridamole; Iloprost; Streptokinase; The Xa factor inhibitor is such as DX9065a; Magnesium; And tissue plasminogen activator.Other example comprises: plasminogen; The 1ys-plasminogen; α-2-antiplasmin; Urokinase; Aminocaproic acid; Ticlopidine; Clopidogrel; Trapidil (triazolopyrimidine); Naftidrofuryl; Auriritricarboxylic acid; With the glycoprotein iib/iiia inhibitor, such as abciximab, eptifibatide and tirogiban.Other activating agent that can influence solidification rate comprises glycosaminoglycan, danaparoid, 4 hydroxy coumarin, warfarin sodium, dicoumarol, phenprocoumon, indane-1,3-diketone, acenocoumarol, anisindione and rodenticide comprise Bromadiolone, Talon, diphenadione, rozol and pidnone.

Described polymer formulations can for or comprise that hydrophilic polymer gel, itself have antithrombotic and form characteristic.For example, described compositions can be coating form, and it can comprise hydrophilic Biodegradable polymeric, can this compositions be removed from apparatus surface with physics mode within a certain period of time, reduces the adhesion of platelet and apparatus surface thus.The device gel combination can comprise polymer or polymer blend.Representational example comprises the PLURONIC polymer of alginate, chitosan and sulfated chitosan and hyaluronic acid, dextran sulfate, PLURONIC polymer (for example F-127 or F87), chain elongation, various polyester-the polyether block copolymers of isomorphism type (for example AB, ABA or BAB not, wherein A is a polyester, such as PLA, PGA, PLGA, PCL etc.), the example comprises MePEG-PLA, PLA-PEG-PLA etc.).In one embodiment, described antithrombotic formation compositions can comprise the cross-linked gel that is combined to form by the molecule that has two or more terminal electrophilic groups and two or more nucleophilic groups (for example PEG).

Described polymer formulations may further include the activating agent from one of following type compound: anti-inflammatory agent (for example dexamethasone, cortisone, fludrocortisone, prednisone, prednisolone, 6 α-methylprednisolone, triamcinolone, betamethasone and aspirin); The MMP inhibitor (for example: batimistat; Marimistat; Be included in the representational example of the TIMP in the following document: U.S. Patent number 5,665,777; 5,985,911; 6,288,261; 5,952,320; 6,441,189; 6,235,786; 6,294,573; 6,294,539; 6,563,002; 6,071,903; 6,358,980; 5,852,213; 6,124,502; 6,160,132; 6,197,791; 6,172,057; 6,288,086; 6,342,508; 6,228,869; 5,977,408; 5,929,097; 6,498,167; 6,534,491; 6,548,524; 5,962,481; 6,197,795; 6,162,814; 6,441,023; 6,444,704; 6,462,073; 6,162,821; 6,444,639; 6,262,080; 6,486,193; 6,329,550; 6,544,980; 6,352,976; 5,968,795; 5,789,434; 5,932,763; 6,500,847; 5,925,637; 6,225,314; 5,804,581; 5,863,915; 5,859,047; 5,861,428; 5,886,043; 6,288,063; 5,939,583; 6,166,082; 5,874,473; 5,886,022; 5,932,577; 5,854,277; 5,886,024; 6,495,565; 6,642,255; 6,495,548; 6,479,502; 5,696,082; 5,700,838; 6,444,639; 6,262,080; 6,486,193; 6,329,550; 6,544,980; 6,352,976; 5,968,795; 5,789,434; 5,932,763; 6,500,847; 5,925,637; 6,225,314; 5,804,581; 5,863,915; 5,859,047; 5,861,428; 5,886,043; 6,288,063; 5,939,583; 6,166,082; 5,874,473; 5,886,022; 5,932,577; 5,854,277; 5,886,024; 6,495,565; 6,642,255; 6,495,548; 6,479,502; 5,696,082; 5,700,838; 5,861,436; 5,691,382; 5,763,621; 5,866,717; 5,902,791; 5,962,529; 6,017,889; 6,022,873; 6,022,898; 6,103,739; 6,127,427; 6,258,851; 6,310,084; 6,358,987; 5,872,152; 5,917,090; 6,124,329; 6,329,373; 6,344,457; 5,698,706; 5,872,146; 5,853,623; 6,624,144; 6,462,042; 5,981,491; 5,955,435; 6,090,840; 6,114,372; 6,566,384; 5,994,293; 6,063,786; 6,469,020; 6,118,001; 6,187,924; 6,310,088; 5,994,312; 6,180,611; 6,110,896; 6,380,253; 5,455,262; 5,470,834; 6,147,114; 6,333,324; 6,489,324; 6,362,183; 6,372,758; 6,448,250; 6,492,367; 6,380,258; 6,583,299; 5,239,078; 5,892,112; 5,773,438; 5,696,147; 6,066,662; 6,600,057; 5,990,158; 5,731,293; 6,277,876; 6,521,606; 6,168,807; 6,506,414; 6,620,813; 5,684,152; 6,451,791; 6,476,027; 6,013,649; 6,503,892; 6,420,427; 6,300,514; 6,403,644; 6,177,466; 6,569,899; 5,594,006; 6,417,229; 5,861,510; 6,156,798; 6,387,931; 6,350,907; 6,090,852; 6,458,822; 6,509,337; 6,147,061; 6,114,568; 6,118,016; 5,804,593; 5,847,153; 5,859,061; 6,194,451; 6,482,827; 6,638,952; 5,677,282; 6,365,630; 6,130,254; 6,455,569; 6,057,369; 6,576,628; 6, youngster 0,924; 6,472,396; 6,548,667; 5,618,844; 6,495,578; 6,627,411; 5,514,716; 5,256,657; 5,773,428; 6,037,472; 6,579,890; 5,932,595; 6,013,792; 6,420,415; 5,532,265; 5,639,746; 5,672,598; 5,830,915; 6,630,516; 5,324,634; 6,277,061; 6,140,099; 6,455,570; 5,595,885; 6,093,398; 6,379,667; 5,641,636; 5,698,404; 6,448,058; 6,008,220; 6,265,432; 6,169,103; 6,133,304; 6,541,521; 6,624,196; 6,307,089; 6,239,288; 5,756,545; 6,020,366; 6,117,869; 6,294,674; 6,037,361; 6,399,612; 6,495,568; 6,624,177; 5,948,780; 6,620,835; 6,284,513; 5,977,141; 6,153,612; 6,297,247; 6,559,142; 6,555,535; 6,350,885; 5,627,206; 5,665,764; 5,958,972; 6,420,408; 6,492,422; 6,340,709; 6,022,948; 6,274,703; 6,294,694; 6,531,499; 6,465,508; 6,437,177; 6,376,665; 5,268,384; 5,183,900; 5,189,178; 6,511,993; 6,617,354; 6,331,563; 5,962,466; 5,861,427; 5,830,869; With 6,087,359); Cytokine inhibitor (chlorpromazine, Mycophenolic Acid, rapamycin, 1 alpha-hydroxy vitamin D ₃); (representational example is included in the following document IMPDH (inosine monophosphate dehydrogenase) inhibitor (for example Mycophenolic Acid, ribavirin, amino thiadiazoles, thiophenfurin, tiazofurine, viramidine): U.S. Patent number 5,536,747; 5,807,876; 5,932,600; 6,054,472; 6,128,582; 6,344,465; 6,395,763; 6,399,773; 6,420,403; 6,479,628; 6,498,178; 6,514,979; 6,518,291; 6,541,496; 6,596,747; 6,617,323; With 6,624,184, Application No. 2002/0040022A1,2002/0052513A1,2002/0055483A1,2002/0068346A1,2002/0111378A1,2002/0111495A1,2002/0123520A1,2002/0143176A1,2002/0147160A1,2002/0161038A1,2002/0173491A1,2002/0183315A1,2002/0193612A1,2003/0027845A1,2003/0068302A1,2003/0105073A1,2003/0130254A1,2003/0143197A1,2003/0144300A1,2003/0166201A1,2003/0181497A1,2003/0186974A1,2003/0186989A1 and 2003/0195202A1; With PCT application number WO 00/24725A1, WO 00/25780A1, WO 00/26197A1, WO 00/51615A1, WO 00/56331A1, WO00/73288A1, WO 01/00622A1, WO 01/66706A1, WO 01/79246A2, WO01/81340A2, WO 01/85952A2, WO 02/16382A1, WO 02/18369A2, WO02/051814A1, WO 02/057287A2, WO 02/057425A2, WO02/060875A1, WO 02/060896A1, WO 02/060898A1, WO02/068058A2, WO 03/020298A1, WO 03/037349A1, WO03/039548A1, WO 03/045901A2, WO 03/047512A2, WO03/053958A1, WO 03/055447A2, WO 03/059269A2, WO03/063573A2, WO 03/087071A1, WO 99/001545A1, WO 97/40028A1, WO 97/41211A1, WO 98/40381A1 and WO 99/55663A1); (representational example is included in the following document p38 map kinase inhibitor (MAPK) (for example GW-2286, CGP-52411, BIRB-798, SB220025, RO-320-1195, RWJ-67657, RWJ-68354, SCIO-469): U.S. Patent number 6,300,347; 6,316,464; 6,316,466; 6,376,527; 6,444,696; 6,479,507; 6,509,361; 6,579,874 and 6,630,485; With U.S. Patent Application Publication No. 2001/0044538A1,2002/0013354A1,2002/0049220A1,2002/0103245A1,2002/0151491A1,2002/0156114A1,2003/0018051A1,2003/0073832A1,2003/0130257A1,2003/0130273A1,2003/0130319A1,2003/0139388A1,2003/0139462A1,2003/0149031A1,2003/0166647A1 and 2003/0181411A1; With PCT publication number WO 00/63204A2, WO 01/21591A1, WO 01/35959A1, WO 01/74811A2, WO 02/18379A2, WO02/064594A2, WO 02/083622A2, WO 02/094842A2, WO02/096426A1, WO 02/101015A2, WO 02/103000A2, WO03/008413A1, WO 03/016248A2, WO 03/020715A1, WO03/024899A2, WO 03/031431A1, WO 03/040103A1, WO03/053940A1, WO 03/053941A2, WO 03/063799A2, WO03/079986A2, WO 03/080024A2, WO 03/082287A1, WO 97/44467A1, WO 99/01449A1 and WO 99/58523A1); And the immunosuppressant (analog of rapamycin, everolimus, ABT-578, azathioprine, azithromycin, rapamycin, comprise tacrolimus and derivant thereof (for example EP 0184162B1 and United States Patent (USP) 6,258, described in 823 those) and everolimus and derivant thereof (for example United States Patent (USP) 5,665,772).The representational example of other of sirolimus analog and derivant comprises those materials that find in ABT-578 and the following document: PCT publication number WO 97/10502, WO 96/41807, WO 96/35423, WO96/03430, WO 96/00282, WO 95/16691, WO 95/15328, WO95/07468, WO95/04738, WO 95/04060, WO 94/25022, WO 94/21644, WO94/18207, WO 94/10843, WO 94/09010, WO 94/04540, WO 94/02485, WO 94/02137, WO 94/02136, W093/25533, WO 93/18043, WO93/13663, WO 93/11130, WO 93/10122, WO 93/04680, WO 92/14737 and WO 92/05179; With United States Patent (USP) 6,342,507; 5,985,890; 5,604,234; 5,597,715; 5,583,139; 5,563,172; 5,561,228; 5,561,137; 5,541,193; 5,541,189; 5,534,632; 5,527,907; 5,484,799; 5,457,194; 5,457,182; 5,362,735; 5,324,644; 5,318,895; 5,310,903; 5,310,901; 5,258,389; 5,252,732; 5,247,076; 5,225,403; 5,221,625; 5,210,030; 5,208,241; 5,200,411; 5,198,421; 5,147,877; 5,140,018; 5,116,756; 5,109,112; 5,093,338; With 5,091,389.

Other example that can be included in the bioactivator in the present composition comprises: tyrosine kinase inhibitor, such as imantinib, ZK-222584, CGP-52411, CGP-53716, NVP-AAK980-NX, CP-127374, CP-564959, PD-171026, PD-173956, PD-180970, SU-0879 and SKI-606; The MMP inhibitor is such as nimesulide, PKF-241-466, PKF-242-484, CGS-27023A, SAR-943, primomastat, SC-77964, PNU-171829, AG-3433, PNU-142769, SU-5402 and Dexlipotam; The p38 map kinase inhibitor, such as, comprise CGH-2466 and PD-98-59; Immunosuppressant, such as argyrin B, macrolide, ADZ-62-826, CCI-779, tilomisole, amcinonide, FK-778, AVE-1726 and MDL-28842: cytokine inhibitor, such as TNF-484A, PD-172084, CP-293121, CP-353164 and PD-168787; The NFKB inhibitor is such as AVE-0547, AVE-0545 and IPL-576092; The HMGCoA reductase inhibitor is such as Pitavastatin (pravestatin), atorvastatin, fluvastatin, dalvastatin, glenvastatin, Pitavastatin, CP-83101, U-20685; Programmed cell death antagonist (troloxamine, TCH-346 (N-methyl 1-N-propargyl-10-amino methyl-dibenzo (b, f) Evil heptan because of) for example; And aspartic acid specific cysteine proteinase inhibitors (PF-5901 (benzyl alcohol, α-amyl group-3-(2-quinolyl methoxyl group)-) for example; And jnk inhibitor (for example AS-602801).

In one aspect of the method, described compositions may further include antibiotic (for example amoxicillin, trimethoprim-sulfamethoxazole, azithromycin, clarithromycin, amoxycillin with clavulanate potassium, cefprozil, cefuroxime, cefpodoxime or cefdinir).

In certain aspects, will comprise that the polymer composition of fibre modification inhibitor and the internal metabolism that can change activating agent make up with the activating agent that strengthens described fibre modification inhibitor effect.The one class therapeutic agent that can be used to change drug metabolism comprises the activating agent that can suppress by Cytochrome P450 (CYP) oxidation anti-scarring agent.In one embodiment, the compositions that comprises fibre modification inhibitor (for example paclitaxel, rapamycin, everolimus) and CYP inhibitor is provided, can be with itself and any device as herein described, include, but are not limited to stent, graft, sticking patch, valve, coating and film combinations (for example coating).The representational example of CYP inhibitor comprises flavonoid, pyrroles's antifungal agent, macrolide antibiotics, hiv protease inhibitor and antisense scant polymer.The device that comprises the combination of fibre modification inhibitor and CYP inhibitor can be used for the treatment of various proliferative diseasees, and these diseases can cause the unwanted cicatrization of organizing, and comprise neointimal hyperplasia, surgical operation adhesion and tumor growth.

In one aspect of the method, can will comprise that (for example the combination of the polymer composition of anthracyclines (for example doxorubicin or mitoxantrone), fluorine miazines (for example 5-fluorouracil), antifol (for example methotrexate and/or podophyllotoxin (for example etoposide)) and traditional antibiotic and/or antifungal is to improve effect for anti-infective.Can with described anti-infective further with antithrombotic agent and/or anti-platelet agents (heparin for example, dextran sulfate, danaparoid, lepirudin, hirudin, AMP, adenosine, 2-chlorine adenosine, aspirin, Phenylbutazone, indomethacin, Meclofenamate, hydrochloroquine, dipyridamole, iloprost, ticlopidine, clopidogrel, abciximab, eptifibatide, tirofiban, streptokinase and/or tissue plasminogen activator) make up to improve effect.

Although for task of explanation provides above-mentioned therapeutic agent, it should be understood that the present invention is not limited to this.For example, although be specifically related to above-mentioned activating agent, it should be understood that the analog, derivant and the conjugate that the present invention includes this class activating agent.As explanation, the chemically available form commonly used that paclitaxel not only is meant paclitaxel be should understand, but also analog (for example aforesaid taxotere) and paclitaxel conjugate (for example paclitaxel-PEG, paclitaxel-glucosan or paclitaxel-xylose (xylos)) referred to.In addition, just as apparent to those skilled in the art, belong to the scope of a class although can notice activating agent listed above, many in the in fact listed activating agent have multiple biological activity.In addition, can use (promptly with compound mode) simultaneously or send more than one therapeutic agent successively.

H. the compositions and and the production method that comprise therapeutic agent

The invention provides and variously can be used near the fibre modification of the tissue suppression therapy position (for example operative site) and/or the compositions of infection.In different embodiments, discharge the concrete pharmaceutically active agents that is positioned described position or intervention place by part or whole body and suppress fibre modification and/or infection.In other embodiments, discharge the device or the adjacent concrete pharmaceutically active agents of implant that are positioned and have imported the host by part or whole body and suppress fibre modification and/or infection.In certain embodiments, provide in the inhibition implanting device and the compositions of fibre modification or prevent mean/implant original position " narrow " on every side.In other embodiments, provide in inhibition or the prevention implanting device and the infection compositions that infects on every side.

Exist and can be used for therapeutic agent delivery to intervening the optimized big metering method in position.Several in them have hereinafter been described.

1) whole body of therapeutic agent, zone and local delivery

Variously pass whole body, zone and the local delivery that the medicine technology can be used for infection and/or fibrosis therapeutic agent.

For the systemic delivery therapeutic agent, several route of administration may be suitable for providing the whole body contact of therapeutic agent, comprising: (a) intravenous; (b) oral; (c) subcutaneous; (d) intraperitoneal; (e) in the sheath; (f) suction and intranasal; (g) Sublingual or transbuccally; (h) rectum; (i) intravaginal; (j) intra-arterial; (k) intracardiac; (l) transdermal; (m) ophthalmic; (n) intramuscular.Therapeutic agent can be given so that ward off disease development as lasting low dosage therapy, prolong the alleviation of disease or alleviate symptom in the activities diseases.Perhaps, therapeutic agent can be given as the higher dosage in " beating " therapy so that induce the disease in the acute activity to alleviate.Can use the lowest dose level that to realize these purposes, and this lowest dose level can change according to the effect of patient, disease severity, the preparation that gives activating agent, therapeutic agent with the different of toleration and route of administration.

For zone and local delivering therapeutic agents, several technology may be suitable for preferably being implemented near the level that improves therapeutic agent in the zone of being treated.These technology comprise: (a) be used for (in general fibre modification inhibitor part, zone or systemic delivery are passed medicine conduit and/or syringe and syringe needle to described device or implant surrounding tissue, under the radiology guideline, pass the medicine conduit or it is directly inserted tissue by the circulation propelling, reach required anatomical location up to them; The fibre modification inhibitor can discharge with high local concentrations from catheter lumen subsequently, so that the medicine of therapeutic dose is delivered to device or implant tissue on every side); (b) medicine location technology is such as the medicine of passing of magnetic, ultrasonic or MRI-guiding; (c) be designed for the chemical modification (for example being oriented to antibody impaired or the callus composition, described component of organization such as macrophage, neutrophil cell, smooth muscle cell, fibroblast, extracellular matrix composition, neovascularity tissue) that the increase activating agent is absorbed into the medicine or the preparation of damaged tissues; (d) be designed for the chemical modification that makes medicine be positioned the medicine or the preparation of hemorrhage or damaged vascular system; And/or (e) direct injection therapeutic agent under normal or the visible condition of endoscope for example, for example subcutaneous, intramuscular, intra-arterial etc.

2) therapeutic agent is impregnated into device or implant tissue on every side

Alternatively, can be before the operation that undergos surgery, in the process or afterwards with infection and/or suppress fibrotic therapeutic agent and handle tissue cavity or perform the operation bag.This step can be carried out according to several modes, comprising: (a) the activating agent part is coated with that (useful especially to this embodiment is to be applied in the polymer supports that discharge described activating agent in several hours-a few time limits in week into the anatomic space of having placed described device or surface.The compositions that can be used for this application comprises: for example fluid, microsphere, paste, gel, microgranule, spray, aerosol, solid implant and other preparation, described compositions is released into described device or implant with implanted zone with therapeutic agent); (b) particulate form of therapeutic agent also is used for formulation delivered and goes into implant site; (c) contain the preparation of sprayable collagen protein, such as COSTASIS and crosslinked deutero-poly-(ethylene glycol)-collagen composition (for example at United States Patent (USP) 5,874,500 and 5, described in 565,519, and be called " CT3 " in this article (all from AngiotechPharmaceuticals, Inc., Canada) coat implant site (or implant/apparatus surface) separately or with the form of having loaded therapeutic agent; (d) contain the preparation of sprayable PEG, such as COSEAL or ADHIBIT (Angiotech Pharmaceuticals, Inc.), SPRAYGEL or DURASEAL are (all from Confluent Surgical, Inc., Boston MA) coats implant site (or implant/apparatus surface) separately or with the form of having loaded therapeutic agent; (e) contain the preparation of fibrin, (all from Baxter HealthcareCorporation, Fremont CA) coats implant site (or implant/apparatus surface) such as FLOSEAL or TISSEEL; (f) contain hyaluronic preparation, such as RESTYLANE or PERLANE (all from Q-Med AB, Sweden), HYLAFORM (Inamed Corporation (Santa Barbara, CA)), SYNVISC (Biomatrix, Inc., Ridgefield, NJ), (all from Genzyme Corporation, Cambridge MA) coats implant site (or implant/apparatus surface) with the form of having loaded therapeutic agent for SEPRAFILM or SEPRACOAT; (g) polymer gel that is used to perform the operation and implants, such as REPEL (Life Medical Sciences, Inc., Princeton, NJ) or FLOGEL (Baxter Healthcare Corporation) coat implant site (or implant/apparatus surface) with the form of having loaded therapeutic agent; (h) be used for fixing the prosthese of having placed therapeutic agent and the orthopedics " cement (cements) " of tissue and coat implant site (or implant/apparatus surface); (i) contain the surgical adhesive of cyanoacrylate binding agent, such as DERMABOND (Johnson ﹠amp; Johnson, Inc., New Brunswick, NJ), INDERMIL (U.S.SurgicalCompany, Norwalk, CT), GLUSTITCH (Blacklock Medical ProductsInc., Canada), TISSUMEND II (Veterniary Products Laboratories,, Phoenix, AZ), VETBOND (3M Company, St.Paul, MN), HISTOACRYL BLUE (Davis ﹠amp; Geck, St.Louis, MO) (Colgate-Palmolive Company, NewYork NY) coat implant site (or implant/apparatus surface) with the form of having loaded therapeutic agent with the agent of ORABASESMOOTHE-N-SEAL liquid-state protective; And/or (j) based on proteinic sealer or binding agent, such as BIOGLUE (Cryolife, Inc.) and TISSUEBOND (TissueMed Ltd.) coats implant site (or implant/apparatus surface) with the form of having loaded therapeutic agent.

Can be separately or unite with fibre modification inhibitor/compositions and to be used for auxiliaryly preventing that both form as the reactant of reaction reagent by comprising one of following ingredients or its for preferred polymers substrate that fibrous tissue forms: tetramethylolmethane gathers (ethylene glycol) ether four-sulfydryl] (4-is with ramose sulfydryl PEG, be included in and have the structure that is connected base between sulfydryl and the polyethylene glycol backbone end) and poly-(ethylene glycol) ether four-succinimido glutarate of tetramethylolmethane] (4-is with ramose NHS PEG, also is included in to have between NHS base and the polyethylene glycol backbone end to be connected basic structure).Another kind of preferred compositions comprise one of following ingredients or its both as reaction reagent: tetramethylolmethane gathers (ethylene glycol) ether four-amino] (4-is with ramose amino PEG, be included between amino and the polyethylene glycol backbone end and have the structure that is connected base) and tetramethylolmethane gather (ethylene glycol) ether four-succinimido glutarate] (4-is with ramose NHSPEG, also be included in NHS basic with the polyethylene glycol backbone end between have be connected basic structure).The chemical constitution of these reactants such as United States Patent (USP) 5,874 are shown in 500.Randomly collagen protein or collagen derivative (for example methylated collagen albumen) are joined in the reactant that contains poly-(ethylene glycol) so that form preferred crosslinked substrate, this substrate can be as the auxiliary polymer support that prevents therapeutic agent that fibrous tissue forms or independent compositions.

3) slow releasing preparation of therapeutic agent

As mentioned above, can with required therapeutic agent and polymer composition (can for biodegradable or non-biodegradable) or the non-polymer compositions be mixed, fusion, conjugation, otherwise just required therapeutic agent is modified containing described polymer composition (can for biodegradable or non-biodegradable) or non-polymer compositions, thereby in time limit time expand, discharged therapeutic agent.With regard to many in the above-mentioned embodiment, may need local delivery and localization to continue to send fibre modification inhibitor and/or anti-infective.For example, can with required therapeutic agent and polymer composition (can for biodegradable or non-biodegradable) or the non-polymer compositions be mixed, fusion, conjugation, otherwise just required therapeutic agent is modified containing described polymer composition (can for biodegradable or non-biodegradable) or non-polymer compositions, thereby discharged described therapeutic agent in the time limit at certain hour.

The representational example that is suitable for sending the Biodegradable polymeric of above-mentioned therapeutic agent comprises albumin, collagen protein, gelatin, hyaluronic acid, starch, cellulose and cellulose derivative (regenerated cellulose for example, methylcellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose, Cellacefate, cellulose acetate succinate, Hydroxypropyl Methylcellulose Phathalate), casein, glucosan, polysaccharide, fibrinogen, poly-(ether-ether) segmented copolymer based on poly-(ethylene glycol) and poly-(mutual-phenenyl two acid bromide two alcohol ester), (for example United States Patent (USP) 6 for tyrosine-derived polycarbonate-based, 120,491), poly-(hydroxy acid), poly-(D, the L-lactide), poly-(D, L-lactide-co-glycolide), poly-(Acetic acid, hydroxy-, bimol. cyclic ester), poly-(butyric ester) Ju diethyleno dioxide ketone, poly-(alkyl carbonate) and poly-(ortho esters), polyesters, poly-(hydroxypentanoic acid) Ju diethyleno dioxide ketone, polyesters, poly-(malic acid), poly-(hydroxymalonic acid .), poly-(acrylamide), polyanhydrides, group of polyphosphazenes, poly-(aminoacid), poly-(oxirane)-poly-(ester) block copolymer (X-Y for example, X-Y-X, Y-X-Y, R-(Y-X) _nOr R-(X-Y) _nWherein X is a poly(ethylene oxide) (for example poly-(ethylene glycol, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, Mount Olive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is a polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Er Evil heptan is because of-2 ketone (PLGA for example, PLA, PCL Ju diethyleno dioxide ketone and copolymer thereof), and R is multifunctional initiator) and copolymer and admixture (generally referring to, Illum, L., Davids, S.S. (eds.) " polymer in the controlled drug delivery " (" Polymers in Controlled Drug Delivery ") Wright, Bristol, 1987; Arshady, " controlled release magazine " (J.Controlled Release) 17:1-22,1991; Pitt, " International Journal of Pharmaceutical Medicine " be 59:173-196 (Int.J.Phar.), and 1990; Holland etc., " controlled release magazine " (J.Controlled Release) 4:155-0180,1986).

The representational example that is suitable for sending the polymer that can not degrade of above-mentioned therapeutic agent comprises: poly-(ethylene-co-vinyl acetate) (" EVA ") copolymer; The aromatic polyester class is such as poly-(PETP); Silicone rubber; Acrylate copolymer (polyacrylate, polyacrylic acid, polymethylacrylic acid, polymethyl methacrylate, poly-(butyl methacrylate)), poly-(alkyl cyanoacrylate) (for example poly-(ethyl cyanoacrylate), poly-(butyl cyanoacrylate) poly-(hexyl cyanoacrylate) poly-(octyl cyanoacrylate)); Acrylic resin; Polyethylene; Polypropylene; Polyamide-based (nylon 6,6); Polyurethanes (for example CHRONOFLEX AL and CHRONOFLEX AR (all from CardioTech Intemational, Inc., Woburn, MA), TECOFLEX and BIONATE (polymer Technology Group, Inc., Emeryville, CA)); Poly-(ester urethane); Poly-(ether urethane); Poly-(ester-urea); Polyethers (poly-(oxirane); Poly-(expoxy propane); Based on the polyoxyalkylene ether block copolymers of oxirane and expoxy propane, such as from BASF Corporation (Mount Olive, PLURONIC polymer NJ) (for example F-127 or F87) and poly-(butanediol); The polymer of styrene-based (polystyrene, poly-(styrene sulfonic acid), poly-(styrene)-block-poly-(isobutene .)-block-poly-(styrene), poly-(styrene)-poly-(isoprene) block copolymer); And polyvinyl (polyvinylpyrrolidone, poly-(vinyl alcohol), poly-(vinylacetate phthalic acid ester) and copolymer and admixture.Can also research and develop and be following polymer: anionic (for example alginate, chondrus ocellatus Holmes polysaccharide, carboxymethyl cellulose, poly-(acrylamido-2-methyl propane sulfonic acid) and copolymer thereof, poly-(methacrylic acid and copolymer thereof and poly-(acrylic acid) and copolymer and admixture thereof; Or cationic (for example chitosan, poly-L-Lysine, polyaziridine and poly-(allylamine)) and admixture thereof (generally referring to, Dunn etc., " journal of applied " (J.Applied polymer Sci.) 50:353-365,1993; Cascone etc., " material science magazine-medical material " (J.Materials Sci.:Materials in Medicine) 5:770-774,1994; Shiraishi etc., " bio-pharmaceutical bulletin " (Biol.Pharm.Bull.) 16 (11): 1164-1168,1993; Thacharodi and Rao, and " International Journal of Pharmaceutical Medicine " (Int ' l J.Pharm.) 120:115-118,1995; Miyazaki etc., " International Journal of Pharmaceutical Medicine " (Int ' l J.Pharm.) 118:257-263,1995).

Some example that is used to implement preferred polymers carrier of the present invention comprises: poly-(ethylene-co-vinyl acetate); Polyurethanes; Poly-(D, L-lactic acid) oligomer and polymer; Poly-(L-lactic acid) oligomer and polymer; Poly-(glycolic); The copolymer of lactic acid and glycolic; The copolymer of lactide and Acetic acid, hydroxy-, bimol. cyclic ester; Poly-(caprolactone); Poly-(valerolactone); Polyanhydrides; The copolymer of poly-(caprolactone) or poly-(lactic acid) and Polyethylene Glycol (for example MePEG); X-Y, X-Y-X, Y-X-Y, R-(Y-X) _nOr R-(X-Y) _nThe block copolymer of form, wherein X is a polyalkylene oxide (for example poly-(ethylene glycol, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASFCorporation, Mount Olive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is a polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Er Evil heptan is because of-2 ketone, and R is multifunctional initiator); Silicone rubber; Poly-(styrene) block-poly-(isobutene .)-block-poly-(styrene); Poly-(acrylate) polymer and admixture; The admixture of above-mentioned arbitrary substance, mixture or copolymer.Other preferred polymer comprises: collagen protein; Polymer based on poly-(alkylene oxide); Polysaccharide is such as the copolymer of hyaluronic acid, chitosan and fucosan class (fucans) and polysaccharide and degradable polymer.

Other representational polymer that can continue localizes sends infection and/or suppress fibrotic therapeutic agent comprises: carboxylic acid polyalcohol, poly-acetate esters, polycarbonate-based, polyethers, polyethylene kind, the polyethylene butylaldehyde group, polysilanes, polyureas, polyoxide, polystyrene type, polysulfide, polysulfones, polysulfonides, the polyvinylhalide class, pyrrolidinone compounds, rubber, heat curing copolymer, crosslinkable acrylic acid and methacrylate polymer, ethylene acrylic acid co polymer, styrene acrylic copolymer, vinyl acetate polymer and copolymer, ethylene acetal polymer and copolymer, epoxy resin, the melamine class, other amino resins, novolac polymer and copolymer thereof, the water-insoluble cellulose ester polymer (comprises cellulose-acetate propionate, cellulose acetate, cellulose acetate-butyrate, celluloid, Cellacefate and composition thereof), polyvinylpyrrolidone, polyethylene glycols, poly(ethylene oxide), polyvinyl alcohol, polyethers, polysaccharide, hydrophilic polyurethane, poly-hydroxy acrylate, glucosan, xanthan gum, hydroxypropyl cellulose and N-vinyl pyrrolidone, the N-vinyl lactam, the N-vinyl butyrate lactam, the N-caprolactam, other vinyl compound that has the polarity side group, the acrylate and the methacrylate that have hydrophilic esterification group, hydroxy acrylate and acrylic acid homopolymer and copolymer and combination thereof; Homopolymer and copolymer, polrvinyl chloride and the polrvinyl chloride vinyl acetate of cellulose esters and ethers, ethyl cellulose, hydroxyethyl-cellulose, celluloid, cellulose acetate, cellulose acetate-butyrate, cellulose-acetate propionate, natural and synthetic elastomer, rubber, acetal, styrene polybutadiene, acrylic resin, poly-inclined to one side vinylidene chloride, Merlon, vinyl compound.

The representational example that relates to the patent of passing medicine polymer and preparation thereof comprises PCT publication number WO 98/19713, WO 01/17575, WO 01/41821, WO 01/41822 and WO01/15526 (and corresponding U. S. application), United States Patent (USP) 4,500,676,4,582,865,4,629,623,4,636,524,4,713,448,4,795,741,4,913,743,5,069,899,5,099,013,5,128,326,5,143,724,5,153,174,5,246,698,5,266,563,5,399,351,5,525,348,5,800,412,5,837,226,5,942,555,5,997,517,6,007,833,6,071,447,6,090,995,6,106,473,6,110,483,6,121,027,6,156,345,6,214,901,6,368,611,6,630,155,6,528,080, RE37,950,6,46,1631,6,143,314,5,990,194,5,792,469,5,780,044,5,759,563,5,744,153,5,739,176,5,733,950,5,681,873,5,599,552,5,340,849,5,278,202,5,278,201,6,589,549,6,287,588,6,201,072,6,117,949,6,004,573,5,702,717,6,413,539,5,714,159,5,612,052 and U.S. Patent Application Publication No. 2003/0068377,2002/0192286,2002/0076441 and 2002/0090398.

Can also be as required with different composition fusion or polymerization polymer as herein described so that the bioactivator of delivery treatments dosage, this to those skilled in the art should be apparent.

The polymer support that is used for infection and/or suppresses fibrotic therapeutic agent can be made the various forms with required release characteristics and/or particular characteristics, this depends on compositions for use.For example, can be formed in contact certain trigger situation, the polymer support of release therapeutic agent (for example during such as pH, referring to Heller etc., " the chemically delivery system of self regulation " (" ChemicallySelf-Regulated Drug Delivery Systems ")-" polymer in the medicine " (polymer sin Medicine) III, Elsevier Science Publishers B.V., Amsterdam, 1988, pp.175-188; Kang etc., " journal of applied " (J.Applied polymer Sci.) 48:343-354,1993; Dong etc., " controlled release magazine " (J.Controlled Release) 19:171-178,1992; Dong and Hoffman, " controlled release magazine " (J.Controlled Release) 15:141-152,1991; Kim etc., " controlled release magazine " (J.Controlled Release) 28:143-152,1994; Comeio-Bravo etc., " controlled release magazine " (J.Controlled Release) 33:223-229,1995; Wu and Lee, " drug research " (Pharm.Res.) 10 (10): 1544-1547,1993; Serres etc., " drug research " (Pharm.Res.) 13 (2): 196-201,1996; Peppas, " pH and thermal sensitivity delivery system basis " (" Fundamentals of pH-and Temperature-Sensitive Delivery Systems ")-(eds.) such as Gumy, " beat and pass medicine " (Pulsatile Dmg Delivery), WissenschaftlicheVerlagsgesellschaft mbH, Stuttgart, 1993, pp.41-55; Doelker, " cellulose derivative " (" Cellulose Derivatives ") 1993 ,-Peppas and Langer (eds.), " biopolymer " be I (Biopolymers), Springer-Verlag, Berlin).The representational example of pH-sensitive polymer comprises: poly-(acrylic acid) and derivant thereof (comprise that homopolymer for example is such as poly-(amino carboxylic acid); Poly-(acrylic acid); Poly-(methacrylic acid); The copolymer of the copolymer of this class homopolymer and poly-(acrylic acid) and/or acrylate or acrylamide monomer, such as aforesaid those.Other pH sensitive polymer comprises: polysaccharide, such as Cellacefate; Hydroxypropyl Methylcellulose Phathalate; HPMC-AS; Acetic acid benzenetricarboxylic acid cellulose; And chitosan.Other pH sensitive polymer comprises any mixture of pH sensitive polymer and water-soluble polymer.

Equally, can be by sending infection and/or (for example suppress fibrotic therapeutic agent for the polymer support of thermal sensitivity, referring to Chen etc., " be used for vagina and pass medicine and the new hydrogel grafted thermal sensitivity PLURONIC of bioadhesive polyacrylic acid skeleton " (Proceed.Intem.Symp.Control.Rel.Bioact.Mater.) 22:167-168 of (" Novel Hydrogels of aTemperature-Sensitive PLURONIC Grafted to a Bioadhesive Polyacrylic acid Backbone for Vaginal Drug Delivery ")-" international control release biological active material symposium proceedings ", Controlled Release Society, Inc., 1995; Okano, (" Molecular Design ofStimuli-Responsive Hydrogels for Temporal Controlled Drug Delivery ")-" the international control release biological active material symposium proceedings " that " be used for the MOLECULE DESIGN that sequencing contro is passed the irritant reaction hydrogel of medicine " be 22:111-112 (Proceed.Intem.Symp.Control.Rel.Bioact.Mater.), Controlled Release Society, Inc., 1995; Johnston etc., " drug research " (Pharm.Res.) 9 (3): 425-433,1992; Tung, and " International Journal of Pharmaceutical Medicine " (Int ' lJ.Pharm.) 107:85-90,1994; Harsh and Gehrke, J.Controlled Release 17:175-186,1991; Bae etc., " drug research " (Pharm.Res.) 8 (4): 531-537,1991; Dinarvand and D ' Emanuele, " controlled release magazine " be 36:221-227 (J.ControlledRelease), and 1995; Yu and Grainger, " new thermal sensitivity amphiphilic gel: poly-N-isopropyl acrylamide-altogether-sodium acrylate-altogether-n-N-alkyl acrylamide network structure is synthetic to be characterized with materialization " (" Novel Thermo-sensitive Amphiphilic Gels:PolyN-isopropylacrylamide-co-sodium acrylate-co-n-N-alkylacrylamide NetworkSynthesis and Physicochemical Characterization ")-" chemistry and scientific development biology " (Dept.of Chemical ﹠amp; Biological Sci.), Oregon Graduate Institute ofScience ﹠amp; Technology, Beaverton, OR, pp.820-821; Zhou and Smid, " physical hydrogel of association star polymer " (" Physical Hydrogels of Associative StarPolymers ") Polymer Research Institute, Dept.of Chemistry, College ofEnvironmental Science and Forestry, State Univ.ofNew York, Syracuse, NY, pp.822-823; Hoffman etc., " porous and water ' structure in the irritant reaction hydrogel ' sign " (" Characterizing Pore Sizes and Water ' Structure ' inStimuli-Responsive Hydrogels ") Center for Bioengineering, Univ.ofWashington, Seattle, WA, p.828; Yu and Grainger, " the thermal sensitivity swelling character in crosslinked-N-N-isopropylacrylamide network structure: cationic, anionic and both sexes hydrogel " (" Thermo-sensitive Swelling Behavior in CrosslinkedN-isopropylacrylamide Networks:Cationic, Anionic and AmpholyticHydrogels ")-" chemistry and scientific development biology " (Dept.of Chemical ﹠amp; BiologicalSci.), Oregon Graduate Institute of Science﹠amp; Technology, Beaverton, OR, pp.829-830; Kim etc., Pharm.Res.9 (3): 283-290,1992; Bae etc., " drug research " (Pharm.Res.) 8 (5): 624-628,1991; Kono etc., " controlled release magazine " (J.Controlled Release) 30:69-75,1994; Yoshida etc., J.Controlled Release32:97-102,1994; Okano etc., J.Controlled Release 36:125-133,1995:Chun and Kim, " controlled release magazine " (J.Controlled Release) 38:39-47,1996; D ' Emanuele and Dinarvand, and " International Journal of Pharmaceutical Medicine " (Int ' l J.Pharm.) 118:237-242,1995; Katono etc., " controlled release magazine " (J.Controlled Release) 16:215-228,1991; Hoffman, " the thermal reversibility hydrogel that contains the biological activity kind " (" Thermally ReversibleHydrogels Containing Biologically Active Species ")-(eds.) such as Migliaresi, " polymer in the medicine " (polymer s in Medicine) III, Elsevier Science PublishersB.V., Amsterdam, 1988, pp.161-167; Hoffman, " application in treatment and diagnosis of thermal reversibility polymer and hydrogel " (" Applications ofThermally Reversible polymer s and Hydrogels in Therapeutics and Diagnostics ") the-the 3rd international delivery system latest development symposium (Third Intemational Symposium on Recent Advances inDrug Delivery Systems), Salt Lake City, UT, February, 24-27,1987, pp.297-305; Gutowska etc., " controlled release magazine " (J.Controlled Release) 22:95-104,1992; Palasis and Gehrke, " controlled release magazine " (J.Controlled Release) 18:1-12,1992; Paavola etc., " drug research " (Pharm.Res.) 12 (12): 1997-2002,1995).

Hot glue cohesion compound and gelation temperature (LCST (℃)) representational example comprise: homopolymer, such as poly-(N-methyl-N-n-propyl group acrylamide), 19.8; Poly-(N-n-propyl group acrylamide), 21.5; Poly-(N-methyl-N-isopropyl propyl group acrylamide), 22.3; Poly-(N-n-propyl methyl amide), 28.0; Poly-(N-N-isopropylacrylamide), 30.9; Poly-(N, n-diethyl acrylamide), 32.0; Poly-(N-isopropyl methyl acrylamide), 44.0; Poly-(N-cyclopropyl acrylamide), 45.5; Poly-(N-ethyl-methyl acrylamide), 50.0; Poly-(N-methyl-N-ethyl acrylamide), 56.0; Poly-(N-cyclopropyl Methacrylamide), 59.0; Poly-(N-ethyl acrylamide), 72.0.In addition, can by between the above-mentioned monomer of preparation (in) copolymer or prepare hot glue and condense compound by this class homopolymer and other water-soluble polymer are merged, (for example acrylic acid and derivant thereof are such as methacrylic acid for described other water-soluble polymer such as acrylic monomer; Acrylate monomer and derivant thereof are such as butyl methacrylate, butyl acrylate, lauryl acrylate; With acrylamide monomer and derivant thereof, such as N-butyl acrylamide and acrylamide).

Other representational example of hot glue cohesion compound comprises: cellulose ether derivative, and such as hydroxypropyl cellulose, 41 ℃; Methylcellulose, 55 ℃; Hydroxypropyl emthylcellulose, 66 ℃; And ethylhydroxyethylcellulose, poly(ethylene oxide)-the polyester block copolymer of X-Y, Y-X-Y and X-Y-X structure, wherein the X in the poly(ethylene oxide) in poly(ethylene oxide) and Y be biodegradable polyester (for example PLG-PEG-PLG) and PLURONICs, such as F-127,10-15 ℃; L-122,19 ℃; L-92,26 ℃; L-81,20 ℃; And L-61,24 ℃.

The representational example that relates to the patent of hot glue cohesion compound and preparation comprises: United States Patent (USP) 6,451,346; 6,201,072; 6,117,949; 6,004,573; 5,702,717; With 5,484,610; With PCT publication number WO 99/07343; WO 99/18142; WO 03/17972; WO01/82970; WO 00/18821; WO 97/15287; WO 01/41735; WO 00/00222 and WO 00/38651.

Can by sealing in polymer, dissolving in polymer, by ionic interaction in conjunction with or be encapsulated in the microcapsule and connect infection and/or to suppress fibrotic therapeutic agent.In certain embodiments of the invention, provide the therapeutic combination of non-capsule preparations form, such as silk, thin film or the spray of microsphere (scope is big or small to micron in nanometer), paste, all size.In one aspect, anti-scarring agent can be mixed biodegradable magnetic millimicro ball.For example, can use the millimicro ball so that anti-scarring agent is replenished the endovascular device of implantation, such as the stent that contains weak magnetic alloy (for example, referring to Z.Forbes, B.B.Yellen, G.Friedman, K.Barbee. " based on the targeting drug delivery means of uniform magnetic field " (" An approach totargeted drug delivery based on uniform magnetic fields ") IEEE Trans.Magn.39 (5): 3372-3377 (2003)).

Of the present invention aspect some in, can and/or suppress fibrotic therapeutic combination and make in-500 mu m ranges that have 50nm the form of microsphere, microgranule and/or the nanoparticle of size arbitrarily infection, this depends on concrete application.These compositionss can be.Can form these compositionss by spray drying method, polishing, coacervation, W/O Emulsion method, W/O/W Emulsion method and solvent evaporated method.In others, these compositionss can comprise microemulsion, Emulsion, liposome and micelle.Alternatively, also be easy to this based composition is coated with as " spray ", its curable one-tenth is as device/applied thin film of implant surface coating or coating or dress lining implant site tissue.Can prepare this class spray by the microsphere of various grade sizes, comprise: for example 0.1 μ m-3 μ m, 10 μ m-30 μ m and 30 μ m-100 μ m.

This based composition that comprises anti-infective and/or fibrosis agent can also be prepared into various " paste " or gel form.For example, in one embodiment of the invention, provide under a kind of temperature and to be the therapeutic combination of solid or semisolid (for example environment body temperature or be lower than 37 ℃ arbitrary temp) for liquid (for example temperature is greater than 37 ℃, such as 40 ℃, 45 ℃, 50 ℃, 55 ℃ or 60 ℃) and under another kind of temperature.Be easy to use various technology to prepare this class " hot paste " (for example, referring to PCT publication number WO 98/24427).Other paste can be coated with as liquid, the body environment that they go into aqueous because of the water soluble ingredient stripping and the encapsulation drug precipitation of this paste solidifies.These " pastes " of containing therapeutic agent are used in particular for being coated on the tissue surface that contacts implant or device with " gel ".

In others of the present invention, provide to be suitable for containing and to discharge the hydrophobicity infection and/or suppress the polymer support of fibrotic chemical compound and/or contain hydrophobic compound and the carrier of carbohydrate, protein or polypeptides in combination.In certain embodiments, described polymer support contains or comprises district, bag or the granule of one or more chemical compounds.For example, in one embodiment of the invention, hydrophobic compound can be mixed the substrate that contains hydrophobicity treatment chemical compound, subsequently this substrate be mixed polymer support.Can use various substrate in this respect, comprise: for example carbohydrate and polysaccharide, such as starch, cellulose, glucosan, methylcellulose, sodium alginate, heparin, chitosan and hyaluronic acid, protein or polypeptide class, such as albumin, collagen protein and gelatin.In alternate embodiment, hydrophobic compound can be included in hydrophobic in-core, and this core is included in the hydrophilic shell.

Can and/or suppress fibrotic therapeutic agent and send described infection as solution.Described therapeutic agent directly can be mixed solution to form uniform solution or dispersion liquid.In certain embodiments, this solution is aqueous solution.This aqueous solution may further include buffer salt and viscosity modifier (for example hyaluronic acid, alginate, carboxymethyl cellulose (CMC) etc.).In another aspect of the present invention, this solution can comprise biocompatible solvent or liquid oligomer and/or polymer, such as ethanol, DMSO, glycerol, PEG-200, PEG-300 or NMP.These compositionss may further include polymer, such as degradable polyester, wherein said polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Er Evil heptan is because of-2 ketone or X-Y, Y-X-Y, R-(Y-X) _n, R-(X-Y) _nWith the block copolymer of X-Y-X form (X (for example poly-(ethylene glycol in poly(ethylene oxide) wherein, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, Mount Olive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Er Evil heptan is multifunctional initiator because of-2 ketone (for example PLG-PEG-PLG) and R).

In another aspect of the present invention, described infection and/or suppress fibrotic therapeutic agent and may further include second kind of carrier.This second kind of carrier can be following form: microsphere (for example PLGA, PLLA, PDLLA, PCL, gelatin, poly-diethyleno dioxide ketone, poly-(alkyl cyanoacrylate)); Millimicro ball (PLGA, PLLA, PDLLA, PCL, gelatin, poly-diethyleno dioxide ketone, poly-(alkyl cyanoacrylate)); Liposome; Emulsion; Microemulsion; Micelle (SDS, X-Y, Y-X-Y, R-(Y-X) _n, R-(X-Y) _nWith the block copolymer of X-Y-X form (X (for example poly-(ethylene glycol in poly(ethylene oxide) wherein, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, Mount Olive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Er Evil heptan is multifunctional initiator because of-2 ketone (for example PLG-PEG-PLG) and R); Zeolites or cyclodextrin.

Other carrier that can be used to equally to contain and send infection as herein described and/or suppress fibrotic therapeutic agent comprises: hydroxypropyl cyclodextrin (Cserhati and Hollo, " International Journal of Pharmaceutical Medicine " be 108:69-75 (Int.J.Pharm.), and 1994); Liposome is (for example, referring to Sharma etc., " cancer research " (Cancer Res.) 53:5877-5881,1993; Sharma and Straubinger, " drug research " (Pharm.Res.) 11 (60): 889-896,1994; WO 93/18751; United States Patent (USP) 5,242,073); Liposome/gel (WO 94/26254); Nanocapsule (Bartoli etc., " microencapsulation magazine " (J.Microencapsulation) 7 (2): 191-197,1990); Micelle (Alkan-Onyuksel etc., " drug research " (Pharm.Res.) 11 (2): 206-212,1994); Implant (Jampel etc., " scientific research of ophthalmology vision " (Invest.Ophthalm.Vis.Science) 34 (11): 3076-3083,1993; Walter etc., " cancer research " (Cancer Res.) 54:22017-2212,1994); Nanoparticle (Violante and Lanzafame PAACR); The nanoparticle of modification (United States Patent (USP) 5,145,684); Nanoparticle (surface modification) (United States Patent (USP) 5,399,363); Micelle (surfactant) (United States Patent (USP) 5,403,858); Synthetic phospholipid chemical compound (United States Patent (USP) 4,534,899); Gas matchmaker (gas borne) dispersion (United States Patent (USP) 5,301,664); Liquid emulsion, foam, spray, gel, lotion, cream, ointment, dispersive vesicles, granule or drop, solid-or liquid-aerosol, microemulsion (United States Patent (USP) 5,330,756); Polymer shell (nanocapsule-and microcapsule) (United States Patent (USP) 5,439,686); Emulsion (Tarr etc., " drug research " be 4:62-165 (Pharm.Res.), and 1987); (Hagan etc., " international control release biological active material symposium proceedings " (Pro.Intern.Symp.Control.Rel.Bioact.Mater.) 22,1995 for the millimicro ball; Kwon etc., " drug research " (Pharm.Res.) 12 (2): 192-195; Kwon etc., " drug research " (Pharm.Res.) 10 (7): 970-974; Yokoyama etc., " controlled release magazine " be 32:269-277 (J.Contr.Rel.), and 1994; Gref etc., " science " be 263:1600-1603 (Science), and 1994; Bazile etc., " pharmaceutical science magazine " be 84:493-498 (J.Pharm.Sci.), and 1994); And implant (United States Patent (USP) 4,882,168).

In another aspect of the present invention, polymer support can be the material that forms in position.In one embodiment, precursor can polymerization and/or the monomer or the macromonomer of crosslinked unsaturated group for containing.Then, for example described monomer or macromonomer can be injected on the surface of treatment region or treatment region, and use radioactive source (for example visible light or UV light) or free radical system (for example potassium peroxydisulfate and ascorbic acid or ferrum and hydrogen peroxide) to make its polymerization in position.Can be before reagent be injected therapentic part, simultaneously or carry out polymerization procedure afterwards immediately.The representational case description of compositions that carries out Raolical polymerizable is in following document: WO01/44307, WO 01/68720, WO 02/072166, WO 03/043552, WO93/17669, WO 00/64977; United States Patent (USP) 5,900,245,6,051,248,6,083,524,6,177,095,6,201,065,6,217,894,6,639,014,6,352,710,6,410,645,6,531,147,5,567,435,5,986,043,6,602,975; U.S. Patent Application Publication No. 2002/012796A1,2002/0127266A1,2002/0151650A1,2003/0104032A1,2002/0091229A1 and 2003/0059906A1.

In certain aspects, need to use to can be used as the liquid administration, but on medicine-feeding part, form the compositions of hydrogel subsequently.The compositions that this class can be formed in position hydrogel is more suitable in to any part administration as liquid administration and they from various different devices, because their unshapeds still.Original position forms the example of hydrogel comprises that but the mixture of photoactivation of water-soluble copolyester prepolymer and Polyethylene Glycol is so that generate the hydrogel barrier.Designed and dissolved in cold water, but under body temperature, form and organize the block copolymer of the polyethylene oxide polymer of adherent insoluble hydrogel (for example from BASF Corporation, Mount Olive, the PLURONIC chemical compound of NJ) and poloxamer class (Leach, Deng, " U.S.'s obstetrics and gynecology magazine " be 162:1317-1319 (1990) (Am.J.Obstet.Gynecol.)).

Described in this paper other parts, the invention provides crosslinked polymer substrate and polymer support, they can help to prevent that fibrous connective tissue from forming or growth.Said composition can contain and send the fibre modification inhibitor near implanting device.When hope at the device surrounding wetting, when using or not using fibre modification-inhibitor, following compositions is particularly useful.Can prepare this base polymer material by following material, for example: (a) synthetic; (b) naturally occurring material; Or (c) mixture of synthetic and natural occuring article matter.Described substrate can be prepared by following ingredients: for example (a) a kind of-composition, promptly self-reactive compounds; Or (b) two or more compositions that react each other.In general, these materials are liquid before sending, and can spray thus, otherwise just it can be squeezed out so that send described compositions from delivery apparatus (for example syringe).After sending, described component substances react each other and/or and somatic reaction so that required effect is provided.In some cases, Fan Ying material must be deposited separately before the patient is sent in maintenance each other, and just is mixed with each other before the patient is sent, so that they keep fluid form before sending.In aspect the present invention is preferred, to the desired area delivery matrices composition in the health, polymerization takes place with liquid state this moment in position.

First kind and second kind of synthetic polymer

In one embodiment, prepare crosslinking polymer composition through the following steps (in other words, be crosslinked substrate): at first make first kind of synthetic polymer that contains two or more nucleophilic groups and the second kind of polymer reaction that contains two or more electrophilic groups, wherein said electrophilic group can with the nucleophilic group covalent bond.In one embodiment, described first kind and the second kind of polymer non-immunogenic of respectively doing for oneself.In another embodiment, described substrate is insensitive to the enzymatic lysis of for example matrix metalloproteinase (for example collagenase), and estimates that thus they have in vivo than based on the longer persistency of the compositions of collagen protein.

Term used herein " polymer " refers in particular to poly-alkylates (polyalkyls), polyamino acid, polyalkylene oxide class and polysaccharide.In addition, for external or oral application, described polymer can be polyacrylic acid or carbomer.Term used herein " synthetic polymer " refers to polymer that non-natural exists and that produce by chemosynthesis.Like this, can get rid of naturally occurring protein especially, such as collagen protein and naturally occurring polysaccharide, such as hyaluronic acid.Comprise synthetic collagen protein and synthetic hyaluronic acid and derivant thereof.The synthetic polymer that contains nucleophilic group or electrophilic group is also referred to as in this article " multifunctional activatory synthetic polymer ".Term " multifunctional activatory " (or be merely " activatory ") refers to have or had through chemical modification and two or morely can react the nucleophilic group that forms covalent bond or the synthetic polymer of electrophilic group (being that nucleophilic group and electrophilic group react) each other.The type of multifunctional activatory polymer comprises that difunctionality is activatory, four senses are activatory and the ramose polymer of star.

Be used for multifunctional activatory synthetic polymer of the present invention and must contain at least two, more preferably at least three functional groups are so that form three-dimensional cross-linked network structure with the synthetic polymer that contains a plurality of nucleophilic groups (i.e. " many-nucleophilic polymer ").In other words, they must be that difunctionality is activatory and more preferably trifunctional or four senses are activatory at least.If first kind of synthetic polymer is the activatory synthetic polymer of difunctionality base, second kind of synthetic polymer must contain three or three above functional groups so that obtain three-dimensional cross-linked network structure so.Most preferably described first kind and second kind of synthetic polymer contain at least three functional groups.

The synthetic polymer that contains a plurality of nucleophilic groups generally also is called " many-nucleophilic polymer " in this article.In order to be used for the present invention, many-nucleophilic polymer must contain at least two, more preferably at least three nucleophilic groups.If use the synthetic polymer that only contains two nucleophilic groups, must use so and contain the synthetic polymer of three or three above electrophilic groups so that obtain three-dimensional cross-linked network structure.

Preferred many-the nucleophilic polymer that is used for the present composition and method comprises synthetic polymer, and they contain or are contained a plurality of nucleophilic groups by modification, such as primary amino radical and sulfydryl.Preferred many-nucleophilic polymer comprises: (i) synthesized and contained the synthetic polypeptide class of two or more primary amino radicals or sulfydryl; The polyethylene glycols that is (ii) contained two or more primary amino radicals or sulfydryl by modification.In general, sulfydryl tends to carry out more lentamente than the reaction of primary amino radical and electrophilic group with the reaction of electrophilic group.

In one embodiment, many nucleophilics polypeptide is synthetic and introduced amino acid residue (such as lysine) that contains primary amino radical and/or the synthetic polypeptide of the aminoacid (such as cysteine) that contains sulfydryl.Especially preferably poly-(lysine), i.e. a kind of polymer of synthetic generation of amino acid lysine (145MW).Prepared and no matter under which kind of situation, all had 6 poly-(lysines) that are equivalent to about 870-about 580,000 molecular weight to about 4,000 primary amino radicals.

Be used for the molecular weight that poly-(lysine) of the present invention preferably has about 1,000-about 300,000 scopes; The molecular weight of 5,000-about 100,000 scope more preferably from about; The molecular weight of 8,000-about 15,000 scopes most preferably from about.Poly-(lysine) of different molecular weight available from PeninsulaLaboratories, Inc. (Belmont, Calif.) and Aldrich Chemical (Milwaukee, WI).

Can be according to method listed in the following document, modify Polyethylene Glycol to contain a plurality of primary amino radicals or sulfydryl by chemical mode: for example the 22nd chapter " gathers (ethylene glycol) chemistry " (Poly (ethyleneGlycol) Chemistry) in " biotechnology and biological medicine are used " (Biotechnical andBiomedical Applications), J.Milton Harris, ed., Plenum Press, N.Y. (1992).Modified and polyethylene glycols that contain two or more primary amino radicals is called " polyamino PEGs " in this article, modified and polyethylene glycols that contain two or more sulfydryls is called " many sulfydryls PEGs " in this article.Term used herein " Polyethylene Glycol (class) " comprises to be modified and/or deutero-Polyethylene Glycol (class).

The amino acids PEG of various ways can (Huntsville Ala.) and from Huntsman Chemical Company (Utah) obtains with title " Jeffamine " from Shearwater Polymers by commercial sources.Be used for amino acids PEG of the present invention and comprise Huntsman ' s Jeffamine diamidogen (" D " series) and triamine (" T " series), its each molecule contains two and three primary amino radicals respectively.

Can also be with the polyamines class as the synthetic polymer that contains a plurality of nucleophilic groups, described polyamines class is such as ethylenediamine (H ₂N-CH ₂-CH ₂-NH ₂), tetra-methylenedimine (H ₂N-(CH ₂) ₄-NH ₂), five methylene diamine (cadaverine) (H ₂N-(CH ₂) ₅-NH ₂), hexamethylene diamine (H ₂N-(CH ₂) ₆-NH ₂), two (2-aminoethyl) amine (HN-(CH ₂-CH ₂-NH ₂) ₂) and three (2-aminoethyl) amine (N-(CH ₂-CH ₂-NH ₂) ₃).

The synthetic polymer that contains a plurality of electrophilic groups also is called " many-electrophilic polymer " in this article.In order to be used for the present invention, multifunctional activatory synthetic polymer must contain at least two, and more preferably at least three electrophilic groups are so that form three-dimensional cross-linked network structure with many nucleophilic polymer.The preferred many electrophilic polymer that are used for the present composition are to contain two or more polymer that can form the succinimido of covalent bond with the nucleophilic group on another molecule.Succinimido with contain primary amino radical (NH ₂) material, such as polyamino PEG, poly-(lysine) or collagen protein kickback.Succinimido and the material that contains sulfydryl (SH) are such as many sulfydryls PEG or a little less than containing the synthetic polypeptide class reaction of a plurality of cysteine residues.

Term used herein " contains two or more succinimidos " and refers to and comprises that the polymer that contains two or more succinimidos that preferably is purchased and those must be derived by chemical mode and contain the polymer of two or more succinimidos.Term used herein " succinimido " is in order to the version of the succinimido that comprises sulfosuccinimide base and other this class " generality ".On the sulfosuccinimide base, exist sodium sulfite partly to be used to increase the dissolubility of polymer.

Hydrophilic polymer, and particularly various deutero-polyethylene glycols is preferred for compositions of the present invention.Term used herein " PEG " refers to and has repetitive structure (OCH ₂-CH ₂) _nPolymer.Shown in the structure such as United States Patent (USP) 5,874,500 accompanying drawings 4-13 of the PEG of some four specific sense activated form, the document is incorporated herein by reference.The example of suitable PEGS comprises PEG succinyl phosphorons amino propyl acid ester (SE-PEG), PEG succinimido succinamide (SSA-PEG) and PEG succinimidyl carbonate (SC-PEG).In one aspect of the invention, by making tetramethylolmethane gather (ethylene glycol) ether four-sulfydryl] (4-is with ramose sulfydryl PEG) and poly-(ethylene glycol) ether four-succinimido glutarate of tetramethylolmethane] (4-is with ramose NHS PEG) reaction forms crosslinked substrate as reaction reagent.The structure of these reactants such as United States Patent (USP) 5,874 are shown in 500.These materials respectively carry nuclear, described nuclear has can observed through the following steps structure: the residue of oxirane derivative is added on each hydroxyl on the tetramethylolmethane, and derive terminal hydroxyl (deriving from oxirane) then and contain sulfydryl (being with ramose sulfydryl PEG) or N-hydroxyl and succinimido (being with ramose NHS PEG) so that form 4-so that form 4-, between the skeleton of oxirane derivative and reactive functional group, randomly exist is connected basic, wherein this product as COSEAL available from Angiotech Pharmaceuticals Inc.Randomly, " D " may reside in one of these molecules or they on both, as hereinafter discussed in detail.

As mentioned above, be used for preferred activated polyglycol derivant of the present invention and contain succinimido as reactive group.Yet different activated groups can be connected along on the position on the PEG molecular length.For example, PEG can be derivatized to the activatory PEG propionic aldehyde of sense (A-PEG) or the activatory PEG glycidyl ether of sense (E-PEG) or activatory PEG-isocyanates of sense (I-PEG) or the activatory PEG-vinyl sulfone of sense (V-PEG).

Hydrophobic polymer also can be used to prepare compositions of the present invention.Be used for hydrophobic polymer of the present invention and preferably contain and maybe can derive and contain two or more electrophilic groups, such as succinimido, most preferably two, three or four electrophilic groups.Term used herein " hydrophobic polymer " refers to the polymer that contains relative fraction oxygen or nitrogen-atoms.

The hydrophobic polymer that has contained two or more succinimidos comprises, but be not limited to two (sulfosuccinimide base) esters (BS3) of disuccinimidyl suberate (DSS), suberic acid, dithio two (succinyl phosphorons amino propyl acid ester) (DSP), two (2-succinimido oxygen base ketonic oxygen base) ethyl sulfone (BSOCOES), with 3,3 '--dithio two (sulfosuccinimide base propionic ester (DTSPP) and analog and derivants.(Rockford, Ill.), catalog number (Cat.No.) is respectively 21555,21579,22585,21554 and 21577 to the above-mentioned polymer that relates to available from Pierce.

Be used for preferred hydrophobic polymer of the present invention and generally have the carbochain that is no more than about 14 carbon.The polymer that has the carbochain of being longer than 14 carbon basically has extremely low dissolubility in aqueous solution, and has the extremely long response time with the synthetic polymer aqueous solution that contains a plurality of nucleophilic groups the time like this.

Some polymer can be derived and contained two or more functional groups such as polyacid, such as succinimido.Be used for polyacid of the present invention and include, but are not limited to tricarboxylic acids, tetrabasic carboxylic acid, 1,5-pentanedicarboxylic acid., suberic acid (octanedioicacid) (suberic acid (suberic acid)) and thapsic acid (thapsic acid) based on two (trimethylolpropanes) based on trimethylolpropane.In these polyacid many available from DuPont Chemical Company (Wilmington, DE).According to conventional method, can N arranged by N-hydroxy-succinamide (NHS) with suitable mole, there is reaction down in N '-dicyclohexylcarbodiimide (DCC) and derives polyacid to contain two or more succinimidos with chemical mode.

Polyhydric alcohol such as trimethylolpropane and two (trimethylolpropane) can change into carboxylic acid form with several different methods, derive to produce trifunctional and the activatory polymer of four senses respectively by in the presence of DCC, reacting then with NHS, as describing in the US application serial No. 08/403,358.Polyprotic acid such as 1,5-pentanedicarboxylic acid. (HOOC-(CH ₂) ₅-COOH), suberic acid (HOOC-(CH ₂) ₆-COOH), and thapsic acid (HOOC-(CH ₂) ₁₄-COOH) derive and produce the activatory polymer of difunctionality by adding succinimido.

Polyamines such as ethylenediamine, tetra-methylenedimine, five methylene diamine (cadaverine), hexamethylene diamine, diethylenetriamine, can be chemically derived become polyprotic acid with three (2-amino-ethyl) amine, it can react to derive in the presence of DCC then and contain two or more succinimidos by the N-hydroxy-succinamide with suitable mole, as describing in the US application serial No. 08/403,358.Many these polyamines can obtain from DuPont Chemical Company by commercial sources.

In preferred embodiments, described first kind of polymer contains a plurality of nucleophilic groups (hereinafter being expressed as " X "), and it can react with second kind of synthetic polymer that contains a plurality of electrophilic groups (hereinafter being expressed as " Y "), obtains covalently bound derivatized polymers, as:

Polymer-X _m+ polymer-Y _n→ polymer-Z-polymer

M≤2 wherein, n≤2, and m+n≤5;

Wherein the typical X group comprises-NH ₂,-SH ,-OH ,-PH ₂, CO-NH-NH ₂Deng, wherein the X group is at polymer-X _mIn can be identical or different;

Wherein typical Y comprises-CO ₂-N (COCH ₂) ₂,-CO ₂H ,-CHO ,-CHOCH ₂(epoxide) ,-N=C=O ,-SO ₂-CH=CH ₂,-N (COCH) ₂(the 5-unit heterocycle that promptly between two CH groups, has two keys) ,-S-S-(C ₅H ₄N) etc., wherein Y group at polymer-Y _nIn can be identical or different; And

Wherein Z is connected the functional group who produces because of nucleophilic group (X) with electrophilic group (Y).

As mentioned above, the present invention also pays close attention to X and Y can be identical or different, and promptly synthetic polymer can have two different electrophilic groups or two different nucleophilic groups, such as having glutathion.

In one embodiment, skeleton at least a in the synthetic polymer comprises alkylene oxide residue, for example from the residue of oxirane, expoxy propane and composition thereof.Term ' skeleton ' refers to the major part of polymer.

For example, the synthetic polymer that contains alkylene oxide residue can be described by formula X-polymer-X or Y-polymer-Y, and wherein X and Y are as above-mentioned definition and term " polymer " expression-(CH ₂CH ₂O) _n-or-(CH (CH ₃) CH ₂O) _n-or-(CH ₂-CH ₂-O) _n-(CH (CH ₃) CH ₂-O) _n-.In these situations, synthetic polymer can be for dual functional.

Required functional group X or Y be usually by connecting base (hereinafter being expressed as " Q ") and polymer backbone coupling, and many in them are known or possible.The mode that has the different functionalized polymerics of many preparations, some in them is following listed:

Polymer-Q ₁-X+ polymer-Q ₂-Y → polymer-Q ₁-Z-Q ₂-polymer

Typical Q group comprises :-O-(CH ₂) _n-;-S-(CH ₂) _n-;-NH-(CH ₂) _n-;-O ₂C-NH-(CH ₂) _n-;-O ₂C-(CH ₂) _n-;-O ₂C-(CR ¹H) _n-; With-O-R ₂-altogether-and NH-, this method provides the synthetic polymer of following part-structure respectively: polymer-O-(CH ₂) _n-(X or Y); Polymer-S-(CH ₂) _n-(X or Y); Polymer-NH-(CH ₂) _n-(X or Y); Polymer-O ₂C-NH-(CH ₂) _n-(X or Y); Polymer-O ₂C-(CH ₂) _n-(X or Y); Polymer-O ₂C-(CR ¹H) _n-(X or Y); And polymer-O-R ₂-altogether-NH-(X or Y).In these structures, n=1-10, R ¹=H or alkyl (are CH ₃, C ₂H ₅Deng); R ²=CH ₂Or CO-NH-CH ₂CH ₂And Q ₁And Q ₂Can be identical or different.

For example work as Q ₂=OCH ₂CH ₂(there is not Q in this case ₁); Y=-CO ₂-N (COCH ₂) ₂And X=-NH ₂,-SH or-OH, the reaction of generation and and the Z group can be as follows:

Polymer-NH ₂+ polymer-O-CH ₂-CH ₂-CO ₂-N (COCH ₂) ₂→

Polymer-NH-is common-CH ₂-CH ₂-O-polymer;

Polymer-SH+ polymer-O-CH ₂-CH ₂-CO ₂-N (COCH ₂) ₂→

Polymer-S-COCH ₂CH ₂-O-polymer; With

Polymer-OH+ polymer-O-CH ₂-CH ₂-CO ₂-N (COCH ₂) ₂→

Polymer-O-COCH ₂CH ₂-O-polymer.

If exist, the extra group that hereinafter is expressed as " D " can be inserted in polymer and be connected between the base.A purpose of this class D group is to influence crosslinking polymer composition degradation rate in vivo, for example increases degradation rate or reduces degradation rate.This is useful in many cases, for example when with the medicine doped matrix and need to increase or reduce the depolymerization rate with influence according to required direction pass the medicine characteristic time.Comprise shown in being explained as follows of cross-linking reaction of first kind and the second kind synthetic polymer that respectively carries D and Q group.

Polymer-D-Q-X+ polymer-D-Q-Y → polymer-D-Q-Z-Q-D-polymer

Some useful biodegradable group " D " comprises by one or more a-hydroxy acid, for example lactic acid, glycolic and cyclisation product thereof (for example lactide, Acetic acid, hydroxy-, bimol. cyclic ester), 6-caprolactone and amino acids formed polymer.These polymer can be called: polylactide, poly-Acetic acid, hydroxy-, bimol. cyclic ester, poly-(being total to-lactide-Acetic acid, hydroxy-, bimol. cyclic ester); Poly--6-caprolactone; Polypeptide (be also referred to as polyamino acid, for example various two-or three-peptide class) and poly-(acid anhydride).

In the conventional method that is used for preparing the crosslinking polymer composition that the context of the invention uses, first kind of synthetic polymer that will contain a plurality of nucleophilic groups mixes with the second kind of synthetic polymer that contains a plurality of electrophilic groups.Forming three-dimensional cross-linked network structure occurs as the result of the reaction of the electrophilic group on the nucleophilic group on first kind of synthetic polymer and the second kind of synthetic polymer.

Be used to prepare first kind of synthetic polymer of the present composition and the concentration of second kind of synthetic polymer can change according to the different of many factors, comprise that the type of used concrete synthetic polymer and molecular weight and required and final use use.In general, when will be many-amino PEG is during as described first kind of synthetic polymer, its preferred working concentration is in about 0.5-about 20 weight percentage ranges of final composition, and the working concentration of described second kind of synthetic polymer is in the scope of about 0.5-about 20 percentage by weights of final composition.For example, having gross weight is that 1 final composition that restrains (1000 milligrams) can contain 5-about 200 milligrams many-amino PEG and the about 5-second kind of about 200 milligrams synthetic polymer of having an appointment.

The application of first kind and second kind synthetic polymer of higher concentration can cause forming finer and close cross-linked structure, produces comparatively hard, more firm gel.Be used to organize the general concentration of using first kind and the second kind synthetic polymer that belongs to the higher end points of preferred concentration range for of compositions of increase.Be used as biological adhesive or be used to prevent that the compositions of adhering from needn't can contain lower polymer concentration so firm and thus.

Will be also and the water reaction because contain the polymer of a plurality of electrophilic groups, thus usually with aseptic, dried forms is preserved and use second kind of synthetic polymer to prevent since this type of electrophilic group be exposed to aqueous medium usually the hydrolysis of generation cause the forfeiture of crosslinked ability.The method of synthetic hydrophilic polymer that contains a plurality of electrophilic groups with the preparation of aseptic, dried forms is at United States Patent (USP) 5,643, provides in 464.For example, exsiccant synthetic polymer can be compression molded into thin slice or film, and it can use gamma-rays then, preferred e-bundle radiosterilization.Gained desciccator diaphragm or sheet can be cut into desirable size or chop littler granule.Therefore compare, the polymer that contains a plurality of electrophilic groups is not that water is reactive and can preserve in aqueous solution usually.

In certain embodiments, can be with above-mentioned electrophilic group-or nucleophilic group-end capped polymer and synthetic or naturally occurring combination of polymers.Existence synthetic or naturally occurring polymer can strengthen the machinery and/or the sticking property of the compositions of original position formation.Can be included in the naturally occurring polymer of the material that original position forms and comprise naturally occurring protein from the polymer of naturally occurring polymer-derived; as collagen; collagen derivant (as methylated collagen); fibrinogen, thrombin, albumin; fibrin; with the derivant of naturally occurring polysaccharide,, comprise deacetylated and the acidifying glycosaminoglycans derivant of desulfurization as glycosaminoglycans.

In one aspect, comprise that the compositions of naturally occurring protein and aforesaid first kind and second kind synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of collagen protein and aforesaid first kind and second kind synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of methylated collagen albumen and aforesaid first kind and second kind synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of fibrinogen and aforesaid first kind and second kind synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of thrombin and aforesaid first kind and second kind synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of albumin and aforesaid first kind and second kind synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of fibrin and aforesaid first kind and second kind synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of naturally occurring polysaccharide and aforesaid first kind and second kind synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of glycosaminoglycans and aforesaid first kind and second kind synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of deacetylated glycosaminoglycans and aforesaid first kind and second kind synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of desulfurization acidify glycosaminoglycans and aforesaid first kind and second kind synthetic polymer is used to form crosslinked substrate of the present invention.

In one aspect, comprise that the compositions of naturally occurring protein and aforesaid first kind of synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of collagen protein and aforesaid first kind of synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of methylated collagen albumen and aforesaid first kind of synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of fibrinogen and aforesaid first kind of synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of thrombin and aforesaid first kind of synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of albumin and aforesaid first kind of synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of fibrin and aforesaid first kind of synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of naturally occurring polysaccharide and aforesaid first kind of synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of glycosaminoglycans and aforesaid first kind of synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of deacetylated glycosaminoglycans and aforesaid first kind of synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of desulfurization acidify glycosaminoglycans and aforesaid first kind of synthetic polymer is used to form crosslinked substrate of the present invention.

In one aspect, comprise that the compositions of naturally occurring protein and aforesaid second kind of synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of collagen protein and aforesaid second kind of synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of methylated collagen albumen and aforesaid second kind of synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of fibrinogen and aforesaid second kind of synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of thrombin and aforesaid second kind of synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of albumin and aforesaid second kind of synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of fibrin and aforesaid second kind of synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of naturally occurring polysaccharide and aforesaid second kind of synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of glycosaminoglycans and aforesaid second kind of synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of deacetylated glycosaminoglycans and aforesaid second kind of synthetic polymer is used to form crosslinked substrate of the present invention.In one aspect, comprise that the compositions of desulfurization acidify glycosaminoglycans and aforesaid second kind of synthetic polymer is used to form crosslinked substrate of the present invention.

Contain and to cause with the existence of the functional group's of functional group on multiple activatory synthetic polymer reaction protein or polysaccharide component mixing and/or forming crosslinked synthetic polymer-naturally occurring polymeric matrix during crosslinked described synthetic polymer.Especially, when naturally occurring polymer (protein or polysaccharide) also contains nucleophilic group, during such as primary amino radical, can react with primary amino radical and the electrophilic group on described first kind of synthetic polymer on these compositions on described second kind of synthetic polymer, thereby make these other one-tenth be divided into the ingredient of described polymeric matrix.For example, be rich in the protein of lysine, especially can react with the electrophilic group on the synthetic polymer such as collagen protein.

In one aspect, naturally occurring protein is can be the polymer of collagen protein.Term used herein " collagen protein " or " collagen substance " refer to the collagen protein of form of ownership, comprise that those process, otherwise be exactly adorned collagen protein and in order to comprise the collagen protein from any source of any type, comprise, but the collagen protein, collagen protein analog, collagen derivative, the collagen protein of modification and the collagen protein of degeneration that are not limited to extract from tissue or produce with recombination form are such as gelatin.

In general, the collagen protein from any source can be included in the compositions of the present invention; For example, can be from people or other mammal source, such as extracting and collagen purification albumen in the corium of cattle or pig and the Placenta Hominis, or collagen protein can recombinate, otherwise production.The solution of collagen protein that is prepared the non-immunogenic basically of purification by Corii Bovis seu Bubali is well-known in the art.U.S. Patent No. 5,428 has disclosed in 022 from people's Placenta Hominis and has extracted and the proteic method of collagen purification.United States Patent (USP) 5,667 has disclosed in 839 and has used transgenic animal, comprises that the breast of transgenic milch cow is produced the proteic method of recombinant human collagen.The collagen protein of any type includes, but are not limited to I type, II type, III type, IV type or its combination in any and can be used for compositions of the present invention, but, and general preferred I type.Can use the collagen protein that contains atelopeptide or end peptide; Yet, when the collagen protein that uses from the xenogenesis source, during such as bovine collagen albumen, general preferred atelopeptide collagen protein, this be because of its immunogenicity with contain the collagen protein of holding peptide and compare due to the reduction.

As yet not by such as heating, shine or being preferred for compositions of the present invention, but, can use crosslinked in advance collagen protein in advance with the crosslinked collagen protein of chemical cross-linking agent.Uncrosslinked atelopeptide fiber collagen protein is available from Inamed Aesthetics (Santa Barbara, CA), its collagen concentration is respectively 35mg/ml and 65mg/ml, and trade mark is respectively ZYDERM I collagen protein and ZYDERM II collagen protein.(Santa Barbara, CA), its collagen concentration is 35mg/ml to the atelopeptide fibril collagen protein of glutaraldehyde cross-linking, and trade mark is the ZYPLAST collagen protein available from Inamed Corporation.

Be used for collagen protein of the present invention generally at the about 20mg/ml of the concentration of aqueous suspension-about 120mg/ml; Preferred about 30mg/ml-about 90mg/ml.

The non-protofibre collagen protein can be used for being used as the compositions of biological adhesive because of its viscosity.Term " non-protofibre (nonfibrillar) collagen protein " refers to any modification that is essentially the non-protofibre form under pH7 or the collagen substance of unmodified, and is shown as the optical clarity by the collagen protein aqueous suspension.

The collagen protein that has been the non-protofibre form can be used for compositions of the present invention.Term used herein " non-protofibre collagen protein " is in order to the collagen protein type of the non-protofibre that is included as native form and become to be the collagen protein of non-protofibre form by chemical modification about neutral pH.For the collagen protein of the non-protofibre (or microfibril) of native form comprises IV type, VI type and VII type.

The collagen protein that is the chemical modification of non-protofibre form under neutral pH comprises succinylation collagen protein and methylated collagen albumen; they both all can be according to the United States Patent (USP) 4 of authorizing 14 days Augusts in 1979 of Miyata etc.; 164; the preparation of method described in 559 is incorporated herein by reference the full content of the document.Methylated collagen albumen is particularly preferred for bioadhesive compositions because of its intrinsic viscosity, as disclosed in the U.S. Patent application serial number 08/476,825.

The collagen protein that is used for crosslinking polymer composition of the present invention begins to be the fibril form, gives its non-protofibre by adding one or more fiber decomposing agents then.Described fiber decomposing agents must exist so that give collagen protein with capacity be essentially non-protofibre as mentioned above under pH7.Be used for fiber decomposing agents of the present invention and include, but are not limited to various biocompatibility alcohols, aminoacid (for example arginine), inorganic salt (for example sodium chloride and potassium chloride) and carbohydrate (for example various saccharides comprise sucrose).

In one aspect, described polymer can be collagen protein or collagen derivative, for example methylated collagen albumen.The example that original position forms compositions uses poly-(ethylene glycol) ether four-sulfydryl of tetramethylolmethane] (4-is with ramose (armed) sulfydryl PEG), poly-(ethylene glycol) ether four-succinimido glutarate of tetramethylolmethane] (4-is with ramose NHS PEG) and methylated collagen albumen is as reaction reagent.Said composition can produce cross-linked hydrogel when mixing with suitable reducing.(for example, referring to United States Patent (USP) 5,874,500; 6,051,648; 6,166,130; 5,565,519 and 6,312,725).

In one aspect of the method, naturally occurring polymer can be glycosaminoglycans.Glycosaminoglycan, for example hyaluronic acid contains anion and functionalized cationic base along each polymeric chain, can form intramolecularly and/or intermolecular ionic cross-linked bond and can cause hyaluronic thixotroping (or shear thinning) property.

In certain aspects, the glycosaminoglycans of can deriving.For example, can by deacetylated, desulfurization acidify or they both and by chemical mode derive glycosaminoglycans contain can be used in synthetic polymer molecule on the primary amino radical of electrophilic group reaction.One of can be according to the method described above or their both deutero-glycosaminoglycans comprise following material: hyaluronic acid, chondroitin sulfate A, chondroitin sulfate B (dermatan sulfate), chondroitin sulfate C, chitin (can be derivatized to chitosan), keratan sulfate, keratosulfate and heparin.Derive by deacetylated and/or desulfurization acidify and to describe in further detail in the u.s. patent application serial number 08/146,843 common transfer, that authorize that covalentlying bind in of glycosaminoglycans and gained glycosaminoglycans derivant and synthetic hydrophilic polymer submitted on November 3rd, 1993.

Usually, collagen is added first kind of synthetic polymer, then collagen and first kind of synthetic polymer are fully mixed to realize homogeneous compositions.Add second kind of synthetic polymer then and be mixed in collagen/first kind of the synthetic polymer blends, wherein it causes forming the cross-linked network of homogeneity with primary amino radical on first kind of synthetic polymer of covalent bond or the primary amino radical on sulfydryl and the collagen.Multiple deacetylated and/or desulfurization acidify glycosaminoglycans derivant can be attached in the compositions with the above-mentioned similar manner of describing about collagen.In addition, the introducing such as the hydrocolloid of carboxymethyl cellulose can promote tissue to adhere to and/or dilatancy.

Using of crosslinked synthetic polymer compositions

Can be before first kind and second kind of synthetic polymer be crosslinked, during or use compositions of the present invention afterwards with two kinds of synthetic polymers.Some purposes discussed in detail increases as tissue below, may need compositions crosslinked before using, and other application adheres to as tissue, needs compositions preceding the using of crosslinked reaching " balance ".Crosslinkedly reach equilibrated point and be defined as the point that compositions feels that no longer viscosity or sense of touch are clamminess in this article.

In order to use compositions before crosslinked, first kind of synthetic polymer and second kind of synthetic polymer can be included in the independent cylinder of two compartment syringes.In this case, be expressed into that time patient's the tissue, two kinds of unactual mixing of synthetic polymer from the syringe needle point up to two kinds of polymer.This allows most cross-linking reactions to react in position, avoid the syringe needle blocking problem, if two kinds of synthetic polymers mix too early and sending crosslinked too fast between preceding two kinds of components from syringe needle, the syringe needle blocking problem takes place so usually as mentioned above, the syringe needle diameter that the application requirements of double-chamber syringe uses is less, this is in implementing meticulous facial tissue, such as being favourable when circumocular soft tissue increases art.

Alternatively, can be before being delivered to tissue site mix first kind of synthetic polymer and second kind of synthetic polymer according to said method, after mixing then immediately (preferably, in about 60 seconds) be expelled to desirable tissue site.

In another embodiment of the present invention, mix first kind of synthetic polymer and second kind of synthetic polymer, then it is extruded and allows crosslinked in blocks or other solid form.Then linked solid is dewatered to remove all unconjugated water basically.The gained drying solid can be milled or is ground into granule; be suspended in non-aqueous fluid carrier then; comprise; but be not limited in collagen, glycogen, glycerol, dextrose, maltose, fatty acid (as Semen Maydis oil, soybean oil and Oleum sesami) triglyceride and the lecithin of hyaluronic acid, dextran sulfate, glucosan, the noncrosslinking collagen of succinyl groupization, methylated noncrosslinked.The granule suspensoid can be by small size needle injection to tissue site.In case in tissue, crosslinked polymer beads can expand rehydration and size 5 times at least.

Hydrophilic polymer+multiple crosslinkable composition

As mentioned above, can be with described first kind and/or second kind of synthetic polymer and hydrophilic polymer, for example collagen protein or methylated collagen albumen merge, and are formed for compositions of the present invention.In a general embodiment, be used for the combination that compositions of the present invention comprises hydrophilic polymer and two or more crosslinkable compositions.This embodiment is described in further detail in this section.

The hydrophilic polymer composition:

The hydrophilic polymer composition can be synthetic or naturally occurring hydrophilic polymer.Naturally occurring hydrophilic polymer includes, but are not limited to: protein, and such as collagen protein and derivant, fibronectin, albumin, globulin, fibrinogen and fibrin, preferred especially collagen protein; The carboxylic acid polysaccharide is such as polymannuronic acid and polygalacturonic acid; Amination polysaccharide, particularly glycosaminoglycan, for example hyaluronic acid, chitin, chondroitin sulfate A, B or C, keratan sulfate, keratosulfate and heparin; With activatory polysaccharide, such as glucosan and starch derivatives.The naturally occurring hydrophilic polymer that collagen protein (for example methylated collagen albumen) and glycosaminoglycan preferably use for this paper.

In general, the collagen protein from any source can be included in the compositions of the present invention; For example, can be from people or other mammal source, such as extracting and collagen purification albumen in the corium of cattle or pig and the Placenta Hominis, or collagen protein can recombinate, otherwise production.The solution that is prepared the non-basically antigen collagen protein of purification by Corii Bovis seu Bubali is well-known in the art.For example, referring to the U.S. Patent number 5,428,022 of Palefsky etc., wherein disclosed from people's Placenta Hominis and extracted and the proteic method of collagen purification.Referring to the United States Patent (USP) 5,667,839 of Berg, wherein disclosed and used transgenic animal in addition, comprised that the milk of transgenic milch cow is produced the proteic method of recombinant human collagen.Except as otherwise noted, term used herein " collagen protein " or " collagen substance " refer to the collagen protein of form of ownership, comprise that those process, otherwise are exactly the collagen protein of modifying.

The collagen protein of any type includes, but are not limited to I type, II type, III type, IV type or its combination in any and can be used for compositions of the present invention, but, and general preferred I type.Can use the collagen protein that contains atelopeptide or end peptide; Yet, when using from the time such as the collagen protein in this class source of bovine collagen albumen, general preferred atelopeptide collagen protein, this be because of its immunogenicity with contain the collagen protein of holding peptide and compare due to the reduction.

Before be not preferred in the compositions of the present invention, although can use previous crosslinked collagen by the crosslinked collagen of method such as heat, radiation or chemical cross-linking agent.Noncrosslinking non-end peptide fiber collagen can (Santa Barbara be Calif.) respectively with trade mark from McGhan Medical Corporation by commercial sources

I collagen and

II collagen obtains with the concentration of 35mg/ml and 65mg/ml.The non-end peptide fiber collagen of glutaraldehyde cross-linking can be by commercial sources from McGhan Medical Corporation with trade mark

Collagen obtains with the concentration of 35mg/ml.

Although not necessarily necessary, be used for collagen protein of the present invention generally at the about 20mg/ml of the concentration of aqueous suspension-about 120mg/ml; Preferred about 30mg/ml-about 90mg/ml.

Although preferred complete collagen protein, the collagen protein of degeneration, recombinant gelatins also can be used for compositions of the present invention usually.Gelatin has the additional beneficial effect than the faster degraded of collagen protein.

The non-protofibre collagen protein generally obtains preferably because of its bigger surface area and bigger reactive group concentration.Term " non-protofibre collagen protein " refers to any modification that is essentially the non-protofibre form under pH7 or the collagen substance of unmodified, and is shown as the optical clarity by the collagen protein aqueous suspension.

The collagen protein that has been the non-protofibre form can be used for compositions of the present invention.Term used herein " non-protofibre collagen protein " is in order to the collagen protein type of the non-protofibre that is included as native form and become to be the collagen protein of non-protofibre form by chemical modification about neutral pH.For the collagen protein of the non-protofibre (or microfibril) of native form comprises IV type, VI type and VII type.

The collagen protein that is the chemical modification of non-protofibre form under neutral pH comprises succinylation collagen protein, propylated collagen protein, ethylization collagen protein, methylated collagen albumen etc.; they all can be according to the United States Patent (USP) 4 of Miyata etc.; 164; the preparation of method described in 559 is incorporated herein by reference the full content of the document.Methylated collagen albumen is particularly preferred for bioadhesive compositions because of its intrinsic viscosity, as disclosed in the United States Patent (USP) 5,614,587 of Rhee etc.

The collagen protein that is used for crosslinking polymer composition of the present invention begins to be the fibril form, gives its non-protofibre by adding one or more fiber decomposing agents then.Described fiber decomposing agents must exist so that give collagen protein with capacity be essentially non-protofibre as mentioned above under pH7.Be used for fiber decomposing agents of the present invention and include, but are not limited to various biocompatibility alcohols, aminoacid, inorganic salt and carbohydrate, preferred especially biocompatibility alcohols.Preferred biocompatibility alcohols comprises glycerol and propylene glycol.The non-biocompatible alcohols is not preferred for the present invention such as ethanol, methanol and isopropyl alcohol, produces potential illeffects because they permeate the patient who accepts it.Preferred amino acids comprises arginine.Preferred inorganic salt comprises sodium chloride and potassium chloride.Although can be used to implement the present invention such as this class carbohydrate of the various sugar that comprise sucrose, they are not preferred equally with the fiber decomposing agents of other type, because they may have cytotoxic effect in vivo.

Because the fibril collagen protein has the surface area and the reactive group that be lower than its concentration littler than non-protofibre, so the fibril collagen protein is more not preferred.Yet as United States Patent (USP) 5,614, disclosed in 587, the mixture of the plain collagen protein of fibril collagen protein or non-protofibre and fibril can be preferred for purpose and be that the compositions that retains in vivo for a long time, condition are and do not require optical clarity.

Synthetic hydrophilic polymer also can be used for the present invention.Useful synthesis hydrophilic polymer includes, but are not limited to: polyalkylene oxide class, particularly Polyethylene Glycol and poly-(oxirane-poly-(expoxy propane) copolymer comprises block copolymer and random copolymer; Polyalcohols, such as glycerol, polyglycereol (particularly hyperbranched polyglycereol), propylene glycol and the propylene glycol that replaces with one or more polyalkylene oxides, for example one-, two-and three-polyoxy ethylization glycerol, one-and two-polyoxy ethylization propylene glycol and-and two-polyoxy ethylization trimethylene glycol; Polyoxy ethylization sorbitol, polyoxy ethylization glucose; Acrylate copolymer and analog thereof and copolymer, such as polyacrylic acid itself, polymethylacrylic acid, poly-(ethoxy-methacrylate), poly-(hydroxy ethyl methacrylate), poly-(methyl alkyl sulfoxide methacrylate), poly-(methyl alkyl sulfoxide acrylate) and above-mentioned arbitrary substance and/or with other acrylate kind, such as the copolymer of acrylic acid ammonia ethyl ester and succinic acid one-2-(acryloxy)-ethyl ester; Poly; Poly-(acrylamide) is such as polyacrylamide itself, poly-(Methacrylamide), poly-(DMAA) and poly-(N-isopropyl-acrylamide); Poly-(enol) class is such as poly-(vinyl alcohol); Poly-(N-vinyl lactam) is such as poly-(vinyl pyrrolidone), poly-(N-caprolactam) and copolymer thereof; Ju oxazoline class comprises poly-(Jia oxazolin) and poly-(ethyl oxazoline); With the polyethylene amine.Must emphasize just as will be understood by the skilled person in the art, the not limit of the above-mentioned polymer of enumerating, and can use various other synthetic hydrophilic polymeies.

Crosslinkable composition:

Compositions of the present invention also comprises multiple crosslinkable composition.Described crosslinkable composition participates in producing the reaction of crosslinked substrate separately.Before finishing cross-linking reaction, the crosslinkable composition provides and has made the inventive method produce necessary cohesive.

The crosslinkable composition is selected, made crosslinked generation be used for the non-immunogenic substrate of biocompatibility of the various application of context, the various application in the described context comprise that preventing that adhesion, bioactivator from sending, organizing increases and other application.Crosslinkable composition of the present invention comprises: have the composition A of m nucleophilic group, wherein m 〉=2; Have the electrophilic group that n can react with m nucleophilic group, wherein n 〉=2 and m+n 〉=4 with composition B.Can also have the third optional composition, i.e. optional member C, it have at least one for electrophilic group and can with the functional group of the nucleophilic group reaction of composition A, or have at least one can with the functional group of the electrophilic group reaction of composition B.Therefore, if exist, be present in functional group's sum sum 〉=5 of composition A, B and C so; Be total functional group 〉=5 that m+n+p draws, wherein p is the sense radix on the composition C, and as noted, 〉=1.Described composition be separately biocompatibility with non-immunogenic, and at least a composition is made up of hydrophilic polymer.In addition, as understandable, described compositions can contain extra crosslinkable components D, E, F etc.They have one or more nucleophilic groups or electrophilic group, and thus by participating in the formation of crosslinked biomaterials with other composition covalent bond.

M on a composition A nucleophilic group all can be identical, and perhaps alternatively, A can contain two or more different nucleophilic groups.Similarly, the electrophilic group of the n on the B component can be identical, perhaps can have two or more different electrophilic groups.Functional group on the optional components C is if nucleophilic, and is can or can be not identical with nucleophilic group on the component A, and on the contrary, if parent's electricity, the functional group on the optional components C is can or can be not identical with electrophilic group on the B component.

Therefore, described composition can be represented by following structural:

(I) R ¹(-[Q ¹] _q-X) _m(composition A),

(II) R ²(-[Q ²] _r-Y) _n(composition B) and

(III) R ³(-[Q ³] _s-Fn) _p(optional member C),

Wherein:

R ¹, R ²And R ³Be independently selected from C ₂-C ₁₄Alkyl, contain heteroatomic C ₂-C ₁₄The group that alkyl, hydrophilic polymer and hydrophobic polymer are formed, condition is R ¹, R ²And R ³In at least one is a hydrophilic polymer, preferred synthetic hydrophilic polymer;

On behalf of component A, X go up one of m nucleophilic group, and the last a plurality of X parts of A can be identical or different;

Y represents one of n electrophilic group on the B component, and the last a plurality of Y parts of A can be identical or different;

Fn represents the functional group on the optional components C;

Q ¹, Q ²And Q ³Be linking group;

M 〉=2, n 〉=2, m+n is 〉=4, q and r are 0 or 1 independently, when having optional components C, p 〉=1, and s is 0 or 1 independently.

Reactive group:

In fact X can be nucleophilic group arbitrarily, as long as can react with electrophilic group Y.Similarly, in fact Y can be electrophilic group arbitrarily, as long as can react with X.A kind of restriction of reality is only arranged, and promptly X should quite soon and carry out when mixing with aqueous medium automatically with the reaction of Y, does not need heating or has toxicity or non-biodegradable catalysts or other chemical reagent.In addition preferably, although not necessarily necessary, be reflected under the situation that does not need ultraviolet or other irradiation and take place.Ideal situation is that the reaction of X and Y should be finished in 60 minutes, in preferred 30 minutes.Most preferably reaction is carried out in about 5-15 minutes or 15 minutes.

The example that is suitable as the nucleophilic group of X includes, but are not limited to-NH ₂,-NHR ⁴,-N (R ⁴) ₂,-SH ,-OH ,-COOH ,-C ₆H ₄-OH ,-PH ₂,-PHR ⁵,-P (R ⁵) ₂,-NH-NH ₂,-CO-NH-NH ₂,-C ₅H ₄N etc., wherein R ⁴And R ⁵Be alkyl, be generally alkyl or monocyclic aryl, preferred alkyl and low alkyl group most preferably.The organic metal part also is useful nucleophilic group for the purposes of this invention, and particularly those play the group of carbanion donor.Yet, not preferred organic metal nucleophilic group.The example of organic metal part comprises: Ge Liya functional group-R ⁶MgHal, wherein R ⁶Be carbon atom (replace or unsubstituted), and Hal is halogen, is generally bromine, iodine or chlorine, preferred bromine; With the functional group who contains lithium, be generally the lithium alkylide part; The functional group who contains sodium.

Skilled person in the art will appreciate that and to make some nucleophilic group activation so that can react with alkali with electrophilic group.For example, when having nucleophilic sulfydryl and hydroxyl in the compositions crosslinkable, said composition must be mixed with alkaline aqueous solution so that remove deprotonation and provide-S-or-O-kind and can reacting with electrophilic group.Unless need alkali to participate in cross-linking reaction, otherwise preferred non-nucleophilic alkali.In certain embodiments, described alkali can be used as the composition existence of buffer solution.Describe in suitable alkali and the corresponding cross-linking reaction E part hereinafter.

Must be in cross-linkable composition, promptly the electrophilic group that provides on the composition B is selected reacting with specific nucleophilic group.Therefore, when X partly is amino, select Y so that react with amino.Similarly, when X partly was the sulfydryl part, corresponding electrophilic group was sulfydryl-reactive group etc.

As an example, when X was amino (general, as to be decided to be primary amino radical but differ), the electrophilic group that is present on the Y was amino reactive group, such as, but be not limited to: (1) carboxylic acid esters comprises cyclic ester class and " activatory " esters; (2) the acid chloride part (CO-Cl); (3) anhydrides ((CO)-O-(CO)-R); (4) ketone and aldehydes comprise α, beta-unsaturated aldehyde class and ketone, such as-CH=CH-CH=O and-CH=CH-C (CH ₃)=O; (5) halogenide; (6) isocyanates (N=C=O); (7) sulfocarbimide (N=C=S); (8) epoxide; (9) activatory hydroxyl (for example,, activatory) such as carbonyl dimidazoles or sulfonic acid chloride with activator commonly used; (10) olefines comprises conjugated alkenes, such as ethylidene sulfonyl (SO ₂CH=CH ₂) and similar functional group, comprise acrylate (CO ₂-C=CH ₂), methacrylate (CO ₂-C (CH ₃)=CH ₂)), ethyl acrylate (CO ₂-C (CH ₂CH ₃)=CH ₂) and ethyleneimino (CH=CH-C=NH).Because carboxylic moiety itself is to insensitive with the reaction of nucleophilic amine, so the composition that contains carboxylic moiety is activated so that become amine-reactive.Can activate according to variety of way, but be usually included in dehydrant, exist the chemical compound of following and suitable hydroxyl to react such as dicyclohexylcarbodiimide (DCC) or 1,3-Dicyclohexylurea (DHU).For example, can make the N-hydroxyl-butanimide of carboxylic acid and alkoxyl-replacement or N-hydroxysulphosuccinimide form reactive electrophilic group, be respectively N-hydroxy-succinamide ester and N-hydroxysulphosuccinimide in that reaction in the presence of the DCC is arranged.Can also be by providing the reactive acid anhydride component with acyl halide such as acid chloride (for example chloroacetic chloride) reaction activating carboxy acid.In another example, for example, can use the thionyl chloride or the acid chloride that can carry out exchange reaction that carboxylic acid is changed into acid chloride.The concrete reagent that carries out this class priming reaction is conventionally known to one of skill in the art with operating procedure and is described in relevant textbook and the document.

Similarly, when X is sulfydryl, be present on the Y electrophilic group for the group of sulfydryl partial reaction.This class reactive group comprises that those form the group of thioester bond when reacting with sulfydryl, is described in group among the PCT publication number WO 00/62827 of Wallace etc. such as those.As detailed explanation wherein, this class " sulfydryl reaction " group includes, but are not limited to: the mixed acid anhydride class; The ester derivant of phosphorus; Paranitrophenol, to the ester derivant of nitrothiphenol and Pentafluorophenol; The esters of the hydroxylamine that replaces comprises N-hydroxyl phthalimide esters, N-hydroxy-succinamide esters, N-hydroxysulphosuccinimide ester and N-hydroxyl glutarimide esters; The esters of I-hydroxybenzotriazole; 3-hydroxyl-3,4-dihydro-phentriazine-4-ketone; 3-hydroxyl-3,4-dihydro-chinazoline-4-ketone; The carbonylic imidazole derivant; Acid chloride; The ethylene ketone; And isocyanates.Auxiliary reagent can be used to promote the formation of key owing to used the sulfydryl reactive group, for example, 1-ethyl-3-[3-dimethylamino-propyl] carbodiimide can be used to promote sulfydryl and carboxylic group coupling.

Except that the sulfydryl reactive group that forms thioester bond, can use various other sulfydryl reactive functional group bases that form other type bonds.For example, the chemical compound and the sulfydryl formation imino group-thioester bond that contain the imidic acid methyl ester derivation.Alternatively, can use the sulfydryl reactive group that forms disulfide bond with sulfydryl; This class group generally has structure-S-S-Ar, wherein Ar is for replacing or unsubstituted nitrogenous heteroaromatic moiety or non--heterocyclic aromatic group of partly being replaced by electron withdraw group, make Ar can for: for example 4-pyridine radicals, o-nitrophenyl ,-nitrobenzophenone, right-nitrobenzophenone, 2,4-dinitrophenyl, 2-nitro-4 benzoic acid, 2-nitro-4-pyridine radicals etc.In this class situation, auxiliary reagent, promptly Shi Du oxidant can be used to promote disulfide bond to form such as hydrogen peroxide.

Another kind of sulfydryl reactive group and sulfydryl form thioether bond.This class group is particularly including maleimide amino, haloalkyl, epoxy, imino group and the '-aziridino of maleimide amino, replacement and olefines (comprising conjugated alkenes); such as ethylidene sulfonyl, ethylidene imino group, acrylate, methacrylate and α, beta-unsaturated aldehyde class and ketone.Preferred especially this class sulfydryl reactive group is because thioether bond can provide crosslinked and longer faster body internal stability.

When X be-during OH, electrophilic functional group on the residual components and hydroxyl reaction.With regard to carboxylic moiety, can activate hydroxyl as mentioned above, maybe can make it having in the presence of the alkali and having enough reactive electrophilic reagent reaction, such as ethylene oxide moiety, aziridine part, acyl halide or anhydride.

When X is the organic metal nucleopilic reagent, during such as Ge Liya functional group or lithium alkylide part, contain the functional group of carbonyl for those with the suitable electrophilic functional group of its reaction, as an example, comprise ketone and aldehydes.

It is also understood that some functional group can be used as nucleopilic reagent or as the electrophilic reagent reaction, this depends on the reaction gametophyte and/or the reaction condition of selection.For example, carboxylic moiety plays nucleopilic reagent having in the presence of the great alkali, but generally plays electrophilic reagent, makes to carry out nucleophillic attack and simultaneously with the nucleopilic reagent substituted hydroxy that obtains on carbonyl carbon.

Covalent bond in the cross-linked structure that produces when concrete nucleophilic composition is with concrete electrophilic composition covalent bond in cross-linkable composition comprises as the lower part and (has for clarity sake omitted the optional base Q that is connected ¹And Q ²), but only as an example:

Table

Connect base:

Functional group X on the optional member C can directly examine be connected with chemical compound with FN with Y and (be respectively the R on the optional member C ¹, R ²Or R ³), or they can be by connecting base connection indirectly, and wherein long connection base is also referred to as " chain extender ".At structural formula (I), (II) with (III), optional connection base is by Q ¹, Q ²And Q ³Expression wherein exist to connect base, and this moment, q, r and s equaled 1 (wherein R, X, Y, Fn, mn and p are as above-mentioned definition).

Suitable connection base is well-known in the art.For example, referring to International Patent Publication No. WO 97/22371.Connect base and be used to the steric hindrance problem of avoiding relevant with the direct key of intermolecular formation sometimes.Connecting base can also be used for several multifunctional activatory chemical compounds being connected to each other and obtaining bigger molecule.In preferred embodiments, connect the degradation characteristic that base can be used to change compositions behind administration and the gained gel formation.For example, can will connect base introducing composition A, B or optional member C to promote hydrolysis, prevention hydrolysis or to be that enzymatic degradation provides the site.

Provide the example of the linking group in hydrolyzable site to comprise: ester bond; Anhydride bond is as the anhydride bond by obtaining in conjunction with 1,3-propanedicarboxylic acid and succinic acid; Original acid ester key; The orthocarbonic acid ester bond is as the propylene carbonate key; Amido link; The phosphoric acid ester bond; The alpha-hydroxy acid key is such as obtaining by introducing lactic acid and glycolic; Based on the key of lactone, such as can be by introducing caprolactone, valerolactone, gamma-butyrolacton and-diethyleno dioxide ketones being obtained; And amido link, as the amido link in dimer, oligomer or poly-(aminoacid) fragment.The example of non-degradable linking group comprises butanimide, propanoic acid and carboxylic formic acid ester bond.See, for example, PCT WO 99/07417.The example of the degradable key of enzyme comprises Leu-Gly-Pro-Ala, and it can pass through degraded by collagenase; And Gly-Pro-Lys, it can be degraded by fibrinolysin.

Linking group can also strengthen or suppress the reactivity of multiple nucleophilic and electrophilic group.For example, the electron withdraw group in of sulfydryl and two carbon can be estimated because the reduction nucleophilicity reduces the effectiveness in its coupling.Carbon-to-carbon double bond and carbonyl will also have this effect.On the contrary, the electron withdraw group adjacent with carbonyl (for example, the reactive carbonyl of glutaryl-N-hydroxy-succinamide base) can increase the reactivity of carbonyl carbon about the nucleopilic reagent that enters.On the contrary, thus the neutral body bulky group can be used to reduce reactivity and reduces coupling speed owing to sterically hindered near the functional group.

As an example, gone out concrete linking group and respective components structure at the following table middle finger:

Table

Connect base	Constituent structure
		-O-(CH 2) n-	Composition A:R 1-O-(CH 2) n-X composition B:R 2-O-(CH 2) n-Y optional member C:R 3-O-(CH 2) n-Z
-S-(CH 2) n-	Composition A:R 1-S-(CH 2) n-X composition B:R 2-S-(CH 2) n-Y optional member C:R 3-S-(CH 2) n-Z
		-NH-(CH 2) n-	Composition A:R 1-NH-(CH 2) n-X composition B:R 2-NH-(CH 2) n-Y optional member C:R 3-NH-(CH 2) n-Z
-O-(CO)-NH-(CH 2) n-	Composition A:R 1-O-(CO)-NH-(CH 2) n-X composition B:R 2-O-(CO)-NH-(CH 2) n-Y optional member C:R 3-O-(CO)-NH-(CH 2) n-Z
		-NH-(CO)-O-(CH 2) n-	Composition A:R 1-NH-(CO)-O-(CH 2) n-X composition B:R 2-NH-(CO)-O-(CH 2) n-Y optional member C:R 3-NH-(CO)-O-(CH 2) n-Z
-O-(CO)-(CH 2) n-	Composition A:R 1-O-(CO)-(CH 2) n-X composition B:R 2-O-(CO)-(CH 2) n-Y optional member C:R 3-O-(CO)-(CH 2) n-Z
		-(CO)-O-(CH 2) n-	Composition A:R 1-(CO)-O-(CH 2) n-X composition B:R 2-(CO)-O-(CH 2) n-Y optional member C:R 3-(CO)-O-(CH 2) n-Z
-O-(CO)-O-(CH 2) n-	Composition A:R 1-O-(CO)-O-(CH 2) n-X composition B:R 2-O-(CO)-O-(CH 2) n-Y optional member C:R 3-O-(CO)-O-(CH 2) n-Z
		-O-(CO)-CHR 7-	Composition A:R 1-O-(CO)-CHR 7-X composition B:R 2-O-(CO)-CHR 7-Y optional member C:R 3-O-(CO)-CHR 7-Z
-O-R 8-(CO)-NH-	Composition A:R 1-O-R 8-(CO)-NH-X composition B:R 2-O-R 8-(CO)-NH-Y optional member C:R 3-O-R 8-(CO)-NH-Z

In last table, n is generally 1 to about 10, R ⁷Be generally alkyl, typically be alkyl or aryl, preferred alkyl, low alkyl group most preferably, R ⁸Be alkylene, contain heteroatomic alkylene, the alkylene of replacement, the heteroatomic alkylene that perhaps contains replacement is generally alkylidene or arlydene (also have optional that replace and/or contain heteroatomic), and preferred low-grade alkylidene (for example, methylene, ethylene, positive propylidene, positive butylidene, or the like), phenylene, perhaps the amide alkylidene (for example ,-(CO)-NH-CH ₂).

Other General Principle of considering about linking group is as follows: if will use higher molecular weight component, they preferably have aforesaid biodegradable key, thereby do not produce greater than 20,000 molar fragments during absorbing in health again.In addition, in order to promote water intersolubility and/or dissolubility, can wish to add enough electric charges or hydrophilic.Use known chemosynthesis can easily introduce hydrophilic group, only otherwise cause undesirable reduction of undesirable expansion or compressive strength.Particularly, poly-alkoxyl fragment can weaken gel strength.

The component core:

" core " of every kind of crosslinkable component comprises nucleophilic or the bonded molecular structure of electrophilic group.For component A, use formula (I) R ¹-[Q ¹] _q-X) _m, for B component, use formula (II) R ²(-[Q ²] _r-Y) _n, for optional components C, use formula (III) R ³(-[Q ³] _s-Fn) _p, " core " group is R ¹, R ²And R ³Each molecule core of the reactive component of compositions crosslinkable is selected from synthetic and naturally occurring hydrophilic polymer, hydrophobic polymer and C usually ₂-C ₁₄Alkyl, 0 to 2 is selected from N, the hetero atom of O and S, condition is crosslinkable component A, B comprises the molecule core of synthetic hydrophilic polymer with at least one of the C that chooses wantonly.In preferred embodiments, at least one of A and B comprises the molecule core of synthetic hydrophilic polymer.

The hydrophilic crosslinkable component

On the one hand, crosslinkable component is a hydrophilic polymer.Term used herein " hydrophilic polymer " refers to synthetic polymer, and it has mean molecule quantity and effectively makes this polymer be the composition of " hydrophilic " as defined above.As above discuss, the synthetic crosslinkable hydrophilic polymer that can be used for this paper includes, but are not limited to: polyalkylene oxide, especially Polyethylene Glycol and poly-(oxirane-poly-(expoxy propane) copolymer comprises block and random copolymer; Polyhydric alcohol, as glycerol, polyglycereol (especially hyperbranched polyglycereol), by the propylene glycol and the trimethylene glycol of one or more polyalkylene oxide classes replacements, for example, for example, single-, two-and three-polyoxy ethylization glycerol, single-and two-polyoxy ethylization propylene glycol, and single-and two-polyoxy ethylization propylene glycol; Polyoxy ethylization sorbitol, polyoxy ethylization glucose; Acrylate copolymer and analog thereof and copolymer, as polyacrylic acid self, polymethylacrylic acid, poly-(hydroxyethyl-methacrylic acid), poly-(hydroxyethyl acrylic acid), poly-(methyl alkyl sulfoxide methacrylate), poly-(methyl alkyl sulfoxide acrylate) and front any copolymer and/or with the other acrylic species such as the copolymer of amino-ethyl acrylate and list-2-(propenyloxy group) ethyl succinate; Poly; Poly-(acrylamide), own as poly-(acrylamide), poly-(MAAm), poly-(DMAA) and poly-(N-isopropyl-acrylamide); Poly-(enol) is as poly-(vinyl alcohol); Poly-(N-vinyl lactam), as poly-(vinyl pyrrolidone), poly-(N-caprolactam), and copolymer; The Ju oxazoline comprises poly-(Jia oxazolin) and poly-(ethyl oxazoline); And polyvinylamine.The polymer tabulation that must emphasize the front is not limit, as will be apparent to those skilled in the art, can use many other synthetic hydrophilic polymeies.

Synthetic crosslinkable hydrophilic polymer can be homopolymer, block copolymer, random copolymer, perhaps graft copolymer.In addition, polymer can be a line style or branched, if branched, can be highly branched, dendritic, super branched or star polymer by bottom line.This polymer can comprise biodegradable fragment and block, and it is distributed in the molecular structure of whole polymer or with single block and exists, and perhaps is present in the block copolymer.Biodegradable fragment is that degraded is so that those fragments of fracture covalent bond.Usually, biodegradable fragment is the fragment of hydrolysis or original position enzymatic lysis in the presence of water.Biodegradable fragment can be made up of small molecule segment, and described small molecule segment is such as ester bond, anhydride bond, original acid ester key, orthocarbonic acid ester bond, amido link, phosphonate bond or the like.Bigger biodegradable " block " will be made up of oligomerization that mixes hydrophilic polymer or poly fragment usually.Illustrational biodegradable oligomerization and polymeric segment for example comprise, poly-(aminoacid) fragment, poly-(ortho esters) fragment, poly-(orthocarbonic ester) fragment, or the like.

Other suitable synthetic crosslinkable hydrophilic polymer comprises the polypeptide class of chemosynthesis, and is particularly synthetic and introduced the aminoacid (such as lysine) that contains primary amino radical and/or many nucleophilics polypeptide class of the aminoacid (such as cysteine) that contains sulfydryl.Especially preferably poly-(lysine), promptly a kind of polymer (145MW) by the synthetic amino acid lysine that produces.Prepared poly-(lysine), no matter under which kind of situation, it all has 6-about 4,000 primary amino radicals, is equivalent to about 870-about 580,000 molecular weight.Be used for molecular weight that poly-(lysine) of the present invention preferably have in about scope of 1,000-about 300,000, more preferably in about scope of 5,000-about 100,000, and most preferably in about scope of 8,000-about 15,000.Poly-(lysine) of different molecular weight available from Peninsula Laboratories, and Inc. (Belmont, Calif.).

Described synthetic crosslinkable hydrophilic polymer can be homopolymer, block copolymer, random copolymer or graft copolymer.In addition, what described polymer can be for line style or branching, and if branching, so can for minimum level to highly branched, dendritic, excessive branching or star-type polymer.This polymer can comprise biodegradable chain link and block, and they can fully be distributed in separately in the molecular structure of polymer or as single block and exist, as are present in the block copolymer.Biodegradable chain link is degraded to interrupt the chain link of covalent bond for those.In general, biodegradable chain link is for having in the presence of the water hydrolysis and/or the chain link of enzymatic lysis in position.Biodegradable chain link can be made up of the micromolecule chain link, such as ester bond, anhydride bond, original acid ester key, orthocarbonic acid ester bond, amido link, phosphoric acid ester bond etc.Bigger biodegradable " block " generally is made up of the oligomeric or polymerization chain link of introducing in the hydrophilic polymer.Comprise poly-(aminoacid) chain link for biodegradable illustrative is oligomeric as an example with the polymerization chain link, poly-(ortho esters) chain link, poly-(orthocarbonic ester) chain link etc.

As noted above, although can use multiple different synthetic crosslinkable hydrophilic polymer in the present composition, but preferred synthetic crosslinkable hydrophilic polymer is Polyethylene Glycol (PEG) and polyglycereol (PG), especially highly branched polyglycereol.The PEG of various ways is widely used in the modification of bioactive molecule, because PEG lacks toxicity, antigenicity and immunogenicity (that is, being biocompatible), can prepare so that have the dissolubility of wide region, and the conformation of common not interferases activity and/or peptide.For some application, especially preferred synthetic crosslinkable hydrophilic polymer is Polyethylene Glycol (PEG), it has about 100 to about 100, the molecular weight of 000 mole scope, although for highly branched PEG, can use more high molecular weight polymers-up to 1,000,000 or above-condition be to mix biodegradable site will have molecular weight less than about 30,000 to guarantee all catabolites.Yet for most PEG, preferred molecular weight is about 1,000 to about 20,000, and more preferably from about 7,500 in about 20,000 scopes.Most preferably, Polyethylene Glycol has about 10,000 mole.

Naturally occurring crosslinkable hydrophilic polymer includes, but are not limited to: protein, and as collagen, fibronectin, albumin, globulin, fibrinogen and fibrin, especially preferred collagen; Carboxylated polysaccharide is as polymannuronate and polygalacturonic acid; The amination polysaccharide, glycosaminoglycans especially, as hyaluronic acid, chitin, chondroitin sulfate A, B or C, keratan sulfate, keratosulfate and heparin; With activatory polysaccharide, as glucosan and starch derivatives.Collagen and glycosaminoglycans are the examples that is used for the preferred naturally occurring hydrophilic polymer of this paper, and methylated collagen is a preferred hydrophilic.

Any hydrophilic polymer of this paper must contain, and perhaps activate and contain functional group, that is, nucleophilic or electrophilic group, it makes can be crosslinked.The activation of PEG is discussed below; Yet, will understand, following discussion is used to illustrate purpose and can uses similar techniques to other polymer.

At first, with regard to PEG, various functionalized polyethylene glycols effectively such as protein modification (referring to Abuchowski etc., " as the enzyme of medicine " (Enzymes as Drugs), JohnWiley ﹠amp; Sons:New York, N.Y. (1981) pp.367-383; With Dreborg etc., " medicament carrier system therapy evaluation summary " (Crit.Rev.Therap.Drug Carrier Syst.) (1990) 6:315).Chemistry of peptides is (referring to Mutter etc., " peptide class " (The Peptides), Academic:NewYork, N.Y.2:285-332; With Zalipsky etc., " peptide protein matter research magazine " (Int.J.PeptideProtein Res.) (1987) 30:740) and polymeric medicine synthetic (referring to Zalipsky etc., " European polymer magazine " be (1983) 19:1177 (Eur.Polym.J.); With Ouchi etc., " macromolecular science and The Chemicals " be (1987) A24:1011 (J.Macromol.Sci.Chem.)) use in this class field.

The PEG of activated form, comprise multifunctional activatory PEG be purchased and be easy to use known method preparation.For example, referring to " poly-(ethylene glycol) chemistry-biotechnology and biological medicine are used " (Poly (ethylene Glycol) Chemistry:Biotechnical and BiomedicalApplications) the 22nd chapter, J.Milton Harris, ed., Plenum Press, NY (1992); With Shearwater Polymers, Inc.Catalog, " polyethyleneglycol derivative " (Polyethylene GlycolDerivatives), Huntsville, Alabama (1997-1998).

Some of PEG are specific, the structure of the activatory form of four senses is at United States Patent (USP) 5,874, show among Fig. 1 to 10 of 500, and they are by with activatory PEG and polyamino PEG, promptly have the vague generalization product that the PEG of two or more primary amino radicals reacts.Illustrated activatory PEG has tetramethylolmethane (2,2-two (hydroxymethyl)-1, ammediol) core.As will be apparent to those skilled in the art, this type of activatory PEG can be easily by (promptly with the hydroxyl of the exposure in the PEGization polyhydric alcohol, terminal hydroxyl on the PEG chain) changes into carboxylic group (usually by in the presence of nitrogenous base, reacting), obtain by obtaining multifunctional activatory PEG then with esterifications such as N-hydroxy-succinamide, N-hydroxysulphosuccinimides with anhydride.

Hydrophobic polymer:

Compositions crosslinkable of the present invention can also comprise hydrophobic polymer, although for most purposes, and the preferred hydrophilic polymer.Polylactic acid and polyglycolic acid are the examples of operable two kinds of hydrophobic polymers.For other hydrophobic polymer, contain the short chain oligomer of about 14 carbon atoms at most with only using, to avoid the relevant problem of dissolubility between the reaction period.

Low molecular weight compositions:

Point out that as top the molecule core of one or more crosslinkable components can also be a low molecular weight compound, promptly contain and be selected from N, O, 0 to 2 heteroatomic C of S and combination thereof ₂-C ₁₄Alkyl.This molecule core can replace with nucleophilic group or with electrophilic group.

When low-molecular-weight molecule nuclear was replaced by primary amino radical, described composition can be ethylenediamine (H for example ₂N-CH ₂CH ₂-NH ₂), tetra-methylenedimine (H ₂N-(CH ₄)-NH ₂), pentanediamine (cadaverine) (H ₂N-(CH ₅)-NH ₂), hexamethylene diamine (H ₂N-(CH ₆)-NH ₂), two (2-aminoethyl) amine (HN-[CH ₂CH ₂-NH ₂] ₂) or three (2-aminoethyl) amine (N-[CH ₂CH ₂-NH ₂] ₃).

Low molecular weight diol and polyhydric alcohol comprise trimethylolpropane, two (trimethylolpropane), tetramethylolmethane and diglycerol, they all need with the alkali activation so that promote their reactions as nucleopilic reagent.This type of dihydroxylic alcohols and polyhydric alcohol can also be functionalized to provide two-and many-carboxylic acid, functional group, it is above-mentioned as this paper, also can be under certain conditions as nucleopilic reagent.Being used for polyprotic acid of the present invention comprises, but be not limited to, tricarboxylic acids based on trimethylolpropane, tetrabasic carboxylic acid based on two (trimethylolpropanes), 1,5-pentanedicarboxylic acid., suberic acid (octanedioic acid) (suberic acid (suberic acid)), and hexadecandioic acid (hexadecane diacid) (thapsic acid), all these can be by commercial sources acquisition and/or easily synthetic with known technology.

Low-molecular-weight two-comprise with many-electrophilic reagent, for example, two succinimido suberates (DSS), two (sulfosuccinimide base) suberate (BS ₃), dithio two (succinyl phosphorons amino propyl acid ester) (DSP), two (2-butanimide oxygen base ketonic oxygen base) ethyl sulfone (BSOCOES) and 3,3 '-dithio two (sulfosuccinimide base propionic ester) are (DTSPP) and their analog and derivant.Chemical compound above-mentioned can (Rockford III.) obtains from Pierce by commercial sources.This two-and many-electrophilic reagent can also be from two-and polyprotic acid synthesize, for example, in the presence of DCC, react by N-hydroxy-succinamide with suitable mole.Can use multiple known technology that polyhydric alcohol such as trimethylolpropane and two (trimethylolpropane) are changed into carboxylic acid form, produce trifunctional and four functional activated polymers then by in the presence of DCC, deriving with NHS.

Delivery system:

The suitable delivery system that is used for homogenizing dry powder composite (containing at least two kinds of crosslinkable polymer) and two kinds of buffer can comprise many compartments sprayer unit, one of them and a plurality of compartments contain powder, the buffer that provides aqueous environments required is provided for one and a plurality of compartments, thereby compositions is exposed to aqueous environments when leaving compartment.To organize many devices of sealant/hemorrhage be well known in the art and can be used for enforcement of the present invention to be suitable for sending multicomponent.Alternatively, can use the controlled extrusion system delivering compositions of any kind, perhaps it can be sent so that dry powder form is manual, and is exposed to aqueous environments in site of administration.

Homogenizing dry powder compositions and two kinds of buffer can be by placing independent syringe cylinder conveniently to form under aseptic condition each of three kinds of compositions (dried powder, acidic buffer and alkaline buffer).For example, compositions, first kind of buffer and second kind of buffer can be deposited separately in the many compartments injector system with a plurality of tubes, mixing head and outlet opening.Can add first kind of buffer dissolved composition and form homogeneous phase solution holding in the tube of compositions, it be expressed in the mixing head then.Can simultaneously second kind of buffer be expressed in the mixing head.At last, resulting composition can be expressed on the surface by the hole.

For example, the syringe cylinder that holds dried powder and alkaline buffer can be the part of double syringe system (for example, the dual barrel syringe of describing in the United States Patent (USP) 4,359,049 of Redl etc.).In this embodiment, can add acidic buffer, thereby produce homogeneous phase solution to the syringe cylinder that also holds dried powder.In other words, acidic buffer can be added (for example, injection) in the syringe cylinder that holds dried powder, thereby produce the homogeneous phase solution of first kind and second kind component.This homogeneous phase solution can be expressed in the mixing head then, and alkaline buffer is expressed in the mixing head simultaneously.In mixing head, homogeneous phase solution and alkaline buffer are mixed together, thereby form reactant mixture.Afterwards, reactant mixture is expressed on the surface (for example, tissue) by the hole, forms film on this surface, and it can be used as confining bed and barrier layer or analog.When forming by homogeneous phase solution in the mixing mixing head and alkaline buffer, reactant mixture begins to form three dimensional matrix immediately.Therefore, be expressed into tissue from mixing head fast after reactant mixture is preferably formed, thereby form three dimensional matrix organizationally and it can adhere to this tissue.

Other system that merges two kinds of reaction liquids is that this area is well-known and comprise the United States Patent (USP) 6,454,786 of the system described in the following document: Holm etc.; 6,461,325 of Delmotte etc.; 5,585,007 of Antanavich etc.; 5,116,315 to of Capozzi etc.; With 4,631,055 of Redl etc.

Store and operation:

Because crosslinkable component contains the electrophilic group with water reaction, thus close electric component or component usually with aseptic, dried forms is stored and use to prevent that water from separating.The method for preparing the synthetic hydrophilic polymer that contains a plurality of electrophilic groups of aseptic, dried forms proposes in the common specified U.S. Patent number 5,643,464 of Rhee etc.For example, dry synthetic polymer can be compression molded into thin slice or film, it can use gamma-rays then, preferred e-bundle radiosterilization.Gained desciccator diaphragm or sheet can be cut into desirable size or be cut into littler granule.

Therefore the component that contains multiple nucleophilic group is not that water is reactive usually, and can dry storage or store in aqueous solution.If store with dry, granular solids, the various ingredients of compositions crosslinkable can be mixed in single container and store so.All components just take place before using at once with mixing of water, saline or other aqueous medium.

In alternative embodiment, linked can be mixed in the single aqueous medium, and wherein they can all be not reactive, that is, and and such as in low pH buffer.Afterwards, they can be sprayed on the target tissue with high pH buffer, and their fast reactions afterwards also form gel.

The suitable liquid medium of preserving compositions crosslinkable comprises aqueous buffer solution, and as sodium dihydrogen phosphate/sodium hydrogen phosphate, sodium carbonate/bicarbonate, glutamate, Glu or acetate, concentration is 0.5 to 300mM.Usually, be the sulfydryl reactive component that preparation replaces with dimaleoyl imino or succinimido in about 5 to 6 the dilution buffer liquid at water or pH, as PEG.The pK value that is used to prepare many sulfydryls component such as sulfydryl-PEG can be used for realizing containing quick-gelatinizing time of compositions of the mixture of sulfydryl-PEG and SG-PEG for about buffer of 8 to 10.5.These comprise carbonate, borate and AMPSO (3-[(1,1-dimethyl-2-hydroxyethyl) amino] 2-hydroxyl-propane-sulfonic acid).By contrast, use the combination of dimaleoyl imino PEG and sulfydryl-PEG, for preferably about 5 to 9 the pH of liquid medium that is used to prepare sulfydryl PEG.

Collagen protein+fibrinogen and/or thrombin (for example Costasis)

On the other hand, polymer composition can comprise collagen, and it makes up with fibrinogen and/or thrombin.(see, for example, U.S. Patent number 5,290,552; 6,096,309; With 5,997,811).For example, waterborne compositions can comprise fibrinogen and FXIII, blood plasma especially, and collagen, its consumption is enough to the multiviscosisty compositions, thrombin, the polymerization of the fibrinogen that its consumption is enough to exist in the catalyst composition, and Ca ²⁺And randomly, antifibrinolytic agent, its consumption is enough to hinder the degraded of gained viscosity grumeleuse.Compositions can be mixed with two-part compositions, it only mixes before use, and wherein fibrinogen/FXIII and collagen are formed first kind of component, thrombin and antifibrinolytic agent and Ca ²⁺Form second kind of component.

The blood plasma that provides fibrinogen to originate can be from obtaining the patient of its delivering compositions.After the standard fabrication, blood plasma can " tale quale " uses, and described standard fabrication comprises the centrifugal cellular component that goes out blood.Alternatively, the further processing to concentrate fibrinogen of blood plasma can be prepared cryoprecipitate.Can with blood plasma approximately-20 ℃ freezing at least about 1 hour, then at about 4 ℃ of frozen overnight blood plasma with the preparation cryoprecipitate that slowly thaws.The centrifugal blood plasma that thaws also comprises the cryoprecipitate that remains 1/5 blood plasma and prepares cryoprecipitate to provide by removing about 4/5 blood plasma.Can use other fibrinogen/FXIII prepared product, as cryoprecipitate, patient from body fibrin sealant, fibrinogen analog or other single donor or commercial fibrin sealant material.About 0.5ml provides about 1 to the 2ml binding compositions to about 1.0ml blood plasma or blood plasma-cryoprecipitate, and it enough is used for the middle ear surgical operation.Because preparation and the multiple variation for preparing the method for said preparation, other plasma proteins (for example, albumin, plasminogen, Feng's von willebrand's factor (von Willebrandsfactor), VIII factor or the like) can exist or can not be present in fibrinogen/FXII separator.

Collagen protein, the preferably hypoallergenic collagen protein is present in the compositions, and its consumption is enough to make compositions dense thick and increase the cohesive of preparation.Described collagen protein can be (non-end peptide collagen atelopeptide) collagen protein or end peptide collagen protein, for example natural collagen protein.Except that thickener composition, collagen protein also increases fibrin by macromole grid or the support effect that absorbs as the netted structure of fibrin.This feasible use is lower than various spissated fibrinogens from body fibrin virgin rubber goods (being AFGs) concentration relatively the viscosity grumeleuse is produced bigger intensity and durability.

Can be to be at least " near natural " aspect its architectural feature with the collagen protein formal description of using.It further can be characterized by under about 5 pH and obtain insoluble fibre; Unless be crosslinked or as the ingredient of complex composition, bone for example, otherwise it is generally by the minimum diameter that has greater than 50nm by weight, and about 1-25 volume %'s is fibrous usually, and aspect fibriilar helical structure, do not change basically if any.In addition, collagen composition must be able to promote the gelling of surgical operation adhesion compositions.

Can use many by the obtainable collagen protein preparation of commercial sources.ZYDERMCollagen Implant (ZCI) has and has in 90% volume content by 5 to 10nm diameter fibers, and remaining 10% is the distribution of fiber diameters of forming greater than the diameter fibers of about 50nm.ZCI can be with the isotonic saline solution of phosphate-buffered, and fiber slurry and solution among the pH7.2 obtain, and available thin gauge needle injection.As different, can use the crosslinked with collagen albumen that obtains with ZYPLAST with ZCI.ZYPLAST is the external source of ZCI crosslinked (glutaraldehyde) form basically.The diameter that this material has a high level is greater than the fibril of about 50nm and keep insoluble in wide pH scope.Crosslinked have an endogenous crosslinked effect of finding in many tissues in the analogue body.

Thrombin as the catalyst of fibrinogen so that fibrin to be provided---a kind of insoluble polymer and be present in the compositions with the polymeric amount of the fibrinogen that exists in the enough catalysis patient blood plasma.Thrombin also activates FXIII---and a kind of plasma proteins of covalent cross-linking in the catalysis fibre albumen makes that the gained grumeleuse is insoluble.Usually, thrombin is with about 0.01 to about 1000 or the activity of bigger NIH unit (NIHu), and usually about 1 to about 500NIHu, the most common about concentration of 200 to about 500NIHu is present in the adhesive composition.Thrombin can be from multiple animal origin, easily from cattle.Thrombin can be commercially available from multiple source, comprises Parke-Davis, and it is packed in the bottle with buffer salt and stabilizing agent lyophilizing usually, and it provides about 1000 NIHu to 10, the thrombin activity of 000 NIHu.Usually by sterile distilled water or the reconstruct of isotonic saline solution adding powder are prepared thrombin.Alternatively, can use the coagulating agent in thrombin analog or reptile source.

Compositions can additionally comprise the antifibrinolytic agent of effective dose to strengthen the integrity of agglutination gelled block between the emergence period.Many antifibrinolytic agents are known and comprise aprotinin, Cl-esterase inhibitor and epsilon-amino-just-caproic acid (EACA).Epsilon-amino-just-caproic acid is unique antifibrinolytic agent of FDA approval, and is effective under the concentration of the final adhesive composition of about 40mg/ml at about 5mg/ml, is more typically about 20 and arrives about 30mg/ml.EACA can obtain by the solution of commercial sources with concentration with about 250mg/ml.Easily, with commercial solution with distilled water diluting so that the solution of desired concentration to be provided.Wish that this solution is used for the freeze dried thrombin of reconstruct to obtain desirable concentration of thrombin.

Original position form based on other case description of the material of protein cross following down in: United States Patent (USP) RE38158 for example; 4,839,345; 5,514,379,5,583,114; 6,458,147; 6,371,975; 5,290,552; 6,096,309; U.S. Patent Application Publication No. 2002/0161399; 2001/0018598 and PCT publication number W003/090683; WO 01/45761; WO99/66964 and WO 96/03159).

The autoreaction chemical compound

On the one hand, from formed crosslinked substrate, discharge therapeutic agent to small part from the autoreaction chemical compound.Autoreaction chemical compound used herein comprises the core that replaces with minimum three reactive groups.Reactive group can be directly connected to the core of chemical compound, and perhaps reactive group can be connected to the core of chemical compound indirectly, and for example, reactive group connects core by one or more linking groups.

Each that must be present in three reactive groups in the autoreaction chemical compound can be carried out binding reaction with at least one of remaining two reactive group.In order to illustrate, mention when these chemical compound reactions form crosslinked substrate, reactive group on chemical compound of the most common generation and the reaction of the reactive group on another chemical compound.That is, term " autoreaction " is not intended to and refers to that each autoreaction chemical compound must react with himself, but carries out cross-linking reaction when many identical autoreaction chemical compounds make up, then these chemical compounds formation substrate that will react to each other.These chemical compounds can react with other chemical compound that has with they identical chemical constitutions for " autoreaction " is meant them.

The autoreaction chemical compound comprises at least 4 components: a core and three reactive groups.In one embodiment, the autoreaction chemical compound can characterize by through type (I), and wherein R is a core, and reactive group passes through X ¹, X ²And X ³Expression, joint (L) is optional to be present between core and the functional group.

Core R is connected to the multivalence part (that is, it is at least trivalent) of at least three groups and passable, perhaps for example can contain hydrophilic polymer, hydrophobic polymer, amphipathic nature polyalcohol, C _2-14Alkyl or contain heteroatomic C _2-14Alkyl.Linking group L ¹, L ², and L ³Can be identical or different.Symbol p, q and r are 0 (when not having joint) or 1 (when having joint).Reactive group X ¹, X ²And X ³Can be identical or different.Each of these reactive groups and at least one other reactive group reaction form three dimensional matrix.Therefore, X ¹Can with X ²And/or X ³Reaction, X ²Can with X ¹And/or X ³Reaction, X ³Can with X ¹And/or X ²Reaction or the like.The trivalent core can be directly or indirectly in conjunction with three functional groups, and the tetravalence core will be directly or indirectly in conjunction with four functional groups, or the like.

Each side chain has a reactive group usually.Yet the present invention also comprises the autoreaction chemical compound, and wherein side chain contains more than one reactive group.Thereby in another embodiment of the present invention, the autoreaction chemical compound has formula (II):

[X′-(L ⁴) _a-Y′-(L ⁵) _b] _c——R′

Wherein: a and b are the integer of 0-1; C is the integer of 3-12; R ' is selected from hydrophilic polymer, hydrophobic polymer, amphipathic nature polyalcohol, C _2-14Alkyl and contain heteroatomic C _2-14Alkyl; X ' and Y ' are reactive group and can be identical or different; L ⁴And L ⁵Be linking group.Each reactive group and another reactive group formation three dimensional matrix that reacts to each other.This chemical compound is essentially non-reacted in initial environment, but when being exposed to the change of initial environment, have reactivity, form three dimensional matrix in the environment of this change thereby described change provides the many autoreaction chemical compounds of the environment of change to interact.In a preferred embodiment, R is a hydrophilic polymer.In another preferred embodiment, X ' is that nucleophilic group and Y ' are electrophilic group.

Following autoreaction chemical compound is an example of formula (II) chemical compound:

R wherein ⁴Have formula:

Therefore, in formula (II), a and b are 1; C is 4; Nuclear R ' is a hydrophilic polymer, i.e. four sense activated polyglycol (C (CH ₂-O-) ₄X ' is an electrophilic reaction base succinimido; Y ' is necleophilic reaction base-CH-NH ₂L ⁴For-C (O)-O-; And L ⁵For-(CH ₂-CH ₂-O-CH ₂) _x-CH ₂-O-C (O)-(CH ₂) ₂-.

Autoreaction chemical compound of the present invention is easy to by technology well-known in the art synthetic.The typical case is synthetic as follows:

The selective response base makes chemical compound essentially no reactivity in initial environment.When being exposed to the specific change of initial environment, the environment of change is provided, make this responding property of chemical compound and many autoreaction chemical compounds in the environment that changes, to interact and form three dimensional matrix.The example that changes in the initial environment is discussed in more detail below, but comprises the adding aqueous medium, and the change of pH is exposed to ultraviolet radiation, the change of temperature, perhaps catalytic oxidation reduction initiator.

Can also select core and reactive group so that the chemical compound with one or more following features is provided: be biocompatible, right and wrong are immunogenic, do not stay any toxicity, inflammatory or immunogenic response product in site of administration.Similarly, can select core and reactive group so that the substrate of the gained with one or more these features is provided.

In one embodiment of the invention, immediately or behind the environment that changes being exposed to immediately, the autoreaction chemical compound just interacts and forms three dimensional matrix basically.Term " basically immediately " is intended to refer to be less than 5 minutes, preferably is less than in 2 minutes, and term " immediately " is intended to refer to be less than in 1 minute, preferably is less than in 30 seconds.

In one embodiment, autoreaction chemical compound and gained substrate are not subjected to the enzymatic cutting of matrix metalloproteinase such as collagenase, and therefore are not easy degradation in vivo.In addition, the autoreaction chemical compound can easily be controlled to strengthen some character according to every kind of components selection and amount, for example, and compressive strength, dilatancy, viscosity, hydrophilic, optical transparency or the like.

In a preferred embodiment, R is a hydrophilic polymer.In another preferred embodiment, X is a nucleophilic group, and Y is an electrophilic group, and Z is electrophilic or nucleophilic group.Other embodiments describe in detail below.

When the compressive strength of less expansible substrate of hope or increase, the interaction of higher degree, for example, crosslinked is useful.In those embodiments, can wish that n is the integer of 2-12.In addition, when utilizing many autoreaction chemical compounds, described chemical compound can be identical or different.

A. reactive group

Before the use, the autoreaction chemical compound is preserved to guarantee that chemical compound keeps non-reacted basically before use in initial environment.When changing this environment, make chemical compound have reactivity and then chemical compound lot react to each other and form desirable substrate.Thereby the character by the reactive group that relates to is determined initial environment, and the environment that changes.

The reactive group number can be identical or different.Yet, in one embodiment of the invention, the number approximately equal of reactive group.As above hereinafter used, term " about " refers to the ratio of the 2:1 of a kind of reactive group molal quantity and another differential responses base molal quantity to 1:2.The reactive group mol ratio of usually preferred 1:1:1.

Usually, when character was liquid, the autoreaction compound concentrations was about 1 to 50wt% in the environment that changes, and about 2 arrived 40wt% usually.The preferred concentration of chemical compound depends on many factors in the liquid, comprises the type (being the type of molecule core and reactive group) of chemical compound, the final use of their molecular weight and gained three dimensional matrix.For example, use the chemical compound of higher concentration, or use more that the chemical compound of highly functionalization will cause forming tightr crosslinked network, produce harder, more firm gel.Therefore, be intended to be used to organize the compositions of increase will use the autoreaction chemical compound of the higher-end concentration that falls into preferred concentration range for usually.Being intended to does not need for thin film and therefore contains the autoreaction chemical compound of low concentration as biological adhesive or the compositions that adheres to prevention.

1) electrophilic and necleophilic reaction base

In one embodiment of the invention, reactive group is electrophilic and nucleophilic group, and it carries out nucleophilic substitution, nucleophilic addition, or both.Term " parent's electricity " refers to be subject to nucleophillic attack, promptly is easy to and the reactive group of the nucleophilic group reaction that enters.The electrophilic group of this paper be positively charged or electron deficiency, be generally electron deficiency.Term " nucleophilic " refer to be rich in electronics, have as the unshared electron pair of reaction site and with the reactive group of positively charged or the reaction of electron deficiency site.For this type of reactive group, the change in the initial environment comprises the change that adds aqueous medium and/or pH.

In one embodiment of the invention, X1 (being also referred to as X herein) can be nucleophilic group, and (being also referred to as Y herein) can for electrophilic group or vice versa for X2, and X3 (being also referred to as Z herein) can be electrophilic or nucleophilic group.

X can be any nucleophilic group almost, if can with electrophilic group Y and also with Z (when Z be close electric (Z _EL) time) react.Similarly, Y can be any electrophilic group almost, if can with X and also with Z (when Z is nucleophilic (Z _NU) time) react.Unique restriction is actual restriction, is X and Y, X and Z _ELOr Y and Z _NUBetween reaction should be quite fast and when mixes, react automatically with aqueous medium, do not need to heat or possible deleterious or abiotic degradable catalysts or other chemical agent.Although is not essential preferably also, reacts and do not need ultraviolet or other radiation.In one embodiment, X and Y, X and Z _ELOr Y and Z _NUBetween be reflected at 60 minutes, finish in preferred 30 minutes.Most preferably, be reflected at about 5 to 15 minutes or shorter time in finish.

Suitable to X or Fn _NUThe example of nucleophilic group include, but are not limited to :-NH ₂,-NHR ¹,-N (R ¹) ₂,-SH ,-OH ,-COOH ,-C ₆H ₄-OH ,-H ,-PH ₂,-PHR ¹,-P (R ¹) ₂,-NH-NH ₂,-CO-NH-NH ₂,-C ₅H ₄N or the like, wherein R ¹Be alkyl and each R ¹Can be identical or different.R ¹Be generally alkyl or monocyclic aryl, preferred alkyl, most preferably low alkyl group.Organic metal part also is useful nucleophilic group for purpose of the present invention, especially as those organic metal parts of carbanion donor.The example of organic metal part comprises: Grignard degree of functionality-R ²MgHal, wherein R ²Be carbon atom (replacement or unsubstituted), Hal is a halogen, usually bromine, iodine or chlorine, preferably bromine; The functional group of containing lithium, lithium alkylide group usually; The functional group of containing sodium.

Those of ordinary skills will understand that some nucleophilic group must be with the alkali activation reacting with electrophilic group.For example, when having close electric sulfydryl and hydroxyl in the autoreaction chemical compound, chemical compound must and provide-S with the aqueous base reaction so that except that deprotonation ^-Or-O ^-Kind is reacting with electrophilic group.Participate in reaction unless wish alkali, preferred non-nucleophilic base.In some embodiments, alkali can exist with the component of buffer.Suitable alkali and corresponding cross-linking reaction are described hereinafter.

The selection of the electrophilic group that provides on the autoreaction chemical compound must be provided, thus may with specific nucleophilic group reaction.Therefore, when the X reactive group is amino, select Y and any Z _ELGroup is to react with amino.Similarly, when the X reactive group was the sulfydryl part, corresponding electrophilic group was the sulfydryl reactive group, or the like.Usually, suitable to Y or Z _ELThe example of electrophilic group include, but not limited to-CO-Cl ,-(CO)-O-(CO)-R (wherein R is an alkyl) ,-CH=CH-CH=O and-CH=CH-C (CH ₃)=O, halogen ,-N=C=O ,-N=C=S ,-SO ₂CH=CH ₂,-O (CO)-C=CH ₂,-O (CO)-C (CH ₃)=CH ₂,-S-S-(C ₅H ₄N) ,-O (CO)-C (CH ₂CH ₃)=CH ₂,-CH=CH-C=NH ,-COOH ,-(CO) O-N (COCH ₂) ₂,-CHO ,-(CO) O-N (COCH ₂) ₂-S (O) ₂OH and-N (COCH) ₂

When X is amino (although needing not to be primary amino radical usually), Y and Z _ELThe electrophilic group of last existence is the amine reactive group.Limit as an example and not, representative amine reactive group comprises following group or its free radical: (1) carboxylate comprises cyclic ester and " activation " ester; (2) the acid chloride group (CO-Cl); (3) anhydride ((CO)-O-(CO)-R), wherein R is an alkyl; (4) ketone and aldehyde comprise α, beta-unsaturated aldehyde and ketone, as-CH=CH-CH=O and-CH=CH-C (CH ₃)=O; (5) halogen group; (6) NCO (N=C=O); (7) sulfo-isocyanide acyl group group (thioisocyanato) (N=C=S); (8) epoxide; (9) activatory hydroxyl (for example, with conventional activator such as N,N'-carbonyldiimidazole or sulfonic acid chloride activation); (10) alkene comprises the alkene of puting together, as ethylene sulfonyl (SO ₂CH=CH ₂) and similar functional group, comprise acrylate (O (CO)-C=CH ₂), methacrylate (O (CO)-C (CH ₃)=CH ₂), ethyl acrylate (O (CO)-C (CH ₂CH ₃)=CH ₂) and the vinyl imino group (CH=CH-C=NH).

In one embodiment, amine-reactive group contains the electrophilic reactivity carbonyl to the nucleophillic attack sensitivity of primary amine or secondary amine, and for example above-mentioned carboxylic acid esters and aldehydes and carboxyl are (COOH).

Because hydroxy-acid group itself is difficult for and the nucleophilic amine reaction, the component of hydroxy-acid group must activate so that be that amine is reactive so contain.Can finish activation with several different methods, but be usually directed in the presence of dehydrant such as dicyclohexylcarbodiimide (DCC) or 1,3-Dicyclohexylurea (DHU), react with the suitable chemical compound that contains hydroxyl.For example, carboxylic acid N-hydroxyl-butanimide that can replace with alkoxyl or N-hydroxysulphosuccinimide react in the presence of DCC and form reactive electrophilic group respectively, N-hydroxyl-succinimide ester or N-hydroxysulphosuccinimide ester.Carboxylic acid can also be by reacting with carboxylic acid halides such as acyl chlorides (for example, chloroacetic chloride), so that the reactive acid anhydride group to be provided.In another example, can use-case carboxylic acid be changed into acid chloride groups as thionyl chloride or acid chloride that can exchange reaction.The particular agent that is used for implementing this type of priming reaction and step are that those of ordinary skills are known and describe at relevant teaching material and document.

Therefore, in one embodiment, the amine reactive group is selected from succinimido ester (O (CO)-N (COCH ₂) ₂), sulfosuccinimide base ester (O (CO)-N (COCH ₂) ₂-S (O) ₂OH), dimaleoyl imino (N (COCH) ₂), epoxy, isocyanide acyl, sulfo-isocyanide acyl, and ethylsulfonyl.

Similarly, when X is sulfydryl, Y and Z _ELThe electrophilic group of last existence is the group with the sulfydryl partial reaction.This type of reactive group comprises when reacting with sulfydryl those groups that form thioester bond, those that describe in WO 00/62827 as Wallace etc.As explaining in detail that therein the sulfydryl reactive group includes, but are not limited to: blended anhydride; The ester derivant of phosphorus; The ester derivant of paranitrophenol, p-nitrophenyl thiophenol and Pentafluorophenol; The ester of the azanol that replaces comprises N-hydroxyl phthalimide ester, N-hydroxy-succinamide ester, N-hydroxysulphosuccinimide ester and N-hydroxyl glutarimide ester; The ester of I-hydroxybenzotriazole; 3-hydroxyl-3,4-dihydro-phentriazine-4-ketone; 3-hydroxyl-3,4-dihydro-chinazoline-4-ketone; The carbonylic imidazole derivant; Acyl chlorides; Ketenes; And isocyanates.Use these sulfydryl reactive groups, auxiliary reagent also can be used to promote key to form, for example, 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide can be used to promote sulfydryl is coupled to the group that contains carboxyl.

Except forming the sulfydryl reactive group of thioester bond, can use multiple other sulfydryl reactive functional group base that forms other type bonds.For example, the chemical compound and the sulfydryl formation imino group-thioester bond that contain the methylene imine ester derivant.Alternatively, can use the sulfydryl reactive group that forms disulfide bond with sulfydryl; This type of group has structure-S-S-Ar usually, wherein Ar replaces or the unsubstituted heteroaryl moieties of nitrogen or the non-heterocyclic aryl that partly replaces with electrophilic of containing, thereby Ar can be for for example, 4-pyridine radicals, o-nitrophenyl ,-nitrobenzophenone, right-nitrobenzophenone, 2,4-dinitrophenyl, 2-nitro-4 benzoic acid, 2-nitro-4-pyridine radicals or the like.In this type of situation, auxiliary reagent, that is, gentle oxidant as hydrogen peroxide, can be used to promote disulfide bond to form.

Except that the sulfydryl reactive group that forms thioester bond, can use various other sulfydryl reactive functional groups that form other type bonds.For example, the chemical compound and the sulfydryl formation imino group-thioester bond that contain the imidic acid methyl ester derivation.Perhaps, can use the sulfydryl reactive group that forms disulfide bond with sulfydryl; This class group generally has structure-S-S-Ar, wherein Ar is for replacing or unsubstituted nitrogenous heteroaromatic moiety or non--heterocyclic aromatic group of partly being replaced by electron withdraw group, make Ar can for: for example 4-pyridine radicals, o-nitrophenyl ,-nitrobenzophenone, right-nitrobenzophenone, 2,4-dinitrophenyl, 2-nitro-4 benzoic acid, 2-nitro-4-pyridine radicals etc.In this class situation, auxiliary reagent, promptly Shi Du oxidant can be used to promote disulfide bond to form such as hydrogen peroxide.

Another kind of sulfydryl reactive group and sulfydryl form thioether bond.This class group is particularly including maleimide amino, haloalkyl, epoxy, imino group and the '-aziridino of maleimide amino, replacement and olefines (comprising conjugated alkenes); such as ethylidene sulfonyl, ethylidene imino group, acrylate, methacrylate and α, beta-unsaturated aldehyde class and ketone.

When X be-during OH, electrophilic functional group on the residual components and hydroxyl reaction.With regard to carboxylic moiety, can activate hydroxyl as mentioned above, maybe can make it having in the presence of the alkali and having enough reactive electrophilic group reaction, such as ethylene oxide moiety, aziridine part, acyl halide or anhydride etc.

When X is the organic metal nucleophilic group, during such as Ge Liya functional group or lithium alkylide part, contain the functional group of carbonyl for those with the suitable electrophilic functional group of its reaction, as an example, comprise ketone and aldehydes.

It is also understood that some functional group can be used as nucleophilic or as the electrophilic group reaction, this depends on the reaction gametophyte and/or the reaction condition of selection.For example, carboxylic moiety plays nucleophilic group having in the presence of the great alkali, but generally plays electrophilic group, makes to carry out nucleophillic attack and simultaneously with the nucleophilic group substituted hydroxy that obtains on carbonyl carbon.

These and other embodiment is as described below, and wherein the covalent bond that produces when specific necleophilic reaction base and specific electrophilic reaction base covalent bond on the autoreaction chemical compound comprises the key in the following table, but only as an example:

Table

With regard to the autoreaction chemical compound that contains electrophilic and necleophilic reaction base, initial environment is generally dry and aseptic.Because electrophilic group and water reaction, so prevented hydrolysis with aseptic dried forms storage.The synthetic polymer in-mold of drying can be pressed into thin slice or film, can use gamma-rays or e-light beam irradiates that it is sterilized then.Gained desciccator diaphragm or sheet can be cut into required size or be cut into the granule of reduced size.Change exsiccant initial environment and generally comprise the interpolation aqueous medium.

In one embodiment, initial environment can be aqueous medium, such as in low pH buffer, promptly has the buffer that is lower than about 6.0 pH, and wherein electrophilic and nucleophilic group are non-reacted.The suitable liquid medium that is used to store this compounds comprises aqueous buffer, and such as sodium dihydrogen phosphate/sodium hydrogen phosphate, sodium carbonate/bicarbonate, glutamate, Glu or acetate, concentration is 0.5-300mM.Change initial low pH aqueous environments and generally comprise pH increased to and be at least pH7.0, more preferably pH is increased to and be at least pH9.5.

In another embodiment, changing exsiccant initial environment comprises: the autoreaction chemical compound is dissolved in first kind of buffer solution having at the pH of about 1.0-5.5 scopes so that form homogeneous solution; (ii) will have at second kind of buffer solution of about 6.0-11.0 scope pH and add described homogeneous solution to.Described buffer solution is aqueous solution and can be any pharmaceutically acceptable alkalescence or acidic composition.Term " buffer " refers to acidity or alkaline aqueous solution when using in general sense, wherein this can work the function that cushioning effect is provided arbitrarily or not play this function (promptly anti-pH changes when adding acid or alkali) in the present composition.For example, the autoreaction chemical compound can be even dry powder form.Then with this powder with have buffer solution at the pH of about 1.0-5.5 scopes and merge and form even acidic aqueous solution, and then with this solution with have buffer at about 6.0-11.0 scope pH and merge and form reaction solution.For example, 0.375 gram dry powder can be merged and after mixing, obtain homogeneous solution with 0.75 gram acidic buffer, wherein this solution and 1.1 be restrained the alkaline buffers merging and obtain forming at once basically the reactant mixture of three dimensional matrix.

The acidic buffer solution that has at the pH of about 1.0-5.5 scopes comprises following solution: citric acid, hydrochloric acid, phosphoric acid, sulphuric acid, AMPSO (3-[(1,1-dimethyl-2-ethoxy) amino] 2-hydroxyl-propane-sulfonic acid), acetic acid, lactic acid and combination thereof, they are as explanation, but are not limited to them.In preferred embodiments, acidic buffer solution is the solution of citric acid, hydrochloric acid, phosphoric acid, sulphuric acid and combination thereof.Acidic buffer preferably has certain pH, makes it can stop the reactivity of nucleophilic group on nuclear, and is irrelevant with the accuracy of acidulant.For example, pH 2.1 generally is enough to stop the nucleophilicity of sulfydryl.When nuclear contains amido as nucleophilic group, general preferred lower pH.

In general, acidic buffer is an acid solution, and when contacting with nucleophilic group, this solution gives those nucleophilic groups relative non-nucleophilicity.

Typical acidic buffer is a hydrochloric acid solution, and about 6.3mM of the concentration that it has and pH are in 2.1-2.3 scopes.Can promptly prepare this buffer by also with concentrated hydrochloric acid and hydration by the dilute with water concentrated hydrochloric acid.Similarly, can also prepare this buffer A through the following steps expediently: 1.23 gram concentrated hydrochloric acid are diluted to 2 liters of volumes; Or with 1.84 the gram concentrated hydrochloric acid be diluted to 3 liters of volumes; Or with 2.45 the gram concentrated hydrochloric acid be diluted to 4 liters of volumes; Or with 3.07 the gram concentrated hydrochloric acid be diluted to 5 liters of volumes; Or with 3.68 the gram concentrated hydrochloric acid be diluted to 6 liters of volumes.Because safety preferably is added to the water concentrated acid.

The alkaline buffer solution that has at the pH of about 6.0-11.0 scopes comprises following solution: glutamate, Glu, acetate, carbonate (carbonate) and bicarbonate (carbonate salts) (for example sodium carbonate, sodium carbonate monohydrate and sodium bicarbonate), borate, phosphate (phosphate) and hydrophosphate (phosphate salts) (a for example hypophosphite monohydrate sodium dihydrogen and a sodium hydrogen phosphate) and combination thereof, they are as explanation, but are not limited to them.In preferred embodiments, alkaline buffer solution is the solution of carbonate, phosphate and combination thereof.

In general, in the time of in the homogeneous solution that joins described chemical compound and first kind of buffer, alkaline buffer be in and the aqueous solution of acidic buffer effect, make nucleophilic group on the nuclear (because of the effect of acidic buffer masked) recovered its nucleophilicity, nucleophilic group and electrophilic group on the nuclear are reacted to each other.

Typical alkaline buffer is carbonate and phosphatic aqueous solution.Can prepare this buffer by alkaline solution and saline solution are merged.Can obtain 2 liters of liquor capacities and prepare this saline solution by 4.7g biphosphate sodium-hydrate, 49.3g sodium carbonate monohydrate and enough water are incorporated into.Similarly, obtain 6 liters of liquor capacities and prepare 6 liters of solution by 104.0g biphosphate sodium-hydrate, 147.94g sodium carbonate monohydrate and enough water are incorporated into.Can be by with 7.2g sodium hydroxide and 180.0g hydration and prepare alkaline buffer.Generally can prepare alkaline buffer in the saline solution by alkaline solution is joined as required, finally evenly be had the mixture of required pH, for example pH is 9.65-9.75.

In general, be present in that alkaline kind in the alkaline buffer should have enough alkalescence so as in and the acidity that produces of acidic buffer, but self nucleophilic like this not, so as it basically with nuclear on electrophilic group react.Owing to this reason, thus in this embodiment of the present invention the preferred alkali of " soft " relatively, such as carbonate and phosphate.

For the preparation of three dimensional matrix of the present invention is described, can merges the mixture of autoreaction chemical compound and first kind of acidic buffer (for example acid solution, for example dilute hydrochloric acid solution) and form homogeneous solution.This homogeneous solution and second kind of alkaline buffer (alkaline solution for example for example contains the aqueous solution of phosphate and carbonate) are mixed, and the reactive group on this moment autoreaction chemical compound nuclear reacts each other at once basically and forms three dimensional matrix.

2) redox reaction base

In one embodiment of the invention, reactive group is a vinyl, and as styrene derivative, radical polymerization takes place when causing with redox initiator for it.Term " oxidoreduction " refers to be subject to the activatory reactive group of oxidation-reduction.Term " vinyl " refers to be formed by redox initiator activation and reaction back the reactive group of free radical.X, Y can be identical with different vinyls with Z, for example, the methacrylic acid group.

For the autoreaction chemical compound that contains the vinyl reactive group, initial environment will be generally aqueous environments.The change of initial environment comprises the adding redox initiator.

3) oxidative coupling reaction base

In one embodiment of the invention, reactive group carries out oxidative coupling reaction.For example, X, Y and Z can be halogen group, as chlorine, have adjacent electron-withdrawing group having on the carbon of halogen (for example, " L " connect base on).Representative electron-withdrawing group comprises nitro, aryl or the like.

For this type of reactive group, the change in the initial environment comprises the change of pH.For example, at alkali, exist down as KOH, so the autoreaction chemical compound carries out dehydrogenation, the chlorine coupling reaction forms two keys between carbon atom, illustrate as following:

For the autoreaction chemical compound that contains the oxidative coupling reaction base, initial environment usually can be for dry and aseptic, perhaps non-alkaline medium.The change of initial environment generally includes adding alkali.

4) light-initiated reactive group

In one embodiment of the invention, reactive group is light-initiated group.For this type of reactive group, the change of initial environment comprises and is exposed to ultraviolet radiation.

In one embodiment of the invention, X can be azido (N ₃), Y can for alkyl as-CH (CH ₃) ₂, or vice versa.Be exposed to ultraviolet radiation then the bonding of key below providing will be provided between group :-NH-C (CH ₃) ₂-CH ₂-.In another embodiment of the present invention, X can be benzophenone ((C ₆H ₄)-C (O)-(C ₆H ₅)) base, Y can be alkyl, as-CH (CH ₃) ₂, or vice versa.Be exposed to ultraviolet radiation then the bonding of key below providing will be provided between group:

For the autoreaction chemical compound that contains light-initiated reactive group, the environment that initial environment will cover for ultraviolet radiation usually.This can store in ultraviolet radiation impermeability container for for example.

The change of initial environment will generally include and be exposed to ultraviolet radiation.

5) thermosensitive response base

In one embodiment of the invention, reactive group is the responsive to temperature group, and it carries out photochemical reaction.For this type of reactive group, therefore the change in the initial environment comprises the change of temperature.Term " temperature sensitivity " refer under a temperature or in the temperature range for chemically inert and in different temperatures or temperature range for reactive reactive group.

In one embodiment of the invention, X, Y and Z are identical or different vinyl.

For the autoreaction chemical compound that contains temperature sensitive reactive group, initial environment is usually in about 10 to 30 ℃ scope.

The change of initial environment will comprise the change temperature usually in about 20 to 40 ℃ scope.

B. connect base

Reactive group can be directly connected to core, and perhaps they can connect indirectly by linking group, and long linking group is also referred to as " cahin extension agent ".In the formula in the above (I), optional linking group passes through L ¹, L ²And L ³P is wherein worked as in representative, and q and r equal at 1 o'clock, have linking group.

Suitable linking group is well known in the art.See, for example, the WO 97/22371 of Rhee etc.When can being used to avoid having, linking group forms relevant sterically hindered problem with intermolecular Direct Bonding.Linking group can additionally be used for some autoreaction chemical compounds are linked together and obtain bigger molecule.In one embodiment, linking group can be used for use with the gained gel formation after change the degraded character of compositions.For example, linking group can be used to promote hydrolysis, hinders hydrolysis, and the enzymatic degradation site perhaps is provided.

The example of linking group that the hydrolyzable site is provided is particularly including ester bond; Anhydride bond is as the anhydride bond by obtaining in conjunction with glutarate and succinate; Original acid ester key; The orthocarbonic acid ester bond is as the propylene carbonate key; Amido link; The phosphoric acid ester bond; The alpha-hydroxy acid key, as can be by obtaining in conjunction with lactic acid and hydroxyacetic acid those; Based on the key of lactone, as can by in conjunction with caprolactone, valerolactone, gamma-butyrolacton and to-Er Evil ketone available those; And amido link, as the amido link in dimer, oligomer or poly-(aminoacid) fragment.The example of non-degradable linking group comprises butanimide, propanoic acid and carboxylic methyl ester key.See, for example, the WO 99/07417 of Coury etc.The example of the degradable key of enzyme comprises Leu-Gly-Pro-Ala, and it can pass through degraded by collagenase; And Gly-Pro-Lys, it can be degraded by fibrinolysin.

Can also comprise that linking group is to strengthen or to suppress the reactivity of multiple reactive group.For example, the electron withdraw group in of sulfydryl and two carbon can estimate that reduction owing to nucleophilicity reduces the effectiveness in its coupling.Carbon-to-carbon double bond and carbonyl will also have this effect.On the contrary, can increase the reactivity of carbonyl carbon to the nucleophilic group of gained with the adjacent electron withdraw group of carbonyl (for example reaction carbonyl of glutaryl-N-hydroxy-succinamide base).On the contrary, near the steric hindrance macoradical reactive group can be used to reduce reactive and thus as the coupling rate of steric hindrance effect.

As an example, gone out concrete linking group and corresponding chemical formula at the following table middle finger:

Table

Connect base	Constituent structure
		-O-(CH 2) x-	-O-(CH 2) x-X -O-(CH 2) x-Y -O-(CH 2) x-Z
-S-(CH 2) x-	-S-(CH 2) x-X -S-(CH 2) x-Y -S-(CH 2) x-Z
		-NH-(CH 2) x-	-NH-(CH 2) x-X -NH-(CH 2) x-Y -NH-(CH 2) x-Z
-O-(CO)-NH-(CH 2) x-	-O-(CO)-NH-(CH 2) x-X -O-(CO)-NH-(CH 2) x-Y -O-(CO)-NH-(CH 2) x-Z
		-NH-(CO)-O-(CH 2) x-	-NH-(CO)-O-(CH 2) x-X -NH-(CO)-O-(CH 2) x-Y -NH-(CO)-O-(CH 2) x-Z
-O-(CO)-(CH 2) x-	-O-(CO)-(CH 2) x-X -O-(CO)-(CH 2) x-Y -O-(CO)-(CH 2) x-Z
		-(CO)-O-(CH 2) x-	-(CO)-O-(CH 2) n-X -(CO)-O-(CH 2) n-Y -(CO)-O-(CH 2) n-Z
-O-(CO)-O-(CH 2) x-	-O-(CO)-O-(CH 2) x-X -O-(CO)-O-(CH 2) x-Y -O-(CO)-O-(CH 2) x-Z
		-O-(CO)-CHR 2-	-O-(CO)-CHR 2-X -O-(CO)-CHR 2-Y -O-(CO)-CHR 2-Z
-O-R 3-(CO)-NH-	-O-R 3-(CO)-NH-X -O-R 3-(CO)-NH-Y -O-R 3-(CO)-NH-Z

In last table, x is generally 1 to about 10, R ²Be generally alkyl, typically be alkyl or aryl, preferred alkyl, low alkyl group most preferably, R ³Be alkylene, contain heteroatomic alkylene, the alkylene of replacement, what perhaps replace contains heteroatomic alkylene, is generally alkylidene or arlydene (once more, optional that replace and/or contain hetero atom), preferred low-grade alkylidene (for example, methylene, 1, the 2-ethylidene, positive propylidene, positive butylidene, or the like), phenylene, perhaps the amide alkylidene (for example ,-(CO)-NH-CH ₂).

Other General Principle of considering about linking group is as follows.If will use the autoreaction chemical compound of higher molecular weight, it preferably has aforesaid biodegradable key so, thereby does not produce greater than 20,000 molar fragments during absorbing in health again.In addition, in order to promote water intersolubility and/or dissolubility, can wish to add enough electric charges or hydrophilic.Use known chemosynthesis can easily introduce hydrophilic group, as long as they do not cause undesirable reduction of undesirable expansion or compressive strength.Particularly, poly-alkoxyl fragment can weaken gel strength.

C. Core

" core " of every kind of autoreaction chemical compound comprises the bonded molecular structure of reactive group.The molecule core can be polymer, and it comprises synthetic polymer and naturally occurring polymer.In one embodiment, core is for containing the unitary polymer of repeated monomer.Polymer can be for hydrophilic, hydrophobic or amphipathic.The molecule core can also be a lower-molecular-weight component, as C _2-14Alkyl or contain heteroatomic C _2-14Alkyl.Contain heteroatomic C _2-14Alkyl can have the N of being selected from, 1 or 2 hetero atom of O and S.In preferred embodiments, the autoreaction chemical compound comprises the molecule core of synthetic hydrophilic polymer.

1) hydrophilic polymer

As mentioned above, term used herein " hydrophilic polymer " refers to polymer, and it has mean molecule quantity and natural give or through selecting to make the composition of " hydrophilic " on this polyalcohol integral.Preferred polymer is for highly pure or be purified to highly pure state, thus this polymer for or the treated pharmaceutical purity that becomes.Most hydrophilic polymeies can by mix can be used for aqueous solution form hydrogen bond enough numbers oxygen (nitrogen perhaps more infrequently) atom and become water dissolvable.

Synthetic hydrophilic polymer can be homopolymer; Block copolymer comprises two-block and three-block copolymer; Random copolymer; Or graft copolymer.In addition, what described polymer can be for line style or branching, and if branching, so can for minimum level to highly branched, dendritic, excessive branching or star-type polymer.This polymer can comprise biodegradable chain link and block, and they can fully be distributed in separately in the molecular structure of polymer or as single block and exist, as are present in the block copolymer.Biodegradable chain link is degraded to interrupt the chain link of covalent bond for those.In general, biodegradable chain link is for having in the presence of the water hydrolysis and/or the chain link of enzymatic lysis in position.Biodegradable chain link can be made up of the micromolecule chain link, such as ester bond, anhydride bond, original acid ester key, orthocarbonic acid ester bond, amido link, phosphonate bond etc.Bigger biodegradable " block " generally is made up of the oligomeric or polymerization chain link of introducing in the hydrophilic polymer.Comprise poly-(aminoacid) chain link for the biodegradable property illustrated is oligomeric as an example with the polymerization chain link, poly-(acetas) chain link, poly-(orthocarbonic ester) chain link etc.Other biodegradable chain link that can form the ingredient of hydrophilic polymer nuclear comprises: polyesters, such as polylactide; Polyethers is such as polyalkylene oxide; Polyamide-based, such as protein; And polyurethanes.For example, the autoreaction chemical compound endorses the diblock copolymer of thinking four sense activated polyglycol and polylactide.

The synthetic hydrophilic polymer that can be used for this paper includes, but are not limited to: polyalkylene oxide, especially Polyethylene Glycol (PEG) and poly-(oxirane)-poly-(expoxy propane) copolymer comprises block and random copolymer; Polyhydric alcohol, as glycerol, polyglycereol (PG) and especially highly branched polyglycereol, propylene glycol; The polyhydric alcohol that the dihydroxylic alcohols of poly-(oxyalkylene)-replace and poly-(oxyalkylene) replace, as single-, two-and three-polyoxy ethylization glycerol, single-and two-polyoxy ethylization propylene glycol, and single-and two-polyoxy ethylization trimethylene glycol; Polyoxy ethylization sorbitol, polyoxy ethylization glucose; Poly-(acrylic acid) and analog and copolymer, as polyacrylic acid self, polymethylacrylic acid, poly-(hydroxyethyl-methacrylate), poly-(hydroxyethylmethacry,ate), poly-(methyl alkyl sulfoxide methacrylate), poly-(methyl alkyl sulfoxide acrylate) and front any copolymer and/or with the other acrylate kind such as the copolymer of amino-ethyl acrylate and list-2-(propenyloxy group) ethyl succinate; Poly; Poly-(acrylamide), own as poly-(acrylamide), poly-(MAAm), poly-(DMAA) and poly-(N-isopropyl-acrylamide), and copolymer; Poly-(enol) is as poly-(vinyl alcohol) and copolymer thereof; Poly-(N-vinyl lactam), as poly-(vinyl pyrrolidone), poly-(N-caprolactam), and copolymer; The Ju oxazoline comprises poly-(Jia oxazolin) and poly-(ethyl oxazoline); And polyvinylamine, and any copolymer of front.The polymer tabulation that must emphasize the front is not limit, as will be apparent to those skilled in the art, can use many other synthetic hydrophilic polymeies.

It will be appreciated by one of skill in the art that in fact to prepare synthetic polymer that as Polyethylene Glycol, and as commonly used in this area, term used herein " molecular weight " refers to the weight average molecular weight of many molecules of any given sample with definite molecular weight.Thereby the sample of PEG 2,000 can contain molecular weight ranges and be for example statistics mixture of 1,500 to 2,500 daltonian polymer molecule, and a molecule and another molecule are slightly different within the specific limits.The explanation of certain limit molecular weight points out that mean molecule quantity can be the arbitrary value between the specified scope, and can comprise the molecule outside these scopes.Thereby about 800 to about 20,000 molecular weight ranges shows at least about 800, up to the mean molecule quantity of about 20kDa.

Other suitable synthetic hydrophilic polymer comprises polypeptide, especially many nucleophilics polypeptide of chemosynthesis, and it synthesizes and mixes aminoacid (for example, lysine) that contains primary amino radical and/or the aminoacid (as cysteine) that contains mercapto.Especially preferably poly-(lysine), it is the polymer of the synthetic generation of amino acid lysine (145MW).Prepared and had 6 poly-(lysines) to about 4,000 primary amino radicals, molecular weight corresponding to about 870 to about 580,000.Be used for poly-(lysine) of the present invention and preferably have about 1,000 to about 300,000 molecular weight; 5,000 to about 100,000 molecular weight more preferably from about; 8,000 to about 15,000 molecular weight most preferably from about.Poly-(lysine) of variable molecular weight can be by commercial sources from Peninsula Laboratories, and (Belmont Calif.) obtains Inc..

Although can use the synthetic hydrophilic polymer of many differences in the The compounds of this invention, preferred synthesis hydrophilic polymer is PEG and PG, especially highly branched PG.The PEG of various ways is widely used in the modification of bioactive molecule, because PEG lacks toxicity, antigenicity and immunogenicity (that is, being biocompatible), can prepare so that have the dissolubility of wide region, and the conformation of common not interferases activity and/or peptide.For some application, especially preferred synthetic hydrophilic polymer is PEG, it has about 100 to the interior molecular weight of about 100,000 scopes, although for highly branched PEG, can use the much higher polymer of molecular weight, up to 1,000,000 or more than, condition is to add biodegradable site will have the molecular weight less than about 30,000 to guarantee all catabolites.Yet for most PEG, preferred molecular weight is about 1,000 to about 20,000, and more preferably from about 7,500 in about 20,000 scopes.Most preferably, Polyethylene Glycol has about 10,000 molecular weight.

Naturally occurring hydrophilic polymer includes, but are not limited to: protein, and as collagen protein, fibronectin, albumin, globulin, fibrinogen, fibrin and thrombin, especially preferred collagen protein; Carboxylated polysaccharide is as polymannuronate and polygalacturonic acid; The amination polysaccharide, glycosaminoglycans especially, as hyaluronic acid, chitin, chondroitin sulfate A, B or C, keratan sulfate, keratosulfate and heparin; With activatory polysaccharide, as glucosan and starch derivatives.Collagen protein and glycosaminoglycans are the preferred naturally occurring hydrophilic polymeies that is used for this paper.

Unless otherwise indicated, term used herein " collagen protein " refers to the collagen protein of form of ownership, comprises the collagen protein of processing or modifying.Thereby, can be used for chemical compound of the present invention from the collagen protein in any source; For example, can originate as cattle or pig dermis and extraction of people's Placenta Hominis and collagen purification albumen from people or other mammal, perhaps can recombinate or pass through other method produces.From the collagen protein preparation purification in the solution of Corii Bovis seu Bubali, nonantigenic substantially is well known in the art.For example, the U.S. Patent number 5,428 of Palefsky etc., 022 discloses from extraction of people's Placenta Hominis and the proteic method of collagen purification, and the U.S. Patent number 5,667 of Berg, 839 disclose transgenic animal, comprise producing the proteic method of recombinant human collagen in the milk of transgenic milch cow.At the U.S. Patent number 6,413,742 of Olsen etc., 6,428,978 and the Berg etc. of Olsen etc. 6,653,450 in the not genetically modified recombined collagen described in yeast and other cell line express.

The collagen protein of any type includes, but are not limited to I type, II type, III type, IV type or its combination in any and can be used for chemical compound of the present invention, but, and general preferred I type.Can use the collagen protein that contains non-end peptide (atelopeptide) or end peptide; Yet, when using from the time such as the collagen protein of this class natural origin of bovine collagen albumen, general preferred atelopeptide collagen protein, this be because of its immunogenicity with contain the collagen protein of holding peptide and compare due to the reduction.

As yet not by such as heating, shine or being preferred for compositions of the present invention, but, can use crosslinked in advance collagen protein in advance with the crosslinked collagen protein of chemical cross-linking agent.

Although not necessarily necessary, be used for collagen protein of the present invention generally at the about 20mg/ml of the concentration of aqueous suspension-about 120mg/ml; Preferred about 30mg/ml-about 90mg/ml.Although preferred complete collagen protein also can use the collagen protein of degeneration, so-called gelatin.Gelatin has the additional beneficial effect of degrading more fast than collagen protein.

The non-protofibre collagen protein generally is preferred for chemical compound of the present invention, but, also can use the fibril collagen protein.Term " non-protofibre collagen protein " refers to any modification that is essentially the non-protofibre form or the collagen substance of unmodified, promptly there is no the molecular collagen of tight association with other collagen molecules that forms fiber.In general, the non-protofibre collagen solution is more more transparent than fibril collagen solution.For the collagen protein type of the non-protofibre (or microfibril) of native form comprises IV type, VI type and VII type.

Collagen protein for the chemical modification of non-protofibre form under neutral pH comprises succinylation collagen protein and methylated collagen albumen, and they all can be according to the method preparation described in the United States Patent (USP) 4,164,559 of Miyata etc.Containing the methylated collagen albumen that reacts amido is the composition that preferably contains nucleophile in the present composition.On the other hand, methylated collagen is the component that exists except substrate of the present invention forms in the reaction first and second kinds of components.Methylated collagen albumen for example is described in the United States Patent (USP) 5,614,587 of Rhee etc.

The collagen protein that is used for the present composition begins to be the fibril form, gives its non-protofibre by adding one or more fiber decomposing agents then.Described fiber decomposing agents must exist so that give collagen protein with capacity be essentially non-protofibre as mentioned above under pH7.Be used for fiber decomposing agents of the present invention and include, but are not limited to various biocompatibility alcohols, aminoacid, inorganic salt and carbohydrate, preferred especially biocompatibility alcohols.Preferred biocompatibility alcohols comprises glycerol and propylene glycol.The non-biocompatible alcohols is not preferred for the present invention such as ethanol, methanol and isopropyl alcohol, because they produce potential illeffects to the patient body of accepting it.Preferred amino acids comprises arginine.Preferred inorganic salt comprises sodium chloride and potassium chloride.Although can be used to implement the present invention such as this class carbohydrate of the various sugar that comprise sucrose, they are not preferred equally with the fiber decomposing agents of other type, because they may have cytotoxic effect in vivo.

The preference degree that the fibril collagen protein is used for The compounds of this invention is lower.Yet as disclosed in the United States Patent (USP) 5,614,587 of Rhee etc., the mixture of the plain collagen protein of fibril collagen protein or non-protofibre and fibril can be preferred for purpose and be the chemical compound that retains in vivo for a long time.

2) hydrophobic polymer

The core of autoreaction chemical compound can also comprise hydrophobic polymer, comprises the multifunctional kind of low-molecular-weight, although for most purposes, and the preferred hydrophilic polymer.Usually, this paper " hydrophobic polymer " contains the oxygen and/or the nitrogen-atoms of relative small scale.Be used for preferred hydrophobic polymer of the present invention and have carbochain no longer than about 14 carbon.Therefore polymer with the carbochain of being longer than 14 carbon basically has the dissolubility of non-constant usually in aqueous solution, have the response time of growing very much when with the aqueous solution that contains the synthetic polymer of a plurality of nucleophilic groups for example.Thereby the use of short chain oligomer can be avoided the relevant problem of dissolubility between the reaction period.Polylactic acid and polyglycolic acid are two kinds of especially examples of suitable hydrophobic polymer.

3) amphipathic polymer

Usually, amphipathic nature polyalcohol has hydrophilic segment and hydrophobic (perhaps lipophilic) part.Hydrophilic segment can be at an end of core, hydrophobic part is in end opposite, and perhaps hydrophilic and hydrophobic part can random distribution (random copolymer) or be sequence or grafting form (block copolymer) the amphipathic nature polyalcohol core with formation autoreaction chemical compound.Hydrophilic and hydrophobic part can comprise any of above-mentioned hydrophilic and hydrophobic polymer.

Alternatively, the amphipathic nature polyalcohol core can be the hydrophilic polymer modified with hydrophobic part (for example, alkylation PEG or the hydrophilic polymer of modifying with and a plurality of aliphatic chains), perhaps the hydrophobic polymer of modifying with hydrophilic segment (for example, " PEGization " phospholipid is as Pegylation phospholipid).

4. Lower-molecular-weight component

Point out that as top the molecule core of autoreaction chemical compound can also be a low molecular weight compound, it is defined as C in this article _2-14Alkyl or contain heteroatomic C _2-14Alkyl, it contains 1 to 2 hetero atom and their combination that is selected from N, O, S.This molecule core can replace with any reactive group described herein.

Alkane is suitable C _2-14Alkyl molecule core.The representative alkane that replaces with hydrophilic primary amino radical and Y electrophilic group comprises ethylene amines (H ₂N-CH ₂CH ₂-Y), tetramethylene amine (H ₂N-(CH ₄)-Y), pentamethylene amine (H ₂N-(CH ₅)-Y) and hexa-methylene amine (H ₂N-(CH ₆)-Y).

Low molecular weight diol and polyhydric alcohol also are suitable C _2-14Alkyl and comprise trimethylolpropane, two (trimethylolpropane), tetramethylolmethane and diglycerol.Polyprotic acid also is suitable C _2-14Alkyl and comprise tricarboxylic acids based on trimethylolpropane, based on the tetrabasic carboxylic acid of two (trimethylolpropanes), 1,5-pentanedicarboxylic acid., suberic acid (suberic acid), and hexadecandioic acid (hexadecane diacid) (thapsic acid).

Low-molecular-weight two-and many-electrophilic reagent be the heteroatomic C that contains that suits _2-14Alkyl molecule core.These comprise, for example, and two succinimido suberates (DSS), two (sulfosuccinimide base) suberate (BS ₃), dithio two (succinyl phosphorons amino propyl acid ester) (DSP), two (2-succinimido oxygen base ketonic oxygen base) ethyl sulfone (BSOCOES) and 3,3 '-dithio two (sulfosuccinimide base propionic ester) (DTSPP) and their analog and derivant.

In one embodiment of the invention, autoreaction chemical compound of the present invention comprises the low molecular weight material core, has many acrylate parts and many mercaptos.

D. Preparation

Be easy to the synthetic autoreaction chemical compound hydrophilic, hydrophobic or amphipathic polymer nuclear or low-molecular-weight nuclear that contains, the required functional group that their quilts can be crosslinked, promptly nucleophilic and electrophilic group are functionalized.The preparation of the autoreaction chemical compound that has Polyethylene Glycol (PEG) nuclear for example, hereinafter has been discussed.Yet the purpose that should understand following discussion is to explain and can use technology and other polymer of phosphoric acid.

At first, with regard to PEG, various functionalized PEGs effectively such as protein modification (referring to Abuchowski etc., " as the enzyme of medicine " (Enzymes as Drugs), John Wiley﹠amp; Sons:New York, N.Y. (1981) pp.367-383; With Dreborg etc., " medicament carrier system therapy evaluation summary " (Crit.Rev.Therap.Drug Carrier Syst.) (1990) 6:315), chemistry of peptides is (referring to Mutter etc., " peptide class " (The Peptides), Academic:New York, N.Y.2:285-332; With Zalipsky etc., " the international peptide protein matter of peptide research magazine " (Int.J.PeptideProtein Res.) (1987) 30: 740) and polymeric medicine synthetic (referring to Zalipsky etc., " European polymer magazine " be (1983) 19:1177 (Eur.Polym.J.); With Ouchi etc., " macromolecular science and The Chemicals " be (1987) (J.Macromol.Sci.Chem.) A24: 1011) use in this class field.

The PEG of functionalized form, comprise multifunctional activatory PEG be purchased and be easy to use known method preparation.For example, referring to " poly-(ethylene glycol) chemistry-biotechnology and biological medicine are used " (Poly (ethylene Glycol) Chemistry:Biotechnical and BiomedicalApplications) the 22nd chapter, J.Milton Harris, ed., Plenum Press, NY (1992).

The multiple functionalized form of special concern PEG and they comprise PEG succinimido glutarate, PEG succinyl phosphorons amino propyl acid ester, PEG succinimido butyrate, PEG butanimide yl acetate, PEG succinimido succinamide, PEG succinimidyl carbonate, PEG propionic aldehyde, PEG glycidyl ether, PEG-isocyanates and PEG-vinyl sulfone.The PEG of many these class forms is described in the United States Patent (USP) 5,328,955 and 6,534 of Rhee etc., in 591.Similarly, various forms of many-amino PEG is available from following source: such as PEG Shop, the SunBio portion of South Korea ( Www.sunbio.com); Nippon Oil and Fats (Yebisu Garden PlaceTower, 20-3 Ebisu 4-chome, Shibuya-ku, Tokyo); Nektar Therapeutics (SanCarlos, California, former Shearwater Polymers, Huntsville, Alabama); And Huntsman ' s Performance Chemicals Group (Houston, Texas), the name be called

The polyoxyalkylene amine.Be used for of the present invention many-amino PEGs comprises Jeffamine two amines (" D " series) and three amines (" T " series), each molecule contains two and three primary amino radicals.Similarly poly-(sulfydryl) PEGs is also available from Nektar Therapeutics, and for example tetramethylolmethane gathers (ethylene glycol) ether four-sulfydryl form (molecular weight 10,000).Can modify the reactive group of PEG to comprise that other is required of these multiple functionalized forms then.

With the butanimide radical reaction terminal hydroxyl being changed into the reaction esters is a kind of technology that is used to prepare the nuclear that has electrophilic group.Can modify this nuclear then to comprise nucleophilic group, such as primary amine class, thio-alcohol and hydroxyl.Other reagent that transforms hydroxyl comprises carbonyl dimidazoles and sulfonic acid chloride.Yet, as described herein, can advantageously use various electrophilic groups and corresponding nucleophilic group reaction.The example of this class electrophilic group comprises: the acid chloride part; Anhydrides, ketone, aldehydes, isocyanates, isothiocyanate, epoxide and olefines comprise conjugated alkenes, such as ethylidene sulfonyl (SO ₂CH=CH ₂) and similar functional group.

Other in-situ cross-linked material

The original position of having described multiple other type forms material, and it can unite use with anti-scarring agent according to the present invention.It can be biocompatible cross linked polymer that original position forms material, and it can reaction in-situ and the water solublity precursor formation of crosslinked parent's electricity and nucleophilic group (see, for example, U.S. Patent number 6,566,406) from having.It can be hydrogel that original position forms material, it can be combined to form by physics and chemical crosslinking process, wherein natural or synthetic component forms physical crosslinking by one or more, described component reaches certain hour at deposition site stabilize water gel formation precursor solution and has more elastic chemical crosslinking with enough formation and (see, for example, U.S. Patent number 6,818,018).When the dried hydrogel precursor be exposed to from the aqueous fluids of physiological environment the time can form original position and form material (see, for example, U.S. Patent number 6,703,047).It can be hydrogel matrix that this original position forms material, and it is dispersed or dissolved in the controlled release that hydrophobic relatively speed dressing agent formation mixture provides relative low-molecular-weight treatment kind by at first treating kind; Described mixture forms the microgranule that is dispersed in the biological absorbable hydrogel, thereby discharges water-soluble therapeutic agents (see, for example, 6,632,457) in a controlled manner.It can be multicomponent hydrogel system (see, for example, U.S. Patent number 6,379,373) that original position forms material.It can be the multiple-limb block copolymer that original position forms material, it comprises the prostheses molecule, as residue of polyol, with at least three copolymer branches of covalently bound prostheses molecule, each copolymer branch comprises the inner hydrophobic polymer segments and the segmental outside hydrophilic polymer fragment of covalently bound this hydrophobic polymer of covalently bound prostheses molecule, and wherein prostheses molecule and hydrophobic polymer fragment define the hydrophobic core district and (see, for example, 6,730,334).Original position forms material can comprise the gel formation macromonomer, and it comprises at least 4 polymer blocks, and at least two blocks are hydrophobic and at least one block is hydrophilic, and comprises crosslinkable group (see, for example, 6,639,014).It can be the water-soluble macromolecule monomer that original position forms material, and it comprises at least one the hydrolyzable key that forms from carbonic ester Huo Er Evil ketone groups, at least one water-soluble polymer block, with at least one polymerisable group (see, for example, U.S. Patent number 6,177,095).Original position forms material can comprise polyalkylene block copolymers, and it forms weak physical crosslinking and has the gel of sticking with paste the sample denseness to be provided at physiological temp.(see, for example, U.S. Patent number 4,911,926).It can be heat irreversible gel (see, for example, U.S. Patent number 5,126,141) from polyoxyalkylene polymers and ionic polysaccharide preparation that original position forms material.It can be the gel formation compositions that original position forms material, it comprise chitin derivatives (see, for example, U.S. Patent number 5,093,319), chitosan grumeleuse (see, for example, U.S. Patent number 4,532,134), perhaps hyaluronic acid (see, for example, U.S. Patent number 4,141,973).Original position forms the in-situ modification that material can be alginate (see, for example, U.S. Patent number 5,266,326).Can form original position from the unsaturated water-soluble macromolecule monomer of ethylenic and form material, described macromonomer can contact with tissue, cell and bioactive molecule and be cross-linked to form gel (see, for example, U.S. Patent number 5,573,934).Original position forms material and can comprise and the unsaturated cyano compound that contains the cyano group that is connected carbon atom, unites the urethane prepolymer (see, for example, U.S. Patent number 4,740,534) of use as cyano group (methyl) acrylic acid and ester thereof.It can be biodegradable hydrogel that original position forms material, and it is by from the monomeric light-initiated radical polymerization effect polymerization of water-soluble macromolecule (see, for example, U.S. Patent number 5,410,016).Original position forms material and can form from two kinds of component mixtures, described mixture comprises that proteinic first of the serum albumin in the aqueous buffer solution that comprises the pH with about 8.0-11.0 scope and the second portion that comprises bi-functional cross-linking agent water compatible or water soluble (see, for example, U.S. Patent number 5,583,114).

On the other hand, operable original position formation material comprises those materials based on protein cross.For example, original position formation material can and gather the biodegradable hydrogel that (ethylene glycol) polymer solution is formed by reorganization or natural human serum albumin, and wherein described solution crosslinking forms mechanical on-liquid covered structure when mixing, and it is as sealant.See, for example, U.S. Patent number 6,458,147 and 6,371,975.Original position forms material can be by forming based on two kinds of fibrinogen and thrombin independent mixture, described mixture when before application site or on distribute the formation biological adhesive together during mixing and form the fibrin sealant.See, for example, U.S. Patent number 6,764,467.Original position forms material can be made up of the collagen protein and the albumin of supersound process, described collagen protein and albumin when with glutaraldehyde and aminoacid or chemistry of peptides when crosslinked formation develop the cohesive material of adhesion properties.See, for example, U.S. Patent number 6,310,036.Original position forms the viscogel of the hydration that material can be made up of aqueous solution, and it is basically by have amino protein (for example, gelatin, albumin) composition, described protein and N-hydroxyl polyurethane compound crosslink at side chain.See, for example, U.S. Patent number 4,839,345.It can be from the hydrogel in conjunction with cross-linking agent (for example, the multivalence derivant of Polyethylene Glycol or poly alkylene glycol) protein or polysaccharide main chain (for example, albumin or polymannuronate) preparation that original position forms material.See, for example, U.S. Patent number 5,514,379.Original position forms material can be made up of polymerisable collagen composition, and said composition is applied to organize and is exposed to initiator then with the polymerization collagen protein, thereby forms sealing on the wound opening in tissue.See, for example, U.S. Patent number 5,874,537.It can be two kinds of component mixtures that original position forms material, it by the protein in the aqueous buffer solution of the pH with about 8.0-11.0 scope (for example, serum albumin) and the difunctional polyethylene glycol oxide type of water solublity cross-linking agent form, this cross-linking agent changes into strong elasticity binding compositions with liquid, its original position seal tissue.See, for example, U.S. Patent number 5,583,114 and RE38158 and PCT publication number WO 96/03159.Original position forms material can be made up of the protein in the liquid carrier, surfactant and lipid, and it is crosslinked and be used as original position sealant or bonding agent by adding cross-linking agent that this original position forms material.See, for example, Application No. 2004/0063613A1 and PCT publication number WO 01/45761 and WO 03/090683.Original position forms material and can be made up of two kinds of liquid components that do not contain enzyme, mix described component by component being assigned to the conduit that uses at the vascular puncture position, wherein when mixing, two kinds of liquid component chemical crosslinkings form the mechanical on-liquid substrate in airtight vascular puncture site.See, for example, Application No. 2002/0161399A1 and 2001/0018598A1.Original position forms the crosslinked albumin compositions that material can be made up of albumin preparation and carbodiimide preparation, and described preparation mixes to be used as biological adhesive or sealant under the crosslinked condition of albumin allowing.See, for example, PCT publication number WO 99/66964.Original position forms material can be made up of collagen and peroxidase and hydrogen peroxide, thereby collagen is through being cross-linked to form the semi-solid gel that seals wound.See, for example, PCT publication number WO 01/35882.

On the other hand, operable original position formation material comprises those materials based on the polymer of isocyanates and isothiocyanate end-blocking (capped).For example, original position forms material can be made up of isocyanate-terminated polymer, and described polymer is a fluid composition, its when contacting body fluid or organizing by in-situ polymerization be cross-linked to form solid adhesive.See, for example, PCT publication number WO 04/021983.It can be the moisturecuring encapsulant composition that original position forms material, and it is made up of active isocyanide acyl-end capped isocyanate prepolymer that contains the polyol component with 2,000 to 20,000 molecular weight and isocyanuric acid esterification catalyst.See, for example, U.S. Patent number 5,206,331.

In another embodiment, described reagent can carry out electrophilic-necleophilic reaction and produce crosslinked substrate.Contain such as amine, sulfydryl, hydroxyl ,-PH ₂Or CO-NH-NH ₂This class nucleophilic group and/or can be used as nucleopilic reagent with the end capped polymer of these nucleophilic groups, and contain such as succinimido, carboxylic acid, aldehyde, epoxide, isocyanates, vinyl, vinyl sulfone, maleimide ,-S-S-(C ₅H ₄N) or this class electrophilic group of activatory esters and/or can be used as electrophilic reagent such as being used for the synthetic polymer of peptide with these electrophilic groups are end capped.For example, 4-be with ramose mercaptan deutero-poly-(ethylene glycol) (for example poly-(ethylene glycol) ether four-sulfydryl of tetramethylolmethane) can with 4 be with the deutero-Polyethylene Glycol of ramose NHS-(for example poly-(ethylene glycol) ether four-succinimido glutarate of tetramethylolmethane) in alkali condition (pH〉about 8) reaction down.The representational case description of compositions that carries out this class electrophilic-nucleophilic cross-linking reaction is in following document: for example United States Patent (USP) 5,752, and 974; 5,807,581; 5,874,500; 5,936,035; 6,051,648; 6,165,489; 6,312,725; 6,458,889; 6,495,127; 6,534,591; 6,624,245; 6,566,406; 6,610,033; 6,632,457; With PCT application publication number WO 04/060405 and WO 04/060346.

In another embodiment, electrophilic-or nucleophilic-end capped polymer may further include and can improve original position and form the machinery of compositions and/or the polymer of adhesion characteristic.This polymer can be the degradable polymer that maybe can not degrade.For example, this polymer can be collagen protein or collagen derivative, for example methylated collagen albumen.The example that original position forms compositions uses poly-(ethylene glycol) ether four-sulfydryl of tetramethylolmethane) (4-is with ramose sulfydryl PEG), poly-(ethylene glycol) ether four-succinimido glutarate of tetramethylolmethane) (4-is with ramose NHS PEG) and methylated collagen albumen is as reaction reagent.Said composition can produce cross-linked hydrogel (for example, referring to United States Patent (USP) 5,874,500 when mixing with suitable reducing; 6,051,648; 6,166,130; 5,565,519 and 6,312,725).

In another embodiment, can use the reagent that can form covalent bond with the tissue that is coated with.Contain such as succinimido, aldehyde, epoxide, isocyanates, vinyl, vinyl sulfone, maleimide ,-S-S-(C ₅H ₄N) or this class electrophilic group of activatory esters and/or can be used as reagent such as being used for the synthetic polymer of peptide with these electrophilic groups are end capped.For example, can be with the deutero-Polyethylene Glycol of ramose NHS-(for example poly-(ethylene glycol) ether four-succinimido glutarate of tetramethylolmethane) to be coated with organizationally with 4 with solid form or solution form.In this embodiment preferred, under alkali condition (pH〉about 8), be with the deutero-Polyethylene Glycol coating of ramose NHS-organizationally with 4.The representational example of other of the compositions of operable this character is disclosed in PCT application publication number WO 04/060405 and WO 04/060346 and the Application No. 10/749,123.

In another embodiment, original position formation material polymer can be polyester.The polyesters that can be used for original position formation compositions comprises poly-(hydroxy ester).In another embodiment, described polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone.Representational case description is in United States Patent (USP) 5,874,500 in these type of composition; 5,936,035; 6,312,725; 6,495,127 and PCT publication number WO2004/028547 in.

In another embodiment, the polymer of electrophilic-end can be comprised partially or completely that the micromolecule of electrophilic group or oligomer (for example 1,3-propanedicarboxylic acid two succinimide esters) replace.

In another embodiment, the polymer of nucleophilic-end can be comprised partially or completely that the micromolecule of nucleophilic group or oligomer (for example dicysteine, two lysines, three lysines etc.) replace.

Other example that operable original position forms material comprises that those materials based on protein cross (are described in the following document: United States Patent (USP) RE38158 for example; 4,839,345; 5,514,379,5,583,114; 6,310,036; 6,458,147; 6,371,975; US patent application publication number 2004/0063613A1,2002/0161399A1 and 2001/0018598A1; And PCT publication number WO 03/090683, WO 01/45761, WO 99/66964 and WO 96/03159) and those materials based on isocyanates or the end capped polymer of isothiocyanate (for example, referring to PCT publication number WO04/021983).

Other example that original position forms material can comprise the reagent that contains one or more alpha-cyanoacrylate ester moieties.These reagent can be used for preparation poly-(alkyl cyanoacrylate) or poly-(carboxyalkyl cyanoacrylate) (for example poly-(ethyl cyanoacrylate), poly-(butyl cyanoacrylate), poly-(isobutyl cyanoacrylate), poly-(hexyl cyanoacrylate), poly-(methoxy-propyl cyanoacrylate) and poly-(octyl cyanoacrylate)).

The example that is purchased cyanoacrylate of the present invention be can be used for and DERMABOND, INDERMIL, GLUSTITCH, VETBOND, HISTOACRYL, TISSUMEND, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUIDPROTECTANT comprised.

In another embodiment, described cyanoacrylate compositions may further include additive, and these additives are used to the reaction rate of stablizing described reagent and/or changing cyanoacrylate and/or give poly-(cyanoacrylate) plasticising and/or change the degradation rate that gathers (cyanoacrylate).For example, can will mix with 2-alkoxyalkyl cyanoacrylate (for example 2-methoxy-propyl cyanoacrylate) based on the polymer of carbonic acid Sanya methyl ester or based on the oxalate polymer of the copolymer of poly-(ethylene glycol) or 6-caprolactone.Representational case description is at United States Patent (USP) 5,350 in these compositionss, in 798 and 6,299,631.

In another embodiment, can be by the heterochain polymer end-blocking being prepared cyanoacrylate compositions with the alpha-cyanoacrylate ester group.Preferred every the chain of cyanoacrylate-end capped heterochain polymer has at least two alpha-cyanoacrylate ester groups.This heterochain polymer can comprise absorbable poly-(ester), poly-(ester-carbonic ester), poly-(ether-carbonic ester) and poly-(ether-ester).Be described in United States Patent (USP) 5,653, poly-(ether-ester) in 992 and 5,714,159 can be used as heterochain polymer.Three-dimensional poly-(6-caprolactone-be total to-carbonic acid Sanya methyl ester) is the example of operable poly-(ester-carbonic ester).Described heterochain polymer can be polyethers.。The example of operable polyethers comprises the block copolymer (for example the PLURONICS family of polymer includes, but are not limited to PLURONIC F127 or F68) of poly-(ethylene glycol), poly-(propylene glycol) and poly-(ethylene glycol) and poly-(propylene glycol).The representational case description of these compositionss is in U.S. Patent No. 6,699, in 940.

In another aspect of the present invention, can use non-polymer chemical compound (for example carrier) to send infection and/or suppress fibrotic bioactivator.These non-polymeric carriers can comprise: sucrose derivative (for example SAIB, oleic acid sucrose ester), steroid, such as cholesterol, stigmasterol, cupreol and estradiol; Cholesteryl ester is such as cholesterol ester stearic acid; C ₁₂-C ₂₄Fatty acid is such as lauric acid, myristic acid, Palmic acid, stearic acid, arachidic acid, behenic acid and lignoceric acid; C ₁₈-C ₃₆One-, two-and triacylglycerol esters, such as glycerin mono-fatty acid ester, glycerol list linoleate, glyceryl monolaurate, glycerol list docosane acid esters, monomyristin, glycerol monodicenoate, dipalmitin, glycerol didocosanoate, glycerol two myristinates, glycerol didecenoate, glycerol tridocosanoate, myristin, glycerol tridecenoate, glycerol tristearate and composition thereof; The sucrose-fatty esters is such as sucrose distearate and sucrose palmitate; The Span class is such as sorbitan monostearate, sorbitan monopalmitate and sorbitan tristearate; C ₁₆-C ₁₈Aliphatic alcohols, Zhu such as Whale ceryl alcohol, myristyl alcohol, octadecanol, and fatty acid are such as Zong Lv Suan Whale wax ester and cetearyl palmitate; The anhydrides of fatty acid is such as stearic anhydride; Phospholipid comprises phosphatidylcholine (lecithin), Phosphatidylserine, PHOSPHATIDYL ETHANOLAMINE, phosphatidylinositols and soluble derivative thereof; Sphingol and derivant thereof; Sphingomyelins class (spingomyelins) such as stearyl, palmityl and tricosyl sphingomyelins class (spingomyelins); Ceramide type is such as stearyl and palmityl ceramide type; Glycosphingolipids; Lanoline and lanolin alcohols, calcium phosphate, sintering and unsintered hydroxyapatite, zeolites; And combination and mixture.

Relate to that representational example comprises in the patent of non-polymer delivery system and preparation: United States Patent (USP) 5,736,152; 5,888,533; 6,120,789; 5,968,542; With 5,747,058.

In certain embodiments of the invention, provide and comprised (i) the fibre modification inhibitor and/or the (ii) therapeutic combination of anti-infective.These therapeutic combinations can comprise one or more other therapeutic agents (such as above-mentioned those), for example anti-inflammatory agent, antithrombotic agent and/or anti-platelet agents.Can comprise with other activating agent of described therapeutic combination coupling: for example, other component is such as surfactant (for example, PLURONICS is such as F-127, L-122, L-101, L-92L-81, with L-61), antiseptic and antioxidant.

Provide the compositions that comprises following ingredients among the present invention in one aspect: i) fibrosis agent and ii) polymer or form the chemical compound of polymer in position.Be the preferred fibrosis agent and the fibrosis agent type that can be included in the present composition below, but whole absolutely not:

1a. anagocytic fibrosis agent (anti-fibrotic agent).

2a. suppress the fibrosis agent that blood vessel takes place.

3a. be suppressed to the fibrosis agent of fibrocyte migration.

4a. suppress the fibrosis agent of fibroblast proliferation.

5a. suppress the fibrosis agent of extracellular matrix deposition.

6a. suppress the fibrosis agent of tissue reconstruction (remodeling).

7a. be the fibrosis agent of angiogenesis inhibitor.

8a. be the fibrosis agent of 5-lipoxidase inhibitor or antagonist.

9a. be the fibrosis agent of chemokine receptor anagonists.

10a. be the fibrosis agent of cell cycle inhibitor.

11a. be the fibrosis agent of taxane.

12a. be the fibrosis agent of anti-microtubule agent.

13a. be the fibrosis agent of paclitaxel.

14a. be the fibrosis agent of cathepsin inhibitors.

15a. be the fibrosis agent of paclitaxel analogs or derivant.

16a. be the fibrosis agent of vinca alkaloids.

17a. be the fibrosis agent of camptothecine or its analog or derivant.

18a. be the fibrosis agent of podophyllotoxin.

19a. be the fibrosis agent of etoposide or its analog or derivant.

20a. be the fibrosis agent of anthracycline.

21a. be the fibrosis agent of doxorubicin or its analog or derivant.

22a. be the fibrosis agent of mitoxantrone or its analog or derivant.

23a. be the fibrosis agent of platinum compounds.

24a. be the fibrosis agent of nitroso ureas.

25a. be the fibrosis agent of nitroimidazole.

26a. be the fibrosis agent of antifol.

27a. be the fibrosis agent of cytidine analog.

28a. be the fibrosis agent of pyrimidine analogue.

29a. be the fibrosis agent of fluoropyrimidine analogue.

30a. be the fibrosis agent of purine analogue.

31a. be the fibrosis agent of chlormethine or its analog or derivant.

32a. be the fibrosis agent of hydroxyurea.

33a. be the fibrosis agent of mitomycin or its analog or derivant.

34a. be the fibrosis agent of alkyl sulfonate esters.

35a. be the fibrosis agent of Benzoylamide or its analog or derivant.

36a. be the fibrosis agent of nicotiamide or its analog or derivant.

37a. be the fibrosis agent of halogeno-sugar or its analog or derivant.

38a. be the fibrosis agent of DNA alkylating agent.

39a. be the fibrosis agent of anti-microtubule agent.

40a. be the fibrosis agent of topoisomerase enzyme inhibitor.

41a. be the fibrosis agent of dna cleavage agent.

42a. be the fibrosis agent of antimetabolite.

43a. suppress the fibrosis agent of ADA Adenosine deaminase.

44a. suppress the synthetic fibrosis agent of purine ring.

45a. be the fibrosis agent of nucleotide interconversion inhibitor.

46a. suppress the reductive fibrosis agent of dioxy folic acid.

47a. the fibrosis agent of blocking-up thymidine monophosphate.

48a. cause the fibrosis agent of DNA infringement.

49a. be the fibrosis agent of DNA intercalator.

50a. be the fibrosis agent of rna synthesis inhibitor.

51a. be the fibrosis agent of pyrimidine synthesis inhibitors.

52a. the inhibition ribonucleotide is synthetic or the fibrosis agent of function.

53a. the inhibition thymidine monophosphate is synthetic or the fibrosis agent of function.

54a. suppress the synthetic fibrosis agent of DNA.

55a. the fibrosis agent that causes dna adduct to form.

56a. the synthetic fibrosis agent of Profilin matter.

57a. suppress the fibrosis agent of microtubule function.

58a. be the fibrosis agent of the inhibitors of kinases of cyclin dependent.

59a. be the fibrosis agent of epidermal growth factor kinase inhibitor.

60a. be the fibrosis agent of elastatinal.

61a. be the fibrosis agent of factor Xa inhibitor.

62a. be the fibrosis agent of farnesyl transferase inhibitor.

63a. be the fibrosis agent of fibrinogen antagonist.

64a. be the fibrosis agent of guanylate cyclase stimulant.

65a. be the fibrosis agent of heatshock protein 90 antagonisies.

66a. be the fibrosis agent of geldanamycin or its analog or derivant.

67a. be the fibrosis agent of guanylate cyclase stimulant.

68a. be the fibrosis agent of HMGCoA reductase inhibitor.

69a. be the fibrosis agent of simvastatin or its analog or derivant.

70a. be the fibrosis agent of hydroorotic acid (hydroorotate) dehydrogenase inhibitor.

71a. be the fibrosis agent of IKK2 inhibitor.

72a. be the fibrosis agent of IL-1 antagonist.

73a. be the fibrosis agent of ICE antagonist.

74a. be the fibrosis agent of IRAK antagonist.

75a. be the fibrosis agent of IL-4 agonist.

76a. be the fibrosis agent of immunomodulator.

77a. be the fibrosis agent of sirolimus or its analog or derivant.

78a. be the fibrosis agent of nitric oxide inhibitor.

79a. be the fibrosis agent of everolimus or its analog or derivant.

80a. be the fibrosis agent of tacrolimus or its analog or derivant.

81a. be the fibrosis agent of TNF alpha inhibitor.

82a. be the fibrosis agent of biolmus or its analog or derivant.

83a. be the fibrosis agent of tresperimus or its analog or derivant.

84a. be the fibrosis agent of auranofin or its analog or derivant.

85a. be the fibrosis agent of 27-0-demethylation rapamycin or its analog or derivant.

86a. be the fibrosis agent of gusperimus or its analog or derivant.

87a. be the fibrosis agent of pimecrolimus or its analog or derivant.

88a. be the fibrosis agent of ABT-578 or its analog or derivant.

89a. be the fibrosis agent of inosine monophosphate dehydrogenase (IMPDH) inhibitor.

90a. be the fibrosis agent of Mycophenolic Acid or its analog or derivant.

91a. be 1-α-25 dihydroxyvitamin D ₃Or the fibrosis agent of its analog or derivant.

92a. be the fibrosis agent of leukotriene inhibitors.

93a. be the fibrosis agent of MCP-1 antagonist.

94a. be the fibrosis agent of MMP inhibitor.

95a. be the fibrosis agent of NF kB inhibitor.

96a. be the fibrosis agent of NF kB inhibitor, wherein said NF kB inhibitor is Bay 11-7082.

97a. be the fibrosis agent of NO antagonist.

98a. be the fibrosis agent of p38 map kinase inhibitor.

99a. be the fibrosis agent of p38 map kinase inhibitor, wherein said p38MAP inhibitors of kinases is SB 202190.

100a. be the fibrosis agent of phosphodiesterase inhibitor.

101a. be the fibrosis agent of TGF beta inhibitor.

102a. be the fibrosis agent of TXA2. antagonist.

103a. be the fibrosis agent of TNF alpha-2 antagonists.

104a. be the fibrosis agent of tace inhibitor.

105a. be the fibrosis agent of tyrosine kinase inhibitor.

106a. be the fibrosis agent of vitronectin inhibitor.

107a. be the fibrosis agent of fibroblast growth factor inhibitor.

108a. be the fibrosis agent of kinases inhibitor.

109a. be the fibrosis agent of pdgf receptor kinase inhibitor.

110a. be the fibrosis agent of endothelial growth factor receptor kinase inhibitor.

111a. be the fibrosis agent of RAR antagonists.

112a. be the fibrosis agent of platelet-derived growth factor receptor kinase inhibitor.

113a. be the fibrosis agent of fibrinogen antagonist.

114a. be the fibrosis agent of antimycotic agent.

115a. be the fibrosis agent of antimycotic agent, wherein said antimycotic agent is sulconizo1e.

116a. be the fibrosis agent of diphosphate.

117a. be the fibrosis agent of E.C. 3.1.1.32 inhibitor.

118a. be the fibrosis agent of histamine H 1/H2/H3 receptor antagonist.

119a. be the fibrosis agent of macrolide antibiotic.

120a. be the fibrosis agent of GPIIb/IIIa receptor antagonist.

121a. be the fibrosis agent of Endothelin (endothelin) receptor antagonist.

122a. be the fibrosis agent of peroxisome Proliferator-activated receptor agonist.

123a. be the fibrosis agent of estrogen receptor activity agent.

124a. be the fibrosis agent of somatostatin (somastostatin) analog.

125a. be the fibrosis agent of neurokinin 1 antagonist.

126a. be the fibrosis agent of neurokinin 3 antagonisies.

127a. be the fibrosis agent of VLA-4 antagonist.

128a. be the fibrosis agent of osteoclast inhibitor.

129a. be the fibrosis agent of DNA topoisomerase ATP hydrolysis inhibitor.

130a. be the fibrosis agent of hypertensin I conversion enzyme inhibitor.

131a. be the fibrosis agent of angiotension II antagonists.

132a. be the fibrosis agent of enkephalinase inhibitor.

133a. be the fibrosis agent of peroxisome Proliferator-activated receptor gamma agonist insulin sensitiser thing.

134a. be the fibrosis agent of inhibitors of protein kinase C.

135a. be the fibrosis agent of ROCK (rho-correlates kinases) inhibitor.

136a. be the fibrosis agent of CXCR3 inhibitor.

137a. be the fibrosis agent of Itk inhibitor.

138a. be cPLA2 A ₂The fibrosis agent of-alpha inhibitor.

139a. be the fibrosis agent of PPAR agonist.

140a. be the fibrosis agent of immunosuppressant.

141a. be the fibrosis agent of Erb inhibitor.

142a. be the fibrosis agent of programmed cell death agonist.

143a. be the fibrosis agent of lipocortin (lipocortin) agonist.

144a. be the fibrosis agent of VCAM-1 antagonist.

145a. be the fibrosis agent of collagen antagonist.

As mentioned above, the invention provides comprise above-mentioned 146 kinds (be each and following 98 kinds in the fibrosis agent of 1a-145a) enumerate or the fibrosis agent type (be each compositions in polymer of 1b-97b) and the chemical compound:

1b. cross linked polymer.

2b. polymer with the mammalian tissues reaction.

3b. be the polymer of naturally occurring polymer.

4b. be proteinic polymer.

5b. be the polymer of carbohydrate.

6b. be Biodegradable polymeric.

7b. be crosslinked and Biodegradable polymeric.

8b. nonbiodegradable polymer.

9b. collagen protein.

10b. methylated collagen albumen.

11b. fibrinogen.

12b. thrombin.

13b. albumin.

14b. plasminogen (plasminogen).

15b. Feng's von willebrand's factor (von Willebrands factor).

16b. Factor IX (Factor III).

17b. hypoallergenic tropocollagen.

18b. non-end peptide (Atelopeptidic) collagen protein.

19b. collagen protein.

20b. crosslinked with collagen albumen.

21b. aprotinin (aprotinin).

22b. gelatin.

23b. protein conjugate.

24b. gelatin conjugate.

25b. hyaluronic acid.

26b. derivatives of hyaluronic acids.

27b. synthetic polymer.

28b. the polymer that forms by the reactant that comprises the chemical compound that contains synthesizing isocyanate.

29b. contain the chemical compound of synthesizing isocyanate.

30b. the polymer that forms by the reactant that comprises the chemical compound that contains thiol synthesis.

31b. contain the chemical compound of synthetic mercaptan.

32b. by the polymer that the reactant that comprises synthetic chemical compound forms, described synthetic chemical compound contains at least two mercaptos.

33b. contain the synthetic compound of at least two mercaptos.

34b. by the polymer that the reactant that comprises synthetic chemical compound forms, described synthetic chemical compound contains at least three mercaptos.

35b. contain the synthetic chemical compound of at least three mercaptos.

36b. by the polymer that the reactant that comprises synthetic chemical compound forms, described synthetic chemical compound contains at least four mercaptos.

37b. contain the synthetic chemical compound of at least four mercaptos.

38b. by the polymer that comprises that the reactant that contains amino synthetic compound forms.

39b. contain amino synthetic compound.

40b. by the polymer that the reactant that comprises synthetic chemical compound forms, described synthetic chemical compound contains at least two amino.

41b. contain the synthetic compound of at least two amino.

42b. by the polymer that the reactant that comprises synthetic chemical compound forms, described synthetic chemical compound contains at least three amino.

43b. contain the synthetic compound of at least three amino.

44b. by the polymer that the reactant that comprises synthetic chemical compound forms, described synthetic chemical compound contains at least four amino.

45b. contain the synthetic compound of at least four amino.

46b. by the polymer that the reactant that comprises synthetic chemical compound forms, described synthetic chemical compound comprises carbonyl-oxygen-succinimido.

47b. comprise the synthetic compound of carbonyl-oxygen-succinimido.

48b. by the polymer that the reactant that comprises synthetic compound forms, described synthetic compound comprises at least two carbonyl-oxygen-succinimido.

49b. comprise at least two synthetic compounds that comprise carbonyl-oxygen-succinimido.

50b. by the polymer that the reactant that comprises synthetic compound forms, described synthetic compound comprises at least three carbonyl-oxygen-succinimido.

51b. comprise at least three synthetic compounds that comprise carbonyl-oxygen-succinimido.

52b. by the polymer that the reactant that comprises synthetic compound forms, described synthetic compound comprises at least four carbonyl-oxygen-succinimido.

53b. comprise at least four synthetic compounds that comprise carbonyl-oxygen-succinimido.

54b. the polymer that forms by the reactant that comprises the synthetic compound that contains polyalkylene oxide.

55b. contain the synthetic compound of polyalkylene oxide.

56b. by the polymer that the reactant that comprises synthetic compound forms, described synthetic compound comprises polyalkylene oxide and biodegradable polyester block.

57b. comprise the synthetic compound of polyalkylene oxide and biodegradable polyester block.

58b. by the polymer that the reactant that comprises the synthetic compound that contains polyalkylene oxide forms, described synthetic compound has reactive amino.

59b. contain the synthetic compound that has reactive amino of polyalkylene oxide.

60b. by the polymer that the reactant that comprises the synthetic compound that contains poly(ethylene oxide) forms, described synthetic compound has reactive mercapto.

61b. contain the synthetic compound that has reactive mercapto of polyalkylene oxide.

62b. by the polymer that the reactant that comprises the synthetic compound that contains polyalkylene oxide forms, described synthetic compound has reactive carbonyl-oxygen-succinimido.

63b. contain the synthetic compound of having of polyalkylene oxide of reactive carbonyl-oxygen-succinimido.

64b. by the polymer that the reactant that comprises synthetic compound forms, described synthetic compound comprises biodegradable polyester block.

65b. comprise the synthetic compound of biodegradable polyester block.

66b. by the polymer that the reactant that comprises synthetic polymer forms, described synthetic polymer forms going up in whole or in part by lactic acid or lactide.

67b. going up the synthetic polymer that forms by lactic acid or lactide in whole or in part.

68b. by the polymer that the reactant that comprises synthetic polymer forms, described synthetic polymer forms going up in whole or in part by glycolic or Acetic acid, hydroxy-, bimol. cyclic ester.

69b. going up the synthetic polymer that forms by glycolic or Acetic acid, hydroxy-, bimol. cyclic ester in whole or in part.

70b. the polymer that forms by the reactant that comprises polylysine.

71b. polylysine.

72b. by the polymer that comprises that the reactant of (a) protein with the chemical compound that (b) comprises the polyalkylene oxide part forms.

73b. by comprising (a) protein and (b) polymer that forms of the reactant of polylysine.

74b. by the polymer that comprises that (a) protein and the reactant that (b) has the chemical compound of at least four mercaptos form.

75b. by the polymer that comprises that (a) protein and the reactant that (b) has the chemical compound of at least four amino form.

76b. by the polymer that comprises that (a) protein and the reactant that (b) has the chemical compound of at least four carbonyl-oxygen-succinimido form.

77b. by the polymer that comprises that (a) protein and the reactant that (b) has the chemical compound in biodegradable district form, described biodegradable district is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone.

78b. by the polymer that comprises that the reactant of (a) collagen protein with the chemical compound that (b) comprises the polyalkylene oxide part forms.

79b. by comprising (a) collagen protein and (b) polymer that forms of the reactant of polylysine.

80b. by the polymer that comprises that (a) collagen protein and the reactant that (b) has the chemical compound of at least four mercaptos form.

81b. by the polymer that comprises that (a) collagen protein and the reactant that (b) has the chemical compound of at least four amino form.

82b. by the polymer that comprises that (a) collagen protein and the reactant that (b) has the chemical compound of at least four carbonyl-oxygen-succinimido form.

83b. by the polymer that comprises that (a) collagen protein and the reactant that (b) has the chemical compound in biodegradable district form, described biodegradable district is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and c-caprolactone.

84b. by the polymer that comprises that the reactant of (a) methylated collagen albumen with the chemical compound that (b) comprises the polyalkylene oxide part forms.

85b. by comprising (a) methylated collagen albumen and (b) polymer that forms of the reactant of polylysine.

86b. by the polymer that comprises that (a) methylated collagen albumen and the reactant that (b) has the chemical compound of at least four mercaptos form.

87b. by the polymer that comprises that (a) methylated collagen albumen and the reactant that (b) has the chemical compound of at least four amino form.

88b. by the polymer that comprises that (a) methylated collagen albumen and the reactant that (b) has the chemical compound of at least four carbonyl-oxygen-succinimido form.

89b. by the polymer that comprises that (a) methylated collagen albumen and the reactant that (b) has the chemical compound in biodegradable district form, described biodegradable district is formed by the reactant that is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone.

90b. by the polymer that comprises that hyaluronic reactant forms.

91b. the polymer that forms by the reactant that comprises derivatives of hyaluronic acids.

92b. by comprising that number-average molecular weight is the polymer that the reactant of poly-(ethylene glycol) ether four-sulfydryl of 3,000-30,000 tetramethylolmethane forms.

93b. number-average molecular weight is 3,000 and 30,000 poly-(ethylene glycol) ether four-sulfydryl of tetramethylolmethane.

94b. by comprising that number-average molecular weight is the polymer of the reactant formation of poly-(ethylene glycol) ether four of 3,000-30,000 tetramethylolmethane-amino.

95b. number-average molecular weight is 3,000-30,000 poly-(ethylene glycol) ether four-amino of tetramethylolmethane.

96b. the polymer that forms by the reactant that comprises following ingredients: (a) have 3,000-30,000 number-average molecular weight and comprise the synthetic compound of polyalkylene oxide district and a plurality of nucleophilic groups; (b) has 3,000-30,000 number-average molecular weight and comprise the synthetic compound of polyalkylene oxide district and a plurality of electrophilic groups.

97b. the mixture of following ingredients: (a) have 3,000-30,000 number-average molecular weight and comprise the synthetic compound of polyalkylene oxide district and a plurality of nucleophilic groups; (b) has 3,000-30,000 number-average molecular weight and comprise the synthetic compound of polyalkylene oxide district and a plurality of electrophilic groups.

As mentioned above, the invention provides and comprise above-mentioned 146 kinds (1a-fibrosis agent of 145a) enumerating or each in the fibrosis agent type and the above-mentioned 98 kinds (compositionss of each in polymer of 1b-97b) and the chemical compound: therefore, in all fields, the invention provides 146 * 98=14,308 kinds of described compositionss.

In certain embodiments of the invention, described therapeutic combination can also comprise radiopaque echogenic material and nuclear magnetic resonance (MRI) reaction material (being the MRI contrast agent) so that help said composition to develop under ultrasonic, x line fluoroscopic examination and/or MRI condition.For example, compositions can (for example be made with echogenic or radio-opaque material, such as the powdery tantalum for echogenic or radiopaque, tungsten, brium carbonate, bismuth oxide, barium sulfate, metrizamide (metrazimide), iopamidol, iohexol, Iopromide, iobitridol, iomeprol, iopentol, ioversol, ioxilan, iodixanol, iotrolan, the acetrizoic acid derivant, the amidotrizoic acid derivant, the iotalamic acid derivant, ioxithalamic acid (ioxithalamic acid) derivant, the metrizoic acid derivant, iodamide, lypophylic agents, adipiodone and ioglycamic acid; Or provide the microsphere of acoustic interface or vesicle to make) by interpolation.In order under MRI, to develop, contrast agent (for example gadolinium (III) chelate or iron oxide compound) can be mixed compositions.

Alternatively or in addition, can use fluorescence or described compositions be developed under visible light by other spectrum mode.The developing agent that can comprise for this purpose comprises dyestuff, pigment and day stain.In one aspect, said composition may further include coloring agent to improve compositions in vivo and/or the development of exsomatizing.Common situation is that when sending into the host, compositions may be difficult to develop, especially in implant or organization edge.Coloring agent can be mixed incidence rate or the order of severity of compositions to reduce or eliminate this problem.Coloring agent provides unique color, contrast or unique fluorescent characteristics of increase to compositions.In one aspect, provide the compositions that comprises coloring agent, made that its is convenient visible (under visible light or use fluorescent technique) and be easy to from its implant site, distinguish.In one aspect of the method, coloring agent can be included in liquid or the semi-solid combination.For example, can make the single component dyeing of two kinds of component cpds, make that this mixture is fully dyeed when merging in stripped or body.

Coloring agent can be for example endogenous compound (for example aminoacid or vitamin) or nutrient or food and can be hydrophobicity or hydrophilic compounds.Preferred coloring agent has extremely low toxicity or does not have toxicity under working concentration.Preferred security and normally enter intravital coloring agent by absorbing in addition is such as beta-carotene.Painted nutraceutical representational example (under visible light) comprising: fatsoluble vitamin, such as vitamin A (yellow); Water soluble vitamins is such as vitamin B12 (pink) and folic acid (yellow-orange); Carotenoid is such as beta-carotene (Huang-purple) and lycopene (redness).Other example of coloring agent comprises natural product (berry and fruit) extract, such as anthracene cyanogen element (anthrocyanin) (purple) and Stigma Croci extract (peony).Coloring agent can be fluorescence or phosphorescent chemical compound, such as Ipotensil alcohol (α-tocopherolquinol) (vitamin e derivative) or L-tryptophan.

In one aspect, compositions of the present invention comprises one or more coloring agent, is also referred to as dyestuff, and they are to pass to compositions with observable colour developing, and the effective dose of example gel exists.The example of coloring agent comprises: be suitable for the dyestuff of food, be called F.D.﹠amp such as those; C. the material of dyestuff; And natural colorant, such as Pericarpium Vitis viniferae extract, Radix Betae Hydrargyri Oxydum Rubrum, beta-carotene, roucou, carmine, Rhizoma Curcumae Longae, Fructus Capsici etc.Can also use derivant, analog and isomer arbitrarily in the above-mentioned coloring compound.The method of coloring agent being mixed implant or therapeutic combination changes according to the characteristic and the different of desired location of coloring agent.For example, can select the hydrophobicity coloring agent to be used for hydrophobic matrix.Coloring agent can be mixed carrier matrix, such as micelle.In addition, can control environment pH so that further control color and intensity.

In one aspect, compositions of the present invention comprises one or more antiseptic or bacteriostatic agent, they exist with the effective dose of bacterial growth in and/or the composite inhibiting anticorrosion to compositions, for example bismuth tribromophenate, methyl hydroxybenzoate, bacitracin, nipagin A, nipasol, erythromycin, chlorocresol, benzalkonium chloride etc.The example of antiseptic comprises oxybenzoic acid esters, methaform, benzylalcohol, phenethanol, dehydroacetic acid, sorbic acid etc.In one aspect, compositions of the present invention comprises one or more antibacterial (being also referred to as antibacterial (bacteriacidal)).

In one aspect, compositions of the present invention comprises the antioxidant that one or more exist with effective dose.The example of antioxidant comprises sulphite, alpha-tocopherol, beta-carotene and ascorbic acid.

In addition, compositions of the present invention should preferably have the stable shelf life of some months at least and can produce under aseptic condition and keep.Can make said composition aseptic and/or use method as known in the art that they are carried out latter stage sterilization by preparation under gnotobasis.Also the combination of these two kinds of methods can be used to prepare the compositions of sterile form.Can also be by using gamma-radiation or electron beam sterilization method to sterilize in latter stage.

In one aspect, chemical compound of the present invention and compositions are aseptic.Prepare many aseptic medicines and this standard by USP XXII＜1211〉determine.Term " USP " refer to American Pharmacopeia (referring to www.usp.org, Rockville, MD).Sterilization in this embodiment can be by acceptable and USP XXII＜1211 in the industry〉in listed many modes carry out, comprise gaseous sterilization, ionizing radiation, if or suitable use filter.Sterilization can keep by so-called sterile working, and this sterile working is also in USP XXII＜1211〉in the regulation.The acceptable gas that is used for gaseous sterilization comprises oxirane.The accessible radiation type that is used for ionization radiation method for example comprises gamma-rays and the electron beam from cobalt 60 source.The gamma-rays of typical doses is 2.5 Mrad.Can use to have suitable aperture, the filter of 0.22 μ m and suitable material for example, for example politef (for example from E.I.DuPont De Nemours and Company, Wilmington, the TEFLON of DE) filters.

In one aspect of the method, compositions of the present invention is included in and makes in its container that is used for described purpose, promptly as pharmaceutical composition.Belonging to important container characteristics is: allow to add the spatial volume of forming medium, described composition medium such as water or other aqueous medium, for example saline; Be the acceptable optical transmission characteristics that prevents the compositions in the luminous energy infringement container (with reference to SP XXII＜661 〉); The acceptable limit (with reference to USP XXII) of extracting in the container material; The barrier capacity of acceptable moisture (with reference to USP XXII＜671 〉) or oxygen.With regard to oxygen penetrates, this can by be included in the container, the malleation of noble gas (as high purity nitrogen) or rare gas (as argon) controls.

The typical material that is used to make pharmaceutical containers comprises USPI type-III type and NP type glass (with reference to USP XXII＜661 〉), polyethylene, TEFLON, siloxanes and gray-butyl rubber.With regard to non-intestinal, preferred USPI type-III type glass and polyethylene.

E. the using method of compositions

Compositions of the present invention can be used for various application.For example these compositionss can be used for: (a) prevention tissue adhesion; (b) treatment or prevention inflammatory arthritis; (c) prevention cartilage loss; (d) treatment or prevention hypertrophic cicatrix/keloid; (e) treatment or prevention angiopathy; (f) coating medical implant and device.The more detailed description of several concrete application is as described below.

The prevention of adhesion

The invention provides the compositions that is used for Film with Preventing Adhesion (for example surgical operation adhesion).This polymer composition can comprise one or more therapeutic activity agent (for example anti-scarring agent), and these activating agents provide the pharmacology to change to cell and/or the acellular process that relates in generation of surgery surgical adhesions and/or the development.Described and to have formed the therapeutic activity agent that reduces the surgical operation adhesion by suppressing fiber or scar tissue.The present invention provides the surgical operation adhesion barrier in one aspect of the method, and they comprise anti-scarring agent or comprise the compositions of anti-scarring agent.

The surgical operation adhesion is the unusual fibre bundle that can be used as the scar tissue that the agglutination result behind the operation technique any opening or the minimum level invasive forms in vivo, and described operation technique comprises abdominal part, gynecological, heart thorax, spinal column, shaping, blood vessel, ENT, ophthalmology, Urology Surgery, nerve or orthopaedic surgery.The surgical operation adhesion is generally the connective tissue structure that forms between the adjacent affected area in the body.Briefly, the damage regional area causes inflammation and the healing reaction that reaches top at healing and scar tissue in forming.If cicatrization causes the fibrous tissue bundle to form or adjacent anatomical structures adhesion (should be isolating), think that so surgical adhesions has taken place to be formed.The scope of adhesion can be from fragility be easy to separated structures to only providing the isolating densification of surgical incision tough and tensile fibre structure.Although many adhesions are benign, some can produce significant clinical problem and be to repeat operating main cause.The operation (Adhesiolysis) that destroys adhesion leads to the failure usually and recurs, and causes himself complete procedure of repetition because destroy the related operation wound of adhesion.It is a significant clinical problem and according to commenting meter 2002 in the U.S. 473,000 routine Adhesiolysis to be arranged that operation destroys adhesion.According to the relevant group of diagnosis (DRGs), the hospital general's expense that is used for these operations may be at least 10,000,000,000 dollars every year.

Because all operation techniques include the operation manipulation of tissue there is to a certain degree wound, so in fact any operation (no matter whether can finish well) all has the probability that causes significant clinically adhesion to form.Operation wound, such as cut, operation, retraction or sew up and because of inflammation, infection (for example fungus or mycobacterium), hemorrhage or exist foreign body can cause adhesion.Operation wound can also be because of organizing due to drying, ischemia or the hot injury.Because the cause of disease difference of surgical operation adhesion, so no matter be still to undergo surgery, all may there be adhesion formation with the form of the standard open technology that comprises one or more big relatively incisions with so-called minimum level infringement form therapy, the laparoscopy of conduit (for example based on).Although any surgical intervention all may lead to complications, the problem that exists in the particularly following operation of surgical operation adhesion: GI performs the operation (causing intestinal obstruction); Gynecilogical operation (causing pain and/or infertile); Tendon is repaired (causing shortening and flexion deformity); Joint capsule operation (causing the capsule contracture); With N﹠M reparation operation (causing function reduction or forfeiture).

The surgical operation adhesion can cause various normally serious and unpredictable clinical complications; In them some only showed with regard to self after initial operation is finished in 1 year.The complication that causes because of the surgical operation adhesion is the main cause of operative therapy failure and is intestinal obstruction and infertile main cause.Other complication relevant with adhesion comprises chronic back pain or pelycalgia, intestinal obstruction, urethral obstruction and drainage malfunction.The post-operative complication that redemption causes because of adhesion generally needs another kind of operation.Yet, last time surgical outcome and the adhesion that forms of the further concurrent conduct of operation subsequently.In addition, second kind of operation may cause the lasting circulation of further adhesion and other postoperative complication.

Place medical apparatus and implant and also increased the risk that the surgical operation adhesion takes place.Except that above-mentioned mechanism, the device of implantation may cause " foreign body " reaction, and wherein immune system is identified as foreign body with this implant and causes the inflammatory reaction that finally causes scar tissue to form.To the antixenic concrete form of medical apparatus placing response is implant complete closed (" isolation ") (encapsulation) in the scar tissue capsule.The device of implanting and the fiber kystis of implant can make any operation technique complicated, and breast increase and reconstruction operations, joint replacement, hernia prothesis, artificial vascular graft, stent placement and neurosurgery especially easily take place this complicated.In each case; implant is by fibrous connective tissue capsule encapsulation, and this fibrous connective tissue capsule can damage or influence the function (for example breast implant, artificial joint, surgical mesh, blood vessel graft, stent or cerebral dura mater sticking patch) of surgery implant.

Adhesion generally begins a few days ago interior after surgery formation.In general, it is a kind of inflammatory reaction that adhesion forms, and wherein the factor discharges, and makes vascular permeability increase and causes fibrinogen to flow into and fibrin deposits.The substrate of this formation of deposits cross-over connection adjacent tissue.Fibroblast is accumulated, and adheres to this substrate, and deposition collagen protein and induction of vascular take place.If the situation of this cascade (cascade) can obtain prevention in 4-5 days after surgery, adhesion forms and just can be inhibited so.

Check various forms of adhesion preventions, comprised (1) prevention fibrin deposition; (2) alleviate the local organization inflammation; (3) remove the fibrin deposit.Be physical barriers prevention fibrin deposition machinery or that form by viscosity solution by using.Barrier has with physics mode defence adjacent tissue and contacts with each other and reduce the advantage that they form the probability of cicatrix each other thus.Although many research worker and commodity have used the adhesion defensive barrier, it is remarkable to have reported a large amount of technical difficulties and mortality.By giving medicine, reduce inflammation such as cortex steroidal and NSAID (non-steroidal anti-inflammatory drug).Yet not encouraging because of the result who uses these medicines to produce in animal model, this is due to the dose limitation that causes because of the inflammatory reaction degree with because of systemic side effects.At last, use protease and plasmin to study and removed the fibrin deposit.The clinical potential complication of these enzymes of using is the excessive hemorrhage probability (surgical hemostasis is the key of operation technique success) of postoperative.

The number of polymers compositions (for example surgical operation adhesion barrier) that is used for the prevention of surgical surgical adhesions can be used to implement the present invention separately or with one or more anti-scarring agent combinations.Should notice that some polymer composition self can help to prevent the fibrous tissue on the operative site to form.In certain embodiments, described polymer composition can form barrier between tissue surface or organ.

For example, be coated in the surgical operation adhesion barrier on the tissue surface and this barrier can be made up of the aqueous solution with the hydrophilic polymer material (for example polypeptide class or polysaccharide) greater than 50,000 molecular weight and 0.01%-15% weight concentration scope.For example, referring to United States Patent (USP) 6,464,970.The surgical operation adhesion barrier can be crosslinkable system, and it has at least three kinds of compound of reactions, and they have the polymer molecule nuclear that has at least a functional group separately.For example, referring to United States Patent (USP) 6,458,889.The surgical operation adhesion barrier can and or not be made up of with therapeutic agent non-agglomerative polyoxyalkylene compositions.For example, referring to United States Patent (USP) 6,436,425.The surgical operation adhesion barrier can be made up of anionic polymer, and this anionic polymer has bisulfate and the sulfur content that suppresses mononuclear cell or macrophage intrusion that rise greater than 5%.For example, referring to United States Patent (USP) 6,417,173.The surgical operation adhesion barrier can be for comprising the waterborne compositions of surfactant, pentoxifylline (pentoxifylline) and polyoxyalkylene polyethers.For example, referring to United States Patent (USP) 6,399,624.The surgical operation adhesion barrier can be formed by crosslinked two kinds of synthetic polymers, a kind of nucleophilic group that has in the described polymer, and another kind has electrophilic group, makes them form the substrate that can be used to mix bioactive compound.For example, referring to United States Patent (USP) 6,323,278; 6,166,130; 6,051,648 and 5,874,500.The surgical operation adhesion barrier can be made up of hyaluronic acid compositions, is described in United States Patent (USP) 6,723 such as those, the hyaluronic acid compositions in 709,6,531,147 and 6,464,970.The surgical operation adhesion barrier can be the polymer tissue coating, by the polymerization initiator coating is formed this coating with using radical initiator polymeric water-soluble macromolecule monomer under the UV influence of light to cover it organizationally and then.For example, referring to United States Patent (USP) 6,177,095 and 6,083,524.The surgical operation adhesion barrier can be made up of mobile prepolymer material, it be launched into tissue surface and then in position contact activation can change into the material that causes coating can not mobile polymer form.For example, referring to United States Patent (USP) 6,004,547 and 5,612,050.The surgical operation adhesion barrier can for form hydrogel, from the absorbable polyester copolymer of solvation, they can optionally segmentedly be combined into the water-setting micelle of adaptation when the contact aqueous environments.For example, referring to United States Patent (USP) 5,612,052.The surgical operation adhesion barrier can be for effectively suppressing effective carrier on cell intrusion or Fibrotic anionic polymer (for example dermatan sulfate, dextran sulfate, many sulphuric acid pentosan or alginate) and the medicine, and wherein this carrier can be semisolid.For example, referring to United States Patent (USP) 6,756,362,6,127,348 and 5,994,325.The surgical operation adhesion barrier can be for comprising the acidifying water gel of the about 2.0-about 6.0 scope pH of having of carboxylated polysaccharide and polyethers.For example, referring to United States Patent (USP) 6,017,301.The surgical operation adhesion barrier can by have about 40,000-500,000 Dalton molecular weight be used to suppress aixs cylinder and form to the dextran sulfate of outgrowth.For example, referring to United States Patent (USP) 5,705,178.The surgical operation adhesion barrier can be the biocompatible hydrogel of fragmentation, and is that it is at least the part aquation and be substantially free of water, and wherein said hydrogel comprises gelatin and absorbs water when being delivered to moistening tissue target position.For example, referring to United States Patent (USP) 6,066,325.The surgical operation adhesion barrier can be water miscible degradable macromonomer, and this monomer is made up of at least two crosslinkable substituent groups, and described substituent group can be crosslinked with the locational macromonomer of other limitation under the polymerization initiator influence.For example, referring to United States Patent (USP) 6,465,001.The surgical operation adhesion barrier can be the biocompatibility binding compositions, and it comprises at least a Arrcostab cyanoacrylate monomer and polymerization initiator or accelerator.For example, referring to United States Patent (USP) 6,620,846.

In one embodiment, can use the polymer that can form covalent bond with the tissue that is coated with.Contain such as succinimido, aldehyde, epoxide, isocyanates, vinyl, vinyl sulfone, maleimide ,-S-S-(C ₅H ₄N) or this class electrophilic group of activatory esters and/or can be used as reagent such as being used for the synthetic polymer of peptide with these electrophilic groups are end capped.For example, can be with the deutero-Polyethylene Glycol of ramose NHS-(for example poly-(ethylene glycol) ether four-succinimido glutarate of tetramethylolmethane) to be coated with organizationally with 4 with solid form or solution form.In this embodiment, be with the deutero-Polyethylene Glycol of ramose NHS-to be dissolved in acid solution (pH is about 2-3) with 4 and use the common coating of alkaline buffer (pH〉about 8) then organizationally.The fibre modification inhibitor directly can be mixed 4 and be with the deutero-Polyethylene Glycol of ramose NHS-, described acid solution or alkaline buffer.In another embodiment, the fibre modification inhibitor can be mixed second kind of carrier, it can be mixed 4 then and be with the deutero-Polyethylene Glycol of ramose NHS-, described acid solution and/or alkaline buffer.Second kind of carrier can comprise microgranule and/or the microsphere of being made by degradable polymer.Degradable polymer can comprise polyesters, wherein said polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) n, (wherein X (for example gathers (ethylene glycol to the block copolymer of R-(X-Y) n and X-Y-X in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, MountOlive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator).

In another embodiment, begin to be coated with tissue reactive polymer and then that fibre modification is inhibitor coated at the tissue that wraps quilt.The fibre modification inhibitor directly can be coated with and maybe it can be mixed second kind of carrier organizationally.Second kind of carrier can comprise microsphere (as mentioned above), microgranule (as mentioned above), gel (hyaluronic acid for example, carboxymethyl cellulose, glucosan, poly-(oxirane)-poly-(expoxy propane) block copolymer and admixture thereof, association complex and cross-linked composition) and thin film (degradable polyesters, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) _n, R-(X-Y) _nWith the block copolymer of X-Y-X (X (for example poly-(ethylene glycol in polyalkylene oxide wherein, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, Mount Olive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, glucosan, poly-(oxirane)-poly-(expoxy propane) block copolymer and admixture thereof, association complex and cross-linked composition.

Can be separately or unite with fibre modification inhibitor/compositions and to be used for auxiliaryly preventing that both form as the reactant of reaction reagent by comprising one of following ingredients or its for preferred polymers substrate that fibrous tissue forms: tetramethylolmethane gathers (ethylene glycol) ether four-sulfydryl] (4-is with ramose sulfydryl PEG, be included in and have the structure that is connected base between sulfydryl and the polyethylene glycol backbone end) and poly-(ethylene glycol) ether four-succinimido glutarate of tetramethylolmethane] (4-is with ramose NHS PEG, also is included in to have between NHS base and the polyethylene glycol backbone end to be connected basic structure).Another kind of preferred compositions comprise one of following ingredients or its both as reaction reagent: tetramethylolmethane gathers (ethylene glycol) ether four-amino] (4-is with ramose amino PEG, be included between amino and the polyethylene glycol backbone end and have the structure that is connected base) and tetramethylolmethane gather (ethylene glycol) ether four-succinimido glutarate] (4-is with ramose NHSPEG, also be included in NHS basic with the polyethylene glycol backbone end between have be connected basic structure).The chemical constitution of these reactants such as United States Patent (USP) 5,874 are shown in 500.Randomly collagen protein or collagen derivative (for example methylated collagen albumen) are joined in the reactant that contains poly-(ethylene glycol) so that form preferred crosslinked substrate, this substrate can be as the auxiliary polymer support that prevents therapeutic agent that fibrous tissue forms or independent compositions.

The surgical operation adhesion barrier that can merge one or more anti-scarring agents of the present invention also comprises and is purchased product.The example that can mix the surgical operation adhesion barrier compositions of fibre modification activating agent comprises: (a) contain the sprayable preparation of collagen protein, such as COSTASIS or CT3 (Angiotech Pharnaceuticals, Inc., Canada); (b) contain the sprayable preparation of PEG, such as COSEAL or ADHIBIT (Angiotech Pharmaceuticals, Inc.), SPRAYGEL or DURASEAL (both from Confluent Surgical, Inc., Boston, MA) or FOCALSEAL (Genzyme Corporation, Cambridge, MA); (c) contain hyaluronic preparation, (both are all from Q-Med AB such as RESTYLANE or PERLANE, Sweden), HYLAFORM (Inamed Corporation, Santa Barbara, CA), SYNVISC (Biomatrix, Inc., Ridgefield, NJ), SEPRAFILM or SEPRACOAT (both are all from Genzyme Corporation); (d) contain preparation such as the FLOSEAL of fibrinogen or TISSEAL (both are all from Baxter Healthcare Corporation, Fremont, CA); (e) polymer gel, such as REPEL (Life Medical Sciences, Inc., Princeton, NJ) or FLOWGEL (Baxter Healthcare Corporation, Deerfield, IL); (f) contain the operation binding agent of cyanoacrylate, such as DERMABOND (Johnson﹠amp; Johnson, Inc., New Brunswick, NJ), INDERMIL (U.S.Surgical Company, Norwalk, CT), GLUSTITCH (Blacklock Medical Products Inc., Canada), TISSUMEND (Veterinary Products Laboratories, Phoenix, AZ), VETBOND (3M Company, St.Paul, MN), HISTOACRYL BLUE (Davis﹠amp; Geck, St.Louis, MO) and ORABASE SOOTHE-N-SEAL LIQUIDPROTECTANT (Colgate-Palmolive Company, New York, NY); (g) dextran sulfate gel, such as the product of ADCON scope (available from Wright Medical Technology, Inc.Arlington, TN); (h) based on the compositions of lipid, such as ADSURF (BritanniaPharmaceuticals Ltd., United Kingdom); (j) film composite, such as INTERCEED (Ethicon, Inc., Somerville, NJ) and HYDROSORB (MacroPoreBiosurgery, Inc., San Diego, CA/Medtronic Sofamor Danek, Memphis, TN).

For more clearly statement, several concrete application and Therapeutic Method are more specifically described, comprising:

I) the adhesion prevention in the operation of spinal column and neurosurgery

Backache be account in the spending of U.S. health care first reason and annual account in the cost more than 50,000,000,000 dollars (1,000 hundred million dollars in the whole world).Have in the U.S. and to surpass that 1,200 ten thousand people suffer from the degenerative disc disease (DDD) of some form and 10% (1,200,000) wherein need operation proofread and correct its problem.

In healthy individual, spinal column is by forming by the isolated spine plate of intervertebral disc that forms strong joint and absorb spinal compression in motor process.Intervertebral disc is made up of the inside gel-like substance that is called vertebral pulp, and is the firm fibrous cartilage capsule that is called annulus fibrosis around the vertebral pulp.Vertebral pulp is made up of collagen protein fibril in the gelatinised matrix that is embedded in glycosaminoglycan and water and connective tissue cell (similar fibroblast and chondrocyte) relaxed configuration.Fibrous ring becomes the fibrous cartilage concentric ring of vertebral body to form by a large amount of grapplings.The DDD of common cause takes place when tearing in the fibre modification ring produces the weak zone of localization, and described tearing makes vertebral pulp bulging, outstanding or sequestrum forms and the fibre modification ring enters spinal canal and/or vertebral foramen.The common pressuring nerve tissue of bulging or prolapse of intervertebral disc is such as spinal cord fiber or spinal cord and nerve roots fiber.To causing neural machine dysfunction (numb, weak, tingling), disabled pain, intestinal or bladder imbalance and can cause long term disability from the spinal cord of damaged spinal disc or the compressing of nerve root.Although the DDD of many situations returns spontaneous regression, but a large amount of needs of patients are with the operation of minimum level invasive, and the form that promptly micro-dish excision, major operation are excised little meniscus, spinal fusion (using various technology and device to merge the adjacent vertebrae plate) and/or implanted artificial dish is carried out surgical operation.The invention provides the method that in operation control DDD, is coated with antiblocking agent or fibrosis agent.

It is mandatory and urgent that spinal disc is removed when having significant neurological handicap, particularly intestinal or vesical dysfunction cauda equina syndrome.Also randomly implement alleviating pain and eliminate less nervous symptoms.Spinal nerve root is by leaving spinal canal for the vertebral foramen of nerve compression infringement common site (on the vertebra and the bone opening of vertebra between down).In order in the back surgery process, to enter vertebral foramen once more, excise vertebral tissue usually, promptly a kind of process that is called laminectomy.

The spinal nerve root of RLD compressive lesion is being implemented in the process of open operation excision (laminectomy) patient to be placed the improved position of kneeling under generalized anesthetic state.In postmedial line, implement incision and disintegrated tissue to expose suitable gap; Cut ligamenta flava and in some cases part bone thin layer so that fully manifest.The careful nerve root retraction that makes is to expose part outstanding in the ring and damaged.In general, the tear place from ring enters the dish chamber and uses pituitary forceps to take out the lax fragment of vertebral pulp.Also take out the fragment of any other dish of disk space inside or external isolation modestly.Tear if exist in the dura mater, so with the stitching thread sealing dura mater that increases with fibrin adhesive ﹠ usually.

Microsurgical operation for herniated lumbar disc (Microlumbar disc excision) (micro-dish excision) can be carried out and has replaced in a large number the surgical selection of laminectomy as prolapse of intervertebral disc or nerve root involvement as out-patient's operation.Make 1 inch otch down from the spinous process on the dish of being encroached on to spinous process.Use operating microscope, will organize to cut open downwards and take out bone, up to can clearly identifying nerve root to ligamenta flava and from thin slice.Make the careful retraction of nerve root and under the amplification condition, observe tearing in the ring.Clamp the fragment of tear place taking-up dish and take out any isolated dish fragment with little meniscus through encircling.Because used laminectomy, so tearing of any dura mater, repaired in the space of washing tray to go out the fragment of any dish and with absorbable stitching thread sealing tissue.Should notice that above-mentioned (abdominal part) means also can be used for open and endoscope's lumbar discectomy art.Neck is operated similar with thorax dish excision and lumbar surgery and also can be according to rear portion means (use laminectomy) or as using the preceding diskectomy that merges carry out.

Back surgery makes the spinal column dura mater expose usually such as laminectomy, diskectomy and micro-dish excision and loses protection.As a result of, between dura mater and surrounding tissue, form scar tissue usually.This cicatrix is formed by the impaired musculus sacrospinalis that covers on the vertebrae plate resection position.The result sticks together between muscular tissue and the fragility dura mater, reduces spinal column thus and from the motion of the nerve root wherein left, it is slow to produce pain, persistent nervous symptoms and post-operative recovery.What take place in epidural and dura mater tissue similarly, sticks in complication in spinal cord injury (for example repressive and crush injury) situation.In addition, cicatrix in dura mater and peripheral nerve root and adhesion form and mean that the feasible spinal operation of (proofreading and correct and repetition) subsequently more is difficult to carry out technically.

In order to prevent that adhesion from taking place, the barrier that reduces cicatrix can be inserted between dura mater cover and the other muscular tissue of laminectomy posterior spinal.Perhaps (or comprising this situation), with separately or the adhesion barrier that contains the fibre modification inhibitor be coated in (or being impregnated into surrounding tissue) on the spinal nerves, it left spinal canal and strode across space (being the laminectomy position) between the vertebra this moment.This can reduce cell and the blood vessel infringement enters the epidural space from the muscle of covering and the spongy bone of exposure, and reduces the complication relevant with the cicatrization of vertebra tube chamber, spinal cord and/or nerve root thus.In the operating process of micro-dish excision, importantly described barrier can be used as spray, gel or flowing material and sends, and can give them by the delivery port of endoscope.Need to prove once more, can with separately or the adhesion barrier that contains the fibre modification inhibitor be sprayed on (or being impregnated into its surrounding tissue) on the spinal nerves, it left spinal canal and strode across space (being the laminectomy position) between the vertebra this moment.The present invention discloses independent use or merged the barrier compositions of fibre modification inhibitor, can in surgical tray excision and micro-dish excision process, use special use delivery catheter, directly send them by endoscope or by syringe needle or other applicator.When existing dura mater damaged, the fibre modification inhibitor helps to make the dura mater healing and prevents complication, such as the CSF flow blockage.

In one aspect of the method, adhesion forms and can perform the operation relevant with neurosurgery (brain).Neurosurgery is attended by the serious post-operative complication of possibility, and these complication are usually because of operation wound and unwanted fibre modification or gliosis (gliosis is to form as scar tissue in the brain of neurogliocyte action result).Intracranial hemorrhage increase, infection, cerebrospinal fluid spill with pain only be some complication that causes because of the adhesion after the neurosurgery.For example, if normal cerebrospinal fluid (CSF) circulated after scar tissue had interrupted brain or spinal operation, cerebrospinal fluid may be accumulated and exert pressure (causing intracranial pressure to increase) to surrounding tissue so, thereby produces severe complications (forming (uncal herneation), cerebral lesion and/or death such as uncal herniation).In this article, separately or the adhesion barrier that has merged the fibre modification inhibitor can be used for preventing the adhesion of over-drastic dura mater cicatrization and various neurosurgeries to form.

Exist can use separately or load in a large number therapeutic agent (for example fibre modification inhibitor or anti-infective) be coated on spinal column or neurosurgery position (or be coated on place on the intravertebral implant surface-such as artificial dish, bar, screw, spinal column protect frame, pass Teat pipette, nerve stimulation device; Or be coated on the implant that places brain-such as drainage tube, bypass, pass Teat pipette, nerve stimulation device) on compositions be used for preventing the surgical operation adhesion of neurosurgery.Should notice that some polymer self helps to prevent the fibrous tissue on spinal column or the neurosurgery position to form.These compositionss especially separately or with suppress fibrotic compositions and unite and be used to implement the present embodiment.

Various polymer compositions be can make and or spinal column or neurosurgery position (for example soak into or soak near implant-organizational interface) are not impregnated at the tissue on the surgical site with other therapeutic agent that is used for the prevention of surgical surgical adhesions.

In one embodiment, can use the polymer that can form covalent bond with the tissue that is coated with.Contain such as succinimido, aldehyde, epoxide, isocyanates, vinyl, vinyl sulfone, maleimide ,-S-S-(C ₅H ₄N) or this class electrophilic group of activatory esters and/or can be used as reagent such as being used for the synthetic polymer of peptide with these electrophilic groups are end capped.For example, can be with the deutero-Polyethylene Glycol of ramose NHS-(for example poly-(ethylene glycol) ether four-succinimido glutarate of tetramethylolmethane) to be coated with organizationally with 4 with solid form or solution form.In this embodiment, be with the deutero-Polyethylene Glycol of ramose NHS-to be dissolved in acid solution (pH is about 2-3) with 4 and use the common coating of alkaline buffer (pH〉about 8) then organizationally.The fibre modification inhibitor directly can be mixed 4 and be with the deutero-Polyethylene Glycol of ramose NHS-, described acid solution or alkaline buffer.

In another embodiment, the fibre modification inhibitor can be mixed second kind of carrier, it can be mixed 4 then and be with the deutero-Polyethylene Glycol of ramose NHS-, described acid solution and/or alkaline buffer.Second kind of carrier can comprise microgranule and/or the microsphere of being made by degradable polymer.Degradable polymer can comprise polyesters, wherein said polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) _n, R-(X-Y) _nWith the block copolymer of X-Y-X (X (for example poly-(ethylene glycol in polyalkylene oxide wherein, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, Mount Olive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator).

In another embodiment, begin to be coated with tissue reactive polymer and then that fibre modification is inhibitor coated at the tissue that wraps quilt.The fibre modification inhibitor directly can be coated with and maybe it can be mixed second kind of carrier organizationally.Second kind of carrier can comprise microsphere (as mentioned above), microgranule (as mentioned above), gel (hyaluronic acid for example, carboxymethyl cellulose, glucosan, poly-(oxirane)-poly-(expoxy propane) block copolymer and admixture thereof, association complex and cross-linked composition) and thin film (degradable polyesters, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) _n, R-(X-Y) _nBlock copolymer with X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, Mount Olive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, glucosan, poly-(oxirane)-poly-(expoxy propane) block copolymer and admixture thereof, association complex and cross-linked composition.

Can be separately or unite the preferred polymer substrate that forms for the auxiliary fibr tissue that prevents from causing above-mentioned adhesion both form as the reactant of reaction reagent: pentaerythrite PEG ether four-sulfydryl by comprising one of following composition or its with fibre modification inhibitor/composition] (4-is with the sulfydryl PEG of branch; Be included between sulfydryl and polyethylene glycol backbone end with the structure that is connected base) and pentaerythrite PEG ether four-succinimido glutarate] (4-is with the NHS PEG of branch, also is included between NHS base and polyethylene glycol backbone end with being connected basic structure). Another kind of preferred compositions comprise one of following ingredients or its both as reaction reagent: tetramethylolmethane gathers ( ethylene glycol ) ether four-amino] ( 4-is with ramose amino PEG； be included between amino and the polyethylene glycol backbone end and have the structure that is connected base ) and tetramethylolmethane gather ( ethylene glycol ) ether four-succinimido glutarate] ( 4-is with ramose NHS PEG； also be included in NHS basic with the polyethylene glycol backbone end between have be connected basic structure ) .The chemical constitution of these reactants such as United States Patent ( USP ) 5；874 are shown in 500.Randomly collagen protein or collagen derivative ( for example methylated collagen albumen ) are joined in the reactant that contains poly- ( ethylene glycol ) so that form preferred crosslinked substrate, this substrate can be as the auxiliary polymer support that prevents therapeutic agent that fibrous tissue forms or independent compositions.

Be used for the prevention of surgical surgical adhesions can be impregnated into spinal column or neurosurgery position (for example soaking on the surgical site or near implant-organizational interface, soaking into) with or do not comprise the various products that are purchased with other other example that suppresses the polymer composition of fibre modification (and/or infection) therapeutic agent.Confluent Surgical for example, Inc. has produced their DURASEAL, strengthens the synthetic water gel of the dura mater sealing sewed up for being designed for craniotomy operation back.By ConfluentSurgical, the product description of Inc. research and development is in United States Patent (USP) 6,379,373 for example.FzioMed, (San Luis Obispo CA) has produced OXIPLEX/SP Gel to Inc., and it is sold as the adhesion barrier that is used for spinal operation.OXIPLEX/SP Gel is used for alleviating the pain and the radiculalgia of laminectomy, laminotomy and diskectomy.By FzioMed, the product description of Inc. research and development is in United States Patent (USP) 6,566,345 and 6,017,301 for example.Anika Therapeutics, (Wobum MA) is is researching and developing and is being used to prevent inner adhesion or synulotic INCERT-S behind the spinal operation Inc..INCERT-S is the ingredient of the hyaluronic acid therapy of the biological absorbable chemical modification of possible gang.By Anika Therapeutics, the product description of Inc. research and development is at for example United States Patent (USP) 6,548,081; 6,537,979; 6,096,727; 6,013,679; In 5,502,081 and 5,356,883.Life Medical Sciences, (Little Silver, NJ) researching and developing RELIEVE may be the biologically absorbable polymer that the adhesion behind the spinal operation forms as being designed for prevention or alleviating to Inc..By byLife Medical Sciences, the product description of Inc. research and development is at for example United States Patent (USP) 6,696,499; 6,399,624; 6,211,249; In 6,136,333 and 5,711,958.Wright MedicalTechnology, Inc. selling the ADCON series of products, they are dextran sulfate gels, at first by Gliatech, Inc. (Beachwood, OH) research and development are used for suppressing to occur in the low back laminectomy in NE path or the postoperative epidural fibre modification of laminotomy operation.ADCON provides spinal cord and nerve root behind the lumbar surgery and the barrier between muscle and the bone on every side.The ADCON series of products are described in for example United States Patent (USP) 6,417,173; 6,127,348; 6,083,930; In 5,994,325 and 5,705,178.

Can use separately or load therapeutic agent (for example fibre modification inhibitor or anti-infective) be coated on or be impregnated into spinal column or neurosurgery position (or on implant surface) be used for Film with Preventing Adhesion other be purchased material and comprise: (a) contain the sprayable preparation of collagen protein, such as COSTASIS or CT3; (b) contain the sprayable preparation of PEG, such as COSEAL, ADHIBIT, FOCALSEAL or SPRAYGEL; (c) contain the preparation of fibrinogen, such as FLOSEAL or TISSEAL (both are all from Baxter Healthcare Corporation, Fremont, CA); (d) contain hyaluronic preparation, such as RESTYLANE, PERLANE, HYLAFORM, SYNVISC, SEPRAFILM or SEPRACOAT; (e) polymer gel that is used to perform the operation and implants is such as REPEL or FLOWGEL; (f) contain the operation binding agent of cyanoacrylate, such as DERMABOND, INDERMIL, GLUSTITCH, TISSUMEND, VETBOND, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEALLIQUID PROTECTANT; (h) based on the compositions of lipid, such as ADSURF; (j) film composite, such as INTERCEED (Ethicon, Inc., Somerville, NJ) and HYDROSORB (MacroPore Biosurgery, Inc., San Diego, CA/MedtronicSofamor Danek, Memphis, TN).Those skilled in the art obviously should expect being purchased compositions and commodity of future generation and/or research and development subsequently and being suitable for using in the present invention of above-mentioned non-special citation.

As mentioned above, can directly or indirectly the compositions that is used for the prevention of surgical surgical adhesions be coated on the tissue at spinal column or neurosurgery position.Can according to any-mode as herein described give these polymer compositions (with or not with therapeutic agent).Typical method be included in when operation use endoscope, ultrasonic, CT, MRI or fluoroscopic guidance directly coating and/or with combine coating at operative site apparatus for placing or implant.Being used for the device of spinal column and neurosurgery operation or the representational example of implant includes, but are not limited to dura mater sticking patch, spinal prostheses (for example artificial dish, injectable dish filler or filler, spinal implant, spinal cord renucleation thing, disc spacers), merges and protect frame, nerve stimulation device, implantable Teat pipette, bypass, drainage tube, electrode and the bone anchoring device (for example anchor plate and bone screw) passed.

In opening or endoscopic procedure process with described polymer composition with or be not coated with the inhibitor coated infra of fibre modification tabulation face or by wherein said mode: (a) before surgical operation, in the process or operative site surface (for example forming gel or mesh) afterwards as Injectable solution, paste, gel, original position; (b) before surgical operation, in the process or the surface of operating position surrounding tissue afterwards (for example forming gel or mesh) as Injectable solution, paste, gel, original position; (c) at operative site by the said composition part being coated with anatomic space (such as cavum subdurale or in sheath) (useful especially be to use the described activating agent of polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, solid implant and release of release fibre modification inhibitor in the time limits in several hours-a few week and it can be sent other preparation) into the zone of insertion device for this embodiment; (d) by inject operative site neutralization tissue on every side as solution, transfusion or slow releasing preparation percutaneous; And/or (e) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent, anti-infective and/or anti-platelet agents).

In comprising some application of placing medical apparatus or implant, need go up coating fibrosis (and/or infection) compositions in the position adjacent (preferably near implant-organizational interface) with implant.Can in opening or endoscopic procedure process, finish this process through the following steps: with described polymer composition with or be not coated with the inhibitor coated infra of fibre modification tabulation face or by wherein said mode: (a) before implant procedure, in the process or implant surface (for example forming gel or mesh) afterwards as Injectable solution, paste, gel, original position; (b) before implant is just implanted, in the process or the surface of adjacent tissue afterwards (for example as Injectable solution, paste, gel, original position formation gel or mesh); (c) before implant is implanted, in the process or the surface of implant afterwards and implant surrounding tissue (for example as Injectable solution, paste, gel, original position formation gel or mesh); (d) by the said composition part being coated with the anatomic space (such as cavum subdurale (sudural space) or in sheath) of having placed implant (for the useful especially polymer support-fluid that is to use release fibre modification inhibitor in several hours-a few time limits in week of this embodiment, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, solid implant and discharge described activating agent and it can be sent other preparation into the zone of insertion device); (e) by inject implant tissue on every side as solution, transfusion or slow releasing preparation percutaneous; And/or (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent, anti-infective and/or anti-platelet agents).

In one aspect, described polymer composition can be delivered to tissue (or device/organizational interface) with spray or gel form in opening, endoscope or the operating process based on conduit.Can as mentioned above the fibre modification inhibitor directly be mixed the surgical operation adhesion barrier or it is mixed second kind of carrier (polymerization or non-polymeric), then it be mixed adhesion barrier.Can comprise system, hyaluronic acid and cross-linked-hyaluronic acid compositions for the example of the polymer composition of spray or gel form based on poly-(ethylene glycol).These compositionss maybe can be formed them as original position the material coating of cross-linked gel as final compositions coating.

In one aspect of the method, activatory polymer is dissolved in has the biological acceptable buffer that is lower than (lower that) 6.8pH.Have greater than second kind of biology of 7.5pH under the operation of acceptable buffer the gained solution coat at required tissue surface having then.By extruding, brush, spraying or by arbitrarily other easily mode this reactant mixture is coated on the tissue site.After being coated on described compositions on the operative site,, can remove any excessive solution from operative site so if think necessary.Should in time use usual manner closed surgery position (for example stitching thread, nail or biological adhesive) this moment.In one embodiment, can use activatory polymer, this polymer can form covalent bond with the tissue that it is coated with.Contain such as succinimido, aldehyde, epoxide, isocyanates, vinyl, vinyl sulfone, maleimide ,-S-S-(C ₅H ₄N) or this class electrophilic group of activatory esters and/or can be used as reagent such as being used for the synthetic polymer of peptide with these electrophilic groups are end capped.For example, can be with the deutero-Polyethylene Glycol of ramose NHS-(for example poly-(ethylene glycol) ether four-succinimido glutarate of tetramethylolmethane) to be coated with organizationally with 4 with solid form or solution form.In this embodiment, be with the deutero-Polyethylene Glycol of ramose NHS-to be dissolved in acid solution (pH is about 2-3) with 4 and use the common coating of alkaline buffer (pH〉about 8) then organizationally.The fibre modification inhibitor of fibrosis directly can be mixed 4 and be with the deutero-Polyethylene Glycol of ramose NHS-, described acid solution or alkaline buffer.In another embodiment, the fibre modification inhibitor can be mixed second kind of carrier, it can be mixed 4 then and be with the deutero-Polyethylene Glycol of ramose NHS-, described acid solution and/or alkaline buffer.Second kind of carrier can comprise microgranule and/or the microsphere of being made by degradable polymer.Degradable polymer can comprise polyesters, wherein said polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) n, the block copolymer of R-(X-Y) n and X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, Mount Olive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator.In another embodiment, begin to be coated with the tissue reactive polymer, and then with the inhibitor coated tissue at the bag quilt of fibre modification.The fibre modification inhibitor directly can be coated with and maybe it can be mixed second kind of carrier organizationally.Second kind of carrier can comprise microsphere (as mentioned above), microgranule (as mentioned above), gel (hyaluronic acid for example, carboxymethyl cellulose, glucosan, poly-(oxirane)-poly-(expoxy propane) block copolymer and admixture thereof, association complex and cross-linked composition) and thin film (degradable polyesters, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) _n, R-(X-Y) _nBlock copolymer with X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, MountOlive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, glucosan, poly-(oxirane)-poly-(expoxy propane) block copolymer and admixture thereof, association complex and cross-linked composition.

In one aspect of the method, activatory polymer can be coated on the operative site with solid-state.This activatory polymer can react as the tissue surface that the polymer water compound is coated with it.Before the activatory polymer of applying solid and/or will have afterwards organizationally greater than the biological acceptable buffer coating of 7.5 pH.In one embodiment, can use activatory polymer, this polymer can form covalent bond with the tissue that it is coated with.Contain such as succinimido, aldehyde, epoxide, isocyanates, vinyl, vinyl sulfone, maleimide ,-S-S-(C ₅H ₄N) or this class electrophilic group of activatory esters and/or can be used as reagent such as being used for the synthetic polymer of peptide with these electrophilic groups are end capped.For example, can be with the deutero-Polyethylene Glycol of ramose NHS-(for example poly-(ethylene glycol) ether four-succinimido glutarate of tetramethylolmethane) organizationally with 4 with the solid form coating.The fibre modification inhibitor of fibrosis directly can be mixed 4 and be with deutero-Polyethylene Glycol of ramose NHS-or alkaline buffer.In another embodiment, the fibre modification inhibitor can be mixed second kind of carrier, it can be mixed 4 then and be with deutero-Polyethylene Glycol of ramose NHS-and/or alkaline buffer.Second kind of carrier can comprise microgranule and/or the microsphere of being made by degradable polymer.Degradable polymer can comprise polyesters, wherein said polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) _n, R-(X-Y) _nBlock copolymer with X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, Mount Olive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator.In another embodiment, begin to be coated with tissue reactive polymer and then that fibre modification is inhibitor coated at the tissue that wraps quilt.The fibre modification inhibitor directly can be coated with and maybe it can be mixed second kind of carrier organizationally.Second kind of carrier can comprise microsphere (as mentioned above), microgranule (as mentioned above), gel (hyaluronic acid for example, carboxymethyl cellulose, glucosan, poly-(poly-(expoxy propane) block copolymer of oxirane L and admixture thereof, association complex and cross-linked composition) and thin film (degradable polyesters, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) _n, R-(X-Y) _nBlock copolymer with X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, Mount Olive, the PLURONIC of NJ and PLLRRONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, glucosan, poly-(oxirane)-poly-(expoxy propane) block copolymer and admixture thereof, association complex and cross-linked composition.

The ii) adhesion prevention in the gynecilogical operation operation

In one aspect, adhesion forms and may operate relevant with gynecilogical operation.In the industrialization world, implement among 60-90% the patient of gynecological's major operation tissue adhesion to take place and represented one of infertile common cause.Sticking in can ovary, form between fallopian tube, intestinal or the pelvis wall.Fibre bundle can make the accessory structure (ovary and fallopian tube) of proper motion be connected with other tissue, makes them lose mobility, entanglement or distortion.If it is firm that adhesion makes around the fallopian tube, fallopian tube self compression or distortion, they can be blocked ovum and enter and pass through oviducal path from ovary so, cause infertile.Peritubal adhesion can also be disturbed sperm to be transported to ovum and also can cause infertile.Other complication relevant with adhesion comprises chronic pelvic pain, dyspareunia (dysparunia), urethral obstruction and drainage malfunction.

Several prods be purchased or for control gynecological adhesion research and development.Life Medical Sciences, Inc. is producing product REPEL, REPEL-CV, RESOLVE and RELIEVE, and they are in the different conceptual phases and can be used for preventing gynecological and the surgical operation adhesion of other operation.By Life Medical Sciences, the product description of Inc. research and development is at for example United States Patent (USP) 6,696,499; 6,399,624; 6,211,249; In 6,136,333 and 5,711,958.ConfluentSurgical, Inc. have produced the SPRAYGEL of their unique sprayable adhesion barrier, and researching and developing it is in order to be used for pelvis and intrauterine operation technique.By Confluent Surgical, the product description of Inc. research and development is in United States Patent (USP) 6,379,373 for example.Closure Medical Corp. (Raleigh, NC) be researching and developing based in the body that can be used for the closed surgery otch of cyanoacrylate with binding agent or can with gynecological and the general surgery compatible implant of transferring from one department to another.By Closure Medical, the product description of Corp. research and development is at for example United States Patent (USP) 6,620,846; 6,579,469; 6,565,840; In 6,547,467 and 5,981,621.

Can use separately or load therapeutic agent (for example fibre modification inhibitor or anti-infective) be coated on or be impregnated into gynecilogical operation position (or on device or implant surface) be used to prevent opening or endoscope's gynecilogical operation other be purchased material and comprise: (a) contain the sprayable preparation of collagen protein, such as COSTASIS or CT3; (b) contain the sprayable preparation of PEG, such as COSEAL, ADHIBIT, FOCALSEAL or SPRAYGEL; (c) contain the preparation of fibrinogen, such as FLOSEAL or TISSEAL; (d) contain hyaluronic preparation, such as RESTYLANE or PERLANE, HYLAFORM, SYNVISC, SEPRAFILM or SEPRACOAT; (e) polymer gel that is used to perform the operation and implants is such as FLOWGEL; (f) contain the operation binding agent of cyanoacrylate, such as DERMABOND, INDERMIL, GLUSTITCH, TISSUMEND, VETBOND, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUID PROTECTANT; (g) dextran sulfate gel is such as ADCON series gel; (h) based on the compositions of lipid, such as ADSURF.Those skilled in the art obviously should expect being purchased compositions and commodity of future generation and/or research and development subsequently and being suitable for using in the present invention of above-mentioned non-special citation.

Different medical condition is implemented the gynecilogical operation operation, comprise uterectomy (excision uterus), myomectomy (excision leiomyoma of uterus), endometriosis (excision operation), infertile (external fertilization, Adhesiolysis), childbirth control (Unterbindung des Eileiter), sterillization counter-rotating, pain, dysmenorrhea, anovulatory dysfunctional uterine hemorrhage, ectopic pregnancy, ovarian cyst, gynecologic malignant tumor and other disease in a large number.Although still can pass through the many operations of open operation technology implementation, progressively carry out gynecilogical operation recently by the endoscope that inserts through umbilicus (umbilicus).In fact, the operation of any pelvic organs or pelvis sidewall all can cause cascade, and it finally causes the formation of pelvis adhesion.In many cases, must in multiple surgical procedures, destroy these adhesions so that treatment pain or infertile.Being preferably in opening or the endoscopic procedure process barrier of will be separately or containing fibre modification inhibitor (and/or anti-infective) directly is coated on and is subjected to infringement zone (as solid, thin film, paste, gel, liquid or another kind of this class preparation).In preferred embodiments, under the direct endoscopic vision condition, described barrier (separately or contain fibre modification inhibitor and/or anti-infective) is sprayed in the operation process on the pelvic organs (with intestinal, pelvis and abdominal part sidewall) of institute at operation or manipulation.Because adhesion takes place in the zone at the actual tissue one segment distance place that has inserted instrument in the distance surgical procedures usually, thus suggestion with described barrier (with or not with therapeutic agent) be coated on the endopelvic extensive region (even might whole adnexa, the pelvic surface of sacrum in pelvis sidewall and uterus).Preferred barrier comprises liquid, gel, paste, spray or other preparation that can send by endoscope, and they adhere to the tissue of being treated and keep the sufficiently long time so that delivering therapeutic agents and/or Film with Preventing Adhesion form on the position.As alternative, therapeutic agent directly can be sent peritoneal cavity (before operation technique, in the process or afterwards) as injectable form, make and to pass medicine (preferred multiple dosing and/or slow releasing preparation) with sufficiently high dosage and sufficiently long time, so that adhesion and the complication of prevention from wherein producing.Ideal adhesion therapy can reduce adhesion incidence rate, quantity and toughness and improve patient's result by the needs that ease the pain, improve fertility and limit repeating surgical intervention.

As mentioned above, the compositions that is used for the prevention of surgical surgical adhesions directly or indirectly can be coated on the tissue at gynecological position.Can according to any way as herein described give described polymer composition (with or not with fibrosis or anti-infective therapy's agent).Typical method is included in the directly coating or use endoscope, ultrasonic, CT, MRI or fluoroscopic guidance coating of when operation.If the device of place implanting, the compositions of Film with Preventing Adhesion can be coated on implant surface or the surrounding tissue so and at operative site in conjunction with placing medical apparatus or implant.The representational example that is used for the implant of gynecological's operation includes, but are not limited to reproduction-urinary system stent, filler, sterillization device (for example valve, folder, pincers) and pharyngotympanic tube and stops up implant and plug.

Can be in opening or endoscope's gynecilogical operation process with described polymer composition with or be not coated with the inhibitor coated infra tabulation face of fibre modification or by wherein said mode: (a) the pelvis sidewall in surgical procedures, adnexa, uterus and adjacent tissue of being encroached on (for example forming gel or mesh) arbitrarily as Injectable solution, paste, gel, original position; (b) before surgical operation, in the process or the tissue surface around implanting device afterwards or implant and/or the implant (for example forming gel or mesh) as Injectable solution, paste, gel, original position; (c) by described compositions is injected anatomic space (being peritoneal cavity or the pelvic cavity) (useful especially polymer support-fluid that in several hours-a few time limits in week, discharges the fibre modification inhibitor that is to use of operative site through intraperitoneal or endoscope for this embodiment, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, solid implant and discharge described activating agent and it can be sent into existing adhesion to form other preparation in the zone of risk); (d) as solution, inject tissue as transfusion or as the slow releasing preparation percutaneous; (e) by guide catheter or hysteroscope described compositions is injected fallopian tube lumen in the position of required pipe and (promptly pass through vagina, conduit or endoscope are inserted in cervix uteri and uterus, up to moving forward into fallopian tube lumen) (for the useful especially polymer support-fluid that in several hours-a few time limits in week, discharges the fibre modification inhibitor that is to use of this embodiment, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, solid implant and discharge described activating agent and it can be sent into existing adhesion to form other preparation in the fallopian tube zone of risk); And/or (f) combination in any by said method.Can also use in the manner described above conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent, anti-infective and/or anti-platelet agents).

In comprising some application of placing gynecological's medical apparatus or implant, need go up coating fibrosis (and/or infection) compositions in the position adjacent (preferably near implant-organizational interface) with implant.Can in opening or endoscopic procedure process, finish this process through the following steps: with described polymer composition with or be not coated with the inhibitor coated infra of fibre modification tabulation face or by wherein said mode: (a) before implant procedure, in the process or implant surface (for example forming gel or mesh) afterwards as Injectable solution, paste, gel, original position; (b) before implant is implanted at once, in the process or the surface (for example forming gel or mesh) of adjacent tissue afterwards as Injectable solution, paste, gel, original position; (c) before implant is implanted, in the process or the surface of implant afterwards and implant surrounding tissue (for example as Injectable solution, paste, gel, original position formation gel or mesh); (d) by said composition is locally applied to placed implant anatomic space (such as fallopian tube lumen, cavity of uterus, peritoneal cavity or pelvic cavity) (for the useful especially polymer support-fluid that in several hours-a few time limits in week, discharges the fibre modification inhibitor that is to use of this embodiment, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, solid implant and discharge described activating agent and it can be sent other preparation into the zone of insertion device); (e) by inject implant tissue on every side as solution, transfusion or slow releasing preparation percutaneous; And/or (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent, anti-infective and/or anti-platelet agents).

In one aspect, described polymer composition can be delivered to gynecoid pelvis tissue (or device/organizational interface) with spray or gel form in opening, endoscope or the operating process based on conduit.Can as mentioned above the fibre modification inhibitor directly be mixed the surgical operation adhesion barrier or it is mixed second kind of carrier (polymerization or non-polymeric), then it be mixed adhesion barrier.Can comprise system, hyaluronic acid and cross-linked-hyaluronic acid compositions for the example of the polymer composition of spray or gel form based on poly-(ethylene glycol).These compositionss maybe can be formed them as original position the material coating of cross-linked gel as final compositions coating.

In one aspect of the method, activatory polymer is dissolved in has the biological acceptable buffer that is lower than (lower that) 6.8pH.Have greater than second kind of biology of 7.5pH under the operation of acceptable buffer the gained solution coat at required tissue surface having then.By extruding, brush, spraying or by arbitrarily other easily mode this reactant mixture is coated on the tissue site.After being coated on described compositions on the operative site,, can remove any excessive solution from operative site so if think necessary.Should in time use usual manner closed surgery position (for example stitching thread, nail or biological adhesive) this moment.In one embodiment, can use activatory polymer, this polymer can form covalent bond with the tissue that it is coated with.Contain such as succinimido, aldehyde, epoxide, isocyanates, vinyl, vinyl sulfone, maleimide ,-S-S-(C ₅H ₄N) or this class electrophilic group of activatory esters and/or can be used as reagent such as being used for the synthetic polymer of peptide with these electrophilic groups are end capped.For example, can be with the deutero-Polyethylene Glycol of ramose NHS-(for example poly-(ethylene glycol) ether four-succinimido glutarate of tetramethylolmethane) to be coated with organizationally with 4 with solid form or solution form.In this embodiment, be with the deutero-Polyethylene Glycol of ramose NHS-to be dissolved in acid solution (pH is about 2-3) with 4 and use the common coating of alkaline buffer (pH〉about 8) then organizationally.The fibre modification inhibitor of fibrosis directly can be mixed 4 and be with the deutero-Polyethylene Glycol of ramose NHS-, described acid solution or alkaline buffer.In another embodiment, the fibre modification inhibitor can be mixed second kind of carrier, it can be mixed 4 then and be with the deutero-Polyethylene Glycol of ramose NHS-, described acid solution and/or alkaline buffer.Second kind of carrier can comprise microgranule and/or the microsphere of being made by degradable polymer.Degradable polymer can comprise polyesters, wherein said polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) _n, R-(X-Y) _nBlock copolymer with X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, Mount Olive, the PLLRRONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator.In another embodiment, begin to be coated with tissue reactive polymer and then that fibre modification is inhibitor coated at the tissue that wraps quilt.The fibre modification inhibitor directly can be coated with and maybe it can be mixed second kind of carrier organizationally.Second kind of carrier can comprise microsphere (as mentioned above), microgranule (as mentioned above), gel (hyaluronic acid for example, carboxymethyl cellulose, glucosan, poly-(oxirane)-poly-(expoxy propane) block copolymer and admixture thereof, association complex and cross-linked composition) and thin film (degradable polyesters, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) n, the block copolymer of R-(X-Y) n and X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, MountOlive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, glucosan, poly-(oxirane)-poly-(expoxy propane) block copolymer and admixture thereof, association complex and cross-linked composition.

In one aspect of the method, activatory polymer can be coated on the operative site with solid-state.This activatory polymer can react as the tissue surface that the polymer water compound is coated with it.Before the activatory polymer of applying solid and/or will have afterwards organizationally greater than the biological acceptable buffer coating of 7.5 pH.In one embodiment, can use activatory polymer, this polymer can form covalent bond with the tissue that it is coated with.Contain such as succinimido, aldehyde, epoxide, isocyanates, vinyl, vinyl sulfone, maleimide ,-S-S-(C ₅H ₄N) or this class electrophilic group of activatory esters and/or can be used as reagent such as being used for the synthetic polymer of peptide with these electrophilic groups are end capped.For example, can be with the deutero-Polyethylene Glycol of ramose NHS-(for example poly-(ethylene glycol) ether four-succinimido glutarate of tetramethylolmethane) organizationally with 4 with the solid form coating.The fibre modification inhibitor of fibrosis directly can be mixed 4 and be with deutero-Polyethylene Glycol of ramose NHS-or alkaline buffer.In another embodiment, the fibre modification inhibitor can be mixed second kind of carrier, it can be mixed 4 then and be with deutero-Polyethylene Glycol of ramose NHS-and/or alkaline buffer.Second kind of carrier can comprise microgranule and/or the microsphere of being made by degradable polymer.Degradable polymer can comprise polyesters, wherein said polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) _n, R-(X-Y) _nBlock copolymer with X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, Mount Olive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator.In another embodiment, begin to be coated with tissue reactive polymer and then that fibre modification is inhibitor coated at the tissue that wraps quilt.The fibre modification inhibitor directly can be coated with and maybe it can be mixed second kind of carrier organizationally.Second kind of carrier can comprise microsphere (as mentioned above), microgranule (as mentioned above), gel (hyaluronic acid for example, carboxymethyl cellulose, glucosan, poly-(poly-(expoxy propane) block copolymer of oxirane L and admixture thereof, association complex and cross-linked composition) and thin film (degradable polyesters, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) _n, R-(X-Y) _nBlock copolymer with X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, Mount Olive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, glucosan, poly-(oxirane [poly-(expoxy propane) block copolymer and admixture thereof, association complex and cross-linked composition.

The iii) adhesion prevention in the abdominal operation operation

In one aspect, adhesion can be relevant with abdominal surgery.Implementing abdominal postoperative, adhesion forms and can produce the intestinal ring that the relevant tissue fibers bundle that influences the normal fluid motion of intestinal becomes winding or distortion.Winding can be by intestinal mobile part or overall the obstruction, cicatrix can compression around intestinal, and volvulus (twisting) can take place, or arrival and the blood flow that leaves intestinal may be obstructed.Because winding, volvulus or fiber band, so the result generally is an intestinal obstruction partially or completely; Need the disease of decompression at once may need operation and may cause death.The infarction (blood flow that arrives intestinal interrupts) that causes because of adhesion or volvulus is the medical science emergency case, the intestinal that it needs surgical removal to be encroached on usually, and if can't adopt the mode of invasive to treat, so also may cause death.Peritoneal adhesion (adhesion between stomach wall and the following organ) has been represented another kind of main health care problem, it can cause pain, intestinal obstruction and other potential serious post-operative complication, and their relevant with all types of abdominal operations (are 50-90% for the laparotomy incidence rate).

As mentioned above, adhesion barrier is generally used for controlling the abdominal part adhesion after opening or the endoscopic procedure.The various barriers that are purchased are suitable in control abdominal part adhesion and fibre modification inhibitor coupling (and/or anti-infective).Confluent Surgical, Inc. have produced their SPRAYGEL, and it is unique for being used for the sprayable adhesion barrier of abdominal part and pelvic surgical procedure research and development.By Connuentnt Surgical, the product description of Inc. research and development is in United States Patent (USP) 6,379,373 for example.ClosureMedical Corp. (Raleigh, NC) be researching and developing maybe can be the transfer from one department to another graft of the compatibility of gastrointestinal, oncology and general surgery based on can being used for sealing in the body of intravital operative incision of cyanoacrylate with binding agent.By Closure Medical, the product description of Corp. research and development is at for example United States Patent (USP) 6,620,846; 6,579,469; 6,565,840; In 6,547,467 and 5,981,621.Genzyme Corporation has has researched and developed and has contained the hyaluronic biomaterial that is used to reduce abdominal part and pelvic surgery posterior synechiae incidence rate, such as SEPRAFILM and SEPRACOAT (for example, referring to United States Patent (USP) 6,780,427; 6,531,147; 6,521,223 and 6,010,692.

Can use separately or load therapeutic agent (for example fibre modification inhibitor or anti-infective) be coated on or be impregnated into abdominal part position (or on device or implant surface of implanting) be used to prevent opening or endoscope's abdominal part operation other be purchased material and comprise: (a) contain the sprayable preparation of collagen protein, such as COSTASIS or CT3; (b) contain the sprayable preparation of PEG, such as COSEAL, ADHIBIT, FOCALSEAL or DURASEAL; (c) contain the preparation of fibrinogen, such as FLOSEAL or TISSEAL; (d) contain hyaluronic preparation, such as RESTYLANE or PERLANE, HYLAFORM or SYNVISC; (e) polymer gel that is used to perform the operation and implants is such as REPEL or FLOWGEL; (f) contain the operation binding agent of cyanoacrylate, such as DERMABOND, INDERMIL, GLUSTITCH, TISSUMEND, VETBOND, HISTOACRYL BLUE and ORABASESOOTHE-N-SEAL LIQUID PROTECTANT; (g) dextran sulfate gel is such as ADCON series gel; (h) based on the compositions of lipid, such as ADSURF.Those skilled in the art obviously should expect being purchased compositions and commodity of future generation and/or research and development subsequently and being suitable for using in the present invention of above-mentioned non-special citation.

Different medical condition is implemented the abdominal operation operation, comprise hernia repair (abdominal part, veutro, groin, otch), intestinal obstruction, inflammatory bowel (ulcerative colitis, Crohn disease), appendectomy, wound (penetrating wound, blunt wound (blunt tauma)), tumor resection, infect (abscess, peritonitis), cholecystectomy, gastroplasty (bariatrician operation), esophagus and pyloric stenosis, colostomy, turn to ileostomy (diversion iliostomy), anus-rectal fistula, hemorrhoidectiomy, splenectomy, the liver tumor excision, pancreatitis, intestinal perforation, upper and lower gastrointestinal hemorrhage and intestinal ischemia.Although still can pass through the many operations of open operation technology implementation, progressively carry out abdominal operation recently by the endoscope that inserts through umbilicus (umbilicus).In fact, the operation of any abdominal viscera or peritoneum all can cause cascade (cascade), and it finally causes forming the abdominal part adhesion.In many cases, must in multiple surgical procedures, destroy these adhesions so that treatment pain or intestinal obstruction.Being preferably in opening or the endoscopic procedure process barrier of will be separately or containing fibre modification inhibitor (and/or anti-infective) directly is coated on and is subjected to infringement zone (as solid, thin film, paste, gel, liquid or another kind of this class preparation).In preferred embodiments, in the operating process under the direct endoscopic vision condition described barrier (separately or contain fibre modification inhibitor and/or anti-infective) is sprayed on institute in the surgical intervention process on the abdomen organ of operation or manipulation (as large intestine and small intestinal, stomach, liver, spleen, gallbladder etc.), visceral peritoneum and veutro (wall) peritoneum.Because adhesion takes place in the zone at the actual tissue one segment distance place that has inserted instrument in the distance surgical procedures usually, thus suggestion with described barrier (with or not with therapeutic agent) be coated on the extensive region of abdominal part (even might whole internal organs and stomach wall).Preferred barrier comprises film, liquid, gel, paste, spray or other preparation that can send by endoscope, and they adhere to the tissue of being treated and keep the sufficiently long time so that delivering therapeutic agents and/or Film with Preventing Adhesion form on the position.As alternative, therapeutic agent directly can be sent peritoneal cavity (before operation technique, in the process or afterwards) as injectable form, make and to pass medicine (preferred multiple dosing and/or slow releasing preparation) with sufficiently high dosage and sufficiently long time, so that adhesion and the complication of prevention from wherein producing.Ideal adhesion therapy can reduce adhesion incidence rate, quantity and toughness and improve patient's result by the needs that ease the pain, prevent intestinal obstruction and limit repeating surgical intervention.

As mentioned above, the compositions that is used for the prevention of surgical surgical adhesions directly or indirectly can be coated on the tissue of abdominal part operation.Can according to any way as herein described give described polymer composition (with or not with fibrosis or anti-infective therapy's agent).Typical method is included in the directly coating or use endoscope, ultrasonic, CT, MRI or fluoroscopic guidance coating of when operation.If the device of place implanting, the compositions of Film with Preventing Adhesion can be coated on implant surface or the surrounding tissue so and at operative site in conjunction with placing medical apparatus or implant.The representational example that is used for the implant of abdominal part operation includes, but are not limited to the hernia mesh, the fat restraint device of using, implantable pick off, implantable pump, peritoneal dialysis catheters, peritoneum is passed the medicine conduit, the GI conduit that is used for drain or liquid feeding, door body diverter, the ascites diverter, gastrostomy or percutaneous add fluid catheter, the endoscopic catheters of jejunostomy, the colostomy device, drainage tube, bile T-shape conduit, the hemostasis implant, the nutrition device, colon and gallbladder stent, the cover operations device, the gastric banding implant, scrotiform endoscope, anti-reflux device and esophagus stent.

Can be in opening or endoscope's abdominal operation process with described polymer composition with or be not coated with the inhibitor coated infra tabulation face of fibre modification or by wherein said mode: (a) peritoneal cavity in surgical procedures, visceral peritoneum, abdomen organ, stomach wall and any adjacent invaded tissue (for example forming gel or mesh) that is subjected to as Injectable solution, paste, gel, original position; (b) before surgical operation, in the process or the tissue surface around implanting device afterwards or implant and/or the implant (for example forming gel or mesh) as Injectable solution, paste, gel, original position; (c) by described compositions is injected the anatomic space (being peritoneal cavity) (useful especially being to use in several hours-a few time limits in week discharges the described activating agent of polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, solid implant and release of fibre modification inhibitor for this embodiment, and it can be sent into existing adhesion to form other preparation in the zone of risk) of operative site through intraperitoneal or endoscope; (d) as solution, inject tissue as transfusion or as the slow releasing preparation percutaneous; (e) described compositions is injected by guide catheter or endoscope's (gastroscope, ERCP, colonoscope) in the desired position gastrointestinal tract chamber (for this embodiment useful especially be to use to contain in several hours-a few time limits in week discharge the described activating agent of Injectable composition-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, solid implant and release of the polymer support of fibre modification inhibitor, and it can be sent other preparation into the gastrointestinal region that has adhesion formation risk); And/or (f) combination in any by said method.Can also use in the manner described above conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent, anti-infective and/or anti-platelet agents).

In comprising some application of placing abdominal part or gastrointestinal medical apparatus or implant, need go up coating fibrosis (and/or infection) compositions in the position adjacent (preferably near implant-organizational interface) with implant.Can in opening or endoscopic procedure process, finish this process through the following steps: with described polymer composition with or be not coated with the inhibitor coated infra of fibre modification tabulation face or by wherein said mode: (a) before implant procedure, in the process or implant surface (for example forming gel or mesh) afterwards as Injectable solution, paste, gel, original position; (b) before implant is implanted at once, in the process or the surface (for example forming gel or mesh) of adjacent tissue afterwards as Injectable solution, paste, gel, original position; (c) before implant is implanted, in the process or the surface of implant afterwards and implant surrounding tissue (for example as Injectable solution, paste, gel, original position formation gel or mesh); (d) by the said composition part being coated with into the anatomic space of having placed implant (such as gastrointestinal tract chamber or peritoneal cavity) (be to use the described activating agent of polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, solid implant and release of release fibre modification inhibitor in the time limits in several hours-a few week and it can be sent other preparation) into the zone of insertion device for this embodiment is useful especially; (e) by inject implant tissue on every side as solution, transfusion or slow releasing preparation percutaneous; And/or (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent, anti-infective and/or anti-platelet agents).

In one aspect, described polymer composition can be delivered to abdominal part (or device/organizational interface) with spray or gel form in opening, endoscope or the operating process based on conduit.Can as mentioned above the fibre modification inhibitor directly be mixed the surgical operation adhesion barrier or it is mixed second kind of carrier (polymerization or non-polymeric), then it be mixed adhesion barrier.Can comprise system, hyaluronic acid and cross-linked-hyaluronic acid compositions for the example of the polymer composition of spray or gel form based on poly-(ethylene glycol).These compositionss maybe can be formed them as original position the material coating of cross-linked gel as final compositions coating.

In one aspect of the method, activatory polymer is dissolved in has the biological acceptable buffer that is lower than (lower that) 6.8pH.Have greater than second kind of biology of 7.5pH under the operation of acceptable buffer the gained solution coat at required tissue surface having then.By extruding, brush, spraying or by arbitrarily other easily mode this reactant mixture is coated on the tissue site.After being coated on described compositions on the operative site,, can remove any excessive solution from operative site so if think necessary.Should in time use usual manner closed surgery position (for example stitching thread, nail or biological adhesive) this moment.In one embodiment, can use activatory polymer, this polymer can form covalent bond with the tissue that it is coated with.Contain such as succinimido, aldehyde, epoxide, isocyanates, vinyl, vinyl sulfone, maleimide ,-S-S-(C ₅H ₄N) or this class electrophilic group of activatory esters and/or can be used as reagent such as being used for the synthetic polymer of peptide with these electrophilic groups are end capped.For example, can be with the deutero-Polyethylene Glycol of ramose NHS-(for example poly-(ethylene glycol) ether four-succinimido glutarate of tetramethylolmethane) to be coated with organizationally with 4 with solid form or solution form.In this embodiment, be with the deutero-Polyethylene Glycol of ramose NHS-to be dissolved in acid solution (pH is about 2-3) with 4 and use the common coating of alkaline buffer (pH〉about 8) then organizationally.The fibre modification inhibitor of fibrosis directly can be mixed 4 and be with the deutero-Polyethylene Glycol of ramose NHS-, described acid solution or alkaline buffer.In another embodiment, the fibre modification inhibitor can be mixed second kind of carrier, it can be mixed 4 then and be with the deutero-Polyethylene Glycol of ramose NHS-, described acid solution and/or alkaline buffer.Second kind of carrier can comprise microgranule and/or the microsphere of being made by degradable polymer.Degradable polymer can comprise polyesters, wherein said polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) _n, R-(X-Y) _nBlock copolymer with X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, Mount Olive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator.In another embodiment, begin to be coated with tissue reactive polymer and then that fibre modification is inhibitor coated at the tissue that wraps quilt.The fibre modification inhibitor directly can be coated with and maybe it can be mixed second kind of carrier organizationally.Second kind of carrier can comprise microsphere (as mentioned above), microgranule (as mentioned above), gel (hyaluronic acid for example, carboxymethyl cellulose, glucosan, poly-(oxirane [poly-(expoxy propane) block copolymer and admixture thereof, association complex and cross-linked composition) and thin film (degradable polyesters, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) _n, R-(X-Y) _nBlock copolymer with X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, MountOlive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, glucosan, poly-(oxirane)-poly-(expoxy propane) block copolymer and admixture thereof, association complex and cross-linked composition.

In one aspect of the method, activatory polymer can be coated on the operative site with solid-state.This activatory polymer can react as the tissue surface that the polymer water compound is coated with it.Before the activatory polymer of applying solid and/or will have afterwards organizationally greater than the biological acceptable buffer coating of 7.5 pH.In one embodiment, can use activatory polymer, this polymer can form covalent bond with the tissue that it is coated with.Contain such as succinimido, aldehyde, epoxide, isocyanates, vinyl, vinyl sulfone, maleimide ,-S-S-(C ₅H ₄N) or this class electrophilic group of activatory esters and/or can be used as reagent such as being used for the synthetic polymer of peptide with these electrophilic groups are end capped.For example, can be with the deutero-Polyethylene Glycol of ramose NHS-(for example poly-(ethylene glycol) ether four-succinimido glutarate of tetramethylolmethane) organizationally with 4 with the solid form coating.The fibre modification inhibitor of fibrosis directly can be mixed 4 and be with deutero-Polyethylene Glycol of ramose NHS-or alkaline buffer.In another embodiment, the fibre modification inhibitor can be mixed second kind of carrier, it can be mixed 4 then and be with deutero-Polyethylene Glycol of ramose NHS-and/or alkaline buffer.Second kind of carrier can comprise microgranule and/or the microsphere of being made by degradable polymer.Degradable polymer can comprise polyesters, wherein said polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) _n, R-(X-Y) _nBlock copolymer with X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, Mount Olive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, note-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator.In another embodiment, begin to be coated with tissue reactive polymer and then that fibre modification is inhibitor coated at the tissue that wraps quilt.The fibre modification inhibitor directly can be coated with and maybe it can be mixed second kind of carrier organizationally.Second kind of carrier can comprise microsphere (as mentioned above), microgranule (as mentioned above), gel (hyaluronic acid for example, carboxymethyl cellulose, glucosan, poly-(oxirane)-poly-(expoxy propane) block copolymer and admixture thereof, association complex and cross-linked composition) and thin film (degradable polyesters, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) _n, R-(X-Y) _nBlock copolymer with X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, Mount Olive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, glucosan, poly-(oxirane)-poly-(expoxy propane) block copolymer and admixture thereof, association complex and cross-linked composition.

The iv) prevention of the adhesion in the cardiac surgery procedure

In one aspect, adhesion can be relevant with cardiac surgery procedure.With regard to the operation on heart that comprises graft, blood vessel reparation, coronary artery bypass grafting (CABG), congenital heart defect and valve replacement, interim operation and operation again (particularly repeating the CABG operation) are very common.Like this, the cardiac surgeon must be frequently operates implementing operation wound in advance and have the tissue that the thick fiber adhesion that is difficult to cut exists.The postoperative pericardiosymphysis (adhesion between the pericardium two sides) that causes because of initial operation is common.Pericardiosymphysis can produce symptom by being limited in proper motion in the Cardiac cycle process and heart perfusion, and can make patient experience repeat operation on heart and improved operational risk.Breastbone is otomy (open again thoracic wall cut as with surgical exposure heart) and cut apart incidental adhesion and increased risk to the graft latent lesion outward of heart, trunk and the heart again, increase operation time (comprising the time of the patient being implemented cardiopulmonary bypass that increased), and may increase the M ﹠ M of operation technique.The breastbone otomy patient that relates to nearly 6% trunk damage incidence rate and at breastbone massive hemorrhage takes place in the otomy process according to reports again again has mortality rate more than 35%.The reason of 50% mortality rate is the damage that occurs together of ACG according to reports.Also the complication rate with high is relevant because of performing the operation again in interim department of pediatrics cardiac operation under direct vision (required repeat surgery is operated during the heart growth).

As mentioned above, adhesion barrier is generally used for controlling the adhesion after the cardiac operation under direct vision.The various barriers that are purchased are suitable in control operation on heart adhesion and fibre modification inhibitor (and/or anti-infective) coupling.Life Medical Sciences, Inc. is is researching and developing product REPEL, REPEL-CV, RESOLVE and RELIEVE, and they are in the different development and can be used to prevent the surgical operation adhesion of OH and other operation.By Life Medical Sciences, the product description of Inc. research and development is at for example United States Patent (USP) 6,696,499; 6,399,624; 6,211,249; In 6,136,333 and 5,711,958.(Raleigh NC) is is researching and developing based on maybe being the graft of the pulmonary and the compatibility of general surgery training with binding agent in the body that can be used for operative incision in the obturator of cyanoacrylate Closure Medical Corp..By Closure Medical, the product description of Corp. research and development is at for example United States Patent (USP) 6,620,846; 6,579,469; 6,565,840; In 6,547,467 and 5,981,621.Genzyme Corporation has has researched and developed and has contained the hyaluronic biomaterial that is used to reduce cardiothoracic surgeries posterior synechiae incidence rate, such as SEPRAFILM and SEPRACOAT (for example, referring to United States Patent (USP) 6,780,427; 6,531,147; 6,521,223 and 6,010,692.

Can use separately or load therapeutic agent (for example fibre modification inhibitor or anti-infective) be coated on or be impregnated into operation on heart position (or on device or implant surface of implanting) be used to prevent open or endoscope's operation on heart other be purchased material and comprise: (a) contain the sprayable preparation of collagen protein, such as COSTASIS or CT3; (b) contain the sprayable preparation of PEG, such as COSEAL, ADHIBIT, FOCALSEAL or DURASEAL; (c) contain the preparation of fibrinogen, such as FLOSEAL or TISSEAL; (d) contain hyaluronic preparation, such as RESTYLANE or PERLANE, HYLAFORM or SYNVISC; (e) polymer gel that is used to perform the operation and implants is such as REPEL or FLOWGEL; (f) contain the operation binding agent of cyanoacrylate, such as DERMABOND, INDERMIL, GLUSTITCH, TISSUMEND, VETBOND, HISTOACRYL BLUE and ORABASESOOTHE-N-SEAL LIQUID PROTECTANT; (g) dextran sulfate gel is such as ADCON series gel; (h) based on the compositions of lipid, such as ADSURF.Those skilled in the art obviously should expect being purchased compositions and commodity of future generation and/or research and development subsequently and being suitable for using in the present invention of above-mentioned non-special citation.

In fact, the operation of any thoracic wall, pericardium and heart all can cause cascade, and it finally causes the formation of adhesion.In many cases, must in the cardiac operation under direct vision process, destroy these adhesions.Being preferably in open or the endoscope's heart operating process barrier of will be separately or containing fibre modification inhibitor (and/or anti-infective) directly is coated on and is subjected to infringement zone (as solid, thin film, paste, gel, liquid or another kind of this class preparation).In preferred embodiments, in the operating process under the direct endoscopic vision condition described barrier (separately or contain fibre modification inhibitor and/or anti-infective) is sprayed in the surgical intervention process on heart, pericardium, pleura and the thoracic wall of institute at operation or manipulation.Because adhesion takes place in the zone at the actual tissue one segment distance place that has inserted instrument in the distance surgical procedures usually, thus suggestion with described barrier (with or not with therapeutic agent) be coated on the extensive region in the chest (even might whole cardiopulmonary internal organs soak into whole pericardium).Preferred barrier comprises liquid, gel, paste, spray or other preparation of can be in the open surgery process or sending by endoscope, and they adhere to the tissue of being treated and keep the sufficiently long time so that delivering therapeutic agents and/or Film with Preventing Adhesion form on the position.As alternative, therapeutic agent directly can be sent pericardium (before operation technique, in the process or afterwards) as injectable form, make and to pass medicine (preferred multiple dosing and/or slow releasing preparation) with sufficiently high dosage and sufficiently long time, so that adhesion and the complication of prevention from wherein producing.Ideal adhesion therapy can reduce incidence rate, quantity and the toughness of adhesion and improve patient's result by the complication that reduces the repeat surgery intervention.

As mentioned above, the compositions that is used for the prevention of surgical surgical adhesions directly or indirectly can be coated on the tissue of cardiac surgery procedure.Can according to any way as herein described give described polymer composition (with or not with fibrosis or anti-infective therapy's agent).Typical method is included in the directly coating or use endoscope, ultrasonic, CT, MRI or fluoroscopic guidance coating of when operation.If the device of place implanting, the compositions of Film with Preventing Adhesion can be coated on implant surface or the surrounding tissue so and at operative site in conjunction with placing medical apparatus or implant.The representational example that is used for the implant of heart operation includes, but are not limited to cardiac valve (pig, artificial), ventricular assist device, heart pump, artificial heart, stent, by-pass graft thing (artificial and endogenous), sticking patch, heart electrode, defibrillator and pacemaker.

Can be in open or endoscope's operation on heart process with described polymer composition with or be not coated with the inhibitor coated infra tabulation face of fibre modification or by wherein said mode: (a) pericardium in surgical procedures (being impregnated into pericardium), heart, trunk, pleura, lung, thoracic wall and any adjacent invaded tissue (for example forming gel or mesh) that is subjected to as Injectable solution, paste, gel, original position; (b) before surgical operation, in the process or the tissue surface (for example as Injectable solution, paste, gel, original position shaping gel or mesh) around implanting device afterwards or implant and/or the implant; (c) by described compositions is injected anatomic space (being the pericardium) (useful especially Injectable composition-fluid that contains the polymer support of release fibre modification inhibitor in several hours-a few time limits in week that is to use of operative site through intraperitoneal or endoscope for this embodiment, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, solid implant and discharge described activating agent and it can be sent into existing adhesion to form other preparation in the zone of risk); (d) as solution, inject tissue (intrapericardial injection) as transfusion or as the slow releasing preparation percutaneous; (e) by guide catheter or endoscope described compositions is injected the atrium, ventricle, trunk, the chamber of coronary artery or pericardium or wall (contain the Injectable composition-fluid that discharges the polymer support of fibre modification inhibitor in several hours-a few time limits in week to useful especially being to use of this embodiment, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, solid implant and discharge described activating agent and it can be sent into existing adhesion to form other preparation of the heart area of risk); And/or (f) combination in any by said method.Can also use in the manner described above conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent, anti-infective and/or anti-platelet agents).

In some application that comprises relieved dirty medical apparatus or implant, need go up coating fibrosis (and/or infection) compositions in the position adjacent (preferably near implant-organizational interface) with implant.Can in open or endoscopic procedure process, finish this process through the following steps: with described polymer composition with or be not coated with the inhibitor coated infra of fibre modification tabulation face or by wherein said mode: (a) before implant procedure, in the process or implant surface (for example forming gel or mesh) afterwards as Injectable solution, paste, gel, original position; (b) before implant is implanted at once, in the process or the surface (for example as Injectable solution, paste, gel, original position shaping gel or mesh) of adjacent tissue afterwards; (c) before implant is implanted, in the process or the surface of implant afterwards and implant surrounding tissue (for example as Injectable solution, paste, gel, original position shaping gel or mesh); (d) by the said composition part being coated with the anatomic space (pericardium, intracardiac, intra-arterial) of having placed implant (useful especially being to use of this embodiment discharged the described activating agent of polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, solid implant and release of fibre modification inhibitor and it can be sent other preparation into the zone of insertion device in several hours-a few time limits in week); (e) by inject implant tissue on every side as solution, transfusion or slow releasing preparation percutaneous; And/or (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent, anti-infective and/or anti-platelet agents).

In one aspect, described polymer composition can be delivered to heart (or device/organizational interface) with spray or gel form in open, endoscope or the operating process based on conduit.Can as mentioned above the fibre modification inhibitor directly be mixed the surgical operation adhesion barrier or it is mixed second kind of carrier (polymerization or non-polymeric), then it be mixed adhesion barrier.Can comprise system, hyaluronic acid and cross-linked-hyaluronic acid compositions for the example of the polymer composition of spray or gel form based on poly-(ethylene glycol).These compositionss maybe can be formed them as original position the material coating of cross-linked gel as final compositions coating.

In one aspect of the method, activatory polymer is dissolved in has the biological acceptable buffer that is lower than (lower that) 6.8pH.Have greater than second kind of biology of 7.5pH under the operation of acceptable buffer the gained solution coat at required tissue surface having then.By extruding, brush, spraying or by arbitrarily other easily mode this reactant mixture is coated on the tissue site.After being coated on described compositions on the operative site,, can remove any excessive solution from operative site so if think necessary.Should in time use usual manner closed surgery position (for example stitching thread, nail or biological adhesive) this moment.In one embodiment, can use activatory polymer, this polymer can form covalent bond with the tissue that it is coated with.Contain such as succinimido, aldehyde, epoxide, isocyanates, vinyl, vinyl sulfone, maleimide ,-S-S-(C ₅H ₄N) or this class electrophilic group of activatory esters and/or can be used as reagent such as being used for the synthetic polymer of peptide with these electrophilic groups are end capped.For example, can be with the deutero-Polyethylene Glycol of ramose NHS-(for example poly-(ethylene glycol) ether four-succinimido glutarate of tetramethylolmethane) to be coated with organizationally with 4 with solid form or solution form.In this embodiment, be with the deutero-Polyethylene Glycol of ramose NHS-to be dissolved in acid solution (pH is about 2-3) with 4 and use the common coating of alkaline buffer (pH〉about 8) then organizationally.The fibre modification inhibitor of fibrosis directly can be mixed 4 and be with the deutero-Polyethylene Glycol of ramose NHS-, described acid solution or alkaline buffer.In another embodiment, the fibre modification inhibitor can be mixed second kind of carrier, it can be mixed 4 then and be with the deutero-Polyethylene Glycol of ramose NHS-, described acid solution and/or alkaline buffer.Second kind of carrier can comprise microgranule and/or the microsphere of being made by degradable polymer.Degradable polymer can comprise polyesters, wherein said polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) _n, R-(X-Y) _nBlock copolymer with X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, Mount Olive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator.In another embodiment, begin to be coated with tissue reactive polymer and then that fibre modification is inhibitor coated at the tissue that wraps quilt.The fibre modification inhibitor directly can be coated with and maybe it can be mixed second kind of carrier organizationally.Second kind of carrier can comprise microsphere (as mentioned above), microgranule (as mentioned above), gel (hyaluronic acid for example, carboxymethyl cellulose, glucosan, poly-(oxirane)-poly-(expoxy propane) block copolymer and admixture thereof, association complex and cross-linked composition) and thin film (degradable polyesters, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) _n, R-(X-Y) _nBlock copolymer with X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, MountOlive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, glucosan, poly-(oxirane)-poly-(expoxy propane) block copolymer and admixture thereof, association complex and cross-linked composition.

In one aspect of the method, activatory polymer can be coated on the operative site with solid-state.This activatory polymer can react as the tissue surface that the polymer water compound is coated with it.Before the activatory polymer of applying solid and/or will have afterwards organizationally greater than the biological acceptable buffer coating of 7.5 pH.In one embodiment, can use activatory polymer, this polymer can form covalent bond with the tissue that it is coated with.Contain such as succinimido, aldehyde, epoxide, isocyanates, vinyl, vinyl sulfone, maleimide ,-S-S-(C ₅H ₄N) or this class electrophilic group of activatory esters and/or can be used as reagent such as being used for the synthetic polymer of peptide with these electrophilic groups are end capped.For example, can be with the deutero-Polyethylene Glycol of ramose NHS-(for example poly-(ethylene glycol) ether four-succinimido glutarate of tetramethylolmethane) organizationally with 4 with the solid form coating.The fibre modification inhibitor of fibrosis directly can be mixed 4 and be with deutero-Polyethylene Glycol of ramose NHS-or alkaline buffer.In another embodiment, the fibre modification inhibitor can be mixed second kind of carrier, it can be mixed 4 then and be with deutero-Polyethylene Glycol of ramose NHS-and/or alkaline buffer.Second kind of carrier can comprise microgranule and/or the microsphere of being made by degradable polymer.Degradable polymer can comprise polyesters, wherein said polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) _n, R-(X-Y) _nBlock copolymer with X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, Mount Olive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator.In another embodiment, begin to be coated with tissue reactive polymer and then that fibre modification is inhibitor coated at the tissue that wraps quilt.The fibre modification inhibitor directly can be coated with and maybe it can be mixed second kind of carrier organizationally.Second kind of carrier can comprise microsphere (as mentioned above), microgranule (as mentioned above), gel (hyaluronic acid for example, carboxymethyl cellulose, glucosan, poly-(oxirane [poly-(expoxy propane) block copolymer and admixture thereof, association complex and cross-linked composition) and thin film (degradable polyesters, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) _n, R-(X-Y) _nBlock copolymer with X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, Mount Olive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, glucosan, poly-(oxirane)-poly-(expoxy propane) block copolymer and admixture thereof, association complex and cross-linked composition.

The v) prevention of the adhesion in the orthopedic procedure

In one aspect, adhesion can be operated relevant with orthopaedic surgery.Many orthopaedic surgery are carried out (fracture as the result at damage or wound; Laceration of ligament, cartilage, tendon or muscle), these operations make tissue be subjected to the remarkable infringement that can cause excessive cicatrization and adhesion to form.As a result of, orthopedic procedure may cause serious post-operative complication usually, and these complication can be owing to wound that causes damaging or the wound because of performing the operation and self causing.In general, the excessive cicatrization in orthopedics's situation and adhesion form and follow certain pattern: (a) in joint injury, it can cause deformity, make the joint can not full extension, bending or rotation (contracture); (b) in tendon injury, it can stop normal motion and cause shortening; (c) in the cartilage injury, it can cause hyaline cartilage to change into fibrous cartilage, and the result is the afunction joint instability; (d) in muscle injury, it can cause and the adjacent tissue adhesion, strength loss and afunction; (e) in nerve injury, can cause conduction and afunction; If nerve is absorbed in cicatrix (besieged and compression), it can produce pain, feel impaired and the motor function disappearance so; (f) in tendon and ligament, it can cause shortening, range of movement descends and function is impaired.The complication of adhesion can spread; The adhesion that for example forms behind spinal operation can produce lumbago and backache, skelalgia and sphincter imbalance (bladder and intestinal).Owing to this reason, being designed for the strategy that reduces adhesion formation in flesh and the bone-operating is significant clinical problem.Separately or the topical of the Antiblock compositions of the fibre modification inhibitor of having loaded can be used for clinical setting and disease widely so that improve the result that emergency case or selectivity orthopedics intervene the back patient.

As mentioned above, adhesion barrier is generally used for controlling the adhesion of malformation correction postoperative.The various barriers that are purchased are suitable in control orthopedic procedure adhesion and fibre modification inhibitor (and/or anti-infective) coupling.(Raleigh NC) is is researching and developing based on can being used for sealing in the body of intravital operative incision with binding agent of cyanoacrylate and maybe can be the transfer from one department to another graft of the compatibility of orthopedics and general surgery Closure Medical Corp..By Closure Medical, the product description of Corp. research and development is at for example United States Patent (USP) 6,620,846; 6,579,469; 6,565,840; In 6,547,467 and 5,981,621.Life Medical Sciences, Inc. is is researching and developing product REPEL, REPEL-CV, RESOLVE and RELIEVE, and they are in development and can be used for preventing the surgical operation adhesion of orthopedic procedure and spinal operation.By Life Medical Sciences, the product description of Inc. research and development is at for example United States Patent(USP) Nos. 6,696,499; 6,399,624; 6,211,249; 6,136,333 and 5,711,958.

Can use separately or load therapeutic agent (for example fibre modification inhibitor or anti-infective) be coated on or be impregnated into orthopedics position (or on device or implant surface of implanting) be used to prevent opening or endoscope's orthopedic procedure other be purchased material and comprise: (a) contain the sprayable preparation of collagen protein, such as COSTASIS or CT3; (b) contain the sprayable preparation of PEG, such as COSEAL, ADHIBIT, FOCALSEAL or DURASEAL; (c) contain the preparation of fibrinogen, such as FLOSEAL or TISSEAL; (d) contain hyaluronic preparation, such as RESTYLANE, HYLAFORM, PERLANE, SYNVISC, SEPRAFILM, SEPRACOAT, INTERGEL or LUBRICOAT; (e) polymer gel that is used to perform the operation and implants is such as REPEL or FLOWGEL; (f) be used for fixing the orthopedics " cement (cement) " of prosthese and tissue, such as OSTEOBOND (Zimmer), LVC (Wright MedicalTechnology), SIMPLEX P (Stryker), PALACOS (Smith ﹠amp; Nephew) and ENDURANCE (Johnson ﹠amp; Johnson, Inc.); (g) contain the operation binding agent of cyanoacrylate, such as DERMABOND, INDERMIL, GLUSTITCH, TISSUMEND, VETBOND, HISTOACRYL BLUE and ORABASESOOTHE-N-SEAL LIQUID PROTECTANT; (g) contain the implant of hydroxyapatite (or synthetic bone material, such as calcium sulfate, VITOSS (Orthovita) and CORTOSS (Orthovita)); (h) other biocompatible tissue filler, such as those by BioCure, the filler that 3M Company and Neomend produce; (i) polysaccharide gel is such as ADCON series gel; (i) thin film, sponge or mesh are such as INTERCEED, VICRYL mesh and GELFOAM; (o) based on the compositions of lipid, such as ADSURF; (p) OSSIGEL, the viscosity preparation of promptly a kind of hyaluronic acid (HA) and basic fibroblast growth factor (bFGF), design it be for accelerating union of bone fracture (Orquest, Inc.).Those skilled in the art obviously should expect being purchased compositions and commodity of future generation and/or research and development subsequently and being suitable for using in the present invention of above-mentioned non-special citation.

Different situation is implemented the orthopaedic surgery operation, comprise fracture (opening and closure), sprain, dislocation, crush injury, ligament and muscle tear, tendon injury, nerve injury, congenital malformation and deformity, joint replacement and cartilage injury wholly or in part.Although still can pass through the many operations of open operation technology implementation, progressively carry out a large amount of orthopaedic surgery recently by arthroscope through inserting the joint.In fact, any muscle and skeleton (muscle, tendon, joint, bone, cartilage) damage, traumatic injury or orthopedic procedure intervention all can cause cascade, and it finally causes the formation of adhesion.In many cases, must in multiple surgical intervention process, destroy these adhesions (for example cystitomy, tendon release, nerve are captured release, freezed joint etc.).Being preferably in opening or the operating process of arthroscope orthopedics the adhesion barrier of will be separately or containing fibre modification inhibitor (and/or anti-infective) directly is coated on and is subjected to infringement zone (as solid, thin film, paste, gel, liquid or another kind of this class preparation).In preferred embodiments, under the direct visual or visual condition of arthroscope, described barrier (separately or contain fibre modification inhibitor and/or anti-infective) is sprayed on the muscle and skeletal tissue of being encroached in the surgical intervention process.Because adhesion takes place in the zone at the actual tissue one segment distance place that has inserted instrument in the distance surgical procedures usually, thus suggestion with described barrier (with or not with therapeutic agent) be coated on the extensive region around impaired or the repair tissue.Preferred barrier comprises thin film, liquid, gel, paste, spray or other preparation of can be in the open operation operating process or sending by endoscope, and they adhere to the tissue of being treated and keep the sufficiently long time so that delivering therapeutic agents and/or Film with Preventing Adhesion form on the position.Ideal adhesion therapy can reduce adhesion incidence rate, quantity and toughness and improve patient's result by following manner: ease the pain, weak and paraesthesia; Contracture; Increase range of movement; Improve function; Reduce deformity and DB; With the needs that reduce the repetition surgical intervention.

As mentioned above, the compositions that is used for the prevention of surgical surgical adhesions directly or indirectly can be coated on the tissue of orthopedic procedure operation.Can according to any way as herein described give described polymer composition (with or not with fibrosis or anti-infective therapy's agent).Typical method is included in the directly coating or use arthroscope, ultrasonic, CT, MRI or fluoroscopic guidance coating of when operation.If the device of place implanting, the compositions of Film with Preventing Adhesion can be coated on implant surface or the surrounding tissue so and at operative site in conjunction with placing medical apparatus or implant.The representational example that is used for the implant of orthopedics's operation comprises, but be not limited to plate, bar, screw, pin, line, complete and part articular prosthesis (artificial buttocks, knee joint, both shoulders, phalangeal joint), reinforcement sticking patch, tissue filler, synthetic bone implant, bone cement, synthetic graft material, allograft material, autotransplantation material, artificial dish, spinal column protect frame and marrow studding (intermedullary rods).

Can be in opening or arthroscopic surgical procedures with described polymer composition with or be not coated with the inhibitor coated infra tabulation face of fibre modification or by wherein said mode: (a) BJM in surgical procedures, tendon, ligament, cartilage and any adjacent invaded tissue (for example forming gel or mesh) that is subjected to as Injectable solution, paste, gel, original position; (b) before surgical operation, in the process or the tissue surface around the orthopedic device of implantation afterwards or implant and/or the implant (for example forming gel or mesh) as Injectable solution, paste, gel, original position; (c) anatomic space (articular cavity for example by described compositions is gone into to perform the operation the position through intraarticular or endoscope's administration, stndon sheath, nerve root and spinal canal) (useful especially being to use of this embodiment contained the Injectable composition-fluid that discharges the polymer support of fibre modification inhibitor in several hours-a few time limits in week, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, solid implant and discharge described activating agent and it can be sent into existing adhesion to form other preparation in the zone of risk); (d) as solution, inject tissue (intramuscular or intraarticular) as transfusion or as the slow releasing preparation percutaneous; (e) by guide catheter described compositions is injected tissue; And/or (f) combination in any by said method.Can also use in the manner described above conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent, anti-infective and/or anti-platelet agents).

In comprising some application of placing orthopedics's medical apparatus or implant, need go up coating fibrosis (and/or infection) compositions in the position adjacent (preferably near implant-organizational interface) with implant.Can in open, endoscope or orthopedics's operating process, finish this process through the following steps based on conduit: with described polymer composition with or be not coated with the inhibitor coated infra tabulation face of fibre modification or by wherein said mode: (a) before implant procedure, in the process or implant surface (for example forming gel or mesh) afterwards as Injectable solution, paste, gel, original position; (b) before rectificating surgery implant is implanted at once, in the process or afterwards the surface of adjacent tissue (for example forming gel or mesh) as Injectable solution, paste, gel, original position; (c) before implant is implanted, in the process or the surface of implant afterwards and implant surrounding tissue (for example as Injectable solution, paste, gel, original position formation gel or mesh); (d) by the said composition part being coated with the anatomic space (joint capsule, spinal canal, bone marrow, stndon sheath etc.) of having placed implant (useful especially being to use of this embodiment discharged the described activating agent of polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, solid implant and release of fibre modification inhibitor and it can be sent other preparation into the zone of insertion device in several hours-a few time limits in week); (e) by inject rectificating surgery implant tissue on every side as solution, transfusion or slow releasing preparation percutaneous; And/or (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent, anti-infective and/or anti-platelet agents).

In one aspect, described polymer composition can be delivered to muscle and skeletal tissue (or device/organizational interface) with spray or gel form in opening, endoscope or the operating process based on conduit.Can as mentioned above the fibre modification inhibitor directly be mixed the surgical operation adhesion barrier or it is mixed second kind of carrier (polymerization or non-polymeric), then it be mixed adhesion barrier.Can comprise system, hyaluronic acid and cross-linked-hyaluronic acid compositions for the example of the polymer composition of spray or gel form based on poly-(ethylene glycol).These compositionss maybe can be formed them as original position the material coating of cross-linked gel as final compositions coating.

In one aspect of the method, activatory polymer is dissolved in has the biological acceptable buffer that is lower than (lower that) 6.8pH.Have greater than second kind of biology of 7.5pH under the operation of acceptable buffer the gained solution coat at required tissue surface having then.By extruding, brush, spraying or by arbitrarily other easily mode this reactant mixture is coated on the tissue site.After being coated on described compositions on the operative site,, can remove any excessive solution from operative site so if think necessary.Should in time use usual manner closed surgery position (for example stitching thread, nail or biological adhesive) this moment.In one embodiment, can use activatory polymer, this polymer can form covalent bond with the tissue that it is coated with.Contain such as succinimido, aldehyde, epoxide, isocyanates, vinyl, vinyl sulfone, maleimide ,-S-S-(C ₅H ₄N) or this class electrophilic group of activatory esters and/or can be used as reagent such as being used for the synthetic polymer of peptide with these electrophilic groups are end capped.For example, can be with the deutero-Polyethylene Glycol of ramose NHS-(for example poly-(ethylene glycol) ether four-succinimido glutarate of tetramethylolmethane) to be coated with organizationally with 4 with solid form or solution form.In this embodiment, be with the deutero-Polyethylene Glycol of ramose NHS-to be dissolved in acid solution (pH is about 2-3) with 4 and use the common coating of alkaline buffer (pH〉about 8) then organizationally.The fibre modification inhibitor of fibrosis directly can be mixed 4 and be with the deutero-Polyethylene Glycol of ramose NHS-, described acid solution or alkaline buffer.In another embodiment, the fibre modification inhibitor can be mixed second kind of carrier, it can be mixed 4 then and be with the deutero-Polyethylene Glycol of ramose NHS-, described acid solution and/or alkaline buffer.Second kind of carrier can comprise microgranule and/or the microsphere of being made by degradable polymer.Degradable polymer can comprise polyesters, wherein said polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) _n, R-(X-Y) _nBlock copolymer with X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, Mount Olive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator.In another embodiment, begin to be coated with tissue reactive polymer and then that fibre modification is inhibitor coated at the tissue that wraps quilt.The fibre modification inhibitor directly can be coated with and maybe it can be mixed second kind of carrier organizationally.Second kind of carrier can comprise microsphere (as mentioned above), microgranule (as mentioned above), gel (hyaluronic acid for example, carboxymethyl cellulose, glucosan, poly-(oxirane)-poly-(expoxy propane) block copolymer and admixture thereof, association complex and cross-linked composition) and thin film (degradable polyesters, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) n, the block copolymer of R-(X-Y) n and X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, MountOlive, the PLUONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, glucosan, poly-(oxirane)-poly-(expoxy propane) block copolymer and admixture thereof, association complex and cross-linked composition.

In one aspect of the method, activatory polymer can be coated on the operative site with solid-state.This activatory polymer can react as the tissue surface that the polymer water compound is coated with it.Before the activatory polymer of applying solid and/or will have afterwards organizationally greater than the biological acceptable buffer coating of 7.5 pH.In one embodiment, can use activatory polymer, this polymer can form covalent bond with the tissue that it is coated with.Contain such as succinimido, aldehyde, epoxide, isocyanates, vinyl, vinyl sulfone, maleimide ,-S-S-(C ₅H ₄N) or this class electrophilic group of activatory esters and/or can be used as reagent such as being used for the synthetic polymer of peptide with these electrophilic groups are end capped.For example, can be with the deutero-Polyethylene Glycol of ramose NHS-(for example poly-(ethylene glycol) ether four-succinimido glutarate of tetramethylolmethane) organizationally with 4 with the solid form coating.The fibre modification inhibitor of fibrosis directly can be mixed 4 and be with deutero-Polyethylene Glycol of ramose NHS-or alkaline buffer.In another embodiment, the fibre modification inhibitor can be mixed second kind of carrier, it can be mixed 4 then and be with deutero-Polyethylene Glycol of ramose NHS-and/or alkaline buffer.Second kind of carrier can comprise microgranule and/or the microsphere of being made by degradable polymer.Degradable polymer can comprise polyesters, wherein said polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) _n, R-(X-Y) _nBlock copolymer with X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, Mount Olive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator.In another embodiment, begin to be coated with tissue reactive polymer and then that fibre modification is inhibitor coated at the tissue that wraps quilt.The fibre modification inhibitor directly can be coated with and maybe it can be mixed second kind of carrier organizationally.Second kind of carrier can comprise microsphere (as mentioned above), microgranule (as mentioned above), gel (hyaluronic acid for example, carboxymethyl cellulose, glucosan, poly-(poly-(expoxy propane) block copolymer of oxirane L and admixture thereof, association complex and cross-linked composition) and thin film (degradable polyesters, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) _n, R-(X-Y) _nBlock copolymer with X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, Mount Olive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, glucosan, poly-(oxirane)-poly-(expoxy propane) block copolymer and admixture thereof, association complex and cross-linked composition.

The vi) adhesion prevention in reconstructive procedure and the cosmetic surgery operation

In one aspect, adhesion can be relevant with beauty treatment or reconstructive procedure operation.For example, the application of soft tissue implant in cosmetic applications (beauty treatment and rebuild) increases at breast, rebuild behind the breast reconstruction behind the cancer operation, cranial and facial surgery, wound, congenital cranium face is rebuild and the eye plastic surgery in common.

The clinical function of soft tissue implant changes with the difference that can effectively keep the implant of shape in time limit a period of time.In many cases, when these devices were implanted, their experience were from " foreign body " reaction of host tissue on every side.Health is identified as foreign body with implant, and the reaction that can cause inflammation is subsequently by fibrous connective tissue encapsulation implant (adhesion forms).The encapsulation of surgery implant makes various reconstructive procedures and cosmetic surgery complicated, and becomes the difficult problem in the breast reconstruction especially, and wherein the breast implant fibrous capsule that is changed anatomical structure and function is surrounded.The cicatrix capsule of hardening and contraction (being called " cryptomere contracture ") is a most common complication in breast implant or the plastic surgery.Cryptomere (fibroid) contracture can cause that the normal anatomical structures of udder induration, breast and profile disappearance, sense of discomfort, weakness and implant shell break, asymmetric, infection and patient are dissatisfied.In addition, if handle or stimulate described device because of the activity of patient every day, the fiber kystisization of so any soft tissue implant even can take place successfully implanting the back.The implant neutralization is hemorrhage on every side can also to cause the biological cascade that finally causes scar tissue to form.In addition, the implantable prosthesis of some type (such as breast implant) comprise tend to the membrane envelope seepage by implant and may organize around in produce the gel-filled thing (for example siloxanes) of chronic inflammatory reaction (promotion organizes encapsulation and contracture to form).Unwanted synulotic effect is defect correcting, destruction scar tissue (cystitomy or vesiculectomy), replacement implants or the main cause of taking out the extra operation of implant near implant.Separately or the topical of the Antiblock compositions of the fibre modification inhibitor of having loaded can be used for improving looks widely and reconstructive procedure to improve patient's result.

Soft tissue implant is used for various beauty treatments, shaping and reconstructive procedure operation and can be delivered to different body parts, includes, but are not limited to face, nose, breast, lower jaw, buttocks, breast, lip and cheek.Soft tissue implant is used to perform the operation or organizes reconstruction, augmenting tissue or organ, organizational shape's reparation, the aging main body of organizing of draining the generation wound to restore and correction soft tissue folds in a garment or wrinkling (wrinkle).In all soft tissue implant procedures, for increase or postmastectomy breasst reconstruction to place breast implant be the most normal cosmetic surgery implant operation of carrying out.For example, only 2002, just there are 300,000 women of surpassing to accept the breast implant operation.In them, the postmastectomy breast reconstruction of about 80,000 people for carrying out because of cancer.

The depleted process of all soft tissue implants is all similar, and is irrelevant with the placement of anatomic construction.Yet, because breast implant has become the soft tissue implant of broad research, so explain the present invention with them.In general, breast increases or reconstructive procedure comprises that the breast implant that is purchased that will be made up of the capsule that is full of saline or siloxanes is placed into tissue below the mammary gland.Historically, with regard to breast is implanted, use four different cutting parts: anterior axillary line (axillary fossa); Around the mammary areola (around the nipple downside); (breast bases, wherein its contact thoracic wall) and crosses umbilicus (around the umbilicus) under the breast.Usually by means of endoscope by little otch incised tissue (, wherein needing cutting part to pass breast) especially for auxiliary and cross the operation technique of umbilicus.Produce the bag of placing breast implant under gland or in the breast inferior segment.With regard to implant under the gland, incised tissue is so that producing the space that extends downward fold under the breast between glandular tissue and the pectoralis major.With regard to implant under the breast, careful incision pectoralis major is so that produce the space with rib frame surface under pectoralis major.Careful hemostasis is essential (because it can cause complication, such as the cryptomere contracture), thus much, if hemorrhage can not enough control so makes the operation technique of minimum level invasive (anterior axillary line, cross the umbilicus means) to be changed into more open operation technique (around mammary areola).With the difference of selected operation means type, take out breast implant flat usually and make it to increase gradually with in patient's body in being used to place.After realizing accurately placement, fill implant or make it be expanded to required size.

Although use initial operation to satisfy many patients, still existing in the bigger percentage ratio needs the repeat surgery intervention with gauged complication usually.The breast prosthesis encapsulation (being called the cryptomere contracture) that produces the Periprosthetic shell is the common complication that breast increases the back report, wherein reaches to a certain degree discontented of patient's report of 50%.Calcification can take place in increasing the hard fibrous capsule complicated with making the mammogram explanation.A plurality of reasons of cryptomere contracture have obtained identifying, having comprised: foreign body reaction; The silicone gel molecule is by the capsule migration and enter tissue; Autoimmune disease; Genetic predisposition; Infect; Hematoma; Surface character with prosthese.Although do not identify the concrete cause of disease as yet repeatedly, on cellular level, the unusual fibroblast activity that foreign body stimulates is a conforming discovery.The bourse of Periprosthetic contains macrophage and accidental T-and B-lymphocyte, and this prompting inflammatory component reaches pathological changes.Attempted making the level and smooth also textured of implant surface with the minimizing encapsulation, yet the two all can't confirm to have produced uniform good results.The animal model prompting exists capsule thickness to increase and has the tendency increase of the surperficial contracture of impelling the ingrown band texture of lip-deep fibrous tissue.On subpectoral position, place implant and seemed to reduce encapsulation rate in the implant of level and smooth and band texture.

From patient's point of view, above-mentioned bioprocess has produced the disease of a series of common descriptions.Implant dislocation, hard and disadvantageous narrow be that modal placement complication and major part are usually owing to the cryptomere contracture.When around the cicatrix capsule begin hardening and when shrinking, its produce sense of discomfort, shell fragility, asymmetric, the skin dolly dimple forms and dislocation.Take place among about 10% the patient of definite cryptomere contracture after increase and take place in 25%-30% reconstruction case, wherein most of patient's report is unsatisfied with because of the result of beauty treatment (asthetic).Cause asymmetric cicatrization in the reconstruction of 10% increase and 30%, to take place and be the main cause of implementing corrective surgery.Skin corrugate (because of skin is pulled to due to the implant) be the complication of patient's report of 10%-20%.Cicatrization even related to the implant aerofluxus (patient of 1-6%; Saline leak into implant outer and " emptying " it), this moment, inwardly the growth fibrous tissue of going into diaphram valve (making the expansible entry position of implant) made it can not control and seepage.In addition, surpass the patient that 15% enforcement increases and have chronic pain, and many in these cases finally form owing to scar tissue.Other complication that breast increases operation comprises that later stage seepage, hematoma (patient of about 1-6%), seroma (2.5%), hypertrophic cicatrix form (2-5%) and infect (case of about 1-4%).

Correction can comprise several selections, comprises taking out implant, cystitomy (downcut or operation discharges capsule), vesiculectomy (surgical removal fibrous capsule) or placing implant (promptly under the gland under chest muscle) at diverse location.Finally, need extra operation (correction, cystitomy, taking-up, again-implant) among 40% the reconstruction patient surpassing 20% increase patient and surpass, wherein cicatrization and cryptomere contracture are modal reason certainly.Destroy the operation technique possibility of cicatrix and the increase of not enough and about 8% and 25% reconstruction and finally need take out implant with modus operandi.

Fibrous tissue formation, encapsulation and cryptomere contracture can be minimized from the soft tissue implant local delivery or by fibre modification inhibitor or compositions that topical is gone into the soft tissue implant surrounding tissue.On the soft tissue implant surface coated fiber degeneration inhibitors or with its mix soft tissue implant (for example described activating agent is mixed in the implant saline, gel or siloxanes and by the passive surrounding tissue that diffuses into of capsule) fibrillation can be minimized or is very difficult for this to happen.The operation bag that fibre modification inhibitor or compositions is impregnated into the tissue around the soft tissue implant or has placed described implant be prevention increase and plastic surgery in cicatrix and the cryptomere contracture form another kind of tactful.

As mentioned above, the adhesion of beauty treatment implant and fiber kystis are the common complications in beauty treatment (asthetic) and the plastic surgery.The various adhesion barrier that are purchased are suitable for and fibre modification inhibitor (and/or anti-infective) coupling in this complication of control.Be used for preventing other of adhesion of cosmetic surgery to be purchased material and comprise that (it can use separately, or loaded therapeutic agent (for example fibre modification inhibitor or anti-infective), be coated on the soft tissue implant surface, be included in the soft tissue implant in " implant " (being generally saline, siloxanes or gel) or be impregnated into the implant site surrounding tissue): (a) contain the sprayable preparation of collagen protein, such as COSTASIS or CT3; (b) contain the sprayable preparation of PEG, such as COSEAL, ADHIBIT, FOCALSEAL or DURASEAL; (c) contain the preparation of fibrinogen, such as FLOSEAL or TISSEAL; (d) contain hyaluronic preparation, such as RESTYLANE, HYLAFORM, SYNVISC, SEPRAFILM or SEPRACOAT; (e) polymer gel that is used to perform the operation and implants is such as REPEL or FLOWGEL; (f) contain the operation binding agent of cyanoacrylate, such as DERMABOND, INDERMIL, GLUSTITCH, TISSUMEND, VETBOND, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEALLIQUID PROTECTANT; (g) dextran sulfate gel is such as ADCON series gel; (h) based on the compositions of lipid, such as ADSURF.Several (preparations that for example contain PEG, collagen protein or fibrinogen in the mentioned reagent, such as COSEAL, CT3, ADHIBIT, COSTASIS, FOCALSEAL, SPRAYGEL, DURASEAL, TISSEAL and FLOSEAL) based on the additional beneficial effect of hemostasis and blood vessel sealer, this suspicious effect of insufficient hemostatic that obtains in the cryptomere contracture takes place also should have beneficial effect in the embodiment of this invention.Those skilled in the art obviously should expect being purchased compositions and commodity of future generation and/or research and development subsequently and being suitable for using in the present invention of above-mentioned non-special citation.

As mentioned above, the compositions that is used for the prevention of surgical surgical adhesions directly or indirectly can be coated on beauty treatment implant position.Can according to any way as herein described give described polymer composition (with or not with fibrosis or anti-infective therapy's agent).Typical method is included in the directly coating or use endoscope, ultrasonic, CT, MRI or fluoroscopic guidance coating of when operation.If the device of place implanting can be coated on the compositions of Film with Preventing Adhesion on implant surface or the surrounding tissue so, and at operative site in conjunction with placing medical apparatus or implant.The representational example of implant of operation of being used to improve looks includes, but are not limited to implant, tissue filler and buttocks implant under saline breast implant, siloxanes breast implant, lower jaw and mandible implant, nasal implants, cheek implant, lip implant, other facial implant, breast (pectoral) and breast (chest) implant, cheekbone and the cheekbone.

Can be in opening or endoscope's cosmetic surgery process with described polymer composition with or be not coated with the inhibitor coated infra tabulation face of fibre modification or by wherein said mode: (a) before implant procedure, in the process or afterwards soft tissue implant surface (for example forming gel or mesh) as Injectable solution, paste, gel, original position; (b) before implanting soft tissue implant, in the process or the tissue surface of implantation bag afterwards (for example forming gel or mesh) as Injectable solution, paste, gel, original position; (c) before implanting soft tissue implant, in the process or the surface of soft tissue implant afterwards and/or implant surrounding tissue (for example forming gel or mesh) as Injectable solution, paste, gel, original position; (d) by fibrosis agent part being coated on the anatomic space of having placed soft tissue implant (be to use the described activating agent of polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, solid implant and release of release fibre modification inhibitor in several hours-a few time limits in week and it can be sent other preparation) into the zone of the described implant of insertion for this embodiment is useful especially; (e) as solution, inject tissue around the implant as transfusion or as the slow releasing preparation percutaneous; And/or m is by the combination in any of said method.Can also use in the manner described above conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent, anti-infective and/or anti-platelet agents).

The compositions that comprises anti-scarring agent is impregnated into the space (modus operandi generates bag) of will implant soft tissue implant.In comprising some application of placing the beauty treatment soft tissue implant, need go up coating fibrosis (and/or infection) compositions in the position adjacent (preferably near implant-organizational interface) with implant.Can finish this process in open, endoscope or in through the following steps based on the operating process of conduit: with described polymer composition with or be not coated with the inhibitor coated infra tabulation face of fibre modification or by wherein said mode: (a) before implant procedure, in the process or implant surface (for example forming gel or mesh) afterwards as Injectable solution, paste, gel, original position; (b) before soft tissue implant is implanted at once, in the process or the surface (for example forming gel or mesh) of adjacent tissue afterwards as Injectable solution, paste, gel, original position; (c) before implant is implanted, in the process or the surface of soft tissue implant afterwards and implant surrounding tissue (for example as Injectable solution, paste, gel, original position formation gel or mesh); (d) by the said composition part being coated with into placing anatomic space (the operation bag of implant; For example in breast implant, it is space under the gland or under the breast) (be to use the described activating agent of polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, solid implant and release of release fibre modification inhibitor in several hours-a few time limits in week and it can be sent other preparation) into the zone of insertion device for this embodiment is useful especially; (e) by inject soft tissue implant tissue on every side as solution, transfusion or slow releasing preparation percutaneous; And/or (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent, anti-infective and/or anti-platelet agents).

In one aspect, described polymer composition can be delivered to soft tissue implant (or device/organizational interface) with spray or gel form in opening, endoscope or the operating process based on conduit.Can as mentioned above the fibre modification inhibitor directly be mixed the surgical operation adhesion barrier or it is mixed second kind of carrier (polymerization or non-polymeric), then it be mixed adhesion barrier.Can comprise system, hyaluronic acid and cross-linked-hyaluronic acid compositions for the example of the polymer composition of spray or gel form based on poly-(ethylene glycol).These compositionss maybe can be formed them as original position the material coating of cross-linked gel as final compositions coating.

In one aspect of the method, activatory polymer is dissolved in has the biological acceptable buffer that is lower than (lower that) 6.8pH.Have greater than second kind of biology of 7.5pH under the operation of acceptable buffer the gained solution coat at required tissue surface having then.By extruding, brush, spraying or by arbitrarily other easily mode this reactant mixture is coated on the tissue site.After being coated on described compositions on the operative site,, can remove any excessive solution from operative site so if think necessary.Should in time use usual manner closed surgery position (for example stitching thread, nail or biological adhesive) this moment.In one embodiment, can use activatory polymer, this polymer can form covalent bond with the tissue that it is coated with.Contain such as succinimido, aldehyde, epoxide, isocyanates, vinyl, vinyl sulfone, maleimide ,-S-S-(C ₅H ₄N) or this class electrophilic group of activatory esters and/or can be used as reagent such as being used for the synthetic polymer of peptide with these electrophilic groups are end capped.For example, can be with the deutero-Polyethylene Glycol of ramose NHS-(for example poly-(ethylene glycol) ether four-succinimido glutarate of tetramethylolmethane) to be coated with organizationally with 4 with solid form or solution form.In this embodiment, be with the deutero-Polyethylene Glycol of ramose NHS-to be dissolved in acid solution (pH is about 2-3) with 4 and use the common coating of alkaline buffer (pH〉about 8) then organizationally.The fibre modification inhibitor of fibrosis directly can be mixed 4 and be with the deutero-Polyethylene Glycol of ramose NHS-, described acid solution or alkaline buffer.In another embodiment, the fibre modification inhibitor can be mixed second kind of carrier, it can be mixed 4 then and be with the deutero-Polyethylene Glycol of ramose NHS-, described acid solution and/or alkaline buffer.Second kind of carrier can comprise microgranule and/or the microsphere of being made by degradable polymer.Degradable polymer can comprise polyesters, wherein said polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) _n, R-(X-Y) _nBlock copolymer with X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, Mount Olive, the PLURONIC of NJ and PLLRRONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator.In another embodiment, begin to be coated with tissue reactive polymer and then that fibre modification is inhibitor coated at the tissue that wraps quilt.The fibre modification inhibitor directly can be coated with and maybe it can be mixed second kind of carrier organizationally.Second kind of carrier can comprise microsphere (as mentioned above), microgranule (as mentioned above), gel (hyaluronic acid for example, carboxymethyl cellulose, glucosan, poly-(oxirane)-poly-(expoxy propane) block copolymer and admixture thereof, association complex and cross-linked composition) and thin film (degradable polyesters, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) n, the block copolymer of L (X-Y) n and X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, MountOlive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, glucosan, poly-(oxirane)-poly-(expoxy propane) block copolymer and admixture thereof, association complex and cross-linked composition.

In one aspect of the method, activatory polymer can be coated on the operative site with solid-state.This activatory polymer can react as the tissue surface that the polymer water compound is coated with it.Before the activatory polymer of applying solid and/or will have afterwards organizationally greater than the biological acceptable buffer coating of 7.5 pH.In one embodiment, can use activatory polymer, this polymer can form covalent bond with the tissue that it is coated with.Contain such as succinimido, aldehyde, epoxide, isocyanates, vinyl, vinyl sulfone, maleimide ,-S-S-(C ₅H ₄N) or this class electrophilic group of activatory esters and/or can be used as reagent such as being used for the synthetic polymer of peptide with these electrophilic groups are end capped.For example, can be with the deutero-Polyethylene Glycol of ramose NHS-(for example poly-(ethylene glycol) ether four-succinimido glutarate of tetramethylolmethane) organizationally with 4 with the solid form coating.The fibre modification inhibitor of fibrosis directly can be mixed 4 and be with deutero-Polyethylene Glycol of ramose NHS-or alkaline buffer.In another embodiment, the fibre modification inhibitor can be mixed second kind of carrier, it can be mixed 4 then and be with deutero-Polyethylene Glycol of ramose NHS-and/or alkaline buffer.Second kind of carrier can comprise microgranule and/or the microsphere of being made by degradable polymer.Degradable polymer can comprise polyesters, wherein said polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) _n, R-(X-Y) _nBlock copolymer with X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, Mount Olive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, note-butyrolactone, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator.In another embodiment, begin to be coated with tissue reactive polymer and then that fibre modification is inhibitor coated at the tissue that wraps quilt.The fibre modification inhibitor directly can be coated with and maybe it can be mixed second kind of carrier organizationally.Second kind of carrier can comprise microsphere (as mentioned above), microgranule (as mentioned above), gel (hyaluronic acid for example, carboxymethyl cellulose, glucosan, poly-(oxirane)-poly-(expoxy propane) block copolymer and admixture thereof, association complex and cross-linked composition) and thin film (degradable polyesters, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) _n, R-(X-Y) _nBlock copolymer with X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, Mount Olive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, glucosan, poly-(oxirane)-poly-(expoxy propane) block copolymer and admixture thereof, association complex and cross-linked composition.

The vii) activating agent of fibre modification inhibitor and dosage

Of the present invention aspect some in, provide to discharge and can reduce the compositions of synulotic therapeutic agent (being the fibre modification inhibitor) at operative site.In one embodiment of the invention, the surgical operation adhesion barrier can comprise or be suitable for discharge suppressing one or more the activating agent in five kinds of ordinary circumstances of fibre modification (or cicatrization) process, comprising: inflammatory reaction and inflammation, connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation, neovascularization (blood vessel generations), extracellular matrix deposition (ECM) and reinvent (fibrous tissue maturation and body formation).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce the scar tissue undue growth.

The example that is used for the fibre modification inhibitor of surgical operation adhesion barrier comprises following activating agent: the fibre modification inhibitor comprises (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, TAXOTERE and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconizole); (J) p38 map kinase inhibitor (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from the present composition administered agents dosage that is used for surgical operation adhesion prevention, comprise the type of preparation, the location of therapentic part and the disease type of being treated.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.With from generally be used for single whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day one about scope of 180 days.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.In one aspect, medicine obtained discharging in 1-90 days time limits with valid density.

Should give the typical anti-scarring agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or 10 μ g-10mg; Or 10mg-250mg; Or 250mg-1000mg; Or 1000mg-2500mg.The dosage (amount) of lip-deep this activating agent of per unit area of coating anti-scarring agent can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or 1 μ m/mm ²-10 μ g/mm ²Or 10 μ g/mm ²-250 μ g/mm ²250 μ g/mm ²-1000 μ g/mm ²Or 1000 μ g/mm ²-2500 μ g/mm ²

Provide below and can be used for the treatment of with the present invention or the typical doses scope of the various anti-scarring agents of the compositions coupling of prevention of surgical surgical adhesions.(A) cell cycle inhibitor comprises doxorubicin and mitoxantrone.Doxorubicin analog and derivant thereof: accumulated dose is no more than 25mg, and (scope is at 0.1 μ g-25mg); Preferred 1 μ g-5mg.The dosage of per unit area is 0.01 μ g-100 μ g/mm ²Preferred dose is 0.1 μ g/mm ²-10 μ g/mm ²With 10 ^-8-10 ^-4The doxorubicin least concentration of M maintains on implant or the barrier surface.Mitoxantrone and analog thereof and derivant: accumulated dose is no more than 5mg, and (scope is at 0.01 μ g-5mg); The dosage of preferred 0.1 μ g-1mg. per unit area is 0.01 μ g-20 μ g/mm ²Preferred dose is 0.05 μ g/mm ²-3 μ g/mm ²With 10 ^-8-10 ⁴The mitoxantrone least concentration of M maintains on implant or the barrier surface.(B) cell cycle inhibitor comprises paclitaxel and analog thereof and derivant (for example docetaxel): accumulated dose is no more than 10mg, and (scope is at 0.1 μ g-10mg); Preferred 1 μ g-3mg.The dosage of per unit area is 0.1 μ g-10 μ g/mm ²Preferred dose is 0.25 μ g/mm ²-5 μ g/mm ²With 10 ^-8-10 ^-4The paclitaxel least concentration of M maintains on implant or the barrier surface.(C) cell cycle inhibitor, such as podophyllotoxin (for example etoposide): accumulated dose is no more than 10mg, and (scope is at 0.1 μ g-10mg); Preferred 1 μ g-3mg.The dosage of per unit area is 0.1 μ g-10 μ g/mm ²Preferred dose is 0.25 μ g/mm ²-5 μ g/mm ²With 10 ^-8-10 ^-4The etoposide least concentration of M maintains on implant or the barrier surface.(D) immunomodulator comprises sirolimus and everolimus.(be rapamycin, RAPAMUNE): accumulated dose is no more than 10mg, and (scope is at 0.1 μ g-10mg) for sirolimus; Preferred 10 μ g-1mg.The dosage of per unit area is 0.1 μ g-100 μ g/mm ²Preferred dose is 0.5 μ g/mm ²-10 μ g/mm ²With 10 ^-8-10 ^-4The sirolimus least concentration of M maintains on implant or the barrier surface.Everolimus and derivant thereof and analog: accumulated dose should not surpass 10mg, and (scope is at 0.1 μ g-10mg); Preferred 10 μ g-1mg.The dosage of per unit area is 0.1 μ g-100 μ g/mm ²Surface area; Preferred dose is 0.3 μ g/mm ²-10 μ g/mm ²With 10 ^-8-10 ^-4The everolimus least concentration of M maintains on implant or the barrier surface.(E) heatshock protein 90 antagonisies (for example geldanamycin) and analog and derivant: accumulated dose is no more than 20mg, and (scope is at 0.1 μ g-20mg); Preferred 1 μ g-5mg.The dosage of per unit area is 0.1 μ g-10 μ g/mm ²Preferred dose is 0.25 μ g/mm ²-5 μ g/mm ²With 10 ^-8-10 ^-4The geldanamycin least concentration of M maintains on implant or the barrier surface.(F) HMGCoA reductase inhibitor (for example simvastatin) and analog and derivant: accumulated dose is no more than 2000mg, and (scope is at 10.0 μ g-2000mg); Preferred 10 μ g-300mg.The dosage of per unit area is 1.0 μ g-1000 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-500 μ g/mm ²With 10 ^-8-10 ^-3The simvastatin of M maintains on implant or the barrier surface.(G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃) and analog and derivant: accumulated dose is no more than 2000mg, and (scope is at 10.0 μ g-2000mg); Preferred 10 μ g-300mg.The dosage of per unit area is 1.0 μ g-1000 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-500 μ g/mm ²With 10 ^-8-10 ^-3The Mycophenolic Acid least concentration of M maintains on implant or the barrier surface.(H) NF к B inhibitor (for example Bay11-7082) and analog and derivant: accumulated dose is no more than 200mg, and (scope is at 1.0 μ g-200mg); Preferred 1 μ g-50mg.The dosage of per unit area is 1.0 μ g-100 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-50 μ g/mm ²With 10 ^-8-10 ^-4The Bay 11-7082 least concentration of M maintains on implant or the barrier surface.(I) antimycotic agent, for example sulconizo1e) and analog and derivant: accumulated dose is no more than 2000mg, and (scope is at 10.0 μ g-2000mg); Preferred 10 μ g-300mg.The dosage of per unit area is 1.0 μ g-1000 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-500 μ g/mm ²With 10 ^-8-10 ^-3The sulconizo1e least concentration of M maintains on implant or the barrier surface; (J) p38 map kinase inhibitor (for example SB202190) and analog and derivant: accumulated dose is no more than 2000mg, and (scope is at 10.0 μ g-2000mg); Preferred 10 μ g-300mg.The dosage of per unit area is 1.0 μ g-1000 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-500 μ g/mm ²With 10 ^-8-10 ^-3The SB202190 least concentration of M maintains on implant or the barrier surface.

According to another aspect of the present invention, any anti-infective and the present invention can be used for the compositions coupling that the surgical operation adhesion prevents.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned anti-infective and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the disease type of being treated.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.With from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described infection forms agent and discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day one about scope of 180 days.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the disease type of being treated.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.With from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described infection forms agent and discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharged anti-infective with different rates, above-mentioned administration parameter should be used in combination with the rate of release of medicine from compositions, made about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5Or about 10 ^-5M-10 ^-4The lowest activity agent concentration of M maintains on the tissue surface.

Inflammatory arthritis

In one aspect, the invention provides the compositions that is used for the treatment of and prevents inflammatory arthritis.Compositions of the present invention can comprise one or more polymer supports and anti-scarring agent.

Inflammatory arthritis is the serious health problem in the developed country, particularly the quantity that produces in the aging individuality increases gradually, and comprise various diseases, the feature that includes, but are not limited to rheumatoid arthritis, systemic lupus erythematosus (sle), Sjogren's syndrome disease (scleroderma), MCTD, Si Yegelun syndrome, ankylosing spondylitis, behcet syndrome, sarcoidosis and osteoarthritis-all these diseases is that all joint inflammation and/or pain are as remarkable symptom.

In one aspect, compositions of the present invention can be used for the treatment of or prevent osteoarthritis (OA).Osteoarthritis be a kind of cost cost of common weakness high and be present incurable disease.This disease is characterised in that chondrocyte and last differentiation function is unusual eventually, and the cartilage matrix in the articular cartilage that finally causes causing OA and being encroached on the joint is damaged.Age is the strongest risk factor of OA, and big articular trauma, overweight and repeatability to use the joint also be the important risk factor of OA.The pattern in the joint that relates among the OA also is subjected to previous occupation or excessively part-time influence.

OA has constitutional (the special property sent out) and Secondary cases type.Constitutional OA is modal to be relevant with the age.Joint, the particularly use repeatedly such as this class weight-bearing joint of hip, knee joint, foot and the back of the body are upset the joint and inflammation, cause arthralgia and swelling.Final cartilage begins to degenerate by stripping off or form very little crack.In the situation in later stage, exist the cartilage pad between the ossa articularia to lose fully.Losing of cartilage pad makes that generation rubs between the bone, causes pain and limits joint motions.The cartilage inflammation forms new bone to outgrowth (bony spur) around can also stimulating in the joint.

Secondary cases OA can't distinguish with spy's property sent out OA on pathology, but belongs to another kind of disease or disease.Can cause the disease of Secondary cases OA to comprise obesity, joint unusual (birth defect), gout, diabetes and other metabolic disease when wound (for example laceration of ligament, cartilage are torn), the operation (ligament repair, meniscectomy (menisectomy), cartilage are removed) that articulation structure is implemented, birth repeatedly.

In one aspect, compositions of the present invention can be used for the treatment of or prevent rheumatoid arthritis (RA).Rheumatoid arthritis is a kind of inflammatory diseases of unknown cause of chronic recurrent of multisystem.Although many organs all may be encroached on, but RA mainly is the severe form of chronic synovitis, sometimes the joint that causes being encroached on is damaged and ankylosis (Robbins " pathologic basis of disease " (Pathological Basis of Disease), by R.S.Cotran, V.Kumar, and S.L.Robbins, W.B.Saunders Co., 1989).On pathology, this disease is characterised in that the synovial membrane that forms the fine hair shape projection that extends into articular cavity significantly thickens, synovial cell's lining is divided into multilamellar (synovial cell's propagation), synovial membrane by leukocyte infiltration (macrophage, lymphocyte, plasma cell and lymphoid follicle; Be called " inflammatory synovitis ") and interior fibrin deposition of synovial membrane and necrocytosis.The tissue that forms as this process result is called pannus and final this pannus and grows to and be full of articular cavity.Pannus develops into neovascularity network structure widely by synovitis being developed requisite blood vessel generating process.The digestive enzyme that discharges from the pannus histiocyte (matrix metalloproteinase is such as collagenase and stromelysin) and other inflammatory process amboceptor (for example hydrogen peroxide, superoxides, lysosomal enzymes and arachidonic acid (arachadonic acid) metabolite) have destroyed cartilage matrix and have caused the breaking-up of carrying out property of cartilage.Pannus is invaded articular cartilage, causes cartilaginous tissue to corrode and fracture.There is subchondral bone erosion and finally causes bony ankylosis the joint that relates to is final with fibrous ankylosis.

It is generally acknowledged, but what finally be not confirmed is that RA is that a kind of autoimmune disease and many different former sexual stimuluses in joint have activated the immunoreation in the immune genetic susceptible host.Exogenous infection pathogen (Epstein-Barr virus, rubella virus, cytomegalovirus, herpesvirus, people T-cell lymphotropic virus, mycoplasma etc.) and endogenous protein (collagen protein, Dan Baijutang, immunoglobulin) relate to as the pathogen that causes unsuitable host immune response.Autoimmunity works in disease progression and has nothing to do with stimulus object.Especially, related antigen is taken in by antigen-presenting cell (macrophage in the synovial membrane or dendritic cell), processes and is and pass T lymphocyte.The T cell causes cell immune response and stimulates bone-marrow-derived lymphocyte propagation and be divided into plasma cell.Final result produces the excessively uncomfortable immunoreation at host tissue (for example at the antibody of II collagen type, at the antibody from the Fc part (being called " rheumatoid factor ") of body IgG).This result has further enlarged immunoreation and has quickened the breaking-up of cartilaginous tissue.In case cause this cascade, a large amount of amboceptors that cartilage damages will cause the rheumatoid arthritis development.

In rheumatoid arthritis, articular cartilage is damaged when being invaded by pannus tissue (being made up of inflammatory cell, blood vessel and connective tissue).In general, the chronic inflammatory disease in self is not enough to articular surface is produced infringement, in case but fiber vascular tissue has digested this cartilaginous tissue, will produce persistent defective.Can suppress the misgrowth of blood vessel and pannus tissue by using fibrotic compositions of inhibition or fibre modification inhibitor for treating.Anti-scarring agent is mixed these compositionss or other intraarticular can provide the means that can reduce the progression of disease rate with preparation.

Therefore, provide the method for treatment or prevention inflammatory arthritis among the present invention in one aspect, comprised the patient that these needs are arranged is treated the anti-scarring agent of effective dose or comprises the compositions of anti-scarring agent.Inflammatory arthritis comprises various diseases, the feature that includes, but are not limited to rheumatoid arthritis, systemic lupus erythematosus (sle), Sjogren's syndrome disease (scleroderma), MCTD, Si Yegelun syndrome, ankylosing spondylitis, behcet syndrome, sarcoidosis and osteoarthritis-all these diseases is that all joint inflammation and/or pain are as remarkable symptom.

The effective anti-cicatrization therapy that is used for inflammatory arthritis has realized one or more of following target: the order of severity that (i) has alleviated symptom (is encroached on arthralgia, swelling and tenderness; Morning deadlock, weak, tired, anorexia, lose weight); (ii) reduced the seriousness (joint capsule thickens, synovial membrane hypertrophy, joint ooze out, soft tissue contracture, range of movement reduce, ankylosis and fixed joint deformity) of clinical symptom that should disease; (iii) reduced and to have showed (rheumatic nodules, vasculitis, lung tuberosity, interstitial fibrosis, pericarditis, episcleritis, iritis, Felty syndrome, osteoporosis) outside the joint of disease; The frequency and the time limit of disease alleviation/asymptomatic stage have (iv) been increased; (fixedly infringement and residue have v) been prevented; And/or (vi) prevented/weakened should disease chronic development.

According to the present invention, above-mentioned anti-scarring agent arbitrarily can be used to implement the present invention.In certain embodiments of the invention, described compositions can discharge one or more the activating agent in the ordinary circumstance of fibre modification (or cicatrization) process that suppresses relevant with inflammatory arthritis, and the ordinary circumstance of described fibre modification (or cicatrization) process relevant with inflammatory arthritis comprises: (a) formation neovascularity (blood vessel generation); (b) connective tissue cell (such as fibroblast or synovial cell) migration and/or propagation; (c) damage cartilage matrix because of metal proteinase activity; (d) inflammatory reaction that produces by cytokine (such as IL-1, TNF α, FGF, VEGF).Can suppress or alleviate the cartilage loss by one or more situations that suppress in the fibre modification (or cicatrization).

In one aspect, described compositions comprises anti-scarring agent and is applicable to the polymer support of treatment inflammatory arthritis.The polymer and the non-polymer delivery system that are suitable for treating inflammatory arthritis that contain anti-scarring agent have in a large number above been described.Can give anti-scarring agent with the lowest dose level of realizing The above results by whole body (oral, intravenous or by intramuscular or subcutaneous injection).Just only there is a small amount of impaired joint or suffers from regard to the patient of more significant disease in the limited quantity joint, can anti-scarring agent directly be injected joint of being encroached on (intra-articular injection) or the ingredient of operating as the arthroscope that carries out on the joint by the percutaneous needle that inserts joint capsule.In preferred embodiments, the intraarticular that will contain the fibre modification inhibitor has joint after the damage of inducing arthritic height probability subsequently (for example the ligamentum cruciatum in the knee joint is torn, in the knee joint meniscus tear) with preparation.Giving enough time limits (by slow releasing preparation and/or injection repeatedly) with this activating agent is damaged as the cartilage that damages (or be used for the treatment of its operation technique) consequence preventing.

Can give anti-scarring agent according to any way as herein described.Yet preferred medication comprises intravenous, oral, subcutaneous injection or intramuscular injection.Particularly preferred embodiment comprises as intra-articular injection and suppresses fibrotic chemical compound (directly, by arthroscope or radiology guideline or as the IA flushing that enters of open operation operation ingredient).Anti-scarring agent can be given as the long-term low dose therapy so that ward off disease development, the symptom in the active stage disease is alleviated or alleviated to the prolongation disease.Perhaps, described therapeutic agent can be given with higher dosage so that induce the alleviation of the disease of acute active stage as " beating " therapy; Such as the acute inflammation after the traumatic joint injury (intra-articular fracture as described below, laceration of ligament, meniscus tear).Can use the lowest dose level that can realize these purposes, and can according to the effect of the preparation of the order of severity of patient, disease, the activating agent that gives, this activating agent and/or toleration, this activating agent from the joint clearance rate and the difference of route of administration change.

In a preferred embodiment, suppressing fibrotic compositions can be injectable based on hyaluronic compositions for intraarticular.Prevent in the height impact activity (such as running, jumping) the mechanicalness infringement in joint and impact as the hyaluronic acid of the normal composition of synovium of joint liquid lubricated articular surface and helping in normal activity (static, walking).In suffering from the patient of OA, the hyaluronic acid concentration of the elasticity of synovial membrane liquid and viscosity and synovial fluid all descends.Think that this is damaged owing to IA articular cartilage.The HA that intraarticular gives (being generally hyaluronate sodium) penetrates articular cartilage surface, synovial tissue and joint capsule after injection, the certain time time limit.By hyaluronic acid being injected joint (being called viscosity replenishes), can partly recover the home of synovitis, ease the pain and can prevent and further damage and deformity.The representational case description of used hyaluronic acid compositions is at United States Patent (USP) 6,654 in viscosity is replenished, in 120,6,645,945 and 6,635,287.Like this, can give (as single therapy or treat repeatedly circulation process) as intra-articular injection with the material that contains HA and be not enough to the pain osteoarthritis in lenitive patient's knee joint from conservative treatment to be used for the treatment of to exist.Sometimes also give other joint, inject HA to alleviate the symptom of disease in those particular joint such as hip (injecting under the fluoroscopy), ankle, both shoulders and elbow joint.With the difference of particular commodity, the HA material is injected the joint weekly once, continue 5-6 continuous weeks.When effective, the patient reports that they have obtained the remission in time limit more than 6 months or 6 months-at this moment, can repeat this cycle so that prolong the activity of therapy.Although beneficial effect is lasting in some patient, the HA of injection removed (being removed) fast from intravital joint in several days time limits.Can estimate to decompose the time limit that its retention time in the joint of prolongation can improve its effect and increase remission by suppressing HA.By the fibre modification inhibitor is joined among the HA, intra-articular injection has the additional beneficial effect (being " cartilage protection effect ") that helps to prevent the cartilage breaking-up.

Be used for the treatment of inflammatory arthritis the various HA of being purchased compositionss can with one or more activating agent couplings of the present invention, comprise: SYNVISC (Biomatrix, Inc., Ridgefield, NJ)-contain the elastomeric viscous fluid of hylan (derivant of hyaluronate sodium (the hyaluronan)) polymer that derives from rooster comb; HYALGAN (Sanofi-Synthelabo Inc.New York, NY); And ORTHOVISC (Ortho Biotech Products, Bridge water, NJ)-and the HA of the full-bodied injectable forms of highly purified high molecular, it is used for alleviating the patient's who suffers from knee osteoarthritis (OA) pain and improving its joint motions and range of movement.ORTHOVISC is injected knee joint to recover the elasticity and the viscosity of synovial membrane liquid.HYVISC is by Anika Therapeutics (Wobum, MA) the injectable HA product of high molecular that is used for the treatment of osteoarthritis and horse racing limping at present of research and development.Other viscosity supplementary that is used for the treatment of osteoarthritis based on HA comprises SUPARTZ from Seikagaku Corp. (Japan), from Bioniche Life Sciences, Inc. the SUPLASYN of (Canada), from DePuy Orthopaedics, Inc. (Warsaw, ARTHREASE IN) and from the DUROLANE of Q-Med AB (Sweden).

In one aspect, compositions of the present invention can be used for controlling the osteoarthritis of animal (for example horse).Should notice that some HA product (mainly being Boehringer Ingelheim Vetmedica, St.Joseph, the HWISC of MO) is used for the veterinary and uses (generally being used for the treatment of osteoarthritis and the limping of horse).

Be used for the treatment of arthritic other intraarticular and comprise the cortex steroidal with compositions.The most frequently used cortex steroidal that is used for inflammatory arthritis at present is methylprednisolone acetate (DEPO-MRDROL, Pharmacia﹠Upjohn Company, Kalamazoo, MI) and triacinolone acetonide (KENALOG, Bristol-Myers Squibb, New York, NY).By the fibre modification inhibitor being joined in the intraarticular cortex steroidal injection, the intra-articular injection agent has the additional beneficial effect (being " cartilage protection effect ") that helps to prevent the cartilage breaking-up.

The preparation that can be used for these application comprises solution, topical preparation's (for example solution, cream, ointment, gel), Emulsion, micellar solution, gel (crosslinked and noncrosslinking), suspension and/or paste.A kind of form of said preparation is injectable compositions.With regard to the compositions that further contains the polymer that increases preparation viscosity, hyaluronic acid (crosslinked, derive and/or noncrosslinking) is a typical material.These preparations may further include extra polymer (for example collagen protein, poly-(ethylene glycol) or glucosan) and biocompatible solvent (for example ethanol, DMSO or NMP).In one embodiment, can directly mix preparation with suppressing fibrotic therapeutic agent.In another embodiment, the fibre modification inhibitor can be mixed second kind of carrier (for example, aforesaid micelle, liposome, Emulsion, microsphere, nanosphere).Described microsphere and nanosphere can be made up of degradable polymer.Operable degradable polymer comprises poly-(hydroxy ester) (for example PLGA, PLA, PCL etc.) and poly-anhydrides, poe class and polysaccharide (for example chitosan and alginate).

In one embodiment, the fibre modification inhibitor further comprises polymer, and wherein this polymer is a degradable polymer.Degradable polymer can comprise polyesters, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) n, the block copolymer of R-(X-Y) n and X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, Mount Olive, the PLUONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator.In another embodiment, fibre modification inhibitor/polymer composition can further comprise solvent, liquid oligomer or liquid polymers, so that final compositions can be passed through the 18G syringe needle.Operable reagent comprises ethanol, MMP, PEG200, PEG 300 and form are X-Y, Y-X-Y, R-(Y-X) n, the low-molecular-weight liquid polymers of R-(X-Y) n and X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASFCorporation, Mount Olive, the PLUONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator.

In another embodiment, the fibre modification inhibitor can be solution in organic solvent, liquid oligomer or liquid polymers or suspension form.In this embodiment, can use reagent, be X-Y, Y-X-Y, R-(Y-X) such as ethanol, NMP, PEG 200, PEG 300 and form _n, R-(X-Y) _nLow-molecular-weight liquid polymers with X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, Mount Olive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator.

The example that is used for the treatment of the fibre modification inhibitor of inflammatory arthritis comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, TAXOTERE and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconizole); (J) p38 map kinase inhibitor (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Administered agents dosage depends on various factors from the present composition that is used for the treatment of inflammatory arthritis, comprises the type and the therapentic part of preparation.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.In one aspect, medicine obtained discharging in 1-90 days time limits with valid density.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or 10 μ g-10mg; Or 10mg-250mg; Or 250mg-1000mg; Or 1000mg-2500mg.The dosage (amount) of lip-deep this activating agent of per unit area of coating anti-scarring agent can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or 1 μ g/mm ²-10 μ g/mm ²Or 10 μ g/mm ²-250 μ g/mm ²250 μ g/mm ²-1000 μ g/mm ²Or 1000 μ g/mm ²-2500 μ g/mm ²

The typical doses scope of various anti-scarring agents that can be used for the treatment of the compositions coupling of inflammatory arthritis with the present invention is provided below.Following dosage is used in particular for intra-articular administration: (A) cell cycle inhibitor comprises doxorubicin and mitoxantrone.Doxorubicin analog and derivant thereof: accumulated dose is no more than 25mg, and (scope is at 0.1 μ g-25mg); Preferred 1 μ g-5mg.The dosage of per unit area is 0.01 μ g-100 μ g/mm ²Preferred dose is 0.1 μ g/mm ²-10 μ g/mm ²With 10 ^-8-10 ^-4The doxorubicin least concentration of M maintains in the joint.Mitoxantrone and analog thereof and derivant: accumulated dose is no more than 5mg, and (scope is at 0.01 μ g-5mg); Preferred 0.1 μ g-1mg.The dosage of per unit area is 0.01 μ g-20 μ g/mm ²Preferred dose is 0.05 μ g/mm ²-3 μ g/mm ²With 10 ^-8-10 ⁴The mitoxantrone least concentration of M maintains in the joint.(B) cell cycle inhibitor comprises paclitaxel and analog thereof and derivant (for example docetaxel): accumulated dose is no more than 10mg, and (scope is at 0.1 μ g-10mg); Preferred 1 μ g-3mg.The dosage of per unit area is 0.1 μ g-10 μ g/mm ²Preferred dose is 0.25 μ g/mm ²-5 μ g/mm ²With 10 ^-8-10 ^-4The paclitaxel least concentration of M maintains in the joint.(C) cell cycle inhibitor, such as podophyllotoxin (for example etoposide): accumulated dose is no more than 10mg, and (scope is at 0.1 μ g-10mg); Preferred 1 μ g-3mg.The dosage of per unit area is 0.1 μ g-10 μ g/mm ²Preferred dose is 0.25 μ g/mm ²-5 μ g/mm ²With 10 ^-8-10 ^-4The etoposide least concentration of M maintains in the joint.(D) immunomodulator comprises sirolimus and everolimus.(be rapamycin, RAPAMUNE): accumulated dose is no more than 10mg, and (scope is at 0.1 μ g-10mg) for sirolimus; Preferred 10 μ g-1mg.The dosage of per unit area is 0.1 μ g-100 μ g/mm ²Preferred dose is 0.5 μ g/mm ²-10 μ g/mm ²With 10 ^-8-10 ^-4The sirolimus least concentration of M maintains in the joint.Everolimus and derivant thereof and analog: accumulated dose should not surpass 10mg, and (scope is at 0.1 μ g-10mg); Preferred 10 μ g-1mg.The dosage of per unit area is 0.1 μ g-100 μ g/mm ²Surface area; Preferred dose is 0.3 μ g/mm ²-10 μ g/mm ²With 10 ^-8-10 ^-4The everolimus least concentration of M maintains in the joint.(E) heatshock protein 90 antagonisies (for example geldanamycin) and analog and derivant: accumulated dose is no more than 20mg, and (scope is at 0.1 μ g-20mg); Preferred 1 μ g-5mg.The dosage of per unit area is 0.1 μ g-10 μ g/mm ²Preferred dose is 0.25 μ g/mm ²-5 μ g/mm ²With 10 ^-8-10 ^-4The geldanamycin least concentration of M maintains in the joint.(F) HMGCoA reductase inhibitor (for example simvastatin) and analog and derivant: accumulated dose is no more than 2000mg, and (scope is at 10.0 μ g-2000mg); Preferred 10 μ g-300mg.The dosage of per unit area is 1.0 μ g-1000 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-500 μ g/mm ²With 10 ^-8-10 ^-3The simvastatin of M maintains in the joint.(G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃) and analog and derivant: accumulated dose is no more than 2000mg, and (scope is at 10.0 μ g-2000mg); Preferred 10 μ g-300mg.The dosage of per unit area is 1.0 μ g-1000 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-500 μ g/mm ²With 10 ^-8-10 ^-3The Mycophenolic Acid least concentration of M maintains in the joint.(H) NF к B inhibitor (for example Bay 11-7082) and analog and derivant: accumulated dose is no more than 200mg, and (scope is at 1.0 μ g-200mg); Preferred 1 μ g-50mg.The dosage of per unit area is 1.0 μ g-100 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-50 μ g/mm ²With 10 ^-8-10 ^-4The Bay 11-7082 least concentration of M maintains in the joint.(I) antimycotic agent, for example sulconizole) and analog and derivant: accumulated dose is no more than 2000mg, and (scope is at 10.0 μ g-2000mg); Preferred 10 μ g-300mg.The dosage of per unit area is 1.0 μ g-1000 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-500 μ g/mm ²With 10 ^-8-10 ^-3The sulconizole least concentration of M maintains in the joint; (J) p38MAP inhibitors of kinases (for example SB202190) and analog and derivant: accumulated dose is no more than 2000mg, and (scope is at 10.0 μ g-2000mg); Preferred 10 μ g-300mg.The dosage of per unit area is 1.0 μ g-1000 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-500 μ g/mm ²With 10 ^-8-10 ^-3The SB202190 least concentration of M maintains in the joint.

In one aspect of the method, when having severe exacerbation or systemic disease (for example RA), give whole body therapeutic.Should be as mentioned above according to suppressing the anti-scarring agent that the required levels of drugs of inflammatory arthritis pathologic condition gives systemic delivery.These whole-body dose can change according to the effect of the order of severity of patient, disease, the preparation that gives activating agent, this activating agent and/or the difference of toleration and route of administration.For example, with regard to paclitaxel, doxorubicin or geldanamycin, embodiment preferred can be 10-175mg/m ², per 1-4 weeks once, as what can tolerate, every day 10-75mg/m ²Or as tolerating 10-175mg/m ², weekly; Or up to resolution of symptoms.In order to treat the acute exacerbation of severe, can be used as " beating " constitutional treatment and give 50-250mg/m ²The higher dosage of paclitaxel.Can give other anti-scarring agent with the dose,equivalent of being adjusted by the effect and the toleration of activating agent.

According to another aspect of the present invention, can be with above-mentioned any anti-infective and the compositions coupling that is used for the treatment of inflammatory arthritis.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of lip-deep this activating agent of per unit area of coating anti-infective can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M, about 10 ^-7M-10 ^-6M, about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration activating agent of M maintains on the tissue surface.

The prevention (" cartilage protection ") of cartilage loss

In one aspect of the method, the cartilage loss after polymer composition can be used for prevention or reduce damage (for example ligamentum cruciatum is torn and/or meniscus tear).The known for a long time infringement to the joint easily causes the patient at any time time point place osteoarthritis in the joint to take place afterwards, but still not have the method for this situation generation of effectively treatment.And all concentrate on arthritis after treatment has been established from most of focus of medical community and research worker.Established treatment of diseases is comprised anti-inflammatory agent (non-steroidal and steroidal), lubricant or the displacement of synovial membrane liquid, serious disease is implemented operation and joint replacement.

Articular trauma has many forms, from can spraining merely of spontaneous recovery producing the fracture that almost can not rebuild the so many sclerite in joint.The focus for the treatment of these damages is rotation so that the joint returns to normal anatomic status and restarts well-regulated motion.It is relevant with the degree of wound, fracture or dislocation that arthritic risk factor takes place, and no matter whether it is weight-bearing joint, and relevant with the joint self characteristics.In general, big more to the wound degree in joint, then the patient is big more in the danger of later stage of life generation osteoarthritis.Use surgical correction to make the joint reach the preceding anatomical structure of its damage and can't guarantee to prevent arthritis.With regard to intra-articular fracture, for example the tibial plateau fracture is treated and is operation reconstruction joint, makes its recover to get back to conforming level and smooth and complete articular surface, the discomfort " ladder is damaged " or the fragment that wherein do not disturb femur to slide in its surface.Although used the surgical technic that improves in repairing these fracture, the patient who exists this class to fracture still has the high probability in later stage of life generation degenerative arthritis.

On behalf of the patient, anterior cruciate ligament in the knee joint (ACL) damage easily suffer from the representative instance of the damage of potential serious degenerative arthritis.ACL is the ligament that connects preceding tibial plateau and back fossa intercondylaris femoris.It has the not parallel fibrous of different fibre lengths by many, and their fasciculations work and provide tension force and mechanical stability in the range of movement to knee joint from start to finish at it.The Stabilization of ACL has four kinds of major functions, comprising: (a) stop tibia translation forward; (b) prevent the knee joint hyperextension; (c) stress that turns up is played second kind of function of stabilizer, strengthens medial collateral ligament; (d) rotation of tibia on the femur in the control femur process of expansion, and controlled motion thus are such as side-stepping with pivot.In general, the ACL defective causes the tibia subluxation on the femur, makes that the capsular ligaments stretching, extension and the shearing force on meniscus and the articular cartilage of bag quilt are unusual.Delay in diagnosis and the treatment causes the intraarticular infringement to increase and time stable capsule construction stretch.

Although the excessive risk of known generation osteoarthritis, the X-ray scanning image when generally there is not relevant fracture in the patient and has normal scanning after the ACL damage is normal.There is data to prove fully that the people of any ACL of suffering from damage has arthritic height probability takes place: have 50% during after damage 10 years, and be 80% during after damaging 20 years.In general, after ACL fracture, there is unstability in the patient because ligament pivot and rotary course in to stablize aspect the joint be crucial.For example, it is required to be not only the motion that requires to pivot, and such as playing basketball, and is that every day is movable required, is turning round the baby who embraces her when taking out article from refrigerator such as mother.

Typical treatment and control that ACL is torn are to use graft to rebuild the ACL that tears with displacement.Graft can take from any place (autograft) in patient's limbs, gather from corpse (allograft) or can be made by synthetic material.Autotransplantation is that the most extensive ACL of orthopedics that carries out rebuilds.This technology comprises the tissue of gathering patient self, and it can be 1/3rd sections of the centres of kneecap tendon with bone that two ends connect, in one or two between Hams or at one end on have the quadriceps tendon of bone.Synthetic material has the advantage that is easy to obtain, yet synthetic graft is compared the higher mortality of existence with autograft with allograft, and they have can't near the simulation normal ligament mechanical property.Successful ACL rebuilds and depends on many factors, comprises surgical technic, postoperative rehabilitation and relevant Secondary cases ligament unstability.In operative process, arthroscopy is used to determine whether to exist any associated injury that other can be treated simultaneously, such as meniscus tear or cartilage wound.Operation technique is undertaken by little auxiliary incision, wherein bores a passage by tibia and femur, makes and can insert and fixation implant.

Think that at first surgical reconstruction can provide persistent solution: the knee joint of reconstruction of stability and prevention degeneration.But other studies confirm that after joint injury, has inflammation activity cascade, in case cause these cascades, they will produce the joint and damage.This has just explained why surgical repair himself can not exert an influence to the degeneration in the prevention wound joint; The major operation reconstruction of stablizing joint or joint can't solve main potential biological question.Regrettably, in fact can successfully stablize knee joint and make the people return to normal activity although secular data have confirmed operation; But it is to the not influence of incidence rate of osteoarthritis subsequently.As a result of, nursing standard up to now is the emergency repair joint and treats it when finally arthritis taking place.Should note becoming arthritic probability after all there is wound in all joints (comprising knee joint), and related joint generally comprises finger, thumb, metacarpal bone (wrist), elbow, both shoulders, joint of vertebral column (facet, sacrococcygeal region), temporomandibular joint (temperomandibular), otica, hip, ankle, shank and toe, especially big toe.

The fibre modification inhibitor has demonstrated the prevention ligamentum cruciatum such as paclitaxel and has torn the ability that back prevention cartilage damages in zoopery.In inflammatory model and joint injury biomechanical model, observed this effect.In the rabbit arthritis model that the inflammation carrageenin brings out, paclitaxel has demonstrated the effect to cartilage.Anterior cruciate ligament is implemented the Hartley Cavia porcellus of surgical procedure and represented arthritic mechanical model.In general, after cutting off anterior cruciate ligament, arthritis takes place in animal in several weeks.Fibre modification inhibitor paclitaxel is imported the joint significantly stoped the arthritis process and not only protected cartilage, and the bone below having prevented is damaged.

The invention solves the important medical demand that is not met as yet: prevent carrying out property joint degeneration behind the traumatic damage.The compositions that will contain the fibre modification inhibitor after the damage immediately imports the situation cascade that impaired joint (for example by administration around intra-articular injection, the joint, by arthroscope, as the joint lavation in the open surgery operating process of joint) can influence causes the joint to be damaged, such as inflammation-inhibiting and the breaking-up of prevention cartilage matrix.The seriousness of most of ligament injury or pain degree are enough to make the patient to seek immediately medical treatment and nursing (in the pro-24-48 hours); In the joint irreversible change is taking place before this for a long time.If begin this moment to describe to the health professional, the fibre modification inhibitor can be gone into the joint so that stop or slow down breaking-up activity (intraarticular and joint surrounding tissue) through intraarticular so, can prevent that cartilage is damaged.Early stage importing activating agent of the present invention can slow down, alleviates or eliminate the situation cascade that causes osteoarthritis.Give the present invention after can damaging immediately, after conduct is prepared for stabilization procedure to repeat in the time limit process and/or finished operation, give the present invention.

Therefore, provide the method for treatment or the loss of prevention cartilage among the present invention in one aspect, comprised the patient that these needs are arranged is treated the anti-scarring agent of effective dose or comprises the compositions of anti-scarring agent.

The effective anti-cicatrization therapy that is used for the cartilage loss has realized one or more of following target: the order of severity (being encroached on arthralgia, swelling and tenderness) that (i) has alleviated symptom; (ii) reduced the seriousness (joint capsule thickens, synovial membrane hypertrophy, joint ooze out, soft tissue contracture, range of movement reduce, ankylosis and fixed joint deformity) of clinical symptom that should disease; The frequency and the time limit of disease alleviation/asymptomatic stage have (iii) been increased; (iv) delay or prevented the clinical tangible arthritis outbreak of the intraarticular that sustains damage in advance; And/or (v) prevent or reduced fixedly infringement and deformity.

According to the present invention, above-mentioned anti-scarring agent arbitrarily can be used to implement the present invention.In certain embodiments of the invention, described compositions can discharge one or more the activating agent in the ordinary circumstance of fibre modification (or cicatrization) process that suppresses relevant with joint damage, and the ordinary circumstance of described fibre modification (or cicatrization) process relevant with joint damage comprises: (a) formation neovascularity (blood vessel generation); (b) connective tissue cell (such as fibroblast or synovial cell) migration and/or propagation; (c) make the deposition and the reconstruction of extracellular matrix (ECM) because of metal proteinase activity; (d) inflammatory reaction that produces by cytokine (such as IL-1, TNF α, FGF, VEGF).Can alleviate or prevent joint damage and osteoarthritis in the impaired in advance joint to take place by one or more situations that suppress in the fibre modification (or cicatrization).

On the one hand, compositions comprises anti-scarring agent and polymer support, and it is used for the treatment of impaired joint.The polymer and the non-polymer delivery system that are used for the treatment of the cartilage loss that contain anti-scarring agent have in a large number above been described.Can give anti-scarring agent with the lowest dose level of realizing The above results by whole body (oral, intravenous or by intramuscular or subcutaneous injection).Just only there is a small amount of impaired joint or suffers from regard to the patient of more significant disease in the limited quantity joint, anti-scarring agent directly can be coated on IA tissue or directly inject the joint of being encroached on (intra-articular injection).

Can give anti-scarring agent according to any way as herein described.Yet preferred medication comprises intravenous, oral, subcutaneous, intramuscular or intra-articular injection.Can anti-scarring agent directly be injected joint of being encroached on (intra-articular injection) or the ingredient of operating as the arthroscope that carries out on the joint by the percutaneous needle that inserts joint capsule.In preferred embodiments, the intraarticular that will contain the fibre modification inhibitor has joint after the damage of inducing arthritic height probability subsequently (for example the ligamentum cruciatum in the knee joint is torn, in the knee joint meniscus tear) with preparation.Giving enough time limits (by slow releasing preparation and/or injection repeatedly) with this activating agent is damaged as the cartilage that damages (or be used for the treatment of its operation technique) consequence preventing.Anti-scarring agent can be given as the long-term low dose therapy so that ward off disease development, the symptom in the active stage disease is alleviated or alleviated to the prolongation disease.Perhaps, described therapeutic agent can be given with higher dosage as " beat (pulse) " therapy so that induce the alleviation (in immediately time limit after the joint injury) of the disease of acute active stage.Can use the lowest dose level that to realize these purposes, and can change according to preparation, the effect of this activating agent and/or the difference of toleration and route of administration of the order of severity of patient, disease, the activating agent that gives.

Be used for intra-articular injection the various HA of being purchased compositionss can with one or more activating agent couplings of the present invention, comprise: SYNVISC (Biomatrix, Inc., Ridgefield, NJ)-contain the elastomeric viscous fluid of hylan (derivant of hyaluronate sodium (the hyaluronan)) polymer that derives from rooster comb; HYALGAN (Sanofi-Synthelabo Inc.New York, NY); And ORTHOVISC (Ortho Biotech Products, Bridge water, NJ)-and the HA of the full-bodied injectable forms of highly purified high molecular, it is used for alleviating the patient's who suffers from knee osteoarthritis (OA) pain and improving its joint motions and range of movement.ORTHOVISC is injected knee joint to recover the elasticity and the viscosity of synovial membrane liquid.HYVISC is by Anika Therapeutics (Woburn, MA) the injectable HA product of high molecular that is used for the treatment of osteoarthritis and horse racing limping at present of research and development.Other viscosity supplementary that is used for intra-articular injection based on HA comprises SUPARTZ from Seikagaku Corp. (Japan), from Bioniche Life Sciences, Inc. the SUPLASYN of (Canada), from DePuy Orthopaedics, Inc. (Warsaw, ARTHREASE IN) and from the DUROLANE of Q-MedAB (Sweden).By the fibre modification inhibitor is joined among the HA, intra-articular injection has the additional beneficial effect (being " cartilage protection effect ") that helps to prevent the cartilage breaking-up.

In one aspect, compositions of the present invention can be used for controlling the osteoarthritis of animal (for example horse).Should notice that some HA product (mainly being Boehringer Ingelheim Vetmedica, St.Joseph, the HYVISC of MO) is used for the veterinary and uses (generally being used for the treatment of osteoarthritis and the limping of horse).

The fibrotic preparation of inhibition that is used for the treatment of or prevents cartilage to lose can be solution, topical preparation's (for example solution, cream, ointment, gel), Emulsion, micellar solution, gel (crosslinked and noncrosslinking), suspension and/or paste form.A kind of form of said preparation is to be used for the Injectable composition that intraarticular or arthroscope are sent.With regard to further containing the compositions that increases preparation viscosity, hyaluronic acid (crosslinked, derive and/or noncrosslinking) is a typical material.These preparations may further include extra polymer (for example collagen protein, poly-(ethylene glycol) or glucosan) and biocompatible solvent (for example ethanol, DMSO or NMP).In one embodiment, can directly mix preparation with suppressing fibrotic therapeutic agent.In another embodiment, the fibre modification inhibitor can be mixed second kind of carrier (for example, aforesaid micelle, liposome, Emulsion, microsphere, nanosphere).Described microsphere and nanosphere can be made up of degradable polymer.Operable degradable polymer comprises poly-(hydroxy ester) (for example PLGA, PLA, PCL etc.) and poly-anhydrides, poe class and polysaccharide (for example chitosan and alginate).

In one embodiment, the fibre modification inhibitor advances-goes on foot to comprise polymer, and wherein this polymer is a degradable polymer.Degradable polymer can comprise polyesters, wherein this polyester can comprise-kind or multiple residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone and form X-Y, Y-X-Y, R-(Y-X) n, the block copolymer of R-(X-Y) n and X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, Mount Olive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator.In another embodiment, fibre modification inhibitor/polymer composition may further include solvent, liquid oligomer or liquid polymers, makes final composition can pass through the 18G syringe needle.Operable reagent comprises that ethanol, NMP, PEG 200, PEG 300 and form are X-Y, Y-X-Y, R-(Y-X) _n, R-(X-Y) _nLow-molecular-weight liquid polymers with X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASFCorporation, Mount Olive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator.

In another embodiment, the fibre modification inhibitor can be solution in organic solvent, liquid oligomer or liquid polymers or suspension form.In this embodiment, can use reagent, be X-Y, Y-X-Y, R-(Y-X) such as ethanol, NMP, PEG 200, PEG 300 and form _n, R-(X-Y) _nLow-molecular-weight liquid polymers with X-Y-X, wherein X (for example gathers (ethylene glycol in polyalkylene oxide, the block copolymer of poly-(propylene glycol) and poly-(oxirane) and poly-(expoxy propane) is (for example from BASF Corporation, Mount Olive, the PLURONIC of NJ and PLURONIC R series polymer), and Y is biodegradable polyester, wherein this polyester can comprise one or more residues of monomers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, the e-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone (for example PLG-PEG-PLG), and R is multifunctional initiator.

Be used for the treatment of or prevent the example of the fibre modification inhibitor of the cartilage loss behind the traumatic damage to comprise following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconizole); (J) p38 map kinase inhibitor (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Administered agents dosage depends on various factors from the present composition that is used for the treatment of the cartilage loss, comprises the type and the therapentic part of preparation.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.In one aspect, medicine obtained discharging in 1-90 days time limits with valid density.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or 10 μ g-10mg; Or 10mg-250mg; Or 250mg-1000mg; Or 1000mg-2500mg.The dosage (amount) of lip-deep this activating agent of per unit area of coating anti-scarring agent can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or 1 μ g/mm ²-10 μ g/mm ²Or 10 μ g/mm ²-250 μ g/mm ²250 μ g/mm ²-1000 μ g/mm ²Or 1000 μ g/mm ²-2500 μ g/mm ²

The typical doses scope of various anti-scarring agents that can be used for the treatment of the compositions coupling of cartilage loss with the present invention is provided below: (A) cell cycle inhibitor comprises doxorubicin and mitoxantrone.Doxorubicin analog and derivant thereof: accumulated dose is no more than 25mg, and (scope is at 0.1 μ g-25mg); Preferred 1 μ g-5mg.The dosage of per unit area is 0.01 μ g-100 μ g/mm ²Preferred dose is 0.1 μ g/mm ²-10 μ g/mm ²With 10 ^-8-10 ^-4The doxorubicin least concentration of M maintains in the joint.Mitoxantrone and analog thereof and derivant: accumulated dose is no more than 5mg, and (scope is at 0.01 μ g-5mg); Preferred 0.1 μ g-1mg.The dosage of per unit area is 0.01 μ g-20 μ g/mm ²Preferred dose is 0.05 μ g/mm ²-3 μ g/mm ²With 10 ^-8-10 ⁴The mitoxantrone least concentration of M maintains in the joint.(B) cell cycle inhibitor comprises paclitaxel and analog thereof and derivant (for example docetaxel): accumulated dose is no more than 10mg, and (scope is at 0.1 μ g-10mg); Preferred 1 μ g-3mg.The dosage of per unit area is 0.1 μ g-10 μ g/mm ²Preferred dose is 0.25 μ g/mm ²-5 μ g/mm ²With 10 ^-8-10 ^-4The paclitaxel least concentration of M maintains in the joint.(C) cell cycle inhibitor, such as podophyllotoxin (for example etoposide): accumulated dose is no more than 10mg, and (scope is at 0.1 μ g-10mg); Preferred 1 μ g-3mg.The dosage of per unit area is 0.1 μ g-10 μ g/mm ²Preferred dose is 0.25 μ g/mm ²-5 μ g/mm ²With 10 ^-8-10 ^-4The etoposide least concentration of M maintains in the joint.(D) immunomodulator comprises sirolimus and everolimus.(be rapamycin, RAPAMUNE): accumulated dose is no more than 10mg, and (scope is at 0.1 μ g-10mg) for sirolimus; Preferred 10 μ g-1mg.The dosage of per unit area is 0.1 μ g-100 μ g/mm ²Preferred dose is 0.5 μ g/mm ²-10 μ g/mm ²With 10 ^-8-10 ^-4The sirolimus least concentration of M maintains in the joint.Everolimus and derivant thereof and analog: accumulated dose should not surpass 10mg, and (scope is at 0.1 μ g-10mg); Preferred 10 μ g-1mg.The dosage of per unit area is 0.1 μ g-100 μ g/mm ²Surface area; Preferred dose is 0.3 μ g/mm ²-10 μ g/mm ²With 10 ^-8-10 ^-4The everolimus least concentration of M maintains in the joint.(E) heatshock protein 90 antagonisies (for example geldanamycin) and analog and derivant: accumulated dose is no more than 20mg, and (scope is at 0.1 μ g-20mg); Preferred 1 μ g-5mg.The dosage of per unit area is 0.1 μ g-10 μ g/mm ²Preferred dose is 0.25 μ g/mm ²-5 μ g/mm ²With 10 ^-8-10 ^-4The geldanamycin least concentration of M maintains in the joint.(F) HMGCoA reductase inhibitor (for example simvastatin) and analog and derivant: accumulated dose is no more than 2000mg, and (scope is at 10.0 μ g-2000mg); Preferred 10 μ g-300mg.The dosage of per unit area is 1.0 μ g-1000 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-500 μ g/mm ²With 10 ^-8-10 ^-3The simvastatin of M maintains in the joint.(G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃) and analog and derivant: accumulated dose is no more than 2000mg, and (scope is at 10.0 μ g-2000mg); Preferred 10 μ g-300mg.The dosage of per unit area is 1.0 μ g-1000 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-500 μ g/mm ²With 10 ^-8-10 ^-3The Mycophenolic Acid least concentration of M maintains in the joint.(H) NF к B inhibitor (for example Bay 11-7082) and analog and derivant: accumulated dose is no more than 200mg, and (scope is at 1.0 μ g-200mg); Preferred 1 μ g-50mg.The dosage of per unit area is 1.0 μ g-100 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-50 μ g/rmm ²With 10 ^-8-10 ^-4The Bay 11-7082 least concentration of M maintains in the joint.(I) antimycotic agent (for example sulconizole) and analog and derivant: accumulated dose is no more than 2000mg, and (scope is at 10.0 μ g-2000mg); Preferred 10 μ g-300mg.The dosage of per unit area is 1.0 μ g-1000 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-500 μ g/mm ²With 10 ^-8-10 ^-3The sulconizole least concentration of M maintains in the joint; (J) p38 map kinase inhibitor (for example SB202190) and analog and derivant: accumulated dose is no more than 2000mg, and (scope is at 10.0 μ g-2000mg); Preferred 10 μ g-300mg.The dosage of per unit area is 1.0 μ g-1000 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-500 μ g/mm ²With 10 ^-8-10 ^-3The SB202190 least concentration of M maintains in the joint.

According to another aspect, can be with above-mentioned any anti-infective and the preparation coupling that is used for the treatment of or prevents the cartilage loss.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of lip-deep this activating agent of per unit area of coating anti-infective can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration activating agent of M maintains on the tissue surface.

Hypertrophic cicatrix/keloid

In another aspect of the present invention, provide the compositions that is used for the treatment of hypertrophic cicatrix and keloid that contains the activating agent (for example fibre modification inhibitor) for the treatment of effective dose.

Hypertrophic cicatrix and keloid are the dense fibrous tissue's overgrowth as excessive fibroplasia wound healing process result.Hypertrophic cicatrix and keloid take place in skin injury healing back usually.Briefly, wound healing and cicatrization take place in three phases: inflammation, hypertrophy and maturation.First inflammation as the reaction of the serious damage that must be enough to destroy skin is taken place in stage.In this phase process that continues 3-4 days, blood and tissue fluid are formed for the viscosity grumeleuse and the fibrous reticular structure that are bonded to each other with wound surface.After this be proliferative phase, wherein exist capillary tube and connective tissue inwardly to grow and the sealing skin injury from edge of wound.Finally, in case capillary tube and fibroblast proliferation stop, then maturation process begins, wherein cicatrix shrink and become that cell reduces, blood vessel reduces and just looks at smooth and be white.This terminal stage may continue 6-12 months.

If produce too much connective tissue and wound lastingly for cellulous, cicatrix will redden and increase so.If cicatrix remains in the border of original wound, it is called hypertrophic cicatrix so, if but it to expand to original cicatrix outer and enter surrounding tissue, this infringement is called keloid so.Hypertrophic cicatrix and keloid synulotic second and the phase III produce.Several wounds tend to excessive endotheliocyte and fibroblast proliferation especially, comprise burn, open wound and infected wound.With regard to hypertrophic cicatrix, the ripe and appearance that takes place to a certain degree progressively improves.Yet, with regard to keloid, the solid tumor that generation can become very huge.In this class situation, hardly spontaneous improvement may take place.

The keloid and the hypertrophic cicatrix that are positioned on most of position mainly are that beauty treatment is paid close attention to; Yet some keloid or hypertrophic cicatrix can produce contracture, just may cause the sense forfeiture on the joint if cover, if perhaps cover on the face, these keloid or hypertrophic cicatrix can disfigurements so.Keloid and hypertrophic cicatrix all may pain or prurituss.

In one embodiment of the invention, described polymer composition directly can be injected hypertrophic cicatrix or keloid, so that prevent these infringement development.Frequency of injection depends on the release dynamics characteristic and the clinical response of used polymer.This therapy has especially in the known disease (for example the excision position of burn, keloid or hypertrophic cicatrix, easy infection patient's the breast and the wound of back etc.) that can cause hypertrophic cicatrix and keloid to take place of prophylactic treatment and is worth and preferably (since the 1st day backward) and be (promptly in back 3 months of damage) this therapy before hypertrophic cicatrix or keloid take place before proliferative phase or in the process.

Provide local among the present invention in one aspect and injectable compositions, they comprise anti-scarring agent and are suitable for being coated on hypertrophic cicatrix or the keloid or enter wherein polymer support.The polymer and the non-polymer delivery system that are used for the treatment of hypertrophic cicatrix or keloid have in a large number above been described.

The fibre modification inhibitor is mixed a kind of means that topical preparation or injectable formulation are this diseases of treatment.Topical preparation can be the form of solution, suspension, Emulsion, gel, ointment, thin film or mesh.Injectable formulation can be the form of solution, suspension, Emulsion or gel.Can be used to prepare the polymer of these parts or Injectable composition and non-polymer composition as mentioned above.

In another embodiment, can mix second kind of carrier (for example, aforesaid micelle, liposome, Emulsion, microsphere, nanosphere etc.) with suppressing fibrotic therapeutic agent.Microsphere and nanosphere can be made up of degradable polymer.Operable degradable polymer comprises poly-(hydroxy ester) (for example PLGA, PLA, PCL etc.) and poly-anhydrides, poe class and polysaccharide (for example chitosan and alginate).

In addition, the present invention can use various other compositionss and the means that are used for the treatment of hypertrophic cicatrix and keloid.For example, Therapeutic Method can comprise that the angiogenesis inhibitor (for example fumagillol, Thalidomide) that gives effective dose is as reducing excessive synulotic whole body or local treatment.For example, referring to United States Patent (USP) 6,638,949.Therapeutic Method can use by with the polymer that is easy to be adsorbed on body tissue surfaces, such as the bonded hydrophilic polymer of phenylboric acid, the polymer of forming such as Polyethylene Glycol.For example, referring to United States Patent (USP) 6,596,267.Can comprise the cryoprobe that contains cryogen in the Therapeutic Method, it can be positioned at hypertrophic cicatrix or keloid with freezing tissue thus.For example, referring to United States Patent (USP) 6,503,246.Therapeutic Method can be in skin wound or near a certain amount of botulinal method of skin wound place topical administration, thereby promotes healing.For example, referring to United States Patent (USP) 6,447,787.Therapeutic Method can use by becoming membrane carrier, such as containing the fluid composition that one or more are formed with the collodion of steroidal, silicone gel and this class active component of vitamin E such as the part.For example, referring to United States Patent (USP) 6,337,076.The method that Therapeutic Method can form with prevention or treatment scar tissue for the fluoroquinolone that gives the fibrosis consumption.For example, referring to United States Patent (USP) 6,060,474.Therapeutic Method can use is enough to make substrate to control the compositions of the calcium antagonist and the protein synthesis inhibitor of synulotic effective dose in the degraded of cicatrix position.For example, referring to United States Patent (USP) 5,902,609.The compositions of microsphere in pharmaceutically acceptable carrier that Therapeutic Method can use the biology that has basic surface charge not degrade.For example, referring to United States Patent (USP) 5,861,149.Therapeutic Method can use the compositions of endothelial cell growth factor (ECGF) and heparin, can be with its part or by the intralesional injection administration.For example, referring to United States Patent (USP) 5,500,409.

The present invention is used for using the product that is purchased can comprising with the Treatment and composition for of one or more fibre modification inhibitor couplings of hypertrophic cicatrix and keloid and being purchased product.Representational product comprises: for example from Progressive Surgical Products (Westbury, the PROXIDERM outside organization expansion product that is used for wound healing NY); From Smith ﹠amp; The CICA-CARE gel film casting product of NephewHealthcare Ltd (India); With (Eddystone, MEPIFORM PA) is from adherent siloxanes dressing from MolnlyckeHealth Care.

Provide local among the present invention in one aspect and injectable compositions, comprised anti-scarring agent and be suitable for being coated on hypertrophic cicatrix or keloid or be easy to form on the position of hypertrophic cicatrix or keloid or enter wherein polymer support.

In one embodiment of the invention, described polymer composition directly can be injected hypertrophic cicatrix or keloid, so that prevent these infringement development.Frequency of injection depends on used polymer the release dynamics characteristic and the clinical response of (mouthful fruit exists).This therapy prophylactic treatment known can cause having especially in the disease that hypertrophic cicatrix and keloid take place (for example the wound of the cutting part of burn, keloid or hypertrophic cicatrix, easy ill patient's breast and back etc.) be worth and preferably (backward) and be (promptly in back 3 months of damage) this therapy before hypertrophic cicatrix or keloid take place before proliferative phase or in the process since the 1st day.

In one embodiment of the invention, aforesaid independent anti-scarring agent or anti-cicatrization compositions are directly injected hypertrophic cicatrix or keloid, so that prevent these infringement development.Frequency of injection depends on used polymer the release dynamics characteristic and the clinical response of (if existence).This therapy has especially in the known disease (for example the excision position of burn, keloid or hypertrophic cicatrix, easy infection patient's the breast and the wound of back etc.) that can cause hypertrophic cicatrix and keloid to take place of prophylactic treatment and is worth and preferably (since the 1st day backward) and be (promptly after damage in preceding 3 months) this therapy before hypertrophic cicatrix or keloid take place before proliferative phase or in the process.

According to the present invention, the above-mentioned inhibitor of fibre modification arbitrarily can be used to implement the present invention separately or with compound mode.In one embodiment of the invention, the compositions that is used for the treatment of hypertrophic cicatrix or keloid can discharge one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, and four kinds of ordinary circumstances of described fibre modification (or cicatrization) process comprise: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and/or propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).

The example that is used for the treatment of the fibre modification inhibitor of hypertrophic cicatrix and keloid comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconizole); (J) p38 map kinase inhibitor (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Administered agents dosage depends on various factors from the present composition that is used for the treatment of hypertrophic cicatrix and keloid, comprises the type of preparation and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.-individual aspect in, medicine obtained discharging in 1-90 days time limits with valid density.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or 10 μ g-10mg; Or 10mg-250mg; Or 250mg-1000mg; Or 1000mg-2500mg.The dosage (amount) of lip-deep this activating agent of per unit area of coating anti-scarring agent can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or 1 μ g/mm ²-10 μ g/mm ²Or 10 μ g/mm ²-250 μ g/mm ²250 μ g/mm ²-1000 μ g/mm ²Or 1000 μ g/mm ²-2500 μ g/mm ²

The typical doses scope of various anti-scarring agents that can be used for the treatment of the compositions coupling of hypertrophic cicatrix and keloid with the present invention is provided below: (A) cell cycle inhibitor comprises doxorubicin and mitoxantrone.Doxorubicin analog and derivant thereof: accumulated dose is no more than 25mg, and (scope is at 0.1 μ g-25mg); Preferred 1 μ g-5mg.The dosage of per unit area is 0.01 μ g-100 μ g/mm ²Preferred dose is 0.1 μ g/mm ²-10 μ g/mm ²With 10 ^-8-10 ^-4The doxorubicin least concentration of M maintains in wound, keloid and the hypertrophic cicatrix.Mitoxantrone and analog thereof and derivant: accumulated dose is no more than 5mg, and (scope is at 0.01 μ g-5mg); Preferred 0.1 μ g-1mg.The dosage of per unit area is 0.01 μ g-20 μ g/mm ²Preferred dose is 0.05 μ g/mm ²-3 μ g/mm ²With 10 ^-8-10 ⁴The mitoxantrone least concentration of M maintains in wound, keloid and the hypertrophic cicatrix.(B) cell cycle inhibitor comprises paclitaxel and analog thereof and derivant (for example docetaxel): accumulated dose is no more than 10mg, and (scope is at 0.1 μ g-10mg); Preferred 1 μ g-3mg.The dosage of per unit area is 0.1 μ g-10 μ g/mm ²Preferred dose is 0.25 μ g/mm ²-5 μ g/mm ²With 10 ^-8-10 ^-4The paclitaxel least concentration of M maintains in wound, keloid and the hypertrophic cicatrix.(C) cell cycle inhibitor, such as podophyllotoxin (for example etoposide): accumulated dose is no more than 10mg, and (scope is at 0.1 μ g-10mg); Preferred 1 μ g-3mg.The dosage of per unit area is 0.1 μ g-10 μ g/mm ²Preferred dose is 0.25 μ g/mm ²-5 μ g/mm ²With 10 ^-8-10 ^-4The etoposide least concentration of M maintains in wound, keloid and the hypertrophic cicatrix.(D) immunomodulator comprises sirolimus and everolimus.(be rapamycin, RAPAMUNE): accumulated dose is no more than 10mg, and (scope is at 0.1 μ g-10mg) for sirolimus; Preferred 10 μ g-1mg.The dosage of per unit area is 0.1 μ g-100 μ g/mm ²Preferred dose is 0.5 μ gmm ²-10 μ g/mm ²With 10 ^-8-10 ^-4The sirolimus least concentration of M maintains in wound, keloid and the hypertrophic cicatrix.Everolimus and derivant thereof and analog: accumulated dose should not surpass 10mg (scope is at 0.1 μ g-10mg); Preferred 10 μ g-1mg.The dosage of per unit area is 0.1 μ g-100 μ g/mm ²Surface area; Preferred dose is 0.3 μ g/mm ²-10 μ g/mm ²With 10 ^-8-10 ^-4The everolimus least concentration of M maintains in wound, keloid and the hypertrophic cicatrix.(E) heatshock protein 90 antagonisies (for example geldanamycin) and analog and derivant: accumulated dose is no more than 20mg (scope is at 0.1 μ g-20mg); Preferred 1 μ g-5mg.The dosage of per unit area is 0.1 μ g-10 μ g/mm ²Preferred dose is 0.25 μ g/mm ²-5 μ g/mm ²With 10 ^-8-10 ^-4The geldanamycin least concentration of M maintains in wound, keloid and the hypertrophic cicatrix.(F) HMGCoA reductase inhibitor (for example simvastatin) and analog and derivant: accumulated dose is no more than 2000mg (scope is at 10.0 μ g-2000mg); Preferred 10 μ g-300mg.The dosage of per unit area is 1.0 μ g-1000 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-500 μ g/mm ²With 10 ^-8-10 ^-3The simvastatin of M maintains in wound, keloid and the hypertrophic cicatrix.(G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃) and analog and derivant: accumulated dose is no more than 2000mg (scope is at 10.0 μ g-2000mg); Preferred 10 μ g-300mg.The dosage of per unit area is 1.0 μ g-1000 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-500 μ g/mm ²With 10 ^-8-10 ^-3The Mycophenolic Acid least concentration of M maintains in wound, keloid and the hypertrophic cicatrix.(H) NF к B inhibitor (for example Bay11-7082) and analog and derivant: accumulated dose is no more than 200mg (scope is at 1.0 μ g-200mg); Preferred 1 μ g-50mg.The dosage of per unit area is 1.0 μ g-100 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-50 μ g/mm ²With 10 ^-8-10 ^-4The Bay 11-7082 least concentration of M maintains in wound, keloid and the hypertrophic cicatrix.(I) antimycotic agent (for example sulconizole) and analog and derivant: accumulated dose is no more than 2000mg (scope is at 10.0 μ g-2000mg); Preferred 10 μ g-300mg.The dosage of per unit area is 1.0 μ g-1000 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-500 μ g/mm ²With 10 ^-8-10 ^-3The sulconizole least concentration of M maintains in wound, keloid and the hypertrophic cicatrix; (J) p38 map kinase inhibitor (for example SB202190) and analog and derivant: accumulated dose is no more than 2000mg (scope is at 10.0 μ g-2000mg); Preferred 10 μ g-300mg.The dosage of per unit area is 1.0 μ g-1000 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-500 μ g/mm ²With 10 ^-8-10 ^-3The SB202190 least concentration of M maintains in wound, keloid and the hypertrophic cicatrix.

According to another aspect, can be with above-mentioned any anti-infective and the preparation coupling that is used for the treatment of or prevents hypertrophic cicatrix and keloid.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: about 180 days less than 1 day one approximately; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of lip-deep this activating agent of per unit area of coating anti-infective can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M, about 10 ^-7M-10 ^-6M, about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration activating agent of M maintains on the tissue surface.

Angiopathy

The application of polymer composition in the treatment angiopathy that comprise polymer support and one or more fibre modification inhibitor (for example narrow, restenosis or atherosclerosis) is provided among the present invention in one aspect.

Send around the blood vessel

Another aspect of the present invention provides and can send being used for the treatment of of (for example being delivered to blood vessel outside or directly pass into tunica adventitia) or prevented the therapeutic combination of angiopathy (for example narrow, restenosis or atherosclerosis) around blood vessel.

Passing medicated bag around the blood vessel draws together use to be oriented to the syringe needle of target vascular therapy outer membrane face or conduit transdermal administration by ultrasonic, CT, cryptoscope, MRI or endoscope's guiding local with (being generally slow release) treatment preparation (tremulous pulse, vein, from body bypass graft, synthetic bypass graft, AV fistula).Perhaps in direct vision or use extra imaging guide (for example in the operation of by-pass operation, hemodialysis access) in average of operation periods to operate.This generic operation can also carry out in conjunction with operation technique in the blood vessel, such as angioplasty, ATH or stenting, perhaps carries out in conjunction with the tremulous pulse operation technique, inserts such as endarterectomy, blood vessel or graft reparation or graft.For example, in one embodiment, the polymer formulation for paclitaxel can be injected blood vessel wall or is coated on the blood vessel circumferential surface, make drug level in needing most bioactive zone, keep the highest.This result has the probability that minimizing may " rinse out " medicine because of the part that continuous blood flow on drug delivery systems in the blood vessel (such as the stent of the coating medicine) surface is strengthened.Give the obstruction that effective fibre modification inhibitor can reduce tremulous pulse, vein or graft to the blood vessel outer surface, and minimizing and the interior risk (such as restenosis, thromboembolism formation, thrombosis, plaque rupture and systemic drug toxicity) of operating relevant complication of blood vessel.

For example, in suffering from the narrow patient of femoral artery,superficial, can implement balloon angioplasty (promptly by pressurizeing down to the balloon angioplasty conduit of tremulous pulse with to air bag) according to common mode by infringement through lead.Before angioplasty, during angioplasty or after this, ultrasonic, cryptoscope or or guide CT under syringe needle inserted by skin and directly soak into narrow zone in the tremulous pulse with fibre modification inhibitor or compositions (for example being impregnated into the paclitaxel of release polymer) by syringe needle or conduit according to mode on every side.This operation can carried out around tremulous pulse, vein or graft arbitrarily, and the ideal candidate that is suitable for this operation comprises the disease on carotid artery, coronary artery, iliac artery, common femoral artery, shallow femoral artery and popliteal tremulous pulse and the graft anastomotic position.Reasonably the vein position is included in the vein surrounding wetting that has inserted inlying catheter.Similarly, when endoscope or open coronary bypass, periphery by-pass operation or hemodialysis access operation, according to mode infiltration in the identical zone that exists the restenosis incidence rate to increase on every side, spraying or coated fibre modification inhibitor or compositions (for example being impregnated into the paclitaxel of release polymer).This operation can carried out around tremulous pulse, vein or graft arbitrarily, and the ideal candidate that is suitable for this operation comprises the disease on carotid artery, coronary artery, iliac artery, common femoral artery, shallow femoral artery and popliteal tremulous pulse and the AV graft anastomotic position.

According to the present invention, above-mentioned anti-scarring agent arbitrarily can be used to implement the present invention.In one embodiment, the compositions that is used for passing around the blood vessel medicine can be suitable for discharging one or more activating agent of five kinds of ordinary circumstances suppressing fibre modification (or cicatrization) process, and five kinds of ordinary circumstances of described fibre modification (or cicatrization) process comprise: inflammatory reaction and inflammation; Connective tissue cell (such as fibroblast or smooth muscle cell) migration and/or propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).Can suppress or reduce the neointima excessive tissue and grow by suppressing in fibre modification (or cicatrization) situation one or more.

The drug dose of the fibre modification inhibitor that gives from the present composition that is used for sending around the blood vessel depends on various factors, comprises the type of preparation and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.In one aspect, medicine obtained discharging in 1-90 days time limits with valid density.

The several examples of fibre modification inhibitor that are used for passing around the blood vessel compositions of medicine comprise following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconizole); (J) p38 map kinase inhibitor (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or 10 μ g-10mg; Or 10mg-250mg; Or 250mg-1000mg; Or 1000mg-2500mg.The dosage (amount) of lip-deep this activating agent of per unit area of coating anti-scarring agent can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or 1 μ g/mm ²-10 μ g/mm ²Or 10 μ g/mm ²-250 μ g/mm ²250 μ g/mm ²-1000 μ g/mm ²Or 1000 μ g/mm ²-2500 μ g/mm ²

The typical doses scope that can be used for the various anti-scarring agents of blood vessel administration coupling on every side with the present invention is provided below: (A) cell cycle inhibitor comprises doxorubicin and mitoxantrone.Doxorubicin analog and derivant thereof: accumulated dose is no more than 25mg, and (scope is at 0.1 μ g-25mg); Preferred 1 μ g-5mg.The dosage of per unit area is 0.01 μ g-100 μ g/mm ²Preferred dose is 0.1 μ g/mm ²-10 μ g/mm ²With 10 ^-8-10 ^-4The doxorubicin least concentration of M maintains on the outer membrane face of tremulous pulse, vein or graft.Mitoxantrone and analog thereof and derivant: accumulated dose is no more than 5mg (scope is at 0.01 μ g-5mg); Preferred 0.1 μ g-1mg.The dosage of per unit area is 0.01 μ g-20 μ g/mm ²Preferred dose is 0.05 μ g/mm ²-3 μ g/mm ²With 10 ^-8-10 ⁴The mitoxantrone least concentration of M maintains on the outer membrane face of tremulous pulse, vein or graft.(B) cell cycle inhibitor comprises paclitaxel and analog thereof and derivant (for example docetaxel): accumulated dose is no more than 10mg (scope is at 0.1 μ g-10mg); Preferred 1 μ g-3mg.The dosage of per unit area is 0.1 μ g-10 μ g/mm ²Preferred dose is 0.25 μ g/mm ²-5mm ²With 10 ^-8-10 ^-4The paclitaxel least concentration of M maintains on the outer membrane face of tremulous pulse, vein or graft.(C) cell cycle inhibitor, such as podophyllotoxin (for example etoposide): accumulated dose is no more than 10mg, and (scope is at 0.1 μ g-10mg); Preferred 1 μ g-3mg.The dosage of per unit area is 0.1 μ g-10 μ g/mm ²Preferred dose is 0.25 μ gmm ²-5 μ g/mm ²With 10 ^-8-10 ^-4The etoposide least concentration of M maintains on the outer membrane face of tremulous pulse, vein or graft.(D) immunomodulator comprises sirolimus and everolimus.(be rapamycin, RAPAMUNE): accumulated dose is no more than 10mg, and (scope is at 0.1 μ g-10mg) for sirolimus; Preferred 10 μ g-1mg.The dosage of per unit area is 0.1 μ g-100 μ g/mm ²Preferred dose is 0.5 μ g/mm ²-10 μ g/mm ²With 10 ^-8-10 ^-4The sirolimus least concentration of M maintains on the outer membrane face of tremulous pulse, vein or graft.Everolimus and derivant thereof and analog: accumulated dose should not surpass 10mg (scope is at 0.1 μ g-10mg); Preferred 10 μ g-1mg.The dosage of per unit area is 0.1 μ g-100 μ g/mm ²Surface area; Preferred dose is 0.3 μ g/mm ²-10 μ g/mm ²With 10 ^-8-10 ^-4The everolimus least concentration of M maintains on the outer membrane face of tremulous pulse, vein or graft.(E) heatshock protein 90 antagonisies (for example geldanamycin) and analog and derivant: accumulated dose is no more than 20mg, and (scope is at 0.1 μ g-20mg); Preferred 1 μ g-5mg.The dosage of per unit area is 0.1 μ g-10 μ g/mm ²Preferred dose is 0.25 μ gmm ²-5 μ g/mm ²With 10 ^-8-10 ^-4The geldanamycin least concentration of M maintains on the outer membrane face of tremulous pulse, vein or graft.(F) HMGCoA reductase inhibitor (for example simvastatin) and analog and derivant: accumulated dose is no more than 2000mg (scope is at 10.0 μ g-2000mg); Preferred 10 μ g-300mg.The dosage of per unit area is 1.0 μ g-1000 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-500 μ g/mm ²With 10 ^-8-10 ^-3The simvastatin of M maintains on the outer membrane face of tremulous pulse, vein or graft.(G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃) and analog and derivant: accumulated dose is no more than 2000mg, and (scope is at 10.0 μ g-2000mg); Preferred 10 μ g-300mg.The dosage of per unit area is 1.0 μ g-1000 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-500 μ gmm ²With 10 ^-8-10 ^-3The Mycophenolic Acid least concentration of M maintains on the outer membrane face of tremulous pulse, vein or graft.(H) NF к B inhibitor (for example Bay 11-7082) and analog and derivant: accumulated dose is no more than 200mg, and (scope is at 1.0 μ g-200mg); Preferred 1 μ g-50mg.The dosage of per unit area is 1.0 μ g-100 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-50 μ g/mm ²With 10 ^-8-10 ^-4The Bay11-7082 least concentration of M maintains on the outer membrane face of tremulous pulse, vein or graft.(I) antimycotic agent (for example sulconizole) and analog and derivant: accumulated dose is no more than 2000mg (scope is at 10.0 μ g-2000mg); Preferred 10 μ g-300mg.The dosage of per unit area is 1.0 μ g-1000 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-500 μ g/mm ²With 10 ^-8-10 ^-3The sulconizole least concentration of M maintains on the outer membrane face of tremulous pulse, vein or graft; (J) p38MAP inhibitors of kinases (for example SB202190) and analog and derivant: accumulated dose is no more than 2000mg (scope is at 10.0 μ g-2000mg); Preferred 10 μ g-300mg.The dosage of per unit area is 1.0 μ g-1000 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-500 μ g/mm ²With 10 ^-8-10 ^-3The SB202190 least concentration of M maintains on the outer membrane face of tremulous pulse, vein or graft.

According to another aspect, above-mentioned any anti-infective can be united separately or with the fibrosis activating agent and be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ gmm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M, about 10 ^-7M-10 ^-6M, about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration activating agent of M maintains on the tissue surface.

The coating material that is used for medical apparatus and implant

Fibre modification inhibitor of the present invention and compositions can also with implant or implantable device (metal for example, the artificial joint of plastics and/or other material, staple, cranium plate etc.), breast implant (silicone gel adventitia for example, form of foam etc.), the implantation catheter of prolonged application and intubate (about more than 3 days), artificial organ and blood vessel (artificial heart for example, pancreas, kidney, blood vessel etc.), drug delivery systems (comprises the monolithic implant, pump and controlled-release device, such as ALZET Micropump (DURECTCorporation, Cupertino, California), the steroidal ball that is used for tissue metabolism's growth or contraception etc., the stitching thread that is used for application in the corium body, periodontal membrane, eyeshield, couplings such as cornea lenticule.

Suppress the another kind of fibrotic chemical compound and compositions and use the coating material that is as being used for synthetic implant.At the conventional method that is being used for applying synthetic implant surface, make the polyfunctional compound contact the environment of change and then the thin layer of said composition is coated on implant surface, after this main reacting to each other take place.In one embodiment, in order to be reduced to bottom line, select chemical compound so that produce substrate with clean neutral charge with the cell and the fiber-reactive of coating implant.Can be by extruding, brush, spraying or by other easily mode described chemical compound is coated on the implant surface.After chemical compound was coated on implant surface, making reacts to each other continued to the three-dimensional substrate of formation complete sum.

Although this method can be used to apply the surface of the synthetic implant of any type, but it is applied to especially that thrombotic reduces is the implant of main Consideration, such as artificial blood vessel and cardiac valve, blood vessel graft, blood vessel stent, electrical connector and stent/graft combination coincide.This method can also be used to apply implantable surgery with film (for example monofilament polypropylene) or mesh (for example being used for the hernia reparation).Can also use said method coating breast implant so that the cryptomere contracture is minimized.

Can also be coated on the suitable fibrous material suppressing fibrotic chemical compound and compositions, then can with its coated around bone so that provide structural intergrity to bone.That term used herein " suitable fibrous material " refers to is water-fast basically, the biocompatibility of non-immunogenic and in the immiscible fibrous material of cross-linkable composition of the present invention.This fibrous material can comprise the various materials of any class with these characteristics, and can with this paper with cross-linked composition combination, so that form medical and various implants that medicinal application is used in combination or device and/or provide structural intergrity to these implants or device with the present invention.

Fibrotic chemical compound of inhibition of the present invention and compositions can also be used to apply the lenticule of being made by natural existence or synthetic polymer.

Can use the representational example of the medical apparatus of polymer composition coating of the present invention to comprise: the blood vessel stent; The gastrointestinal stent; Trachea/bronchus stent; The Genito-urinary stent; The ENT stent; The intraarticular implant; Intraocular lens; The implant that is used for hypertrophic cicatrix and keloid; Blood vessel graft; Electrical connector coincide; Implantable sensor; Implantable pump; Implantable electric installation is such as implantable nerve stimulator, implantable electric conductance connection; The surgical adhesions barrier; The glaucoma drainage system; Thin film or mesh; Prosthetic heart valve; TT; Penile implant; Interior and the tracheostomy tube of trachea; Peritoneal dialysis catheters; Intracranial pressure monitor; Vena cava filter; CVCs; Ventricular assist device (for example LvAD); Spinal prostheses; Catheter (foley's catheter); Artificial bladder's sphincter; Rectificating surgery implant; With the gastrointestinal drainage tube.

The infiltration of polymer composition around medical apparatus and implant

The another kind of polymer composition as herein described is used can be for being impregnated into said composition in the tissue adjacent with medical apparatus.The polymer composition of theme of the present invention can contain fibrosis agent and/or anti-infective.

Polymer composition can be soaked into around the medical apparatus of implanting: (a) tissue adjacent with medical apparatus by said composition directly and/or indirectly being coated with following part and/or carrying out on it; (b) near medical apparatus-organizational interface; (c) medical apparatus peripheral region; (d) tissue around the medical apparatus.The method that the polymer composition of theme of the present invention is impregnated into the tissue adjacent with medical apparatus comprises this polymer composition is delivered to: (a) have medical device surface (for example as injectable, paste, gel or mesh) in the process in implantation; (b) before implanting medical apparatus at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) after implanting medical apparatus at once medical device surface and/or the tissue (for example forming gel or mesh) around the medical apparatus of implantation as injectable, paste, gel, original position; (d) by the said composition part being coated with the anatomic space (such as cavum subdurale (sudural space) or in sheath) of having placed medical apparatus (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of release therapeutic agent in several hours-a few time limits in week and can pass other preparation) into the described activating agent of release in the zone of this device of insertion for this embodiment is useful especially; (e) by inject medical apparatus tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).In all situations, all the polymer composition of theme of the present invention can be impregnated into all or part of adjacent tissue with described device.

The representational example that can be impregnated into the polymer composition of medical apparatus adjacent tissue comprises: (a) separately or load therapeutic agent (for example anti-scarring agent and/or anti-infective) be impregnated into the sprayable preparation that contains collagen protein with the medical apparatus adjacent tissue, such as COSTASIS (Angiotech Pharmaceuticals, Inc., Canada) and crosslinked poly-(ethylene glycol)-methylated collagen protein composition (for example be described in United States Patent (USP) 5,874,500 and 5, in 565,519); (b) separately or load therapeutic agent (for example anti-scarring agent and/or anti-infective) be impregnated into the sprayable preparation that contains PEG with the medical apparatus adjacent tissue, such as COSEAL (AngiotechPharmaceuticals, Inc.), FOCALSEAL (Genzyme Corporation, Cambridge, MA), (both are all from Confluent Surgical for SPRAYGEL or DURASEAL, Inc., Boston, MA); (c) separately or load therapeutic agent (for example anti-scarring agent and/or anti-infective) be impregnated into the preparation that contains fibrinogen with the medical apparatus adjacent tissue, (both are all from Baxter Healthcare Corporation such as FLOSEAL or TISSEAL, Fremont, CA); (d) separately or being impregnated into and containing of medical apparatus adjacent tissue of hyaluronic preparation of load therapeutic agent (for example anti-scarring agent and/or anti-infective), (both are all from Q-Med AB such as RESTYLANE or PERLANE, Sweden), HYLAFOIRM (Inamed Corporation, SantaBarbara, CA), SYNVISC (Biomatrix, Inc., Ridgefield, NJ), SEPRAFILM or SEPRACOAT (both are all from Genzyme Corporation); (e) separately or load therapeutic agent (for example anti-scarring agent and/or anti-infective) be impregnated into the polymer gel of implanting with the medical operation of medical apparatus adjacent tissue, such as REPEL (Life Medical Sciences, Inc., Princeton, NJ) or FLOWGEL (Baxter Healthcare Corporation); (f) separately or load therapeutic agent (for example anti-scarring agent and/or anti-infective) be impregnated into the orthopedics that is used for fixing prosthese and tissue " cement " with the medical apparatus adjacent tissue, such as OSTEOBOND (Zimmer, Inc., Warsaw, IN), low viscosity cement (LVC); WrightMedical Technology, Inc., Arlington, TN), SIMPLEX P (Stryker Corporation, Kalamazoo, MI), PALACOS (Smith ﹠amp; Nephew Corporation, UnitedKingdom) and ENDURANCE (Johnson ﹠amp; Johnson, Inc., New Brunswick, NJ); (g) separately or load therapeutic agent (for example anti-scarring agent and/or anti-infective) be impregnated into the operation binding agent that contains cyanoacrylate with the medical apparatus adjacent tissue, such as DERMABOND (Johnson ﹠amp; Johnson, Inc.), INDERMIL (U.S.SurgicalCompany, Norwalk, CT), GLUSTITCH (Blacklock Medical Products Inc., Canada), TISSUEMEND (Veterinafy Products Laboratories, Phoenix, AZ), VETBOND (3M Company, St.Paul, MN), HISTOACRYL BLUE (Davis ﹠amp; Geck, St.Louis, MO) and ORABASE SOOTHE-N-SEAL LIQUIDPROTECTANT (Colgate-Palmolive Company, New York, NY); (h) separately or load therapeutic agent (for example anti-scarring agent and/or anti-infective) be impregnated into that (or synthetic bone material is such as calcium sulfate with the implant that contains hydroxyapatite of medical apparatus adjacent tissue; VITOSS and CORTOSS (both are from Orthovita, Inc., and Malvem, PA); (i) solely or load therapeutic agent (for example anti-scarring agent and/or anti-infective) be impregnated into other biocompatible tissue implant with the medical apparatus adjacent tissue, such as those by BioCure, Inc. (Norcross, GA), 3MCompany (St.Paul, MN) and Neomend, Inc. (Sunnyvale, CA) implant of Sheng Chaning; (j) separately or load therapeutic agent (for example anti-scarring agent and/or anti-infective) be impregnated into polysaccharide gel with the medical apparatus adjacent tissue, such as ADCON series gel (available from Gliatech, Inc., Cleveland, OH); And/or (k) separately or load therapeutic agent (for example anti-scarring agent and/or anti-infective) be impregnated into thin film, sponge or mesh with the medical apparatus adjacent tissue, such as INTERCEED (Gynecare Worldwide, Ethicon, Inc. branch, Somerville, NJ), VICRYL mesh (Ethicon, Inc.) and GELFOAM (Pfizer, Inc., New York, NY).

Other example that can be impregnated into the polymer composition of the tissue adjacent with medical apparatus comprises by comprising both compositionss of forming as the reactant of reaction reagent of one of following ingredients or its: tetramethylolmethane gathers (ethylene glycol) ether four-sulfydryl] (4-is with ramose sulfydryl PEG, be included in and have the structure that is connected base between sulfydryl and the polyethylene glycol backbone end) and poly-(ethylene glycol) ether four-succinimido glutarate of tetramethylolmethane] (4-is with ramose NHS PEG, also is included in to have between NHS base and the polyethylene glycol backbone end to be connected basic structure).Another kind of preferred compositions comprise one of following ingredients or its both as reaction reagent: tetramethylolmethane gathers (ethylene glycol) ether four-amino] (4-is with ramose amino PEG, be included between amino and the polyethylene glycol backbone end and have the structure that is connected base) and tetramethylolmethane gather (ethylene glycol) ether four-succinimido glutarate] (4-is with ramose NHS PEG, also be included in NHS basic with the polyethylene glycol backbone end between have be connected basic structure).The chemical constitution of these reactants such as United States Patent (USP) 5,874 are shown in 500.Randomly collagen protein or collagen derivative (for example methylated collagen albumen) are joined in the reactant that contains poly-(ethylene glycol) so that form preferred crosslinked substrate.

The representational example of the medical apparatus of the compositions of medical theme of the present invention is as described below.

Endovascular device

In one aspect, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with endovascular device.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective)." endovascular device " refers to small part and implants device in the vascular system (for example blood vessel).The example that can be used for endovascular device of the present invention comprises: for example the stent of conduit, balloon catheter, air bag, stent, covering, stent graft, adapter and lead coincide.

In one aspect of the method, the polymer composition of theme of the present invention can be impregnated into blood vessel in the adjacent tissue of stent." stent " refers to and comprises and keep the device of blood flow from a part of blood vessel to the cylindrical tube of another part (by metal, weaving, can not degrade or degradable polymer, and/or other suitable material (such as biological tissue) is formed).In one aspect, stent is the interior scaffold (scaffolding) of blood vessel of keeping body passage (for example tremulous pulse) chamber and allowing blood flow.Can have benefited from polymer composition with theme of the present invention is impregnated into the stent of adjacent tissue according to the present invention representational example and comprise stent, such as the stent of coronary artery stent, periphery stent and covering.

Can be used for the stent that stent of the present invention comprises metal stent, polymer stent, biodegradable stent and covering.But stent can self-expanding or airbag inflation, form by metallic compound and/or polymeric material, make with countless design forms, be used for coronary artery or peripheral blood vessel, be grouped into by degradable and/or the one-tenth that can not degrade, covered (so-called " covering stent ") or " cover (sleeve) " by the blood vessel graft material wholly or in part, and can for naked metal or medicament elution.

Stent can comprise: metal or metal alloy, such as rustless steel, spring temper rustless steel (spring tempered stainless steel), stainless steel alloy, gold, platinum, superelastic alloys, cobalt-chromium alloy and other alloy that contains brill (comprise ELGILOY (Combined Metalsof Chicago, Grove Village, IL), PHYNOX (Alloy Wire Intemational, UnitedKingdom) and CONICHROME (Carpenter Technology Corporation, Wyomissing, PA)), titaniferous alloy, platinum-tungsten alloy, Ni-Ti alloy (comprising nickel [Ni] titanium [Ti] memorial alloy (nitino)), ductile metal (comprising tantalum); The material of composite or coating composite and/or other function equivalent; And/or polymer (biology can not degrade or biodegradable) material.The representational example that can be included in the polymer in the stent structure comprises: polyethylene; Polypropylene; Polyurethanes; Polyesters is such as polyethylene terephthalate (for example DACRON or M[YLAR (E.I.DuPont De Nemours and Company, Wilmington, DE)); Polyamide-based; Nomex class (for example from E.I.DuPont De Nemours andCompany KEVLAR); The polyfluoro hydro carbons (for example is purchased (E.I.DuPont De Nemours andCompany) such as poly-(tetrafluoroethene, have and do not have a copolymerization hexafluoropropene) under trade name TEFLON; Silk thread; And these mixture of polymers, admixture and copolymer.Stent can also be made by engineering plastics, such as TLCP (LCP), such as those by p, the polymer that p '-dihydroxy-multinuclear-aromatic compounds or dicarboxyl-multinuclear-aromatic compounds form.

Can be used for other stent type specification of the present invention at following document: for example PCT publication number WO 01/01957 and United States Patent (USP) 6,165,210; 6,099,561; 6,071,305; 6,063,101; 5,997,468; 5,980,551; 5,980,566; 5,972,027; 5,968,092; 5,951,586; 5,893,840; 5,891,108; 5,851,231; 5,843,172; 5,837,008; 5,766,237; 5,769,883; 5,735,811; 5,700,286; 5,683,448; 5,679,400; 5,665,115; 5,649,977; 5,637,113; 5,591,227; 5,551,954; 5,545,208; 5,500,013; 5,464,450; 5,419,760; 5,411,550; 5,342,348; 5,286,254; With 5,163,952.The medicament elution stent that can take out for example is described in Lambert, T. (1993) " american heart sick learn institute magazine " (J.Am.Coll.Cardiol.): 21:483A.In addition, stent can be suitable for for example only at the stent far-end or along the whole therapeutic agent that discharges of stent.

(y, R.L. (1993) " american heart sick learn institute magazine " (J.Am.Coll.Cardiol.): the air bag on the stent device among the 21:185A also is suitable for having the polymer composition of the theme of the present invention that is impregnated into adjacent tissue such as being described in Wilensk.

Except that using more traditional stent, can also use to be in particular the stent of passing the medicine design.The example of passing medicine stent and traditional stent of these special uses comprise those products from Conor Medsystems (Palo Alto, CA) (for example United States Patent (USP) 6,527,799; 6,293,967; 6,290,673; 6,241,762; U.S. Patent application 2003/0199970 and 2003/0167085; With PCT publication number WO 03/015664).

Can have in the blood vessel of polymer composition of the theme of the present invention that is impregnated into adjacent tissue the example of stent comprises and is purchased product.Stent can self-expanding or balloon expanding (for example STRECKER stent of Medi-Tech/Boston Scientific Corporation) maybe can be by the change implanted (for example nickel [Ni] titanium [Ti] memorial alloy stent) of temperature.Operable self-expanding stent comprises the (Natick from Boston ScientificCorporation, MA) coronary artery WALL stent and SCIMEDRADIUS stent and from Cook Group, Inc. (Bloomington, GIANTURCO stent IN).The example of operable balloon expanding stent comprises (the Miami Lakes from Cordis Corporation, FL) CROS SFLEX stent, BX-VELOCITY stent and PALMAZ-SCHATZ hat and helical form stent, Cook Group, Inc. V-FLEX PLUS stent, NIR from Boston Scientific Corporation, EXPRESS and LIBRERTE stent, ACS MULTILINK from Guidant Corporation, MULTILINKPENTA, SPIRIT and CHAMPION stent and Medtronic, Inc. (Minneapolis, MN) coronary artery stent S670 and S7.

Other example of stent that can have a polymer composition of the theme of the present invention that is impregnated into adjacent tissue comprises those products from Boston Scientific Corporation (medicament elution for example TAXUS EXPRESS ² Paclitaxel eluting coronary artery stent systemStent on the line, such as Express ² Coronary artery stent systemWith NIR Elite OTW stent system: the quick exchange stent, such as EXPRESS ² Coronary artery stent systemWith NIR Elite Monorail stent system; With the self-expanding stent, such as Magic WALLSTENT stent system and Radius self-expanding stent); Medtronic, Inc. (Minneapolis, MN) (DRIVERABT578-eluting stent for example, DRIVER ZIPPER MXMany exchange coronary artery stent systems and DRIVERCoronary artery stent system on the line: S7 ZIPPER MXThe coronary artery stent systems that exchange more: The use isolation technicsS7, S670, S660 and the BESTENT2 of coronary artery stent system on the line); GuidantCorporation (cobalt chromium stent for example, such as MUTI-LINK VISION is crown moving Arteries and veins stent system MULTI-LINK ZETA coronary artery stent system System MLUTI-LINK PIXEL coronary artery stent system MULTI-LINK ULTRA coronary artery stent system: and MULTI-LINK FRONTIER); Johnson ﹠amp; Johnson/Cordis Corporation (CYPHER sirolimus-eluting stent for example; PALMAZ-SCHATZ balloon expanding stent; With the S.M.A.R.T. stent); Abbott Vascular (Redwood City, California) (MATRIXLO stent for example; The TRIMAXX stent; With the DEXAMET stent); Conor Medsystems (Menlo Park, California) (for example MED stent and COSTAR stent); AMG GmbH (Germany) (for example PICO Elite stent); Biosensors Intemational (Singapore) (for example MATRIX stent, CHAMPION stent (above-mentioned S-stent) and CHALLENGE stent); Biotronik (Switzerland) (for example MAGIC AMS stent); Clearstream Technologies (Ireland) (for example CLEARFLEX stent); Cook Inc. (Bloomington, Indiana) (for example V-FLEX PLUS stent, ZILVER PTX self-expanding blood vessel stent coating, LOGIX PTX stent (in research and development); DevaX (for example AXESS stent) (Irvine, CA); DISAVascular (Pty) Ltd (South Africa) (for example CHROMOFLEX stent, S-FLEX stent, S-FLEX Micro stent and TAXOCHROMEDES); Intek Technology (Baar, Switzerland) (for example APOLLO stent); Orbus Medical Technologies (Hoevelaken, The Netherlands) (for example GENOUS); Sorin Biomedica (Saluggia, Italy) (for example JANUS and CARBO stent); With the stent from following company: Bard/Angiomed GmbHMedizintechnik KG (Murray Hill, NJ); With Blue Medical Supply ﹠ Equipment (Mariettta, GA), Aachen Resonance GmbH (Germany); EucatechAG (Germany), Eurocor GmbH (Bonn, Gemany), Prot, Goodman, Terumo (Japan), Translumina GmbH (Germany), MIV Therapeutics (Canada), Occam Intemational B.V. (Eindhoven, The Netherlands), Sahaj anand MedicalTechno1ogies PVT LTD. (India); AVI Biopharma/Medtronic/InterventionalTechnologies (Portland, OR) (for example RESTEN NG-coated stent); And Jomed (for example FLEXMASTER medicament elution stent) (Sweden).

In general, insert stent in a comparable manner, with position of being treated or disease independent.Briefly, generally insert check at first in advance, be generally diagnosing image operation, splanchnoscopy or at the operative site direct image, so that determine the suitable location that stent inserts.Push ahead at the position that lead is inserted by wound or plan then, then sends the conduit that allows to be inserted in it compressed format stent.Stent in the blood vessel can be inserted tremulous pulse, push ahead by circulation, reach the anatomical location of speckle in coronary artery or the peripheral circulation up to them such as the femoral artery in the groin and under radioactivity guide.In general, stent can be compressed, and makes that they can be passed very little chamber by ductule inserts, in case and they reach desired location then, just be expanded to large-size.Take out delivery catheter then, make stent keep stable as stent independently.In case expand, stent will impel conduit wall to separate in shape and make their keep open.Check after the insertion is generally X ray and is generally used for confirming suitable location.

Generally, especially modestly stent is put into the blood vessel for the treatment of exactly in radioactivity or direct vision control lower-pilot stent in-position.In certain aspects, stent may further include radiopaque echogenic material or MRI reactive materials (for example MRI contrast agent) so that help device to develop under ultrasonic, cryptoscopy and/or magnetic resonance imaging condition.The then visible material of radiopaque or M can be the form (for example being deposited on the material band on the stent end) of one or more labels, and it can be used for making device orientation and guiding device in the implant procedure process.

In one aspect of the method, the polymer composition of theme of the present invention can be impregnated into and the adjacent tissue of connecting device that coincide.

" coincide electrical connector " refers to need not generally to produce in the mechanical system that produces the manual suture that carries out in coincideing any vessels device of vascular anastomosis (for example tremulous pulse-to-tremulous pulse, vein-to-tremulous pulse, tremulous pulse-to-vein, tremulous pulse-to-synthetic graft, synthetic graft-to-tremulous pulse, vein-to-synthetic graft or synthetic graft-to-venous anastomosis).This term also refers to so identical electrical connector (following), it is designed to be created in semi-automatic vascular anastomosis favourable under the situation of not using stitching and reduces the connect hours basically (reaching several seconds usually), wherein has this class device of a large amount of types and design.This term also refers to help the device that hole in blood vessel graft and the target vessel or opening (for example on blood vessel side or blood vessel end) are connected.Grappling and/or grappling outside coincide electrical connector and the blood vessel can be gone into the blood vessel wall (for example enter and organize in adventitia, the wall or theca interna) and/or the part of device can be retained in the lumen of vessels.

The electrical connector that coincide can also be used for from a kind of structure to the another kind of structure by passage or turn to diverter to produce new flowing.Therefore, this class device (this paper is also referred to as " shunting device ") generally comprises at least a tubular-shaped structures, and wherein tubular-shaped structures limits a cavity configuration.Identical electrical connector can comprise a kind of tubular-shaped structures or multiple tubular-shaped structures, can flow by their blood.Being retained in blood vessel outside (for example outside the blood vessel) to small part and turning to passage of tubular-shaped structures so that provide.The part of device also can be retained in the lumen of vessels and/or in the tissue.

The case description of identical electrical connector is in the co-pending application of submitting on May 24th, 2004, and title is " electrical connector (Anastomotic Corunector Devices) coincide " (U.S.'s serial number 10/853,023).The representational example of identical electrical connector comprises, but be not limited to vascular clamp, vascular suture line, blood vessel nail (staple), vascular forceps, stitching devices, the connecting device that coincide (adapter for example coincide), comprise the adapter (coupler), anastomosis ring and percutaneous original position coronary artery bypass (PISCAB and the PICVA) device that comprise the barrel portion that carries blood.Put it briefly, the connecting device that coincide can be divided into three classes: (1) automatic and improved sewing method and device; (2) micromachine; (3) identical connecting device.

(1) automatic and improved method and apparatus

Automatic and improved sewing method generally helps multiple sutural quick deployment, and normally in one step, and elimination is to the demand of knotting and use aorta side engaging clamp.Stitching devices comprises that those are adapted to pass through through the device hole or other little opening is used stitching thread or other is performed the operation fastener and forms identical device with minimum infringement degree between vessel catheter and hollow organ's structure.Owing to used these devices, can in having the interior body region of limited inlet, use stitching thread and other fastener in quick relatively and automatic mode.Coincide by using minimum level invasive device to set up, can exist and less lose blood and need temporarily not stop blood flow at distance operating position far-end.For example, the stitching devices vessel catheter that can support by the handle that is suitable for coincideing and can be configured in order to fixing by vessel catheter many pins and sutural handle on the axle collar that slides form.For example, referring to United States Patent (USP) 6,709,441.Stitching devices can be by being used to insert stretching, extension with the carrier part that supports graft graft wall part in place be suitable for keeping being connected with blood vessel wall and graft flange to finish identical needle assembly with the propulsion coil fastener and form.For example, referring to United States Patent (USP) 6,709,442.Stitching devices can comprise two oblong interconnection elements, and these elements comprise the crack lining (for example United States Patent (USP) 4,350,160) that is suitable for sewing up.

A kind of representational example of stitching devices is by Perclose-Abbott Labs, RedwoodCity, and the HEARTFLOW device that CA makes is (generally referring to United States Patent (USP) 6,358,258,6,355,050,6,190,396 and 6,036,699 and PCT publication number WO 01/19257).

(Sunnyvale, the nickel that CA) provides [Ni] titanium [Ti] memorial alloy U-CLIP suture clip device is by forming from-sealing nickel [Ni] titanium [Ti] memorial alloy wire loop and pin with rapid release structure of being connected with the toughness element by Coalescent Surgica1.This device is by simplifying sew application and eliminating the knotting structure (generally referring to United States Patent (USP) 6,074,401 and 6,149,658 and PCT publication number WO 99/62406, WO 99/62409, WO 00/59380, WO01/17441) that helps coincideing.

ENCLOSE auxiliary device (the Novare Surgical Systems that coincide, Cupertino, CA) require the surgeon to use the standard suturing skill to produce sutured anastomosis, but do not use the aorta clamps of the side interlock of part obturation, thereby avoided the aorta wall distortion (referring to United States Patent (USP) 6,312,445 and 6,165,186).

In one aspect, automatic and improved sewing method and device can be sent the operation fastener (for example stitching thread or suture clip) of the polymer composition that is suitable for having the theme of the present invention that is impregnated into adjacent tissue.In one aspect of the method, it is identical to finish that automatic and improved sewing method and device can be sent the blood vessel graft of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue.

(2) micromachine

Micromachine is used for producing identical and/or is that graft blood vessel and anastomotic position are fixed.The representational example of micromachine comprises nail (transparent or impenetrable) and folder.

Anastomosis staple and clamp device can adopt various forms and can be made by dissimilar materials.For example follow closely and press from both sides and to form by metal or metal alloy, such as titanium, Ni-Ti alloy or rustless steel or polymeric material, such as siloxanes, poly-(carbamate), rubber or thermoplastic and high-elastic.

Polymeric material can be for finishing the absorbable or biodegradable material that the back dissolving that coincide designs.Biodegradable material comprises: for example comprise one or more monomeric homopolymer and copolymers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, 6-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone.

The various devices that are used for nail and folder importing position have also been described.

A manufacturer that is used to produce identical impenetrable nail be United States SurgicalCorp. (Norwalk, CT).VCS system (Autosuture) is for using the automatic nail fixing device of impenetrable titanium vascular clamp, and described impenetrable titanium vascular clamp makes the organization edge with high compression power of being used for overturning (for example, referring to the United States Patent (USP) 6 that is used to describe the identical connecting device that U.S.Surgical makes with discontinuous manner usually, 440,146,6,391,039,6,024,748,5,833,698,5,799,857,5,779,718,5,725,538,5,725,537,5,720,756,5,360,154,5,193,731 and 5,005,749).

Anastomosis clamp can be made up of shape memory material, such as nickel [Ni] titanium [Ti] memorial alloy, and its self-closing between open U-shape structure and closo structure.For example, referring to United States Patent (USP) 6,641,593.Anastomosis clamp can be made up of line, this line have determine basically can for the shape memory characteristic of spiral closed structure and have releasable with press from both sides the pin that is connected.For example, referring to United States Patent (USP) 6,551,332.Other anastomosis clamp for example is described in the United States Patent (USP) 6,461,365 and 6,514,265.

Automatically nail fixing device is also by Bypass/Ethicon, and (Somerville NJ) makes and be described in for example United States Patent (USP) 6,193,129 to Inc.; 5,632,433; 5,609,285; 5,533,661; 5,439,156; 5,350,104; 5,333,773; 5,312,024; 5,292,053; 5,285,945; 5,275,322; 5,271,544; 5,271,543 and 5,205,459 and WO03/02016 in.Comprise for example can resorbent operation nail (i.e. the polymerization Acetic acid, hydroxy-, bimol. cyclic ester of 65-85 weight %) being described in the United States Patent (USP) 4,741,337 and 4,889,119 of the polymer blend that is rich in Acetic acid, hydroxy-, bimol. cyclic ester.The operation nail of being made by the lactide/glycolides-copolymer and the admixture of poly-(to-diethyleno dioxide ketones) is described in United States Patent (USP) 4,646, in 741.The nail fixing device of other type for example is described in the United States Patent (USP) 5,234,447,5,904,697 and 6,565,582 and US publication 2002/0185517A1.

In one aspect of the method, described micromachine can be anastomosis clamp.For example, anastomosis clamp can be made up of shape memory material, such as such as nickel [Ni] titanium [Ti] memorial alloy, and its self-closing between open U-shape structure is constructed with closo.For example, referring to United States Patent (USP) 6,641,593.Anastomosis clamp can be made up of line, this line have determine basically can for the shape memory characteristic of spiral closed structure and have releasable with press from both sides the pin that is connected.For example, referring to United States Patent (USP) 6,551,332.Other anastomosis clamp for example is described in the United States Patent (USP) 6,461,365,6,187,019 and 6,514,265.

The micromachine stapling apparatus (for example nail or folder) of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue is provided among the present invention in one aspect.

(3) identical connecting device

It is identical to finish that identical connecting device can be used for that article one blood vessel is connected to the second blood vessel, has or not the graft blood vessel all can.In one aspect, identical connecting device helps making under the situation of not using stitching thread or nail hole or the opening (for example at blood vessel side or end) in graft or blood vessel and the target vessel to be dynamically connected certainly.In one aspect of the method, identical connecting device comprises the tubular-shaped structures (following) of determining that blood can mobile chamber.

Help making hole in graft or blood vessel and the target vessel or opening can adopt various forms and can make by various materials from the identical connecting device that is dynamically connected.In general, this class device is made by biocompatible materials, such as polymer or metal or metal alloy.For example this device can be formed by synthetic material, such as fluoropolymer polymer, such as available from W.L Gore ﹠amp; Inflatable poly-(tetrafluoroethene) that Associates, the trade name GORE-TEX of Inc. sell down (ePTFE) or PEP (FEP), polyurethane, polyamide (nylon), siloxanes, polypropylene, polysulfones or polyester.

Identical connecting device can be included as the absorbable or biodegradable material that coincide the back dissolving and design finishing.Biodegradable polymeric comprises: for example comprise one or more monomeric homopolymer and copolymers, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, 6-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2 ketone.

This device can comprise the combination of metal or metal alloy (for example nickel [Ni] titanium [Ti] memorial alloy, rustless steel, titanium, ferrum, nickel, Ni-Ti, cobalt, platinum, tungsten, tantalum, silver, gold, molybdenum, chromium and chromium) or metal and polymer.

This device and the blood vessel outside, the part that is centered around grappling in the tissue around the lumen of vessels and/or device can be retained in the lumen of vessels.

In one aspect, identical adapter can be the artificial opening adapter that forms, and it places on the target vessel inwall, makes tubular graft tubing to be extended from target vessel.This adapter can comprise a plurality of with the concentric ring arrayed organize punctured element and retention finger, its can be by tubular graft tubing sidewall so that make graft and adapter is fixed and is maintained fixed with the form of no leakage body structure.For example, referring to United States Patent (USP) 6,702,829 and 6,699,256.

In one aspect of the method, described identical adapter can be the frame form.For example, the structure of this framework can be for deformable and forficiform, make stretch that element can move in case when inserting target vessel the fixation implant blood vessel.For example, referring to United States Patent (USP) 6,179,849.

In one aspect of the method, described identical adapter can be the ring sampling device, and it is as the identical interface of graft chamber and target vessel chamber split shed.For example, this anastomosis ring can be by stainless steel alloy, titanium alloy, or cobalt alloy is formed and is had a flange that has inflatable diameter.For example, referring to United States Patent (USP) 6,699,257.Anastomosis ring for example also is described in the United States Patent (USP) 6,248,117.

In one aspect of the method, described identical adapter is can be resorbent.Can comprise by resorbent identical connecting device: the polymer blend (i.e. the polymerization Acetic acid, hydroxy-, bimol. cyclic ester of 65-85 weight %) that for example is rich in Acetic acid, hydroxy-, bimol. cyclic ester (for example, referring to United States Patent (USP) 4,741,337 and 4,889,119) or the admixture of lactide/glycolides-copolymer and poly-(to-diethyleno dioxide ketones) (for example, referring to United States Patent (USP) 4,646,741).

In one aspect of the method, described identical adapter comprises biological absorbable elastomeric-type material.The representational case description of elastomeric-type material that is used for absorbable device is in United States Patent (USP) 5,468,253 for example.

In one aspect of the method, described identical adapter can be used for article one blood vessel is connected to the second blood vessel, has or not the graft blood vessel all can.For example, described identical adapter can be for being used in the side to side anastomosis mode, such as the device that makes the interconnection of two blood vessels when transplanting two cardiovasculars arranged side by side.The cylinder sections that described identical adapter can be used as the part opening constitutes, these sections interconnect along periphery by flow openings, this device can be inserted in the infringement mode of minimum level thus, it provides the consistent pressure that inwall is produced with in prototectonics the time subsequently, thereby has prevented seepage.For example, referring to United States Patent (USP) 6,464,709; 6,458,140 and 6,251,116 and U. S. application publication number 2003/0100920A1.

In one aspect of the method, the adapter that coincide can also be integrated into the design of blood vessel graft so that eliminate before deployment and the interface step of connecting.For example, described identical adapter can have lead and in progradation the rear portion lobe of blood vessel dilating opening, and matrix, described matrix be configured to form sealing with openings in blood vessels when graft is connected.For example, referring to United States Patent (USP) 6,702,828.

In one aspect of the method, described identical adapter can be the frame form.For example, described identical adapter can be made up of deformable and forficiform framework, and it has the stretching, extension element that inserts target vessel.For example, referring to United States Patent (USP) 6,179,849.

In one aspect of the method, described identical adapter can comprise that the graft of having incorporated the heating element heater that produces thermal between the fixed structure on the opposite end (for example neck ring or lock ring) and graft and blood vessel into is (for example, referring to United States Patent (USP) 6,652,544 and 6,293,955).

In one aspect of the method, described identical adapter comprises and being used for bypass graft end and two fixed compressible inflatable adnexaes of blood vessel.This additional bypass graft of incorporating into can be designed so that eliminate the preceding graft of deployment and this adnexa step of connecting (for example, referring to United States Patent (USP) 6,494,889).

In one aspect of the method, described identical adapter comprise a pair of be used for end to end or side formula connect the terminal pad element of two blood vessels.One of these elements comprise the hook element, and the tissue that turns up and another element has the receptive cavity that forms a line with described hook with blood vessel locks together (for example, referring to United States Patent (USP) 4,523,592).

Bypass/Ethicon, the representational case description of the identical adapter of Inc. is in U. S. application publication number US2002/0082625A1 and 2003/0100910A1 and United States Patent (USP) 6,036,703,6,036,700,6,015,416 and 5,346,501.

Other identical connecting device is described in: for example United States Patent (USP) 6,036, and 702; 6,508,822; 6,599,303; 6,673,084,5,695,504; 6,569,173; 4,931,057; 5,868,763; 4,624,257; 4,917,090; 4,917,091; 5,697,943; 5,562,690; 5,454,825; 5,447,514; 5,437,684; 5,376,098; 6,652,542; 6,551,334; And 6,726,694 and U. S. application publication number 2003/0120293A1 and 2004/0030348A1 in.

Identical connecting device can comprise active proximal arteries and veins adapter and far-end coronary artery adapter.For example, the aorta adapter that coincide comprises device, and such as by St.Jude Medical, (it is made up of aorta cutter or card punch parts and graft delivery system Inc. for MapleGrove, MN) the SYMMETRY bypass aorta electrical connector of Zhi Zaoing.Aortic punches is the cylindrical cutter that has the reversed acanthoid syringe needle, and described syringe needle is beaten round hole for the center of cutter on aorta wall of rotation grappling and back-pressure are provided.The graft delivery system is for becoming radial expandable nickel [Ni] titanium [Ti] memorial alloy device, and its is with the fixing vein transplantation thing of the little hook that passes vein transplantation thing wall.By the interior and outer shroud that uses minor connector or flange graft and aorta are fixed.This and other identical adapter of St.Jude is described in United States Patent (USP) 6,309,416,6,302,905,6,152,937 and PCT publication number WO 00/27312 and WO 00/27311 in.

By Ethicon, Inc. (Johnson ﹠amp; Johnson, the identical automatically electrical connector of Somerville, the CORLINK that CardioVations branch NJ) produces has used the metal alloy fastener of nickel [Ni] titanium [Ti] memorial alloy to connect blood vessel and the aorta of transplanting.Central cylinder and two groups of several pins that send from every end that it is made by the oval bow of interconnection are formed.Graft is written into the deployment of CORLINK insertion instrument to be opened so that produce identical in a step.

Other example of connecting device of coincideing comprise those by Cardica (referring to United States Patent (USP) 6,719,769,6,419,681 and 6,537,287), Converge Medical (above-mentioned AdvancedBypass Technologies), Onux Medical are (for example, referring to PCT publication number WO01/34037) and Ventrica, Menlo Park, CA (VENTRICA Magnetic VascularPositioner) is (for example, referring to United States Patent (USP) 6,719,768,6,517,558 and 6,352,543) product of Zhi Zaoing.

As mentioned above, identical connecting device can comprise tubular-shaped structures, and this structure is determined can flow by its blood.The device of these types (this paper is also referred to as " shunting device ") can be used as the artificial passage that is used for fluid communication between the blood vessel or conduit works and can be used to make blood to turn to (i.e. shunting) another part or second blood vessel (for example tremulous pulse or vein) or many blood vessels (for example vein and tremulous pulse) to same blood vessel from a part (for example tremulous pulse) of blood vessel.In one aspect of the invention, described stapling apparatus is a shunting device.

Can be with the various identical shunting devices of manipulating that join with a side end to end.Shunting device can be put into patient's body, wherein need produce passage between two or more blood vessel structures or between two different pieces of same blood vessel structure.For example, shunting device can be used for producing makes blood center on blood vessel, and such as the mobile passage of tremulous pulse (for example coronary artery, carotid artery or be the tremulous pulse of lower limb blood supply), and these blood vessels have suffered damage or obstruction wholly or in part.Shunting device can be used for coronary bypass in case because of arterial occlusion from this tremulous pulse, such as in the aorta with blood shunt to the coronary artery downstream.

Construct the identical connecting device of some type so that connect the blood vessel of two adjacency.This device may further include the tubular sections of blood shunt to another blood vessel.If blood vessel is cut off or sustains damage, the adapter of these types is generally used for connected head-to-tail coincideing so.

Shunting device comprises that at least one has the tubular-shaped structures of first end and second end, and it has determined single chamber, can flow by this chamber blood; Or shunting device can comprise more than one tubular-shaped structures, and it has determined a plurality of chambeies, can flow by these chamber blood.Described tubular-shaped structures comprises the outer part of blood vessel and can randomly comprise the internal blood vessel branch.Blood vessel is outside to divide that to be retained in tunica adventitia tissue outside, and the internal blood vessel branch can be retained in lumen of vessels interior or inner membrance, middle level and/or the adventitial tissue.

The structure of tubular sections can adopt various forms.For example barrel portion generally can maybe can comprise the conduit of reticulated structure for (for example two is that pitch or trident) straight, curved or crooked (for example L-shape or helical form), taper, ramose, can flow by their blood.In general, device straight or that bend has single chamber, can flow by this chamber blood, and ramose conduit (for example being generally T-shape and gamma-form device) and conduit network columnar structure (following) has two or more chambeies, can flow by their blood.Tubular-shaped structures for example can have the hollow circular cylinder form and can comprise, also can not comprise supporting structure, such as netted or loose structure.According to the difference of operation, described device can be for biodegradable or non-biodegradable; Expandable or inflexible; Metal and/or polymer; And/or can comprise shape memory material (for example nickel [Ni] titanium [Ti] memorial alloy).In certain aspects, described device can comprise self-expanding stent structure.

Shunting device is generally made by biocompatible materials.The above-mentioned any materials that is used for other style connector can be used to make shunting device, such as synthetic or natural derived polymers or metal or metal alloy.For example, this device can be formed by synthetic material, such as fluoropolymer polymer, such as expandable poly-(tetrafluoroethene) (ePTFE) or PEP (FEP), polyurethane, polyamide (nylon), siloxanes, polypropylene, polysulfones or polyester; And/or natural deutero-material, such as collagen protein or polysaccharide.This device can comprise the combination of metal or metal alloy (for example nickel [Ni] titanium [Ti] memorial alloy, rustless steel, titanium, nickel, Ni-Ti, cobalt, platinum, ferrum, tungsten, tantalum, silver, gold, molybdenum, chromium and chromium) or metal and polymer.The device of other type comprises the combination of natural graft material (for example from body blood vessel, homology blood vessel or xenograft) or synthetic and natural graft material.In one aspect of the method, described shunting device can the back that coincide is dissolved to be absorbed or biodegradable material forms (for example polylactide, gather the copolymer of Acetic acid, hydroxy-, bimol. cyclic ester and lactide and Acetic acid, hydroxy-, bimol. cyclic ester) by being designed for finishing.In one aspect of the method, remollescent bone can be used to make flexible tube-shaped catheter (for example, referring to United States Patent (USP) 6,290,718).

Tubular-shaped structures comprise can for for connect near-end that the near-end blood vessel constructs with for being connected the far-end that distal vessels is constructed.As mentioned above, can be described as " near-end " or " far-end " that the difference with its position for angiemphraxis changes with coincideing." near-end " coincide and can form in the near-end blood vessel, and " far-end " coincide and can form in distal vessels, can or be different from the blood vessel of near-end blood vessel for identical blood vessel.Term " far-end " and " near-end " also can be used to describe blood flows into another blood vessel from a blood vessel by tubular-shaped structures direction.For example, blood can flow into distal vessels from near-end blood vessel (for example aorta), such as coronary artery, so that get around obstruction in the coronary artery.

Tubular-shaped structures can directly be connected with near-end or distal vessels.Perhaps, shunting device can comprise that the graft blood vessel maybe can be configured to accept the graft blood vessel, and it can be connected to finish identical with identical or different blood vessel.The representational example of graft blood vessel comprises: for example be used for blood vessel graft or graft (for example AV graft, AV diverter or AV graft) that hemodialysis is used.

In one aspect, tubular identical adapter comprises near-end that is connected with the near-end blood vessel and the far-end that is used to be connected bypass graft.Bypass graft can be fixing identical to finish with distal vessels.The direction of blood flow can begin and flow into the near-end of tubular-shaped structures from the near-end blood vessel.Blood can flow out and flow into the graft blood vessel by the far-end of tubular-shaped structures.

In one aspect of the method, tubular identical adapter comprise the near-end that is connected with the fixing graft blood vessel of near-end blood vessel with for being connected the far-end that distal vessels is constructed.The direction of blood flow can begin and flow into the near-end of tubular-shaped structures from the near-end blood vessel.Blood can flow out and flow into distal vessels by the far-end of tubular-shaped structures.

Identical shunting device can be in every way with the blood vessel grappling and can use or do not use be connected to form with blood vessel under the sutural situation identical.Shunting device can be connected with the blood vessel outside and/or can be with the part implantable intravascular of this device.For example, the part of the implanting device part that can be retained in (being intracavity) in the lumen of vessels and/or implanting device can be retained in the blood vessel (being in the inner membrance of blood vessel, in the wall and/or in the adventitial tissue).In one aspect, at least one or its part in the tubular-shaped structures can be inserted blood vessel end or inserted vessel side.Can use for example fastener, make device and blood vessel directly fixing such as stitching thread, nail or folder and/or binding agent.Shunting device can be included in not use and make conduit and the fixed interface of target vessel under the sutural situation.This interface can comprise such as hook, barb, pin, pincers or flange or this class of lip and is used to form that device is connected with anastomotic position.

Comprise that the representational example of the identical connecting device of at least one barrel portion includes, but are not limited to be used for the device of the identical operation of headtotail (for example coincide stent and identical overlapping) and is used for a device (for example single chamber and multi-cavity shunting device) of side-to-side anastomosis operation.

In one aspect of the invention, identical connecting device comprises single barrel portion, and it can be as making blood be diverted to the diverter (for example the operation of side-to-side anastomosis) of graft blood vessel from the source blood vessel.In one aspect, the barrel portion end can directly or indirectly be connected with target vessel as mentioned above.The opposite end of barrel portion can be connected with the graft blood vessel, and wherein the graft blood vessel can be fixing identical to finish with target vessel.

Barrel portion can maybe can have bending or curved shape (for example L-shape or helical form) and can meet at right angles with the blood vessel that it is connected or angled direction for straight.In one aspect, conduit can be by fastener for example, such as nail, pincers or hook or by binding agent, radio frequency sealing or by well known to a person skilled in the art that other method makes conduit be fixed into described position.

In one aspect, described identical connecting device can for: for example have the graft of the tubular metal braiding of suture ring on far-end, it provides the articles for use that are used for the target vessel fix in position.For example, referring to United States Patent (USP) 6,235,054.Comprise with the conduit of fixed other type in described position: for example United States Patent (USP) 4,368, and 736 and 4,366,819.

In the connecting device of single chamber of some type, stop in the flange of conduit in being retained in lumen of vessels.For example, conduit can have the tubular bodies that has adapter, and described adapter can have multiple stretching, extension and be configured to be arranged in tubular internal blood vessel circlewise.For example, referring to United States Patent (USP) 6,660,015.In other device, flange can be connected into the tunica adventitia tissue or be connected with its surface.

Single chamber shunting device of other type for example is described in United States Patent (USP) 6,241,743; 6,428,550; 6,241,743; 6,428,550; 5,904,697; 5,290,298; 6,007,576; 6,361,559; 6,648,901,4,931,057 and U. S. application publication number 2004/0015180A1,2003/0065344A1 and 2002/0116018A1 in.

In one aspect of the invention, described identical connecting device comprises more than one chamber, can obtain carrying by their blood.The multi-cavity shunting device can comprise two or more barrel portions of constructing for many (two or many) blood vessels of interconnection.The multi-cavity connecting device can be used for various identical operations.For example, this class device can be used for coronary bypass grafting (CABG) operation so that make the blood of self-closing near-end blood vessel (for example tremulous pulse) to turn to inflow one or more target (being far-end) blood vessel (for example tremulous pulse or vein).

In one aspect, at least one barrel portion can be used as the diverter that the blood between source blood vessel and the target vessel is turned to.In one aspect of the method, can be with this device construction for making the fixed interface of graft blood vessel and target vessel identical to finish.According to the difference of operation, tubular wall can have equal lengths and diameter or have length and the diameter that does not wait, and can comprise expandable barrel portion and/or comprise shape memory material (for example nickel [Ni] titanium [Ti] memorial alloy).In addition, barrel portion can be made by same material or different materials.

In one aspect, one or more ends of barrel portion can be inserted the end or the side of one or more blood vessel.In other embodiments, one or more barrel portions of device can be retained in blood vessel or the graft lumen of vessels.Can use fastener or binding agent or well known to a person skilled in the art that another kind of means randomly fix this device with blood vessel.

At least one wall of multi-lumen connector can be connected with the graft blood vessel.The graft blood vessel can be synthetic graft, such as the combination of ePTFE or polyester graft or natural graft material (for example from body blood vessel, homology blood vessel or xenograft) or synthetic and natural graft material.In certain embodiments, the graft blood vessel can be connected with the end of barrel portion of device and second kind of graft blood vessel can be connected with the opposite end of same barrel portion or the end of another barrel portion.The graft blood vessel can further be connected to finish identical with target vessel.

In one aspect, described device can comprise three or more from the junction extended tubular wall.For example, the multi-cavity device generally can be T-shape or gamma-form (promptly having two or three chambeies respectively).For example, the multi-cavity device can be the tubular graft adapter of T-shape, and it has the stave that extends into target vessel and is positioned at second part that the blood vessel outside that is connected with alternative tubular-shaped structures is provided.For example, referring to United States Patent (USP) 6,152,945 and 5,972,017.Other multi-cavity unit describe of Other is in the literature (for example, referring to United States Patent (USP) 6,152,945; 6,451,033; 5,755,778; 5,922,022; 6,293,965; 6,517,558 and 6,626,914 and US publication 2004/0015180A1).

In one aspect of the method, described device can directly branch to pipe coronarius with blood flow from cardiac component (for example left ventricle) for being used for.For example, this device can be hollow pipe, and it can be used as the reaction of relaxing period process cardiac organization activity partially enclosed by unidirectional valve, allows blood mobile (for example, referring to United States Patent (USP) 6,641,610) in the systole process simultaneously.This device can divide fluid for the rigidity of elongation, it is made up of the steering tube that has two holes, one of them pipe can be deployed in the left ventricle cyocardium, and another can be deployed in the coronary artery (for example, referring to WO 00/15146 and U. S. application publication number 2003/0055371A1).This device can be for being equipped with the tubular utensil of valve, and it is L-or T-shape, is suitable for inserting heart wall so that provide the blood flow from the heart to the coronary vasodilator to exchange (for example, referring to United States Patent (USP) 6,123,682).

In one aspect of the method, described device can comprise the reticulated structure of the tube-shaped catheter that interconnects.For example, this device can comprise generally can be each other with axially or two the directed barrel portions that meet at right angles.Referring to United States Patent (USP) 6,241,761 and 6,241,764.Exchange between two tubular-shaped structures can be undertaken by helping blood mobile flow channel between each pore.

In one aspect of the method, described identical connecting device is resorbent device, it is textural can to have two or three ends, and these ends provide blood vessel interface and the chamber by intersecting under the situation that does not need to sew up, provide fluid communication such as bypass graft or alternative blood vessel.For example, referring to U. S. application publication number 2002/0052572A1 and PCT publication number WO02/24114A2.Coincide connecting it can also be by forming by resorbent tubular-shaped structures, and the structure of described tubular-shaped structures comprises the button junctional complex or is used to make it with fixation of tissue and other element of hemostatic and induces and stop blooding in case the sealing ring of the liquid seepage of stopping blooding.For example, referring to United States Patent (USP) 6,056,762.The adapter that coincide can be designed to have three branches, wherein two branches are suitable for inserting successive blood vessel and enlarging then and form and connect airtight with contraction state, and the 3rd branch is suitable for connecting and sealing the 3rd conduit.For example, referring to United States Patent (USP) 6,019,788.

The example of the identical connecting device of the multi-cavity that is purchased is SOLEM graft adapter (by Jomed, Sweden makes).This device more specifically is described among PCT publication number WO 01/13820 and United States Patent (USP) 6,179,848, D438618 and the D429334, and it comprises the T-shape adapter of being made up of nickel [Ni] titanium [Ti] memorial alloy and is used for the ePTFE graft that far-end coincide.

Another example of adapter of coincideing be used for by-pass operation from CABG Medical, (it for example is described in United States Patent (USP) 6,241 to Inc. for Minneapolis, HOLLY implant system (being in the research and development) MN), in 761 and 6,241,764.

The identical connecting device of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue is provided among the present invention in one aspect.In one aspect, this identical connecting device can be connected with blood vessel and form identical under the situation of not using stitching thread or nail.In certain aspects, this identical connecting device can comprise: determine the tubular-shaped structures in chamber, can flow by this chamber blood; And anti-scarring agent.This device can comprise that this depends on the quantity of the blood vessel that is connected by one, two,, two definite, three or more chamber of three or more tubular-shaped structures.

With endovascular device import in the blood vessel wall, chamber or outer membrane portions or can stimulate or damage the blood vessel endothelium tissue on it and/or can change natural hemodynamics by blood vessel and flow and/or can introduce or quicken in the endovascular device and on every side infection.This stimulation or infringement can stimulate the situation of the biological cascade that causes the fibre modification reaction, thereby can cause cicatrization in the blood vessel, and/or cause the sensitivity that infects is increased.Be impregnated into the polymer composition of theme of the present invention (separately or contain anti-scarring agent and/or anti-infective) with the device that directly contacts blood vessel or install partly (for example installing end portion or edge) adjacent tissue and can suppress above-mentioned one or more cicatrization processes (for example smooth muscle cell proliferation, cell migration, inflammation) according to the present invention, thereby make blood vessel be not easy to form neointimal hyperplasia and narrow, and/or the adapter neutralization infection on every side that can suppress or prevent to coincide.

Therefore, in one aspect in, the polymer composition of theme of the present invention can be only be connected with the part of the endovascular device of contact blood or endothelial tissue.For example, anti-scarring agent can be introduced all or part of adjacent tissue that divides with the internal blood vessel of device.In one aspect of the method, all or part of adjacent tissue of the outer part of the blood vessel that the polymer composition of theme of the present invention can be impregnated into and install.

The adjacent tissue of part or whole surface that in one aspect of the method, the polymer composition of theme of the present invention can be impregnated into and install.In one aspect of the method, the polymer composition of theme of the present invention (for example being impregnated into adjacent tissue) engages (fastener for example is such as nail or folder) with making the fixed anchoring element of device and blood vessel.

As mentioned above, identical electrical connector can comprise and contains fibre modification inhibitor or the anti-infective polymer composition as the means of improving the device clinical efficacy.In another kind of means, fibre modification inhibitor or anti-infective can be mixed on thin film or mesh or its (further being described in more detail below), then it is applied to anastomotic position (for example on the connecting portion of graft blood vessel and blood vessel) in mode around the blood vessel.These thin film or coated thing can with the above-mentioned electrical connector coupling that coincide arbitrarily, and the exterior circumferential of coincideing when generally they being placed operation.In other embodiments, can described bioactive agent delivery be delivered to anastomotic position with the form of spray, paste, gel etc.In another kind of means, described activating agent can be impregnated into and the adjacent tissue of graft blood vessel that is fixed to blood vessel with electrical connector.

In one aspect of the method, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with other special-purpose endovascular device, described special-purpose endovascular device such as coronary artery medicinal infusion lead, such as those available from TherOx, the product of Inc.; Stent upper gasbag device and graft, such as being described in Wilensky, R.L (1993) " the sick institute's magazine of learning of american heart " (J.Am.Coll.Cardiol.): among the 21:185A.

As mentioned above, the invention provides the polymer composition that can be impregnated into the tissue adjacent with endovascular device (for example coincide adapter, stent, pass medicine air bag, catheter in blood vessel), wherein this polymer composition can comprise therapeutic agent (for example anti-scarring agent or anti-infective).The polymer composition that is used for endovascular device in a large number that can be impregnated into and install adjacent tissue (preferably near device-organizational interface) has above been described.

Can thereon said composition be soaked in implantable intravascular around the device by polymer composition directly and/or indirectly being coated with following position or coating: (a) tissue adjacent with endovascular device; (b) near endovascular device-organizational interface; (c) zone around the endovascular device; (d) tissue around the endovascular device.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with endovascular device comprises described polymer composition is delivered to: (a) on the endovascular device surface of implant procedure process (for example as injectable, paste, gel or mesh); (b) in implantable intravascular before the device at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) in the implantable intravascular behind the device at once the endovascular device surface and/or implantable intravascular in tissue (for example forming gel or net) around the device as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed endovascular device (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted endovascular device for this embodiment is useful especially; (e) by inject endovascular device tissue on every side as solution, transfusion or slow releasing preparation percutaneous; And/or (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with endovascular device can contain the fibre modification inhibitor, in four kinds of ordinary circumstances of its inhibition fibre modification (or cicatrization) process one or more comprise: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D.); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because endovascular device is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

The gastrointestinal stent

In one aspect, the polymer composition of theme of the present invention can be impregnated into and the adjacent tissue of gastrointestinal (GI) stent.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).Term " GI stent " refers to and is positioned at gastrointestinal tract, comprises the device in bile duct, ductus pancreaticus, colon and the esophagus.The GI stent for or comprise the scaffold that is used for the treatment of intracavity body passage, described passage is because of disease or infringement, comprises malignant tumor or benign disease and blocked.

In one aspect, described GI stent can be the esophagus stent that is used to keep esophagus open, and food can be transported to stomach from the oral cavity thus.For example, the esophagus stent can carry the net internal layer by the cylinder support, keep net semipermeable membrane outer and that be clipped between the two to form.For example, referring to United States Patent (USP) 6,146,416.The esophagus stent can be for having the radial self-expanding stent of open knitting structure, and it has the elastic film that forms along stent to prevent tissue ingrowth and to have the far-end cover that stops the stent migration.For example, referring to United States Patent (USP) 5,876,448.The esophagus stent can have the cylindrical tube that increases to larger-diameter deformed end part because of grappling pressure so that form by pliable and tough line contexture.For example, referring to United States Patent (USP) 5,876,445.The esophagus stent can be the tubular wall of flexible self-expanding, has wherein introduced the conical sections of at least one truncate along the longitudinal axis.For example, referring to United States Patent (USP) 6,533,810.

In one aspect of the method, described GI stent can be the gallbladder stent that is used to keep bile duct open, and bile can drain be gone into small intestinal thus.For example, the gallbladder stent can be made up of marmem.For example, referring to United States Patent (USP) 5,466,242.The gallbladder stent can be for having a plurality of radial stretching, extension wing of the groove that throws from the helical form core.For example, referring to United States Patent (USP) 5,776,160 and 5,486,191.

In one aspect of the method, described GI stent can be the colon stent.For example, the colon stent can be the tubular bodies of hollow, and it can become radial expansion and fix with the organ inwall that discharges in the adnexa.For example, referring to European patent application publication No. EP1092400A2.

In one aspect of the method, described GI stent can keep the ductus pancreaticus opening to help being secreted into the pancreas stent of small intestinal for being used to.For example, the pancreas stent can be made up of soft biocompatible materials, and this material is the elastic force compliance, and is consistent with the curvature of ductus pancreaticus and contain the perforation that helps drain.For example, referring to United States Patent (USP) 6,132,471.

Can have benefited from the GI stent that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised being purchased product, such as from prosthese in the NIR Biliary stent system of Boston ScientificCorporation and the WALLSTENT.

The GI stent of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue is provided among the present invention in one aspect, and wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with the GI stent have above been described.

Can soak into thereon and with said composition and implanting around the GI stent by polymer composition directly and/or indirectly being coated with following position or coating: (a) tissue adjacent with the GI stent; (b) near GI stent-organizational interface; (c) zone around the GI stent; (d) tissue around the GI stent.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with the GI stent comprises described polymer composition is delivered to: (a) at the GI of implant procedure process stent surface (for example as injectable, paste, gel or mesh); (b) before implanting the GI stent at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the GI stent GI stent surface at once and/or implant tissue (for example forming gel or net) around the GI stent as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed the GI stent (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject GI stent tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with the GI stent is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because the GI stent is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

The trachea and bronchus stent

The invention provides the method that is used for the polymer composition of theme of the present invention is impregnated into trachea or bronchus stent device.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

Can have benefited from that polymer composition with theme of the present invention is impregnated into the trachea of adjacent tissue according to the present invention or the representational example of bronchus stent comprises trachea stent or bronchus stent, comprise metal and polymeric trachea or bronchus stent and have the trachea or the bronchus stent of outer cover (for example polyurethane, poly-(PETP), PTFE or silicone rubber).

The trachea and bronchus stent can for example be made up of the elastoplast axle that has metal clasp, and it expand into the chamber that is used for the open ill part of trachea and has three parts of simulation trachea natural shape along axle.For example, referring to United States Patent (USP) 5,480,431.Trachea/bronchus stent can be T-shape pipe, and this pipe has the tracheostomy cannula part, and these parts are throwed to the outside by the tracheotomy hole that is configured to seal and form fluid-tight.For example, referring to United States Patent (USP) 5,184,610 and 3,721,233.Trachea/bronchus stent can be made up of flexible synthetic polymerized resin, wherein tracheostomy cannula is fixed on the wall of the bronchus end that has two forks, and its being configured on cross section has the T-Y shape of specific curvature so that histologic lesion is reduced to bottom line.For example, referring to United States Patent (USP) 4,795,465. Trachea/bronchus stent can by Be configured to be essentially columniform scaffold, it hasThe shape memory characteristic framework , this framework tool Geometric figure is arranged and have and preventThe coating of epitheliogenic adequate thickness For example, referring to the U.S. Patent application publication number 2003/0024534A1.

Can have benefited from trachea/bronchus stent that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised and be purchased product, such as from prosthese in the WALLSTENT tracheal bronchus of Boston ScientificCorporation with from BryanCorporation (Woburn, UTRAFLEX tracheal bronchus stent system MA) and DUMON tracheal bronchus siloxanes stent.

In one aspect, the invention provides the trachea and bronchus stent of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used for the trachea and bronchus stent have above been described.

Can soak into thereon and with said composition and implanting around trachea / bronchus stent by polymer composition directly and / or indirectly being coated with following position or coating: (a) with tissue that trachea / the bronchus stent is adjacent, (b) near trachea / bronchus stent-organizational interface, (c) zone around trachea / bronchus stent, (d) tissue around trachea / bronchus stent.Being used for polymer composition with theme of the present invention is impregnated into method with trachea / tissue that the bronchus stent is adjacent and comprises described polymer composition is delivered to: (a) on the trachea / bronchus stent surface of implant procedure process (for example as injectable, paste, gel or mesh), (b) before implanting trachea / bronchus stent at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position, (c) implant behind trachea / bronchus stent trachea / bronchus stent surface at once and / or implant tissue (for example forming gel or net) around trachea / bronchus stent as injectable, paste, gel, original position, (d) by described compositions part being coated with into the anatomic space of having placed trachea / bronchus stent (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially, (e) by inject trachea / bronchus stent tissue on every side as solution, transfusion or slow releasing preparation percutaneous, (ii is by the combination in any of said method. Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and / or anti-platelet agents). With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install....

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with the trachea and bronchus stent is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because the trachea and bronchus stent is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, can and be used to implement the present invention with above-mentioned any anti-infective.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/m ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

Reproduction-urinary system stent

In one aspect, the polymer composition of theme of the present invention can be impregnated into and the adjacent tissue of Genito-urinary (GU) stent device.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

Can have benefited from the representational example that the polymer composition of theme of the present invention is impregnated into Genito-urinary (GU) stent of adjacent tissue according to the present invention is comprised ureter and urethra stent, fallopian tube stent, prostate stent, comprise metal and polymeric GU stent and have the GU stent of outer cover (for example polyurethane, poly-(PETP), PTFE or silicone rubber).

In one aspect, the Genito-urinary stent comprises ureter and urethra stent.The ureter stent is the hollow pipe that has along the hole of side on each end and screwed pipe arrangement.The ureter stent is used for alleviate blocking (because of calculus or malignant tumor cause), promote calculus by or operation or post-traumatic ureter are coincide or the seepage healing.These stents are placed by kidney by bladder placement or percutaneous under splanchnoscopy.

The urethra stent is used for the treatment of recurrent urethral stricture, detrusor-external sphincter dyssynergia and the bladder outlet that causes because of benign prostatauxe blocks.In addition, the operation to prostate carries out may cause fibre modification and/or infection such as external exposure or brachytherapy because of the tissue injury that these operations cause.The incidence rate of urethral stricture is about 2% in the radiocurable patients with prostate cancer with external beam.The generation of urethral stricture can also appear in other situation, and such as after urethral catheterization or operation, these operation techniques can cause urothelial to sustain damage.The clinical manifestation of urinary tract obstruction comprises urine line strength and bore reduces, sialorrhea after the intermittence, drainage, urinate and hesitate and nocturia.The complete closure of urethra can cause a large amount of problems, comprises final renal failure.In order to keep urethral opening, can use the urethra stent.That these stents are generally self-expanding and form by metal superalloy, titanium, rustless steel or polyurethane.

For example, ureter/urethra stent can be made up of the main catheter body of flexible polymeric material, and it has the expansion upstream end that has the hydrophilic joint, and described joint dissolves when contact body fluid.For example, referring to United States Patent (USP) 5,401,257.Ureter/urethra stent can be made up of many parts, is included in the closing section on the bladder end that does not contain any fluid passage, makes it can be used as anti-reflux device and works to prevent that urinating adverse current is back into kidney.For example, referring to United States Patent (USP) 5,647,843.Ureter/urethra stent can be made up of such centre pipe, and it is used for making with the shape memory material of the stent of the reservation screwed pipe of ureter grappling by forming to have.For example, referring to United States Patent (USP) 5,681,274.Ureter/urethra stent can be made up of the pliable and tough tubular stent of elongation, the tubular rigidity extension of this stent has formation on two ends bending group and the elongation that is connected with the far-end that allows as the combination function of outside ureteral catheter.For example, referring to United States Patent (USP) 5,221,253 and 5,116,309.Ureter/urethra stent can keep structure by the element, near-end of elongation and elastic part connected to one another is formed, thus they all can with the slidably replacement fluids each other partly that the pucker ﹠ bloat position is provided.For example, referring to United States Patent (USP) 6,685,744.Ureter/urethra stent can be for having the hollow cylindrical tube of the location utensil that pliable and tough connection device and expansion and selectivity shrink.For example, referring to United States Patent (USP) 5,322,501.Ureter/urethra stent can be made up of hard polymer, it good cylinder and shaft type intensity can be provided so as to be advanced into urethra and comparatively softish bladder screwed pipe part so that reduce the risk that is upset.For example, referring to United States Patent (USP) 5,141,502.Ureter/urethra stent can be made up of the tubular sections of elongation, and this sections has a plurality of elements that the flexible walls fluid conduction when preventing to be subjected to oppressing on proximal end region is blocked.For example, referring to United States Patent (USP) 6,676,623.Ureter/urethra stent can be the conduit of being made up of pipeline, and described pipeline is centered around ingredient that conduit on every side potted component contamination-freely insert the assembly of urinary catheter by providing for requiring in disassembling process. For example, referring to U.S. Patent Application Publication No. 2003/0060807A1.

In one aspect of the method, the Genito-urinary stent comprises the prostate stent.For example, the prostate stent can be made up of two polymer rings that pipe arrangement constitutes, and wherein a plurality of connecting wall elements are connected with described ring with parallel mode.For example, referring to United States Patent (USP) 5,269,802.The prostate stent can be made up of thermoplastic and periphery reinforcement coil spring, and this stent can provide rigid mechanical to support, and the natural anatomic that can regulate prostate-urethra simultaneously neatly is crooked.For example, referring to United States Patent (USP) 5,069,169.

In one aspect of the method, the Genito-urinary stent comprises that method Lou Pi Ousitengte fixes Mould and other female genitourinary device.For example, the Genito-urinary device can be for per vaginam inserting Have a female incontinence device that elasticity and flexible support section are formed, it can be by right Vaginal wall produces expansion and near urethral orifice is enlarged and self-supporting.For example, referring to United States Patent (USP) 3,661,155.This Genito-urinary device can be the urethra emptier of being made up of ossphere concave surface wall, Described wall has to be integrated the opening of the body that is connected and has pleat periphery (premetal edge) and wall The connection tubular element of shape body.For example, referring to United States Patent (USP) 6,041,448.

Can have benefited from the Genito-urinary stent that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised and be purchased product, such as from American MedicalSystems, Inc. (Minnetonka, MN) prosthese stent in the UROLUME, from IniecTx, Inc. (San Jose, CA) RELIEVE prostate/urethra endoscope apparatus, from the PERCUFLEX ureter stent of Boston Scientific Corporation with from Cook Group Inc (Bloomington, TARKINGTON urethra stent IN) and FIRLIT-KLUGE urethra stent.

The GU stent of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue is provided among the present invention in one aspect, and wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with the GU stent have above been described.

Can soak into thereon and with said composition and implanting around the GU stent by polymer composition directly and/or indirectly being coated with following position or coating: (a) tissue adjacent with the GU stent; (b) near GU stent-organizational interface; (c) zone around the GU stent; (d) tissue around the GU stent.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with the GU stent comprises described polymer composition is delivered to: (a) at the GU of implant procedure process stent surface (for example as injectable, paste, gel or mesh); (b) before implanting the GU stent at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the GU stent GU stent surface at once and/or implant tissue (for example forming gel or net) around the GU stent as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed the GU stent (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject GU stent tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with the GU stent is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38 map kinase inhibitor (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because the GU stent is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from-as be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000 mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this-result should be apparent.

Ear and nose stent

In one aspect, the polymer composition of theme of the present invention can be impregnated into and the adjacent tissue of ear-nose-larynx (ENT) stent device (for example tear stains stent, pharyngotympanic tube stent, nose stent or nasal sinuses (hole) stent).The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

Nasal sinuses is four pairs of interior hollow area of naming with their location (sieve skeleton, jawbone, frontal bone and sphenoid bone) of bone that are included in skull.The respiratory mucosa that they all are connected directly bone sets off.At inflammation damnification, after respiratory tract infection or allergic rhinitis generation, the sinusitis of suppuration form takes place.Interim secretions can be retained in the nasal sinuses, and this is due to opening (bone) because of fine hair changing function or drain nasal sinuses blocks.Incomplete drain makes nasal sinuses generally be easy to infect hemophilus influenza, streptococcus pneumoniae, Moraxella catarrhalis, Veillonella, dyspepsiacoccus, corynebacterium acnes and some fungal species.

When initial treatment, when invalid, drain must undergo surgery to the nasal sinuses that infects such as antibiotic, intranasal steroidal spray and Decongestant.Operative therapy generally includes debridement of bone with the obstruction of removing dissection and remove the part mucosa.Sometimes stent (integral body remains on the cylindrical tube in the open chamber of bone) is retained in the bone to guarantee even also can keep drain having in the presence of the postoperative swelling.The general ENT stent of being made by rustless steel or plastics is maintained fixed several days or a few week before being removed.

The representational example of ENT stent that has benefited from having the polymer composition of the theme of the present invention that is impregnated into adjacent tissue comprises tear stains stent, pharyngotympanic tube stent, nose stent and nasal sinuses stent.

The tear stains stent is provided among the present invention in one aspect, and it has the polymer composition that is impregnated into adjacent tissue that contains therapeutic agent (for example anti-scarring agent and/or anti-infective).The present invention provides the pharyngotympanic tube stent in one aspect of the method, and it has the polymer composition that is impregnated into adjacent tissue that contains therapeutic agent (for example anti-scarring agent and/or anti-infective).

The present invention provides the nasal sinuses stent in one aspect of the method, and it has the polymer composition that is impregnated into adjacent tissue that contains therapeutic agent (for example anti-scarring agent and/or anti-infective).

The present invention provides the nose stent in one aspect of the method, and it has the polymer composition that is impregnated into adjacent tissue that contains therapeutic agent (for example anti-scarring agent and/or anti-infective).

The ENT stent can be the choanal atresia stent, and this stent is made up of two long hollow pipes by the bridging of pliability transverse pipe.For example, referring to United States Patent (USP) 6,606,995.The ENT stent can be for being used for the inflatable nose stent of being made up of can be outwards expansible highly porous, softness and absorbable foamed materials of postoperative nose filling (packing), and it has NA surface.For example, referring to United States Patent (USP) 5,336,163.The ENT stent can be the nose stent of being made up of deformable cylinder, and wherein respiration channel has the smooth exterior nonabsorbable surface that is used to clog the postoperative nasal cavity.For example, referring to United States Patent (USP) 5,601,594.The ENT stent can be the breather of being made up of the tubular passage of flexible plastic, has the pliable and tough flange of rectangle that is used for endoscope's antrostomy posterior nasal sinuses on the described passage.For example, referring to United States Patent (USP) 5,246,455.Can the serve as reasons bar that is used for pressure between balanced middle ear and the external ear and prolong the ventilation syrinx that joint is formed of ENT stent.For example, referring to United States Patent (USP) 6,042,574.The ENT stent can be the MEV pipe of being made up of incoercible tubular matrix and eccentric band flange.For example, referring to United States Patent (USP) 5,047,053.

Can have benefited from the ENT stent that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised and be purchased product, such as GenzymeCorporation (Ridgefield, NJ) SEPRAGEL nasal sinuses stent and from Medtronic Xomed Surgical Products, Inc. (Jacksonville, MEROGEL nose dressing FL) and nasal sinuses stent.

The ENT stent of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue is provided among the present invention in one aspect, and wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with the ENT stent have above been described.

Can soak into thereon and with said composition and implanting around the ENT stent by polymer composition directly and/or indirectly being coated with following position or coating: (a) tissue adjacent with the ENT stent; (b) near ENT stent-organizational interface; (c) zone around the ENT stent; (d) tissue around the ENT stent.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with the ENT stent comprises described polymer composition is delivered to: (a) at the ENT of implant procedure process stent surface (for example as injectable, paste, gel or mesh); (b) before implanting the ENT stent at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the GU stent ENT stent surface at once and/or implant tissue (for example forming gel or net) around the ENT stent as injectable, paste, gel, original position; (d) by described compositions part being coated with the anatomic space of having placed the ENT stent (useful especially being to use of this embodiment discharged polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of described therapeutic agent and can pass other preparation into the described activating agent of release in the zone of having inserted described device in the time limit in several hours more than one weeks); (e) by inject ENT stent tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with the ENT stent is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because the ENT stent is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm2-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

The ear breather

In one aspect of the method, the polymer composition of theme of the present invention can be impregnated into the tissue (be also referred to as TT) adjacent with the ear breather.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).Acute otitis media is modal bacterial infection, i.e. the highest indication of the frequency of occurrences in the operative therapy, and it is the main cause of anakusis among the child and is the impaired common cause of development of speech.The cost for the treatment of this disease among the child below 5 years old according to estimates only just is 5,000,000,000 dollars in the U.S. every year.In fact, 85% among all children exist at least otitis media outbreak and annual 600,000 people to need operative therapy.The prevalence of otitis media increases, and with regard to serious case, operative therapy is more more economical than conservative control on cost effectiveness (CE).

Acute otitis media (bacterial infections of middle ear) is characterised in that ETD, causes the middle ear purge mechanism to lose efficacy.Otitis media is modal former because streptococcus pneumoniae (30%), hemophilus influenza (20%), branhamella catarrhalis (12%), streptococcus pyogenes (3%) and staphylococcus aureus (1.5%).End product is antibacterial, leukocyte and fluid accumulation, is not passing through in the presence of the ability of pharyngotympanic tube drain, and this result causes the pressure in the middle ear to increase.With regard to many cases, antibiotherapy is that abundant therapy and this disease are resolved.Yet with regard to a large amount of patients, this disease can recur maybe usually and can't be solved fully.In recurrent otitis media or Chronic otitis media with effusion, there are the lasting fluid and the bacterial buildup that produce by diaphragm-operated barometric gradient, cause pain and hearing impairment.Tympanum is implemented windowing (general by the placement TT) can be discharged described barometric gradient and help middle ear drain (by external ear but not a kind of form of pharyngotympanic tube-" pharyngotympanic tube bypass ").

Can use such as above-mentioned TT or eustachian tube implant/stent treatment recurrent otitis media or Chronic otitis media with effusion.Chronic otitis media with effusion, recurrent acute otitis media, tympanum that these breathers are suitable among the child are not opened and the acute otitis media complication.The function reduction that can cause these devices in the excessive formation of these device perivascular granulation tissues.This situation may cause removing the operation technique second time that blocks or insert new equipment subsequently.The fibre modification inhibitor introduced breather or introduce to prevent this granulation tissue overgrowth on it.

Although can't cure, it is the Therapeutic Method of widely used chronic otitis media that TT is placed in operation, because it has improved audition (having improved development of speech successively) and has reduced the sickness rate of acute otitis media.It is modal operation technique that TT is placed on the U.S., will carry out 1,300,000 operations every year and place.

Can have benefited from the polymer composition of theme of the present invention is included, but are not limited to grommet-shape pipe, T-shape pipe, TT, drainage tube, tympanum pipe, otology pipe, myringotomy pipe, eustachian tube implant, pharyngotympanic tube prosthese and pharyngotympanic tube stent according to the representational example that the present invention is impregnated into the ear breather of adjacent tissue.The ear breather is that material is made with politef (for example TEFLON), siloxanes, nylon, polyethylene and other polymer, rustless steel, titanium and gold-plated steel for example.

In one aspect, the ear breather can be for being used for providing for the tympanum ventilation by external auditory meatus the TT of alternative conduit.In general, carry out MEV, wherein on tympanum, do longitudinal incision or opening so that alleviate accumulating and pressure descends and drain is accumulated fluid in the tympanum by operation by implementing myringotomy.TT can be inserted diaphragm-operated operation longitudinal incision so that as normal salpingian bypass, it is the drain tympanum under normal operation.For example, TT can be the even tubular element of being made up of pure titanium or titanium alloy, have and form an end inside concave surface at interval of flange of elongation.For example, referring to United States Patent (USP) 5,645,584.TT can be by the outside flangeless surface composition of the titanium of the nick that is used to make MEV.For example, referring to United States Patent (USP) 4,971,076.TT can be made up of the bar that has joint, and wherein said joint outwards stretches from the bottom vertical of bar.For example, referring to United States Patent (USP) 6,042,574.The TT persistency ear breather that the tubular matrix of elongation is formed of can serving as reasons, described matrix have the flange of being made by incoercible material that connects with eccentric manner.For example, referring to United States Patent (USP) 5,047,053.TT can be made up of medicated cap-Sai, centrosome and end cap, and they form a plurality of chambeies in the pipe each other.For example, referring to United States Patent (USP) 5,851,199.TT can be made up of with the micro-porous resin that forms breathable body sclerosis, contains in the described matrix to migrate to manage the homogeneous dispersion of sidewall surfaces with silver particles that antibacterial activity is provided.For example, referring to United States Patent (USP) 6,361,526.TT can be by tubular bodies and is outwards throwed with definite spiral and form around the rib-like structure of the passage of tubular bodies.For example, referring to United States Patent (USP) 5,775,336.TT can be made up of the integral cutting minor connector that stretches from one of two flanges being used to cut diaphragm-operated lock ring.For example, referring to United States Patent (USP) 5,827,295 and 5,643,280.TT can be made up of the tubular element with two opposing flanges, wherein by the insertion of inducing the cut edge assistance pipe on the diaphragm-operated flange of cutting.For example, referring to United States Patent (USP) 5,489,286,5,466,239,5,254,120 and 5,207,685.Other TT for example is described in the United States Patent (USP) 6,406,453,5,178,623,4,808,171 and 4,744,792.

In one aspect of the method, the ear breather can be used to set up salpingian normal function and attempt solving the narrow problem that prevents its normal function thus.Fluid in the tympanum is generally secreted and recovered salpingian normal function thus from tympanum can provide best ventilation and drain.For example, the breather pharyngotympanic tube stent that hollow tube body with compressible core is formed of can serving as reasons, described core has the flange of the parallel arms and the radial direction of two connections, and this stent is positioned at pharyngotympanic tube to keep opening.For example, referring to United States Patent (USP) 6,589,286.Breather can be the pharyngotympanic tube prosthese of being made up of pliable and tough pipe, described pliable and tough pipe racks radial stretching, extension is arranged in case in the pharyngotympanic tube passage localized flange.For example, referring to United States Patent (USP) 4,015,607.

Can have benefited from the TT that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised and be purchased product.For example, Medtronic Xomed, Inc. (Jackonsville, FL) various ear breathers have been sold, comprise long-term breather and ventilation of tympanic cavity tubular type breather, comprise ARMSTRONG grommet, GOODE T-shape grommet, VENTURI formula breather, SHEEHY type Collar Buttons, REUTERBobbins, COHEN T-shape grommet and SOILEAU TYTAN titanium pipe.Micromedics, Inc. (Eagan, MN) also sell various ear breathers, comprised BAXTERBevel Buttons, TINY TOUMA, SPOONER, TOUMA T-shape pipe, SHOEHORN Bobbins, SHAH and SILVERSTEIN MICROWICK pharyngotympanic tube.(Bartlett TN) has also sold various ear breathers to GyrusENTLLC, comprises ULTRASIL pharyngotympanic tube, RICHARDS COLLAR Bobbins, BALDWIN BUTTERFLY pharyngotympanic tube and PAPARELLA 2000 type pipes.

The ENT stent of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue is provided among the present invention in one aspect, and wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with the ear breather have above been described.

Can soak into thereon and with said composition and implanting around the ear breather by polymer composition directly and/or indirectly being coated with following position or coating: (a) tissue adjacent with the ear breather; (b) near ear submarine snorkel-organizational interface; (c) zone around the ear submarine snorkel; (d) tissue around the ear submarine snorkel.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with the ear submarine snorkel comprises described polymer composition is delivered to: (a) on the ear submarine snorkel surface of implant procedure process (for example as injectable, paste, gel or mesh); (b) before implanting the ear submarine snorkel at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the ear submarine snorkel ear submarine snorkel surface at once and/or implant tissue (for example forming gel or net) around the ear submarine snorkel as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed the ear submarine snorkel (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject ear submarine snorkel tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install.

According to-individual aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with the ear breather is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because the ear breather is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

Intraocular implant

In one aspect of the method, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with intraocular implant.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

In one embodiment, intraocular implant is for being used to prevent the muddy intraocular lens device of crystalline lens (crystalline lens for example).Can include, but are not limited to cataract, myopia, hypermetropia, astigmatism and other oculopathy with the visual impairment of intraocular lens's treatment.The intraocular lens is most commonly used to replace the natural lens of extracing in cataract procedure.Cataract is because of due to the normal crystalline lens transparency of ophthalmic changes.When crystalline lens becomes (for example flavescence and/or muddiness) when opaque by calcification, light can not suitably enter eye and example impaired.

It is the standard technique of recovering the useful vision in the ill or impaired eye that the intraocular lens is implanted eye.In nearly ten years, be Exponential growth in the lenticular quantity of U.S.'s implantable artificial.At present, the annual implantation surpasses 100 ten thousand intraocular lens, and wherein most of (90%) is placed in camera oculi posterior.Intraocular lens's purpose is to replace natural lens (being aphakic eye) or replenish and proofread and correct ametropia (be phakic eye, do not extract natural lens).

The complication that causes because of mechanical trauma, inflammation, infection or optical problem may take place in the intraocular lens who implants.Machinery and inflammation damnification can cause that visual deterioration, chronic pain, secondary cataract, cornea mistake are compensatory, cystoid macular edema, hyphema, uveitis or glaucoma.Use a FAQs that abaissement takes place be because of tissue to operation technique or muddiness that intraocular lens's reaction is caused.Muddiness causes intraocular lens's muddiness, has reduced secular beneficial effect thus.When epithelial cell when breeding and migration take place in the back capsule of intraocular lens back, general produce muddy.Need operation to proofread and correct this reaction subsequently; Yet it relates to the complicated technology process, and can cause the complication of further serious threat vision.Therefore, with fibre modification inhibitor coating intraocular lens or it is mixed the intraocular lens can reduce these complication.

Can have benefited from that polymer composition with theme of the present invention is impregnated into the intraocular lens of adjacent tissue according to the present invention representational example includes, but are not limited to polymethyl methacrylate (PMMA) intraocular lens, siloxanes intraocular lens, achromat, crystalline lens prosthese, the crystalline lens eyeglass is arranged, aphakic lens, many-focus intraocular lens, hydrophilic and hydrophobic acrylic acid intraocular lens, intraocular implant, vision eyeglass and hard ventilative (RGP) eyeglass.

In one aspect, the intraocular lens can be for folding or hard.Can use tubule that folding eyeglass is inserted little cutting part, and insert hard lens by big cutting part.Folding eyeglass can be made up of siloxanes, acrylic acid or hydrogel, and hard lens can be made up of hard polymer compositions (PMMA).

In one aspect, the intraocular lens can be as the cataractous implant of treatment, and wherein Yan natural lens picked-off (being aphakic lens).For example, the intraocular lens can be made up of two eyeglasses that are connected as achromat each other with different refractive indexs and different light intensity degree, and wherein said achromat can be connected in camera oculi posterior or the camera oculi anterior.For example, referring to United States Patent (USP) 5,201,762.The intraocular lens can be by being fixed in the back room through the outstanding column system of the iris that is connected with the maintenance circle.For example, referring to United States Patent (USP) 4,053,953.The intraocular lens can be for having the hard thing of shape memory characteristic, and this specific character can make its degeneration of dying when inserting eye, but will hardening under normal body temperature.For example, referring to United States Patent (USP) 4,946,470.Can apply the intraocular lens with the protein that is combined in implant surface, polypeptide class, polyamino acid class, polyamine class or carbohydrate.For example, referring to United States Patent (USP) 6,454,802 and 6,106,554.Other aphakic intraocular lens's example is described in for example United States Patent (USP) 6,599,317; 6,585,768; 6,558,419; 6,533,813; 6,210,438; 5,266,074; 4,753,654; In 4,718,904 and 4,704,123.

In one aspect of the method, the intraocular lens can be as the correction implant of visual disorder, and wherein Yan natural lens does not picked-off (the crystalline lens eyeglass is promptly arranged).For example, the intraocular lens can be for narrow profile, reduce dazzle the eyes crystalline lens anterior chamber eyeglass arranged, they can and have curved shape by optic zone and form so that central glare is reduced to MIN intermediate zone.For example, referring to United States Patent (USP) 6,596,025.The intraocular lens can for the self centering that inserts the back room eyeglass the crystalline lens eyeglass arranged, wherein arm (being the sense of touch body) outwards stretches and protrudes into pupil, makes barrier film can provide the power of centering to keep the eyeglass fix in position.For example, referring to United States Patent (USP) 6,015,435.The intraocular lens can be made up of circumferential rim and two sense of touch bodies, and described sense of touch body extends to from described edge and is essentially straight line or arc inside lateral direction element near eyeglass.For example, referring to United States Patent (USP) 6,241,777.Other has lenticular intraocular lens's example for example to be described in United States Patent (USP) 6,228, and youngster 5,5,480, in 428 and 5,222,981.

In one aspect of the method, the intraocular lens can be multifocal lens, and it can be regulated changeably so that user can be observed the focusing power that obtains varying level by the different piece of eyeglass.For example, the intraocular lens can be zoomar lens, and it partly is made up of two eyeglasses, has optic zone containing liquid reservoir and contain between the eyeglass of passage of charged solution.For example, referring to United States Patent (USP) 5,443,506.

In one aspect of the method, the intraocular lens can make eyeglass to fold so that insert by access incisions for deformable.For example, the intraocular lens can form by having the eyeglass that is used for eyeglass is remained on the retaining element of ophthalmic, and it is configured to be used for folding or rotates to the insertion state so that allow eyeglass to enter eye by otch from normal optical condition.For example, referring to United States Patent (USP) 5,476,513.The intraocular lens can by based on the view volume of the siloxanes of elastically deformable with form with the retaining element that is connected that is used for view volume is remained on ophthalmic.For example, referring to United States Patent (USP) 5,201,763.The intraocular lens can be made up of the copolymer of three kinds of compositions, and it can be from its original-shape distortion.For example, referring to United States Patent (USP) 5,359,021.The intraocular lens can be made up of the transparent flexible membranes that has capsula interna and the air bag that is connected, and wherein the optical fluid medium branches to air bag and is out of shape during insertion to help the intraocular lens from optical element.For example, referring to United States Patent (USP) 6,048,364.The intraocular lens can be the biological composite of partly being made up of vision part and sense of touch, described vision part is made up of the hydrogel of high water content, the hydrogel of this high water content can fold, and described sense of touch is partly for having the hydrogel of low water content, and it has intensity and rigidity.For example, referring to United States Patent (USP) 5,211,662.Other deformable intraocular lens is described in for example United States Patent (USP) 6,267,784,5,507,806 and U.S. Patent Application Publication No. 2003/0114928A1In.

Can be described in other the relevant device and/or the compositions (for example inserting device) of intraocular lens's coupling: for example United States Patent (USP) 6,629, and 979; 6,187,042; 6,113,633; 4,740,282; And U.S. Patent Application Publication No. 2003/0212409A1 and 2003/0187455A1 In.

Can have benefited from the intraocular lens that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised and be purchased product.Alcon Laboratories for example, (Fort worth TX) has sold folding ACRYSOF intraocular lens to Inc..Bausch ﹠amp; Lomb Surgical, (San Dimas CA) has sold folding SOFLEX SE intraocular lens to Inc..AdvancedMedical Optics, (Santa Ana CA) has sold the folding intraocular lens of CLARIFLEX, SENSAR acrylic artificial crystalline lens and PHACOFLEX II SI40NB and SI30NB to Inc.

Intraocular implant of the present invention can be used for various operation techniques.For example, intraocular implant can with the corneal graft coupling.Synthetic cornea can be used for the patient who loses vision that causes because of corneal degeneration.The synthetic cornea of implanting can recover patient's vision, yet they induce the fibroid foreign body reaction that limits its application usually.Intraocular implant of the present invention can prevent the foreign body reaction of synthetic cornea and prolong life-span of cornea.In another example, apply polymer composition of the present invention for synthetic cornea self, the reaction that will organize corneal to implant thus is reduced to bottom line.

In one aspect of the method, the intraocular lens can with the treatment ECCE after the secondary cataract coupling.

As mentioned above, the invention provides intraocular lens and other implant with the motif polymerization compositions of the present invention that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).In one aspect, described anti-scarring agent is not the paclitaxel or derivatives thereof.

The number of polymers and the non-polymer delivery system that are used for intraocular implant have above been described.

Can soak into thereon and with said composition and implanting around the intraocular implant by polymer composition directly and/or indirectly being coated with following position or coating: (a) tissue adjacent with intraocular implant; (b) near intraocular implant-organizational interface; (c) zone around the intraocular implant; (d) tissue around the intraocular implant.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with intraocular implant comprises described polymer composition is delivered to: (a) on the intraocular implant surface of implant procedure process (for example as injectable, paste, gel or mesh); (b) before implanting intraocular implant at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the intraocular implant intraocular implant surface at once and/or implant tissue (for example forming gel or net) around the intraocular implant as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed intraocular implant (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject intraocular implant tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install.

The material that the polymer composition of theme of the present invention is impregnated into the process of the tissue adjacent with these implants and selects for these processes makes them can significantly not change the refractive index of intraocular implant or the transmission of visible light of implant or eyeglass.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with intraocular implant is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because intraocular implant is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

Hypertrophic cicatrix and keloid

In one aspect of the method, can make the polymer composition of theme of the present invention be impregnated into and install adjacent tissue to be used for the treatment of hypertrophic cicatrix and keloid.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

The various devices that are used for the treatment of hypertrophic cicatrix and keloid have been described.For example, outside organization's expansion gear that described device can be formed for the stitching steel plate that has an adhesion foam pad by two, described adhesion foam pad applies the low power of constant continuous so that remove hypertrophic cicatrix and keloid to skin and tissue.For example, referring to United States Patent (USP) 6,254,624.This device can be shadowing elements, and it is defeated on scar tissue and be connected with inflatable or suction element in the shadowing elements with adjustable by pressure control unit.For example, referring to United States Patent (USP) 6,013,094.Treatment can be the device that has locking member and grip structure, makes the corium of skin wound and epidermal area to push each other, so that organization edge is adjacent, thereby makes wound to be sealed by the cicatrization of minimum.For example, referring to United States Patent (USP) 5,591,206.

In one aspect of the method, can combine the device treatment hypertrophic cicatrix or the keloid of coating or lamella by use, described coating or lamella can be used to send independent as mentioned above anti-scarring agent and/or anti-infective or anti-scarring agent and/or infection compositions.For example, described coating or lamella can be for by hydrophilic polymer, and such as the copolymer that Polyethylene Glycol is formed, described hydrophilic polymer and the polymer that is easy to be adsorbed on body tissue surfaces are such as the phenylboric acid combination.For example, referring to United States Patent (USP) 6,596,267.Described coating or lamella can be for having soaked into the siloxane sheet of the adhesion certainly layer of antioxidant and/or antibacterial.For example, referring to United States Patent (USP) 6,572,878.Can serve as reasons outer soft layer and of described coating or lamella as the wound dressing skin that adheres to inner gel lining composition certainly of the dressing that contact wound.For example, referring to United States Patent (USP) 6,548,728.Described coating or lamella can be the fluid composition of being made up of the film forming carrier, and described one-tenth membrane carrier is such as the collodion that contains circumference or various active component, and described active component such as part is with steroidal, silicon gel and vitamin E.For example, referring to United States Patent (USP) 6,337,076.Described coating or lamella can have silicone elastomer or silicon gel layer for having the binder of scar treatment pad in the described pad.For example, referring to United States Patent (USP) 6,284,941 and 5,891,076.

The Therapeutic Method and the device that are used for hypertrophic cicatrix and keloid can be impregnated into adjacent tissue or hypertrophic cicatrix and keloid tissue coupling with the polymer composition with theme of the present invention, and these Therapeutic Method and device comprise and be purchased product.Representational product comprises: for example from Progressive Surgical Products (Westbury, the PROXIDERM outside organization expansion product that is used for wound healing NY), from Smith ﹠amp; The CICA-CARE gel lamella casting product of Nephew HealthcareLtd. (India) and from Molnlycke HealthCare (Eddystone, MEPIFORM PA) is from adhering to siloxanes dressing.

In one aspect, the device that is used for the treatment of hypertrophic cicatrix and keloid can have the polymer composition of the theme of the present invention that is impregnated into adjacent tissue, and wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).Described polymer composition can be the part with or injectable polymer composition, they comprise anti-scarring agent and/or anti-infective and are suitable for being coated on hypertrophic cicatrix or the keloid or are coated with polymer support into wherein.Fibre modification inhibitor and/or anti-infective are mixed topical preparation or injectable formulation is a kind of means of this disease of treatment.Topical preparation can be solution, suspension, Emulsion, gel, ointment, cream, thin film or mesh form.Injectable formulation can be solution, suspension, Emulsion or gel form.Can be used to prepare these local with or the polymerization of Injectable composition and non-polymeric composition as mentioned above.

Can said composition be soaked into around the device that is used for hypertrophic cicatrix and keloid by polymer composition directly and/or indirectly being coated with following position or being coated with thereon: (a) with the adjacent tissue of device that is used for hypertrophic cicatrix and keloid; (b) tissue and the near interface that is used for the device of hypertrophic cicatrix and keloid; (c) be used for zone around the device of hypertrophic cicatrix and keloid; (d) be used for tissue around the device of hypertrophic cicatrix and keloid.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with the device that is used for hypertrophic cicatrix and keloid comprises described polymer composition is delivered to: (a) at the apparatus surface that is used for hypertrophic cicatrix and keloid (for example as injectable, paste, gel or mesh) of implant procedure process; (b) before implantation is used for the device of hypertrophic cicatrix and keloid at once or the tissue surface of process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the device be used for hypertrophic cicatrix and keloid at once the apparatus surface that is used for hypertrophic cicatrix and keloid and/or implantation be used for hypertrophic cicatrix and keloid device around tissue (for example forming gel or net) as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed the device that is used for hypertrophic cicatrix and keloid (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject the device tissue on every side that is used for hypertrophic cicatrix and keloid as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with being used for the treatment of the device of hypertrophic cicatrix and keloid is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.The definite dosage that gives constitutes by not isostructure and size because be used for the treatment of the device of hypertrophic cicatrix and keloid, so can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

Blood vessel graft

The method that the polymer composition of theme of the present invention is impregnated into the tissue adjacent with blood vessel graft is provided among the present invention in one aspect.Blood vessel graft device with the polymer composition that is impregnated into adjacent tissue that contains fibre modification inhibitor and/or anti-infective can suppress or reduce granulation tissue undue growth and/or inhibition or prevention infection, thereby can improve the clinical efficacy of these devices.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

Blood vessel graft can be (being intracavity) graft in outer graft of blood vessel or the blood vessel.Blood vessel graft can for, but be not limited to periphery bypass applications or coronary artery bypass application form.Blood vessel graft can be used for replacing or replacing impaired or ill vein or tremulous pulse, includes, but are not limited to be subjected to the blood vessel of aneurysm, neointimal hyperplasia and thrombosis infringement.Blood vessel graft can also be used to provide blood vessel to import and export, and for example is used for hemodialysis and imports and exports.For example, in order to provide the alternative conduit that makes blood flow cross the impaired or affected areas in vein and the tremulous pulse and the implantable intravascular graft, described vein and tremulous pulse comprise, but be not limited to be subjected to the blood vessel of aneurysm, neointimal hyperplasia and thrombosis infringement, yet, described graft can cause further complication, includes, but are not limited to infection, inflammation, thrombosis and neointimal hyperplasia.For example, the material mispairing because of operation wound and abnormal blood flow kinetics and stitching thread place causes using the shortage of blood vessel graft open for a long time.In general, other disease of blood vessel (for example restenosis) takes place along the tremulous pulse bed.

Blood vessel graft has been carried out the improvement of a definite form to attempt reducing the restenosis that takes place on anastomotic position.Improvement comprises: (a) use the Miller cover, it is a bit of natural vein that forms short cover, and described short cover is connected by sewing up with prosthetic implant with the tremulous pulse opening; (b) use the flange graft, wherein this graft has endsocket or the cover that helps a side-to-side anastomosis; (c) use the graft of the chamber have expansion, the chamber of described expansion have be used for anastomotic position sew up than major diameter; (d) graft of the activating agent of adjustable prevention thrombosis of use and/or neointimal hyperplasia.

The representational example of blood vessel graft includes, but are not limited to graft, the interior graft of blood vessel and prosthetic implant in synthetic bypass graft (for example thigh-popliteal, thigh-thigh, axil-thigh etc.), vein transplantation thing (for example on every side with crown) and inner breast (for example crown) graft, two fork blood vessel grafies, the tube chamber.Synthetic graft can be made by various polymeric materials, such as: politef (for example ePTFE) for example; Polyesters is such as the combination of DACRON, polyurethanes and polymeric material.

The endoluminal vascular graft can be used for the treatment of aneurysm.For example.Blood vessel graft can be made up of the tubular graft that has two tubular self-expanding stents, can be with it by implanting with the treatment aneurysm with the operation of minimum infringement degree.For example, referring to United States Patent (USP) 6,168,620.Blood vessel graft can be formed with compressible framework to promote ingrown support by flexible tubular bodies with in the face of having the hole on the localized surface of tubular bodies.For example, referring to United States Patent (USP) 5,693.088。Blood vessel graft can be pitched graft in the blood vessels for having tubular doing with two of two tubular limbs.For example, referring to United States Patent (USP) 6,454,796.Blood vessel graft can be the anti-intracavity that tangles two fork grafts, and it has two independently chambeies by the contact of cross section, single chamber.For example, referring to United States Patent (USP) 6,551,350.Blood vessel graft can be the inner lumen tube of being made up of ePTFE that has the closing line that forms by imbricate, makes this microstructure with the vertical direction orientation.For example, referring to United States Patent (USP) 5,718,973.

In one aspect of the method, blood vessel graft can be as the conduit of narrow or other aberrant angiogenesis of shunt vessel.For example, blood vessel graft can be made up of porous material, and this porous material has along the localized porous hollow fiber layer of inner surface, and described inner surface allows tissue growth, suppresses hemorrhage in the agglutination simultaneously.For example, referring to United States Patent (USP) 5,024,671.Blood vessel graft can be for flexible, integral body, the outside ePTFE rib linear element that the polymer pipe of reinforcement, this pipe racks have micropore ePTFE tubular element and outwards give prominence to from outer wall.For example, referring to United States Patent (USP) 5,609,624.Blood vessel graft can be made up of tubular wall, and this tubular wall has longitudinally extending pleat, and these pleats can be made a response to blood pressure change neatly, keeps the height compliance that reduces with knot simultaneously.For example, referring to United States Patent (USP) 5,653,745.Blood vessel graft can be the ePTFE pipe of the radial support of one-tenth strengthened with the annulus of greater density.For example, referring to United States Patent (USP) 5,747,128.Blood vessel graft can be the porous PTFE pipe, and it is made up of the microstructure of the joint that interconnects by the fibril that has the elastomer coating on outer wall.For example, referring to United States Patent (USP) 5,152,782 and 4,955,899.The blood vessel graft at least three kinds of different fibrous multiple polymer fibers of braiding each other of can serving as reasons, wherein two kinds of fibers can be absorbed and a kind of can not being absorbed.For example, referring to United States Patent (USP) 4,997,440,4,871,365 and 4,652,264.

In one aspect of the method, improve blood vessel graft to reduce thrombosis or the neointimal hyperplasia on the anastomotic position.For example, blood vessel graft can have have with the parallel first kind of diameter of the axle of tubular wall and with the chamber of the expansion of the transversal second kind of diameter of the axle of pipe.For example, referring to United States Patent (USP) 6,589,278.Blood vessel graft can have the sleeve of flange or overlap angular cross section to help the direct end-to-side anastomosis between tremulous pulse and the flange bypass graft end.For example, referring to United States Patent (USP) 6,273,912.Blood vessel graft can be made up of tubular wall that contains non-thrombosis agent in the layer of chamber and the thrombosis layer that forms the blood vessel graft outside.For example, referring to United States Patent (USP) 6,440,166.The level and smooth chamber surface composition that has the small-bore of reducing the adhesion of closed blood composition that blood vessel graft can be made by ePTFE.For example, referring to United States Patent (USP) 6,517,571.Blood vessel graft can be made up of the hollow pipe that contains medicine, and described hollow pipe curl twines the outer wall of porous ePTFE graft, and medicine can obtain allotment by the hole infusion through the graft wall thus.For example, referring to United States Patent (USP) 6,355,063.

In one aspect of the method, blood vessel graft can be the blood vessel of gathering that is used for bypass graft.For example, blood vessel graft can be made up of such as internal mammary artery or inferior epigastric artery the arteries of gathering from the host.For example, referring to United States Patent (USP) 5,797,946.Blood vessel graft can also be made up of saphena, and described saphena can be gathered from the host and be used for coronary artery bypass or periphery by-pass operation operation.For example, referring to United States Patent (USP) 6,558,313.

Other case description of blood vessel graft is at United States Patent (USP) 3,096, and 560,3,805,301,3,945,052,4,140,126,4,323,525,4,355,426,4,475,972,4,530, youngster 3,4,550, and 447,4,562,596,4,601,718,4,647,416,4,878,908,5,024,671,5,104,399,5,116,360,5,151,105,5,197,977,5,282,824,5,405,379, in 5,609,624,5,693,088 and 5,910,168.

The blood vessel graft that can have the polymer composition of the theme of the present invention that is impregnated into adjacent tissue comprises and is purchased product.GORE-TEX blood vessel graft and GORE-TEX INTERING blood vessel graft are by Gore Medical Division (W.L Gore ﹠amp; Associates, Inc.Newark DE) sells.C.R.Bard, (Murray Hill NJ) sells DISTAFLO bypass graft and IMPRA CARBOFLO blood vessel graft to Inc..

The blood vessel graft of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue is provided among the present invention in one aspect, and wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).

The number of polymers and the non-polymer delivery system that are used in conjunction with blood vessel graft have above been described.

Can be by polymer composition directly and/or indirectly being coated with following position or coating is soaked into said composition around the blood vessel graft of implanting thereon: (a) tissue adjacent with blood vessel graft; (b) near blood vessel graft-organizational interface; (c) zone around the blood vessel graft; (d) tissue around the blood vessel graft.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with blood vessel graft comprises described polymer composition is delivered to: (a) on the blood vessel graft surface of implant procedure process (for example as injectable, paste, gel or mesh); (b) before the implantable intravascular graft at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) at once blood vessel graft surface and/or the tissue around the implantable intravascular graft (for example forming gel or net) behind the implantable intravascular graft as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed blood vessel graft (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject blood vessel graft tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install.

Except that fibre modification inhibitor and/or anti-infective, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with the blood vessel graft device can also further contain anti-inflammatory agent (for example dexamethasone (dexamethazone) or aspirin) and/or antithrombotic agent (for example heparin, heparin complex, hydrophobic heparin derivant, dipyridamole or aspirin).The combination of activating agent can be included in the polymer composition that is impregnated into the blood vessel graft adjacent tissue.Make thrombotic and/or fibre modification be alleviated or suppress.In certain embodiments, these activating agents can be included in the Biodegradable polymeric.For example, can use in the hole and/or on graft surface the polymeric material that forms gel, such as the PLURONIC polymer of alginate, chitosan and sulfated chitosan, hyaluronic acid, dextran sulfate, PLURONIC polymer, chain elongation, the polyester-polyether block copolymer of isomorphism type (for example MePEG-PLA, PLA-PEG-PLA etc.) not.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with blood vessel graft is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because blood vessel graft is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on about tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned dosage parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

The hemodialysis access device

In one aspect, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with the hemodialysis access device.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).The dialysis access device that comprises the hemodialysis of fibre modification inhibitor and/or anti-infective can suppress or reduce granulation tissue undue growth and/or inhibition or prevention infection, can improve the clinical efficacy of these devices thus.

When taking out blood, cleaning and make it turn back in the body then, use by needs the hemodialysis access device.Hemodialysis is regulated body fluid and chemical equilibrium and remove the refuse of kidney cleaning that can not be by normal function because of i or I from blood flow.In order to carry out hemodialysis, can obtain blood by hemodialysis access device mouth or blood vessel gateway, wherein implement minor operation so that the inlet by AV fistula or AV access graft to be provided.Complication can take place in these hemodialysis access devices, comprises infection, inflammation, thrombosis and the neointimal hyperplasia of related artery.To cause using hemodialysis access to lack long-term open because of the material mispairing at operation wound, abnormal blood flow kinetics and stitching thread place.In general, other disease of blood vessel (for example restenosis) is along the tremulous pulse bed and/or take place on anastomotic position.

Except that above-mentioned AV fistula or AV access graft, implantable subcutaneous blood hemodialysis transit system also can be used for hemodialysis patients such as the conduit that is purchased, passage and diverter.These access systems can be formed by implanting subcutaneous little metal or polymeric device or multiple arrangement.These devices can be connected with the pliability pipe that allows blood to come in and go out with the insertion blood vessel.

The representational example of hemodialysis access device includes, but are not limited to AV access graft, venous duct, blood vessel graft, implantable passage and AV diverter.Synthetic hemodialysis access device can be made by metal or polymer, such as: politef (for example ePTFE); Polyesters is such as DACRON, polyurethanes; Or the combination of these materials.

In one aspect, the hemodialysis access device can be the AV access graft.For example, the AV access graft can be made up of the implantable self-expanding pliability percutaneous stent-graft of open knitting structure, and described structure has compressible end and has the elastic layer of arranging along the part of its length.For example, referring to United States Patent (USP) 5,755,775 and 5,591, the 226.AV access graft can be made up of the pipe cross-section that generally has the tapered constant diameter of vein end.For example, referring to United States Patent (USP) 6,585,762.The AV access graft can be made up of two micropore ePTFE pipes of from first to last arranging along periphery, and wherein between has inserted polymeric layer, makes that graft can be self-enclosed and show good hot strength and sewing hole resistance to elongation.For example, referring to United States Patent (USP) 6,428,571.The AV access graft can be made up of the coaxial double lumen tube of pipe and outer tube in having, and has self-enclosed non-biodegradable polymer adhesive between two pipes.For example, referring to United States Patent (USP) 4,619,641.The AV access graft can be made up of synthetic textiles, and this fabric has braiding or is knitted into the outside velvet profile of height of tubular prosthese, formed prosthese have can be self-enclosed after the perforation attitude elastic fiber.For example, referring to United States Patent (USP) 6,547,820.The AV access graft can have tubular, and this is tubular to have to have and covered refractive material, such as the adjacent arrangement of porous membrane so that active from the chamber (ablumenal) surperficial substrate tube.For example, referring to United States Patent (USP) 5,910,168.

In one aspect of the method, the hemodialysis access device can be conduit system.For example, conduit system can be made up of the suction and the return route that are suitable for the arrangement of body vessel system and be connected with subcutaneous connecter hole.For example, referring to United States Patent (USP) 6,620,118 and 5,989,206.This conduit system can be for being used for by producing the equipment of AV fistula with the vein arterialization through conduit being inserted vein and conduit being inserted adjacent tremulous pulse.For example, referring to United States Patent (USP) 6,464,665.Conduit system can be made up of the hollow sheath, and it provides percutaneous to import the vessel catheter that produces fistula by the perforation on the blood vessel wall, makes conduit produce fistula between blood vessel required between the blood vessels adjacent.For example, referring to United States Patent (USP) 6,099,542 and 5,830,224.

In one aspect of the method, the hemodialysis access device can be used for the AV fistula.For example, the hemodialysis access device AV fistula assembly that synthetic spiral type stent graft is formed of can serving as reasons has on the described stent graft and has turn-taking that the spirality jaggy that is used to improve the AV function stretches.For example, referring to United States Patent (USP) 6,585,760.

In one aspect of the method, the hemodialysis access device can be implantable gateway, diverter or valve.These devices are implanted subcutaneously to keep blood supply and to use percutaneous puncture to enter.For example, the hemodialysis access device can be made up of the chamber that has towards the entrance and exit of passage, and described passage has makes syringe needle enter the enclosed elastic valve of outlet.For example, referring to United States Patent (USP) 5,741,228.The hemodialysis access device diverter that slidably valve and flexible lid are formed of can serving as reasons, it has the fluid communication pipe between tremulous pulse and the vein end.For example, referring to United States Patent (USP) 5,879,320.The hemodialysis access device can be the diverter of joint form, and described joint has the adapter with two steady arms, and described two steady arms all are inserted into natural blood vessel and a steady arm is suitable for being closed to another blood vessel and need not puncture.For example, referring to United States Patent (USP) 6,019,788.The hemodialysis access device can be for being fixed on the surface that is used for the hemodialysis access device on the AV graft wall dual haemostatic valve of coming in and going out.For example, referring to United States Patent (USP) 6,004,301 and 6,090,067.

Can have benefited from the hemodialysis access device that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised and be purchased product.For example the hemodialysis access device comprises product, such as from Biolink Corp. (Middleboro, MA) LIFESITE (Vasca Inc., Tewksbury, MA) and the DIALOCK conduit, from C.R.Bard, Inc. (Murray Hill, VECTRA vascular access graft NJ) and VENAFLO blood vessel graft and from GoreMedical Division (W.L.Gore ﹠amp; Associates, Inc.Newark, GORE-TEX blood vessel graft DE) and Stretch blood vessel graft.

Provide among the present invention in one aspect to have the hemodialysis access device that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with the hemodialysis access device have above been described.

Can soak into thereon and with said composition and implanting around the hemodialysis access device by polymer composition directly and/or indirectly being coated with following position or coating: (a) tissue adjacent with the hemodialysis access device; (b) near hemodialysis access device-organizational interface; (c) zone around the hemodialysis access device; (d) tissue around the hemodialysis access device.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with the hemodialysis access device comprises described polymer composition is delivered to: (a) on the hemodialysis access device surface of implant procedure process (for example as injectable, paste, gel or mesh); (b) before implanting the hemodialysis access device at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the hemodialysis access device hemodialysis access device surface at once and/or implant tissue (for example forming gel or net) around the hemodialysis access device as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed the hemodialysis access device (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject hemodialysis access device tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install.

Except that fibre modification inhibitor and/or anti-infective, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with the hemodialysis access device can also further contain anti-inflammatory preparation (for example dexamethasone (dexamethazone) or aspirin) and/or antithrombotic agent (for example heparin, heparin complex, hydrophobic heparin derivant, dipyridamole or aspirin).

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with the hemodialysis access device is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because the hemodialysis access device is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on about tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01g-1g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

Thin film and mesh

In one aspect, the polymer composition of theme of the present invention can be impregnated into and thin film or the adjacent tissue of mesh.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).The polymer composition that will comprise the theme of the present invention of fibre modification inhibitor and/or anti-infective is impregnated into the tissue adjacent with thin film or mesh can be reduced to bottom line with near the fibre modification the implant (or cicatrization), and can reduce or prevent to form adhesion between implant and the surrounding tissue and/or can suppress or prevent near the implant position infection.In certain aspects, thin film or mesh can be as passing drug carrier (for example as delivery apparatus around the blood vessel of neointimal hyperplasia (neointimal hyperplasia) on the prevention anastomotic position).

Thin film or mesh can adopt various forms, include, but are not limited to perform the operation barrier, surgical adhesions barrier, film (for example barrier film), surgery with sheet, surgical patch (for example cerebral dura mater sticking patch), the coated material of surgery (for example around blood vessel, the blood vessel, adventitia, the coated material of periadventitial and outer membrane), mesh (for example mesh around the blood vessel), binder, liquid binder, surgical dressing, gauze, fabric, adhesive tape, surgery with film, polymeric matrix, shell, peplos, organize surgery usefulness substrate, stent and the coating of covering and other type.

In one aspect, described device comprises that thin film maybe can be form of film.This thin film can form many geometries.With the difference of using, it maybe can be the elastomeric polymer sheet that approaches that this thin film can form tubular.In general, thin film has less than 5,4,3,2 or the thickness of 1mm, is more preferably less than 0.75mm, 0.5mm, 0.25mm or 0.10mm thickness.Can also produce the thin film that has less than 50 μ m, 25 μ m or 10 μ m thickness.Thin film is generally flexible, has good tensile and (for example greater than 50, is preferably greater than 100 and more preferably greater than 150 or 200N/cm ²), good cohesive (promptly with moist or wet surface adhering) and have controlled permeability.Thin polymer film (can for porous or non-porous) is used in particular for applying to device or implant surface and tissue, chamber or organ surface.

Can pass through several method, for example comprise preparing thin film, or thin film can form in the therapentic part original position by casting with by spraying.For example, sprayable preparation can be coated on the therapentic part, form solid film then there.

In one aspect of the method, described device can comprise that polymer maybe can be polymer form, and wherein some polymer is the mesh form at least.Mesh used herein is by many fibers or the material (being fibrous material) formed of silk, wherein said fiber or thread with this class mode (for example interwoven, knotting, weaving, overlapping, lopping, knitting, interweave, winding, net are knitted, felt etc.) be arranged in loose structure.In general, mesh is softish material, makes it have the coated external surface peripheral in body passage or chamber or its part of enough pliabilities.Mesh can provide support and is suitable for discharging a certain amount of therapeutic agent structure (for example blood vessel or chamber wall).

Mesh material can adopt various forms.For example, mesh can for braiding, knitting or non-type of weave and can comprise at random fiber or silk directed toward each other or that arrange with oldered array or pattern.In one embodiment, for example, mesh can be form of fabric, such as: for example knitting, interweave, crochet, braiding, non-braiding (for example melt jet or wet-apply) or net woven fabric.In one embodiment, mesh can comprise natural or synthetic Biodegradable polymeric, and it can form knitting mesh, the mesh that weaves mesh, injection, fabric mesh, the mesh that interweaves, lopping mesh etc.Preferred mesh or coated thing have the winding silk thread that forms loose structure, and it can be knitted for for example knitting, braiding or net.

Being used for the structure of device and characteristic depends on and uses and the load and the release characteristics of required mechanicalness (being pliability, hot strength and elasticity), degradation characteristic and required therapeutic agent to selection.Mesh should have mechanicalness, makes this device keep enough intensity, till organization healing.The factor that influences mesh pliability and mechanical strength comprises: for example porous, fabric thickness, fibre diameter, polymer are formed (for example type of monomer and initiator), processing conditions and are used to prepare the additive of described material.

In general, mesh has enough porous so that fluid flows through the hole of fibrous reticular structure and helps tissue ingrowth.In general, the gap of mesh should be at a distance of enough wide so that eye visible or make fluid pass through the hole.Yet, can also make the material of apparatus tight structure.Fluid depends on various factors by the flow in mesh gap, comprising: the density of the counting of suture or silk thread for example.For example, can also make the porous mesh through the following steps: the gap of filling mesh with another kind of material (for example granule or polymer); Or processing mesh (for example by heating) is so that reduce the aperture and produce non-pars fibrosa.The fluid that flows through mesh of the present invention can change with the difference of fluid behaviour, such as viscosity, hydrophilic/hydrophobic, ion concentration, temperature, elasticity, pseudoplastic behavior, granule content etc.Preferred described gap can not stop the therapeutic agent that soaks into or apply discharging from mesh, and described gap preferably can not stop the exchange of tissue fluid on the coating position.

Mesh material should be enough pliable and tough, so as can be coated on all parts or its part of the outer surface in body passage or chamber.Flexible mesh material is generally flexible braiding or knitting form, and the thickness that it has is at about 25 microns-about 3000 microns; Preferred about 50-about 1000 microns.Be suitable for coated mesh material general thickness around tremulous pulse and vein at about 100-400 microns.

Diameter and the length dimension of described fiber or silk can be according to the different of material forms (for example knitting, braiding or non-knitting) and required elasticity, porous, surface area, pliability and hot strength and in certain limit.Fiber can have length arbitrarily, the scope from short silk to long line (being that length is at several microns-hundreds of rice).With the difference of using, fiber can have monofilament or multifilament structure.

Mesh can comprise the fiber with same size or different size, and fiber can be formed by system or dissimilar Biodegradable polymerics.For example, braided material can comprise the coated thing and the fabric strand of rule or irregular array, and can on the fabric direction, comprise one type polymer, and upwards comprise the polymer (having and first kind of degradation characteristic that polymer is identical or different) of another kind of type at coated object space.The degradation characteristic of fabric polymer can be different with the degradation characteristic of coated thing polymer or identical with it.Similarly, knit materials can comprise the fiber of one or more types (for example monofilament, multifilament) and size and can comprise the fiber of being made by identical or different types of biological degradable polymer.

The structure of mesh (for example fibre density and porous) can influence the amount that load is gone into device or the therapeutic agent on it.For example, have the fabric that is characterised in that low fibre density and highly porous loose braiding and have lower silk thread counting, cause total fiber volume and surface area to descend.As a result of, can be with fixed carrier: the load amount of fiber or the activating agent on it of therapeutic agent ratio can be lower than and has high fibre density and low porous fabric.Preferred mesh also should not cause biologically deleterious inflammation or toxic reaction, should be able to have the acceptable shelf life and be easy to sterilization fully in vivo by metabolism.

Described device can comprise the multiple mesh material of combination in any or arrangement.For example, the part of device can be knit materials, and another coatedly can be braided material.In another embodiment, described device can have one deck above (for example knit layer and layers of knitted material or with another same type or dissimilar knit layer fusions).In certain embodiments, for example, repeatedly structure (device that for example has two-layer or multilayer material) can be used to improve the performance (for example be used to improve the hardness of device or be used for modifier porous, elasticity or hot strength) of device or be used to increase the loading of medicine.

For example, multi-ply construction can be useful in the device of the therapeutic agent that contains more than one types.For example, can load one type activating agent of the ground floor of mesh material, and can the load activating agent of another kind of type of the second layer.Not two-layer can connection or connect (for example merge each other, such as by heat welded or ultrasonic welding) and can or have that different polymer are formed and/or the dissimilar fabric of structure forms by the fabric of same type.

In certain aspects, mesh can comprise the part of non-mesh form.For example, described device can comprise form and combinations thereof such as thin film, sheet, paste.For example, described device can have multi-ply construction, and this structure has thin layer and one or more layers mesh material layer that comprises therapeutic agent.For example, described thin layer can be inserted between the two-layer mesh layer or can only be inserted on mesh material one side.Thin layer can comprise first kind of therapeutic agent, and can comprise identical or different activating agent in one or more layers of mesh.In another embodiment, described device can comprise two-layer at least mesh.In one aspect, the two-layer at least fusion each other in the two-layer at least mesh.

In one aspect, provide the multi-layered devices that may further include thin layer.Thin layer can be between two-layer at least mesh two-layer.In another embodiment, described the delivery apparatus that comprises mesh, wherein said mesh comprises Biodegradable polymeric and first kind of therapeutic agent.This device may further include thin film, and this thin film comprises second kind of therapeutic agent, and promptly this device can have the identical or different composition of non-first kind of therapeutic agent.For example, in one embodiment, be suitable for mesh layer and thin layer that coated device around vein or tremulous pulse comprises the therapeutic agent of having loaded.Can this device is coated around body passage or chamber, make thin layer contact the outer surface in described passage or chamber.Therefore, described device can be sent suitable dose of active and can provide enough mechanical strength to improve and to keep the structural intergrity in body passage or chamber.

In one aspect, described mesh or thin film comprise polymer.Described polymer can be a Biodegradable polymeric.The biodegradable compositions that can be used to prepare mesh comprises polymer, these polymer comprise albumin, collagen protein, hyaluronic acid and derivant, sodium alginate and derivant, chitosan and derivant, gelatin, starch, cellulose derivative (methylcellulose for example, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose, cellulose acetate succinate, Hydroxypropyl Methylcellulose Phathalate), casein, glucosan and derivant, polysaccharide, poly-(caprolactone), fibrinogen, poly-(hydroxy acid), poly-(L-lactide) poly-(D, the L lactide), poly-(D, the L-lactide-co-glycolide), poly-(L-lactide-co-glycolide), the copolymer of lactic acid and glycolic, the copolymer of 6-caprolactone and lactide, the copolymer of Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone, lactide and 1, the copolymer of 4-diox-2-ketone, comprise unitary polymer of one or more residues of monomers and copolymer, described monomer is the D-lactide, the L-lactide, D, the L-lactide, Acetic acid, hydroxy-, bimol. cyclic ester, 6-caprolactone, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone or 1,5-Dioxepane-2-ketone, poly-(Acetic acid, hydroxy-, bimol. cyclic ester), poly-(butyric ester), poly-(alkyl carbonate) and poly-(ortho esters), polyesters, poly-(hydroxypentanoic acid) Ju diethyleno dioxide ketone, poly-(PETP), poly-(malic acid), poly-(hydroxymalonic acid .), poly-anhydrides, group of polyphosphazenes, poly-(aminoacid).These compositionss comprise the admixture and the combination of the copolymer and the above-mentioned polymer of above-mentioned polymer.(generally referring to Illum, L., Davids, S.S. (eds.) " controlled release is passed the polymer in the medicine " (" Polymers inControlled Drug Delivery ") Wright, Bristol, 1987; Arshady, " controlled release magazine " (J.Controlled Release) 17:1-22,1991; Pitt, " International Journal of Pharmaceutical Medicine " be 59:173-196 (Int.J.Phar.), and 1990; Hollan etc. " controlled release magazine " (J.Controlled Release) 4:155-0180,1986).

In one aspect, described mesh or thin film comprise biodegradable or resorbent polymer, these polymer are formed by one or more monomers, described monomer is selected from lactide, Acetic acid, hydroxy-, bimol. cyclic ester, e-caprolactone, carbonic acid Sanya methyl ester, 1,4-diox-2-ketone, 1,5-Dioxepane-2-ketone, 1, the group that 4-Dioxepane-2-ketone, hydroxyl valerate and butyric ester are formed.In one aspect, described polymer can comprise: the copolymer of lactide and Acetic acid, hydroxy-, bimol. cyclic ester for example.In one aspect of the method, described polymer comprises poly-(caprolactone).In one aspect of the method, described polymer comprises poly-(lactic acid), poly-(L-lactide)/poly-(D, L-lactide) admixture or L-lactide and D, the copolymer of L-lactide.In one aspect of the method, described polymer comprises the copolymer of lactide and e-caprolactone.In one aspect of the method, described polymer comprises polyester (for example poly-(lactide-co-glycolide).The lactide that described poly-(lactide-co-glycolide) can have: the Acetic acid, hydroxy-, bimol. cyclic ester proportion is at about 20:80-about 2:98, and lactide: the ratio of Acetic acid, hydroxy-, bimol. cyclic ester is about 10:90 or lactide: the ratio of Acetic acid, hydroxy-, bimol. cyclic ester is about 5:95.In one aspect, described poly-(lactide-co-glycolide) is poly-(L-lactide-co-glycolide).Other example of Biodegradable material comprises polyglactin 370 (polyglactin), polyglycolic acid, from body, allos and heteroplasm (for example pericardium or submucous layer of small intestine) and oxidation, regenerated cellulose.These meshes can be knitting, braiding or non-woven mesh.The example of non-braiding mesh comprises the electrospinning material.

The polymer manufacture that mesh and thin film can not be degraded by biology.The representational example of the biological compositions that can not degrade comprises: ethylene-altogether-vinyl acetate copolymer; Based on acrylic acid and based on the polymer of methacrylic acid (for example poly-(acrylic acid); Poly-(methacrylic acid); Poly-(methyl methacrylate); Poly-(hydroxyethyl meth acrylate); Poly-(alkyl cyanoacrylate); Poly-(alkyl acrylate); Poly-(alkyl methacrylate)); TPO is such as poly-(ethylene) or poly-(propylene); Polyamide-based (for example nylon 6,6); Poly-(urethane) (for example poly-(ester urethane); Poly-(ether urethane); Poly-(carbonic ester urethane); Poly-(ester-urea)); Polyesters (for example PET, polybutylene terepthatlate and polyhexene terephthalate); Polyethers (poly-(oxirane); Poly-(expoxy propane); Poly-(oxirane)-poly-(expoxy propane) copolymer, diblock and triblock copolymer; Poly-(1, the 4-butanediol)); Contain the polymer of siloxanes and based on the polymer of vinyl (polyvinylpyrrolidone, poly-(vinyl alcohol), poly-(vinylacetate phthalic acid ester), poly-(styrene-altogether-isobutene .-altogether-styrene); Fluorine-containing polymer (fluoropolymer polymer) is such as PEP (FEP) or politef (for example intumescent PTFE).

Mesh or thin-film material can comprise the combination of the above-mentioned biodegradable and biological polymer that can not degrade.The example of operable other polymer is that anionic (for example alginate, carrageenin, hyaluronic acid, dextran sulfate, chondroitin sulfate, Sensor Chip CM 5, carboxymethyl cellulose and poly-(acrylic acid)) or cationic (for example chitosan, poly-1-lysine, polymine and poly-(allyl amine)) are (generally referring to Dunn etc., " journal of applied " (J.Applied Polymer Sci.) 50:353,1993; Cascone etc., " material science magazine-medical material " (J.Materials Sci.:Materials in Medicine) 5:770,1994; Shiraishi etc., " bio-pharmaceutical bulletin " be 16:1164 (Biol.Pharm.Bull.), and 1993; Thacharodi and Rao, " International Journal of Pharmaceutical Medicine " (Int ' l J.Pharm.) 120:115,1995; Miyazaki etc., " International Journal of Pharmaceutical Medicine " (Int ' l J.Pharm.) 118:257,1995).Preferred polymer (copolymer and the admixture that comprise these polymer) comprises poly-(ethylene-be total to-vinylacetate), poly-(carbonic ester urethane), poly-(hydroxy acid) (for example poly-(D, L-lactic acid) oligomer and polymer, poly-(L-lactic acid) oligomer and polymer, poly-(D-lactic acid) oligomer and polymer poly (glycolic), the copolymer of lactic acid and glycolic, the copolymer of lactide and Acetic acid, hydroxy-, bimol. cyclic ester, poly-(caprolactone), lactide or Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone) copolymer, poly-(valerolactone), poly-(anhydride), copolymer by caprolactone and/or lactide and/or Acetic acid, hydroxy-, bimol. cyclic ester and/or Polyethylene Glycol preparation.

Various polymer and the non-polymer thin film and the mesh that can be associated with anti-scarring agent have been described.For example, described thin film or mesh can discharge the biodegradable polymer substrate of described activating agent in the controlled release mode for what adapt with tissue.For example, referring to United States Patent (USP) 6,461,640.Described thin film or mesh can be for having soaked into the siloxane sheet of adhesion certainly of antioxidant and/or antibacterial.For example, referring to United States Patent (USP) 6,572,878.Described thin film or mesh can be for being suitable for covering the softness cover that has connecting hole and perforation of the bone dissec in the spinal column.For example, referring to United States Patent (USP) 5,868,745 and Application No. 2003/0078588.Described thin film or mesh can-lactide poly-for having the mocromembrane of absorption again of non-porous polymer host material monolayer.For example, referring to United States Patent (USP) 6,531,146 and U. S. application number 2004/0137033.Described thin film or mesh can be flexible nerve decompression device, and it has the outer surface that is made of microstructure and forms so that reduce fibrous tissue around coated nerve in pipe the time.For example, referring to United States Patent (USP) 6,106,558.Described thin film or mesh can be for being enclosed in spinal column on every side to suppress the collagen film of absorption again of cell adhesion.For example, referring to United States Patent (USP) 6,221,109.Described thin film or the mesh wound dressing skin from adhesion inner liner formed of outer soft layer of can serving as reasons as the dressing of contact wound.For example, referring to United States Patent (USP) 6,548,728.Described thin film or mesh can be for having the binder of scar treatment pad, and described scar treatment rim strip has silicone elastomer or silicone gel.For example, referring to United States Patent (USP) 6,284,941 and 5,891,076.Described thin film or mesh can be for containing the crosslinkable system of at least three kinds of compound of reactions, and described chemical compound has the polymer molecule nuclear that has at least a functional group separately.For example, referring to United States Patent (USP) 6,458,889.Described thin film or mesh can be made up of the artificial fabric with three dimensional structure that two surfaces are separated, and one in wherein said two surfaces the postoperative cell is grown (colonization) surely and open, and another is connected with the collagen-based materials thin film.For example, referring to United States Patent (USP) 6,451,032.Described thin film or mesh can be made of two kinds of synthetic polymers, a kind of nucleophilic group that has, and another kind has electrophilic group, makes them form the substrate that can be used to mix bioactive compound.For example, referring to United States Patent (USP) 6,323,278; 6,166,130; 6,051,648 and 5,874,500.That described thin film or mesh can be served as reasons is assorted-thin film that difunctionality tissue adhesion bonding agent is formed, described tissue adhesion bonding agent rises and makes host material, such as collagen protein with accept to organize covalently bound effect.For example, referring to United States Patent (USP) 5,580,923.Described thin film or mesh can for as prevent the fitness warp-knitted fabric that oxidized regenerated cellulose that the physical barriers of tissue adhesion works or other biology can resorbent materials.For example, referring to United States Patent (USP) 5,007,916.Be used to implement mesh of the present invention and also be described in United States Patent (USP) 6,575, the title of 887 and 2003 on JIUYUE submission in 26, is co-pending application (U.S.'s serial number (U.S.'s serial number 10/673,046) of " coated thing around the blood vessel " (" Perivascular Wraps ").

In one aspect, described mesh goes for the operation technique of hernia prothesis or other type.The mesh fabric that is used to connect the hernia reparation is disclosed in United States Patent (USP) 6,638, in 284,5,292,328,4,769,038 and 2,671,444.Can by knitting, weave, interweave, otherwise just by making multi cord yarn (for example by polymeric material, monofilament or the multifilament yarn made such as polypropylene and polyester) form the grating texture production operation mesh of supporting.Knitting and the braided fabric and the application of these fabrics in surgical repair that are made of various synthetic fibers also have been discussed: United States Patent (USP) 3,054,406 in following document; 3,124,136; 4,193,137; 4,347,847; 4,452,245; 4,520,821; 4,633,873; 4,652,264; 4,655,221; 4,838,884 and 5,002,551 and European patent application EP 334,046.Implantable hernia mesh is described in United States Patent (USP) 6,610, in 006,6,368,541 and 6,319,264.The hernia mesh that is used to repair Hernia hiatus for example is described in the United States Patent (USP) 6,436,030.The hernia mesh that is used to repair abdominal part (for example abdomen and umbilicus) hernia is described in United States Patent (USP) 6,383, in 201.Anti-infective hernia mesh for example is described in the United States Patent (USP) 6,375,662.Be suitable for merging the fibre modification derivant to produce the mesh that promotes fibrous tissue growth such as the hernia mesh that is described in the above-mentioned patent.

In one aspect, the fibre modification inhibitor can be mixed biodegradable or soluble thin film or mesh, before implanting prosthetic/graft or afterwards, this thin film or mesh be applied on therapentic part then.The typical material that is used to make these thin film or mesh is hyaluronic acid (crosslinked or noncrosslinking), cellulose derivative (for example hydroxypropyl cellulose), PLGA, collagen protein and crosslinked poly-(ethylene glycol).

Described thin film or mesh can be the tissue grafts form, and it can be the graft or the xenograft of autograft, allograft, biograft, biogenetic derivation.Tissue grafts can derive from various types of organizations.The representational example that can be used to prepare the tissue of biograft includes, but are not limited to rectus sheath, peritoneum, bladder, pericardium, vein, tremulous pulse, diaphragm and pleura.The graft of biogenetic derivation can be gathered from the host, makes its load anti-scarring agent, and in circumvascular mode it is applied to the position (for example anastomotic position) that may damage with neointimal hyperplasia subsequently.In case implant, then activating agent (for example paclitaxel) discharges and can penetrate blood vessel wall from this graft and forms neointimal hyperplasia with the prophylactic treatment position.In certain embodiments, biograft can be as the backsheet layer that has sealed compositions (gel or the paste of the anti-scarring agent of for example having loaded).

Can have benefited from having the thin film of polymer composition of the theme of the present invention that is impregnated into adjacent tissue and mesh according to the present invention comprises and is purchased product.Can mix the thin film of fibre modification activating agent and the example of mesh comprises based on INTERCEED (the Johnson ﹠amp that gathers (ethylene glycol) and poly-(butylene terephthalate); Johnson, Inc.), ((Shrewsbury is NJ) with from Johnson ﹠amp for Osteotech, Inc. for poly-(ether-ether) segmented copolymer for PRECLUDE (W.L.Gore) and POLYACTIVE; Johnson. the absorbable hemostatic gauze print of SURGICAL.Another kind of mesh be the artificial polypropylene mesh that is called the biological operation of SEPRAMESH complex with biological absorber coatings again (Genzyme Corporation, Cambridge, MA).The biology that one side of this mesh has applied hyaluronate sodium and carboxymethyl cellulose is absorbed layer again, makes the isolating interim physical barriers of following tissue and organ surface and mesh thereby formed.The opposite side of this mesh is not coated, makes complete tissue be similar to sky polypropylene mesh and inwardly grows.In one embodiment, the fibre modification derivant only is coated on the uncoated side of SEPRAMESH, and is not coated on hyaluronate sodium/carboxymethyl cellulose coated side.Other thin film and mesh comprise: (a) the BARDMARLEX mesh (C.R.Bard, Inc.), it is to have low porous very fine and close knitting fabric construction; (b) monofilament polypropylene mesh, such as available from Ethicon, Inc.Somerville, the PROLENE of NJ (for example, referring to United States Patent (USP) 5,634,931 and 5,824,082)); (c) (all from Cook Surgical, Inc.), they are for being used for strengthening the specifically-built device of soft tissue in open and the laparoscopic procedure repair of inguinal hernia for SURGISIS GOLD and SURGISIS IHM soft tissue graft thing; (d) thin-walled polypropylene operation mesh, such as available from Atrium MedicalCorporation (Hudson, NH), commodity are called PROLITE, PROLITE ULTRA and LITEMESH; (e) COMPOSIX hernia mesh (C.R.Bard, Murray Hill, NJ), (this sticking patch comprises the two-layer synthetic mesh of generally being made by polypropylene of inertia and is described in United States Patent (USP) 6 wherein to have mixed the mesh sticking patch, in 280,453) and comprise the silk of strengthening and keeping the device of flat configuration; (f) (from C.R.Bard, Inc.), it is the polypropylene mesh that is made of the monofilament polypropylene to the VISILEX mesh; (g) available from C.R.Bard, other mesh of Inc., they comprise PERFIX Plug, KUGEL hernia sticking patch, 3D MAX mesh, LHI mesh, DULEX mesh and VENTRALEX hernia sticking patch; (h) the polypropylene monofilament hernia mesh of other type and pad product comprise from HerniameshUSA Inc. (Great Neck, HERTRA mesh 1,2 NY) and 2A, HERMESH 3,4﹠amp; 5 and HERNIAMESH pad T1, T2 and T3.

Other example that is purchased mesh of polymer composition that can have benefited from having the theme of the present invention that is impregnated into adjacent tissue is as described below.A kind of example comprises the artificial polypropylene mesh of selling that has biological absorber coatings again under trade name SEPRAMESH biological operation complex (Genzyme Corporation).The biology that one side of this mesh has applied hyaluronate sodium and carboxymethyl cellulose is absorbed layer again, makes the isolating interim physical barriers of following tissue and organ surface and mesh thereby formed.The opposite side of this mesh is not coated, makes complete tissue be similar to sky polypropylene mesh and inwardly grows.In one embodiment, will comprise that the polymer composition of the theme of the present invention of fibre modification derivant and/or anti-infective only is coated on the uncoated side of SEPRAMESH, and not be coated on hyaluronate sodium/carboxymethyl cellulose coated side.Boston Scientific Corporation has sold TRELEX NATURL mesh, and it is made up of the knitting polypropylene material of uniqueness.Ethicon, Inc. have made absorbable VICRYL (polyglactin 910) mesh (knitting and braiding) and MERSILENE polyester fiber mesh.(Midland MI) has sold the mesh material that is formed by silicone elastomer to Dow Corning Corporation, is called SILASTIC Rx medical grade sheet (Platinum Cured).(Norwalk CT) has sold by can absorb the mesh of selling that polyglycolic acid is made under trade name DEXON mesh product United States Surgical/Syneture.(Obernburg Germany) has sold CELGARD microporous polypropylene fibers and film to Membrana Accurel Systems.Ethicon, the Gynecare Worldwide of branch of Inc. has sold the mesh material of being made by oxidation hypertrophy cellulose that is called INTERCEED TC7.(Plainsboro NJ) has made DURAGEN PLUS adhesion barrier substrate to Integra Life SciencesCorporation, and it can and be used to recover dural barrier as the adhesion behind anti-spinal column and the craniotomy.From MacroPore Biosurgery, the Inc. (thin film of the interim wound holder that San Diego, CA) HYDROSORB cover form for the adhesion that is used for controlling specific spinal column and uses.

The polymer and the non-polymeric carriers system that can be used for combination film and mesh have in a large number above been described.Be used for mixing on thin film or mesh or the method for mixing wherein comprises with suppressing fibrotic compositions: (a) (directly or indirectly) make the fibrotic compositions of thin film or mesh and inhibition fix (for example pass through nebulization or soaking method as mentioned above, wherein use or do not use carrier); (b) will suppress fibrotic compositions mixes or is impregnated into thin film or mesh and (for example as mentioned above by nebulization or soaking method, wherein use or do not use carrier; (c) by using hydrogel this class material coating thin film or the mesh that suppresses fibrotic compositions such as adsorbing successively; (d) with the part that suppresses fibrotic compositions structure thin film or mesh self or thin film or mesh; Or (e) by making fibre modification inhibitor and thin film or meshed surface or coating or being connected thin film or the direct covalent bond of the junctional complex of meshed surface (micromolecule or polymer).With regard to the device of coating, can apply according to following this class mode: (a) only apply a surface of thin film or mesh, or (b) both sides all or part of of coating thin film or mesh.

In one aspect, the invention provides the thin film or the mesh of the polymer composition that can have the theme of the present invention that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).In certain embodiments, described polymer composition is for playing the polymer composition of surgical adhesions barrier action.

Described can with the polymer composition of the present invention surface and mesh coupling.This based composition can be this class form of example gel, spray, liquid and paste or can be by monomer or the polymerization in position of prepolymer (prepolymeric) composition.For example, said composition can be the polymer tissue coating, and it can form by the polymerization initiator coating is covered with the water solublity macromonomer organizationally and then, and described water-soluble macromolecule can use radical initiator polymerization under the UV light action.For example, referring to United States Patent (USP) 6,177,095 and 6,083,524.Said composition can be for comprising the Aquo-composition of surfactant, pentoxifylline and polyoxyalkylene polyethers.For example, referring to United States Patent (USP) 6,399,624.Said composition can for can be when the contacting hydrous environment optionally segmentation be combined into fitness water-setting micelle the formation hydrogel, from the absorbable polyester copolymer of solvation.For example, referring to United States Patent (USP) 5,612,052.Said composition can be made up of flowable prepolymer material, this prepolymer material can be emitted to tissue surface and then in position the contact activation energy so that causing that the material of coating changes into can not mobile polymer form.For example, referring to United States Patent (USP) 6,004,547 and 5,612,050.Said composition can be made up of the admixture of gas with the oxygen that has 1-20% volume ratio.For example, referring to United States Patent (USP) 6,428,500.Said composition can suppress forming greater than 5% the bisulfate and the anionic polymer of sulfur content of mononuclear cell or macrophage intrusion by having had.For example, referring to United States Patent (USP) 6,417,173.Said composition can by with or do not form with the non-agglomerative polyoxyalkylene compositions of therapeutic agent.For example, referring to United States Patent (USP) 6,436,425.Can be coated in said composition on the tissue surface and said composition can be formed at the water solublity of the hydrophilic polymer material (for example polypeptide class or polysaccharide) of 0.01%-15% weight by having greater than 50,000 molecular weight and concentration range.For example, referring to United States Patent (USP) 6,464,970.

Representational example with the polymer composition of thin film or mesh adjacent tissue be can be impregnated into and system, hyaluronic acid and cross-linked-hyaluronic acid compositions comprised based on poly-(ethylene glycol).These compositionss maybe can be formed them as original position the material coating of cross-linked gel as the final composition coating.

Can include, but are not limited to other compositions of thin film and mesh coupling: (a) the sprayable preparation that contains PEG, such as COSEAL, SPRAYGEL, FOCALSEAL or DURASEAL; (b) contain hyaluronic preparation, such as RESTYLANE, HYLAFORM, PERLANE, SYNVISC, SEPRAFILM, SEPRACOAT, INTERGEL; (c) polymer gel is such as REPEL or FLOWGEL; (d) dextran sulfate gel is such as the series of products of ADCON; (e) based on the compositions of lipid, such as ADSURF (Brittania Pharmaceuticals).

Can be by in gnotobasis, making thin film or the mesh device of thin film or mesh (or comprise) and/or can using method as known in the art their sterilizations the most at last, the combination of described method such as gamma-rays or electron beam sterilization method or these two kinds of methods.

Thin film and mesh can be applied any tissue that maybe can be easy to take place fibre modification or neointimal hyperplasia at any bodily conduit.Before implantation, can prune thin film or mesh or from the massive material sheet, downcut so that be complementary with the structure of the hole of widening, pipe or anatomical area, perhaps on bottom line, cover the area of organizing that exposes.Can make thin film or mesh crooked or form definite shape so that be complementary with the particular configuration of put area.Thin film or mesh can also be rolled into cover scrotiform or cylindrical and be placed on the required exterior circumferential of organizing.The thin film of sheet form of relative bulk or mesh can be provided and be cut into mouldable ad hoc structure then and coated tissue or the shape of tissue surface topography structure.Perhaps, thin film or mesh can be prefabricated into one or more patterns that can use subsequently.Thin film and mesh generally can and can be placed or be placed on the desired location in the operative site by endoscopic technique for rectangular shape by direct operation.Can be by thin film or mesh is coated on himself (promptly from adhesion) or by making itself and stitching thread, nail (staples), sealer etc. fixing and with they fix in position.Perhaps, thin film or mesh are easy to and organize adhesion and can not need extra fixed structure thus.

Thin film of the present invention or mesh can be used for various indications, include, but are not limited to: (a) surgical adhesions between the prevention of postoperative tissue (for example gynecilogical operation, vasovasostomy, hernia reparation, nerve root decompression operation and laminectomy); (b) prevention hypertrophic cicatrix or keloid (for example because of tissue burn or other wound due to); (c) prevention neointimal hyperplasia and/or restenosis (for example because of insert blood vessel graft or hemodialysis access device due to); (d) can cause synulotic device and implant coupling (for example as the cover around the breast implant or mesh to reduce or suppress cicatrization) with as described herein; (e) prevention infection (for example because of tissue burn, operation or other wound due to); Or (f) can cause device and the implant coupling infected with as described herein.

In one embodiment, thin film or mesh can be used to prevent to perform the operation, adhesion between the tissue after damage or the disease.Adhesion forms, and promptly belonging to the systemic complex process of normal growth each other modal is that result as surgical operation and/or wound takes place.In general, it is the inflammatory reaction of releasing factor that adhesion forms, and makes vascular permeability increase and causes fibrinogen to flow into and fibrin deposits.This formation of deposits the substrate of bridge joint adjacent tissue.Fibroblast is accumulated, and adheres with substrate.Deposition collagen protein and induction of vascular take place.If can prevent this situation cascade in 4-5 days after surgery, so just can suppress adhesion and form.Adhesion forms or unwanted scar tissue is accumulated and encapsulation makes various operations exist complicated and be actually and cause abdominal cavity or Intrapelvic any opening or endoscopic surgery complicated operationization.The encapsulation of operation transplantation thing makes that also breast reconstruction, joint replacement, hernia prothesis, the operation of artificial blood vessel's graft and neurosurgery are complicated.In each case, implant is endangered or is influenced the fibrous connective tissue capsule encapsulation of surgery implant (for example breast implant, artificial joint, surgical mesh eye, blood vessel graft, dura mater sticking patch) function.In other zone of proofreading and correct chronic sinusitis or removing chronic inflammatory disease (for example also chronic inflammatory disease and cicatrization can take place in the operation process of foreign body, infection (fungus, mycobacterium).Can cause the operation technique of surgical adhesions can comprise the operation of heart, spinal column, nerve, pleura, thorax and gynecological.Yet adhesion can also take place as the result of other process, includes, but are not limited to nonoperative mechanical damage, ischemia, hemorrhage, radiotherapy, inflammation, inflammatory pelvic disease and/or the foreign body reaction relevant with infection.This unusual cicatrization has disturbed the normal physiological function effect, and in recent case, can force and/or follow up a case by regular visits to, proofread and correct or other operation technique.For example, these postoperative surgical adhesions take place in implementing 60-90% patient of gynecological's major operation and have represented ileac main cause in the industrialization world.These adhesions are the main cause of operative therapy failure and are intestinal obstruction and infertile main cause.The complication of other adhesion treatment comprises chronic pelvic pain, urethral obstruction and drainage malfunction.

At present, the preventative therapy that gave in 4-5 days after surgery is used to suppress adhesion and forms.Check various forms of adhesion preventive measures, comprised the reconstruction of (1) prevention fibrin; (2) alleviate the local organization inflammation; (3) remove the fibrin deposit.Be health adhesion barrier prevention fibrin deposition machinery or that form by viscosity solution by using.Although many research worker are used adhesion prevention barrier, still there are many technical difficulties.

Provide the thin film and the mesh of polymer composition to be used as the surgical adhesions barrier among the present invention in one aspect with the theme of the present invention that is impregnated into adjacent tissue that comprises anti-scarring agent.

In one aspect, have the thin film of polymer composition of the theme of the present invention that is impregnated into adjacent tissue that comprises anti-scarring agent and the surgical adhesions that mesh can be used for preventing epidural and dura mater tissue, and this is the factor that causes back surgery failure and the complication relevant with spinal injury (for example compressing and crush injury).In the dura mater and the cicatrization around the nerve root to relate to the spinal operation that makes subsequently more difficult technically.In order in the back surgery process, to enter vertebral foramen, destroy vertebral tissue usually.Back surgery need make the spinal column dura mater expose with not protected such as laminectomy and diskectomy usually.As a result of, scar tissue forms between dura mater and surrounding tissue usually.This cicatrix is formed by the impaired erector spinae muscle that covers the laminectomy position.This causes sticking together between muscular tissue and fragility dura mater, and the mobility of spinal column and nerve root is descended, and causes pain and post-operative recovery slow.In order to prevent that adhesion from taking place, can be inserted between dura mater cover and the other muscular tissue of spinal column at the barrier that will reduce cicatrix behind the laminotomy.This has just reduced cell and blood vessel and has invaded epidural space from the muscle that covers and the spongy bone of exposure, and reduced thus with hold spinal column and/or nerve root in the relevant complication of pipe.

In one aspect of the method, the thin film of polymer composition and the mesh with the theme of the present invention that is impregnated into adjacent tissue that comprises anti-scarring agent can be used to prevent to repair the fibre modification that takes place between mesh and the surrounding tissue from hernia.Hernia is the unusual projection (turning up) by the organ of defective or natural openings in epiphragma, muscle or the bone or other body structure.Hernia self is not dangerous, if but their stenosis are narrow, so just may become extremely serious problem.The operation that is used for the hernia reparation comprises artificial mesh or gauze sample material with prosthese (this paper is called " hernia mesh "), and they support hernia or other body structure of reparation in agglutination.Hernia need undergo surgery usually and repair with complication prevention.The situation that may need to use the hernia mesh includes, but are not limited between groin (inguina1) (being groin (groin)), umbilicus, veutro, thigh, abdominal part, diaphragm, epigastrium, stomach esophagus, ceasma, flesh, by the mesentery, peritoneum, the reparation of deviating from (rectoceca1), uterus and cystocele of rectum vagina, rectum.The hernia reparation generally comprises and makes its normal position that turns back to internal organs and with stitching thread damaged on the closure wall basically, if not bigger breach is arranged, so mesh is placed on the damaged opening of going up with the sealing hernia.Make the polymer composition of the theme of the present invention that comprises anti-scarring agent be impregnated into the adjacent fibre modification of hernia mesh that the tissue adjacent with hernia reparation mesh can reduce or prevent and implant, the probability with adhesion between stomach wall or other tissue and the mesh self is reduced to bottom line and reduces further complication and stomachache thus.

In one aspect of the method, have the thin film of polymer composition of the theme of the present invention that is impregnated into adjacent tissue that comprises anti-scarring agent and mesh and can be used to prevent hypertrophic cicatrix or keloid (for example because of tissue burn or other wound due to).Hypertrophic cicatrix and keloid are the results of excessive fibroplasia wound healing reaction.Briefly, wound healing and cicatrization take place at three phases: inflammation, hypertrophy and maturation.First inflammation takes place as the reaction to the seriousness damage that is enough to destroy skin in stage.In this stage of lasting 3-4 days, blood and tissue fluid have formed and have been used for adhesion grumeleuse and the fibrous reticular structure bonded to each other with wound surface.After this be proliferative phase, wherein exist capillary tube and connective tissue inwardly to grow and the sealing skin injury from edge of wound.At last, in case capillary tube and fibroblast proliferation stop, just beginning maturation process, wherein cicatrix is shunk and cell tails off, blood vessel tails off just looks at flat and turn white.This terminal stage may continue 6-12 months.If more connective tissues produce and wound continues residual cell; Cicatrix just may redden and swell so.If cicatrix remains in the original wound boundaries, it is called hypertrophic cicatrix so, and if it expands to beyond the original cicatrix and enter surrounding tissue, infringement is called keloid so.Synulotic second and the phase III in produce hypertrophic cicatrix and keloid.Several wounds are easy to endothelium and fibroblast hyper-proliferative especially, comprise burn, open wound and infected wound.With regard to hypertrophic cicatrix, the ripe and generation that occurs to a certain degree progressively improves.Yet, with regard to keloid, the solid tumor that wound may become very huge.In this class situation hardly spontaneous improvement may take place.The thin film that can place the polymer composition with the theme of the present invention that is impregnated into adjacent tissue that comprises anti-scarring agent and mesh are to contact wound or burn position so that prevention hypertrophic cicatrix or keloid form.

In one aspect of the method, have the thin film of polymer composition of the theme of the present invention that is impregnated into adjacent tissue that comprises anti-scarring agent and the outside (surface) that mesh can be used for anti-scarring agent is delivered to body passage or chamber.Example bag tremulous pulse, vein, heart, esophagus, stomach, duodenum, small intestinal, large intestine, biliary tract, ureter, bladder, urethra, lacrimal passage, trachea, bronchus, bronchioles, nasal airway, pharyngotympanic tube, external auditory meatus maya1, deferent duct and the fallopian tube of body passage.The example in chamber comprises abdominal cavity, oral cavity, peritoneal cavity, pericardial cavity, pelvic cavity, internal organs chamber, pleural space and cavity of uterus on every side.

Can comprise that with the disease example of mesh treatment or prevention the iatrogenic complication of tremulous pulse and venous cannulation, complication, the gastrointestinal channel of blood vessel cutting break and the complication of cutting, restenosis (restonotic) complication and the neointimal hyperplasia relevant with vascular surgery (for example by-pass operation) with the thin film of polymer composition with the theme of the present invention that is impregnated into adjacent tissue that comprises anti-scarring agent.

In one aspect, can from the polymer composition of the theme of the present invention that is impregnated into the tissue adjacent, anti-scarring agent be delivered to the outer wall in body passage or chamber with thin film or mesh, purpose is to prevent and/or alleviate the hypertrophy biological respinse of the best-of-breed functionality effect that may hinder or stop described passage or chamber, comprising: for example the iatrogenic complication of tremulous pulse and venous cannulation, rupture of heart, aneurysm, cardiac valve cracking, graft are placed (for example A-V-bypass, periphery bypass, CABG), fistulization, passage breaks and the surgical wound reparation.

Described thin film or mesh can use with the form of coated thing around the blood vessel, so that prevention is because of the restenosis on the anastomotic position that inserts blood vessel graft or hemodialysis access device and cause.In this case, have the blood vessel of polymer composition of the theme of the present invention that is impregnated into adjacent tissue that comprises anti-scarring agent around coated thing can be used in combination with blood vessel graft so that suppress cicatrization on the anastomotic position.Can when operation with blood vessel around the mode in (adventitia week) thin film or mesh are placed or coated in identical outer periphery.Have the thin film of polymer composition of the theme of the present invention that is impregnated into adjacent tissue that contains anti-scarring agent or mesh can with synthetic bypass graft (strand-popliteal, thigh-thigh, anterior axillary line-thigh etc.), vein transplantation thing (periphery and crown), interior breast (crown) graft of body or hemodialysis graft (AV fistula, AV access graft) coupling.

In order further to understand this class disease, the representational complication of the integrity in cause being harmful to health passage or chamber is more specifically discussed hereinafter.

In one aspect, the polymer composition of theme of the present invention can be impregnated into and the adjacent tissue of coronary bypass grafting thing (" CABG ").The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

In one aspect, the polymer composition of theme of the present invention can be impregnated into and the adjacent tissue in periphery by-pass operation position.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

In one aspect, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with A-V fistula.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

In one aspect, the polymer composition of theme of the present invention can be impregnated into and the adjacent tissue in periphery by-pass operation position.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

In one aspect, the polymer composition of theme of the present invention can be impregnated into and the adjacent tissue of closing device that coincide.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

In one aspect, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with the transplant operation position.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with mesh with thin film is suitable for containing and/or discharges one or more activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, and four kinds of ordinary circumstances of described fibre modification (or cicatrization) process comprise: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because thin film and mesh are made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on about tissue surface can be in following scope: about 0.01 μ gmm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mrm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

The glaucoma drainage system

In one aspect, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with the glaucoma drainage system.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

Various types of glaucoma drainage systems can be used to implement this aspect.Some glaucoma drainage system comprises plate and pipe.The function of pipe is the upper surface from intraocular delivery to the episcleral layer plate with water.The episcleral layer plate firmly merges with raphe sclerae and is covered by the sheet of Tenon tissue and conjunctiva.The function of plate is to cause that big annular bleb forms, and this big annular bleb develops into specific fiber blood vessel bleb lining and expanded by water.This exactly fiber blood vessel bleb lining causes regulating water breaks away from and determine to insert the intraocular pressure (IOP) that obtains after the implant from eye terminal level.Excessive as the fruit fiber vascular reaction, Zhuan Zhi drain ability will descend so.In one aspect of the invention, will comprise the whole or coated adjacent tissue that the polymer composition of fibre modification inhibitor is impregnated into and installs, and make the fibre modification inhibitor that discharges regulate healing reaction, device is correctly worked.In another aspect of the present invention, will comprise the whole or coated adjacent tissue that the polymer composition of anti-infective (separately or with the coupling of fibre modification inhibitor) is impregnated into and installs, and make the anti-infective that discharges suppress or prevention infection.

For example, the glaucoma drainage system can be for being used for the conduit that cell is inwardly grown and connected with the sclera drainage plate that is connected episcleral porous rear surface with having.For example, referring to United States Patent (USP) 5,882,327.But the glaucoma drainage system can be made up of collapsible and episcleral layer plate and drainage tube roll extrusion, and this device can be delivered to the implant position by the injection delivery system thus.For example, referring to United States Patent (USP) 6,589,203.The glaucoma drainage system can be the pressure regulator of substrate plate composition, and described substrate plate is formed by the thin pliability elastomeric material (for example silicone rubber) with the fixed accommodating chamber that is connected with pipe.For example, referring to United States Patent (USP) 5,752,928.The glaucoma drainage system can be complementary so that the elastic plate of the closure elements of limit fluid is formed with the valveless elastic drainage tube that is connected by having with sclera.For example, referring to United States Patent (USP) 5,476,445.The glaucoma drainage system can be made up of the ridge shape plate of outside stretching, extension, on the one side for concave surface so that match and be suitable for side with sclera curvature and be connected with side, pipe stretches between ridge shape plate so that exchange thus.For example, referring to United States Patent (USP) 4,457,757.The glaucoma drainage system can be made up of thin oval elastic plate, and this plate has and is used to make the center positioning hole of scar tissue growth and is connected the elastic drainage tube that is used for and carries out the plate of fluid communication.For example, referring to United States Patent (USP) 5,397,300.The glaucoma drainage system can be made up of the pipe that has periphery hole, has on the described looping pit for being placed on the terminal pad on the port of export of pipe on the eyeball surface.For example, referring to United States Patent (USP) 5,868,697.The glaucoma drainage system can be for have the pipe of Flow-rate adjustment structure, passing through flow and have at least one looping pit that seals with absorbable material in pipe in the described Flow-rate adjustment structure compressed pipe temporarily.For example, referring to United States Patent (USP) 6,203,513.The glaucoma drainage system can be made up of with the porous liquid absorption pad of the major limitation fluid flow with the thread extension that is connected the pipe that has interface components.For example, referring to United States Patent (USP) 5,300,020.The glaucoma drainage system can be for having the elastomeric polymer drainage system that passage prolongs between end that becomes radial projection in body and flange.For example, referring to United States Patent (USP) 4,968,296.The glaucoma drainage system can be for making ophthalmic turn to the diverter of access to plant part, described device to produce branch from anterior chamber's aqueous humor so that provide fluid communication along the direction of Schlemm's canal.For example, referring to United States Patent (USP) 6,626,858.

Can have benefited from the glaucoma drainage system that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised and be purchased product, cylindrical tube for example, such as AQUAFLOW collagen protein glaucoma drainage system (STAAR Surgical Company, Monrovia CA) can be used to implement the present invention.Other example of glaucoma drainage system comprises Molteno Glaucoma Implant (the Single PlateMolteno Implant from MoltenoOpthalmic Limited (New Zealand), Pressure Ridge Single Plate Molteno Implant (D1), Microphthalmic Plate Molteno Implant (M1), Double Plate MoltenoImplant (R2/L2) and Pressure Ridge Double Plate Molteno Implant (DR2/DL2), BAERVELDT Glaucoma Implants (Models BG-101-350, BG-102-350, BG-103-250; Pfizer, New York, NY) with from New World Medical, Inc. (Rancho Cucamonga, CA) Ahmed Glaucoma Valve (Models FP7, S2, S3, PS2, PS3, B1.

The glaucoma drainage system of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue is provided among the present invention in one aspect, and wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with the glaucoma drainage system have above been described.

Can soak into thereon and with said composition and implanting around the glaucoma drainage system by polymer composition directly and/or indirectly being coated with following position or coating: (a) tissue adjacent with the glaucoma drainage system; (b) near glaucoma drainage system-organizational interface; (c) zone around the glaucoma drainage system; (d) tissue around the glaucoma drainage system.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with the glaucoma drainage system comprises described polymer composition is delivered to: (a) on the glaucoma drainage system surface of implant procedure process (for example as injectable, paste, gel or mesh); (b) before implanting the glaucoma drainage system at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the glaucoma drainage system glaucoma drainage system surface at once and/or implant tissue (for example forming gel or net) around the glaucoma drainage system as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed the glaucoma drainage system (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject glaucoma drainage system tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install.

In one aspect, said method can be used for the polymer composition of theme of the present invention is impregnated into all or part of adjacent tissue of the plate of device.

In one aspect of the method, said method can be used for all or part of adjacent tissue of the pipe that the polymer composition with theme of the present invention is impregnated into and installs.

In one aspect of the method, said method can be used for polymer composition plate that is impregnated into and installs and all or part of adjacent tissue of managing both with theme of the present invention.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with the glaucoma drainage system is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and Mi Tuo anthracene); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38 map kinase inhibitor (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because the glaucoma drainage system is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.-as, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on about tissue surface can be in following scope: about 0.01 μ g/mm ²-1/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

Prosthetic heart valve

In one aspect, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with prosthetic heart valve.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

Prosthetic heart valve is to be used to replace the natural cardiac valve of defective that causes because of congenital malformation, infection, part closure or wearing and tearing.Prosthetic heart valve generally is made up of the closer (occluder) that is connected with the closer substrate, and described closer substrate is connected with the suture ring of generator anchorage heart tissue successively.The substrate of closer is for ring-type and channel of blood flow is provided.Can exist one or more closers as alternative, so that regulate blood flow with open and closed form.For prosthetic heart valve and heart tissue are fixed, the suture ring of generally being made up of the knit goods pipe is rolled into annular and fixes with the periphery of prosthese closer substrate.General use stitching thread, sealer, binding agent, nail or use metal or polymer filaments clamp suture ring and heart tissue are fixed.

Although progressively refinement the design of prosthetic heart valve, complication still continue to take place.Because suture ring is made by synthetic material usually, so thrombosis, fibre modification and pannus occur at prosthetic heart valve usually.This cicatrization has hindered the function of valve and passing in time usually, may need operation technique and displacement for the second time.Suture ring generally is made up of synthetic polymer, includes, but are not limited to polyester (for example DACRON), politef (for example TEFLON), siloxanes and polypropylene.Suture ring is made up of the braided material of sewing up on implant material and the implant usually.The surface of suture ring is coarse because of covering cloth usually.This situation is easily damaged suture ring in early days after surgery and cicatrization is taken place, and serious pannus/fibre modification wherein takes place in the some months after implantation.The erosive consequence of fibre modification may be violent on the prosthetic heart valve, and possible catastrophic.For example, fibre modification can suppress its valve closure function by the suitable opening and the closed ability of restriction valve closer.Fibre modification extends to lobule from suture ring.This fibre modification can make lobule merge on its junction, twists each lobule and/or makes lobule sclerosis, makes them can't suitably open or closed.This fibrotic final result is generally valvular stenosis and inadequacy.Prosthetic heart valve also may be the source of infecting in the surrounding tissue of implant position.

The prosthetic heart valve that has two kinds of main types, promptly machinery and prosthetic heart valve biology.In general, mechanical prosthetic heart valve and biological prosthetic heart valve all use synthetic suture ring.Their main distinction is the closer type difference used.The closer of mechanical prosthetic heart valve can be made up of ball-cage prosthesis assembly (ball and cage assembly), single leaf dish valve (disk valves) or bilobate dish valve.The valvular closer of bioprosthesis is organized by the animal or human of simulation natural cardiac valve outward appearance that it replaced and function and is formed.The bioprosthesis heart valve leaflets is made up of chemically treated tissue usually.The valve of gathering is fixed in glutaraldehyde or the similar fixative so that they are suitable for the human body implantation.

In one aspect, described prosthetic heart valve can be mechanical prosthetic, and it generally is made up of the hard lobule that biocompatible substance (for example RESEARCH OF PYROCARBON (pyrolitic carbon), titanium or DACRON) forms.Mechanical prosthetic heart valve can be for shrouding the dish of ball component, bilobate, SANYE or inclination.Modal is bifolium because the blood dynamics characteristic of this valve blood flow comparatively steadily and turbulent flow good.For example, mechanical prosthetic can by have outside suture ring and be used for blood flow internal edge substrate and at least fistula sealing lobule form.For example, referring to United States Patent (USP) 6,068,657.Mechanical prosthetic can be formed by having as pivot and the centre bore of valve cover configuration and the annular valve cover of first and second valve leaflets.For example, referring to United States Patent (USP) 4,808,180 and 5,026,391.Mechanical prosthetic can be designed to have annular solid, it has at least one lobule as the pivot configuration, makes that it can be by moving to determine the magnet that pressure is applied on the lobule power between open and make position.For example, referring to United States Patent (USP) 6,638,303.Mechanical prosthetic can have annular solid, and it has a plurality of formation inlet inclined-plane and support the hinge of valve body at least one lobule.For example, referring to United States Patent (USP) 6,645,244 and 5,919,226.Mechanical prosthetic can form obducent supportive pliability cylindrical frame that tip that the SANYE valve device uses supports stent and form as being connected surperficial suture ring by having.For example, referring to United States Patent (USP) 5,258,023.Mechanical prosthetic can have the valve chamber of increase, and this chamber is made up of with the stitching cover that is used to described cover is connected with heart tissue the monolithic lobe mask that has at least one removable closer that is connected with described cover.For example, referring to United States Patent (USP) 6,007,577 and 6,391,053.The removable valve assemblies that mechanical prosthetic can slide by suture ring with on the suture ring central shaft is formed.For example, referring to United States Patent (USP) 5,032,128.Mechanical prosthetic can be the cylindrical stent of high-flexibility, and it is made up of a plurality of independently adjacent stent elements, and these elements have can become the radial mutual point and the Colaesce of moving and supporting a plurality of pliability lobules.For example, referring to United States Patent (USP) 6,558,418 and 6,338,740.Other mechanical prosthetic heart valve for example is described in the United States Patent (USP) 6,395,025,6,358,278,6,176,877,6,139,575 and 5,984,958.

In one aspect of the method, described prosthetic heart valve can be bioprosthetic device, and it is generally the pliability lobule that biomaterial (for example pig valve or bovine pericardium valve) forms.Can be with the stent frame supporting tissue valve with the stronger lobule of structure and durability is provided.Can also implant no stent tissue valve prosthesis by using the porcine aorta that still connects to gather pig valve.For example, can handle available from the bioprosthesis cardiac valve of donor (for example pig) reducing antigen, thus the inflammatory reaction when preventing to transplant.For example, referring to United States Patent (USP) 6,592,618.The bioprosthesis cardiac valve can be made up of the biological organization material of arranging around the mechanical annular holder that provides to the small part suture ring.For example, referring to United States Patent (USP) 6,582,464.The bioprosthesis cardiac valve can be made up of with the flexible material covering of sewing up pipe and be connected with Bicuspid valve xenograft Bicuspid valve (for example pig).For example, referring to United States Patent (USP) 5,662,704.The bioprosthesis cardiac valve can be by forming with the natural tissues cardiac valve that can the obducent artificial stent frame of covering fabric be connected.For example, referring to United States Patent (USP) 3,983,581; 4,035,849; 5,861,028; 6,350,282 and 6,585,766.The bioprosthesis cardiac valve can not have the stent valve for self-supporting, and it can be made up of the tubular bodies in mammal source.For example, referring to United States Patent (USP) 5,156,621 and 6,342,070.

In one aspect of the method, can use the technology of minimum level invasive to insert described prosthetic heart valve in place.For example, prosthetic heart valve can be delivered to the inflatable device of implant site and can expand into a plurality of lobules that are connected with the stent system with folded state for being suitable for.For example, referring to United States Patent (USP) 6,454,799.

In one aspect of the method, described device can be the cardiac valve ingredient.For example, this device can be for accepting the implantable cyclic rings of prosthetic heart valve.For example, referring to United States Patent (USP) 6,106,550.This device can be for having the suture ring of the periphery taper silk thread that is used to connect prosthetic heart valve.For example, referring to United States Patent (USP) 6,113,632.This device can be for being used for being sewed up by hard ring adnexa, knit goods the suture ring of the mechanical prosthetic heart valve that cover and sealing ring form.For example, referring to United States Patent (USP) 5,071,431.

Can have benefited from that the polymer composition of theme of the present invention is impregnated into the prosthetic heart valve of adjacent tissue and ingredient (for example ring-type suture ring) thereof according to the present invention comprises and is purchased product, such as from Edwards Lifesciences (Irvine, CA) Carpentier-EdwardsPERIMOUNT (CEP) cell biological prosthese, Carpentier-Edwards S.A.V. aorta bioprosthesis and Edwards PRIMA PLUS rustless steel bioprosthesis, from St.Jude Medical (St.Paul, MN) SJM REGENT valve and from Medtronic (Minneapolis, MOSAIC biological valvular prosthesis MN).

The prosthetic heart valve of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue is provided among the present invention in one aspect, and wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with prosthetic heart valve have above been described.

Can be by polymer composition directly and/or indirectly being coated with following position or coating is soaked into said composition around the implanting prosthetic cardiac valve thereon: (a) tissue adjacent with prosthetic heart valve; (b) near prosthetic heart valve-organizational interface; (c) zone around the prosthetic heart valve; (d) tissue of prosthetic heart valve.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with prosthetic heart valve comprises described polymer composition is delivered to: (a) on the prosthetic heart valve surface of implant procedure process (for example as injectable, paste, gel or mesh); (b) before the implanting prosthetic cardiac valve at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) at once prosthetic heart valve surface and/or the tissue around the implanting prosthetic cardiac valve (for example forming gel or net) behind the implanting prosthetic cardiac valve as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed prosthetic heart valve (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject prosthetic heart valve tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install.

In certain aspects, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent: (a) surface of cyclic rings (particularly mechanical valve prosthesis) with following surface; (b) lobe leaf surface (particularly bioprosthesis valve); And/or (c) above-mentioned combination arbitrarily.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with prosthetic heart valve is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because prosthetic heart valve is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or 10 μ g-10mg; Or 10mg-250mg; Or 250mg-1000mg; Or 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

Penile implant

In one aspect, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with the penile implant device.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).In one aspect, be impregnated in the polymer composition of theme of the present invention of the tissue adjacent and loaded anti-cicatrization medicine to prevent fiber kystis with penile implant.In one aspect of the method, being impregnated into the anti-infective of having loaded in the polymer composition of theme of the present invention of the tissue adjacent with penile implant (separately or with anti-cicatrization medicine combination) infects and/or encapsulation to prevent fiber.

Penile implant is used for the treatment of erectile dysfunction and is generally flexible post, twisting post or has the inflatable device of pump.The shape of deformity or undermined penis can be formed and can be used to erection function is provided, increase or provide to penile implant by post, screwed pipe, expandable catheter and/or pressure chamber.For example, penile implant can be for injecting balanic proper mucous membrane so that increase the balanic implantable polymeric material of male genital organ.For example, referring to United States Patent (USP) 6,418,934.Penile implant can partly be made up of a pair of curved elongate of making each other in the silicone rubber of mirror image, and it has variable peripheral wall thickness.For example, referring to United States Patent (USP) 6,537,204.Penile implant can be by being suitable for covering the spongy body lateral surface about not covering it side be used to increase the penis volume.For example, referring to United States Patent (USP) 6,015,380.Penile implant can be expandable self-contained implant, and it is formed fluid by having from the cylinder that storage is delivered to the pump of the pressure chamber with dropping valve.For example, referring to United States Patent (USP) 4,898,158 and 4,823,779.Penile implant can be made up of the elongation post with short relatively base section, is coated with on the described base section and contains a plurality of openings and expansible hydrophilic material layer when it absorbs water.For example, referring to United States Patent (USP) 4,611,584.Penile implant can be made up of at least one expandable pipe, and this pipe can carry out fluid communication with the mount board of the manual pump control that is subjected to implanting in the scrotum.For example, referring to United States Patent (USP) 6,475,137.Penile implant can be flexible double-walled part cylindrical shroud, and it has the bellows sample structure that is suitable for deformity of penis.For example, referring to United States Patent (USP) 5,669,870.Penile implant can be used to proofread and correct erectile dysfunction by partly being made up of at least one pliability, and described pliability is partly with by managing and be loaded with the pressure chamber that fluidic reservoir is connected, the fluid flow that makes pressurization when valve is open.For example, referring to United States Patent (USP) 4,917,110.Penile implant can be had the rustless steel pad of the cylinder encirclement of siloxanes ring by the quilt of many chain supports and form, and described siloxanes ring can vertically move the reaction of expanding or shrinking as to penis.For example, referring to United States Patent (USP) 5,433,694.Penile implant can enclose long and length by being made up of cylindrical shroud to increase, and described cylindrical shroud has the elasticity outer plate and is formed on from nonelastic of the inside of accepting fluidic closed bag under the pressure of fluid origin.For example, referring to United States Patent (USP) 5,445,594.Penile implant can make that this implant is to have flexible structure and unyielding hard structured extending product by having the interweave cover of outer elastic surface with the helical arrangement of the inner surface that has groove and rib.For example, referring to United States Patent (USP) 5,512,033.Penile implant can be for having the polymeric matrix of isolating chondroblast, and described chondroblast forms the cartilage structure with controllable biological mechanical property and hot strength on described matrix and inside deposition thus when implanting.For example, referring to United States Patent (USP) 6,547,719.Penile implant can make vasodilation be delivered to the erection body with the treatment impotence by supply pump, deformable reservoir and the conduit/dispensing catheter implanted are formed.For example, referring to United States Patent (USP) 6,679,832.Other penile implant for example is described in the United States Patent (USP) 6,579,230,5,704,895,5,250,020,5,048,510 and 4,875,472.

Can have benefited from the penile implant that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised and be purchased product, such as: for example from MentorCorporation (Santa Barbara, CA) TITAN inflatable prosthetic penile and AMS penile prosthesis product line, comprise Systems from American Medical, Inc. (Minnetonka, MN) AMS 700 CX CXM, AMS AMBICOR and AMS Malleable 600M.

The penile implant of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue is provided among the present invention in one aspect, and wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with penile implant have above been described.

Can be by polymer composition directly and/or indirectly being coated with following position or coating is soaked into said composition around the implantable penile implant thereon: (a) tissue adjacent with penile implant; (b) near penile implant-organizational interface; (c) zone around the penile implant; (d) tissue of penile implant.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with penile implant comprises described polymer composition is delivered to: (a) on the penile implant surface of implant procedure process (for example as injectable, paste, gel or mesh); (b) before the implantable penile implant at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) at once penile implant surface and/or the tissue around the implantable penile implant (for example forming gel or net) after the implantable penile implant as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed penile implant (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject penile implant tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install.

The infection (preceding after surgery usually 6 months) that placing penile implant can concurrent coagulase negative staphylococcus (comprising staphylococcus epidermidis), staphylococcus aureus, bacillus pyocyaneus, enterococcus, Serratia and candida mycoderma Pseudomonas (Candida) cause.Infect and to be characterised in that heating, erythema, scleroma and from the suppuration drain of operative site.Route of infection is the otch by when operation, although and used best aseptic operation technology, still there is penile implant to infect up to 3%.In order to help to resist this situation, use antibiotic solution lavation in average of operation periods usually.

The polymer composition that will contain anti-infective is impregnated into the tissue adjacent with penile implant can become possibility so that obtain the germ killing drugs level in the part, reduce the incidence rate that antibacterial grows (with local infection and failure of apparatus take place subsequently) surely thus, produce negligible system simultaneously and expose medicine.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with penile implant is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because penile implant is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or 10 μ g-10mg; Or 10mg-250mg; Or 250mg-1000mg; Or 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ gmm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day one about scope of 180 days.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent;

Endotracheal tube and tracheostoma intubate

In one aspect, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with the tracheostoma Intubaction device with endotracheal tube.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).Anti-scarring agent and endotracheal tube or tracheostoma intubate (for example breast pipe) or adjacent tissue combined to be used to prevent the artificial airway narrow and/or infect.

Endotracheal tube and tracheostoma intubate are used to keep air flue when needs ventilation auxiliary facilities.The endotracheal tube tendency is used for setting up the air flue of acute environment, and the tracheostoma intubate is used when needs prolong ventilation or have fixing the obstruction in last air flue.

In one aspect, it may be the required mechanical gas passage of non-ventilation in damage or the operation process that endotracheal tube provides.Endotracheal tube can have single chamber or two-chamber and can have single chamber or two-chamber, and can have flange or the air bag that is used for cohesive position in the trachea.For example, endotracheal tube can be formed by having the interior and outer pliability pipe that prevents to push ahead to the flange of the radial stretching, extension of one-tenth of larynx.For example, referring to United States Patent (USP) 5,259,371.Endotracheal tube can have the removable two-chamber that adheres to, and wherein first tubular cavity can take out from air flue, and second tubular cavity intactly keeps.For example, referring to United States Patent (USP) 6,443,156.Endotracheal tube can have the trachea part bronchus part that connects with the angle that forms single chamber, and when being positioned at the airbag inflation of pipe, its blocking-up air communication is crossed the bronchus part thus.For example, referring to United States Patent (USP) 6,609,521.The cylindrical portion that endotracheal tube can be connected by the tapering part that passes through other than ring type of fistula different-diameter is grouped into, so that replenish the glottis that extends from described tapering part that has a plurality of thin and softish sealing gill shape things.For example, referring to United States Patent (USP) 5,429,127.Endotracheal tube can be made up of barrel portion, and this barrel portion has visualizer, so that in the guidance that direction of rotation is provided for the beveled tip on the far-end when air flue is pushed ahead.For example, referring to United States Patent (USP) 6,568,393.Endotracheal tube can be made up of the light reflective coating hole and the multiple pliability passage that promote the image transmission, wherein a kind ofly be suitable for accepting fibre-optic bundle, and another kind is connected with inflatable cuff, and another kind is suitable for accepting ductile stilet (stylette) so that help to insert and taking-up.For example, referring to United States Patent (USP) 6,629,924.Endotracheal tube can be made up of hollow pliability cylindrical tube that has collar flange at the tip and the adapter that has the ring-type ridge, and described ring-type ridge is assemblied on the outer proximal surface of tube portion with concentric manner.For example, referring to United States Patent (USP) 5,251,617.Endotracheal tube can be made up of the person in charge who has sealing expansion inflated type sheathed catheter capsule, and it has the two-chamber that is used for lavation and suction so that remove the secretions that may collect in trachea.For example, referring to United States Patent (USP) 5,143,062.Other endotracheal tube for example is described in the United States Patent (USP) 6,321,749,5,765,559,5,353,787,5,291,882 and 4,977,894.

The tracheostoma intubate can be used to provide the bypass supply of gas when throat blocks.The tracheostoma intubate with insert the tucker coupling of trachea to help to breathe by the pore percutaneous in the adjacent intercartilaginous neck.For example, the tracheostoma intubate can be the tubular sleeve pipe that soft flexible plastic forms, and it has inclination, narrows down, angled and reclinate tapered distal end is so that locate in trachea.For example, referring to United States Patent (USP) 5,058,580.The tracheostoma intubate can be assemblied in and can form with the pipe of removable connector on the exposed ends of the seal of tube by having.For example, referring to United States Patent (USP) 5,606,966.The tracheostoma intubate can be formed by having the arc shrouds that stretches laterally and having with the rotatable tubular elbow of described sleeve pipe machinery fluid communication.For example, referring to United States Patent (USP) 5,259,376 and 5,054,482.The tracheostoma intubate can produce sonic vibration and forms with two air flues of the breathing electromagnetic shaker of the speech that allows to hear by having.For example, referring to United States Patent (USP) 4,773,412.The tracheostoma intubate can be made up of the inner sleeve that holds in the mode that can take out in trocar sheath, wherein between trocar sheath and trachea, have sealing shroud, break away from and allow to pronounce from trachea by second passage that forms between interior and the trocar sheath so that prevent air basically.For example, referring to United States Patent (USP) 4,573,460.The tracheostoma intubate can be by first hole in the neck outside that is oriented to wearing and tearing, provide and the 3rd connecting hole controlling air-flow formed in second hole of trachea interior orientation with by valve.For example, referring to United States Patent (USP) 5,957,978.The tracheostoma intubate can be by hollow pipe, have the inflatable air bag of orthographic projection and provide the flange of throat external stability to form.For example, referring to United States Patent (USP) 6,612,305.The tracheostoma intubate can and have by the high degree of flexibility material with wire reinforcement and can form along the neck ring jugularia partly that pipe slides.For example, referring to United States Patent (USP) 5,443,064.Other tracheostoma intubate for example is described in the United States Patent (USP) 6,662,804,6,135,110 and 5,983,895.

Can have benefited from the endotracheal tube that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised and be purchased product, such as from Nellcor Puritan BennettInc. (Pleasanton, CA) HI-LO tracheal intubation, LASER-FLEX tracheal intubation and ENDOTROL tracheal intubation, from Hudson RCI (Temecula, CA) SHERIDAN endotracheal tube and from C.R.Bard, Inc. (Murray Hill, BARD endotracheal tube NJ).

Can have benefited from the tracheostoma intubate that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised and be purchased product, such as from Nellcor Puritan BennettInc. (Pleasanton, CA) SHILEY TRACHEOSOFT XLT tracheostoma intubate, PHONATE speech valve and reusable nothing are overlapped telescopic tracheostoma intubate, from Portex, Inc. (Keene, PER-FIT percutaneous expansion (Dilational) tracheostoma NH) is rescued instrument bag, PORTEX BLUE LINE Cuffed tracheostoma intubate and BIVONA do not have cover tracheostoma intubate and from the CRYSTALCLEAR tracheostoma intubate of Rusch (Germany).

The endotracheal tube and the tracheostoma Intubaction device of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue are provided among the present invention in one aspect, and wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with endotracheal tube and tracheostoma Intubaction device have above been described.

Can soak into thereon and with said composition and implanting around endotracheal tube and the tracheostoma Intubaction device by polymer composition directly and/or indirectly being coated with following position or coating: (a) tissue adjacent with the tracheostoma Intubaction device with endotracheal tube; (b) near endotracheal tube and the tracheostoma Intubaction device-organizational interface; (c) zone around endotracheal tube and the tracheostoma Intubaction device; (d) tissue of endotracheal tube and tracheostoma Intubaction device.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with penile implant comprises described polymer composition is delivered to: (a) at endotracheal tube and tracheostoma Intubaction device surface (for example as injectable, paste, gel or the mesh) of implant procedure process; (b) before implanting endotracheal tube and tracheostoma Intubaction device at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind endotracheal tube and the tracheostoma Intubaction device endotracheal tube and tracheostoma Intubaction device surface at once and/or implant tissue (for example forming gel or net) around endotracheal tube and the tracheostoma Intubaction device as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed endotracheal tube and tracheostoma Intubaction device (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject endotracheal tube and tracheostoma Intubaction device tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with the tracheostoma Intubaction device with endotracheal tube is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because endotracheal tube and tracheostoma Intubaction device are made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or 10 μ g-10mg; Or 10mg-250mg; Or 250mg-1000mg; Or 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day one about scope of 180 days.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

Peritoneal dialysis catheters

In one aspect, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent so that pass medicine with peritoneal dialysis catheters peritoneum implant.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

Peritoneal dialysis catheters is generally provides the conduit two covers and that passage is arranged that enters peritoneum.Modal peritoneal dialysis catheters is designed to smooth basic Hough (Tenckhoff) conduit, Swan Neck Missouri conduit and Toronto Westem conduit.In peritoneal dialysis, peritoneum works as semipermeable membrane, is exchanged with downward Concentraton gradient by its solute.Continuous peritoneum discrepancy conduit is implanted enduringly so that those need pass in and out the dialysis of peritoneum repeatedly.The peritoneal catheter of implanting can be used for peritoneal dialysis or medicine is delivered to the device of peritoneum.These conduits can be made up of synthetic material, provide flexible polymer such as siloxanes, rubber, polyurethane or other.They can be designed to be configured to straight shape pipe maybe can for bending and can be molded as heteroid different shape is provided, comprise helical form and screwed pipe shape.Peritoneal catheter can be made up of maybe can be cut into partly a kind of successive element makes the conduit fix in position so that at one end upward form flange, cover, pearl or dish.

For example, peritoneal catheter can be the T-shape chamber of the elastic foldable that has the gateway, and described gateway has the liquid of can collecting or distribute, such as the flexible fluid passage of the prolongation of dialysis solution.For example, referring to United States Patent (USP) 5,322,519.Peritoneal catheter can and flow out conduit by the inflow of two paired looping cross sections of linearity be formed, and they connect fluted FLUID TRANSPORTATION branch.For example, referring to United States Patent (USP) 6,659,134.Peritoneal catheter can be made up of the multitube tubing that has the fluid bore in the outer membrane structure that wraps in fluid permeability, and described fluid permeability outer membrane structure has the permission fluid flow, does not organize adherent slit but can not make.For example, referring to United States Patent (USP) 5,254,084.Peritoneal catheter has 1/2nd spiral coils and flows and can be made up of a plurality of inflows and the tap hole that are positioned near its periphery and the length to provide radial, and has the coating of ultralow temperature isotropism carbon in abdomen on the cross section.For example, referring to United States Patent (USP) 5,098,413.Peritoneal catheter can be the pliability pipe of the elongation that has an end that is connected with the sheet at a pair of interval, this pipe outwards extend into have at least one cover body cavity so that the prevention catheter infections.For example, referring to United States Patent (USP) 4,368,737.Peritoneal catheter can be made up of two parts, and these two parts comprise the retainer part of the lasting stomach wall of inwardly growing and send and extract the pliability tube portion of the elongation of dialysis solution.For example, referring to United States Patent (USP) 4,278,092.Peritoneal catheter can be the pliability pipe, and it has the natural curved sections between near-end and the far-end and comprises the flange that becomes non-perpendicular angle to stretch to periphery with catheter shaft.For example, referring to United States Patent (USP) 4,687,471.Peritoneal catheter can be the percutaneous access apparatus, and this device is by being used for the outstanding cylindrical neck part of skin, being used for grappling and going into the annular casing part of dermis/subcutaneous tissue and can pass described neck and the cover conduit with the pliability bellows-shaped that can form an angle of 90 degrees is partly formed.For example, referring to United States Patent (USP) 4,886,502.Peritoneal catheter can have perforation at Qi Bishang for the pipe of flexible elongation, and these perforation can pass through fluid by means of the device that the centre bore that impels pipe enters fastening cylindrical helical form structure.For example, referring to United States Patent (USP) 4,681,570.The case description of other peritoneal catheter that is used to dialyse is in United States Patent (USP) 6,290,669,5,752,939 and 5,171,227 for example.

In one aspect of the method, peritoneal catheter can be used for peritoneal administration.For example, peritoneal catheter can be the subcutaneous injection pipe guide, and it has the receiving chamber that has the permeable membrane that holds injection needle, and this device can be done and the abdominal cavity interconnection by hollow.For example, referring to United States Patent (USP) 4,400,169.Peritoneal catheter can be made up of the porous shell of the inner chamber of the entrance and exit conduit of determining to have non-porous material, and described entrance and exit conduit is connected with the opening of shell and forms two passages.For example, referring to United States Patent (USP) 5,100,392.

The prolonged application peritoneal catheter can cause catheter infections or obstruction because of fibrin forms.Synthetic peritoneal catheter and drug delivery systems with polymer composition of the theme of the present invention that mixes adjacent tissue that contains anti-scarring agent can prevent narrow.Synthetic peritoneal catheter and drug delivery systems with polymer composition of the theme of the present invention that mixes adjacent tissue that contains anti-infective can prevent or suppress to infect.

Can have benefited from the peritoneal catheter that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised and be purchased product, for example, (Bloomington IN) sells long-term (Chronic) peritoneal dialysis catheters of helical form and Tenckhoff chronic peritoneal dialysis conduit to Cook Critical Care.(Salt Lake City UT) has sold Tenckhoff and HEMOSPLIT peritoneal dialysis catheters to Bard Access Systems.CardioMed Supplies, (ON Canada) has sold single cover and double detour peritoneal dialysis catheters and single cover and two cover screwed pipe shape peritoneal dialysis catheters to Inc.The direct sum screwed pipe shape Tenckhof conduit of sales slip and two covers and other company of other type peritoneal catheter comprise BaxterInternationa1, Inc. (Deerfield, IL), (Lexin, on is MA) with Gambro AB (Sweden) for Fresenius Medical Care.

The peritoneum discrepancy conduit and the implant of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue are provided among the present invention in one aspect, and wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with peritoneal dialysis implant and conduit have above been described.

Can said composition be soaked into around the implantation peritoneum is come in and gone out conduit and implant by polymer composition directly and/or indirectly being coated with following position or being coated with thereon: (a) with peritoneum discrepancy conduit or the adjacent tissue of implant; (b) near peritoneum discrepancy conduit or the implant-organizational interface; (c) zone around peritoneum discrepancy conduit or the implant; (d) tissue around peritoneum discrepancy conduit or the implant.Being used for polymer composition with theme of the present invention is impregnated into the come in and go out method of the conduit tissue adjacent with implant of peritoneum and comprises described polymer composition is delivered to: (a) at the peritoneum of implant procedure process come in and go out conduit or implant surface (for example as injectable, paste, gel or mesh); (b) come in and go out before conduit or the implant at once or the tissue surface in the process (for example forming gel or mesh) implanting peritoneum as injectable, paste, gel, original position; (c) implant peritoneum come in and go out after conduit and the implant at once peritoneum come in and go out conduit or implant surface and/or implant come in and go out tissue (for example forming gel or net) around conduit or the implant of peritoneum as injectable, paste, gel, original position; (d) placed the come in and go out anatomic space (useful especially being to use of this embodiment discharged polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of described therapeutic agent and can pass other preparation into the described activating agent of release in the zone of having inserted described device in the time limit in several hours more than one weeks) of conduit or implant of peritoneum by described compositions part is coated with; (e) by inject peritoneum discrepancy conduit or implant tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with conduit with the peritoneal dialysis implant is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Implant and conduit are made of not isostructure and size because peritoneum is come in and gone out, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on about tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

Central nervous system's part flow arrangement or pressure monitoring device

In one aspect, the polymer composition of theme of the present invention can be impregnated into device, such as CNS part flow arrangement or the adjacent tissue of pressure monitoring device with central nervous system (CNS).The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).CNS device with polymer composition of the theme of the present invention that is impregnated into adjacent tissue that comprises anti-scarring agent can prevention of restenosis block with the device that causes hydrocephalus and intracranial pressure to increase.CNS device with polymer composition of the theme of the present invention that is impregnated into adjacent tissue that comprises anti-scarring agent can prevent or suppress the infection in this device fabric tissue.

Hydrocephalus in the brain or cerebrospinal fluid (CSF) accumulate be run into usually because of congenital malformation, infection, hemorrhage or neurosurgery disease that malignant tumor causes.Incoercible fluid produces pressure to brain, causes cerebral lesion, if do not handle, even can cause death.The CNS part flow arrangement is to be placed in the ventricles of the brain so that make CSF flow to other body chamber and discharge hydraulic conduit from brain.Chamber CSF is diverted to many drains position by artificial part flow arrangement, comprises pleura (ventriculopleural shunt device), jugular vein, caval vein (VA part flow arrangement), gallbladder and peritoneum (VP part flow arrangement; The most common).

The representational example of CNS device comprises: CNS part flow arrangement for example, such as ventricles of the brain thoracic cavity part flow arrangement, jugular vein and caval vein (VA) part flow arrangement and ventriculoperitoneal part flow arrangement (VP part flow arrangement), such as gallbladder and peritoneum part flow arrangement; EVD (EVD) device; And intracranial pressure (ICP) monitoring device.Other CNS device comprises: for example prevent fibrotic dura mater sticking patch of vertebrae plate resection postoperative epidural and implant; With the device that is used for infusion under the continuous arachnoidea.

In one aspect, the CNS device can be for being used for the fluid conduction part flow arrangement of drain brain.For example, the CNS device can be the marrowbrain part flow arrangement is made up of two pipes, wherein in pipe will be supplied to peritoneotome from the fluid in the ventricles of the brain, and the purpose of arrangement outer tube be when volume of fluid joins in the outer tube pressure applied on the pipe.For example, referring to United States Patent (USP) 5,405,316.The CNS device can be for being suitable for connecting the ventricular drainage system of ventricular drainage conduit, and described ventricular drainage conduit is used to accept cerebrospinal fluid and has be used to control the fluidic valve that flows through wherein.For example, referring to United States Patent (USP) 5,772,625.The CNS device can be the ventricular shunt apparatus system, and this system is by being used to prevent the brain check-valves that cerebrospinal fluid refluxes and providing from the csf flow of the ventricular catheter flow velocity transformational structure to peritoneum or auricle conduit.For example, referring to United States Patent (USP) 4,781,673.The CNS device can be for having the part flow arrangement element of flow restriction passage, and described flow restriction passage is connected with conduit so that will be from the drainage of cerebrospinal fluid of the ventricles of the brain to sagittal sinus.For example, referring to United States Patent (USP) 6,283,934.The CNS device can be the chamber end of chamber-heart part flow arrangement, described chamber-heart part flow arrangement has the far-end of sealing, this far-end has adjacent with it outer passage, and these passages, prevent to block so that provide umbrella sample liner that fluid is passed through for porous and inflatable simultaneously.For example, referring to United States Patent (USP) 3,690,323.The CNS device can be the hydrocephalus valve, and it carries the chamber of the entrance and exit valve of the cerebrospinal fluid that leaves brain to form by having with controlled pressure.For example, referring to United States Patent (USP) 5,069,663.The CNS device can be the hydrocephalus device of being made up of the shell of outer flexible, and described pliability hull shape becomes fluid accumulator and holds the self-regulating valve with the pleat film that forms slit-like opening of nonobstructive, and this device has the entrance and exit pipe.For example, referring to United States Patent (USP) 5,728,061.The CNS device can be the cerebrospinal fluid drain part flow arrangement of being made up of implantable basic control unit, and described implantable basic control unit makes marrowbrain space conduit and the conduit interconnection of fluid conduction being gone into body cavity.For example, referring to United States Patent (USP) 6,585,677.The CNS device can be the shunt device of cerebrospinal fluid of being made up of ventricular catheter, and described ventricular catheter is connected with flexible drainage tube, and described still property drainage tube has the tubular covering of outer flexible, from wherein extracting drainage tube out.For example, referring to United States Patent (USP) 4,950,232.The CNS device can be the intracranial pressure isocon, and this Guan Youcheng is radial and form from the thin film that the opening of ventricles of the brain pipe outwards stretches, and described ventricles of the brain pipe racks has a plurality of side openings so that the cerebrospinal fluid of the ventricles of the brain is branched to the lip-deep cavum subdurale of brain.For example, referring to United States Patent (USP) 5,000,731.Other CNS part flow arrangement for example is described in the United States Patent (USP) 6,575,928,5,437,626 and 4,631,051.

In one aspect of the method, the CNS device can be pressure monitoring device.For example, pressure monitoring device can be intracranial pressure sensor, and it is assemblied in the health skull on the position of monitoring pressure and is the device that externally sends from the pressure of skull.For example, referring to United States Patent (USP) 4,003,141.Pressure monitoring device can be the differential pressure sensitive device of remote measurement, and it is made up of the sealing conductive rings of thin plate, and when wherein two kinds of health pressure reduction on opposite side changed, described ring moved with flexible barrier film.For example, referring to United States Patent (USP) 4,593,703.Pressure monitoring device can be made up of radiopaque liquid, and described liquid is included in the resiliency compressible container that silastic material makes, and wherein the volume of liquid is variable as the function that is applied to pressure on the container or power.For example, referring to United States Patent (USP) 3,877,137.The probe that pressure monitoring device can be served as reasons and be had the chamber and be connected the threaded dried composition of lock nut inserts and enters subarachnoid space with its opening by scalp.For example, referring to United States Patent (USP) 4,600,013.Pressure monitoring device can be made up of external wireless transceiver unit and implantable cavity resonator unit, and described cavity resonator unit has electrolyte chamber of filling and the predetermined resonance frequencies that is used for frequency electromagnetic waves.For example, referring to United States Patent (USP) 5,873,840.Pressure monitoring device can be implantable pick off, and it can detect physiological parameter (for example cerebrospinal fluid flow) and produce, processes and transmit signal then to external receiver.For example, referring to United States Patent (USP) 6,533,733.Other CNS pressure monitoring device for example is described in the United States Patent (USP) 6,248,080 and 6,210,346.

Can have benefited from the CNS part flow arrangement that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised being purchased product, such as from Codman ﹠amp; .Shurtleff, and Inc. (Raynham, MA), i.e. Johnson ﹠amp; The Codman HAKIM program controlled valve of Johnson Company.Other example comprises Integra Neuro Sciences (P1ainsboro, NJ) HEYER-SCHULTE neurosurgery part flow arrangement, HERMETIC CSF drainage system and OSV II SMART VALVE system and Medtronic, Inc. (Minneapo1is, MN) part flow arrangement external member comprises STRATA, DELTA, CSF-Snap and CSF-flow-control part flow arrangement external member.

Can have benefited from the pressure monitoring CNS device that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised and be purchased product, such as from Imegra NeuroSciences (Plainsboro, VENT XI X pressure monitoring test kit NJ) and CAMINO MicroVentricular Bolt ICP monitoring tube.

The CNS device of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue is provided among the present invention in one aspect, and wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with the CNS device have above been described.

Can soak into thereon and with said composition and implanting around the CNS device by polymer composition directly and/or indirectly being coated with following position or coating: (a) tissue adjacent with the CNS device; (b) near CNS device-organizational interface; (c) zone around the CNS device; (d) tissue around the CNS device.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with the CNS device comprises described polymer composition is delivered to: (a) at the CNS of implant procedure process apparatus surface (for example as injectable, paste, gel or mesh); (b) before implanting the CNS device at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the CNS device CNS apparatus surface at once and/or implant tissue (for example forming gel or mesh) around the CNS device as injectable, paste, gel, original position; (d) by described compositions part being coated with the anatomic space of having placed the CNS device (useful especially being to use of this embodiment discharged polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of described therapeutic agent and can pass other preparation into the described activating agent of release in the zone of having inserted described device in the time limit in several hours more than one weeks); (e) by inject CNS device tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with the CNS device is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because the CNS device is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on about tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

IVCF

In one aspect, the polymer composition of theme of the present invention can be soaked into as the tissue adjacent with the IVCF device.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).The term IVCF is to be used to capture embolus and to prevent their devices by the blood flow migration.The example of IVCF includes, but are not limited to catcher, intravascular filter, clot filter, vein filter and main vascular filter (body vessel filter) in vascular filter, hemofilter, implantable hemofilter, vena cava filter (caval filters), vena cava filter (vena cava filters), caval vein defecator, thrombosis filter, thrombus filter, anti-migration filter, defecator, percutaneous filtration system, the blood vessel.

IVCF is captured clot and is formed embolus to prevent them to be delivered to the other parts of health.If speckle or clot move and are delivered to lung and cause pulmonary infarction by blood flow, so may threat to life.In order to prevent that this class situation from taking place, IVCF is placed in the large vein of health to prevent to suffer from patient's body that dvt forms and lung embolus (or being in the danger of generation) occurs.Major part in these filters is made up of synthetic polymer or metal usually.These filters can be various structures, include, but are not limited to basket, cone, umbrella or ring-type.The shape of filter must provide enough abilities of capturing, and allows enough blood flow mistakes simultaneously.Except that the function shape, filter can also have other design feature, comprises being used to prevent the arrangement of moving or the Zhou Bianhuan of anchor feature (for example ridge, minor connector or sharp keen point).If filter contacts with the blood vessel wall that is used for grappling, the fibre modification reaction can take place so.This fibre modification reaction can cause the taking-up difficulty of filter.This is the short relatively concrete difficult problem of time bar that filter is held in place.Filter can also become infection site.The polymer composition that will contain fibre modification inhibitor and/or anti-infective is impregnated into the tissue adjacent with filter can reduce or prevent that the restenosis that causes because of the fibroplasia reaction or device from blocking and/or can prevent or suppress infection on the filter position.

In one aspect, IVCF can be designed to various structures.For example, IVCF can be made up of strainer elements in the fixed a plurality of tube chambers of retainer in the filter structure that is released into open stent sample structure.For example, referring to United States Patent (USP) 6,267,776.IVCF can be made up of the part of capturing embolus, and that wherein captures embolus is partly with many with the ramose elongation filter of helical arrangement line and the anchor portion that has a plurality of minor connectors.For example, referring to United States Patent (USP) 6,391,045.IVCF can be formed by having the echo of generation structural feature, and making to develop by ultrasonogram determines the position of filter.For example, referring to United States Patent (USP) 6,436,120.IVCF can be made up of a plurality of heart yearn minor connectors for outwards radiation grappling, and these minor connectors are interconnected into filter basket by compression material.For example, referring to United States Patent (USP) 5,370,657.IVCF can be made up of the conical geometry top head that has a plurality of bifurcated stent bars, and described bifurcated stent bar has and is used for and fixed hook of blood vessel and pad.For example, referring to United States Patent (USP) 5,059,205.IVCF can be made up of the defecator that shape memory characteristics/elastic material is made, and this device forms on expansion/recovery wet end far-end so that locate with the invasive of minimum level.For example, referring to United States Patent (USP) 5,893,869.IVCF can be made up of element in the tube chamber of a plurality of retainers connections, and when discharging retainer, strainer elements is converted to endovascular open configuration in the tube chamber thus.For example, referring to United States Patent (USP) 6,517,559 and 6,267,776.IVCF can be made up of the outer catheter and the inner catheter that have the collapsible mesh spline filter basket of being made by elastic yarn or plastic monofilament on far-end.For example, referring to United States Patent (USP) 5,549,626.IVCF can be formed and have two layers of surface and handle so that endothelial cell growth and antiproliferative properties are provided by being connected a plurality of radial minor connector on the health element.For example, referring to United States Patent (USP) 6,273,901.IVCF can be made up of the fabric of accepting of the filter screen of the trap particles that is configured to slide along lead.For example, referring to United States Patent (USP) 6,605,102.IVCF can be for having the impermanency utensil of the cylindrical and conical sections of having of single high memory coil curve.For example, referring to United States Patent (USP) 6,059,825. OtherIVCF for example is described in the United States Patent (USP) 6,623,506,6,391,044,6,231,589,5,984,947,5,695,518 and 4,817,600.

Can have benefited from the vena cava filter that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised and be purchased product.The example that can have benefited from mixing the vena cava filter of fibre modification inhibitor includes, but are not limited to by Cook Inc. (Bloomington, IN) G of Xiao Shouing

NTHER TU lip vena cava filter and GIANTURCO-ROEHM BIRD ' S NEST filter.(Murray Hill NJ) has sold SIMON-NITINOL FILTER and RECOVERY filter to C.R.Bard.(Miami Lakes, the CordisEndovascular of subsidiary FL) has sold the TRAPEASE permanent vena cava filter in DVT patients to Cordis Corporation.(Bethlehem PA) has sold VENA TECH LP vena cava filter and VENA TECH-LGM vena cava filter to B.Braun MedicalInc..(Natick MA) has sold GREENFIELD vena cava filter on the line to Boston Scientific Corporation.

The IVCF of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue is provided among the present invention in one aspect, and wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with IVCF have above been described.These polymer compositions can comprise one or more fibre modification inhibitor, make the granulation undue growth be inhibited or reduce; And/or these polymer compositions can comprise one or more anti-infectives, with prevention or suppress to infect.

Can soak into thereon and with said composition and implanting around the IVCF by polymer composition directly and/or indirectly being coated with following position or coating: (a) tissue adjacent with IVCF; (b) near IVCF-organizational interface; (c) zone around the IVCF; (d) tissue around the IVCF.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with IVCF comprises described polymer composition is delivered to: (a) on the IVCF surface of implant procedure process (for example as injectable, paste, gel or mesh); (b) before implanting IVCF at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the IVCF IVCF surface at once and/or implant tissue (for example forming gel or mesh) around the IVCF as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed IVCF (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject IVCF tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with vena cava filter (for example IVCF) is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because IVCF is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

Gastrointestinal device

In one aspect, the polymer composition of theme of the present invention can be impregnated into and the adjacent tissue of gastrointestinal (GI) device.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).There are many gastrointestinal tract devices that feeding is used and drain is used that are used for.If there is over-drastic fibroplasia reaction in these devices or has infection on this setting position, the function of these pipes is just may suffer damage so.The polymer composition that will contain fibre modification inhibitor and/or anti-infective is impregnated into the tissue adjacent with described device can regulate this fibroplasia reaction (for example prevent narrow and/or device blocks), thus the performance of holdout device and/or can prevent or the locational infection of restraining device.

The various GI pipes that are used for drain or feeding can be used for the present invention.These devices can include, but are not limited to be used for the GI pipe of drain or feeding, door body diverter, the diverter that is used for drain or feeding, the ascites diverter, nasogastric tube or through nasointestinal tube, gastrostomy feeding pipe or percutaneous feeding tube, jejunum is made a mouthful endoscopy and is checked, the colonic diversion device, drainage tube, bile T-shape pipe, biopsy forceps, the cholelithiasis removal device, endoscope retrogradation ERCP (cholangiopancretography) (ERCP) installs, swelling gasbag, the nutrition device, stent, hidden (low profile) device, virtual coloscope is checked (VC) device, scrotiform endoscope and retracting device.

The GI device can be made up of synthetic material, includes, but are not limited to rustless steel, metal, Ultimum Ti (nitinol), glass, resin or polymer.

In one aspect, the GI device can be for being used to check or provide the instrument that enters gastrointestinal tract inside.It can comprise the video that is used for diagnostic purpose still image or visual form.Use the operation of these devices to include, but are not limited to enteroscopy, colonoscopy or EGD, wherein endoscope enters esophagus or anal canal so that estimate the part in GI road.For example, the GI device can be for having the endoscope of the tubular bodies that is used to hold viewing lens and therapeutic instrument.For example, referring to United States Patent (USP) 5,421,323.The GI device can be for inserting the multi-cavity endoscopic catheters that is used to implement endoscopic retrograde cholangiopancreatography by endoscope, wherein first chamber has the line by it, second chamber provides the radiopaque contrast agent of infusion identifying the conduit that blocks, and the 3rd chamber provides the conduit of swelling gasbag.For example, referring to United States Patent (USP) 5,788,681 and 5,843,028.The GI device can be the video-endoscope system that is made up of deglutible capsule, transmitter and receiving system.For example, referring to United States Patent (USP) 5,604,531.The GI device endoscope that the encapsulation ultrasonic transducer capsule that has the dynamo-electric sector scanning device of autonomous type is formed that can serve as reasons, it can be used for TEE.For example, referring to United States Patent (USP) 4,977,898 and 4,834,102.The GI device can be for having the endoscope that sterilizes that is assemblied in the image sensor on cylindrical capsule and the separable disposable passage.For example, referring to United States Patent (USP) 5,643,175.The GI device can be that the body pipe invades instrument, and it can be made up of so that be connected tissue in navigation procedure two-way mantle friction, thus the risk that reduces puncture with body cavity and pipe insertion conduit, time that lead is relevant with endoscope are provided.For example, referring to United States Patent (USP) 6,589,213.The GI device can be the colon access apparatus, and it reaches several days so that monitoring and treatment colorectum disease by having the pliability pipe that is used for the tether that discharges from colonoscope, this device can being placed in the colon.For example, referring to United States Patent (USP) 6,149,581.The GI device is suitable for bile duct or ductus pancreaticus by forming through the sub-endoscope that the pliers path inserts by the duodenal parent endoscope of insertion with by nipple.For example, referring to United States Patent (USP) 4,979,496.

In one aspect of the method, the GI device can be as the conduit of long-term tube feeding.These GI devices can include, but are not limited to percutaneous feeding tube, nutrition device/conduit, gastrostomy feeding pipe, concealed device and nasogastric tube.Can these long-term tube feeding be advanced through the GI road or advance through stomach wall by nasolacrimal duct by gastrostomy.For example, the GI device can be for being suitable for as making food enter intravital conduit by stomach wall and having retainer and the nutrition conduit of retractable synchronizer.For example, referring to patent 4,826,481.The GI device can be the nutrition pipe, and it has by having the conduit that thin pig tail catheter and air bag cushion allow convenient insertion and take out.For example, referring to United States Patent (USP) 6,582,395.The GI device can be for being used for fluid is gone into the nutrition device of stomach, and it is made up of socket, pliability feeding tube, liquid overflow pipe and probe, and these parts are connected with the positive pole of lead.For example, referring to United States Patent (USP) 5,242,429.The GI device can maintain its underwent operative opening on the coat of the stomach by helping fixed prolongation concentric lips for having the hollow cylindrical prolate body of spring-biased valve.For example, referring to United States Patent (USP) 4,344,435.The GI device can be nasogastric tube, and it has the opening of arranging along its far-end, has the pliable and tough sheath of pairing introducer that becomes longitudinal extension along pipe on the described far-end.For example, referring to United States Patent (USP) 5,334,167.Other GI unit describe that is used as feeding tube or relevant apparatus is at for example United States Patent (USP) 6,582,395; 5,989,225; 5,720,734; 5,716,347; 5,503,629; 5,342,321; 4,861,334; In 4,758,219 and 4,057,065.

In one aspect of the method, the GI device can be used for the lavation or the suction in GI road.For example these GI devices can be used to remove the poisonous substance or the blood of absorption, so that the disease that treatment is relevant with absorption, reduce pressure to stomach, guarantee the partially draining in postoperative GI road, postoperative is removed gas and treatment disease, such as intestinal obstruction or paralytic ileus, for example, the GI pipe can extend and be configured to insert have control over bleeding slidably with therapy equipment and with the GI road of the paired fluid reservoir of pipe.For example, referring to United States Patent (USP) 5,947,926.GI can be for through the pliable and tough pipe of stomach nose, it have curved or crooked leading end so that on dissecting, adapt and help being advanced into the esophagus stomach function regulating.For example, referring to United States Patent (USP) 5,690,620.The GI stationary curved so as fixing stretch from the nostril down through stomach nose extension tubing, thereby the intranasal pressure necrosis of having avoided the effect because of power to cause.For example, referring to United States Patent (USP) 4,363,323.The GI device can be made up of suction, nursing and expansion chamber, can it be inserted by stomach wall and coat of the stomach by modus operandi.For example, referring to United States Patent (USP) 4,543,089.The GI device can and have the irrigating tube that overlaps fluid-tight that adds that is used for unidirectional lavation intestinal by drainage tube and form.For example, referring to United States Patent (USP) 4,637,814.The GI device can be the untight thin-walled in two ends, air bag sample pipe, and the purpose that forms this shape is to extend by the part of digestive tube at least, so that the food solid of digestion passes through, and the treatment disease relevant with absorption thus.For example, referring to United States Patent (USP) 4,315,509 and 4,134,405.

In one aspect of the method, the GI device can be the colonic diversion device.For example, the colonic diversion device can be the artificial anus, and it is formed by having cylindrical hollow tubular holder, and described cylinder has the flange of the radial stretching, extension of a pair of one-tenth so that interface components.For example, referring to United States Patent (USP) 4,781,176.The colonic diversion device can be made up of the interior and outer air bag that is connected with the ring-type support plate by the pipe that is used to connect aperture or rectum.For example, referring to United States Patent (USP) 5,569,216.

In one aspect of the method, the GI device can be for being used to control the hemorrhage mechanical hemostasis device of GI.The hemostasis device that is used to retrain blood flow can include, but are not limited to pincers, folder, nail and stitching thread.For example, hemostasis device can be for by anchor and the dried compression clamp of forming, described anchor and driedly have transverse holes and can fix or can be along dried mobile pad (bolster).For example, referring to United States Patent (USP) 6,387, youngster 4.Hemostasis device can be right for the hollow intermediate plate of the endoscope that is made up of deformable material folder and penetrate tissue.For example, referring to United States Patent (USP) 5,989,268.

In one aspect of the method, the GI device can be for removing the utensil in the GI road that blocks.For example, the GI device can be the dilating catheter of being made up of the guard shield pipe, and described guard shield pipe racks has the tension releasing tube that extends from its inside that is used to change the swelling gasbag structure.For example, referring to United States Patent (USP) 6,537,247.

In one aspect of the method, the GI device can play a part medicine is delivered to the GI road.For example, can give the GI device and it can be made up of the porous body of two Room by the oral cavity, one of them chamber has the aperture of getting rid of liquid medicine under pressure, and the circuit that produces gas is contained in second chamber, and described gas can be oppressed first chamber to discharge medicine.For example, referring to United States Patent (USP) 5,925,030.The GI device can be for having the collapsible oval stomach anchor of border and long and narrow intestinal payload assembly, and described intestinal payload assembly contains slow-releasing agent, desmoenzyme or non-pathogenic microorganism.For example, referring to United States Patent (USP) 4,878,905.The GI device can be for being used for the Ingestible device with substance delivery selection part to the GI road, and it comprises that the electromagnetic radiation receptor that is used for to the functional unit energy supply of device is so that insert or the allotment material.For example, referring to United States Patent (USP) 6,632,216.

In one aspect of the method, the GI device can be for being used to provide the part flow arrangement that exchanges between two body systems.Part flow arrangement can be used for the treatment of abnormal conditions, is transferred to the position that it can be handled by health such as shunting closed in the body passage or with unwanted fluid accumulation from body cavity.For example, part flow arrangement can be used to replace the means of systemic vein circulation peritoneal fluid as treatment ascites that enter.Part flow arrangement can include, but are not limited to a body diverter and peritoneovenous shunt device.For example, described diverter can serve as reasons have that the cylindrical chamber that is used to aspirate fluid and discharges fluidic pumping utensil and hole form with implantable pump.For example, referring to United States Patent (USP) 4,725,207.Described diverter can be implantable peritoneovenous shunt system, and it is made up of two chambers ascites gathering-device, pump (for example magnetically-actuated or compressible drive) and anti-reflux conduit, and they all connect by the pliability pipe.For example, referring to United States Patent (USP) 4,657,530 and 4,610,658.Described diverter can be made up of the peritoneal cavity that is connected with hollow plastic implantation valve module, and described hollow plastic is implanted valve module can make fluid by arriving duct of Arantius under pressure.For example, referring to United States Patent (USP) 5,520,632.Described diverter can be the collapsible shape memory characteristic metal fabric of the metal strand that has many braidings, and it has the fluid central passage and can send with the generator gate body by body passage with folded state and shunt.For example, referring to United States Patent (USP) 6,468,303.The GI device can run through dissector for the laparoscopy of being made up of inflatable air bag and hollow cognate plugger, and it is used to penetrate tissue to be provided for the anatomic working space of laparoscopic procedure.For example, referring to United States Patent (USP) 5,836,961 and 5,817,123.

Can have benefited from the GI device that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised and be purchased product.

In one aspect, the GI device that is used for the feed purpose comprises various devices.For example, gastrostomy tube is such as the Ross Products of Abbott Laboratories branch (Columbus, OH) DURA-G polyurethane gastrostomy tube of Xiao Shouing and MAGNA-PORT gastrostomy tube.Moss Tubes, (West Sand Lake NY) has sold MOSS G-pipe Ponsky method test kit to Inc..Other nutrition pipe comprises: for example by the Abbott Laboratories RossProducts of branch (Columbus, OH) the EASY-FEED nutrition device group of Xiao Shouing.(Basel Switzerland) has sold the COMPAT intestine delivery system to NovartisAG.(Wheeling IL) has sold the CORFLO feeding tube to VIASYS HealthcareMedsystems Division.BostonScientific Corporation has sold the ENDOVIVE enteral feeding system.Nasogastric tube, such as Moss Tubes, Inc. (West Sand Lake, NY) Mark IV Nasal (SIL) Tubes of Xiao Shouing.C.R.B ard, (Covington Georgia) has also sold various per nasal stomach feeding tubes in the Bard Medical branch of Inc. and Andersen Products Limited (England, United Kingdom).Concealed device, such as C.R.Bard, (Billerica MA) has sold hidden displacement gastrostomize device and Bard Button displacement gastrostomize device to the Bard Endoscopic Technologies of Inc. branch.

In one aspect of the method, the GI device can comprise lavation or suction gastrointestinal tract, such as Nellcor Puritan Bennett Inc. (Pleasanton, CA) LAVACUATOR gastrointestinal tract of Xiao Shouing and VENTROL Levine pipe.

In one aspect of the method, the GI device comprises that those are used as the device of a body diverter or other part flow arrangement, such as W.L. Gore ﹠amp; Associates, Inc. (Newark, DE) the VIATORRTIPS endoprosthesis of Xiao Shouing.Denver Biomedical, Inc. (Golden, CO) the Denver ascites diverter of Xiao Shouing.Becton, Dickinson and Company (Franklin Lakes, NJ) the LEVEEN diverter of Xiao Shouing.

In one aspect of the method, the GI device comprises the colonic diversion device, such as ColoplastCorporation (Marietta, GA) the ASSURA Pouches and the COLOPLASTPouches of Xiao Shouing.ConvaTec (Princeton, NJ), ESTEEM SYNERGY standard closed-end type bag and SUR-FIT NATURA closed-end type bag that a tame Bristol-Myers Squibb Company sells.(Berkeley CA) has sold MICROSKIN artificial anus bag system to Cymed Ostomy Company.(Libertyville IL) has sold KARAYA 5 monolithic bag systems, CONTOUR I monolithic ostomy bag system and CENTERPOINTLOCK (CPL) biplate bag system to Hollister Inc..(Inc. has also sold various artificial anus bags to Bard Medical Division for Covington, Georgia) of C.R.Bard.

In one aspect of the method, the GI device can comprise dilating catheter, such as C.R.Bard, and the Bard Endoscopic Technologies of Inc. branch (Billerica, MA) the multistage balloon dilator of the ELIMINATOR of Xiao Shouing.(Natick MA) sells by Boston ScientificCorporation for CREFixed Wire and Wireguided balloon dilator.

The GI device of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue is provided among the present invention in one aspect, and wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with the GI device have above been described.These polymer compositions can comprise one or more fibre modification inhibitor, make the granulation undue growth be inhibited or reduce; And/or these polymer compositions can comprise one or more anti-infectives, so that prevention or suppress to infect.

Can soak into thereon and with said composition and implanting around the GI device by polymer composition directly and/or indirectly being coated with following position or coating: (a) tissue adjacent with the GI device; (b) near GI device-organizational interface; (c) zone around the GI device; (d) tissue around the GI device.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with the GI device comprises described polymer composition is delivered to: (a) at the GI of implant procedure process apparatus surface (for example as injectable, paste, gel or mesh); (b) before implanting the GI device at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the GI device GI apparatus surface at once and/or implant tissue (for example forming gel or mesh) around the GI device as injectable, paste, gel, original position; (d) by described compositions part being coated with the anatomic space of having placed the GI device (useful especially being to use of this embodiment discharged polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of described therapeutic agent and can pass other preparation into the described activating agent of release in the zone of having inserted described device in the time limit in several hours more than one weeks); (e) by inject GI device tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with the GI device is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because the GI device is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day one about scope of 180 days.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

The central vein conduit

In one aspect, the polymer composition of theme of the present invention can be impregnated into and the adjacent tissue of central vein conduit (CVC) device.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).With regard to purpose of the present invention, term " central vein conduit " should be interpreted as to comprise any catheter or the pipeline that is used to deliver a fluid to big (center) vein (for example jugular vein, pulmonary vein, femoral vein, iliac vein, postcava, superior vena cava, axillary vein) of health.The CVC device is generally and inserts body passage so that the form of a hollow pipe intubate in injection or the extracting bodily fluid.CVCs can be inserted large vein, such as superior vena cava, wherein the part of conduit is arranged in vivo, and that the coupling part extends to is external so that the inlet that enters blood circulation to be provided.CVCs can be used for administration (for example chemotherapy or antibiotherapy) or intravenous alimentation, pressure monitoring or regular blood-sample withdrawal.

Can design the CVCs that has or do not have cover or flange.Cover is used to prevent that conduit from sliding or become infection.CVCs can have a chamber or a plurality of chamber and have many size ranges to be suitable for necessary requirement.They can be made up of synthetic material, include, but are not limited to polyurethane, polyethylene, siloxanes, copolymer and other polymer composition.

Infection or inflammation to the conduit reaction may take place in CVCs general long-term reservation in vivo and thus.CVC comes in and goes out the chamber may be by the blood of grumeleuse or thrombosis obstruction.Some CVCs can also utilize the surface of coating and processing so that will infect and/or the risk of inflammation is reduced to bottom line.The polymer composition that will contain fibre modification inhibitor and/or anti-infective is impregnated into and installs adjacent tissue can regulate excessive fibroplasia reaction to device, can prevent narrow and/or device block/maybe can prevent or the locational infection of restraining device.

In one aspect, CVC can be designed for the special-purpose blood circulation of actual conditions/purpose.For example, especially can be fabricated to the CVC that hemodialysis is used by using as the pin sample two-chamber elongation that medicine or additive are gone into the conduit of health through AV turnover fistula or implant.For example, referring to United States Patent (USP) 5,876,366.CVC can be made up of the indwelling casing tube that has outlet on far-end that is suitable for placing in superior vena cava, the fluid medicament can be delivered to sleeve pipe subcutaneous tissue zone on every side thus basically.For example, referring to United States Patent (USP) 5,817,072.

In one aspect of the method, CVC can be designed for pass in and out many conduits of blood circulation.For example, CVC can be the overall flexibility conduit of elongation, it has a plurality of independently chambeies, these chambeies can be suitable for connecting the independent fluid conveyer device, fluid can be infused into vein separately under unmixing situation thus, and can extract blood out and can in fluid infusion, monitor vein pressure.For example, referring to US 4,072,146.CVC can serve as reasons the fluid passage that has formation pliability chamber, center and be assemblied in the multi-cavity catheter that a plurality of collapsible chamber around the center cavity of the fluid passage that wherein also has formation is formed.For example, referring to United States Patent (USP) 4,406,656.

In one aspect of the method, CVC can have the utensil that is used to prevent the infection that causes because of life-time service.For example, CVC can be made up of polyurethane, wherein has thin hydrophilic layer having loaded on the antibiotic surface that is used to suppress to insert the ramoplanin part that antibacterial grows surely on the rear tube.For example, referring to United States Patent (USP) 5,752,941.CVC can be embedded with the polymeric material that extends to surperficial lower floor and form non-infiltration surface-treated antibacterial metal (for example silver) outer surface and forms by having.For example, referring to United States Patent (USP) 5,520,664.

In one aspect of the method, CVC can be used to provide the instrument of expansion by the mode of CVC injection or extracting bodily fluid.For example, the CVC instrument can be made up of the syringe body that has two barriers, and described barrier has two independent fluid conduits, and these conduits have independent plunger and valve body.For example, referring to United States Patent (USP) 5,411,485.The CVC instrument can and a plurality ofly be made up of available from syringe passage and the barrier handled by syringe plunger the sheet of upper and lower molding.For example, referring to United States Patent (USP) 5,417,667.The CVC instrument can be Unitarily molded substrate plate, and it is the relative guiding valve that carries out the syringe of fluid communication assembling with inlet that its formation has a plurality of.For example, referring to United States Patent (USP) 5,454,792.The CVC instrument can with the turnover that is easy to pass in and out instrument combination is provided, can be by realizing by between multi-way joint and CVC, forming with the adapter of bidirectional fluid exchange.For example, referring to United States Patent (USP) 5,308,322.CVC can be valve module, and it can be provided for controlling the CVC far-end of the fluid passage of the channel of blood flow that inserts to it from conduit.For example, referring to United States Patent (USP) 5,030,210.

Other example of central vein conduit comprises total parenteral nutrition conduit, the central vein conduit that inserts, directed flow air bag-inserted pulmonary artery catheter, the central vein of life-time service discrepancy conduit (such as Hickman pipeline and Broviac conduit) on every side.The representational case description of this class conduit is at United States Patent (USP) 3,995, and 623,4,072,146,4,096,860,4,099,528,4,134,402,4,180,068,4,385,631,4,406,656,4,568,329,4,960,409,5,176,661,5,916,208.

Can have benefited from the CVCs that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised and be purchased product.For example the Bard Access system of branch of C.R.Bard (SaltLake City, UT has sold HICKMAN, BROVIAC and LEONARD central vein conduit, they are purchased as SureCuff tissue ingrowth cover and the antibiotic cover of VitaCuff.(Irvine CA) has sold VANTEX conduit and PRESEP CENTRALVENOUS OXIMETRY conduit to EdwardLifesciences.(Bloomington IN) has sold conduit and other CVC assembly and dish that the SPECTRUM antibiotic soaks into to Cook Critical Care.(Reading PA) has sold the ARROWGARD BLUE conduit with single chamber or multi-cavity to ArrowIntemational.

Various central vein conduits can be used for hemodialysis, the conduit that includes, but are not limited to implant fully, such as Lifesite (Vasca Inc., Tewksbury, Mass.) and Dialock (Biolink Corp., Middleboro, Mass.).The central vein conduit is easily infected, and the present invention is used to prevent or the aspect that suppresses to infect as mentioned above.

The CVC device of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue is provided among the present invention in one aspect, and wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with the CVC device have above been described.These polymer compositions can comprise one or more fibre deformation inhibitor and/or one or more anti-infectives, be subjected to that the granulation tissue undue growth is inhibited or minimizing and/or CVC setting position on infection be inhibited or prevent.

Can soak into thereon and with said composition and implanting around the CVC device by polymer composition directly and/or indirectly being coated with following position or coating: (a) tissue adjacent with the CVC device; (b) near CVC device-organizational interface; (c) zone around the CVC device; (d) tissue around the CVC device.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with the CVC device comprises described polymer composition is delivered to: (a) at the CVC of implant procedure process apparatus surface (for example as injectable, paste, gel or mesh); (b) before implanting the CVC device at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position;-(c) implant behind the CVC device CVC apparatus surface at once and/or implant tissue (for example forming gel or mesh) around the CVC device as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed the CVC device (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject CVC device tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install.

In certain aspects, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent: (a) outer surface that divides of CVC device internal blood vessel and/or the CVC device sections that passes skin with following surface; (b) outer surface that divides of the internal blood vessel of CVC device and/or the CVC device sections that passes skin, the wherein inside of CVC device and/or the external coated polymer composition that comprises therapeutic agent (for example anti-infective); (c) surface of subcutaneous " cover " around the CVC device; (d) other surface of CVC device; (e) above-mentioned combination arbitrarily.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with the CVC device is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because the CVC device is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

Ventricular assist device

In one aspect, the polymer composition of theme of the present invention can be impregnated into and the adjacent tissue of ventricular assist device (VAD).The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

VADs is used for auxiliary natural heart with blood pumping in whole body.The example of VADs and other relevant apparatus include, but are not limited to heart-assist device in left ventricular assist device, right ventricular assist device, two ventricular assist devices, heart-assist device, assist, artificial heart auxiliary device, implantable cardiac aid system, implantable ventricular assist device, heart assisting pump and the ventricle.

VADs is used for the treatment of heart failure, and its cardiac can not be to keep the required speed of enough blood flows with blood pumping in whole body.Heart failure includes, but are not limited to acute myocardial infarction, cardiomyopathy, heart valve function obstacle, over-drastic cardiac operation and uncontrolled arrhythmia.VADs by increasing failure heart pumpability and heart is rested and reorganized so that recover the heart that its normal pump function assist depletion.In general, VADs generally by the blood pump that is connected between ventricle and the aorta, connect pump and form with the sleeve pipe of heart and the driving control station of driving and control device.The most frequently used VAD that exists is left VAD because the left ventricle of heart than right ventricle common be easier to ill; Yet VADs is used for from left ventricle, right ventricle or two Room pump blood.VADs can be categorized as the pumping driver of beating (for example intra-aortic balloon pump) or continuous (for example mutual piston-type pump or rotary pump (centrifugal or axial impeller)) works.

Yet, VADs can exist and implant or prolong use relevant medical science complication, such as infection, septic embolus, hemorrhage, conduct to the inflammation of the reaction of histologic lesion with solidify or thrombosis that blood stasis brings out.Middle cardiac complication can hinder the application of VAD and the consequence that can cause life to be on the hazard.The polymer composition that will contain anti-scarring agent and/or anti-infective is impregnated into the tissue adjacent with VAD and can prevents narrow and/or device blocks and/or can prevent or the locational infection of restraining device.

In one aspect, VAD can be pulsate pump.These devices can have pliability bag or dividing plate, and they can be compressed and discharge so that the pump action of beating is provided.A kind of pulsate pump of spiral is aortic balloon pump (IABP), it is a kind of bagging apparatus of beating that can use minimum level invasive operational applications, and described aortic balloon pump can be penetrated blood tool function when keeping SAP in left ventricle.For example, VAD can be IABP, and it is a kind of by the interim removable holder in the aortic arch of aorta decline, and wherein aorta has blood pressure lowering and the pressurization position of keeping by pumping and blocking-up air bag.For example, referring to United States Patent (USP) 6,228,018.VAD can and have pumping chamber by the separated big and small diameter portion of pliability dividing plate/film for the IABP conduit.For example, referring to United States Patent (USP) 5,928,132.VAD can be pulsate pump, and this pump is made up of by the hydraulic pump of the telescopic pump action of beating the sleeve pipe that has epitheca and chamber, turnover valve, fluid accumulator and generation blood.For example, referring to United States Patent (USP) 6,007,479.

In one aspect of the method, VAD can be for providing the almost continuous pump of stable state blood flow, and it can comprise the trickle parts of beating.Pump can comprise continuously: mutual piston-type pump, such as pneumatic means or magnetic force rotating device; And rotary pump, such as centrifugal or axial impeller.For example, AD can be implantable device, the magnetic suspension rotor element that it has stator component and works as centrifugal pump, and wherein impeller is delivered to aorta with blood from the left ventricle extraction and with it, reduces the pressure of left ventricle thus.For example, referring to United States Patent (USP) 5,928,131.VAD can be made up of implantable mutual piston, and described piston is used to drive the implantable pump blood that controlled by external electromagnets and constructs.For example, referring to United States Patent (USP) 5,089,017.

In one aspect of the method, VAD can be the device of the pumpability that is used for one of auxiliary left ventricle or right ventricle.For example, VAD can flow out conduit and shrinks one of described chamber, expands another chamber simultaneously and form with the actuator that positive excavationg pump is provided by having a pair of storing apparatus with chamber of entrance and exit, at least one ventricle.For example, referring to United States Patent (USP) 6,264,601.VAD can by the chamber on pump, the pump with use liquids and gases in return the means pipe that is connected described pump and chamber form.For example, referring to United States Patent (USP) 6,146,325.

In one aspect of the method, VAD can be for being in particular the device of left ventricle design.For example, VAD can be for being suitable for participating in using the inlet flow rate pressure transducer and can regulating the left ventricle that the controller of pump speed carries out and the blood pump of the mobile exchange between the aorta based on sensor feedback.For example, referring to United States Patent (USP) 6,623,420.VAD can be by being adapted to pass through congested expansion and can shrinking with the bag of discharge blood with by the using gases material and form through the utensil that conduit arrives the resistance that comprises described bag of cover change.For example, referring to United States Patent (USP) 6,569,079.VAD can serve as reasons the inflatable bladder that has the entrance and exit utensil and a pair of opposite side that is positioned at this capsule so that the plate of capsule distortion form.For example, referring to United States Patent (USP) 5,599,173.

In one aspect of the method, VAD can be for being designed to the device of two ventricular assist devices.For example, VAD two ventricular assist devices that self-supporting cup with the annular baffle that forms fluid chamber around the cardiac chambers is formed of can serving as reasons, thus it can have with the fluid chamber exchange to regulate pressure entrance/hole that positive and negative is pressed.For example, referring to United States Patent (USP) 5,908,378,5,749,839 and 5,738,627.

In one aspect of the method, VAD can replenish from heart external position pump blood circulation implant system for being used for.For example, VAD can be the outer pumping system of heart, and it is by forming with the control circuit of pump (for example beating or rotary pump) paired inflow and outflow conduit and synchronous primer pump aspect the fluid.For example, referring to United States Patent (USP) 6,610,004,6,428,464 and 6,200,260.

In one aspect of the method, the VAD-relevant apparatus can be used in combination with VADs or as independent use with the treatment patients with congestive heart failure.For example, the VAD-relevant apparatus can be served as reasons and is applied to stiffening device that the cover on the heart forms to force cardiac dilatation to preset limit.For example, referring to United States Patent (USP) 6,582,355,6,567,699,6,241,654 and 6,169,922.

Can have benefited from the VADs that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised being purchased product, for example, (Pleasanton CA) has sold the HHEARTMATE left ventricular assist system to Thoratec Corporation.(ON Canada) has sold WORLDHEART NOVACOR left ventricular assist system to WorldHeart Corporation.(Reading PA) has sold the LIONHEART left ventricular assist system to ArrowIntemational.

The LVAD of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue is provided among the present invention in one aspect, and wherein this polymer composition can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with VADs have above been described.These polymer compositions can comprise one or more fibre modification inhibitor and/or one or more anti-infectives, make the granulation undue growth be inhibited or minimizing and/or the locational infection of VAD are inhibited or prevent.

Can soak into thereon and with said composition and implanting around the VAD by polymer composition directly and/or indirectly being coated with following position or coating: (a) tissue adjacent with VAD; (b) near the VAD-organizational interface; (c) zone around the VAD; (d) tissue around the VAD.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with VAD comprises described polymer composition is delivered to: (a) on the VAD surface of implant procedure process (for example as injectable, paste, gel or mesh); (b) before implanting VAD at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the VAD VAD surface at once and/or implant tissue (for example forming gel or mesh) around the VAD as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed VAD (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject VAD tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with VADs (LVAD ' s) is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because VADs is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 big.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on about tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for list-infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

Spinal implant

In one aspect, the polymer composition of theme of the present invention can be impregnated into and the adjacent tissue of spinal implant (for example spinal prostheses).The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).Term used herein " spinal prostheses " refers to and is positioned at spinal column, goes up or neighbouring and improve the device of the function that spinal column carries out in host.Spinal prostheses can be used for the treatment of spinal column or its composition or its partial denaturation or impaired after spinal column.In health hosts, spinal column is made up of the spine plate that separates by the intervertebral disc that forms firm connection and absorption spinal compression.Intervertebral disc is made up of the inner gel sample material that is called vertebral pulp, and wherein vertebral pulp has the high-toughness fibres cartilage fibres on every side that is called annulus fibrosis.When infringement occurred to intervertebral disc, spinal column malfunction, crippling pain and long term disability can take place in the host.In general, the intervertebral disc infringement needs operation, and this operation uses various technology and device that the adjacent vertebrae plate is merged usually.The fused vertebrae sections moves and alleviating pain on damaged spinal disc by the restriction vertebra.When only merging a spinal levels, the host does not have any significant motion limitation.Yet when merging two or more stage, the proper motion of back may be restricted, and the predisposition conducting is crossed the banded extra-stress of remaining vertebra and caused pain relief to be resolved thus.

In one aspect, can use and induce the impaired spinal levels of spinal prostheses treatment that merges between the lamina of vertebra.When only having a spinal levels impaired, can carry out this step.In one aspect of the method, can use the active spinal prostheses treatment of the vertebra of keeping in vertebral joint compromised spine sections.When infringement takes place an above spinal segments, can carry out this step.

The example of spinal prostheses comprises, but be not limited to: spinal disc and relevant apparatus comprise prosthese, spinal implant, artificial spine dish, intervertebral implant, implantable spinal implant, implantable bone graft, artificial lumbar vertebra dish, nucleus of spinal tract implant and disc spacers in spinal implant, spinal disc prosthese, lumbar disc implant, neck dish implant, intervertebral disc, implantable prosthesis, spinal prostheses, artificial dish, prosthetic implant, prosthese spinal disc, the spinal disc.The term spinal prostheses also comprises fusion cage (cage) and relevant apparatus, comprises merging basket, fusion cage device, amboceptor cage, amboceptor implant, fusing device, fusion cage anchoring device, bone anchor tool, bone fixer, bone anchoring device, fusion equalization chamber, fusion cage anchor plate, anchor bone plate and bone screw.

Spinal prostheses of the present invention can be made up of homogenous material or different materials, (for example includes, but are not limited to the allograft bone material, referring to US 6,143,033), metal (for example, referring to US 4,955,908) and/or synthetic material is (for example, referring to US 6,264,695,6,419,706,5,824,093 and 4,911,718).Prosthese must be a biocompatibility.It can be grouped into by biodegradable or non-biodegradable one-tenth, and this need decide according to the used function of device.For example, referring to US 4,772,287.Spinal prostheses can for inert on the biology and as the mechanical implement of stabilizing spine (for example, referring to US 4,955,908 and 5,716,415) or it can be bioactive and be used for promoting merging (for example, referring to US 5,489 with the adjacent vertebrae plate, 308 and 6,520,993).

In one aspect, described prosthese can be the fusion cage for promoting that vertebral fusion designs with activity between the restriction adjacent vertebrae.Fusion cage can be for being installed in amboceptor device in the intervertebral space or they can comprise intervertebral space and spinal column proparea.Fusion cage can have difformity.For example, fusion cage can have rectangular shape or shape can be for cylindrical and have a plurality of openings and a spiral thread.Fusion cage can have ectosome and cavity, can be used to insert the material of promote osteogenesis in the cavity, also can not insert this material.For example, described prosthese can be for merging between vertebral body, and it has between the vertebral body of threaded post on the outstanding profile in the fixed dome of the assembly outer end of using plate, fastener and bone screw merges.For example, referring to US6,156,037.Described prosthese can be for having threaded outer surface, and it is suitable for promoting the fusion with bone structure when the material with induction of bone growth is packed into the cage body.For example, referring to US 4,961,740,5,015,247,4,878,915 and 4,501,269.Described prosthese can be for having the general tubular shell of spiral thread, and described spiral thread is given prominence to by a plurality of pilums that have the hole that promotes inside growth of bone and mechanical anchor.For example, referring to US 6,071,310 and 5,489,308.Other United States Patent (USP) of describing threaded spinal implant comprises U.S. Patent number 5,263,953,5,458,638 and 5,026,373.

In one aspect of the method, described prosthese can for for promoting vertebral fusion so that suppress the bone anchoring device that the activity between the adjacent vertebrae designs.For example, bone stake, bar, hook, line, chock, plate bolt and other parts can be used for vertebra stage fix in position.Described fixture can be installed in the intervertebral space or it can comprise that intervertebral space and spinal column proparea or it enter to comprise the spinal column proparea.Bone anchoring device can be stabilized in device in the intervertebral district so that help with the fusion cage coupling.For example, described prosthese can be solid ring bodies form, and it has the central opening that a plurality of isolating bones outstanding on upper surface and lower surface are connected tooth and have the material that can fill promote osteogenesis.For example, referring to US 6,520,993.Described prosthese can have dish sample body, and it has the welding sample bump of arranging so that promote the original position lateral stability on the apparent surface.For example, referring to US 4,917,704.Described prosthese can be made up of relative latter end, and they can keep the height of the intervertebral space with the less integral central element of diameter, and wherein the collagen material is arranged in the ring-type bag between two latter ends.For example, referring to US 6,146,420.Described prosthese can be by forming with first and second side surface of the upper and lower surperficial extends parallel that is connected adjacent vertebrae each other.For example, referring to US 5,716,415.Described prosthese can be for by the hollow intervertebral space with have at least one and be used for fixing the fusion equalization chamber that forms into the end in the hole of surrounding bone.For example, referring to US 6,066,175.Described prosthese can be made up of the metallic object that coning is tapered from veutro to back of the body end and have a plurality of fish platees that stretch from the offside that has the opening that is used for bone screw.For example, referring to US 4,955,908.Described prosthese can have protuberance with the plate that is connected adjacent vertebrae be arranged between the engagement plate with demarcation strip and it maintained the collating unit of lordosis in arranging and form by a pair of.For example, referring to US 6,576,016.Described prosthese can promote a plurality of implants of bone by the disk space of intervertebral space fusion for inserting side by side.For example, referring to US5,522,899.Described prosthese can be anchoring device, and it is by having for connecting vertebral implant (for example fusion cage) core of constructing and the end that is suitable for engaging with the bone section of vertebra with fixed form.For example, referring to US 6,306,170.Described prosthese can be the bone anchoring device of being made up of hone lamella and joint utensil (for example bone screw).For example, referring to US 6,342,055,6,454,769,6,602,257 and 6,620,163.

In one aspect of the method, described prosthese can be the alternative of spinal fusion body.Described prosthese can be for for providing the dish that normal activity designs between the lamina of vertebra.This dish can be used to simulate the natural impact absorption function of natural disc.This dish can be made up of central core and end member spare, and end member spare will coil and lean on to adjacent vertebrae, or it can be used for only replacing the part (for example vertebral pulp) of natural disc.For example, described dish can be for being clipped in two elastic parts between the rigid plate.For example, referring to US6,162,252; 5,534,030,5,017,437 and 5,031,437.Described dish can be the prosthese dish nuclear by hydrogel core and the growth that allows this core distortion and reductive constraint pliability sheath to form.For example, referring to US 5,824,093.Described dish can by rigidity upper and lower recessed-protruding element and allowing the nucleome between the active concave surface to form.For example, referring to US 6,156,067.Described dish can be the part spinal prostheses, it is by elastomeric material, such as siloxane polymer or the elastomer that has covered the shell of the contact adjacent vertebrae that rigid material makes make.For example, referring to US6,419,706.Described dish can only replace vertebral pulp by using spinal cord renucleation thing, and described spinal cord renucleation thing can be formed with the hydrophobic and aqueous-favoring inflatable biosimulation plastics that are fit to natural size and shape by having in the original position expansion.For example, referring to US 6,264,695.Described dish can be made up of the centronucleus that the biocompatibility elastomer forms, and coated on the described elastomer have a multilamellar lamella of being made by elastomer and fiber.For example, referring to US 4,911,718.Described dish can be made up of the capsula interna with the outer field fluid filled of powerful inert fiber, and described fiber has soaked into the biology absorbing material again that promotes tissue ingrowth.For example, referring to US 4,772,287.

In one aspect of the method, described spinal implant can be for alleviating the device that spinal column compressing or minimizing can be used as the adhesion of spinal operation and/or wound result formation.For example, described device can be protector, it by be installed on the dorsal surface protective cover on one deck at least form in case prevent that postoperative from forming with the spinal dural adhesion of spinal column.For example, referring to United States Patent (USP) 5,437,672 and 5,868,745 and Application No. 2003/0078588.Described device can be sticking patch flange and the stitching flange that stretches along periphery around this sticking patch, make tissue below the sticking patch be isolated and can't grow with the adhesion cicatrix effectively.For example, referring to United States Patent (USP) 5,634,944.Described device can be gone into barrier for protective insert, and it is by in the spinal column or the biocompatibility protective cover that uses behind the operation on vertebra forms so that the tissue adhesion that prevents to cause on the spinal nerves because of being bonded in.For example, referring to United States Patent (USP) 4,013,078.Described device can be used for nerve decompression, and the surface local anatomical structure that constitutes by the microstructure that has by outside stretching, extension reduces the fibrous tissue adjacent with nervous tissue and forms simultaneously.For example, referring to United States Patent (USP) 6,106,558 and Application No. 2003/0078673.

Can have benefited from that the polymer composition of theme of the present invention is impregnated into the spinal prostheses of adjacent tissue and other spinal implant according to the present invention comprises and is purchased product.(Memphis TN) has sold the threaded fusing device of fusion cage product I NTERFIX to Medtronic SofamorDanek.(Minneapolis MN) has sold emerging system fusion cage product and CERVI-LOK neck fixed system fixture between the BAK/C body of cervical vertebra to Centerpulse Spine-Tech.(Austin TX) has sold SC-ACUFIX throat plate system to SpinalConcepts.DePuy Spine, (Raynham MA) has sold spinal disc, ACROFLEX TDR prosthese and the artificial dish of CHARITE to Inc..Synthes-Stratec (Switzerland) has sold the PRODIS system, comprises that PRODISC neck-C IDE coils substitute.Raymedica, (Minneapolis MN) has sold PDN (PROSTHETIC DISC NUCLEUS) to Inc..

The spinal implant of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue is provided among the present invention in one aspect, and wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with spinal implant have above been described.The tissue that polymer composition is impregnated into and spinal implant is adjacent that will comprise the theme of the present invention of fibre modification inhibitor and/or anti-infective can be minimized near the fibre modification the implant (cicatrization) and/or can reduce or prevent that adhesion between implant and the surrounding tissue from forming and/or can suppress or prevent near the infection of implant.

The spinal implant of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue is provided among the present invention in one aspect, and wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective) so that cicatrization between restraining device and the surrounding bone and adhesion and/or inhibition or the locational infection of prevention implant.

Can be by polymer composition directly and/or indirectly being coated with following position or coating is soaked into said composition around spinal implant thereon: (a) tissue adjacent with spinal implant; (b) near spinal implant-organizational interface; (c) zone around the spinal implant; (d) tissue around the spinal implant.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with spinal implant comprises described polymer composition is delivered to: (a) on the spinal implant surface of implant procedure process (for example as injectable, paste, gel or mesh); (b) come in and go out before conduit and the implant at once or the tissue surface in the process (for example forming gel or mesh) implanting peritoneum as injectable, paste, gel, original position; (c) implant behind the spinal implant spinal implant surface at once and/or implant tissue (for example forming gel or mesh) around the spinal implant as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed spinal implant (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject spinal implant tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install.

In one aspect, will comprise that the polymer composition of the theme of the present invention of anti-scarring agent and/or anti-infective is impregnated into and the adjacent tissue of spinal implant (for example implantable cage or dish).In certain aspects, spinal implant can be applied (or it is contained by change) fibre modification derivant (for example silk or Pulvis Talci) on the part of this device, and the polymer composition that comprises the theme of the present invention of anti-scarring agent can be impregnated into the tissue adjacent with this device another part.For example, the outer surface of described implant (for example spinal implant) be can coated fiber degeneration derivant so that improve adhesion between described device and the surrounding tissue, tissue that the polymer composition that will comprise the theme of the present invention of anti-scarring agent simultaneously is impregnated into and this device is inner adjacent will be so that will organize and the adhesion of implant inside is reduced to bottom line.The method of the combination of fibre modification derivant and use fibre modification derivant and spinal implant is described in (U.S.'s serial number 60/524 on November 20th, 2003,023) and the title of submitting on June 9th, 2004 (U.S.'s serial number 60/578,471) be in the co-pending application of " medical implant and fibre modification derivant " (" Medical implant andFibrosis-Inducing Agents ").

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with spinal implant is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because spinal implant is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or 10 μ g-10mg; Or 10mg-250mg; Or 250mg-1000mg; Or 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/1mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

Nerve stimulation device

In one aspect, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with nerve stimulation device, wherein pulse generator is delivered to nervous tissue's (for example CNS, peripheral nervous, autonomic nerve) so that regulate its activity with electric pulse.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

Have a large amount of nerve stimulation apparatuses, wherein the generation of fibre modification reaction can be to the function generation harmful effect of device or because of implanting or having used this device to produce bad biological question.In general, the fibrosis encapsulation of electric conductance (or the fibrous tissue growth between electric conductance and the target nerve tissue) makes pulse successively decrease slowly, be affected or interrupt from installing to the fax of organizing.This can cause the device role not good enough or ineffective fully, or the required energy increase of resistance that applies because of cicatrix (or neuroglia) tissue that overcomes insertion may cause consuming excessively battery life.Near the infection the implant position also may be introduced or promote to the implantable neural stimulating apparatus.

Nerve stimulation device is as the alternative or complementary therapy of chronic neurodegenerative disease, and chronic neurodegenerative disease generally uses pharmacotherapy, invasive therapy or behavior/life style to change treatment.Nerve stimulation can be used for blocking-up, shelters or stimulate the intravital signal of telecommunication with the therapy apparatus dysfunction, include, but are not limited to pain, epilepsy, anxiety neurosis, depression, ulcer, dvt formation, amyotrophy, obesity, joint stiffness, muscular spasm, osteoporosis, skoliosis, spinal disc degeneration, spinal cord injury, deafness, urinary system malfunction and gastroparesis.Nerve stimulation can be transferred into neural many different pieces, comprises spinal cord, brain, vagus nerve, sacral nerves, nervus gastrica, acoustic nerve and organ, bone, muscle and tissue.Like this, researched and developed the nerve stimulator that is suitable for different anatomical structures and nervous system feature.Can have benefited from that polymer composition with theme of the present invention is impregnated into the nerve of adjacent tissue according to the present invention and the representational example of neurosurgery implant and device comprises: for example be used for Dexedrine device by pain relief; The device that is used for infusion under the continuous arachnoidea; Implantable electrode; Stimulating electrode; Implantable pulse generator; Electric conductance; Stimulating catheter leads; Neural stimulation system; Electrostimulator; Cochlear implant; Auditory stimulator and micro-stimulator.

Can also be based on the energy source nerve stimulation device of classifying, described energy source comprises: battery powered, radio frequency (RF) power supply or this combination of two types.With regard to battery powered nerve stimulator, the not rechargeable battery of implanting is used for energy supply.Battery and lead all and to implant and nerve stimulation device is fully in vivo thus by modus operandi.The setting of the nerve stimulator of Zhi Ruing is controlled by external magnet by the patient fully.The life-span of implant generally is subjected to the restriction in battery life time limit and the scope in 2-4 years, this depended on purposes and energy requirement.With regard to the nerve stimulation device of RF-energy supply, the source that radio frequency consumes from the outside is transferred to the passive receptor of implantation.Because power supply is easy to recharge or is replaceable, so radio system can become bigger energy source, and can use multi-lead in these systems thus.Instantiation comprises: have the nerve stimulator of battery supply, described battery supply is included in wherein so that powered in 8 hour time limit, wherein can be by external radio-frequency connecting device charging (for example, referring to United States Patent (USP) 5,807,397); Or by the external transmitter control of using digital signal and by the micro-stimulator (for example, referring to United States Patent (USP) 6,061,596) of radio frequency powered.

The example that is purchased the nerve stimulation product comprises that by Medtronic (Minneapolis, MN) quadrupole leading of the 3272 MATTRIX receptors of Zhi Zaoing, 3210 MATTRX transmitters and 3487APISCES-QUAD formed the nerve stimulator of radio frequency powered to Inc..Medtronic has also sold battery powered ITREL 3 nerve stimulators and SYNERGY nerve stimulator; Be used for sacral nerve stimulation so that the INTERSIM Therapy of control urine; With lead, such as 3998SPECIFY lead and 3587A RESUME II lead.

Another example of nerve stimulation device is the gastric peristalsis pacemaker, and guiding substance is wriggled by the GI road so that transmit electricity irritation by stages wherein to be arranged with a plurality of electrodes along the GI road.For example, referring to United States Patent (USP) 5,690,691.The representational example of gastric stimulation devices is from Medtronic, Inc. (Minneapolis, ENTERRA Gastric Electrical Stimulation (GES) MN).

Nerve stimulation device, particularly leading must be with the location of accurate way very to guarantee to stimulate the correct region of anatomy that is transferred in the nervous system.The all or part of of nerve stimulation device can be moved after surgery, or excessively cicatrix (neuroglia) tissue growth can occur around implant, and this can cause the effect of these devices to reduce (as mentioned above).Nerve stimulation device with polymer composition of the theme of the present invention that is impregnated into the tissue adjacent with the electrode-tissue interface can be used to increase the effect and/or the movable time limit (the particularly battery powered device of implanting fully) of implant.Nerve stimulation device can also have benefited from discharging the therapeutic agent that can suppress near the infection in implant position.Therefore, the nerve stimulator that the invention provides the polymer composition with the theme of the present invention that is impregnated into adjacent tissue leads, and wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with nerve stimulation device have above been described.

Can be by polymer composition directly and/or indirectly being coated with following position or coating is soaked into said composition around the nerve stimulation device of implanting thereon: (a) tissue adjacent with nerve stimulation device; (b) near nerve stimulation device-organizational interface; (c) zone around the nerve stimulation device; (d) tissue around the nerve stimulation device.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with nerve stimulation device comprises described polymer composition is delivered to: (a) on the nerve stimulation device surface of implant procedure process (for example as injectable, paste, gel or mesh); (b) before the implantable neural stimulating apparatus at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) at once nerve stimulation device surface and/or the tissue around the implantable neural stimulating apparatus (for example forming gel or mesh) behind the implantable neural stimulating apparatus as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed nerve stimulation device (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject nerve stimulation device tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with nerve stimulation device is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because nerve stimulation device is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

(1) is used for the treatment of the nerve stimulation of chronic pain

In one aspect, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with the control chronic pain with nerve stimulation device.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

Chronic pain is a most important clinical problem in all medical domains.For example, there are 5 million peoples of surpassing to disable in the U.S. according to estimates because of backache.The Financial cost of chronic back pain is huge, causes annual forfeiture to surpass 100,000,000 working days, and cost is 500-1,000 hundred million dollars according to estimates.Reported that about 4,000 ten thousand Americans suffer from recidivity headache and medical treatment cost that should disease is annual above 4,000,000,000 dollars.The medical expense that also has 8 million peoples to report that chronic neck or prosopodynia and annual cost took place for they in the U.S. is estimated as 2,000,000,000 dollars.Think that the cost of pain of control tumor patient is near 12,000,000,000 dollars.Chronic pain makes the cost that loses the American public of work capacity and consumption more than cancer or cardiopathic people surpass the summation of cancer and heart disease cost.Except that the health consequence, chronic pain has also spent a large amount of other costs, comprising that employment forfeiture, marriage are discorded, depression and prescription medicine drug dependence.Therefore, undoubtedly, reduce sickness rate relevant and cost and remain remarkable challenge medical health system with persistent ache.

The intractable severe pain that causes because of damage, skoliosis, spinal disc degeneration, spinal cord injury, malignant tumor, arachnoiditis, chronic disease, pain syndrome (for example failed back syndrome, complexity regional pain syndrome) and other reason is weak and common difficult medical problem.In many patients, use analgesic continuously, particularly reduce because of drug resistance, effectiveness and the probability of addiction can't become feasible solution as this class medicine of anesthetics.In the effort of resisting this disease, researched and developed the nerve stimulation device of treatment severe intractable pain, and this severe intractable pain has tolerated other traditional treatment form, changes such as pharmacotherapy, invasive therapy (operation) or behavior/life style.

Nerve stimulation is worked with the blocking-up pain perception by the low-voltage electricity irritation being passed to spinal cord or specific peripheral nervous basically.There is " gate " in the gate-control theory of pain (Ronald Melzack and PatrickWall) supposition the pain management signal flows to the posterior horn of spinal cord of brain from peripheroceptor.Can be according to inferring health by activating other (non-pain) the fiber inhibition of pain signal (" closed shutter ") in the cornu dorsale.Nerve stimulation device is implanted the spinal cord epidural space so that stimulate the nontoxic nerve fiber in the cornu dorsale and shelter pain perception.As a result of, the tingling (being called paraesthesia) of non-pain generally takes place in the patient.By means of nerve stimulation, most of patient's report has pain relief (alleviating 50%), the level of activation of improvement to increase and uses anesthetics to reduce.

Pain control neural stimulation system passes to leading (general 1 or 2) of spinal cord or targeting peripheral nerve by the power supply that produces electricity irritation, with electricity irritation and is connected power supply and the power lug of leading is formed.Neural stimulation system can be battery powered, radio frequency powered or the two combination.In general, the nerve stimulation device that has both types: operation is implanted and is positioned at intravital those nerve stimulation devices (promptly implant battery and lead) fully and has those nerve stimulation devices of body (leading and radio frequency receiver) and external (power supply and antenna) element.With regard to battery powered nerve stimulator in the body, implant whole not rechargeable batteries of implanting and lead by operation.The setting of the nerve stimulator of Zhi Ruing is controlled by external magnet by the host fully, and implant has the life-span in 2-4 years.With regard to the nerve stimulator of radio frequency powered, the source that radio frequency consumes from the outside is transferred to the passive receptor of implantation.Radio system can become bigger energy source, and can use multi-lead in these systems thus.

The nerve stimulation device that has the spinal cord stimulation that can be used for pain control, posture location and other treatment for diseases in a large number.The example of concrete nerve stimulation device comprises the device that those are made up of the stimulator of pick off that detects the spinal column position and a series of pulses of emission automatically, and described pulse amplitude when the back of the body is in dorsal position descends.For example, referring to United States Patent (USP) 5,031,618 and 5,342,409.Neural Stimulator can be by electrode and generationBased on being equivalent to body movement at interval Pulse andThe control circuit of the regeneration period of resting stage and conduct treatment pain is formed. For example, referring to United States Patent (USP) 5,354,320. Can implantedly parallel with the spinal cord axleIn the epidural space Nerve stimulator can be with transfer of data To produce can by link coupled many-receptor of the spinal cord stimulation pulse of electrodes transfer.For example, ginseng See the patent No. 6,609,031.Nerve stimulator can be carried nervous tissue for power supply sheath and three at least Stimulating catheter for the electrode that stimulates leads.For example, referring to United States Patent (USP) 6,510,347.Neural thorn Sharp device can lead for the epidural spinal cord of self centering, and it has fixed stake district so that make in injection hard Expansible leading keeps stable when changing agent.For example, referring to United States Patent (USP) 6,308,103.Be used to induce The nerve stimulator of electrical activity is described in the spinal cordFor example United States Patent (USP) 6,546, in 293,6,236,892,4,044,774 and 3,724,467.

Can have benefited from the nerve stimulation device that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised and be purchased product.The nerve stimulation device that is purchased that is used to control chronic pain comprises from Medtronic the SYNERGY of Inc., INTREL, X-TREL and MATTRIX neural stimulation system.Percutaneous in this system leads and can be quadripolar (4 electrodes), such as PISCES-QUAD, PISCES-QUAD PLUS and PISCES-QUAD compact; Or (8 electrodes) of the ends of the earth, lead such as OCTAD.Operation is led from as quadripolar, such as SPECIFY lead, RESUMEII leads, RESUMETL leads and ON-POINT PNS leads, so that produce the paraesthesia of multiple stimulation combination and extensive region.The center neural stimulation system can be described in for example United States Patent (USP) 6,671,544 with relevant leading; 6,654,642; 6,360,750; 6,353,762; 6,058,331; 5,342,409; In 5,031,618 and 4,044,774.Nerve stimulation is led, and can have benefited from discharging therapeutic agent such as these, and this therapeutic agent can reduce the cicatrization on the electrode-tissue interface, so that increase the efficient of impulse propagation and increase the time limit of leading and working clinically.Nerve stimulation is led, and can also have benefited from discharging therapeutic agent such as these, and this therapeutic agent can prevent or suppress near the infection the implant position.In one aspect, described device comprises the leading of polymer composition that is used to control the nerve stimulation device of chronic pain and/or has the theme of the present invention that comprises anti-scarring agent and/or anti-infective that has been impregnated into and has implanted device and/or led the adjacent tissue in place.In one aspect of the method, the invention provides to have and be impregnated into and implant or the leading of the polymer composition of the theme of the present invention that comprises anti-scarring agent and/or anti-infective of tissue that the implanted epidural space that leads is adjacent.Other can be used for implementing as mentioned above the system that is purchased of the present invention and comprise and can drive rechargeable PRECISION spinal cord stimulation system (Advanced Bionics Corporation, Sylmar, the CA that reaches 16 electrodes; Be Boston Scientific Company) (for example, referring to United States Patent (USP) 6,735,474; 6,735,475; 6,659,968; 6,622,048; 6,516,227 and 6,052,624).Available from the AdvancedNeuromodulation system, Inc. (Plano, TX; For example,, 276,6,609,031 and 5,938,690) GENESIS XP spinal cord stimulation device and available from Cyberonics referring to United States Patent (USP) 6,748, Inc. (Houston, TX; For example, vagal stimulation (VNS) therapy system referring to United States Patent (USP) 6,721,603 and 5,330,515) also has benefited from the polymer composition that the present invention has the theme of the present invention that is impregnated into adjacent tissue.

With regard to effective lenitive nerve stimulation, lead and must accurately divide adjacent location with spinal cord that is subjected to electricity irritation or targeting peripheral pars nervosa, and irrelevant with concrete design feature.Nerve stimulator can move after surgery or excessive tissue is grown or extracellular matrix deposition can occur around nerve stimulator, and this can cause the function of these devices to descend.Nerve stimulation device with the polymer composition that is impregnated into of the present invention theme adjacent with the electrode-tissue interface can be used to increase the time limit that these devices work clinically.Nerve stimulation device can also have benefited from discharging the therapeutic agent that can prevent or suppress near the infection in implant position.In one aspect, the invention provides and be used to control the nerve stimulation device of polymer composition that having of chronic pain is impregnated into the theme of the present invention of the tissue adjacent with implant part (particularly leading), wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with the control chronic pain of nerve stimulation device have above been described.

Can by polymer composition directly and/or indirectly is coated with following position or coating thereon and with said composition soak into control the nerve stimulation device of chronic pain in being used to of implanting around: (a) with the adjacent tissue of nerve stimulation device that is used to control chronic pain; (b) be used to control near the nerve stimulation device-organizational interface of chronic pain; (c) be used to control zone around the nerve stimulation device of chronic pain; (d) be used to control tissue around the nerve stimulation device of chronic pain.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with the nerve stimulation device that is used to control chronic pain comprises described polymer composition is delivered to: (a) on the nerve stimulation device surface that is used to control chronic pain of implant procedure process (for example as injectable, paste, gel or mesh); (b) before the implantable neural stimulating apparatus at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the nerve stimulation device be used to control chronic pain at once be used to control the nerve stimulation device surface of chronic pain and/or implant tissue (for example forming gel or mesh) around the nerve stimulation device that is used to control chronic pain as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed the nerve stimulation device that is used to control chronic pain (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in several hours-a few time limits in week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject the nerve stimulation device tissue on every side that is used to control chronic pain as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand the polymer composition of theme of the present invention can be impregnated into and install all or part of, only comprise install, only lead, the tissue of electrode and/or its bordering compounding only.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with the nerve stimulation device that is used for controlling chronic pain is suitable for discharging one or more activating agent of four kinds of ordinary circumstances suppressing fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.The definite dosage that gives constitutes by not isostructure and size because be used to control the nerve stimulation device of chronic pain, so can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

(2) be used for the treatment of Parkinsonian nerve stimulation

In one aspect, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with the treatment parkinson disease with nerve stimulation device.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

The nerve stimulation device of implanting brain is used to control the symptom relevant with parkinson disease or essential tremor.In general, these devices are two chambers stimulator devices (similar with cardiac pacemaker) of dividing to the brain of controlled motion function the both sides stimulus delivery.Electricity irritation is used to alleviate because of the symptom that parkinson disease self cause (tremble, tetanic, bradykinetic, motion can not) or as the resultant symptom of drug side effect (dyskinesia) that is used for the treatment of disease.Two stimulating electrodes are implanted brains (usually at nucleus hypothalamicus both sides or internal part of globus pallidus) to be used for the reactive parkinson disease of levodopa and to implant an electrode (at nucleus ventralis intermedius thalami) being used for the treatment of and trembling.By using stereotactic head frame and MRI or guide CT that electrode is implanted brain.Install connection electrode by extending the nerve stimulation (producing pulse extends) that (turning round under scalp and the neck skin) implant down near the skin clavicle.Neuropathist can carry out optimization to installing control by using the Noninvasive control device adjustment stimulus parameter through telemetry and nerve stimulator transmission subsequently.The patient also can use the magnet switching system and use control device control device (in the limit that neuropathist sets) to be provided with.The form of also having studied this deep brain stimulation is so that treatment pain, epilepsy, psychosis (obsessive-compulsive disorder) and dystonia.

Describe several devices that this class is used that are used for, having comprised: for example had the nerve stimulator and the implantable electrode of pliability insulation cladding material, the cortical tissue that it is used to organize monitoring and stimulates brain and other tissue.For example, referring to United States Patent (USP) 6,024,702.Nerve stimulator (pulse generator) can be for the electric control module of intracranial implantation with to determine a plurality of electrodes of frequency use stimulating electrical signal cerebral tissue.For example, referring to United States Patent (USP) 6,591,138.Can serve as reasons at least two electrode that is suitable for cranium and to be suitable for implant head subcutaneous with the control module that transmits the output signal of telecommunication and the system that is used to provide the peripheral hardware of two-way communication to form of nerve stimulator.For example, referring to United States Patent (USP) 6,016,449.Nerve stimulator can change the implantable assembly of the electrical activity of brain for being used for of being made up of pick off and two electrodes.For example, referring to United States Patent (USP) 6,466,822.

Can have benefited from the nerve stimulation device that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised and be purchased product.The example that is purchased that is used for the treatment of the device of parkinson disease and essential tremor comprises Medtronic, the ACTIVA system of Inc. (for example, referring to United States Patent (USP) 6,671,544 and 6,654,642).This system forms by being connected to the two chambers of the KINETRA nerve stimulator, SOLETRA nerve stimulator or the INTREL nerve stimulator that further are connected to the extension (insulated conductor) that DBS leads.DBS leads and is become by four that the use the polyurethane bunchy curling leads of thin insulation.The strand lead is separately with the long electrode ending of 1.5mm.In one aspect, can implant the invention provides and be used for the treatment of Parkinsonian nerve stimulation device with polymer composition of the theme of the present invention that has been impregnated into and has implanted device and/or led the adjacent tissue in place, wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).In one aspect of the method, the invention provides to have and be impregnated into and implant the leading (for example DBS leads) of polymer composition of the theme of the present invention that comprises anti-scarring agent and/or anti-infective of maybe implantation being led the adjacent tissue in place.In one aspect of the method, the DBS that the invention provides the polymer composition with the theme of the present invention that comprises anti-scarring agent and/or anti-infective that is impregnated into and implants the adjacent cerebral tissue in the electrode place of maybe implantation being led leads.

Above described and be used in conjunction with Parkinsonian number of polymers of the treatment of nerve stimulation device and non-polymer delivery system.

Can thereon said composition be soaked in being used for the treatment of around the Parkinsonian nerve stimulation device of implanting by polymer composition directly and/or indirectly being coated with following position or coating: (a) be used for the treatment of the adjacent tissue of Parkinsonian nerve stimulation device; (b) be used for the treatment of near Parkinsonian nerve stimulation device-organizational interface; (c) be used for the treatment of Parkinsonian nerve stimulation device zone on every side; (d) be used for the treatment of Parkinsonian nerve stimulation device tissue on every side.Being used for polymer composition with theme of the present invention is impregnated into and comprises with the method that is used for the treatment of the adjacent tissue of Parkinsonian nerve stimulation device described polymer composition is delivered to: (a) on being used for the treatment of of implant procedure process Parkinsonian nerve stimulation device surface (for example as injectable, paste, gel or mesh); (b) before implantation is used for the treatment of Parkinsonian nerve stimulation device at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant and to be used for the treatment of behind the Parkinsonian nerve stimulation device being used for the treatment of Parkinsonian nerve stimulation device surface and/or implanting the tissue (for example forming gel or mesh) that is used for the treatment of around the Parkinsonian nerve stimulation device at once as injectable, paste, gel, original position; (d) by described compositions part being coated with into having placed the anatomic space that is used for the treatment of Parkinsonian nerve stimulation device (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in several hours-a few time limits in week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) be used for the treatment of Parkinsonian nerve stimulation device tissue on every side by injecting as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand the polymer composition of theme of the present invention can be impregnated into and install all or part of, only comprise install, only lead, the tissue of electrode and/or its bordering compounding only.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, be impregnated into the polymer composition that is used for the treatment of the theme of the present invention of the adjacent tissue of Parkinsonian nerve stimulation device and be suitable for discharging one or more activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.The definite dosage that gives constitutes by not isostructure and size because be used for the treatment of Parkinsonian nerve stimulation device, so can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

(3) The vagal stimulation that is used for the treatment of epilepsy

In one aspect, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with the treatment epilepsy with nerve stimulation device.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

Nerve stimulation device is used to control the vagal stimulation in the drug resistant epilepsy (that is, although use antuepileptic to carry out suitable Drug therapy, epilepsy still can't be controlled).Although use pharmacotherapy to continue to exist epilepsy maybe can not tolerate the side effect of its Drug therapy the epileptic who has carried out multiple trial about 30% aspect this disease of control.Suffer from the treatment-resistant epilepsy and have benefited from the vagal stimulation therapy the U.S. 2,500,000 patients that have an appointment according to estimates.Like this, inadequate epilepsy control remains significant difficult medical problem, and wherein many patients exist self-respect decline, school achievement difference and the limited consequence as its disease of life style.

Vagus nerve (being also referred to as the 10th cranial nerve) mainly contains and imports sensory fiber into, and the information that they carry from neck, thorax and abdominal part arrives on the nuclear bundle soltarius (nucleus tractussoltarius) and norepinephrine energy in arrival brain and the spinal cord and 5-hydroxy tryptamine energy neural modulation system of brain stem.Confirmed that vagal stimulation (VNS) induces carrying out property EEG to change, changed the both sides cerebral blood flow and change the blood flow that arrives thalamus.Reason is not still understood although epilepsy is controlled really cutter, but having shown clinically, VNS can stop postepileptic epilepsy, alleviate the order of severity and the seizure frequency of epilepsy, prevention epilepsy during preventative use in a period of time, the quality of making the life better, and reduce dosage, number of times and the side effect (causing alertness, emotion, memory to be improved) of antuepileptic.

In VNS, can perform the operation and implant bipolar electric conductance, make it will be sent to left vagus nerve in the neck from the electricity irritation of pulse generator.Pulse generator is the battery powered device of lithium carbon monofluoride (lithium carbon monofluoride) that accurate stimulus modelity is passed to vagal implantation.Pulse generator can be by neuropathist's operation sequence (service routine rod) so that be fit to the device of individual patient, and the patient can provide and use external magnet switching device simultaneously.Can as epilepsy directly the long-term electricity irritation of treatment for example be described in the United States Patent (USP) 6,016,449, make implantable nerve stimulator and relative persistent deep brain electrode coupling thus.Implantable nerve stimulator can be made up of implantable electric conductance, described implantable electric conductance has the bifurcated that has two or more independent end stages or extremity separately, they respectively carry at least one sensing or stimulating electrode, and it is neuropathic with other that this electric conductance can be used for the treatment of epilepsy.For example, referring to United States Patent (USP) 6,597,953.

Can have benefited from the nerve stimulation device that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised and be purchased product.The example that is purchased of VNS system is Cyberonics, Inc. the product of Sheng Chaning comprises that Model 300 and Model 302 lead, Model 101 and Mode1102R pulse generator, Model 201 program rods and Model 250 program development softwares and Model220 magnet.These are by Cyberonics, and the product description that Inc. makes is in United States Patent (USP) 5,540,730 and 5,299,569 for example.

With regard to regard to the effective vagal stimulation of epilepsy, leading must be accurately and the left vagus nerve adjacent positioned, and irrelevant with concrete design feature.Occur growth of excessive scar tissue or extracellular matrix deposition on every side if lead at VNS, so this situation can reduce the effect of device.VNS device with polymer composition of the theme of the present invention that is impregnated into adjacent tissue can be used to increase the time limit that these devices work clinically.The VNS device can also have benefited from discharging the therapeutic agent that can prevent or suppress near the infection in implant position.In one aspect, described device comprises the VNS device and/or leads, they have comprise anti-scarring agent and/or anti-infective be impregnated into that implantation maybe will be implanted described VNS device and/or the polymer composition of the theme of the present invention of the adjacent tissue in place that leads.In one aspect of the method, the invention provides leading of polymer composition with the theme of the present invention that comprises anti-scarring agent and/or anti-infective that is impregnated into and implants the described adjacent tissue of place's vagus nerve that leads.

In one aspect of the method, the invention provides the nerve stimulation device of the polymer composition with the theme of the present invention that is used for the treatment of epilepsy that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention comprises therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system of the nerve stimulation device that is used for the combined treatment epilepsy have above been described.

Can said composition be soaked into around the nerve stimulation device of implanting that is used for the treatment of epilepsy by polymer composition directly and/or indirectly being coated with following position or being coated with thereon: (a) with the adjacent tissue of nerve stimulation device that is used for the treatment of epilepsy; (b) be used for the treatment of near the nerve stimulation device-organizational interface of epilepsy; (c) be used for the treatment of zone around the nerve stimulation device of epilepsy; (d) be used for the treatment of tissue around the nerve stimulation device of epilepsy.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with the nerve stimulation device that is used for the treatment of epilepsy comprises described polymer composition is delivered to: (a) on the nerve stimulation device surface that is used for the treatment of epilepsy of implant procedure process (for example as injectable, paste, gel or mesh); (b) before implantation is used for the treatment of the nerve stimulation device of epilepsy at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the nerve stimulation device be used for the treatment of epilepsy the nerve stimulation device surface that is used for the treatment of epilepsy at once and/or implant tissue (for example forming gel or mesh) around the nerve stimulation device that is used for the treatment of epilepsy as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed the nerve stimulation device that is used for the treatment of epilepsy (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject the nerve stimulation device tissue on every side that is used for the treatment of epilepsy as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand the polymer composition of theme of the present invention can be impregnated into and install all or part of, only comprise install, only lead, the tissue of electrode and/or its bordering compounding only.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with being used for the treatment of the nerve stimulation device of epilepsy is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF к B inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.The definite dosage that gives constitutes by not isostructure and size because be used for the treatment of the nerve stimulation device of epilepsy, so can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

(4) The vagal stimulation (VNS) that is used for the treatment of other disease

In one aspect, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with the treatment neurological disorder with nerve stimulation device.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

Have been found that at VNS in the application of treatment epilepsy, some patient emotion is taken place improved in therapeutic process.Like this, checked VNS to be used to control the treatment-resistant mood disorders at present, such as depression and anxiety.Depression remains a huge clinical difficult problem in the Western countries, wherein surpass 1% (there are 2,500 ten thousand people in the U.S.) and suffer from the depression that is not enough to treat with pharmacotherapy.In the process of the following disease of control, checked vagal stimulation: such as anxiety (panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder), obesity, migraine, sleep disorder, dementia, Alzheimer and other chronic or degeneration neurological disorder.Also checked the application of VNS in the medically tangible obesity of treatment.

The implantable nerve stimulator that is used for the treatment of neurological disorder can be made up of implantable electric conductance, described implantable electric conductance has the bifurcated that has two or more independent end stages or extremity separately, they respectively carry at least one sensing or stimulating electrode, and it is neuropathic with other that this electric conductance can be used for the treatment of epilepsy.For example, referring to United States Patent (USP) 6,597,953.Described implantable nerve stimulator can be treatment Alzheimer and dull-witted device, and especially for the neuroregulation or the stimulation of left vagus nerve, it is by implantable leading-receptor, stimulated in vitro device and primary coil group.For example, referring to United States Patent (USP) 6,615,085.

Can have benefited from the nerve stimulation device that is used for the treatment of neurological disorder that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised and be purchased product.Cyberonics, Inc. have made and have been purchased the VNS system, comprise that Model 300 and Model 302 lead, Model 101 and Model 102R pulse generator, Model 201 program rods and Model 250 program development softwares and Model 220 magnets.These and other is by Cyberonics, and the product that Inc. makes can be used for the treatment of neurological disorder, comprises that depression is (for example, referring to United States Patent (USP) 5,299,569), dull-witted (for example, referring to United States Patent (USP) 5,269,303), migraine (for example, referring to United States Patent (USP) 5,215,086), sleep disorder are (for example, referring to United States Patent (USP) 5,335,657) and fat (for example, referring to United States Patent (USP) 6,587,719,6,609,025,5,263,480 and 5,188,104).

Be important to note that the basis of treatment is with above-mentioned those are identical to the described treatment of epilepsy.Used device is also similar with the treatment principle.As above described to the treatment epilepsy, growth of excessive scar tissue or extracellular matrix deposition appear on every side if lead at VNS, and so this situation can reduce the effect of device.The VNS device can have benefited from discharging and can reduce synulotic therapeutic agent on the electrode-tissue interface so that increase the efficient of pulse transmission and increase the function that these devices are treated depression, anxiety, obesity, sleep disorder and dementia clinically.The VNS device can also have benefited from discharging and can prevent or suppress the therapeutic agent that infects on the implant position.In one aspect, described device comprises the VNS device and/or leads, they have comprise anti-scarring agent and/or anti-infective be impregnated into that implantation maybe will be implanted described VNS device and/or the polymer composition of the theme of the present invention of the adjacent tissue in place that leads.In one aspect of the method, the invention provides leading of polymer composition with the theme of the present invention that comprises anti-scarring agent and/or anti-infective that is impregnated into and implants the described adjacent tissue of place's vagus nerve that leads.

In one aspect of the method, the invention provides the nerve stimulation device of the polymer composition with the theme of the present invention that is used for the treatment of neurological disorder that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention comprises therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system of the nerve stimulation device that is used for the combined treatment neurological disorder have above been described.

Can said composition be soaked into around the nerve stimulation device of implanting that is used for the treatment of neurological disorder by polymer composition directly and/or indirectly being coated with following position or being coated with thereon: (a) with the adjacent tissue of nerve stimulation device that is used for the treatment of neurological disorder; (b) be used for the treatment of near the nerve stimulation device-organizational interface of neurological disorder; (c) be used for the treatment of zone around the nerve stimulation device of neurological disorder; (d) be used for the treatment of tissue around the nerve stimulation device of neurological disorder.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with the nerve stimulation device that is used for the treatment of neurological disorder comprises described polymer composition is delivered to: (a) on the nerve stimulation device surface that is used for the treatment of neurological disorder of implant procedure process (for example as injectable, paste, gel or mesh); (b) before implantation is used for the treatment of the nerve stimulation device of neurological disorder at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the nerve stimulation device be used for the treatment of neurological disorder the nerve stimulation device surface that is used for the treatment of neurological disorder at once and/or implant tissue (for example forming gel or mesh) around the nerve stimulation device that is used for the treatment of neurological disorder as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed the nerve stimulation device that is used for the treatment of neurological disorder (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject the nerve stimulation device tissue on every side that is used for the treatment of neurological disorder as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand the polymer composition of theme of the present invention can be impregnated into and install all or part of, only comprise install, only lead, the tissue of electrode and/or its bordering compounding only.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with being used for the treatment of the nerve stimulation device of neurological disorder is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.The definite dosage that gives constitutes by not isostructure and size because be used for the treatment of the nerve stimulation device of neurological disorder, so can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

(5) The sacral nerve stimulation that is used for bladder control problem

In one aspect, be impregnated into the tissue adjacent with the treatment bladder disease with neural stimulation system.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

Sacral nerve stimulation is used to control and the patient who has the control problem of urinating, such as urge incontinence, nonobstructive urine retention or frequent micturition.The millions of people suffers from urinate control problem and very big percentage ratio (estimating to surpass 60%) and does not obtain the abundant treatment that other can utilize therapy, enlarges or surgical correction such as medicine, absorption pad, external gathering-device, bladder.This may be to cause serious social anxiety disorder and cause the people to become isolated and depressed.

The appropriate electricity irritation of sacral nerves is used to influence the function (accepting all structures) of bladder, sphincter and pelvic floor from the nerve distribution of sacral nerves.Implanted the position adjacent and nerve stimulator was implanted subcutaneously buttocks or abdominal part conducting operation with sacral nerves; Both connect by extending.The application of tined lead make not have is sewed up that grappling is led and placed to lead with the invasive of minimum level under local anesthesia becomes possibility.The attending doctor utilizes the programmer of portable programmer adjusting device and patient's control to be used for regulating and sets and switching device.Regulating impulse is so that provide the symptom of urinate control and reduction of patient.

Several neural stimulation systems that are used for sacral nerve stimulation have been described, wherein electricity irritation targeting bladder, pelvic floor flesh, intestinal and/or sexual organ.For example, nerve stimulator can use the minimum level invasive to perform the operation it is anchored in the rumpbone for by electrostimulator with have insulation and protect the electric stimulation that leading of sheath form.For example, referring to United States Patent (USP) 5,957,965.In one aspect of the method, nerve stimulator can be used to control pelvis, sphincter or bladder muscle tissue.For example, nerve stimulator can be the intramuscular electrostimulator, and it is by pulse generator and be used for the elongation medical lead that electricity irritation or sensing derive from the signal of telecommunication of muscular tissue and form.For example, referring to United States Patent (USP) 6,434,431.Another kind of neural stimulation system by nothing lead, tubular micro-stimulator forms, it is implanted in to need to stimulate with the pelvic floor flesh of treatment urinary incontinence or continuous nervous tissue locates.For example, referring to United States Patent (USP) 6,061,596.

The neural stimulation system that is used for the treatment of bladder disease that has the polymer composition of the theme of the present invention that is impregnated into adjacent tissue according to the present invention comprises and is purchased product.The example that is purchased that is used for the treatment of the neural stimulation system of bladder disease is Medtronic, the INTERSTIM sacral nerve stimulation system that Inc. makes.For example, referring to United States Patent (USP) 6,104,960,6,055,456 and 5,957,965.

With regard to the control therapy of effectively urinating, leading must be accurately and sacral nerves, bladder, sphincter or pelvic muscle adjacent positioned (depending on used particular system), and irrelevant with concrete design feature.If occur growth of excessive scar tissue or extracellular matrix deposition on every side leading, effect just may reduce so.Sacral nerve stimulation device (such as INTERSTIM) with polymer composition of the theme of the present invention that is impregnated into the tissue adjacent with electrode-tissue can be used to increase the efficient of pulse transmission and increase the time limit that these devices work clinically.Can also have benefited from discharging the therapeutic agent that can prevent or suppress near the infection the implant position such as these nerve stimulation devices.In one aspect, described device comprises the sacral nerve stimulation device and/or leads, and they have and comprise being impregnated into and implanting and maybe will implanting described sacral nerve stimulation device and/or the polymer composition of the theme of the present invention of the adjacent tissue in place that leads of anti-scarring agent and/or anti-infective.In one aspect of the method, the invention provides leading of polymer composition with the theme of the present invention that comprises anti-scarring agent and/or anti-infective that is impregnated into and implants the described adjacent tissue of place's sacral nerves that leads.

With regard to regard to the device that directly stimulates the design of bladder or pelvic muscles tissue, may need different slightly embodiments.In this respect, described device comprises bladder or pelvic muscle stimulating apparatus, leads and/or pick off, and they have and the polymer composition of implanting the theme of the present invention that comprises anti-scarring agent and/or anti-infective that maybe will implant the described sacral nerve stimulation device and/or the adjacent tissue that leads.In one aspect of the method, the invention provides to have with implanting and maybe will implant described leading and/or the leading and/or pick off of the polymer composition of the theme of the present invention that comprises anti-scarring agent and/or anti-infective of the tissue (for example muscle) that pick off is adjacent.

In one aspect of the method, the invention provides the neural stimulation system of the polymer composition with the theme of the present invention that is used for the treatment of bladder disease that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention comprises therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system of the neural stimulation system that is used for the combined treatment bladder disease have above been described.

Can said composition be soaked into around the neural stimulation system of implanting that is used for the treatment of bladder disease by polymer composition directly and/or indirectly being coated with following position or being coated with thereon: (a) with the adjacent tissue of neural stimulation system that is used for the treatment of bladder disease; (b) be used for the treatment of near the neural stimulation system-organizational interface of bladder disease; (c) be used for the treatment of zone around the neural stimulation system of bladder disease; (d) be used for the treatment of tissue around the neural stimulation system of bladder disease.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with the neural stimulation system that is used for the treatment of bladder disease comprises described polymer composition is delivered to: (a) on the neural stimulation system surface that is used for the treatment of bladder disease of implant procedure process (for example as injectable, paste, gel or mesh); (b) before implantation is used for the treatment of the neural stimulation system of bladder disease at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the neural stimulation system be used for the treatment of bladder disease the neural stimulation system surface that is used for the treatment of bladder disease at once and/or implant tissue (for example forming gel or mesh) around the neural stimulation system that is used for the treatment of bladder disease as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed the neural stimulation system that is used for the treatment of bladder disease (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject the neural stimulation system tissue on every side that is used for the treatment of bladder disease as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand the polymer composition of theme of the present invention can be impregnated into and install all or part of, only comprise install, only lead, the tissue of electrode and/or its bordering compounding only.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with being used for the treatment of the neural stimulation system of bladder disease is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.The definite dosage that gives constitutes by not isostructure and size because be used for the treatment of the neural stimulation system of bladder disease, so can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm2-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

(6) The nervus gastrica that is used for the treatment of the GI disease stimulates

In one aspect, the polymer composition of theme of the present invention can be impregnated into the adjacent tissue of device of treatment GI disease.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective.

Neurogastric nerve stimulator (supplying with the other parts in GI road on the harmonization of the stomach) is used in control significant clinically fat or influence gastric emptying and satiety with the GI impaired relevant problem of moving.Morbid obesity has arrived popular ratio and thought has influenced the American more than 2,500 ten thousand, and has caused significant health problem, such as diabetes, heart attack, apoplexy and death.The electricity irritation of nervus gastrica appropriateness is used to influence the function of GI road stomach function regulating (all are accepted from the neurogastric neural structure that distributes).To conduct the operation implantation position adjacent and nerve stimulator was implanted subcutaneously with nervus gastrica; Both connect by extending.The attending doctor utilizes the programmer of portable programmer adjusting device and patient's control to be used for regulating and sets and switching device.Regulating impulse is so that provide satiety and the hunger sensation of reduction of patient generation.This can cause food ration (with heat thus) to reduce and make patient's success weight reduction.Relevant apparatus comprises the device of the gastric emptying that is used for stimulating the gastric motility impaired subjects, the device that promotes to exist excretory nerve stimulator of intestinal (stimulation is transferred into colon) among the patient of constipation and targeting to suffer from the dyskinetic patient's of other GI intestinal.

Described several these class devices, for example comprised, the pick off of electrical activity in the sensation gastrointestinal tract, it with based on natural gastrointestinal electrical activity emission with suppress the pulse generator coupling of asynchronous pulse row.For example, referring to United States Patent (USP) 5,995,872.Other nerve stimulation device is sent to colon and rectum with pulse so that handle constipation and they are made up of the stimulus generator of electric conductance, electrode and implantation.For example, referring to United States Patent (USP) 6,026,326.Nerve stimulator can be pulse generator and electrode, and they carry out electricity irritation so that treatment is fat to the neural muscular tissue of internal organs.For example, referring to United States Patent (USP) 6,606,523.Nerve stimulator can be the implantable pulse generator of sealing, and it is with the gastrointestinal tract electrical coupling and launch the electricity irritation of two kinds of speed so that treat the gastroparesis of suffering from the impaired patient of gastric emptying.For example, referring to United States Patent (USP) 6,091,992.Nerve stimulator can be led by electrical signal control, connection lead and adnexa and form, and its produces the stomach basilar part is produced successive low-voltage electricity irritation with control appetite.For example, referring to United States Patent (USP) 6,564,101.Other is used for the nerve stimulator that gastrointestinal tract carries out electricity irritation for example is described in the United States Patent (USP) 6,453,199,6,449,511 and 6,243,607.

The device that is used for the treatment of the GI disease that has the polymer composition of the theme of the present invention that is impregnated into adjacent tissue according to the present invention comprises and is purchased product.The example that is purchased that is used for nervus gastrica stimulating apparatus of the present invention is the implantable gastric stimulator of TRANSCEND (IGS), and it is at present by Transneuronix, and (Mt.Arlington NJ) researches and develops Inc..IGS is a kind of programme controlled bipolar pulse generator, and it is sent to coat of the stomach to treat obesity by leading with the little electric pulse of bursting.For example, referring to United States Patent (USP) 6,684,104 and 6,165,084.

With regard to effectively nervus gastrica stimulated to satiety control (or gastroparesis), leading must be accurately and the nervus gastrica adjacent positioned, and irrelevant with concrete design feature.If occur growth of excessive scar tissue or extracellular matrix deposition on every side leading, effect just may reduce so.Have the polymer composition of the theme of the present invention that is impregnated into the tissue adjacent with electrode-tissue the nervus gastrica stimulating apparatus (with other implantation for influence the device of GI mobility design) can be used to increase the efficient that pulse transmits and increase these and install the time limit of working clinically.The nervus gastrica stimulating apparatus (with other implantation for influence the device of GI mobility design) can also have benefited from discharging the therapeutic agent that can prevent or suppress near the infection in implant position.In one aspect, described device comprises the nervus gastrica stimulating apparatus and/or leads, and they have and comprise being impregnated into and implanting and maybe will implanting described nervus gastrica stimulating apparatus and/or the polymer composition of the theme of the present invention of the adjacent tissue in place that leads of anti-scarring agent and/or anti-infective.

In one aspect of the method, the invention provides the device of the polymer composition with the theme of the present invention that is used for the treatment of the GI disease that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention comprises therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system of the device that is used for combined treatment GI disease have above been described.

Can said composition be soaked into around the device of implanting that is used for the treatment of the GI disease by polymer composition directly and/or indirectly being coated with following position or being coated with thereon: (a) with the adjacent tissue of device that is used for the treatment of the GI disease; (b) be used for the treatment of near the device-organizational interface of GI disease; (c) be used for the treatment of zone around the device of GI disease; (d) be used for the treatment of tissue around the device of GI disease.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with the device that is used for the treatment of the GI disease comprises described polymer composition is delivered to: (a) at the apparatus surface that is used for the treatment of the GI disease (for example as injectable, paste, gel or mesh) of implant procedure process; (b) before implantation is used for the treatment of the device of GI disease at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the device be used for the treatment of the GI disease at once the apparatus surface that is used for the treatment of the GI disease and/or implantation be used for the treatment of the GI disease device around tissue (for example forming gel or mesh) as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed the device that is used for the treatment of the GI disease (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject the device tissue on every side that is used for the treatment of the GI disease as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand the polymer composition of theme of the present invention can be impregnated into and install all or part of, only comprise install, only lead, the tissue of electrode and/or its bordering compounding only.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with being used for the treatment of the device of GI disease is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.The definite dosage that gives constitutes by not isostructure and size because be used for the treatment of the device of GI disease, so can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm2-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

(7) be used for the treatment of deaf cochlear implant

In one aspect, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with cochlear implant.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

Nerve stimulation also is used to stimulate the acous cochlear implant form of proofreading and correct sensorineural deafness.Acoustic processor is captured from the sound of environment and is processed into the digital signal that is sent to cochlear implant through antenna by skin.The cochlear implant of implanting in the cochlea adjacent with acoustic nerve by operation changes into digital information the signal of telecommunication that communicates with acoustic nerve by electrode array.Cochlear implant is used to get around non-functional cochlear transducer effectively and directly makes and import the acoustic fibers depolarization into.This can excite nerve and pass the signal to the auditory center in the brain and make the patient " hear " sound that detects by acoustic processor.This treatment is used for having the adult's (and can use sonifer to understand a sentence up to 50% speech) or the child who has 90dB hearing loss in the ears more than 12 months or 12 months of 70dB or the above hearing loss of 70dB.

Although the incident that do not meet accident in many implant procedures takes place, complication takes place in the patient of about 12-15%.Histological evaluation to cochlear implant has disclosed damage and the cicatrization that several forms can take place.Operation wound can bring out cochlea fibre modification, cochlea neossification and the damage of film snail (comprising sensory nerve element disappearance).The foreign body reaction that takes place along implant and electrode can produce the fibrous tissue reaction of losing efficacy relevant with implant along electrode array.Near the infection the implant position can also be introduced or promote to the implantable neural stimulating apparatus.

The various suitable cochlear implant system or " bionic ear " that are used in combination with the present invention have been described.For example, nerve stimulator can be made up of a plurality of element of transducers, and they detect damping and then the corresponding neuron that connects cranial nerve are produced stimulus signal.For example, referring to United States Patent (USP) 5,061,282.Nerve stimulator can be for having sound-electricity irritation encoder, the implantable receptor-stimulator of health and can be based on the cochlear implant of the exomonental electrode of the signal of telecommunication that receives.For example, referring to United States Patent (USP) 4,532,930.Nerve stimulator can be for installing in the cochlea, and it is formed by the transducer that sound signal is changed into the signal of telecommunication with to the electrode array that electricity irritation is carried out in acous precalculated position.For example, referring to United States Patent (USP) 4,400,590.Nerve stimulator can be stimulus generator, and it is used for active reticent (active silence).For example, referring to United States Patent (USP) 6,175,767.Nerve stimulator can be the Mechatronic Systems of implanting under the cranium, and it has the input transducer and the mechanic sound vibration is changed into the output stimulator of the signal of telecommunication.For example, referring to United States Patent (USP) 6,235,056.Nerve stimulator can be contained in the cochlear implant that is used to store and provide the rechargeable battery of electric energy in the implant for having.For example, referring to United States Patent (USP) 6,067,474.Other for example is described in the United States Patent (USP) 6,358,281,6,308,101 and 5,603,726 as nerve stimulator of cochlear implant.

Can have benefited from the cochlear implant that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised and be purchased product.Several devices that are purchased can be used for treating the patient who suffers from remarkable sensorineural hearing loss and are applicable to the present invention.For example, (Boston Scientific Corp., Nattick is MA) by processing sound and digital signal is sent to operation implants the HIRES AURIA processor of the HIRES 90K implant of internal ear and form in HIRESOLUTION bionic ear system.For example, referring to United States Patent (USP) 6,636,768,6,309,410 and 6,259,951.The title that HIRES 90K implant is produced is sent to the polymer composition that neural electrode array can have benefited from having the theme of the present invention that is impregnated into the tissue adjacent with electrode-neural interface.The PULSARci cochlear implant (MED-ELGMBH, Innsbruck, Austria, for example, referring to United States Patent (USP) 6,556,870 and 6,231,604) and NUCLEUS 3 cochlear implant systems (Cochlear Corp., Lane Cove, Australia, for example, referring to United States Patent (USP) 6,807,445; 6,788,790; 6,554,762; 6,537,200 and 6,394,947) be purchased example for other of cochlear implant, its electrode can have benefited from having the polymer composition that is impregnated into of the present invention theme adjacent with electrode-neural interface.

With regard to regard to the effective cochlear implant of sensorineural hearing loss, lead must be accurately with import the acoustic fibers adjacent positioned into, and irrelevant with concrete design feature.If occur growth of excessive scar tissue or extracellular matrix deposition on every side leading, effect just may reduce so.Having the cochlear implant that is impregnated into the polymer composition of the theme of the present invention of electrode-neural interface adjacent tissue can increase the efficient that pulse transmits and increase the time limit that these devices work clinically.Cochlear implant can also have benefited from discharging the therapeutic agent that can prevent or suppress near the infection in implant position.In one aspect, described device comprises cochlear implant and/or leads, they have comprise anti-scarring agent and/or anti-infective be impregnated into that implantation maybe will be implanted described cochlear implant and/or the polymer composition of the theme of the present invention of the adjacent tissue in place that leads.In one aspect of the method, the invention provides and have the leading of polymer composition that is impregnated into the theme of the present invention that comprises anti-scarring agent and/or anti-infective of the tissue that cochlear tissue is adjacent on every side that leads.

In one aspect of the method, the invention provides the cochlear implant of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention comprises therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with cochlear implant have above been described.

Can be by polymer composition directly and/or indirectly being coated with following position or coating is soaked into said composition around the cochlear implant of implanting thereon: (a) tissue adjacent with cochlear implant; (b) near cochlear implant-organizational interface; (c) zone around the cochlear implant; (d) tissue around the cochlear implant.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with cochlear implant comprises described polymer composition is delivered to: (a) on the cochlear implant surface of implant procedure process (for example as injectable, paste, gel or mesh); (b) before implanting cochlear implant at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the cochlear implant cochlear implant surface at once and/or implant tissue (for example forming gel or mesh) around the cochlear implant as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed cochlear implant (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject cochlear implant tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand the polymer composition of theme of the present invention can be impregnated into and install all or part of, only comprise install, only lead, the tissue of electrode and/or its bordering compounding only.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with cochlear implant is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because cochlear implant is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

(8) Be used for the electricity irritation of stimulation of bone growth

In one aspect, the polymer composition of theme of the present invention can be impregnated into and the adjacent tissue of electric bony spur excitation device.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

Electricity irritation can also be used for stimulation of bone growth.For example, described stimulating apparatus can be electrode and the generator with strain responses piezoelectric, and described material can be given birth to reaction to promote the corresponding sell of one's property with the nature bone grappling of implantable bone prosthese by producing electric charge.For example, referring to United States Patent (USP) 6,143,035.If occur growth of excessive scar tissue or extracellular matrix deposition on every side leading, effect just may be impaired so.Electric bony spur excitation device with polymer composition of the theme of the present invention that is impregnated into the tissue adjacent with the electrode-tissue interface can increase the efficient of pulse transmission and increase these device functions clinically.Electricity bony spur excitation device can also have benefited from discharging the therapeutic agent that can prevent or suppress near the infection in implant position.In one aspect, described device comprises electric bony spur excitation device and/or leads, they have comprise anti-scarring agent and/or anti-infective be impregnated into that implantation maybe will be implanted described electric bony spur excitation device and/or the polymer composition of the theme of the present invention of the adjacent tissue in place that leads.In one aspect of the method, the invention provides to have and be impregnated into the leading of polymer composition of organizing the theme of the present invention that comprises anti-scarring agent and/or anti-infective of adjacent tissue with the electric conductance surrounding bone.

In one aspect of the method, the invention provides the electric bony spur excitation device of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention comprises therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with electric bony spur excitation device have above been described.

Can said composition be soaked into around the electric bony spur excitation device of implanting by polymer composition directly and/or indirectly being coated with following position or being coated with thereon: (a) with the adjacent tissue of electric bony spur excitation device; (b) near electric bony spur excitation device-organizational interface; (c) zone around the electric bony spur excitation device; (d) tissue around the electric bony spur excitation device.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with electric bony spur excitation device comprises described polymer composition is delivered to: (a) on the electric bony spur excitation device surface of implant procedure process (for example as injectable, paste, gel or mesh); (b) before implanting electric bony spur excitation device at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the electric bony spur excitation device electric bony spur excitation device surface at once and/or implant tissue (for example forming gel or mesh) around the electric bony spur excitation device as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed electric bony spur excitation device (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject electric bony spur excitation device tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand the polymer composition of theme of the present invention can be impregnated into and install all or part of, only comprise install, only lead, the tissue of electrode and/or its bordering compounding only.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with electric bony spur excitation device is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because electric bony spur excitation device is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000 mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

Although above described a large amount of nerve stimulation devices, the unwanted tissue reaction after they all have similar design feature and produce similar implantation, and can bring out or promote infection in the implant band of position.Should pay close attention to the nerve stimulation commodity that are purchased nerve stimulation device and of future generation and/or follow-up research and development that above do not pay particular attention to and be can expect and be suitable for using in the present invention, this to those skilled in the art should be apparent.Nerve stimulation device particularly leads and must be transferred into anatomical position correct in the nervous system to guarantee to stimulate with the location of accurate way very.The all or part of of nerve stimulation device can be moved after surgery, or excessively cicatrix (or neuroglia) tissue growth can occur in implant, and this can cause the performance of these devices to reduce.Have and be impregnated into the effect and/or the movable time limit (the particularly battery powered device of implanting fully) that can increase implant with the nerve stimulation apparatus of the polymer composition of the theme of the present invention of electrode-neural interface adjacent tissue.The nerve stimulation apparatus can also have benefited from discharging the therapeutic agent that can prevent or suppress near the infection in implant position.In one aspect, the invention provides the nerve stimulation apparatus of polymer composition with the theme of the present invention that comprises therapeutic agent (for example anti-scarring agent and/or anti-infective) that is impregnated into adjacent tissue.The number of polymers and the non-polymer delivery system that are used in conjunction with the nerve stimulation apparatus have above been described.These compositionss may further include one or more fibre modification inhibitor, make granulation, fiber or neuroglia (gliotic) tissue growth excessively be inhibited or reduce; And/or these compositionss may further include one or more anti-infectives, near the infection inhibition or the prevention implant position thus.

Rhythm of the heart control (CRM) device

In one aspect, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with rhythm of the heart control device.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

Described medical apparatus can also be the cardiac pacing apparatus, and wherein pulse generator is sent to cardiac muscular tissue's (being generally special-purpose Conductive fiber) with electric pulse by leading of implantation.In general, electric conductance is made up of connector assembly, the body that leads (being conductor) and electrode.Electric conductance can be for unipolar, and wherein they are suitable for only using an electrode that effective therapy is provided.Also multipole leading be can utilize, bipolar, three utmost points and quadrupole leading comprised.Electric conductance can also have insulation and protect sheath, and they can comprise polyurethane or siloxanes-rubber coating.The representational example of electric conductance includes, but are not limited to that medical lead, cardiac lead, pacemaker lead (pacer 1eads), pace-making lead that (pacing leads), pacemaker lead (pacemakerleads), endocardial lead, endocardial pacing lead, cardioversion/defibrillator leads, cardioversion leads, epicardial lead, visceral pericardium defibrillator lead, sticking patch defibrillator, sticking patch lead, electric sticking patch, through vein lead, initiatively fixedly lead, passive fixedly lead and sensing is led.Use the representational example of the CRM device of electric conductance to comprise: pacemaker, LVAD ' s, defibrillator, implantable sensor and other electric cardiac stimulus device.

Have a large amount of pacemaker devices, wherein the generation of fibre modification reaction is enough to produce harmful effect to the function of device and maybe can produces infringement to cardiac muscular tissue.In general, the fibre modification encapsulation of pacemaker lead (or lead and the target center muscular tissue between the growth of fibrous tissue) slowed down, influenced or interrupted pulse and given from the fax of installing cardiac muscle.For example, find fibre modification on the electrode-myocardium interface in heart usually, this is owing to the electric injury that comes focus point on the self-conductance.The fibre modification damage can extend into Tricuspid valve, and this can cause perforation.Fibre modification can cause ubclavian vein thrombosis, the life-threatening disease of promptly a kind of possibility.Electric conductance with polymer composition of the theme of the present invention that is impregnated into the tissue adjacent with the electrode-tissue interface can help to prolong the clinical performance of these devices.Fibre modification not only can make the not good enough or complete failure of described apparatus function, and it can cause the battery life excessive descent, needs energy to increase because overcome the resistance that the scar tissue of insertion applies.Similarly, the fibre modification encapsulation of the sensing element of rate responsive pacemaker (following) can influence the ability that pacemaker is identified and proofread and correct rhythm abnormality, thereby causes cardiac pacing inappropriate or can't correctly work when needed.Cardiac pacing apparatus and/or electric conductance can also have benefited from discharging the therapeutic agent that can prevent or suppress near the infection in implant position.

Several different electric pacemakers are used for the treatment of various rhythm abnormalities, comprise pacemaker, implantable electric converter defibrillator (ICD), left ventricular assist device (LVAD) and vagus nerve stimulator (the vagus nerve stimulation fiber carries out innervation to heart successively).The pulse generation part of device is sent to the muscle (cardiac muscle) of heart or conducting tissue to influence the rhythm of the heart or contraction by leading of implanting with electric pulse.Pace-making can be oriented to one or more chambers of heart.Cardiac pacemaker can be used for blocking, shelter or the signal of telecommunication of cardiac stimulus so that the therapy apparatus dysfunction, include, but are not limited to that atrial rhythm is unusual, conduction abnormalities and sinus rhythm be unusual.If generation chamber arrhythmia (such as asystole or ventricular tachycardia), ICDs is used for ventricular depolarization and rebuilds the rhythm of the heart so, and LVADs is used for the ventricular systole of auxiliary failure heart.

The representational example of describing the patent of pacemaker and pacemaker lead comprises United States Patent (USP) 4,662,382,4,782,836,4,856,521,4,860,751,5,101,824,5,261,419,5,284,491,6,055,454,6,370,434 and 6,370,434.The representational example of electric conductance comprises leading that those find on various cardiac devices, such as cardiac stimulator (for example, referring to United States Patent (USP) 6,584,351 and 6,115,633), pacemaker is (for example, referring to United States Patent (USP) 6,564,099,6,246,909 and 5,876,423), implantable electric converter-defibrillator (ICDs), other defibrillator device (for example, referring to United States Patent (USP) 6,327,499), defibrillator or need pacemaker catheter (for example, referring to United States Patent (USP) 5,476,502) and left ventricular assist device (for example, referring to United States Patent (USP) 5,503,615).

Transmit the cardiac rhythm devices that electricity beats and particularly lead and to locate the correct anatomical position that is transferred in the heart to guarantee to stimulate in accurate mode.The all or part of of pacemaker can be moved after surgery, or excessively cicatrix (neuroglia) tissue growth can occur around implant, and this can cause the effect of these devices to reduce (as mentioned above).Rhythm of the heart control device with polymer composition of the theme of the present invention that is impregnated into the tissue adjacent with the electrode-tissue interface can be used to increase the effect and/or the movable time limit (the particularly battery powered device of implanting fully) of implant.Rhythm of the heart control device can also have benefited from discharging the therapeutic agent that can prevent or suppress near the infection in implant position.In one aspect, the invention provides to have to be impregnated into and to implant and maybe will implant described rhythm of the heart control device and/or the rhythm of the heart control device of the polymer composition of the theme of the present invention that comprises anti-scarring agent and/or anti-infective of locating adjacent tissue of leading and/or lead.In one aspect of the method, the invention provides the leading of polymer composition with the theme of the present invention of organizing adjacent tissue that has been impregnated into and has implanted the described place of leading.

In one aspect of the method, the invention provides the rhythm of the heart control device of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with rhythm of the heart control device have above been described.

Can be by polymer composition directly and/or indirectly being coated with following position or coating is soaked into said composition around the rhythm of the heart control device of implanting thereon: (a) tissue adjacent with rhythm of the heart control device; (b) near rhythm of the heart control device-organizational interface; (c) zone around the rhythm of the heart control device; (d) tissue around the rhythm of the heart control device.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with rhythm of the heart control device comprises described polymer composition is delivered to: (a) on the rhythm of the heart control device surface of implant procedure process (for example as injectable, paste, gel or mesh); (b) before implanting rhythm of the heart control device at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the rhythm of the heart control device rhythm of the heart control device surface at once and/or implant tissue (for example forming gel or mesh) around the rhythm of the heart control device as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed rhythm of the heart control device (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject rhythm of the heart control device tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand the polymer composition of theme of the present invention can be impregnated into and install all or part of, only comprise install, only lead, the tissue of electrode and/or its bordering compounding only.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with rhythm of the heart control device is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because rhythm of the heart control device is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

For the purpose of clearer, several concrete rhythm of the heart control device and Therapeutic Method have been described more specifically hereinafter.

(1) Cardiac pacemaker

In one aspect, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with cardiac pacemaker.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

Rhythm abnormality is that extremely common and incidence rate exists with age and potential coronary artery disease or myocardial infarction and increases in the clinical practice.There are a series of arrhythmia, but generally they are divided into following situation: heartbeat slow excessively (bradyarrhythmia-such as heart block, sinus node dysfunction) or too fast (tachyarrhythmia-such as atrial fibrillation, WPW syndrome,, ventricular fibrillation).Pacemaker works by transmitting electric pulse (pacemaker impulse), and described electric pulse is sent to the electrode (on the head that is leading) that electric pulse is delivered to the heart that starts heartbeat through electric conductance.Lead and electrode can be arranged in one indoor (right atrium or right ventricle-be called list-chamber pacemaker) or all can have electrode (being called dual chamber pacemaker) at right atrium and right ventricle.Can electric conductance be implanted in (for example epicardial lead) on the heart outside by operation technique, or they can pass through conduit, lead or stilet and are connected with the heart endocardial surface.In some pacemaker, device has been set the rhythm and pace of moving things generation function of heart and has been started with well-regulated frequency.In other pacemaker, device has only increased the owned pacing function of heart and " as required " works so that pace-making assosting effect (being called " suitable-frequency " pacemaker) to be provided as required; This pacemaker receives the feedback (and starting thus) from the rhythm of the heart that is positioned at the electrode sensor on leading.Other pacemaker of rate-responsive pacemaker has special-purpose pick off, and they detect the change (such as motion, the respiratory frequency of arm and lower limb) and the adjusting increasing or decreasing of beating thus of body movement.

A large amount of pacemakers and pacemaker lead are applicable to the present invention.For example, pace-making leads and can have the resistance to fracture of increase, because it is formed by being assemblied in the endoceliac elongation screw-like conductor that leads, it can carry out electrical coupling with standard conductor thus.For example, referring to United States Patent (USP) 6,061,598 and 6,018,683.Pace-making leads to have and has the screw-like conductor that sheath is protected in insulation, and this leads and have the toleration of antifatigue in the district between rib and clavicle.For example, referring to United States Patent (USP) 5,800,496.Pace-making lead can by by contain conductor slidably in and outer overlapped tubes is formed and be expanded to second kind of structure than length from first kind of short structure.For example, referring to United States Patent (USP) 5,897,585.Pace-making leads and can have the comparatively hard utensil of first that temporarily makes the body that leads by the intracavity use magnetic-Pheological fluid of hardening when contacting magnetic field.For example, referring to United States Patent (USP) 5,800,497.The pace-making spiral structure that many lines can serving as reasons that two titanium alloys make or wire harness are formed that leads.For example, referring to United States Patent (USP) 5,423,881.Pace-making leads and can be made up of the line of spiral structure form, and described spiral structure has the line of being made up of rustless steel by having, and described rustless steel has at least 22% nickel and 2% molybdenic composition.For example, referring to United States Patent (USP) 5,433,744.Other pace-making leads and for example is described in the United States Patent (USP) 6,489,562,6,289,251 and 5,957,967.

In one aspect of the method, be used to implement electric conductance of the present invention and can have the movable retaining element that is used for conjunctive tissue.For example, electric conductance can have the helical structure that rigidly fixes that has fine recesses, and the size of described groove can be reduced to bottom line with the foreign body reaction after implanting.For example, referring to United States Patent (USP) 6,078,840.Electric conductance can have the electrode/anchor portion that has the biconial self-propelled spiral electrode that is used to connect blood vessel wall.For example, referring to United States Patent (USP) 5,871,531.Electrode can have the rigid insulation electrode that carries spiral electrode.For example, referring to United States Patent (USP) 6,038,463.Electrode can have use introducer protect the sheath design the grappling cover in case with blood in the insertion process by protecting the mobile minimum that is reduced to of sheath.For example, referring to United States Patent (USP) 5,827,296.Electrode can be made up of insulation conductance part and the standing part that leads in, and the described standing part that leads in has the vertical rigidity helical element that can tighten into tissue.For example, referring to United States Patent (USP) 4,000,745.

Be used to implement suitable leading of the present invention and comprise that also many-the utmost point that has the multiple electrode that is connected with the body that leads leads.For example, electric conductance can lead for many-utmost point, and wherein this leads and has two inner conductors and three and have and link coupled two electrodes of capacitor, and described capacitor and electrode lead and combine.For example, referring to United States Patent (USP) 5,824,029.Electrode can be for having two straight line portioies and the body that leads that has the crooked second portion that contains bonding conductor and electrode, and wherein electrode is bipolar.For example, referring to United States Patent (USP) 5,995,876.In one aspect of the method, can implant electric conductance by using conduit, lead or stilet.For example, electric conductance can be made up of the flexible seal that the elongation insulation with the chamber that has the conductor that is assemblied in the body that leads is led body and had an expandable part that lead can pass through.For example, referring to United States Patent (USP) 6,192,280.

Can have benefited from the cardiac pacemaker that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised and be purchased product.Be suitable for implementing pacemaker of the present invention and comprise Medtronic, KAPPA SR 400 series list-chamber rate-responsive pacemaker systems, 400 serial pairs-chamber rate-responsive pacemaker system of KAPPADR, KAPPA 900 and 700 series list-chamber rate-responsive pacemaker system and KAPPA 900 and the 700 pairs-chamber rate-responsive pacemaker systems of Inc..The pacemaker system of Medtronic is used various leading, comprise CAPSURE Z Novus, CAPSUREFIX Novus, CAPSUREFIX, CAPSURE SP Novus, CAPSURESP, CAPSURE EPI and CAPSURE VDD, they can have benefited from having the polymer composition of the theme of the present invention that is impregnated into adjacent tissue.The pacemaker system that Medtronic makes is described in for example United States Patent (USP) 6,741,893 with relevant leading; 5,480,441; 5,411,545; 5,324,310; 5,265,602; 5,265,601; In 5,241,957 and 5,222,506.Medtronic has also made various steroidal-eluting and has led, and comprises that those are described in for example United States Patent (USP) 5,987,746; 6,363,287; 5,800,470; 5,489,294; Product in 5,282,844 and 5,092,332.GuidantCorp. (Indianapolis, IN) the INSIGNIA list-chamber of Zhi Zaoing and two-chamber system, PULSARMAX II DR two-chamber fitness-frequency pacemaker, PULSAR MAX II SR list-chamber fitness-frequency pacemaker, DISCOVERY II DR be two-chamber fitness-frequency pacemaker, DISCOVERY II SR list-chamber fitness-frequency pacemaker, DISCOVERY II DDD pair-chamber pacemaker and the DISCOVERY II SSI list-chamber pacemaker system also are to be used to implement suitable pacemaker system of the present invention.On the other hand, can have benefited from having the polymer composition of the theme of the present invention that is impregnated into adjacent tissue from leading of Guidant pacemaker system.The pacemaker system that Guidant makes is described in for example United States Patent (USP) 6,473,648 with relevant leading; 6,345,204; 6,321,122; 6,152,954; 5,769,881; 5,284,136; In 5,086,773 and 5,036,849.From St.Jude Medical, Inc. (St.Paul, pacemaker system MN) and lead AFFINITYDR, AFFINITY VDR, AFFINITY SR, AFFINITY DC, ENTITY, IDENTITY, IDENTITY ADX, INTEGRITY, INTEGRITY DR, INTEGRITY Adx, MICRONY, REGENCY, TRILOGY and VERITY Adx also go for the present invention and pass and sensing with the fax that improves pacemaker lead.The pacemaker system that St.JudeMedical makes is described in for example United States Patent(USP) Nos. 6,763,266 with relevant leading; 6,760,619; 6,535,762; 6,246,909; 6,198,973; 6,183,305; In 5,800,468 and 5,716,390.Perhaps, the fibre modification inhibitor can be impregnated into electrode-peripheral region, myocardium interface in the present invention.Should pay close attention to the pacemaker commodity that are purchased pacemaker and of future generation and/or follow-up research and development that do not pay particular attention to and they are suitable for using in the present invention, this to those skilled in the art should be apparent.

With regard to the pacemaker of effective control cardiac arrhythmia, leading must be accurately and targeting cardiac muscular tissue adjacent positioned, and irrelevant with concrete design feature.If occur growth of excessive scar tissue or extracellular matrix deposition on every side leading, effect just may suffer damage so.Have and be impregnated into the efficient that can increase pulse transmission and rhythm and pace of moving things sensing with the pacemaker of the polymer composition of the theme of the present invention of electrode-nerve and/or pick off-organizational interface's adjacent tissue, increase effect and battery life thus.Pacemaker lead can also have benefited from discharging the therapeutic agent that can prevent or suppress near the infection in implant position.Implant and maybe implantation to be had the polymer composition with the theme of the present invention of the described cardiac pacemaker and/or the adjacent tissue in place that leads of being impregnated into that comprises anti-scarring agent and/or anti-infective.In one aspect of the method, the invention provides to have and be impregnated into and implant the pacemaker lead of polymer composition of the theme of the present invention that comprises anti-scarring agent and/or anti-infective of the adjacent tissue of cardiac muscular tissue at place of leading.

In one aspect of the method, the invention provides the cardiac pacemaker of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention comprises therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with cardiac pacemaker have above been described.

Can be by polymer composition directly and/or indirectly being coated with following position or coating is soaked into said composition around the cardiac pacemaker of implanting thereon: (a) tissue adjacent with cardiac pacemaker; (b) near cardiac pacemaker-organizational interface; (c) zone around the cardiac pacemaker; (d) tissue around the cardiac pacemaker.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with cardiac pacemaker comprises described polymer composition is delivered to: (a) on the cardiac pacemaker surface of implant procedure process (for example as injectable, paste, gel or mesh); (b) before implantable heart pacer at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) at once cardiac pacemaker surface and/or the tissue around the implantable heart pacer (for example forming gel or mesh) behind the implantable heart pacer as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed cardiac pacemaker (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject cardiac pacemaker tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand the polymer composition of theme of the present invention can be impregnated into and install all or part of, only comprise install, only lead, the tissue of electrode and/or its bordering compounding only.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with cardiac pacemaker is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because cardiac pacemaker is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

(2) Implantable electric converter defibrillator (ICD) system

In one aspect, the polymer composition of theme of the present invention can be impregnated into adjacent tissue with implantable electric converter defibrillator (ICD) system.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

Implantable electric converter defibrillator (ICD) system class is similar to pacemaker (and many pacemaker system that comprises), but is used for the treatment of tachyarrhythmia, such as ventricular tachycardia or ventricular fibrillation.The battery-powered microcomputer of ICD is formed, and described battery is connected with capacitor to help the ICD charging and to store enough energy so that send therapy when needed.ICD uses pick off monitoring cardiomotility and described computer analysis data so that determine and determine whether to exist arrhythmia when arrhythmia occurs.The ICD that inserts by vein leads, and (being called " through vein " leads; In some system, by operation implant the epicardial lead that leads-be called-and be sewn on the heart surface) be connected into pace-making/computer unit.Usually place leading by insulated conductor and containing sensing element (being used to detect the rhythm of the heart) and the electrode tip of the coil of laying a foundation is formed of right ventricle.List-chamber ICD has one and places leading of ventricle defibrillation and pace-making ventricle, and two-chamber ICD gives ventricular defibrillation and pace-making atrium and ventricle.In some cases, need additionally lead and be placed on the subcutaneous or heart surface adjacent with the rib frame.In the patient of needs control ventricle and atrium tachyarrhythmia, place the atrium with treatment atrial tachycardia, atrial fibrillation and other arrhythmia second coil.If the detection tachyarrhythmia produces pulse so and is transmitted to the electric shock coil by leading, the electric charge that this coil transmission is enough and being enough to the muscle depolarization and to cardioversion or defibrillation.

Several icd systems and their suitable the present invention of enforcement have been described.The representational case description of ICD and associated components is at United States Patent (USP) 3,614, and 954,3,614,955,4,375,817,5,314,430,5,405,363,5,607,385,5,697,953,5,776,165,6,067,471,6,169,923 and 6,152,955.Several ICD lead and are applicable to enforcement the present invention.For example, defibrillator leads and can be linear transducer and coil block, and it forms comprising on the ring that makes loop systems and the link coupled conductor system of pulse generator.For example, referring to United States Patent (USP) 5,897,586.Defibrillator leads and can have the body that leads of elongation, and it has the elongation electrode that extends from the body that leads, and makes the tubular sheath that protects of insulation be assemblied in around the electrode slidably.For example, referring to United States Patent (USP) 5,919,222.Defibrillator leads and can wherein assemble a plurality of wire electrodes for have the conductor that sheath is protected in insulation that has that leads be connected of assembling pad temporarily temporarily.For example, referring to United States Patent (USP) 5,849,033.Other defibrillator leads and for example is described in the United States Patent (USP) 6,052,625.In one aspect of the method, electric conductance can be suitable for pace-making, defibrillation or the two application.For example, electric conductance can for electric insulation, the elongation the body that leads protect sheath, it coated a plurality of from contact with each other the isolating conductor that leads.For example, referring to United States Patent (USP) 6,434,430.Electric conductance can be made up of the inner chamber that is suitable for receiving the hardening component (for example lead) that transmits the fluoro-visible medium.For example, referring to United States Patent (USP) 6,567,704.The conduit that electric conductance can be formed for the pliability non-conductor electric probe of elongation, described probe is included in the transmission signal of telecommunication, comprises that this depends on the requirement of being experienced by control element in the electric conductance approach of defibrillation pulse and pacemaker impulse.For example, referring to United States Patent (USP) 5,476,502.Electric conductance can have low resistance and to ring-type stress favorable mechanical resistance, and these characteristics can be by forming and realize by forming wire stylet that conducting material layer and electric insulation protect the spiral winding that the sheath cover layer covers.For example, referring to United States Patent (USP) 5,330,521.Going for other electric conductance that pace-making and/or defibrillation use for example is described in the United States Patent (USP) 6,556,873.

Can have benefited from the ICDs that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised and be purchased product.Be suitable for implementing the ICDs of being purchased of the present invention and comprise Medtronic, the GEM III DR of Inc. pair-chamber ICD, GEM III VR ICD, GEM II ICD, GEMICD, GEM III AT atrial arrhythmia and ventricular arrhythmia ICD, JEWEL AF pair-chamber ICD, MICRO JEWEL ICD, MICRO JEWEL II ICD, JEWEL Plus ICD, JEWEL ICD, JEWEL ACTIVE CAN ICD, JEWEL PLUS ACTIVE CANICD, MAXIMO DR ICD, MAXIMO VR ICD, MARQUIS DR ICD, MARQUIS VR system and INTRINSIC pair-chamber ICD.Icd system has used various leading, comprise that SPRINT FIDELIS, SPRINT QUATRO SECURE steroidal-eluting bipolar lead, subcutaneous lead system Model 6996SQ subcutaneously lead, TRANSVENE 6937A leads and 6492 one pole auricular pacemakings lead through vein, they can have benefited from having the polymer composition of the theme of the present invention that is impregnated into adjacent tissue.The icd system that Medtronic makes is described in for example United States Patent (USP) 6,038,472 with relevant leading; 5,849,031; 5,439,484; 5,314,430; 5,165,403; In 5,099,838 and 4,708,145.The VITALITY 2DR that Guidant Corp. makes is two-and chamber ICD, VITALITY 2 VR list-chamber ICD, VITALITY AVT be two-chamber ICD, VITALITY DS be two-and chamber ICD, VITALITY DS VR list-chamber ICD, VITALITY EL couple-chamber ICD, VENTAK PRIZM 2 DR couple-chamber ICD and VENTAK PRIZM 2 VR list-chamber icd systems also implement icd system of the present invention for suitable being used to.On the other hand, can have benefited from having the polymer composition of the theme of the present invention that is impregnated into adjacent tissue from leading of icd system.Guidant has sold FLEXTEND bipolar lead, EASYTRAK lead system, FINELINE leads and ENDOTAK RELIANCE ICD leads.The icd system that Guidant makes is described in for example United States Patent (USP) 6,574,505 with relevant leading; 6,018,681; 5,697,954; 5,620,451; 5,433,729; 5,350,404; 5,342,407; In 5,304,139 and 5,282,837.Biotronik, Inc. (Genmany) have sold that the POLYROX endocardium leads, the quadrupole ICD of KENTROX SL leads, AROX bipolar lead and the bipolar epicardial lead of MAPOX be (for example, referring to United States Patent (USP) 6,449,506; 6,421,567; 6,418,348; 6,236,893 and 5,632,770).From CONTOUR MD ICD, PHOTON μ DR ICD, PHOTON μ VR ICD, ATLAS+HF ICD, EPIC HF ICD, the EPIC+HF icd system of St.Jude Medical and lead also can have benefited from having the polymer composition of the theme of the present invention that is impregnated into adjacent tissue so as to improve that fax that ICD leads is passed and sensing (for example, referring to United States Patent (USP) 5,944,746; 5,722,994; 5,662,697; 5,542,173; 5,456,706 and 5,330,523).Perhaps, can in the present invention the fibre modification inhibitor be impregnated into electrode-peripheral region, myocardium interface.Should pay close attention to the ICD commodity that are purchased ICD and of future generation and/or follow-up research and development that do not pay particular attention to and they are suitable for using in the present invention, this to those skilled in the art should be apparent.

With regard to the ICDs of effective control cardiac arrhythmia, leading must be accurately and targeting cardiac muscular tissue adjacent positioned, and irrelevant with concrete design feature.If occur growth of excessive scar tissue or extracellular matrix deposition on every side leading, effect just may suffer damage so.Have and be impregnated into the efficient that can increase pulse transmission and rhythm and pace of moving things sensing with the ICDs of the polymer composition of the theme of the present invention of electrode-nerve and/or pick off-organizational interface's adjacent tissue, increase effect thus, prevent unsuitable cardioversion and improve battery life.ICDs can also have benefited from discharging the therapeutic agent that can prevent or suppress near the infection in implant position.In one aspect, described device comprises ICDs and/or leads, and they have and comprise being impregnated into implantation and maybe will implanting polymer composition with the theme of the present invention of the described ICD and/or the adjacent tissue in place that leads of anti-scarring agent and/or anti-infective.In one aspect of the method, the invention provides the ICD of polymer composition with the theme of the present invention that comprises anti-scarring agent and/or anti-infective that is impregnated into and leads the adjacent tissue of cardiac muscular tissue on every side.

In one aspect of the method, the invention provides the ICDs of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention comprises therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with ICDs have above been described.

Can be by polymer composition directly and/or indirectly being coated with following position or coating is soaked into said composition around the ICDs that implants thereon: (a) tissue adjacent with ICD; (b) near the ICD-organizational interface; (c) zone around the ICD; (d) tissue around the ICD.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with ICD comprises described polymer composition is delivered to: (a) on the ICD surface of implant procedure process (for example as injectable, paste, gel or mesh); (b) before implanting ICD at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the ICD ICD surface at once and/or implant tissue (for example forming gel or mesh) around the ICD as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed ICD (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject ICD tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand the polymer composition of theme of the present invention can be impregnated into and install all or part of, only comprise install, only lead, the tissue of electrode and/or its bordering compounding only.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with ICDs is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because ICDs is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day one about scope of 180 days.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

(3) Be used for the treatment of ARR vagal stimulation

In one aspect, the polymer composition of theme of the present invention can be impregnated into and the adjacent tissue of vagal stimulation (VNS) device.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

Nerve stimulation device can also be used for vagus nerve stimulation and influence cardiac rhythm.Because vagus nerve provides neural distribution to heart, comprise conducting system (comprising the SA joint), so vagus nerve stimulation can be used for the treatment of following disease: such as low kinemic other arrhythmia of supraventricular arrhythmia, angina pectoris, atrial tachycardia, atrial flutter, atrial fibrillation and generation.

As mentioned above, in VNS, can perform the operation and implant bipolar electric conductance, make it will be sent to left vagus nerve in the neck from the electricity irritation of pulse generator.Pulse generator is the battery powered device of lithium carbon monofluoride (lithium carbon monofluoride) that accurate stimulus modelity is passed to vagal implantation.Pulse generator can be by cardiologist's operation sequence (service routine rod) so that treat concrete arrhythmia.

For example, at United States Patent (USP) 6,597, described such as these products in 953 and 6,615,085.For example, nerve stimulator can be vns device, and it produces pulse with the frequency that changes automatically based on the vagus nerve firing rate.For example, referring to United States Patent (USP) 5,916,239 and 5,690,681.Nerve stimulator can be for detecting the tachycardia characteristic and the electricity irritation that exists being passed to the device of nervous system with the compacting heart rate based on EGM.For example, referring to United States Patent (USP) 5,330,507.Nerve stimulator can be implantable cardiac stimulus systems, and it is by forming with lower member: two pick offs, and one is used for atrial signal and one and is used for ventricular cardiac signal; And pulse generator and control unit, so that guarantee sympathetic-vagal stimulation balance.For example, referring to United States Patent (USP) 6,477,418.Nerve stimulator can be for imposing on vagal device with the programme-control frequency with electric pulse, and described programme-control frequency can be regulated to keep lower heart rate.For example, referring to United States Patent (USP) 6,473,644.Nerve stimulator can provide electricity irritation so that induce the electroencephalogram reading to change as to the treatment of epilepsy means to vagus nerve, operation on heart is existed to be controlled in the normal parameter simultaneously.For example, referring to United States Patent (USP) 6,587,727.

Can have benefited from the VNS device that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised and be purchased product.The example that is purchased of VNS system is Cyberonics, Inc. the product of Sheng Chaning comprises that Model 300 and Model 302 lead, Model 101 and Model 102R pulse generator, Model 201 program rods and Model 250 program development softwares and Model 220 magnets.These are by Cyberonics, and the product description that Inc. makes is at for example United States Patent (USP), 5,928, in 272,5,540,730 and 5,299,569.

With regard to regard to the effective vagal stimulation of arrhythmia, leading must be accurately and the left vagus nerve adjacent positioned, and irrelevant with concrete design feature.Occur growth of excessive scar tissue or extracellular matrix deposition on every side if lead at VNS, so this situation can reduce the effect of device.Having the VNS device that is impregnated into the polymer composition of the theme of the present invention of electrode-tissue interface adjacent tissue can be used to increase the pulse transmission efficiency and increase the time limit that these devices work clinically.The VNS device can also have benefited from discharging the therapeutic agent that can prevent or suppress near the infection in implant position.In one aspect, described device comprises the VNS device and/or leads, they have comprise anti-scarring agent and/or anti-infective be impregnated into that implantation maybe will be implanted described VNS device and/or the polymer composition of the theme of the present invention of the adjacent tissue in place that leads.In one aspect of the method, the invention provides leading of polymer composition with the theme of the present invention that comprises anti-scarring agent and/or anti-infective that is impregnated into and implants the described adjacent tissue of place's vagus nerve that leads.

In one aspect of the method, the invention provides the VNS device of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention comprises therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with the VNS device have above been described.

Can be by polymer composition directly and/or indirectly being coated with following position or coating is soaked into said composition around the VNS device of implanting thereon: (a) tissue adjacent with the VNS device; (b) near VNS device-organizational interface; (c) zone around the VNS device; (d) tissue around the VNS device.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with the VNS device comprises described polymer composition is delivered to: (a) at the VNS of implant procedure process apparatus surface (for example as injectable, paste, gel or mesh); (b) before implanting the VNS device at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the VNS device VNS apparatus surface at once and/or implant tissue (for example forming gel or mesh) around the VNS device as injectable, paste, gel, original position; (d) by described compositions part being coated with the anatomic space of having placed the VNS device (useful especially being to use of this embodiment discharged polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of described therapeutic agent and can pass other preparation into the described activating agent of release in the zone of having inserted described device in the time limit in several hours more than one weeks); (e) by inject VNS device tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand the polymer composition of theme of the present invention can be impregnated into and install all or part of, only comprise install, only lead, the tissue of electrode and/or its bordering compounding only.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with the VNS device is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because the VNS device is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10 mg; Or about 10 mg-250 mg; Or about 250 mg-1000 mg; Or about 1000 mg-2500 mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

Although above described a large amount of rhythms of the heart controls (CRM) device, the unwanted tissue reaction after they all have similar design feature and produce similar implantation, and can bring out or promote infection in the implant band of position.Should pay close attention to the CRM product that is purchased CRM device and of future generation and/or follow-up research and development that does not above pay particular attention to and be foreseeable and be suitable for using in the present invention that this to those skilled in the art should be apparent.The CRM device particularly leads and must be transferred into anatomical position correct in atrium and/or the ventricle to guarantee to stimulate with the location of accurate way very.The all or part of of CRM device can be moved after surgery, or excessively cicatrix (or neuroglia) tissue growth can occur in implant, and this can cause the performance of these devices to reduce.Have and be impregnated into the effect and/or the movable time limit (the particularly battery powered device of implanting fully) that can increase implant with the CRM device of the polymer composition of the theme of the present invention of electrode-tissue interface adjacent tissue.The CRM device can also have benefited from discharging the therapeutic agent that can prevent or suppress near the infection in implant position.In one aspect, the invention provides the CRM device of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention comprises therapeutic agent (for example anti-scarring agent and/or anti-infective).These compositionss may further include one or more fibre modification inhibitor, make granulation, fiber or glial tissue overgrowth be inhibited or reduce; And/or these compositionss may further include one or more anti-infectives, near the infection inhibition or the prevention implant position thus.

Implantable sensor

In one aspect, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with implantable sensor.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

The implantable sensor that can be used for interior physiological level of detection bodies or change is provided.Have a large amount of sensor devices, wherein the appearance of fibre modification reaction produces harmful effect device or implantation to described device or uses the biological question of this device.The suitable clinical function effect of the pick off of implanting is depended on the direct dissection of target tissue and/or body fluid and is contacted.Can degrade electric device and reduce the characteristic of device-organizational interface of cicatrization around the implanting device, and device possibly can't proper function.Forming scar tissue between sensing device and adjacent (target) tissue can stop physics, chemistry and/or bio information mobile (for example fluid levels, levels of drugs, metabolite level, glucose level, pressure etc.) to arrive the detection architecture of pick off.Similarly, if " foreign body " reaction occurs and the pick off that causes inserting by cicatrix encapsulation (being that health is because of fibrous tissue and pick off " disconnection "), pick off will receive the bio information that the organism of non-integral reflects so.If the situation of sensor capsule inside (being the level that detects in the microenvironment) and the situation of these situations and capsule outside inconsistent (i.e. a microenvironment in the body as a whole), it can write down the information of unrepresentative whole body level so.Implantation can be inserted near the infection that pick off could also introduce or promote that the implant position is.

Pick off or transducer can be positioned at the body deep so that monitor various physiological propertys, such as temperature, pressure, strain, fluid flow, metabolite level (for example electrolyte, glucose), levels of drugs, chemical characteristic, electrical characteristics, magnetic etc.The representational example that is used to implement implantable sensor of the present invention comprises blood and organizes monitor, electrolyte pick off, blood constituent pick off, temperature sensor, pH pick off, optical pickocff, amperometric sensor, pressure transducer, biosensor, sensing impulse repeater, strain pick off, activity sensor and magnetoresistive transducer.

The implantable sensor and the transducer of a large amount of types have been described.For example, implantable sensor can be microelectronic device, and it is implanted in around the large intestine so that by detecting the rectum inclusions and stimulating the contraction of wriggling property to control intestinal function with emptying at the flood.For example, referring to United States Patent (USP) 6,658,297.Implantable sensor can be used for measuring the pH in GI road.The representational example of this class pH sensing device is from Medtronic, Inc. (Minneapolis, BRAVO pH monitoring system MN).Implantable sensor can be the ingredient of GI conduit or probe, and it comprises the Sensor section and the sensitive polymer material that irreversible change takes place that electricity or optical detecting device connect when contacting the cumulative action of external agency.For example, referring to United States Patent (USP) 6,006,121.Implantable sensor can be the ingredient of central vein conduit (CVC) (for example jugular vein conduit) system.For example, device can be made up of the catheter body that has at least one oxygen sensor and far-end heat exchange zone, wherein catheter body uses cryogen to form and returns tube chamber so that intravital heat exchange to be provided, thereby prevents the ischemia that causes because of cause overheated of severe cerebral trauma or because of apoplexy.For example, referring to United States Patent (USP) 6,652,565.CVC can comprise hot piece and measure the temperature sensor of blood heat.For example, referring to United States Patent (USP) 6,383,144.

In one aspect, the invention provides the implantable sensor of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with implantable sensor have been described.

Can be by polymer composition directly and/or indirectly being coated with following position or coating is soaked into said composition around the implantable sensor of implanting thereon: (a) tissue adjacent with implantable sensor; (b) near implantable sensor-organizational interface; (c) zone around the implantable sensor; (d) tissue around the implantable sensor.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with implantable sensor comprises described polymer composition is delivered to: (a) on the implantable sensor surface of implant procedure process (for example as injectable, paste, gel or mesh); (b) before implanting implantable sensor at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the implantable sensor implantable sensor surface at once and/or implant tissue (for example forming gel or mesh) around the implantable sensor as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed implantable sensor (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject implantable sensor tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand the polymer composition of theme of the present invention can be impregnated into and install all or part of, only comprise device, only pick off, the tissue of detector and/or its bordering compounding only.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with implantable sensor is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because implantable sensor is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

Several concrete implantable sensor device and Therapeutic Method are hereinafter more specifically described.

(1) Blood and glucose monitor

In one aspect, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with glucose monitor.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

Glucose monitor is used to detect blood glucose and changes, and is used in particular for controlling and treating the patient who suffers from diabetes.Diabetes are the Metabolic disorders in a kind of glucose metabolism, and it has encroached on number in the developed country in the world with ten million people.This disease is characterised in that health can not normally utilize and metabolize carbohydrates, particularly glucose.In general, in the blood between the glucose in glucose and the bodily tissue cell subtly the coordinated balance hormone insulin that produced by pancreas keep.If there be the underproduce with blood sugar lowering level (type i diabetes) of defective and insulin in pancreas, although or the pancreas insulin produces fully, if but health becomes to the blood sugar reducing function of insulin insensitive (type ii diabetes), the result is exactly diabetes so.Accurate detection to blood sugar level is that the control of diabetes patient is necessary, because the dosage of insulin and/or other blood sugar lowering and timing administration change and progressively increase with the glucose level to drug reaction.If dosage is too high, blood sugar level will be low excessively so, causes confusion of consciousness and even may cause loss of consciousness.If dosage is low excessively, blood sugar level will be too high so, and the metabolism that causes excessive thirst, urinates and be called ketoacidosis changes.If regularly administration is incorrect, blood sugar level may be in two extreme big ups and downs-think situation that produces some long-term diabetic complication, such as heart disease, renal failure and blind so.Because in extreme case, all these diseases all may be life-threatening, so careful and continuous detecting glucose level is the critical aspects in the diabetes control.The mode of a kind of test glucose level change and continuous detecting was to implant glucose detector when glucose level was too high or too low in diabetics.Because detecting blood sugar level, glucose monitor changes, so by external injection or give insulin by implantable insulin pump and blood sugar level can be maintained acceptable physiological range.

The blood and the tissue glucose monitor of a large amount of types are applicable to enforcement the present invention.For example, can use the conduit on the stent platform glucose monitor to be delivered to vascular system through the chamber.For example, referring to United States Patent (USP) 6,442,413.Glucose monitor can be made up of the glucose-sensitive living cells, these glucose-sensitive living cells monitoring blood sugar levels and produce detectable electricity or optical signalling as the reaction that concentration of glucose is changed.For example, referring to United States Patent (USP) 5,101,814 and 5,190,041.Glucose monitor can be the pliable and tough electrode of the minor diameter that is implanted subcutaneously, and it can be by forming for the analyte-reactive enzyme of electrochemical glucose monitor design.For example, referring to United States Patent (USP) 6,121,009 and 6,514,718.Implantable sensor can be sent system for the ring insulin of sealing, wherein has sensing device, and it can and stimulate insulin pump or pancreas that insulin is provided based on electrical signal detection patient's blood sugar level then.For example, referring to United States Patent (USP) 6,558,345 and 6,093,167.Other glucose monitor for example is described in the United States Patent (USP) 6,579,498,6,565,509 and 5,165,407.The glucose monitor of minimum invasive comprises the GLUCOWATCH G2 BIOGRAPHER (referring to cygn.com) from Cygnus Inc.; For example, referring to United States Patent (USP) 6,546,269; 6,687,522; 6,595,919 and Application No. 20040062759A1; 20030195403A1; And 20020091312A1.

Can have benefited from the glucose monitor that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised and be purchased product.Be purchased blood in a large number and the tissue glucose monitoring device is suitable for implementing the present invention.Although in fact can use any implantable glucose monitor, for the purpose of clearer, several concrete examples that are purchased and research and develop sections have been described hereinafter.

From Medtronic MiniMed, CONTINUOUS GLUCOSEMONITORING system (CGMS) (Northridge, the CA of Inc.; Referring to minimed.com); For example, referring to United States Patent (USP) 6,520,326; 6,424,847; 6,360,888; 5,605,152; 6,804,544; With Application No. 20040167464A1.The CGMS system is stored the primary structure glucose readings by operation implantation subcutaneous tissue of abdomen and every 5 minutes.The polymer composition of theme of the present invention is impregnated into the activity that the tissue adjacent with pick off can prolong this device, because usually must be with its taking-up after several days (about 3), partly cause is that it has lost susceptiveness as the result of local organization to device reaction.

CONTINUOUSGLUCOSE MONITORING device from TheraSense (Alameda, CA is referring to therasense.com) has used the disposable micro electrochemical sensor, and it is subcutaneous to make spring-loading insertion device that this pick off is inserted the patient.This pick off was measured one time the glucose level in the interstitial fluid every 5 minutes, it has the ability that stores the result who is about to analyze usefulness.For example, referring to US20040186365A1, US20040106858A1 and US20030176183A1.Reach one month and have high and the horizontal alarm of LG although this device can store data, must it be replaced once every several days, because as the antixenic result to implant, it has lost accuracy.The polymer composition of theme of the present invention is implanted the tissue adjacent with this pick off can prolong its activity, improve its performance and reduce the replacement frequency.Can have benefited from another kind of electrochemical sensor of the present invention is from Isense (Portland, the implantable electrochemical sensor of multilamellar OR).This system by semipermeable membrane, the catalytic membrane that produces electric current is being arranged in the presence of the glucose and is reducing interferential specific membrane from other material.

Design SMSI glucose sensor (Medicine and Sciences, the pick off of Inc., Montgomery County, Maryland; Referring to s4ms.com) be subcutaneous in order in short out-patient's operation technique, to implant.Sensor design is become every a few minutes to measure a gap glucose automatically, and without any need for the intervention of user.The outer reader of pick off implant and corpusculum carries out wireless telecommunications, makes that user can be continuously or monitoring glucose level as required.Reader is designed to follow the tracks of the rate of change of glucose level and warns user to be about to take place hypoglycemia-or hyperglycemia.The about 6-12 of the operation lifetime of pick off implant month, after this it can be replaced.

Animas Corporation (West Chester, PA; Animascorp.com) researching and developing based on spectrographic method or place the optical sensing of vein placed around to measure the implantable glucose sensor of near infrared absorption of blood.The glucose sensor of Animas can be strapped on the insulin infusion pumps so that closed loop control to blood sugar level is provided.Scar tissue on pick off has twisted correct ability and this pick off of gathering optical information of device can have benefited from the present invention thus.

DexCom, Inc. (San Diego, CA; See dexcom.com) researching and developing its continuous glucose monitoring system, this is the implantable sensor of the outer receptor wireless transmission continuous blood sugar reading of a kind of donor.Receptor was showed the Trend value of once current glucose currency and 1-hour, 3-hour and 9-hour and acoustic warning sound when detecting high or low glucose skew every 30 seconds.This device is characterised in that implantable sensor is placed in the subcutaneous tissue and to 1 type and type 2 diabetes mellitus patient continuous detecting tissue (interstitial fluid) glucose level.This device can also comprise in sensor regions that requirement obtains the micro structure arrangement of precise information in the long-time time limit.DexCom, the glucose monitoring device of Inc. research and development and related system for example are described in the United States Patent (USP) 6,741,877,6,702,857 and 6,558,321.Regrettably, although the battery of monitoring device and circuit allow to work for a long time, the foreign body reaction of implant and/or encapsulation have influenced the percentage ratio of device implant of the ability of accurate test glucose level in the extended period.The polymer composition of theme of the present invention is impregnated into the tissue adjacent with this device can makes it possible to implant back accurate test glucose level in the long-time time limit, reduce the quantity of failure of apparatus and reduced metathetical incidence rate.

Also the glucose monitoring system of glucose response polymer as the detection architecture ingredient used in special concern in the embodiment of this invention.M-Biotech (Salt Lake City UT) is is researching and developing continuous monitor system, it by the merging of subcutaneous implantation the hydrogel of pressure transducer form.For example, referring to United States Patent (USP); With.This hydrogel reacts by the change of contraction or expansion to concentration of glucose, and monitors described expansion or contraction by pressure transducer.Transducer changes into linearity the signal of telecommunication and wireless signal is sent to display device.Cybersensors (Berkshire, UK) (for example produced external receptor/transmitter of implanting subcutaneous capsule sample pick off and capture data and driving capsule by the RF signal, referring to GB 2335496 and United States Patent (USP) 6,579,498), authorize) by UK Patent andTrademark Office.Physical sensors and RF microchip are formed and contained to this sensor capsule by the affine polymer of glucose; Whole capsule further is closed in the semipermeable membrane.The affine polymer of glucose reveals rheology change (in the 3-15nM scope) and viscosity decline when concentration of glucose increases by becoming than thin list when the contact glucose.Can and can convert it into signal by the reversible reaction of physical sensors checkout gear.Above-mentioned these systems be suitable for polymer composition with theme of the present invention be impregnated into as the adjacent tissue of pick off of implantation provided by the invention.

(it is made up of based on the subcutaneous pin of the implantation of silicon the biocompatibility of little (150 μ m wide * 2mm is long) another kind of glucose sensing device for Mentor, OH) research and development by Advanced Biosensors.This device transmits subepidermal glucose level and with the wireless mode Data transmission.Regrettably, the foreign body reaction of implant and/or encapsulation have influenced the accurately ability of detection glucose level more than 7 days of device.The polymer composition of theme of the present invention is impregnated into the useful life that the tissue adjacent with this device can make its accurate test glucose level of long-time time limit and prolong this device.

With regard to accurate detection physics, chemical physiological property, described device must with organize adjacent accurate location, and irrelevant with the specific design feature of blood, tissue or the interstitial fluid glucose monitoring device implanted.Especially, the detector of sensing arrangement must contact the G/W flat contact with identical (or representative) of finding in blood flow.If excessive scar tissue growth or extracellular matrix deposition occur around device, this possibility affecting glucose is from being organized into the mobile of detector and making this failure of apparatus so.Similarly, if " foreign body " reaction takes place and the glucose sensor that causes implanting by the fibrous tissue encapsulation, this pick off will detect the glucose level in the capsule so.If the glucose level of the glucose level of capsule inside and capsule outside inconsistent (promptly as a whole in vivo), it can write down the information of unrepresentative whole body level so.This can cause clinicist or patient to give the blood sugar lowering (such as insulin) of wrong dosage, and its consequence may be serious.Blood, tissue or interstitial fluid glucose monitoring device with polymer composition of the theme of the present invention that is impregnated into the tissue adjacent with implant can reduce the cicatrization of implant and/or the efficient and the accuracy of encapsulation and increase glucose detection, the administration error of insulin is reduced to bottom line, help to keep normal blood sugar level, increase time limit and/or the metathetical frequency of minimizing implant that these devices work clinically.Can also have benefited from discharging the therapeutic agent that can prevent or suppress near the infection the implant position such as these glucose monitoring devices.In one aspect, described device comprises blood, tissue or interstitial fluid glucose monitoring device, and they have the polymer composition that is impregnated into and implants the theme of the present invention that comprises anti-scarring agent and/or anti-infective that maybe will implant the adjacent tissue in described device place.In one aspect of the method, the invention provides the glucose monitoring device of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with the glucose monitoring device have above been described.

Can be by polymer composition directly and/or indirectly being coated with following position or coating is soaked into said composition around the glucose monitoring device of implanting thereon: (a) tissue adjacent with the glucose monitoring device; (b) near glucose monitoring device-organizational interface; (c) zone around the glucose monitoring device; (d) tissue around the glucose monitoring device.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with the glucose monitoring device comprises described polymer composition is delivered to: (a) at the glucose monitoring apparatus surface (for example as injectable, paste, gel or mesh) of implant procedure process; (b) before implanting the glucose monitoring device at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the glucose monitoring device glucose monitoring apparatus surface at once and/or implant tissue (for example forming gel or mesh) around the glucose monitoring device as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed the glucose monitoring device (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject glucose monitoring device tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand the polymer composition of theme of the present invention can be impregnated into and install all or part of, only comprise device, only pick off, the tissue of detector and/or its bordering compounding only.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with the glucose monitoring device is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because the glucose monitoring device is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

(2) Pressure and strain gauge

In one aspect, the polymer composition of theme of the present invention can be impregnated into and pressure and/or the adjacent tissue of strain gauge.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

Pressure or stress monitoring device can be used for the pressure or the stress of increase in the detection bodies.Implantable pressure transducer and pick off are used for the application of interim or long term body organ, tissue or blood vessel so that the record absolute pressure.Proposed many different designs and operating system and they have been placed the patient's who has various medical conditions interim or prolonged application.Can utilize the intrinsic pressure pick off in interim use several days or several weeks, yet, pressure transducer that can be long-term or permanent implanted also used.Pressure transducer can detect many successive body pressures, such as, but be not limited to blood pressure and fluid flow, interior pressure, intracranial pressure and the mechanical pressure relevant of aneurysmal sack with fracture.

The pressure monitor of a large amount of types is applicable to enforcement the present invention.For example, implantable sensor can lead by use, sensor assembly, sensor circuit (comprising electric conductance) and provide the device of voltage to detect on the selection part and the absolute pressure of body fluid under the Ambient Operating Temperature.For example, referring to United States Patent (USP) 5,535,752.Implantable sensor can be for providing the intracranial pressure monitor that can change into the analog and digital signal of digit pulse by electricity.For example, referring to United States Patent (USP) 6,533,733.Implantable sensor can be for being enclosed in the baroceptor of air chamber, it be used to transmit the reference pressure data in case with implantable medical apparatus, be used in combination such as pacemaker.For example, referring to United States Patent (USP) 6,152,885.Implantable sensor can be suitable for inserting body passage so that monitoring and the relevant parameter of fluid that flows through intracavity implant (for example stent).For example, referring to United States Patent (USP) 5,967,986.Implantable sensor can be for having the passive sensor that having of induction apparatus-capacitor circuit is suitable for the resonant frequency of patient's skull sensation intracranial pressure.For example, referring to United States Patent (USP) 6,113,553.Implantable sensor can be self-powered strain sensor-based system, and its produces strain signal as the reaction to the stress that can produce on bone anchoring device.For example, referring to United States Patent (USP) 6,034,296.Implantable sensor can be the resonant frequency parts.This conduit can comprise wire electrode and be used to pour into tinsel brinish chamber on every side that designing it is in order to measure by the potential difference of GI wall with in order to measure pressure simultaneously.For example, referring to United States Patent (USP) 5,551,425.Implantable sensor can be the ingredient of CNS device; For example, be assemblied in the intracranial pressure sensor on the monitoring pressure position in the health skull and outwards transmit the device of pressure from skull.For example, referring to United States Patent (USP) 4,003,141.Implantable sensor can be the parts of left ventricular assist device.For example, VAD can be for being suitable for using the inlet flow rate pressure transducer and can participating in the blood pump of flow exchange between left ventricle and the aorta based on the controller that sensor feedback is regulated pump speed.For example, referring to United States Patent (USP) 6,623,420.

Can have benefited from having the pressure of polymer composition of theme of the present invention and/or stress sensing apparatus comprises and is purchased product according to the present invention.Be purchased in a large number with experimental pressure and stress sensing apparatus and be suitable for implementing the present invention.As explanation, the selection to these devices and implant is described in next paragraph.

From CardioMEMS (Atlanta, GA; @cardiomems.com, cooperative venture between Georgia InstituteofTechnology and the Cleveland Clinic) device can insert aneurysmal sack and be full of fluid so that pressure in the monitoring capsule and warning are given in the medical specialist capsule, may reach to cause disruptive level.Endovascular aneurysm repair (EVAR) use aneurysmal stent graft of separation from circulation is usually carried out.Yet blood continues to leak into aneurysmal sack to be caused having accumulated in the capsule emerging pressure and produces disruptive risk.Behind EVAR, the CardioMEMS device implanted aneurysmal sack so that monitor pressure in the isolating capsule, be in the patient who increases in the risk of rupture thereby detect.Pressure transducer is characterised in that the induction-capacitive resonance circuit that has variable condenser.Because electric capacity is with the pressure change in the environment of having placed capacitor, so it can detect the change of local pressure.By using external activating system generation data, the oscillating current in the described external activating system inductive transducer and detection frequency of oscillation (being used for calculating pressure then).Regrettably, although circuit allows to work for a long time, but the foreign body reaction of implant and/or encapsulation have influenced the ability (promptly device has detected the pressure in the capsule microenvironment, but is not aneurysmal sack as a whole) of accurate pressure level in the device detection aneurysm.Near the infection the implant position can also introduced or promote to implanted sensor.The polymer composition of theme of the present invention is impregnated into the quantity that the tissue adjacent with this device makes it possible to after implantation accurately long-time accurate detected pressures level of time limit and reduce failure of apparatus.

MicroStrain Inc. (Williston, VT ， @microstrain.com) has has researched and developed the wireless implantable sensor family that is used to measure strain in the body, position and motion.These pick offs can be measured: for example nystagmus quivers, the cornea implant degree of depth, the orientation sensor that is used for improved crown goods, the strain of mayer (mayer) ligament, the spinal ligament strain, the spine strain, the strain of elbow ligament, emg and ekg data, be used to measure the 3DM-G of direction and motion, the strain of wrist ligament, be used to measure the hip replacement pick off of micromotion, the implant attenuation, the strain of knee joint ligament, the tibiofibular ligaments strain, the heel string strain, the strain of arch of foot support, pressure in the foot shoe pad.The said firm provides the false knee joint that can specifically measure the also real-time Data transmission of compressing power in the body.Describe this technology and comprise that with the parts that are used to make the device that is used for this technology patent comprises US 6,714,763; 6,625,517; 6,622,567; 6,588,282; 6,529,127; 6,499,368; 6,433,629; 5,887,351; 5,777,467; 5,497,147; With 4,993,428.Describe this technology and comprise 20040113790 with the U.S. Patent application that is used to make the parts of the device that is used for this technology; 20040078662; 20030204361; 20030158699; 20030047002; 20020190785; 20020170193; 20020088110; 20020085174; 20010054317; With 20010033187.

Mesotec (Hannover, Germany with several German Research institutes (for example Fraunhofer Institute of Microelectronic Circuits and Systems) cooperation; @mesotec.com) researched and developed implantable intraocular pressure sensing system, be called MESOGRAPH, it can the continuous detecting intraocular pressure.For example, in order to identify glaucomatous outbreak, it is ideal.Can in the standard procedures operating process, implant based on the pick off of CMOS and with its Irritability ground and be connected with the external unit that is integrated into spectacle frame.Glasses are connected with the portable data device by cable successively.The frequency modulation RF carrier that use is operated under 13.56MHz and convertible load arrives data transaction in glasses to upstream, and energy arrives the catchment to pick off simultaneously.By changing the polysilicon diaphragm diameter in the microstructure pump breach capacitor on the wafer, the pressure limit of sensor response is suitable at 50kNm-2-3.5MNm-2.This device is formed by being used for link coupled meticulous collapsible coil of remote measurement and minimum miniaturization pressure transducer.Make this pick off and be used for reading for a long time and detecting continuously intraocular pressure based on microtechnique.Wafer and coil are integrated into improved soft intraocular lens, can in current routine operation operation, this improved soft intraocular lens be implanted patient's eye.Regrettably, this device is successfully implanted back inefficacy usually at first, because the foreign body reaction of implant and/or encapsulation have influenced the ability (promptly this device has detected the pressure in the microenvironment of capsule around the implant, but is not intraocular pressure as a whole) that it accurately detects the intraocular pressure level.Near the infection the implant position can also be introduced or promote to implanted sensor.The polymer composition of theme of the present invention is impregnated into the quantity that the ocular tissue adjacent with this device makes it possible to after implantation accurately long-term detected pressures level and reduce failure of apparatus.

In order accurately to detect physics and/or physiological property (such as pressure), described device must accurately be positioned in the tissue and receive the information of representational situation as a whole, and irrelevant with the specific design feature of pressure and/or strain gauge.If growth of excessive scar tissue or extracellular matrix deposition occur around device, this pick off may receive error message so, and this information has been damaged the effect of pick off or scar tissue and can be blocked bio information and flow to pick off.For example, many devices lost efficacy successfully implanting the back at first, because the encapsulation of implant causes it to detect the stress level (promptly this device has detected the pressure in the microenvironment of capsule around the implant, but is not the pressure of overall situation) of non-correlation.Pressure and stress sensing device with polymer composition of the theme of the present invention that is impregnated into the tissue adjacent with implant can increase detection efficiency and increase the time limit that these devices work clinically.Can also have benefited from discharging the therapeutic agent that can prevent or suppress near the infection the implant position such as these pressure and stress sensing device.In one aspect, described device comprises the implantable sensor device, and they have the polymer composition that is impregnated into and implants the theme of the present invention that comprises anti-scarring agent and/or anti-infective that maybe will implant the adjacent tissue in described device place.In one aspect of the method, the invention provides the pressure or the stress sensing device of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with pressure or stress sensing device have above been described.

Can said composition be soaked into around pressure of implanting or stress sensing device by polymer composition directly and/or indirectly being coated with following position or being coated with thereon: (a) with pressure or the adjacent tissue of stress sensing device; (b) near pressure or the stress sensing device-organizational interface; (c) zone around pressure or the stress sensing device; (d) tissue around pressure or the stress sensing device.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with pressure or stress sensing device comprises described polymer composition is delivered to: (a) at pressure or stress sensing device surface (for example as injectable, paste, gel or the mesh) of implant procedure process; (b) before implantable pressure or stress sensing device at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) at once pressure or the tissue around stress sensing device surface and/or implantable pressure or the stress sensing device (for example forming gel or mesh) behind implantable pressure or the stress sensing device as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed pressure or stress sensing device (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) pass through as the tissue around solution, transfusion or slow releasing preparation percutaneous injection pressure or the stress sensing device; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand the polymer composition of theme of the present invention can be impregnated into and install all or part of, only comprise device, only pick off, the tissue of detector and/or its bordering compounding only.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with pressure or stress sensing device is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because pressure or stress sensing device are made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/m ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

(3) Cardiac sensor

In one aspect, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with the cardiac sensor device.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

In one aspect of the method, described implantable sensor can be the device of constructing for the characteristic that detects in heart or the cardiac muscular tissue.Cardiac sensor is used to detect the time bar parameter relevant with cardiac performance of locating to monitor of fixing time that means in office as along prolongation.In general, usually heart is monitored so that detect and heart disease, such as the relevant change of chronic heart failure (CHF).By the monitoring pattern relevant, can detect deterioration (parameter is such as cardiac output, ejection fraction, pressure, ventricular wall motion etc.) based on hemodynamics variation with cardiac function.To carry out disease control among the CHF patient be important to existing in this constant direct detection.By using implantable sensor monitoring of blood kinetic determination value, can detect the hemodynamics variation crisis and select suitable medicine and intervention.

The cardiac sensor of a large amount of types is applicable to enforcement the present invention.For example, implantable sensor can be for introducing the activity sensor of magnet and magnetoresistive transducer, and it can provide variable active signal as the ingredient of cardiac devices.For example, referring to United States Patent (USP) 6,430,440 and 6,411,849.Implantable sensor can be monitored intraventricular blood pressure by wireless telecommunications being emitted to remote control unit.For example, referring to United States Patent (USP) 6,409,674.Implantable sensor can be the heart wall motion pick off based on accelerometer, and it is transduceed the acceleration of heart tissue to cardiac stimulus device by using the signal of telecommunication.For example, referring to United States Patent (USP) 5,628,777.Implantable sensor can be implanted and have the chambers of the heart of extra implantable intravascular with the pick off of flow and pressure in the detection chambers of the heart.For example, referring to United States Patent (USP) 6,277,078.

The cardiac sensor of polymer composition that can have benefited from being impregnated into the theme of the present invention of adjacent tissue according to the present invention comprises and is purchased product.Be applicable to that implementing the cardiac sensor that is purchased of the present invention comprises Biotronik (Biotronik GmbH ﹠amp; Co., Berlin, Germany is referring to biotronik.com) CARDIAC AIRBAG icd system, it is that a kind of providing transmitted the rhythm and pace of moving things monitoring device that 30 joules of shock therapys reach the recovery shock ability of 3 ventricular fibrillation outbreaks.Except that recovery shock ability, this system can also provide bradycardia pace-making and VT monitoring.PROTOS family pacemaker from Biotronik (referring to biotronikusa.com) has also been introduced the pace-making sensor capability that is called closed loop stimulation.

Blood flow and perfused tissue monitor can also can be used to monitor non-heart tissue.The research worker of OakRidge National Laboratory been has has been researched and developed a kind of wireless senser, and it will monitor the blood flow of arrival transplant organ so that transplant rejection is carried out earlier detection.

Medtronic (Minneapolis, MN; Referring to medtronic.com) be the implantable product of researching and developing of its CHRONICLE, designing it is blood flow, heart rate and the physical exertion that directly places intraventricular pick off continuous monitoring patient in order to use.The patient regularly is downloaded to apparatus for household use with information, and this device is transferred to the clinicist with this physiological data on Internet.

With regard to accurately detecting physics and/or physiological property (such as pressure, flow velocity etc.), described device must accurately be positioned in cardiac muscle, ventricle or the trunk and receive the information of representational situation as a whole, and irrelevant with the design feature of cardiac sensor.If excessive scar tissue growth or extracellular matrix deposition around sensing device, occur, this pick off may receive error message so, and this information has been damaged the effect or the scar tissue of pick off and can be blocked the detector arrangement that bio information flow to pick off.For example, many cardiac sensors lost efficacy successfully implanting the back at first, because the encapsulation of implant causes it to detect the level (promptly this device has detected the condition in the microenvironment of capsule around the implant, but is not the pressure of overall situation) of non-correlation.Can also have benefited from discharging the therapeutic agent that can prevent or suppress near the infection the implant position such as these cardiac sensors.Cardiac sensor with polymer composition of the theme of the present invention that is impregnated into the tissue adjacent with implant can increase detection efficiency and increase the time limit that these devices work clinically.In one aspect, described device comprises the implantable sensor device, and they have the polymer composition that is impregnated into and implants the theme of the present invention that comprises anti-scarring agent and/or anti-infective that maybe will implant the adjacent tissue in described device place.In one aspect of the method, the invention provides the heart sensing device of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with the heart sensing device have above been described.

Can be by polymer composition directly and/or indirectly being coated with following position or coating is soaked into said composition around the cardiac sensor device of implanting thereon: (a) tissue adjacent with the cardiac sensor device; (b) near cardiac sensor device-organizational interface; (c) zone around the cardiac sensor device; (d) tissue around the cardiac sensor device.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with the cardiac sensor device comprises described polymer composition is delivered to: (a) at the cardiac sensor apparatus surface (for example as injectable, paste, gel or mesh) of implant procedure process; (b) before implanting the cardiac sensor device at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the cardiac sensor device cardiac sensor apparatus surface at once and/or implant tissue (for example forming gel or mesh) around the cardiac sensor device as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed the cardiac sensor device (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject cardiac sensor device tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand the polymer composition of theme of the present invention can be impregnated into and install all or part of, only comprise device, only pick off, the tissue of detector and/or its bordering compounding only.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with the cardiac sensor device is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because the cardiac sensor device is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

(4) Respiration pickup

In one aspect, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with the respiration pickup device.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

Described implantable sensor can be the device of constructing for the characteristic that detects in the respiratory system.Respiration pickup can be used to detect the change of breathing pattern.For example, respiration pickup can be used to detect sleep apnea, and it is a kind of airways disorders.There is two types sleep apnea.In a kind of situation, health can not produce automatically and cause and requisite neuromuscular stimulation of control breathing cycle in good time.In another kind of situation, when exhaling on the air flue muscle contraction and thus air flue become and block.Apneic cardiovascular consequence comprises cardiac arrhythmia (bradycardia, atrioventricular block, chamber property premature contraction) and hematodinamics obstacle (pulmonary hypertension and systemic hypertension).This causes autonomic stimulation metabolism and mechanical effect and the probability that finally causes mortality rate to increase.In order to treat this disease, implantable sensor can be used to monitor the respiratory function effect, so that detect apnea episodes, the appropriate reaction thus electricity irritation of the nerve of last air flue muscle (for example to) maybe can provide other treatment.

The respiration pickup of a large amount of types is applicable to enforcement the present invention.For example, implantable sensor can provide the ingredient of gas to host's aerating system for the breathing element conduct that can produce breath signal of implanting the thoracic cavity.For example, referring to United States Patent (USP) 6,357,438.Implantable sensor can be made up of the sensing element that is connected with the body that leads, it be inserted into the thoracic cavity in the bone (for example manubrium) of communication so that detect respiratory change.For example, referring to United States Patent (USP) 6,572,543.

With regard to accurate detection physics and/or physiological property, described device must be accurately with organize adjacent positioned, and irrelevant with the design feature of respiration pickup.If excessive scar tissue growth or extracellular matrix deposition around pulmonary function or air flue sensing device, occur, this pick off may receive error message so, and this information has been damaged the effect or the scar tissue of pick off and can be blocked the detector arrangement that bio information flow to pick off.For example, many respiration pickups (pulmonary function sensing device) are successfully implanted the back inefficacy at first, because the encapsulation of implant causes it to detect the level (promptly this device has detected the condition in the microenvironment of capsule around the implant, but is not respiratory system function as a whole) of non-correlation.Can also have benefited from discharging the therapeutic agent that can prevent or suppress near the infection the implant position such as these respiration pickups.Respiration pickup with polymer composition of the theme of the present invention that is impregnated into the tissue adjacent with implant can increase detection efficiency and increase the time limit that these devices work clinically.In one aspect, described device comprises the implantable sensor device, and they have the polymer composition that is impregnated into and implants the theme of the present invention that comprises anti-scarring agent and/or anti-infective that maybe will implant the adjacent tissue in described device place.In one aspect of the method, the invention provides the respiration pickup device of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with the respiration pickup device have above been described.

Can be by polymer composition directly and/or indirectly being coated with following position or coating is soaked into said composition around the respiration pickup device of implanting thereon: (a) tissue adjacent with the respiration pickup device; (b) near respiration pickup device-organizational interface; (c) zone around the respiration pickup device; (d) tissue around the respiration pickup device.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with the respiration pickup device comprises described polymer composition is delivered to: (a) at the respiration pickup apparatus surface (for example as injectable, paste, gel or mesh) of implant procedure process; (b) before implanting the respiration pickup device at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the respiration pickup device respiration pickup apparatus surface at once and/or implant tissue (for example forming gel or mesh) around the respiration pickup device as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed the respiration pickup device (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject respiration pickup device tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand the polymer composition of theme of the present invention can be impregnated into and install all or part of, only comprise device, only pick off, the tissue of detector and/or its bordering compounding only.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with the respiration pickup device is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because the respiration pickup device is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

(5) Hearing transducer

In one aspect, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with the hearing transducer device.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

Described implantable sensor can be the device of constructing for the characteristic that detects in the auditory system.Respiration pickup is used as the ingredient of implantable hearing system to be used to recover the conduction and the internal ear hearing impairment of pure sensory nerve anakusis or merging.Auditory system can comprise that transmission is by the processor processing of implanting and be passed to the implantable sensor of the signal of telecommunication of the implantable electromechanical transducer that middle ear or internal ear are worked.Hearing transducer works as the mike of auditory system and play the sound that will accidental propagate in air and changes into action of electric signals.

Hearing transducer as a large amount of types of the ingredient of auditory system is suitable for implementing the present invention.For example, implantable sensor can produce the ingredient of electroacoustic frequency signal as the auditory system of recovering anakusis.For example, referring to United States Patent (USP) 6,334,072.Implantable sensor can be for by machinery or magnetic and vibration acoustic components, and such as the link coupled capacitance sensor of malleus, it detects the capacitance that changes in time that causes because of vibration.For example, referring to United States Patent (USP) 6,190,306.Implantable sensor can be electromagnetic transducer.It has permanent magnet and coil and based on the magnetic flux magnetic linkage that changes in time of vibration, described vibration is provided for the output stimulator so that cochlea is carried out machinery or electricity irritation.For example, referring to United States Patent (USP) 5,993,376.

Can have benefited from the hearing transducer that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised and be purchased product.Being suitable for implementing the hearing transducer device that is purchased of the present invention comprises: from Advanced Bionics (Sylmar, Califmia, Boston ScientificCompany is referring to advancedbionics.com) HIRES 90K bionic ear implant, HIRESOLUTION SOUND, CLARION CII bionic ear and CLARION 1.2; Also referring to United States Patent (USP) 6,778,858; 6,754,537; 6,735,474; 6,731,986; 6,658,302; 6,636,768; 6,631,296; 6,628,991; 6,498,954; 6,487,453; 6,473,651; 6,415,187; With 6,415,185; NUCLEUS 3 cochlear implants from Cochlear (Lane Cove NSW, Australia is referring to cochlear.com); Also referring to United States Patent (USP) 6,810,289; 6,807,455; 6,788,790; 6,782,619; 6,751,505; 6,736,770; 6,700,982; 6,697,674; 6,678,564; 6,620,093; 6,575,894; 6,570,363; 6,565,503; 6,554,762; 6,537,200; 6,525,512; 6,496,734; 6,480,820; 6,421,569; 6,411,855; 6,394,947; 6,392,386; 6,377,075; 6,301,505; 6,289,246; 6,116,413; 5,720,099; 5,653,742; 5,645,585; With U.S. Patent Application Publication No. 2004/0172102A1 and 2002/0138115A1; PULSAR CI 100 and COMBI 40+ cochlear implant from Med-El (Austria is referring to medel.com); Also referring to U.S. Patent application 20040039245A1, U.S. Patent number 6,600,955; 6,594,525; 6,556,870; With 5,983,139; From AllHear, Inc. (Aurora, Oregon; Referring to allhear.com) the ALLHEAR implant; Also referring to WO 01/50816; EP 1245134; With from MXM (France; Referring to mxmlab.com) DIGISONIC CONVEX, DIGISONIC AUDITORY BRAINSTEM and DIGISONIC MULTI-ARRAY implant; Also referring to United States Patent (USP) 5,123,422; EP 0219380; WO 04/002193; EP 1 244 400 A1:US 6,428,484; US 20020095194A1; WO 01/50992.

With regard to accurate detection sound, described device must accurately be positioned in ear, and irrelevant with the design feature of hearing transducer.If excessive scar tissue growth or extracellular matrix deposition around hearing transducer, occur, this pick off may receive error message so, and this information has been damaged the effect or the scar tissue of pick off and can be blocked the detector arrangement that bio information flow to pick off.Can also have benefited from discharging the therapeutic agent that can prevent or suppress near the infection the implant position such as these hearing transducers.Hearing transducer with polymer composition of the theme of the present invention that is impregnated into the tissue adjacent with implant can increase detection efficiency and increase the time limit that these devices work clinically.In one aspect, described device comprises the implantable sensor device, and they have the polymer composition that is impregnated into and implants the theme of the present invention that comprises anti-scarring agent and/or anti-infective that maybe will implant the adjacent tissue in described device place.In one aspect of the method, the invention provides the hearing transducer device of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with the hearing transducer device have above been described.

Can be by polymer composition directly and/or indirectly being coated with following position or coating is soaked into said composition around the hearing transducer device of implanting thereon: (a) tissue adjacent with the hearing transducer device; (b) near hearing transducer device-organizational interface; (c) zone around the hearing transducer device; (d) tissue around the hearing transducer device.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with the hearing transducer device comprises described polymer composition is delivered to: (a) at the hearing transducer apparatus surface (for example as injectable, paste, gel or mesh) of implant procedure process; (b) before implanting the hearing transducer device at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the hearing transducer device hearing transducer apparatus surface at once and/or implant tissue (for example forming gel or mesh) around the hearing transducer device as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed the hearing transducer device (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject hearing transducer device tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand the polymer composition of theme of the present invention can be impregnated into and install all or part of, only comprise device, only pick off, the tissue of detector and/or its bordering compounding only.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with the hearing transducer device is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because the hearing transducer device is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

(6) Electrolyte and metabolite pick off

In one aspect, the polymer composition of theme of the present invention can be impregnated into and electrolyte and/or the adjacent tissue of metabolite sensor device.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

In one aspect of the method, implantable sensor can be used for detecting the electrolyte and the metabolite of blood.For example, implantable sensor can be the device of metabolite or electrolytical composition level in the radiation source monitoring of blood that is oriented to blood by emission, make it with a plurality of detector generation reciprocal actions of output signal are provided.For example, referring to United States Patent (USP) 6,122,536.Implantable sensor can be the bio-sensing transponder, and it is formed by the photoreceptor with the dyestuff of change to the optical characteristics of the reaction of environmental change, sensation optical change with the transponder that data pass to the remote control reader.For example, referring to United States Patent (USP) 5,833,603.Implantable sensor can be for being used to detect the monolithic bio-electronic device of at least a analyte in the animal body.For example, referring to United States Patent (USP) 6,673,596.Other pick off of measuring chemical analyte for example is described in the United States Patent (USP) 6,625,479 and 6,201,980.

If occur excessive scar tissue growth or extracellular matrix deposition around the pick off, this pick off may receive error message so, and this information has been damaged the effect or the scar tissue of pick off and can be blocked the detector arrangement that bio information flow to pick off.For example, many electrolyte or metabolite pick off lost efficacy successfully implanting the back at first, because the encapsulation of implant causes it to detect the level (promptly this device has detected the condition in the microenvironment of capsule around the implant, but not blood levels) of non-correlation.Sensing device with polymer composition of the theme of the present invention that is impregnated into the tissue adjacent with implant can increase the efficient of electrolyte and/or metabolite detection and increase the time limit that these devices work clinically.Can also have benefited from discharging the therapeutic agent that can prevent or suppress near the infection the implant position such as these electrolyte and/or metabolite sensor device.In one aspect, described device comprises implantable electrolyte and/or metabolite sensor device, and they have the polymer composition that is impregnated into and implants the theme of the present invention that comprises anti-scarring agent and/or anti-infective that maybe will implant the adjacent tissue in described device place.In one aspect of the method, the invention provides the electrolyte and/or the metabolite sensor device of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with electrolyte and/or metabolite sensor device have above been described.

Can said composition be soaked into around electrolyte of implanting and/or metabolite sensor device by polymer composition directly and/or indirectly being coated with following position or being coated with thereon: (a) with electrolyte and/or the adjacent tissue of metabolite sensor device; (b) near electrolyte and/or the metabolite sensor device-organizational interface; (c) zone around electrolyte and/or the metabolite sensor device; (d) tissue around electrolyte and/or the metabolite sensor device.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with electrolyte and/or metabolite sensor device comprises described polymer composition is delivered to: (a) at electrolyte and/or metabolite sensor device surface (for example as injectable, paste, gel or the mesh) of implant procedure process; (b) before implanting electrolyte and/or metabolite sensor device at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind electrolyte and/or the metabolite sensor device electrolyte and/or metabolite sensor device surface at once and/or implant tissue (for example forming gel or mesh) around electrolyte and/or the metabolite sensor device as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed electrolyte and/or metabolite sensor device (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject electrolyte and/or metabolite sensor device tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand the polymer composition of theme of the present invention can be impregnated into and install all or part of, only comprise device, only pick off, the tissue of detector and/or its bordering compounding only.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with electrolyte and/or metabolite sensor device is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because electrolyte and/or metabolite sensor device are made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

Although above described a large amount of implantable sensor devices, the unwanted foreign body tissue reaction after they all have similar design feature and produce similar implantation, and can introduce or promote infection in the implant band of position.Should pay close attention to the pick off commodity that are purchased sensor device and of future generation and/or follow-up research and development that above do not pay particular attention to and be foreseeable and be suitable for using in the present invention that this to those skilled in the art should be apparent.Sensor device, particularly sensing element must detect on the correct in vivo anatomical position guaranteeing with the location of accurate way very.The all or part of of sensor device can be moved after surgery, or excessively cicatrix (or neuroglia) tissue growth can occur in implant, and this can cause the performance of these devices to reduce.Fibrous capsule around the pick off forms and can hinder bio information and flow to detector and/or cause this device to detect the relevant level of non-physiology (promptly detect in the capsule but not the level of the outside definite physiological level of capsule).This situation not only produces incomplete or coarse reading, but also can make clinicist or patient make incorrect decision based on the information that produces.Have and be impregnated into the effect and/or the movable time limit that can increase implant with the implantable sensor device of the polymer composition of the theme of the present invention of pick off-organizational interface's adjacent tissue.The implantable sensor device can also have benefited from discharging the therapeutic agent that can prevent or suppress near the infection in implant position.In one aspect, the invention provides the implantable sensor device of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention comprises therapeutic agent (for example anti-scarring agent and/or anti-infective).These compositionss may further include one or more fibre modification inhibitor, make granulation, fiber or neointima tissue growth excessively be inhibited or reduce; And/or these compositionss may further include one or more anti-infectives, near the infection inhibition or the prevention implant position thus.

Implantable drug delivery systems and pump

In one aspect, the polymer composition of theme of the present invention can be impregnated into and implantable drug delivery systems or the adjacent tissue of pump.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

Implantable drug delivery systems and pump discharge therapeutic agent to control the device of various medical conditions for the locus specificity that prolongation is provided.When needing topical remedy to influence, (only influence the disease of specific region) or when the systemic delivery activating agent is invalid or inefficacious, (cause toxicity or serious side reaction, cause medicine inactivation before arriving target spot, produce the symptom/disease control of difference, and/or cause treating dependency), to use usually and pass medicine implant and pump.Another advantage of implantable pump has been to improve patient's compliance.Many patients can forget regularly take medicine (particularly youngster, middle-aged and elderly people, chronic patient, mentally disabled person), and use implantable pump, and this problem can be eased.With regard to many patients, it can make symptom be controlled better (dosage progressively increases with the order of severity of symptom usually), has good disease control (particularly the insulin in diabetics is sent) and lower the pharmaceutical requirements Drug therapy of pain (particularly to).

Countless pass the medicine implant and pump has been used for various clinical practices, comprise the insulin pump of the program controlled that is used for the treatment of diabetes, give anesthetics (morphine for example, fentanyl) with alleviating pain (cancer for example, back problems, HIV, postoperative) (in the spinal column) pump in the sheath, part and the systemic chemotherapy that is used for the treatment of cancer sent (the Hepatic artery 5-FU infusion that for example is used for liver tumor), be used for the treatment of cardiopathic medicine (anti-arrhythmic that for example is used for rhythm abnormality), be used for neurological disorder (multiple sclerosis for example, spinal cord injury, brain injury, pass medicine in the sheath of the spasmolytic of the spasticity the cerebral palsy) (anti-spasmotic drugs) (for example baclofen) or be used for part/regional antibiotic (osteomyelitis for example of control infection, septic arthritis).In general, be implanted subcutaneously and pass Teat pipette and it is made up of pump unit that has medicine storage and pliability conduit, may be delivered into target tissue by its medicine.Pump stores and discharges the therapeutic drug levels (depend on application) of medicine to reach part or whole body of recipe quantity by conduit.The center of pump has the self-enclosed gateway that is covered by dividing plate, makes to insert syringe needle (by skin and dividing plate) so that recharge pump with medicine as required by percutaneous.The general implantable Teat pipette of passing that has two types.The constant speed pump is usually by the gas energy supply and be designed to make up a prescription as successive doses with preprogrammed constant speed under pressure.The flow of medicine and flow velocity are in that needs are immovable when passing medicine for a long time is best and regulated by length, temperature and the water level of used conduit.Program controlled speed pump has used battery powered pump and constant voltage reservoir so that regularly based on passing medicine by the mode of clinicist or patient's setting program.With regard to the program controlled infusion device, can be based on the medicine that can send little dispersion dosage according to the program setting scheme that individual clinical response changes.

In general, the implant delivery Teat pipette is so that pass medicine with scalable dosage, and in some applications, it can be used to regulate the implantable sensor coupling (so-called " closed loop " system) of the information of passing medicine with gathering.The implantable Teat pipette of passing can work in every way and passs medicine, includes, but are not limited to: pass medicine (for example pick off stimulation) when (a) only changing in detection bodies; (b) as continuous sustained release drug delivery (for example constant current); (c) in the mode of beating, pass medicine (for example non--constant current) with prescribed dose; (d) pass medicine by the program controlled mode; (e) by pass medicine (for example in ophthalmic, the sheath, intraperitoneal, intra-arterial or intracardiac) for the device of concrete region of anatomy design.Pass outside the medicine divided by ad hoc fashion or to ad-hoc location, can also pass Teat pipette (for example driving force is passed medicine by it) based on mechanical delivery technique classification.For example, the frame for movement that is used to pass medicine comprises, but be not limited to osmotic pumps, metering system, wriggling (cylinder) pump, electric driving pump, eye with passing Teat pipette and implant, elasticity pump, spring-contraction pump, air driven pump (for example induced), the fluid dispenser of hydraulic pump, piston-dependency pump and non--piston-dependency pump, dispense chamber, infusion pump, passive pump, infusion liquid pump and osmotic drive by electrolytic cell or chemical reaction.

The clinical function of implantable drug delivery systems or pump depends on device, the particularly conduit or the parts that make up a prescription, it can effectively be kept with the direct dissection of target tissue and contact (for example cavum subdurale in the spinal cord (sudural space), lumen of artery, peritoneum, interstitial fluid) and not by scar tissue encapsulation or obstruction.Regrettably, in many cases, when these devices were implanted, they experienced as mentioned above from " foreign body " reaction of host tissue on every side.With regard to implantable pump, pass medicine catheter lumen, catheter tip, the parts or send film and may be blocked of making up a prescription by scar tissue, cause drug flux to slow down or stop fully.Perhaps, complete pump, conduit and/or the parts that make up a prescription can be by cicatrix encapsulation (promptly installing by fibrous tissue " isolation " on matrix), make medicine be delivered to target tissue (being that cicatrix has stoped normal medicine motion and has been distributed to tissue on the capsule opposite side from implantable pump) by halves.The medicine that the generation of these situations all can cause flowing to required target tissue or organ invalid or incomplete (and the forfeiture of clinical beneficial effect), and encapsulation can also cause topical remedy to accumulate (in capsule) and extra clinical complication (topical remedy's toxicity for example; Medicine is isolated, and suddenly a large amount of medicines " is dumped " subsequently and goes into surrounding tissue).In addition, the tissue around the implantable pump can inadvertently be subjected to the antixenic infringement of inflammation, causes afunction and/or histologic lesion (for example the scar tissue in the spinal canal produces pain or hinders cerebrospinal fluid and flows).Implant near the infection that implantable drug delivery systems or pump could also introduce or promote that the implant position is.

Discharge one or more therapeutic agents with reduce device-organizational interface (particularly pass the medicine conduit or the parts that make up a prescription in and on every side) go up the synulotic implantable clinical performance that Teat pipette can help to prolong these devices of passing.Suppress fibre modification can guarantee from device, to join the medicine and the possible drug toxicity of correct consumption with suitable speed can be unhidden in fibrous capsule.With regard to the device that comprises electricity or battery component, the function that fibre modification not only can cause device to rise is not good enough or complete failure, and battery life consumes excessively can cause the resistance that applies at the scar tissue that overcomes insertion to increase institute's energy requirement increasing the time.Implant near the infection that implantable drug delivery systems or pump could also introduce or promote that the implant position is.

In fact, any implantable pump all can have benefited from the present invention.In one aspect, pass Teat pipette and can pass medicine with continuous, constant current, slow release mode.For example, passing Teat pipette can be for being suitable for providing the passive pump of the constant current medicine that is subjected to pressure sensation chamber and valve chamber adjusting, and wherein constant flow rate can change over new constant flow rate.For example, referring to United States Patent (USP) 6,589,205.In one aspect of the method, pass Teat pipette and can in the non-constant current or the mode of beating, pass medicine with prescribed dose.For example, pass that Teat pipette can adopt regular pump so that by continuous filled chamber and the relief valve fluid medicine flow that provides the medicine of big pulse to produce to beat then.For example, referring to United States Patent (USP) 6,312,409.In one aspect of the method, pass Teat pipette can follow procedure work so that make up a prescription in very specific mode.For example, pass Teat pipette and can be the infusion liquid pump of program controlled, it is made up of the infusion liquid chamber of variable-volume and the fluid power and the displacement reservoir of variable-volume control, wherein by based on the microprocessor of programming value liquid stream being taken a sample and regulating thus to keep the liquid stream of follow procedure work.For example, referring to United States Patent (USP) 4,443,218.

In one aspect of the method, can be applicable to the Teat pipette (for example driving force) of passing of the present invention based on the different medicine mechanical technique manufacturings of passing.For example, pass the Teat pipette implant that the piston of separating two chambers forms of can serving as reasons, the activating agent of water-swellable is contained in one of them chamber, and another chamber is contained and sent with leuprorelin (Leuprorelin) preparation.For example, referring to United States Patent (USP) 5,728,396.Pass Teat pipette and can be non-cylindric osmotic pump system, it can not rely on piston and infused drug and with dissect implant position fit.For example, referring to United States Patent (USP) 6,464,688.Pass Teat pipette and can be the liquid dispenser of osmotic drive, it is made up of pliability inner pouch that contains pharmaceutical composition and the hole that can send said composition.For example, referring to United States Patent (USP) 3,987,790.Pass Teat pipette and can be the graft of sending of imbibition, it is made up of the chamber of containing the compositions that can penetrate the fluid passage, and has the rigid enclosure of prolongation so that stop temporary transient mechanical force.For example, referring to United States Patent (USP) 5,234,692 and 5,234,693.Passing Teat pipette can be for having isolating reservoir, metering device, substitute reservoir, medicine storage and all being included in the pump in the infusion of drug hole in the storing apparatus.For example, referring to United States Patent (USP) 6,629,954.Passing Teat pipette can make medicine form according to the mobile valve of unidirectional direction by the dispense chamber with dispensing channel with under compression stress.For example, referring to United States Patent (USP) 6,283,949.Can use the variable capacity medicament chamber to regulate pressure reduction and carry out the spring driving passing Teat pipette based on spring.For example, referring to United States Patent (USP) 4,772,263.Other case description of passing Teat pipette is at for example United States Patent (USP) 6,645,176; 6,471,688; 6,283,949; 5,137,727 and 5,112,614.

Can have benefited from that the polymer composition of theme of the present invention is impregnated into the implantable drug delivery systems of adjacent tissue and pump according to the present invention comprises and is purchased product.For example, exist osmotic drive be purchased be suitable for implementing the Teat pipette of passing of the present invention.These osmotic pumps comprise that (they are used to send various medicines and other therapeutic agent of sending by permeating method (for example, referring to United States Patent (USP) 6,283,953 for Mountain View, DUROS implant CA) and ALZET osmotic pumps from AlzaCorporation; 6,270,787; 5,660,847; 5,112,614; 5,030,216 and 4,976,966).

As mentioned above, the polymer composition of theme of the present invention being impregnated into and passing the adjacent tissue of Teat pipette can improve the performance and/or the prevention of described device or suppress near the implant position infection.In one aspect, the invention provides the implantable drug delivery systems and the pump of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with implantable drug delivery systems and pump have above been described.

Can said composition be soaked into around implantable drug delivery systems of implanting and pump by polymer composition directly and/or indirectly being coated with following position or being coated with thereon: (a) with implantable drug delivery systems or the adjacent tissue of pump; (b) near implantable drug delivery systems or the pump-organizational interface; (c) zone around implantable drug delivery systems or the pump; (d) tissue around implantable drug delivery systems or the pump.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with implantable drug delivery systems or pump comprises described polymer composition is delivered to: (a) at implantable drug delivery systems or pump surface (for example as injectable, paste, gel or the mesh) of implant procedure process; (b) before implanting implantable drug delivery systems or pump at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind implantable drug delivery systems or the pump implantable drug delivery systems or pump surface at once and/or implant implantable drug delivery systems or pump around tissue (for example forming gel or mesh) as injectable, paste, gel, original position; (d) by described compositions part being coated with the anatomic space of having placed implantable drug delivery systems or pump (useful especially being to use of this embodiment discharged polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of described therapeutic agent and can pass other preparation into the described activating agent of release in the zone of having inserted described device in the time limit in several hours more than one weeks); (e) by inject implantable drug delivery systems or pump tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand the polymer composition of theme of the present invention can be impregnated into and install all or part of, only comprise device, only pump, only conduit, the make up a prescription tissue of parts and/or its bordering compounding only.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with implantable drug delivery systems or pump is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because implantable drug delivery systems or pump are made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

Should pay close attention to being purchased of above not paying particular attention to pass Teat pipette and of future generation and/or follow-up research and development to pass the medicine product be predictable and be suitable for using in the present invention.

Several concrete Teat pipette and Therapeutic Method passed have hereinafter more specifically been described.

(1) The implantable insulin pump that is used for diabetes

In one aspect, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with insulin pump.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

Insulin pump be used to suffer from the patient of diabetes in case replace by every day the manual injection insulin to the demand of glucose level control.The accurate dropping of dosage and the opportunity that gives insulin are the piths of effective control of diabetes.If insulin dose is too high, blood sugar level will descend suddenly so, causes confusion of consciousness and even may cause loss of consciousness.If insulin dose is low excessively, blood sugar level will excessively raise so, and the metabolism that causes excessive thirst, urinates and be called ketoacidosis changes.If it is incorrect to give the opportunity of insulin, blood sugar level may be in two extreme big ups and downs-a kind of situation that is considered to produce some long-term diabetic complication, such as heart disease, renal failure and blind so.Because in extreme case, all these diseases all may be life-threatening, so accurate dose and opportunity of giving insulin are that prevention short-term and long-term diabetic complication are requisite.

Implantable pump gives insulin automatically and eliminates the dosage and the periodic human error that may have the long-term health consequence.This pump has termly, and repeatedly inject blood flow, peritoneal cavity or hypodermic ability with a minute low dose with insulin every day.Make to this pump by direct implantable pump and to recharge insulin in every month once or twice.This has just reduced the external frequency injection that the patient must carry out and has made the preprogrammed variable insulin to be released into blood flow in different time points; Promptly more approaching simulation Normal Pancreas function also is decreased to bottom line with the fluctuation of blood sugar level.Insulin pump can extract one the patient and bleed the back by the signal enabling of external generation, and it is analyzed and make the decision of the amount of insulin that need send.Yet the most extensive application thereupon of this technology is to produce closed loop " artificial pancreas ", and it can the continuous detecting blood sugar level (by the pick off of implanting) and provide the feedback of implantable pump so that regulate insulin administration to diabetics.

The insulin pump of a large amount of types is applicable to enforcement the present invention.For example, passing Teat pipette can be by by living cells group with regulate the signal of telecommunication that glucose or glucagon or insulin send and forms and comprise implantable sensor and pass Teat pipette.For example, referring to United States Patent (USP) 5,474,552.Passing Teat pipette can be made up of the single channel conduit of the pick off that has implantable intravascular, and described pick off passes to the infusion device of subcutaneous implantation with hematochemistry, makes up a prescription by conduit then.For example, referring to United States Patent (USP) 5,109,850.

Can have benefited from the insulin pump that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised and be purchased product.Be suitable for implementing the insulin pump device that is purchased of the present invention and comprise MiniMed, Inc. (Northridge, MINIMED 2007 implantable insulin pump systems CA) from Medtronic.The MINIMED pump is sent insulin delivery into peritoneal cavity with the short form of bursting and is provided insulin (for example, referring to United States Patent (USP) 6,558,345 and 6,461,331) in the mode similar to Normal Pancreas to health.(Medtronic MiniMedInc., Northridge CA) send the intraperitoneal regular iletin in the mode of beating to MINIMED 2001 implantable insulin pump systems from the negative pressure reservoir.The feature of these two kinds of devices all is long duct, and it is conveyed into peritoneal cavity with the pump that insulin is implanted subcutaneously.As mentioned above, peritoneum passs the medicine catheter lumen or catheter tip can partially or completely be blocked by scar tissue, can cause drug flux to slow down or stop fully.Can also have benefited from discharging the treatment that can prevent or suppress near the infection conduit and/or the implant position such as these insulin pump devices.In one aspect of the invention, described device delivery catheter, they have the polymer composition of the theme of the present invention that comprises anti-scarring agent and/or anti-infective, and said composition is impregnated into and implants maybe will implant the adjacent tissue of described delivery catheter so that keep opening and/or prevent to organize fibre modification and/or inhibition on every side or preventing conduit or near the infection in implant position of delivery catheter chamber.In one aspect of the method, the invention provides the insulin pump of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used for the bound insulin pump have above been described.

Can be by polymer composition directly and/or indirectly being coated with following position or coating is soaked into said composition around the insulin pump of implanting thereon: (a) tissue adjacent with insulin pump; (b) near insulin pump-organizational interface; (c) zone around the insulin pump; (d) tissue around the insulin pump.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with insulin pump comprises described polymer composition is delivered to: (a) on the insulin pump surface of implant procedure process (for example as injectable, paste, gel or mesh); (b) before implantable insulin pump at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) at once insulin pump surface and/or the tissue around the implantable insulin pump (for example forming gel or mesh) behind the implantable insulin pump as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed insulin pump (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) pass through as the tissue around solution, transfusion or the slow releasing preparation percutaneous infusing insulin pump; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand the polymer composition of theme of the present invention can be impregnated into and install all or part of, only comprise device, only pump, only conduit, the make up a prescription tissue of parts and/or its bordering compounding only.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with insulin pump is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because insulin pump is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.-as, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm2; Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

Should pay close attention to being purchased of above not paying particular attention to pass Teat pipette and of future generation and/or follow-up research and development to pass the medicine product be foreseeable and be suitable for using in the present invention.

(2) Pass Teat pipette in the sheath

In one aspect, the polymer composition of theme of the present invention can be impregnated into sheath in pass the adjacent tissue of Teat pipette.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).Have and pass Teat pipette in the sheath of polymer composition of the theme of the present invention that is impregnated into the tissue adjacent and can be used for medicine is sent into spinal cord so that pain management and movement disorder with described pump.

Chronic pain is a most important clinical problem in all medical domains.For example, there are 5 million peoples of surpassing to disable in the U.S. according to estimates because of backache.The Financial cost of chronic back pain is huge, causes annual forfeiture to surpass 100,000,000 working days, and cost is 500-1,000 hundred million dollars according to estimates.Think that the cost of pain of control tumor patient is near 12,000,000,000 dollars.Chronic pain makes the cost that loses the American public of work capacity and consumption more than cancer or cardiopathic people surpass the summation of cancer and heart disease cost.Except that the health consequence, chronic pain has also spent a large amount of other costs, comprising that employment forfeiture, marriage are discorded, depression and prescription medicine drug dependence.Therefore, undoubtedly, reduce sickness rate relevant and cost and remain remarkable challenge medical health system with persistent ache.

The intractable severe pain that causes because of damage, disease, skoliosis, spinal disc degeneration, spinal cord injury, malignant tumor, arachnoiditis, chronic disease, pain syndrome (for example failed back syndrome, complexity regional pain syndrome) and other reason is weak and common difficult medical problem.In many patients, use analgesic continuously, particularly reduce because of drug resistance, effectiveness and the probability of addiction can't become feasible solution as this class medicine of anesthetics.In the effort of resisting this disease, researched and developed the interior drug delivery systems of sheath of treatment severe intractable pain, and this severe intractable pain has tolerated other traditional treatment form, changes such as pharmacotherapy, invasive therapy (operation) or behavior/life style.

Designed and passed Teat pipette in the sheath and use it for by the pain therapy medicine directly being sent and alleviating pain into the cerebrospinal fluid of the intrathecal space around the spinal cord.In general, pain perception is directly passed to the pain receptor that comprises in the spinal cord of brain, so need the medicine of smaller dose just to obtain to alleviate owing to this therapy is delivered to portion of pain therapy officina.Morphine and other anesthetics (being generally fentanyl and sufentanil) are that the most frequently used active agent delivery and many patients use is lower than and can have obtained good mitigation with the dosage that systemic delivery obtains.Pass in the sheath medicine also allow to give can not be by-brain barrier the pain therapy medicine (such as ziconotide; Be the N-type calcium channel blocker that Elan Pharmaceuticals produces) and only effective by this administration the time thus.

Pump also is used to control neurological disorder and movement disorder in the sheath.Baclofen (being sold as baclofen by Novartis) is spasmolytic (the anti-spasmotic)/muscle relaxant that is used for the treatment of spasticity and improves the patient's who suffers from multiple sclerosis, cystic fibrosis and spinal cord injury mobility.Verified this medicine is passed the Teat pipette administration in by sheath more effective and produce less side effect when going into CSF.By giving the effort well afoot of activating agent treatment epilepsy, Alzheimer, parkinson disease and amyotrophic lateral sclerosis (ALS-Lou Gehrig ' s disease) in the sheath, and these activating agents are may toxicity too high and can not maybe can't pass through blood-brain barrier by systemic delivery.For example, the test of the reorganization brain-deutero-neurotrophic factor that in ALS patient, has carried out giving in the sheath (r-BDNF that Amgen produces).

Delivery system is made up of medication infusion pump in the sheath and spinal column inner catheter in the sheath, and both are all implanted fully for they.Described pump installation is implanted subcutaneous abdomen area, just more than the waistline or below, and can recharge by the medicine percutaneous is injected reservoir.With conduit at the subcutaneous intrathecal space of pushing ahead and moving to spinal column from pump.When operation, pump in a continuous manner or the mode that is subjected to clinicist or patient's control with the medicine of recipe quantity give to cerebrospinal fluid as replying to symptom.

Pump is applicable to enforcement the present invention in the implantable sheath of a large amount of types.For example, be used to pass can forming of the implantable pump of medicine by two osmotic pumps, described pump has for sending with different rates and reaches two kinds and pass semipermeable membrane that regimen constructs and the auxiliary delivery system with internal fixation, when main delivery system reached its end in service life or lost efficacy unexpectedly, this delivery system can work on thus.For example, referring to United States Patent (USP) 6,471,688.Implantable pump can be made up of the battery operated pump unit that has medicine storage, conduit and electrode, and the implanted patient's epidural space of described electrode is so that come alleviating pain by through conduit the liquid pain relief agents being delivered to desired location.For example, referring to United States Patent (USP) 5,458,631.

Described and similarly passed Teat pipette, they are used for activating agent is infused into the brain zone so that at treatment various chronic neurogenetic diseases (such as above-mentioned those diseases that are used for sending in the sheath) the neuronic irritability of local influence.Can implant implantable pump through abdominal part, make up a prescription by conduit then, described conduit advances from the abdominal implant position, arrives entry site in the head by neck, and arrives the topical therapeutic position in the brain then.The pump that medicine is delivered to brain can be discharged medicine at diverse location, include, but are not limited to thalamus before, abdomen outside thalamus, internal part of globus pallidus sections, black substance mesh portion, nucleus hypothalamicus, external part of globus pallidus sections and neostriatum.For example, pass Teat pipette and can partly be made up of the implantable pump that is connected with conduit, described conduit is used for drug dose being infused to during to symptom in sensor the precalculated position of brain, can treat neurological disorder (for example epilepsy) thus.For example, referring to United States Patent (USP) 5,978,702.Can will be in implantable pump and the brain predetermined adjacent implantation of infusion site, thus can infusion can change at least a medicine of the predetermined close of brain neuron excitement, make neural degeneration be prevented and/or treated.For example, referring to United States Patent (USP) 5,735,814.Implantable pump can comprise the therapeutic agent reservoir that is stored between experimenter's galea aponeurotica and the cranium, and medicine can be allocated to desired area by pumping action thus.For example, referring to United States Patent (USP) 6,726,678.

Can have benefited from passing in polymer composition with theme of the present invention is impregnated into adjacent tissue according to the present invention the sheath Teat pipette comprises and is purchased product.Exist be purchased in a large number be suitable for implementing delivery system in the implantable sheath of the present invention.SYNCHROMeD EL infusion system is by Medtronic, and Inc. makes and is suitable for the interior baclofen therapy (ITB therapy) of long-term sheath (for example, referring to United States Patent (USP) 6,743,204; 6,669,663; 6,635,048; 6,629,954; 6,626,867; 6,102,678; 5,978,702 and 5,820,589).The SYNCHROMED pump is a kind of battery operated device of program controlled, and it can store and delivering drugs based on the dosage regimen of programming.Medtronic, (Minneapolis MN) has also sold its ISOMED constant current infusion system to Inc., and it is used for morphine sulfate is directly sent the means of intrathecal space as the treatment chronic pain.ArrowInternational has produced Model 3000 infusion pumps, and it provides activating agent, such as the constant current administration to intrathecal space of morphine and baclofen.(Kiel Gernmany) has produced the Archimedes that is used for giving in the sheath pain and spasmolytic (antispasmotic) medicine to Tricumed Medizintechnik GmbH

The implantable infusion pump of constant current.(Plano TX) has produced the AccuRx that is used for the treatment of pain and neuromuscular disorder to Advanced Neuromodulation System

Infusion pump.The feature of all these devices all is long duct, and it will go into intrathecal space in the spinal cord from the active agent delivery of the pump of subcutaneous implantation.As mentioned above, pass medicine catheter lumen or catheter tip in the sheath and can partially or completely be blocked, can cause drug flux to slow down or stop fully by scar tissue.Another kind of because of passing complication that medicine may cause in the sheath for forming fibrous tissue in subdural space, it can block CSF and flow and cause severe complications (for example cerebral edema, intracranial pressure increase).Can also have benefited from discharging the therapeutic agent that can prevent or suppress near the infection conduit and/or the implant position such as drug delivery systems in these sheaths.In one aspect of the invention, described device delivery catheter, they have the polymer composition of the theme of the present invention that comprises anti-scarring agent and/or anti-infective, and said composition is impregnated into and implants maybe will implant the adjacent tissue of described delivery catheter so that keep opening and/or prevent to organize fibre modification and/or inhibition on every side or preventing conduit or near the infection in implant position of delivery catheter chamber.In one aspect of the method, the invention provides the interior drug delivery systems of sheath of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with drug delivery systems in the sheath have above been described.

Can thereon said composition be soaked in the sheath of implanting around the drug delivery systems by polymer composition directly and/or indirectly being coated with following position or coating: (a) with sheath in the adjacent tissue of drug delivery systems; (b) near the interior drug delivery systems-organizational interface of sheath; (c) zone around the drug delivery systems in the sheath; (d) tissue around the drug delivery systems in the sheath.Be used for polymer composition with theme of the present invention be impregnated into sheath in the method for the adjacent tissue of drug delivery systems comprise described polymer composition be delivered to: (a) in the sheath of implant procedure process drug delivery systems surface (for example as injectable, paste, gel or mesh); (b) in implanting sheath before the drug delivery systems at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant in the sheath behind the drug delivery systems at once the sheath drug delivery systems surface and/or implant the tissue around the drug delivery systems in the sheath (for example forming gel or mesh) as injectable, paste, gel, original position; (d) placed the anatomic space of drug delivery systems in the sheath (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in several hours-a few time limits in week and can pass other preparation) by described compositions part is coated with into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject the tissue around the drug delivery systems in the sheath as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand the polymer composition of theme of the present invention can be impregnated into and install all or part of, only comprise device, only pump, only conduit, the make up a prescription tissue of parts and/or its bordering compounding only.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, be impregnated into sheath in the polymer composition of theme of the present invention of the adjacent tissue of drug delivery systems be suitable for discharging one or more activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because drug delivery systems is made of not isostructure and size in the sheath, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

Should pay close attention to the above special interior drug delivery systems commodity of quoting from of sheath that are purchased the interior drug delivery systems of sheath and of future generation and/or follow-up research and development is foreseeable and is suitable for using in the present invention.

(3) The implantable Teat pipette of passing that is used for chemotherapy

In one aspect, the polymer composition of theme of the present invention can be impregnated into chemotherapy and pass the adjacent tissue of Teat pipette.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

Describedly pass the pump that Teat pipette can be used for the treatment of the chemotherapeutic of cancer for allotment.The pump that is used to the treatment cancer to make up a prescription is used for chemotherapeutics is delivered to the body part zone.Although in fact any malignant tumor all can be treated (promptly by medicine directly being infused into the blood vessel of solid tumor or supply tumor) in this manner, present treatment is still carried out around control liver (liver) tumor.For example, FUDR (2 '-deoxidation 5-floxuridine) is used for adenocarcinoma (colon, mammary gland, stomach) the taking stopgap measures property control to being transferred to liver.In the hepatic artery ligation therapy, medicine is sent into the tremulous pulse for the liver blood supply by implantable pump.This make higher drug level arrive liver (medicine is not diluted in blood, but may occur) in intravenous administration and prevented by liver remove (if intravenous administration, so medicine by hepatic metabolism and from blood flow, remove fast); Both of these case all makes the medicine of higher concentration arrive tumor.

The implantable pump of a large amount of types is suitable for sending in the embodiment of this invention chemotherapeutics.For example, implantable pump can have the dispense chamber that has dispensing channel and trigger, hold the reservoir of storage and be used at the dividing plate of filling reservoir.For example, referring to United States Patent (USP) 6,283,949.Medtronic, Inc. have sold its ISOMED constant current infusion system, and it can be used for sending infusion floxuridine in the long-term blood vessel so that treatment constitutional or metastatic carcinoma with fixed flow rate.(Kiel Germany) has sold the implantable infusion pump of its ARCHIMEDES DC to Tricumed MedizintechnikGmbH, and it is suitable for (for example sending chemotherapy with constant flow rate at the tumor near zone specially, referring to United States Patent (USP) 5,908,414 and 5,769,823).Arrow International has produced provides Model 3000 infusion pumps of the chemotherapeutics administration being gone into tumor with constant current.The feature of all these devices all is conduit, and it will directly be conveyed into the tremulous pulse of tumor or supply tumor from the chemotherapeutics of the pump of subcutaneous implantation.As mentioned above, pass medicine catheter lumen or catheter tip and can partially or completely be blocked, can cause drug flux to slow down or stop fully by scar tissue.If place in the intravascular, passing medicine catheter lumen or catheter tip so can influence medicine and flow into blood vessel thus partially or completely by the neointima tissue blockage.Can also have benefited from discharging the therapeutic agent that can prevent or suppress near the infection conduit and/or the implant position such as these chemotherapeutic drug delivery systems.In one aspect of the invention, described device delivery catheter, they have the polymer composition of the theme of the present invention that comprises anti-scarring agent and/or anti-infective, and said composition is impregnated into and implants maybe will implant the adjacent tissue of described delivery catheter so that keep opening and/or prevent to organize fibre modification and/or inhibition on every side or preventing conduit or near the infection in implant position of delivery catheter chamber.In one aspect of the method, the chemotherapy that the invention provides the polymer composition with the theme of the present invention that is impregnated into adjacent tissue is passed Teat pipette, and wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with drug delivery systems in the sheath have above been described.

Can said composition be soaked into around the chemotherapy of implanting is passed Teat pipette by polymer composition directly and/or indirectly being coated with following position or being coated with thereon: (a) pass the adjacent tissue of Teat pipette with chemotherapy; (b) chemotherapy is passed near Teat pipette-organizational interface; (c) chemotherapy is passed Teat pipette zone on every side; (d) chemotherapy is passed Teat pipette tissue on every side.Being used for polymer composition with theme of the present invention is impregnated into the method for passing the adjacent tissue of Teat pipette with chemotherapy and comprises described polymer composition is delivered to: (a) pass Teat pipette surface (for example as injectable, paste, gel or mesh) in the chemotherapy of implant procedure process; (b) before implanting chemotherapy to pass Teat pipette at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implanting chemotherapy passs behind the Teat pipette at once chemotherapy and passs the Teat pipette surface and/or implant chemotherapy and pass tissue (for example forming gel or mesh as injectable, paste, gel, original position) around the Teat pipette; (d) by described compositions part being coated with into having placed the anatomic space that chemotherapy passs Teat pipette (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in several hours-a few time limits in week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) pass Teat pipette tissue on every side by inject chemotherapy as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand the polymer composition of theme of the present invention can be impregnated into and install all or part of, only comprise device, only pump, only conduit, the make up a prescription tissue of parts and/or its bordering compounding only.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, be impregnated into the polymer composition of passing the theme of the present invention of the adjacent tissue of Teat pipette with chemotherapy and be suitable for discharging one or more activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.The definite dosage that gives because passing Teat pipette, chemotherapy constitutes, so can also change with the different of size, surface area and design of device by not isostructure and size.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/m ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

Should pay close attention to above the chemotherapy that is purchased of special citation passs the chemotherapy of Teat pipette and of future generation and/or follow-up research and development to pass the Teat pipette commodity is foreseeable and be suitable for using in the present invention.

(4) Be used for the treatment of the cardiopathic Teat pipette of passing

In one aspect, the polymer composition of theme of the present invention can be impregnated into and pass the adjacent tissue of Teat pipette.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

Describedly pass the pump that Teat pipette can be used for the treatment of cardiopathic medicine for allotment.Be used to allocate the pump for the treatment of cardiopathic medicine and can be used for the treatment of following disease: include, but are not limited to atrial fibrillation and other rhythm of the heart disease.Atrial fibrillation is infringement millions of people's heart disease form.It is a kind of like this disease, and its cardiac is coordinated normally to shrink and is damaged, and mainly is the atrial abnormality and the uncontrolled activity of heart.In general, contraction takes place with controlled sequence with the contraction of other chamber of heart.When right atrium can't shrink, contraction will disengaging order or shrink invalidly, blood flow to ventricle from the atrium process is damaged.Atrial fibrillation can cause weakness, rapid breathing, angina pectoris, dizziness and other reduces because of ventricular filling and cardiac output reduces the symptom that causes.Apoplexy can be used as grumeleuse and forms in the atrium of shrinking difference, interrupts relaxing and being sent to cerebral arteries by blood flow, and it becomes wedging thing and block blood flow (may cause cerebral lesion and death) in this process.In general, by medical science or electrical conversion (defibrillation) treatment atrial fibrillation, yet, may there be complication, wherein said therapy can cause significant pain or have the probability that causes life-threatening ventricular arrhythmia.The pain relevant with electroshock is serious and unacceptable for many patients, and this is because when described device is sent electrotherapy, and they consciously and vigilance.Medical therapy comprises by intravenous injection, sends anti-arrhythmic by oral administration or by the Teat pipette local delivery.

Described and be used for the treatment of heart disease and be applicable to the implantable pump of implementing a large amount of types of the present invention.For example, pass Teat pipette and can be the implantable cardiac electrode, it transmits stimulation energy and is making up a prescription with the stimulation location adjacent.For example, referring to United States Patent (USP) 5,496,360.Pass Teat pipette and can have a plurality of siloxanes dividing plates so that help filling medicine storage in the pump that conduit is implanted subcutaneously, described conduit was carried superior vena cava and was entered right atrium so that pass medicine through vein by subclavian vein.For example, referring to United States Patent (USP) 6,296,630.As mentioned above, pass medicine catheter lumen or catheter tip and can partially or completely be blocked, can cause drug flux to slow down or stop fully by scar tissue.If place in the intravascular, passing medicine catheter lumen or catheter tip so can influence medicine and flow into blood vessel or right atrium thus partially or completely by the neointima tissue blockage.Can also have benefited from discharging the therapeutic agent that can prevent or suppress near the infection conduit and/or the implant position such as these drug delivery systems.In one aspect of the invention, described device delivery catheter, they have the polymer composition of the theme of the present invention that comprises anti-scarring agent and/or anti-infective, and said composition is impregnated into and implants maybe will implant the adjacent tissue of described delivery catheter so that keep opening and/or prevent to organize fibre modification and/or inhibition on every side or preventing conduit or near the infection in implant position of delivery catheter chamber.In one aspect of the method, the invention provides the cardiopathic Teat pipette of passing that is used for the treatment of of polymer composition with the theme of the present invention that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).Above described and be used for cardiopathic number of polymers and the non-polymer delivery system of passing Teat pipette of combined treatment.

Can thereon said composition be soaked into passing around the Teat pipette of implanting by polymer composition directly and/or indirectly being coated with following position or coating: (a) be used for the treatment of the cardiopathic adjacent tissue of Teat pipette of passing; (b) be used for the treatment of near cardiopathic passing Teat pipette-organizational interface; (c) be used for the treatment of the cardiopathic Teat pipette zone on every side of passing; (d) be used for the treatment of the cardiopathic Teat pipette tissue on every side of passing.Being used for polymer composition with theme of the present invention is impregnated into and is used for the treatment of cardiopathic method of passing the adjacent tissue of Teat pipette and comprises described polymer composition is delivered to: (a) on the cardiopathic Teat pipette surface (for example as injectable, paste, gel or mesh) of passing of being used for the treatment of of implant procedure process; (b) implantation be used for the treatment of cardiopathic pass Teat pipette before at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant be used for the treatment of cardiopathic pass behind the Teat pipette at once be used for the treatment of cardiopathic pass the Teat pipette surface and/or implant be used for the treatment of the cardiopathic tissue of passing around the Teat pipette (for example forming gel or mesh) as injectable, paste, gel, original position; (d) be used for the treatment of the cardiopathic anatomic space of passing Teat pipette (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in several hours-a few time limits in week and can pass other preparation) by described compositions part being coated with into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially into having placed; (e) be used for the treatment of the cardiopathic Teat pipette tissue on every side of passing by injecting as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand the polymer composition of theme of the present invention can be impregnated into and install all or part of, only comprise device, only pump, only conduit, the make up a prescription tissue of parts and/or its bordering compounding only.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, be impregnated into and one or more the activating agent that is used for the treatment of in four kinds of ordinary circumstances that the cardiopathic polymer composition of passing the theme of the present invention of the adjacent tissue of Teat pipette is suitable for discharge suppressing fibre modification (or cicatrization) process, comprise: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.The definite dosage that gives constitutes by not isostructure and size because be used for the treatment of the cardiopathic Teat pipette of passing, so can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000 mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

Should pay close attention to above the heart that is purchased of special citation passs the heart of Teat pipette and of future generation and/or follow-up research and development to pass the medicine product is foreseeable and be suitable for using in the present invention.

(5) Other passs the medicine implant

In one aspect, the polymer composition of theme of the present invention can be impregnated into and the adjacent tissue of implantable pump that is used for continuous delivery of pharmaceutically active agents.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

Several other implantable pumps of being used for continuous delivery of pharmaceutically active agents useful among the present invention been have have been researched and developed.For example Debiotech S.A. (Switzerland) has has researched and developed the MIP device, and it is a kind of silicon Micropump that is used for the implantable pressure-startup of passing the medicine application of program controlled.This high performance Micropump is based on making it keep MEMS (little-electro-mechanical) system of low flow velocity.(Cupertino, DUROS sufentanil implant CA) is a kind of titanium cylinder of the piston that contains medicine storage and driven by osmotic engine from DurectCorporation.Available from Alza Corporation (MountainView, CA) VIADUR (leuprorelin acetate) implant uses identical DUROS implant technology to send leuprorelin with the reduction testosterone levels in 12 months time limits, thereby the treatment carcinoma of prostate is (for example, referring to United States Patent (USP) 6,283,953; 6,270,787; 5,660,847; 5,112,614; 5,030,216 and 4,976,966).The fiber kystis of device can cause losing efficacy in many ways, comprising: block semipermeable membrane (flowing into the function that osmotic engine influences this machine by preventing fluid); Block outlet (influencing the medicine bleeder); And/or complete encapsulation (producing the microenvironment that stops drug distribution).Many other passed medicine implant, osmotic pumps etc. and existed similar problem-fiber kystis to stop drug release to go into surrounding tissue.Can also have benefited from discharging the therapeutic agent that can prevent or suppress near the infection conduit and/or the implant position such as these drug delivery systems.In one aspect of the invention, drug delivery systems has the polymer composition of the theme of the present invention that comprises anti-scarring agent and/or anti-infective, said composition be impregnated into and implant maybe will implant the adjacent tissue of described device in case prevent or suppress encapsulation, prevent semipermeable membrane block, keep the delivery catheter chamber opening, prevent to organize near the infection fibre modification on every side and/or inhibition or prevention conduit or the implant position.In one aspect of the method, the invention provides the implantable pump that is used for continuous delivery of pharmaceutically active agents of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with the implantable pump of continuous delivery of pharmaceutically active agents have above been described.

Can said composition be soaked into around the implantable pump of implanting that is used for continuous delivery of pharmaceutically active agents by polymer composition directly and/or indirectly being coated with following position or being coated with thereon: (a) with the adjacent tissue of implantable pump that is used for continuous delivery of pharmaceutically active agents; (b) be used near the implantable pump-organizational interface of continuous delivery of pharmaceutically active agents; (c) be used for zone around the implantable pump of continuous delivery of pharmaceutically active agents; (d) be used for continuous delivery of pharmaceutically active agents implantable pump pass tissue around the Teat pipette.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with the implantable pump that is used for continuous delivery of pharmaceutically active agents comprises described polymer composition is delivered to: the implantable pump surface (for example as injectable, paste, gel or mesh) that (a) is used for continuous delivery of pharmaceutically active agents; (b) before implantation is used for the implantable pump of continuous delivery of pharmaceutically active agents at once or the tissue surface of process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the implantable pump be used for continuous delivery of pharmaceutically active agents the implantable pump surface that is used for continuous delivery of pharmaceutically active agents at once and/or implant tissue (for example forming gel or mesh) around the implantable pump that is used for continuous delivery of pharmaceutically active agents as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed the implantable pump that is used for continuous delivery of pharmaceutically active agents (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject the implantable pump tissue on every side that is used for continuous delivery of pharmaceutically active agents as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand the polymer composition of theme of the present invention can be impregnated into and install all or part of, only comprise device, only pump, only conduit, the make up a prescription tissue of parts and/or its bordering compounding only.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with being used for the implantable pump of continuous delivery of pharmaceutically active agents is suitable for discharging one or more activating agent of four kinds of ordinary circumstances suppressing fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.The definite dosage that gives constitutes by not isostructure and size because be used for the implantable pump of continuous delivery of pharmaceutically active agents, so can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm2-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

Although above described a large amount of implantable pumps, the unwanted fibrous tissue after they all have similar design feature and produce similar implantation is reacted, and can introduce or promote the infection in the implant band of position.Should pay close attention to the above not special implantable pump product of quoting from that is purchased sensor device and of future generation and/or follow-up research and development and be foreseeable and be suitable for using in the present invention that this to those skilled in the art should be apparent.The clinical function of implantable drug delivery systems or pump depends on device, and particularly the conduit or the parts that make up a prescription can effectively be kept and contact with the direct dissection of target tissue (for example cavum subdurale in the spinal cord (sudural space), lumen of artery, peritoneum, interstitial fluid) and not by scar tissue encapsulation or obstruction.With regard to implantable pump, pass medicine catheter lumen, catheter tip, the parts or send film and may be blocked of making up a prescription by scar tissue, cause drug flux to slow down or stop fully.Perhaps, complete pump, conduit and/or the parts that make up a prescription can be by cicatrix encapsulation (promptly installing by fibrous tissue " isolation " on matrix), make medicine be delivered to target tissue (being that cicatrix has stoped normal medicine motion and has been distributed to tissue on the capsule opposite side from implantable pump) by halves.The medicine that the generation of these situations all can cause flowing to required target tissue or organ invalid or incomplete (and the forfeiture of clinical beneficial effect), and encapsulation can also cause topical remedy to accumulate (in capsule) and extra clinical complication (topical remedy's toxicity for example; Medicine is isolated, and suddenly a large amount of medicines " is dumped " subsequently and goes into surrounding tissue).With regard to the device that comprises electricity or battery component, the function that fibre modification not only can cause device to rise is not good enough or complete failure, and battery life consumes excessively can cause the resistance that applies at the scar tissue that overcomes insertion to increase institute's energy requirement increasing the time.Implant near the infection that implantable drug delivery systems or pump could also introduce or promote that the implant position is.Synulotic implantable pump can be used to increase effect in device-organizational interface to reduce to discharge therapeutic agent, prolong clinical performance, guarantee medicine, and reduce the risk of the hidden drug toxicity in fibrous capsule of possibility with suitable speed correct consumption of allotment from device.The implantable sensor device can also have benefited from discharging the therapeutic agent that can prevent or suppress near the infection in implant position.In one aspect, the invention provides the implantable pump of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention comprises therapeutic agent (for example anti-scarring agent and/or anti-infective).These compositionss may further include one or more fibre modification inhibitor, make granulation, fiber or neointima tissue growth excessively be inhibited or reduce; And/or these compositionss may further include one or more anti-infectives, near the infection inhibition or the prevention implant position thus.

Soft tissue implant

In one aspect, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with soft tissue implant.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

The soft tissue implant that has a large amount of types, wherein the generation of fibre modification reaction produces harmful effect to the function or the outward appearance of the tissue around implant or the implant.In general, the fibre modification encapsulation of soft tissue implant (or the fibrous tissue growth between implant and the surrounding tissue) can cause fibroid contracture and other may cause the problem of the not good enough and patient's discomfort (comfort) of outward appearance.Therefore, the invention provides soft tissue implant with the polymer composition that comprises anti-scarring agent and/or anti-infective theme of the present invention that is impregnated into adjacent tissue, form so that suppress scar tissue, thereby the encapsulation of soft tissue implant (with relevant fibroid contracture) is reduced to bottom line or prevents its generation and/or inhibition or near the infection in prevention implant position.

Soft tissue implant is used for various beauty treatments, shaping and reconstruction operations operation and may be delivered into many different pieces of health, includes, but are not limited to face, nose, breast, chin, buttocks, breast, lip and cheek.Soft tissue implant is used to perform the operation or the space of organizing of wound generation rebuilds, and enhanced tissue or organ carry out the profile reparation, the integral body of aging tissue is recovered and correction soft tissue folds in a garment or wrinkling (wrinkle) tissue.Soft tissue implant can be used for enhanced tissue so that beauty treatment (aesthetics) is strengthened or relevant with plastic surgery behind disease or the excision.Can have benefited from polymer composition with theme of the present invention is impregnated into the soft tissue implant of adjacent tissue according to the present invention representational example comprises: for example implant and buttocks implant under saline breast implant, siloxanes breast implant, triglyceride breast implant, chin and lower jaw implant, nasal implants, cheek implant, lip implant and other face's implant, breast shield and breast implant, cheekbone and the cheekbone of filling.

Soft tissue implant has a large amount of structures and can be formed by various materials, such as so that anatomical structure and the feature around adapting to.In one aspect, be applicable to soft tissue implant of the present invention, such as siloxanes, poly-(tetrafluoroethene), polyethylene, polyurethane, polymethyl methacrylate, polyester, polyamide and polypropylene by polymer formation.Soft tissue implant can be for having filled the hull shape formula (or peplos) of implanting this class flowing material of saline.

In one aspect, soft tissue implant comprises or siloxanes or dimethyl siloxane or formed by them.The siloxanes implant can be solid, and remains pliability and very durable and stable.With different durometers they are made (hardness) soft or very hard, determine by extent of polymerization.Short polymer chain produces the lower liquid silicon of viscosity, and makes chain lengthening produce gel-like substance, and the dosage of polymer chain produces high-viscosity silicone rubber.Siloxanes can also be mixed into granule with water and hydrogel carrier so that fibrous tissue is inwardly given birth to.Designing these implants is in order to increase the soft tissue area under the non-bone structure.In certain aspects, can will fix with following bone based on the implant (for example chin implant) of siloxanes with one or more titanium screws.The siloxanes implant can be used for the tissue of diverse location in the intensive aspect, comprising: for example breast, nose, chin, cheekbone (for example cheek) and breast/breast shield zone.Have low viscous silicone gel and be mainly used in the filling breast implant, and full-bodied siloxanes is used for tissue expander and saline is filled and the shell of the breast implant that siloxanes is filled.For example, (Santa Barbara, CA) (Santa Barbara CA) has made breast implant to Inamed Corporation with Mentor Corporation.

In one aspect of the method, soft tissue implant comprises that poly-(tetrafluoroethene) (PTFE) or by it forms.In certain aspects, poly-(tetrafluoroethene) is expandable politef (ePTFE).The PTFE that is used for soft tissue implant can be formed by the expandable polymer of solid PTFE joint, and it has the thin PTFE fibril of the interconnection that forms grid pattern, produces the biocompatible materials of softish durability.Sheet and solid block that the soft tissue implant of being made by PTFE is generally used for being easy to the carve and paint profile and is superimposed as desired thickness.These implants are porous and can be integrated into tissue on every side that this helps to keep the suitable anatomical position of implant.The PTFE implant generally is not hard as the siloxanes implant.In addition, opposite with the siloxanes implant, the bone resorption degree below the ePTFE implant is lower.The soft tissue implant of being made up of PTFE can be used for increasing the tissue of (augmentation) health diverse location, comprising: for example face, breast, lip, nose and chin and lower jaw and cheekbone district and be used for the treatment of muffle and the glabella folds in a garment.GORE-TEX (W.L.Gore ﹠amp for example; Associates, Inc., Newark DE) is a kind of inflatable synthetic PTFE that can be used to form the face's implant that increases purpose.

In one aspect of the method, soft tissue implant comprises polyethylene or is formed by it.The polyethylene implant is generally used for, and for example chin is strengthened.The polyethylene implant can make them can be integrated into surrounding tissue for porous, and this provides alternative for use is used for stable titanium screw.Polyethylene implant be can utilize, chemical resistance, hot strength and hardness comprised with different biochemical characteristics.The polyethylene implant can be used for face rebuilds, and comprises cheekbone, chin, nose and cranial implants.For example (Newnan GA) has made MEDPOR to Porex Surgical Products Group, and it is a kind of highdensity porous polyethylene implant that face rebuilds that is used for.Porous makes blood vessel and soft tissue inwardly grow so that introduce implant.

In one aspect of the method, soft tissue implant comprises polypropylene or is formed by it.The polypropylene implant is the high density polymer that has with the loose weave of polyethylene similar characteristic.These implants have good tensile and can be used as braiding mesh utilization, such as PROLENE (Ethicon, Inc., Sommerville, NJ) or MARLEX (C.R.Bard, Inc., Billerica, MA).For example, can be with the polypropylene implant as the breast implant.

In one aspect of the method, soft tissue implant comprises polyamide or is formed by it.Polyamide is a nylon compound, and it is woven into mesh, and it can implantedly be used for, and face rebuilds and increase.These implants are easy to be shaped and sew up and take place in a period of time and absorb.SUPRAMID and SUPRAMESH (Minneapolis MN) is the product based on nylon that is used to strengthen for S.Jackson, Inc., yet, because of its absorption characteristic again, so their application is restricted.

In one aspect of the method, soft tissue implant comprises polyester or is formed by it.The biological polyesters that can not degrade, such as MERSILENE Mesh (Ethicon, Inc.) and DACRON (available from Invista, Wichita KS) can be suitable for as the implant that requires hot strength and stable application, such as the reinforcement of breast, chin and nose.

In one aspect of the method, soft tissue implant comprises polymethyl methacrylate or is formed by it.Although these implants have porous widely, they have high molecular and have comprcssive strength and rigidity.Methyl methacrylate, (Norwalk, the sclerous tissues that CT) makes displacement (HTR) polymer can be used for chin and cheekbone increases and skull lower jaw surface of bone (craniomaxillofacial) is rebuild such as U.S.SurgicalCorporation.

In one aspect of the method, soft tissue implant comprises polyurethane or is formed by it.Polyurethane can be as the foam that covers breast implant.This polymer promotes tissue ingrowth, causes occurring in breast implant low capsule contracture rate.

Can have benefited from the polymer composition of theme of the present invention is comprised according to the example that is purchased the polymer soft tissue implant that the present invention is impregnated into adjacent tissue: from Surgiform Technology, Ltd. (Columbia Station, OH); ImplantTech Associates (Ventura, CA); Inamed Corporation (Santa Barbara, CA; Referring to M766A Spectrum Catalog); Mentor Corporation (Santa Barbara, CA); With Allied Biomedical (Ventura, siloxanes implant CA).The breast implant that saline is filled is made by Inamed and Mentor and can be had benefited from implanting with the combination of fibre modification inhibitor.Poly-(tetrafluoroethene) soft tissue implant that is purchased that is suitable for being used in combination with the fibre modification inhibitor comprises the ﹠amp from W.L.Gore; Associates, Inc. (Newark, DE) poly-(tetrafluoroethene) cheek, chin and nasal implants.Can have benefited from the polymer composition of theme of the present invention is comprised the (Fairburu from Porex Surgical Inc. according to the polyethylene soft anatomic implants that is purchased that the present invention is impregnated into adjacent tissue, GA), the polyethylene implant of commodity MEDPOR biomaterial by name.The MEDPOR biomaterial is made up of the high density porous polyethylene material of the omnidirectional's grid with interconnected pores, and this makes it can be integrated into host tissue.

When implantation, excessively the scar tissue growth can be in all or part of the occurring of implant on every side, and this can cause the performance decline (as mentioned above) of these devices.Soft tissue implant with polymer composition of theme of the present invention can be used to strengthen outward appearance, increase the life-span, reduce demand to orthopaedic surgery or repeat surgery operation, reduce the incidence rate of pain and other symptom and improve the clinical function of implant.Soft tissue implant can also have benefited from discharging near the therapeutic agent that infects prevention or a kind of implant position.Therefore, in one aspect, the invention provides the soft tissue implant of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with soft tissue implant have above been described.

Can be by polymer composition directly and/or indirectly being coated with following position or coating is soaked into said composition around the soft tissue implant of implanting thereon: (a) tissue adjacent with soft tissue implant; (b) near soft tissue implant-organizational interface; (c) zone around the soft tissue implant; (d) soft tissue implant passs tissue around the Teat pipette.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with soft tissue implant comprises described polymer composition is delivered to: (a) soft tissue implant surface (for example as injectable, paste, gel or mesh); (b) before implanting soft tissue implant at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the soft tissue implant soft tissue implant surface at once and/or implant tissue (for example forming gel or mesh) around the soft tissue implant as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed soft tissue implant (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject soft tissue implant tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with soft tissue implant is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because soft tissue implant is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

For the purpose of clearer, several concrete soft tissue implants and Therapeutic Method have been described more specifically hereinafter.

(1) Breast implant

In one aspect, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with breast implant.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

Be used for postmastectomy increase or the breast implant of breast reconstruction to place be one of the most normal cosmetic surgery operation of carrying out.For example, only in 2002, just there are 300,000 women of surpassing to accept the breast implant operation.In these women, about 80,000 people have accepted the postmastectomy breast reconstruction that causes because of cancer.Because incidence of breast cancer and present cosmetic surgery trend, the quantity of breast implant operation increases probably.

In general, breast increases or reconstruction operations comprises the breast implant of being made up of the capsule that is full of saline or siloxanes that is purchased is put into submammary tissue.Implant four kinds of different cutting parts being used for breast traditionally: under anterior axillary line (axillary fossa), mammary areola week (around the nipple downside), the breast (breast bases, wherein its supports thoracic wall) and cross umbilicus (around the umbilicus).Usually cut open from tissue (be used in particular for the anterior axillary line and cross the umbilicus operation, wherein need the passage from the cutting part to the breast) by little otch by means of endoscope.Under gland or the breast inferior segment produce the bag be used to place breast implant.With regard to implant under the gland, cut open from tissue so that between glandular tissue and pectoralis major, produce the space that extends downward breast underfold trace.With regard to implant under the breast, careful cuing open from pectoralis major to produce space and the shallow surface of rib frame under the pectoralis major.Must carefully stop blooding (because it can cause complication, such as the capsule contracture), if hemorrhage control is not enough, so so many hemorrhage will making must change into the invasive operation of minimum level (anterior axillary line, cross the umbilicus pathway) more open operation technique (around areola).According to the difference of the surgical approach type of selecting, breast implant is gone up reduced and rolled-up so that place it in patient's body usually.After realizing accurately the location, fill implant or make before be inflated into required size.

Although many patients are satisfied to initial operation technique, significantly complication takes place in the patient of percentage ratio, and these complication need intervention repeatedly to proofread and correct usually.The pseudomamma encapsulation that produces Periprosthetic shell (being called the capsule contracture) is the complication after the breast of the most common report increases, and the patient up to 50% reports dissatisfied.Calcification can occur in fibrous capsule, and it can add in the hardness of fibrous capsule and make the interpretation of mammogram complicated.Identified a plurality of reasons of capsule contracture, having comprised: the surface character that foreign body reaction, silicone gel molecule move and enter tissue, autoimmune disease, heredodiathesis, infection, hematoma and prosthese by capsule.Although do not identified the specificity etiology as yet repeatedly on cellular level, the unusual fibroblast activity that foreign body stimulates is a conforming discovery.The Periprosthetic lens capsule tissue contains macrophage and accidental T-and the B-lymphocyte of containing, thereby prompting reaches the inflammatory component of this process.Carried out level and smooth and veined trial so that reduce encapsulation at implant surface, yet, do not confirm that the two all can produce good results consistently.The animal model prompting exists capsule thickness to increase and promotes the surperficial tendency that goes up the surperficial contracture of the ingrown band texture of fibrous tissue (textured) to increase.In the chest muscle upper/lower positions, place implant and seem to reduce encapsulation the rate level and smooth and implant of being with texture.

From patient's point of view, above-mentioned bioprocess causes the disease of a series of common descriptions.The complication that implant dislocation, hard and disadvantageous shape are the most common placement implants and modal be owing to the capsule contracture.When cicatrix capsule on every side began hardening and shrinks, it produced uncomfortable, and the shell fragility is asymmetric, skin depressions and dislocation.It is about 10% that definite capsule contracture takes place in increasing the patient of postoperative, and account for 25%-30% in rebuilding case, and wherein most of patient's report is dissatisfied to cosmetic result.Cause asymmetric cicatrization to account for increasing art 10% and account for 30% of Reconstruction, and be the main cause of corrective procedure.Skin wrinkling (because of skin being pulled down to the contracture of implant) is the complication of 10%-20% patient report.When fibrous tissue inwardly growth go into diaphram flap valve (implant that is used to expand goes out the implantation site) it had no control over oneself and during seepage, cicatrization even relate to implant (the deflation) (patient of 1-6% of collapsing; Saline leaks out also " flat fall " from implant).In addition, the patient who surpasses 15% enforcement heighten operation exists the many scar tissues that finally are attributable in chronic pain and these cases to form.Other complication of breast heighten operation comprises that later stage seepage, hematoma (patient of about 1-6%), seroma (2.5%), hypertrophic cicatrix form (2-5%) and infect (case of about 1-4%).

The tangible implant infection (taking place in the case of about 1-4%) that breast implant pollutes and other reason causes during because of the pollution saline in the implant, operation implantation forces removes implant.Anti-infective is released into the capsule contracture formation that the tissue around the implant can reduce the incidence rate of breast implant infection and help prevention infection to bring out.

Correction can comprise several selections, comprises removing implant, cystitomy (downcut or operation discharges capsule), vesiculectomy (surgical removal fibrous capsule) or implant being put into diverse location (promptly under the gland under chest muscle).Finally, need extra operation (modification, cystitomy, excision, reimplantation) surpassing 20% heighten operation patient and surpass among 40% the Reconstruction patient, because cicatrization and capsule contracture and modal reason apart from each other.The operation that destroys cicatrix may be also insufficient, and the Reconstruction of about 8% heighten operation and 25% finally requires operation to remove implant.The polymer composition that will comprise the theme of the present invention of anti-scarring agent and/or anti-infective is impregnated into and implants maybe will be implanted the adjacent tissue in breast implant place and fibrous tissue formation, encapsulation, capsule contracture can be reduced to bottom line and/or inhibition or prevent near the described implant position infection.For example, carried out attempting from breast implant, giving steroidal or it being impregnated into the breast bag of expectation, but this method causes soft tissue atrophy and distortion.Ideal fibre modification inhibitor only can the targeting fibrous capsule composition and can not endanger around soft tissue.With the polymer composition of theme of the present invention be impregnated into the tissue adjacent with the breast implant position can with to chest muscle down or the fibroid contracture of the gland reaction that contains gel or brinish breast implant of placing down be reduced to bottom line or prevent this from occurring.The polymer composition of theme of the present invention is impregnated into and implants maybe will implant the adjacent tissue in described implant place, comprise that tissue around breast implant or the operation bag can prevent that breast from increasing cicatrization among art and the plastic surgery and capsule contracture and inhibition or preventing near the described implant position infection.

A large amount of breast implants are applicable to be implemented the present invention and can be used for beauty treatment and the reconstruction purpose.Breast implant can be by being full of fluid, and such as saline solution, the pliability soft shell of polysiloxanes or silicone gel is formed.For example, breast implant can be made up of the outer polymer shell, and described shell has and is full of a plurality of ducted bodies that contain the elastic deformable material of liquid salt aqueous solution.For example, referring to United States Patent (USP) 6,099,565.Breast implant can be made up of the adventitia of sulfuration silicone rubber, and described sulfuration silicone rubber adventitia forms the waterproof shell of the hollow sealing that contains the Polyethylene Glycol aqueous solution.For example, referring to United States Patent (USP) 6,312,466.Breast implant can be made up of the adventitia that the packing material of flexible nonabsorbable material and catalytic hydrogenation (shorting) compositions (for example vegetable oil) is made.For example, referring to United States Patent (USP) 6,156,066.Breast implant can be formed by softish pliability adventitia with by the deformable elastic filling material of the part of compartment interior structural support.For example, referring to United States Patent (USP) 5,961,552.Breast implant can be made up of the conical shell that the biology that is full of the monofilament layer that forms the resiliency compressible fabric can not be degraded.For example, referring to United States Patent (USP) 6,432,138.Breast implant can be made up of the shell that contains the aseptic continuous implant material that continuous polyolefin or polypropylene yarn make.For example, referring to United States Patent (USP) 6,544,287.Breast implant can be made up of the adventitia that contains the keratin hydrogel.For example, referring to United States Patent (USP) 6,371,984.Breast implant can be made up of the collapsible shell of hollow that the resilient material of pliability forms, and it has the base part with indeformable element of elasticity and the bonding implant material reinforcement that wherein comprises.For example, referring to United States Patent (USP) 5,104,409.Breast implant can be made up of level and smooth imporosity polymer peplos, and it has the non-woven porous outer layer that adheres to that the drawing of fiber of Merlon urethane polymer is made, and wherein includes implant material still.For example, referring to United States Patent (USP) 5,376,117.Can implant second kind of prosthese structure breast implant implanting between chest muscle and the breast tissue by operation under chest muscle.For example, referring to United States Patent (USP) 6,464,726.Breast implant can and have the interconnected cell that forms at random prevents the capsule contracture with the promotion tissue ingrowth open grain surface composition by the pliable and tough shell of even silicone elastomer of the unit structure with inside stuffing.For example, referring to United States Patent (USP) 5,674,285.Breast implant can be for having the tectal plastic implant of heparin, and described heparin cover layer and surface combination are so that the every capsule of prevention or the dry tissue cavity of treatment blood forms and/or shrinkage.For example, referring to United States Patent (USP) 4,713,073.Breast implant can be the elastomeric polymer adventitia of sealing, it have filled viscoelastic material (for example chondroitin sulfate) multi-cellular structure so that predetermined shape is provided.For example, referring to United States Patent (USP) 5,344,451.

Can have benefited from having breast implant into the polymer composition of the theme of the present invention of adjacent tissue according to the present invention comprises and is purchased product.Be purchased INAMED Corporation (Santa Barbara, those products CA) that breast implant comprises coming breast implant self-sales saline-filling and siloxanes-filling.The breast implant of saline-filling of INAMED comprises 68 type saline substrate and 363LF type and other various models, profile, shape and size product.The breast implant of siloxanes-filling of INAMED comprises 10 types, 20 types and 40 types and other various models, profile, shape and size product.INAMeD has also sold the breast tissue dilator, and such as INAMED133V type series tissue expander, they are used to promote quick tissue adhesion so that the stationarity of dilator is increased to greatest extent.(Santa Barbara CA) has sold the Contour Profile Style breast implant (obtaining with various models, profile, shape and size) of saline-filling and allowing by using simple chamber operation postoperative to add in 6 months or removing the adjustable breast implant of SPECTRUM postoperative that saline is regulated udder size to Mentor Corporation.Mentor has also produced the Contour Profile of various models, profile, shape and size

Gel (siloxanes) breast implant.Can have benefited from discharging such as these breast implants and can reduce synulotic therapeutic agent in implant-organizational interface so that the incidence rate of fibroid contracture is reduced to bottom line.Also have benefited from discharging the therapeutic agent that can prevent or suppress near the infection the described implant position such as these breast implants.

As mentioned above, implant dislocation (implant moves after placement or migration) can produce various complication, such as the main cause that moves and be the dissatisfied and corrective procedure of patient asymmetric and below breast underfold trace.In one embodiment, give lower surface (promptly in the face of the surface of the chest muscle of breast implant under the gland or in the face of the surface of the thoracic wall of breast implant under the chest muscle) the fibrotic activating agent of coating promotion of breast implant or compositions and suppress fibrotic activating agent or compositions for another side (promptly in the face of the surface of the breast tissue of breast implant under the gland or in the face of the surface of the chest muscle of breast implant under the chest muscle) coating.Can be directly or the polymer composition of the theme of the present invention by will containing required activating agent be impregnated into the tissue adjacent or its and make up arbitrarily and carry out this class coating with required surface.This embodiment has and promotes fibre modification and make breast implant be fixed into anatomical position that it places (promptly, the gland that breast implant is fixed into prevent the implant migration is the space down or under the chest muscle), can prevent the advantage of the complication relevant simultaneously with fiber kystis on the shallow surface of breast implant.The representational example that promotes fibre modification and be suitable for the activating agent that send on (deeply) surface under breast implant comprises silk, fine hair, silicon dioxide, bleomycin, neomycin, Pulvis Talci, metallic beryllium, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, copper, cytokine (for example, wherein said cytokine is selected from bone morphogenetic protein, decalcified bone matrix, TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-1, IL-1-β, IL-8, the group that IL-6 and growth hormone are formed), (for example, wherein the final activating agent of irritation cell is selected from dexamethasone to the activating agent that stimulates cellular proliferation, isotretinoin, 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstilbestrol (diethylstibesterol), ciclosporin A, N (group that ω-nitro-L-arginine methyl esters (N (ω-nitro-L-arginine methyl esters)) and all-trans retinoic acid (ATRA) are formed) and analog and derivant.As alternative or in addition, with the lower surface that contains the compositions coating breast implant that promotes fibrotic activating agent, the compositions that comprises the fibre modification derivant can be impregnated near the space (for example, the substrate of the bag of operation generation) of placing breast implant of tissue below.

The breast implant of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue is provided among the present invention in one aspect, and wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with breast implant have above been described.

Can be by polymer composition directly and/or indirectly being coated with following position or coating is soaked into said composition around the breast implant of implanting thereon: (a) tissue adjacent with breast implant; (b) near breast implant-organizational interface; (c) zone around the breast implant; (d) breast implant passs tissue around the Teat pipette.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with breast implant comprises described polymer composition is delivered to: (a) breast implant surface (for example as injectable, paste, gel or mesh); (b) before implanting breast implant at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the breast implant breast implant surface at once and/or implant tissue (for example forming gel or mesh) around the breast implant as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed breast implant (for example operation generate bag) (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in several hours-a few time limits in week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject breast implant tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with breast implant is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because breast implant is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

(2) Face's implant

In one aspect, the polymer composition of theme of the present invention can be impregnated into and the adjacent tissue of face's implant.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).

Described soft tissue implant can be face's implant, comprises the implant that is used for (submalar) district (for example cheek implant) under cheek-face middle region or the cheek.Take place with aging (for example cheek hollow and face middle part soft tissue is sagging), face middle part hypoplasia (dish face deformity), wound after and behind the tumor resection during the short and small relevant significant change of deformity and slight demifacet, carry out increase art cheek and cheek under usually.Can also carry out increasing art under cheek and the cheek so that the cheek profile of significance height and point (sharp) is provided for cosmetic purpose.Implant can be improved the balance of face and coordinate enhance wrinkle excision or rhinoplastic effect usually by further under placement cheek and the cheek.

There is the face's implant to be used in a large number to improve looks and to rebuild purpose.For example, face's implant can for have wide head and be used for the face middle part or the thin tear-drop shaped profile of the narrow tail of taper of facial subgenal area so that recover and the fullness of softening cheek.For example, referring to United States Patent (USP) 4,969,901.Face's implant can be made up of the flexible material of the upper surface of lower surface with general concave surface bended and convex bending, and it is used to increase subgenal area.For example, referring to United States Patent (USP) 5,421,831.Face's implant can be for by Boping face-piece and module prosthese that the pad that covers tissue and provide required profile is formed.For example, referring to United States Patent (USP) 5,514,179.Face's implant can be made up of moldable siloxanes, and it is having the grid of level and vertical sleeve so that help tissue ingrowth in the face of on the concave surface rear surface of bone.For example, referring to United States Patent (USP) 5,876,447.Face's implant can be formed by the closed chamber crosslinked polyethylene foam that forms shell with near the shape that meets the human face.For example, referring to United States Patent (USP) 4,920,580.Face's implant can apply the device of the corium plug (plug) of the donor skin behind the laser beam certainly for collecting, and the described laser beam that applies is used to the skin epidermis of ablating, and exposes corium thus and can be inserted in facial skin recess position by this corium plug then.For example, referring to United States Patent (USP) 5,817,090.Face's implant can be made up of the siloxanes-elastomer that has open-cell structure, and wherein silicone elastomer is coated with from the teeth outwards as solid, this layer of this after fixing.For example, referring to United States Patent (USP) 5,007,929.Face's implant can be the lower jaw or the premaxillary teeth implant of hollow perforation, and they for example are made up of the fixed bone screw accepter that crosses of alveolar ridge the band by adjacency, referring to United States Patent (USP) 4,828,492.

Face's implant that can have benefited from having the polymer composition of the theme of the present invention that is impregnated into adjacent tissue comprises and is purchased product.Being suitable for implementing the face's implant that is purchased of the present invention comprises: Tissue Technologies, (San Francisco CA) has sold the ULTRASOFT-RC face implant of being made by the soft slick and sly synthetic e-PTFE that is used for facial soft tissue increase to Inc..TissueTechnologies, Inc. have also sold the ULTRASOFT that is made and be applicable to fully especially lip edge and muffle pleat by the tubular e-PTFE that is suitable for the increase of face area soft tissue.Various faces implant comprises available from ImplanTech Associates: BINDER SUBMALAR face implant, BINDER SUBMALAR II face implant, TERINO MALAR SHELL, COMBINED SUBMALAR SHELL, FLOWERS TEAR TROUGH implant; Solid silicone face and cheek implant from Allied Biomedical; The subcutaneous increase material of making by the microporosity ePTFE that supports to organize fast fusion (S.A.M.) and from W.L. Gore ﹠amp; Associates, the TRIMENSIONAL 3-D implant of making of Inc..

Can have benefited from discharging the synulotic therapeutic agent that can reduce in implant-organizational interface such as these face's implants, so that the appearance of fibroid contracture is minimized.Can also have benefited from discharging the therapeutic agent that can prevent or suppress near the infection the described implant position such as these face's implants.The polymer composition that will comprise the theme of the present invention of anti-scarring agent and/or anti-infective be impregnated into and implant maybe will implant the adjacent tissue in face implant place can with to for beauty treatment or the fibroid contracture of rebuilding the reaction of face's implant that purpose places minimize or prevent this from occurring and/or can suppress or prevent near the described implant position infection.The fibre modification inhibitor can reduce capsule contracture, asymmetric, skin depressions, rigid and surgical operation (for example cystitomy, vesiculectomy, modification and excision) and improve the satisfaction of patient to operation technique repeatedly.

With regard to regard to effective face implant in beauty treatment or the reconstructive procedure, implant must accurately be located in vivo, and irrelevant with concrete design feature.Face's implant can move after surgery and realize that it is important that implant combines with following periosteum and osseous tissue.Described and had the grid of level and vertical sleeve so that help face's implant of tissue ingrowth in the face of on the concave surface rear surface of bone.Face's implant dislocation (moving or migration after the implant placement) can cause asymmetric and be the main cause that the patient is dissatisfied and modification is performed the operation.In one embodiment, go up coated fiber degeneration derivant or compositions at lower surface (promptly facing the surface of periosteum and bone) for face's implant, and (promptly in the face of skin and hypodermic surface) go up coating fibrotic activating agent of inhibition or compositions on its another surface.Can be directly or the polymer composition of the theme of the present invention by will containing required activating agent be impregnated into the tissue adjacent or its and make up arbitrarily and carry out this class coating with required surface.The anatomical position that this embodiment has the promotion fibre modification and face's implant and it are put into is fixed (promptly, make face's implant and the following bone fixing to prevent the implant migration), can prevent the advantage of the complication relevant simultaneously with encapsulation on the shallow surface of implant.The representational example that promotes fibre modification and be suitable for the activating agent that send on (deeply) surface under face's implant comprises silk, fine hair, silicon dioxide, bleomycin, neomycin, Pulvis Talci, metallic beryllium, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, copper, cytokine (for example, wherein said cytokine is selected from bone morphogenetic protein, decalcified bone matrix, TGD β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-1, IL-1-β, IL-8, the group that IL-6 and growth hormone are formed), (for example, wherein the value-added activating agent of irritation cell is selected from dexamethasone to the value-added activating agent of irritation cell, isotretinoin, 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, the group formed of diethylstilbestrol, ciclosporin A, N (ω-nitro-L-arginine methyl esters) and all-trans retinoic acid (ATRA)) and analog and derivant.As alternative or in addition, with the lower surface that contains the compositions coating face implant that promotes fibrotic activating agent, the polymer composition that comprises the theme of the present invention of fibre modification derivant can be impregnated into and near the adjacent tissue in surface or space (for example, periosteum surface) of placing face's implant of tissue below.

Face's implant of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue is provided among the present invention in one aspect, and wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with face's implant have above been described.

Can be by polymer composition directly and/or indirectly being coated with following position or coating is soaked into said composition around face's implant of implanting thereon: (a) tissue adjacent with face's implant; (b) near implant-organizational interface of face; (c) zone around face's implant; (d) face's implant passs tissue around the Teat pipette.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with the face implant comprises described polymer composition is delivered to: (a) face's implant surface (for example as injectable, paste, gel or mesh); (b) before implanting face's implant at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant after face's implant face's implant surface at once and/or implant tissue (for example forming gel or mesh) around face's implant as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed face's implant (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject face's implant tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with the face implant is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because face's implant is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

(3) Chin and lower jaw implant

In one aspect, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with the lower jaw implant with chin.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).With the polymer composition of theme of the present invention be impregnated into the tissue adjacent with described implant position can with to for beauty treatment or the fibroid contracture of rebuilding the reaction of the implant that purpose places be reduced to bottom line or prevent this from occurring.

A large amount of chins and lower jaw implant can be used for beauty treatment and rebuild purpose.For example, the chin implant can be novel solid moon shape implant, it both sides be tapered and form corresponding tail and have be positioned at outside crooked protuberate on the mandibular surface with chin profile that produces nature and the structure that forms jaw.For example, referring to United States Patent (USP) 4,344,191.The chin implant can for have 45 the degree axis of symmetry the novel solid selene, it on the chin position, have comparatively softish than low-durometer material so that the simulated fat pad.For example, referring to United States Patent (USP) 5,195,951.The chin implant can have the concave surface rear surface of cooperating with the irregular bone surface of lower jaw and have the convex surface front surface that is used to expand and provide the protuberantia of nature chin profile.For example, referring to United States Patent (USP) 4,990,160.The chin implant can have the porous convex surface that politef is made, and it has the void space that is enough to make the ingrown size of soft tissue, and the concave surface that siloxanes is made is non-porous inwardly growing so that prevent osseous tissue basically.For example, referring to United States Patent (USP) 6,277,150.

Can have benefited from that the polymer composition of theme of the present invention is impregnated into the chin of adjacent tissue and lower jaw implant according to the present invention comprises and is purchased product.The example that is purchased of chin and lower jaw implant comprises: TERLNO EXTENDED ANATOMICAL chin implant, GLASGOLDWAFER, FLOWERS MANDIBULAR GLOVE, MITTELMAN PREJOWL-CHIN, GLASGOLD WAFER implant and from other model of ImplatTechAssociates; With solid silicone chin implant from Allied Biomedical.

The polymer composition that will comprise the theme of the present invention of anti-scarring agent and/or anti-infective is impregnated into and implants will implant maybe that the described chin tissue adjacent with lower jaw implant place can reduce at the cicatrization in implant-organizational interface so that minimizing and/or can suppress or prevent near the described implant position infection the fibroid contracture.With the polymer composition of theme of the present invention be impregnated into the tissue adjacent with the lower jaw implant with described chin can reduce to for beauty treatment or rebuild purpose in chin and lower jaw, place implant reaction the fibroid contracture or prevent this from occurring.The fibre modification inhibitor can reduce capsule contracture, asymmetric, skin depressions, rigid and surgical operation (for example cystitomy, vesiculectomy, modification and excision) and improve the satisfaction of patient to operation technique repeatedly.

With regard to regard to effective chin or lower jaw implant in beauty treatment or the reconstructive procedure, implant must accurately be located in vivo, and irrelevant with concrete design feature.Chin or lower jaw implant can move after surgery and realize that it is important that implant combines with following periosteum and osseous tissue.Chin or the dislocation of lower jaw implant (moving or migration after the implant placement) can cause asymmetric and be the main cause that the patient is dissatisfied and modification is performed the operation.In one embodiment, go up coated fiber degeneration derivant or compositions at lower surface (promptly facing the surface of periosteum and lower jaw) for chin or lower jaw implant, and (promptly in the face of skin and hypodermic surface) go up coating fibrotic activating agent of inhibition or compositions on its another surface.Can be directly or the polymer composition of the theme of the present invention by will containing required activating agent be impregnated into the tissue adjacent or its and make up arbitrarily and carry out this class coating with required surface.This embodiment has and promotes fibre modification and make chin or the lower jaw implant is fixed (that is, make implant and following lower jaw fixing to prevent that implant from moving) with following lower jaw that the while can be prevented the advantage of the complication relevant with encapsulation on the shallow surface of implant.The representational example that promotes fibre modification and be suitable for the activating agent that send on (deeply) surface under chin or the lower jaw implant comprises silk, fine hair, silicon dioxide, bleomycin, neomycin, Pulvis Talci, metallic beryllium, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, copper, inflammatory cytokine (for example, wherein said inflammatory cytokine is selected from bone morphogenetic protein, decalcified bone matrix, TGF β, PDGF, VEGF, bFGF, TNE α, NGF, GM-CSF, IGF-1, IL-1-β, IL-8, the group that IL-6 and growth hormone are formed), (for example, wherein the value-added activating agent of irritation cell is selected from dexamethasone to the value-added activating agent of irritation cell, isotretinoin, 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, the group formed of diethylstilbestrol, ciclosporin A, N (ω-nitro-L-arginine methyl esters) and all-trans retinoic acid (ATRA)) and analog and derivant.As alternative or in addition, with containing the lower surface that the compositions that promotes fibrotic activating agent applies chin or lower jaw implant, the polymer composition that comprises the theme of the present invention of fibre modification derivant can be impregnated into and near the adjacent tissue in surface or space (for example, periosteum surface) of placing described implant of tissue below.

The chin and the lower jaw implant of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue are provided among the present invention in one aspect, and wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with chin and lower jaw implant have above been described.

Can be by polymer composition directly and/or indirectly being coated with following position or coating is soaked into said composition around chin of implanting and lower jaw implant thereon: (a) tissue adjacent with the lower jaw implant with chin; (b) near chin and the lower jaw implant-organizational interface; (c) zone around chin and the lower jaw implant; (d) chin and lower jaw implant passs tissue around the Teat pipette.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with the lower jaw implant with chin comprises described polymer composition is delivered to: (a) chin and lower jaw implant surface (for example as injectable, paste, gel or mesh); (b) before implanting chin and lower jaw implant at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant after chin and the lower jaw implant chin and lower jaw implant surface at once and/or implant tissue (for example forming gel or mesh) around chin and the lower jaw implant as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed chin and lower jaw implant (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject chin and lower jaw implant tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with the lower jaw implant with chin is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because chin and lower jaw implant are made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

(4) Nasal implants

In one aspect, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with nasal implants.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).With the polymer composition of theme of the present invention be impregnated into the tissue adjacent with described implant position can with to for beauty treatment or the fibroid contracture of rebuilding the reaction of the implant that purpose places be reduced to bottom line or prevent this from occurring.

A large amount of nasal implantses are suitable for implementing being used to improving looks and rebuild the present invention of purpose.For example, nasal implants can for elongation and have contouredly, it has concave surface to determine being suitable for location on the bridge of the nose face so that strengthen the frontal view of nose and the dorsal part support end of profile view on the side of selecting.For example, referring to United States Patent (USP) 5,112,353.Nasal implants can leak the hard basically level siloxanes of formal construction and the soft siloxanes on the tip is formed by water.For example, referring to United States Patent (USP) 5,030,232.Nasal implants mainly can be made up of following ingredients: the aromatic substituted acrylic acid hydrophobic monomer is that main component and remainder material are cross-linking monomer and optionally one or more are selected from the extra composition of the group that UV-light-absorbing compound and blue light absorption chemical compound form.For example, referring to United States Patent (USP) 6,528,602.Nasal implants can be formed with the synthetic cartilage material of hydrophilic of the controlled big aperture that replaces fibrous tissue in vivo by having random distribution.For example, referring to United States Patent (USP) 4,912,141.

Can have benefited from the nasal implants that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised and be purchased product.Be applicable to implement the example that is purchased nasal implants of the present invention comprise from ImplantTech Associates FLOWERS DORSAL, RIZZODORSAL, SHIRAKABE and DORSAL COLUMELL nasal implants and from the solid silicone nasal implants of AlliedBiomedical.

Can have benefited from discharging such as these nasal implantses and can reduce synulotic therapeutic agent in implant-organizational interface so that minimizing with fiber kystis.Can also have benefited from discharging such as these nasal implantses and can prevent or suppress near infect the implant position therapeutic agent.With the polymer composition of theme of the present invention be impregnated into and implant maybe will implant the adjacent tissue in described nasal implants place can be with to for beauty treatment or rebuild purpose and in nose, place the fibroid contracture of the reaction of implant and minimize or prevent this from occurring.The fibre modification inhibitor can reduce capsule contracture, asymmetric, skin depressions, rigid and surgical operation (for example cystitomy, vesiculectomy, modification and excision) and improve the satisfaction of patient to operation technique repeatedly.

With regard to regard to effective nasal implants in beauty treatment or the reconstructive procedure, implant must accurately be located in vivo, and irrelevant with concrete design feature.Nasal implants can move after surgery and realize that it is important that implant combines with following cartilage and/or osseous tissue.Nasal implants implant dislocation (moving or migration after the implant placement) can cause asymmetric and be the main cause that the patient is dissatisfied and modification is performed the operation.In one embodiment, go up coated fiber degeneration derivant or compositions at lower surface (promptly facing the surface of cartilage and/or bone) for nasal implants, and (promptly in the face of skin and hypodermic surface) go up coating fibrotic activating agent of inhibition or compositions on its another surface.Can be directly or the polymer composition of the theme of the present invention by will containing required activating agent be impregnated into the tissue adjacent or its and make up arbitrarily and carry out this class coating with required surface.This embodiment has and promotes fibre modification and make nasal implants and following cartilage or bone fixed (promptly, make nasal cartilages or the bone below implant and the nose fixing to prevent the implant migration), can prevent the advantage of the complication relevant simultaneously with encapsulation on the shallow surface of implant.The representational example that promotes fibre modification and be suitable for the activating agent that send on (deeply) surface under nasal implants comprises silk, fine hair, silicon dioxide, bleomycin, neomycin, Pulvis Talci, metallic beryllium, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, copper, inflammatory cytokine (for example, wherein said inflammatory cytokine is selected from bone morphogenetic protein, decalcified bone matrix, TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-1, IL-1-β, IL-8, the group that IL-6 and growth hormone are formed), (for example, wherein the value-added activating agent of irritation cell is selected from dexamethasone to the value-added activating agent of irritation cell, isotretinoin, 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, the group formed of diethylstilbestrol, ciclosporin A, N (ω-nitro-L-arginine methyl esters) and all-trans retinoic acid (ATRA)) and analog and derivant.As alternative or in addition, with containing the compositions coating nasal implants lower surface that promotes fibrotic activating agent, the polymer composition that comprises the theme of the present invention of fibre modification derivant can be impregnated into and near the adjacent tissue in surface or space (for example, nasal cartilages or bone surface) of placing described implant of tissue below.

The nasal implants of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue is provided among the present invention in one aspect, and wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with nasal implants have above been described.

Can be by polymer composition directly and/or indirectly being coated with following position or coating is soaked into said composition around the nasal implants of implanting thereon: (a) tissue adjacent with nasal implants; (b) near nasal implants-organizational interface; (c) zone around the nasal implants; (d) nasal implants passs tissue around the Teat pipette.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with nasal implants comprises described polymer composition is delivered to: (a) nasal implants surface (for example as injectable, paste, gel or mesh); (b) before implanting nasal implants at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant behind the nasal implants nasal implants surface at once and/or implant tissue (for example forming gel or mesh) around the nasal implants as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed nasal implants (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject nasal implants tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with nasal implants is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because nasal implants is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

(5) The lip implant

In one aspect, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with the lip implant.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).With the polymer composition of theme of the present invention be impregnated into the tissue adjacent with described implant position can with to for beauty treatment or the fibroid contracture of rebuilding the reaction of the implant that purpose places be reduced to bottom line or prevent this from occurring.

There is the lip implant to be used in a large number to improve looks and to rebuild purpose.For example, the lip implant can be made up of the expandable fibrillation politef that the biology of the inner chamber with longitudinal extension can not be degraded, and fibrous tissue wherein can take place inwardly grow so that provide soft tissue to increase.For example, referring to United States Patent (USP) 5,941,910 and 5,607,477.The lip implant can comprise that the softish elasticity that is ductile can not absorb the prosthese granule again, and they have coarse irregular surface structure, are dispersed in the non-retentivity compatibility physiology carrier.For example, referring to United States Patent (USP) 5,571,182.

Can have benefited from the lip implant that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised and be purchased product.Be applicable to that implementing the example that is purchased the lip implant of the present invention comprises: from Tissue Technologies, (it has the hose-shaped design of being made by synthetic ePTFE to Inc. for San Francisco, SOFTFORM CA); (Branchburg, NJ) the ALLODERM sheet of Xiao Shouing (Allograft Dermal Matrix Grafts) also can be as the implant that enlarges lip by LifeCell Corporation.The ALLODERM sheet is very soft and be easy to enlarge lip with diffusion way.(Newark DE) has sold the implantable line of solid that also can be used for the lip implant for W.L.Gore and Associates.

The polymer composition that will comprise the theme of the present invention of anti-scarring agent and/or anti-infective is impregnated into and implants will implant maybe that the adjacent tissue in described lip implant place can reduce at the cicatrization in implant-organizational interface so that minimizing and/or can suppress or prevent near the described implant position infection the fibroid contracture.With the polymer composition of theme of the present invention be impregnated into the tissue adjacent with described lip implant can reduce to for beauty treatment or rebuild purpose in lip, place implant reaction the fibroid contracture or prevent this from occurring.That the fibre modification inhibitor can reduce is asymmetric, skin depressions, rigid and intervene repeatedly and improve the satisfaction of patient to operation technique.

In one embodiment of the invention, in one aspect in, suppress fibrotic compositions for described lip implant coating, and in one aspect of the method, promote ingrown compositions of fibrous tissue or chemical compound to its coating.Can be directly or the polymer composition of the theme of the present invention by will containing required activating agent be impregnated into the tissue adjacent or its and make up arbitrarily and carry out this class coating with required surface.This embodiment has the fibre modification of promotion and lip implant and adjacent tissue is fixed, and can prevent the advantage of the complication relevant with fiber kystis on the shallow surface of implant simultaneously.The representational example that promotes fibre modification and be suitable for the activating agent that send on (deeply) surface under the lip implant comprises silk, fine hair, silicon dioxide, bleomycin, neomycin, Pulvis Talci, metallic beryllium, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, copper, inflammatory cytokine (for example, wherein said inflammatory cytokine is selected from bone morphogenetic protein, decalcified bone matrix, TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-1, IL-1-β, IL-8, the group that IL-6 and growth hormone are formed), (for example, wherein the value-added activating agent of irritation cell is selected from dexamethasone to the value-added activating agent of irritation cell, isotretinoin, 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, the group formed of diethylstilbestrol, ciclosporin A, N (ω-nitro-L-arginine methyl esters) and all-trans retinoic acid (ATRA)) and analog and derivant.As alternative or in addition,, the polymer composition that comprises the theme of the present invention of fibre modification derivant directly can be injected the lip of the described implant of placement with containing the compositions coating lip implant lower surface that promotes fibrotic activating agent.

The lip implant of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue is provided among the present invention in one aspect, and wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with the lip implant have above been described.

Can be by polymer composition directly and/or indirectly being coated with following position or coating is soaked into said composition around the lip implant of implanting thereon: (a) tissue adjacent with the lip implant; (b) near lip implant-organizational interface; (c) zone around the lip implant; (d) the lip implant passs tissue around the Teat pipette.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with the lip implant comprises described polymer composition is delivered to: (a) lip implant surface (for example as injectable, paste, gel or mesh); (b) before implanting the lip implant at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant after the lip implant lip implant surface at once and/or implant tissue (for example forming gel or mesh) around the lip implant as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed the lip implant (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject lip implant tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with nasal implants is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because the lip implant is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

(6) The breast implant

In one aspect, the polymer composition of theme of the present invention can be impregnated into the tissue adjacent with the breast implant.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).With the polymer composition of theme of the present invention be impregnated into the tissue adjacent with described implant position can with to for beauty treatment or the fibroid contracture of rebuilding the reaction of the implant that purpose places be reduced to bottom line or prevent this from occurring.

Existing in a large number can be with the coupling of fibre modification inhibitor and be used to improve looks and rebuild the breast implant of purpose.For example, the breast implant can be made up of the unit cuboid that has by the appropriate concave surface cross section of edge part.For example, referring to United States Patent (USP) 5,112,352.The hollow shell that the breast implant can be formed by the pliability elasticity adventitia that is full of the gel that contains polyacrylamide and polyacrylamide derivative or viscous liquid.For example, referring to United States Patent (USP) 5,658,329.

Can have benefited from the breast implant that the polymer composition of theme of the present invention is impregnated into adjacent tissue according to the present invention comprised and be purchased product.Be applicable to that the breast implant that is purchased of the present invention comprises solid silicone implant from Allied Biomedical.Can have benefited from discharging such as these breast implants and can reduce enough synulotic therapeutic agents in implant-organizational interface so that the incidence rate of fibroid contracture is minimized.Can also have benefited from discharging the therapeutic agent that can prevent or suppress near the infection the described implant position such as the breast implant.

As mentioned above, implant dislocation (implant moves after placement or migration) can produce various complication, such as asymmetric and be that the patient is dissatisfied and revise the main cause of operation.In one embodiment, give the lower surface surface of thoracic wall (promptly in the face of) the fibrotic activating agent of coating promotion of breast implant or compositions and give another side (promptly face-to-face to the surface of chest muscle) coating fibrotic activating agent of inhibition or compositions.Can be directly or the polymer composition of the theme of the present invention by will containing required activating agent be impregnated into the tissue adjacent or its and make up arbitrarily and carry out this class coating with required surface.This embodiment has and promotes fibre modification and make the breast implant be fixed into anatomical position that it places (promptly, the breast implant is fixed into prevent space under the chest muscle of implant migration), can prevent the advantage of the complication relevant simultaneously with encapsulation on the shallow surface of breast implant.The representational example that promotes fibre modification and be suitable for the activating agent that send on (deeply) surface under the breast implant comprises silk, fine hair, silicon dioxide, bleomycin, neomycin, Pulvis Talci, metallic beryllium, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, copper, cytokine (for example, wherein said cytokine is selected from bone morphogenetic protein, decalcified bone matrix, TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-1, IL-1-β, IL-8, the group that IL-6 and growth hormone are formed), (for example, wherein the final activating agent of irritation cell is selected from dexamethasone to the activating agent that stimulates cellular proliferation, isotretinoin, 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstilbestrol (diethylstibesterol), ciclosporin A, N (group that ω-nitro-L-arginine methyl esters (N (ω-nitro-L-arginine methyl esters)) and all-trans retinoic acid (ATRA) are formed) and analog and derivant.As alternative or in addition, with the lower surface that contains the compositions coating breast implant that promotes fibrotic activating agent, the polymer composition that comprises the theme of the present invention of fibre modification derivant can be impregnated into below near the space of placing the breast implant tissue (for example, the chest muscle that generates of operation following bag substrate).

The breast implant of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue is provided among the present invention in one aspect, and wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with the breast implant have above been described.

Can be by polymer composition directly and/or indirectly being coated with following position or coating is soaked into said composition around the breast implant of implanting thereon: (a) tissue adjacent with the breast implant; (b) near breast implant-organizational interface; (c) zone around the breast implant; (d) the breast implant passs tissue around the Teat pipette.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with the breast implant comprises described polymer composition is delivered to: (a) breast implant surface (for example as injectable, paste, gel or mesh); (b) before implanting the breast implant at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant after the breast implant breast implant surface at once and/or implant tissue (for example forming gel or mesh) around the breast implant as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed the breast implant (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject breast implant tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with the breast implant is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because the breast implant is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

(7) Autologous tissue's implant

In one aspect, the polymer composition of theme of the present invention can be impregnated into and the adjacent tissue of autologous tissue's implant.The polymer composition of theme of the present invention can contain therapeutic agent (for example anti-scarring agent and/or anti-infective).Autologous tissue's implant includes, but are not limited to fatty tissue, autologous fat implant, skin implant, skin or tissue plug, muscular tissue flap and cell extraction implant.The fatty tissue implant can also be called autologous fat implant, fat graft, free-fat transfer, autologous fat transfer/graft, skin fat implant, fat etching (liposculpture), peptide-lipid constructs (lipostructure), volume recovery (volume restoration), little-fat injection (micro-lipoiniection) and fat injection.

Many decades increases the soft tissue that autologous tissue's implant is used for shaping and reconstruction operations.For example, autologous tissue's implant can be used to enlarge soft tissue position (for example breast or penis increase), thereby face's cicatrization (for example acne cicatrix) is minimized, improve face's volume (for example facial hemiatrophy) in the disease and face is aging, minimize such as inhaling cheek and upper thread (for example wrinkle).These injectable autologous tissue implants are biocompatibility, and are general, stable, persistent and natural look.Autologous tissue's implant comprise remove from a zone of health tissue or cell (for example from abdominal part or strand superfluous adipose cell) and rebuild or their such simple operations is implanted in another zone of the health that increases again at needs then.Autologous tissue is softish and the sensation nature.Can form by various connective tissues from the body soft tissue implant, include, but are not limited to fat (adipose) or fat (fat), skin histology, fibroblast, muscular tissue or other connective tissue and relevant cell.Introduce autologous tissue's implant to correct various defectives, it is non-immunogenic, and is easy to obtain and cheap.

In one aspect, autologous tissue's implant can be made up of fat (fat) or fat (adipose).The extraction of fatty tissue and implant procedure comprise suction of fat from hypodermic layer, fill by means of suction syringe pump stomach wall, and are injected into the subcutaneous tissue that covers recess then.Autologous fat can be used to protect other tissue (for example postoperative neuroprotective root) as the implant (for example being used for physical handicap or cosmetic purpose) of body surface recess or it usually.Fat graft need can also be used to the health protuberantia of soft tissue bedding and padding to prevent the sensitivity to pressure.When fatty bedding and padding lack, the skin of covering may with the bone adhesion, cause sense of discomfort and even produce pain, for example, (being also referred to as calcaneus (calcaneous)) takes place in this situation when calcanean spur or bone outthrust appear on the calcaneus plantar region.In this case, fat transplantation can provide position between necessary filling between bone and the skin.For example, United States Patent (USP) 5,681 has been described in 561 and has been comprised anabolic hormone, aminoacid, vitamin and inorganic ions so that in case the autologous fat transplantation thing of the survival rate of just improving lipocyte of implanting.

In one aspect of the method, autologous tissue's implant can be made up of the base of a fruit shape lobe that generally derives from the back of the body (for example latissimus dorsi myocutaneous flap) or abdominal part (for example abdominal part flesh flesh skin or TRAM lobe) anyhow.Base of a fruit shape lobe can also derive from buttocks, thigh or groin.Make the disengaging of these lobes and health and reconnect blood vessel by the use microsurgical procedure then.These muscular tissue lobes are most commonly used to the closed and reconstruction of mastectomy postoperative.To some other conventional defective that comprises in the head and neck district of using of muscular tissue lobe, the covering of the defective that produces because of big head and neck excision especially; Extra application comprises the odd-shaped thoracic wall defective of the non-mammectomy of covering.Latissimus dorsi m. also can be as counter-rotating lobe (reverse flap) so that closed spinal column birth defect, such as spina bifida or the bulging of spinal cord spinal meninges based on its waist borer.For example, United States Patent (USP) 5,765 has been described the method for autologous tissue's implant of using-system lobe form in 567, and described tissue flap has can be used for that profile is corrected and the skin island of the expansion of breast tissue reconstruction.Tissue flap can be free flap or the lobe that connects by natural vessel pedicle.

In one aspect of the method, the autologous skin fibroblast suspended substance that can be used to provide beauty treatment to increase can be provided autologous tissue's implant.For example, referring to United States Patent (USP) 5,858,390,5,665,372 and 5,591,444.Described in this United States Patent (USP) by the autologous skin fibroblast being injected corium and correcting the beauty treatment of skin and the method for aesthetic drawback near adjacent subcutaneous tissue with defective.Can corrigent by this method typical defect comprise the skin recess in wrinkle (rhytids), stretch marks, depressed scar, atraumatic source, from the cicatrization and the atelocheilia of acne vulgaris.The fibroblast of injection and experimenter have histocompatibility and have been unfolded by the certain hour time limit of going down to posterity in the cell culture system in nonprotein culture medium.

In one aspect of the method, described autologous tissue implant can be the corium plug of the donor skin after applying laser beam of collecting, the described laser beam that applies is used to the skin epidermis of ablating, and exposes corium thus and can be inserted in facial skin recess position by this corium plug then.For example, referring to United States Patent (USP) 5,817,090.This autologous tissue implant can be used for the treatment of the facial skin recess, such as acne cicatrix recess and wrinkle.Skin graft also is used to correct the skin recess, wherein removes epidermis by dermabrasion.

With regard to the situation of synthetic other successive synthetic implant (above-mentioned), autologous tissue's implant also exists migration, compressing, becomes the tendency that infects or produce pain and lopsided capsule contracture.The polymer composition that will comprise the theme of the present invention of therapeutic agent (for example anti-scarring agent and/or anti-infective) be impregnated into and implant maybe will implant the adjacent tissue of described autologous tissue implant can be with for beauty treatment or rebuild purpose and place the fibroid contracture of the reaction of autologous tissue's implant in vivo and minimize or prevent this from occurring and/or can suppress or prevent near the described implant position infection.

Can have benefited from discharging such as these autologous tissue's implants and can reduce in implant-organizational interface synulotic therapeutic agent so that fiber kystis is minimized.Can also have benefited from discharging such as these autologous tissue's implants and can prevent or suppress near infect the implant position therapeutic agent.In one aspect, the invention provides autologous tissue's implant of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue, wherein the polymer composition of theme of the present invention can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with the autograft thing have above been described.

Can be by polymer composition directly and/or indirectly being coated with following position or coating is soaked into said composition around autologous tissue's implant of implanting thereon: (a) tissue adjacent with autologous tissue's implant; (b) near implant-organizational interface of autologous tissue; (c) zone around autologous tissue's implant; (d) autologous tissue's implant passs tissue around the Teat pipette.Being used for method that polymer composition with theme of the present invention is impregnated into the tissue adjacent with the autologous tissue implant comprises described polymer composition is delivered to: (a) autologous tissue's implant surface (for example as injectable, paste, gel or mesh); (b) before implanting autologous tissue's implant at once or the tissue surface in the process (for example forming gel or mesh) as injectable, paste, gel, original position; (c) implant after autologous tissue's implant autologous tissue's implant surface at once and/or implant tissue (for example forming gel or mesh) around autologous tissue's implant as injectable, paste, gel, original position; (d) by described compositions part being coated with into the anatomic space of having placed autologous tissue's implant (be to use polymer support-fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the solid implant of the described therapeutic agent of release in the time limits in several hours-a few week and can pass other preparation) into the described activating agent of release in the zone of having inserted described device for this embodiment is useful especially; (e) by inject autologous tissue's implant tissue on every side as solution, transfusion or slow releasing preparation percutaneous; (f) combination in any by said method.Can also use conjoint therapy (be therapeutic agent combination and with the combination of antithrombotic agent and/or anti-platelet agents).With regard to all situations, should understand all or part of adjacent tissue that the polymer composition of theme of the present invention can be impregnated into and install.

According to an aspect, above-mentioned inhibitor of fibre modification arbitrarily and/or anti-infective can be used to implement the present invention.In one aspect of the invention, the polymer composition that is impregnated into the theme of the present invention of the tissue adjacent with the autologous tissue implant is suitable for discharging one or more the activating agent in four kinds of ordinary circumstances that suppress fibre modification (or cicatrization) process, comprising: form neovascularity (blood vessel generation); Connective tissue cell (such as fibroblast or smooth muscle cell) migration and propagation; Extracellular matrix (ECM) deposition; And reconstruction (the ripe and body formation of fibrous tissue).By suppressing one or more situations in the fibre modification (or cicatrization), can suppress or reduce granulation tissue overgrowth.

The example that is used for fibre modification inhibitor of the present invention comprises following activating agent: cell cycle inhibitor comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) taxanes (for example paclitaxel, taxotere and docetaxel); (C) podophyllotoxin (for example etoposide); (D) immunomodulator (for example sirolimus, everolimus, tacrolimus); (E) heatshock protein 90 antagonisies (for example geldanamycin); (F) HMGCoA reductase inhibitor (for example simvastatin); (G) inosine monophosphate dehydrogenase inhibitor (for example Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃); (H) NF kB inhibitor (for example Bay 11-7082); (I) antimycotic agent (for example sulconazole); (J) p38MAP inhibitors of kinases (for example SB202190); And the analog of above-mentioned activating agent and derivant.

Depend on various factors from being used for prevention or suppressing fibrotic present composition administered agents dosage, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Because autologous tissue's implant is made of not isostructure and size, so the definite dosage that gives can also change with the different of size, surface area and design of device.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single systemic chemotherapy dosage coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-scarring agent discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical fibrosis agent of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-scarring agent in compositions can be in following scope: about 0.01 μ g-10 μ g; Or about 10 μ g-10mg; Or about 10mg-250mg; Or about 250mg-1000mg; Or about 1000mg-2500mg.The dosage (amount) of coating per unit area device of anti-scarring agent or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²Or about 1000 μ g/mm ²-2500 μ g/mm ²

According to another aspect, above-mentioned any anti-infective can be used to implement the present invention.Typical anti-infective comprises: (A) anthracyclines (for example doxorubicin and mitoxantrone); (B) fluorine miazines (for example 5-FU); (C) antifol (for example methotrexate); (D) podophyllotoxin (for example etoposide); (E) camptothecine; (F) hydroxyl ureas; (G) platinum complexes (for example cisplatin); And the analog of above-mentioned activating agent and derivant.

Be used for preventing or the compositions administered agents dosage that suppresses to infect depends on various factors from the present invention, comprise the type of preparation, the location of therapentic part and the type of the disease for the treatment of.Yet some principle can be applied in the application in this field.Can be the function of (therapentic part) dosage of per unit area with medication dose calculation, can measure the total drug dose that gives and can measure the suitable surface concentration of active medicine.For topical application, with from generally be used for single infection whole-body dose coating concentration more than several times to this concentration 50%, 20%, 10%, 5% so that be lower than 1% scope and use medicine.In certain aspects, described anti-infective discharges from described polymer composition in the time bar that can determine according to the time that is impregnated into the tissue adjacent with described device with valid density, and described release time is approximately less than 1 day-about 180 days scope.In general, release time can also be at following time range: approximately less than 1 day-about 180 days; About 7 days-about 14 days; About 14 days-about 28 days; About 28 days-about 56 days; About 56 days-about 90 days; About 90 days-about 180 days.

Should give the typical anti-infective of use separately or coupling according to following administration guideline.The total amount (dosage) of anti-infective in compositions can be in following scope: about 0.01 μ g-1 μ g; Or about 1 μ g-10 μ g; Or about 10 μ g-1mg; Or about 1mg-10mg; Or about 10mg-100mg; Or about 100mg-250mg; Or about 250mg-1000mg.The dosage (amount) of coating per unit area device of anti-infective or this activating agent on the tissue surface can be in following scope: about 0.01 μ g/mm ²-1 μ g/mm ²Or about 1 μ g/mm ²-10 μ g/mm ²Or about 10 μ g/mm ²-100 μ g/mm ²Or about 100 μ g/mm ²-250 μ g/mm ²Or about 250 μ g/mm ²-1000 μ g/mm ²When different polymer compositions discharge described anti-infective with different rates, should the rate of release coupling from compositions with above-mentioned administration parameter and medicine, make about 10 ^-8M-10 ^-7M or about 10 ^-7M-10 ^-6M about 10 ^-6M-10 ^-5M or about 10 ^-5M-10 ^-4The least concentration preparation of M maintains on the tissue surface.

(for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to promote the antibacterial activity of described compositions for anthracyclines (for example doxorubicin and mitoxantrone), fluorine miazines (for example 5-FU), antifol, based on discussion provided herein, this result should be apparent.

Although above described the example of a large amount of soft tissue implants, the unwanted tissue reaction after they all have similar design feature and produce similar implantation, and can bring out or promote infection in the implant band of position.Should pay close attention to the above not special soft tissue implant commodity of quoting from that are purchased soft tissue implant and of future generation and/or follow-up research and development and be foreseeable and be suitable for using in the present invention that this to those skilled in the art should be apparent.The beauty treatment implant must be with the location of accurate way very to guarantee that correct in vivo anatomical position increases.The all or part of of cosmetic apparatus can be moved after surgery, or excessively the scar tissue growth can occur around implant, and this can cause the performance of these devices to reduce.Have and be impregnated into the effect and/or the movable time limit that can increase implant with the soft tissue implant of the polymer composition of the theme of the present invention of implant-organizational interface's adjacent tissue.Soft tissue implant can also have benefited from discharging the therapeutic agent that can prevent or suppress near the infection in implant position.In one aspect, the invention provides the soft tissue implant of the polymer composition with the theme of the present invention that is impregnated into adjacent tissue, wherein said polymer composition can comprise therapeutic agent (for example anti-scarring agent and/or anti-infective).The number of polymers and the non-polymer delivery system that are used in conjunction with soft tissue implant have above been described.These compositionss may further include one or more fibre modification inhibitor, make granulation or fibrous tissue growth excessively be inhibited or reduce; And/or these compositionss may further include one or more anti-infectives, near the infection inhibition or the prevention implant position thus.

The present invention provides the following method that is used to implant medical apparatus in different aspect and embodiment:

1. medical apparatus

The method that is used to implant medical apparatus is provided among the present invention in one aspect, has comprised: (a) soaked into implanted or implanted the host tissue of described medical apparatus: i) fibrosis agent with following composition; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host.

Randomly provide among the present invention in all fields: be used to implant the method for medical apparatus, comprise: (a) soaking into the fibrosis agent will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into anti-infective will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises fibrosis agent and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Method with being used to implant medical apparatus comprises: (a) soaking into the compositions that comprises fibrosis agent, anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host.

With regard to above-mentioned each side, one or more (for example any two) in the following feature can define the present invention with the further mode with the device that uses in the inventive method: described device is endovascular device; Described device is the gastrointestinal stent; Described device is the trachea and bronchus stent; Described device is the Genito-urinary stent; Described device is ear and nose stent; Described device is ear breather (ear ventilation); Described device is an intraocular implant; Described device is a blood vessel graft; Described device comprises thin film or mesh; Described device is the glaucoma drainage system; Described device is prosthetic heart valve or its composition; Described device is a penile implant; Described device is endotracheal tube or tracheostoma intubate; Described device is a peritoneal dialysis catheters; Described device is central nervous system's part flow arrangement or pressure monitoring device; Described device is an IVCF; Described device is a gastrointestinal device; Described device is the central vein conduit; Described device is a ventricular assist device; Described device is a spinal implant; Described device is implantable electric installation; Described device is an implantable sensor; Described device is implantable pump; And/or described device is a soft tissue implant.

2. endovascular device

The present invention provides the method that is used to implant medical apparatus in one aspect of the method, comprising: (a) soak into implanted or implanted the host tissue of described medical apparatus with following composition: i) fibrosis agent; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is an endovascular device.

Randomly provide among the present invention in all fields: be used to implant the method for medical apparatus, comprise: (a) soaking into the fibrosis agent will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into anti-infective will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises fibrosis agent and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Method with being used to implant medical apparatus comprises: (a) soaking into the compositions that comprises fibrosis agent, anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host.

With regard to above-mentioned each side, one or more (for example any two) in the following feature can define the present invention with the further mode with the device that uses in the inventive method: described medical apparatus is conduit; Described medical apparatus is a bag catheter; Described medical apparatus is an air bag; Described medical apparatus is the stent graft; Described medical apparatus is lead (guidewire); Described medical apparatus is a stent; Described medical apparatus is a stent in the blood vessel; Described medical apparatus is the metal stent; Described medical apparatus is the polymer stent; Described medical apparatus is biodegradable stent; Described medical apparatus is the biological stent that can not degrade; Described medical apparatus is the self-expanding stent; Described medical apparatus is the balloon expanding stent; Described medical apparatus is for covering stent; Described medical apparatus is the medicament elution stent; Described medical apparatus is the stent that comprises the radiopaque material; Described medical apparatus is the stent that comprises echogenic material; Described medical apparatus is the stent that comprises the MRI reaction material; Described medical apparatus is the electrical connector that coincide; Described medical apparatus is tremulous pulse-arterial anastomosis electrical connector; Described medical apparatus is vein-arterial anastomosis electrical connector; Described medical apparatus is tremulous pulse-venous anastomosis electrical connector; Described medical apparatus is the identical electrical connector of tremulous pulse-synthetic graft; Described medical apparatus is synthetic graft-arterial anastomosis electrical connector; Described medical apparatus is the identical electrical connector of vein-synthetic graft; Described medical apparatus is synthetic graft-venous anastomosis electrical connector; Described medical apparatus is a vascular clamp; Described medical apparatus is the vascular suture line; Described medical apparatus is a vascular forceps; Described medical apparatus is a stitching devices; Described medical apparatus is the adapter that coincide; Described medical apparatus is automatic or improved stitching devices; Described medical apparatus is the identical electrical connector of micromachine (micromehical); Described medical apparatus is to help making under the situation of not using stitching thread or nail hole in graft or blood vessel and the target vessel or opening from the identical connecting device that is dynamically connected; Described medical apparatus is the connecting device that coincide, and it comprises tubular graft tubing and can put into the sidewall of target vessel, makes tubular graft to stretch from target vessel; Described medical apparatus is frame form's an identical adapter; Described medical apparatus is the identical adapter of annular; Described medical apparatus is can resorbent identical adapter; Described medical apparatus is to comprise that biology can absorb the identical adapter with elastomeric material again; Described medical apparatus is to be suitable for identical adapter that article one blood vessel and second blood vessel are connected with the graft blood vessel; Described medical apparatus is to be suitable for identical adapter that article one blood vessel and second blood vessel are connected without the graft blood vessel; Described medical apparatus is the identical adapter of incorporating in the blood vessel graft design; Described medical apparatus is the identical adapter that comprises the graft of introducing fixed structure; Described medical apparatus is to comprise the identical adapter that is used for bypass graft end and two fixed compressible inflatable adnexaes of blood vessel; Described medical apparatus be comprise a pair of be used for end to end or side formula connect the identical adapter of the terminal pad element of two blood vessels; Described medical apparatus is an active proximal arteries and veins adapter; Described medical apparatus is a far-end coronary artery adapter; The shunting device of described medical apparatus for making by biocompatible materials; Described medical apparatus the described medical apparatus of shunting device that part metals at least or metal alloy the make shunting device that partial synthesis polymer at least makes of serving as reasons of serving as reasons; The shunting device that described medical apparatus is served as reasons and made to the natural derived polymers of small part; Described medical apparatus be comprise can with the identical adapter of the direct-connected tubular-shaped structures of near-end blood vessel; Described medical apparatus be comprise can with the identical adapter of the direct-connected tubular-shaped structures of distal vessels; Described medical apparatus is the tubular identical adapter with the near-end that can be connected with the near-end blood vessel and the far-end that can be connected with bypass graft; Described medical apparatus be have can with the tubular identical adapter of the fixed graft blood vessel of near-end blood vessel near-end that is connected and the far-end that can be connected with distal vessels; Described medical apparatus is the identical electrical connector that is suitable for connected head-to-tail identical operation; Described medical apparatus is the stent that coincide; Described medical apparatus is the cover that coincide; Described medical apparatus is the identical electrical connector that is suitable for the identical operation that a side joins; Described medical apparatus is single chamber shunting device; Described medical apparatus is the multi-cavity shunting device; Described medical apparatus is the identical connecting device that comprises the single barrel portion that can be used as the diverter that makes blood be diverted to the graft blood vessel from the source blood vessel; Described medical apparatus is to comprise an above barrel portion and wherein at least one barrel portion can be as the identical connecting device that makes the diverter that blood turns between source blood vessel and target vessel; Described medical apparatus be comprise barrel portion and wherein the one or more ends in the barrel portion can insert the end of one or more blood vessel or the identical connecting device of side; Described medical apparatus is the identical electrical connector of multi-cavity that at least one device wall is connected with the graft blood vessel; Described medical apparatus is the identical electrical connector that comprises from three or more tubular wall of joint location stretching, extension; Described medical apparatus is the identical electrical connector of multi-cavity that is generally T-shape; Described medical apparatus is the identical electrical connector of multi-cavity that is generally Y shape; Described medical apparatus is to comprise the identical electrical connector that blood flow is directly branched to pipe coronarius from cardiac component; Described medical apparatus is the identical electrical connector of reticulated structure that comprises the tube-shaped catheter of interconnection; With described medical apparatus is to be configured the identical electrical connector that contains two or more ends, and described two or more ends can provide the blood vessel interface and pass through to intersect the fluid communication in chamber under the situation that does not need to sew up.

3. gastrointestinal stent

The present invention provides the method that is used to implant medical apparatus in one aspect of the method, comprising: (a) soak into implanted or implanted the host tissue of described medical apparatus with following composition: i) fibrosis agent; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is the gastrointestinal stent.

Randomly provide among the present invention in all fields: be used to implant the method for medical apparatus, comprise: (a) soaking into the fibrosis agent will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into anti-infective will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises fibrosis agent and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Method with being used to implant medical apparatus comprises: (a) soaking into the compositions that comprises fibrosis agent, anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host.

With regard to above-mentioned each side, one or more (for example any two) in the following feature can define the present invention with the further mode with the device that uses in the inventive method: described medical apparatus is the esophagus stent; Described medical apparatus is gallbladder (billary) stent; Described medical apparatus is the colon stent; With described medical apparatus be the pancreas stent.

4. trachea and bronchus stent

The present invention provides the method that is used to implant medical apparatus in one aspect of the method, comprising: (a) soak into implanted or implanted the host tissue of described medical apparatus with following composition: i) fibrosis agent; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is trachea or bronchus stent.

Randomly provide among the present invention in all fields: be used to implant the method for medical apparatus, comprise: (a) soaking into the fibrosis agent will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into anti-infective will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises fibrosis agent and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Method with being used to implant medical apparatus comprises: (a) soaking into the compositions that comprises fibrosis agent, anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host.

With regard to above-mentioned each side, one or more (for example any two) in the following feature can define the present invention with the further mode with the device that uses in the inventive method: described medical apparatus is the trachea stent; Described medical apparatus is the bronchus stent; Described medical apparatus is a metal trachea stent; Described medical apparatus is a metal bronchus stent; Described medical apparatus is a polymerization trachea stent; With described medical apparatus be polymerization bronchus stent.

5. Genito-urinary stent

The present invention provides the method that is used to implant medical apparatus in one aspect of the method, comprising: (a) soak into implanted or implanted the host tissue of described medical apparatus with following composition: i) fibrosis agent; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is the Genito-urinary stent.

Randomly provide among the present invention in all fields: be used to implant the method for medical apparatus, comprise: (a) soaking into the fibrosis agent will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into anti-infective will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises fibrosis agent and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Method with being used to implant medical apparatus comprises: (a) soaking into the compositions that comprises fibrosis agent, anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host.

With regard to above-mentioned each side, one or more (for example any two) in the following feature can define the present invention with the further mode with the device that uses in the inventive method: described medical apparatus is the ureter stent; Described medical apparatus is the urethra stent; Described medical apparatus is the fallopian tube stent; Described medical apparatus is the prostate stent; Described medical apparatus is a metal Genito-urinary stent; With described medical apparatus be polymerization Genito-urinary stent.

6. ear and nose stent

The present invention provides the method that is used to implant medical apparatus in one aspect of the method, comprising: (a) soak into implanted or implanted the host tissue of described medical apparatus with following composition: i) fibrosis agent; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is ear and nose stent.

Randomly provide among the present invention in all fields: be used to implant the method for medical apparatus, comprise: (a) soaking into the fibrosis agent will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into anti-infective will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises fibrosis agent and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Method with being used to implant medical apparatus comprises: (a) soaking into the compositions that comprises fibrosis agent, anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host.

With regard to above-mentioned each side, one or more (for example any two) in the following feature can define the present invention with the further mode with the device that uses in the inventive method: described medical apparatus is the tear stains stent; Described medical apparatus is pharyngotympanic tube stent (Eustachiantube stent); Described medical apparatus is the nose stent; With described medical apparatus be the hole stent.

7. ear breather

The present invention provides the method that is used to implant medical apparatus in one aspect of the method, comprising: (a) soak into implanted or implanted the host tissue of described medical apparatus with following composition: i) fibrosis agent; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is the ear breather.

Randomly provide among the present invention in all fields: be used to implant the method for medical apparatus, comprise: (a) soaking into the fibrosis agent will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into anti-infective will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises fibrosis agent and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Method with being used to implant medical apparatus comprises: (a) soaking into the compositions that comprises fibrosis agent, anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host.

With regard to above-mentioned each side, one or more (for example any two) in the following feature can define the present invention with the further mode with the device that uses in the inventive method: described medical apparatus is the tubular pipe of ventilation of tympanic cavity; Described medical apparatus is the T-pipe; Described medical apparatus is a TT; Described medical apparatus is a drainage tube; Described medical apparatus is the tympanum pipe; Described medical apparatus is the otology pipe; Described medical apparatus is that myringotomy is with managing; Described medical apparatus is the eustachian tube implant; Described medical apparatus is the pharyngotympanic tube prosthese; With described medical apparatus be the pharyngotympanic tube stent.

8. intraocular implant

The present invention provides the method that is used to implant medical apparatus in one aspect of the method, comprising: (a) soak into implanted or implanted the host tissue of described medical apparatus with following composition: i) fibrosis agent; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is an intraocular implant.

Randomly provide among the present invention in all fields: be used to implant the method for medical apparatus, comprise: (a) soaking into the fibrosis agent will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into anti-infective will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises fibrosis agent and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Method with being used to implant medical apparatus comprises: (a) soaking into the compositions that comprises fibrosis agent, anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host.

With regard to above-mentioned each side, one or more (for example any two) in the following feature can define the present invention with the further mode with the device that uses in the inventive method: described medical apparatus is intraocular lens (intraocular) device that is used to prevent lenticular opacity; Described medical apparatus is the polymethyl methacrylate intraocular lens; Described medical apparatus is the siloxanes intraocular lens; Described medical apparatus is an achromat; Described medical apparatus is crystalline lens prosthese (pseudophako); Described medical apparatus is for there being crystalline lens eyeglass (phakic lens); Described medical apparatus is aphakic lens (aaphakic lens); Described medical apparatus is many-focus intraocular lens; Described medical apparatus is hydrophilic and hydrophobic acrylic acid intraocular lens; Described medical apparatus is an intraocular implant; Described medical apparatus is the vision eyeglass; Described medical apparatus is hard ventilative eyeglass; Described medical apparatus is folding intraocular lens; Described medical apparatus is the rigidity intraocular lens; Described medical apparatus is the rectification implant that is used for visual disorder; Described medical apparatus is to be applicable to the intraocular implant that is used in combination with graft with cornea; With described medical apparatus be applicable to treat ECCE after the intraocular implant that is used in combination of secondary cataract.

9. the medical apparatus that is used for the treatment of hypertrophic cicatrix or keloid

The application provides the method that is used to implant medical apparatus in one aspect of the method, comprising: (a) soak into implanted or implanted the host tissue of described medical apparatus with following composition: i) fibrosis agent; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is the medical apparatus that is used for the treatment of hypertrophic cicatrix or keloid.

Randomly provide among the present invention in all fields: be used to implant the method for medical apparatus, comprise: (a) soaking into the fibrosis agent will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into anti-infective will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises fibrosis agent and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Method with being used to implant medical apparatus comprises: (a) soaking into the compositions that comprises fibrosis agent, anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host.

With regard to above-mentioned each side, one or more (for example any two) in the following feature can define the present invention with the further mode with the device that uses in the inventive method: described with device be used for the treatment of hypertrophic cicatrix or keloid comprise putting of outside organization's expansion gear; Described device is the device that comprises shadowing elements that is used for the treatment of hypertrophic cicatrix or keloid, and wherein said shadowing elements can be pressed on the scar tissue; With described medical apparatus is to be used for the treatment of comprising locking element and grabbing the device of structure of hypertrophic cicatrix or keloid, makes the corium of skin wound and epidermal area to be pressed together.

10. blood vessel graft

The present invention provides the method that is used to implant medical apparatus in one aspect of the method, comprising: (a) soak into implanted or implanted the host tissue of described medical apparatus with following composition: i) fibrosis agent; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is a blood vessel graft.

Randomly provide among the present invention in all fields: be used to implant the method for medical apparatus, comprise: (a) soaking into the fibrosis agent will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into anti-infective will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises fibrosis agent and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Method with being used to implant medical apparatus comprises: (a) soaking into the compositions that comprises fibrosis agent, anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host.

With regard to above-mentioned each side, one or more (for example any two) in the following feature can define the present invention with the further mode with the device that uses in the inventive method: described medical apparatus is the outer graft of blood vessel; Described medical apparatus is a graft in the blood vessel; Described medical apparatus is the blood vessel graft that is suitable for replacing the blood vessel that is subjected to the aneurysm infringement; Described medical apparatus is to be applicable to the blood vessel graft that replaces the blood vessel that is subjected to the neointimal hyperplasia infringement; Described medical apparatus is the blood vessel graft that is suitable for replacing the blood vessel that is subjected to the thrombosis infringement; Described medical apparatus provides blood vessel to advance the blood vessel graft of path for being suitable for; Described medical apparatus passes through the blood vessel graft of the alternative conduit of the impaired or affected areas of intravenous for being suitable for providing blood flow; Described medical apparatus passes through the blood vessel graft of the alternative conduit of the impaired or affected areas of intra-arterial for being suitable for providing blood flow; Described medical apparatus is synthetic bypass graft; Described medical apparatus is strand-popliteal bypass grafts; Described medical apparatus is a thigh-thigh bypass graft; Described medical apparatus is anterior axillary line-thigh bypass graft; Described medical apparatus is the vein transplantation thing; Described medical apparatus is the PeV graft; Described medical apparatus is the Coronary vein graft; Described medical apparatus is inner breast transplant; Described medical apparatus is two fork blood vessel grafies; Described medical apparatus is a graft in the tube chamber; With described medical apparatus be the prosthese blood vessel graft.

11. hemodialysis access device

The present invention provides the method that is used to implant medical apparatus in one aspect of the method, comprising: (a) soak into implanted or implanted the host tissue of described medical apparatus with following composition: i) fibrosis agent; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is the hemodialysis access device.

Randomly provide among the present invention in all fields: be used to implant the method for medical apparatus, comprise: (a) soaking into the fibrosis agent will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into anti-infective will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises fibrosis agent and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Method with being used to implant medical apparatus comprises: (a) soaking into the compositions that comprises fibrosis agent, anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host.

With regard to above-mentioned each side, one or more (for example any two) in the following feature can define the present invention with the further mode with the device that uses in the inventive method: described medical apparatus is the AV fistula graft; Described medical apparatus is the AV access graft; Described medical apparatus is a venous duct; Described medical apparatus is a blood vessel graft; Described medical apparatus is implantable passage; With described medical apparatus be the AV part flow arrangement.

12. comprise the medical apparatus of thin film or mesh

The present invention provides the method that is used to implant medical apparatus in one aspect of the method, comprising: (a) soak into implanted or implanted the host tissue of described medical apparatus with following composition: i) fibrosis agent; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is the device that comprises thin film or mesh.

Randomly provide among the present invention in all fields: be used to implant the method for medical apparatus, comprise: (a) soaking into the fibrosis agent will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into anti-infective will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises fibrosis agent and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Method with being used to implant medical apparatus comprises: (a) soaking into the compositions that comprises fibrosis agent, anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host.

With regard to above-mentioned each side, one or more (for example any two) in the following feature can define the present invention with the further mode with the device that uses in the inventive method: described medical apparatus is the operation barrier; Described medical apparatus is the surgical adhesions barrier; Described medical apparatus is the surgery sheet; Described medical apparatus is a surgical patch; Described medical apparatus is the coated material of surgery; Described medical apparatus is the coated material of blood vessel; Described medical apparatus is a coated material around the blood vessel; Described medical apparatus is the coated material of adventitia; Described medical apparatus is the coated material of periadventitial; Described medical apparatus is an outer membrane; Described medical apparatus is a mesh around the blood vessel; Described medical apparatus is a binder; Described medical apparatus is the liquid binder; Described medical apparatus is a surgical dressing; Described medical apparatus is a gauze; Described medical apparatus is a fabric; Described medical apparatus is an adhesive tape; Described medical apparatus is the surgery film; Described medical apparatus is a polymeric matrix; Described medical apparatus is for organizing covering; Described medical apparatus is a surgery substrate; Described medical apparatus is a peplos; With described medical apparatus for organizing covering.

13. glaucoma drainage system

The present invention provides the method that is used to implant medical apparatus in one aspect of the method, comprising: (a) soak into implanted or implanted the host tissue of described medical apparatus with following composition: i) fibrosis agent; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is the glaucoma drainage system.

Randomly provide among the present invention in all fields: be used to implant the method for medical apparatus, comprise: (a) soaking into the fibrosis agent will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into anti-infective will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises fibrosis agent and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Method with being used to implant medical apparatus comprises: (a) soaking into the compositions that comprises fibrosis agent, anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host.

In certain embodiments, described medical apparatus is the glaucoma drainage system that comprises plate and pipe.

14. prosthetic heart valve or its composition

The present invention provides the method that is used to implant medical apparatus in one aspect of the method, comprising: (a) soak into implanted or implanted the host tissue of described medical apparatus with following composition: i) fibrosis agent; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is prosthetic heart valve or its composition.

Randomly provide among the present invention in all fields: be used to implant the method for medical apparatus, comprise: (a) soaking into the fibrosis agent will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into anti-infective will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises fibrosis agent and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Method with being used to implant medical apparatus comprises: (a) soaking into the compositions that comprises fibrosis agent, anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host.

With regard to above-mentioned each side, one or more (for example any two) in the following feature can define the present invention with the further mode with the device that uses in the inventive method: described medical apparatus is mechanical prosthetic heart valve; Described medical apparatus is biological prosthetic heart valve; Described medical apparatus is the implantable cyclic rings that is used to accept prosthetic heart valve; Described medical apparatus is the suture ring that is used to be connected to the periphery taper of prosthetic heart valve; With described medical apparatus be the suture ring that is used for mechanical prosthetic heart valve.

15. penile implant

The present invention provides the method that is used to implant medical apparatus in one aspect of the method, comprising: (a) soak into implanted or implanted the host tissue of described medical apparatus with following composition: i) fibrosis agent; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is a penile implant.

Randomly provide among the present invention in all fields: be used to implant the method for medical apparatus, comprise: (a) soaking into the fibrosis agent will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into anti-infective will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises fibrosis agent and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Method with being used to implant medical apparatus comprises: (a) soaking into the compositions that comprises fibrosis agent, anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host.

With regard to above-mentioned each side, one or more (for example any two) in the following feature can define the present invention with the further mode with the device that uses in the inventive method: described medical apparatus is the penile implant of pliability bar; Described medical apparatus is the penile implant of twisting bar; With described medical apparatus be the penile implant that has the inflatable device of pump.

16. endotracheal tube or tracheostoma intubate

The present invention provides the method that is used to implant medical apparatus in one aspect of the method, comprising: (a) soak into implanted or implanted the host tissue of described medical apparatus with following composition: i) fibrosis agent; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is endotracheal tube or tracheostoma intubate.

Randomly provide among the present invention in all fields: be used to implant the method for medical apparatus, comprise: (a) soaking into the fibrosis agent will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into anti-infective will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises fibrosis agent and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Method with being used to implant medical apparatus comprises: (a) soaking into the compositions that comprises fibrosis agent, anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host.

With regard to above-mentioned each side, one or more (for example any two) in the following feature can define the present invention with the further mode with the device that uses in the inventive method: described medical apparatus is endotracheal tube; Described medical apparatus is for being with unicameral endotracheal tube; Described medical apparatus is the endotracheal tube that has two-chamber; With described medical apparatus be the tracheostoma intubate.

17. luring, peritoneum analyses conduit

The present invention provides the method that is used to implant medical apparatus in one aspect of the method, comprising: (a) soak into implanted or implanted the host tissue of described medical apparatus with following composition: i) fibrosis agent; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is a peritoneal dialysis catheters.

Randomly provide among the present invention in all fields: be used to implant the method for medical apparatus, comprise: (a) soaking into the fibrosis agent will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into anti-infective will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises fibrosis agent and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Method with being used to implant medical apparatus comprises: (a) soaking into the compositions that comprises fibrosis agent, anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host.

In certain embodiments, described medical apparatus is the peritoneal dialysis catheters that is suitable for medicine is delivered to peritoneum.

18. central nervous system's part flow arrangement or pressure monitoring device

The present invention provides the method that is used to implant medical apparatus in one aspect of the method, comprising: (a) soak into implanted or implanted the host tissue of described medical apparatus with following composition: i) fibrosis agent; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is central nervous system's part flow arrangement or pressure monitor.

Randomly provide among the present invention in all fields: be used to implant the method for medical apparatus, comprise: (a) soaking into the fibrosis agent will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into anti-infective will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises fibrosis agent and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Method with being used to implant medical apparatus comprises: (a) soaking into the compositions that comprises fibrosis agent, anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host.

With regard to above-mentioned each side, one or more (for example any two) in the following feature can define the present invention with the further mode with the device that uses in the inventive method: described medical apparatus is ventricles of the brain thoracic cavity part flow arrangement; Described medical apparatus is the jugular vein part flow arrangement; Described medical apparatus is the caval vein part flow arrangement; Described medical apparatus is the ventriculoperitoneal part flow arrangement; Described medical apparatus is the gallbladder part flow arrangement; Described medical apparatus is the peritoneum part flow arrangement; Described medical apparatus is the EVD device; Described medical apparatus is the monitoring intracranial pressure device; Described medical apparatus is the dura mater sticking patch; Described medical apparatus is the fibrotic implant of prevention vertebrae plate resection postoperative epidural; Described medical apparatus is the device that is used for infusion under the continuous arachnoidea; Described medical apparatus is the drain part flow arrangement that is used for the brain drain fluids; With described medical apparatus be pressure monitoring device.

19. IVCF

In certain embodiments, the invention provides provides the method that is used to implant medical apparatus, comprising: (a) soak into implanted or implanted the host tissue of described medical apparatus with following composition: i) fibrosis agent; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is an IVCF.

Randomly provide among the present invention in all fields: be used to implant the method for medical apparatus, comprise: (a) soaking into the fibrosis agent will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into anti-infective will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises fibrosis agent and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Method with being used to implant medical apparatus comprises: (a) soaking into the compositions that comprises fibrosis agent, anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host.

With regard to above-mentioned each side, one or more (for example any two) in the following feature can define the present invention with the further mode with the device that uses in the inventive method: described medical apparatus is vascular filter; Described medical apparatus is a hemofilter; Described medical apparatus is a vena cava filter; Described medical apparatus is a vena cava filter; Described medical apparatus is the thrombosis filter; Described medical apparatus is the antimigration filter; Described medical apparatus is the percutaneous filtration system; Described medical apparatus is a catcher (intravascular trap) in the blood vessel; Described medical apparatus is an intravascular filter; Described medical apparatus is the clot filter; Described medical apparatus is a vein filter; With described medical apparatus be body vascular filter (body vessel filter).

20. gastrointestinal device

The present invention provides the method that is used to implant medical apparatus in one aspect of the method, comprising: (a) soak into implanted or implanted the host tissue of described medical apparatus with following composition: i) fibrosis agent; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is a gastrointestinal device.

Randomly provide among the present invention in all fields: be used to implant the method for medical apparatus, comprise: (a) soaking into the fibrosis agent will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into anti-infective will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises fibrosis agent and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Method with being used to implant medical apparatus comprises: (a) soaking into the compositions that comprises fibrosis agent, anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host.

With regard to above-mentioned each side, one or more (for example any two) in the following feature can define the present invention with the further mode with the device that uses in the inventive method: described medical apparatus is drainage tube; Described medical apparatus is a feeding tube; Described medical apparatus is a door body diverter; Described medical apparatus is the ascites diverter; Described medical apparatus is a nasogastric tube or through nasointestinal tube; Described medical apparatus is gastrostomy feeding pipe or percutaneous feeding tube; Described medical apparatus is that jejunum is made a mouthful endoscope tube; Described medical apparatus is the colonic diversion device; Described medical apparatus is a bile T-shape pipe; Described medical apparatus is a biopsy forceps; Described medical apparatus is the cholelithiasis removal device; Described medical apparatus is endoscope retrogradation ERCP (cholangiopancretography) device; Described medical apparatus is a swelling gasbag; Described medical apparatus is the nutrition device; Described medical apparatus is a stent; Described medical apparatus is hidden (low profile) device; Described medical apparatus is the virtual coloscope testing fixture; Described medical apparatus is a scrotiform endoscope; Described medical apparatus is a retracting device; Described medical apparatus is the gastrointestinal device that is suitable for checking gastrointestinal tract inside; Described medical apparatus is the gastrointestinal device that is suitable for lavation or suction usefulness; Described medical apparatus is the colonic diversion device; Described medical apparatus is the mechanical hemostasis device that is suitable for controlling gastrointestinal hemorrhage; Described medical apparatus is the gastrointestinal gastrointestinal device that is suitable for clean blocked; Described medical apparatus is for being used to provide the gastrointestinal device that exchanges between the two individual systems; Described medical apparatus is a door body diverter (p0ortosystemicshunt); With described medical apparatus be dilating catheter.

21. central vein conduit

The present invention provides the method that is used to implant medical apparatus in one aspect of the method, comprising: (a) soak into implanted or implanted the host tissue of described medical apparatus with following composition: i) fibrosis agent; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is the central vein conduit.

Randomly provide among the present invention in all fields: be used to implant the method for medical apparatus, comprise: (a) soaking into the fibrosis agent will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into anti-infective will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises fibrosis agent and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Method with being used to implant medical apparatus comprises: (a) soaking into the compositions that comprises fibrosis agent, anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host.

With regard to above-mentioned each side, one or more (for example any two) in the following feature can define the present invention with the further mode with the device that uses in the inventive method: described medical apparatus is the central vein conduit that has cover; Described medical apparatus is not for the central vein conduit of cover; Described medical apparatus is the central vein conduit that has flange; Described medical apparatus is not flanged central vein conduit; Described medical apparatus is for being suitable for providing the central vein conduit of blood circulation gateway; Described medical apparatus is for being suitable for providing the central vein conduit of many conduits of systemic vascular of coming in and going out; Described medical apparatus is the central vein conduit that is used to prevent the device that infects as the life-time service result; The central vein conduit of described medical apparatus for being suitable for using with the instrument that provides control by the device of central vein tube injection or extracting bodily fluid; Described medical apparatus is the total parenteral nutrition conduit; The central vein conduit that described medical apparatus inserts around being; Described medical apparatus is directed flow air bag-inserted pulmonary artery catheter; With described medical apparatus be the central vein of the life-time service conduit of coming in and going out.

22. ventricular assist device

The present invention provides the method that is used to implant medical apparatus in one aspect of the method, comprising: (a) soak into implanted or implanted the host tissue of described medical apparatus with following composition: i) fibrosis agent; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is a ventricular assist device.

Randomly provide among the present invention in all fields: be used to implant the method for medical apparatus, comprise: (a) soaking into the fibrosis agent will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into anti-infective will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises fibrosis agent and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Method with being used to implant medical apparatus comprises: (a) soaking into the compositions that comprises fibrosis agent, anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host.

With regard to above-mentioned each side, one or more (for example any two) in the following feature can define the present invention with the further mode with the device that uses in the inventive method: described medical apparatus is left ventricular assist device; Described medical apparatus is a right ventricular assist device; Described medical apparatus is two ventricular assist devices; Described medical apparatus is a heart-assist device; Described medical apparatus is an assist; Described medical apparatus is artificial heart-assist device; Described medical apparatus is the implantable cardiac aid system; Described medical apparatus is a heart assisting pump; With described medical apparatus be heart-assist device in the ventricle.

23. spinal implant

The present invention provides the method that is used to implant medical apparatus in one aspect of the method, comprising: (a) soak into implanted or implanted the host tissue of described medical apparatus with following composition: i) fibrosis agent; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is a spinal implant.

Randomly provide among the present invention in all fields: be used to implant the method for medical apparatus, comprise: (a) soaking into the fibrosis agent will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into anti-infective will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises fibrosis agent and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Method with being used to implant medical apparatus comprises: (a) soaking into the compositions that comprises fibrosis agent, anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host.

With regard to above-mentioned each side, one or more (for example any two) in the following feature can define the present invention with the further mode with the device that uses in the inventive method: described medical apparatus is spinal disc; Described medical apparatus is a spinal implant; Described medical apparatus is the vertebra disc prosthesis; Described medical apparatus is the lumbar disc implant; Described medical apparatus is a neck dish implant; Described medical apparatus is an intervertebral disc; Described medical apparatus is a spinal prostheses; Described medical apparatus is artificial dish; Described medical apparatus is a prosthese in the spinal disc; Described medical apparatus is an intervertebral implant; Described medical apparatus is implantable spinal implant; Described medical apparatus is the implantable bone graft; Described medical apparatus is artificial lumbar disc; Described medical apparatus is the enlargement of lymph nodes implant; Described medical apparatus is a disc spacers; Described medical apparatus is a fusion cage; Described medical apparatus is for merging basket; Described medical apparatus is the fusion cage device; Described medical apparatus is the amboceptor cage; Described medical apparatus is the amboceptor implant; Described medical apparatus is the fusion cage anchoring device; Described medical apparatus is the bone anchor tool; Described medical apparatus is for merging equalization chamber; Described medical apparatus is an anchor bone plate; With described medical apparatus be bone screw.

24. electric installation

The present invention provides the method that is used to implant medical apparatus in one aspect of the method, comprising: (a) soak into implanted or implanted the host tissue of described medical apparatus with following composition: i) fibrosis agent; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is an electric installation.

Randomly provide among the present invention in all fields: be used to implant the method for medical apparatus, comprise: (a) soaking into the fibrosis agent will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into anti-infective will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises fibrosis agent and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Method with being used to implant medical apparatus comprises: (a) soaking into the compositions that comprises fibrosis agent, anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host.

With regard to above-mentioned each side, one or more (for example any two) in the following feature can define the present invention with the further mode with the device that uses in the inventive method: described medical apparatus is nerve stimulator; Described medical apparatus is the spinal cord stimulation device; Described medical apparatus is the brain stimulation device; Described medical apparatus is a vagus nerve stimulator; Described medical apparatus is the sacral nerve stimulation device; Described medical apparatus is the nervus gastrica stimulator; Described medical apparatus is the acoustic nerve stimulator; Described medical apparatus is delivered to organ with stimulation; Described medical apparatus is delivered to bone with stimulation; Described medical apparatus is delivered to muscle with stimulation; Described medical apparatus is delivered to tissue with stimulation; Described medical apparatus is the device that is used for infusion under the continuous arachnoidea; Described medical apparatus is implantable electrode; Described medical apparatus is implantable pulse generator; Described medical apparatus is an electric conductance; Described medical apparatus is a stimulation lead; Described medical apparatus is that simulate catheter is led; Described medical apparatus is a cochlear implant; Described medical apparatus is a mini stimulator; Described medical apparatus is battery powered; Described medical apparatus is the radio frequency power supply; Described medical apparatus is battery and radio frequency duplicate supply; Described medical apparatus is a rhythm of the heart control device; Described medical apparatus is a cardiac pacemaker; Described medical apparatus is an implantable electric converter defibrillator system; Described medical apparatus is that heart leads; Described medical apparatus is a pacemaker lead; Described medical apparatus is that endocardium leads; Described medical apparatus is that cardioversion/defibrillator leads; Described medical apparatus is an epicardial lead; Described medical apparatus leads for the visceral pericardium defibrillator; Described medical apparatus is the sticking patch defibrillator; Described medical apparatus leads for the sticking patch defibrillator; Described medical apparatus is electric sticking patch; Described medical apparatus is for to lead through vein; Described medical apparatus fixedly leads for movable; Described medical apparatus is passively fixedly to lead; Described medical apparatus is that sensing is led; Described medical apparatus is a defibrillator; Described medical apparatus is an implantable sensor; Described medical apparatus is a left ventricular assist device; Described medical apparatus is a pulse generator; Described medical apparatus is that sticking patch leads; Described medical apparatus is electric sticking patch; Described medical apparatus is a cardiac stimulator; Described medical apparatus is the electric installation pick off; Described medical apparatus is the electric installation pump; Described medical apparatus is the dura mater sticking patch; Described medical apparatus is a ventricle peritoneal shunt device; Described medical apparatus is the ventricles of the brain-atrium diverter; Described medical apparatus is for being suitable for treatment or the fibrotic electric installation of prevention vertebrae plate resection postoperative epidural; Described medical apparatus is the electric installation that is suitable for treating or preventing rhythm abnormality; Described medical apparatus is to be suitable for treating or to prevent the unusual electric installation of atrial rhythm; Described medical apparatus is the electric installation that is suitable for treating or preventing conduction abnormalities; Described medical apparatus is to be suitable for treating or to prevent the unusual electric installation of sinus rhythm; Described medical apparatus is to be suitable for treating or the electric installation of prevent irritation; Described medical apparatus is the electric installation that is suitable for treating or preventing epilepsy; Described medical apparatus is for being suitable for treatment or preventing Parkinsonian electric installation; Described medical apparatus is for being suitable for treatment or preventing ataxic electric installation; Described medical apparatus is to be suitable for treating or the electric installation of prevention of obesity; Described medical apparatus is the electric installation that is suitable for treating or preventing depression; Described medical apparatus is to be suitable for treating or the electric installation of prevention of anxiety; Described medical apparatus is the electric installation that is suitable for treating or preventing anakusis; Described medical apparatus is to be suitable for treating or the electric installation of pre-ulcer; Described medical apparatus is the electric installation that is suitable for treating or preventing dvt formation; Described medical apparatus is for being suitable for treatment or preventing amyotrophic electric installation; Described medical apparatus is the electric installation that is suitable for treating or preventing joint stiffness; Described medical apparatus is the electric installation that is suitable for treating or preventing muscular spasm; Described medical apparatus is to be suitable for treating or the electric installation of prevention of osteoporosis; Described medical apparatus is for being suitable for treatment or preventing scoliotic electric installation; Described medical apparatus is the electric installation that is suitable for treating or preventing the spinal disc degeneration; Described medical apparatus is the electric installation that is suitable for treating or preventing spinal cord injury; Described medical apparatus is for being suitable for treatment or the parafunctional electric installation of prevention urinary system device; Described medical apparatus is the electric installation that is suitable for treating or preventing gastroparesis; Described medical apparatus is the electric installation that is suitable for treating or preventing malignant tumor; Described medical apparatus is the electric installation that is suitable for treating or preventing arachnoiditis; Described medical apparatus is the electric installation that is suitable for treating or preventing chronic disease; Described medical apparatus is to be suitable for treating or the electric installation of prevention of migraine; Described medical apparatus is the electric installation that is suitable for treating or preventing sleep disorder; Described medical apparatus is to be suitable for treating or preventing dull-witted electric installation; With described medical apparatus be the electric installation that is suitable for treating or preventing Alzheimer.

25. pick off

The present invention provides the method that is used to implant medical apparatus in one aspect of the method, comprising: (a) soak into implanted or implanted the host tissue of described medical apparatus with following composition: i) fibrosis agent; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is a pick off.

Randomly provide among the present invention in all fields: be used to implant the method for medical apparatus, comprise: (a) soaking into the fibrosis agent will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into anti-infective will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises fibrosis agent and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Method with being used to implant medical apparatus comprises: (a) soaking into the compositions that comprises fibrosis agent, anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host.

With regard to above-mentioned each side, one or more (for example any two) in the following feature can define the present invention with the further mode with the device that uses in the inventive method: described medical apparatus is blood or tissue glucose monitor; Described medical apparatus is the electrolyte pick off; Described medical apparatus is the blood constituent pick off; Described medical apparatus is temperature sensor; Described medical apparatus is the pH pick off; Described medical apparatus is an optical pickocff; Described medical apparatus is an amperometric sensor; Described medical apparatus is a pressure transducer; Described medical apparatus is a biosensor; Described medical apparatus is the sensing impulse repeater; Described medical apparatus is the strain pick off; Described medical apparatus is a magnetoresistive transducer; Described medical apparatus is a cardiac sensor; Described medical apparatus is a respiration pickup; Described medical apparatus is a hearing transducer; Described medical apparatus is the metabolite pick off; Described medical apparatus is for detecting the pick off of mechanical alteration; Described medical apparatus is for detecting the pick off that physics changes; The pick off that described medical apparatus changes for monitoring electrochemistry; Described medical apparatus is for detecting the pick off that magnetic changes; Described medical apparatus is for detecting the pick off that quickens change; Described medical apparatus is for detecting the pick off that ionizing radiation changes; Described medical apparatus is for detecting the pick off that sound wave changes; Described medical apparatus is for detecting the pick off of chemical modification; The pick off that described medical apparatus changes for detection of drugs concentration; Described medical apparatus is for detecting the pick off of hormone change; With described medical apparatus be the pick off that detected air pressure changes.

26. pump

The present invention provides the method that is used to implant medical apparatus in one aspect of the method, comprising: (a) soak into implanted or implanted the host tissue of described medical apparatus with following composition: i) fibrosis agent; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is a pump.

Randomly provide among the present invention in all fields: be used to implant the method for medical apparatus, comprise: (a) soaking into the fibrosis agent will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into anti-infective will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises fibrosis agent and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Method with being used to implant medical apparatus comprises: (a) soaking into the compositions that comprises fibrosis agent, anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host.

With regard to above-mentioned each side, one or more (for example any two) in the following feature can define the present invention with the further mode with the device that uses in the inventive method: described medical apparatus is the pump of sending that is suitable for insulin; Described medical apparatus is the pump that is suitable for sending anesthetics; Described medical apparatus is the pump that is suitable for sending chemotherapeutics; Described medical apparatus is the pump that is suitable for sending anti-arrhythmic; Described medical apparatus is for being suitable for sending the pump of spasmolytic (anti-spasmotic drug); Described medical apparatus is the pump that is suitable for sending the spasmolytic activating agent; Described medical apparatus is for being suitable for sending antibiotic pump; Described medical apparatus is only at the pump that detects the medicine of sending when the host is intravital to be changed; Described medical apparatus is to be applicable to the pump of sending as the medicine of continuous slow release; Described medical apparatus is the pump that is suitable for sending in the mode of beating the medicine of prescribed dose; Described medical apparatus is the pump of passing Teat pipette of program controlled; Described medical apparatus is to be suitable for the pump that ophthalmic is passed medicine; Described medical apparatus is the pump that is suitable for passing in the sheath medicine; Described medical apparatus is to be suitable for the pump that intraperitoneal is passed medicine; Described medical apparatus is to be suitable for the pump that intra-arterial is passed medicine; Described medical apparatus is the pump that is suitable for passing in the heart medicine; Described medical apparatus is an implantable osmotic pump; Described medical apparatus is the ocular delivery Teat pipette; Described medical apparatus is measurable system; Described medical apparatus is wriggling (cylinder) pump; Described medical apparatus is electric driving pump; Described medical apparatus is the elasticity pump; Described medical apparatus is that spring shrinks pump; Described medical apparatus is an air driven pump; Described medical apparatus is a hydraulic pump; Described medical apparatus is piston-dependency pump; Described medical apparatus is non--piston-dependency pump; Described medical apparatus is a dispense chamber; Described medical apparatus is an infusion pump; With described medical apparatus be passive pump.

27. soft tissue implant

The present invention provides the method that is used to implant medical apparatus in one aspect of the method, comprising: (a) soak into implanted or implanted the host tissue of described medical apparatus with following composition: i) fibrosis agent; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is a soft tissue implant.

Randomly provide among the present invention in all fields: be used to implant the method for medical apparatus, comprise: (a) soaking into the fibrosis agent will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into anti-infective will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises fibrosis agent and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Be used to implant the method for medical apparatus, comprise: (a) soaking into the compositions that comprises anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host; Method with being used to implant medical apparatus comprises: (a) soaking into the compositions that comprises fibrosis agent, anti-infective and polymer will be implanted or implanted the host tissue of described medical apparatus: with (b) described medical apparatus is implanted described host.

With regard to above-mentioned each side, one or more (for example any two) in the following feature can define the present invention with the further mode with the device that uses in the inventive method: described medical apparatus is the beauty treatment implant; Described medical apparatus is attached most importance to and is built implant; Described medical apparatus is a breast implant; Described medical apparatus is the breast implant that comprises siloxanes; Described medical apparatus is for comprising brinish breast implant; Described medical apparatus is face's implant; Described medical apparatus is the chin implant; Described medical apparatus is the lower jaw implant; Described medical apparatus is the lip implant; Described medical apparatus is a nasal implants; Described medical apparatus is the cheek implant; Described medical apparatus is the breast implant; Described medical apparatus is the buttocks implant; Described medical apparatus is autologous tissue's implant; Described medical apparatus is the autologous tissue's implant that comprises fatty tissue; Described medical apparatus is the autologous tissue's implant that comprises the autologous fat implant; Described medical apparatus is the autologous tissue's implant that comprises the skin implant; Described medical apparatus is the autologous tissue's implant that comprises the skin plug; Described medical apparatus is the autologous tissue's implant that comprises the tissue plug; Described medical apparatus is the autologous tissue's implant that comprises the muscular tissue lobe; Described medical apparatus is for comprising base of a fruit shape lobe, autologous tissue's implant; Described medical apparatus is for comprising base of a fruit shape lobe, autologous tissue's implant, wherein said base of a fruit shape lobe is from the back of the body, abdominal part, buttocks, thigh or groin; Described medical apparatus is the autologous tissue's implant that comprises the cell extraction implant; Described medical apparatus is the autologous tissue's implant that comprises autologous skin fibroblast suspension; Described medical apparatus is a tissue filler; With described medical apparatus be fat graft.

The present invention provides the following method that is used to prevent surgical adhesions in different aspect and embodiment:

In one aspect, the invention provides the method that is used for the prevention of surgical surgical adhesions, comprise to the position that these needs are arranged send organize the reactive polymer compositions in case provide the bag quilt tissue and with the fibre modification inhibitor be delivered to the bag quilt tissue.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, be included in by cerebral dura mater cover and the spinal column in the vertebrae plate resection postoperative patient delivering compositions, wherein said composition prevention of surgical surgical adhesions between the musculature.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, be included on the vertebrae plate resection position among this patient who needs with a kind of compositions bag by spinal nerves, wherein said composition prevention of surgical surgical adhesions.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, comprise a kind of compositions is impregnated into the tissue around the spinal nerves on the vertebrae plate resection position, wherein said composition prevention of surgical surgical adhesions among the patient of these needs.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, comprise a kind of compositions is delivered to surgical tray excision position among the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, comprise a kind of compositions is delivered to fiber disc excision position among the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, comprise a kind of compositions is delivered to neurosurgery (brain) operation technique position, wherein said composition prevention of surgical surgical adhesions among the patient of these needs.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, comprise the spinal surgery position that a kind of compositions of prevention of surgical surgical adhesions is impregnated into the patient of these needs.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, comprise the epidural tissue that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, comprise the cerebral dura mater tissue that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, comprise the gynecological position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, comprise the pelvis sidewall that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, comprise the peritoneal cavity that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, comprise the pelvic cavity that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, comprise the laparotomy position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, comprise the endoscopic procedure position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, comprise the hernia reparation position, wherein the said composition prevention of surgical surgical adhesions that a kind of compositions are delivered to the patient of these needs.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, comprise the cholecystectomy position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, comprise the cardiac surgery procedure position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, comprise the heart transplant operation position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, comprise the cardiovascular reparation position, wherein the said composition prevention of surgical surgical adhesions that a kind of compositions are delivered to the patient of these needs.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, comprise the cardiac valve replacement position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

In one aspect of the method, the invention provides the method for prevention pericardium surgical operation adhesion, comprise the pericardium surgical site that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, comprise the orthopaedic surgery operating position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, comprise the laceration of ligament position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, comprise the joint injury position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, comprise the tendon injury position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, comprise the cartilage injury position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, comprise the muscle injury position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, comprise the nerve injury position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, comprise the cosmetic surgery operating position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, comprise the reconstruction operations operating position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

In one aspect of the method, the invention provides the method for prevention of surgical surgical adhesions, comprise the breast implant position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

The method of prevention surgical adhesions as described herein can be further by one in the following feature, the two or more definition: described compositions is sent with the placement of medical implant combine; Described compositions sent with the placement of medical implant combine, and described compositions is placed the tissue adjacent with described medical implant; Described compositions sent with the placement of medical implant combine, and described compositions is placed on the described medical implant; Described compositions is sent by endoscope; Described compositions is sent by syringe needle; Described compositions is passed through catheter delivery; When operation, send described compositions; Send described compositions with use cryptoscope guiding.

The present invention provides the following method that is used for the treatment of inflammatory arthritis in different aspect and embodiment:

In one aspect, the invention provides the method that is used for the treatment of inflammatory arthritis, comprise that said composition comprises to patient's delivery treatments compositions that these needs are arranged: a) polymer and/or form the chemical compound and the b of polymer in position) the fibrosis agent.

In one aspect of the method, the invention provides the method that is used to prevent inflammatory arthritis, comprise that said composition comprises polymer and fibrosis agent to patient's delivery treatments compositions that these needs are arranged.

In one aspect of the method, the invention provides the method that is used for the treatment of osteoarthritis, comprise that said composition comprises polymer and fibrosis agent to patient's delivery treatments compositions that these needs are arranged.

In one aspect of the method, the invention provides the method that is used to prevent osteoarthritis, comprise that said composition comprises polymer and fibrosis agent to patient's delivery treatments compositions that these needs are arranged.

In one aspect of the method, the invention provides the method that is used for the treatment of the constitutional osteoarthritis, comprise that said composition comprises polymer and fibrosis agent to patient's delivery treatments compositions that these needs are arranged.

In one aspect of the method, the invention provides the method that is used to prevent the constitutional osteoarthritis, comprise that said composition comprises polymer and fibrosis agent to patient's delivery treatments compositions that these needs are arranged.

In one aspect of the method, the invention provides the method that is used for the treatment of the Secondary cases osteoarthritis, comprise that said composition comprises polymer and fibrosis agent to patient's delivery treatments compositions that these needs are arranged.

In one aspect of the method, the invention provides the method that is used to prevent the Secondary cases osteoarthritis, comprise that said composition comprises polymer and fibrosis agent to patient's delivery treatments compositions that these needs are arranged.

In one aspect of the method, the invention provides the method that is used for the treatment of rheumatoid arthritis, comprise that said composition comprises polymer and fibrosis agent to patient's delivery treatments compositions that these needs are arranged.

In one aspect of the method, the invention provides the method that is used to prevent rheumatoid arthritis, comprise that said composition comprises polymer and fibrosis agent to patient's delivery treatments compositions that these needs are arranged.

The method of treatment inflammatory arthritis as herein described can be further by one in the following feature, the two or more definition: described compositions is sent by intravenous; Described compositions is passed through oral delivery; Described compositions is sent by subcutaneous injection; Described compositions is sent by intramuscular injection; With described compositions is sent by intraarticular.

The present invention provides the following method that is used for hypertrophic cicatrix or keloid in different aspect and embodiment:

In one aspect, the invention provides method, comprise this patient is sent: a) fibrosis agent the patient treatment hypertrophic cicatrix pimple of needs; Or b) comprise i) fibrosis agent and ii) polymer and/or form the compound compositions of polymer in position.

In one aspect of the method, the invention provides method, comprise this patient is sent: a) fibrosis agent the patient treatment keloid of needs; Or b) comprise i) fibrosis agent and ii) polymer and/or form the compound compositions of polymer in position.

In certain embodiments, described activating agent or compositions are directly injected cicatrix or keloid.In some other embodiment, described activating agent or compositions part are coated on cicatrix or the keloid.

The present invention provides the following method that is used to reduce bone loss in different aspect and embodiment:

In one aspect, the invention provides the method that patient to needs reduces the cartilage loss after the joint injury, comprise this patient is sent: a) fibrosis agent; Or b) comprise i) fibrosis agent and ii) polymer and/or form the compound compositions of polymer in position.

In one aspect of the method, the invention provides the method that patient to needs prevents the cartilage loss after the joint injury, comprise this patient is sent: a) fibrosis agent; Or b) comprise i) fibrosis agent and ii) polymer and/or form the compound compositions of polymer in position.

In one aspect of the method, the method for the cartilage loss after the invention provides patient to needs and reducing ligamentum cruciatum and tear comprises this patient is sent: a) fibrosis agent; Or b) comprise i) fibrosis agent and ii) polymer and/or form the compound compositions of polymer in position.

In one aspect of the method, the method for the cartilage loss after the invention provides patient to needs and preventing ligamentum cruciatum to tear comprises this patient is sent: a) fibrosis agent; Or b) comprise i) fibrosis agent and ii) polymer and/or form the compound compositions of polymer in position.

In one aspect of the method, the invention provides the method that patient to needs reduces the cartilage loss behind the meniscus tear, comprise this patient is sent: a) fibrosis agent; Or b) comprise i) fibrosis agent and ii) polymer and/or form the compound compositions of polymer in position.

In one aspect of the method, the invention provides the method that patient to needs prevents the cartilage loss behind the meniscus tear, comprise this patient is sent: a) fibrosis agent; Or b) comprise i) fibrosis agent and ii) polymer and/or form the compound compositions of polymer in position.

In certain embodiments, described activating agent or compositions are sent through intraarticular.

The present invention provides the following method that is used for the treatment of angiopathy in different aspect and embodiment:

In one aspect, the invention provides method, comprise this patient is sent: a) fibrosis agent the patient treatment angiopathy of needs; Or b) comprise i) fibrosis agent and ii) polymer and/or form the compound compositions of polymer in position.In certain embodiments, described activating agent or compositions intravascular week are sent.

In one aspect of the method, the invention provides, comprise this patient is sent: a) fibrosis agent the narrow method of the patient treatment of needs; Or b) comprise i) fibrosis agent and ii) polymer and/or form the compound compositions of polymer in position.In certain embodiments, described activating agent or compositions intravascular week are sent.

In one aspect of the method, the invention provides method, comprise this patient is sent: a) fibrosis agent the patient treatment restenosis of needs; Or b) comprise i) fibrosis agent and ii) polymer and/or form the compound compositions of polymer in position.In certain embodiments, described activating agent or compositions intravascular week are sent.

In one aspect of the method, the invention provides, comprise this patient is sent: a) fibrosis agent the atherosclerotic method of the patient treatment of needs; Or b) comprise i) fibrosis agent and ii) polymer and/or form the compound compositions of polymer in position.In certain embodiments, described activating agent or compositions intravascular week are sent.

The present invention provides compositions in different aspect and embodiment, comprising: i) fibrosis agent; Ii) polymer or form the chemical compound of polymer in position.

The further feature relevant with method and composition

In addition, with regard to each aspect of above-mentioned aspect, one or more (for example any two) in the following feature can be used for further defining the present invention in the mode of fibrosis agent, wherein these features can with any one or multiple merging in the said apparatus (for example, above-mentioned aspect further defines by said apparatus, and further is defined as follows): the regeneration of fibrosis agent inhibit cell; The fibrosis agent suppresses blood vessel and takes place; The fibrosis agent is suppressed to the fibrocyte migration; The fibrosis agent suppresses fibroblast proliferation; The fibrosis agent suppresses extracellular matrix deposition; The fibrosis agent suppresses tissue reconstruction; The fibrosis agent is an angiogenesis inhibitor; The fibrosis agent is 5-lipoxidase inhibitor or antagonist; The fibrosis agent is a chemokine receptor anagonists; The fibrosis agent is a cell cycle inhibitor; The fibrosis agent is a taxane; The fibrosis agent is anti-microtubule agent; The fibrosis agent is a paclitaxel; The fibrosis agent is not a paclitaxel; The fibrosis agent is the analog or the derivant of paclitaxel; The fibrosis agent is a vinca alkaloids; The fibrosis agent is camptothecine or its analog or derivant; The fibrosis agent is a podophyllotoxin; The fibrosis agent is a podophyllotoxin, and wherein podophyllotoxin is etoposide or its analog or derivant; The fibrosis agent is an anthracyclines; The fibrosis agent is an anthracyclines, and wherein anthracyclines is doxorubicin or its analog or derivant; The fibrosis agent is an anthracyclines, and wherein anthracyclines is mitoxantrone or its analog or derivant; Fibrosis is a platinum compounds; The fibrosis agent is a nitroso ureas; The fibrosis agent is a nitroimidazole; The fibrosis agent is an antifol; The fibrosis agent is a cytidine analog; The fibrosis agent is a pyrimidine analogue; The fibrosis agent is a fluoropyrimidine analogue; The fibrosis agent is a purine analogue; The fibrosis agent is chlormethine or its analog or derivant; The fibrosis agent is a hydroxyurea; The fibrosis agent is mitomycin (mytomicin) or its analog or derivant; The fibrosis agent is an alkyl sulfonic ester; The fibrosis agent is Benzoylamide or its analog or derivant; The fibrosis agent is nicotiamide or its analog or derivant; The fibrosis agent is halogeno-sugar or its analog or derivant; The fibrosis agent is the DNA alkylating agent; The fibrosis agent is anti-microtubule agent; The fibrosis agent is a topoisomerase enzyme inhibitor; The fibrosis agent is the DNA cutting agent; The fibrosis agent is an antimetabolite; The fibrosis agent suppresses ADA Adenosine deaminase; It is synthetic that the fibrosis agent suppresses purine ring; The fibrosis agent is a nucleotide interconversion inhibitor; The fibrosis agent inhibit dihydrofolate reduction; Fibrosis agent blocking-up thymidine monophosphate; The fibrosis agent causes the DNA infringement; The fibrosis agent is the DNA intercalator; The fibrosis agent is a rna synthesis inhibitor; The fibrosis agent is a pyrimidine synthesis inhibitors; Synthetic or the function of fibrosis agent inhibit ribonucleotide; The fibrosis agent suppresses the synthetic or function of thymidine monophosphate; It is synthetic that the fibrosis agent suppresses DNA; The fibrosis agent causes dna adduct to form; Fibrosis agent Profilin matter is synthetic; The fibrosis agent inhibit microtubule function; The fibrosis agent is the protein kinase inhibitors that cyclin relies on; The fibrosis agent is the epidermal growth factor kinase inhibitor; The fibrosis agent is an elastatinal; The fibrosis agent is a factor Xa inhibitor; The fibrosis agent is Farnesyltransferase inhibitor (farnesyltransferseinhibitor); The fibrosis agent is the fibrinogen antagonist; The fibrosis agent is the guanylate cyclase stimulant; The fibrosis agent is heatshock protein 90 antagonisies; The fibrosis agent is heatshock protein 90 antagonisies, and wherein heatshock protein 90 antagonisies are geldanamycin or its analog or derivant; The fibrosis agent is the guanylate cyclase stimulant; The fibrosis agent is the HMGCoA reductase inhibitor; The fibrosis agent is the HMGCoA reductase inhibitor, and wherein the HMGCoA reductase inhibitor is simvastatin or its analog or derivant; The fibrosis agent is water hydroorotic acid salt (hydroorotate) dehydrogenase inhibitor; The fibrosis agent is the IKK2 inhibitor; The fibrosis agent is the IL-1 antagonist; The fibrosis agent is the ICE antagonist; The fibrosis agent is the IRAK antagonist; The fibrosis agent is the IL-4 agonist; The fibrosis agent is an immunomodulator; The fibrosis agent is sirolimus or its analog or derivant; The fibrosis agent is not a sirolimus; The fibrosis agent is everolimus or its analog or derivant; The fibrosis agent is tacrolimus or its analog or derivant; The fibrosis agent is not a tacrolimus; The fibrosis agent is biolmus or its analog or derivant; The fibrosis agent is tresperimus or its analog or derivant; The fibrosis agent is auranofin or its analog or derivant; The fibrosis agent is the nor-rapamycin of 27-0-(demethylrapamycin) or its analog or derivant; The fibrosis agent is gusperimus or its analog or derivant; The fibrosis agent is pimecrolimus or its analog or derivant; The fibrosis agent is ABT-578 or its analog or derivant; The fibrosis agent is inosine monophosphate dehydrogenase (IMPDH) inhibitor; The fibrosis agent is the IMPDH inhibitor, and wherein the IMPDH inhibitor is Mycophenolic Acid or its analog or derivant; The fibrosis agent is the IMPDH inhibitor, and wherein the IMPDH inhibitor is 1-α-25 dihydroxyvitamin D ₃Or its analog or derivant; The fibrosis agent is the leukotriene inhibitor; The fibrosis agent is the MCP-1 antagonist; The fibrosis agent is the MMP inhibitor; The fibrosis agent is the NF kB inhibitor; The fibrosis agent is the NF kB inhibitor, and wherein the NF kB inhibitor is Bay 11-7082; The fibrosis agent is the NO antagonist; The fibrosis agent is the p38 map kinase inhibitor; The fibrosis agent is the p38 map kinase inhibitor, and wherein the p38MAP inhibitors of kinases is SB 202190; The fibrosis agent is a phosphodiesterase inhibitor; The fibrosis agent is the TGF beta inhibitor; The fibrosis agent is the TXA2. antagonist; The fibrosis agent is the TNF alpha-2 antagonists; The fibrosis agent is a tace inhibitor; The fibrosis agent is a tyrosine kinase inhibitor; The fibrosis agent is a vitronectin inhibitor; The fibrosis agent is a fibroblast growth factor inhibitor; The fibrosis agent is a kinases inhibitor; The fibrosis agent is a pdgf receptor kinase inhibitor; The fibrosis agent is an endothelial growth factor receptor kinase inhibitor; The fibrosis agent is a RAR antagonists; The fibrosis agent is the platelet derived growth factor receptor inhibitors of kinases; The fibrosis agent is the fibrinogen antagonist; The fibrosis agent is an antimycotic agent; The fibrosis agent is an antimycotic agent, and wherein antimycotic agent is a sulconazole; The fibrosis agent is a diphosphate; The fibrosis agent is the E.C. 3.1.1.32 inhibitor; The fibrosis agent is a histamine H 1/H2/H3 receptor antagonist; The fibrosis agent is a macrolide antibiotics; The fibrosis agent is the GPIIb/IIIa receptor antagonist; The fibrosis agent is an endothelin-receptor antagonists; The fibrosis agent is the peroxisome Proliferator-activated receptor agonist; The fibrosis agent is the estrogen receptor activity agent; The fibrosis agent is a somatostatin analogue; The fibrosis agent is neurokinin 1 antagonist; The fibrosis agent is neurokinin 3 antagonisies; The fibrosis agent is the VLA-4 antagonist; The fibrosis agent is the osteoclast inhibitor; The fibrosis agent is a DNA topoisomerase ATP hydrolysis inhibitor; The fibrosis agent is a hypertensin I conversion enzyme inhibitor; Fibrosis agent angiotensin II invertase antagonist; The fibrosis agent is an enkephalinase inhibitor; The fibrosis agent is a peroxisome Proliferator-activated receptor gamma agonist insulin sensitiser thing; The fibrosis agent is an inhibitors of protein kinase C; The fibrosis agent is ROCK (p-associated kinase) inhibitor; The fibrosis agent is the CXCR3 inhibitor; The fibrosis agent is the Itk inhibitor; The fibrosis agent is the cytosol phospholipase A ₂-alpha inhibitor; The fibrosis agent is the PPAR agonist; The fibrosis agent is an immunosuppressant; The fibrosis agent is the Erb inhibitor; The fibrosis agent is the programmed cell death agonist; The fibrosis agent is the lipocortin agonist; The fibrosis agent is the VCAM-1 antagonist; The fibrosis agent is a collagen antagonist; The fibrosis agent is α 2 integrin antagonisies; The fibrosis agent is the TNF alpha inhibitor; The fibrosis agent is a nitric oxide inhibitor; The fibrosis agent is a cathepsin inhibitors; The fibrosis agent is not an antiinflammatory; The fibrosis agent is not a steroidal; The fibrosis agent is not sugared cortex steroidal; The fibrosis agent is not a dexamethasone; The fibrosis agent is not a beclometasone; The fibrosis agent is not a dipropionate; The fibrosis agent is not an anti-infective; The fibrosis agent is not an antibiotic; And/or the fibrosis agent is not an antifungal.

In addition, with regard to each aspect of above-mentioned aspect, one or more (for example any two) in the following feature can be used for further defining the present invention in the mode of anti-infective, wherein these features can with any one or multiple merging in the said apparatus (for example, above-mentioned aspect further defines by said apparatus, and further is defined as follows): anti-infective is an anthracyclines; Anti-infective is a doxorubicin; Infection is a mitoxantrone; Anti-infective is the fluorine pyrimidine; Anti-infective is 5-fluorouracil (5-FU); Anti-infective is an antifol; Anti-infective is a methotrexate; Infection is a podophyllotoxin; Infection is an etoposide; Infection is a camptothecine; Infection is a hydroxyurea; Infection is a platinum complexes; And/or infection is a cisplatin.Described compositions can further randomly comprise antithrombotic agent.

In addition, with regard to each aspect of above-mentioned aspect, one or more (for example any two) in the following feature can be used for further defining the present invention in the mode of polymer, wherein any one in these features or a plurality of can (for example the merging with any one or multiple, fibrosis agent and the anti-infective in the said apparatus, above-mentioned aspect further defines by concrete device and concrete fibrosis agent, further is defined as follows): described polymer is formed by the reactant that comprises naturally occurring polymer; Described polymer is by comprising that proteinic reactant forms; Described polymer is formed by the reactant that comprises carbohydrate; Described polymer is formed by the reactant that comprises Biodegradable polymeric; Described polymer is formed by the reactant that comprises the polymer that biology can not be degraded; Described polymer is formed by the reactant that comprises collagen protein; Described polymer is by comprising that the proteic reactant of methylated collagen forms; Described polymer is formed by the reactant that comprises fibrinogen; Described polymer is formed by the reactant that comprises thrombin; Described polymer is formed by the reactant that comprises blood plasma; Described polymer is formed by the reactant that comprises calcium salt; Described polymer is formed by the reactant that comprises anti-fibrinolytic protein lytic agent (antifibronolytic agent); Described polymer is formed by the reactant that comprises the fibrinogen analog; Described polymer is by comprising that albuminised reactant forms; Described polymer is formed by the reactant that comprises plasminogen; Described polymer is formed by the reactant that comprises Feng's von willebrand's factor (von Willebrands factor); Described polymer is formed by the reactant that comprises Factor IX; Described polymer is formed by the reactant that comprises hypoallergenic tropocollagen; Described polymer is formed by the reactant that comprises hypoplasia peptide (atelopeptidic) collagen protein; Described polymer is formed by the reactant that comprises end peptide collagen protein; Described polymer is by comprising that the proteic reactant of crosslinked with collagen forms; Described polymer is formed by the reactant that comprises aprotinin; Described polymer is formed by the reactant that comprises epsilon-amino-just-caproic acid; Described polymer is formed by the reactant that comprises protein conjugate; Described polymer is formed by the reactant that comprises the gelatin conjugate; Described polymer is formed by the reactant that comprises synthetic polymer; Described polymer is formed by the reactant that comprises the chemical compound that contains buffered isocyanates; Described polymer is formed by the reactant that comprises the chemical compound that contains thiol synthesis; Described polymer is formed by the reactant that comprises the synthetic compound that contains two sulfydryls at least; Described polymer is formed by the reactant that comprises the synthetic compound that contains three sulfydryls at least; Described polymer is formed by the reactant that comprises the synthetic compound that contains four sulfydryls at least; Described polymer is by comprising that the reactant that contains amino synthetic compound forms; Described polymer is formed by the reactant that comprises the synthetic compound that contains two amino at least; Described polymer is formed by the reactant that comprises the synthetic compound that contains three amino at least; Described polymer is formed by the reactant that comprises the synthetic compound that contains four amino at least; Described polymer is formed by the reactant that comprises the synthetic compound that contains carbonyl-oxygen-succinimido; Described polymer is formed by the reactant that comprises the synthetic compound that contains two carbonyl-oxygen-succinimido at least; Described polymer is formed by the reactant that comprises the synthetic compound that contains three carbonyl-oxygen-succinimido at least; Described polymer is formed by the reactant that comprises the synthetic compound that contains four carbonyl-oxygen-succinimido at least; Described polymer is formed by the reactant that comprises the synthetic compound that contains polyalkylene oxide; Described polymer is formed by the reactant that comprises the synthetic compound that contains polyalkylene oxide and biodegradable polyester block; Described polymer is by comprising that the reactant that has the amino synthetic compound of reaction that contains polyalkylene oxide forms; Described polymer is by comprising that the reactant that has the synthetic compound that reacts sulfydryl that contains polyalkylene oxide forms; Described polymer is formed by the reactant that comprises the synthetic compound that has reaction carbonyl-oxygen-succinimido that contains polyalkylene oxide; Described polymer is formed by the reactant that comprises the synthetic compound that contains biodegradable polyester block; Described polymer is by comprising that the reactant that forms in whole or in part from the synthetic polymer of lactic acid or lactide forms; Described polymer is by comprising that the reactant that forms in whole or in part from the synthetic polymer of glycolic or Acetic acid, hydroxy-, bimol. cyclic ester forms; Described polymer is formed by the reactant that comprises polylysine; Described polymer is formed by reactant, and these reactants comprise (a) protein and (b) comprise the chemical compound of polyalkylene oxide part; Described polymer by comprise (a) protein and (b) reactant of polylysine form; Described polymer is by comprising that (a) protein and the reactant that (b) has the chemical compound of at least four sulfydryls form; Described polymer is by comprising that (a) protein and the reactant that (b) has the chemical compound of at least four amino form; Described polymer is by comprising that (a) protein and the reactant that (b) has the chemical compound of at least four carbonyl-oxygen-succinimido form; Described chemical compound is formed by reactant, and these reactants comprise (a) protein and (b) have the chemical compound in the biodegradable district that is formed by reactant that described reactant is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone; Described polymer is by comprising that the reactant of (a) collagen protein with the chemical compound that (b) contains the polyalkylene oxide part forms; Described polymer by comprise (a) collagen protein and (b) reactant of the chemical compound of polylysine form; Described polymer is by comprising that (a) collagen protein and the reactant that (b) has the chemical compound of at least four sulfydryls form; Described polymer is by comprising that (a) collagen protein and the reactant that (b) has the chemical compound of at least four amino form; Described polymer is by comprising that (a) collagen protein and the reactant that (b) has the chemical compound of at least four carbonyl-oxygen-succinimido form; Described chemical compound is formed by reactant, and these reactants comprise (a) collagen protein and (b) have the chemical compound in the biodegradable district that is formed by reactant that described reactant is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone; Described polymer is by comprising that the reactant of (a) methylated collagen albumen with the chemical compound that (b) contains the polyalkylene oxide part forms; Described polymer by comprise (a) methylated collagen albumen and (b) reactant of polylysine form; Described polymer is by comprising that (a) methylated collagen albumen and the reactant that (b) has the chemical compound of at least four sulfydryls form; Described polymer is by comprising that (a) methylated collagen albumen and the reactant that (b) has the chemical compound of at least four amino form; Described polymer is by comprising that (a) methylated collagen albumen and the reactant that (b) has the chemical compound of at least four carbonyl-oxygen-succinimido form; Described chemical compound is formed by reactant, and these reactants comprise (a) methylated collagen albumen and (b) have the chemical compound in the biodegradable district that is formed by reactant that described reactant is selected from lactic acid, lactide, glycolic, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone; Described polymer is by comprising that hyaluronic reactant forms; Described polymer is formed by the reactant that comprises derivatives of hyaluronic acids; Described polymer is 3,000-30,000 reactant formation by the number-average molecular weight that comprises poly-(ethylene glycol) ether four-sulfydryl of tetramethylolmethane; Described polymer is by comprising that number-average molecular weight that tetramethylolmethane gathers (ethylene glycol) ether four-amino is that 3,000-30,000 reactant forms; Described polymer is formed by reactant, and these reactants comprise: (a) have 3,000-30,000 the number-average molecular weight and the synthetic compound of a plurality of nucleophilic groups; (b) has 3,000-30,000 number-average molecular weight and comprise the synthetic compound of polyalkylene oxide district and a plurality of electrophilic groups; Described compositions comprises coloring agent, and described compositions is aseptic.

Provide the following example and them never to play the limit effect by explanation.

Embodiment

Embodiment 1

The microsphere for preparing drug loading by spray drying

With 3.6 gram methoxyl groups poly-(ethylene glycol 5000))-block-(poly-(DL-lactide). (65:35MePEG:PDLLA weight ratio) is dissolved in the 200ml dichloromethane.Add 400mg medicine (Mycophenolic Acid (MPA), chlorpromazine (CPZ) or paclitaxel (PTX)) and spray drying gained solution.Inlet temperature is 50 ℃, outlet temperature＜39 ℃, aspiration rates 100%, flow velocity 700 l/ hours.Under room temperature and vacuum, the microsphere dried overnight of collecting produced the even spheroidal particle that has less than about 10 microns (be typically about 0.5-about 2 microns) sizes.

Embodiment 2

The microsphere (＜10 microns) of loading MPA by w/o/w Emulsion method preparation

10% polyvinyl alcohol (PVA) solution that 100ml is prepared recently and 10ml pH3 join in the 600ml beaker with the saturated acetic acid solution of MPA.Acidifying PVA solution was stirred 30 minutes with 2000rpm.Simultaneously, preparation 400mgMPA and the solution of 800mgMePEG5000-PDLLA (65:35) in the 20ml dichloromethane.Polymer/dichloromethane solution is added drop-wise in the PVA solution, uses Fisher DYNA-MIX agitator to stir simultaneously with 2000rpm.After interpolation is finished, with this solution restir 45 minutes.Microspheres solution is gone to the conical centrifuge tubes of several disposable scale polypropylene, with the saturated acetic acid solution washing of the MPA of pH3, and with 2600rpm centrifugal 10 minutes.Decantation water layer and washing, centrifugal repeatedly and decantation 3 times.The microsphere through washing that lyophilization and vacuum drying merge is to remove any unnecessary water.

Embodiment 3

The microsphere that contains MPA (50-100 micron) by the preparation of w/o/w Emulsion method

Use 1%PVA solution and 500rpm mixing speed, use the microsphere that has about 50-100 micron mean size with the preparation of embodiment 2 identical operations steps.

Embodiment 4

The microsphere that contains CPZ and PTX by the preparation of w/o/w Emulsion method

Use the microsphere that contains PTX and CPZ with the preparation of embodiment 2 identical operations steps, but PVA solution and wash solution needn't be by acidifys and saturated with medicine.

Embodiment 5

The micelle that contains paclitaxel

MePEG2000 (41g) and MePEG2000-PDLLA (60:40) (410g) are merged in container and be heated with stirring to 75 ℃.After polymer melts fully and mixes, make temperature reduce to 55 ℃.Simultaneously, the preparation in oxolane PTX solution (46g/200ml) and under constant agitation the impouring polymer solution.Continue to stir and continue 1 hour again.The dry micelle that contains PTX desolvates and in grinding on 2mm sieve after the cooling to remove under 50 ℃ and vacuum.

Embodiment 6

Four functional poly-(ethylene glycol) succinimido glutarates, (PEG-SG4), non--the gelling preparation

Give fill in the 1ml syringe (syringe 1) of the hybrid junctioin that Luer locking running-on has been installed PEG-SG4 (100mg) (Sunbio, Inc., Orinda, CA).Fill 0.25ml6.3mM HCl solution (pH2.1) for the syringe (syringe 2) of 1ml capping.Fill 0.25ml0.12M monobasic sodium phosphate and 0.2M sodium carbonate (pH9.7) buffer for the syringe (syringe 3) of 1ml capping.With the acid solution of the solid contents of syringe 1 and syringe 2 by repeatedly described inclusions being gone to another syringe and mixes through hybrid junctioin from a syringe.After mixing fully, with one of whole mixture impouring syringe.Make the syringe that contains described mixture be connected (the auxiliary spraying-applicator of MICROMEDICS air (Model SA-6105)) then with an inlet of applicator.The syringe 3 that contains pH9.7 solution is connected on another inlet of applicator.As applicator manufacturer describes in detail, said preparation is coated on tissue surface.

Embodiment 7

Gelling preparation (premix) I

(50mg) (Sunbio Inc.) (is called " premix ") to fill PEG-SG4 (50mg) and PEG-SH4 (four functional poly-(ethylene glycol) mercaptan) in the 1ml syringe (syringe 1) to the hybrid junctioin that Luer locking running-on has been installed.Fill 0.25ml6.3mM HCl solution (pH2.1) for the syringe (syringe 2) of 1ml capping.Fill 0.25ml 0.12M monobasic sodium phosphate and 0.2M sodium carbonate (pH9.7) buffer for the syringe (syringe 3) of 1ml capping.Operating procedure described in the use embodiment 6 is with these compositions mixing and be coated on tissue surface.

Embodiment 8

Four functional poly-(ethylene glycol) amine, (PEG-N4) gelling preparations

Give and to fill PEG-SG4 (50mg) and PEG-SH4 (four senses are gathered (ethylene glycol) mercaptan) (10,25 or 40mg) in the 1ml syringe (syringe 1) of the hybrid junctioin that Luer locking running-on has been installed.Fill 0.25ml 6.3mM HCl solution (pH2.1) for the syringe (syringe 2) of 1ml capping.Fill 0.25ml 0.12M monobasic sodium phosphate and 0.2M sodium carbonate (pH9.7) buffer for the syringe (syringe 3) of 1ml capping.Give and to fill PEG-N4 (Sunbio, Inc.) (40,25 or 10mg) mixture (total 50mg) in the 1ml syringe (syringe 4) of the hybrid junctioin that Luer locking running-on has been installed to make PEG-SH4 (in syringe 1) and PEG-N4 (in syringe 4).With the inclusions of syringe 1 and syringe 2 by repeatedly described inclusions being gone to another syringe and mixes through hybrid junctioin from a syringe.After mixing fully, all preparations are pushed one of syringe.Make it be connected (the auxiliary spraying-applicator of MICROMEDICS air (Model SA-6105)) then with an inlet of applicator.The syringe 3 that contains pH9.7 solution is connected on another inlet of applicator.Syringe 4 is connected by hybrid junctioin with the syringe 3 that contains pH9.7 solution.After mixing the inclusions of syringe 3 and 4 fully, this mixture is pushed one of syringe, make then on its second inlet that is connected applicator.As applicator manufacturer describes in detail, said preparation is coated on tissue surface.

Embodiment 9

Mycophenolic Acid in PEG-SG4 and MPA disodium salt (NA ₂MPA)

MPA disodium salt (Na ₂ MPA) preparation: by MPA (1,10 or 100g) being dissolved in IPA (being respectively 44ml, 440ml or 4.4L) preparation Na2MPA.The 1MNaOH (aqueous solution) of 2 molar equivalents is joined in this solution fast, simultaneously vigorous stirring.Make the gained slurry reach boiling then, up to producing clarifying yellow solution.Stop stirring and making this solution be cooled to room temperature.Gained crystallization cake is moved mechanically, filter, with a large amount of IPA washings and drying and obtain Na in a vacuum ₂The white height crystalline fiber (productive rate is generally 70-80%) of MPA.

Give the middle PEG-SG4 (100mg) of filling of 1ml syringe (syringe 1) of the hybrid junctioin that Luer locking running-on has been installed.Fill 0.25ml 6.3mMHCl solution (pH2.1) for the syringe (syringe 2) of 1ml capping.Fill 0.25ml0.12M monobasic sodium phosphate and 0.2M sodium carbonate (pH9.7) buffer for the syringe (syringe 3) of 1ml capping.Give the MPA (5mg) and the Na that fill the sieve of all crossing (sifted)＜100 micron in the 1ml syringe (syringe 4) of the hybrid junctioin that Luer locking running-on has been installed ₂MPA (95mg).With the inclusions of syringe 4 and syringe 2 by repeatedly described inclusions being gone to another syringe and mixes through hybrid junctioin from a syringe.Then this solution is used for dissolving again the solid of syringe 1.After mixing fully, all preparations are pushed one of syringe.Make it be connected (the auxiliary spraying-applicator of MICROMEDICS air (Model SA-6105)) then with an inlet of applicator.The syringe 3 that contains pH9.7 solution is connected on another inlet of applicator.As applicator manufacturer describes in detail, said preparation is coated on tissue surface.

Embodiment 10

Mycophenolic Acid in premix

Give the mixture of filling PEG-SH4 (50mg), PEG-SG4 (50mg) and MPA (100mg, the sieve of mistake＜100 micron) in the 1ml syringe (syringe 1) of the hybrid junctioin that Luer locking running-on has been installed.Fill 0.25ml6.3 mM HCl solution (pH2.1) for the syringe (syringe 2) of 1ml capping.Fill 0.35ml0.24M monobasic sodium phosphate and 0.4M sodium carbonate (pH10.0) buffer for the syringe (syringe 3) of 1ml capping.Operating procedure described in the use embodiment 6 is with described composition mixing and be coated on tissue surface.

Embodiment 11

Mycophenolic Acid in premix and MPA disodium salt (NA ₂MPA)

Give the middle PEG-SG4 (50mg) of filling of 1ml syringe (syringe 1) of the hybrid junctioin that Luer locking running-on has been installed and the mixture of PEG-SH4 (50mg).Fill 0.25ml6.3mM HCl solution (pH2.1) for the syringe (syringe 2) of 1ml capping.Fill 0.25ml0.12M monobasic sodium phosphate and 0.2M sodium carbonate (pH9.7) buffer for the syringe (syringe 3) of 1ml capping.Give the MPA (5mg) and the Na of the sieve of filling equal mistake＜100 micron in the 1ml syringe (syringe 4) of the hybrid junctioin that Luer locking running-on has been installed ₂MPA (95mg).Operating procedure described in the use embodiment 9 is with described composition mixing and be coated on tissue surface.

Embodiment 12

Chlorpromazine in premix

Give the mixture of filling PEG-SG4 (50mg), PEG-SH4 (50mg) and CPZ (5 or 10mg) in the 1ml syringe (syringe 1) of the hybrid junctioin that Luer locking running-on has been installed.Fill 0.25ml6.3 mM HCl solution (pH2.1) for the syringe (syringe 2) of 1ml capping.Fill 0.25ml0.12M monobasic sodium phosphate and 0.2M sodium carbonate (pH9.7) buffer for the syringe (syringe 3) of 1ml capping.Operating procedure described in the use embodiment 6 is with described composition mixing and be coated on tissue surface.

Embodiment 13

The microsphere of the paclitaxel loaded in premix

Give the mixture of microspheres of filling PEG-SG4 (50mg), the PEG-SH4 (50mg) by the spray drying preparation in the 1ml syringe (syringe 1) of the hybrid junctioin that Luer locking running-on has been installed and loading the MePEG5000-PDLLA (65:35) of 10%PTX (0.5 or 2mg) (using the operating procedure described in the embodiment 17 to prepare).Fill 0.25ml6.3mM HCl solution (pH2.1) for the syringe (syringe 2) of 1ml capping.Fill 0.25ml0.12M monobasic sodium phosphate and 0.2M sodium carbonate (pH9.7) buffer for the syringe (syringe 3) of 1ml capping.Operating procedure described in the use embodiment 1 is with described composition mixing and be coated on tissue surface.

Embodiment 14

The microsphere of loading CPZ in premix

Give the mixture of microspheres of filling PEG-SG4 (50mg), the PEG-SH4 (50mg) by the spray drying preparation in the 1ml syringe (syringe 1) of the hybrid junctioin that Luer locking running-on has been installed and loading the MePEG5000-PDLLA (65:35) of 10%PTX (50 or 100mg) (using the operating procedure described in the embodiment 17 to prepare).Fill 0.25ml6.3mM HCl solution (pH2.1) for the syringe (syringe 2) of 1ml capping.Fill 0.25ml0.12M monobasic sodium phosphate and 0.2M sodium carbonate (pH9.7) buffer for the syringe (syringe 3) of 1ml capping.Operating procedure described in the use embodiment 6 is with described composition mixing and be coated on tissue surface.

Embodiment 15

The microsphere of loading MPA in premix

Give the mixture of microspheres of filling PEG-SG4 (50mg), the PEG-SH4 (50mg) by the spray drying preparation in the 1ml syringe (syringe 1) of the hybrid junctioin that Luer locking running-on has been installed and loading the MePEG5000-PDLLA (65:35) of 10%MPA (25 or 75mg) (using the operating procedure described in the embodiment 17 to prepare).Fill 0.25ml6.3mM HCl solution (pH2.1) for the syringe (syringe 2) of 1ml capping.Fill 0.35ml0.24M monobasic sodium phosphate and 0.4M sodium carbonate (pH10.0) buffer for the syringe (syringe 3) of 1ml capping.Operating procedure described in the use embodiment 6 is with described composition mixing and be coated on tissue surface.

Embodiment 16

The micelle that loads PTX is mixed premix

Give the middle PEG-SG4 (50mg) of filling of 1ml syringe (syringe 1) of the hybrid junctioin that Luer locking running-on has been installed and the mixture of PEG-SH4 (50mg).Fill 1.5ml6.3mM HCl solution (pH2.1) for the 2ml serum tube.Fill 0.25ml0.12M monobasic sodium phosphate and 0.2M sodium carbonate (pH9.7) buffer for the syringe (syringe 2) of 1ml capping.Filling is loaded the micelle (2mg or 8mg) (as preparation among the embodiment 21) of 10%PTX and is dissolved with the solution of 1ml pH2.1 again to the 2ml serum tube.Use the 1ml syringe to remove 0.25ml micellar solution; This syringe is connected with the syringe 1 that contains solid PEG-SG4 and PEG-SH4; And by repeatedly described inclusions being gone to another syringe and mixes described composition through hybrid junctioin from a syringe.After mixing fully, whole mixture is pushed one of syringe.Make it be connected (the auxiliary spraying-applicator of MICROMEDICS air (Model SA-6105)) then with an inlet of applicator.The syringe 3 that contains pH9.7 solution is connected on another inlet of applicator.As applicator manufacturer describes in detail, said preparation is coated on tissue surface.

Embodiment 17

Four functional poly-(ethylene glycol) butanimide glutarates (PEG-SG4), non-gelling preparation

Contain PEG-SG4 (400mg) for middle filling of 3ml syringe (syringe 1) of the hybrid junctioin that Luer locking running-on has been installed.Fill 1.0ml6.3mM HCl solution (pH2.1) for the syringe (syringe 2) of 3ml capping.Fill 1ml0.12M monobasic sodium phosphate and 0.2M sodium carbonate (pH9.7) buffer for the syringe (syringe 3) of 3ml capping.Operating procedure described in the use embodiment 6 is with described composition mixing and be coated on tissue surface.

Embodiment 18

Gelling preparation (premix) II

Give the middle PEG-SG4 (200mg) of filling of 3ml syringe (syringe 1) of the hybrid junctioin that Luer locking running-on has been installed and the mixture of PEG-SH4 (200mg).Fill 1.0ml6.3mM HCl solution (pH2.1) for the syringe (syringe 2) of 3ml capping.Fill 1ml0.12M monobasic sodium phosphate and 0.2M sodium carbonate (pH9.7) buffer for the syringe (syringe 3) of 3ml capping.Operating procedure described in the use embodiment 6 is with these compositions mixing and be coated on tissue surface.

Embodiment 19

Load the premix of MPA

Give the middle mixture of filling PEG-SG4 (200mg), PEG-SH4 (200mg) and MPA (200mg or 400mg) of 3ml syringe (syringe 1) of the hybrid junctioin that Luer locking running-on has been installed.Fill 1.0ml6.3mM HCl solution (pH2.1) for the syringe (syringe 2) of 3ml capping.Fill 1.5ml0.24M monobasic sodium phosphate and 0.4M sodium carbonate (pH10) buffer for the syringe (syringe 3) of 3ml capping.Operating procedure described in the use embodiment 6 is with these compositions mixing and be coated on tissue surface.

Embodiment 20

Be used to estimate influence that different chemical compounds produce the nitric oxide of macrophage

Filler test is assaied

Mouse macrophage cell line RAW264.7 is handled to remove cell and bed board in each hole on 6 orifice plates from bottle with pancreatin.With about 2 x 10 ⁶Individual cell inoculation is in the 2ml culture medium that contains 5% heat-inactivated fetal bovine serum (FBS).Hatch RAw 264.7 cells 1.5 hours to allow to be attached to plastics at 37 ℃.Preparing concentration with DMSO is 10 ^-2The mitoxantrone of M and serial dilution obtain a series of stock solution concentration (10 for 10 times ^-8M to 10 ^-2M).Remove culture medium then and in containing the fresh culture of 5%FBS with 1ng/mL reorganization Mus IFN γ and 5ng/mL LPS with or not with the mitoxantrone incubated cell.By the mitoxantrone DMSO storage liquid that directly adds 1/1000 dilution for preparing previously to every hole mitoxantrone is added cell.Hatch at 37 ℃ and to contain IFN γ, add deduct 24 hours (Chem.Ber. (1879) 12:426 of flat board of mitoxantrone of LPS; J.AOAC (1977) 60-594; " biochemistry summary yearbook " be (1994) 63:175 (Ann.Rev.Biochem.)).

When 24 hours finish, from the cell harvesting supernatant and measure the generation of nitrite.By the 50 μ l supernatant of five equilibrium in 96 orifice plates and add 50 μ l Greiss reagent A (0.5g sulfanilamide, 1.5mLH ₃PO ₄, 48.5mL ddH ₂O) and 50 μ l Greiss reagent B (0.05gN-(1-naphthyl)-ethylenediamine, 1.5 mLH ₃PO ₄, 48.5mL ddH ₂O) with each sample of triplicate test.Under absorbing, 562nm directly reading optical density on the microtest plate spectrophotometer.Behind the subtracting background in triplicate absorption mean deviation is obtained concentration value from nitrite standard curve (1 μ M is to 2mM).Determine 50% (IC by average nitrite concentration and positive control (with IFN γ and LPS stimulated cells) ₅₀) inhibition concentration.Determine the IC of mitoxantrone with the meansigma methods of the duplicate experiment of n=4 ₅₀Value (is seen accompanying drawing 2 (IC ₅₀=927nM)).The IC of the added compound below this test method determination ₅₀Value: IC ₅₀(nM): paclitaxel, 7; CNI-1493,249; Halofuginone, 12; Geldanamycin, 51; Anisomycin, 68; 17-AAG, 840; Anisomycin, 769.

Embodiment 21

Be used to estimate that different anti-scarring agents produce the TNF-α of macrophage

Filler test is assaied

Thereby human macrophage cell line THP-1 is seeded in every hole in 12 orifice plates contains 1 X 10 in the culture medium that 2mL contains 10%FCS ⁶Individual cell.By 20mg zymosan A is resuspended in 2mL ddH ₂Among the O and homogenate up to obtaining the zymosan that unit for uniform suspension preparation is opsonified.With the zymosan of 250g precipitation homogenate and be resuspended in its final concentration in the 4ml human serum and in 37 ℃ of water-baths, hatch and made it possible to conditioning in 20 minutes with 5mg/mL.Prepare Bay11-7082 and the serial dilution that concentration is 10-2M with DMSO and obtain a series of storage liquid concentration (10-8M to 10 for 10 times ^-2M) (" IMMUNOLOGY KEY WORDS INDEX (J.Immunol.) (2000) 165:411-418; 1.5ml0.24M (2000) 164:4804-4811; " immunological method magazine " (J.Immunol Meth.) (2000) 235 (1-2): 33-40).

Stimulate the THP-1 cell to produce TNF α by adding 1mg/mL through the zymosan of conditioning.By the DMSO storage liquid that directly adds 1/1000 dilution for preparing previously to every hole Bay 11-7082 is added the THP-1 cell.Every kind of drug level of test in triplicate hole.Hatched dull and stereotyped 24 hours at 37 ℃.

After stimulating in 24 hours, collect supernatant and produce with quantitative TNF α.Use the reorganization human TNF alpha to obtain standard curve by ELISA and measure TNF α concentration in the supernatant.Be used in the bag be cushioned liquid (the 0.1M sodium carbonate, pH9.5) in the dilution the anti-human TNF alpha capture antibody of 100 μ l 4 ℃ spend the night the bag by 96 hole MaxiSorb plates.The dilution of used capture antibody is batch special and rule of thumb determines.Then that capture antibody is air-breathing and with dull and stereotyped 3 times of lavation buffer solution (PBS, 0.05% tween 20) washing.At room temperature use dull and stereotyped 1 hour of 200 μ l/ hole Assay Diluent (PBS, 10%FCS pH7.0) sealing.Wash dull and stereotyped 3 times with lavation buffer solution the sealing back.Be prepared as follows standard and sample diluting liquid: (a) with sample supernatant dilution 1/8 and 1/16; (b) with 500pg/mL preparation reorganization human TNF alpha and serial dilution to produce the standard curve of 7.8pg/mL to 500pg/nL.Sample supernatant and standard will and join with the dull and stereotyped back of capture antibody coating incubated at room 2 hours with triplicate mensuration.Washing dull and stereotyped 5 times and with 100 μ l Working Detector (the anti-human TNF alpha detection of biotinylation antibody+avidin-HRP) was incubated at room 1 hour.After this is hatched, add 100 μ l substrate solution (Substrate Solution) (tetramethyl benzidine, H with plate washing 7 times and to flat board ₂O ₂) and incubated at room 30 minutes.In the hole, add stop bath (Stop Solution) (2NH then ₂SO ₄) and under 450nm, read the yellow reaction thing with the λ correction of 570nm.Determine average absorption and deduct average background from triplicate data readings.Obtain TNF α concentration value from standard curve.By relatively average T NF α concentration and positive control (using the THP-1 cell through the zymosan stimulation of conditioning) are determined 50% inhibition concentration (IC ₅₀).The meansigma methods of the duplicate experiment of N=4 is used for determining that Bay 11-7082 (sees accompanying drawing 3; IC ₅₀=810nM)) and rapamycin (IC ₅₀=51nM; Accompanying drawing 4) IC ₅₀Value.Use this test method(s) to determine the IC of following added compound ₅₀Value: IC ₅₀(nM): geldanamycin, 14; Mycophenolic acid, 756; Second, 792; Chlorpromazine, 6; CNI-1493,0.15; SKF86002,831; 15-deoxy prostaglandin J2,742; Fascaplysin, 701; Podophyllotoxin, 75; Mithramycin, 570; Daunorubicin, 195; Celastrol, 87; Chromomycin A3,394; Vinorelbine, 605; Vinblastine, 65.

Embodiment 22

Be used for estimating the surgical adhesions model of rat fibre modification inhibitor

Anti-cellulosic generative capacity with preparation in the rat caecum sidewall model evaluation body.With halothane anesthesia Sprague Dawley rat.Use aseptic preventive measure, open abdominal part by median incision.Caecum exposes and the emersion abdominal cavity.With the #10 knife blade endways 1.5cm to the scraping totally 45 times continuously of the back side of caecum and the outside of belly.Control blade angle and pressure are hemorrhage and avoid serious tissue injury to produce the pore shape.The left side of abdominal part is shunk and turn up to expose peritoneal wall part near caecum.Excision muscle (transverse abdomen) shallow-layer 1 X 2cm ²Area, what stay the second layer (internal oblique) from muscle tears the shape fiber.The surface of tamponade scraping is up to stopped bleeding.Then the caecum of being swiped is placed on the sidewall wound and and connect by two sutures.Preparation is used on both sides and the peritoneum sidewall both sides through striking off at the caecum through swiping.Place other two sutures by totally 4 sutures caecum is connected to injured sidewall and with two-layer closed abdominal incision.After 7 days, after death estimate animal, the degree and the seriousness of adhesion quantitatively and are qualitatively marked.

Embodiment 23

Be used for estimating the surgical adhesions model of rabbit fibre modification inhibitor

Ability with anti-cellulosic generation in rabbit cornua uteri (uterine horn) the model evaluation preparation body.The female rabbit of ripe New Zealand white (NZW) is anaesthetized sb. generally.Use aseptic preventive measure, at center line with two layer open abdominal paries to expose the uterus.Two cornua uteris all rise from the abdominal cavity and estimate size with the conduit of french scale (French Scale).Think that the last #8 of french scale (2.5-4.5mm diameter) is suitable for this model to the angle of #14.Hemorrhage with the scraping in the zone of 45 of #10 knife blade to two cornua uteris up to observing the pore shape at long 2.5cm and wide 0.4cm with relative peritoneal wall.The surface of tamponade scraping is up to stopped bleeding.And by place swipe area edge 2mm far away two sutures relative with peritoneal wall are fixed with each angle.Use preparation and with three layers of closed abdominal part.After 14 days, after death estimate animal, the degree and the seriousness of adhesion quantitatively and are qualitatively marked.

Embodiment 24

Be used to estimate the screening test of the influence of different chemical compound on cell proliferation

The fibroblast that 70-90% converges is handled with pancreatin, be seeded in the culture medium of 96 orifice plates with 600 cells/well once more and allow to spend the night adherent.Preparing concentration with DMSO is 10 ^-2The mitoxantrone of M and serial dilution obtain a series of stock solution concentration (10 for 10 times ^-8M to 10 ^-2M).With drug dilution liquid with 1000 times of culture medium dilutions and be added to cell and obtain cumulative volume 200 μ l/ holes.With every kind of drug level of in triplicate hole test.Hatch 72 hours (" external toxicology " (In vitro toxicol.) (1990) 3:219 of flat board that contain fibroblast and mitoxantrone at 37 ℃; " biotechnology and histochemistry " be (1993) 68:29 (Biotech.Histochem.); " biochemistry yearbook " be (1993) 213:426 (Anal.Biochem.)).

For finishing test, by the air-breathing culture medium of removing of gentleness.Add CYQUANT 400X GR dye indicator (Molecular Probes to 1 * lysis (Cell Lysis) buffer; Eugene, 1/400 diluent OR), and in the hole of flat board, add 200 μ l mixture.Hatched dull and stereotyped 3-5 minute in the room temperature lucifuge.In fluorescence microtest plate reader with～480 nm excitation wavelengths and～the 520nm emission maximum reads fluorescence.By meansigma methods and average relative fluorescence unit and the definite 50% inhibition concentration (IC of DMSO contrast that gets triplicate hole ₅₀).Meansigma methods with the duplicate experiment of n=4 is determined IC ₅₀Value.Determine the IC of following chemical compound with this test method(s) ₅₀Value: IC ₅₀(nM): mitoxantrone, 20 (accompanying drawings 5); Rapamycin, 19 (accompanying drawings 6); Paclitaxel, 23 (accompanying drawings 7); Mycophenolic acid, 550; Second (mofetil), 601; GW8510,98; Simvastatin, 885; Doxorubicin, 84; Geldanamycin, 11; Anisomycin, 435; 17-AAG, 106; Bleomycin, 86; Halofuginone, 36; Gemfibrozil, 164; Ciprofibrate, 503; Bezafibrate, 184; Epirubicin hydrochloride, 57; Hycamtin, 81; Fascaplysin, 854; Tamoxifen, 13; Etanidazole, 55; Gemcitabine, 7; Puromycin, 254; Mithramycin, 156; Daunorubicin, 51; L (-)-perilla alcohol, 966; Celastrol, 271; Anacitabine, 225; Oxaliplatin, 380; Chromomycin A3,4; Vinorelbine, 4; Idarubicin, 34; Nogalamycin, 5; 17-DMAG, 5; Epothilone d (epothilone D), 2; Vinblastine, 2; Vincristine, 7; Cytosine arabinoside, 137.

Embodiment 25

The mesh that contains paclitaxel damages the evaluation of neointimal hyperplasia growth in the carotid artery model as the example of estimating the fibre modification inhibitor to the rat balloon

Illustrate the mesh system that contains paclitaxel with rat air bag damage carotid artery model and place the effect of neointimal hyperplasia being grown in back 14 days.

Matched group

With 1.5% halothane anesthesia in the oxygen heavily for the Wistar rat of 400-500g and expose left external carotid artery.(Baxter, Irvine CA) stretch into left common carotid artery downwards up to aorta by the arteriotomy in the external carotid artery with A 2 French FOGARTY balloon embolectomy conduits.With enough saline expanding baloons to produce slight resistance (about 0.02ml) and it by withdrawing to the carotid bifurcation twisting.Then the balloon venting is also repeated this step twice again.This technology produces the expansion of arterial wall and degrading of endothelium.Connect external carotid artery after removing conduit.Right common carotid artery does not have impaired and with comparing.

Taxol treatment around the local vascular

At once, the long-range end fragment of the 1cm of tremulous pulse exposed and with the mesh that contains 1 x 1cm paclitaxel (on the 10:90 PLG mesh in the 50:50 PLG coating 345 μ g paclitaxels) processing after the left common carotid artery damage.Close wound then and animal was kept 14 days.

Histology and immunohistochemistry

During execution, animal was implemented euthanasia with carbon dioxide with the formaldehyde of 10% phosphate-buffered in 15 minutes with the 100mmHg pressure injection.Gather in the crops two carotid artery and in fixative, spend the night.Handle the fixed tremulous pulse of institute and use paraffin embedding.Cutting the thick continuous transverse section of 3 μ m with the every 2mm of respective horizontal inside and outside the implantation region of impaired left neck artery and in the contrast right carotid.Transverse section is used for cell counting with the dyeing of the h and E of Mayer and is used for morphometric and stereologic analysis and is used for the extracellular matrix components evaluation with the five colors (pentachrome) dyeing of Movat.

The result

From accompanying drawing 8-10, obviously use paclitaxel mesh preparation that the blood vessel of paclitaxel is sent on every side and cause significantly reducing of neointimal hyperplasia.

Embodiment 26

The influence that paclitaxel and other anti-microtubule agent produce matrix metalloproteinase

A. Material and method

1) The AP-1 transcriptional activity that IL-1 stimulates is subjected to the inhibition of paclitaxel

With the construct transfection that contains the CAT reporter gene that AP-1 drives and add IL-1, IL-1 (50ng/ml) stimulates and hatched 24 hours lacking or exist under the condition of multiple concentration paclitaxel with chondrocyte.Taxol treatment reduces CAT activity (meansigma methods ± SD) in the mode that relies on concentration.According to t check, P＜0.05, with asterisk ( ^*) data that mark are compared with the inductive CAT activity of IL-1 has significance.Shown in the result represent independent experiment three times.

2) Paclitaxel influences .AP-1 DNA to the inductive AP-1 dna binding activity of IL-1

Measure in conjunction with active with radiolabeled people AP-1 sequence probe and gel mobility shift assay.Will from need not or with not commensurability paclitaxel (10 ^-7To 10 ^-5M) use the extract and the excess probe of the chondrocyte of IL-1 β (20ng/ml) processing to hatch on ice then 30 minutes, carry out native gel electrophoresis then." com " swimming lane contains excessive unlabelled AP-1 oligonucleotide.Shown in the result represent independent experiment three times.

3) Paclitaxel is to the influence of inductive MMP-1 of IL-1 and MMP-3 mRNA expression

With cell with multiple concentration (10 ^-7To 10 ^-5M) taxol treatment 24 hours was handled 18 hours with IL-1 β (20ng/ml) in the presence of paclitaxel then again.Separate total RNA, and measure MMP-1 mRNA level by rna blot analysis.Peel off trace and usefulness subsequently ³²The rat GAPDH cDNA of P-labelling surveys once more, and described cDNA is as housekeeping gene.Shown in the result represent independent experiment four times.Carry out the quantitative of collagenase-1 and molten stromatin expression of enzymes mRNA level.With MMP-1 and the GAPDH normalization of MMP-3 expression.

4) Other anti-microtubule agent is to the influence of collagenase expression

From calf cartilage fresh separated chondrocyte culture of former generation.With cell with 2.5 x 10 ⁶/ ml plating is in 100 x 20mm culture dishs and containing 37 ℃ of following night incubation in the Ham ' s F12 culture medium of 5%FBS.With the cell hunger of in serum-free medium, spending the night, handled 6 hours with the anti-microtubule agent of multiple concentration then.Also additionally hatched dull and stereotyped 18 hours to each dull and stereotyped IL-1 (20ng/ml) that adds then.Separate total RNA and with its electrophoresis on denaturant gel by acidify guanidinium isothiocyanate method.On 1% denaturant gel, analyze the RNA sample (15 μ g) of degeneration by gel electrophoresis, with its transfer to nylon membrane and with ³²The collagenase cDNA probe hybridization of P-labelling. ³²Be marked with the application of sample of guaranteeing about equally in the glyceraldehyde phosphate dehydrogenase of P-labelling (GAPDH) the cDNA conduct.The scan exposure film is also used the IMAGEQUANT quantitative analysis.

B. The result

1) The promoter of matrix metalloproteinase family

Accompanying drawing 11A shows that except gelatinase B all matrix metalloproteinases all contain transcribes element AP-1 and PEA-3.The activation of transcription factor AP-1 is depended in the expression of definite matrix metalloproteinase such as collagenase and molten stromatin enzyme.Thereby the inhibitor of AP-1 can suppress expression of MMPs mRNA.

2) Paclitaxel is to the influence of AP-1 transcriptional activity

As diagrammatic among the accompanying drawing 11B, IL-1 stimulates 5 times of AP-1 transcriptional activities.The pretreatment of the chondrocyte of transient transfection has been reduced the activity of the inductive AP-1 reporter gene of IL-1 CAT with paclitaxel.Thereby paclitaxel is to rely on the mode (10 of concentration ^-7To 10 ^-5M) reduce the inductive AP-1 activity of IL-1 in the chondrocyte.These data interpretation paclitaxels are active strong inhibition agent of AP-1 in the chondrocyte.

3) Paclitaxel is to the influence of AP-1 dna binding activity

In order to prove that the active paclitaxel of AP-1 suppresses is not because non-special influence uses chondrocyte nucleus lysate to check that paclitaxel is to the bonded influence of the inductive AP-1 of IL-1 to oligonucleotide.As shown in accompanying drawing 11C, from being 10 with concentration ^-7To 10 ^-5IL-1 is inductive in the lysate that 24 hours chondrocyte of M paclitaxel pretreatment obtains reduces in conjunction with activity.The paclitaxel of AP-1 transcriptional activity suppresses DNA bonded to be reduced closely related with AP-1.

4) Paclitaxel is to the influence of collagenase and molten stromatin expression of enzymes

Because the paclitaxel active strong inhibition agent that is AP-1, so checked that paclitaxel is to the two kinds of important inductive collagenases of matrix metalloproteinase IL-1 participating in inflammatory diseases and the influence of molten stromatin expression of enzymes.In brief, as shown in accompanying drawing 11D, IL-1 induces increases collagenase and molten stromatin enzyme mRNA level in the chondrocyte.Significantly reduced collagenase and molten stromatin enzyme mRNA level in 24 hours with paclitaxel pretreatment cartilage.10 ^-5During the M paclitaxel, have fully and suppress.The result shows that paclitaxel suppresses two kinds of matrix metalloproteinases fully under the concentration similar to suppressing the AP-1 activity.

5) Other anti-microtubule agent is to the influence of collagenase expression

Accompanying drawing 12A-H illustrates anti-microtubule agent and suppresses collagenase expression.By adding the expression of proinflammatory cytokine IL-1 stimulation collagenase.Anti-microtubule agent, particularly LY290181, hexanediol, deuterium oxide, GEE, ethylene glycol bisthioglycolate-(succinimido succinate), tubercidin, AIF with multiple concentration ₃, and Epothilones preincubate chondrocyte all be low to moderate 1 x 10 ^-7Prevent the inductive collagenase expression of IL-1 under the concentration of M.

C. Discuss

Paclitaxel is 10 ^-6Can vitro inhibition collagenase and molten stromatin expression of enzymes under the concentration of M.---except gelatinase B all matrix metalloproteinases induce required step---explains, can suppress to rely on other matrix metalloproteinases of AP-1 so estimate paclitaxel because this inhibition can be by the active inhibition of AP-1.The level of these matrix metalloproteinases raises in all inflammatory diseasess and plays an important role in substrate degradation, cell migration and propagation and blood vessel generation.Thereby the paclitaxel of the expression of matrix metalloproteinase such as collagenase and molten stromatin enzyme suppresses and can have beneficial effect to inflammatory diseases.

Except the inhibition effect of paclitaxel to collagenase expression, LY290181, hexanediol, deuterium oxide, GEE, AIF ₃, tubercidin, Epothilones and ethylene glycol bisthioglycolate-(succinimido succinate) all be low to moderate 1 x 10 ^-7Prevent the inductive collagenase expression of IL-1 under the concentration of M.Thereby anti-microtubule agent can suppress the AP-1 approach under multiple concentration.

Embodiment 27

The inhibition that paclitaxel takes place blood vessel

A. Chicken chorio-allantois (" CAM ") test

With fertilization, national Embryo Gallus domesticus is hatched does not have shell after 3 days and cultivate.In this step, by removing air chamber eggshell emptying the contents of eggs on every side.The end opposite of separating inner shell membrane then and wearing out shell skids off from blunt nosed gently to allow the contents of eggs.The contents of eggs is emptied in the aseptic glass bowl of round bottom also with culture dish blanketing lid.Then these being placed relative humidity is 90% and 3%CO ₂Incubator in and cultivated 3 days.

(MI) with 0.25,0.5, the aliquot of the per 10 μ l of 1,5,10,30 μ g 0.5% methylcellulose is mixed for Sigma, St.Louis with paclitaxel.Because paclitaxel is insoluble in water, so produce fine particle with bead.With 10 mul aliquots samples of this solution on Parafilm dry 1 hour, form diameter 2mm dish.Carefully place the growing edge of each CAM then at the basin that will contain paclitaxel on the 6th day of hatching.By the methylcellulose dish that will not have paclitaxel in identical time-histories place obtain on the CAM contrast.After exposing (hatching 8 days) in 2 days, use the stereomicroscopy vascular system.A kind of White-opalescent solution Liosyn II is expelled among the CAM to increase the visibility of vascular details.With of the vascular system imaging of Zeiss stereoscopic microscope to undyed live embryo, this stereoscopic microscope interface be television camera (Dage-MTI Inc., Michigan City, IN).These video signals show with 160 x magnifications and with imaging analysis system (Vidas, Kontron then; Etching Gernmany) catches.(Model 3000 at scanner-recorder then; Matrix Instruments, Orangeburg NY) goes up generation image egative film.

The film that does not have the shell embryo with the flushing of 2% glutaraldehyde in the 0.1M sodium cacodylate buffer liquid 8 day age; The extra fixative of injection under CAM.After the original position 10 minutes, remove CAM and at room temperature placed fresh fixative 2 hours.The washing of in the cacodylate buffer that contains 6% sucrose, spending the night then.The purpose zone is fixed 1.5 hours after 4 ℃ in 1% Osmic acid..Be organized in then in the ethanol of gradient series and dewater, with the expoxy propane solvent exchange, and embedding in the Spurr resin.Cut slice with diamond knife, place on the copper grid, and with Joel 1200EX electron micrograph.Similarly, cutting 0.5mm cuts into slices and is used for light microscopy with C.I. 49410. dyeing.

At the 11st day that grows, Embryo Gallus domesticus was used to corrode forming technique.(Redding CA) is expelled to the CAM vascular system for Ted Pella, Inc. with the Mercox resin to use No. 30 hypodermic needles.Moulding material is made up of 2.5g Mercox CL-2B polymer and the 0.05g catalyst (55% benzoyl peroxide) with 5 minutes polymerization times.After the injection, allow plastics to leave standstill 1 hour, in baking oven, spend the night under 65 ℃ then in the room temperature original position.50% aqueous solution that then CAM is placed sodium hydroxide is to digest all organic principles.Plastics casting distilled water thorough washing, air-dry, with gold/palladium bag quilt, and with Philips 501B sem observation.

The result of this test is as follows.At the 6th day that hatches, the embryo was positioned at the center of network of the radial expansion of blood vessel; CAM and embryo are contiguous to grow.The blood vessel of these growths is approaching and observation easily with the surface, makes this system become the ideal model that the research blood vessel takes place.The blood capillary network work of CAM, undyed can be used the imaging of stereoscopic microscope Non-Invasive.

Cross section by CAM has shown the ectoderm of being made up of two cell sides, the wideer mesoderm that contains the blood capillary adjacent with following ectoderm, adventitial cell and inner single endoderm cell's layer.On the ultramicroscope level, illustrated the typical CONSTRUCTED SPECIFICATION of CAM blood capillary.Usually, these blood vessels and close combination of ectodermic inner cell side.

Being exposed to concentration is 0.25,0.5,1,5,10, or the paclitaxel of 30 μ g used the stereomicroscopy CAm of equipment video/computer interface so that estimate the influence that blood vessel is taken place under reactive conditions after 48 hours.This imaging scheme is used with 160 x magnifications, and it allows the hemocyte in the direct observation blood capillary; Thereby can easily estimate and write down blood flow in the purpose zone.For this research, the inhibition of blood vessel generation is defined as the zone (measuring the 2-6mm diameter) of the CAM that lacks blood capillary network and vascular flow.In whole experiment, estimate avascular area (table 1) with 4 no blood vessel gradients.This yardstick is represented overall inhibition degree, 3 on the no blood vessel gradient yardstick of maximum inhibition representative.Paclitaxel is very consistent and induced maximum avascular area (6mm diameter or do not have 3 on the blood vessel gradient yardstick) in 48 hours, and this depends on its concentration.

Table 1

No blood vessel gradient

*-show that positive angiogenesis inhibitor replys

Be displayed in Table 2 the experimental data of the dependent dose of variable concentrations paclitaxel effect.

Table 2

Reagent Delivery vector Concentration Inhibition/n

Paclitaxel methylcellulose (10 μ l) 0.25 μ g 2/11

Reagent Delivery vector Concentration Inhibition/n

Methylcellulose (10 μ l) 0.5 μ g 6/11

Methylcellulose (10 μ l) 1 μ g 6/15

Methylcellulose (10 μ l) 5 μ g 20/27

Methylcellulose (10 μ l) 10 μ g 16/21

Methylcellulose (10 μ l) 30 μ g 31/31

The CAM that has also shown typical taxol treatment, transparent methylcellulose dish are positioned at the central authorities on the avascular area through being measured as the 6mm diameter.Under higher a little amplification, the periphery of this type of avascular area is fairly obvious; The function blood vessel is redirected away from the paclitaxel source usually on every side.Never observe this angular reorientation of blood flow under normal operation.Another feature of paclitaxel effect is the formation of blood island in avascular area, represents hemocyte to assemble.

In a word, this research is illustrated paclitaxel and is applied to behind the CAM 48 hours, and blood vessel is suppressed.Blood vessel suppresses to form avascular area, and it is by three transition period representatives of paclitaxel effect.Disruptive blood capillary is contained in the most affected district, center of avascular area, and it has the erythrocyte that exosmoses; This shows and does not have intercellular contact between endotheliocyte.Entoderm and ectodermic cell keep their intercellular contact, so these germinal layers are kept perfectly; Yet they are thickening a little.Because near the normal blood vessels district, so blood vessel keeps their junctional complex and therefore is kept perfectly.Periphery in the taxol treatment district, other angiogenic growths are suppressed, and this typical case by blood vessel is redirected or " elbow (elbowing) " effect proves.

Embodiment 28

Be used to estimate the screening test of paclitaxel to the influence of smooth muscle cell migration

Before the mensuration, with former generation human smooth muscular cells in the smooth muscle cell minimal medium that contains insulin and human alkaline fibroblast growth factor (bFGF) hungry 16 hours.Measure for migration, cell is handled to remove cell from culture plate with pancreatin, be diluted to 2-2.5 * 10 with the washing of migration culture medium and with the migration culture medium ⁵The concentration of individual cell/mL.The migration culture medium is made up of the improved Eagle culture medium of no phenol red Dulbecco (DMEM) that contains 0.35% human serum albumin.The smooth muscle cell (about 20,000-25,000 cell) that adds 100 μ l volumes to the top of Boyden chamber assembly (Chemicon QCM CHEMOTAXIS 96-hole migration plate).Adding cumulative volume to base apertures is 150 μ l, and concentration is the chemical reagent of 10ng/mL: derivative growth factor of recombined human blood platelet (rhPDGF-BB).Preparing concentration with DMSO is 10 ^-2The paclitaxel of M and serial dilution obtain a series of storage liquid concentration (10 for 10 times ^-8M to 10 ^-2M).Directly add the 1/1000 paclitaxel DMSO storage liquid for preparing previously of diluting by the cell in top chamber, paclitaxel is added cell.Hatch and allowed cell migration in dull and stereotyped 4 hours.

When 4 hour phase finished, the cell that abandons in the top chamber also separated adherent smooth muscle cell to filter bottom 30 minutes at 37 ℃ with cell detachment solution (Chemicon).With the cell removed with the lysis buffer cracking that contains the bonded CYQUANT GR of DNA dyestuff and incubated at room 15 minutes.In fluorescence microtest plate reader with～480nm excitation wavelength and～the 520nm excitation maximum reads fluorescence.Will be behind the subtracting background fluorescence (the contrast chamber that does not have chemoattractant) from relative fluorescence unit's mean deviation in triplicate hole from obtain the average of migrating cell down to the standard curve of the smooth muscle cell of 98 cells/well serial dilutions from 25,000 cells/well.There is the average of comparing migrating cell down with positive control (replying the smooth muscle cell chemotaxis of rhPDGF-BB) by Ramulus et folium taxi cuspidatae, determines 50% inhibition concentration (IC ₅₀).See accompanying drawing 13 (IC ₅₀=0.76nM).Reference: " biotechnology " be (2000) 29:81 (Biotechniques); " immunological method magazine " be (2001) 254:85 (J.ImmunolMethods).

Embodiment 29

Being used to estimate different chemical compounds assays to the filler test of the influence of the IL-1 β generation of macrophage

Thereby human macrophage cell line THP-1 plating is contained in each hole in 12 orifice plates in the 2ml culture medium of 10%FCS and contain 1 * 10 ⁶Individual cell.By 20mg zymosan A is resuspended in 2mL ddH ₂Among the O and homogenate up to obtaining the zymosan that unit for uniform suspension preparation is opsonified.With the zymosan of 250g precipitation homogenate and be resuspended in its final concentration in the 4ml human serum and in 37 ℃ of water-baths, hatch and made it possible to conditioning in 20 minutes with 5mg/mL.Preparing concentration with DMSO is 10 ^-2The geldanamycin of M and serial dilution obtain a series of storage liquid concentration (10 for 10 times ^-8M to 10 ^-2M).

Stimulate the THP-1 cell to produce IL-1 β by adding 1mg/mL through the zymosan of conditioning.By the DMSO storage liquid that directly adds 1/1000 dilution for preparing previously to every hole geldanamycin is added the THP-1 cell.Every kind of drug level of test in triplicate hole.Hatched dull and stereotyped 24 hours at 37 ℃.

After stimulating in 24 hours, collect supernatant and produce with quantitative IL-1 β.Use recombined human IL-1 β to obtain standard curve by ELISA and measure IL-1 β concentration in the supernatant.Be used in the bag be cushioned liquid (the 0.1M sodium carbonate, pH9.5) in the dilution the anti-people IL-1 of 100 μ l β capture antibody 4 ℃ spend the night the bag by 96 hole MaxiSorb plates.The dilution of used capture antibody is batch special and rule of thumb determines.Wash dull and stereotyped 3 times with the capture antibody sucking-off and with lavation buffer solution (PBS, 0.05% tween 20) then.At room temperature with dull and stereotyped 1 hour of 200 μ l/ holes test diluents (PBS, 10%FCS pH7.0) sealing.Wash dull and stereotyped 3 times with lavation buffer solution the sealing back.Be prepared as follows standard and sample diluting liquid: (a) with sample supernatant dilution 1/4 and 1/8; (b) prepare recombined human IL-1 β and serial dilution to produce the standard curve of 15.6pg/mL with 1000pg/mL to 1000pg/mL.Sample supernatant and standard will and join with the dull and stereotyped back of capture antibody coating incubated at room 2 hours with triplicate mensuration.Washing dull and stereotyped 5 times and with 100 μ l work monitoring liquid (Working Detector) (the anti-human TNF alpha detection of biotinylation antibody+avidin-HRp) was incubated at room 1 hour.After this is hatched, add 100 μ l substrate solution (tetramethyl benzidine, H with plate washing 7 times and to flat board ₂O ₂) and incubated at room 30 minutes.In the hole, add stop bath (Stop Solution) (2NH then ₂SO ₄) and under 450nm, read the yellow reaction thing with the λ correction of 570nm.Determine average absorption and deduct average background from triplicate data readings.Obtain IL-1 β concentration value from standard curve.Determine 50% inhibition concentration (IC by average IL-1 β concentration and positive control (using THP-1 cell) through the zymosan stimulation of conditioning ₅₀).The meansigma methods of the duplicate experiment of N=4 is used for determining the IC of geldanamycin ₅₀Value (IC ₅₀=20nM).See accompanying drawing 14.Use this test method(s) to determine the IC of following added compound ₅₀Value: IC ₅₀(nM): mycophenolic acid 2888nM); Anisomycin, 127; Rapamycin, 0.48; Halofuginone, 919; IDN-6556,642; Epirubicin hydrochloride, 774; Hycamtin, 509; Fascaplysin, 425; Daunorubicin, 517; Celastrol, 23; Oxaliplatin, 107; Chromomycin A3,148.

List of references: " IMMUNOLOGY KEY WORDS INDEX (J.Immunol.) (2000) 165:411-418; " IMMUNOLOGY KEY WORDS INDEX (J.Immunol.) (2000) 164:4804-4811; " immunological method magazine " (J.Immunol Meth.) (2000) 235 (1-2): 33-40.

Embodiment 30

Be used to estimate the screening test of different chemical compounds to the influence of the IL-8 generation of macrophage

Thereby human macrophage cell line THP-1 plating is contained in each hole in 12 orifice plates in the 2ml culture medium of 10%FCS and contain 1 * 10 ⁶Individual cell.By 20mg zymosan A is resuspended in 2mL ddH ₂Among the O and homogenate up to obtaining the zymosan that unit for uniform suspension preparation is opsonified.With the zymosan of 250g precipitation homogenate and be resuspended in its final concentration in the 4ml human serum and in 37 ℃ of water-baths, hatch and made it possible to conditioning in 20 minutes with 5mg/mL.Preparing concentration with DMSO is 10 ^-2The geldanamycin of M and serial dilution obtain a series of storage liquid concentration (10 for 10 times ^-8M to 10 ^-2M).

Stimulate the THP-1 cell to produce IL-1 β by adding 1mg/mL through the zymosan of conditioning.By the DMSO storage liquid that directly adds 1/1000 dilution for preparing previously to every hole geldanamycin is added the THP-1 cell.Every kind of drug level of test in triplicate hole.Hatched dull and stereotyped 24 hours at 37 ℃.

After stimulating in 24 hours, collect supernatant and produce with quantitative IL-8.Use recombined human IL-8 to obtain standard curve by ELISA and measure IL-8 concentration in the supernatant.Be used in the bag be cushioned liquid (the 0.1M sodium carbonate, pH9.5) in the dilution the anti-people IL-8 of 100 μ l capture antibody 4 ℃ spend the night the bag by 96 hole MaxiSorb plates.The dilution of used capture antibody is batch special and rule of thumb determines.Then that capture antibody is air-breathing and with dull and stereotyped 3 times of lavation buffer solution (PBS, 0.05% tween 20) washing.At room temperature with dull and stereotyped 1 hour of 200 μ l/ holes test diluents (PBS, 10%FCS pH7.0) sealing.Wash dull and stereotyped 3 times with lavation buffer solution the sealing back.Be prepared as follows standard and sample diluting liquid: (a) with sample supernatant dilution 1/100 and 1/1000; (b) prepare recombined human IL-8 and serial dilution to produce the standard curve of 3.1pg/mL with 200pg/mL to 200pg/mL.Sample supernatant and standard will and join with the dull and stereotyped back of capture antibody coating incubated at room 2 hours with triplicate mensuration.Washing dull and stereotyped 5 times and with 100 μ l work monitoring liquid (the anti-human TNF alpha detection of biotinylation antibody+avidin-HRP) was incubated at room 1 hour.After this is hatched, add 100 μ l substrate solution (Substrate Solution) (tetramethyl benzidine, H with plate washing 7 times and to flat board ₂O ₂) and incubated at room 30 minutes.In the hole, add stop bath (StopSolution) (2N H then ₂SO ₄) and under 450nm, read the yellow reaction thing with the λ correction of 570nm.Determine average absorption and deduct average background from triplicate data readings.Obtain the IL-8 concentration value from standard curve.Determine 50% inhibition concentration (IC by average IL-8 concentration and positive control (using THP-1 cell) through the zymosan stimulation of conditioning ₅₀).The meansigma methods of the duplicate experiment of N=4 is used for determining the IC of geldanamycin ₅₀Value (IC ₅₀=27nM).See accompanying drawing 15.Use this test method(s) to determine the IC of following added compound ₅₀Value: IC ₅₀(nM): 17-AAG, 56; Mycophenolic acid, 549; Resveratrol, 507; Rapamycin, 4; 41; SP600125,344; Halofuginone, 641; D-mannose-6-phosphate, 220; Epirubicin hydrochloride, 654; Hycamtin, 257; Mithramycin, 33; Daunorubicin, 421; Celastrol, 490; Chromomycin A3,36.

List of references: " IMMUNOLOGY KEY WORDS INDEX (J.Immunol.) (2000) 165:411-418; " IMMUNOLOGY KEY WORDS INDEX (J.Immunol.) (2000) 164:4804-4811; " immunological method magazine " (J.Immunol Meth.) (2000) 235 (1-2): 33-40.

Embodiment 31

Be used to estimate the screening test of different chemical compounds to the influence of the MCP-1 generation of macrophage

Thereby human macrophage cell line THP-1 plating is contained in each hole in 12 orifice plates in the 2ml culture medium of 10%FCS and contain 1 * 10 ⁶Individual cell.By 20mg zymosan A is resuspended in 2mL ddH ₂Among the O and homogenate up to obtaining the zymosan that unit for uniform suspension preparation is opsonified.With the zymosan of 250g precipitation homogenate and be resuspended in its final concentration in the 4ml human serum and in 37 ℃ of water-baths, hatch and made it possible to conditioning in 20 minutes with 5mg/mL.Preparing concentration with DMSO is 10 ^-2The geldanamycin of M and serial dilution obtain a series of storage liquid concentration (10 for 10 times ^-8M to 10 ^-2M).

Stimulate the THP-1 cell to produce IL-1 β by adding 1mg/mL through the zymosan of conditioning.By the DMSO storage liquid that directly adds 1/1000 dilution for preparing previously to every hole Eldanamycin is added the THP-1 cell.Every kind of drug level of test in triplicate hole.Hatched dull and stereotyped 24 hours at 37 ℃.

After stimulating in 24 hours, collect supernatant and produce with quantitative MCP-1.Use recombined human MCP-1 to obtain standard curve by ELISA and measure MCP-1 concentration in the supernatant.Be used in the bag be cushioned liquid (the 0.1M sodium carbonate, pH9.5) in the dilution the anti-people MCP-1 of 100 μ l capture antibody 4 ℃ spend the night the bag by 96 hole MaxiSorb plates.The dilution of used capture antibody is batch special and rule of thumb determines.Then that capture antibody is air-breathing and with dull and stereotyped 3 times of lavation buffer solution (PBS, 0.05% tween 20) washing.At room temperature (PBS, 10%FCSpH7.0) sealing is dull and stereotyped 1 hour with 200 μ l/ holes test diluent (Assay Diluent).Wash dull and stereotyped 3 times with lavation buffer solution the sealing back.Be prepared as follows standard and sample diluting liquid: (a) with sample supernatant dilution 1/100 and 1/1000; (b) prepare recombined human MCP-1 and serial dilution to produce the standard curve of 7.8pg/mL with 500pg/mL to 500pg/mL.Sample supernatant and standard will and join with the dull and stereotyped back of capture antibody coating incubated at room 2 hours with triplicate mensuration.Washing dull and stereotyped 5 times and with 100 μ l work monitoring liquid (the anti-human TNF alpha detection of biotinylation antibody+avidin-HRP) was incubated at room 1 hour.After this is hatched, add 100 μ l substrate solution (tetramethyl benzidine, H with plate washing 7 times and to flat board ₂O ₂) and incubated at room 30 minutes.In the hole, add stop bath (2N H then ₂SO ₄) and under 450nm, read the yellow reaction thing with the λ correction of 570nm.Determine average absorption and deduct average background from triplicate data readings.Obtain the MCP-1 concentration value from standard curve.Determine 50% inhibition concentration (IC by average MCP-1 concentration and positive control (using THP-1 cell) through the zymosan stimulation of conditioning ₅₀).The meansigma methods of the duplicate experiment of N=4 is used for determining the IC of geldanamycin ₅₀Value (IC ₅₀=7nM).See accompanying drawing 16.Use this test method(s) to determine the IC of following added compound ₅₀Value: IC ₅₀(nM): 17-AAG, 135; Anisomycin, 71; Mycophenolic acid, 764; Second, 217; Mitoxantrone, 62; Chlorpromazine, 0.011; 1-α-25 dihydroxyvitamin D ₃, 1; Bay 58-2667,216; 15-deoxy prostaglandin J2,724; Rapamycin, 0.05; CNI-1493,0.02; BXT-51072,683; Halofuginone, 9; CYC202,306; Hycamtin, 514; Fascaplysin, 215; Podophyllotoxin, 28; Gemcitabine, 50; Puromycin, 161; Mithramycin, 18; Daunorubicin, 570; Celastrol, 421; Chromomycin A3,37; Vinorelbine, 69; Tubercidin, 56; Vinblastine, 19; Vincristine, 16.

List of references: " IMMUNOLOGY KEY WORDS INDEX (J.Immunol.) (2000) 165:411-418; " IMMUNOLOGY KEY WORDS INDEX (J.Immunol.) (2000) 164:4804-4811; " immunological method magazine " (J.Immunol Meth.) (2000) 235 (1-2): 33-40.

Embodiment 32

Be used to estimate the screening test of the influence of paclitaxel on cell proliferation

The smooth muscle cell that 70-90% converges is handled with pancreatin, be seeded in the culture medium of 96 orifice plates with 600 cells/well once more and allow to spend the night adherent.Prepare paclitaxel and the serial dilution that concentration is 10-2M with DMSO and obtain a series of stock solution concentration (10 for 10 times ^-8M to 10 ^-2M).With drug dilution liquid with 1000 times of culture medium dilutions and be added to cell and obtain cumulative volume 200 μ l/ holes.With every kind of drug level of in triplicate hole test.Hatch the flat board 72 hours that contains cell and paclitaxel at 37 ℃.

For finishing to measure, pick up by gentleness and remove culture medium.Add CYQUANT 400X GR dye indicator (Molecular Probes to 1 * lysis (Cell Lysis) buffer; Eugene, 1/400 diluent OR), and in the hole of flat board, add 200 μ l mixture.Hatched dull and stereotyped 3-5 minute in the room temperature lucifuge.In fluorescence microtest plate reader with～480nm excitation wavelength and～the 520nm emission maximum reads fluorescence.By meansigma methods and average relative fluorescence unit and the definite 50% inhibition concentration (IC of DMSO contrast that gets triplicate hole ₅₀).Meansigma methods with the duplicate experiment of n=3 is determined IC ₅₀Value.See accompanying drawing 17 (IC ₅₀=7nm) determine with this test method(s) below the IC of added compound ₅₀Value: IC ₅₀(nM): mycophenolic acid, 579; Second, 463; Doxorubicin, 64; Mitoxantrone, 1; Geldanamycin, 5; Anisomycin, 276; 17-AAG, 47; Cytosine arabinoside, 85; Halofuginone, 81; Ametycin, 53; Etoposide, 320; Cladribine, 137; Lovastatin, 978; Epirubicin hydrochloride, 19; Hycamtin, 51; Fascaplysin, 510; Podophyllotoxin, 21; CA, 221; Gemcitabine, 9; Puromycin, 384; Mithramycin, 19; Daunorubicin, 50; Celastrol, 493; Chromomycin A3,12; Vinorelbine, 15; Idarubicin, 38; Nogalamycin, 49; Itraconazole, 795; 17-DMAG, 17; Epothilone d, 5; Tubercidin, 30; Vinblastine, 3; Vincristine, 9.

It is the influence of RAW 264.7 to fibroblast and mouse macrophage that this test can be used for assessing compound.In accompanying drawing 18, shown and be used to estimate the result (IC of paclitaxel the influence of Mus RAW264.7 macrophage proliferation ₅₀=134nM).

List of references: " external toxicology " (In vitro toxicol.) (1990) 3:219; " biotechnology and histochemistry " be (1993) 68:29 (Biotech.Histochem.); " biochemistry yearbook " be (1993) 213:426 (Anal.Biochem.).

Embodiment 33

Administrable is to estimate fibrotic inhibition around the blood vessel of paclitaxel

(0.33ml/kg) anaesthetizing by intramuscular injection Innovar (Innovar) heavily is the WISTAR rat of 250-300g.After the calmness, they are carried out halothane anesthesia.After general anesthesia is finished, reject the hair in neck region, clamp skin and clean with povidone iodine.Produce longitudinal incision and expose external carotid artery at left neck artery.Two root knot bindings are placed the external carotid artery action arteries and veins otomy of going forward side by side.Introduce No. 2 French Fogarty balloon catheters and pass left common carotid artery and use the saline swelling gasbag to carotid artery then.Conduit passes carotid artery up and down three times.Remove conduit then and on left external carotid artery, tie a knot with ligature.

Then the paclitaxel (33%) in the ethene-vinyl acetate copolymer (EVA) is expelled to 10 common carotid artery in the rat in mode on every side.Common carotid artery is injected only EVA in other 10 rats.(paclitaxel can also be coated on the EVA film, and the EVA film places around the common carotid artery in mode on every side then).Put to death at the 14th day from 5 rats of every group and at the 28th day and put to death last 5.Observe losing weight or other diseases of systemic disease of rat.After 14 or 28 days, anesthetized animal also exposes left neck artery in the mode of initial experiment.Separate carotid artery, with it with 10% buffered formaldehyde fixed and carry out histological examination.

As measuring by the standard type determination and analysis, the neointimal hyperplasia degree has statistics and significantly reduces, and shows drug-induced the reducing that fibre modification is replied.

Embodiment 34

Carry out the MIC test by microtitration meat soup dilution process

A. the MIC of many kinds of Gram-negatives and positive bacteria test

Basic as Amsterdam, D.1996 Loman, V., ed. " antibiotic in the laboratory medicine " (Antibiotics in laboratory medicine), 4th ed.Williams and Wilkins, Baltimore, " sensitivity tests in the antimicrobial drug liquid medium within " of MD (" Susceptibilitytesting of antimicrobials in liquid media "), p.52-111, the MIC that carries out of middle description tests.In brief, test multiple chemical compound at Pseudomonas aeruginosa (P.aeruginosa), Klebsiella pneumonia (K.pneumoniae), escherichia coli (E.coli), staphylococcus epidermidis (S.epidermidis) and staphylococcus aureus (S with MIC, aureus) (the minimal inhibitory concentration test of antibacterial activity, under anaerobic use 96 hole polystyrene microtitration plates (Falcon 1177) and Mueller Hinton culture fluid to hatch 24 hours at 37 ℃.(MHB is used for most tests, and just C721 (streptococcus pyogenes (S.pyogenes)) uses Todd Hewitt culture fluid, and hemophilus influenza (Haemophilus influenzae) is used haemophilus test media (HTM)).To test in triplicate.The result is provided in the table 1 below.

Table 1

Therapeutic agent is at the minimal inhibitory concentration of multiple Gram-negative and positive bacteria

Bacterial isolates	Pseudomonas aeruginosa	Klebsiella pneumonia	Escherichia coli	Staphylococcus aureus	Staphylococcus epidermidis	Streptococcus pyogenes
								PAE/K799	ATCC13883	UB1005	ATCC25923
	H187	C238	C498	C622	C621	C721
								Wt	wt	wt	wt	wt	wt

Medicine	Gram-negative	Gram-negative	Gram-negative	Gram-positive	Gram-positive	Gram-positive
							Doxorubicin
	10 -5	10 -6	10 -4	10 -5	10 -6	10 -7
							Mitoxantrone	10 -5	10 -6	10 -5	10 -5	10 -5	10 -6
5-fluorouracil	10 -5	10 -6	10 -6	10 -7	10 -7	10 -4
							Methotrexate	N	10 -6	N	10 -5	N	10 -6
Etoposide	N	10 -5	N	10 -5	10 -6	10 -5
							Camptothecine	N	N	N	N	10 -4	N
Hydroxyurea	10 -4	N	N	N	N									10 -4
							Cisplatin	10 -4	N	N	N	N	N
Tubercidin	N	N	N	N	N	N
							The 2-purinethol	N	N	N	N	N	N
Ismipur	N	N	N	N	N	N
							Cytosine arabinoside	N	N	N	N	N	N

Activity is represented with molar concentration

The Wt=wild type

The N=non-activity

B. The MIC of antibiotic-resistant bacteria

In as above-mentioned MIC test, tested the following chemical compound of variable concentrations: mitoxantrone, cisplatin, tubercidin, methotrexate, 5-fluorouracil, etoposide, 2-purinethol, doxorubicin, Ismipur, camptothecine, hydroxyurea and cytosine arabinoside are to the clinical isolates of methicillin resistance staphylococcus aureus and the antibacterial activity of vancomycin resistance sheet coccus clinical isolates.Demonstrate and suppress growth (MIC value＜1.0 * 10 ^-3) chemical compound comprise: mitoxantrone (two kinds of bacterial strains), methotrexate (vancomycin resistance sheet coccus), 5-fluorouracil (two kinds of bacterial strains), etoposide (two kinds of bacterial strains) and 2-purinethol (vancomycin resistance sheet coccus).

Embodiment 35

The preparation of buffer release liquid

By in beaker, adding 8.22g sodium chloride, the single alkali sodium phosphate (monohydrate) of 0.32g and 2.60g two alkali sodium phosphates (anhydrous) preparation buffer release liquid.Add 1LHPLC level water and agitating solution up to all salt dissolvings.If desired, use pH to pH7.4 ± 0.2 of 0.1N NaOH or 0.1N phosphoric acid regulator solution.

Embodiment 36

Be used for measuring the releasing research of therapeutic agent from the polymer composition release characteristics

Can measure the release characteristics of therapeutic agent from polymer composition according to following operating procedure.

Discharge and extraction

Sample is placed the culture tube of 16 * 125mm band screw-cap.16ml buffer release liquid (embodiment 35) is added in this pipe.Sample is placed on 37 ℃ of swiveling wheels in the baking oven (30rpm).In different time at interval (2 hours, 5 hours, 8 hours, 24 hours and every day) then, in baking oven, take out sample, put into pallet and take off medicated cap at fume hood.As much as possiblely from pipe, take out buffer release liquid and put it into second culture tube.Use Oxford pipettor bottle that the 16ml release medium is joined in the pipe that contains sample then.With new PTFE lining medicated cap capping sample.All samples is put back on the swiveling wheel device in the baking oven.

Use p1000 pipettor (PIPETMAN) and cleaning pipette tip from every duplicate samples, to take out and discard the 1ml release medium.Use Oxford pipettor bottle in every duplicate samples, to add the 1ml dichloromethane.With corresponding each sample cell of PTFE lining screw-cap capping.With hands with the violent jolting of every duplicate samples 5 seconds.Be placed on sample on the labquake rotator and rotated 15 minutes.With 1500rpm with centrifugal 10 minutes of sample.Sample cell is gone to fume hood and opens lid.Use pasteur pipet and vacuum system to take out most of supernatant (water).Take out the supernatant of last part with glass syringe.Sample cell is gone to the perforation drying system, heat block is set to 1.5 (45 ° of c) and forwards in the described system.Dry all samples on the perforation drying system in nitrogen current (about 45 minutes).Again add a cover to sample cell, put into plastic bag, with the date and time labelling bag of sample and be stored under-20 ° of c (cold closet) up to analysis.

The external standard preparation

Will be from Hauser Chemical Research, the paclitaxel of Inc. (GMP level) is as the reference standard of this mensuration.Accurate weighing paclitaxel (100mg) quantitatively shifts and arrives volume (1mg/ml) at the 100ml volumetric flask and with ACN.Use volumetric pipet that this standard solution of 5ml is transferred to the 100ml volumetric flask and reaches volume (50 μ g/ml) with ACN.Serial dilution liquid (with ACN with 5ml in right amount to 10ml) is used for preparing respectively 25,12.5,6.25,3.13,1.56,0.781 and 0.391 μ g/ml solution.When the same day sample being carried out the HPLC analysis, use the small size insert that the aliquot (～100 μ l) of each standard substance is put into independent autosampler vial and gone to HPLC.

Contrast and system suitability sample preparation

Will be from Hauser Chemical Research, the paclitaxel of Inc. and 7-table-China fir alcohol (7-epi-taxel) are as the reference standards of this test.The accurate weighing of 25mg 7-Biao-Te element (7-epi-taxel) also quantitatively is transferred to the 25ml volumetric flask and arrives volume (1mg/ml) with ACN.Use volumetric pipet that this standard solution of 5ml is transferred to the 100ml volumetric flask and reaches volume (1mg/ml) with ACN.Use volumetric pipet that this standard solution of 5ml is transferred to the 100ml flask and reaches volume (50 μ g/ml 7-Biao-Te element) with ACN.With the mixture of 50/50 paclitaxel standard substance (25 μ g/ml) and 7-table-taxol standard substance (25 μ g/ml) with comparing and the system suitability sample.Be dissolved in ACN (50 μ g/ml paclitaxel) and 7-Biao-Te element be dissolved in the identical culture tube of ACN (50 μ g/ml 7-Biao-Te element) preparation by aliquot each paclitaxel of 5ml.Add a cover and jolting.Be cooled to standby.When the same day sample being carried out the HPLC analysis, use the small size insert that the aliquot (～150 μ l) of each standard substance is put into two independent autosampler vials and gone to HPLC.One duplicate samples is used for system suitability.Another duplicate samples is as control sample.

The dissolving again of sample

From cold closet, take out analytic sample, put into fume hood and make pipe reach room temperature.Open and cover and 1ml water/acetonitrile (50/50) is joined in each pipe with the Oxford pipettor.Again covered medicated cap and vortex 60 seconds to sample cell.With 1500rpm with centrifugal 15 minutes of sample cell.In fume hood, about 500 each sample of μ l are transferred to independent HPLC autosampler vial by pasteur pipet with cleaning.Close the lid for every autosampler vial and go to HPLC.Dispose sample cell and pasteur pipet.

HPLC analyzes

Following chromatography condition is used for the paclitaxel analysis:

Immobile phase	ODS (Hypersil ODS，Hewlett Packard，125 x 4mm ID，5μm)
		Guard column	Hypersil ODS guard column
Mobile phase	Acetonitrile (ACN)/water (H 2O)45/55
		Flow velocity	1.0ml/ minute
Volume injected	10μL
		Detect	Ultraviolet under 232nm
Running time	15 minutes
		Column temperature	28.0℃

5 acetonitrile samples of injection are to guarantee balance when beginning.5 control samples of injection behind the acetonitrile sample, behind the standard curve sample once, in the whole sample group after per 10 duplicate samples once, and be the verification system performance setting sample when end once.Once the standard curve sample is carried out chromatography by injection when every group of sample begins.

Data analysis

Use Hp ChemStation Batch Mode that all standard substance, control sample and release sample are carried out paclitaxel peak area integration and generate the Batch Report that stores with the xls form.Use the data of Excel evaluation from Batch Report.Descriptive statistics) and the % coefficient of variation (100 * standard deviation/meansigma methods) calculate the peak area standard deviation (Excel: of control sample.The amount (μ g) of every part of standard curve sample being calculated the paclitaxel of injection based on the concentration and the 10 μ L injection volumes of preparation.Use Excel: the slope intercept of regression analysis standard curve (amount of the paclitaxel of peak area one injection).The amount of the paclitaxel of the release sample that calculates injection in separately.Use formula to set up the amount (μ g) of the paclitaxel of every 16ml sample release.The amount of using the amount/sample of paclitaxel and establishing the paclitaxel that discharges in a period of time sample time.

Embodiment 37

The preparation of medicine in comprising the carrier of triblock copolymer

Paclitaxel is mixed the preparation that comprises triblock copolymer and diluent (following), carry out through the following steps: in the time of at ambient temperature with stirring paclitaxel is dissolved in diluent, adds triblock copolymer then, stirred at least 2 hours once more.The triblock copolymer that is used to add higher concentration time limit long period.For example, finish 33% triblock copolymer by stirring at least 15 hours (spending the night) interpolation.Described diluent is for passing through ratio terminal addition carbonic acid Sanya methyl ester 90%/Acetic acid, hydroxy-, bimol. cyclic ester 10% deutero-PEG 300NF or the PEG 400 with 400:100.Described triblock copolymer is the ABA copolymer, and it has the B block that the molecular weight that has that contains polymerization carbonic acid Sanya methyl ester (90%) and Acetic acid, hydroxy-, bimol. cyclic ester (10%) is about the block A of 900g/mol and contains PEG 400.Paclitaxel effectively can be mixed said preparation with the concentration of 0.015-0.45mg/ml.The amount of triblock copolymer in said preparation changes between 2.3-50%w/w, and PEG 400 is used as diluent.By the gamma-radiation that contacts about 2.5kGy product is sterilized.

Embodiment 38

The preparation of medicine in the cosolvent carrier

Paclitaxel is inserted the preparation that comprises water and PEG 300NF.At first paclitaxel was dissolved in PEG 300NF at least 2 hours by stirring at ambient temperature: the 90:10 mixture of water.In case medicine dissolution, just with the PEG 300NF of said composition and equal portions: the 50:50 mixture of water merges.Final composition is for being dissolved in 70:30 PEG 300NF: the paclitaxel of the mixture of water.Mix the paclitaxel that concentration is 0.45-4.5mg/ml.Make said composition pass through 0.22 μ m filter membrane so that it is aseptic.

Embodiment 39

Measure the maximum tolerated dose (MTD) of medicine after intra-articular injection

Use the male Hartley Cavia porcellus of 5% isoflurane in the ages in indoor anesthesia at least 6 week of sealing.Weigh and go to operating-table then to animal, keep anesthesia by contact 2% isoflurane with nose cone there.The knee breadth at knee area on the scraping both legs and the two above-knee femoral head places of measurement.The skin sterilization above-knee to the right side.Use general means that the 25G syringe needle is imported Synovial cavity and injects the 0.1mL test formulation.After injection 3 or 7 days, by putting to death animal at deep anaesthesia (5% isoflurane) injection of heart 0.7mL pentobarbital sodium.For every kind of preparation, sample size is N=3.

Before execution, estimate the knee joint function by the change and the tenderness sign that read the walking behavior.After execution, weigh to animal immediately.Measure two knee breadth degree at femoral head place then with caliper.Cut open through the following steps from knee joint: the crosscut quadriceps tendon, cut and Patella on the upset tibia by the outside and inboard joint capsule.Estimate the knee joint inflammation by reading swelling, vascularization, water sign long-pending and subcutaneous tissue color and internal joint structure.Take the photograph sheet and find so that from data, seek.Organize under the uncomprehending situation in treatment and to write down all data by the observer.

After measured, the MTD of medicine in test formulation is confirmed as the MTD of unobservable knee joint inflammation.

Evaluation during based on 7 days finds that paclitaxel is being 0.075mg/ml from the MTD in the three block gel preparations of embodiment A.Evaluation demonstration to said preparation after 3 days can tolerate the dosage that is up to 0.15mg/ml.0.015mg/ml dosage shows the sign that inflammation is only arranged after 7 days.Evaluation during based on 3 days finds that the MTD of paclitaxel in the cosolvent preparation is 1.5mg/ml.

Embodiment 40

The evaluation of the localized tissue distribution of medicine after intra-articular injection

As above in the knee joint of animal, inject the paclitaxel MTD dosage that each preparation is determined described in 4.2.After injection 3 or 7 days, animal is implemented euthanasia by the intracardiac injection pentobarbital sodium.Cut open from knee joint and collect synovial membrane, anterior cruciate ligament, fat pad, meniscus and cartilage.Each is organized in the saline solution simply flushing, and trace is dry and be stored in separately in the scintillation vial to the paclitaxel analysis at-20 ℃.

From the collection sample of weighing, extract paclitaxel by using the homogenize of Polytron PT2000 homogenizer from three animals.Instrument be set at 3-9 and extraction time be 1 minute.Extracting solution is 50/50 acetonitrile (ACN)/water that 1mL contains 0.2 μ g/mL10-deacetylation taxol (10-DAT) and 0.1% formic acid.Use the BeckmanJ6-HC centrifuge with 3000rpm with centrifugal 10 minutes of extract.Supernatant is filtered into the HPLC bottle by Acrodisc CR (13mm, 0.45 μ) syringe filter to be analyzed to be used for LC/MS/MS.Use IEC Micromax centrifuge does not produce some fat pad sample of clarified supernatant with the 10000rpm recentrifuge before filtration.

By the LC/MS/MS method, use internal calibration to measure content of taxol in the extract.For using the paclitaxel of 0.2 μ g/mL10-DAT, the calibration curve scope is at 0.01-1 μ g/mL.The LC/MS/MS system is made up of Waters 2695 separation modules and Waters Micromass QuattoMicro three-Quad mass spectrograph.LC method and MS/MS method are as described below.

Make confirmed in this way from cartilage, meniscus, ligament, fat and the synovial membrane of treatment animal, to have reclaimed can the mensuration level paclitaxel.Be maintained until in few 7 day time limit the level of organizing of medicine and the extra verified time limit that this tissue level can be kept more than 21-28 days of research, this depends on the dose of paclitaxel that gives.In addition, produced the tissue concentration in ligament, fat, synovial membrane and meniscal tissue by injection from the paclitaxel of the formulation delivered that contains the 0.015mg/ml paclitaxel of embodiment A greater than 6-11 times of the paclitaxels of sending with 15mg/ml in PAXCEED.Therefore, it is the drug delivery system of effectiveness.

Embodiment 41

The evaluation of the localized tissue distribution of medicine after intra-articular injection

Treat animal according to the mode described in the embodiment 39.By intra-articular injection 0.5ml preparation evaluation rabbit.By using Freezer/Mill, SPEX CertiPrep 6850 homogenizes are extracted paclitaxel from each tissue sample from three animals.Extract the sample that grinds with containing acetic acid (3.4mM) and LiCl (4 to, 8 μ M) the 12mL solution in 50/50 ACN/ water.At room temperature, carry out on the Labquake Shaker extracting in 30 minutes with Tube Rotator.By Acrodisc CR (13mm, 0.45 μ) syringe filter extract being filtered into the HPLC bottle analyzes to be used for LC/MS/MS.

By the LC/MS/MS method, use external calibration to measure content of taxol in the extract.For using the paclitaxel of 0.2 μ g/mL 10-DAT, the calibration curve scope is at 0.01-1 μ g/mL.The LC/MS/MS system is made up of Waters 2695 separation modules and Waters Micromass QuattoMicro three-Quad mass spectrograph.LC method and MS/MS method are as described below.

Make and confirmed that in this way the exist concentration of paclitaxel in cartilage, meniscus, ligament, fat and the synovial membrane of treatment animal organizes up to 3.25 μ g/g.With the organizing level to be maintained until in few 14 day time limit and this tissue level can be kept time limit more than 21-28 days of medicine, this depends on the dose of paclitaxel that gives.

Embodiment 42

Be used for estimating the spinal operation adhesion model of fibre modification inhibitor rabbit

Cicatrization and adhesion widely takes place after relating to the lumbar surgery of vertebra usually.Must remove densification and thick fiber tissue with spinal column and adjacent muscle adhesion by operation.Regrettably, fibrous adhesion improves behind second operation usually.From surrounding tissue, breed and move by fibroblast and form adhesion at operative site.These cells cause the healing after the tissue loss.In case they migrate to wound, they have just set up protein, such as collagen protein to repair damaged tissues.Obstruction, compression and the contraction of local surrounding tissue are brought out in these cell hyperproliferations and secretion, and follow side effect.

The spinal column adhesion model of rabbit laminectomy as herein described is used to study the preventive effect of local sustained release fibrosis medicine to the spinal column adhesion.

Comprise 5-6 animals in each experimental group so that carry out significant statistical analysis.Test has the preparation of variable concentrations fibrosis medicine so that estimate the inhibitory action that adhesion is formed to control animals.

By IM injection ketamine/xylazine (zylazine) anesthesia rabbit.Insert endotracheal tube to keep the anesthesia of using halothane.Lie prostrate to place under heat pad end on the operating-table and the scraping back skin and preparation on half to carry out aseptic operation animal.Do vertical center line skin incision and down to waist sacrum fascia from L-1-L-5.Cut fascia to expose the tip of spinous process.Cut the other muscle of spinous process open and make its withdrawal from the spinous process of L-4 and layer.On L-4, carry out laminectomy by removing the spinous process that has careful bilateral notching layer, produce little 5 * 10mm laminectomy defective thus.Use Gelfoam to realize hemostasis.Test formulation is coated on the loss position and uses Vicrvl stitching thread wound closure.Animal is placed in the couveuse, up to from anesthesia, recovering and then it being put back in its cage.

In operation 2 weeks of back, use and similar as mentioned above operating procedure anesthetized animal.Use pentobarbital sodium (euthanyl) that animal is implemented euthanasia.Thick at incision of skin, in scientific literature, mark for the quantity of adhesion by dissection and analysis laminectomy position and use to the marking system that this class loss is announced.

Embodiment 43

Be used for estimating the tendon surgical adhesions model of fibre modification inhibitor rabbit

Whether the adhesion that this model is used to study tendon can obtain prevention by the fibrotic medicine of the known inhibition of local sustained release.To the polymer formulations drug loading and with around the impaired tendon of its implantation rabbit.In not using the animal that suppresses fibrotic preparation, stick in 3 weeks of flexor tendon loss and take place, condition is fixedly being kept of tendon in this time limit process.The anatomical features of tendon in the tendon agglutination that the advantage of rabbit is them and cell behavior are similar to the people's, and just the healing speed in rabbit is far faster than the people.

Skin and preparation on anesthesia rabbit and the scraping right hind are used for aseptic operation.By the auxiliary aseptic operation that carries out of operating microscope.Do vertical center line skin incision on the volvar surface of the adjacent phalanx in the 2nd and 4 toes.The vagina synovialis of careful exposure tendon and do lateral dissection so that enter FDP apart from FDS bifurcated far-end.Progressively mention FDP and pass its half material and do cross sections and implement tendon injury by using curved forceps.The preparation that will contain testing drug is coated on around the tendon in the sheath of one of two toes of selecting at random.Make another toe keep not doing treatment and with comparing.Use 6-0 nylon suture repairing sheath then.The 6-0 nylon suture is passed that horizontal metacarpal bone ligament is fixed into tendon/sheath complex so that tendon and sheath are fixed as the single unit that promotes that adhesion forms.With 4-0 interrupted suture line wound closure.Binder is applied to rear solid end on every side so that further strengthen the fixing of toe and guarantee that animal can walk.Regain animal and they are put back in its cage.

Operation 3 weeks of back, anesthetized animal.Behind incision of skin, cut the tissue plane around the vagina synovialis open and gather the tendon/sheath complex of monoblock and change in the formaldehyde of 10% phosphate-buffered so that carry out histopathological analysis.Then animal is implemented euthanasia.After paraffin embedding, downcut the thin transverse section of 5-um of series every 2mm by tendon/sheath complex.Use H﹠amp; E and Movat ' s stain are grown to estimate adhesion to section statining.Use the computer that is connected with digital microscope photographing unit (Nikon Micropublisher cooled photographing unit (cooled camera)) with each microscope slide digitized processing.Use image analysis software (ImagePro) to carry out morphometric analysis then.Mensuration is defined as the adhesion thickness of the spatial material of obturation (obliterating) synovial fluid and area and preparation for treating group and control animals is compared.

Embodiment 44

Paclitaxel is at the H that suppresses the ACL damage _ARTLEYThe evaluation of the cartilage infringement in the Cavia porcellus osteoarthritis model

The purpose of this research is to be determined at the generation whether paclitaxel that gives in the hyaluronic acid preparation can delay or prevent the Cavia porcellus knee osteoarthritis.

Operation technique

Use the male Hartley Cavia porcellus of 5% isoflurane in the ages in indoor anesthesia at least 6 week of sealing.Weigh and go to operating-table then to animal, keep anesthesia by contact 2% isoflurane with nose cone there.The knee breadth at knee area on the scraping both legs and the two above-knee femoral head places of measurement.The skin sterilization above-knee to the right side.Use general means that the 20G syringe needle is imported knee joint and downcuts anterior cruciate ligament with the tip of syringe needle.In the preliminary experiment that expression can use this technology reliably anterior cruciate ligament to be cut into slices, implement this operation.

2 weeks after initial operation are with isoflurane (5 induce-2% keep) anesthetized animal and weigh.The knee breadth at knee area on the scraping both legs and the two above-knee femoral head places of measurement.The skin sterilization above-knee to the right side.Use nearly middle means that the 25G syringe needle is imported Synovial cavity and injects the 0.1mL test formulation.Duplicate injection weekly amounts to and carries out 5 injections.For each preparation, sample size is N=12.The paclitaxel and the control formulation of two kinds of dosage of test.

In 10 weeks after damage, (5% isoflurane) put to death animal by injection of heart 0.7mL pentobarbital sodium and weighed under deep anaesthesia.Get final knee measured value.Do not damaging the skin of removing under the hypodermic situation on the territory, knee.Gather the knee joint of monoblock then and put it into formaldehyde (37%)/acetic acid solution (5:1 ratio) and be used for fixing.Sample sent into independent laboratory so that carry out the joint tissue preparation and cartilage infringement sign is estimated by the pathologist.

Briefly, make the knee joint section so that check cartilage and use H﹠amp; The E stain dyes to microscope slide.The pathologist uses corresponding knee joint section to be marked from the microscope slide of every animal according to following grade in unwitting mode: harmless to cartilage; The Dan Baijutang disappearance; The cartilage wearing and tearing; Cartilage lacks to the limit (tidemark); Lack to bone with cartilage.Make up bar and comparison according to each group.Compare the decline that demonstrates aspect the cartilage infringement with matched group with the paclitaxel treatment that low dosage (dosage 1) and median dose (dosage 2) are carried out with statistical significance.Referring to accompanying drawing 19 and 20.

Embodiment 45

Use chondrus ocellatus Holmes polysaccharide behind the paclitaxel treatment-bring out and antigen-Dan Baijutang disappearance index in the rabbit arthritis model that brings out

Use Liggins and Burt (2001) is described prepares all microspheres at the oil-in-water solvent evaporated method.The foreign minister is the 1-5%PVA of 100ml in water.Inner phase is for containing the 10ml dichloromethane solution of 5%w/v total solid (polymer and paclitaxel).At room temperature this dispersion is stirred 2 hours to form microsphere.By changing mixing speed and the PVA concentration between 900-2100rpm, produce different magnitude range.From the foreign minister, separate microsphere and use distilled water flushing.By the sieve that the microsphere suspension is crossed have 38,53,75 and 106 μ m mesh sizes some microsphere further is divided into discrete magnitude range.Use Coulter LS130 granular size analysis-e/or determining microsphere size distribution.Microsphere is suspended in the water that contains a small amount of Tween 80 preventing and assembles, after this carry out the granular size analysis.Use microscope slide, measure chitosan particle size scope by light microscopy with class's labelling of 5 μ m.Dry and moistening sample are carried out light microscopy.

Use Dupont Thernmal Analysis DSC to measure the thermal characteristics of microsphere.About 5mg microsphere is put into unencapsulated aluminum dish and obtained differential thermogram with 10 ℃/minute the rate of heat addition.Use the Rigaku x-ray diffractometer, measure by the X-ray powder diffraction and obtain the crystallinity evidence.Use source 5-35 ° of 2 θ of CuK α X-ray scanning with 1 ° of 2 θ/minute speed and the ladder increment scanning samples of 0.02 ° of 2 θ.

Use the Hitachi scanning electron microscope to measure the configuration of surface of microsphere.With 100

Gold-palladium coating coating microsphere is also observed under 1000 * amplification.

Use Liggins ﹠amp; The method of Burt (2001) is measured content of taxol and the release in vitro from microsphere.In order to carry out the total content analysis, microsphere that will about 5mg (accurately weighing) is dissolved in the 1ml dichloromethane, subsequently with 15ml 60:40 acetonitrile: the water vigorous stirring.This solvent mixture is divided into two approximately equalised volumes, and sedimentary polymer group is arranged between the two.By HPLC, use paclitaxel amount separately in two parts of WatersHPLC system measurement then.Mobile phase is the 58:37:5 acetonitrile: water: methanol, flow velocity are 1ml/ minute.Use 20 μ l volume injected, the NovapakC18 post also carries out UV at the 232nm place and detects.

Use said method (Kim etc. " rheumatoid arthritis magazine " are 1995:22:1714-21. (J.Rheumatol)) in rabbit, to reproduce the arthritis of antigen induced.Briefly, be that the female New Zealand white rabbit of 2.5-2.8kg is used for biocompatibility and efficacy study with body weight.Animal is lived away from home can freely drink water and get in the suspension cage of food.Make animal adapt to 7 days, after this carry out all experiments.In some animal, bring out arthritis as bio-compatible property testing and the positive control that is used for efficacy study.Under the narcotism of bringing out, carry out all knee joint injections by intramuscular injection ketamine HCl (40mg/kg) and xylazine (5mg/kg).When partly finish the life cycle of this research, use intravenous T-61 to put to death animal.Cuing open immediately after the execution in knee joint and stuck-at-0% formalin, after this carry out histologic analysis.

Set up the arthritis of antigen induced by the bovine serum albumin (BSA) that is injected in the Freund's complete adjuvant (FCA) for three times.Injection for the first time is made up of emulsifying in 1ml FCA and the 5mg BSA that dilutes in 1ml PBS.After 3 weeks, the subcutaneous booster injection of emulsive 2.5mg BSA among the lml FCA of every rabbit acceptance usefulness 1ml PBS dilution.After 4 weeks, every rabbit is received in emulsifying among the 1mlFCA and does not have the kneed booster injection second time of injection of the 0.5mg BSA among the PBS of pyrogen at 0.3mL.After final booster injection 5 days, carry out intra-articular injection with test article and treat rabbit.

In rabbit, set up arthritis that chondrus ocellatus Holmes polysaccharide brings out and treat rabbit according to the mode identical with the arthritis model of antigen induced.At the 1st, 3,8,16 and 21 day to the chondrus ocellatus Holmes polysaccharide among the injection 0.3ml1% of all rabbit in the chondrus ocellatus Holmes polysaccharide group PBS at no pyrogen.Load the microsphere of 20% paclitaxel also for half animal injection 35mg at the 6th day.Put to death all animals and cutd open abscission joint at the 29th day and be used for histologic analysis.

Putting to death rabbit post-evaluation synovial membrane inflammation.With arthrodesis in formalin and decalcification in 10% formic acid that more renews liquid repeatedly.Be embedded in the joint of decalcification in the paraffin and preparation contains the section of synovial membrane, cartilage and bone.With hematoxylin and eosin (H﹠amp; E) to the cellularity dyeing of section and with Safranine O Dan Baijutang content is dyeed.Assess synovial membrane inflammation and cartilage degradation by respectively the other synovial membrane of knee joint and a burst condyle articular cartilage being carried out blind formula Histological evaluation.Fine hair hypertrophy, fibroblast proliferation, fibre modification, blood vessel generation, mononuclear cell and polymorphonuclear cell are soaked into deciding grade and level be the index of synovial membrane inflammation.With regard to cartilage degradation, to surperficial burn into Dan Baijutang content and the downright bad classification of chondrocyte.Based on erythema, swelling and cellular infiltration to the cellular infiltration and the swelling that are divided into 0-4 integer grade mark (0, normal; 4, maximum).Slight influence is assessed as 0.5; This is the non-integer scoring of unique use.Be 0 (normally) 1 (almost being the disappearance fully of painted Dan Baijutang) also with the scoring of Dan Baijutang disappearance.

The effect of polyester microsphere in the arthritis of treatment antigen induced of the paclitaxel loaded that the microsphere evaluation of using reference substance and loading 20%10-35 and 35-105 μ mPLA gives by intra-articular injection.Treat the joint, right side of the group of 5 rabbit with 40mg microsphere or independent PBS.Independent PBS is accepted in the joint, left side.Put to death animal in back 14 days and check synovial membrane inflammation and cartilage degradation by Histological method as mentioned above in treatment.

The PLA microsphere that selection contains 20% paclitaxel is used for efficacy study.Table 1 has represented to inject the result of the PLA microsphere of 40mg reference substance and paclitaxel loaded in having the arthritic rabbit of antigen induced.Arthroncus that untreated arthritis rabbit has scoring is 3 and 4.9 x 10 is arranged in joint fluid ⁷Individual cell.Can not alleviate the arthritis of antigen induced at the microsphere of the paclitaxel loaded of 10-35 μ m magnitude range.In fact, in this group the amount of cellular infiltration than untreated arthritis rabbit raise (table 1).Yet, to compare with matched group, the microsphere that 35-105 μ m paclitaxel is loaded in injection has significantly alleviated arthroncus and has significantly reduced the cell quantity in the joint fluid (descending 50% approximately) (table 1).Also in the 35-105 of matched group and paclitaxel loaded μ m microsphere group, estimated the cartilage degradation that is expressed as Dan Baijutang disappearance and chondrocyte necrosis.By injection contrast PLA microsphere in infected animal Dan Baijutang disappearance or chondrocyte necrosis there is not influence.Yet, significantly be lower than untreated animal (table 1 and accompanying drawing 21A-21C) with the Dan Baijutang disappearance of the animal of the microsphere of paclitaxel loaded treatment.Accompanying drawing 21A illustrates the knee joint with normal histology's outward appearance, and wherein successive cartilage upper strata and dye-free color dropout are represented normal protein polysaccharide content (scoring 0).Accompanying drawing 21B represents the trilaminar contrast microsphere arthritis knee joint of Dan Baijutang disappearance to the section bottom, is called severe disappearance (scoring 3).In accompanying drawing 21C, the arthritis knee joint of paclitaxel microsphere treatment only slightly lacks on the cartilage top layer, surface complete (scoring 1).

The microsphere of paclitaxel loaded prevents the effect of Dan Baijutang disappearance not have in the arthritis of antigen induced remarkable (accompanying drawing 21D-F) in the arthritis that chondrus ocellatus Holmes polysaccharide brings out.Accompanying drawing 21E is illustrated in the equal severe of Dan Baijutang disappearance in all layers of cartilage, and top layer be kept perfectly (scoring 4).Less (accompanying drawing 21F, the scoring 2) that the knee joint that uses paclitaxel microsphere treatment chondrus ocellatus Holmes polysaccharide to bring out causes painted color to descend, and protective effect does not have in the model of antigen induced observed significantly (accompanying drawing 21C).

The arthritis of antigen induced is used for measuring the effect of these researchs.Although this animal model needs certain hour to take place, it reflects many aspects of human body rheumatoid arthritis, and such as releasing and activity of inflammatory cytokines (such as TNF-α), the disappearance of Dan Baijutang and leukocyte infiltration go into to have the joint of chronic inflammatory disease.To compare from the arthritic result that chondrus ocellatus Holmes polysaccharide brings out from the result of this model and those, but the arthritic method of acute (non-chronic) form of bringing out strong and reproduction level is set up and provided to the arthritis that described chondrus ocellatus Holmes polysaccharide brings out fast in rabbit.Because the arthritic severe Dan Baijutang disappearance that is characterised in that chondrus ocellatus Holmes polysaccharide brings out is measured the effect of intraarticular paclitaxel to the Dan Baijutang disappearance so this model also is used for this research.The efficacy study that comprises the mensuration of arthroncus, Dan Baijutang disappearance and chondrocyte necrosis shows that the 35-105 μ m microsphere that single injection 40mg loads 20% paclitaxel has significantly alleviated all aspects of chronic arthritis disease in the rabbit (table 1 and accompanying drawing 21A-C).The effect of the microsphere of paclitaxel loaded prevention Dan Baijutang disappearance in the arthritis model that brings out of the prevention chondrus ocellatus Holmes polysaccharide not result to the arthritis model of antigen induced is remarkable.

The effect that table 1.40mG reference substance and scope are estimated in the average score (N=5) of PLA microsphere in swelling, cellular infiltration, Dan Baijutang disappearance and chondrocyte necrosis of loading 20% paclitaxel of 10-35 and 35-105 μ m size

With relate in this description and/or the request for data table in the full content of listed all above-mentioned United States Patent (USP)s, U.S. Patent Application Publication text, U.S. Patent application, foreign patent, foreign patent application and non-patent publication us be incorporated herein by reference.

Can although described specific embodiments of the present invention, can under the situation that does not break away from essence of the present invention and scope, carry out various modifications from above understanding for task of explanation.Therefore, the present invention is not limited by they, and is only limited by the claim that awaits the reply.

Claims (83)

1. be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus: i) fibrosis agent with following composition; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host.

2. be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus: i) fibrosis agent with following composition; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is an endovascular device.

3. be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus: i) fibrosis agent with following composition; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is the gastrointestinal stent.

4. be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus: i) fibrosis agent with following composition; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is the trachea and bronchus stent.

5. be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus: i) fibrosis agent with following composition; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is the Genito-urinary stent.

6. be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus: i) fibrosis agent with following composition; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is ear and nose stent.

7. be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus: i) fibrosis agent with following composition; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is the ear breather.

8. be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus: i) fibrosis agent with following composition; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is an intraocular implant.

9. be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus: i) fibrosis agent with following composition; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is the medical apparatus that is used for the treatment of hypertrophic cicatrix or keloid.

10. be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus: i) fibrosis agent with following composition; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is a blood vessel graft.

11. be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus: i) fibrosis agent with following composition; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is a blood hemodialysis path.

12. be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus: i) fibrosis agent with following composition; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is the medical apparatus that comprises thin film or mesh.

13. be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus: i) fibrosis agent with following composition; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is the glaucoma drainage system.

14. be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus: i) fibrosis agent with following composition; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is prosthetic heart valve or its ingredient.

15. be used to implant the method for medical apparatus, comprise: (a) soak into host tissue, wherein said medical apparatus is with implanted or implanted following composition: i) fibrosis agent; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is a penile implant.

16. be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus: i) fibrosis agent with following composition; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is endotracheal tube or tracheostoma intubate.

17. be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus: i) fibrosis agent with following composition; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is a peritoneal dialysis catheters.

18. be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus: i) fibrosis agent with following composition; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is central nervous system's part flow arrangement or pressure monitoring device.

19. be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus: i) fibrosis agent with following composition; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is an IVCF.

20. be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus: i) fibrosis agent with following composition; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is a gastrointestinal device.

21. be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus: i) fibrosis agent with following composition; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is the central vein conduit.

22. be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus: i) fibrosis agent with following composition; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is a ventricular assist device.

23. be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus: i) fibrosis agent with following composition; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is a spinal implant.

24. be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus: i) fibrosis agent with following composition; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is an electric installation.

25. be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus: i) fibrosis agent with following composition; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is a pick off.

26. be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus: i) fibrosis agent with following composition; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is a pump.

27. be used to implant the method for medical apparatus, comprise: (a) soak into implanted or implanted the host tissue of described medical apparatus: i) fibrosis agent with following composition; Ii) anti-infective; Iii) polymer; The compositions that iv) comprises fibrosis agent and polymer; The compositions that v) comprises anti-infective and polymer; Or vi) comprise the compositions of fibrosis agent, anti-infective and polymer; (b) described medical apparatus is implanted described host, wherein said medical apparatus is a soft tissue implant.

28. be used for the method for prevention of surgical surgical adhesions, comprise the position that these needs are arranged sent and organize the reactive polymer compositions, and the fibre modification inhibitor is delivered to the tissue of described bag quilt so that the tissue of bag quilt is provided.

29. the method for prevention of surgical surgical adhesions is included in by cerebral dura mater cover and the spinal column in the vertebrae plate resection postoperative patient delivering compositions, wherein said composition prevention of surgical surgical adhesions between the musculature.

30. the method for prevention of surgical surgical adhesions is included on the vertebrae plate resection position among this patient who needs with a kind of compositions bag by spinal nerves, wherein said composition prevention of surgical surgical adhesions.

31. the method for prevention of surgical surgical adhesions comprises a kind of compositions is impregnated into the tissue around the spinal nerves on the vertebrae plate resection position, wherein said composition prevention of surgical surgical adhesions among the patient of these needs.

32. the method for prevention of surgical surgical adhesions comprises a kind of compositions is delivered to surgical tray excision position among the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

33. the method for prevention of surgical surgical adhesions comprises a kind of compositions is delivered to micro-dish excision position among the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

34. the method for prevention of surgical surgical adhesions comprises a kind of compositions is delivered to neurosurgery (brain) operation technique position, wherein said composition prevention of surgical surgical adhesions among the patient of these needs.

35. the method for prevention of surgical surgical adhesions comprises the spinal surgery position that a kind of compositions of prevention of surgical surgical adhesions is impregnated into the patient of these needs.

36. the method for prevention of surgical surgical adhesions comprises the epidural tissue that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

37. the method for prevention of surgical surgical adhesions comprises the cerebral dura mater tissue that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

38. the method for prevention of surgical surgical adhesions comprises the gynecological position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

39. the method for prevention of surgical surgical adhesions comprises the tissue surface of pelvis sidewall that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

40. the method for prevention of surgical surgical adhesions comprises the peritoneal cavity that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

41. the method for prevention of surgical surgical adhesions comprises the pelvic cavity that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

42. the method for prevention of surgical surgical adhesions comprises the laparotomy position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

43. the method for prevention of surgical surgical adhesions comprises the endoscopic procedure position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

44. the method for prevention of surgical surgical adhesions comprises the hernia reparation position, wherein the said composition prevention of surgical surgical adhesions that a kind of compositions are delivered to the patient of these needs.

45. the method for prevention of surgical surgical adhesions comprises the cholecystectomy position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

46. the method for prevention of surgical surgical adhesions comprises the cardiac surgery procedure position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

47. the method for prevention of surgical surgical adhesions comprises the heart transplant operation position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

48. the method for prevention of surgical surgical adhesions comprises the cardiovascular reparation position, wherein the said composition prevention of surgical surgical adhesions that a kind of compositions are delivered to the patient of these needs.

49. the method for prevention of surgical surgical adhesions comprises the cardiac valve replacement position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

50. the method for prevention pericardium surgical operation adhesion comprises the pericardium surgical site that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

51. the method for prevention of surgical surgical adhesions comprises the orthopaedic surgery operating position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

52. the method for prevention of surgical surgical adhesions comprises the laceration of ligament position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

53. the method for prevention of surgical surgical adhesions comprises the joint injury position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

54. the method for prevention of surgical surgical adhesions comprises the tendon injury position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

55. the method for prevention of surgical surgical adhesions comprises the cartilage injury position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

56. the method for prevention of surgical surgical adhesions comprises the muscle injury position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

57. the method for prevention of surgical surgical adhesions comprises the nerve injury position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

58. the method for prevention of surgical surgical adhesions comprises the cosmetic surgery operating position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

59. the method for prevention of surgical surgical adhesions comprises the reconstruction operations operating position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

60. the method for prevention of surgical surgical adhesions comprises the breast implant position that a kind of compositions is delivered to the patient of these needs, wherein said composition prevention of surgical surgical adhesions.

61. be used for the treatment of the method for inflammatory arthritis, comprise that said composition comprises to patient's delivery treatments compositions that these needs are arranged: a) polymer and/or form the chemical compound and the b of polymer in position) the fibrosis agent.

62. be used to prevent the method for inflammatory arthritis, comprise that said composition comprises polymer and fibrosis agent to patient's delivery treatments compositions that these needs are arranged.

63. be used for the treatment of the method for osteoarthritis, comprise that said composition comprises polymer and fibrosis agent to patient's delivery treatments compositions that these needs are arranged.

64. be used to prevent the method for osteoarthritis, comprise that said composition comprises polymer and fibrosis agent to patient's delivery treatments compositions that these needs are arranged.

65. be used for the treatment of the method for constitutional osteoarthritis, comprise that said composition comprises polymer and fibrosis agent to patient's delivery treatments compositions that these needs are arranged.

66. be used to prevent the method for constitutional osteoarthritis, comprise that said composition comprises polymer and fibrosis agent to patient's delivery treatments compositions that these needs are arranged.

67. be used for the treatment of the method for Secondary cases osteoarthritis, comprise that said composition comprises polymer and fibrosis agent to patient's delivery treatments compositions that these needs are arranged.

68. be used to prevent the method for Secondary cases osteoarthritis, comprise that said composition comprises polymer and fibrosis agent to patient's delivery treatments compositions that these needs are arranged.

69. be used for the treatment of the method for rheumatoid arthritis, comprise that said composition comprises polymer and fibrosis agent to patient's delivery treatments compositions that these needs are arranged.

70. be used to prevent the method for rheumatoid arthritis, comprise that said composition comprises polymer and fibrosis agent to patient's delivery treatments compositions that these needs are arranged.

71. the method to the patient treatment hypertrophic cicatrix of needs comprises this patient is sent: a) fibrosis agent; Or b) comprise i) fibrosis agent and ii) polymer and/or form the compound compositions of polymer in position.

72. the method to the patient treatment keloid of needs comprises this patient is sent: a) fibrosis agent; Or b) comprise i) fibrosis agent and ii) polymer and/or form the compound compositions of polymer in position.

73. the method to the patient of needs reduces the cartilage loss after the joint injury comprises this patient is sent: a) fibrosis agent; Or b) comprise i) fibrosis agent and ii) polymer and/or form the compound compositions of polymer in position.

74. the method to the patient of needs prevents the cartilage loss after the joint injury comprises this patient is sent: a) fibrosis agent; Or b) comprise i) fibrosis agent and ii) polymer and/or form the compound compositions of polymer in position.

75. the method for the cartilage loss after the patient of needs reduced ligamentum cruciatum and tear comprises this patient is sent: a) fibrosis agent; Or b) comprise i) fibrosis agent and ii) polymer and/or form the compound compositions of polymer in position.

76. the method for the cartilage loss after preventing ligamentum cruciatum to tear to the patient of needs comprises this patient is sent: a) fibrosis agent; Or b) comprise i) fibrosis agent and ii) polymer and/or form the compound compositions of polymer in position.

77. the method to the patient of needs reduces the cartilage loss behind the meniscus tear comprises this patient is sent: a) fibrosis agent; Or b) comprise i) fibrosis agent and ii) polymer and/or form the compound compositions of polymer in position.

78. the method to the patient of needs prevents the cartilage loss behind the meniscus laceration of ligament comprises this patient is sent: a) fibrosis agent; Or b) comprise i) fibrosis agent and ii) polymer and/or form the compound compositions of polymer in position.

79. the method to the patient treatment angiopathy of needs comprises this patient is sent: a) fibrosis agent; Or b) comprise i) fibrosis agent and ii) polymer and/or form the compound compositions of polymer in position.

80., comprise this patient sent: a) fibrosis agent to the narrow method of the patient treatment of needs; Or b) comprise i) fibrosis agent and ii) polymer and/or form the compound compositions of polymer in position.

81. the method to the patient treatment restenosis of needs comprises this patient is sent: a) fibrosis agent; Or b) comprise i) fibrosis agent and ii) polymer and/or form the compound compositions of polymer in position.

82., comprise this patient sent: a) fibrosis agent to the atherosclerotic method of the patient treatment of needs; Or b) comprise i) fibrosis agent and ii) polymer and/or form the compound compositions of polymer in position.

83. a compositions, it comprises: i) fibrosis agent; Ii) polymer or form the chemical compound of polymer in position.

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