CN101420970A - Implantable sensors and implantable pumps and anti-scarring agents - Google Patents

Abstract

Pump contacting with tissue, sensor and scar formation preventing agent are combined in use to prevent scar from forming. Otherwise, while all the pump and sensor are implanted into an animal body, scar is possible to be formed.

Description

Implantable sensor and implantable pump and anti-scarring agent

Background of invention

Invention field

Generality of the present invention relates to implantable sensor, drug delivery device and drug delivery pump, more specifically, relates to compositions and this type of device of preparation and uses this type of device so that the method for their opposing inflammatories and fibroid scar tissue overgrowth.

Association area is described

Secular, site-specific that implantable drug delivery device and pump provide therapeutic agent discharge to treat the device of multiple medical conditions.When hope localization drug effect (promptly this disease only influences the specific region) or when system's delivery efficiency of medicament low or invalid and cause toxicity, serious side effects, medicine to arrive target tissue before symptom/disease of inactivation, difference control and/or during drug dependence, utilize medicine to send implant and pump usually.Implantable pump also can be sent the systemic drug level for a long time and help the patient to avoid " Feng Hegu " of the blood levels drug level relevant with intermittent whole body administration in mode constant, that regulated.For many patients, this can cause better symptom control (usually can according to the seriousness titration dosage of symptom), and better disease administers (especially the insulin in the diabetes is sent) and lower medicine needs (being particularly useful for the pain medication).Developed countless drug delivery devices, implant and pump for a series of certain medical diseases, and the concrete structure of device and send mechanism and depend on concrete treatment.For example, implant sent by medicine and pump has been used for the various clinical application, comprise the insulin pump able to programme that is used for the treatment of diabetes, (for example use anesthetis, morphine, fentanyl) (for example is used to ease the pain, cancer, back problems, HIV, the operation back) (in the spinal column) pump in the sheath, part and systemic delivery chemotherapeutant are with the treatment cancer (for example, the Hepatic artery 5-FU infusion of liver neoplasm), be used for cardiac conditions treatment medication (for example, the anti-arrhythmic that is used for rhythm abnormality), spasm (for example, the multiple sclerosis that is used for nervous disorders, spinal cord injury, brain injury, the cerebral palsy) sends spasmolytic medicine (for example, baclofen) in the sheath, perhaps be used for infection control (for example, osteomyelitis, septic arthritis) part/regional antibiotic.

Usually, most drug is sent by subcutaneous implantation (approaching easily under the skin, still discrete position) and by pump installation with medicine storage and flexible catheter and is formed, and delivers drugs into target tissue by this conduit.The therapeutic drug levels (depend on application) of medicine to realize part or whole body of scheduled volume stored and discharged through conduit to pump.The center of pump has the self-styled inlet that is covered by barrier film, thereby if desired, can recharge this pump with medicine by percutaneous (by skin and barrier film) insertion syringe needle.Two types implantable drug delivery pump is arranged usually.The constant rate of speed pump is usually by gas-powered and be designed under pressure the constant rate of speed with pre-programmed and distribute medicine as successive doses.The amount of drug flow and speed are subjected to the length, temperature of used conduit and the adjusting of height, when needs constant, when long-term medicine is sent, they are best.Although limitation is arranged, the advantage of these pumps is simple, has movable part seldom, does not need the battery energy and has the long life-span.Speed pump able to programme utilizes battery-powered pump and constant pressure storage with can be by the mode of doctor or patient's programming delivering drugs periodically.For programmable infusion device, can be based on the scheme of being programmed with little, discrete doses delivering drugs, this scheme can change according to the clinical response of individuality.Programmable drug delivery pump can with the external transmitter communication, this transmitter is by the low frequency wave that the passes skin specified dosage regimen of programming, and comprises speed, every dose time and amount.Speed pump able to programme is used and is provided better dosimetry more widely, but because their complexity, they need more maintenances and have the shorter life-span.

The clinical function of implantable drug delivery device or pump depends on this device, especially conduit, it can effectively keep the tight anatomy contact with target tissue (for example, (sudural) space, lumen of artery, peritoneum under the dura mater in the spinal cord)) close anatomy contact and be not subjected to the coating or the obstruction of scar tissue.Unfortunately, in many cases, when implanting these devices in the health, they stand from " foreign body " reaction of host tissue on every side.The device that health identification is implanted is external, and it causes inflammatory reaction, then coats this implant with fibrous connective tissue.Wound to anatomical structure and implant surrounding tissue during device is implanted also can cause cicatrization (that is fibre modification).At last, if device is subjected to patient's daily routines operation (some patient touches hypodermic implant continuously) or stimulates, even fibrous encapsulation that also can generating means after successfully implanting.For drug delivery pump, conductor housing or chamber may be subjected to the obstruction of scar tissue, and it can cause drug flow to slow down or stop fully.Alternatively, conduit can be subjected to the coating (that is, health " separates " device with fibrous tissue) of cicatrix thus medicine is delivered to target tissue (that is, cicatrix prevents to move to from the correct medicine of conduit the another side of capsule) by halves.Any of these development can cause the drug efficiency lowland or flow to the target tissue by halves or organ (with the forfeiture clinical benefit), and second kind can also cause topical remedy accumulation (in capsule) and other clinical complication (for example, topical remedy's toxicity; The medicine that high amount of drug unexpected " toppling over " is gone into after the surrounding tissue is isolated).In addition, the tissue around implantable pump or the conduit can be subjected to the antixenic unintentional infringement of inflammatory, causes loss function and/or tissue injury (for example, the scar tissue in the spinal canal causes pain or blocks flowing of cerebrospinal fluid).

Often (always not being) device of being used in combination with drug delivery pump is the implantable sensor device.Implantable sensor is the device of variation that is used to detect the level of body function and/or crucial physiological metabolism thing, chemistry, hormone or biological factor.Implantable sensor can be used for multiple physics of sensing and/or physiological property, includes, but not limited to light, machinery, chemistry, electrochemical, temperature, tension force, pressure, magnetic force, acceleration, ionizing radiation, sound wave or chemical modification.Usually, sensor technology and the associating of implantable drug delivery pump, thus the pick off acknowledge(ment) signal uses this information to regulate the release dynamics of medicine then.The application of the most extensive pursuit of this technology is to produce closed loop " artificial pancreas ", and it can continuous detecting blood sugar level (by the pick off of implanting) and provides feedback to regulate insulin using to diabetics to implantable pump.Other representative example of implantable sensor comprises, blood/tissue glucose monitor, electrolyte pick off, blood constitutent pick off, temperature sensor, pH pick off, optical pickocff, amperometric sensor, pressure transducer, biosensor, sensing responder, tension pick-up, activity sensor and magnetoresistive transducer.Send the problem that pump faces the spitting image of said medicine, the correct clinical function of institute's implanted sensor depends on the tight anatomy of target tissue and/or body fluid and contacts.Cicatrization around the implanted sensor can reduce the electric component and the feature of device-organizational interface, and tissue may not correctly be brought into play function.For example, the coating that is subjected to cicatrix when the pick off that " foreign body " reaction takes place and implant is when (that is, health " separates " pick off with fibrous tissue), and pick off is accepted inaccurate biological information.If pick off is just detecting the situation in the capsule, and these situations not with the outer situation consistent (normally like this) of capsule, it will produce inaccurate reading.Similarly, if scar tissue changes physics or chemical information to the flowing of the testing agency of pick off, its handled information will not reflect those situations that are present in the target tissue.

Summary of the invention

In brief, the invention discloses medicament, it suppresses one or more aspects of the production of excess fibre (cicatrix) tissue.On the one hand, the invention provides compositions, it is used for sending selected therapeutic agent by medical apparatus that contains pick off or drug delivery pump or implant, and the method for making and use these implants and device.Thereby compositions of describing and method are used for sending medicament with treatment level over a period to come with drug delivery composition coating pick off or pump, described treatment level prevents that enough the pick off of delivery catheter and/or implantation is covered by in the fibrous tissue, thereby improves and/or the extension fixture function.Alternatively, described contain the fibre modification inhibitor topical application of compositions (for example, topical agent, injection, liquid, gel, spray, microsphere, paste, wafer), its pump that can be applied to and implant (especially delivery catheter) and/or the adjacent tissue of implanting of pick off, thus the fibre modification inhibitor is sent to prevent that enough delivery catheter or pick off from being blocked by fibrous tissue or coat with treatment level over a period to come.At last, described many specific implantable pumps, pick off and composite set, it is owing to producing good clinical effectiveness with the medicament coating that reduces the accumulation of excessive cicatrization and fibrous tissue and other associated advantages.

In one aspect of the invention, the implant and the medical apparatus of medicine coating or medicine dipping are provided, it reduces fibre modification in the tissue around drug delivery pump of implanting or the pick off, perhaps suppress this device/implant surface (especially drug delivery tube chamber and sensor surface) and go up the cicatrix development, thereby strengthen the effect of this method.For example, fibrous tissue can reduce or block therapeutic agent from conduit to the flowing of target tissue, perhaps prevent the sensor implanted reading accurately.In multiple embodiments, suppress fibre modification by being confined to discharge with the part of the particular agent of implanting device adjacent tissue or whole body.

The reparation of machinery or surgical intervention (as the implantation of pump or pick off) back tissue comprises two kinds of different processes: (1) regeneration (damaging cells is by the cell replacement of same type) and (2) fibre modification (damaging cells is substituted by connective tissue).The several general component of fibre modification (or cicatrization) process comprises: the infiltration of inflammatory cell and inflammatory reaction, the migration and the propagation of connective tissue cell (as fibroblast or smooth muscle cell), the deposition of extracellular matrix (ECM), the formation of neovascularity (angiogenesis) and reinvent (fibrous tissue ripe and tissue)." suppressing (minimizing) fibre modification " used herein can be understood as to refer to reduce or limit fibrous tissue and forms (promptly, by reducing or inflammation-inhibiting process, connective tissue cell migration or propagation, ECM produce, angiogenesis, and/or in reinventing one or more) medicament or compositions.In addition, the numerous therapeutic agent of describing among the present invention will have the additional benefits that also reduces tissue regeneration when suitable.

In certain embodiments of the invention, implant or device (for example, pick off or pump) one or more mechanism of being suitable for quoting by this paper discharge to suppress fibrotic medicaments.In some other embodiments of the present invention, implant or device contain a kind of medicament, when it keeps being associated with this implant or device, suppress this implant or device and prevent fibre modification between the tissue of described implant or device by the direct contact between described medicament and described implant or the device tissue on every side.

In related fields of the present invention, the implantable pump and the pick off that comprise implant or device are provided, wherein suppress fibrotic medicament in this implant or the device releaser." release of medicament " refers to that any statistics of this medicament or its subfraction exists significantly, and described subfraction dissociates and/or (or inner) keeps activity on the surface of this device/implant from this device/implant.In another aspect of this invention, provide the method for producing medical apparatus or implant, it comprises the step of coating (for example, spraying, immersion, coating or drug administration pass through) medical apparatus or implant.In addition, this implant or medical apparatus can so be constructed and be made this device itself comprise in the inhibition implant or fibrotic material on every side.Can utilize multiple implantable pump and pick off in the context of the present invention, depend on the site and the character of desirable treatment.

In multiple embodiments of the present invention, pump or the pick off of implanting further is coated with compositions or chemical compound, said composition or chemical compound after implantation, fibre modification suppressed activating agent begin postpone a period of time.The representative example of this type of medicament comprises heparin, PLGA/MePEG, PLA and Polyethylene Glycol.In other embodiments, fibre modification-inhibition implant or device before using, between or activation afterwards (for example, nonactive medicament at first is activated into minimizing or suppresses the medicament that the interior fibre modification of body is reacted device on).

In multiple embodiments of the present invention, around the tissue compositions or the compound treatment that contains the fibre modification inhibitor of pump of implanting (especially drug delivery tube) and/or pick off.Described contain the fibre modification inhibitor topical application of compositions (for example, partial, injectable, liquid, gel, spray, microsphere, paste, wafer) or chemical compound, it can be applied to the surface of pump or pick off or be penetrated into and pump or the adjacent tissue of pick off, thereby medicament was sent to prevent that enough drug delivery tube and/or pick off from being blocked by fibrous tissue or coat with treatment level in a period of time.This can replace carrying out with inhibitor coated this device of fibre modification or implant, perhaps except with carrying out inhibitor coated this device of fibre modification or the implant.The local application of fibre modification inhibitor can be before pump or pick off self be implanted, during or take place afterwards.

In multiple embodiments of the present invention, pump of implanting or pick off are in one aspect, part or surface go up with suppressing fibrotic compositions coating, and this device on the other hand, be coated with (for example, will install body and be fixed to the specific anatomical space) with epulotic compositions or chemical compound on part or the surface.The representative example of promotion fibre modification and synulotic medicament comprises the component of silk, silicon dioxide, crystalline silica, bleomycin, quartzy dust, neomycin, Talcum, metallic beryllium and oxide thereof, tretinoin chemical compound, copper, leptin, somatomedin, extracellular matrix; Fibronectin, collagen, fibrin, perhaps Fibrinogen, polylysine, poly-(ethylene-co-vinyl acetate), chitosan, N-carboxybutyl chitosan and RGD protein; The polymer of vinyl chloride or vinyl chloride; Be selected from cyanoacrylate and the crosslinked poly-proteic binding agent of (ethylene glycol)-methylated collagen; Inflammatory cytokine (for example, TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-1, IL-1, IL-1-β, IL-8, IL-6, and growth hormone); Connective Tissue Growth Factor (CTGF) and analog and derivant.

The method that the present invention also provides treatment to carry out the patient of surgical operation, endoscopy or minimally-invasive treatment is wherein placed pump and the pick off of implanting as the part of this method.As used herein, be appreciated that in " inhibition fibre modification " finger device or on every side the statistics of variables of scar tissue significantly reduce or implant (conduit and/or pick off) and tissue between improvement in the interface, the permanent inhibition that it can or can not cause any complication or device/implant to lose efficacy.

Medicament and compositions are used to produce the implant and the medical apparatus of new medicine coating, its reduce on the foreign body reaction of implant and the restraint device surface, among or the growth of reactive tissue on every side, thereby strengthen the property.Can provide than the tangible clinical advantages of uncoated device with the implantable pump and the pick off that prevent the scar tissue undue growth through design or improve the selected medicament coating of conductivity.

For example, on the one hand, the present invention relates to implantable pump and pick off, it comprises medical implant and (i) anti-scarring agent and (ii) comprise at least a in the compositions of anti-scarring agent.Exist this medicament in order to the inhibition cicatrization, otherwise when this implant places in the animal body, cicatrization can take place.On the other hand, the present invention relates to method, wherein implant and (i) anti-scarring agent and (ii) comprise at least a being placed in the animal in the compositions of anti-scarring agent, and described medicament inhibition cicatrization, otherwise cicatrization will take place.Summarize these and other aspect of the present invention below.

Thereby, multiple independently aspect, the invention provides device, the compositions that it comprises implantable pump and/or pick off and anti-scarring agent or comprises anti-scarring agent, wherein this medicament suppresses cicatrization.These and other device of more detailed description below.

In each of said apparatus, aspect independent, the invention provides: medicament is a cell cycle inhibitor; Medicament is an anthracycline; Medicament is a taxane; Medicament is a podophyllotoxin; Medicament is an immunomodulator; Medicament is the heat shock protein 90 antagonist; Medicament is the HMGCoA reductase inhibitor; Medicament is an inosine monophosphate dehydrogenase inhibitor; Medicament is the NF kB inhibitor; Medicament is the P38MAP inhibitors of kinases.At this paper these and other activating agent is described in more detail.

Aspect other, for each said apparatus of each above-mentioned medicament combination, for every kind of combination, disclosing described medicament independently can be present in the compositions with polymer.In an embodiment aspect this, polymer is biodegradable.In another embodiment aspect this, the polymer right and wrong are biodegradable.Provide other characteristics and the feature of polymer in more detail at this paper, they are used to every kind of combination of device and above-mentioned medicament to describe the present invention.

Except device, the present invention also provides method.For example, in additional aspects of the present invention, for every kind of said apparatus, with for device each with the combinations thereof of anti-scarring agent, the invention provides method, wherein specific device is implanted in the animal, and installed bonded particular agent with this and suppress otherwise contingent cicatrization.Every kind of device that this paper identifies can be " specific device ", and every kind of anti-scarring agent that this paper identifies can be " anti-scarring agent ", wherein every kind of possible combination of the present invention's generator and medicament in independent embodiment.

Can before device places animal, medicament be combined with device.For example, medicament (compositions that perhaps comprises this medicament) can be coated on the implant, then the gained device is placed animal.In addition, or alternatively, medicament can place animal will or placing position in the animal near device independently.For example, can or place the contact medical apparatus or experience synulotic tissue, adjacent reagent spray with this tissue, and/or in the tissue.For this reason, the invention provides implantable pump and/or pick off and anti-scarring agent or the compositions that comprises anti-scarring agent are implanted the animal reservoir, wherein this medicament suppresses cicatrization.

In every kind of preceding method, aspect independent, the invention provides: medicament is a cell cycle inhibitor; Medicament is an anthracycline; Medicament is a taxane; Medicament is a podophyllotoxin; Medicament is an immunomodulator; Medicament is the heat shock protein 90 antagonist; Medicament is the HMGCoA reductase inhibitor; Medicament is an inosine monophosphate dehydrogenase inhibitor; Medicament is the NF kB inhibitor; Medicament is the P38 map kinase inhibitor.Describe in more detail at this paper and can suppress fibrotic these and other activating agent.

Aspect other, for uniting every kind of preceding method of use with every kind of aforementioned medicament, for every kind of combination, disclosing described medicament independently can be present in the compositions with polymer.In an embodiment aspect this, polymer is biodegradable.In another embodiment aspect this, the polymer right and wrong are biodegradable.Provide other characteristics and the feature of polymer in more detail at this paper, they are used to above-mentioned medicament device and every kind of combination to describe the present invention.

When reference following detailed and accompanying drawing, these and other aspect of the present invention will become apparent.In addition, provided multiple references at this paper, they are describing method and/or compositions (for example, polymer) in more detail, and so complete being incorporated herein by reference.

The accompanying drawing summary

Fig. 1 is the diagram how the showed cell cycle inhibitor acts on the one or more steps in the biological pathway.

Fig. 2 has shown to be used to assess the chart of mitoxantrone to the Screening test result of the influence of the nitric oxide production of THP-1 macrophage.

Fig. 3 has shown to be used to assess the chart of Bay 11-7082 to the Screening test result of the influence of the TNF-α production of THP-1 macrophage.

Fig. 4 has shown to be used to assess the chart of rapamycin concentrations to the Screening test result of the influence of the TNF-α production of THP-1 macrophage.

Fig. 5 has shown to be used to assess the chart of mitoxantrone to the Screening test result of the influence of human fibroblasts propagation.

Fig. 6 has shown to be used to assess the chart of rapamycin to the Screening test result of the influence of human fibroblasts propagation.

Fig. 7 has shown to be used to assess the chart of paclitaxel to the Screening test result of the influence of the propagation of human fibroblasts.

Fig. 8 is for showing the int carotid picture from rat air bag damage model.

Fig. 9 is for showing the impaired carotid picture from rat air bag damage model.

The carotid picture of Figure 10 for showing that paclitaxel/mesh is handled in the rat air bag damage model.

Figure 11 A has roughly described the transcriptional regulatory of matrix metalloproteinase.

Figure 11 B is a trace, and it illustrates IL-1 stimulates the AP-1 transcriptional activity.

Figure 11 C is that be presented at the to use by oneself IL-1 that reduces in the lysate of the pretreated chondrocyte of paclitaxel is inductive in conjunction with active figure.

Figure 11 D is a trace, and it shows that IL-1 induces on rna level increases collagenase and stromelysin in the chondrocyte, and this induce can be by suppressing with the paclitaxel pretreatment.

Figure 12 A-H is a trace, and it has shown the effect of multiple anti-microtubule medicament in suppressing collagenase expression.

Figure 13 shows to be used to assess the figure of paclitaxel to the Screening test result of the influence of smooth muscle cell migration.

Figure 14 shows to be used to assess the figure of geldanamycin to the result of the Screening test method of the influence of the IL-1 β production of THP-1 macrophage.

Figure 15 shows to be used to assess the figure of geldanamycin to the result of the Screening test method of the influence of the IL-8 production of THP-1 macrophage.

Figure 16 shows to be used to assess the figure of geldanamycin to the result of the Screening test method of the influence of the MCP-1 production of THP-1 macrophage.

Figure 17 shows to be used to assess the figure of paclitaxel to the result of the Screening test method of smooth muscle cell proliferation influence.

Figure 18 shows to be used to assess the figure of paclitaxel to the result of the Screening test method of Mus RAW 264.7 macrophage cell line proliferations influence.

Figure 19 is a rectangular histogram, and it has shown with respect to being exposed to uncoated PU film, is exposed to the area of granulation tissue in the carotid artery of polyurethane (PU) film around the blood vessel of silk bag quilt.

Figure 20 is a rectangular histogram, and it has shown with respect to being exposed to uncoated PU film, is exposed to the area of granulation tissue in the carotid artery of PU film around the blood vessel of stitching thread coating.

Figure 21 is a rectangular histogram, and it has shown with respect to matched group (wherein only coating tremulous pulse with PU film around the blood vessel), be exposed to the silk powder of natural and purification and the carotid artery that coats with PU film around the blood vessel in the area of granulation tissue.

Figure 22 is a rectangular histogram, and it has shown with respect to matched group (wherein only coating tremulous pulse with PU film around the blood vessel), with Pulvis Talci spray and the carotid artery that coats with PU film around the blood vessel in the area (at 1st month and 3rd month) of granulation tissue.

Detailed Description Of The Invention

Definition

Before proposing the present invention, the definition that at first is illustrated in some term that hereinafter uses is helpful for the understanding of the present invention.

" medical apparatus ", " implant ", " device ", " medical implant ", " implant/device " etc. synonymously are used in reference to and are used for partially or completely being placed in the arbitrary objects of patient body for one or more treatments or prevention purpose design, described treatment or prevention purpose are such as recovering physiological function, alleviate the symptom with disease association, delivering therapeutic agents, the change (perhaps level) of environment in detecting, and/or repair or replace or improve damaged or ill Organ and tissue. Although medical apparatus is usually by synthetic material (for example, medical grade stainless steel, titanium and other metal of biocompatible; The external source polymer, as polyurethane, silicon, PLA, PLGA) form, other material also can be used for structure medical apparatus or implant. Especially can be used for specific medical apparatus of the invention process and implant comprises the medicine that is designed for the delivery treatments level to device and the implant (drug delivery pump) of target tissue and/or is designed for the sensor of the variation that detects body function change and/or crucial physiological metabolism thing, chemistry, hormone or biological factor.

" implantable sensor " refer to implant health for detection of the blood of specific chemicals (for example, glucose, electrolyte, medicine, hormone) or tissue water gentle/and the medical apparatus of the variation of health chemistry, metabolin, function, pressure, mobile, physical arrangement, electrical activity or other variable element. Implantable sensor can have one or more electrodes, and it stretches into external environment condition with the multiple physics of sensing and/or physiological property, includes, but not limited to light, machinery, air pressure, chemistry and electrochemical properties. Sensor can be for detection of the information of for example environment temperature, tension force, pressure, magnetic, acceleration, ionising radiation, sound wave or chemical modification (for example, blood constituent, as sugar). For example, detection for glucose level, sensor can utilize the electrochemical sensor based on enzyme, glucose-response water gel associating pressure sensor, microfilament with electrode, RF microelectronic and glucose are affine combination with polymers physics and biochemistry sensing technology, and near or middle infrared (Mid-IR) emission optical joint spectroscopic detector, only give some instances. The representative example of implantable sensor comprises, blood/tissue glucose monitor, electrolyte sensor, blood constituent sensor, temperature sensor, pH sensor, optical pickocff, amperometric sensor, pressure sensor, biology sensor, sensing responder, tension pick-up, activity sensor and magnetoresistive transducer.

" drug delivery pump " refers to comprise the medical apparatus of pump, and this pump is configured to send bioactivator (for example, medicine) with modulated dosage. these devices are implanted in health and can comprise for the external transmitter of the controlled release of programming medicine, perhaps alternatively, can comprise implantable sensor, if it provides on physiology, need, and cause drug delivery pump and discharge medicine. drug delivery pump can be used for sending almost medicament arbitrarily, but particular instance comprises the insulin that is used for the treatment of diabetes, the Anticonvulsants that is used for the medicine, the chemotherapeutant that is used for the treatment of cancer that ease the pain, is used for the treatment of motion and disorder of muscle, perhaps is used for the treatment of the antibiotic of infection. the representative example that is used for drug delivery pump of the invention process comprises, but be not limited to, the constant current drug delivery pump, programmable drug delivery pump, pump in sheath, implantable insulin is sent pump, implantable osmotic pump, medicament for the eyes is sent pump and implant, metering system, wriggling (rolling) pump, electrically driven (operated) pump, the elastomer pump, the spring contraction pump, the gas-powered pump (for example, induce by electrolytic cell or chemical reaction), hydraulic pump, rely on the pump of piston and the pump of non-dependence piston, distributor chamber, infusion pump, the passive type pump, the liquid distributor that infusate pump and osmotic pressure drive.

" fibre modification ", " cicatrization " or " fibre modification reaction " refer to that response damage or medical intervention form fiber (scar) tissue. Suppressing fibre modification or synulotic therapeutic agent can so carry out by one or more mechanism, described mechanism comprises: inflammation-inhibiting is replied, the migration or the propagation that suppress phoirocyte (as fibroblast, smooth muscle cell and VSMC), suppress Angiogenesis, induce ECM to produce (perhaps promoting ECM to decompose), and/or suppress tissue reconstruction. In addition, the multiple therapeutic agent of the present invention's description will also have the other benefit of minimizing regeneration (by the impaired cell of the cell replacement of same type) when suitable.

" inhibition fibre modification ", " minimizing fibre modification ", " fibre modification inhibitor ", " inhibition scar ", " minimizing scar ", " anti--fibre modification ", " anti-cicatrization " etc. synonymously are used in reference to the effect of medicament or composition, the minimizing of the statistically significant that when it causes estimating not have this medicament or composition, fibr tissue forms.

" inhibitor " refers to prevent that biological process from occurring or the slow down speed of biological process generation or the medicament of degree. Described process can be common process, as cicatrization or refer to the particular biological effect, as causes the molecular process of cytokine release.

" antagonist " refers to prevent that biological process from occurring or the slow down speed of biological process generation or the medicament of degree. Although this process can be general process, this refers to drug action mechanism usually, and its Chinese traditional medicine and molecule are competed the bioactive molecule site or prevented molecule and this molecular locus interaction. In these situations, effect is suppressed for this molecular process.

" activator " refers to stimulating organism process or the speed of biological process generation or the medicament of degree. Described process can be general process, as cicatrization or refer to the particular biological effect, as causes the molecular process of cytokine release.

" anti-microtubule agent " can be understood as and for example comprise, by preventing or arbitrary protein matter, peptide, chemicals or other molecule of stable polymerization infringement microtubule function. The compound of the polymerization of stabilize microtubules is called " microtubule stabilizer " at this paper. Can measure resisting-the microtubule activity of particular compound with several different methods, for example comprise Smith etc. (Cancer Lett 79 (2): 213-219,1994) and Mooberry etc., the determination method that (Cancer Lett.96 (2): 261-266,1995) describes.

" host ", " people ", " experimenter ", " patient " etc. synonymously are used in reference to biology (people or animal), and device of the present invention will be implanted in this biology.

" implantation " refers to will install wholly or in part and be placed in host. When certain part of installing reached or extend to the host outside, device was that part is implanted.

" release of medicament " refers to the existence of the statistically significant of medicament or its subfraction, and described medicament or its subfraction dissociate and/or (perhaps the inside) maintenance activity on the surface of device/implant from implant/device.

" biodegradable " refers to the material that degradation process is mediated and/or carried out therein by biosystem at least partly. " degraded " refers to the chain splitting process, by this process, polymer chain cut into oligomer and monomer. Chain splitting can occur by number of mechanisms, and described mechanism for example comprises, by chemical reaction (for example, hydrolysis) or by heat or photodissociation process. For example, use gel permeation chromatography (GPC) characterize polymers to degrade, gel permeation chromatography monitors and corrodes and the change of medicine deenergized period polymer molecular weight. The erosion process degraded of carrying out in biodegradable that also refer to mediate by biosystem and/or biosystem. " erosion " refers to the process that material wherein comes off from body. In the situation of polymer system, material can be monomer, oligomer, the part of main polymer chain, or the part of polymer body. Erosion comprises (i) surface erosion, wherein corrodes and only acts on stromal surface but not inside; (ii) body corrodes, wherein whole system cracking in whole matrix by fast hydrating and polymer chain. The type that depends on polymer, corrode usually by three kinds of fundamental mechanisms occur (referring to for example, Heller, J., CRC Critical Review in Therapeutic Drug Carrier Systems (1984), 1 (1), 39-90); Siepmann, J. etc., Adv.Drug Del.Rev. (2001), 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) by hydrolysis, ionization or protonated side group make initial water-insoluble polymer solubilising; (3) by the main chain cracking, hydrophobic polymer is converted into soluble small molecular. Characterize the technology that corrodes and comprise heat analysis (for example DSC), X-ray diffraction, SEM (SEM), electron spin resonance spectroscopy (EPR), NMR imaging, and recording quality loss in the erosion experiment process. , for framboid, can apply photon correlation spectroscopy (PCS) and other grain diameter measurement technology and monitor that erodible device size in time develops.

As used herein, " analog " refer to structurally be similar to parent compound, but the chemical compound of slightly different on forming (for example atom or functional group are different, increase or remove). Analog can have or can not have chemistry or the physical property different from original compound, and can or can not have biology and/or the chemism of improvement. For example, with parent compound, compare, analog can be more hydrophilic or it can have the reactivity of change. Analog can be simulated chemistry and/or the BA (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 restructuring) variant that the natural or non-natural of original compound exists. The example of analog have mutein (namely wherein at least one amino acid lacked, increased or by the protein analogue of another amino acid substitution). The analog of other type comprises the chirality variant of other type of isomers (enantiomter, diastereoisomer etc.) and compound, and constitutional isomer. Analog can be side chain or the ring-type variant of straight chain compound. For example, straight chain compound can have a side chain or be substituted and give (hydrophily or the bioavilability for example improved) analog of some ideal performance.

As used herein, " derivative " refers to the form of chemistry or the biological modification of compound, and its structure is similar to parent compound and (in fact or in theory) is derived from this parent compound. " derivative " is that with the difference of " analog " parent compound can be the raw material that produce " derivative ", and parent compound not necessarily produces " analog " as raw material. Derivative can or can not have the chemistry different from parent compound or physical property. For example, with parent compound, compare, derivative can be more hydrophilic or it can have the reactivity of change. Derivatization (being modification) can comprise the one or more parts (for example functional group changes) in displacer molecule. For example, hydrogen atom can be replaced by halogen such as fluorine or chlorine, and perhaps hydroxyl (OH) can be by carboxylic moiety (COOH) displacement. Term " derivative " also comprises conjugate and the prodrug (namely can be converted into the derivative of the chemical modification of original 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 compound. For example, by substitute one or two hydrogen atom on nitrogen-atoms with acyl group (acyl group prodrug) or carbamate groups (carbamate prodrugs), can form prodrug. The information relevant with prodrug is such as seeing Fleisher etc. more specifically, Advanced Drug Delivery Reviews 19 (1996) 115; Design of Prodrugs, H.Bundgaard (ed.), Elsevier, 1985; Or H.Bundgaard, Drugs of the Future 16 (1991) 443. All solvates of parent compound also be used for to be described in term " derivative ", for example hydrate or the adduct adduct of alcohol (for example with), active metabolite and salt. The type of the salt that can prepare depends on the character of compound interior section. For example, acidic-group, for example hydroxy-acid group for example can form alkali metal salt or alkali salt (sodium salt for example, sylvite, magnesium salts and calcium salt, also have the salt of the quaternary ammonium ion that with physiology, can tolerate, and the acid-addition salts of the organic amine that can tolerate with ammoniacal liquor and physiology, the organic amine that described physiology can tolerate is as for example triethylamine, monoethanolamine or three-(2-ethoxy) amine). Basic group can be for example forms acid-addition salts, described inorganic acid example hydrochloric acid, sulfuric acid or phosphoric acid, described organic carboxyl acid and sulfonic acid such as acetic acid with inorganic acid or organic carboxyl acid and sulfonic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-methyl benzenesulfonic acid. The compound that contains simultaneously basic group and acidic-group, for example also contain carboxyl except the nitrogen-atoms of alkalescence, can be used as amphion and exist. Can obtain salt by conventional method well known by persons skilled in the art, for example by compound and inorganic or organic acid or alkali are merged in solvent or diluent, perhaps by cation exchange or anion exchange from other salt.

Unless otherwise noted, any concentration range as herein described, percentage range or ratio ranges should be understood to be included in concentration, percentage or the ratio of any integer in this scope and mark thereof, as one of 1/10th and percentage of integer. In addition, unless otherwise noted, as herein described relate to any physical features should be understood to be included in as any digital scope of polymer unit, size or thickness as described in any integer in scope. Be to be understood that term such as " a kind of (a) " " a kind of (an) " above and other local use of this paper refer to the component that " one or more " are enumerated. For example, " a kind of (a) " polymer refers to a kind of polymer or comprises the mixture of two or more polymer. As used herein, term " approximately " refers to ± 15%.

As discussed above, the invention provides the composition, the method and apparatus that relate to medical apparatus and implant (particularly implantable pump and sensor), its greatly increased they be suppressed on described device or implant or on every side, the ability of the formation of reactive cicatricial tissue on surface. What below describe in detail is the method for structure medical apparatus or implant, for generation of the composition and the method that suppress fibrotic medical apparatus or implant, and apply the method for this type of medical apparatus and implant.

A. Comprise and discharge the clinical practice of the implantable sensor and the pump installation of fibre modification-inhibitor

1. Implantable sensor

On the one hand, provide the implantable sensor that comprises anti-scarring agent, it can be used for detecting the physiological level or the variation of health.Many sensor devices are arranged, wherein the generation of fibre modification reaction will influence the function or the implantation of this device unfriendly or use this device at biological question.The correct clinical function of implanted sensor depends on the tight anatomy of target tissue and/or body fluid and contacts.Cicatrization around the implanting device can decomposition apparatus-organizational interface electric component and feature, and this device may not suitably be brought into play function.The formation of scar tissue can prevent the mobile testing agency that arrives pick off of physics, chemistry and/or bio information (for example, fluid levels, levels of drugs, metabolite level, glucose level, pressure or the like) between sensing device and adjacent (target) tissue.Similarly, if coating that pick off that " foreign body " reaction and its cause implanting is subjected to cicatrix takes place when (that is, with fibrous tissue health " being separated " pick off), pick off will be accepted to reflect the biological information that this is biological on the whole.If pick off is just detecting the situation (i.e. detected level in microenvironment) in the capsule, and these situations not consistent with the outer situation of capsule (be in the whole health-microenvironment), it will write down the information of not representing the whole body level.

Pick off or transducer can be positioned at the depths of health to monitor multiple physiological characteristics, as temperature, pressure, tension force, fluid flow, metabolite level (for example, electrolyte, glucose), levels of drugs, chemical property, electrical property, magnetic property, or the like.The representative example that is used for implantable sensor of the invention process comprises, blood and tissue glucose monitor, electrolyte pick off, blood constituent pick off, temperature sensor, pH pick off, optical pickocff, amperometric sensor, pressure transducer, biosensor, sensing responder, tension pick-up, activity sensor and magnetoresistive transducer.

The implantable sensor and the transducer of many types have been described.For example, implantable sensor can be a microelectronic device, controls intestinal function in order to the property contraction of wriggling by detection rectum inclusions and stimulation at one's leisure with the emptying intestinal around its implantation large intestine.See, for example, U.S. Patent number 6,658,297.Implantable sensor can be used for measuring the pH of gastrointestinal tract.The representative example of this type of pH sensing device is from Medtronic, Inc. (Minneapolis, BRAVO pH surveillance MN) (BRAVO pH Monitoring System).Implantable sensor can be the part of GI conduit or probe, and it comprises Sensor section and the responsive polymeric material that connects electricity or optical measuring device, and it experiences irreversible change when being exposed to the cumulative function of external agency.See, for example, U.S. Patent number 6,006,121.Implantable sensor can be the assembly of central venous catheter (CVC) (for example, jugular vein conduit) system.For example, this device can be made up of catheter body with at least one oxygen sensor and far-end heat exchange zone, wherein catheter body is supplied with by coolant and return cavity forms providing body intravital heat exchange, thus prevent owing to ischemia that seriously brain trauma or apoplexy cause cause overheated.See, for example, U.S. Patent number 6,652,565.CVC can comprise caloic and the temperature sensor that is used to measure blood heat, sees, for example, U.S. Patent number 6,383,144.

With some specific implantable sensor device and treatments of more detailed description below.

A. Blood and glucose monitors

Glucose monitors is used to detect the change of blood glucose, is used in particular for handling and the treatment diabetics.Diabetes are Metabolic disorders of glucose metabolism, and it torments the tens of millions of people of developed country in the world.The feature of this disease is that health can not suitably utilize and metabolism sugar, especially glucose.Under the normal condition, in the blood in glucose and the bodily tissue cell balance of the fine adjustments between the glucose by insulin---a kind of hormone that pancreas produces is kept.Defectiveness and the islets of langerhans that the produces q.s not blood sugar lowering level (type i diabetes) usually if pancreas becomes, although if perhaps produce enough pancreas insulins, but health becomes to the glucose reduction effect insensitive (type ii diabetes) of insulin, causes diabetes so.The accurate detection of blood sugar level is essential during for the processing of diabetics, because according to the change titration insulin of glucose level in the response medicine and/or the dosage and the arrangement of time of other Hypoylycemic agents administration.If dosage is too high, blood sugar level decline is too low so, causes confusion of consciousness and may lose consciousness.If dosage is too low, blood glucose level rises De Taigao causes excessive thirst, urinates and metabolic change (being called ketoacidosis) so.If the arrangement of time of medicament administration is incorrect, so blood sugar level can two extreme between big ups and downs-think that this is some long-term complications that causes diabetes, as heart disease, renal failure and blind a kind of situation.Because in egregious cases, all these situations can be life-threatening, and careful and persistent surveillance glucose level is the critical aspects during diabetes are handled.As become Tai Gao or when too low of glucose level in the diabetics, test glucose level change and continuously a kind of method of sensing be to implant glucose sensor.Because glucose sensor detects the change of blood sugar level, thus can by outside injection or by implantable insulin pump administration of insulin with the maintenance blood sugar level in acceptable physiological range.

The blood of many types and tissue glucose monitor are suitable in the enforcement of the present invention.For example, use the conduit on the stent platform glucose monitors can be delivered to vascular system through the chamber.See, for example, U.S. Patent number 6,442,413.Glucose monitors can be made up of and the change of response glucose concentration produces detectable electricity or optical signal the living cells of the glucose-sensitive of monitor blood glucose levels.See, for example, U.S. Patent number 5,101,814 and 5,190,041.Glucose monitors can be the flexible electrode of the minor diameter of subcutaneous implantation, and it can be made up of analyte-responsive enzyme, and it is designed to the electrochemical glucose pick off.See, for example, U.S. Patent number 6,121,009 and 6,514,718.Implantable sensor can be the closed-loop insulin delivery system, and the sensing equipment based on electrical signal detection patient's blood sugar level is wherein arranged, and stimulates insulin pump or pancreas that insulin is provided then.See, for example, U.S. Patent number 6,558,345 and 6,093,167.Other insulin monitor is for example, U.S. Patent number 6,579,498; Describe in 6,565,509 and 5,165,407.Wicresoft's glucose monitors comprises the GLUCOWATCH G2BIOGRAPHER from Cygnus Inc. (seeing cygn.com); See, for example, U.S. Patent number 6,546,269; 6,687,522; 6,595,919 and Application No. 20040062759A1; 20030195403A1; And 20020091312A1.

Manyly be suitable for implementing the present invention by available blood of commercial sources and tissue glucose sensing device.Although can utilize almost any implantable glucose sensor,, the example of some particular business and development is described below for clearer.

From Medtronic MiniMed, Inc. (Northridge, CA; See minimed.com) CONTINUOUS GLUCOSE MONITORING SYSTEM (CGMS); For example see U.S. Patent number 6,520,326; 6,424,847; 6,360,888; 5,605,152; 6,804,544; With Application No. 20040167464A1.The CGMS system is implanted the subcutaneous tissue of abdominal part and preserved the tissue glucose reading in per 5 minutes by operation.Can prolong the activity of this device with fibre modification-inhibitor coated pick off, because it must remove usually, in part because owing to the local organization reaction of this this device caused its susceptiveness forfeiture after a couple of days (about 3 days).

From TheraSense (Alameda, CA, see therasense.com) CONTINUOUSGLUCOSE MONITORING DEVICE, it utilizes disposable, miniaturized electric chemical sensor, with the insertion device that spring is housed this pick off is inserted under patient's the skin.The glucose level that pick off was measured in the interstitial fluid in per 5 minutes can be used for analyzing in the future by saving result.See, for example, US20040186365A1; US20040106858A1 and US20030176183A1.Although this device can be stored one month data and high and LG level are had warning, it must be changed every several days because owing to implant foreign body reaction, this device has been lost its accuracy.The activity that utilizes this pick off association fiber degeneration-inhibitor can prolong it strengthens its performance and reduces the replacing frequency.The another kind of electrochemical sensor that can be benefited from the present invention is from Isense (Portland, the implantable electrochemical sensor of multilamellar OR).This system produces the catalytic film of electric current and the interferential specific membrane that is used to reduce from other material and forms by semipermeable membrane, in the presence of glucose.

SMSI glucose sensor (Sensors for Medicine and Sciences, Inc., Montgomery County, Maryland; See s4ms.com) subcutaneous through being designed in of short duration outpatient's step to implant.This sensor design is become matter glucose between a few minutes measure automatically, without user intervention.The pick off implant wirelessly with little outside reader communication, allow user's continuous monitoring or monitor glucose level when needed.Reader is designed to be able to follow the tracks of that the rate of change of glucose level and warning user approach is low-or hyperglycemia.The service life of described pick off implant is month 6-12 month, it can be changed afterwards.

Animas Corporation (West Chester, PA; Animascorp.com) researching and developing a kind of implantable glucose sensor, it is based on placing the spectrum around the vein or the near infrared absorption of light sensing measurement blood.The Animas glucose monitors can tie up to insulin infusion pumps so that the closed loop control of blood sugar level to be provided.Scar tissue around the pick off twisted this device correctly collect optical information ability and can be from being benefited with uniting the use of fibre modification inhibitor.

DexCom, Inc. (San Diego, CA; See dexcom.com) researching and developing their Continuous Glucose Monitoring System, it is the implantable sensor that the continuous blood sugar reading is wirelessly transmitted to outside receptor.Receptor showed current dextrose equivalent in per 30 seconds, and 1 hour, 3 hours and 9 hours Trend value, and sent chimes of doom when detecting height or LG deviation.The feature of this device is an implantable sensor, and it places subcutaneous tissue and is 1 type and type 2 diabetes mellitus continuous monitoring tissue (interstitial fluid) glucose level.This device can also comprise the unique micro structure arrangement in the sensor regions, and it allows to obtain accurate data in long-time.For example, U.S. Patent number 6,741,877; In 6,702,857 and 6,558,321 DexCom has been described, the glucose monitoring arrangement and the related system of Inc. exploitation.Unfortunately, although the battery of monitoring arrangement and circuit allow long-term performance function, the foreign body reaction of this device and/or the long-term ability of test glucose level exactly of coating influence this device in the device of certain percentage.This device and fibre modification inhibitor (are for example united, by with medicament coating implant and/or pick off, medicament is incorporated in the polymer of forming this device, and/or it is penetrated in the tissue around the implant) can allow in its long term after implantation accurately test glucose level, the device number that reduces to lose efficacy and reduce to change incidence rate.

Also the particularly important is in the enforcement of the present invention and utilize the glucose surveillance of glucose-responsive polymer as the part of their testing agency.(Salt Lake City UT) is is researching and developing successive surveillance to M-Biotech, and its subcutaneous implantation by glucose-response water gel associating pressure transducer is formed.See, for example, U.S. Patent number.Hydrogel expands or shrinks by the change of contraction or expansion response glucose concentration and by the pressure transducer detection is described.Transducer changes into the signal of telecommunication with information and sends wireless signal to display device.(Berkshire UK) has produced the pick off of capsule sample to Cybersensors, implants it subcutaneous and catches data with outside receiver/transmitter and also by the RF signal this capsule energy supply (is seen, for example, GB2335496 and U.S. Patent number 6,579,498), British patent and trademark office are authorized).Physical sensors and RF microchip are formed and contained to sensor capsule by the affine polymer of glucose; Further coat whole capsule with semipermeable membrane.The affine polymer of glucose demonstrates rheology and changes when being exposed to glucose (3-15nM scope), along with the concentration of glucose increase becomes thinner and thickness more not.This reversible reaction can detect and change into signal by physical sensors.These aforementioned system provide the pick off that will implant and the capital chance of fibre modification-inhibitor and combination of compositions.Not only medicament can be coated on the surface of pick off or penetrate in the tissue around the pick off, and it can also mix glucose-responsiveness aquagel and the polymer of forming this implant.

Advanced Biosensors (Mentor OH) is developing another kind of glucose sensing device, its by implant down little (150 μ m are wide, and 2mm is long) of skin, biocompatible, based on the pin composition of silicon.Glucose level and wirelessly transmitting data in this device sensing corium.Unfortunately, the coating of foreign body reaction and/or implant influences the ability of this device in accurate test glucose level more than 7 days.This device and fibre modification combination can be allowed its accurate test glucose level and the useful life that prolongs this device in the longer time.

No matter the specific design of implantable blood, tissue or interstitial fluid glucose sensing apparatus, in order accurately to detect physics, chemistry and/or physiological characteristics, device must accurately place with organize adjacent.Particularly, the detector of sensing mechanism must be exposed to the glucose level with identical (or representative) found in blood flow.If excessive scar tissue growth or extracellular matrix deposition take place around this device, this can damage glucose from organizing to the mobile of detector and making it invalid so.Similarly, become and coated by fibrous tissue if glucose sensor that " foreign body " reaction and its cause being implanted takes place, pick off will detect the glucose level in the capsule so.(that is, in the whole health) glucose level is inconsistent, and it will write down the information of not representing the whole body level so if glucose level in the capsule and capsule are outer.This can cause doctor or patient to use the hypoglycemic drug (as insulin) of wrong dosage, and this has potential serious consequence.Blood, tissue or the interstitial fluid glucose sensing apparatus that release can reduce the coating of cicatrization and/or implant can increase the efficient and the accuracy of glucose detection, minimize insulin dose administration mistake, correct blood sugar level is kept in help, increase the persistent period that these devices are brought into play function clinically, and/or reduce the frequency that implant is changed.On the one hand, described device comprises blood, tissue and interstitial fluid glucose monitoring arrangement, and this device is with anti-scarring agent or comprise that the compositions of anti-scarring agent is coated with.Fibre modification-inhibitor can also be incorporated into implantation pick off assembly and discharge from this assembly.This embodiment especially can be used for using glucose-responsive polymer and the implant of hydrogel (can load with the activating agent medicine) and the implant of utilizing pick off (it also can load fibre modification-inhibitor) semipermeable membrane on every side.Alternatively, perhaps in addition, the compositions that comprises anti-scarring agent can be infiltrated and be implanted or will implant around the tissue of glucose sensor.

B. Pressure and tension pick-up

On the other hand, implantable sensor can be a pressure monitor.Pressure monitor can be used to detect pressure or the tension force that increases in the health.Implantable pressure transducer and pick off are used for temporarily or write down absolute pressure at organ, tissue and blood vessel for a long time.Propose many different design and operating systems and be placed on the temporary transient and life-time service of the patient with multiple medical conditions.Can obtain to be used for several days or the intrinsic pressure pick off of the temporary transient use in several weeks, yet, long-term or permanent implantable pressure transducer also can be used.Pressure transducer can detect the body pressure of many types, as but be not limited to pressure, intracranial pressure and the mechanical pressure relevant in blood pressure and fluid flow, the aneurysmal sack with fracture.

The pressure monitor of many types is suitable for use in the enforcement of the present invention.For example, implantable sensor is by using lead, sensor assembly, sensor circuit (comprising electric conductor) and providing the equipment of voltage can detect the body fluid absolute pressure in selected site and running temperature on every side.See, for example, U.S. Patent number 5,535,752.Implantable sensor can be the intracranial pressure monitor, and it provides analog data signal, and its electricity is changed into digit pulse.See, for example, U.S. Patent number 6,533,733.Implantable sensor can be the baroceptor in the air chamber of being packaged in of uniting use with implantable medical energy converter device such as pacemaker, and it is used to obtain with reference to pressure data.See, for example, U.S. Patent number 6,152,885.Implantable sensor can be suitable for being inserted into body passage to monitor and the parameter of being correlated with by the fluid flow of intracavity implant (for example, stent).See, for example, U.S. Patent number 5,967,986.Implantable sensor can be the passive sensor with Inductor-Capacitor, and it has the skull that is suitable for the patient resonant frequency with the sensing intracranial pressure.See, for example, U.S. Patent number 6,113,553.Implantable sensor can be self-powered tension force sensor-based system, and its response can produce tension signal at the tension force that bone anchoring device produces.See, for example, U.S. Patent number 6,034,296.Implantable sensor can be the assembly of perfusion cannula.Conduit can comprise that wire electrode and tinsel are used for the chamber of infusion of saline on every side, and it is designed for measures the potential difference and the while gaging pressure of striding the GI wall.See, for example, U.S. Patent number 5,551,425.Implantable sensor can be the part of CNS device; Intracranial pressure pick off for example, its intracranial that is installed in health treat monitor pressures the position and will be from the outside equipment of transmission of the pressure of skull.See, for example, U.S. Patent number 4,003,141.Implantable sensor can be the assembly of left ventricular assist device.For example, VAD is suitable for participating in the blood pump that fluid is communicated with between left ventricle and the aorta, and it uses inlet flowing pressure pick off and controller, and it can regulate the speed of pump based on sensor feedback.See, for example, U.S. Patent number 6,623,420.Many and pressure and tension pick-up devices experimental stage available by commercial sources are suitable for enforcement of the present invention.In order to illustrate, one group of these device and implant are described in the paragraph below:

From CardioMEMS (Atlanta, GA; @cardiomems.com, the partnership business of Georgia Instituteof Technology and the Cleveland Clinic) device can be inserted into the pressure that monitors in the aneurysmal sack in the capsule, thereby fill fluid in medical specialist is reported to the police about capsule, it may arrive and cause disruptive level.Usually carry out endovascular aneurysm repair (EVAR) with the stent graft, described graft isolates aneurysm from circulation.Yet the lasting leakage of blood in aneurysmal sack causes the pressure in the capsule constantly to increase and may cause disruptive danger.Behind the EVAR CardioMEMS device implanted in the aneurysmal sack with monitor the pressure in the isolating capsule so that detect which patient be in the ever-increasing risk of rupture.The feature of described pressure transducer is the inductor-capacitor resonant circuit with variable condenser.Because the pressure change in the environment that electric capacity is placed along with this capacitor is so it can detect the variation of local pressure.Produce data by using the external excitation system that in pick off, induces oscillating current and detecting frequency of oscillation (it is used for calculating pressure then).Unfortunately, although Circuits System allows long-term performance function, but foreign body reaction and/or the coating of implant influenced the ability that this device accurately detects stress level in the aneurysm (that is, this device detects the pressure in the microenvironment of capsule, rather than the pressure of aneurysm integral body).This device (is for example combined with the fibre modification inhibitor, by with medicament coating implant and/or pick off, medicament is mixed the polymer of making implant, and/or it is penetrated in the capsule around the implant) can allow it after implantation longer period accurate detected pressures level and reduce the quantity of failure of apparatus.

MicroStrain Inc. (Williston, VT) developed the wireless implantable sensor of a class, be used to measure the intravital tension force of body, position and motion.These pick offs can be measured, for example, nystagmus quivers, the power in the degree of depth of cornea implant, the orientation sensor that is used for improved crown prep, spinal ligament tension force, spine tension force, the tough belt tension of elbow, emg and ekg data, the 3DM-G that is used for direction of measurement and motion, the tough belt tension of wrist, the hip replacement pick off that is used to measure micromotion, implant consumption, the tough belt tension of knee joint, tibiofibular ligaments tension force, heel string tension force, arch support tension force, the shoe pad.The said firm provides knee prostheses, and it can in-vivo measurement compression stress and real-time transmission data.Describing this technology and being used to produces the patent of the device assembly of this technical description and comprises US6,714,763; 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.Describing this technology and being used to produces the U.S. Patent application of the device assembly of this technical description and comprises 20040113790; 20040078662; 20030204361; 20030158699; 20030047002; 20020190785; 20020170193; 20020088110; 20020085174; 20010054317; With 20010033187.

Mesotec (Hannover, Germany; @mesotec.com) with German Research institute of several families (for example, Fraunhofer Institute of Microelectronic Circuits and Systems) implantable intraocular pressure sensing system been has has been researched and developed in cooperation, be called MESOGRAPH, it can the continuous monitoring intraocular pressure.For example, in order to identify glaucomatous outbreak, this is ideal.Based on the external device (ED) that the pick off of CMOS can be implanted during standard operating procedure and inductively connection is integrated into spectacle frame.Glasses connect the portable data device by cable again.Modulated RF carrier wave that use is operated under 13.56MHz and convertible load arrive glasses with data relay, and power arrives pick off downwards.By the membranous diameter of polysilicon in the micromechanics vacuum gap capacitor on the change chip, the pressure limit of pick off response can be regulated between the 3.5MNm-2 at 50kNm-2.This device is formed with very little miniaturization pressure transducer by being used for the coupled meticulous collapsible coil of remote measurement.This pick off is based on microtechnology production and be used for the successive long-term reading and the supervision of intraocular pressure.Chip and coil are integrated in the soft intraocular lens of improvement, and this intraocular lens can be in current general surgery operating period implantation patient's eyes.Unfortunately, after initial successful implantation, this device is out of order usually because the foreign body reaction of implant and/or coat influence stress level in its accurate detection eye ability (promptly, pressure around this device detection implant in the microenvironment of capsule, rather than overall intraocular pressure).This device (is for example combined with the fibre modification inhibitor, by with medicament coating implant and/or pick off, medicament is mixed the polymer of making implant, and/or it is penetrated in the ocular tissue around the implant) can allow it after implantation longer period accurate detected pressures level and reduce the number of out of order device.

The specific design feature of pipe pressure or tension pick-up not, in order accurately to detect physics and/or physiological characteristics (as pressure), device must accurately be placed in the tissue and the information of integral status is represented in acceptance.If growth of excessive scar tissue or extracellular matrix deposition take place around device, the information that pick off may acceptance error so, it can endanger the effect of pick off, and perhaps scar tissue can be blocked biological information flowing to pick off.For example, many devices are out of order after initial successful implantation, because the coating of implant causes it to detect incoherent stress level (that is, the pressure around this device detection implant in the microenvironment of capsule, rather than the pressure of bigger environment).Release can reduce the pressure of synulotic therapeutic agent and efficient that tension sensing device can increase detection and increase the persistent period that these devices are brought into play function clinically.On the one hand, this device comprises the implantable sensor device, and it is with anti-scarring agent or comprise that the compositions of anti-scarring agent is coated with.Can mix fibre modification-inhibitor and discharge described inhibitor to component (for example, polymer) as the structure division of institute's implanted sensor from described component.Alternatively, perhaps additionally, the compositions that comprises anti-scarring agent can be penetrated into device and implant maybe in the tissue around will implantation place.

C. Cardiac sensor

On the other hand, implantable sensor can be the device that is configured to detect the character in heart or the cardiac muscular tissue.Cardiac sensor can be used to detect as putting the parameter relevant with cardiac performance that monitors arbitrarily preset time in long-term.Usually, often carry out the supervision of heart to detect and heart disease, as the relevant change of chronic heart failure (CHF).By monitoring the pattern relevant, can detect decline (parameter such as cardiac output, ejection fraction, pressure, ventricular wall motion or the like) based on hemodynamics variation with cardiac function.Should monitor directly constantly that it was important handling for disease among the patient who shows CHF.By using implantable sensor directly to monitor the hemodynamics measurement, can detect the hemodynamics crisis and select suitable medication and intervention.

The cardiac sensor of many types is suitable in the enforcement of the present invention.For example, can be in conjunction with the activity sensor of Magnet as the implantable sensor of the part of cardiac devices or the magnetoresistive transducer of variable active signal is provided.See, for example, U.S. Patent number 6,430,440 and 6,411,849.Implantable sensor can be by monitoring the blood pressure in the ventricle to the communication of remote control unit transmitting radio.See, for example, U.S. Patent number 6,409,674.Implantable sensor can be based on the cardiac wall motion pick off of accelerometer, and it is transformed into cardiac stimulus device by using the signal of telecommunication with the acceleration of heart tissue.See, for example, U.S. Patent number 5,628,777.Implantable sensor can be implanted in the chamber of heart, with pressure and the flow in the other sensor chambers of the heart in the implantable intravascular.See, for example, U.S. Patent number 6,277,078.

Be suitable for implementing of the present inventionly comprising Biotronik ' s (Biotronik GmbH ﹠amp by the obtainable heart sensing device of commercial sources; Co., Berlin, biotronik.com sees in Germany) CARDIAC AIRBAG ICD SYSTEM, it is a rhythm and pace of moving things monitoring arrangement, it provides the rescue shock of sending 30 joules of shock therapys ability reaching in three duration of seizure of ventricular fibrillation.Except rescue shock ability, this system also provides bradycardia pace-making and VT to monitor.PROTOS series pacemakers from Biotronik (seeing biotronikusa.com) also combines the pace-making pick off that is called closed loop stimulation (ClosedLoop Simulation).

Also can and organize the infusion monitor to monitor non-heart tissue with blood flow.The research worker of Oak Ridge NationalLaboratory has been developed wireless senser, and it monitors that blood flow to institute's transplant organ is with the earlier detection transplant rejection.

Medtronic (Minneapolis, MN; See medtronic.com) just developing their implantable product of CHRONICLE, it is designed so that with the intracardiac pressure, heart rate and the physical exertion that directly are positioned the pick off continuous monitoring patient in the heart chamber.The patient regularly downloads this information to the domestic device, its with this physiological data by internet security be transferred to the doctor.

No matter the specific design feature of cardiac sensor, in order accurately to detect physics and/or physiological property (as pressure, flow velocity, or the like), device must be positioned in cardiac muscle, chamber or the trunk exactly and receive the information of representing integral status.If excessive scar tissue growth takes place around the sensing device, pick off may accept to damage the error message of its effect so, and perhaps scar tissue may be blocked biological information flowing to the testing agency of pick off.For example, many cardiac monitoring devices are being out of order after successfully transplanting at first, because the coating of graft causes it to detect incoherent level (promptly this device detects the situation in the microenvironment of capsule around graft, rather than more the pressure of overall situation).The heart sensing device that release can reduce the therapeutic agent of spot formation can increase the persistent period of detecting effect and increasing these device clinical positions.On the one hand, described device comprises with anti-scarring agent or comprises the implantable sensor device of the compositions coating of anti-scarring agent.Fibre modification-inhibitor also can be incorporated into as in the component (as polymer) of the part of the structure of the cardiac sensor implanted and from as described in component discharge.Alternatively, or additionally, the compositions that comprises anti-scarring agent can be penetrated into that described device is implanted or with in the tissue around the implantation position.

D. Respiration pickup

On the other hand, implantable sensor can be the device that is configured to detect character in the respiratory system.Respiration pickup can be used for detecting the change of breathing pattern.For example, respiration pickup can be used to detect sleep apnea.Under a kind of situation, health can not produce automatically with appropriate time and start and essential neuromuscular stimulation of control breathing cycle.In another kind of situation, thereby upper respiratory tract muscle shrinks the air flue obstruction that becomes in intake period.Apneic cardiovascular consequence comprises heart rate disease (bradycardia, atrioventricular block, chamber property premature contraction) and hematodinamics disease (lung and systemic hypertension).The mortality rate that this causes autonomic stimulation metabolic and mechanism and may finally cause increasing.In order to treat this situation, thereby can monitor that respiratory function can provide the suitable reaction electricity irritation of upper respiratory tract muscle nerve (for example, to) or other treatment to detect apnea episodes with implantable sensor.

The respiration pickup of many types is suitable in the enforcement of the present invention.For example, can be the breathing element of implanting the thoracic cavity as being used for providing the implantable sensor of part of the aerating system of gas to the host, it can produce breath signal.See, for example, U.S. Patent number 6,357,438.Implantable sensor can be made up of the sensing element that connects wire body, and itself and the communication of intrathoracic chamber are to detect respiratory change.See, for example, U.S. Patent number 6,572,543.

No matter the specific design feature of respiration pickup, in order accurately to detect physics and/or physiological property, device must be exactly with organize adjacent positioned.If excessive scar tissue growth or extracellular matrix deposition take place around pulmonary function and respiratory tract sensing device, pick off may accept to damage the error message of its effect so, and perhaps scar tissue may be blocked biological information flowing to the testing agency of pick off.For example, many pulmonary function sensing devices are out of order after successfully transplanting at first, because the coating of graft causes it to detect incoherent level (i.e. situation in the microenvironment of capsule around this device detection graft, rather than the function of respiratory system integral body).The breathing sensing device that release can reduce the therapeutic agent of spot formation can increase the persistent period of detecting effect and increasing these device clinical positions.On the one hand, described device comprises with anti-scarring agent or comprises the implantable sensor device of the compositions coating of anti-scarring agent.Fibre modification-inhibitor also can be incorporated into as the component (as polymer) of the part of the structure of the respiration pickup implanted and from as described in component discharge.Alternatively, or additionally, the compositions that comprises anti-scarring agent can be penetrated into described device and implants maybe with in the tissue around the position of implanting.

E. Hearing transducer

On the other hand, implantable sensor can be the device that is configured to detect character in the auditory system.Hearing transducer is as the part of implantable auditory system, and it is used for pure sensory nerve hearing loss or compound conduction and internal ear hearing disability.Hearing system can comprise implantable sensor, and it sends the signal of telecommunication, and this signal of telecommunication is by the processor processing of implanting and send to implantable electromechanical transducer, and this transformer action is in middle ear and internal ear.Hearing transducer changes into the signal of telecommunication as the microphone of auditory system and with incident airborne sound.

Hearing transducer as many types of the part of auditory system is suitable for use in the enforcement of the present invention.For example, the implantable sensor as hearing disability recovery system part can produce electric audio signal.See, for example, U.S. Patent number 6,334,072.Implantable sensor can be a capacitive sensor, and it is the coupled vibrations acoustic components mechanically or magnetically, and as malleus, it detects the capacitance that changes in time that produces from vibration.See, for example, U.S. Patent number 6,190,306.Implantable sensor can be an electromagnetic transducer, and it has permanent magnet and coil and based on the magnetic linkage that changes in time of vibration, provide it to output driver with mechanically with the electricity irritation cochlea.See, for example, U.S. Patent number 5,993,376.

Be suitable for of the invention processly comprising: from Advanced Bionics (Sylmar by the obtainable audition sensing device of commercial sources, California, a Boston Scientific Company sees advancedbionics.com) HIRES 90K Bionic Ear Implant, HIRESOLUTIONSOUND, CLARION CII Bionic Ear and CLARION 1.2; Also referring to U.S. Patent number 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; With NUCLEUS3 cochlear implant from Cochlear (Lane Cove NSW, cochlear.com sees in Australia); Also referring to U.S. Patent number 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 COMBI40+ cochlear implant from Med-E1 (medel.com sees in Austria); 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 Al1Hear, Inc. (Aurora, Oregon; See al1Hear.com) the AL1HEAR implant; Also referring to WO 01/50816; EP 1 245 134; With from MXM (France; See mxmlab.com) DIGISONIC CONVEX, DIGISONIC AUDITORY BRAINSTEM and DIGISONIC MULTI-ARRAY implant; Also referring to U.S. Patent number 5,123,422; EP0219380; WO 04/002193; EP 1 244 400 A1; US 6,428, and 484; US20020095194A1; WO 01/50992.

No matter the specific design feature of hearing transducer, in order accurately to detect sound, device must be positioned in ear exactly.If excessive scar tissue growth or extracellular matrix deposition take place around the hearing transducer, pick off may accept to damage the error message of its effect so, and perhaps scar tissue may be blocked sound wave flowing to the testing agency of pick off.The audition sensing device that release can reduce the therapeutic agent of spot formation can increase sound detection efficient and increase the persistent period that these install clinical positions.On the one hand, described device comprises with anti-scarring agent or comprises the implantable sensor device of the compositions coating of anti-scarring agent.Fibre modification-inhibitor also can be incorporated into as in the component (as polymer) of the structure division of the hearing transducer implanted and from as described in component discharge.Alternatively, or additionally, the compositions that comprises anti-scarring agent can be penetrated into that described device is implanted or with in the tissue around the implantation position.

F. Electrolyte and metabolite pick off

On the other hand, can detect electrolyte and metabolite in the blood with implantable sensor.For example, implantable sensor can be by monitoring the device of metabolite in the blood or electrolytical composition level to blood emission radioactive source, thereby it interacts with many detectors that output signal is provided.See, for example, U.S. Patent number 6,122,536.Implantable sensor can be the bio-sensing transponder, the dyestuff of the optical property that it changes by having the variation in the response environment, the light-sensitive element of sensing optical change and be used for transfer of data is formed to remote reader's transponder.See, for example, U.S. Patent number 5,833,603.Implantable sensor can be the monolithic bio-electronic device that is used to detect at least a analyte in the animal health.See, for example, U.S. Patent number 6,673,596.Other pick off of measuring chemical analyte is for example, and U.S. Patent number 6,625 is described in 479 and 6,201,980.

If excessive scar tissue growth or extracellular matrix deposition take place around the pick off, pick off may accept to damage the error message of its effect so, and perhaps scar tissue may be blocked metabolite or electrolyte flowing to the testing agency of pick off.For example, many metabolite/electrolyte sensing device is out of order after successfully transplanting at first, because the coating of graft causes it to detect incoherent level (i.e. situation in the microenvironment of capsule around this device detection graft, rather than blood levels).The sensing device that release can reduce the therapeutic agent of spot formation can increase metabolite/electrolyte detection efficiency and increase the persistent period that these install clinical positions.On the one hand, described device comprises with anti-scarring agent or comprises the implantable sensor device of the compositions coating of anti-scarring agent.Fibre modification-inhibitor also can be incorporated into as in the component (as polymer) of the part of the structure of the hearing transducer implanted and from as described in component discharge.Alternatively, or additionally, the compositions that comprises anti-scarring agent can be penetrated into that described device is implanted or with in the tissue around the implantation position.

Although above described many examples of implantable sensor, all the sensors all have similar design feature and implant after cause similar unwanted foreign body tissue reaction.Those skilled in the art it is evident that the commercial sensor product of commercial sensor device above-mentioned and the next generation and/or continuation exploitation will be use in the present invention expection and suitable.Sensor device, especially sensing element must be located to guarantee that anatomical location enforcement correct in health detects in point-device mode.The all or part sensor device can move after operation, perhaps excessive scar tissue growth can take place around implant, and it can cause the reduction of these device performances.The formation of fibrous capsule can hinder biological information flowing and/or cause device to detect not being level relevant on the physiology (that is, detect in the capsule level rather than the outer true physiological level of capsule) to detector around the pick off.This not only can cause incomplete or inaccurate reading, and can cause doctor or patient to do the treatment decision that makes mistake based on the information that is produced.The implantable sensor device that discharges the therapeutic agent that reduces cicatrization (or fibre modification) at pick off-organizational interface can be used to increase the effect and/or the active persistent period of implant.On the one hand, the invention provides implantable sensor device, the compositions that it comprises anti-scarring agent or comprises anti-scarring agent.Use description to many polymerizations of implantable sensor device and non-polymeric delivery system below.These compositionss can also comprise one or more fibre modification-inhibitor, thereby the undue growth of granulation, fiber or neointima (neointimal) tissue is suppressed or reduces.

The method that the fibrotic compositions of inhibition is attached to these sensor devices comprises: (a) directly will suppress fibrotic compositions and (for example invest pick off, by spray method described as follows or dipping method, use or without carrier), (b) directly will suppress fibrotic compositions and (for example be attached to sensing device, by following spray method or dipping method, use or without carrier), (c) by using material coating sensor device such as hydrogel, described material absorbs again and suppresses fibrotic compositions, (d) interweave in sensor device by being coated with the line (perhaps polymer itself forms line) that suppresses fibrotic compositions, (e) sensing device is inserted into the sleeve (sleeve) or the mesh that comprise the fibrotic compositions of inhibition or be coated with the fibrotic compositions of inhibition; (f) make up sensing device itself (the perhaps part of device and/or detector) with suppressing fibrotic compositions, or (g) by with direct covalent bond sensing device of fibre modification-inhibitor or joint (micromolecule or polymer), this joint coating or be connected to device (or detector) surface.Each of these methods has been illustrated with pick off, detector or electrode and according to the bonded method of fibre modification of the present invention-inhibition (being also referred to as anti-cicatrization herein) agent.

For these pick offs, detector and electrode, can carry out coating process in such a manner: (a) part (as detector) of coating sensing device; Perhaps (b) is coated with whole sensing device with suppressing fibrotic compositions.In addition, or alternatively, fibre modification-inhibitor can with the material mixing that is used to make this device, thereby fibre modification-inhibitor is mixed (incorporate) to final products.In these modes, can prepare medical apparatus with coating, its floating coat is for for example, and is uniform, heterogeneous, successive, discontinuous, perhaps figuratum.

On the other hand, the implantable sensor device can comprise their the interior many storages of structure, and each storage is configured to hold and protects curative drug (for example, one or more fibre modification-inhibitor).Storage can form from the divets of apparatus surface or the passage the device body.On the one hand, the hole from apparatus structure forms storage.Storage can hold the medicine (for example, fibre modification-inhibitor) of single type or the medicine (for example, fibre modification-inhibitor and anti-infective) of more than one types.Can be with carrier (for example, polymerization or the non-polymeric material) compounding pharmaceutical that is loaded in the storage.Storage through filling can be used as medicine and sends the storehouse, and it can discharge medicine from the release dynamics of carrier according to medicine in one period.In certain embodiments, can load storage with many layers.Every layer of different pharmaceutical that can comprise the medicine with specified quantitative (dosage), every layer can have different compositionss further to be fit to from the amount and the type of the medicine of substrate release.The multilamellar carrier can also comprise the barrier layer that prevents drug release.Barrier layer for example can be used for, and the control medicine is from the effusive direction of hole.Thereby the coating of this medical apparatus can directly contact the implantable sensor device, and perhaps when at sensor device with contain when having something (as polymeric layer) to insert between the coating of fibre modification-inhibitor, described coating can this device of mediate contact.

Except with fibre modification-inhibitor in conjunction with on the implantable sensor device or within, or alternatively, fibre modification-inhibitor can directly or indirectly be applied to the tissue adjacent with sensor device (preferred proximity transducer-organizational interface).This can be by using or not using polymer, non-polymer or second carrier, with fibre modification-inhibitor: (a) be applied to pick off and/or detector surface (for example, as injection, paste, gel or mesh) in implantation step; (b) before pick off is implanted, at once before or during the surface (for example, as injectable, paste, gel, original position formation gel or mesh) that is applied to organize; (c) after implanting at once, pick off is applied to the surface of pick off and/or the pick off of being implanted and/or detector tissue (for example, forming gel or mesh) on every side as injection, paste, gel, original position; (d) will (be to use polymer support in the anatomy space of placing by the fibrosis agent being applied topically to implantable sensor for what this embodiment was particularly useful, it discharges fibre modification-inhibitor-fluid, suspensoid, Emulsion, microemulsion, microsphere, paste, gel, microparticle, spray, aerosol, solid-state implant in a few hours to several weeks, other preparation that discharges described medicament can be delivered to the zone that device inserts); (e),, perhaps be applied to implantable sensor tissue on every side by percutaneous injection as slow releasing preparation as infusate as solution; (f) combination in any by said method realizes.Can also use combination treatment (that is the combination of the combination of therapeutic agent and antithrombotic, antiplatelet and/or anti-infective).

Can mention that some polymer support self can help prevent the fibrosis of the pick off that forms fibrous tissue and/or implanted on pick off to coat.These carriers (hereinafter describing) especially can be united the enforcement that is used for this embodiment separately or with the fibrotic compositions of inhibition.Below polymer support can permeate (as describing in the paragraph in front) neighbouring and comprise to pick off-organizational interface: (a) the sprayable preparation that contains collagen, (for example gather (ethylene glycol)-collagen compositions as COSTASIS and crosslinked derivatization, at U.S. Patent number 5,874,500 and 5,565, describe in 519 and be called " CT3 " in this article (all from Angiotech Pharmaceuticals, Inc., Canada), described preparation is independent or load fibre modification-inhibitor, is applied to implant site (perhaps detectors/sensors surface); (b) the sprayable preparation that contains PEG, as COSEAL (Angiotech Pharmaceuticals, Inc.), FOCALSEAL (Genzyme Corporation, Cambridge, MA), SPRAYGEL or DURASEAL are (from Confluent Surgical, Inc., Boston, MA), described preparation is independent or load fibre modification-inhibitor, is applied to implant site (perhaps detectors/sensors surface); (c) contain the preparation of fibrinogen, as FLOSEAL or TISSEAL (all from BaxterHealthcare Corporation, Fremont, CA), described preparation is independent or load fibre modification-inhibitor, is applied to implant site (perhaps detectors/sensors surface); (d) contain hyaluronic preparation, as RESTYLANE or PERLANE (all from Q-Med AB, Sweden), HYLAFORM (Inamed Corporation, Santa Barbara, CA), SYNVISC (Biomatrix, Inc., Ridgefield, NJ), SEPRAFILM or SEPRACOAT (all from GenzymeCorporation), described preparation loads fibre modification-inhibitor, is applied to implant site (perhaps detectors/sensors surface); (e) be used for the polymer gel that surgical operation is implanted, as REPEL (LifeMedical Sciences, Inc., Princeton, NJ) or FLOWGEL (Baxter HealthcareCorporation), described preparation is independent or load fibre modification-inhibitor, is applied to implant site (perhaps detectors/sensors surface); (f) orthopedic " cement ", it is used for prosthese and tissue are remained on the appropriate location, and it loads fibre modification-inhibitor, be applied to implant site (perhaps detectors/sensors surface), as OSTEOBOND (Zimmer, Inc., Warsaw, IN), from Wright MedicalTechnology, Inc. (Arlington, TN) low viscosity cement (LVC), SIMPLEX P (Stryker Corporation, Kalamazoo, MI), PALACOS (Smith ﹠amp; NephewCorporation, United Kingdom), and ENDURANCE (Johnson ﹠amp; Johnson, Inc., New Brunswick, NJ); (g) contain the operation adhesive of cyanoacrylate, as DERMABOND (Johnson ﹠amp; Johnson, Inc., New Brunswick, NJ), INDERMIL (U.S.Surgical Company, Norwalk, CT), and GLUSTITCH (Blacklock MedicalProducts Inc., Canada), TIS SUMEND (Veterinary Products Laboratories, Phoenix, AZ), VETBOND (3M Company, St.Paul, MN), HISTOACRYLBLUE (Davis ﹠amp; Geck, St.Louis is MO) with ORABASE SOOTHE-N-SEALLIQUID PROTECTANT (Colgate-Palmolive Company, New York, NY), described binding agent is independent or load fibre modification-inhibitor, is applied to implant site (perhaps detectors/sensors surface); (h) contain hydroxyapatite (perhaps synthetic bone material, as calcium sulfate, VITOSS and CORTOSS (can be from Orthovita, Inc., Malvern PA) obtains) implant, it loads fibre modification-inhibitor, is applied to implant site (perhaps detectors/sensors surface); (i) other biocompatible tissue filling agent, it is independent or load fibre modification-inhibitor, as BioCure, Inc. (Norcross, GA), 3M Company ﹠amp; Neomend, (Sunnyvale, CA) those of Zhi Zaoing, described filler are applied to implant site (perhaps detectors/sensors surface) to Inc.; (j) polysaccharide gel, as ADCON series gel (can be from Gliatech, Inc., Cleveland, OH obtains), described gel separately or load fibre modification-inhibitor be applied to implant site (perhaps detectors/sensors surface); And/or (k) membrane, sponge or mesh, as INTERCEED (Gynecare Worldwide, Ethicon, Inc., Somerville, the branch company of NJ), VICRYL mesh (Ethicon, and GELFOAM (Pfizer, Inc. Inc.),, New York, NY), it is independent or load fibre modification-inhibitor, is applied to implant site (perhaps detectors/sensors surface).

Can be used to help prevent the preferred polymeric matrix of the fibre-coated of the pick off that on pick off, forms fibrous tissue and/or implanted to form separately or with fibre modification inhibitor/compositions associating by reactant as reaction reagent, described reactant comprise following one or both: tetramethylolmethane gathers (ethylene glycol) ether four-sulfydryl] (4-arm sulfydryl PEG, it is included in the structure that has linking group between the end of sulfydryl and polyethylene glycol backbone) and poly-(ethylene glycol) ether four-succinimido 1,3-propanedicarboxylic acid of tetramethylolmethane] (4-arm NHS PEG, it is included in the structure that has linking group between the end of NHS base and polyethylene glycol backbone once more).Another kind of preferred composition comprise as pharmacy response following one or both: tetramethylolmethane gather (ethylene glycol) ether four-amino] (4-arm amino PEG, it is included in the structure that has linking group between the end of amino and polyethylene glycol backbone) and poly-(ethylene glycol) ether four-succinimido 1,3-propanedicarboxylic acid of tetramethylolmethane] (4-arm NHS PEG, it is included in the structure that has linking group between the end of NHS base and polyethylene glycol backbone once more).The chemical constitution of these reactants is for example, and U.S. Patent number 5,874 shows in 500.Randomly, the reactant adding collagen of poly-to containing (ethylene glycol) or collagen derivant are (for example, methylated collagen) forming preferred crosslinked substrate, its can be used as be used for the treatment of agent or independently the polymer support of compositions around the pick off of being implanted, form fibrous tissue to help prevent.

As those skilled in the art with conspicuous, following possible any anti-scarring agent can be separately or use in conjunction in the enforcement of this embodiment.Because sensor device is made with multiple structure and size, so the definite dosage of using will become along with device size, surface area and design.Yet some principle can be applied to this area.Can be used as the function calculation drug dose of the dosage of per unit area (part of applied device), can measure the total drug dose of using and can determine the suitable surface concentration of active medicine.No matter medicinal application is in the method for device (that is, as coating, be attached in the constituent of pick off or be penetrated into surrounding tissue), separately or the fibre modification-inhibitor of uniting use use under can administration below instructing:

Medicine and dosage: operable therapeutic agent includes but not limited to: anti-microtubule agent, comprise that taxanes (for example, paclitaxel and many Xi Tasai), other microtubule stabilizer and anti-microtubule medicine, Mycophenolic Acid, sirolimus, tacrolimus, everolimus, ABT-578, and catharanthus alkaloid (for example, vinblastine and vincristine sulfate) and analog and derivant.With more detailed description certain drug afterwards and their corresponding dosage, yet, usually, they can be with the single whole-body dose (for example, be used for the dosage that per os and intravenous are used) several times to the part of single whole-body dose (for example, be applied to usually the single system dose application concentration 50%, 10%, 5%, or even less than 1%) concentration is used.In certain embodiments, medicine discharged with valid density in 1-90 days.Comprise taxanes, as paclitaxel and analog thereof and derivant (for example, many Xi Tasai) anti-microtubule agent, and catharanthus alkaloid, comprise that vinblastine and vincristine sulfate and analog thereof and derivant should use with following parameter: accumulated dose is no more than 10mg (0.1 μ g is to the 10mg scope); Preferred accumulated dose 1 μ g is to 3mg.The per unit area dosage of device is 0.05 μ g/mm ²-10 μ g/mm ²Preferred dose/unit are is 0.20 μ g/mm ²-5 μ g/mm ²Keep 10 at apparatus surface ^-9-10 ^-4The medicine of M Cmin.The immunomodulator that comprises sirolimus, ABT-578 and everolimus: sirolimus (that is, and rapamycin, RAPAMUNE): accumulated dose is no more than 10mg (0.1 μ g is to the 10mg scope); Preferred 10 μ g are to 1mg.Per unit area dosage is 0.1 μ g-100 μ g/mm ²Surface area; Preferred dose is 0.5 μ g/mm ²-10 μ g/mm ²Keep 10 at apparatus surface ^-8-10 ^-4The Cmin of M.Everolimus and derivant thereof and analog: accumulated dose is no more than 10mg (0.1 μ g is to the 10mg scope); Preferred 10 μ g are to 1mg.Per unit area dosage is 0.1 μ g-100 μ g/mm ²Surface area; Preferred dose is 0.3 μ g/mm ²-10 μ g/mm ²On apparatus surface, keep Cmin 10 ^-8-10 ^-4The everolimus of M.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 10.0 μ g are to 2000mg); Preferred 10 μ g are to 300mg.The per unit area dosage of device is: every mm ²1.0 μ g-1000 μ g; Preferred dose is 2.5 μ g/mm ²-500 μ g/mm ²On apparatus surface, keep Cmin 10 ^-8-10 ^-3The Mycophenolic Acid of M.

2. Implantable pump

On the other hand, provide the implantable pump that comprises anti-scarring agent, it can be used to deliver a medicament the purpose position.Secular, site-specific that implantable drug delivery device and pump provide therapeutic agent discharge to handle the device of multiple medical conditions.When hope localizes drug influence (promptly, described disease only influences the specific region) or when the systemic delivery inefficiency of activating agent or invalid (promptly, cause toxicity and serious side effects, before arriving target tissue, medicine causes inactivation, produce weak symptom/disease control, and/or cause drug dependence) time, utilize medicine to send implant and pump usually.Implantable pump can also be sent systemic drug level and help for a long time in mode constant, that regulated and avoid " Feng Hegu " with the intermittent blood level drug level that is administered systemically relevant.Another advantage of implantable pump is to improve patient's compliance.Many patients forget regularly take medicine (the especially patient of child, old people, chronic disease and mental handicap), but are to use implantable pump, and this problem is alleviated.This can cause better symptom control (can progressively increase dosage according to the seriousness of symptom usually) for many patients, better disease handles (especially sending for the insulin in the diabetics) and lower medicine needs (especially for the pain medication).

In using, various clinical used countless medicines to send implant and pump, comprise the programmable insulin pump that is used for treating diabetes, (for example be used to use anesthetics, morphine, fentanyl) with (for example, the cancer that eases the pain, back problems, HIV, operation back) (in the spinal column) pump in the sheath (for example is used for the treatment of the part of chemotherapeutant of cancer and systemic delivery, the Hepatic artery 5-FU infusion of liver neoplasm), be used for the treatment of the medicine (for example, being used for the anti--arrhythmia medicine of rhythm abnormality) of cardiac conditions, (for example be used for neurological disorder, multiple sclerosis, spinal cord injury, brain injury, cerebral palsy) spasticity the spasmolytic medicine (for example, baclofen) sends in the sheath, perhaps be used for infecting part/regional antibiotic of handling (for example, osteomyelitis, septic arthritis).Usually, the subcutaneous implantation of drug delivery pump and be made up of pump installation with medicine storage and flexible catheter is delivered to target tissue by this conduit medicine.The therapeutic drug levels (depend on application) of medicine to realize part or whole body of scheduled volume stored and discharged through conduit to pump.The center of pump has the self-styled inlet that is covered by barrier film, thereby if desired, can recharge this pump with medicine by percutaneous (by skin and barrier film) insertion syringe needle.Two types implantable drug delivery pump is arranged usually.The constant rate of speed pump is usually by the gas energy supply and be designed under pressure the constant rate of speed with pre-programmed and distribute medicine with successive doses.The amount of drug flow and speed are subjected to the length, temperature of used conduit and the adjusting of height, when needs constant, when long-term medicine is sent, they are best.Speed pump able to programme utilizes battery-powered pump and constant pressure storage periodically with can be by the mode delivering drugs of doctor or patient programming.For programmable infusion device, can be based on the scheme of being programmed with little, discrete doses delivering drugs, this scheme can change according to the clinical response of individuality.

Usually, implant is sent the dosage delivering drugs of pump to be regulated, and in some applications, can be used in combination with implantable sensor, and described pick off is collected and is used to regulate the information (so-called " closed loop " system) that medicine is sent.Implantable drug delivery pump can be worked and delivering drugs in many ways, and described mode includes, but are not limited to: (a) only ought detect in the health delivering drugs when changing (for example, pick off stimulates); (b) with continuous slow release (for example, constant current) delivering drugs; (c) with pulse mode (for example, non-constant current) with the predetermined close delivering drugs; (d) by programmable mode delivering drugs; (e) by being designed for the device delivering drugs of particular anatomical position (for example, in the ophthalmic, sheath, intraperitoneal, intra-arterial and intracardiac).Except with the ad hoc fashion delivering drugs or be delivered to specific part, can also classify to drug delivery pump based on their mechanical delivery technique (for example, the driving force that medicine is sent can take place) by it.For example, being used for the machinery that medicine sends includes, but are not limited to, osmotic pumps, metering system, wriggling (roller) pump, electrically driven (operated) pump, eye drug delivery pump and implant, the elastomer pump, spring-contraction pump, the gas-powered pump is (for example, induce by electrolytic cell and chemical reaction), the fluid distributor of pump, distributor chamber, infusion pump, passive pump, infusate pump and the osmotic drive of hydraulic pump, the pump that relies on piston and non-dependence piston.

The clinical function of implantable drug delivery device or pump depends on device, especially conduit or medicament distribution assembly, it can effectively keep contacting and not being subjected to the tight anatomy of target tissue (for example, space, lumen of artery, peritoneum, interstitial fluid under the dura mater in the spinal cord) coating and the obstruction of scar tissue.Unfortunately, in many cases, when these devices were implanted in healths, they were subjected to from host tissue around as the aforementioned " foreign body " reaction.For implantable pump, drug delivery tube chamber, catheter tip, allocation component or send the obstruction that film can be subjected to scar tissue, described scar tissue can cause drug flow to slow down or stop fully.Alternatively, entire pump, conduit and/or allocation component can be subjected to the coating (that is, health " separates " device with fibrous tissue) of cicatrix thereby medicine is delivered to target tissue (that is, cicatrix prevents from the correct medicine motion of implantable pump and is assigned to tissue on the another side of capsule) by halves.Any of these development can cause medicine invalid or flow to target tissue or organ (with the loss clinical benefit) by halves, can also cause topical remedy accumulation (in the capsule) and other clinical complication (for example, topical remedy's toxicity and coat; The medicine that high amount of drug unexpected " toppling over " is gone into after the surrounding tissue is isolated).In addition, the tissue around the implantable pump can be subjected to antixenic being not intended to of inflammatory and damage, and causes loss function and/or disorganization (for example, the scar tissue in the spinal canal causes pain or blocks flowing of cerebrospinal fluid).

The implantable drug delivery pump that release is used to reduce synulotic one or more therapeutic agents of device-organizational interface's (especially around neutralization of drug delivery tube or medicament distribution assembly) can help to prolong the clinical performance of these devices.Fibrotic inhibition can be guaranteed to distribute the isolation that do not become of the medicine of correct amount and genotoxic potential medicine with constant rate of speed from device the fibroid capsule.For the device that comprises electricity or battery component, fibre modification not only can cause not optimum ground or can not work fully of device, also cause very big consumption, because the resistance of the increase that the scar tissue that needs multipotency more to overcome intervention causes to battery life.

Almost any implantable pump can be benefited from the present invention.On the one hand, drug delivery pump can be with continuous, constant current, slow release mode delivering drugs.For example, drug delivery pump can be passive pump, and it is suitable for providing the constant current of medicine, the adjusting of its can be under pressure sensing chamber and valve box, and constant current speed can change over new constant current speed in the valve box.See, for example, U.S. Patent number 6,589,205.On the other hand, drug delivery pump can be sent pre-metered doses of medication with non-constant current or pulse mode.For example, drug delivery pump adapt to conventional pumps with by chamber of continuous filling then relief valve flow with the liquid medicine that pulse produces pulsation of injecting that medicine is provided.See, for example, U.S. Patent number 6,312,409.On the other hand, thus the drug delivery pump of can programming is distributed medicine in very specific mode.For example, drug delivery pump can be programmable infusate pump, it is by the infusate chamber of variable-volume, form with variable-volume controlling liquid pressure and alternative storage, wherein by microprocessor based on the value of being programmed to the liquid flow sampling and adjust in view of the above and keep the liquid flow of being programmed.See, for example, U.S. Patent number 4,443,218.

On the other hand, can be suitable for drug delivery pump of the present invention based on different mechanical techniques (for example, the driving force) production of delivering drugs.For example, the implant that drug delivery pump can be made up of piston, piston is separated two chambers, and the expandable medicament of water is contained in one of them chamber, and another chamber contains and is useful on the leuproside preparation of sending.See, for example, U.S. Patent number 5,728,396.Drug delivery pump can the cylindric osmotic pump system of right and wrong, and it can not rely on the piston infused drug and meets the anatomy implant site.See, for example, U.S. Patent number 6,464,688.Drug delivery pump can be the liquid distributor that osmotic pressure drives, and it is made up of the flexible internal bag and the passage that contain pharmaceutical composition, can send described compositions at this passage.See, for example, U.S. Patent number 3,987,790.Drug delivery pump can be that implant is sent in the liquid imbibition, and it is made up of compartment, and this compartment has the assembly that can permeate that passes of liquid, and this implant also has the hard sleeve of prolongation in order to resist instantaneous mechanical force.See, for example, U.S. Patent number 5,234,692 and 5,234,693.Drug delivery pump can be the pump with isolating hydraulic pressure storage, metering device, discharge capacity storage, medicine storage and infusion of drug mouth, and it is included in the canning.See, for example, U.S. Patent number 6,629,954.Drug delivery pump can distribute the distributor chamber and the valve of passage to form by having, and described valve is under pressure and makes that medicine can be with one-way flow.See, for example, U.S. Patent number 6,283,949.Drug delivery pump can be based on the spring driven pump of spring, and it regulates different pressure with the variable-volume medicament chamber.See, for example, U.S. Patent number 4,772,263.Other example of drug delivery pump is for example, U.S. Patent number 6,645,176; 6,471,688; 6,283,949; Describe in 5,137,727 and 5,112,614.

In addition, exist available and be suitable for implementing the drug delivery pump that osmotic pressure of the present invention drives by commercial sources.These infiltration press pumps comprise that (it can be used for sending multiple medicine and other therapeutic agent (is seen by chemosmotic method for Mountain View, DUROS Implant CA) and ALZET Osmotic Pump from Alza Corporation, for example, U.S. Patent number 6,283,953; 6,270,787; 5,660,847; 5,112,614; 5,030,216 and 4,976,966).

As mentioned above, drug delivery pump can make up to improve device performance with the fibrotic medicament of inhibition.Fibre modification-inhibitor can also be attached to and discharge from the material (for example, component devices conduit, the polymer of semipermeable membrane or the like) that is used to construct this device.Alternatively and additionally, fibre modification-inhibitor can infiltrate the zone around device-organizational interface.It will be apparent to one skilled in the art that it will be expection and suitablely to use in the present invention that the commercial drug delivery pump do not mentioned specially and commercial medicine of future generation and/or exploitation subsequently are sent product.

To describe some special drug delivery pump and processing in more detail, comprising:

A. The implantable insulin pump that is used for diabetes

On the one hand, to send pump can be insulin pump to insulin.Insulin pump is used for diabetics to replace the needs by manual injection insulin glucose level control every day.The dosage of insulin administration and periodic accurate control are the key components of effectively handling diabetes.If insulin dose is too high, blood sugar level sharply descends, and causes confusion of consciousness and possibility even loss of consciousness.If dosage is too low, blood glucose level rises De Taigao causes excessive thirst, urinates and metabolic change (being called ketoacidosis) so.If the timing of medicament administration is incorrect, so blood sugar level can two extreme between big ups and downs-think that this is some long-term complications that causes diabetes, as heart disease, renal failure and blind a kind of situation.Because down extreme, all these conditions can be life-threatening, the accurate administration of insulin and timing are essential for short-term that prevents diabetes and long-term complications.

Implantable pump automatization insulin use and eliminated dosage and periodic human error, it has the long-term health consequence.Described pump can be termly, every day repeatedly with low dose with injection of insulin to blood flow, peritoneal cavity and subcutaneous tissue.By being injected directly into pump chamber, recharged pump once or twice with insulin in every month.This has reduced the frequency injection of the external application that the patient must stand and has allowed the insulin of the variable of pre-programmed to be discharged into blood flow with different time; This is similar Normal Pancreas function and the situation that minimizes the blood sugar level fluctuation.The patient is extracted the liquid of bleeding, analyze and make the decision of the amount of insulin that need send after, can be by the outside signal activation insulin pump that produces.Yet the most extensive application of carrying out of this technology is to produce closed loop " artificial pancreas ", and it can continuous detecting blood sugar level (by the pick off of implanting) and provides feedback to regulate insulin using to diabetics to implantable pump.

Polytype insulin pump is suitable for enforcement of the present invention.For example, drug delivery pump can comprise implantable sensor and drug delivery pump by being made up of the signal of telecommunication of sending of a large amount of living cells and adjusting glucose or glucagon or insulin.See, for example, U.S. Patent number 5,474,552.Drug delivery pump can be by the forming of the pick off of single channel conduit and implantable intravascular, and this pick off sends to the infusion device of subcutaneous implantation with hematochemistry, and it distributes medicine by conduit then.See, for example, U.S. Patent number 5,109,850.

Suitable enforcement is of the present invention to comprise the MiniMed from Medtronic by the obtainable insulin pump device of commercial sources, Inc. (Northridge, MINIMED 2007 ImplantableInsulin Pump System CA).The MINIMED pump is delivered to peritoneal cavity with of short duration, frequent quick-fried spray with insulin delivery and is provided insulin (see, for example, U.S. Patent number 6,558,345 and 6,461,331) in the mode that is similar to Normal Pancreas to health.(Medtronic MiniMed Inc., Northridge CA) sends the intraperitoneal regular iletin with pulse mode from the negative pressure storage to The MINIMED 2001 Implantable Insulin PumpSystem.The feature of these two kinds of devices all is to have a long duct, and it is transported to the abdominal cavity with insulin from the conduit of subcutaneous implantation.As mentioned above, peritoneum drug delivery tube chamber or catheter tip can be subjected to the partially or completely obstruction of scar tissue, and this can cause drug flow to slow down or stop fully.In the present invention, insulin send conduit can with suppress fibrotic medicament and combine to keep the opening of delivery catheter chamber.Fibre modification-inhibitor can also be incorporated into and discharge from the material that is used to construct delivery catheter.Alternatively, or other, and fibre modification-inhibitor can be penetrated in device-organizational interface zone on every side.

It will be apparent to one skilled in the art that it will be expection and suitablely to use in the present invention that the commercial drug delivery pump do not mentioned specially and commercial medicine of future generation and/or exploitation subsequently are sent product.

B. Drug delivery pump in the sheath

On the other hand, with the sheath of fibre modification-inhibitor combination in drug delivery pump can be used to deliver a medicament spinal cord and be used for pain management and movement disorder.

Chronic pain is a most important clinical problem in all medical science.For example, estimate to disable owing to backache the people of the U.S. more than 500 ten thousand.The cost of chronic back pain is huge, causes annual the loss for 100,000,000 working days, and estimated cost is hundred million dollars of 500-1000.The cost of treatment tumor patient pain is near 12,000,000,000 dollars.Chronic back pain makes the cost of manying more that the people is disabled and American public being caused more than cancer and cardiopathic sum than cancer or heart disease.Except the health consequence, chronic pain also has many other costs, comprises that unemployment, marriage are discord, depression and prescription drug addiction.Therefore, apparent, reduce the huge challenge that sickness rate relevant with lasting pain and cost remain medical health system.

The serious pain of intractable that injured, disease, skoliosis, spinal disc degeneration, spinal cord injury, malignant tumor, arachnoiditis, chronic disease, pain syndrome (for example, failed back syndrome, complex region pain syndrome) and other reason cause is to make people's weakness and common medical problem.In many patients, continue to use analgesic, especially as the medicine of anesthetics and since toleration, inefficacy and addiction may rather than effective solution route.In the effort that addresses this problem, to have developed the interior drug delivery device of sheath and treated other conventional therapy mode such as Drug therapy, invade treatment (operation), perhaps behavior/life style changes the serious refractory back pain that resistance is arranged.

Designed drug delivery pump in the sheath and be used for easing the pain by the cerebrospinal fluid that pain medication medicine is delivered to the intrathecal space around the spinal cord.Usually, the pain sensation directly is transferred in the pain receptor of brain, so need more low dose of medicine to be alleviated because this therapy is delivered locally to pain medication in the spinal cord.Morphine and other anesthetis (fentanyl and sufentanil usually) are that the most frequently used delivery agents and many patients accepts better alleviation with being lower than the dosage that alleviates that can realize with systemic delivery.Thereby in the sheath medicine send also allow to use do not pass blood-brain barrier and only when using by this approach effective pain medication (as ziconotide; The N-type calcium channel blocker that Elan Pharmaceuticals makes).

Pump also is used for the treatment of the nerve and the dyskinesia in the sheath.Baclofen (going on the market with Lioresal) by Novartis be used for the treatment of have multiple sclerosis, spasticity and improve the spasmolytic/muscle relaxant of motility among the patient of gallbladder fibre modification and spinal cord injury.Verified when drug delivery pump is applied to CSF in by sheath, this medicine is more effective and cause littler side effect.Also attempt treating epilepsy, the cerebral tumor, Alzheimer, parkinson disease and Amyetropic lateral sclerosis (ALS-Lou Gehrig ' s disease) by using the medicament that systemic administration is had very much toxicity or do not passed blood brain barrier in the sheath.For example, in ALS patient, carried out the test of administered recombinant Brain Derived Neurotrophic Factor in the sheath (r-BDNF that Amgen makes).

Drug delivery system is made up of medication infusion pump in the sheath and spinal column inner catheter in the sheath, and they are all implanted fully.Pump installation is implanted below the skin of abdomen part, just on belt or down and can be by the medicine percutaneous injection is recharged to storage.Conduit has passage and extends from the intrathecal space of pump to spinal column under skin.When operation, pump in a continuous manner or the mode that responds symptom control with doctor or patient with the medicament administration of ormal weight in cerebrospinal fluid.

Pump is suitable for being used for enforcement of the present invention with fibre modification-inhibitor combination in the implantable sheath of many types.For example, the implantable pump that is used for delivering drugs can be made up of two osmotic pumps and semipermeable membrane, it is configured to send nearly two kinds of medicines with different rates and sends scheme, and have built-in stock of drugs delivery system, thereby when main delivery system reaches its service life or is out of order unexpectedly, can continue sending of medicine.See, for example, U.S. Patent number 6,471,688.Implantable pump can be made up of battery operated pump installation, eases the pain by sending liquid pain relief agent through conduit to desirable position with the spatial medicine storage of epidural space, conduit and the electrode of implanting the patient.See, for example, U.S. Patent number 5,458,631.

Described similar drug delivery pump, it is used for that medicament is infused into the brain zone and treats multiple chronic neurodegenerative disease (as in the above about sending those diseases of description in the sheath) with the neuronic irritability of local influence.Implantable pump can be that abdominal part is implanted, and it distributes medicine by conduit then, and this conduit arrives the topical therapeutic position in the brain then from the entry site of abdominal part implant site by neck arrival head.Pump to the brain delivery medicine can discharge medicine at a plurality of positions, described position comprises, but be not limited to preceding thalamus, abdomen outside thalamus, pallidal inner section, black substance reticular part (parsreticulate), subthalamic nucleus, pallidal outer portion part and neostriatum.For example, drug delivery pump can partly be made up of implantable pump, and this pump part connecting duct, described conduit are used for drug dose being infused into the precalculated position of brain, thereby can treating nervous disorders (for example, epilepsy) when sensor arrives symptom.See, for example, U.S. Patent number 5,978,702.Implantable pump can implant with brain in predetermined infusion site adjacent, thereby can infusion can change the predetermined close of at least a medicine of the neuronal excitability level of brain, thereby prevent and/or treat neural degeneration.See, for example, U.S. Patent number 5,735,814.Implantable pump can comprise the therapeutic agent storage, and it is preserved between experimenter's galea aponeurotica and cranium, its Chinese medicine by to the pump action at purpose position with distributing.See, for example, U.S. Patent number 6,726,678.

Many available implantable, interior drug delivery systems of sheath of commercial sources that pass through of the invention process that are suitable for are arranged.By Medtronic, the SYNCHROMED EL Infusion System that Inc. makes be used for baclofen treatment (ITB treatment) in the chronic sheath (see, for example, U.S. Patent number 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 programmable, battery operated device, its storage and based on the programming the dosage regimen delivering drugs.Medtronic, (Minneapolis MN) also sells their ISOMED Constant-Flow Infusion System to Inc., and it is used for morphine sulfate directly is delivered to intrathecal space treatment chronic pain.Arrow International produces the Model3000 infusion pump, and it provides medicament such as morphine and baclofen to use to the constant speed of intrathecal space.TricumedMedizintechnik GmbH (Kiel, Germany) produces

The implantable infusion pump of constant current is used for using in the sheath pain and spasmolytic medicine.(Plano TX) produces Advanced Neuromodulation Systems

Infusion pump is used for the treatment of pain and neuromuscular disorder.The feature of all these devices is to have a long conduit, and it is transported to intrathecal space the spinal cord with activating agent from the pump of subcutaneous implantation.As described above, drug delivery tube chamber or catheter tip can be subjected to the partially or completely obstruction of scar tissue in the sheath, and this can cause drug flow to slow down or stop fully.The another kind of possible complication that medicine is sent in the sheath is to form fibrous tissue in the subdural space space, and it can block CSF and flow and cause severe complication (for example, hydrocephalus, intracranial pressure rising).In the present invention, fibre modification in the surrounding tissue be opened and/or be prevented to drug delivery tube can to keep the delivery catheter chamber with the fibrotic medicament combination of inhibition.Fibre modification-inhibitor also can be incorporated into, perhaps from being used to construct the material release of delivery catheter.Alternatively, or additionally, fibre modification-inhibitor can be penetrated in the zone around device-organizational interface.Anti-infective is as catheter coatings and/or implant, and use or do not use fibre modification-inhibitor, also be useful for enforcement of the present invention.

It will be apparent to one skilled in the art that it will be use in the present invention expection and suitable that interior drug delivery pump of the commercial sheath of not mentioning specially and commercial medicine of future generation and/or exploitation subsequently are sent product.

C. Be used for chemotherapeutic implantable drug delivery pump

On the other hand, drug delivery pump can be to distribute the pump of the chemotherapeutic agent that is used for the treatment of cancer.Distribute the pump of the medicine that is used for the treatment of cancer to be used for sending chemotherapeutant to the regional area of health.Although almost any malignant tumor can be potentially treated (that is, by to solid tumor or to the direct infused drug of blood vessel of supplying with tumor) with this mode, current treatment centers on the treatment of liver neoplasm.For example, FUDR (2 '-deoxidation 5-floxuridine) is used to transfer to the palliative treatment of the adenocarcinoma (colon, mammary gland, stomach) of liver.In the hepatic artery ligation treatment, deliver drugs in the tremulous pulse of liver blood supply by implantable pump.This allow higher drug level reach liver (medicine not can in the blood vessel as during intravenous is used, being diluted) and prevent liver removing (if intravenous use, so medicine by liver metabolism and can remove fast from blood flow); Either way allow the medicine of higher concentration to arrive tumor.

The implantable pump of many types is suitable for sending chemotherapeutant in enforcement of the present invention.For example, implantable pump can have and have the distributor chamber that distributes passage and executor, has the storage shell of storage and is used to recharge the barrier film of storage.See, for example, U.S. Patent number 6,283,949.Medtronic, Inc. sell their ISOMED Constant-Flow Infusion System, and it can be used for sending with fixed flow rate, and the infusion floxuridine is used for the treatment of constitutional or metastatic cancer in the chronic blood vessel.Tricumed Medizintechnik GmbH (Kiel, Germany) sells their implantable infusion pump of ARCHIMEDESDC, sends chemotherapeutant with constant rate of speed in it is particularly suitable near tumor and (sees, for example, U.S. Patent number 5,908,414 and 5,769,823).Arrow International produces Model 3000 pumps, and it provides chemotherapeutant to use to the constant speed of tumor.All these apparatus features are the tremulous pulsies that chemotherapeutant transported directly to tumor or supply tumor from the pump of subcutaneous implantation.As mentioned above, drug delivery tube chamber or catheter tip can be subjected to the partially or completely obstruction of scar tissue, and this can cause drug flow to slow down or stop fully.If place in the blood vessel, drug delivery tube chamber or catheter tip can be subjected to the partially or completely obstruction of neointima tissue so, and this can damage, and medicine is vasotropic to flow.In the present invention, drug delivery tube can be opened to keep the delivery catheter chamber with the fibrotic medicament combination of inhibition.Fibre modification-inhibitor also can be incorporated into, perhaps from being used to construct the material release of delivery catheter.Alternatively, or additionally, fibre modification-inhibitor can be penetrated in the zone around device-organizational interface.Anti-infective is as catheter coatings and/or implant, with or not with the auxiliary use of fibre modification-inhibitor, also be useful for enforcement of the present invention.

It will be apparent to one skilled in the art that commercial chemical therapeutic agent delivery pump and the commercial chemical therapeutic agent delivery product of future generation and/or exploitation subsequently do not mentioned specially will be uses in the present invention expection and suitable.

D. Be used for the treatment of cardiopathic drug delivery pump

On the other hand, drug delivery pump can be to distribute the pump that is used for the treatment of cardiopathic medicine.Distribute the pump that is used for the treatment of cardiopathic medicine can be used for the treatment of the disease that includes, but are not limited to atrial fibrillation and other heart rhythm disorders.Atrial fibrillation is the heart disease that torments a kind of form of millions of people.It is so a kind of disease, and the normal coordination of its cardiac is shunk and is damaged, and mainly is because the unusual and uncontrolled effect in heart atrium causes.Under the normal condition, the contraction of other chamber of contraction and heart is with controlled occurring in sequence.When right atrium shrinks failure, shrink out-of-sequence, perhaps ineffective contraction, the contraction from the atrium to the ventricle is damaged.Atrial fibrillation is because the ventricular filling that reduces can cause weakness, rapid breathing, angina, dizziness and other symptom with the cardiac output that reduces.Owing to form clot in the atrium of not good enough contraction, it is loose to break, and moves to the tremulous pulse of brain by blood flow, and they become wedge shape and block blood flow (it can cause brain injury and death) there, and apoplexy can take place.Usually, transform (defibrillation) treatment atrial fibrillation by medical science or electricity, yet, can there be complication, thus, described treatment causes great pain or has the possibility that causes life-threatening ventricular arrhythmia.For many patients, the pain relevant with galvanic shock is serious in unacceptable, because when device is sent electrotherapy, they are clear-headed and vigilance.Medical therapy comprises by intravenous injection sends anti-arrhythmic, dosage forms for oral administration or by drug delivery pump local application anti-arrhythmic.

The implantable pump of having described many types is used for distributing the cardiopathic medicine of treatment and being suitable for enforcement of the present invention.For example, drug delivery pump can be implantable heart electrode, and it is sent stimulation energy and distributes medicine adjacent in stimulation location.See, for example, U.S. Patent number 5,496,360.Drug delivery pump can have many siloxanes barrier films and help to fill medicine storage in the pump of subcutaneous implantation, and described pump has conduit, its via subclavian vein through vein by superior vena cava and arrive right atrium so that delivering drugs.See, for example, U.S. Patent number 6,296,630.As above describe, drug delivery tube chamber or catheter tip can be subjected to the partially or completely obstruction of scar tissue, and this can cause drug flow to slow down or stop fully.If place in the blood vessel, drug delivery tube chamber or catheter tip can be subjected to the partially or completely obstruction of neointima tissue so, and this can damage medicine flowing to blood vessel or right atrium.In the present invention, drug delivery tube can be opened to keep the delivery catheter chamber with the fibrotic medicament combination of inhibition.Fibre modification-inhibitor also can be incorporated into, perhaps from being used to construct the material release of delivery catheter.Alternatively, or additionally, fibre modification-inhibitor can be penetrated in the zone around device-organizational interface.Anti-infective is as catheter coatings and/or implant, with or not with the auxiliary use of fibre modification-inhibitor, also be useful for enforcement of the present invention.

It will be apparent to one skilled in the art that and send pump and commercial cardiac drug of future generation and/or exploitation subsequently by the commercial cardiac drug of not mentioning specially to send product will be expection and suitablely to use in the present invention.

E. Other medicines are sent implant

Develop some other implantable pumps and be used for sending continuously medicament.

For example, Debiotech S.A. (Switzerland) has developed the MIP device, and it is the silicon Micropump that is used for the implantable pressure-driving of programmable drug delivery applications.This efficient Micropump is based on MEMS (Micro-Electro-Mechanical) system, and it allows it to keep low flow velocity.From DurectCorporation (Cupertino, DUROS sufentanil implant CA) is the titanium cylinder, it contains the piston that medicine storage and osmotic engine drive.From Alza Corporation (MountainView, CA) VIADUR (leuproside) thus use identical DUROS implanted prosthetics send in during 12 months leuprorelin with reduce testosterone levels treatment carcinoma of prostate (see, for example, U.S. Patent number 6,283,953; 6,270,787; 5,660,847; 5,112,614; 5,030,216 and 4,976,966).The fibrous encapsulation of device can cause fault in many ways: block semipermeable membrane (its will by preventing the work of liquid to this engine of flow impairment of osmotic engine), block outlet (will damage the medicine bleeder), and/or coat (it prevents generation the microenvironment of medicament distribution) fully.Many other medicines delivery apparatus, osmotic pumps or the like exist similar problem-fibrous encapsulation to prevent the suitable release that medicine is organized towards periphery.In the present invention, medicine send implant can with suppress fibrotic medicament and make up and prevent to coat, prevent the obstruction of semipermeable membrane and/or keep delivery port open.Alternatively, or additionally, fibre modification-inhibitor can be penetrated into medicine and send in the implant surrounding tissue.

Although many implantable pumps described above, all have similar design feature and implant after cause similar undesired fibrous tissue reaction.The clinical function of implantable drug delivery device or pump depends on device, especially conduit or medicament distribution assembly can effectively keep contacting and not being subjected to the anatomy closely of target tissue (for example, space, lumen of artery, peritoneum, interstitial fluid under the dura mater in the spinal cord) coating and the obstruction of scar tissue.For implantable pump, drug delivery tube chamber, catheter tip, allocation component or send the obstruction that film can be subjected to scar tissue, described scar tissue can cause drug flow to slow down or stop fully.Alternatively, alternatively, the coating that entire pump, conduit and/or allocation component can be subjected to cicatrix (promptly, health " separates " device with fibrous tissue) thus medicine is delivered to target tissue (that is, cicatrix prevents motion of correct medicine and the distribution of organizing to the another side of the capsule of capsule from implantable pump) by halves.Any of these development can cause medicine to the invalid of target tissue or organ or not exclusively mobile (with the loss clinical benefit), can also cause drug accumulation (in the capsule) and other clinical complication (for example, topical remedy's toxicity and coat; The medicine that high amount of drug unexpected " toppling over " is gone into after the surrounding tissue is isolated).For the implantable pump that comprises electricity or battery component, fibre modification not only can cause device can not work best or at all, can also cause very big consumption, because the resistance of the increase that the scar tissue that needs multipotency more to overcome intervention causes to battery life.

Discharge the implantable pump that reduces synulotic therapeutic agent in device-organizational interface and can be used to increase effect, prolong clinical performance, guarantee to distribute the medicine of correct amount and reduce the genotoxic potential medicine isolated danger that in fibrous capsule, becomes from device with suitable speed.On the one hand, the invention provides implantable pump, the compositions that it comprises fibre modification-inhibitor or comprises fibre modification-inhibitor.Many polymer and the non-polymer delivery system that is used for implantable pump described above.These compositionss can also comprise one or more fibre modification-inhibitor, thereby the undue growth of granulating or fibrous tissue is suppressed or reduces.

To suppress that fibrotic compositions is mixed on the implantable drug delivery pump or innerly comprise: (a) directly will suppress fibrotic compositions and invest implantable pump to reduce in the synulotic method of device-organizational interface (especially in drug delivery tube or the medicament distribution assembly with on every side), conduit and/or medicament distribution assembly are (for example, by spray method described as follows or dipping method, use or without carrier), (b) directly will suppress fibrotic compositions and be attached to implantable pump, conduit and/or medicament distribution assembly are (for example, by spray method described as follows or dipping method, use or without carrier), (c) by using material to be coated with implantable pump such as hydrogel, conduit and/or medicament distribution assembly, described material absorbs again and suppresses fibrotic compositions, (d) interweave to implantable pump by being coated with the line (perhaps polymer itself forms line) that suppresses fibrotic compositions, in conduit and/or the medicament distribution modular construction, (e) with implantable pump, conduit and/or medicament distribution assembly are inserted into and comprise sleeve or the mesh that suppresses fibrotic compositions or be coated with the fibrotic compositions of inhibition; (f) make implantable pump itself (perhaps all or part of of conduit and/or medicament distribution assembly) with suppressing fibrotic compositions, or (g) by with the implantable pump of the direct covalent bond of fibre modification-inhibitor, conduit and/or medicament distribution assembly surface or joint (micromolecule or polymer), this joint coating or be connected to apparatus surface.Each of these methods has been illustrated implantable pump and the method that makes up according to fibre modification of the present invention-inhibition (being also referred to as anti-cicatrization herein) agent.

For implantable pump, can carry out coating process in such a manner: (a) part of apparatus for coating (as conduit, drug delivery port, semipermeable membrane); Perhaps (b) is coated with whole device with suppressing fibrotic compositions.In addition, or alternatively, fibre modification-inhibitor can with the material mixing that is used to make implantable pump, thereby fibre modification-inhibitor is attached to final products.In these modes, can prepare medical apparatus with coating, its floating coat is for for example, and is uniform, heterogeneous, successive, discontinuous, perhaps figuratum.

On the other hand, implantable drug delivery device can comprise their the interior many storages of structure, and each storage is configured to hold and protects curative drug (for example, one or more fibre modification-inhibitor).Storage can be formed by the divets of apparatus surface or micropore or the passage in the device body.On the one hand, the hole from apparatus structure forms storage.Storage can hold the medicine (for example, fibre modification-inhibitor) of single type or the medicine (for example, fibre modification-inhibitor and anti-infective) of more than one types.Can be with carrier (for example, polymerization or the non-polymeric material) compounding pharmaceutical that is loaded in the storage.Storage through filling can be used as medicine and sends storehouse work, and it can discharge medicine from the kinetics that carrier discharges according to medicine in one period.In certain embodiments, can load storage with many layers.Every layer of different pharmaceutical that can comprise the medicine with specified quantitative (dosage), every layer can have different compositionss further to be fit to from the amount and the type of the medicine of substrate release.The multilamellar carrier can also comprise the barrier layer that prevents drug release.Barrier layer for example can be used for, and the control medicine is from the effusive direction of hole.Thereby the coating of this medical apparatus can directly contact pump, and perhaps when at pump with contain when having something (as polymeric layer) to insert between the coating of fibre modification-inhibitor, described coating can the mediate contact pump.

Except (or as alternative) is attached to fibre modification-inhibitor on implantable pump, conduit and/or the medicament distribution assembly or interior, fibre modification-inhibitor can directly or indirectly be applied to the tissue adjacent with implantable pump (preferably in tissue near medicine from place that device is sent).This can be by using or not using polymeric, non-polymer or second carrier, fibre modification-inhibitor (a) is applied to implantable pump, conduit and/or medicament distribution assembly surface (for example, as injection, paste, gel or mesh) in implantation step; (b) before implantable pump, conduit and/or medicament distribution assembly are implanted, at once before or during the surface (for example, as injection, paste, gel, original position formation gel or mesh) that is applied to organize; (c) tissue around the surface that is applied to implantable pump, conduit and/or medicament distribution assembly after the implantation at once and/or implantable pump, conduit and/or medicament distribution assembly (for example, forming gel or mesh) as injection, paste, gel, original position; (d) by the fibrosis agent being applied topically to implantable pump, conduit and/or medicament distribution assembly the anatomy space of placing (is to use polymer support for what this embodiment was particularly useful, it discharges fibre modification-inhibitor-liquid, suspensoid, Emulsion, microemulsion, microsphere, paste, gel, microparticle, spray, aerosol, solid-state implant and other preparation in a few hours to several weeks, its release can be delivered to the medicament that implantable pump, conduit and/or medicament distribution assembly insert the zone); (e),, perhaps be applied to implantable pump, conduit and/or medicament distribution assembly tissue on every side by percutaneous injection as slow releasing preparation as infusate as solution; (f) combination in any by said method realizes.Can also use combination treatment (that is the combination of the combination of therapeutic agent and antithrombotic formation, antiplatelet and/or anti-infective).

Can mention that some polymer support self can help prevent forms fibrous tissue around implantable pump, conduit and/or the medicament distribution assembly.These carriers (hereinafter describing) especially can be united the enforcement that is used for this embodiment separately or with the fibrotic compositions of inhibition.Below polymer support can permeate near implantable pump, conduit and/or the medicament distribution assembly of (as describing in the paragraph in front) auto levelizer and the organizational interface and comprise: the preparation that (a) contains sprayable collagen, as COSTASIS and CT3, described preparation is independent or load fibre modification-inhibitor, is applied to implant site (perhaps implantable pump, conduit and/or medicament distribution assembly surface); (b) contain the preparation of sprayable PEG, as COSEAL, FOCALSEAL, SPRAYGEL or DURASEAL, described preparation can be applied to implant site (perhaps implantable pump, conduit and/or medicament distribution assembly surface); (c) contain the preparation of fibrinogen, as FLOSEAL or TISSEAL, described preparation separately or load fibre modification-inhibitor is applied to implant site (perhaps implantable pump, conduit and/or medicament distribution assembly surface); (d) contain hyaluronic preparation, as RESTYLANE, HYLAFORM, PERLANE, SYNVISC, SEPRAFILM, SEPRACOAT, described preparation loads fibre modification-inhibitor, is applied to implant site (perhaps implantable pump, conduit and/or medicament distribution assembly surface); (e) be used for the polymer gel that surgical operation is implanted, as REPEL or FLOWGEL, described preparation loads fibre modification-inhibitor, is applied to implant site (perhaps pump, conduit and/or medicament distribution assembly surface); (f) orthopedic " cement ", it is used for prosthese and tissue are remained on the appropriate location, it loads fibre modification-inhibitor, be applied to implant site (perhaps pump, conduit and/or medicament distribution assembly surface), as OSTEOBOND, low viscosity cement (LVC), SIMPLEX P, PALACOS, and ENDURANCE; (g) contain the operation adhesive of cyanoacrylate, as DERMABOND, INDERMIL, GLUSTITCH, TISSUMEND, VETBOND, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEALLIQUID PROTECTANT, described binding agent is independent or load fibre modification-inhibitor, is applied to implant site (perhaps pump, conduit and/or medicament distribution assembly surface); (h) contain the implant of hydroxyapatite (perhaps synthetic bone material, as calcium sulfate, VITOSS and CORTOSS), it loads fibre modification-inhibitor, is applied to implant site (perhaps pump, conduit and/or medicament distribution assembly surface); (i) other biocompatible tissue filling agent, its independent or loading fibre modification-inhibitor, as BioCure, Inc. (Norcross, GA), 3M Company and Neomend, Inc. (Sunnyvale, CA) those of Zhi Zaoing, described filler are applied to implant site (perhaps pump, conduit and/or medicament distribution assembly surface surface); (j) polysaccharide gel, as ADCON series gel, described gel is independent or load fibre modification-inhibitor, is applied to implant site (perhaps pump, conduit and/or medicament distribution assembly surface); And/or (k) membrane, sponge or mesh, as INTERCEED VICRYL MESH, with GELFOAM, described gel separately or load fibre modification-inhibitor is applied to implant site (perhaps pump, conduit and/or medicament distribution assembly surface).

Can be used to help prevent pump separately or with fibre modification inhibitor/compositions associating being implanted, the preferred polymeric matrix that forms fibrous tissue around conduit and/or the medicament distribution assembly is formed by the reactant as pharmacy response, described reactant comprise following one or both: tetramethylolmethane gathers (ethylene glycol) ether four-sulfydryl] (4-arm sulfydryl PEG, it is included in the structure that has linking group between the end of sulfydryl and polyethylene glycol backbone) and poly-(ethylene glycol) ether four-succinimido 1,3-propanedicarboxylic acid of tetramethylolmethane] (4-arm NHS PEG, it is included in the structure that has linking group between the end of NHS base and polyethylene glycol backbone once more).Another kind of preferred composition comprise as pharmacy response following one or both: tetramethylolmethane gather (ethylene glycol) ether four-amino] (4-arm amino PEG, it is included in the structure that has linking group between the end of amino and polyethylene glycol backbone) and poly-(ethylene glycol) ether four-succinimido 1,3-propanedicarboxylic acid of tetramethylolmethane] (4-arm NHS PEG, it is included in the structure that has linking group between the end of NHS base and polyethylene glycol backbone once more).The chemical constitution of these reactants is for example, and U.S. Patent number 5,874 shows in 500.Randomly, with collagen or collagen derivant (for example, methylated collagen) add the reactant contain poly-(ethylene glycol) forming preferred crosslinked substrate, its can be used as therapeutic agent or independently the polymer support of compositions around the pump of being implanted, conduit and/or medicament distribution assembly, form fibrous tissue to help prevent.

As those skilled in the art with conspicuous, following possible any anti-scarring agent can be separately or use in conjunction in the enforcement of this embodiment.Because implantable pump and their drug delivery mechanisms (for example, conduit, port or the like) are made with multiple structure and size, so the definite dosage of using will become along with device size, surface area and design.Yet some principle can be applied to this area.Can be used as the function calculation drug dose of the dosage of per unit area (part of applied device), can measure the total drug dose of using and can determine the suitable surface concentration of active medicine.No matter medicinal application is in the method (that is, as coating, perhaps being penetrated into surrounding tissue) of device, separately or the fibre modification-inhibitor of uniting use use under can administration below instructing:

Medicine and dosage: operable therapeutic agent includes but not limited to: anti-microtubule agent, comprise that taxanes (for example, paclitaxel and many Xi Tasai), other microtubule stabilizer and anti-microtubule medicine, Mycophenolic Acid, sirolimus, tacrolimus, everolimus, ABT-578 and catharanthus alkaloid (for example, vinblastine and vincristine sulfate) and analog and derivant.Medicine can be with the single whole-body dose (for example, be used for per os and intravenous and use used dosage) several times to the part of single whole-body dose (for example, be applied to usually the single system dose application concentration 50%, 10%, 5% and even less than 1%) concentration use.Comprise taxanes, as paclitaxel and analog thereof and derivant (for example, many Xi Tasai), and catharanthus alkaloid, comprise that the anti-microtubule agent of vinblastine and vincristine sulfate and analog thereof and derivant should be used with following parameter: accumulated dose is no more than 10mg (0.1 μ g is to the 10mg scope); Preferred accumulated dose 1 μ g is to 3mg.The per unit area dosage of device is 0.05 μ g/mm ²-10 μ g/mm ²Preferred dose/unit are is 0.20 μ g/mm ²-5 μ g/mm ²Keep 10 at apparatus surface ^-9-10 ^-4The medicine of M Cmin.Immunomodulator comprises sirolimus, ABT-578 and everolimus.Sirolimus (that is, and rapamycin, RAPAMUNE): accumulated dose is no more than 10mg (0.1 μ g is to the 10mg scope); Preferred 10 μ g are to 1mg.Per unit area dosage is 0.1 μ g-100 μ g/mm ²Surface area; Preferred dose is 0.5 μ g/mm ²-10 μ g/mm ²On apparatus surface, keep Cmin 10 ^-8-10 ^-4M.Everolimus and derivant thereof and analog: accumulated dose is no more than 10mg (0.1 μ g is to the 10mg scope); Preferred 10 μ g are to 1mg.Per unit area dosage is 0.1 μ g-100 μ g/mm ²Surface area; Preferred dose is 0.3 μ g/mm ²-10 μ g/mm ²Keep 10 at apparatus surface ^-8-10 ^-4The everolimus of M Cmin.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 10.0 μ g are to 2000mg); Preferred 10 μ g are to 300mg.The per unit area dosage of device is: every mm ²1.0 μ g-1000 μ g; Preferred dose is 2.5 μ g/mm ²-500 μ g/mm ²On apparatus surface, keep Cmin 10 ^-8-10 ^-3The Mycophenolic Acid of M.

B. The therapeutic agent that implantable sensor and drug delivery pump device use

As described previously, numerous therapeutic agent is fit to suppress implantable sensor and drug delivery pump fibrous tissue accumulation on every side in the mode of firm description potentially.The invention provides medical apparatus, it comprises and being suppressed near this device, i.e. the medicament of tissue accumulation between the host that implants of medical apparatus and this medical apparatus.Therefore, this medicament is effectively for this purpose, have and be present in the one or more positions that allow to realize this purpose with the amount of effective this purpose of realization, and this device is designed to allow described medicament generation beneficial effect.And these therapeutic agents can separately or be united use, in order near the accumulation of middle scar tissue anti-locking apparatus-organizational interface, so that improve the clinical performance and the life-span of these implants.

Can easily identify suitable fibre modification agent as those models that provide among the embodiment 34-47 based on (animal) model in external and the body.Suppressing fibrotic medicament can also identify by the body inner model, and described body inner model is included in and suppresses the neointimal hyperplasia development in the rat airbag neck artery model (embodiment 39 and 47).The algoscopy that provides among the embodiment 38 and 46 can be used for determining whether medicament can be suppressed to the cell proliferation of fibrocyte and/or smooth muscle cell.In one aspect of the invention, medicament suppresses the IC of cell proliferation ₅₀Be about 10 ^-6To about 10 ^-10M.The algoscopy that provides among the embodiment 42 can be used for determining whether medicament can suppress the migration of fibrocyte and/or smooth muscle cell.In one aspect of the invention, described medicament suppresses the IC of cell migration ₅₀Be about 10 ^-6To about 10 ^-9M.The algoscopy that herein provides can be used for determining whether medicament can suppress inflammatory process, comprise that nitric oxide produces (embodiment 34) in the macrophage, and/or the TNF-α of macrophage produces (embodiment 35), and/or the IL-1 of macrophage produces (embodiment 43), and/or the IL-8 of macrophage production (embodiment 44), and/or macrophage is to the inhibition (embodiment 45) of MCP-1.In one aspect of the invention, medicament suppresses any IC of these inflammatory processes ₅₀Be about 10 ^-6To about 10 ^-10M.The algoscopy that provides among the embodiment 40 can be used for determining whether medicament can suppress MMP and produce.In one aspect of the invention, medicament suppresses the IC that MMP produces ₅₀Be about 10 ^-4To about 10 ^-8M.The algoscopy that provides among the embodiment 41 (being also referred to as the CAM algoscopy) can be used for determining whether medicament can suppress angiogenesis.In one aspect of the invention, medicament suppresses the IC of angiogenesis ₅₀Be about 10 ^-6To about 10 ^-10M.Reduce the medicament of surgical operation adhesion formation and can identify that described body inner model comprises rabbit surgical operation adhesion model (embodiment 37) and rat caecum sidewall model (embodiment 36) by the body inner model.These forms of pharmacologically active agents (following) can be delivered to tissue separately or by carrier (this paper description) with suitable dosage then, to treat clinical problem described herein.Identified to be used for many treatment chemical compounds of the present invention, it comprises:

1. Angiogenesis inhibitor

In one embodiment, pharmaceutically active compound is angiogenesis inhibitor (for example, 2-ME (NSC-659853); PI-88 (the 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)-and 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, the Malaysia hydrohalogenic acid salt), 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-Zhi Fangyanghemeiyizhiji ﹠amp; Antagonist

In another embodiment; pharmaceutically active compound be 5-lipoxidase inhibitor or antagonist (for example; 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 5-2,4,5-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 '-xenyl]-the 4-yl) oxygen] 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) sulfo-)-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) sulfo-]-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) sulfo-)-α, alpha-alpha-dimethyl-5-(2-quinolyl methoxyl group)-); docebenone (2; 5-cyclohexadiene-1,4-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 ， ﹠amp; 5)

In another embodiment, pharmaceutically active compound is one or more hypotypes (1, the 3 ， ﹠amp that suppresses CCR; 5) (for example, ONO-4128 (1,4 for chemokine receptor anagonists, 9-thriazaspiro (5.5) hendecane-2,5-diketone, 1-butyl-3-(cyclohexyl methyl)-9-((2,3-dihydro-1,4-Ben Bing dioxine-6-yl) methyl-), L-381, CT-112 (the L-arginine, L-threonyl-1-threonyl-1-seryl-1-glutaminyl-1-valyl-1-arginyl-1-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] 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, pharmacologically active chemical compounds is a cell cycle inhibitor.The representative instance of these reagent comprises taxanes (for example, paclitaxel (below in more detail discuss) and many Xi Tasai) (people such as Schiff, Nature 277:665-667,1979; Long and Fairchid, CancerResearch 54:4355-4361,1994; Ringel and Horwitz, J.Nat ' lcancer Inst.83 (4): 288-291,1991; People such as Pazdur, Cancer Treat.Rev.19 (40): 351-386,1993), etanidazole, nimorazole (B.A.Chabner and D.LLongo.Cancer Chemotherapy andBiotherapy-Principles and Practice.Lippincott-Raven Publishers, New York, 1996, the 554th page), perfluorochemical with hyperbaric oxygen, transfusion, erythropoietin, BW12C, nicotiamide, hydralazine, BSO, WR-2721, ludR, DUdR, etanidazole, WR-2721, BSO, mono-substituted keto-aldehyde chemical compound (LG.Egyud.Keto-aldehyde-amine additionproducts and method of making same. U.S. Patent number 4,066,650, on January 3rd, 1978), nitre imidazoles (K.C.Agrawal and M.Sakaguchi.Nitroimidazole radiosensitizersfor Hypoxic tumor cells and compositions thereof. U.S. Patent number 4, on July 31st, 462,992,1984), 5-replaces-4-nitre imidazoles (people such as Adams, Int.J.Radiat.Biol.Relat.Stud.Phys.Chem.Med.40 (2): 153-61,1981), SR-2508 (people such as Brown, Int.J.Radiat.Oncol., Biol.Phys.7 (6): 695-703,1981), 2H-isoindoledione (J.A.Myers, 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 (people such as V.G.Beylin, Process for preparing chiral (((2-bromoethyl)-amino) methyl)-nitro-1H-imidazole-1-ethanol and relatedcompounds. U.S. Patent number 5,543, on August 6th, 527,1996; U.S. Patent number 4,797,397; On January 10th, 1989; U.S. Patent number 5,342, on August 30th, 959,1994), the nitroaniline derivant (W.A.Denny, etc.Nitroaniline derivatives and their use as anti-tumoragents. U.S. Patent number 5,571,845, on November 5th, 1996), DNA-affinic hypoxia-selective cytotoxin (M.V.Papadopoulou-Rosenzweig.DNA-affinic hypoxia selectivecytotoxins. U.S. Patent number 5, on February 11st, 602,142,1997), halogenated DNA part (R.F.Martin.Halogenated DNA ligand radiosensitizers for cancer therapy. U.S. Patent number 5, on June 24th, 641,764,1997), 1, (W.W.Lee etc. 1,2 for 2,4 benzotriazine oxides, 4-benzotriazine oxides as radiosensitizers and selective cytotoxic agents. U.S. Patent number 5, on April 1st, 616,584,1997; U.S. Patent number 5,624, on April 29th, 925,1997; Process for Preparing1,2,4Benzotriazine oxides. U.S. Patent number 5,175,287, on December 29th, 1992), nitrogen oxide (people such as J.B.Mitchell, Use of Nitric oxide releasingcompounds as hypoxic cell radiation sensitizers. U.S. Patent number 5,650,442, on July 22nd, 1997), 2-nitre imdazole derivatives (2-Nitroimidazole derivativesuseful as radiosensitizers for hypoxic tumor cells. U.S. Patent number 4,797 such as M.J.Sut, on January 10th, 397,1989; T.Suzuki.2-Nitroimidazole derivative, production thereof, 5,270,330,1993 years Decembers of andradiosensitizer containing the same as active ingredient. U.S. Patent number 14 days; 2-Nitroimidazole derivative such as T.Suzuki, productionthereof, 5,270,330,1993 years Decembers of and radiosensitizer containing the same as active ingredient. U.S. Patent number 14 days; T.Suzuki.2-Nitroimidazole derivative, production thereof and radiosensitizer containing the same as activeingredient; Patent No. EP 0 513 351B1, on January 24th, 1991), fluorine-containing nitro-pyrrole derivant (T.Kagiya.Fluorine-containing nitroazole derivatives and radiosensitizercomprising the same. U.S. Patent number 4,927,941, May 22 nineteen ninety), copper (M.J.Abrams.Copper Radiosensitizers. U.S. Patent number 5,100,885, on May 31st, 1992), the cancer therapy of associated form (D.H.Picker etc., 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.Method and Materials forsensitizing neoplastic tissue to radiation. U.S. Patent number 4,894, on January 16th, 3641990), platinum complex (K.A.Skov.Platinum Complexes with one radiosensitizingligand. U.S. Patent number 4, on May 1st, 921,963.1990; K.A.Skov.PlatinumComplexes with one radiosensitizing ligand. patent No. EP 0 287 317 A3), fluorine-containing nitro-pyrrole (T.Kagiya, Fluorine-containing nitroazole derivatives andradiosensitizer comprising the same. U.S. Patent number 4,927,941.1990 on May 22), Benzoylamide (W.W.Lee.Substituted Benzamide Radiosensitizers. U.S. Patent number 5,032,617, on July 16th, 1991), autobiotic (L.G.Egyud.Autobiotics and theiruse in eliminating nonselfcells in vivo. U.S. Patent number 5,147,652.1992 on JIUYUE 15), Benzoylamide and nicotiamide (Benzamide and NictoinamideRadiosensitizers. U.S. Patent number 5 such as W.W.Lee, 215,738, on June 1st, 1993), acridine-intercalator (M.Papadopoulou-Rosenzweig.Acridine Intercalator based hypoxia selectivecytotoxins. U.S. Patent number 5,294,715, on March 15th, 1994), fluorine-containing nitre imidazoles (Fluorine containing nitroimidazole compounds. U.S. Patent number 5 such as T.Kagiya, 304,654, on April 19th, 1994), hydroxylated texaphyrins (people Hydroxylated texaphrins. U.S. Patent number 5 such as J.L.Sessler, 457,183, October 10 nineteen ninety-five), the derivant of hydroxylated compounds (Heterocyclic compound derivative such as T.Suzuki, productionthereof and radiosensitizer and antiviral agent containing said derivative asactive ingredient. publication number 011106775A (Japan), on October 22nd, 1987; Heterocyclic compound derivative such as T.Suzuki, production thereof and radiosensitizer, antiviral agent and anti cancer agent containing said derivative as activeingredient. publication number 01139596A (Japan), on November 25th, 1987; Heterocyclic compound derivative such as S.Sakaguchi, its production and radiosensitizercontaining said derivative as active ingredient; Publication number 63170375 A (Japan), on January 7th, 1987), fluorine-containing 3-nitro-1,2,4-triazole (Novelfluorine-containing 3-nitro-1 such as T.Kagitani, 2,4-triazole and radiosensitizer containing samecompound. publication number 02076861 A (Japan), on March 31st, 1988), 5-sulfo-terazole derivatives or its salt (Radiosensitizer for Hypoxic cell. publication number 61010511A (Japan) such as E.Kano, on June 26th, 1984), nitrothiazole (Radiation-sensitizingagent. publication number 61167616A (Japan) such as T.Kagitani on January 22nd, 1985), imdazole derivatives (Imidazole derivative. publication number 6203767A (Japan) such as S.Inayma on August 1st, 1985; Publication number 62030768 A (Japan) on August 1st, 1985; Publication number 62030777 A (Japan) on August 1st, 1985), 4-nitro-1,2,3-triazole (Radiosensitizer. publication number 62039525 A (Japan) such as T.Kagitani, on August 15th, 1985), 3-nitro-1,2,4-triazole (Radiosensitizer. publication number 62138427 A (Japan) such as T.Kagitani, on December 12nd, 1985), system cancer effect regulator (H.Amagase.Carcinostatic action regulator. publication number 63099017 A (Japan), on November 21st, 1986), 4,5-dinitro imdazole derivatives (S.Inayama.4,5-Dinitroimidazole derivative. publication number 63310873 A (Japan) on June 9th, 1987), nitro-triazole chemical compound (T.Kagitanil.Nitrotriazole Compound. publication number 07149737A (Japan) on June 22nd, 1993), cisplatin, doxorubin, misonidazole, mitomycin, tiripazamine, nitroso ureas, mercaptopurine, methotrexate, fluorouracil, bleomycin, vincristine, carboplatin, epirubicin, doxorubicin, cyclophosphamide, vindesine, etoposide (I.F.Tannock.Review Article:Treatment of Cancer with Radiation and Drugs.Journal of Clinical Oncology 14 (12): 3156-3174,1996), camptothecine (Local delivery of chemotherapy and concurrent external beam radiotherapyprolongs survival in metastatic brain tumor models.Cancer Research56 (22): 5217-5223 such as Ewend M.G., 1996) and paclitaxel (Taxol:a novel radiationsensitizer.International Journal of Radiation Oncology and Biological Physics22 (3): 613-617 such as Tishler R.B., 1992).

Many above-mentioned cell cycle inhibitors also have extensively multiple analog and derivant, and it includes, 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, cell cycle inhibitor is a paclitaxel, and is a kind of by forming the chemical compound that anomomitotic spindle destroys mitosis (M-phase) in conjunction with tubulin, or its analog or derivant.In brief, paclitaxel is a kind of height diterpene-kind compound (Wani etc. derivatively, J.Am.Chem.Soc.93:2325,1971), it is from mountain mahogany (Taxusbrevifolia) (Pacific yew (Pacific Yew)) and Taxomyces Andreanae results and exsiccant leaves and the endogenetic fungus acquisition (Stierle etc. of Pacific yew, Science 60:214-216,1993).(it is construed as at this paper and comprises preparation ＂ paclitaxel ＂, prodrug, analog and derivant such as for example TAXOL (Bristol-Myers Squibb company, NewYork, NY), taxotere (Aventis Pharmaceuticals, France), docetaxel, the 10-deacetylate analog of paclitaxel and 3 ' N-of paclitaxel take off benzoyl-3 ' uncle N--butoxy carbonyl analog) technology that can use those skilled in the art to be familiar with easily be prepared (see, for example, Schiff etc., Nature277:665-667,1979; Long and Fairchild, Cancer Research 54:4355-4361,1994; Ringel and Horwitz, J.Natl.Cancer Inst.83 (4): 288-291,1991; Pazdur etc., CancerTreat.Rev.19 (4): 351-386,1993; WO 94/07882; WO 94/07881; WO 94/07880; WO 94/07876; 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 Letters35 (52): 9709-9712,1994; J.Med.Chem.35:4230-4237,1992; J.Med.Chem.34:992-998,1991; J.Natural Prod.57 (10): 1404-1410,1994; J.Natural Prod.57 (11): 1580-1583,1994; J.Am.Chem.Soc.110:6558-6560,1988), or from many commercial source acquisitions, described commercial source for example comprises, Sigma Chemical Co., and St.Louis, (T7402-is from mountain mahogany (Taxus brevifolia) for Missouri.

The representative instance 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, fluorine paclitaxel, 9-deoxidation taxanes, (13-acetyl group-9-deoxy baccatine III III, 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, 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, N-dimethylamino) propiono) paclitaxel; 2 ' ortho position carboxylbenzoyl paclitaxel; 2 ' aliphatic carboxylic acid derivates of paclitaxel, prodrug { 2 ' (N, N-diethylamino 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-diethylamino propiono) paclitaxel, 2 ', 7-two (N, N-diethylamino 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 the 7-of 10-deacetylate paclitaxel A protection-10-deacetylate Baccatine III; 10-deacetylate paclitaxel B; with 10-deacetylate paclitaxel, 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.

On the one hand, described cell cycle inhibitor is the taxane that has as shown in the formula (C1):

Wherein the part that Lycoperdon polymorphum Vitt is outstanding is can be substituted, and Tu Chu part is not the taxane core.Wish to exist side chain (among the figure " A " of labelling) so that chemical compound has good activity as cell cycle inhibitor.Examples for compounds with this structure comprises paclitaxel (Merck index entry 7117); docetaxel (taxotere, Merck index entry 3458) and 3 '-go phenyl-3 '-(4-nitrobenzophenone)-N-to remove benzoyl-N-(uncle-butoxy carbonyl)-10-deacetylate paclitaxel.

On the one hand, suitable taxanes such as paclitaxel and its analog and derivant are disclosed in U.S. Patent number 5,440,056, and it has structure (C2):

Wherein X can be oxygen (paclitaxel), hydrogen (9-deoxidation derivative), sulfo-acyl group (thioacyl) 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; R ₉Be selected from hydrogen, alkanoyl, the alkanoyl of replacement, and aminoalkanoyl radical; Wherein substituent group is meant hydroxyl, sulfydryl, allalkoxyl, carboxyl, halogen, thio alkoxy, N, the N-dimethylamino, alkyl amino, dialkyl amido, nitro and-OSO ₃H, and/or can be meant and contain these substituent groups; R ₂Be selected from hydrogen or oxy radical, as hydrogen, hydroxyl, alkoyl, alkanoyl oxygen base, aminoalkanoyl radical oxygen base and peptidyl alkanoyl oxygen base, R ₃Be selected from hydrogen or oxy radical, as hydrogen, hydroxyl, alkoyl, alkanoyl oxygen base, aminoalkanoyl radical oxygen base and peptidyl alkanoyl oxygen base can be to contain silyl-group or sulfur-containing group 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, as hydrogen, hydroxyl alkoyl, alkanoyl oxygen base, aminoalkanoyl radical oxygen base and peptidyl alkanoyl oxygen base.

On the one hand, open in pct international patent application WO 93/10076 as effective paclitaxel analogs of cell cycle inhibitor and derivant in the present invention.As open in this publication, 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.

Openly taxane can be in the replacement of any position except the methyl that exists for WO 93/10076.Substituent group can comprise for example hydrogen, alkanoyl oxygen base, alkenoyl oxygen base, aroyl oxygen base.In addition, oxo group can with labelling 2,4,9, and/or 10 carbon connects.Equally, the oxetanes ring can be connected to carbon atom 4 and 5.In addition, oxirane can be connected to the carbon of labelling 4.

On the one hand, in the present invention effectively based on the cell cycle inhibitor of taxane at United States Patent (USP) 5,440, open in 056, its open 9-deoxidation taxanes.These are chemical compounds that the carbon place of labelling 9 lacks the oxygen base in the taxane structure (formula C4) shown in above.Taxane-ring can be replaced by H, OH, O-R or O-CO-R at the carbon place (independently) of labelling 1,7 and 10, and wherein R is alkyl or aminoalkyl.In addition, it can be at the carbon place (independently) of labelling 2 and 4 by aryol, alkanoyl, and aminoalkanoyl radical or alkyl replace.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 replace with alkanoyl H or replacement or unsubstituted.

Usually taxanes, particularly paclitaxel are considered to by as anti-microtubule agent with more specifically play cell cycle inhibitor as stabilizing agent.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.

On the other hand; anti-microtubule agent (microtubule inhibitor) be 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.

On the other hand, cell cycle inhibitor is a catharanthus alkaloid.Catharanthus alkaloid has following universal architecture.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.Other substituent group comprises that wherein methyl is replaced with unsaturated ring can be by adding side group such as alkyl, thiazolinyl, alkynyl, halogen, ester group, amide groups or amino by the molecule of derivatization thus by other alkyl.

Typical catharanthus alkaloid is a vinblastine, vincristine, and vincristine sulfate, vindesine and vinorelbine, 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 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.

On the other hand, cell cycle inhibitor is a camptothecine, or its analog or derivant.Camptothecine has following formula:

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 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 alkanes of these groups.R ₃H or short-chain alkyl such as C typically 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.Exemplary chemical 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 effectively as cell cycle inhibitor, and wherein they can play topoisomerase I inhibitor and/or dna cleavage agent.They have shown and have been effective to treat proliferative disease, for example comprise NSC pulmonary carcinoma, small cell lung cancer, and cervical cancer.

On the other hand, cell cycle inhibitor is a 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 lurtotecan dihydrochloride (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)-).

On the other hand, cell cycle inhibitor is an anthracycline.Anthracycline has following universal architecture, 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 independently, NO ₂, NH ₂, F, Cl, Br, I, CN, H or be derived from one of these group; R _5-7All be 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 the coupling 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 with group such as aryl, the saturated or fractional saturation 5 or the 6 yuan of heterocycles that contain at least one nuclear nitrogen form secondary amine (referring to United States Patent (USP) 5,843,903).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 _3-4The alkylidene that constitutes.R ₁₂Can be H, alkyl, aminoalkyl, amino, hydroxyl, sulfydryl, phenyl, benzyl or methyl mercapto (referring to United States Patent (USP) 4,296,105).

Typical anthracycline is a 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 an anthracycline, mitoxantrone, menogaril, nogalamycin, Aclacnomycin A, Olivomycin A, chromomycin A ₃, and 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; The island cell carcinoma; And bladder cancer; And soft tissue sarcoma.

On the other hand, cell cycle inhibitor is a platinum compounds.Usually, platinum complex can be Pt (II) or Pt (IV), and has this basic structure:

Wherein X and Y are the anion leaving groups, as sulfate radical, and phosphate radical, carboxylate radical, and halogen; R ₁And R ₂Be alkyl, amine, aminoalkyl, and can further being replaced is inertia or bridging group basically.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.Referring to for example United States Patent (USP) 4,588,831 and 4,250,189.

Suitable platinum complex can comprise a plurality of Pt atoms.Referring to for example 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 a cisplatin, carboplatin, and oxaliplatin and rice platinum, it has following array structure:

The cisplatin carboplatin

These chemical compounds are considered to for example as the alkylating agent of DNA, play cell cycle inhibitor by combining with DNA.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.

On the other hand, cell cycle inhibitor is a nitroso ureas.Nitroso ureas has following universal architecture (C5), and wherein the typical R group shows below.

The R group:

Other suitable R group comprises cycloalkane, alkane, the group that halogen replaces, sugar, aryl and heteroaryl, phosphono and sulfonyl.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, and cyclohexyl, or by 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 saturated 5 or 6 yuan of heterocycles such as pyrrolidine together, piperidines, morpholine, thiomorpholine, N-low alkyl group piperazine, wherein heterocycle can randomly replace with 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.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 described, and the R of formula (C5) can be the alkyl of 2-6 carbon atom and can use ester, sulfonyl, or hydroxyl replaces.It can also be with carboxylic acid or CONH ₂Group replaces.

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

These nitroso-urea compounds are considered to by combining with DNA, promptly by playing cell cycle inhibitor 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, the island cell carcinoma; Small cell lung cancer; Melanoma; And the brain cancer.

On the other hand, cell cycle inhibitor is the nitre imidazoles, and wherein typical nitre imidazoles is a metronidazole, benznidazole, and etanidazole, and misonidazole, it has following array structure:

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.

On the other hand, 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 universal architecture:

The identity of R group can be selected from organic group, particularly at United States Patent (USP) 5,166, and those groups of illustrating in 149 and 5,382,582.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 hydroxyl.R ₇Be the side chain of following universal architecture:

Wherein for methotrexate n=1, for Pteropterin n=3.Can be with the 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 e 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) H

Trimetrexate 3 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 HO CH ₃H

bond

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.

On the other hand, cell cycle inhibitor is a cytidine analog, as cytosine arabinoside or derivatives thereof or analog, it comprises 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 1e H F F CH

Azacitidine H H OH N

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 for example comprises, cancer of pancreas, breast carcinoma, cervical cancer, NSC pulmonary carcinoma, and cancer of biliary duct.

On the other hand, cell cycle inhibitor is a pyrimidine analogue.On the one hand, pyrimidine analogue has following universal architecture:

Wherein 2 ', 3 ' and 5 ' of sugared ring (difference R ₂, R ₃And R ₄) can be H, hydroxyl, phosphoryl (referring to for example United States Patent (USP) 4,086,417) or ester (referring to for example United States Patent (USP) 3,894,000).Ester can be an 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 replace with halogen such as fluorine or difluoro cytidine such as gemcitabine.Alternatively, sugar can be another heterocyclic group such as furyl or alkane, alkyl ether or connection alkane such as C (O) NH (CH ₂) ₅CH ₃Amide replace.2 ° of amine can be used the aliphatic acyl (R that is connected with amide ₁) (referring to for example United States Patent (USP) 3,991,045) or the replacement of urethane (referring to for example 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 (referring to for example 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, open in 000 (referring to for example 2 '-O-palmityl-arabinose (ara)-cytidine, 3 '-O-benzoyl-arabinose-cytidine and more than other example of 10); United States Patent (USP) 3,991,045 (referring to for example N4-acyl group-1-β-D-arabinofuranosyl adenin cytosine, and the multiple acyl derivative of wherein listing, as the palmityl derivant).

On the other hand, cell cycle inhibitor is the fluoro-pyrimidine analogue.As 5-fluorouracil, or its analog or derivant, it comprises 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, it comprises idoxuridine (5-IudR), 5-bromouracil deoxyribose (5-BudR), a 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, island cell carcinoma, carcinoma of penis, and carcinoma vulvae.

On the other hand, cell cycle inhibitor is a purine analogue.Purine analogue has following universal architecture:

X carbon typically wherein; R ₁Be H, halogen, the phenyl of amine or replacement; R ₂Be H, the primary, the second month in a season or tertiary amine, sulfur-containing group, typically-and SH, alkane, or cycloalkane, heterocycle or sugar; R ₃Be H, sugar (typically furanose or pyranose structure), the sugar of replacement or ring-type or heterocycle alkane or aryl.For the chemical compound of the type referring to for example 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) 5,446,139 describe the suitable purine analogue of the type, and it shows in following formula:

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

On the other hand, cell cycle inhibitor is a chlormethine.Many suitable chlormethine are known and suitably are used as cell cycle inhibitor in the present invention.Suitable chlormethine is also referred to as cyclophosphamide.

Preferred chlormethine has following universal architecture:

Wherein A is:

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

The example of suitable chlormethine is at United States Patent (USP) 3,808, and open in 297, 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.Referring to for example 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:

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

R ₁ R ₂ R ₃

Cyclophosphamide H CH ₂CH ₂CI H

Ifosfamide CH ₂CI H H

Perfosfamide CH ₂CI H OOH

Torofosfamide CH ₂CI CH ₂CH ₂CI H

Chlormethine can be an 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 a 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

CH ₂COOH H H

Chlorambucil COOH NH ₂H

Melphalan H forms phenyl ring together

Chlormaphazin

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.Hydroxyurea has following universal architecture:

Suitable hydroxyl urea is for example disclosing in the United States Patent (USP) 6,080,874, wherein R ₁Be:

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

Other suitable hydroxyl urea is for example disclosing in the United States Patent (USP) 5,665,768, wherein R ₁Be cycloalkenyl group, N-(3-(5-(4-fluorobenzene sulfenyl)-furyl)-2-ring penta-1-yl) N-hydroxyl urea 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 urea is for example disclosing in the United States Patent (USP) 4,299,778, wherein R ₁It is the phenyl that replaces with one or more fluorine atoms; R ₂It is cyclopropyl; R ₃With X be H.

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

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

On the one hand, the hydroxyl urea has following array structure:

The hydroxyl urea

The hydroxyl urea is considered to by being used for suppressing the effect that DNA has synthesized cell cycle inhibitor.

On the other hand, cell cycle inhibitor is mitomycin (mytomicin), as ametycin, or its analog or derivant, 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, and described cell proliferation disorders is as for example esophageal carcinoma, hepatocarcinoma, bladder cancer, and breast carcinoma.

On the other hand, 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.

On the other hand, cell cycle inhibitor is a Benzoylamide.Also having on the other hand, 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 hydroxylated alkane such as the OCH that H or ether connect ₂CH ₂OH, 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 (referring to for example United States Patent (USP) 4,258,052); R ₂Be H, OR ₆, SR ₆Or NHR ₆, R wherein ₆It is alkyl; R ₃Be H, the low alkyl group that low alkyl group, ether connect as-O-Me or-O-ethyl (referring to for example 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, in 738 open (enumerating about 32 kinds of chemical compounds).

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, and is open in 738,

On the other hand, 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

On the other hand, described cell cycle inhibitor is a diazonium compound, such as azaserine, or its analog or derivant, comprise 6-diazonium-5-oxo-1-nor-leucine and 5-diazouracil (also being pyrimidine analogue).Exemplary chemical 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 pazelliptine as other chemical compound according to cell cycle inhibitor of the present invention; Wortmannin; Metoclopramide; RSU; Buthionine sulfoxime; Rhizoma Curcumae Longae; Curcumin; AG337, a kind of thymidylate synthase inhibitor; Levamisole; Lentinan, a kind of polysaccharide; Razoxane, a kind of EDTA analog; Indomethacin; Chlorpromazine; α and interferon-; MnBOPP; Gadolinium texaphrin; 4-amino-1,8-naphthylenediamine (naphthalimide); The staurosporine derivatives of CGP; And SR-2508.

Therefore, on the one hand, described cell cycle inhibitor is the DNA alkylating agent.On the other hand, described cell cycle inhibitor is anti-microtubule agent.On the other hand, described cell cycle inhibitor is a topoisomerase enzyme inhibitor.On the other hand, described cell cycle inhibitor is the dna cleavage agent.On the other hand, described cell cycle inhibitor is a kind of antimetabolite. on the other hand, described cell cycle inhibitor is by suppressing ADA Adenosine deaminase performance function (for example, as purine analogue).On the other hand, described cell cycle inhibitor is synthetic and/or as nucleotide interconversion inhibitor performance function (for example, as purine analogue such as purinethol) by suppressing purine ring.On the other hand, described cell cycle inhibitor is by suppressing dihydrofolate reduction and/or bringing into play function (for example, methotrexate) as breast adenosine monophosphate blocking-up thing.On the other hand, described cell cycle inhibitor is brought into play function (for example, bleomycin) by causing DNA damage.On the other hand, described cell cycle inhibitor is by bringing into play function (doxorubicin for example, aklavine as the synthetic inhibitory action of DNA intercalating agent and/or RNA, or detorubicin (acetic acid, diethoxy-, 2-[4-[(3-amino-2,3,6-three deoxies-α-1-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)-)).On the other hand, described cell cycle inhibitor synthesizes and brings into play function (for example, N-phosphono acetyl group-1-aspartate (ester)) by suppressing pyrimidine.On the other hand, described cell cycle inhibitor is brought into play function (for example, hydroxyurea) by suppressing ribonucleotide.On the other hand, described cell cycle inhibitor is brought into play function (for example, 5-fluorouracil) by suppressing thymidine 5'-monophosphate.On the other hand, described cell cycle inhibitor synthesizes and brings into play function (for example, cytosine arabinoside) by suppressing DNA.On the other hand, described cell cycle inhibitor is brought into play function (for example, platinum compounds) by the formation that causes dna adduct.On the other hand, described cell cycle inhibitor synthesizes by Profilin matter and brings into play function (for example, altheine enzyme).On the other hand, described cell cycle inhibitor is brought into play function (for example, taxanes) by suppressing the microtubule function.On the other hand, the one or more steps of described cell cycle inhibitor in the biological pathway that Fig. 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 Diseases in Goodman andGilman ' s The Pharmacological Basis of Therapeutics the 9th edition, McGraw-HillHealth Professions 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, cell cycle inhibitor is a 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, 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; lantrunculin D; actinomycin D, Ro-31-7453 (3-(6-nitro-1-methyl-3-indyl)-4-(1-methyl-3-indyl) pyrroles-2,5-diketone); PNU-151807; brostallicin, 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)), and doxorubicin (5,12-aphthacene diketone; 10-((3-amino-2; 3,6-three deoxies-α-1-lysol-hexose pyrans glycosyl) the 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-1-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-, a hydrochlorate); nitacrine (1; the 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; the 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) (the third two are closed (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-1-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)-and hybar X, 5-fluoro-1-(tetrahydrochysene-2-furyl)-), razoxane (2; the 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, (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-), and pirarubicin (piraubicin) (5,12-aphthacene diketone; 10-((3-amino-2; 3,6-three deoxidations-4-O-(tetrahydrochysene-2H-pyrans-2-yl)-α-1-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-1-lysol-hexose pyranose) oxygen base)-the 2-naphthacenyl)-2-oxo ethyl ester (2S-is suitable)-); trofosfamide (3-2-(chloroethyl)-2-(two (2-chloroethyl) amino) tetrahydrochysene-2H-1,3,2-oxygen azepine phosphorus (phosphorin) 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-1-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 kinases inhibitor of cyclin dependant

In another embodiment, pharmaceutically active compound is kinases inhibitor (for example, the R-roscovitine of cyclin dependant, 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, and 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, AZD-5438, ZK-CDK or its analog or derivant).

6. EGF (epidermal growth factor) receptor kinase inhibitor

In another embodiment, pharmaceutically active compound be EGF (epidermal growth factor) inhibitors of kinases (for example, erlotinib (4-quinazoline amine, N-(3-ethynyl phenyl)-6,7-two (2-methoxy ethoxy)-, one hydrochlorate), erbstatin (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. Elastase inhibitor

In another embodiment; pharmaceutically active compound be elastase inhibitor (for example; 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) sulfo-)-); MDL-100948A; MDL-104238 (N-(4-(4-morpholinyl carbonyl) benzoyl)-1-valyl-N '-(3; 3; 4; 4; 4-five fluoro-1-(1-Methylethyl)-2-oxo butyl)-1-2-azetamide); MDL-27324 (L-prolineamide (Prolinamide); N-((5-(dimethylamino)-1-naphthyl) sulfonyl)-1-alanyl-1-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-1-lysyl-1-prolyl-1-valinal); Ro-31-3537 (N α-(1-diamantane (obsolete) sulfonyl)-N-(4-carboxylbenzoyl)-1-lysyl-alanyl-1-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-thiophene-1-azabicyclo [4.2.0] oct-2-ene-2-yl) carbonyl)-, S, 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-thiophene (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]-1-is valyl-N-[3, and 3,3-three fluoro-1-(1-Methylethyl)-2-oxopropyl]-, a sodium salt), Roche R-665, or its analog or derivant).

8. The Xa factor inhibitor

In another embodiment, pharmaceutically active compound be the Xa factor inhibitor (for example, 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-1-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; pharmaceutically active compound be the Farnesyltransferase inhibitor (for example; dichloro benzoprim (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))-1-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)-and the pyridin-3-yl methyl amine, J-104126, L-639749, L-731734 (the 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))-, UCF-116-B, (the 3H-oxireme is (oxireno) [8,8a] azulenes [4,5-b] furan-8 (4aH)-ketone also also for ARGLABIN, 5,6,6a, 7,9a, 9b-six hydrogen-1,4a-dimethyl-7-methylene-, (3aR, 4aS, 6aS, 9aS, 9bR)-), it is from ARGLABIN-Paracure, Inc. (Virginia Beach, VA), or its analog or derivant).

10. The fibrinogen antagonist

In another embodiment, pharmaceutically active compound is fibrinogen antagonist (for example, 2 (S)-((p-toluenesulfonyl) amino)-3-(((5; 6,7,8-tetrahydrochysene-4-oxo-5-(2-(piperidin-4-yl) ethyl-4H-pyrazolo (pyrazolo)-(1; 5-a) (1,4) diaza

-2-yl) carbonyl)-and amino) propanoic acid, streptokinase (kinases (activation-enzyme), strepto--), urokinase (kinases (activation-enzyme), urine-), activator of plasminogen, pamiteplase, Monteplase, heberkinase, anistreplase, alteplase, preceding-urokinase, picotamide (1,3-benzenedicarboxamide, 4-methoxyl group-N, N '-two (3-pyridylmethyl)-), or its analog or derivant).

11. The guanylate cyclase stimulus object

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

12. The heat shock protein 90 antagonist

In another embodiment, described pharmaceutically active compound is heat shock protein 90 antagonist (for example a, 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, described pharmaceutically active compound is HMGCoA reductase inhibitor (for example, BCP-671, BB-476, fluvastatin (6-heptenoic acid, 7-(3-(4-fluorophenyl)-1-(1-Methylethyl)-1H-indole-2-yl)-3, the 5-dihydroxy-, a 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-xenyl-, 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, and Pitavastatin (the 6-heptenoic acid, 7-(2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl)-3, the 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]-mistake 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 ^*), 8a β))-), HBS-107, the 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 ^*), 8a 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 ^*), 8a β))-), or its analog or derivant).

14. The hydroorotic acid dehydrogenase inhibitor

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

15. The IKK2 inhibitor

In another embodiment, described pharmaceutically active compound is IKK2 inhibitor (for example, MLN-120B, SPC-839, or its analog or derivant).

16. IL-1, ICE and IRAK antagonist

In another embodiment; described pharmaceutically active compound is IL-1; ICE or IRAK antagonist are (for example; E-5090 (2-propanoic acid; 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 (chromen)-7-yl) Methanesulfomide), AV94-88, (the 6H-pyridazine is (Pyridazino) (1 also for pralnacasan; 2-a) (1,2) diaza

-1-Methanamide; N-((2R, 3S)-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)-the 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 (thiacyclohexane 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)-1-valyl-N-((1S)-3-((2; 6-dichloro-benzoyl base) oxygen base)-1-(2-ethyoxyl-2-oxoethyl)-2-oxopropyl)-); L-709049 (the L-aminopropanamide, N-acetyl group-1-tyrosyl-1-valyl-N-(2-carboxyl-1-formyl ethyl)-, (S)-); TA-383 (1H-imidazoles); 2-(4-chlorphenyl)-4,5-dihydro-4, the 5-xenyl-; monohydrochloride; cis-), EI-1507-1 (6a, 12a-epoxy benzene (a) anthracene)-1; 12 (2H; 7H)-and diketone, 3,4-dihydro-3; 7-dihydroxy-8-methoxyl group-3-methyl-); ethyl 4-(3, the 4-Dimethoxyphenyl)-6,7-dimethoxy-2-(1; 2; 4-triazol-1-yl methyl) quinoline-3-carboxylation's (ester), EI-1941-1, TJ-114; Antril (Synergen) (interleukin 1 receptor antagonist (x is reductive for people's isoform); the N2-1-methionyl-)), IX-207-887 (acetic acid, (10-methoxyl group-4H-benzo [4; 5] encircle heptan [1; 2-b] inferior thiophene-4-yl)-), K-832, or its analog or derivant).

17. The IL-4 agonist

In another embodiment, pharmaceutically active compound is IL-4 agonist (for example, acetic acid glatiramer (glatiramir) (L-glutamic acid is with the polymer of L-alanine, L-lysine and L-tyrosine, acetate)), or its analog or derivant).

18. Immunomodulator

In another embodiment; pharmaceutically active compound is 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; NPC15669 (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)-1-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), argyrin B ((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 immunoglobulin G 1 (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-base 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 its 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 can see following PCT publication number: WO97/10502, WO96/41807, WO96/35423, WO96/03430, WO96/00282, WO95/16691, WO95/15328, WO95/07468, WO95/04738, WO95/04060, WO94/25022, WO94/21644, WO94/18207, WO94/10843, WO94/09010, WO94/04540, WO94/02485, WO94/02137, WO94/02136, WO93/25533, WO93/18043, WO93/13663, WO93/11130, WO93/10122, WO93/04680, WO92/14737, and WO92/05179.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.

Sirolimus is provided below, everolimus, the structure of tacrolimus:

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

Everolimus

Tacrolimus

Sirolimus

The analog of other sirolimus and derivant comprise tacrolimus and its 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, WO96/41807, WO 96/35423, and WO 96/03430, and WO 96/00282, WO 95/16691, WO95/15328, and WO 95/07468, WO 95/04738, and WO 95/04060, and WO 94/25022, WO94/21644, WO 94/18207, and WO 94/10843, and WO 94/09010, WO 94/04540, WO94/02485, WO 94/02137, and WO 94/02136, WO 93/25533, WO 93/18043, WO93/13663, and 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.

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

19. Inosine monophosphate dehydrogenase inhibitor

In another embodiment, pharmaceutically active compound be inosine monophosphate dehydrogenase (IMPDH) inhibitor (for example, Mycophenolic Acid, (4-is olefin(e) acid, and 6-(1 for mycophenolate mofetil, 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 (4-thiazole carboxamides, 2-β-D-ribofuranosyl-), viramidine, amino thiadiazoles, thiophenfurin, the thiophene furan is held up woods), or its analog or derivant.Other representative example is included in 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, US publication 2002/0040022A1,2002/0052513A1,2002/0055483A1,2002/0068346A1,2002/0111378A1,2002/0111495A1,2002/0123520A1,2002/0143176A1,2002/0147160A1,2002/0161038A1,2002/0173491A1,2002/0183315A1,2002/0193612A1,2003/0027845A1,2003/0068302A1,2003/0105073A1,2003/0130254A1,2003/0143197A1,2003/0144300A1,2003/0166201A1,2003/0181497A1,2003/0186974A1,2003/0186989A1,2003/0195202A1, with PCT publication number WO00/24725A1, WO 00/25780A1, WO 00/26197A1, WO 00/51615A1, WO00/56331A1, WO 00/73288A1, WO 01/00622A1, WO 01/66706A1, WO01/79246A2, WO 01/81340A2, WO 01/85952A2, WO 02/16382A1, WO02/18369A2, WO 02/51814A1, WO 02/57287A2, WO 02/57425A2, WO02/60875A1, WO 02/60896A1, WO 02/60898A1, WO 02/68058A2, WO03/20298A1, WO 03/37349A1, WO 03/39548A1, WO 03/45901A2, WO03/47512A2, WO 03/53958A1, WO 03/55447A2, WO 03/59269A2, WO03/63573A2, WO 03/87071A1, WO 90/01545A1, WO 97/40028A1, WO97/41211A1 is among WO 98/40381A1 and the WO 99/55663A1).

20. Leukotriene inhibitors

In another embodiment; pharmaceutically active compound be leukotriene inhibitors (for example; ONO-4057 (benzenpropanoic acid; 2-(4-carboxyl butoxy)-6-((6-(4-methoxyphenyl)-5-vinyl) 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 arachidonyl fluorophosphonate); 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-vinyl) 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, described pharmaceutically active compound be the MCP-1 antagonist (for example, nitro naproxen (2-naphthalene 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 ₃, or its analog or derivant).

22. The MMP inhibitor

In another embodiment, described pharmaceutically active compound is matrix metalloproteinase (MMP) inhibitor (for example, 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)-); Marimastat (N-(2,2-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)-1-leucyl-N, the 3-dimethyl-); PS-508; CH-715, nimesulide (the 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 '-xenyl)-5-(N-(4-Nitrobenzol) piperazinyl barbituric acid, 6-methoxyl group-1,2; 3; 4-tetrahydrochysene-norharman-1-carboxylic acid, Ro-31-4724 (the L-alanine, N-(2-(2-(hydroxyl amino)-2-oxoethyl)-4-methyl isophthalic acid-oxo amyl group)-1-leucyl-; ethyl ester); the prinomastat (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 '-xenyl)-4-yl)-b-((((3S)-tetrahydrochysene-4,4-dimethyl-2-oxo-3-furyl) amino) carbonyl)-; 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)-1-(2-((((4,5-dihydro-5-sulfo--1; 3; 4-thiadiazoles-2-yl) amino)-and carbonyl) amino)-1-oxo-3-(pentafluorophenyl group) propyl group)-4-(2-pyrimidine radicals) piperazine, and 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 ' xenyl)-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).Other representative example is included in 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, in 359.

23. The NF kB inhibitor

In another embodiment, described pharmaceutically active compound be NF κ B (NFKB) inhibitor (for example, 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 antagonist

In another embodiment, described pharmaceutically active compound be the NO antagonist (for example, NCX-4016 (benzoic acid, 2-(acetyl group oxygen base)-, 3-((nitrooxy methyl) phenylester), NCX-2216, L-arginine, or its analog or derivant).

25. The P38 map kinase inhibitor

In another embodiment, described pharmaceutically active compound P38 map kinase inhibitor (for example, GW-2286; 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-(methyl sulfinyl) phenyl]-the 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).Other representative example is included in 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, US publication 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, WO01/74811A2, WO 02/18379A2, WO 02/064594A2, WO 02/083622A2, WO02/094842A2, WO 02/096426A1, WO 02/101015A2, WO 02/103000A2, WO03/008413A1, WO 03/016248A2, WO 03/020715A1, WO 03/024899A2, WO03/031431A1, WO 03/040103A1, WO 03/053940A1, WO 03/053941A2, WO03/063799A2, WO 03/079986A2, WO 03/080024A2, WO 03/082287A1, WO97/44467A1 is among WO 99/01449A1 and the WO 99/58523A1.

26. Phosphodiesterase inhibitor

In another embodiment; described pharmaceutically active compound be phosphodiesterase inhibitor (for example; CDP-840 (pyridine; 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-); ((N-(2 for 8-methoxy quinoline-5-for D-4418; 5-dichloropyridine-3-yl)) 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(2,6-two chloro-4-pyridine radicals) ethyl ketone oxime Methanamide); 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), grey chain bacterium acid (α-1-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-(the 5-oxo is base)-7-propyl group-), and sildenafil citrate (piperazine, ((3-(4 for 1-; 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 salt (ester)-(1:1)); (also (1 ', 2 ': 1,6) pyrido (3 for pyrazine for tadalafil; 4-b) indole 1; the 4-diketone, 6-(1,3-benzo dioxole-5-yl)-2; 3; 6,7,12; 12a-six hydrogen-2-methyl-; (6R-is trans)), and Vardenafil (piperazine, (3-(1 for 1-; 4-dihydro-5-methyl (4-oxo-7-propyl imidazole also (5; 1-f) (1,2,4)-triazine-2-yl)-and 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; the 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; the 6-dioxo; have trans-4-(((2-amino-3,5-dibromo phenyl) methyl) amino) ring chemical compound of alcohol (1:1)), 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-imidazo (1; 2-a) pyridine-6-base-6-methyl-2-oxo-; monohydrochloride-), 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, the 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-auinoline carboxylic 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, 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, pharmaceutically active compound is TGF beta inhibitor (for example, Man-6-P, LF-984, tamoxifen (acetamide, 2-(4-(1,2-diphenyl-1-butylene base) phenoxy group)-N, the N-dimethyl-, (Z)-), tranilast, or its analog or derivant).

28. The TXA2. antagonist

In another embodiment, pharmaceutically active compound is TXA2. antagonist (for example, a 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) amyl group amino sulfonyl)))-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/tace inhibitor

In another embodiment; pharmaceutically active compound be TNFa antagonist or tace inhibitor (for example; 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-imidazo (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)-1-3-(2 '-naphthyl) alanyl-1-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) thiacyclohexane-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 (1-235-Tumor Necrosis Factor Receptors (people) fusion rotein) with 236-467-immunoglobulin G 1 (people γ 1-chain Fc fragment); diacerein (2-anthracene carboxylic acid; 4,5-two (acetoxyl group)-9,10-dihydro-9; the 10-dioxo-, or its analog or derivant).

30. Tyrosine kinase inhibitor

In another embodiment, pharmaceutically active compound be tyrosine kinase inhibitor (for example, 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-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; described pharmaceutically active compound be vitronectin inhibitor (for example; 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. The long factor inhibitors of fibroblast cattle

In another embodiment, described pharmaceutically active compound be fibroblast growth factor inhibitor (for example, 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, described pharmaceutically active compound is kinases inhibitor (for example, KP-0201448, NPC15437 (amide, 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, 9H-two indole (1,2; 3-gh:3 ', 2 ', 1 '-Im) pyrrolo-(3,4-j) (1; 7) benzo two azonines-11-yl)-and the N-methyl-, (9 α, 10 β, 11 β; 13 α)-), fasudil (1H-1,4-diaza

Six hydrogen-1-(5-isoquinolyl sulfonyl)-), and dexniguldipine (3, the 5-dipicolinic acid, 1,4-dihydro-2,6-dimethyl-4-(3-nitrobenzophenone)-, 3-(4,4-xenyl-piperidino) propyl group methyl ester, a hydrochlorate, (R)-), LY-317615 (1H-pyrroles-2,5-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-5,21:12,17-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, described pharmaceutically active compound is pdgf receptor kinase inhibitor (for example, RPR-127963E, or its analog or derivant).

35. Endothelial growth factor receptor kinase inhibitor

In another embodiment, described pharmaceutically active compound is endothelial growth factor receptor kinase inhibitor (for example, CEP-7055, SU-0879 ((E)-3-(3,5-two-tert-butyl-4-hydroxy phenyl)-and 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, described pharmaceutically active compound 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, pharmaceutically active compound be platelet-derived growth factor receptor kinase inhibitor (for example, leflunomide (the 4-Isoxazolecarboxamidederivatives, 5-methyl-N-(4-(trifluoromethyl) phenyl)-, or its analog or derivant).

38. The Fibronogin antagonist

In another embodiment, described pharmaceutically active compound 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, described pharmaceutically active compound be antifungal (for example, miconazole, 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)-), biphenyl card azoles (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, described pharmaceutically active compound is diphosphate (for example a, 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, described pharmaceutically active compound be the E.C. 3.1.1.32 inhibitor (for example, 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; described pharmaceutically active compound be histamine H 1/H2/H3 receptor antagonist (for example; 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 antibiotic

In another embodiment; described pharmaceutically active compound be macrolide antibiotic (for example; 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-1-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; the pyrans glycosyl (hexopyranosyl) of 6-dideoxy-3-C-methyl-3-O-methyl-α-1-ribose-) 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; described pharmaceutically active compound be GPIIb IIIa receptor antagonist (for example; 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)-1-lysyl glycyl-1-α-aspartoyl-1-tryptophanyl-1-prolyl-; cyclic (1-〉6)-disulphide); xemilofiban hydrochloride, or its analog or derivant).

45. Endothelin-receptor antagonists

In another embodiment, described pharmaceutically active compound be endothelin-receptor antagonists (for example, 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; described pharmaceutically active compound be peroxisome Proliferators activated receptor agonist (for example; 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).

On the one hand, pharmaceutically active compound is the peroxisome Proliferator-activated receptor alfa agonists, as GW-590735, GSK-677954, GSK501516, pioglitazone hydrochloride (2, the 4-thiazolidinedione, 5-[[4-[2-(5-ethyl-2-pyridine radicals) ethyoxyl] phenyl] methyl]-, a hydrochlorate (+/-)-, perhaps its analog or derivant).

47. Estrogen receptor reagent

In another embodiment, described pharmaceutically active compound is estrogen receptor reagent (for example, estradiol, a 17-, or its analog or derivant).

48. Somatostatin analogs

In another embodiment, described pharmaceutically active compound is somatostatin or somatostatin analogs (for example, angiopeptin (angiopeptin), or its analog or derivant).

49. Neurokinin 1 antagonist

In another embodiment; described pharmaceutically active compound be neurokinin 1 antagonist (for example; 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, described pharmaceutically active compound 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, described pharmaceutically active compound be neurokinin (for example, 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, described pharmaceutically active compound is VLA-4 antagonist (for example, GSK683699, or its analog or derivant).

53. The osteoclast inhibitor

In another embodiment, described pharmaceutically active compound is osteoclast inhibitor (for example, ibandronic acid (phosphonic acids, [1-hydroxyl-3-(methyl amyl amino) propylidene] two-), an Alendronate sodium, or its analog or derivant).

54. DNA topoisomerase ATP hydrolysis inhibitor

In another embodiment; described pharmaceutically active compound be DNA topoisomerase ATP hydrolysis inhibitor (for example; 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)-), and pirarubicin (5,12-aphthacene diketone; 10-[[3-amino-2; 3,6-three deoxidations-4-O-(tetrahydrochysene-2H-pyrans-2-yl)-α-1-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, described pharmaceutically active compound be hypertensin I conversion enzyme inhibitor (for example, 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; described pharmaceutically active compound be angiotension II antagonists (for example; 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, described pharmaceutically active compound is enkephalin enzyme inhibitor (for example, Aventis a 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, described pharmaceutically active compound be peroxisome Proliferators activated receptor gamma agonist insulin sensitizer (for example, 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, LY-674, or LSN-862), or its analog or derivant).

59. Inhibitors of protein kinase C

In another embodiment, described pharmaceutically active compound is an 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) oxadiazole ring 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, described pharmaceutically active compound is ROCK (the related kinases of a 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, described pharmaceutically active compound is the CXCR3 inhibitor, as T-487, and T0906487 or its analog or derivant.

62. The Itk inhibitor

In another embodiment, described pharmaceutically active compound is the Itk inhibitor, as BMS-509744 or its analog or derivant.

63. CPLA2 A ₂ -alpha inhibitor

In another embodiment, described pharmaceutically active compound is cPLA2 A ₂-alpha inhibitor is as efipladib (PLA-902) or its analog or derivant.

64. The PPAR agonist

In another embodiment, described pharmaceutically active compound is PPAR antagonist (for example, Metabolex ((-)-phenylacetic acid, 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 (2,4-thiazolidinedione, 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, described pharmaceutically active compound is immunosuppressant (for example, a 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, described pharmaceutically active compound be the Erb inhibitor (for example, 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, described pharmaceutically active compound is that (for example, CEFLATONIN (CGX-635) is (from Chemgenex Therapeutics 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, described pharmaceutically active compound be the lipocortin agonist (for example, 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, described pharmaceutically active compound is VCAM-1 antagonist (for example, DW-908e, or its analog or derivant).

70. Collagen antagonist

In another embodiment, described pharmaceutically active compound be collagen antagonist (for example, 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, described pharmaceutically active compound is α 2 integrin antagonisies (for example, E-7820, or its analog or derivant).

72. The TNF alpha inhibitor

In another embodiment, described pharmaceutically active compound 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, described pharmaceutically active compound is nitric oxide inhibitor (for example, guanidine (guanidio) ethyl disulphide, or its analog or derivant).

74. Cathepsin inhibitors

In another embodiment, described pharmaceutically active compound is cathepsin inhibitors (for example, SB-462795 or its analog or a derivant).

Combination treatment

Except mixing the fibre modification inhibitor, one or more forms of pharmacologically active agents can also be mixed this compositions to improve or to strengthen effect.On the one hand, compositions can also comprise in the therapentic part or pathological process on every side have the chemical compound that suppresses effect.The representative example of therapeutic activity agent comprises in addition, by example and be not limited to, antithrombotic agents, antiproliferative, antiinflammatory, tumor medicament, enzyme, receptor antagonist or agonist, hormone, antibiotic, antimicrobial, antibody, cytokine inhibitor, IMPDH (inosine monophosphate dehydrogenase) inhibitor, tyrosine kinase inhibitor, MMP inhibitor, p38MAP inhibitors of kinases, immunosuppressant, programmed cell death antagonist, Caspase (caspase) inhibitor, and jnk inhibitor.

On the one hand, the present invention also provides the combination (and compositions and method of making implantable pump and sensor device) of implantable pump or implantable sensor device, and it comprises that anti-fiber forms agent and anti-infective, and it has reduced possibility of infection.

Infection is the common complication that the foreign body of for example medical apparatus is implanted.Foreign material provides microorganic adhesion and has built group's desired site.Also suppose in the microenvironment around the foreign material, the host defense that infects to be suffered damage.These factors make medical implant to infect especially responsive and in most cases (if not can not) be difficult to eliminate this infection.

The invention provides medicament (for example, chemotherapeutant), it can discharge from compositions, and has effective antimicrobial acivity under very low dose.Multiple anti-infective can be united use with the present composition.Can easily measure suitable anti-infective based on the algoscopy that provides among the embodiment 52.What discuss in more detail below is the representative example of more operable medicaments: (A) anthracycline (for example, doxorubicin and mitoxantrone), (B) the fluorine pyrimidine is (for example, 5-FU), (C) antifol (for example, methotrexate), (D) podophyllotoxin (for example, etoposide), (E) camptothecine, (F) hydroxyurea and (G) platinum complex (for example, cisplatin).

(A). Anthracyclines

Anthracycline has following universal architecture, 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, C1, 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, this class group of 5 or 6 yuan of heterocycles of containing the saturated or fractional saturation of at least one ring nitrogen.On the other hand, 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 anthracycline 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.Chromatogr.17 (18): 3911-3923 such as Quaglia, 1994), annamycin (Zou etc., J.Pharm.Sci.82 (11): 1151-1154,1993), ruboxyl (Rapoport etc., J.Controlled Release58 (2): 153-162,1999), anthracycline disaccharide doxorubicin analog (Pratesi etc., Clin.Cancer Res.4 (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 ' lAcad.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-1-lysol-hexose pyrans glycosyl)-and α-1-lysol-hexose pyrans glycosyl] adriamicinone doxorubicin disaccharide analog (Monteagudo etc., Carbohydr.Res.300 (1): 11-16,1997), 2-pyrrolin and doxorubicin (Proc.Nat ' lAcad.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.Cancer58 (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.Acta 1118 (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.CancerClin.Oncol.) 20 (7): 919-26,1984), alkylation cyano group morpholinyl doxorubicin derivant (Scudder etc., " National Cancer Institute's magazine " (J.Nat ' lCancer Inst.) 80 (16): 1294-8,1988), deoxidation dihydro iodooxorubicin (EPA 275966), 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.Chemother.16:285-70-285-77,1983), 3 '-deaminizating-3 '-(Horton etc. " antibiotic magazine " (J.Antibiot.) 37 (8): 853-8 for the hydroxyl doxorubicin, 1984), 4-demethoxylation doxorubicin analog (Barbieri 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), (" Japanese pharmacy " be 1468:20 (PharmaJapan) for SM 5887,1995), 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 doxorubicin, 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 " (Tetrahedron) 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., " body in " (InVivo) 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; Hiroshima 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 are chosen as 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 "Journal of Inorganic Biochemistry" (J.Inorg.Biochem.) 56 (4) :249-64, 1994), methyl-D-glucopyranoside mercaptopurine derivatives (Da Silva et al, "European Pharmaceutical Chemistry Journal "(Eur.J.Med.Chem.) 29 (2) :149-52, 1994) and s-alkynyl derivatives mercaptopurine (Ratsino other, Khim.-Farm.Zh.15 (8) :65-7, 1981), containing the indoline ring and a modified Ornithine or glutamic acid methotrexate derivatives (Matsuoka and other "chemical drugs Briefing" (Chem. Pharm.Bull.) 45 (7) :1146-1150, 1997), containing an alkyl-substituted benzene ring C Methotrexate Derivatives (Matsuoka and other "chemical drugs Briefing" (Chem.Pharm.Bull.) 44 (12): 2287-2293,1996) containing benzoxazine or benzothiazine derivatives portion Methotrexate (Matsuoka other "Journal of Medicinal Chemistry" (J.Med.Chem.) 40 (1) :105-111, 1997), 10 - Deaza aminopterin analogues (DeGraw other "Journal of Medicinal Chemistry" (J.Med.Chem.) 40 (3): 370-376,1997), 5 - deaza aminopterin and 5,10 - bis deaza analogs of aminopterin methotrexate (Piper and other "Journal of Medicinal Chemistry" (J.Med.Chem.) 40 (3) :377-384, 1997), containing diethylene Indoline part methotrexate derivatives (Matsuoka et al, "chemical drugs Briefing" (Chem. Pharm.Bull.) 44 (7) :1332-1337, 1996), lipophilic methotrexate derivatives amide (Pignatello and other "drugs and biopharmaceuticals Technology World Conference" (WorldMeet.Pharm., Biopharm.Pharm.Technol.) 563-4,1995), containing L-threo - (2S, 4S) -4 - fluoro-acid And DL-3, 3 - difluoro-glutamic acid methotrexate analogues (Hart other "Journal of Medicinal Chemistry" (J.Med. Chem.) 39 (1) :56-65, 1996), methotrexate tetrahydroquinazoline base analogs (Gangjee, et al, "miscellaneous Chem ring "(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" (Pteridines) 3 (1-2) :131-2, 1992), D-glutamic acid or D-erythrou, threo -4 - fluoro-glutamic acid methotrexate analogues (McGuire and other "students Of chemical and pharmacology "(Biochem.Pharmacol.) 42 (12) :2400-3, 1991), β, γ-methylene Base methotrexate analogues (Rosowsky et al, "pteridine" (Pteridines) 2 (3) :133-9, 1991), 10 - deaza aminopterin (10-EDAM) analogues (Braakhuis et al, "pteridine Biochemistry - pteridine International Seminar class of folic acid derivatives "(Chem.Biol.Pteridines, Proc.Int.Symp. Pteridines Folic Acid Deriv.) ,1027-30, 1989), γ-tetrazole analogs methotrexate (Kalman and other "pteridine Biochemistry - pteridine folic acid derivatives of the International Symposium" (Chem. Biol.Pteridines, Proc.Int.Symp.Pteridines Folic Acid Deriv.) ,1154-7, 1989), N-(L-α-amino acid) methotrexate derivatives (Cheung et al, "heterocyclic" (Heterocycles) 28 (2) :751-8, 1989), aminopterin meta and ortho isomers (Rosowsky et al, "Pharmaceutical Chemistry Journal "(J.Med.Chem.) 32 (12): 2582,1989), hydroxymethyl methotrexate (DE 267495), γ-fluoro methotrexate (McGuire et al, "Cancer Research" (Cancer Res.) 49 (16): 4517-25,1989), poly-glutamyl methotrexate derivatives (Kumar and other "Cancer Research" (Cancer Res.) 46 (10) :5020-3, 1986), KAI - diphosphonate methotrexate analogues (WO 88/06158), α-and γ-substituted methotrexate analogues (Tsushima and other "Tetrahedron" (Tetrahedron) 44 (17): 5375-87,1988), 5 - methyl-5 - deaza methotrexate analogues (4,725,687), Nδ-acyl -Nα-(4 - amino-4 - deoxy butterfly acyl)-L-ornithine derivative (Rosowsky other "Journal of Medicinal Chemistry" (J.Med.Chem.) 31 (7) :1332-7, 1988), 8 - deaza methotrexate analogues (Kuehl, etc. "Cancer Research" (Cancer Res.) 48 (6) :1481-8, 1988), similar acivicin methotrexate Substance (Rosowsky other "Journal of Medicinal Chemistry" (J.Med.Chem.) 30 (8) :1463-9, 1987), Polymerization Cisplatin methotrexate derivatives (Carraher other "Polymer Science and Technology" (Polym.Sci. Technol.) (Plenum), 35 (Adv.Biomed.Polym.) :311-24, 1987), methotrexate-γ-two Dimyristoyl phosphatidyl ethanolamine (Kinsky et al, "Journal of Biochemistry and Biophysics" (Biochim.Biophys.Acta) 917 (2) :211-18, 1987), like methotrexate polyglutamate Substance (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 derivatives (Kisliuk so Chem.Biol.Pteridines, Pteridines Folic Acid Deriv., Proc.Int.Symp.Pteridines Folic Acid Deriv.: Chem., Biol.Clin.Aspects :989-92, 1986), methotrexate deoxyuridine monophosphate derivatives Substance (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 analogue (Delcamp etc., Chem.Biol.Pteridines, Pteridines Folic Acid Deriv., Proc.Int.Symp.Pteridines Folic Acid Deriv.: Chem., Biol.Clin.Aspects :: 807-9,1986), 2ω-diamino containing alkanoic acid (alkanoid acid) methotrexate analogues (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) and 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, "miscellaneous Chem ring "(J.Heterocycl.Chem.) 22 (1) :5-6, 1985), cysteic acid and homocysteine ​​methyl Acid methotrexate analogues (4,490,529), γ-t-butyl methotrexate esters (Rosowsky other "drugs Journal of Chemistry "(J.Med.Chem.) 28 (5) :660-7, 1985), fluorinated methotrexate analogues (Tsushima et al, "heterocyclic" (Heterocycles) 23 (1) :45-9, 1985), folate methotrexate Purine analogs (Trombe, "J. Bacteriol" (J.Bacteriol.) 160 (3) :849-53, 1984), phosphine Acyl glutamic 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 conjugate Substance (Rosowsky other "Journal of Medicinal Chemistry" (J.Med.Chem.) 27 (7) :888-93, 1984), two Lysine and three lysine methotrexate derivatives (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 biologic drugs" (Adv.Exp.Med.Biol.,) 163 (Folyl Antifolyl Polyglutamates) :95-100, 1983), 3 ', 5'-dichloro-methotrexate (Rosowsky & Yu, "Journal of Medicinal Chemistry" (J.Med.Chem.) 26 (10) :1448-52, 1983), diazo ketones and chlorine Methyl 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 "drugs of Journal "(J.Med.Chem.) 25 (7) :877-80, 1982), lectin derivatives of methotrexate (Lin Etc. JNCI66 (3) :523-8, 1981), methotrexate polyglutamate derivatives (Galivan, "Molecular Pharmacology "(Mol.Pharmacol.) 17 (1) :105-10, 1980), methotrexate halogenated derivatives (Fox, JNCI58 (4): J955-8, 1977), 8 - alkyl -7,8 - dihydro analogues (Chaykovsky et al, "Drug Journal of Chemistry "(J.Med.Chem.) 20 (10): J1323-7, 1977), 7 - methyl methotrexate derivatives And dichloro-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" (J.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 ₂Be alkyl and the R that contains 1-4 carbon 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.PharmacalRes.) 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., DaltonTrans.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 " (CancerRes.) 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.Cancer Res.) 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.-ContainingPolym.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, (Schroyen etc. " European clinical cancer oncology magazine " (Eur.J.CancerClin.Oncol.) 24 (8): 1309-12 for iproplatin and JM40 platinum analogs, 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 DaxueXuebao) 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-(PtCl2-(NH2Me) 2)) (Brammer etc., " chemical association and chemical communication magazine " (J.Chem.Soc., Chem.Commun.) 6:443-5,1987), aliphatic tricarboxylic acids platinum complexes (EPA185225) 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.

Because medical implant is made with various configurations and size, definite dosage changes with the different of part of size, surface area and the design of device and applied implant.Yet some principle can be applied in the application of this area.With medication dose calculation is the function of the dosage on the per unit area device of the coating (part), can determine total dosage and can measure the surface concentration of suitable active medicine.Should under following administration guideline, give the preferred anticarcinogen of use separately or coupling, and with medicinal application is irrelevant in the method for heart implant.

(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 polymer support to use, the accumulated dose that is coated on the doxorubicin on 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 (promptly as medicine coating and/or mix the medication amount of function of surface area of the implant part of (incorporate)) 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, 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 ^-8-10 ^-4The doxorubicin least concentration of M.Must guarantee that lip-deep drug level 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 should find out easily that from 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 implant, or do not use the polymer support 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-3mg 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-20 μ g/mm ²The scope of surface area.In particularly preferred embodiments, should be with 0.05 μ g/mm ²-5 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 ^-4-10 ^-8The 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 should find out easily that from 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) 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 implant polymer, or do not use the polymer support 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 0.05 μ g-200mg/mm ²The scope of surface area.In particularly preferred embodiments, should be with 0.5 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, 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 should find out that from 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 the heart implant, or do not use the polymer support 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, 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 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 should find out that from 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.

(for example understand anthracycline easily based on discussion provided herein, doxorubicin or mitoxantrone), the fluorine pyrimidine (for example, 5-fluorouracil), the combination of antifol (for example, methotrexate and/or podophyllotoxin) (for example etoposide) can be used for the antibacterial activity of enhancing composition.

On the other hand, anti-infective (for example, anthracycline (for example, doxorubicin or mitoxantrone), fluorine pyrimidine (for example, 5-fluorouracil), antifol is (for example, methotrexate and/or podophyllotoxin (for example, etoposide)) can make up to strengthen effect with conventional antibiotic and/or antifungal.Anti-infective can also with antithrombotic agents and/or anti-platelet agents (for example, heparin, dextran sulfate, danaparoid, lepirudin, hirudin, AMP, adenosine, 2-chlorine adenosine, aspirin, Phenylbutazone, indomethacin, meclofenamic acid, hydrogen chloroquine, dipyridamole, iloprost, ticlopidine, clopidogrel, abciximab, eptifibatide, tirofiban, streptokinase, and/or tissue plasminogen activator) make up to strengthen effect.

Except mixing above-mentioned therapeutic agent (being anti-infective or fibre modification inhibitor), one or more other forms of pharmacologically active agents can also be incorporated in this compositions and the device to improve or to strengthen effect.The representative example of other therapeutic activity agent comprises, for example and not limit, antithrombotic agents, antiproliferative, antiinflammatory, tumor medicament, enzyme, receptor antagonist or agonist, hormone, antibiotic, antimicrobial, antibody, cytokine inhibitor, IMPDH (inosine monophosphate dehydrogenase) inhibitor, tyrosine kinase inhibitor, MMP inhibitor, p38MAP inhibitors of kinases, immunosuppressant, programmed cell death antagonist, Caspase inhibitor, and jnk inhibitor.

The compositions that implantable pump and sensor device and implantable pump and sensor device use can also comprise antithrombotic agents and/or anti-platelet agents and/or thrombolytic agent, and it reduces the probability that medical implant is implanted back thrombosis incident.In multiple embodiments of the present invention, will install in one side with the compositions coating that suppresses fibre modification (and/or restenosis), and at the another side of device with preventing that thrombotic compositions or chemical compound are coated with.The representative example of antithrombotic agents and/or anti-platelet agents and/or thrombolytic agent comprises heparin; heparin fragment; the organic salt of heparin; heparin complex (for example; the Benzalkonium heparin; three (dodecyl) ammonium heparin); glucosan; sulfated sugar; as dextran sulfate; warfarin; coumarin; heparinoid; danaparoid; argatroban; the sulphuric acid chitosan; chondroitin sulfate; danaparoid; lepirudin; hirudin; AMP; adenosine; 2-chlorine adenosine; acetylsalicylic acid; Phenylbutazone; indomethacin; meclofenamate sodium; the hydrogen chloroquine; dipyridamole; iloprost; streptokinase; the Xa factor inhibitor; as DX9065a; magnesium, and tissue plasminogen activator.Other example comprises plasminogen, lys-plasminogen, α-2-antiplasmin, urokinase, aminocaproic acid, ticlopidine, clopidogrel, trapidil (triazolopyrimidine), naftidrofuryl, auriritricarboxylic acid and glycoprotein iib/iiia inhibitor, as abciximab, eptifibatide and tirogiban.Other medicament that can influence blood coagulation speed comprises glycosaminoglycan, danaparoid, 4-hydroxyl courmarin, warfarin sodium, dicoumarol, phenprocoumon, indane-1,3-diketone, acenocoumarol, anisindione and subtract the Mus agent comprise Bromadiolone, Talon, diphenadione, rozol and pidnone.

Be used for implantable pump and sensor device compositions can for or comprise the hydrophilic polymer gel, himself have antithrombotic and form character.For example, compositions can be the form of coating, and it can comprise hydrophilic, Biodegradable polymeric, its can be in time from the surperficial physiology of device remove, thereby reduce the adhesion of platelet to apparatus surface.Gel combination can comprise polymer or polymeric blends.Representative example comprises polyester-polyether block copolymer (for example, AB of alginate, chitosan and sulphuric acid chitosan, hyaluronic acid, dextran sulfate, PLURONIC polymer (for example, F-127 or F87), the PLURONIC polymer of chain extension, multiple configuration, ABA, or BAB, wherein A is a polyester, as PLA, PGA, PLGA, PCL or the like), the example comprises MePEG-PLA, PLA-PEG-PLA, or the like).In one embodiment, thrombosis resisting composition can comprise molecule (for example, the cross-linked gel that is combined to form PEG) with two or more terminal electrophilic groups and two or more nucleophilic groups.

The compositions that implantable pump and sensor device and implantable pump and sensor device use can also comprise in the therapentic part or pathological process on every side have the chemical compound that suppresses effect.In some aspects, described medicament is selected from a kind of of following classification chemical compound: antiinflammatory (for example, dexamethasone, cortisone, fludrocortisone, prednisone, prednisolone, 6 α-methylprednisolone, Qu Anxi, betamethasone, and aspirin); The MMP inhibitor (for example, batimastat (batimistat), Marimastat (marimistat), the representative example of TIMP, it is included in 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; 5,639,746; 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, in 359), cytokine inhibitor (chlorpromazine, Mycophenolic Acid, rapamycin, 1 alpha-hydroxy vitamin D ₃), IMPDH (inosine monophosphate dehydrogenase) inhibitor (for example, Mycophenolic Acid, ribavirin, amino thiadiazoles, thiophenfurin, tiazofurine, viramidine) (representative example is included in 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 publication number WO 00/24725A1, WO 00/25780A1, WO 00/26197A1, WO00/51615A1, WO 00/56331A1, WO 00/73288A1, WO 01/00622A1, WO01/66706A1, WO 01/79246A2, WO 01/81340A2, WO 01/85952A2, WO02/16382A1, WO 02/18369A2, WO 02/051814A1, WO 02/057287A2, WO02/057425A2, WO 02/060875A1, WO 02/060896A1, WO 02/060898A1, WO02/068058A2, WO 03/020298A1, WO 03/037349A1, WO 03/039548A1, WO03/045901A2, WO 03/047512A2, WO 03/053958A1, WO 03/055447A2, WO03/059269A2, WO 03/063573A2, WO 03/087071A1, WO 99/001545A1, WO97/40028A1, WO 97/41211A1, among WO 98/40381A1 and the WO 99/55663A1), p38 map kinase inhibitor (MAPK) is (for example, GW-2286, CGP-52411, BIRB-798, SB220025, RO-320-1195, RWJ-67657, RWJ-68354, SCIO-469) (representative example is included in 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, 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 and PCT publication number WO 00/63204A2, WO 01/21591A1, WO 01/35959A1, WO01/74811A2, WO 02/18379A2, WO 02/064594A2, WO 02/083622A2, WO02/094842A2, WO 02/096426A1, WO 02/101015A2, WO 02/103000A2, WO03/008413A1, WO 03/016248A2, WO 03/020715A1, WO 03/024899A2, WO03/031431A1, WO 03/040103A1, WO 03/053940A1, WO 03/053941A2, WO03/063799A2, WO 03/079986A2, WO 03/080024A2, WO 03/082287A1, WO97/44467A1, WO 99/01449A1, in WO 99/58523A1), and immunomodulator (rapamycin, everolimus, ABT-578, azathioprine, azithromycin, forms of rapamycin analogs (for example comprises tacrolimus and derivant thereof, EP 0184162B1 and at U.S. Patent number 6, those that describe in 258,823) and everolimus and derivant thereof (for example, U.S. Patent number 5,665,772).Other representative example of sirolimus analog and derivant comprises ABT-578 and at PCT publication number WO 97/10502, WO 96/41807, and WO 96/35423, WO 96/03430, and WO 96/00282, and WO 95/16691, WO 95/15328, and WO 95/07468, and WO 95/04738, WO 95/04060, and WO 94/25022, and WO 94/21644, WO 94/18207, and WO 94/10843, and WO 94/09010, WO 94/04540, WO 94/02485, and WO 94/02137, and WO 94/02136, W0 93/25533, WO 93/18043, and WO 93/13663, and WO 93/11130, WO 93/10122, WO 93/04680, WO 92/14737 and WO 92/05179 and 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, those that find in 389.

Can comprise tyrosine kinase inhibitor with other example of the bioactivator of implantable pump according to the present invention and sensor device combination, as imatinib (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, 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 is as comprising CGH-2466 and PD-98-59; Immunosuppressant, as argyrin B, macrolide, ADZ-62-826, CCI-779, tilomisole, amcinonide, FK-778, AVE-1726, and MDL-28842; Cytokine inhibitor, as TNF-484A, PD-172084, CP-293121, CP-353164, and PD-168787; The NFKB inhibitor, as, AVE-0547, AVE-0545, and IPL-576092; The HMGCoA reductase inhibitor, as, pravastatin (pravestatin), atorvastatin, fluvastatin, dalvastatin, glenvastatin, Pitavastatin, CP-83101, U-20685; Programmed cell death antagonist (for example, troloxamine, TCH-346 (N-methyl-N-propargyl-10-amino methyl-dibenzo (b, f) oxepin); With Caspase inhibitor (for example, PF-5901 (benzyl alcohol, α-amyl group-3-(2-quinolyl methoxyl group)-), and jnk inhibitor (for example, AS-602801).

On the other hand, implantable pump and sensor device can also comprise antibiotic (for example, amoxicillin, trimethoprim-sulfamethoxazole, azithromycin, clarithromycin, amoxycillin with clavulanate potassium, cefprozil, cefuroxime, cefpodoxime, or cefdinir).

In some aspects, the polymer composition that comprises the fibre modification inhibitor with can modify the medicament combination of the metabolism of medicament in the body with fortifying fibre degeneration inhibitors effect.The one class therapeutic agent that can be used to change drug metabolism comprises the medicament that can suppress by Cytochrome P450 (CYP) oxidation anti-scarring agent.In one embodiment, provide compositions, it comprises fibre modification inhibitor (for example, paclitaxel, rapamycin, everolimus) and CYP inhibitor, and they can make up (for example, coating) with any device described herein.The representative example of CYP inhibitor comprises flavone, pyrroles's antifungal, 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 multiplely can cause undesirable synulotic proliferative disorders of organizing, and comprises neointimal hyperplasia, surgical operation adhesion and tumor growth.

In various embodiments of the present invention, install combination or on face, part or a surface, be coated with the compositions that suppresses fibre modification (and/or restenosis), and on device another face, part or surface, be coated with fibrotic compositions of promotion or chemical compound.Promote the representative example of fibrotic medicament comprise silk and other stimulant (for example, Talcum, fine hair (comprises animal down, wood shavings and synthetic floss), Pulvis Talci, copper, metallic beryllium (or its oxide), silica flour, silicon, crystalline silicate), polymer is (for example, polylysine, polyurethane, polyethylene terephthalate, PTFE, poly-(alkyl cyanoacrylate) and poly-(ethylene-be total to-vinylacetate); The polymer of vinyl chloride and vinyl chloride; Peptide with high-lysine content; The somatomedin and the inflammatory cytokine that relate to angiogenesis, the fibroblast migration, fibroblast proliferation, the synthetic and tissue remodeling of ECM is as epidermal growth factor (EGF) family, transforming growth factor (TGF-α), transforming growth factor (TGF-β-1, TGF-β-2, TGF-β-3, platelet derived growth factor (PDGF), fibroblast growth factor (acidity-aFGF; And alkalescence-bFGF), fibroblast stimulating factor-1, activin, VEGF (comprises VEGF-2, VEGF-3, VEGF-A, VEGF-B, VEGF-C, placental growth factor-PIGF), angiogenin, insulin like growth factor (IGF), hepatocyte growth factor (HGF), Connective Tissue Growth Factor (CTGF), bone marrow colony stimulating factor (CSFs), monocyte chemoattractant protein, granulocyte-macrophage colony stimutaing factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), M-CSF (M-CSF), erythropoietin, interleukin (IL-1 particularly, IL-8, and IL-6), tumor necrosis factor-alpha (TNF-α), nerve growth factor (NGF), interferon-' alpha ', interferon-beta, histamine, endothelin-1, Angiotensin II, growth hormone (GH) and synthetic peptide, the analog of these factors or derivant also are suitable for discharging in described from behind concrete implant and the device.Other example comprises CTGF (Connective Tissue Growth Factor); Inflammatory microcrystal (for example, the crystal mineral is such as crystalline silicate); Bromocriptine, methysergide, methotrexate, chitosan, N-carboxylic butyl chitosan, carbon tetrachloride, thioacetamide, fibrosin, ethanol, bleomycin, generally natural existence or the synthetic peptide that comprises Arg-Gly-Asp (RGD) sequence at one or two end (seen, for example U.S. Patent number 5,997, and 895), with organize adhesive agent, such as cyanoacrylate and crosslinked poly-(ethylene glycol)-methylated collagen composition.The example of other fibre modification derivant comprises bone morphogenetic protein (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15 and BMP-16).In these BMP, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7 are particularly useful.Bone morphogenetic protein exists, for example, and U.S. Patent number 4,877,864; 5,013,649; 5,661,007; 5,688,678; 6,177,406; 6,432,919; With 6,534,268 and Wozney, J.M. etc., (1988) Science:242 (4885); Be described among the 1528-1534.

The component that other representative example of fibre modification derivant comprises extracellular matrix (for example, fibronectin, fibrin, fibrinogen, collagen protein (for example, bovine collagen albumen), comprise fibrous and non-fibrous collagen protein, the adhesiveness glycoprotein, proteoglycan (for example, heparin sulfate, chondroitin sulfate, dermatan sulfate), hyaluronan, be rich in the acidic secretion protein (SPARC) of cysteine, thrombospondin, tenacin and cell adhesion molecule (comprise and integrate element, vitronectin, fibronectin, laminin, hyaluronic acid, elastin laminin, bitronectin), with the protein of in basement membrane, finding, and fibrosin), inhibitor with matrix metalloproteinase, such as TIMPs (tissue depressant of matrix metalloproteinase) and synthetic property TIMPs, for example, Marimastat (marimistat), batimastat (batimistat), doxycycline, tetracycline, minocycline, TROCADE, Ro-1130830, CGS 27023A, and BMS-275291, and analog and derivant.

Although provide top therapeutic agent, be appreciated that to the invention is not restricted to described therapeutic agent in order to illustrate purpose.For example, although mention top medicament especially, understanding be the present invention includes analog, derivant and the conjugate of this type of medicament.As illustrating, paclitaxel can be interpreted as not only refer to paclitaxel usually by the available form of chemical method, also comprise analog (for example, taxotere as mentioned above) and the paclitaxel conjugate is (for example, paclitaxel-PEG, paclitaxel-glucosan or paclitaxel-xylose).In addition, as apparent to those skilled in the art, although the medicament that provides above can mention in the context of a class that in fact many listed medicaments have the various biological activity.In addition, more than one therapeutic agent once (that is, combination) is used, perhaps delivery order.

C. Dosage

Because implantable sensor and implantable pump (with their drug delivery tube or port) are made with multiple configuration and size, so the exact dose of using will become along with device size, surface area and design.Yet, as mentioned above, in the application of this area, can use some principle.Can calculate the function of drug dose as the dosage of the per unit area of the part of applied device.The total drug dose of being used can be measured and the suitable surface concentration of active medicine can be measured.Drug level to be used is the several times to 10% that are generally used for the concentration of use in the application of single whole-body dose, 5%, or even less than 1%.In certain embodiments, in 1-90 days period, discharge medicine with valid density.No matter medicinal application is in the method for device, the fibre modification inhibitor separately or combination can instruct with following administration and use:

As mentioned above, implantable sensor and pump can combine with the compositions that comprises anti-scarring agent and use.In the device or on the total amount (dosage) of anti-scarring agent can be 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 the per unit area anti-scarring agent of the apparatus surface that medicament is used is about 0.01 μ g/mm ²-1 μ g/mm ², or 1 μ g/mm ²-10 μ g/mm ², or 10 μ g/mm ²-250 μ g/mm ², 250 μ g/mm ²-1000 μ g/mm ², or 1000 μ g/mm ²-2500 μ g/mm ²

It will be apparent to one skilled in the art that may be arbitrarily above-mentioned anti--fibre modification agent can separately or make up the enforcement that is used for this embodiment.

Aspect multiple, the invention provides the implantable sensor and the pump of the angiogenesis inhibitor that contains the dosage that provides above.At different aspect, the invention provides the 5-lipoxidase inhibitor that contains the dosage that provides above or the implantable sensor and the pump of antagonist.At different aspect, the invention provides the implantable sensor and the pump of the chemokine receptor anagonists that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the cell cycle inhibitor that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the anthracycline (for example, doxorubicin and mitoxantrone) that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the taxane (for example, the analog of paclitaxel or paclitaxel or derivant) that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the podophyllotoxin (for example, etoposide) that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the catharanthus alkaloid that contains the dosage that provides above.At different aspect, the invention provides the camptothecine that contains the dosage that provides above or the implantable sensor and the pump of its analog or derivant.At different aspect, the invention provides the implantable sensor and the pump of the platinum compounds that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the nitroso ureas that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the nitre imidazoles that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the antifol that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the cytidine analog that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the pyrimidine analogue that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the fluoropyrimidine analogue that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the purine analogue that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the chlormethine that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the hydroxyurea that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the ametycin that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the alkyl sulfonic ester that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the Benzoylamide that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the nicotiamide that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the halogeno-sugar that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the DNA alkylating agent that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the anti-microtubule agent that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the topoisomerase enzyme inhibitor that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the dna cleavage agent that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the antimetabolite that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the ADA Adenosine deaminase that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the synthetic medicament of inhibition purine ring that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the nucleotide interconversion inhibitor that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the medicament of the inhibition dihydrofolate reduction that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the medicament of the blocking-up thymidine monophosphate function that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the medicament that causes DNA damage that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the DNA intercalator that contains the dosage that provides above.At different aspect, the invention provides implantable sensor and the pump that contain the dosage that provides above for the medicament of rna synthesis inhibitor.At different aspect, the invention provides implantable sensor and the pump that contain the dosage that provides above for the medicament of pyrimidine synthesis inhibitors.At different aspect, the invention provides the implantable sensor and the pump of the synthetic medicament of inhibition ribonucleotide that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the synthetic medicament of inhibition thymidine monophosphate that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the synthetic medicament of inhibition DNA that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the medicament that causes dna adduct formation that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the synthetic medicament of Profilin matter that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the medicament of the inhibition microtubule function that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the immunomodulator (for example, sirolimus, everolimus, tacrolimus or its analog or derivant) that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the heat shock protein 90 antagonist (for example, geldanamycin) that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the HMGCoA reductase inhibitor (for example, simvastatin) that contains the dosage that provides above.At different aspect, the invention provides the inosine monophosphate dehydrogenase inhibitor (for example, Mycophenolic Acid, 1-α-25 dihydroxyvitamin D that contain the dosage that provides above ₃) implantable sensor and pump.At different aspect, the invention provides the NF kB inhibitor (for example, implantable sensor Bay11-7082) and the pump that contain the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the antifungal (for example, sulconazole (sulconizole)) that contains the dosage that provides above.At different aspect, the invention provides the p38 map kinase inhibitor (for example, implantable sensor SB202190) and the pump that contain the dosage that provides above.At different aspect, the wood invention provides the implantable sensor and the pump of the kinases inhibitor of the cyclin dependence that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the epidermal growth factor kinase inhibitor that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the elastase inhibitor that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the Xa factor inhibitor that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the Farnesyltransferase inhibitor that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the fibrinogen antagonist that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the guanylate cyclase stimulant that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the hydroxyl orotic acid dehydrogenase inhibitor that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the IKK2 inhibitor that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the IL-1 antagonist that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the ICE antagonist that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the IRAK antagonist that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the IL-4 antagonist that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the leukotriene inhibitors that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the MCP-1 antagonist that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the MMP inhibitor that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the NO antagonist that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the phosphodiesterase inhibitor that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the TGF beta inhibitor that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the TXA2. antagonist that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the TNF alpha-2 antagonists that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the tace inhibitor that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the tyrosine kinase inhibitor that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the vitronectin inhibitor that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the fibroblast growth factor inhibitor that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the kinases inhibitor that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the pdgf receptor kinase inhibitor that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the endothelial growth factor receptor kinase inhibitor that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the RAR antagonists that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the platelet derived growth factor receptor inhibitors of kinases that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the fibrinogen antagonist that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the di 2 ethylhexyl phosphonic acid that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the E.C. 3.1.1.32 inhibitor that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the histamine H 1/H2/H3 receptor antagonist that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the macrolide antibiotics that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the GPIIb IIIa receptor antagonist that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the endothelin-receptor antagonists that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the peroxisome proliferator-activated receptor stimulating agent that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the estrogen receptor agent that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of somatostatin (somastostatin) analog that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of neurokinin 1 antagonist that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of neurokinin 3 antagonisies that contain the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the VLA-4 antagonist that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the osteoclast inhibitor that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the DNA topoisomerase ATP hydrolysis inhibitor that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the hypertensin I conversion enzyme inhibitor that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the angiotension II antagonists that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the enkephalinase inhibitor that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the peroxisome Proliferator-activated receptor gamma agonist insulin sensitiser thing that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the inhibitors of protein kinase C that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of ROCK (kinases that rho-the is relevant) inhibitor that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the CXCR3 inhibitor that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the Itk inhibitor that contains the dosage that provides above.At different aspect, the invention provides the cPLA2 A that contains the dosage that provides above ₂The implantable sensor of-alpha inhibitor and pump.At different aspect, the invention provides the implantable sensor and the pump of the PPAR agonist that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the immunosuppressant that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the Erb inhibitor that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the programmed cell death agonist that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the lipocortin agonist that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the VCAM-1 antagonist that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the collagen antagonist that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the α 2 integrin antagonisies that contain the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the TNF alpha inhibitor that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the nitric oxide inhibitor that contains the dosage that provides above.At different aspect, the invention provides the implantable sensor and the pump of the cathepsin inhibitors that contains the dosage that provides above.

The representative dosage range of the multiple fibrosis agent that can be used in combination with implantable sensor of the present invention and pump is provided below.A) comprise the cell cycle inhibitor of doxorubicin and mitoxantrone.Doxorubicin analog and derivant thereof: accumulated dose is no more than 25mg (0.1 μ g is to the 25mg scope); Preferred 1 μ g is to 5mg.Per unit area dosage is 0.01 μ g-100 μ g/mm ²Preferred dose is 0.1 μ g/mm ²-10 μ g/mm ²To on apparatus surface, keep 10 ^-8-10 ^-4The doxorubicin of M Cmin.Mitoxantrone and analog thereof and derivant: accumulated dose is no more than 5mg (0.01 μ g is to the 5mg scope); Preferred 0.1 μ g is to 1mg.Per unit area dosage is 0.01 μ g-20 μ g/mm ²Preferred dose is 0.05 μ g/mm ²-3 μ g/mm ²To on apparatus surface, keep 10 ^-8-10 ^-4The mitoxantrone of M Cmin.B) comprise the cell cycle inhibitor of paclitaxel and analog thereof and derivant (for example, many Xi Tasai): accumulated dose is no more than 10mg (0.1 μ g is to the 10mg scope); Preferred 1 μ g is to 3mg.Per unit area dosage is 0.05 μ g-10 μ g/mm ²Preferred dose is 0.2 μ g/mm ²-5 μ g/mm ²To on apparatus surface, keep 10 ^-9-10 ^-4The paclitaxel of M Cmin.Cell cycle inhibitor such as podophyllotoxin (for example, etoposide): accumulated dose is no more than 10mg (0.1 μ g is to the 10mg scope); Preferred 1 μ g is to 3mg.Per unit area dosage is 0.1 μ g-10 μ g/mm ²Preferred dose is 0.25 μ g/mm ²-5 μ g/mm ²To on apparatus surface, keep 10 ^-8-10 ^-4The etoposide of M Cmin.(D) comprise the immunomodulator of sirolimus and everolimus.Sirolimus (that is, and rapamycin, RAPAMUNE): accumulated dose is no more than 10mg (0.1 μ g is to the 10mg scope); Preferred 10 μ g are to 1mg.Per unit area dosage is 0.1 μ g-100 μ g/mm ²Preferred dose is 0.5 μ g/mm ²-10 μ g/mm ²To on apparatus surface, keep 10 ^-8-10 ^-4The M Cmin.Everolimus and derivant thereof and analog: accumulated dose is no more than 10mg (0.1 μ g is to the 10mg scope); Preferred 10 μ g are to 1mg.Per unit area dosage is 0.1 μ g-100 μ g/mm ²Preferred dose is 0.3 μ g/mm ²-10 μ g/mm ²To on apparatus surface, keep 10 ^-8-10 ^-4The everolimus of M Cmin.(E) heat shock protein 90 antagonist (for example, geldanamycin) and analog and derivant: accumulated dose is no more than 20mg (0.1 μ g is to the 20mg scope); Preferred 1 μ g is to 5mg.Per unit area dosage is 0.1 μ g-10 μ g/mm ²Preferred dose is 0.25 μ g/mm ²-5 μ g/mm ²To on apparatus surface, keep 10 ^-8-10 ^-4The geldanamycin of M Cmin.(F) HMGCoA reductase inhibitor (for example, simvastatin) and analog and derivant: accumulated dose is no more than 2000mg (10 μ g are to the 2000mg scope); Preferred 10 μ g are to 300mg.Per unit area dosage is 1.0 μ g-1000 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-500 μ g/mm ²To on apparatus surface, keep 10 ^-8-10 ^-3The simvastatin of M Cmin.(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 (10.0 μ g are to the 2000mg scope); Preferred 10 μ g are to 300mg.Per unit area dosage is 1.0 μ g-1000 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-500 μ g/mm ²To on apparatus surface, keep 10 ^-8-10 ^-3The Mycophenolic Acid of M Cmin.(H) NF kB inhibitor (for example, Bay 11-7082) and analog and derivant: accumulated dose is no more than 200mg (1.0 μ g are to the 200mg scope); Preferred 1 μ g is to 50mg.Per unit area dosage is 1.0 μ g-100 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-50 μ g/mm ²To on apparatus surface, keep 10 ^-8-10 ^-4The Bay 11-7082 of M Cmin.(I) antifungal (for example, sulconazole) and analog and derivant: accumulated dose is no more than 2000mg (10.0 μ g are to the 2000mg scope); Preferred 10 μ g are to 300mg.Per unit area dosage is 1.0 μ g-1000 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-500 μ g/mm ²To on apparatus surface, keep 10 ^-8-10 ^-3The sulconazole of M Cmin.(J) (for example, SB202190) and analog and derivant: accumulated dose is no more than 2000mg (10.0 μ g are to the 2000mg scope) to the P38 map kinase inhibitor; Preferred 10 μ g are to 300mg.Per unit area dosage is 1.0 μ g-1000 μ g/mm ²Preferred dose is 2.5 μ g/mm ²-500 μ g/mm ²To on apparatus surface, keep 10 ^-8-10 ^-3The SB202190 of M Cmin.(K) anti-angiogenic agent (for example, bromination halofuginone) and analog and derivant: accumulated dose is no more than 10mg (0.1 μ g is to the 10mg scope); Preferred 1 μ g is to 3mg.Per unit area dosage is 0.1 μ g-10 μ g/mm ²Preferred dose is 0.25 μ g/mm ²-5 μ g/mm ²To on apparatus surface, keep 10 ^-8-10 ^-4The bromination halofuginone of M Cmin.

Except above-described those (for example, sirolimus, everolimus and tacrolimus), other example and the suitable dosage range that are used for the immunomodulator of implantable pump and sensor device comprise following: (A) Biolimus and derivant thereof and analog: accumulated dose is no more than 10mg (0.1 μ g is to the 10mg scope); Preferred 10 μ g are to 1mg.Per unit area dosage is 0.1 μ g-100 μ g/mm ²Preferred dose is 0.3 μ g/mm ²-10 μ g/mm ²To on apparatus surface, keep 10 ^-8-10 ^-4The Biolimus of M Cmin.(B) tresperimus and derivant thereof and analog: accumulated dose is no more than 10mg (0.1 μ g is to the 10mg scope); Preferred 10 μ g are to 1mg.Per unit area dosage is 0.1 μ g-100 μ g/mm ²Preferred dose is 0.3 μ g/mm ²-10 μ g/mm ²To on apparatus surface, keep 10 ^-8-10 ^-4The tresperimus of M Cmin.(C) auranofin and derivant thereof and analog: accumulated dose is no more than 10mg (0.1 μ g is to the 10mg scope); Preferred 10 μ g are to 1mg.Per unit area dosage is 0.1 μ g-100 μ g/mm ²Preferred dose is 0.3 μ g/mm ²-10 μ g/mm ²To on apparatus surface, keep 10 ^-8-10 ^-4The auranofin of M Cmin.(D) 27-0-demethyl rapamycin and derivant thereof and analog: accumulated dose is no more than 10mg (0.1 μ g is to the 10mg scope); Preferred 10 μ g are to 1mg.Per unit area dosage is 0.1 μ g-100 μ g/mm ²Preferred dose is 0.3 μ g/mm ²-10 μ g/mm ²To on apparatus surface, keep 10 ^-8-10 ^-4The 27-0-demethyl rapamycin of M Cmin.(E) gusperimus and derivant thereof and analog: accumulated dose is no more than 10mg (0.1 μ g is to the 10mg scope); Preferred 10 μ g are to 1mg.Per unit area dosage is 0.1 μ g-100 μ g/mm ²Preferred dose is 0.3 μ g/mm ²-10 μ g/mm ²To on apparatus surface, keep 10 ^-8-10 ^-4The gusperimus of M Cmin.(F) pimecrolimus and derivant thereof and analog: accumulated dose is no more than 10mg (0.1 μ g is to the 10mg scope); Preferred 10 μ g are to 1mg.Per unit area dosage is 0.1 μ g-100 μ g/mm ²Preferred dose is 0.3 μ g/mm ²-10 μ g/mm ²To on apparatus surface, keep 10 ^-8-10 ^-4The pimecrolimus of M Cmin and (G) ABT-578 and analog and derivant: accumulated dose is no more than 10mg (0.1 μ g is to the 10mg scope); Preferred 10 μ g are to 1mg.Per unit area dosage is 0.1 μ g-100 μ g/mm ²Preferred dose is 0.3 μ g/mm ²-10 μ g/mm ²To on apparatus surface, keep 10 ^-8-10 ^-4The ABT-578 of M Cmin.

Except above-mentioned those (for example, paclitaxel, taxotere and many Xi Tasai), what be used for some other examples of anti-microtubule agent of ear breather and suitable dosage range comprises the catharanthus alkaloid class, and as vinblastine and vincristine sulfate and analog and derivant: accumulated dose is no more than 10mg (0.1 μ g is to the 10mg scope); Preferred 1 μ g is to 3mg.Per unit area dosage is 0.1 μ g-10 μ g/mm ²Preferred dose is 0.25 μ g/mm ²-5 μ g/mm ²To on apparatus surface, keep 10 ^-8-10 ^-4The medicine of M Cmin.

D. Generation comprises and discharges the implantable sensor of fibre modification inhibitor and drug delivery pump Method

In enforcement of the present invention, implant and medical apparatus the medicine coating or the medicine dipping are provided, it suppresses the fibre modification around implantable sensor or the neutralization of implantable pump.In multiple embodiments, fibre modification is subjected to the inhibition of part, zone or the whole body release of specific forms of pharmacologically active agents, and described activating agent becomes and is positioned and described device or the adjacent tissue of implant.Many implantable sensors or implantable pump are arranged, and wherein the generation of fibre modification reaction will influence the function of device or the biological question that described device is implanted or used unfriendly.Usually, the fibrosis of device coat (the perhaps growth of the fibrous tissue between device and the target tissue) delay, damage or interrupts detecting (pick off) or to/from install to/send (pump) from the medicine of organizing.This can cause device not work best or according to not working, influence disease treatment negatively, and/or shortens the life-span of device.There are many methods can be used to optimize the fibre modification inhibitor and send and be described below wherein certain methods to what get involved the position.

1. Discharge the device and the implant of fibre modification inhibitor

Medical apparatus of the present invention or implant with medicament are coated with or are suitable for discharging this medicament, and described medicament suppresses the surface of implantable sensor and/or implantable pump or goes up fibre modification on every side.On the one hand, the invention provides implantable sensor and implantable pump, the compositions that it comprises anti-scarring agent or comprises anti-scarring agent, thus the undue growth of fibrous tissue or granulation tissue is suppressed or reduces.

On implantable sensor and implantable pump or the method for internal junction condensating fiber degeneration composite inhibiting comprise: (a) directly will suppress fibrotic compositions and (for example invest on the device, by aforesaid spray method or dipping method, use or without carrier), (b) directly will suppress fibrotic compositions (for example is attached in the device, by aforesaid spray method or dipping method, use or without carrier), (c) by using material coating sensor device such as hydrogel, described material absorbs again and suppresses fibrotic compositions, (d) by being coated with in line (perhaps polymer itself forms line) the auto levelizer structure that interweaves that suppresses fibrotic compositions, (e) device is inserted into sleeve or the mesh that comprises the fibrotic compositions of inhibition or be coated with the fibrotic compositions of inhibition; (f) make sensing device (perhaps Zhuan Zhi a part itself with suppressing fibrotic compositions, as detector, drug delivery tube or port), or (g) by with direct covalent bond apparatus surface of fibre modification-inhibitor or joint (micromolecule or polymer), this surface or joint coating or be connected to apparatus surface.Each of these methods has been illustrated implantable sensor or implantable pump and the method that makes up according to fibre modification of the present invention-inhibition (being also referred to as anti-cicatrization herein) agent.

For these devices, thereby can carry out coating process in such a manner with suppressing all or part of (as pick off or the drug delivery tube/mouth) that fibrotic compositions is coated with whole device.Additionally or alternatively, fibre modification-inhibitor can with the material mixing that is used to make implantable sensor or implantable pump, thereby fibre modification-inhibitor is attached to final products.In these modes, can prepare medical apparatus with coating, its floating coat is for for example, and is uniform, heterogeneous, successive, discontinuous, perhaps figuratum.

On the other hand, implantable sensor or medicine send/conduit/mouth device can comprise in their structure that many storages, each storage are configured to hold and protect curative drug (that is one or more fibre modification-inhibitor).Storage can form from the divets of apparatus surface or micropore or the passage the device body.On the one hand, the hole from apparatus structure forms storage.Storage can hold the medicine (for example, fibre modification-inhibitor) of single type or the medicine (for example, fibre modification-inhibitor and anti-infective) of more than one types.Can be with carrier (for example, polymerization or the non-polymeric material) compounding pharmaceutical that is loaded in the storage.Storage through filling can be used as medicine and sends the storehouse, and it can discharge medicine from the release dynamics of carrier according to medicine in one period.In certain embodiments, can load storage with many layers.Every layer of different pharmaceutical that can comprise the medicine with specified quantitative (dosage), every layer can have different compositionss further to be fit to from the amount and the type of the medicine of substrate release.The multilamellar carrier can also comprise the barrier layer that prevents drug release.Barrier layer for example can be used for, and the control medicine is from the effusive direction of hole.Thereby the coating of this medical apparatus can directly contact implantable device, and perhaps when at device with contain when having something (as polymeric layer) to insert between the coating of fibre modification-inhibitor, described coating can this device of mediate contact.

Be attached to fibre modification-inhibitor on implantable sensor device and the implantable pump or outside interior, or alternatively, fibre modification-inhibitor can directly or indirectly be applied to the tissue adjacent with implantable pump with the sensor device interface of tissue and detector, drug delivery tube and/or drug delivery port (preferably near).This can be applied to apparatus surface (for example, as injectable agent, paste, gel or mesh) with fibre modification-inhibitor (a) by using or not using polymeric, non-polymer or second carrier in implantation step; (b) before implantable sensor device and implantable pump are implanted, at once before or during the surface (for example, as injectable agent, paste, gel, original position formation gel or mesh) that is applied to organize; (c) after implanting at once, be applied to the surface of device and/or the pump of being implanted or pick off tissue (for example, forming gel or mesh) on every side as injection, paste, gel, original position; (d) by the fibrosis agent being applied topically to implantable sensor and implantable pump the anatomy space of placing (is to use polymer support for what this embodiment was particularly useful, it discharges fibre modification-inhibitor-fluid, suspensoid, Emulsion, microemulsion, microsphere, paste, gel, microparticle, spray, aerosol, solid-state implant and other preparation in a few hours to several weeks, its release can be delivered to the medicament in the zone that device inserts); (e),, perhaps be applied to implantable sensor or implantable pump tissue on every side by percutaneous injection as slow releasing preparation as infusate as solution; (f) combination in any by said method realizes.Can also use combination treatment (that is, the combination of therapeutic agent and with the combination of antithrombotic formation, antiplatelet and/or anti-infective).

2. The whole body of fibre modification inhibitor, zone and local delivery

Multiple medicine delivery technique can be used for whole body, zone and the local delivery of fibre modification inhibition therapeutic agent.Some of these technology can be suitable for implementation in the level of the preferential rising of implantable sensor and near the fibre modification inhibitor of implantable pump, comprising: (a) use drug delivery tube with the tissue around fibre modification inhibitor part, zone or systemic delivery auto levelizer or the implant.Usually, drug delivery tube advances by circulation or directly be inserted into tissue under radiology instructs and reaches desirable anatomical location up to them.The fibre modification inhibitor can discharge so that the medicine of organizing delivery treatments dosage around device or implant from catheter lumen with high local concentrations then; (b) medicine location technology is sent as magnetic, medicine ultrasonic or that MRI instructs; (c) chemical modification of fibre modification suppressive drug or preparation, it to the absorption of damaged tissues (for example is designed to increase activating agent, at the antibody of component of organization injured or healing, described composition is for example macrophage, neutrophil cell, smooth muscle cell, fibroblast, extracellular matrix components, cardiovascular organization); (d) chemical modification of fibre modification suppressive drug or preparation, it is designed to medicine is localized to the zone of hemorrhage or the vascular system of being damaged; And/or (e) for example, under endoscopic views, the orientation of fibre modification inhibitor is injected or is used.

3. The fibre modification inhibitor is to the infiltration of device or implant surrounding tissue

Alternatively, can before the implantation step, during or handle tissue around implantable sensor or the implantable pump afterwards with the fibre modification inhibitor.The fibre modification inhibitor or comprise the compositions of fibre modification inhibitor can infiltration around device or implant, for example, by with described compositions directly and/or indirect application in (a) tissue adjacent with medical apparatus and/or above; (b) near medical apparatus-organizational interface; (c) medical apparatus peripheral region; (d) the medical apparatus surrounding tissue realizes.Notice that some polymer support self can help to form fibrous tissue around implantable sensor and implantable pump.The following illustrative polymer composition can be used to implement this embodiment separately or with fibre modification inhibition combination of compositions.Below polymer support can permeate near (as describing in the earlier paragraphs) auto levelizer-organizational interface and comprise: (a) the sprayable preparation that contains collagen, as COSTASIS and CT3, its independent or loading fibre modification inhibitor, be applied to implant site (perhaps device, detector, semipermeable membrane, drug delivery tube, and/or drug delivery port surface); (b) the sprayable preparation that contains PEG, as COSEAL, FOCALSEAL, SPRAYGEL or DURASEAL, described preparation separately or load the fibre modification inhibitor is applied to implant site (perhaps device, detector, semipermeable membrane, drug delivery tube, and/or drug delivery port surface); (c) contain the preparation of fibrinogen, as FLOSEAL or TISSEAL, described preparation separately or load the fibre modification inhibitor is applied to implant site (perhaps device, detector, semipermeable membrane, drug delivery tube, and/or drug delivery port surface); (d) contain hyaluronic preparation, as RESTYLANE, HYLAFORM, PERLANE, SYNVISC, SEPRAFILM, SEPRACOAT, described preparation loads the fibre modification inhibitor, is applied to implant site (perhaps device, detector, semipermeable membrane, drug delivery tube, and/or drug delivery port surface); (e) be used for the polymer gel that surgical operation is implanted, as REPEL or FLOWGEL, described preparation separately or load fibre modification-inhibitor is applied to implant site (perhaps device, detector, semipermeable membrane, drug delivery tube, and/or drug delivery port surface); (f) orthopedic " cement ", it is used for prosthese and tissue are remained on the appropriate location, it loads fibre modification-inhibitor, and described preparation separately or load the fibre modification inhibitor is applied to implant site (perhaps device, detector, semipermeable membrane, drug delivery tube, and/or drug delivery port surface), as OSTEOBOND, low viscosity cement (LVC), SIMPLEX P, PALACOS, and ENDURANCE; The operation adhesive that contains cyanoacrylate, as DERMABOND, INDERMIL, GLUSTITCH, TISSUMEND, VETBOND, HISTOACRYL BLUE and

SOOTHE-N-SEALLIQUID PROTECTANT, described preparation separately or load the fibre modification inhibitor are applied to implant site (perhaps device, detector, semipermeable membrane, drug delivery tube, and/or drug delivery port surface); (h) contain hydroxyapatite (perhaps synthetic bone material, as calcium sulfate, VITOSS and CORTOSS) implant, it loads fibre modification-inhibitor, be applied to implant site (perhaps device, detector, semipermeable membrane, drug delivery tube, and/or drug delivery port surface); (i) other biocompatible tissue filling agent, it loads fibre modification-inhibitor, as BioCure, Inc., 3MCompany and Neomend, those that Inc. makes, described filler is applied to implant site (perhaps device, detector, semipermeable membrane, drug delivery tube, and/or drug delivery port surface); (j) polysaccharide gel, as ADCON series gel, described gel separately or load fibre modification-inhibitor is applied to implant site (perhaps device, detector, semipermeable membrane, drug delivery tube, and/or drug delivery port surface); And/or (k) membrane, sponge or mesh, as INTERCEED, VICRYL mesh and GELFOAM, it loads fibre modification-inhibitor, is applied to implant site (perhaps device, detector, semipermeable membrane, drug delivery tube, and/or drug delivery port surface).

Can be used to help prevent the preferred polymeric matrix that around implantable sensor and implantable pump, forms fibrous tissue to form separately or with fibre modification (and gliosis) inhibitor/compositions associating by reactant as pharmacy response, described reactant comprise following one or both: tetramethylolmethane gathers (ethylene glycol) ether four-sulfydryl] (4-arm sulfydryl PEG, it is included in the structure that has linking group between the end of sulfydryl and polyethylene glycol backbone) and poly-(ethylene glycol) ether four-succinimido 1,3-propanedicarboxylic acid of tetramethylolmethane] (4-arm NHS PEG, it is included in the structure that has linking group between the end of NHS base and polyethylene glycol backbone once more).Another kind of preferred composition comprise as pharmacy response following one or both: tetramethylolmethane gather (ethylene glycol) ether four-amino] (4-arm amino PEG, it is included in the structure that has linking group between the end of amino and polyethylene glycol backbone) and poly-(ethylene glycol) ether four-succinimido 1,3-propanedicarboxylic acid of tetramethylolmethane] (4-arm NHS PEG, it is included in the structure that has linking group between the end of NHS base and polyethylene glycol backbone once more).The chemical constitution of these reactants is for example, and U.S. Patent number 5,874 shows in 500.Randomly, the reactant adding collagen of poly-to containing (ethylene glycol) or collagen derivant are (for example, methylated collagen) forming preferred crosslinked substrate, its can be used as be used for the treatment of agent or independently the polymer support of compositions around implantable sensor and implantable pump, form fibrous tissue to help prevent.

4. The extended release preparation of fibre modification inhibitor

As former description, desirable fibre modification inhibitor can mix, admixes, puts together or modify to contain polymers compositions (it can be biodegradable or abiotic degradable), perhaps non-polymer compositions is so that discharge therapeutic agent in over a long time.For many previous embodiments, may need the localization of fibre modification inhibitor to send and localize and continue to send.For example, desirable fibre modification inhibitor can mix, admixes, puts together or modify to contain polymer composition (it can be biodegradable or abiotic degradable), perhaps non-polymer compositions is so that discharge the fibre modification inhibitor in over a long time.In some aspects, polymer composition can comprise biological erodible (bioerodable) or Biodegradable polymeric.The representative example that is suitable for sending the Biodegradable polymeric of fibre modification inhibitor comprises albumin, collagen, gelatin, hyaluronic acid, starch, cellulose and cellulose derivative are (for example, methylcellulose, hyprolose, hydroxypropyl emthylcellulose, carboxymethyl cellulose, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate), casein, glucosan, polysaccharide, fibrinogen, poly-(ether-ether) segmented copolymer, based on poly-(ethylene glycol) and poly-(buthylene Terephthalate), the Merlon of tyrosine-derived (for example, U.S. Patent number 6,120,491), poly-(hydroxy acid), poly-(D, the L-lactide), poly-(D, the L-lactide-co-glycolide), poly-(Acetic acid, hydroxy-, bimol. cyclic ester), poly-(hydroxybutyric acid) Ju diethyleno dioxide ketone, poly-(alkyl carbonate) and poly-(ortho esters), polyester, poly-(hydroxypentanoic acid) Ju diethyleno dioxide ketone, poly-(buthylene Terephthalate), poly-(malic acid), poly-(hydroxymalonic acid .), poly-(acrylamide), poly-anhydride, polyphosphazene, poly-(aminoacid), polyalkylene oxide-poly-(ester) block copolymer (X-Y for example, X-Y-X or Y-X-Y, wherein X is a polyalkylene oxide, Y is polyester (for example, PLGA, PLA, PCL Ju diethyleno dioxide ketone and copolymer thereof) and their copolymer mixture.(see Illum, L., Davids, S.S. (eds.) " Polymers in Controlled Drug Delivery " Wright, Bristol, 1987 usually; Arshady, J.Controlled Release 17:1-22,1991; Pitt, Int.J.Phar.59:173-196,1990; Holland etc., J.Controlled Release 4:155-0180,1986).

The representational example that is suitable for transmitting the nondegradable polymer of fibre modification inhibitor comprises poly-(ethylene-co-vinyl acetate) (＂ EVA ＂) copolymer, silicone rubber, acrylate copolymer (polyacrylic acid, polymethylacrylic acid, poly methyl methacrylate, poly-(butyl methacrylate)), (for example gather (alkyl cyanoacrylate), poly-(ethyl cyanoacrylate), poly-(butyl cyanoacrylate), poly-(hexyl cyanoacrylate), poly-(octyl cyanoacrylate)), polyethylene, polypropylene, polyamide-based (nylon 6,6), polyurethane, 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 (promptly, the copolymer of oxirane and epoxypropane polymer), such as from (the Mount Olive of BASF AG, NJ) PLURONIC polymer, with poly-(1, the 4-butanediol), polymer (the polystyrene of styrene-based, poly-(styrene sulfonic acid), poly-(styrene)-block-poly-(isobutene .)-block-poly-(styrene), gather (styrene)-poly-(isoprene) block copolymer) and polyvinyl (polyvinylpyrrolidone, poly-(vinyl alcohol), poly-(vinyl acetate phthalic acid ester) and copolymer and admixture.The polymer that is developed can also be anionic (for example alginate, carrageenan, 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, or cationic (for example chitosan, poly-L-Lysine, polymine and poly-(allyl amine)) and admixture thereof are (generally referring to Dunn etc., " application polymer science magazine " (J.Applied PolymerSci.) 50:353-365,1993; Cascone etc., " material science magazine: medicinal materials " (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, " 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).

Especially preferred polymer support comprises poly-(ethylene-co-vinyl acetate), polyurethane, poly-(D, L-lactic acid) oligomer and polymer, poly-(L-lactic acid) oligomer and polymer, poly-(glycolic), the copolymer of lactic acid and glycolic, poly-(caprolactone), poly-(valerolactone), polyanhydride, the copolymer of poly-(caprolactone) or poly-(lactic acid) and Polyethylene Glycol (for example, MePEG), silicone rubber, poly-(styrene) block-poly-(isobutene .)-block-poly-(styrene), poly-(acrylate) polymer and top any admixture, mixture or copolymer.Other preferred polymer comprises collagen, based on the polymer of polyalkylene oxide, and polysaccharide, as hyaluronic acid, the copolymer of chitosan and fucosan and polysaccharide and degradable polymer.

Other representational polymer that can continue localized delivery fibre modification inhibitor comprises carboxylic acid polyalcohol, poly-acetate esters, polycarbonate-based, polyethers, polyethylene kind, the polyvinyl butyral resin class, polysilanes, polyureas, polyurethane, the polyoxide class, 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 acetic acid ester polymer and copolymer, vinyl acetal polymer and copolymer, epoxide, melamine, other amino resins, phenol polymer and copolymer thereof, the water-insoluble cellulose ester polymer (comprises cellulose-acetate propionate, cellulose acetate, acetylbutyrylcellulose, celluloid, Cellacefate and composition thereof), polyvinylpyrrolidone, polyethylene glycols, poly(ethylene oxide), polyvinyl alcohol, polyethers, polysaccharide, hydrophilic polyurethane, acrylic polyol, glucosan, xanthan gum, hydroxypropyl cellulose, methylcellulose, with the N-vinyl pyrrolidone, the N-vinyl lactam, the N-vinyl butyrate lactam, the N-caprolactam, other has the homopolymer and the copolymer of the vinyl compound of polarity side group, the acrylate and the methacrylate that have hydrophilic esterification group, hydroxy acrylate and acrylic acid and combination thereof; The homopolymer of cellulose esters and ethers, ethyl cellulose, hydroxyethyl-cellulose, celluloid, cellulose acetate, cellulose acetate-butyrate, cellulose-acetate propionate, polyurethane, polyacrylate, natural and synthetic elastomer, rubber, acetal, nylon, polyester, styrene polybutadiene, acrylic resin, polyvinylidene chloride, Merlon, vinyl compound and copolymer, polrvinyl chloride and polrvinyl chloride acetas.

The representative example of the patent relevant with their preparation with drug delivery polymer comprises PCT publication number WO 98/19713, and WO 01/17575, and WO 01/41821, and WO 01/41822, and WO01/15526 (and their corresponding U. S. application) and U.S. Patent number 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 and 5,714,159,5,612,052 and U.S. Patent Application Publication No. 2003/0068377,2002/0192286,2002/0076441 and 2002/0090398.

Those skilled in the art it is evident that polymer described herein can also mix as required or with the fibre modification-inhibitor of multiple composition copolymerizationization with delivery treatments dosage.

Can make the polymer support of fibre modification inhibitor with various forms, depend on device, compositions or the implant of use, it has required release characteristics and/or has specific character.For example, polymer support can be made so that after being exposed to specific firing event such as pH, discharge the fibre modification inhibitor (referring to for example, Heller etc., " Chemically Self-RegulatedDrug Delivery systems; " Polymers in Medicine III, Elsevier Science PublishersB.V., Amsterdam, 1988, pp.175-188; Kang etc., J.Applied Polymer Sci.48:343-354,1993; Dong etc., J.Controlled Release19:171-178,1992; Dong and Hoffman, J.Controlled Release15:141-152,1991; Kim etc., J.ControlledRelease 28:143-152,1994; Cornejo-Bravo etc., J.Controlled Release33:223-229,1995; Wu and Lee, Pharm.Res.10 (10): 1544-1547,1993; Serres etc., Pharm.Res.13 (2): 196-201,1996; Peppas, (eds.) such as " Fundamentals of pH-andTemperature-Sensitive Delivery systems, " Gurny, Pulsatile DrugDelivery, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1993, pp.41-55; Doelker, " Cellulose Derivatives, " 1993, Peppas and Langer (eds.), Biopolymers I, Springer-Verlag, Berlin).The representative example of pH-sensitive polymer comprises that poly-(acrylic acid) and derivant thereof (for example comprise that homopolymer is as poly-(amino carboxylic acid); Poly-(acrylic acid); Poly-(methacrylic acid), the copolymer of the copolymer of these homopolymer and poly-(acrylic acid) and/or acrylic acid or acrylamide monomer such as above-mentioned those.Other pH sensitive polymer comprises polysaccharide such as acetic acid phthalandione cellulose; Hydroxypropyl Methylcellulose Phathalate; Acetic acid succinic acid HYDROXY PROPYL METHYLCELLULOSE; Acetic acid trimellitic acid cellulose; And chitosan.Other pH sensitive polymer comprises any mixture of pH sensitive polymer and water-soluble polymer in addition.

Equally, can (for example send the fibre modification inhibitor by the temperature sensitive polymer carrier, referring to (Proceed.Intern.Symp.Control.Rel.Bioact.Mater.) 22:167-168 of " being used for the new hydrogel vagina release and the thermal sensitivity PLURONIC grafting of biological adhesive polyacrylic acid backbone " such as Chen (＂ Novel Hydrogels of a Temperature-SensitivePLURONIC Grafted to a Bioadhesive Polyacrylic acid Backbone for VaginalDrug Delivery ＂)-" control release biological active material inner seminar journal ", Controlled Release Society, Inc., 1995; Okano " MOLECULE DESIGN that is used for the S-R hydrogel of temporary transient controlled release " (＂ Molecular Design of Stimuli-Responsive Hydrogels for TemporalControlled Drug Delivery ＂)-" the inner seminar journal of control release biological active material " be 22:111-112 (Proceed.Intern.Symp.Control.Rel.Bioact.Mater.), Controlled ReleaseSociety, Inc., 1995; Johnston etc. " drug research " (Pharm.Res.) 9 (3): 425-433,1992; Tung " International Journal of Pharmaceutical Medicine " (Int ' l J.Pharm.) 107:85-90,1994; Harsh and Gehrke, " controlled release magazine " (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 " (J.Controlled Release) 36:221-227,1995; Yu and Grainger " new thermal sensitivity amphiphilic gel: poly--the N-N-isopropylacrylamide-altogether-sodium acrylate-altogether-N-alkyl acrylamide network structure is synthesized and materialization characterizes ", (＂ Novel Thermo-sensitive Amphiphilic Gels:Poly-N-isopropylacrylamide-co-sodium acrylate-co-N-alkylacrylamideNetwork Synthesis and Physicochemical Characterization ＂)-" chemistry and bioscience development ", (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 Starpolymer ＂), Polymer Research Institute-" chemical developer " (Dept.of Chemistry), College of Environmental Science and Forestry, State Univ.of New York, Syracuse, NY, pp.822-823; Hoffman etc. " irritant reaction hydrogel mesopore size and water ' structure ' sign " (＂ Characterizing Pore Sizes and Water ' Structure ' inStimuli-Responsive Hydrogels ＂), Center for Bioengineering, Univ.ofWashington, Seattle, WA, p.828; Yu and Grainger " the cancellated thermal sensitivity swelling character of crosslinked N-N-isopropylacrylamide: cation, anion and both sexes hydrogel " (＂ Thermo-sensitive Swelling Behavior in CrosslinkedN-isopropylacrylamide Networks:Cationic, Anionic and AmpholyticHydrogels ＂)-" chemistry and bioscience development " (Dept.of Chemical ﹠amp; BiologicalSci.), Oregon Graduate Institute of Science ﹠amp; Technology, Beaverton, OR, pp.829-830; Kim etc. " drug research " (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. " controlled release magazine " are 32:971-102 (J.ControlledRelease), and 1994; Okano etc. " controlled release magazine " (J.Controlled Release) 36:125-133,1995; Chun and Kim " controlled release magazine " (J.Controlled Release) 38:39-47,1996; D ' Emanuele and Dinarvand " 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 hot reversible hydrogel that contains the bioactivator kind " (＂ Thermally Reversible Hydrogels Containing Biologically Active Species ＂)-(eds.) such as Migliaresi " polymer in the medicine " (Polymer in Medicine) III, ElsevierScience Publishers B.V., Amsterdam, 1988, pp.161-167; Hoffman " application in treatment and diagnosis of thermally reversible polymer and hydrogel " (＂ Applications of ThermallyReversible Polymer and Hydrogels in Therapeutics and Diagnostics ＂)-" international symposiums of the 3rd relevant medicine-releasing system latest developments " (Third International Symposium onRecent Advances in Drug Delivery s of system), Salt Lake City, UT, Feb.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 thereof (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; copolymer by preparing between the above-mentioned monomer (between three or three are above) or by with this class homopolymer and other water-soluble polymer, such as acryl monomer (for example acrylic acid and derivant thereof; such as methacrylic acid, acrylate and derivant thereof; such as butyl methacrylate, butyl acrylate, dodecylacrylate and acrylamide monomer and derivant thereof, as N-butyl acrylamide and acrylamide) combination prepares hot glue cohesion compound.

Other representational example of hot glue cohesion compound comprises: cellulose ether derivative, and such as hydroxypropyl cellulose, 41 ℃; Methylcellulose, 55 ℃; Hydroxypropyl emthylcellulose, 66 ℃; With poly(ethylene oxide)-polyester block copolymer of ethylhydroxyethylcellulose, structure X-Y, Y-X-Y and X-Y-X, wherein X is that poly(ethylene oxide) and Y are biodegradable polyester (for example PLG-PEG-PLG); With 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 thereof comprises: U.S. Patent number 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; WO 01/82970; WO00/18821; WO 97/15287; WO 01/41735; WO 00/00222 and WO 00/38651.

The fibre modification inhibitor can be connected by containing in the substrate of polymer, by covalent bonds or be encapsulated in the microcapsule.In certain embodiments of the invention, therapeutic combination is to provide with non-capsule preparations, as microsphere (magnitude range from nanometer to micron), paste, the line of all size, film or spray.

Aspect some, therapeutic combination can be made the form of microsphere, microparticle and/or nano-particle of the present invention, it has any size between about 30nm to 500 μ m, and this depends on concrete application.These compositionss can form these compositionss by spraying-seasoning, polishing, coacervation, W/O emulsion process, W/O/W emulsion process and solvent evaporated method.In another embodiment, these compositionss can comprise microemulsion, Emulsion, liposome and micelle.Alternatively, also easily this based composition is used as ＂ spray ＂, it is solidified into membrane or coating is used as device/implant surface coating or adorns the tissue that serves as a contrast implantation site.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.

Therapeutic combination of the present invention can also be prepared into various ＂ paste ＂ or gel form.For example, in one embodiment of the invention, be formed under a kind of temperature therapeutic combination for liquid (for example being higher than 37 ℃ temperature) and be the form of solid or semisolid (for example at environment body temperature or be lower than under 37 ℃ the arbitrary temp) under the another kind of temperature such as 40 ℃, 45 ℃, 50 ℃, 55 ℃ or 60 ℃.Be easy to use various technology to prepare this class ＂ heat and stick with paste ＂ (for example referring to PCT publication number WO98/24427).Other paste can be used as liquid, it is in vivo because the water soluble ingredient stripping of paste and the drug precipitation sealed are gone into the body environment of aqueous and curing in vivo.These ＂ paste ＂ that contain the fibre modification inhibitor are effective to be coated on the tissue surface that contacts implant or device especially with ＂ gel ＂.

In others of the present invention, therapeutic combination of the present invention can form film or pipe.These films or pipe can be porous or non-porous.This type of film or pipe are usually less than 5,4,3,2, or 1mm is thick, or less than 0.75mm, or less than 0.5mm, or less than 0.25mm, or thick less than 0.10mm.Can also produce thickness less than 50 μ m, film or the pipe of 25 μ m or 10 μ m.This type of film can be resilient, have good tensile strength (for example, greater than 50, or greater than 100, or greater than 150 or 200N/cm ²), good viscosity (that is, adhere to humidity or wetted surface) and have controlled permeability.Fibre modification-the inhibitor that contains in the polymeric film especially can be used for being applied to the surface of device or implant and the surface of tissue, chamber or organ.

In others of the present invention, polymer support is provided, it is adapted to comprise and discharges the hydrophobic fibre degeneration and suppresses chemical compound, and/or comprises the carrier of combination with the hydrophobic compound of carbohydrate, protein or polypeptide.In certain embodiments, described polymer support contains or comprises the zone of one or more hydrophobic compounds, bag or granule.For example, in one embodiment of the invention, hydrophobic compound can be attached in the substrate that comprises hydrophobic fibre degeneration inhibition chemical compound, subsequently substrate be incorporated in the polymer support.Various substrate can be used in this aspect, comprise, for example, carbohydrate and polysaccharide are such as starch, cellulose, dextrose, methylcellulose, sodium alginate, heparin, chitosan and hyaluronic acid, protein or polypeptide be such as albumin, collagen protein and gelatin.In alternative embodiment, hydrophobic compound can be included in the hydrophobic core, and this core is included in the hydrophilic shell.

Other carrier that can be used to equally to contain and transmit fibre modification inhibitor as herein described comprises: hydroxypropyl cyclodextrin (Cserhati and Hollo, Int.J.Pharm.108:69-75,1994), liposome (referring to, for example, Sharma etc., Cancer Res.53:5877-5881,1993; Sharma and Straubinger, Pharm.Res.11 (60): 889-896,1994; WO 93/18751; U.S. Patent number 5,242,073), liposome/gel (WO 94/26254), Nano capsule (Bartoli etc., J.Microencapsulation 7 (2): 191-197,1990), micelle (Alkan-Onyuksel etc., Pharm.Res.11 (2): 206-212,1994), implant (Jampel etc., Invest.Ophthalm.Vis.Science34 (11): 3076-3083,1993; Walter etc., Cancer Res.54:22017-2212,1994), nanoparticle (Violante and Lanzafame PAACR), modified Nano grain (U.S. Patent number 5,145,684), nanoparticle (surface modification) (U.S. Patent number 5,399,363), micelle (surfactant) (U.S. Patent number 5,403,858), synthetic phospholipid chemical compound (U.S. Patent number 4,534,899), gas matchmaker dispersion (U.S. Patent number 5,301,664), liquid emulsion, foam, spray, gel, lotion, cream, ointment, disperse vesicle, granule or droplet solid or liquid aersol, microemulsion (U.S. Patent number 5,330,756), polymerization housing (Nano capsule and microcapsule) (U.S. Patent number 5,439,686), Emulsion (Tarr etc., PharmRes.4:62-165,1987), nanosphere (Hagan etc., Proc.Intern.Symp.Control Rel.Bioact.Mater.22,1995; Kwon etc., Pharm Res.12 (2): 192-195; Kwon etc., Pharm Res.10 (7): 970-974; Yokoyama etc., J.Contr.Rel.32:269-277,1994; Gref etc., Science 263:1600-1603,1994; Bazile etc., J.Pharm.Sci.84:493-498,1994) and implant (U.S. Patent number 4,882,168).

In another aspect of the present invention, polymer support can be the material that original position forms.In one embodiment, precursor can polymerization and/or the monomer or the macromonomer of crosslinked unsaturated group for containing.For example, these monomers or macromonomer can be injected area for treatment or are injected on the area for treatment surface and use radiation source (for example visible light or UV light) or free radical system (for example potassium peroxydisulfate and ascorbic acid or ferrum and hydrogen peroxide) in-situ polymerization then.Can be before reagent being injected the treatment site, simultaneously or carry out polymerization procedure afterwards immediately.The representational case description of compositions that carries out Raolical polymerizable is at WO 01/44307, and WO 01/68720, and WO 02/072166, and WO 03/043552, and WO 93/17669, and WO 00/64977, U.S. Patent number 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 and U.S. Patent Application Publication No. 2002/012796A1,2002/0127266A1,2002/0151650A1,2003/0104032A1 describes among 2002/0091229A1 and the 2003/0059906A1.

In another embodiment, described reagent can carry out electrophilic-necleophilic reaction and generate crosslinked substrate.For example, the 4-arm deutero-Polyethylene Glycol that connects (4-armed) mercaptan can connect the deutero-Polyethylene Glycol of NHS-in alkali condition (pH〉about 8) reaction down with the 4-arm.The representative example of carrying out the compositions of close electricity-nucleophilic cross-linking reaction is described in U.S. Patent number 5,752,974; 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; U.S. Patent Application Publication No. 2003/0077272; In PCT application publication number WO04/060405 and WO04/060346.Other example that operable original position forms material comprises based on those of protein cross and (is described in U.S. Patent number RE38158; 4,839,345; 5,514,379,5,583,114; 6,458,147; 6,371,975; U.S. Patent Application Publication No. 2002/0161399; 2001/0018598 and PCT publication number WO03/090683; WO 01/45761; WO 99/66964 and WO 96/03159).

The crosslinked polymer substrate that can be used to help prevent fibrous connective tissue formation or growth further and is additionally described below, and polymer support.Compositions can contain and send fibre modification-inhibitor near medical apparatus.When hope infiltration around device, when using or not using fibre modification-inhibitor, following compositions is particularly useful.Can be from for example, (a) synthetic material, (b) naturally occurring material, or (c) synthetic and naturally occurring mixtures of material prepares this type of polymeric material.Can be from for example, (a) a kind of component is the autoreactivity chemical compound, or two or more compound substrate that (b) react to each other.Usually, therefore these materials for liquid, and can spray or extrude so that send described compositions from device before sending.After sending, component material reacts to each other, and/or and somatic reaction, desirable effect is provided.In some cases, the material that reacts to each other must keep separating before being delivered to the patient, and only mixes before being delivered to the patient, so that they keep liquid form before sending.Of the present invention preferred aspect, the component of substrate is delivered to purpose position in the health with liquid condition, and in-situ polymerization takes place at this position.

First kind and second kind of synthetic polymer

In one embodiment, by the crosslinked polymer composition of first kind of synthetic polymer that will contain two or more nucleophilic groups and the second kind of synthetic polymer prepared in reaction that contains two or more electrophilic groups (in other words, crosslinked substrate), wherein electrophilic group can the covalent bond nucleophilic group.In one embodiment, every kind all right and wrong are immunogenic for first kind and second kind of polymer.Therefore in another embodiment, described substrate is cut enzymatic, and is for example insensitive and estimate to have persistency in the longer body than the compositions based on collagen to the cutting of matrix metalloproteinase (for example collagenase).

Term " polymer " used herein " refer to poly-alkyl, polyamino acid, polyalkylene oxide and polysaccharide or the like.Additionally, use for outside or per os, described polymer can be polyacrylic acid or carbopol.Term used herein " synthetic polymer " refers to polymer that non-natural exists and that produce by chemosynthesis.Therefore, naturally occurring protein such as collagen and naturally occurring polysaccharide such as hyaluronic acid foreclose especially.Comprise synthetic collagen and synthetic hyaluronic acid and their derivant.The synthetic polymer that contains nucleophilic or electrophilic group is also referred to as " multifunctional activatory synthetic polymer " at this paper.Term " multifunctional activatory " (or simply, " activatory ") refer to synthetic polymer, it is had two or more nucleophilics or electrophilic group by chemical modification, and its can react to each other (that is nucleophilic group and electrophilic group reaction) forms covalent bond.The type of multifunctional activatory synthetic polymer comprises that difunctionality is activatory, four senses are activatory and the polymer of limb ray.

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 with the synthetic polymer that contains a plurality of nucleophilic groups (that is, " many nucleophilic polymer ").In other words, their difunctionality activation at least, and more preferably trifunctional or the activation of four senses.If first kind of synthetic polymer is the activatory synthetic polymer of difunctionality, second kind of synthetic polymer must contain three or more functional groups so that obtain three-dimensional crosslinked network so.Most preferably, first kind and second kind of synthetic polymer contain at least three functional groups.

The synthetic polymer that contains a plurality of nucleophilic groups is also referred to as " many nucleophilic polymer " in this article usually.In order to be used for the present invention, many nucleophilic polymer must contain at least 2, more preferably at least 3 nucleophilic groups.If use the synthetic polymer only contain two nucleophilic groups, must use the synthetic polymer that contains 3 or more electrophilic groups so so that obtain three-dimensional crosslinked network.

The preferred many nucleophilic polymer that are used for the compositions and methods of the invention comprise synthetic polymer, and it contains, and are perhaps modified and contain a plurality of nucleophilic groups, as primary amino radical and sulfydryl.Preferred many nucleophilic polymer comprise: (i) synthetic polypeptide, and it is synthetic and contain two or more primary amino radicals or sulfydryl; (ii) Polyethylene Glycol, it is modified and contain two or more primary amino radicals or sulfydryl.Usually, sulfydryl and the reaction of electrophilic group tend to than the reaction of primary amino radical and electrophilic group carry out slower.

In one embodiment, many nucleophilics polypeptide is synthetic polypeptide, and it synthesizes and mixes amino acid residue (as lysine) that contains primary amino radical and/or the aminoacid (as cysteine) that contains sulfydryl.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 4000 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.) (Milwaukee WI) obtains Inc. with Aldrich Chemical.

Polyethylene Glycol can be according to for example, Poly (Ethylene Glycol) Chemistry:Biotechnical and Biomedical Applications, J.Milton Harris, ed., Plenum Press, the method that provides in the 22nd chapter of N.Y. (1992) contains a plurality of primary amino radicals or sulfydryl through chemical modification.Modified and Polyethylene Glycol that contain two or more primary amino radicals is called " polyamino PEG " in this article.Modified and Polyethylene Glycol that contain two or more sulfydryls is called " many-sulfydryl PEG " in this article.Term used herein " Polyethylene Glycol " comprises modified or deutero-Polyethylene Glycol.

The amino acids PEG of various ways can by commercial sources from the Shearwater polymer (Huntsville, Ala.) with from Huntsman Chemical Company (Utah) with title ＂ Jeffamine " obtain.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.

Polyamine is 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), diethylenetriamine (HN-(CH ₂-CH ₂-NH ₂) ₂) and three (2-amino-ethyl) amine (N-(CH ₂-CH ₂-NH ₂) ₃) also can be as the synthetic polymer that contains a plurality of nucleophilic groups.

The synthetic polymer that contains a plurality of electrophilic groups is also referred to as " how close electric polymer " in this article.For being used for the present invention, multifunctional activatory synthetic polymer must contain at least two, and more preferably at least 3 electrophilic groups are so that the three-dimensional crosslinked network of formation and many nucleophilic polymer.The preferred how close electric polymer that is used for the present composition is to contain two or more succinimidos that can form covalent bond with the nucleophilic group on other molecule.Succinimido with contain primary amino radical (NH ₂) material, as polyamino PEG, poly-(lysine), perhaps collagen has highly reactive.Succinimido with contain the material of sulfydryl (SH), have less reactive as many-sulfydryl PEG or the synthetic polypeptide that contains a plurality of cysteine residues.

Term used herein " contains two or more succinimidos " and is intended to comprise preferably the polymer that contains two or more succinimidos that can obtain by commercial sources, and must be chemically derived to contain the polymer of two or more succinimidos.Term used herein " succinimido " is intended to comprise other variation of sulfosuccinimide base and " general " succinimido.The existence of sodium sulfite part is used to increase the dissolubility of polymer on the sulfosuccinimide base.

Hydrophilic polymer, especially multiple deutero-Polyethylene Glycol is preferred in the compositions of the present invention.Term used herein " PEG " refers to have repetitive structure (OCH ₂-CH ₂) _nPolymer.Some of PEG specific, the activatory structure of four senses is at United States Patent (USP) 5,874, show among Fig. 4 to 13 of 500, here as a reference this patent citation.The example of suitable PEGS comprises PEG succinyl phosphorons amino propyl acid ester (SE-PEG), PEG succinimido butanimide (SSA-PEG) and PEG carbonic acid succinimide ester (SC-PEG).On the one hand, by with poly-(ethylene glycol) ether four-sulfydryl of tetramethylolmethane] (4-arm sulfydryl PEG) and tetramethylolmethane gather (ethylene glycol) ether four-succinimido 1,3-propanedicarboxylic acid] (4-arm NHSPEG) form crosslinked substrate as the reaction reaction original position.The structure of these reactants is at United States Patent (USP) 5,874, shows in 500.Each of these materials all has core, its structure can add the deutero-residue of ethylene oxide by each hydroxyl in tetramethylolmethane, the terminal hydroxyl (derived from ethylene oxide) of deriving is then seen to contain sulfydryl (thereby forming 4-arm sulfydryl PEG) or N-hydroxy-succinamide base (thereby formation 4-arm NHS is PEG), choose wantonly between ethylene oxide main backbone derived and reactive functional groups and have linking group, wherein this product can obtain with COSEAL from AngiotechPharmaceuticals Inc by commercial sources.Randomly, in one or two these molecules, there is group " D ", as more going through below.

As discussed above, be used for preferred activated polyglycol derivant of the present invention and contain succinimido as reactive group.Yet, can connect different activated groups along the site of the length of PEG molecule.For example, PEG can derive the formation official can activatory PEG propionic aldehyde (A-PEG), the perhaps activatory PEG carboxylic acid of sense glycerin ether (E-PEG), the perhaps activatory PEG-isocyanates of sense (I-PEG), the perhaps activatory PEG-vinyl sulfone of sense (V-PEG).

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

The hydrophobic polymer that has contained two or more succinimidos comprises, but be not limited to, two succinimido suberates (DSS), two (sulfosuccinimide base) suberates (BS3), 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) (DTSPP) and their analog and derivant.Above referenced polymer can (Rockford, III.), respectively with catalog number (Cat.No.) 21555,21579,22585,21554 and 21577 obtain from Pierce by commercial sources.

Be used for preferred hydrophobic polymer of the present invention and have carbochain usually no longer than about 14 carbon.Polymer with the carbochain of being longer than 14 carbon in fact has very weak dissolubility in aqueous solution usually, therefore, has the very long response time when with the aqueous solution of the synthetic polymer that contains a plurality of nucleophilic groups.

Some polymer as polyprotic acid, can be derived and contains two or more functional groups, as succinimido.Be used for polyprotic acid of the present invention and include, but not limited to tricarboxylic acids based on trimethylolpropane, based on the tetrabasic carboxylic acid of two (trimethylolpropanes), 1,5-pentanedicarboxylic acid., suberic acid, and hexadecandioic acid (hexadecane diacid) (thapsic acid).Many these polyprotic acid can (Wilmington DE) obtains from DuPont ChemicalCompany by commercial sources.According to conventional methods, can with polyprotic acid by with the N-hydroxy-succinamide (NHS) of suitable mole at N, N '-dicyclohexylcarbodiimide (DCC) exists down reactive chemistry to derive.

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 hexadecandioic acid (hexadecane diacid) (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, first kind of synthetic polymer will contain a plurality of nucleophilic groups (following with " X " representative), and it will react with the second kind of synthetic polymer that contains a plurality of electrophilic groups (with " Y " representative), cause covalently bound polymer, and will be as follows:

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

M≤2 wherein, n≤2, and m+n≤5;

Wherein exemplary X group comprises-NH ₂,-SH ,-OH ,-PH ₂, CO-NH-NH ₂, or the like, polymer-X wherein _mMiddle X group can be identical or different;

Wherein exemplary Y group comprises-CO ₂-N (COCH ₂) ₂,-CO ₂H ,-CHO ,-CHOCH ₂(epoxide) ,-N=C=O ,-SO ₂-CH=CH ₂,-N (COCH) ₂(that is, between two CH bases, having 5 yuan of heterocycles) with two keys ,-S-S-(C ₅H ₄N), or the like, polymer-Y wherein _nMiddle Y group can be identical or different;

Wherein Z is that nucleophilic group (X) and electrophilic group (Y) are united the functional group of generation.

As mentioned above, the present invention also imagines X and Y can be identical or different, and promptly synthetic polymer can have two different electrophilic groups, and perhaps two different nucleophilic groups are as glutathion.

In one embodiment, the main chain of at least a synthetic polymer comprises the alkylene oxide residue, Tathagata autoxidation ethylene, propylene oxide, and composition thereof residue.Term " main chain " refers to the pith of polymer.

For example, the synthetic polymer that contains the alkylene oxide residue can be described by formula X-polymer-X or Y-polymer-Y, and wherein X and Y as above define, term " polymer " " representative-(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 dual functional.

By linking group (following with " Q " representative) coupling polymer main chain, many linking groups are known or possible usually for needed X of functional group or Y.By the method for the multiple functionalized polymeric of many preparations, certain methods is listed below:

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

Exemplary 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-CO-NH-, it provides the synthetic polymer of 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-CO-NH-(X or Y).In these structures, n=1-10, R ¹=H or alkyl (that is CH, ₃, C ₂H ₅, etc.); R ²=CH ₂, or 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 situation ₁); Y=-CO ₂-N (COCH ₂) ₂And X=-NH ₂,-SH, or-during OH, gained reaction and Z group can be as follows:

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

Polymer-NH-CO-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.

Can between polymer and linking group, insert other group (if existence) (below with " D " expression).A purpose of this D group be influence the crosslinked intravital degradation rate of polymer composition, for example, increase degradation rate, perhaps reduce degradation rate.This is useful in many cases, for example, when medicine has been incorporated into substrate, and wishes to increase or reduce depolymerization speed to influence the drug delivery profile of desirable direction.Relate to every kind of first and second kinds of synthetic polymers with D and Q group cross-linking reaction be illustrated in following demonstration.

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

Some useful biodegradable groups " D " comprise from one or more alpha-hydroxy acids, for example, and lactic acid, glycolic, and cyclisation product (for example, lactide, Acetic acid, hydroxy-, bimol. cyclic ester), 6-caprolactone and amino acids formed polymer.This polymer can be called polylactide, poly-Acetic acid, hydroxy-, bimol. cyclic ester, poly-(altogether-lactide-Acetic acid, hydroxy-, bimol. cyclic ester); Poly--6-caprolactone, polypeptide (be also referred to as polyamino acid, for example, multiple dipeptides or tripeptides) and poly-(anhydride).

At the conventional method that is used for preparing the crosslinked polymer composition that is used for the context of the invention, 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.Because the formation of three-dimensional crosslinked network takes place in the reaction between the electrophilic group on nucleophilic group and the second kind of synthetic polymer on first kind of synthetic polymer.

The concentration that is used to prepare first kind of synthetic polymer of the present composition and second kind of synthetic polymer will depend on many factors and become, and described factor comprises type and the molecular weight and the desirable final application of used concrete synthetic polymer.Usually, when using many-amino PEG as first kind of synthetic polymer, it is preferably with about 0.5% to about 20% concentration use of final composition weight, and second kind of synthetic polymer is with about 0.5% to about 20% concentration use of final composition weight.For example, the final composition with 1 gram (1000 milligrams) gross weight contains and has an appointment 5 to about more than 200 milligrams-amino PEG and about 5 to about 200 milligrams of second kind of synthetic polymers.

The use of the higher concentration of first kind and second kind synthetic polymer will cause forming tightr crosslinked network, produce harder, more firm gel.Be intended for use in organizing the compositions of increase will use the concentration of the more high-end preferred concentration range for that is positioned at preferred concentration range for of first kind and second synthetic polymer usually.Plan prevents that as biological adhesive or be used to the compositions of adhesion from not needing for membrane and can contain than low copolymer concentration.

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 mince 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, above-mentioned one or both parent electricity-or the polymer of nucleophilic-end can with 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.

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

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

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

Contain and to cause with the existence of the protein of the functional group of functional group reactions on the how activatory synthetic polymer and polysaccharide component when mixing with synthetic polymer and/or forming crosslinked synthetic polymer-naturally occurring polymeric matrix when crosslinked.Particularly, when naturally occurring polymer (protein or polysaccharide) also contains nucleophilic group, during as primary amino radical, on second kind of synthetic polymer electrophilic group will with the primary amino radical on these components, and the reaction of the nucleophilic group on first kind of synthetic polymer, cause these other components to become the part of polymeric matrix.For example, being rich in the protein of lysine such as collagen can be especially and the reaction of the electrophilic group on the synthetic polymer.

On the one hand, naturally occurring protein is polymer, can be collagen.Term used herein " collagen ", or " collagen-based materials " refers to the collagen of form of ownership, comprise treated or modify and be intended to comprise and include, but are not limited to collagen from any type in any source, collagen from tissue extraction or reorganization generation, the collagen analog, collagen derivant, modified collagen, and denatured collagen, as gelatin.

Usually, compositions of the present invention can comprise the collagen from any source; For example, collagen can be from people or other mammal source, and as cattle or pig dermis and extraction of people's Placenta Hominis and purification, perhaps can recombinate or pass through other method produces.From the collagen formulations purification in the solution of Corii Bovis seu Bubali, nonantigenic substantially is well known in the art.U.S. Patent number 5,428,022 discloses from the method for extraction of people's Placenta Hominis and collagen purification.U.S. Patent number 5,667,839 disclose transgenic animal, comprise the method that produces recombinant human collagen in the milk of transgenic milch cow.Any type, the collagen that includes, but not limited to I, II, III, IV type or its combination can be used for compositions of the present invention, although usually preferred type i collagen.Can use the collagen protein that contains non-end peptide (atelopeptide) or end peptide; Yet, when the collagen that uses from the xenogenesis source, during as bovine collagen, preferred non-end peptide collagen usually because with contain the collagen of holding peptide and compare it and have the immunogenicity that reduces.

Be not preferred in the compositions of the present invention in the past, although crosslinked collagen before can using by the crosslinked collagen of method such as heat, radiation or chemical cross-linking agent.Noncrosslinking non-end peptide fiber collagen can (Santa Barbara CA), obtains with trade mark ZYDERM I collagen and the ZYDERM II collagen concentration with 35mg/ml and 65mg/ml respectively from Inamed Aesthetics by commercial sources.The non-end peptide fiber collagen of glutaraldehyde cross-linking can (Santa Barbara CA) obtains with the concentration of trade mark ZYPLAST collagen with 35mg/ml from InamedCorporation by commercial sources.

Be used for collagen of the present invention and be generally aqueous suspension, its concentration arrives about 120mg/ml for about 20mg/ml; Preferred about 30mg/ml is to about 90mg/ml.

Because its viscosity concordance, non-fiber collagen can be preferred for being intended to as in the compositions of biological adhesive.Term " non-fiber collagen " refers to point out as the optical clarity of the waterborne suspension by collagen, be essentially any modification of non-fibers form or the collagen-based materials of unmodified under pH7.

Can be used for compositions of the present invention for the collagen of non-fibers form.Term " non-fiber collagen " is intended to comprise the collagen-type of the non-fiber of native form as used herein, thereby and is the collagen of non-fibers form through chemical modification under neutral pH or about neutral pH.The non-fiber of native form (perhaps microfibre) collagen-type comprises IV, VI or VII form.

In neutral pH is that the collagen of the chemical modification of non-fibers form comprises succinyl group collagen and methylated collagen; they both can be according to the U.S. Patent number of authorizing 14 days Augusts in 1979 of Miyata etc. 4; the method preparation of describing in 164,559 is quoted as a reference described patent is complete.Because its inherent viscosity, methylated collagen is preferred for as in the disclosed biological viscosity compositions in the US application serial No. 08/476,825.

The collagen that is used for crosslinked polymer composition of the present invention can begin with fibers form, makes non-fibrosis by adding one or more fiber distintegrants then.The fiber distintegrant must exist with capacity makes that collagen is non-fiber shape basically under pH7, as above-mentioned.Be used for fiber distintegrant of the present invention and include, but not limited to multiple biocompatible alcohol, aminoacid (for example, arginine), inorganic salt (for example, sodium chloride and potassium chloride), and sugar (the multiple sugar that for example, comprises sucrose).

On the one hand, polymer can be collagen or collagen derivant, for example, and methylated collagen.The example that original position forms compositions uses poly-(ethylene glycol) ether four-sulfydryl of tetramethylolmethane] (4-arm sulfydryl PEG), poly-(ethylene glycol) ether four-succinimido 1,3-propanedicarboxylic acid of tetramethylolmethane] (4-arm NHS PEG) as pharmacy response and methylated collagen as pharmacy response.Said composition can produce crosslinked hydrogel when mixing with the buffer agent that suits.(see, for example, U.S. Patent number 5,874,500; 6,051,648; 6,166,130; 5,565,519 and 6,312,725).

On the other hand, naturally occurring polymer can be a glycosaminoglycans.Glycosaminoglycans can contain anion and Cationic functional groups as hyaluronic acid in every polymeric chain, it can form intramolecularly and/or intermolecular ionomer, and is responsible for hyaluronic thixotroping (perhaps shear thinning) character.

In some aspects, glycosaminoglycans can be derived.For example, can by deacetylated, desulfurization acidify or both chemically derived glycosaminoglycans with obtain can with the primary amino radical of electrophilic group reaction on the synthetic polymer molecule.Can comprise following according to one or both deutero-glycosaminoglycans of said method: 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, two kinds of unactual mixing of synthetic polymer are expressed into that time patient's the tissue up to two kinds of polymer from the syringe needle point.This allows most cross-linking reactions to react in position, avoids the syringe needle blocking problem, if two kinds of synthetic polymers mix too early and send crosslinked too fast between preceding two kinds of components from syringe needle, the syringe needle blocking problem takes place so usually.Use as above-mentioned pair of compartment syringe allows the syringe of use than minor diameter, when in delicate tissue, when carrying out step as around eyes, is favourable than minor diameter.

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+many crosslinkable components

As mentioned above, first kind and/or second kind of synthetic polymer can with hydrophilic polymer, for example collagen or methylated collagen are combined to form and can be used for compositions of the present invention.In a common embodiment, can be used for compositions of the present invention and comprise that hydrophilic polymer makes up two or more crosslinkable components.This embodiment is the chapters and sections more detailed description below.

The hydrophilic polymer component:

The hydrophilic polymer component can be synthetic or naturally occurring hydrophilic polymer.Naturally occurring hydrophilic polymer can include, but are not limited to: protein, and as collagen and derivant thereof, 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 (for example, methylated collagen) and glycosaminoglycans are the preferred naturally occurring hydrophilic polymeies that is used for this paper.

Usually, can use collagen in the compositions of the inventive method from any source; For example, for example, collagen can be from people or other mammal source, and as cattle or pig dermis and extraction of people's Placenta Hominis and purification, perhaps can recombinate or pass through other method produces.From the collagen formulations purification in the solution of Corii Bovis seu Bubali, nonantigenic substantially is well known in the art.5,428,022 of U.S. Patent number Palefsky etc., it discloses from the method for extraction of people's Placenta Hominis and collagen purification.Also referring to the U.S. Patent number 5,667,839 of Berg, it discloses transgenic animal, comprises the method that produces recombinant human collagen in the milk of transgenic milch cow.Unless otherwise noted, term used herein " collagen " or " collagen-based materials " refer to the collagen of form of ownership, comprise the collagen of processing or modifying.

Any type, the collagen that includes, but not limited to I, II, III, IV type or its combination can be used for compositions of the present invention, although usually preferred type i collagen.Can use and contain non-end peptide or end peptide collagen; Yet, when the collagen that uses from natural origin, during as bovine collagen, preferred non-end peptide collagen usually because it with contain the collagen of holding peptide and compare and have littler immunogenicity.

Be not preferred in the compositions of the present invention in the past, although crosslinked collagen before can using 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.

It is common to be used for collagen of the present invention, although be not essential, is waterborne suspension, and its concentration arrives about 120mg/ml for about 20mg/ml, and preferably about 30mg/ml is to about 90mg/ml.

Although preferred complete collagen also can use the collagen of degeneration, so-called gelatin in compositions of the present invention.Gelatin has the benefit than the faster degraded of collagen.

Because the bigger concentration of surface area that it is bigger and reactive group, preferred non-fiber collagen usually.Term " non-fiber collagen " refers to point out as the optical clarity of the waterborne suspension by collagen, be essentially any modification of non-fibers form or the collagen-based materials of unmodified under pH7.

Can be used for compositions of the present invention for the collagen of non-fibers form.Term " non-fiber collagen " is intended to comprise the collagen-type of the non-fiber of native form as used herein, thereby and is the collagen of non-fibers form through chemical modification under neutral pH or about neutral pH.The non-fiber of native form (perhaps microfibre) collagen-type comprises IV, VI or VII form.

In neutral pH is that the collagen of the chemical modification of non-fibers form comprises succinyl group collagen, propylated collagen, ethylization collagen and methylated collagen or the like; they both can be according to the U.S. Patent number 4 of Miyata etc.; 164; the method preparation of describing in 559 is quoted as a reference described patent is complete.Because its inherent viscosity, preferable methyl collagen especially, open in the U.S. Patent number 5,614,587 as Rhee etc.

The collagen that is used for cross-linkable composition of the present invention can begin with fibers form, makes non-fibrosis by adding one or more fiber distintegrants then.The fiber distintegrant must exist with capacity makes that collagen is non-fiber basically under pH7, as above-mentioned.Be used for fiber distintegrant of the present invention and include, but not limited to multiple biocompatible alcohol, aminoacid, inorganic salt, and sugar, especially preferred biocompatible alcohol.Preferred biocompatible alcohol comprises glycerol and propylene glycol.The alcohol of biocompatible, as ethanol, methanol and isopropyl alcohol since they the potential adverse effect of the patient body of accepting them is not preferred among the present invention.Preferred amino acids comprises arginine.Preferred inorganic salt comprises sodium chloride and potassium chloride.Although sugar, as comprise that the multiple sugar of sucrose can be used for enforcement of the present invention, they are preferred not as the fiber distintegrant of other type, because they have the cells in vivo toxic effect.

Because fiber collagen has the reactive group of small surface area and low concentration than non-fiber collagen, so fiber collagen is more not preferred.Yet, disclosed in 587 as United States Patent (USP) 5,614, if do not need optical clarity, fiber collagen so, perhaps non-fiber collagen and fibrocollagenous mixture can be preferred in the long-standing in vivo compositions of meaning.

Can also use synthetic hydrophilic polymer among the present invention.Useful synthesis hydrophilic polymer includes, but not limited to polyalkylene oxide, and especially Polyethylene Glycol and poly-(ethylene oxide)-poly-(propylene oxide) copolymer comprises block and random copolymer; Polyhydric alcohol, as glycerol, polyglycereol (especially highly branched polyglycereol), propylene glycol and the propylene glycol that replaces with one or more polyalkylene oxides, for example, single-, two-and three-polyoxyethylene glycerol, single-and two-polyoxyethylated propylene glycol, and single-and two-polyoxyethylene trimethylene glycol; The polyoxyethylene sorbitol, the polyoxyethylene 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 acrylic acid 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.

Crosslinkable component:

Compositions of the present invention can comprise many crosslinkable components.Every kind of crosslinkable component participates in causing the reaction of crosslinked substrate.Before finishing cross-linking reaction, crosslinkable component provides necessary adhesion properties, and it makes can carry out the inventive method.

Select crosslinkable component to make crosslinked generation can be used for biocompatible, the non-immunogenic substrate of multiple background, described background comprises that adhesion prevents, bioactivator is sent, organizes increase, and other application.Crosslinkable component of the present invention comprises: component A, it has m nucleophilic group, wherein m 〉=2, and B component, its have can with n electrophilic group, wherein n of m nucleophilic group reaction 2 and m+n 4.Can also have the third optional component: optional component C, it has at least one functional group, this functional group be parent electricity and can with the nucleophilic group reaction of component A, perhaps functional group be nucleophilic and can with the electrophilic group reaction of B component.Thereby component A, B and C go up total summation 〉=5 of the functional group's (when existing) that exists; That is, total functional group of obtaining of m+n+p necessary 〉=5; Wherein p goes up functional group's number for component C, and as noted, 〉=1.Every kind of component all is biocompatible and non-immunogenic, and at least a component comprises hydrophilic polymer.And as will be appreciated, compositions can contain other linked D, E, F or the like, forms in the formation of crosslinked biomaterial by the covalent bond with other component thereby have one or more reactive nucleophilics or electrophilic group and participation.

M nucleophilic group on the component A can be all 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, represent described component by following structural formula

(I) R ¹(-[Q ¹] _q-X) _m(component A),

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

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

Wherein:

R ¹, R ²And R ³Be independently selected from C ₂To C ₁₄Alkyl contains heteroatomic C ₂To C ₁₄Alkyl, and hydrophilic polymer, and hydrophobic polymer, condition are R ¹, R ²And R ³At least one be 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:

X can be any nucleophilic group almost, as long as can react with electrophilic group Y.Similarly, Y can be any electrophilic group almost, as long as can react with X.Unique restriction is actual restriction, is that the reaction between X and the Y should quite soon and react when mixing with aqueous medium automatically, does not need heating or the deleterious or abiotic degradable catalysts of possibility or other chemical agent.Also preferred, although be not essential, react and do not need ultraviolet or other radiation.Ideally, be reflected at 60 minutes between X and the Y, finish in preferred 30 minutes.Most preferably, be reflected at about 5 to 15 minutes or shorter time in finish.

The example of suitable nucleophilic group as X includes, but 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, or the like, R wherein ⁴And R ⁵Be alkyl, be generally alkyl or monocyclic aryl, preferred alkyl, most preferably low alkyl group.Organic metal part also is the operable nucleophilic group of the present invention, especially as the organic metal part of carbanion donor.Yet, not preferred organic metal nucleopilic reagent.The example of organic metal part comprises: Grignard degree of functionality-R ⁶MgHal, wherein R ⁶Be carbon atom (replacement or unsubstituted), Hal is a halogen, usually bromine, iodine or chlorine, preferably bromine; The degree of functionality that contains lithium, lithium alkylide group usually; The degree of functionality that contains sodium.

It will be appreciated by one of skill in the art that some nucleophilic group must be with the alkali activation reacting with electrophilic reagent.For example, when having close electric sulfydryl and hydroxyl in the compositions crosslinkable, compositions must and provide-S with the aqueous alkali reaction so that except that deprotonation ^-Or-O ^-Kind is reacting with electrophilic reagent.Participate in cross-linking 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.

Must carry out in the compositions crosslinkable, i.e. the selection of electrophilic group on the B component, thus may react with specific nucleophilic group.Thereby, when X partly is amino, select Y group to react with amino.Similarly, when X partly was the sulfydryl part, corresponding electrophilic group was the sulfydryl reactive group, or the like.

As an example, when X was amino (although common not necessarily primary amino radical), the electrophilic group of the last existence of Y was amino reactive group, as, be not limited to: (1) carboxylate comprises cyclic ester and ＂ activation ＂ ester; (2) the acid chloride group (CO-Cl); (3) anhydride ((CO)-O-(CO)-R); (4) ketone and aldehyde comprise α, beta-unsaturated aldehyde and ketone, as-CH=CH-CH=O and-CH=CH-C (CH ₃)=O; (5) halogenide; (6) isocyanates (N=C=O); (7) isothiocyanate (N=C=S); (8) epoxide; (9) activatory hydroxyl (for example, with conventional activator such as carbonyl dimidazoles 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 (CO ₂-C=CH ₂), methacrylate (CO ₂-C (CH ₃)=CH ₂)), ethyl acrylate (CO ₂-C (CH ₂CH ₃)=CH ₂) and the vinyl imino group (CH=CH-C=NH).Because hydroxy-acid group itself is difficult for the reaction with nucleophilic amine, 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 well known by persons skilled in the art and describe at relevant teaching material and document.

Similarly, when X was sulfydryl, the electrophilic group of the last existence of Y was 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 PCT publication number WO 00/62827 as Wallace etc.As explaining in detail that therein this type of " sulfydryl reactivity " 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-hydroxyl sulfonation glutarimide 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 can be used to promote key to form, for example, 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide can be used for 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 degree that forms other type bonds.For example, the chemical compound that contains the methylene imine ester derivant can form imino group-thioester bond with sulfydryl.Alternatively, the sulfydryl reactive group can be used for forming 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.

Another kind of sulfydryl reactive group and sulfydryl form thioether bond.This type of group comprises maleimide amino, haloalkyl, epoxy, imino group and aziridino and the alkene (comprise and put together alkene) of maleimide amino, replacement; as ethylene sulfonyl, aziridinyl, acrylic acid, methacrylic acid; and α, β-undersaturated aldehyde and ketone or the like.Such sulfydryl reactive group is especially preferred, because thioether bond can provide crosslinked and longer faster body internal stability.

When X be-during OH, the close electric functional group on all the other components must and hydroxyl reaction.Hydroxyl can be as above about the hydroxy-acid group activation, perhaps it can be in the presence of alkali directly and enough reactive electrophilic reagents, as epoxide group, aziridine group, carboxylic acid halides or anhydride reaction.

When X is organic metal nucleopilic reagent such as Grignard degree of functionality or alkyl lithio, be to contain those of carbonyl with the suitable close electric functional group of its reaction, for example comprise ketone and aldehyde.

Understand that also some functional group can be used as nucleopilic reagent or electrophilic reagent reaction, this depends on selected reaction gametophyte and/or reaction condition.For example, hydroxy-acid group can still usually as electrophilic reagent, allow to follow the replacement hydroxyl in the affine attack of carbonyl carbon with the nucleopilic reagent that arrives as the nucleopilic reagent reaction in the presence of great alkali.

Everyly below (only as an example) (, omit optional linking group Q when causing during the electric component of specific parent covalent bond in the cross-linked structure to comprise in the crosslinkable component of specific nucleophilic component covalent bond for clear ¹And Q ²):

Table

Linking group:

X of functional group on the optional components C and Y and FN can be directly connected to the chemical compound core (R on the difference optional components C ¹, R ²Or R ³), perhaps they can directly connect by linking group, and long linking group is also referred to as " cahin extension agent ".At structural formula (I), (II) and (III) in, optional linking group passes through Q ¹, Q ²And Q ³Q is wherein worked as in representative, and r and s equal at 1 o'clock, has linking group (Y, Fn, m n and p such as front define for R, X).

Suitable linking group is well known in the art.See, for example, International Patent Publication No. WO 97/22371.Linking group can be used to avoid form relevant sterically hindered problem with intermolecular direct key sometimes.Linking group can additionally be used for some multifunctional activatory chemical compounds are linked together and obtain bigger molecule.In preferred embodiments, linking group can be used to use with the gained gel formation after change the degraded character of compositions.For example, linking group can be incorporated among component A, B or the optional components C to promote hydrolysis, hinders hydrolysis, and the enzymatic degradation site perhaps is provided.

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 as can be by obtaining in conjunction with lactic acid and glycolic; Based on the key of lactone, as can be by obtaining in conjunction with caprolactone, valerolactone, gamma-butyrolacton with to-Er Evil ketone; 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.Compare, thereby the neutral body bulky group can be used to reduce reactivity and reduces coupling speed near the functional group owing to sterically hindered.

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

Table

Linking group	Component structure
		-O-(CH 2) n-	Component A:R 1-O-(CH 2) n-X B component: R 2-O-(CH 2) n-Y optional components C:R 3-O-(CH 2) n-Z

Linking group	Component structure
		-S-(CH 2) n-	Component A:R 1-S-(CH 2) n-X B component: R 2-S-(CH 2) n-Y optional components C:R 3-S-(CH 2) n-Z
-NH-(CH 2) n-	Component A:R 1-NH-(CH 2) n-X B component: R 2-NH-(CH 2) n-Y optional components C:R 3-NH-(CH 2) n-Z
		-O-(CO)-NH-(CH 2) n-	Component A:R 1-O-(CO)-NH-(CH 2) n-X B component: R 2-O-(CO)-NH-(CH 2) n-Y optional components C:R 3-O-(CO)-NH-(CH 2) n-Z
-NH-(CO)-O-(CH 2) n-	Component A:R 1-NH-(CO)-O-(CH 2) n-X B component: R 2-NH-(CO)-O-(CH 2) n-Y optional components C:R 3-NH-(CO)-O-(CH 2) n-Z
		-O-(CO)-(CH 2) n-	Component A:R 1-O-(CO)-(CH 2) n-X B component: R 2-O-(CO)-(CH 2) n-Y optional components C:R 3-O-(CO)-(CH 2) n-Z
-(CO)-O-(CH 2) n-	Component A:R 1-(CO)-O-(CH 2) n-X B component: R 2-(CO)-O-(CH 2) n-Y optional components C:R 3-(CO)-O-(CH 2) n-Z
		-O-(CO)-O-(CH 2) n-	Component A:R 1-O-(CO)-O-(CH 2) n-X B component: R 2-O-(CO)-O-(CH 2) n-Y optional components C:R 3-O-(CO)-O-(CH 2) n-Z
-O-(CO)-CHR 7-	Component A:R 1-O-(CO)-CHR 7-X B component: R 2-O-(CO)-CHR 7-Y optional components C:R 3-O-(CO)-CHR 7-Z
		-O-R 8-(CO)-NH-	Component A:R 1-O-R 8-(CO)-NH-X B component: R 2-O-R 8-(CO)-NH-Y optional components 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 (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 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 hetero atom is selected from N, 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.

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 preferably 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, and especially Polyethylene Glycol and poly-(ethylene oxide)-poly-(propylene oxide) copolymer comprises block and random copolymer; Polyhydric alcohol, as glycerol, polyglycereol (especially highly branched polyglycereol), propylene glycol and the propylene glycol that replaces with one or more polyalkylene oxides, for example, for example, single-, two-and three-polyoxyethylene glycerol, single-and two-polyoxyethylated propylene glycol, and single-and two-polyoxyethylated propylene glycol; The polyoxyethylene sorbitol, the polyoxyethylene 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, dendrimeric, 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 of chemosynthesis, and is especially synthetic and in conjunction with containing the aminoacid (as lysine) of primary amino radical and/or containing many nucleophilics polypeptide of the aminoacid (for example, cysteine) of sulfydryl.Especially preferably poly-(lysine), it is the polymer of the synthetic generation of lysine (145MW).Prepared and had 6 poly-(lysines) to about 4000 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..

Synthetic crosslinkable hydrophilic polymer can be homopolymer, block copolymer, random copolymer, perhaps graft copolymer.In addition, polymer can be linear or branched, if branched, can be highly branched, dendrimeric, 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 cutting 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 the oligomerization or the poly fragment that are attached in the hydrophilic polymer usually.Biodegradable oligomerization of the property illustrated and poly fragment for example comprise, poly-(aminoacid) fragment, poly-(ortho esters) fragment, poly-(orthocarbonic ester) fragment, or the like.

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.

For PEG, at first, multiple functionalized poly (ethylene glycol) has been effective to (see Abuchowski etc., Enzymes as Drugs, John Wiley ﹠amp such as protein modification; Sons:New York, N.Y. (1981) pp.367-383; With Dreborg etc., Crit.Rev.Therap.Drug C arrier Syst. (1990) 6:315), chemistry of peptides (is seen Mutter etc., The Peptides, Academic:New York, N.Y.2:285-332; With Zalipsky etc., Int.J.Peptide Protein Res. (1987) 30:740) and the synthetic of polymeric drug (see Zalipsky etc., Eur.Polym.J. (1983) 19:1177; With Ouchi etc., J.Macromol.Sci.Chem. (1987) A24:1011) in the field.

The activated form of PEG comprises multifunctional activatory PEG, can obtain by commercial sources, and use the known method preparation easily.For example, see Poly (ethylene Glycol) Chemistry:Biotechnical and Biomedical Applications, J.Milton Harris, ed., Plenum Press, the 22nd chapter of NY (1992); With Shearwater Polymers, Inc.Catalog, PolyethyleneGlycol Derivatives, 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 N-hydroxy-succinamide, N-hydroxysulphosuccinimide or the like esterification 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 polymer of about 14 carbon atoms at most with only using, to avoid the relevant problem of dissolubility between the reaction period.

Lower-molecular-weight component:

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 replacing the low-molecular-weight core with primary amino radical, component can be for example, ethylenediamine (H ₂N-CH ₂CH ₂-NH ₂), butanediamine (H ₂N-(CH ₄)-NH ₂), five methylene diamine (cadaverine) (H ₂N-(CH ₅)-NH ₂), hexamethylene diamine (H ₂N-(CH ₆)-NH ₂), two (2-amino-ethyl) amine (HN-[CH ₂CH ₂-NH ₂] ₂), or three (2-amino-ethyl) 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.Be used for polyprotic acid of the present invention and include, but not limited to tricarboxylic acids based on trimethylolpropane, based on the tetrabasic carboxylic acid of two (trimethylolpropanes), 1,5-pentanedicarboxylic acid., suberic acid, and hexadecandioic acid (hexadecane diacid), 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 the like.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 of two kinds of reaction liquids of combination is well known in the art, and comprises the U.S. Patent number 6,454,786 of Holm etc.; 6,461,325 of Delmotte etc.; 5,585,007 of Antanavich etc.; 5,116,315 and the Redl etc. of Capozzi etc. 4,631,055 in the system described.

Preserve and handle:

Because crosslinkable component contains the electrophilic group with water reaction, thus one or more close electric components usually with aseptic, dried forms is preserved 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 mince littler granule.

Therefore the component that contains multiple nucleophilic group is not that water is reactive and can kept dry or preserve in aqueous solution usually.If preserve with dry, granular solids, the various ingredients of compositions crosslinkable can be mixed in single container and preserve so.All components should be up to just taking place with preceding with mixing of water, saline or other aqueous medium.

In alternative embodiment, linked can be mixed in a kind of 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, water or pH are the sulfydryl reactive component that the preparation of about 5 to 6 dilution buffer liquid replaces with maleimide amino or succinimido, as PEG.The pK that is used to prepare many sulfydryls component such as sulfydryl-PEG is the quick-gelatinizing time of the compositions of about buffer of 8 to 10.5 mixture of can be used for realizing containing sulfydryl-PEG and SG-PEG.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+fibrinogen and/or thrombin are (for example, Costasis)

Also having on the other hand, polymer composition can comprise collagen, its combination 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 operation on the middle ear.Because preparation and the multiple variation for preparing the method for said preparation, other plasma proteins (for example, albumin, plasminogen, vWF ELISA, VIII factor or the like) can exist or can not be present in fibrinogen/FXIII separator.

Collagen, preferably hypoallergenic collagen is present in the compositions with the amount of the bond property of enough thickener compositions and increase preparation.Collagen can be non-end peptide collagen or end peptide collagen, for example, and natural collagen.Except thickener composition, collagen also comes increased fiber albumen by macromole lattice structure or support as the absorption of fibrin network.This has provided the greater strength and the durability of gained gelled block, and (for example, AFG) compare, this grumeleuse has the fibrinogen of relative low concentration with multiple spissated self property fibrin virgin rubber preparation.

It is " near natural " at least in its architectural feature that used form of collagen can be described as.It can further be characterized by at the pH that is higher than 5 and cause insoluble fibre; Remove non-crosslinked or as the complex combination thing, the part of bone for example, it is usually by fibrous greater than 50nm of in a small amount diameter by weight, about 1 to 25% volume usually, and the change of very little (if there is) is basically arranged in fibriilar helical structure.In addition, collagen compositions must be able to strengthen the gelation in the surgical adhesions compositions.

Can use many by the obtainable collagen formulations of commercial sources.ZYDERM CollagenImplant (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 obtain with fiber slurry and the solution in the isotonic saline solution (pH7.2) of phosphoric acid buffer, and available thin gauge needle injection.As different, can use the crosslinked with collagen 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.Collagen has the endogenous crosslinked effect that simulation is found in the body in many tissues.

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 from multiple source (comprising Parke-Davis), packs in the bottle with buffer salt and stabilizing agent lyophilizing usually, and it provides about 1000NIHU to 10, the thrombin activity of 000NIHU.Usually by sterile distilled water or the reconstruct of isotonic saline solution adding powder are prepared thrombin.Alternatively, can use the coagulant 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, C1-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.

Other case description that forms material based on proteinic crosslinked original position is in for example, U.S. Patent number RE38158; 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 WO 03/090683; WO 01/45761; WO 99/66964 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, and for example, reactive group connects core by one or more linking groups.

At least one the key that each that must be present in three reactive groups in the autoreaction chemical compound can experience with remaining two reactive group forms reaction.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 experiences cross-linking reaction when many identical autoreaction chemical compounds combinations, 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 ³Representative, 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 interact and form three dimensional matrix.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:

Thereby in formula (II), a and b are 1; C is 4; Core R ' is a hydrophilic polymer, four sense activated polyglycol (C (CH ₂-O-) ₄X ' is the electrophilic reaction base, succinimido; Y ' is necleophilic reaction base-CH-NH ₂L ⁴For-C (O)-O-; L ⁵For

-(CH ₂-CH ₂-O-CH ₂) _x-CH ₂-O-C(O)-

(CH ₂) ₂-。

Can easily synthesize autoreaction chemical compound of the present invention by technology well known in the art.Provide representative synthetic below:

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 less than 5 minutes, and preferably less than in 2 minutes, term " immediately " is intended to refer to less than in 1 minute, preferably 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 preferred embodiments, R is a hydrophilic polymer.In another preferred embodiment, X is a nucleophilic group, and Y is an electrophilic group, and Z is close electricity 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 of reactive group equates basically.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.Usually preferred 1:1:1 mol ratio.

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 that falls into preferred concentration range for usually.Being intended to does not need for film and therefore contains the autoreaction chemical compound of low concentration as biological adhesive or the compositions that adheres to prevention.

1. Parent's electricity and necleophilic reaction base

In one embodiment of the invention, reactive group is close electricity and nucleophilic group, its experience 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 close electricity or nucleophilic group.

X can be any nucleophilic group almost, if can with electrophilic group Y and with Z (when Z be the electric (Z of parent _EL) time) react.Similarly, Y can be any electrophilic group almost, if can with X and 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 degree of functionality that contains lithium, lithium alkylide group usually; The degree of functionality that contains 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 be 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) isocyanate group (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 acrylic acid (O (CO)-C=CH ₂), methacrylic acid (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, the amine reactive group contains the electrophilic reaction carbonyl of the nucleophillic attack that is subject to primary amine or secondary amine, for example, and carboxylate above-mentioned and aldehyde, and carboxyl is (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 can react formation reactive electrophilic group, N-hydroxyl-succinimide ester or N-hydroxysulphosuccinimide ester respectively with N-hydroxyl-butanimide or the N-hydroxysulphosuccinimide that alkoxyl replaces in the presence of DCC.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 degree 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, the sulfydryl reactive group can be used for forming 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.

Another kind of sulfydryl reactive group and sulfydryl form thioether bond.This type of group comprises maleimide amino, haloalkyl, epoxy, imino group and aziridino and the alkene (comprise and put together alkene) of maleimide amino, replacement; as ethylene sulfonyl, aziridinyl, acrylate, methacrylate; and α, β-undersaturated aldehyde and ketone or the like.

When X be-during OH, the close electric functional group on all the other components must and hydroxyl reaction.Hydroxyl can be as above about the hydroxy-acid group activation, perhaps it can be in the presence of alkali directly and enough reactive electrophilic groups, react as epoxide group, aziridine group, carboxylic acid halides or anhydride or the like.

When X is organic metal nucleopilic reagent such as Grignard degree of functionality or alkyl lithio, be to contain those of carbonyl with the suitable close electric functional group of its reaction, for example comprise ketone and aldehyde.

Understand that also some functional group can be used as nucleopilic reagent or electrophilic reagent reaction, this depends on selected reaction gametophyte and/or reaction condition.For example, hydroxy-acid group can be in the presence of great alkali as the nucleophilic group reaction, but usually as electrophilic group, allow the nucleophillic attack on carbonyl carbon and follow the replacement hydroxyl with the nucleophilic group of introducing.

Be elucidated later herein below these and other embodiment, the covalent bond that produces after specific necleophilic reaction base and the specific electrophilic reaction base covalent bond on the autoreaction chemical compound in its mesostroma comprises (only as an example) following table:

Table

For the autoreaction chemical compound that contains parent's electricity and necleophilic reaction base, initial environment usually can be for dry and aseptic.Because electrophilic group and water reaction, so will prevent hydrolysis with aseptic, dried forms preservation.Dry synthetic polymer can be compression molded into thin slice or film, it can restraint radiosterilization with γ or e-then.Gained desciccator diaphragm or sheet can be cut into desirable size or mince littler granule.The change of exsiccant initial environment will comprise the adding aqueous medium usually.

In one embodiment, initial environment can be an aqueous medium, as low pH buffer, promptly has the pH less than about 6.0, and wherein all right and wrong are reactive for parent's electricity and nucleophilic group.The suitable liquid medium of preserving this compounds 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.The change of initial low pH aqueous environments will generally include increase pH and arrive pH7.0 at least, more preferably increase pH and arrive pH9.5 at least.

In another embodiment, the change of initial dry environment comprises and the autoreaction chemical compound is dissolved in to form homogeneous phase solution in first kind of buffer of pH in about 1.0 to 5.5 scopes and (ii) add pH to this homogeneous phase solution be second kind of buffer of about 6.0 to 11.0.Buffer can be aqueous and can be any pharmaceutically acceptable alkalescence and acidic composition.Term " buffer " is used to refer to acidity and alkaline aqueous solution with ordinary meaning, and wherein this solution can provide the buffering effect function of (that is, adding the resistance that pH is changed behind the bronsted lowry acids and bases bronsted lowry) with bringing into play in compositions of the present invention.For example, the autoreaction chemical compound can be the form of even dried powder.This powder makes up to form the homogeneous phase acidic aqueous solution with the buffer with about pH of 1.0 to 5.5 then, and this solution is combined to form reaction solution with the buffer with about pH of 6.0 to 11.0 then.For example, the 0.375g dried powder can be used for providing homogeneous phase solution with the combination of 0.75g acidic buffer after mixing, and wherein the combination of this solution and 1.1g alkaline buffer is to provide the reactant mixture that forms three dimensional matrix basically immediately.

Acidic buffer with about pH of 1.0 to 5.5 comprises (being used to illustrate and do not limit): citric acid, hydrochloric acid, phosphoric acid, sulphuric acid, AMPSO (3-[(1,1-dimethyl-2-hydroxyethyl) amino] 2-hydroxyl-propane sulfonic acid), the solution of acetic acid, lactic acid and their combination.In preferred embodiments, acidic buffer is the solution of citric acid, hydrochloric acid, phosphoric acid, sulphuric acid and their combination.No matter accurate acidulant, acidic buffer preferably has the reactive pH that hinders nucleophilic group on the core.For example, 2.1 pH enough hinders the nucleophilicity of sulfydryl usually.When core contains amido as nucleophilic group, preferred usually low pH.Usually, acidic buffer is an acid solution, and it is when contact during nucleophilic group, makes the non-relatively nucleophilic of those nucleophilic groups.

Representative acidic buffer is the hydrochloric acid solution, has the concentration of about 6.3mM and 2.1 to 2.3 pH.Can promptly, prepare this buffer by also with dense hydrochloric acid and hydration by the dense hydrochloric acid of dilute with water.Similarly, this buffer A can also be by diluting 2 liters of volumes with the dense hydrochloric acid of 1.23g, perhaps with 3 liters of volumes of the dense hydrochloric acid dilution of 1.84g, perhaps with 4 liters of volumes of the dense hydrochloric acid dilution of 2.45g, perhaps, perhaps 6 liters of volumes of the dense hydrochloric acid dilution of 3.68g are prepared easily 5 liters of volumes of the dense hydrochloric acid dilution of 3.07g.Reason for safety preferably is added to concentrated acid in the water.

Alkaline buffer with about pH of 6.0 to 11.0 comprises (as illustrating and not limiting): glutamate, Glu, acetate, carbonate and bicarbonate are (for example, sodium carbonate, crystal carbonate and sodium bicarbonate), borate, phosphate and hydrophosphate (for example, one hypophosphite monohydrate sodium dihydrogen and sodium hydrogen phosphate), and the combination solution.In preferred embodiments, alkaline buffer is the solution of carbonate, phosphate and combination thereof.

Usually, alkaline buffer in when the homogeneous phase solution that adds chemical compound and first kind of buffer with the aqueous solution of the effect of acidic buffer, thereby nucleophilic group obtains their nucleophilic feature (sheltering by the effect of acidic buffer) once more on the core, thereby allows the electrophilic group on nucleophilic group and the core to interact.

Representative alkaline buffer is carbonate and phosphatic aqueous solution.This buffer can be by preparing aqueous slkali and salt solution mix.Can be by with 34.7g one hypophosphite monohydrate sodium dihydrogen, 49.3g crystal carbonate and enough hydrations of 2 liters of liquor capacities are provided and prepare described saline solution.Similarly, by 104.0g one hypophosphite monohydrate sodium dihydrogen just, 147.94g crystal carbonate and enough hydrations of 6 liters of saline solution are provided and prepare 6 liters of solution.Can be by with 7.2g sodium hydroxide and 180.0g hydration and prepare alkaline buffer.Usually on demand aqueous slkali is added saline solution and prepare alkaline buffer, finally provide to have desirable pH, for example, the mixture of 9.65 to 9.75 pH.

Usually, the alkaline kind that exists in the alkaline buffer should be enough alkalescence with in and the acidity that provides of acidic buffer, thereby but needn't self nucleophilic like this it will react substantially with the electrophilic group on the core.Owing to this reason, the preferred alkali of " soft " relatively in this embodiment of the present invention is as carbonate and phosphate.

In order to illustrate the preparation of three dimensional matrix of the present invention, the mixture of autoreaction chemical compound and first kind of acidic buffer (for example, acid solution, for example, rare hydrochloric acid solution) can be merged and form homogeneous phase solution.This homogeneous phase solution and second kind of alkaline buffer (for example, alkaline solution for example, contains the aqueous solution of phosphate and carbonate) mix, so the formation three dimensional matrix interact with each other immediately basically of the reactive group on the autoreaction chemical compound core.

2. The redox reaction base

In one embodiment of the invention, reactive group is a vinyl, and as styrene derivative, it experiences radical polymerization when causing with redox initiator.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. The oxidative coupling reaction base

In one embodiment of the invention, reactive group experience 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 dehydrogenation of autoreaction chemical compound experience, 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. The Photoinitiated reactions base

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 preserve in ultraviolet radiation impermeability container for for example.

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

5. The temperature sensitivity reactive group

In one embodiment of the invention, reactive group is the responsive to temperature group, and it experiences 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. Linking group

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 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, as can be by obtaining in conjunction with lactic acid and glycolic 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 formic acid ester bond.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 affinity 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 nucleophilic group of introducing.Compare, the neutral body bulky group can be used to reduce reactivity and therefore reduce coupling speed owing to sterically hindered near the reactive group.

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

Table

Linking group	Component 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

Linking group	Component structure
		-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 make 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, perhaps graft copolymer.In addition, polymer can be a line style or branched, if branched, can be highly branched, dendrimeric, 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 exists with single block, perhaps is present in the block copolymer.Biodegradable fragment is preferably degraded so that rupture 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 the oligomerization or the poly fragment that are attached in the hydrophilic polymer usually.The property illustrated oligomerization and poly fragment for example comprise, poly-(aminoacid) fragment, poly-(ortho esters) fragment, poly-(orthocarbonic ester) fragment, or the like.Other the biodegradable fragment that forms the hydrophilic polymer core comprises polyester, as polylactide, and polyethers, as polyalkylene oxide, polyamide, as protein, and polyurethane.For example, the core of autoreaction chemical compound can be the diblock copolymer of 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-polyoxyethylene glycerol, single-and two-polyoxyethylated propylene glycol, and single-and two-polyoxyethylene trimethylene glycol; The polyoxyethylene sorbitol, the polyoxyethylene 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 acrylic species such as the copolymer of amino-ethyl acrylic acid 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 mean molecule quantity 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 2000 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 sulfydryl.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 4000 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 " refers to the collagen of form of ownership, comprises the collagen of processing or modifying.Thereby, can be used for chemical compound of the present invention from the collagen in any source; For example, can originate as cattle or pig dermis and extraction of people's Placenta Hominis and collagen purification from people or other mammal, perhaps can recombinate or pass through other method produces.From the collagen formulations purification in the solution of Corii Bovis seu Bubali, nonantigenic substantially is well known in the art.The U.S. Patent number 5,428,022 of Palefsky etc. discloses from the method for extraction of people's Placenta Hominis and collagen purification.The U.S. Patent number 5,667,839 of Berg discloses transgenic animal, comprises the method that produces 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 recombinant collagen described in yeast and other cell line express.

Any type, the collagen that includes, but not limited to I, II, III, IV type or its combination can be used for compositions of the present invention, although usually preferred type i collagen.Can use the collagen that contains non-end peptide or end peptide; Yet, when the collagen that uses from natural origin, during as bovine collagen, preferred non-end peptide collagen usually because it with contain the collagen of holding peptide and compare and have littler immunogenicity.

In the past not by being preferred in the compositions of the present invention, although crosslinked collagen before can using such as heat, radiation or the crosslinked collagen of chemical cross-linking agent.

It is common to be used for collagen of the present invention, although be not essential, is waterborne suspension, and its concentration arrives about 120mg/ml for about 20mg/ml, and preferably about 30mg/ml is to about 90mg/ml.Although preferred intact collagen also can use the collagen of degeneration, so-called gelatin.Gelatin has the benefit than the faster degraded of collagen.

Non-fiber collagen is preferred in the chemical compound of the present invention usually, although also can use fiber collagen.Term " non-fiber collagen " refers to be essentially any modification of non-fibers form or the collagen-based materials of unmodified, and promptly not combining closely with other other tropocollagen molecule forms the molecule collagen of fiber.Usually, non-fibrocollagenous solution is more transparent than viscose original solution.The non-fiber of native form (perhaps microfibre) collagen-type comprises IV, VI and VII type.

In neutral pH is that the collagen of the chemical modification of non-fibers form comprises succinyl group collagen and methylated collagen; they both can be according to the U.S. Patent number 4 of Miyata etc.; 164; the method preparation of describing in 559; succinyl group collagen contains reactive amino, is the component that preferably contains nucleopilic reagent 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 is for example, and is open in the U.S. Patent number 5,614,587 of Rhee etc.

The collagen that is used for the present composition can begin with fibers form, makes non-fibrosis by adding one or more fiber distintegrants then.The fiber distintegrant must exist with capacity makes that collagen is non-fiber basically under pH7, as above-mentioned.Be used for fiber distintegrant of the present invention and include, but not limited to multiple biocompatible alcohol, aminoacid, inorganic salt, and sugar, especially preferred biocompatible alcohol.Preferred biocompatible alcohol comprises glycerol and propylene glycol.The alcohol of biocompatible, as ethanol, methanol and isopropyl alcohol since they the potential adverse effect of the patient body of accepting them is not preferred among the present invention.Preferred amino acids comprises arginine.Preferred inorganic salt comprises sodium chloride and potassium chloride.Although sugar, as comprise that the multiple sugar of sucrose can be used for enforcement of the present invention, they are preferred not as the fiber distintegrant of other type, because they have the cells in vivo toxic effect.

Fiber collagen more is not preferred for chemical compound of the present invention.Yet disclosed in the United States Patent (USP) 5,614,587 as Rhee etc., fiber collagen, perhaps non-fiber collagen and fibrocollagenous mixture can be preferred in the long-standing in vivo chemical compound of meaning.

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 nature polyalcohol

Usually, amphipathic nature polyalcohol has hydrophilic segment and hydrophobic (perhaps lipophilic) part.Hydrophilic segment can be a section 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 polymer) 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 hydrophilic 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, 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-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.

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 sulfydryls.

D. Preparation

Can be easy to synthetic autoreaction chemical compound hydrophilic to contain, hydrophobic or amphipathic nature polyalcohol core or low-molecular-weight core, it is with allowing to crosslinked desirable functional group, and promptly nucleophilic and electrophilic group are functionalized.For example, be discussed below the preparation of the autoreaction chemical compound of (PEG) core that has Polyethylene Glycol.Yet the discussion that understanding is following is used to illustrate and can uses similar techniques for other polymer.

About PEG, at first, (seeing Abuchowski etc., Enzymes asDrugs, John Wiley ﹠amp such as protein modification; Sons:New York, N.Y. (1981) pp.367-383; With (1990) Crit.Rev.Therap.Drug Carrier Syst. such as Dreborg 6: 315), chemistry of peptides is (referring to Mutter etc., The Peptides, Academic:New York, N.Y.2:285-332; With (1987) Int.J.Peptide Protein Res. such as Zalipsky 30: 740) and polymeric drug synthetic (referring to (1983) Eur.Polym.J. such as Zalipsky 19: 1177; With (1987) J.Macromol.Sci.Chem. such as Ouchi A24: 1011) etc. multiple functionalized PEG has effectively been used in the field.

The functionalized form of PEG comprises multiple functionalized PEG, can obtain by commercial sources, and also can easily prepare with known method.For example, see Poly (ethylene Glycol) Chemistry:Biotechnical and Biomedical Applications, J.Milton Harris, ed., Plenum Press, the 22nd chapter of NY (1992).

The multiple functionalized form of PEG is even more important and comprises PEG 1,3-propanedicarboxylic acid succinimide ester, PEG succinyl phosphorons amino propyl acid ester, succinimido butyrate, PEG acetic acid succinimide ester, PEG succinimido butanimide, PEG carbonic acid succinimide ester, PEG propionic aldehyde, PEG glycidyl ether, PEG-isocyanates and PEG-vinyl sulfone(Remzaol.Many these type of forms of PEG are at the U.S. Patent number 5,328,955 and 6,534 of Rhee etc., describe in 591.Similarly, the various ways of polyamino PEG can by commercial sources from such as SunBio of South Korea ( Www.sunbio.com) the PEG Shop of branch company, Nippon Oil and Fats (Yebisu GardenPlace Tower, 20-3 Ebisu 4-chome, Shibuya-ku, Tokyo), Nektar Therapeutics (San Carlos, California was Shearwater Polymers in the past, Huntsville, Alabama) and from Huntsman ' s Performance Chemicals Group (Houston, source Texas) is with title The polyoxygenated enamine obtains.Can be used for polyamino PEG of the present invention and comprise Jeffamine diamidogen (" D " series) and triamine (" T " series), its each molecule contains two and three primary amino radicals.Similarly poly-(sulfydryl) PEG also can be from Nektar Therapeutics, and for example, the form of gathering (ethylene glycol) ether four sulfydryls (molecular weight 10,000) with tetramethylolmethane obtains.The multiple functionalized form of these of PEG can be modified then and be comprised the reactive group of other hope.

With the butanimide radical reaction terminal hydroxyl being changed into active ester is a kind of technology that preparation has the core of electrophilic group.Can modify this core then, comprise with nucleophilic group such as primary amine, mercaptan and hydroxyl modified.Other reagent that transforms hydroxyl comprises N,N'-carbonyldiimidazole and sulfonic acid chloride.Yet, to discuss as this paper, multiple electrophilic group can be advantageously used in and corresponding nucleophilic group reaction.The example of this type of electrophilic group comprises acid chloride groups; Anhydride, ketone, aldehyde, isocyanates, isothiocyanate, epoxide and alkene comprise conjugated alkene, as ethylsulfonyl (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 has more elastic chemical crosslinking at deposition site stabilize water gel formation precursor solution certain hour with enough formation and (sees, 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 multi-arm block copolymer that original position forms material, it comprises the prostheses molecule, as residue of polyol, with at least three copolymer arms of covalently bound prostheses molecule, each copolymer arm 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 fluid 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 and the albumin of supersound process, described collagen 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 ployalkylene 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 compositions, and said composition is applied to organize and is exposed to initiator then with polymerization collagen, forms sealing in tissue on the wound opening.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 fluid sealant under the crosslinked condition of albumin allowing.See, for example, PCT publication number WO99/66964.Original position forms material can be made up of collagen and peroxidase and hydrogen peroxide, thereby collagen is through being cross-linked to form semi-solid gel, and it seals wound.See, for example, PCT publication number WO01/35882.

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 sealant 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, fibrous tissue can be formed on the part that agent is applied to whole device or device.In certain embodiments, described medicament exists as the part of coating on the surface of implantable sensor or implantable pump.Coating can partly cover or can cover fully the surface of implantable sensor or implantable pump.In addition, coating can directly or indirectly contact implantable sensor or implantable pump.For example, implantable sensor or implantable pump can be with first kind of coating coating, then with the second kind of coating coating that comprises anti-scarring agent.

Can be coated with implantable sensor or implantable pump with multiple coating process, described method comprises by flooding, spray, smear, pass through vacuum deposition, perhaps by known other any method of those of ordinary skills.

As mentioned above, can will resist fiber to generate agent with above-mentioned polymer coating be applied on suitable implantable sensor or the implantable pump.Except aforementioned coating composition and method, multiple other coating composition known in the art and method.The representative example of these coating compositions and method is described in U.S. Patent number 6,610,016; 6,358,557; 6,306,176; 6,110,483; 6,106,473; 5,997,517; 5,800,412; 5,525,348; 5,331,027; 5,001,009; 6,562,136; 6,406,754; 6,344,035; 6,254,921; 6,214,901; 6,077,698; 6,603,040; 6,278,018; 6,238,799; 6,096,726,5,766,158,5,599,576,4,119,094; 4,100,309; 6,599,558; 6,369,168; 6,521,283; 6,497,916; 6,251,964; 6,225,431; 6,087,462; 6,083,257; 5,739,237; 5,739,236; 5,705,583; 5,648,442; 5,645,883; 5,556,710; 5,496,581; 4,689,386; 6,214,115; 6,090,901; 6,599,448; 6,054,504; 4,987,182; 4,847,324; With 4,642,267; U.S. Patent Application Publication No. 2002/0146581,2003/0129130,2001/0026834; 2003/0190420; 2001/0000785; 2003/0059631; 2003/0190405; 2002/0146581; 2003/020399; 2001/0026834; 2003/0190420; 2001/0000785; 2003/0059631; 2003/0190405; With 2003/020399; With PCT publication number WO02/055121; WO 01/57048; WO01/52915; With WO 01/01957.

In another aspect of this invention, can send bioactive fiber degeneration-inhibitor with non-polymeric reagent.These non-polymeric reagent can comprise sucrose derivative (for example, sucrose acetate isobutyrate, sucrose oleate), and sterol is as cholesterol, stigmasterol, β-sitoesterol and estradiol; Cholesteryl ester is as the stearic acid cholesteryl ester; C ₁₂-C ₂₄Fatty acid is as lauric acid, myristic acid, Palmic acid, stearic acid, arachidic acid, behenic acid and lignoceric acid; C ₁₈-C ₃₆Monoglyceride, diester and triglyceride, as monooleate glyceride, a glyceryl linoleate, Tegin L 90, a behenic acid glyceride, a myristin, a decylenic acid glyceride, glycerol-1,3-dipalmitate, two behenic acid glyceride, two myristins, two decylenic acid glyceride, three behenic acid glyceride, three myristins, three decylenic acid glyceride, glyceryl tristearate and their mixture; Sucrose fatty acid ester is as sucrose distearate and sucrose palmitate; Sorbitan fatty acid esters is as sorbitan monostearate, sorbitan monopalmitate and sorbitan tristearate; C ₁₆-C ₁₈Aliphatic alcohol is as hexadecanol, tetradecyl alchohol, octadecanol and cetostearyl alcohol; The ester of aliphatic alcohol and fatty acid is as hexadecyl palmitate and Palmic acid octadecanol and hexadecanol ester (cetearylpalmitate); The anhydride of fatty acid is as stearic anhydride; Phospholipid comprises phosphatidylcholine (lecithin), Phosphatidylserine, PHOSPHATIDYL ETHANOLAMINE, phosphatidylinositols and lysoderivatives thereof; Sphingol and derivant thereof; Spingomyelins is as stearoyl, palmityl and two tridecanoyl spingomyelins; Ceramide is as stearoyl and palmityl ceramide; Glycosphingolipids; Lanoline and lanolin alcohol, calcium phosphate, sintering and unsintered hydroxyapatite, zeolite and combination thereof and mixture.

The representative example that relates to the patent of non-polymer delivery system and their preparation comprises U.S. Patent number 5,736,152; 5,888,533; 6,120,789; 5,968,542; With 5,747,058.

Fibre modification-inhibitor can be sent with solution.Fibre modification-inhibitor can directly be incorporated in the solution so that homogeneous phase solution or dispersion to be provided.In certain embodiments, described solution is aqueous solution.Aqueous solution can also comprise buffer salt, and viscosity aromatics modifier (for example, hyaluronic acid, alginate, CMC or the like).In another aspect of this invention, described solution can comprise biocompatible solvent, as ethanol, DMSO, glycerol, PEG-200, PEG-300 or NMP.

In another aspect of this invention, fibre modification-inhibitor can also comprise second kind of carrier.Second kind of carrier can be following form: microsphere (for example, PLGA, PLLA, PDLLA, PCL, gelatin; polydioxanone, poly-(alkyl cyanoacrylate), nanometer spheroid (for example, PLGA, PLLA, PDLLA, PCL, gelatin, polydioxanone, poly-(alkyl cyanoacrylate), liposome, Emulsion, microemulsion, micelle are (for example, SDS, X-Y, the block copolymer of X-Y-X or Y-X-Y form, wherein X is poly-(oxyalkylene) or its alkyl ether, and Y is polyester (for example, PLGA, PLLA, PDLLA, the PCL polydioxanone)), zeolite or cyclodextrin.

In another aspect of this invention, these fibre modification-inhibitor/second kind of carrier compositions can a) directly be incorporated in implantable sensor and the implantable pump or above, b) be incorporated in the solution, c) be incorporated in gel or the viscosity solution, d) be incorporated into the compositions that is used for being coated with implantable sensor or implantable pump, or e) after with coating composition coating implantable sensor or implantable pump, be incorporated in implantable sensor or the implantable pump or on.

For example, the PLGA microsphere that loads fibre modification-inhibitor can be incorporated into polyurethane coated solution, and it is applied on implantable sensor or the implantable pump then.

In another example, can allow part dry then, thereby the surface still have viscosity with polyurethane coated implantable sensor or implantable pump.The concrete form of fibre modification-inhibitor or fibre modification-inhibitor/second kind of carrier can be applied on all or part of viscous coating after the device drying then.

In another example, implantable sensor or implantable pump can be coated with one of above-mentioned coating.Can soften coating with heat treatment method then, afterwards fibre modification-inhibitor or fibre modification-inhibitor/second kind of carrier are applied to the part (for example, outer surface) of whole implantable sensor or implantable pump or implantable sensor or implantable pump.

In another aspect of this invention, implantable sensor or the implantable pump through coating with fibre modification reaction in inhibition or the minimizing body further is coated with postponing fibre modification-inhibitor release and/or active chemical compound or compositions.The representative example of this type of reagent comprises any biological inert material, and as gelatin, PLGA/MePEG film, PLA, polyurethane, silicone rubber, surfactant, lipoid, perhaps Polyethylene Glycol, and bioactive materials is as heparin (for example, solidifying to induce).

For example, in one embodiment of the invention, the fibre modification on implantable sensor or the implantable pump is suppressed activating agent be coated with the top with physical barriers.This barrier can comprise abiotic degradable material or biodegradable material, as gelatin, PLGA/MePEG film, PLA or Polyethylene Glycol or the like.In one embodiment, the diffusion rate of therapeutic agent is slower than the diffusion rate of therapeutic agent in the dope layer in the barrier coatings.For PLGA/MePEG, in case PLGA/MePEG is exposed to blood or body fluid, MePEG will stripping from PLGA, stays the passage that arrives the bottom that contains fibre modification-inhibitor by PLGA, and described fibre modification-inhibitor can be spread to tissue then and begins its biologic activity.

In another embodiment of the present invention, for example, can use polymer (for example, PLG, PLA, polyurethane) that the particle form of activated fibre degeneration-inhibitor is applied on implantable sensor or the implantable pump.Slowly dissolving or degraded (for example, MePEG-PLGA or PLG) and second kind of polymer not containing activating agent can be coated with on ground floor.In case top layer dissolving or degraded, the layer below it exposes, it allows activating agent to be exposed to therapentic part or discharges from coating.

In another aspect of this invention, the outer further processing of the coating of implantable sensor through being coated with that fibre modification in the inhibition body is reacted and implantable pump is with the skin of crosslinked this coating.This can be by carrying out plasma treatment procedure and finish through the implantable sensor or the implantable pump of coating.By changing the RF power setting, can changing the character of crosslinking degree and finishing about persistent period of the position of plasma, processing and the gas composition of introducing plasma chamber.

By using inert molecule coating implantable sensor or the implantable pump surface that prevents near avtive spot by sterically hindered, perhaps, also can utilize the protection of bioactivity surface in order to the inactive form coating surface of postactivated fibre modification-inhibitor.For example, implantable sensor or implantable pump can be coated with enzyme, described enzyme causes the release or the activation fiber degeneration-inhibitor of fibre modification-inhibitor.

Suitable implantable sensor or another example of implantable pump face coat comprise anticoagulant, as heparin or heparin quaternary amine complex (for example, heparin-benzalkonium chloride complex), its can be coated on fibre modification-inhibitor above.The existence of anticoagulant has postponed blood coagulation.Along with the dissolving of anticoagulant, anticoagulating active can stop, and the implantable sensor that exposes recently or implantable pump table can suppress or reduce and fibre modification takes place in adjacent tissue take place or wrap by implantable sensor or implantable pump.

Suitable implantable sensor or another example of implantable pump face coat (being particularly useful for the coating of the drug delivery tube of implantable pump) comprise anti-infective, as antibiotic, 5-FU, mitoxantrone, methotrexate and/or doxorubicin, it can mix in the coating, and this coating can contain or not contain fibre modification-inhibitor.The existence of anti-infective prevents the infection in the implant surrounding tissue and (for example can prevent the relevant infection of serious device, use the meningitis that drug delivery pump causes in the sheath, the peritonitis of using the intraperitoneal drug delivery pump to cause is used cardiac drug to send pump and is caused endocarditis).

On the other hand, implantable sensor or implantable pump can be with the fibre modifications of inactive form-inhibitor coated, in case disposed described device, just can activated fiber degeneration-inhibitor.This activation can by after implanting implantable sensor or implantable pump (as described below) or fibre modification-inhibitor has been administered to treatment region (by injection, spraying, washing, drug delivery tube or air bag) after another kind of material be expelled to treatment region realize.Aspect this, can use the fibre modification-inhibitor coated implantable sensor or the implantable pump of inactive form.In case implanted implantable sensor or implantable pump, can be with activating substance injection be applied to use in the therapentic part of fibre modification-inhibitor of inactive form or above.

An example of this method comprises with bioactive fiber degeneration-inhibitor, is coated with implantable sensor or implantable pump in a usual manner.The coating that contains activated fibre degeneration-inhibitor can cover and these two kinds of materials then can be with condensation reaction by the ester bond combination with Polyethylene Glycol then.Before implantable sensor or implantable pump are disposed, esterase is expelled in the tissue on every side of device outside, this esterase allows the key between cracking ester and the fibre modification-inhibition therapeutic agent medicament start fibre modification and suppresses.

On the one hand, anti-scarring agent can be positioned in the hole or space of implantable sensor or implantable pump again.For example, implantable sensor or implantable pump can be constructed with hole (for example, divets or hole), ditch, chamber, hole, passage or the like, it forms space or hole in the implantable sensor or the implantable pump housing.(partially or completely filling) can be filled with fibre modification-inhibitor or the compositions that comprises fibre modification-inhibitor in these spaces.

On the other hand, implantable sensor or implantable pump can comprise many storages in its structure, and each storage is configured to hold and protect medicine.Storage can form by the divets of apparatus surface or by the space in the apparatus structure.On the one hand, storage is formed by the space in the apparatus structure.Storage can hold one type the medicine or the medicine of more than one types.Can be with the carrier that is loaded into storage (for example, polymer or non-polymer material) compounding pharmaceutical.Storage through filling can be used as medicine and sends the storehouse and play a role, and it can discharge medicine from the release dynamics of carrier according to medicine in one period.In certain embodiments, can load storage with many layers.Every layer of different pharmaceutical that can comprise the medicine with specified quantitative (dosage), every layer can have different compositions further to be fit to from the amount and the type of the medicine of substrate release.The multilamellar carrier can also comprise the barrier layer that prevents drug release.Barrier layer for example can be used for, and the control medicine is effusive direction from the space.

In certain embodiments of the invention, therapeutic combination can also comprise other composition, (for example, PLURONICS is as F-127 as surfactant, L-122, L-101, L-92, L-81, and L-61), antiinflammatory (for example, dexamethasone or aspirin), anticoagulant is (for example, heparin, high activity heparin, heparin quaternary amine complex are (for example, heparin benzalkonium chloride complex)), anti-infective (for example, 5-fluorouracil, triclosan, rifamycin and silver compound), antiseptic, antioxidant and/or anti-platelet agents.

In certain embodiments of the present invention, therapeutic agent or carrier can also comprise radiopaque, and echogenic material and nuclear magnetic resonance (MRI) responsive materials (being the MRI contrast agent) is to help will to install development under ultrasonic, fluoroscopy and/or MRI.For example, device can or (for example be used echogenic or radio-opaque material such as powdery tantalum with the said composition coating by echogenic or radiopaque compositions manufacturing; tungsten; brium carbonate; bismuth oxide, barium sulfate; metrazimide, iopamidol, iohexol; iopromide; iobitridol, iomeprol, iopentol; ioversol; ioxilan, iodixanol, iotrolan; the acetrizoic acid derivant; the amidotrizoic acid derivant, iotalamic acid derivant, ioxithalamicacid derivant; the metrizoic acid derivant; iodamide, lypophylic agents, adipiodone and ioglycamic acid manufacturing or have the framboid or the bubble at sound wave interface by adding).Use echogenic coating can obtain development by the device of ultra sonic imaging.Echogenic coating for example is described in, and U.S. Patent number 6,106 is in 473 and 6,610,016.In order under MRI, to develop, contrast agent (for example gadolinium (III) chelate or iron oxides chemical compound) can be attached among the device or on, as for example as the component in the coating or the device voidage in (for example in inner chamber, storage, or in being used to form the structural material of device).In some embodiments, medical apparatus can comprise radiopaque or MRI visable indicia (for example, band), and it can be used at implantation process described device being carried out orientation and guidance.

In another embodiment, these reagent can be included in the coating identical with therapeutic agent, and perhaps they can be included in and contain in the coating (as mentioned above) that is coated with before or after the therapeutic agent layer.

Alternatively or in addition, under visible light, use fluorescence, or by other spectrophotography, implantable pump and pick off can develop.Can be comprised that the developing agent that is used for this purpose comprises dyestuff, pigment and other coloring agent.On the one hand, described medical implant may further include coloring agent to improve the development of implant in vivo and/or in vitro.Usually, implant may be difficult to develop after insertion, particularly at the edge of implant.Thereby colorant combination can be reduced or eliminated the incidence rate or the seriousness of this problem to medical implant.Described coloring agent provides unique color, enhanced contrast, or provide unique fluorescent characteristic to described device.On the one hand, provide the solid implant that comprises coloring agent, thereby easily develop (under visible light or use fluorescent technique) and easily itself and its implantation site is distinguished.In yet another aspect, coloring agent can be included in liquid or the semi-solid combination.For example, can carry out the one-component in two component mixtures painted, thereby when in vitro or in vivo making up, described mixture is by fully painted.

Described coloring agent is passable, for example is that interior source compound (for example, aminoacid or vitamin) or nutrient or food material can be hydrophobicity or hydrophilic compounds also.Preferably, on employed concentration, described coloring agent has low-down toxicity or does not have toxicity.Also preferred coloring agent is safe and enters in the body by absorption usually, such as beta-carotene.The representative example of coloured nutrient (under visible light) comprises fatsoluble vitamin such as vitamin A (yellow); Water soluble vitamins such as vitamin B12 (pink-red) and folic acid (yellow-orange); Carotenoid such as beta-carotene (yellow-purple) and lycopene (redness).Other example of coloring agent comprises that natural product (berry and fruit) extract is such as anthracene cyanogen element (anthrocyanin) (purple) and Stigma Croci extract (dark red).Described coloring agent can be fluorescence or phosphorescent compounds such as alpha-tocopherol chinol (tocopherolquinol) (vitamin e derivative) or L-tryptophan.Can also use any derivant, analog and isomer of above-mentioned colored compound.The character that colorant combination can be depended on coloring agent to the method in implant or the therapeutic combination changes with its required location.For example, can select the hydrophobicity coloring agent to be used for hydrophobic base.Described coloring agent can be mixed carrier matrix, in micelle.In addition, thus the pH that can control environment further controls described color and intensity.

On the one hand, compositions of the present invention comprises that one or more are also referred to as the coloring agent of dyestuff, and it will be to give described compositions, and example gel exists with observable painted effective dose.The example of coloring agent comprises that the dyestuff that is suitable for food is such as being known as F.D.﹠amp; C. those of dyestuff and natural colorant be such as Pericarpium Vitis viniferae extract, beet red powder, beta-carotene, cheese Huang (annatto), fuchsin, Rhizoma Curcumae Longae, Fructus Capsici powder etc.Can also use any derivant, analog and isomer of above-mentioned coloring compound.The character that colorant combination can be depended on coloring agent to the method in implant or the therapeutic combination changes with its desired position.For example, can select the hydrophobicity coloring agent to be used for hydrophobic base.Described coloring agent can be mixed carrier matrix, in micelle.In addition, thus the pH that can control environment further controls described color and intensity.

In one aspect, compositions of the present invention comprises one or more antiseptic or antibacterial, its effective dose with the bacterial growth in and/or the composite inhibiting anticorrosion to compositions exists, for example, bismuth tribromophenate, methyl hydroxybenzoate, bacitracin, nipagin A, nipasol, erythromycin, 5-fluorouracil, methotrexate, doxorubicin, mitoxantrone, rifamycin, chlorocresol, benzalkonium chloride etc.The example of antiseptic comprises oxybenzoic acid esters, chlorobutanol, benzylalcohol, phenethanol, dehydroactic acid, sorbic acid etc.In one aspect, compositions of the present invention comprises that one or more kill antibacterial (being also referred to as antibacterial) reagent.

On the one hand, device of the present invention and compositions comprise the antioxidant that one or more exist with effective dose.The example of antioxidant comprises sulphite, alpha-tocopherol and ascorbic acid.

Of the present invention aspect some, device of the present invention and therapeutic combination should be biocompatibility and in the period of a few hours, a couple of days or several months, discharge one or more fibre modification inhibitor.As mentioned above, " release of medicament " is meant that any statistics of medicament or its subfraction exists significantly, and described medicament or its subfraction break away from and/or (or inner) maintenance activity on the surface of compositions from compositions.Compositions of the present invention can discharge described anti-scarring agent in one or more stages, and described one or more stages have similar or different performance (for example, discharging) curve.Can be so that described therapeutic agent offers tissue with following amount: can be continuable, intermittently or successive; In one or more stages; And/or delivery rate; Effectively reduce or suppress any or various ingredients of fibre modification (or the scar scar forms), comprise: the formation of neovascularity (angiogenesis), the migration and the propagation of connective tissue cell (as fibroblast or smooth muscle cell), the deposition of extracellular matrix (ECM), and reconstruction (maturation of fibrous tissue and systematism).

Therefore, can make a plan to influence fibre modification (or the scar scar forms) to rate of release by discharge anti-scarring agent in the moment that makes at least a fibrotic component be suppressed or reduce.In addition, predetermined rate of release can reduce medicament load and/or concentration and minimum drug irrigation may be provided, and therefore improves pharmaceutically-active effect.Any in the described at least a anti-scarring agent can be fulfiled one or more functions, comprise the formation (angiogenesis) that suppresses neovascularity, the migration and the propagation that suppress connective tissue cell (as fibroblast or smooth muscle cell), suppress the deposition of extracellular matrix (ECM) and suppress to rebuild (maturation of fibrous tissue and systematism).In one embodiment, described rate of release can provide the anti-scarring agent of sustainable level to susceptible tissue site.In another embodiment, described rate of release is constant basically.Described speed can reduce and/or improve in time, and it can randomly comprise the period that does not discharge basically.Described rate of release can comprise a plurality of speed.In one embodiment, described a plurality of rates of release can comprise the speed that is selected from down group: substantial constant, reduce, and improve, do not discharge basically.

Make offer on the device, among or near the total amount of anti-scarring agent can be that scope is the amount of about 0.01 μ g (microgram) to about 2500mg (milligram).Usually, the amount of described anti-scarring agent can be that about 0.01 μ g is to about 10 μ g; Or 10 μ g to about 1mg; Or 1mg is to about 10mg; Or 10mg is to about 100mg; Or 100mg is to about 500mg; Or 500mg is to about 2500mg.

On the described device, among or near the amount on the surface of anti-scarring agent can be every mm ²Apparatus surface amasss less than 0.01 μ g to about 2500 μ g.Usually, the amount of anti-scarring agent can be less than 0.01 μ g; Or 0.01 μ g to about 10 μ g; Or 10 μ g to about 250 μ g; Or 250 μ g to about 2500 μ g.

On the described device, among or near anti-scarring agent can in a period, discharge from compositions, described period from the implantation time begins to measure and scope is approximately less than 1 day to about 180 days.Usually, also can be approximately less than 1 day to about 7 days release time; 7 days to about 14 days; 14 days to about 28 days; 28 days to about 56 days; 56 days to about 90 days; 90 days to about 180 days.

Can be based on the amount of measuring from the characteristic of the medicament release in vitro of compositions as the anti-scarring agent that discharges from compositions of time function.By with anti-scarring agent in suitable buffer (as 0.1M phosphate buffer (pH7.4)) 37 ℃ be placed on compositions or the device in, can measure in-vitro release rate.The sample of buffer takes out then to analyze by HPLC on time, and exchange buffering liquid is to avoid any saturation effect.

Based on in-vitro release rate, every day, the burst size of anti-scarring agent can be that about 0.01 μ g (microgram) is to about 2500mg (milligram).Usually, the anti-scarring agent amount that can discharge every day can be that 0.01 μ g is to about 10 μ g; Or 10 μ g to about 1mg; Or 1mg is to about 10mg; Or 10mg is to about 100mg; Or 100mg is to about 500mg; Or 500mg is to about 2500mg.

In one embodiment, anti-scarring agent is offered the susceptible tissue in mode plan, that continue and/or control, this causes the efficient and/or the effect that increase.In addition, rate of release can the beginning and the stage of release subsequently in one of or both in change.Release for same substance and/or different material also can have the other stage.

In addition, therapeutic combination of the present invention and device should preferably have the stable shelf life of several months, and can produce under aseptic condition and keep.Many medicines be manufactured into aseptic and this standard by USP XXII＜1211 regulation.Term " USP " be meant American Pharmacopeia (referring to www.usp.org, Rockville, MD).Sterilization can accept by industry with USP XXII＜1211 listed multiple mode finishes, and comprises gas sterilization, ionizing radiation or filtration when suitable.Sterilization can keep by so-called sterile working, and this sterile working is also in USPXXII＜1211〉regulation.The acceptable gas that is used for gas sterilization comprises oxirane.The acceptable emission types that is used for the ionizing radiation method comprises γ, for example from cobalt 60 source and electron beam.Gamma-emitting typical doses is 2.5MRad.Filtration can use have suitable aperture (for example 0.22 μ m) and suitably the filter of material finish, described material is politef (for example from E.I.DuPont De Nemours and Company, Wilmington, the TEFLON of DE) for example.

On the other hand, compositions of the present invention and device are included in the container, this container allows them to be used for their its intended purposes, for example as pharmaceutical composition.The important performance of container is: the volume of free space allows to add and constitutes medium, as water or other aqueous medium, for example saline; Acceptable light transmission features is so that prevent compositions (with reference to USP XXII＜661 〉) in the luminous energy damage container; The acceptable scope of extractable (with reference to USP XXII) in the container material; To dampness (with reference to USPXXII＜671 〉) or the acceptable barrier ability of oxygen.In the situation of oxygen infiltration, 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 prepare drug container comprises USP I to II type and NP type glass (with reference to USP XXII＜661 〉), polyethylene, TEFLON, silicon, and Lycoperdon polymorphum Vitt-butyl rubber.

In one embodiment, product container can be a thermoforming plastic.In another embodiment, second packing can be used for product.In another embodiment, product can be in sterile chamber, and this container is put into chest, and this chest has the content of label with the explanation chest.

1. With inhibitor coated implantable sensor of fibre modification and pump

As mentioned above, a series of polymer and non-polymer material can be used for described fibre modification inhibitor is attached on implantable sensor or the implantable pump or among.With the compositions that contains these fibre modification-inhibitor, be to be used for fibre modification-inhibitor is attached to implantable sensor or implantable pump inside or top a kind of method only perhaps with fibre modification-inhibitor coated described implantable sensor or implantable pump.

A. Dip coated

Dip coated is an example that can be used for anti-scarring agent and implantable sensor or the bonded coating process of implantable pump.In one embodiment, fibre modification-inhibitor is dissolved in the solvent that is used for fibre modification-inhibitor and is applied to then on implantable sensor or the implantable pump (perhaps the part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port).

Fibre modification-inhibitor and atent solvent

In one embodiment, thus solvent be used for implantable sensor or implantable pump this solvent of atent solvent on any big degree the implantable device of dissolving and not on any big degree by should implantable device absorption.Implantable sensor or implantable pump (perhaps the part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port) can partially or completely immerse time bar specific in fibre modification-inhibitor/solvent solution.Can change the speed (for example, per second 0.001cm is to per second 50cm) of immersion fibre modification-inhibitor/solvent solution.Can remove implantable sensor or implantable pump from solution then.The speed that implantable sensor or implantable pump are withdrawn from solution can change (for example, per second 0.001cm is to per second 50cm).Implantable sensor that is coated with or implantable pump can be air-dry.Dipping process can repeat one or many, this depends on application-specific, wherein higher repetition usually increases the amount that is coated on the medicament on implantable sensor or the implantable pump (perhaps the part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port).Implantable sensor or implantable pump can be dry to reduce residual solvent levels under vacuum.This process will cause fibre modification-inhibitor coated on the surface of device.

Fibre modification-inhibitor and sweller

In one embodiment, solvent for not dissolving implantable sensor or implantable pump but will do not installed the solvent that (perhaps the part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port) absorbs by this.In some cases, will expand to a certain extent implantable sensor or implantable pump of these dissolvings.This implantable sensor or implantable pump can partially or completely immerse time bar specific in fibre modification-inhibitor/solvent solution (several seconds is to a couple of days).Can change the speed (for example, per second 0.001cm is to per second 50cm) of immersion fibre modification-inhibitor/solvent solution.Can remove implantable sensor or implantable pump from solution then.The speed that implantable sensor or implantable pump are withdrawn from solution can change (for example, per second 0.001cm is to per second 50cm).Implantable sensor that is coated with or implantable pump can be air-dry.Dipping process can repeat one or many, and this depends on application-specific.Implantable sensor or implantable pump can be dry to reduce residual solvent levels under vacuum.This process will cause fibre modification-inhibitor to be adsorbed onto in implantable sensor or the implantable pump (perhaps the part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port).Fibre modification-inhibitor can also be present on the surface of implantable sensor or implantable pump (perhaps the part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port).By immersing the solvent that is used for fibre modification-inhibitor through the implantable sensor or the implantable pump of coating, the solvent spray implantable sensor or the implantable pump that perhaps are used for fibre modification-inhibitor can reduce the amount of the fibre modification-inhibitor of surface combination.

Fibre modification-inhibitor and solvent

In one embodiment, solvent is to be absorbed and will dissolve the solvent of this implantable sensor or implantable pump (perhaps the part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port) by implantable sensor or implantable pump.This implantable sensor or implantable pump can partially or completely immerse time bar specific in fibre modification-inhibitor/solvent solution (several seconds is to a few hours).Can change the speed (for example, per second 0.001cm is to per second 50cm) of immersion fibre modification-inhibitor/solvent solution.Then, can from described solution, remove described implantable sensor or implantable pump.The speed that implantable sensor or implantable pump are withdrawn from solution can change (for example, per second 0.001cm is to per second 50cm).Implantable sensor that is coated with or implantable pump can be air-dry.Dipping process can repeat one or many, and this depends on application-specific.Implantable sensor or implantable pump can be dry to reduce residual solvent levels under vacuum.This process will cause fibre modification-inhibitor to absorb in implantable sensor or the implantable pump (perhaps the part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port) and by surface combination.Preferably, the time that is exposed to solvent of implantable sensor or implantable pump does not cause that the important permanent size of device (perhaps the part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port) changes.Fibre modification-inhibitor can also be present on the surface of implantable sensor or implantable pump.By implantable sensor or implantable pump are immersed the solvent that is used for fibre modification-inhibitor, perhaps be used for implantable sensor or the implantable pump of the solvent spray of fibre modification-inhibitor, can reduce the amount of the fibre modification-inhibitor of surface combination through coating.

In one embodiment, fibre modification-inhibitor and polymer are dissolved in the solvent that is used for polymer and fibre modification-inhibitor, be coated on then on implantable sensor or the implantable pump (perhaps the part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port).

In the above description, implantable sensor or implantable pump (the perhaps part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port) can be not modified implantable sensor or implantable pump or before coating process by with polymer-coated, scabble or polish with Cement Composite Treated by Plasma, flame treatment, sided corona treatment, surface oxidation or reduction, surface etching, machinery, perhaps implantable sensor or the implantable pump modified of migration process surface.

In dip coated method on any, can with fibre modification-inhibitor or before containing the compositions coating of fibre modification-inhibitor with plasma polymerization method processing implantable sensor or implantable pump (the perhaps part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port), thus thin polymer is deposited upon on implantable sensor or the implantable pump surface.The example of these class methods comprises the parylene coating of device and uses multiple monomer, as hydrogen cyclosiloxane monomer.If the part (as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port) of device or device by the material that does not allow to mix therapeutic agent with one of said method to surface layer (for example, rustless steel, nitinol) form, the parylene coating is particularly advantageous so.(for example use the parylene coating machine, PDS 2010 LABCOTER2 from Cookson Electronics) and suitable medicament (for example, two-right-xylylene or two chloro-two-right-xylylene) as the coating charging, the parylene prime coat can be deposited on implantable sensor or the implantable pump.The parylene chemical compound can pass through commercial sources, for example, from Specialty Coating Systems, Indianapolis, IN) obtain, comprise PARYLENE N (two-right-xylylene), PARYLENE C (the monochloro derivant of parylene N, with PARYLENE D, the dichloride derivant of parylene N).

B. Spraying implantable sensor and implantable pump

Spraying is operable another kind of coating process.In spraying method, with fibre modification-inhibitor with or not with the solution of polymer or non-polymeric carriers or suspension atomization and guiding will be by gas flow coat cloth implantable sensor or implantable pump (perhaps the part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port).Can use sprayer unit, as spray gun (for example, from Badger Air-brush Company, Franklin Park, the model 2020,360,175,100 of IL, 200,150,350,250,400,3000,4000,5000,6000), paint spraying apparatus, TLC reagent sprayer (for example, Part# 14545 and 14654, Alltech Associates, Inc.Deerfield, IL) and ultrasonic spray apparatus (for example, can be, Milton, those that NY obtains) from Sono-Tek.Can also use powder sprayer and electrostatic atomiser.

In one embodiment, fibre modification-inhibitor is dissolved in the solvent that is used for the fibre modification medicament is sprayed to implantable sensor or implantable pump (perhaps the part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port) then.

Fibre modification-inhibitor and atent solvent

In one embodiment, thus solvent is this solvent of atent solvent medical implantable sensor of dissolving or the implantable pump and be not absorbed on any big degree on any big degree that is used for implantable sensor or implantable pump.Implantable sensor or implantable pump can remain on the appropriate location or be installed to can be at X, Y or Z plane, perhaps on the axle or bar strip that moves in these planar combination, described axle or bar strip have at X, Y or Z plane or the ability that moves on these planar combination.Use a kind of above-mentioned sprayer unit, implantable sensor or implantable pump (perhaps the part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port) thus can spray it partially or completely is coated with through fibre modification-inhibitor/solvent solution.The spray rate (for example, per second 0.001mL is to per second 10mL) that can change fibre modification-inhibitor/solvent solution is to guarantee to obtain the good coating of fibre modification-inhibitor.Can air-dry implantable sensor or implantable pump through coating.Spraying process can repeat one or many, and this depends on application-specific.Implantable sensor or implantable pump can be dry to reduce residual solvent levels under vacuum.This process will cause fibre modification-inhibitor coated on the surface of implantable sensor or implantable pump (perhaps the part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port).

Fibre modification-inhibitor and sweller

In one embodiment, solvent still will be by the solvent of its absorption for not dissolving implantable sensor or implantable pump.Implantable sensor or implantable pump thereby these solvents can expand to a certain extent.Can partially or completely spray implantable sensor or implantable pump (perhaps the part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port) with fibre modification-inhibitor/solvent solution.The spray rate (for example, per second 0.001mL is to per second 10mL) that can change fibre modification-inhibitor/solvent solution is to guarantee to obtain the good coating of fibre modification-inhibitor.Can air-dry implantable sensor or implantable pump through coating.Spraying process can repeat one or many, and this depends on application-specific.Implantable sensor or implantable pump can be dry to reduce residual solvent levels under vacuum.This process will cause fibre modification-inhibitor to be adsorbed onto implantable sensor or implantable pump (perhaps the part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port).Fibre modification-inhibitor can also be present on the surface of implantable sensor or implantable pump.By immersing the solvent that is used for fibre modification-inhibitor through the implantable sensor or the implantable pump of coating, perhaps be used for implantable sensor or the implantable pump of the solvent spray of fibre modification-inhibitor, can reduce the amount of the fibre modification-inhibitor of surface combination through coating.

Fibre modification-inhibitor and solvent

In one embodiment, solvent is will be absorbed by implantable sensor or implantable pump and will dissolve its solvent.Can partially or completely spray implantable sensor or implantable pump (perhaps the part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port) with fibre modification-inhibitor/solvent solution.The spray rate (for example, per second 0.001mL is to per second 10mL) that can change fibre modification-inhibitor/solvent solution is to guarantee to obtain the good coating of fibre modification-inhibitor.Can air-dry implantable sensor or implantable pump through coating.Spraying process can repeat one or many, and this depends on application-specific.Implantable sensor or implantable pump can be dry to reduce residual solvent levels under vacuum.This process will cause fibre modification-inhibitor to be adsorbed onto implantable sensor or implantable pump (perhaps the part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port) and by surface combination.In preferred embodiments, the time that is exposed to solvent of implantable sensor or implantable pump does not cause that its important permanent size changes.Fibre modification-inhibitor can also be present on the surface of implantable sensor or implantable pump.By implantable sensor or implantable pump are immersed the solvent that is used for fibre modification-inhibitor, perhaps be used for implantable sensor or the implantable pump of the solvent spray of fibre modification-inhibitor, can reduce the amount of the fibre modification-inhibitor of surface combination through coating.

In the above description, implantable sensor or implantable pump (the perhaps part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port) can be not modified implantable sensor or implantable pump or before coating process by (for example with polymer, parylene) coating, scabbles or polish, perhaps implantable sensor or the implantable pump modified of migration process surface with Cement Composite Treated by Plasma, flame treatment, sided corona treatment, surface oxidation or reduction, surface etching, machinery.

In one embodiment, fibre modification-inhibitor and polymer are dissolved in the solvent that is used for this polymer and fibrosis agent, spray to then on implantable sensor or the implantable pump (perhaps the part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port).

Fibre modification-inhibitor/polymer and atent solvent

In one embodiment, thus solvent is this solvent of atent solvent this implantable sensor of dissolving or the implantable pump and do not absorbed by it on any big degree on any big degree that is used for implantable sensor or implantable pump.Can partially or completely spray the specific time bar of implantable sensor or implantable pump (perhaps the part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port) with fibre modification-inhibitor/polymer/solvent solution.The spray rate (for example, per second 0.001mL is to per second 10mL) that can change fibre modification-inhibitor/solvent solution is to guarantee to obtain the good coating of fibre modification-inhibitor.Can air-dry implantable sensor or implantable pump through coating.Spraying process can repeat one or many, and this depends on application-specific.Implantable sensor or implantable pump can be dry to reduce residual solvent levels under vacuum.This process will cause fibre modification-inhibitor coated on the surface of this device (perhaps the part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port).

Fibre modification-inhibitor/polymer and sweller

In one embodiment, solvent still will be by the solvent of its absorption for not dissolving implantable sensor or implantable pump.Implantable sensor or implantable pump thereby these solvents can expand to a certain extent.Can partially or completely spray implantable sensor or implantable pump (perhaps the part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port) with fibre modification-inhibitor/polymer/solvent solution.The spray rate (for example, per second 0.001mL is to per second 10mL) that can change fibre modification-inhibitor/solvent solution is to guarantee to obtain the good coating of fibre modification-inhibitor.Can air-dry implantable sensor or implantable pump through coating.Spraying process can repeat one or many, and this depends on application-specific.Implantable sensor or implantable pump can be dry to reduce residual solvent levels under vacuum.This process will cause fibre modification-inhibitor/polymer-coated on the surface of implantable sensor or implantable pump and fibre modification-inhibitor may be adsorbed in this medical apparatus (perhaps the part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port).Fibre modification-inhibitor can also be present on the surface of device.By immersing the solvent that is used for fibre modification-inhibitor through the implantable sensor or the implantable pump of coating, perhaps be used for implantable sensor or the implantable pump of the solvent spray of fibre modification-inhibitor, can reduce the amount of the fibre modification-inhibitor of surface combination through coating.

Fibre modification-inhibitor/polymer and solvent

In one embodiment, solvent is will be absorbed by implantable sensor or implantable pump and will dissolve its solvent.Can partially or completely spray implantable sensor or implantable pump (perhaps the part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port) with fibre modification-inhibitor/solvent solution.The spray rate (for example, per second 0.001mL is to per second 10mL) that can change fibre modification-inhibitor/solvent solution is to guarantee to obtain the good coating of fibre modification-inhibitor.Can air-dry implantable sensor or implantable pump through coating.Spraying process can repeat one or many, and this depends on application-specific.Implantable sensor or implantable pump can be dry to reduce residual solvent levels under vacuum.In preferred embodiments, the time that is exposed to solvent of implantable sensor or implantable pump does not cause that its important permanent size changes (except being coated with those relevant changes with self).Fibre modification-inhibitor can also be present on the surface of device (perhaps the part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port).By implantable sensor or implantable pump are immersed the solvent that is used for fibre modification-inhibitor, perhaps be used for implantable sensor or the implantable pump of the solvent spray of fibre modification-inhibitor, can reduce the amount of the fibre modification-inhibitor of surface combination through coating.

In the above description, implantable sensor or implantable pump (the perhaps part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port) can be not modified implantable sensor or implantable pump or before coating process by (for example with polymer, parylene) coating, scabbles or polish, perhaps implantable sensor or the implantable pump modified of migration process surface with Cement Composite Treated by Plasma, flame treatment, sided corona treatment, surface oxidation or reduction, surface etching, machinery.

The suspension that can prepare in another embodiment, the fibre modification-inhibitor in the polymer solution.By selecting this polymer of dissolving but do not dissolve the solvent of fibre modification-inhibitor, perhaps dissolve this polymer and wherein fibre modification-inhibitor be higher than the solvent of its solubility range, can supending.With above-mentioned similar method, fibre modification-inhibition suspension and polymer solution can be sprayed to implantable sensor or implantable pump (perhaps the part of pick off or pump, as main body, detector, semipermeable membrane, drug delivery tube or drug delivery port) thus go up its polymer-coated with suspension fiber degeneration-inhibitor wherein.

Device below the present invention provides in several different methods and embodiment:

1. pick off

On the one hand, the invention provides device, the compositions that it comprises pick off and anti-scarring agent or comprises anti-scarring agent, the cicatrization between the host that wherein said medicament restraining device and this device are implanted.

This pick off can be by characterizing definitions a kind of, below two or more: this pick off is blood or tissue glucose pick off; This pick off is the electrolyte pick off; This pick off is the blood constituent pick off; This pick off is temperature sensor; This pick off is the pH pick off; This pick off is an optical pickocff; This pick off is an amperometric sensor; This pick off is a pressure transducer; This pick off is a biosensor; This pick off is the sensing responder; This pick off is a tension pick-up; This pick off is a magnetoresistive transducer; This pick off is a cardiac sensor; This pick off is a respiration pickup; This pick off is a hearing transducer; This pick off is the metabolite pick off; This sensor metataxis; This sensor physical change; This sensor electrochemical change; This sensor magnetic variationization; This sensor acceleration change; This sensor ionizing radiation changes; This sensor sound wave changes; This sensor chemical change; This sensor drug level changes; This sensor hormone changes; This sensor air pressure change.

2. blood or tissue glucose monitor (that is pick off)

On the one hand, the invention provides device, the compositions that it comprises blood or tissue glucose monitor (being pick off) and anti-scarring agent or comprises anti-scarring agent, the cicatrization between the host that wherein said medicament restraining device and this device are implanted.

This device can pass through a kind of, the characterizing definition below two or more: use the conduit on the stent platform, device can be delivered to vascular system through the chamber; Device is made up of the glucose-sensitive living cells, and the change of described cell monitor blood glucose levels and response glucose concentration produces detectable electricity or optical signal; The electrode of device for forming by analyte response enzyme; Device is formed for the closed-loop insulin delivery system, and this system comprises detection host's blood sugar level and stimulates insulin pump that the sensing equipment of insulin is provided; With device for the closed-loop insulin delivery system, this system comprises and detects the sensing equipment that host's blood sugar level and stimulating pancreas provide insulin.

3. pressure or tension pick-up

On the one hand, the invention provides device, the compositions that it comprises pressure or tension pick-up and anti-scarring agent or comprises anti-scarring agent, the cicatrization between the host that wherein said medicament restraining device and this device are implanted.

This device can be further by characterizing definitions a kind of, below two or more: this installs monitoring blood pressure; This device monitors fluid flow; This device monitors the pressure in the aneurysmal sack; This device monitors intracranial pressure; This device monitors the mechanical pressure relevant with fracture; This device monitors air pressure; This device monitors that nystagmus quivers; This device monitors the degree of depth of cornea implant; This device monitors intraocular pressure; This device is for having the passive sensor of Inductor-Capacitor circuit; This device is self-powered tension force (strain) sensor-based system; This pick off comprises lead, sensor assembly and sensor circuit and the equipment of voltage is provided.

4. cardiac sensor

On the one hand, the invention provides device, the compositions that it comprises cardiac sensor and anti-scarring agent or comprises anti-scarring agent, the cicatrization between the host that wherein said medicament restraining device and this device are implanted.

This device can be further by characterizing definitions a kind of, below two or more: this device monitors heart output; This device monitors ejection fraction; This device monitors the blood pressure in the ventricle; This device monitors ventricular wall motion; This device monitors the blood flow to transplant organ; This installs monitor heart rate.

5. respiration pickup

On the one hand, the invention provides device, the compositions that it comprises respiration pickup and anti-scarring agent or comprises anti-scarring agent, the cicatrization between the host that wherein said medicament restraining device and this device are implanted.

On the one hand, this device monitoring lung function.

6. hearing transducer

On the one hand, the invention provides device, the compositions that it comprises hearing transducer and anti-scarring agent or comprises anti-scarring agent, the cicatrization between the host that wherein said medicament restraining device and this device are implanted.

This device can be further by characterizing definitions a kind of, below two or more: this device is suitable for the signal of telecommunication is delivered to the implantable electromechanical transducer that acts on middle ear or internal ear; This device produces electric audio signal; This device is and the link coupled capacitance sensor of vibration acoustic components; This device is an electromagnetic transducer.

7. electrolyte or metabolite pick off

On the one hand, the invention provides device, the compositions that it comprises electrolyte or metabolite pick off and anti-scarring agent or comprises anti-scarring agent, the cicatrization between the host that wherein said medicament restraining device and this device are implanted.

This device can be further by characterizing definitions a kind of, below two or more: this installs radiation sources, its at blood to interact with many pick offs that output signal is provided; This device is the bio-sensing responder, and it is made up of following: have the change in the response environment and the dyestuff of the optical property that changes, be used for the optical sensor of sensing optical change; With the responder that is used for transfer of data is arrived remote reader; And this device is the biological electronic installation of monoblock type that detects at least a analyte among the host.

8. pump

The invention provides device, the compositions that it comprises pump and anti-scarring agent or comprises anti-scarring agent, the cicatrization between the host that wherein said medicament restraining device and this device are implanted.

This device can be further by characterizing definitions a kind of, below two or more: this device is suitable for insulin delivery; This device is suitable for sending anesthetics; This device is suitable for sending chemotherapeutant; This device is suitable for sending antiarrhythmic drug; This device is suitable for sending the spasmolytic medicine; This device is suitable for sending spasmolytic; This device is suitable for sending antibiotic; This device is suitable for only detecting delivering drugs when changing in the host; This device is suitable for continuous slow release delivering drugs; This device is suitable for sending pre-metered doses of medication with pulse mode; This device is programmable drug delivery pump; This device is suitable for the intraocular delivery medicine; This device is suitable for delivering drugs in the sheath; This device is suitable for the intraperitoneal delivering drugs; This device is suitable for the intra-arterial delivering drugs; This device is suitable for intracardiac delivering drugs; This device is implantable osmotic pumps; This device is that medicament for the eyes is sent pump; This device is a metering system; This device is wriggling (rolling) pump; This device is electrically driven (operated) pump; This device is the elastomer pump; This device is that spring shrinks pump; This device is the pump of gas-powered; This device is a hydraulic pump; This device is the pump that relies on piston; This device is the pump of non-dependence piston; This device is a distributor chamber; This device is an infusion pump; This device is passive pump.

9. implantable insulin pump

On the one hand, the invention provides device, the compositions that it comprises implantable insulin pump and anti-scarring agent or comprises anti-scarring agent, the cicatrization between the host that wherein said medicament restraining device and this device are implanted.

In one embodiment, implantable insulin pump comprises the pick off of single channel conduit and implantable intravascular, and it is transferred to implantable insulin pump to distribute medicine by conduit with hematochemistry.

10. drug delivery pump in the sheath

On the one hand, the invention provides device, the compositions that it comprises sheath interior drug delivery pump and anti-scarring agent or comprises anti-scarring agent, the cicatrization between the host that wherein said medicament restraining device and this device are implanted.

This device can be further by characterizing definitions a kind of, below two or more: this device is suitable for pain medication directly is delivered in the cerebrospinal fluid of the intrathecal space around the spinal cord; This device is suitable for delivering drugs into brain; This device is suitable for sending in the sheath baclofen; This device also comprises the spinal column inner catheter; This device also comprises drug delivery pump in second kind of sheath; This device also comprises conduit and electrode.

11. be used for chemotherapeutic implantable drug delivery pump

On the one hand, the invention provides device, it comprises the compositions that is used for chemotherapeutic implantable drug delivery pump and anti-scarring agent or comprises anti-scarring agent, the cicatrization between the host that wherein said medicament restraining device and this device are implanted.

This medical apparatus can be further by characterizing definitions a kind of, below two or more: this device is suitable for sending 2-deoxidation 5-floxuridine; The host has solid tumor, and device is suitable for chemotherapeutant is input to solid tumor; The host has tumor, and this device is suitable for chemotherapeutant is infused into the blood vessel of supplying with tumor; The host has liver tumor, and device is suitable for chemotherapeutant is delivered to the tremulous pulse that blood supply is provided for host's liver.

12. be used for the treatment of the drug delivery pump of heart disease

On the one hand, the invention provides device, it comprises drug delivery pump and anti-scarring agent that is used for the treatment of heart disease or the compositions that comprises anti-scarring agent, the cicatrization between the host that wherein said medicament restraining device and this device are implanted.

In one embodiment, device is to send stimulation energy and distribute near the heart electrode of medicine stimulation location.

13. medicine is sent implant (that is pump)

On the one hand, the invention provides device, it comprises the compositions that medicine is sent implant (being pump) and anti-scarring agent or comprised anti-scarring agent, the cicatrization between the host that wherein said medicament restraining device and this device are implanted.

The other feature relevant with pick off

The sensor can also pass through one, two or more following characterizing definition: this medicament suppresses cytothesis; This medicament suppresses Angiogenesis; This medicament suppresses migration of fibroblast cells; This medicament suppresses fibroblast proliferation; This medicament suppresses extrtacellular matrix deposition; This medicament suppresses tissue reconstruction; This medicament is AI; This medicament is 5-lipoxidase inhibitor or antagonist; This medicament is chemokine receptor anagonists; This medicament is cell cycle inhibitor; This medicament is taxane; This medicament is anti-microtubule agent; This medicament is taxol; This medicament is not that taxol, this medicament are analog or the derivatives of taxol; This medicament is catharanthus alkaloid; This medicament is camptothecine or its analog or derivative; This medicament is podophyllotoxin; This medicament is podophyllotoxin, and wherein podophyllotoxin is Etoposide or its analog or derivative; This medicament is anthracycline; This medicament is anthracycline, and wherein anthracycline is Doxorubicin or its analog or derivative; This medicament is anthracycline, and wherein anthracycline is mitoxantrone or its analog or derivative; This medicament is platinum compounds; This medicament is nitroso ureas; This medicament is the nitre imidazoles; This medicament is antifol; This medicament is cytidine analog; This medicament is pyrimidine analogue; This medicament is fluoropyrimidine analogue; This medicament is purine analogue; This medicament is mustargen or its analog or derivative; This medicament is hydroxycarbamide; This medicament is mitomycin C or its analog or derivative; This medicament is alkyl sulfonic ester; This medicament is benzamide or its analog or derivative; This medicament is niacinamide or its analog or derivative; This medicament is halogeno-sugar or its analog or derivative; This medicament is the DNA alkylating agent; This medicament is anti-microtubule agent; This medicament is topoisomerase enzyme inhibitor; This medicament is the DNA cleavage agent; This medicament is antimetabolite; This medicament suppresses adenosine deaminase; It is synthetic that this medicament suppresses purine ring; This medicament is nucleotide interconversion inhibitor; This medicament suppresses dihydrofolate reduction; This medicament blocking-up thymidine monophosphate; This medicament causes DNA damage; This medicament is the DNA intercalator; This medicament is rna synthesis inhibitor; This medicament is pyrimidine synthesis inhibitors; This medicament suppresses ribonucleotide and synthesizes or function; This medicament suppresses thymidine monophosphate and synthesizes or function; It is synthetic that this medicament suppresses DNA; This medicament causes DNA adduct to form; This medicament CKIs matter is synthetic; This medicine agent inhibit microtubule function; This medicament is the protein kinase inhibitors that cyclin relies on; This medicament is the epidermal growth factor kinase inhibitor; This medicament is elastatinal; This medicament is the Xa factor inhibitor; This medicament is the Farnesyltransferase inhibitor; This medicament is the fibrinogen antagonist; This medicament is the guanylate cyclase stimulant; This medicament is the heat shock protein 90 antagonist; This medicament is the heat shock protein 90 antagonist, and wherein the heat shock protein 90 antagonist is geldanamycin or its analog or derivative; This medicament is the guanylate cyclase stimulant; This medicament is the HMGCoA reductase inhibitor; This medicament is the HMGCoA reductase inhibitor, and wherein the HMGCoA reductase inhibitor is Simvastatin or its analog or derivative; This medicament is hydroxyl orotic acid dehydrogenase inhibitor; This medicament is the IKK2 inhibitor; This medicament is the IL-1 antagonist; This medicament is the ICE antagonist; This medicament is the IRAK antagonist; This medicament is the IL-4 activator; This medicament is immunomodulator; This medicament is sirolimus or its analog or derivative; This medicament is not sirolimus; This medicament is everolimus or its analog or derivative; This medicament is tacrolimus or its analog or derivative; This medicament is not tacrolimus; This medicament is biolmus or its analog or derivative; This medicament is tresperimus or its analog or derivative; This medicament is Anranofin or its analog or derivative; This medicament is that 27-0-removes first rapamycin or its analog or derivative; This medicament is Gusperimus or its analog or derivative; This medicament is Elidel or its analog or derivative; This medicament is ABT-578 or its analog or derivative; This medicament is inosine monophosphate dehydrogenase (IMPDH) inhibitor; This medicament is the IMPDH inhibitor, and wherein the IMPDH inhibitor is Mycophenolic Acid or its analog or derivative; This medicament is the IMPDH inhibitor, and wherein the IMPDH inhibitor is 1-α-25 dihydroxy vitamin d3 or its analog or derivative; This medicament is leukotriene inhibitors; This medicament is the MCP-1 antagonist; This medicament is the MMP inhibitor; This medicament is the NF kB inhibitor; This medicament is the NF kB inhibitor, and wherein the NF kB inhibitor is Bay 11-7082; This medicament is the NO antagonist; This medicament is the p38 map kinase inhibitor; This medicament is p38 MAP inhibitors of kinases, and wherein the p38 map kinase inhibitor is SB 202190; This medicament is CD-840; This medicament is the TGF beta inhibitor; This medicament is the thromboxane A2 antagonist; This medicament is the TNFa antagonist; This medicament is tace inhibitor; This medicament is tyrosine kinase inhibitor; This medicament is vitronectin inhibitor; This medicament is fibroblast growth factor inhibitor; This medicament is kinases inhibitor; This medicament is pdgf receptor kinase inhibitor; This medicament is endothelial growth factor receptor kinase inhibitor; This medicament is RAR antagonists; This medicament is the platelet derived growth factor receptor inhibitors of kinases; This medicament is the fibrinogen antagonist; This medicament is antifungal agent, and wherein antifungal agent is sulconazole; This medicament is diphosphonate; This medicament is the phospholipase A1 inhibitor; This medicament is histamine H 1/H2/H3 receptor antagonist; This medicament is macrolide antibiotics; This medicament is GP IIb/IIIa receptor antagonist; This medicament is endothelin-receptor antagonists; This medicament is peroxisome proliferator-activated receptor stimulating agent; This medicament is estrogen receptor agent; This medicament is somatostatin analogs; This medicament is neurokinin 1 antagonist; This medicament is neurokinin 3 antagonists; This medicament is the VLA-4 antagonist; This medicament is the osteoclast inhibitor; This medicament is DNA topoisomerase ATP hydrolysis inhibitor; This medicament is hypertensin I conversion enzyme inhibitor; This medicament is angiotension II antagonists; This medicament is enkephalinase inhibitor; This medicament is peroxisome Proliferator-activated receptor gamma agonist insulin sensitiser thing; This medicament is the protein kinase C inhibitor; This medicament is ROCK (kinases that rho-is relevant) inhibitor; This medicament is the CXCR3 inhibitor; This medicament is the Itk inhibitor; This medicament is cPLA2 A₂-Α inhibitors; the agent is a PPAR Agonists; The agent is immunosuppressant; The agent is Erb inhibitor; programming of the agent is fine Cell death inhibitor; The agent is a lipid cortical protein agonists; the agent is a VCAM-1 antagonist; The agent is a collagen antagonist; the agent is α2 integrin antagonists; the agent is inhibited TNFα Preparation; the agent is a nitric oxide inhibitor; the pharmaceutical cathepsin inhibitors; the agent is not Anti-inflammatory agents; the agent is not glucocorticoids; the agent is not dexamethasone, beclomethasone or Dipropionate; the agent is not anti-infective agent; the agent is not antibiotics; This is not anti-fungal agents Agent; the agent is not beclomethasone; the agent is not dipropionate, the apparatus further comprising coating, The coating comprises an anti-scarring agent and a polymer; The apparatus also includes coating, wherein the coating comprises an anti- Scar-forming agent; The apparatus also includes coating, wherein the coating distributed on the surface of the apparatus; the apparatus Also includes coating, wherein the coating direct contact means; The apparatus also includes coating, wherein the coating indirectly Contact means; The apparatus also includes coating, wherein the coating partially covering means; the apparatus further includes coating Layer, wherein the coating completely cover means; the apparatus further comprises coating wherein the coating is a uniform coating; The device also includes a coating, wherein the coating is non-uniform coating; The apparatus also includes coating, which coating The coating layer is not continuous; The apparatus also includes coating, wherein the coating layer having a pattern; the apparatus further Containing coating, wherein the coating has a thickness of 100μm or smaller; The apparatus also includes coating, The coating having a thickness of 10μm or smaller; The apparatus also includes coating, wherein when the device is deployed The coating adhered to the surface of the device; the apparatus further comprises coating wherein the coating is stable at room temperature for 1 year; The device also includes a coating, wherein the anti-scarring agent is from about 0.0001% by weight to about 1% Present in an amount in the coating; The apparatus also includes coating, wherein the anti-scarring agent is about 1% by weight To about 10% by weight present in the coating; The apparatus also includes coating, wherein the anti-scarring agent is at About 10% by weight to about 25% by weight present in the coating; The apparatus also includes coating, wherein the anti-scar Mark forming agent is about 25 percent by weight to about 70% by weight present in the coating; the coating apparatus further includes Layer, wherein the coating further comprises a polymer; the apparatus further comprises a first composition having a first coating Having a second composition layer and a second layer; the apparatus further comprises a first composition having A first coating layer having a second composition and a second coating, wherein the first composition and the second Different kinds of composition; the apparatus further comprising a polymer; the apparatus further comprises a polymeric carrier; the apparatus Further comprises a polymeric carrier, wherein the polymeric carrier comprises copolymers; the apparatus further comprising a polymer containing , Wherein the polymeric carrier comprises a block copolymer; the apparatus further comprises a polymeric carrier, wherein the poly Vector comprising a random copolymer composition; the apparatus further comprises a polymeric carrier, wherein the polymeric carrier package Containing a biodegradable polymer; the apparatus further comprises a polymeric carrier, wherein the polymeric carrier comprises Non-biodegradable polymer; the apparatus further comprises a polymeric carrier, wherein the polymeric carrier comprises Hydrophilic polymer; the apparatus further comprises a polymeric carrier, wherein the polymeric carrier comprising a hydrophobic polymer Thereof; the apparatus further comprises a polymeric carrier, wherein the carrier comprises a hydrophilic polymer poly region Thereof; the apparatus further comprises a polymeric carrier, wherein the polymeric carrier having a hydrophobic region containing poly Thereof; the apparatus further comprises a polymeric carrier, wherein the polymeric carrier includes a non-conductive polymer; The apparatus further comprises a polymeric carrier, wherein the carrier comprises an elastomeric polymer; the apparatus further comprises a poly Compound carrier, wherein the polymeric carrier includes a hydrogel; the apparatus further comprises a polymeric carrier, wherein Polymeric carrier comprises a silicone polymer; the apparatus further comprises a polymeric carrier, wherein the polymer contains Comprises an elastomeric body; the apparatus further comprises a polymeric carrier, wherein the polymeric carrier comprising a hydrocarbon polymer; The apparatus further comprises a polymeric carrier, wherein the carrier polymer is a polymer comprising styrene derivative; the Device also includes a polymeric carrier, wherein the polymeric carrier comprises a polymer derived from butadiene; the loading Device further comprises a polymeric carrier, wherein the polymeric carrier containing macromer; the apparatus further comprises a poly Compound carrier, wherein the polymeric carrier includes poly (ethylene glycol) polymer; the apparatus further comprising a polymer Carrier, wherein the polymeric carrier containing an amorphous polymer; the apparatus further includes a smooth coating layer, wherein Anti-scarring agent is positioned in the device hole or cavity; anti-scarring agent is positioned on the device through Channel, the cavity or divet; apparatus further includes a second pharmaceutically active agent; apparatus further comprises anti-inflammatory agents; Device also includes a pharmaceutical inhibition of infection; means further comprises inhibiting infection agent, wherein the agent is Anthracycline; apparatus further includes inhibiting infection agent, wherein the agent is doxorubicin; apparatus also Including inhibiting infection agent, wherein the agent is mitoxantrone; apparatus further comprises inhibiting infection drugs Agent, wherein the agent is a fluoropyrimidine; wherein the agent is mitoxantrone; apparatus further includes inhibiting infection The drug, wherein the agent is 5 - fluorouracil (5-FU); apparatus further comprises inhibiting infection agents, Wherein the agent is a folic acid antagonist; apparatus further comprises inhibiting infection agent, wherein the agent is a Aminopterin; apparatus further comprises inhibiting infection agent, wherein the agent is podophyllotoxin; apparatus further Inhibition of infection with agents, wherein the agent is etoposide; apparatus further comprises inhibiting infection agents, Wherein the agent is camptothecin; apparatus further comprises inhibiting infection agent, wherein the agent is hydroxyurea; Device also includes a pharmaceutical inhibition of infection, wherein the agent is a platinum complex; apparatus further includes a sense inhibition Dyeing agents, wherein the agent is cisplatin; apparatus further comprises an anti-thrombotic agent; the apparatus further includes contrast Agent; the apparatus further includes contrast agent, wherein the contrast agent is a radiopaque material, wherein the radiopaque The material comprises a metal, a halogenated compound or a compound containing a barium; the apparatus further includes contrast agent, Wherein the contrast agent is a radiopaque material, wherein the radiopaque material comprises barium, tantalum or technetium; The device also includes a contrast agent, wherein the MRI contrast agent is responsive substance; the apparatus further includes made Contrast agents, wherein the contrast agent containing gadolinium chelates; the apparatus further includes contrast agent, wherein the contrast agent comprises Iron, magnesium, manganese, copper or chromium; the apparatus further includes contrast agent, wherein the contrast agent comprises iron oxide of Thereof; the apparatus further includes contrast agent, wherein the contrast agent comprises a dye, a pigment or colorant; the Apparatus further comprises generating the echo of the material; the apparatus further comprises generating the echo of the material, wherein generating back Form of a coating material for the sound; the device is sterile; anti-scarring agent and apparatus for planting suppression device The adhesion between the host into; the anti-scarring agent means close to the local delivery device group Weave; anti scarring agent on the device deployment (deployment) released into the tissue surrounding the device; Anti-scarring agent released after deployment of the device to the device surrounding tissue, which is the connective tissue Weave; anti scarring agent released after deployment of the device to the device surrounding tissue, which is the muscle tissue Meat tissue; anti scarring agent released after deployment of the device to the device surrounding tissue, where tissue Is the nerve tissue; anti scarring agent released after deployment of the device to the device surrounding tissues, which Organizations are epithelial tissue; anti scarring agent deployment of the device to about 1 year period to an effective concentration Release from the device; anti scarring agent about a month to six month period from the device to the effective concentration Release; anti-scarring agent in the period of approximately 1-90 days from the device to the effective concentration of the release; anti-scar Forming agent in an effective concentration at a constant release rate from the device; anti-scarring agent is loaded from the effective concentration Is set to continuously increasing release rate; anti-scar-forming agent in an effective concentration to continuously reduced from the device Rate of release; deployed from the device to about 90 days period, the anti-scarring agent by diffusion from the pack Containing anti-scar-forming agent in an effective concentration of the release composition; deployed from the device to about 90 days Period , The anti-scarring agent through the erosion of the composition comprising an anti-scarring agent from the composition in an effective Concentration release; apparatus comprises about 0.01μg to about 10μg anti-scarring agent; apparatus comprises approximately 10μg To about 10mg anti-scarring agent; unit contains about 10mg to about 250mg anti-scarring agent; Unit contains about 250mg to about 1000mg anti-scarring agent; devices to contain about 1000mg Approximately 2500mg anti-scarring agent; surface of the device comprises less than about 0.01μg anti-scarring agent / mm ...²The apparatus surface of anti-scarring agent application; The surface of device comprises approximately 0.01 μ g and arrives approximately 1 μ g anti-scarring agent/mm²The apparatus surface of anti-scarring agent application; The surface of device comprises approximately 1 μ g and arrives approximately 10 μ g anti-scarring agent/mm²The apparatus surface of anti-scarring agent application; The surface of device comprises approximately 10 μ g and arrives approximately 250 μ g anti-scarring agent/mm²The apparatus surface of anti-scarring agent application; The surface of device comprises approximately 250 μ g and arrives approximately 1000 μ g anti-scarring agent/mm²The apparatus surface of anti-scarring agent application; The surface of device comprises approximately 1000 μ g and arrives approximately 2500 μ g anti-scarring agent/mm²The apparatus surface of anti-scarring agent application; Described medicament or composition are attached to sensor; Described medicament or composition covalent bond sensor; The non-covalent combined sensor of described medicament or composition; Described device also comprises the coating that absorbs described medicament or composition; Described sensor interweaves with the line that is comprised of described medicament or composition or be coated with described medicament or composition; The part of sensor covers with the sleeve (sleeve) that contains described medicament or composition; Described sensor covers with the sleeve that contains described medicament or composition fully; The part of the sensor mesh covered that contains described medicament or composition; Sensor is fully with the mesh covered that contains described medicament or composition; Described device also comprises the pump of connecting sensor.

The other feature relevant with pump

Said pump can also be passed through one, two or more following characterizing definition: this medicament suppresses cytothesis; This medicament suppresses Angiogenesis; This medicament suppresses migration of fibroblast cells; This medicament suppresses fibroblast proliferation; This medicament suppresses extrtacellular matrix deposition; This medicament suppresses tissue reconstruction; This medicament is AI; This medicament is 5-lipoxidase inhibitor or antagonist; This medicament is chemokine receptor anagonists; This medicament is cell cycle inhibitor; This medicament is taxane; This medicament is anti-microtubule agent; This medicament is taxol; This medicament is not that taxol, this medicament are analog or the derivatives of taxol; This medicament is catharanthus alkaloid; This medicament is camptothecine or its analog or derivative; This medicament is podophyllotoxin; This medicament is podophyllotoxin, and wherein podophyllotoxin is Etoposide or its analog or derivative; This medicament is anthracycline; This medicament is anthracycline, and wherein anthracycline is Doxorubicin or its analog or derivative; This medicament is anthracycline, and wherein anthracycline is mitoxantrone or its analog or derivative; This medicament is platinum compounds; This medicament is nitroso ureas; This medicament is the nitre imidazoles; This medicament is antifol; This medicament is cytidine analog; This medicament is pyrimidine analogue; This medicament is fluoropyrimidine analogue; This medicament is purine analogue; This medicament is mustargen or its analog or derivative; This medicament is hydroxycarbamide; This medicament is mitomycin C or its analog or derivative; This medicament is alkyl sulfonic ester; This medicament is benzamide or its analog or derivative; This medicament is niacinamide or its analog or derivative; This medicament is halogeno-sugar or its analog or derivative; This medicament is the DNA alkylating agent; This medicament is anti-microtubule agent; This medicament is topoisomerase enzyme inhibitor; This medicament is the DNA cleavage agent; This medicament is antimetabolite; This medicament suppresses adenosine deaminase; It is synthetic that this medicament suppresses purine ring; This medicament is nucleotide interconversion inhibitor; This medicament suppresses dihydrofolate reduction; This medicament blocking-up thymidine monophosphate; This medicament causes DNA damage; This medicament is the DNA intercalator; This medicament is rna synthesis inhibitor; This medicament is pyrimidine synthesis inhibitors; This medicament suppresses ribonucleotide and synthesizes or function; This medicament suppresses thymidine monophosphate and synthesizes or function; It is synthetic that this medicament suppresses DNA; This medicament causes DNA adduct to form; This medicament CKIs matter is synthetic; This medicine agent inhibit microtubule function; This medicament is the protein kinase inhibitors that cyclin relies on; This medicament is the epidermal growth factor kinase inhibitor; This medicament is elastatinal; This medicament is the Xa factor inhibitor; This medicament is the Farnesyltransferase inhibitor; This medicament is the fibrinogen antagonist; This medicament is the guanylate cyclase stimulant; This medicament is the heat shock protein 90 antagonist; This medicament is the heat shock protein 90 antagonist, and wherein the heat shock protein 90 antagonist is geldanamycin or its analog or derivative; This medicament is the guanylate cyclase stimulant; This medicament is the HMGCoA reductase inhibitor; This medicament is the HMGCoA reductase inhibitor, and wherein the HMGCoA reductase inhibitor is Simvastatin or its analog or derivative; This medicament is hydroxyl orotic acid dehydrogenase inhibitor; This medicament is the IKK2 inhibitor; This medicament is the IL-1 antagonist; This medicament is the ICE antagonist; This medicament is the IRAK antagonist; This medicament is the IL-4 activator; This medicament is immunomodulator; This medicament is sirolimus or its analog or derivative; This medicament is not sirolimus; This medicament is everolimus or its analog or derivative; This medicament is tacrolimus or its analog or derivative; This medicament is not tacrolimus; This medicament is biolmus or its analog or derivative; This medicament is tresperimus or its analog or derivative; This medicament is Anranofin or its analog or derivative; This medicament is that 27-0-removes first rapamycin or its analog or derivative; This medicament is Gusperimus or its analog or derivative; This medicament is Elidel or its analog or derivative; This medicament is ABT-578 or its analog or derivative; This medicament is inosine monophosphate dehydrogenase (IMPDH) inhibitor; This medicament is the IMPDH inhibitor, and wherein the IMPDH inhibitor is Mycophenolic Acid or its analog or derivative; This medicament is the IMPDH inhibitor, and wherein the IMPDH inhibitor is 1-α-25 dihydroxy vitamin d3 or its analog or derivative; This medicament is leukotriene inhibitors; This medicament is the MCP-1 antagonist; This medicament is the MMP inhibitor; This medicament is the NF kB inhibitor; This medicament is the NF kB inhibitor, and wherein the NF kB inhibitor is Bay 11-7082; This medicament is the NO antagonist; This medicament is the p38 map kinase inhibitor; This medicament is p38 MAP inhibitors of kinases, and wherein the p38 map kinase inhibitor is SB 202190; This medicament is CD-840; This medicament is the TGF beta inhibitor; This medicament is the thromboxane A2 antagonist; This medicament is the TNFa antagonist; This medicament is tace inhibitor; This medicament is tyrosine kinase inhibitor; This medicament is vitronectin inhibitor; This medicament is fibroblast growth factor inhibitor; This medicament is kinases inhibitor; This medicament is pdgf receptor kinase inhibitor; This medicament is endothelial growth factor receptor kinase inhibitor; This medicament is RAR antagonists; This medicament is the platelet derived growth factor receptor inhibitors of kinases; This medicament is the fibrinogen antagonist; This medicament is antifungal agent, and wherein antifungal agent is sulconazole; This medicament is diphosphonate; This medicament is the phospholipase A1 inhibitor; This medicament is histamine H 1/H2/H3 receptor antagonist; This medicament is macrolide antibiotics; This medicament is GP IIb/IIIa receptor antagonist; This medicament is endothelin-receptor antagonists; This medicament is peroxisome proliferator-activated receptor stimulating agent; This medicament is estrogen receptor agent; This medicament is somatostatin analogs; This medicament is neurokinin 1 antagonist; This medicament is neurokinin 3 antagonists; This medicament is the VLA-4 antagonist; This medicament is the osteoclast inhibitor; This medicament is DNA topoisomerase ATP hydrolysis inhibitor; This medicament is hypertensin I conversion enzyme inhibitor; This medicament is angiotension II antagonists; This medicament is enkephalinase inhibitor; This medicament is peroxisome Proliferator-activated receptor gamma agonist insulin sensitiser thing; This medicament is the protein kinase C inhibitor; This medicament is ROCK (kinases that rho-is relevant) inhibitor; This medicament is the CXCR3 inhibitor; This medicament is the Itk inhibitor; This medicament is cPLA2 A₂-Α inhibitors; the agent is a PPAR Agonists; The agent is immunosuppressant; The agent is Erb inhibitor; programming of the agent is fine Cell death inhibitor; The agent is a lipid cortical protein agonists; the agent is a VCAM-1 antagonist; The agent is a collagen antagonist; the agent is α2 integrin antagonists; the agent is inhibited TNFα Preparation; the agent is a nitric oxide inhibitor; the pharmaceutical cathepsin inhibitors; the agent is not Anti-inflammatory agents; the agent is not glucocorticoids; the agent is not dexamethasone, beclomethasone or Dipropionate; the agent is not anti-infective agent; the agent is not antibiotics; This is not anti-fungal agents Agent; the agent is not beclomethasone; the agent is not dipropionate, the apparatus further comprising coating, The coating comprises an anti-scarring agent and a polymer; The apparatus also includes coating, wherein the coating comprises an anti- Scar-forming agent; The apparatus also includes coating, wherein the coating distributed on the surface of the apparatus; the apparatus Also includes coating, wherein the coating direct contact means; The apparatus also includes coating, wherein the coating indirectly Contact means; The apparatus also includes coating, wherein the coating partially covering means; the apparatus further includes coating Layer, wherein the coating completely cover means; the apparatus further comprises coating wherein the coating is a uniform coating; The device also includes a coating, wherein the coating is non-uniform coating; The apparatus also includes coating, which coating The coating layer is not continuous; The apparatus also includes coating, wherein the coating layer having a pattern; the apparatus further Containing coating, wherein the coating has a thickness of 100μm or smaller; The apparatus also includes coating, The coating having a thickness of 10μm or smaller; The apparatus also includes coating, wherein when the device is deployed The coating adhered to the surface of the device; the apparatus further comprises coating wherein the coating is stable at room temperature for 1 year; The device also includes a coating, wherein the anti-scarring agent is from about 0.0001% by weight to about 1% Present in an amount in the coating; The apparatus also includes coating, wherein the anti-scarring agent is about 1% by weight To about 10% by weight present in the coating; The apparatus also includes coating, wherein the anti-scarring agent is at About 10% by weight to about 25% by weight present in the coating; The apparatus also includes coating, wherein the anti-scar Mark forming agent is about 25 percent by weight to about 70% by weight present in the coating; the coating apparatus further includes Layer, wherein the coating further comprises a polymer; the apparatus further comprises a first composition having a first coating Having a second composition layer and a second layer; the apparatus further comprises a first composition having A first coating layer having a second composition and a second coating, wherein the first composition and the second Different kinds of composition; the apparatus further comprising a polymer; the apparatus further comprises a polymeric carrier; the apparatus Further comprises a polymeric carrier, wherein the polymeric carrier comprises copolymers; the apparatus further comprising a polymer containing , Wherein the polymeric carrier comprises a block copolymer; the apparatus further comprises a polymeric carrier, wherein the poly Vector comprising a random copolymer composition; the apparatus further comprises a polymeric carrier, wherein the polymeric carrier package Containing a biodegradable polymer; the apparatus further comprises a polymeric carrier, wherein the polymeric carrier comprises Non-biodegradable polymer; the apparatus further comprises a polymeric carrier, wherein the polymeric carrier comprises Hydrophilic polymer; the apparatus further comprises a polymeric carrier, wherein the polymeric carrier comprising a hydrophobic polymer Thereof; the apparatus further comprises a polymeric carrier, wherein the carrier comprises a hydrophilic polymer poly region Thereof; the apparatus further comprises a polymeric carrier, wherein the polymeric carrier having a hydrophobic region containing poly Thereof; the apparatus further comprises a polymeric carrier, wherein the polymeric carrier includes a non-conductive polymer; The apparatus further comprises a polymeric carrier, wherein the carrier comprises an elastomeric polymer; the apparatus further comprises a poly Compound carrier, wherein the polymeric carrier includes a hydrogel; the apparatus further comprises a polymeric carrier, wherein Polymeric carrier comprises a silicone polymer; the apparatus further comprises a polymeric carrier, wherein the polymer contains Comprises an elastomeric body; the apparatus further comprises a polymeric carrier, wherein the polymeric carrier comprising a hydrocarbon polymer; The apparatus further comprises a polymeric carrier, wherein the carrier polymer is a polymer comprising styrene derivative; the Device also includes a polymeric carrier, wherein the polymeric carrier comprises a polymer derived from butadiene; the loading Device further comprises a polymeric carrier, wherein the polymeric carrier containing macromer; the apparatus further comprises a poly Compound carrier, wherein the polymeric carrier includes poly (ethylene glycol) polymer; the apparatus further comprising a polymer Carrier, wherein the polymeric carrier containing an amorphous polymer; the apparatus further includes a smooth coating layer, wherein Anti-scarring agent is positioned in the device hole or cavity; anti-scarring agent is positioned on the device through Channel, the cavity or divet; apparatus further includes a second pharmaceutically active agent; apparatus further comprises anti-inflammatory agents; Device also includes a pharmaceutical inhibition of infection; means further comprises inhibiting infection agent, wherein the agent is Anthracycline; apparatus further includes inhibiting infection agent, wherein the agent is doxorubicin; apparatus also Including inhibiting infection agent, wherein the agent is mitoxantrone; apparatus further comprises inhibiting infection drugs Agent, wherein the agent is a fluoropyrimidine; wherein the agent is mitoxantrone; apparatus further includes inhibiting infection The drug, wherein the agent is 5 - fluorouracil (5-FU); apparatus further comprises inhibiting infection agents, Wherein the agent is a folic acid antagonist; apparatus further comprises inhibiting infection agent, wherein the agent is a Aminopterin; apparatus further comprises inhibiting infection agent, wherein the agent is podophyllotoxin; apparatus further Inhibition of infection with agents, wherein the agent is etoposide; apparatus further comprises inhibiting infection agents, Wherein the agent is camptothecin; apparatus further comprises inhibiting infection agent, wherein the agent is hydroxyurea; Device also includes a pharmaceutical inhibition of infection, wherein the agent is a platinum complex; apparatus further includes a sense inhibition Dyeing agents, wherein the agent is cisplatin; apparatus further comprises an anti-thrombotic agent; the apparatus further includes contrast Agent; the apparatus further includes contrast agent, wherein the contrast agent is a radiopaque material, wherein the radiopaque The material comprises a metal, a halogenated compound or a compound containing a barium; the apparatus further includes contrast agent, Wherein the contrast agent is a radiopaque material, wherein the radiopaque material comprises barium, tantalum or technetium; The device also includes a contrast agent, wherein the MRI contrast agent is responsive substance; the apparatus further includes made Contrast agents, wherein the contrast agent containing gadolinium chelates; the apparatus further includes contrast agent, wherein the contrast agent comprises Iron, magnesium, manganese, copper or chromium; the apparatus further includes contrast agent, wherein the contrast agent comprises iron oxide of Thereof; the apparatus further includes contrast agent, wherein the contrast agent comprises a dye, a pigment or colorant; the Apparatus further comprises generating the echo of the material; the apparatus further comprises generating the echo of the material, wherein generating back Form of a coating material for the sound; the device is sterile; anti-scarring agent and apparatus for planting suppression device The adhesion between the host into; the anti-scarring agent means close to the local delivery device group Weave; anti scarring agent on the device deployment (deployment) released into the tissue surrounding the device; Anti-scarring agent released after deployment of the device to the device surrounding tissue, which is the connective tissue Weave; anti scarring agent released after deployment of the device to the device surrounding tissue, which is the muscle tissue Meat tissue; anti scarring agent released after deployment of the device to the device surrounding tissue, where tissue Is the nerve tissue; anti scarring agent released after deployment of the device to the device surrounding tissues, which Organizations are epithelial tissue; anti scarring agent deployment of the device to about 1 year period to an effective concentration Release from the device; anti scarring agent about a month to six month period from the device to the effective concentration Release; anti-scarring agent in the period of approximately 1-90 days from the device to the effective concentration of the release; anti-scar Forming agent in an effective concentration at a constant release rate from the device; anti-scarring agent is loaded from the effective concentration Is set to continuously increasing release rate; anti-scar-forming agent in an effective concentration to continuously reduced from the device Rate of release; deployed from the device to about 90 days period, the anti-scarring agent by diffusion from the pack Containing anti-scar-forming agent in an effective concentration of the release composition; deployed from the device to about 90 days Period , The anti-scarring agent through the erosion of the composition comprising an anti-scarring agent from the composition in an effective Concentration release; apparatus comprises about 0.01μg to about 10μg anti-scarring agent; apparatus comprises approximately 10μg To about 10mg anti-scarring agent; unit contains about 10mg to about 250mg anti-scarring agent; Unit contains about 250mg to about 1000mg anti-scarring agent; devices to contain about 1000mg Approximately 2500mg anti-scarring agent; surface of the device comprises less than about 0.01μg anti-scarring agent / mm ...²The apparatus surface of anti-scarring agent application; The surface of device comprises approximately 0.01 μ g and arrives approximately 1 μ g anti-scarring agent/mm²The apparatus surface of anti-scarring agent application; The surface of device comprises approximately 1 μ g and arrives approximately 10 μ g anti-scarring agent/mm²The apparatus surface of anti-scarring agent application; The surface of device comprises approximately 10 μ g and arrives approximately 250 μ g anti-scarring agent/mm²The apparatus surface of anti-scarring agent application; The surface of device comprises approximately 250 μ g and arrives approximately 1000 μ g anti-scarring agent/mm²The apparatus surface of anti-scarring agent application; The surface of device comprises approximately 1000 μ g and arrives approximately 2500 μ g anti-scarring agent/mm²The apparatus surface of anti-scarring agent application; Described medicament or composition are attached to pump; Described medicament or composition covalent bond pump; Described medicament or composition are non-covalent in conjunction with pump; Described device also comprises the coating that absorbs described medicament or composition; Described pump interweaves with the line that is comprised of described medicament or composition or be coated with described medicament or composition; The part of pump covers with the sleeve (sleeve) that contains described medicament or composition; Described pump covers with the sleeve that contains described medicament or composition fully; The part of the pump mesh covered that contains described medicament or composition; Pump is fully with the mesh covered that contains described medicament or composition; Described device also comprises the sensor that connects pump.

The present invention provides to be used to suppress synulotic following method in many aspects and embodiment:

1. pick off

On the one hand, the invention provides and suppress synulotic method, it comprises pick off or anti-scarring agent or the compositions that comprises anti-scarring agent is placed the animal reservoir that wherein said medicament suppresses cicatrization.

This method can be by characterizing definitions a kind of, below two or more: this pick off is blood or tissue glucose monitor; This pick off is the electrolyte pick off; This pick off is the blood constituent pick off; This pick off is temperature sensor; This pick off is the pH pick off; This pick off is an optical pickocff; This pick off is an amperometric sensor; This pick off is a pressure transducer; This pick off is a biosensor; This pick off is the sensing responder; This pick off is a tension pick-up; This pick off is a magnetoresistive transducer; This pick off is a cardiac sensor; This pick off is a respiration pickup; This pick off is a hearing transducer; This pick off is the metabolite pick off; This sensor metataxis; This sensor physical change; This sensor electrochemical change; This sensor magnetic variationization; This sensor acceleration change; This sensor ionizing radiation changes; This sensor sound wave changes; This sensor chemical change; This sensor drug level changes; This sensor hormone changes; This sensor air pressure change.

2. blood or tissue glucose monitor

On the one hand, the invention provides and suppress synulotic method, it comprises blood or tissue glucose monitor (being pick off) or anti-scarring agent or the compositions that comprises anti-scarring agent is placed the animal reservoir that wherein said medicament suppresses cicatrization.

This method can be passed through a kind of, the characterizing definition below two or more: use the conduit on the stent platform, device can be delivered to vascular system through the chamber; Device is made up of the glucose-sensitive living cells, and the change of described cell monitor blood glucose levels and response glucose concentration produces detectable electricity or optical signal; The electrode of device for forming by analyte response enzyme; Device is formed for the closed-loop insulin delivery system, and this system comprises detection host's blood sugar level and stimulates insulin pump that the sensing equipment of insulin is provided; With device for the closed-loop insulin delivery system, this system comprises and detects the sensing equipment that host's blood sugar level and stimulating pancreas provide insulin.

3. pressure or tension pick-up

On the one hand, the invention provides and suppress synulotic method, it comprises pressure or tension force (strain) pick off or anti-scarring agent or the compositions that comprises anti-scarring agent is placed the animal reservoir that wherein said medicament suppresses cicatrization.

This method can be further by characterizing definitions a kind of, below two or more: this installs monitoring blood pressure; This device monitors liquid flow; This device monitors the pressure in the aneurysmal sack; This device monitors intracranial pressure; This device monitors the mechanical pressure relevant with fracture; This device monitors air pressure; This device monitors that nystagmus quivers; This device monitors the degree of depth of cornea implant; This device monitors intraocular pressure; This device is for having the passive sensor of Inductor-Capacitor circuit; This device is the tension force sensor-based system that oneself is powered; This pick off comprises lead, sensor assembly and sensor circuit and the device of voltage is provided.

4. cardiac sensor

On the one hand, the invention provides and suppress synulotic method, it comprises cardiac sensor or anti-scarring agent or the compositions that comprises anti-scarring agent is placed the animal reservoir that wherein said medicament suppresses cicatrization.

This device can be further by characterizing definitions a kind of, below two or more: this device monitors heart output; This device monitors ejection fraction; This device monitors the blood pressure in the ventricle; This device monitors ventricular wall motion; This device monitors the blood flow to transplant organ; This installs monitor heart rate.

5. respiration pickup

On the one hand, the invention provides and suppress synulotic method, it comprises respiration pickup or anti-scarring agent or the compositions that comprises anti-scarring agent is placed the animal reservoir that wherein said medicament suppresses cicatrization.

In one embodiment, this device monitoring lung function.

6. hearing transducer

On the one hand, the invention provides and suppress synulotic method, it comprises hearing transducer or anti-scarring agent or the compositions that comprises anti-scarring agent is placed the animal reservoir that wherein said medicament suppresses cicatrization.

This method can be further by characterizing definitions a kind of, below two or more: this device is to be suitable for the signal of telecommunication is delivered to the implantable electromechanical transducer that acts on middle ear or internal ear; This device produces electric audio signal; This device is and the link coupled capacitance sensor of vibration acoustic components; This device is an electromagnetic transducer.

7. electrolyte or metabolite pick off

On the one hand, the invention provides and suppress synulotic method, it comprises electrolyte or metabolite pick off or anti-scarring agent or the compositions that comprises anti-scarring agent is placed the animal reservoir that wherein said medicament suppresses cicatrization.

This method can be further by characterizing definitions a kind of, below two or more: this installs radiation sources, its at blood to interact with many pick offs that output signal is provided; This device is the bio-sensing responder, and the dyestuff of the optical property that it changes by having the change in the response environment is used for the optical sensor of sensing optical change; With being used for transfer of data is formed to the responder of remote reader; With this device be the biological electronic installation of monoblock type that detects at least a analyte among the host.

8. pump

The invention provides and suppress synulotic method, it comprises pump or anti-scarring agent or the compositions that comprises anti-scarring agent is placed the animal reservoir that wherein said medicament suppresses cicatrization.

This method can be further by characterizing definitions a kind of, below two or more: this device is suitable for insulin delivery; This device is suitable for sending anesthetics; This device is suitable for sending chemotherapeutant; This device is suitable for sending antiarrhythmic drug; This device is suitable for sending the spasmolytic medicine; This device is suitable for sending spasmolytic; This device is suitable for sending antibiotic; This device is suitable for only detecting delivering drugs when changing in the host; This device is suitable for continuous slow release delivering drugs; This device is suitable for sending pre-metered doses of medication with pulse mode; This device is programmable drug delivery pump; This device is suitable for the intraocular delivery medicine; This device is suitable for delivering drugs in the sheath; This device is suitable for the intraperitoneal delivering drugs; This device is suitable for the intra-arterial delivering drugs; This device is suitable for intracardiac delivering drugs; This device is implantable osmotic pumps; This device is that medicament for the eyes is sent pump; This device is a metering system; This device is wriggling (rolling) pump; This device is electrically driven (operated) pump; This device is the elastomer pump; This device is that spring shrinks pump; This device is the pump of gas-powered; This device is a hydraulic pump; This device is the pump that relies on piston; This device is the pump of non-dependence piston; This device is a distributor chamber; This device is an infusion pump; This device is passive pump.

9. implantable insulin pump

On the one hand, the invention provides and suppress synulotic method, it comprises implantable insulin pump or anti-scarring agent or the compositions that comprises anti-scarring agent is placed the animal reservoir that wherein said medicament suppresses cicatrization.

In one embodiment, implantable insulin pump comprises the pick off of single channel conduit and implantable intravascular, and it is transferred to implantable insulin pump to distribute medicine by conduit with hematochemistry.

10. drug delivery pump in the sheath

On the one hand, the invention provides and suppress synulotic method, it comprises drug delivery pump in the sheath or anti-scarring agent or the compositions that comprises anti-scarring agent is placed the animal reservoir that wherein said medicament suppresses cicatrization.

This method can be further by characterizing definitions a kind of, below two or more: this device is suitable for pain medication directly is delivered in the cerebrospinal fluid of the intrathecal space around the spinal cord; This device is suitable for delivering drugs into brain; This device is suitable for sending in the sheath baclofen; This device also comprises the spinal column inner catheter; This device also comprises drug delivery pump in second sheath; This device also comprises conduit and electrode.

11. be used for chemotherapeutic implantable drug delivery pump

On the one hand, the invention provides and suppress synulotic method, it comprises that the compositions that will be used for chemotherapeutic implantable drug delivery pump and anti-scarring agent or comprise anti-scarring agent places the animal reservoir, and wherein said medicament suppresses cicatrization.

This method can be further by characterizing definitions a kind of, below two or more: this device is suitable for sending 2-deoxidation 5-floxuridine; The host has solid tumor, and device is suitable for chemotherapeutant is input to solid tumor; The host has tumor, and this device is suitable for chemotherapeutant is infused into the blood vessel of supplying with tumor; The host has liver tumor, and device is suitable for chemotherapeutant is delivered to the tremulous pulse that blood supply is provided for host's liver.

12. be used for the treatment of the drug delivery pump of heart disease

On the one hand, the invention provides and suppress synulotic method, it comprises that the compositions that will be used for the treatment of the drug delivery pump and the anti-scarring agent of heart disease or comprise anti-scarring agent places the animal reservoir, and wherein said medicament suppresses cicatrization.

In one embodiment, device is to send stimulation energy and distribute near the heart electrode of medicine stimulation location.

13. medicine is sent implant (that is pump)

On the one hand, the invention provides and suppress synulotic method, it comprises that the compositions of medicine being sent implant (that is, pump) and anti-scarring agent or comprising anti-scarring agent places the animal reservoir, wherein said medicament inhibition cicatrization.

Suppress the relevant other feature of synulotic method with using pick off

Suppress synulotic method and can also pass through one, two or more following characterizing definition: this medicament suppresses cytothesis; This medicament suppresses Angiogenesis; This medicament suppresses migration of fibroblast cells; This medicament suppresses fibroblast proliferation; This medicament suppresses extrtacellular matrix deposition; This medicament suppresses tissue reconstruction; This medicament is AI; This medicament is 5-lipoxidase inhibitor or antagonist; This medicament is chemokine receptor anagonists; This medicament is cell cycle inhibitor; This medicament is taxane; This medicament is anti-microtubule agent; This medicament is taxol; This medicament is not that taxol, this medicament are analog or the derivatives of taxol; This medicament is catharanthus alkaloid; This medicament is camptothecine or its analog or derivative; This medicament is podophyllotoxin; This medicament is podophyllotoxin, and wherein podophyllotoxin is Etoposide or its analog or derivative; This medicament is anthracycline; This medicament is anthracycline, and wherein anthracycline is Doxorubicin or its analog or derivative; This medicament is anthracycline, and wherein anthracycline is mitoxantrone or its analog or derivative; This medicament is platinum compounds; This medicament is nitroso ureas; This medicament is the nitre imidazoles; This medicament is antifol; This medicament is cytidine analog; This medicament is pyrimidine analogue; This medicament is fluoropyrimidine analogue; This medicament is purine analogue; This medicament is mustargen or its analog or derivative; This medicament is hydroxycarbamide; This medicament is mitomycin C or its analog or derivative; This medicament is alkyl sulfonic ester; This medicament is benzamide or its analog or derivative; This medicament is niacinamide or its analog or derivative; This medicament is halogeno-sugar or its analog or derivative; This medicament is the DNA alkylating agent; This medicament is anti-microtubule agent; This medicament is topoisomerase enzyme inhibitor; This medicament is the DNA cleavage agent; This medicament is antimetabolite; This medicament suppresses adenosine deaminase; It is synthetic that this medicament suppresses purine ring; This medicament is nucleotide interconversion inhibitor; This medicament suppresses dihydrofolate reduction; This medicament blocking-up thymidine monophosphate; This medicament causes DNA damage; This medicament is the DNA intercalator; This medicament is rna synthesis inhibitor; This medicament is pyrimidine synthesis inhibitors; This medicament suppresses ribonucleotide and synthesizes or function; This medicament suppresses thymidine monophosphate and synthesizes or function; It is synthetic that this medicament suppresses DNA; This medicament causes DNA adduct to form; This medicament CKIs matter is synthetic; This medicine agent inhibit microtubule function; This medicament is the protein kinase inhibitors that cyclin relies on; This medicament is the epidermal growth factor kinase inhibitor; This medicament is elastatinal; This medicament is the Xa factor inhibitor; This medicament is the Farnesyltransferase inhibitor; This medicament is the fibrinogen antagonist; This medicament is the guanylate cyclase stimulant; This medicament is the heat shock protein 90 antagonist; This medicament is the heat shock protein 90 antagonist, and wherein the heat shock protein 90 antagonist is geldanamycin or its analog or derivative; This medicament is the guanylate cyclase stimulant; This medicament is the HMGCoA reductase inhibitor; This medicament is the HMGCoA reductase inhibitor, and wherein the HMGCoA reductase inhibitor is Simvastatin or its analog or derivative; This medicament is hydroxyl orotic acid dehydrogenase inhibitor; This medicament is the IKK2 inhibitor; This medicament is the IL-1 antagonist; This medicament is the ICE antagonist; This medicament is the IRAK antagonist; This medicament is the IL-4 activator; This medicament is immunomodulator; This medicament is sirolimus or its analog or derivative; This medicament is not sirolimus; This medicament is everolimus or its analog or derivative; This medicament is tacrolimus or its analog or derivative; This medicament is not tacrolimus; This medicament is biolmus or its analog or derivative; This medicament is tresperimus or its analog or derivative; This medicament is Anranofin or its analog or derivative; This medicament is that 27-0-removes first rapamycin or its analog or derivative; This medicament is Gusperimus or its analog or derivative; This medicament is Elidel or its analog or derivative; This medicament is ABT-578 or its analog or derivative; This medicament is inosine monophosphate dehydrogenase (IMPDH) inhibitor; This medicament is the IMPDH inhibitor, and wherein the IMPDH inhibitor is Mycophenolic Acid or its analog or derivative; This medicament is the IMPDH inhibitor, and wherein the IMPDH inhibitor is 1-α-25 dihydroxy vitamin d3 or its analog or derivative; This medicament is leukotriene inhibitors; This medicament is the MCP-1 antagonist; This medicament is the MMP inhibitor; This medicament is the NF kB inhibitor; This medicament is the NF kB inhibitor, and wherein the NF kB inhibitor is Bay 11-7082; This medicament is the NO antagonist; This medicament is the p38 map kinase inhibitor; This medicament is the p38 map kinase inhibitor, and wherein the p38 map kinase inhibitor is SB 202190; This medicament is CD-840; This medicament is the TGF beta inhibitor; This medicament is the thromboxane A2 antagonist; This medicament is the TNFa antagonist; This medicament is tace inhibitor; This medicament is tyrosine kinase inhibitor; This medicament is vitronectin inhibitor; This medicament is fibroblast growth factor inhibitor; This medicament is kinases inhibitor; This medicament is pdgf receptor kinase inhibitor; This medicament is endothelial growth factor receptor kinase inhibitor; This medicament is RAR antagonists; This medicament is the platelet derived growth factor receptor inhibitors of kinases; This medicament is the fibrinogen antagonist; This medicament is antifungal agent, and wherein antifungal agent is sulconazole; This medicament is diphosphonate; This medicament is the phospholipase A1 inhibitor; This medicament is histamine H 1/H2/H3 receptor antagonist; This medicament is macrolide antibiotics; This medicament is GP IIb/IIIa receptor antagonist; This medicament is endothelin-receptor antagonists; This medicament is peroxisome proliferator-activated receptor stimulating agent; This medicament is estrogen receptor agent; This medicament is somatostatin analogs; This medicament is neurokinin 1 antagonist; This medicament is neurokinin 3 antagonists; This medicament is the VLA-4 antagonist; This medicament is the osteoclast inhibitor; This medicament is DNA topoisomerase ATP hydrolysis inhibitor; This medicament is hypertensin I conversion enzyme inhibitor; This medicament is angiotension II antagonists; This medicament is enkephalinase inhibitor; This medicament is peroxisome Proliferator-activated receptor gamma agonist insulin sensitiser thing; This medicament is inhibitors of protein kinase C; This medicament is ROCK (kinases that rho-is relevant) inhibitor; This medicament is the CXCR3 inhibitor; This medicament is the Itk inhibitor; This medicament is cPLA2 A₂-Α Inhibitors; The agent is a PPAR agonist; The agent is immunosuppressant; suppression of the agent is Erb Preparation; the agent is programmed cell death inhibitor; the agent is a lipid cortex protein agonists; the VCAM-1 antagonists are agents; the agent is collagen antagonist; the agent is α2 integrin antagonistic Antagonist; the agent is a TNFα inhibitor; the agent is a nitric oxide inhibitor; the agent is to organize Protease inhibitors; than the pharmaceutical anti-inflammatory agents; the agent is not steroids; the agent is not couverture Corticosteroids; the agent is not dexamethasone; the agent is not beclomethasone; the agent is not dipropionate Salts; The agent is not anti-infective agents; the agent is not antibiotics; the agent is not antifungals; The method, wherein the composition comprises a polymer; said method, wherein the composition comprises a polymer, And the polymer is or contains copolymers; said method, wherein the composition comprises a polymer, and And the polymer is or contains a block copolymer; said method, wherein the composition comprises a polymer, And the polymer is a random copolymer or contains; said method, wherein the composition comprises a polymer, And the polymer is or contains a biodegradable polymer; said method, wherein the composition comprises Containing the polymer, and the polymer is or contains non-biodegradable polymer; said method, Wherein the composition comprises a polymer, and the polymer is or contains a hydrophilic polymer; said square Method, wherein the composition comprises a polymer, and the polymer is or contains a hydrophobic polymer; the Said method, wherein the composition comprises a polymer, and the polymer is or contains a hydrophilic region A polymer; said method, wherein the composition comprises a polymer, and the polymer is or contains A polymer having a hydrophobic region; said method, wherein the composition comprises a polymer, and the polymer Matter is, or contains non-conductive polymer; said method, wherein the composition comprises a polymer, and The polymer is or includes an elastic body; said method, wherein the composition comprises a polymer, and the Is or contains a hydrogel polymer; said method, wherein the composition comprises a polymer, and the polymer Is or contains a silicone polymer composition; said method, wherein the composition comprises a polymer, and The polymer is or contains a hydrocarbon polymer; said method, wherein the composition comprises a polymer, and Or the polymer is a polymer containing styrene derivatives; said method, wherein the composition comprises poly Thereof, and the polymer is or contains a polymer derived from butadiene; said method, wherein the group Composition comprises a polymer, and the polymer is or contains macromers;, wherein The composition comprises a polymer, and the polymer is or contains a poly (ethylene glycol) polymer; said square Method, wherein the composition comprises a polymer, and the polymer is or contains an amorphous polymer; the Said method, wherein the composition further comprises a second pharmaceutically active agent; said method, wherein the composition further Include anti-inflammatory agents;, wherein the composition further comprises an agent inhibiting infection; the method described in Wherein the composition further comprises an agent inhibiting infection;, wherein the composition further comprises an anthracene ring mold Prime;, wherein the composition further comprises doxorubicin;, wherein the composition further package With mitoxantrone;, wherein the composition further comprises a fluoropyrimidine; said method, wherein the composition Herein also include 5 - fluorouracil (5-FU);, wherein the composition further comprises a folic acid antagonist; , Wherein the composition further comprises methotrexate;, wherein the composition further comprises a ghost Mortar toxin;, wherein the composition further comprises etoposide; said method wherein the composition Further comprising camptothecin;, wherein the composition further comprises hydroxyurea;, wherein the group Composition also contains a platinum complex;, wherein the composition further comprises cisplatin; the composition further comprises Antithrombotic agents;, wherein the composition further comprises a contrast agent; said method, wherein the composition Also includes contrast agent, wherein the contrast agent is a radiopaque material, wherein the radiopaque material comprises Metal, a halogenated compound or a compound containing a barium;, wherein the composition further comprises making Contrast agents, wherein the contrast agent is a radiopaque material, wherein the radiopaque material comprises barium, tantalum, or By technetium;, wherein the composition further comprises a contrast agent, wherein the MRI contrast agent is or contains a Response material; said method, wherein the composition further comprises a contrast agent, wherein the contrast agent is or contains a Gadolinium chelate;, wherein the composition further comprises a contrast agent, and the contrast agent is or comprises an iron, Magnesium, manganese, copper or chromium;, wherein the composition further comprises a contrast agent, and the contrast agent is Or a compound containing iron oxide; that, wherein the composition further comprises a contrast agent, and imaging Agent is or contains a dye, a pigment or colorant; when applied to about 90 days, the drug through Through diffusion of the agent from a composition containing an effective concentration to release; when applied to about 90 days, From the drug by erosion of the pharmaceutical compositions containing an effective concentration to release; the composition further comprises Inflammatory cytokines; the composition further comprises pharmaceutical stimulate cell proliferation; composition further comprises a polymeric Carrier; composition gels, pastes, or in the form of sprays; sensor or a pharmaceutical composition of the Partially constructed; sensor with said impregnating agents or composition; said method, wherein said agent or Forming the coating composition, and the coating in direct contact sensor; said method, wherein said agent Or a composition for forming a coating, and the coating indirect contact with the sensor; or a pharmaceutical composition as described Coating, and the coating layer partially covering the sensor; said method, wherein said agent or composition is shaped Into the coating, and the coating completely covers the sensor; the drug or a composition located in the sensor Holes or cavities; the drug or composition is positioned in the sensor channel in the cavity or divet; pass Sensor further comprises generating the echo of the material; sensor further comprises generating the echo of the material, wherein generating back Form of a coating material for the sound; sensor is sterile; medicament delivered from the sensor, wherein the medicament in the Sensor Deployment released into the tissue surrounding the sensor; medicament delivered from the sensor, where agents Released after the deployment of the sensor to the sensor surrounding tissue, which is the connective tissue; Pharmacy from Sensor delivery, including drug release after deployment of the sensor to the sensor surrounding tissues, which Organization is a muscle tissue; pharmaceutical delivery from the sensor, the sensor deployment in which agents released into the transfer Sensor surrounding tissue, a tissue of the nervous tissue; agents delivered from the sensor, wherein medicament Released after the deployment of the sensor to the sensor surrounding tissue, where tissue is epithelial tissue; Pharmacy Sensors deployed in approximately one year period from the sensor to the effective concentration of the release; Pharmacy from the sensor Delivery, Pharmacy about a month to six month period from the sensor to the effective concentration of the release; Pharmacy from Sensor delivery, which medicament at about 1-90 day period using the effective concentration of the release from the sensor; drug Agent is delivered from the sensor, wherein the medicament in effective concentrations at a constant release rate from the sensor; medicine from the Sensor delivery, wherein the effective concentration of medicament from the sensor to continuously increasing release rate; Pharmacy Delivered from the sensor, wherein the medicament in effective concentrations from the sensors to continuously reduce the rate of release; drug Agent is delivered from the sensor, wherein the sensor comprises about 0.01μg to about 10μg said agent; agents from Sensor delivery, wherein the sensor comprises about 10μg to about 10mg of the drug; Pharmacy from the sensing Delivery device, wherein the sensor comprises from about 10mg to about 250mg of the drug; Pharmacy from the sensor Delivery, wherein the sensor comprises from about 250mg to about 1000mg of the drug; Pharmacy from the sensor Delivery, wherein the sensor comprises about 1000mg to 2500mg about the medicine; medicine from the sensor Delivery, the sensor surface of said medicament contains less than about 0.01μg / mm ...²The sensor surface of this medicament application; Medicament is sent from sensor, and the surface of sensor comprises approximately 0.01 μ g and arrives the approximately 1 described medicament/mm of μ g²The sensor surface of this medicament application; Medicament is sent from sensor, and the surface of sensor comprises approximately 1 μ g and arrives the approximately 10 described medicament/mm of μ g²The sensor surface of this medicament application; Medicament is sent from sensor, and the surface of sensor comprises approximately 10 μ g and arrives the approximately 250 described medicament/mm of μ g²The sensor surface of this medicament application; Medicament is sent from sensor, and the surface of sensor comprises approximately 250 μ g and arrives the approximately 1000 described medicament/mm of μ g²The sensor surface of this medicament application; Medicament is sent from sensor, and the surface of sensor comprises approximately 1000 μ g and arrives the approximately 2500 described medicament/mm of μ g²The sensor surface of this medicament application; Described method, wherein sensor also comprises coating, and coating is uniform coating; Described method, wherein sensor also comprises coating, and coating is non-uniform coating; Described method, wherein sensor also comprises coating, and coating is discontinuous coating; Described method, wherein sensor also comprises coating, and coating is figuratum coating; Described method, wherein sensor also comprises coating, and coating has 100 μ m or less thickness; Described method, wherein sensor also comprises coating, and coating has 10 μ m or less thickness; Described method, wherein sensor also comprises coating, and coating adheres to the surface of sensor when sensor is disposed; Described method, wherein sensor also comprises coating, and coating was at room temperature stablized 1 year; Described method, wherein sensor also comprises coating, and medicament is approximately 0.0001% to be present in coating to about 1% amount by weight; Described method, wherein sensor also comprises coating, and medicament is approximately 1% to be present in coating to about 10% amount by weight; Described method, wherein sensor also comprises coating, and medicament is approximately 10% to be present in coating to about 25% amount by weight; Described method, wherein sensor also comprises coating, and medicament is approximately 25% to be present in coating to about 70% amount by weight; Described method, wherein sensor also comprises coating, and coating comprises polymer; Described method, wherein this sensor also comprises the first coating with the first composition and has the second coating of the second composition; Described method, wherein this sensor also comprises the first coating with the first composition and has the second coating of the second composition, and wherein the first composition is different with the second composition; Described medicament or composition are attached to sensor; Described medicament or composition covalent bond sensor; The non-covalent combined sensor of described medicament or composition; Described sensor also comprises the coating that absorbs described medicament or composition; Described sensor interweaves with or line that be coated with described medicament or composition that form by described medicament or composition; The part of sensor covers with the sleeve that contains described medicament or composition; Described sensor covers with the sleeve that contains described medicament or composition fully; The part of the sensor mesh covered that contains described medicament or composition; Sensor is fully with the mesh covered that contains described medicament or composition; Sensor is connected to pump; Described medicament or composition were applied to sensor surface before sensor is placed in the host; Described medicament or composition are applied to sensor surface during sensor is placed in the host; Described medicament or composition are applied to sensor surface at once after sensor is placed in the host; Described medicament or composition were applied to the surface that the host organizes around sensor before sensor is placed in the host; Described medicament or composition are applied to the surface that the host organizes around sensor during sensor is placed in the host; Described medicament or composition are applied to the surface that the host organizes around sensor at once after sensor is placed in the host; Described medicament or composition are applied topically to the anatomy space that sensor is placed; Described medicament or composition percutaneous injection are organized in the host on every side to sensor.

Suppress the relevant other feature of synulotic method with using pump

The method of inhibiting scar formation can also be one, two or more of the following features definitions: The inhibition of cell regeneration agent; the agent inhibiting angiogenesis; the pharmaceutical inhibition of fibroblast migration; The pharmaceutical inhibition of fibroblast proliferation; the agent inhibiting deposition of extracellular matrix; the agent suppression group Woven reconstruction; the agent is an angiogenesis inhibitor; the agent is 5 - lipoxygenase inhibitor or antagonist Antagonist; the agent is a chemokine receptor antagonist; the agent is a cell cycle inhibitor; the agent A taxane; the agent is an anti-microtubule agents; the agent is taxol; the agent is not paclitaxel, the Agent is paclitaxel analogues or derivatives; The agent is vinca alkaloids; the agent is hi Tree base or an analogue or derivative thereof; the agent is podophyllotoxin; the agent is podophyllotoxin, which ghost Mortar toxin is etoposide or an analogue or derivative thereof; the agent is anthracyclines; the agent anthracene Ring ADM, which anthracycline is doxorubicin or an analogue or derivative thereof; mold of the pharmaceutical anthracycline Hormone, which is the anthracycline mitoxantrone or an analogue or derivative thereof; the agent is a platinum compound; The agent is a nitrosourea; The agent is imidazole nitrate; the agent is a folic acid antagonist; the agent is a cell Glycoside analogs; the agent is a pyrimidine analogs; the agent is a fluoropyrimidine analogues; the agent is a purine Analogs; the agent is a nitrogen mustard or an analogue or derivative thereof; the agent is hydroxyurea; the agent is Mitomycin C or an analogue or derivative thereof; the agent is an alkyl sulfonate; the agent is benzoyl Amine or an analogue or derivative thereof; the agent is nicotinamide or an analogue or derivative thereof; the agent is Halogenated sugar or an analogue or derivative thereof; the agent is a DNA alkylating agent; the agent is an anti-microtubule Agent; The agent is a topoisomerase inhibitor; The agent is DNA cleaving agent; behalf of the agent is an anti- Metabolites; the pharmaceutical inhibition of adenosine deaminase; the agent inhibiting synthesis of purine ring; the agent is a nucleotide Tautomeric inhibitors; dihydrofolate reductase inhibiting the agent; agents blocking the thymidine monophosphate; the agent Causes DNA damage; the agent is DNA intercalating agent; the agent is an RNA synthesis inhibitors; the Pharmacy is a pyrimidine synthesis inhibitor; the pharmaceutical inhibition of ribonucleotide synthesis or function; suppress the agent Thymidine monophosphate synthesis or function; the agent to inhibit DNA synthesis; the agent causes DNA adducts Form; the agent inhibits protein synthesis; the pharmaceutical inhibition of microtubule function; the agent is a cell cycle Protein-dependent protein kinase inhibitor; the agent is a kinase inhibitor of epidermal growth factor; drug Elastase inhibitor agent; the agent is a factor Xa inhibitor; farnesyl group of the agent is transferred Shift inhibitor; the agent is fibrinogen antagonists; the agent is guanylate cyclase stimulating agent; The agent is a heat shock protein 90 antagonists; the agent is a heat shock protein 90 antagonist, wherein the heat Shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof; the agent is a guanylate Cyclase stimulating agent; the agent is a HMGCoA reductase inhibitor; the agent is a HMGCoA Reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative Biological; The agent is hydroxy orotic acid dehydrogenase inhibitor; The agent is IKK2 inhibitor; drug Agent is IL-1 antagonist; the agent is ICE antagonists; the agent is IRAK antagonist; the agent The IL-4 agonists; the agent is immunomodulators; the agent is sirolimus or an analogue or derivative Biological; The agent is not sirolimus; the agent is everolimus or an analogue or derivative thereof; the Pharmacy is tacrolimus or an analogue or derivative thereof; the agent is not tacrolimus; the agent is biolmus or an analogue or derivative thereof; Peimo the pharmaceutical company is curved or an analogue or derivative thereof; The agent is auranofin or an analogue or derivative thereof; the agent is 27-0 - demethyl rapamycin or Analogs or derivatives; The agent is guanidine stand Secretary Mo or an analogue or derivative thereof; the agent is topiramate America Secretary Mo or an analogue or derivative thereof; the agent is ABT-578 or an analogue or derivative thereof; drug Agent is inosine monophosphate dehydrogenase (IMPDH) inhibitor; the medicine is IMPDH inhibitor, wherein IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof; IMPDH inhibition of the agent is Agent, wherein the IMPDH inhibitor is 1-α-25 dihydroxy vitamin D3 or an analogue or derivative thereof; The agent is a leukotriene inhibitor; the agent is MCP-1 antagonists; the agent is MMP inhibitors; The agent is NFκB inhibitor; The agent is NFκB inhibitors, which NFκB inhibitor is Bay 11-7082; The agent is NO antagonists; The agent is p38MAP kinase inhibitors; drug Agent is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB 202190; drug Agent is a phosphodiesterase inhibitor; the agent is TGFβ inhibitor; the agent is a thromboxane A2 antagonist Agent; The agent is TNFa antagonists; The agent is TACE inhibitors; tyrosine kinase of the agent is Inhibitors; the agent is a vitronectin inhibitor; the agent is fibroblast growth factor inhibition Agent; the agent is a protein kinase inhibitor; the agent is PDGF receptor kinase inhibitors; the agent Endothelial growth factor receptor kinase inhibitor; The agent is a retinoic acid receptor antagonist; the agent is Platelet-derived growth factor receptor kinase inhibitor; The agent is fibrinogen antagonists; drug Agent is an anti-fungal agent, wherein the antifungal agent itraconazole is sulfur; the agent is a bisphosphonate; the agent is phosphorus A1 lipase inhibitor; the agent is a histamine H1/H2/H3 receptor antagonist; the agent is a macrocyclic Esters of antibiotics; the agent is a GP IIb / IIIa receptor antagonists; The agent is endothelin receptor antagonist Agent; The agent is peroxisome proliferator-activated receptor agonists; The agent is estrogen receptor Body agent; The agent is somatostatin analogues; the agent is a neurokinin 1 antagonist; the Agents are antagonists of neurokinin 3; the agent is a VLA-4 antagonists; the pharmaceutical osteoclasts Inhibitor; the agent is a DNA topoisomerase inhibitor of ATP hydrolysis; the agent is angiotensin Peptide I-converting enzyme inhibitors; the agent is an angiotensin II antagonist; the agent is enkephalinase Inhibitors; The agent is a peroxisome proliferator-activated receptor γ agonist insulin sensitizer; The agent is a protein kinase C inhibitor; the agent is a ROCK (rho-associated kinase) inhibitor; The agent is a CXCR3 inhibitor; the agent is Itk inhibitors; the agent is a cytosolic phospholipase A2-α Inhibitors; The agent is a PPAR agonist; The agent is immunosuppressant; suppression of the agent is Erb Preparation; the agent is programmed cell death inhibitor; the agent is a lipid cortex protein agonists; the VCAM-1 antagonists are agents; the agent is collagen antagonist; the agent is α2 integrin antagonistic Antagonist; the agent is a TNFα inhibitor; the agent is a nitric oxide inhibitor; the agent is to organize Protease inhibitors; than the pharmaceutical anti-inflammatory agents; the agent is not steroids; the agent is not couverture Corticosteroids; the agent is not dexamethasone; the agent is not beclomethasone; the agent is not dipropionate Salts; The agent is not anti-infective agents; the agent is not antibiotics; the agent is not antifungals; The method, wherein the composition comprises a polymer; said method, wherein the composition comprises a polymer, And the polymer is or contains copolymers; said method, wherein the composition comprises a polymer, and And the polymer is or contains a block copolymer; said method, wherein the composition comprises a polymer, And the polymer is a random copolymer or contains; said method, wherein the composition comprises a polymer, And the polymer is or contains a biodegradable polymer; said method, wherein the composition comprises Containing the polymer, and the polymer is or contains non-biodegradable polymer; said method, Wherein the composition comprises a polymer, and the polymer is or contains a hydrophilic polymer; said square Method, wherein the composition comprises a polymer, and the polymer is or contains a hydrophobic polymer; the Said method, wherein the composition comprises a polymer, and the polymer is or contains a hydrophilic region A polymer; said method, wherein the composition comprises a polymer, and the polymer is or contains A polymer having a hydrophobic region; said method, wherein the composition comprises a polymer, and the polymer Matter is, or contains non-conductive polymer; said method, wherein the composition comprises a polymer, and The polymer is or includes an elastic body; said method, wherein the composition comprises a polymer, and the Is or contains a hydrogel polymer; said method, wherein the composition comprises a polymer, and the polymer Is or contains a silicone polymer composition; said method, wherein the composition comprises a polymer, and The polymer is or contains a hydrocarbon polymer; said method, wherein the composition comprises a polymer, and Or the polymer is a polymer containing styrene derivatives; said method, wherein the composition comprises poly Thereof, and the polymer is or contains a polymer derived from butadiene; said method, wherein the group Composition comprises a polymer, and the polymer is or contains macromers;, wherein The composition comprises a polymer, and the polymer is or contains a poly (ethylene glycol) polymer; said square Method, wherein the composition comprises a polymer, and the polymer is or contains an amorphous polymer; the Said method, wherein the composition further comprises a second pharmaceutically active agent; said method, wherein the composition further Include anti-inflammatory agents;, wherein the composition further comprises an agent inhibiting infection; the method described in Wherein the composition further comprises an agent inhibiting infection;, wherein the composition further comprises an anthracene ring mold Prime;, wherein the composition further comprises doxorubicin;, wherein the composition further package With mitoxantrone;, wherein the composition further comprises a fluoropyrimidine; said method, wherein the composition Herein also include 5 - fluorouracil (5-FU);, wherein the composition further comprises a folic acid antagonist; , Wherein the composition further comprises methotrexate;, wherein the composition further comprises a ghost Mortar toxin;, wherein the composition further comprises etoposide; said method wherein the composition Further comprising camptothecin;, wherein the composition further comprises hydroxyurea;, wherein the group Composition also contains a platinum complex;, wherein the composition further comprises cisplatin; the composition further comprises Antithrombotic agents;, wherein the composition further comprises a contrast agent; said method, wherein the composition Also includes contrast agent, wherein the contrast agent is a radiopaque material, wherein the radiopaque material comprises Metal, a halogenated compound or a compound containing a barium;, wherein the composition further comprises making Contrast agents, wherein the contrast agent is a radiopaque material, wherein the radiopaque material comprises barium, tantalum, or By technetium;, wherein the composition further comprises a contrast agent, wherein the MRI contrast agent is or contains a Response material; said method, wherein the composition further comprises a contrast agent, wherein the contrast agent is or contains a Gadolinium chelate;, wherein the composition further comprises a contrast agent, and the contrast agent is or comprises an iron, Magnesium, manganese, copper or chromium;, wherein the composition further comprises a contrast agent, and the contrast agent is Or a compound containing iron oxide; that, wherein the composition further comprises a contrast agent, and imaging Agent is or contains a dye, a pigment or colorant; when applied to about 90 days, the drug through Through diffusion of the agent from a composition containing an effective concentration to release; when applied to about 90 days, From the drug by erosion of the pharmaceutical compositions containing an effective concentration to release; the composition further comprises Inflammatory cytokines; the composition further comprises pharmaceutical stimulate cell proliferation; composition further comprises a polymeric Carrier; composition gels, pastes, or in the form of sprays; pump or a pharmaceutical composition of the part Formations; pump the drug or impregnating composition; said method, wherein said pharmaceutical composition or shape Into the coating, and the coating layer in direct contact pump; said method, wherein said pharmaceutical composition is formed or Coating, and the coating layer indirect contact with the pump; said pharmaceutical composition or a coating, and the coating Partially covering the pump; said method, wherein said pharmaceutical composition or a coating, and the coating finish Full coverage of the pump; the drug or composition positioned in a hole or holes in the pump; the drug or composition Positioning the pump channel in the cavity or divet; pump further comprises generating the echo of the material; pump also includes production Echo raw material, wherein the coating material produced in the form of echo; pump is sterile; medicine from the pump Delivery, in which agents deployed in the pump to the pump after releasing the surrounding tissue; drug delivery from the pump, which Drug release at the pump to the pump after deployment surrounding tissue, which is the connective tissue; medicine from the pump Delivery, in which agents deployed in the pump to the pump after releasing the surrounding tissue, where tissue is muscle tissue; Drug delivery from the pump, in which agents deployed in the pump to the pump after releasing the surrounding tissue, where organizations are Nerve tissue; pharmaceutical delivery from the pump, in which agents deployed in the pump to the pump after releasing the surrounding tissue, Which organization is the epithelial tissue; Pharmacy deployed to the pump period of approximately one year from the pump to release an effective concentration Amp; medicine from the pump delivery, Pharmacy in about a month to six month period from the pump to the effective concentration of the release; Drug delivery from the pump, in which agents in approximately 1-90 days period from the pump to release an effective concentration; Pharmacy Delivered from the pump, wherein the medicament in effective concentrations at a constant release rate from the pump; drug delivery from the pump, which With an effective concentration of drug from the pump to continuously increasing release rate; drug delivery from the pump, wherein the medicament With an effective concentration to continuously decrease from the pump rate of release; medicament delivered from the pump, wherein the pump comprises about 0.01μg to about 10μg of said medicament; medicament delivered from the pump, wherein the pump comprises from about 10μg to about 10 mg of the drug; drug delivery from the pump, which pumps containing about 10mg to about 250mg of the drug; Drug delivery from the pump, which pumps about 250mg to about 1000mg contains the medicine; medicine from the pump Delivery, wherein the pump comprises about 1000mg to about 2500mg said agent; pharmaceutical delivery from the pump, the pump The surface of the medicament containing less than about 0.01μg / mm ...²The pump surface of this medicament application; Medicament is sent from pump, and the surface of pump comprises approximately 0.01 μ g and arrives the approximately 1 described medicament/mm of μ g²The pump surface of this medicament application; Medicament is sent from pump, and the surface of pump comprises approximately 1 μ g and arrives the approximately 10 described medicament/mm of μ g²The pump surface of this medicament application; Medicament is sent from pump, and the surface of pump comprises approximately 10 μ g and arrives the approximately 250 described medicament/mm of μ g²The pump surface of this medicament application; Medicament is sent from pump, and the surface of pump comprises approximately 250 μ g and arrives the approximately 1000 described medicament/mm of μ g²The pump surface of this medicament application; Medicament is sent from pump, and the surface of pump comprises approximately 1000 μ g and arrives the approximately 2500 described medicament/mm of μ g²The pump surface of this medicament application; Described method, wherein pump also comprises coating, and coating is uniform coating; Described method, wherein pump also comprises coating, and coating is non-uniform coating; Described method, wherein pump also comprises coating, and coating is discontinuous coating; Described method, wherein pump also comprises coating, and coating is figuratum coating; Described method, wherein pump also comprises coating, and coating has 100 μ m or less thickness; Described method, wherein pump also comprises coating, and coating has 10 μ m or less thickness; Described method, wherein pump also comprises coating, and coating adheres to the surface of pump when pump is disposed; Described method, wherein pump also comprises coating, and coating was at room temperature stablized 1 year; Described method, wherein pump also comprises coating, and medicament is approximately 0.0001% to be present in coating to about 1% amount by weight; Described method, wherein pump also comprises coating, and medicament is approximately 1% to be present in coating to about 10% amount by weight; Described method, wherein pump also comprises coating, and medicament is approximately 10% to be present in coating to about 25% amount by weight; Described method, wherein pump also comprises coating, and medicament is approximately 25% to be present in coating to about 70% amount by weight; Described method, wherein pump also comprises coating, and coating comprises polymer; Described method, wherein this pump also comprises the first coating with the first composition and has the second coating of the second composition; Described method, wherein this pump also comprises the first coating with the first composition and has the second coating of the second composition, and wherein the first composition is different with the second composition; Described medicament or composition are attached to pump; Described medicament or composition covalent bond pump; Described medicament or composition are non-covalent in conjunction with pump; Described pump also comprises the coating that absorbs described medicament or composition; Described pump interweaves with or line that be coated with described medicament or composition that form by described medicament or composition; The part of pump covers with the sleeve that contains described medicament or composition; Described pump covers with the sleeve that contains described medicament or composition fully; The part of the pump mesh covered that contains described medicament or composition; Pump is fully with the mesh covered that contains described medicament or composition; Pump is connected to sensor; Described medicament or composition were applied to the pump surface before pump is placed in the host; Described medicament or composition are applied to the pump surface during pump is placed in the host; Described medicament or composition are applied to the pump surface at once after pump is placed in the host; Described medicament or composition were applied to the surface that the host organizes around pump before pump is placed in the host; Described medicament or composition are applied to the surface that the host organizes around pump during pump is placed in the host; Described medicament or composition are applied to the surface that the host organizes around pump at once after pump is placed in the host; Described medicament or composition are applied topically to the anatomy space that pump is placed; Described medicament or composition percutaneous injection are organized in the host on every side to pump.

The method of the manufacturing installation below the present invention provides in several different methods and embodiment:

1. pick off

On the one hand, the invention provides the method for manufacturing installation, the compositions that it comprises combination sensor and anti-scarring agent or comprises anti-scarring agent, the cicatrization between the host that wherein said medicament restraining device and this device are implanted.

This method can be by characterizing definitions a kind of, below two or more: this pick off is blood or tissue glucose monitor; This pick off is the electrolyte pick off; This pick off is the blood constituent pick off; This pick off is temperature sensor; This pick off is the pH pick off; This pick off is an optical pickocff; This pick off is an amperometric sensor; This pick off is a pressure transducer; This pick off is a biosensor; This pick off is the sensing responder; This pick off is a tension pick-up; This pick off is a magnetoresistive transducer; This pick off is a cardiac sensor; This pick off is a respiration pickup; This pick off is a hearing transducer; This pick off is the metabolite pick off; This sensor metataxis; This sensor physical change; This sensor electrochemical change; This sensor magnetic variationization; This sensor acceleration change; This sensor ionizing radiation changes; This sensor sound wave changes; This sensor chemical change; This sensor drug level changes; This sensor hormone changes; This sensor air pressure change.

2. blood or tissue glucose monitor (that is pick off)

On the one hand, the invention provides the method for manufacturing installation, the compositions that it comprises combination blood or tissue glucose monitor (being pick off) and anti-scarring agent or comprises anti-scarring agent, the cicatrization between the host that wherein said medicament restraining device and this device are implanted.

This method can be passed through a kind of, the characterizing definition below two or more: use the conduit on the stent platform, device can be delivered to vascular system through the chamber; Device is made up of the glucose-sensitive living cells, and the change of described cell monitor blood glucose levels and response glucose concentration produces detectable electricity or optical signal; The electrode of device for forming by analyte response enzyme; Device is formed for the closed-loop insulin delivery system, and this system comprises detection host's blood sugar level and stimulates insulin pump that the sensing equipment of insulin is provided; With device for the closed-loop insulin delivery system, this system comprises and detects the sensing equipment that host's blood sugar level and stimulating pancreas provide insulin.

3. pressure or tension pick-up

On the one hand, the invention provides the method for manufacturing installation, the compositions that it comprises combination pressure or tension pick-up and anti-scarring agent or comprises anti-scarring agent, the cicatrization between the host that wherein said medicament restraining device and this device are implanted.

This method can be further by characterizing definitions a kind of, below two or more: this installs monitoring blood pressure; This device monitors fluid flow; This device monitors the pressure in the aneurysmal sack; This device monitors intracranial pressure; This device monitors the mechanical pressure relevant with fracture; This device monitors air pressure; This device monitors that nystagmus quivers; This device monitors the degree of depth of cornea implant; This device monitors intraocular pressure; This device is for having the passive sensor of Inductor-Capacitor circuit; This device is the tension force sensor-based system that oneself is powered; This pick off comprises lead, sensor assembly and sensor circuit and the equipment of voltage is provided.

4. cardiac sensor

On the one hand, the invention provides the method for manufacturing installation, the compositions that it comprises combination cardiac sensor and anti-scarring agent or comprises anti-scarring agent, the cicatrization between the host that wherein said medicament restraining device and this device are implanted.

This method can be further by characterizing definitions a kind of, below two or more: this device monitors heart output; This device monitors ejection fraction; This device monitors the blood pressure in the ventricle; This device monitors ventricular wall motion; This device monitors the blood flow to transplant organ; This installs monitor heart rate.

5. respiration pickup

On the one hand, the invention provides the method for manufacturing installation, the compositions that it comprises combination respiration pickup and anti-scarring agent or comprises anti-scarring agent, the cicatrization between the host that wherein said medicament restraining device and this device are implanted.

In one embodiment, this device monitoring lung function.

6. hearing transducer

On the one hand, the invention provides the method for manufacturing installation, the compositions that it comprises combination hearing transducer and anti-scarring agent or comprises anti-scarring agent, the cicatrization between the host that wherein said medicament restraining device and this device are implanted.

This method can be further by characterizing definitions a kind of, below two or more: this device is suitable for the signal of telecommunication is delivered to the implantable electromechanical transducer that acts on middle ear or internal ear; This device produces electric audio signal; This device is and the link coupled capacitance sensor of vibration acoustic components; This device is an electromagnetic transducer.

7. electrolyte or metabolite pick off

On the one hand, the invention provides the method for manufacturing installation, the compositions that it comprises combination electrolyte or metabolite pick off and anti-scarring agent or comprises anti-scarring agent, the cicatrization between the host that wherein said medicament restraining device and this device are implanted.

This method can be further by characterizing definitions a kind of, below two or more: this installs radiation sources, its at blood to interact with many pick offs that output signal is provided; This device is the bio-sensing responder, and the dyestuff of the optical property that it changes by having the change in the response environment is used for the optical sensor of sensing optical change; With being used for transfer of data is formed to the responder of remote reader; With this device be the biological electronic installation of monoblock type that detects at least a analyte among the host.

8. pump

The invention provides the method for manufacturing installation, the compositions that it comprises sundstrand pump and anti-scarring agent or comprises anti-scarring agent, the cicatrization between the host that wherein said medicament restraining device and this device are implanted.

This method can be further by characterizing definitions a kind of, below two or more: this device is suitable for insulin delivery; This device is suitable for sending anesthetics; This device is suitable for sending chemotherapeutant; This device is suitable for sending antiarrhythmic drug; This device is suitable for sending the spasmolytic medicine; This device is suitable for sending spasmolytic; This device is suitable for sending antibiotic; This device is suitable for only detecting delivering drugs element when changing in the host; This device is suitable for continuous slow release delivering drugs; This device is suitable for sending pre-metered doses of medication with pulse mode; This device is programmable drug delivery pump; This device is suitable for the intraocular delivery medicine; This device is suitable for delivering drugs in the sheath; This device is suitable for the intraperitoneal delivering drugs; This device is suitable for the intra-arterial delivering drugs; This device is suitable for intracardiac delivering drugs; This device is implantable osmotic pumps; This device is that medicament for the eyes is sent pump; This device is a metering system; This device is wriggling (rolling) pump; This device is electrically driven (operated) pump; This device is the elastomer pump; This device is that spring shrinks pump; This device is the pump of gas-powered; This device is a hydraulic pump; This device is the pump that relies on piston; This device is the pump of non-dependence piston; This device is a distributor chamber; This device is an infusion pump; This device is passive pump.

9. implantable insulin pump

On the one hand, the invention provides the method for manufacturing installation, the compositions that it comprises combination implantable insulin pump and anti-scarring agent or comprises anti-scarring agent, the cicatrization between the host that wherein said medicament restraining device and this device are implanted.

In one embodiment, implantable insulin pump comprises the pick off of single channel conduit and implantable intravascular, and it is transferred to implantable insulin pump to distribute medicine (mediation) by conduit with hematochemistry.

10. drug delivery pump in the sheath

On the one hand, the invention provides the method for manufacturing installation, the compositions that it comprises combination sheath interior drug delivery pump and anti-scarring agent or comprises anti-scarring agent, the cicatrization between the host that wherein said medicament restraining device and this device are implanted.

This method can be further by characterizing definitions a kind of, below two or more: this device is suitable for pain medication directly is delivered in the cerebrospinal fluid of the intrathecal space around the spinal cord; This device is suitable for delivering drugs into brain; This device is suitable for sending in the sheath baclofen; This device also comprises the spinal column inner catheter; This device also comprises drug delivery pump in second sheath; This device also comprises conduit and electrode.

11. be used for chemotherapeutic implantable drug delivery pump

On the one hand, the invention provides the method for manufacturing installation, it comprises the compositions that combination is used for chemotherapeutic implantable drug delivery pump and anti-scarring agent or comprises anti-scarring agent, the cicatrization between the host that wherein said medicament restraining device and this device are implanted.

This method can be further by characterizing definitions a kind of, below two or more: this device is suitable for sending 2 '-deoxidation 5-floxuridine; The host has solid tumor, and device is suitable for chemotherapeutant is input to solid tumor; The host has tumor, and this device is suitable for chemotherapeutant is infused into the blood vessel of supplying with tumor; The host has liver tumor, and device is suitable for chemotherapeutant is delivered to the tremulous pulse that blood supply is provided for host's liver.

12. be used for the treatment of the drug delivery pump of heart disease

On the one hand, the invention provides the method for manufacturing installation, it comprises the compositions that combination is used for the treatment of the drug delivery pump and the anti-scarring agent of heart disease or comprises anti-scarring agent, the cicatrization between the host that wherein said medicament restraining device and this device are implanted.

In one embodiment, device is to send stimulation energy and distribute near the heart electrode of medicine stimulation location.

13. medicine is sent implant (that is pump)

On the one hand, the invention provides the method for manufacturing installation, it comprises the compositions that composition of medicine is sent implant (being pump) and anti-scarring agent or comprised anti-scarring agent, the cicatrization between the host that wherein said medicament restraining device and this device are implanted.

With the relevant other feature of method of making pick off

The method of fabricating a sensor as described above can also be one, two or more of the following features Definition: The inhibition of cell regeneration agent; the agent inhibiting angiogenesis; the agent inhibiting fibroblast Cell migration; the pharmaceutical inhibition of fibroblast proliferation; the agent inhibiting deposition of extracellular matrix; drug Inhibits tissue reconstruction; the agent is an angiogenesis inhibitor; the agent is a 5 - lipoxygenase inhibiting Agent or antagonist; the agent is a chemokine receptor antagonist; the agent is a cell cycle inhibitor; The agent is a taxane; the agent is an anti-microtubule agents; the agent is taxol; the agent is not paclitaxel Alcohol, the agent is paclitaxel analogue or derivative; the agent is a vinca alkaloid; drug Agent is camptothecin or an analogue or derivative thereof; the agent is podophyllotoxin; the agent is podophyllotoxin, Wherein the podophyllotoxin is etoposide or an analogue or derivative thereof; the agent is anthracyclines; drug Agent is an anthracycline, wherein anthracycline is doxorubicin or an analogue or derivative thereof; the agent is Anthracyclines, wherein anthracycline is mitoxantrone or an analogue or derivative thereof; the agent is a platinum-based Compounds; The agent is a nitrosourea; The agent is imidazole nitrate; the agent is folic acid antagonists; drug Agent is a cytidine analogue; the agent is a pyrimidine analogs; the agent is a fluoropyrimidine analogues; the agent Is a purine analogues; the agent is a nitrogen mustard or an analogue or derivative thereof; the agent is hydroxyurea; the Agent mitomycin C or an analogue or derivative thereof; the agent is an alkyl sulfonate; the agent is Benzamide or an analogue or derivative thereof; the agent is a nicotinamide or an analogue or derivative thereof; the Pharmacy halogenated sugar or an analogue or derivative thereof; the agent is a DNA alkylating agent; the agent is Anti-microtubule agent; the agent is a topoisomerase inhibitor; The agent is a DNA cleaving agent; the agent Is an anti-metabolite; the pharmaceutical inhibition of adenosine deaminase; the pharmaceutical synthesis inhibiting purine ring; the agent is Nucleotide interconversion inhibitor; dihydrofolate reductase inhibition of the agent; agents blocking the thymidine monophosphate; The agent causes DNA damage; the agent is a DNA intercalating agent; the pharmaceutical inhibition of RNA synthesis Agent; the agent is a pyrimidine synthesis inhibitor; the pharmaceutical inhibition of ribonucleotide synthesis or function; drug Inhibits synthesis of thymidine monophosphate, or feature; the agent to inhibit DNA synthesis; the agent causes DNA Adduct formation; the agent inhibits protein synthesis; the pharmaceutical inhibition of microtubule function; the agent is a thin Cell cycle-dependent protein kinase inhibitor protein; the agent is a kinase inhibitor of epidermal growth factor Agent; the pharmaceutical elastase inhibitors; the agent is a factor Xa inhibitor; the agent is a method It acyltransferase inhibitors; the agent is a fibrinogen antagonist; the agent is of guanylate Enzyme irritants; the agent is a heat shock protein 90 antagonists; the agent is a heat shock protein 90 antagonist Agent, wherein the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof; drug Agent is a guanylate cyclase stimulating agent; the agent is a HMGCoA reductase inhibitor; the agent is HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or class Analogs or derivatives thereof; whey the agent is a hydroxy acid dehydrogenase inhibitor; The agent is inhibited IKK2 Agent; the agent is IL-1 antagonist; the agent is ICE antagonists; the agent is IRAK antagonist; The agent is IL-4 agonists; The agent is immunomodulatory agents; the agent is sirolimus or similar Objects or derivatives; the agent is not sirolimus; the agent is everolimus or an analogue or derivative Matter; the agent is tacrolimus or an analogue or derivative thereof; the agent is not tacrolimus; drug Agent is biolmus or an analogue or derivative thereof; This is a song Peimo pharmaceutical company or an analogue or derivative Thereof; the agent is auranofin or an analogue or derivative thereof; the agent is 27-0 - demethyl rapamycin Or an analogue or derivative thereof; the agent is guanidine stand Secretary Mo or an analogue or derivative thereof; the agent is Pimecrolimus or an analogue or derivative thereof; the agent is ABT-578 or an analogue or derivative thereof; The agent is inosine monophosphate dehydrogenase (IMPDH) inhibitor; the medicine is IMPDH inhibitors, Which IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof; the agent is IMPDH Inhibitors, which IMPDH inhibitor is 1-α-25 dihydroxyvitamin D3 or an analogue or derivative Biological; the agent is a leukotriene inhibitor; the agent is MCP-1 antagonists; the agent is MMP Inhibitors; The agent is NF κ B inhibitor; The agent is NF κ B inhibitor, wherein NF κ B Inhibitor is Bay 11-7082; The agent is NO antagonists; This is a p38 MAP kinase inhibitor drug Agent; the agent is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB 202190; the agent is a phosphodiesterase inhibitor; the agent is TGFβ inhibitor; the agent is Thromboxane A2 antagonist; the agent is TNFa antagonist; the agent is TACE inhibitors; the Tyrosine kinase inhibitor agent; the agent is a vitronectin inhibitor; the pharmaceutical is fibroblasts Cell growth factor inhibitors; the agent is a protein kinase inhibitor; the agent is PDGF receptor kinase Inhibitors; The agent is endothelial growth factor receptor kinase inhibitor; The agent is retinoic acid receptor antagonists Antagonist; The agent is platelet-derived growth factor receptor kinase inhibitor; The agent is fibrin Original antagonist; the agent is an anti-fungal agent, wherein the antifungal agent itraconazole is sulfur; the agent is a diphosphonic acid Salts; the agent is a phospholipase A1 inhibitor; the agent is histamine H1/H2/H3 receptor antagonist; The agent is a macrolide antibiotic; The agent is GP IIb / IIIa receptor antagonists; the agent is Endothelin receptor antagonist; The agent is peroxisome proliferator-activated receptor agonists; the Pharmaceutical agents are estrogen receptor; the agent is a somatostatin analogue; the agent is a neurokinin Peptide-1 antagonist; the agent is a neurokinin 3 antagonist; the agent is a VLA-4 antagonists; the Pharmacy osteoclasts inhibitors; the agent is a DNA topoisomerase inhibitor of ATP hydrolysis; the Agents are angiotensin I converting enzyme inhibitor; the agent is an angiotensin II antagonist; the Pharmacy is enkephalinase inhibitors; The agent is a peroxisome proliferator-activated receptor γ agonists Insulin sensitizers; The agent is protein kinase C inhibitor; The agent is a ROCK (rho-related Kinase) inhibitor; The agent is CXCR3 inhibitor; The agent is Itk inhibitors; the agent Is a cytosolic phospholipase A2-α inhibitors; The agent is a PPAR agonist; This is immunosuppressive agents Agent; the agent is Erb inhibitors; the agent is programmed cell death inhibitor; the agent is a lipid Cortical protein agonists; the agent is a VCAM-1 antagonist; the agent is a collagen antagonist; drug Agent is α2 integrin antagonists; the agent is a TNFα inhibitor; the agent is a nitric oxide inhibition Preparations; The agent is cathepsin inhibitors; the agent is not anti-inflammatory agents; This is not a steroid drug Alcohol; The agent is not a glucocorticosteroid; the agent is not dexamethasone; chlorine meter times the agent is not Song; The agent is not dipropionate; the agent is not anti-infective agents; the agent is not antibiotics; the The ingredient is not an antifungal agent; composition comprising a polymer; composition comprising a polymer carrier; anti-scarring Inhibits the formation of the device implanted device and the adhesion between the host; the device will be anti-scarring agent Locally delivered to tissue near the device; means comprises an anti-scarring agent having a coating; apparatus includes That contain the drug and coating the surface of the sensor; means containing said medicament and having Direct contact with the sensor layer; apparatus and a medicament containing said coated indirect contact sensor Layer; including the pharmaceutical and device has a partially covered sensor coating; devices with contains And said drug coating layer completely covers the sensor; the device has a uniform coating; the device has a non- Uniform coating; the apparatus having a discontinuous coating; the device has a patterned coating; the apparatus has Coated, the coating having a thickness of 100μm or smaller; the device has coating, wherein the coating with With a thickness of 10μm or smaller; the device has coating, and the coating adhesion when the device is deployed to Surface of the device; the device has a coating, and the coating is stable at room temperature for 1 year; the apparatus has Coating, and wherein the anti-scarring agent is from about 0.0001% by weight to about 1 percent by weight of the Coating; the device has coating and anti-scarring agent is about 1% by weight to about 10% The amount present in the coating; the device has a coating, wherein the anti-scarring agent is by weight from about 10% to about 25% by weight present in the coating; the device has a coating, wherein the anti-scarring agent is About 25 percent by weight to about 70 percent by weight in the coating; the device has a coating, wherein the coating Having a polymer; the apparatus has a first composition having a first coating and a second group A second coating composition; the apparatus has a first composition having a first coating and a first Two kinds of a second coating composition, wherein the first composition and the second composition are different; the group Composition comprising a polymer; the composition comprises the polymeric carrier; the composition comprises a polymer carrier, Wherein the polymeric carrier comprises copolymers; the composition comprises a polymer carrier, wherein the polymeric carrier Containing block copolymer; the composition comprises a polymer carrier, wherein the polymeric carrier contains random copolymer Dimer; the composition comprises a polymer carrier, wherein the polymeric carrier comprising a biodegradable polymeric Thereof; the composition comprises a polymer carrier, wherein the polymeric carrier contains non-biodegradable polymeric Thereof; the composition comprises a polymer carrier, wherein the polymeric carrier comprises a hydrophilic polymer; the group Composition comprises a polymer carrier, wherein the polymeric carrier comprising a hydrophobic polymer; the composition comprises Polymeric carrier, wherein the polymeric carrier comprises a polymer having a hydrophilic region; the composition contains Polymeric carrier, wherein the polymeric carrier comprises a polymer having a hydrophobic region; the composition contains Polymeric carrier, wherein the polymeric carrier comprises a non-conductive polymer; the composition comprising a polymer Carrier, wherein the carrier comprises an elastomeric polymer; the composition comprises a polymer carrier, wherein the polymeric Including a hydrogel material carrier; the composition comprises a polymer carrier, wherein the carrier comprises a silicone polymer Hydrocarbon polymers; the composition comprises a polymer carrier, wherein the carrier comprises an elastomeric polymer; the group Composition comprises a polymer carrier, wherein the polymeric carrier comprising a hydrocarbon polymer; the composition comprises a polymerization Material carrier, wherein the polymeric carrier comprises a polymer of styrene derivatives; the composition comprising a polymer Carrier, wherein the carrier polymer is a polymer comprising a butadiene derivative; the composition comprises a polymer containing , Wherein the polymeric carrier comprises a macromer; the composition comprises a polymer carrier, wherein the poly Vector composition comprising poly (ethylene glycol) polymer; the composition comprises a polymer carrier, wherein the polymer Vector comprises amorphous polymer; The apparatus includes a smooth coating, wherein the anti-scarring agent is located in the Holes or cavities of the device; anti-scarring agent is located in the apparatus of the channel, the cavity or divet; loading The second set contains the pharmaceutically active agent; devices contain anti-inflammatory agents; apparatus comprises inhibiting infection Pharmacy; Means including inhibition of infection agent, wherein the agent is anthracyclines; means includes inhibiting infection Agents, wherein the agent is doxorubicin; means includes inhibiting infection agent, wherein the agent is Mitoxantrone; means includes inhibiting infection agent, wherein the agent is a fluoropyrimidine; means includes suppression System infection agents, wherein the agent is 5 - fluorouracil (5-FU); means includes inhibiting infection drugs Agent, wherein the agent is a folic acid antagonist; means includes inhibiting infection agent, wherein the agent is Methotrexate; apparatus comprises inhibiting infection agent, wherein the agent is podophyllotoxin; means includes Inhibition of infection agent, wherein the agent is etoposide; means includes inhibiting infection agents, which In the agent camptothecin; means includes inhibiting infection agent, wherein the agent is hydroxyurea; loading Including inhibiting infection home agents, wherein the agent is a platinum complex; means includes inhibiting infection drugs Agent, wherein the agent is cisplatin; the method comprising the antithrombotic agents; The apparatus includes contrast agent; the loading Set containing contrast agent, wherein the contrast agent is a radiopaque material, wherein the radiopaque material comprises Metal, a halogenated compound or a compound containing a barium; The apparatus includes contrast agent, wherein the contrast agent A radiopaque material, wherein the radiopaque material comprises barium, tantalum or technetium; the apparatus comprising Contrast agent, wherein the MRI contrast agent is responsive substance; The apparatus includes contrast agent, wherein the contrast Agents containing gadolinium chelates; The apparatus includes contrast agent, wherein the contrast agent comprises iron, magnesium, manganese, copper, or By chromium; The apparatus includes contrast agent, wherein the contrast agent comprises a compound oxide; the apparatus comprising manufacturing Contrast agents, wherein the contrast agent comprises a dye, a pigment or colorant; the apparatus comprising a timber generates echo Materials; The device contains a material to produce echoes, wherein the coating material produced in the form of echo; the apparatus Is sterile; anti-scarring agent released after deployment of the device to the device surrounding tissues; anti-scar Forming agent released after deployment of the device to the device surrounding tissue, which is the connective tissue; resistance Scarring agent released after deployment of the device to the device surrounding tissue, where tissue is muscle group Weave; anti scarring agent released after deployment of the device to the device surrounding tissue, where tissue is God By the organization; anti-scarring agent released after deployment of the device to the device surrounding tissue, where tissue Is epithelial tissue; anti-scarring agent in the unit deployed to the period of approximately one year from the effective concentrations loaded Set release; anti scarring agent about a month to six month period from the effective concentration device releases; Anti-scarring agent in the period of approximately 1-90 days from the device to the effective concentration of the release; anti-scarring agent With an effective concentration constant release rate from the device; anti-scarring agent is not effective concentrations from the device to Increasing the rate of release; anti-scarring agent is an effective means for decreasing concentrations ranging from the rate of release Release; deployed from the unit during the period of about 90 days, anti-scarring agent by diffusion from the containing anti-scar Forming agent marks the effective concentration of the release composition; deployed from the device to about 90 days period, anti- Scarring agent through the erosion of the composition comprising an anti-scarring agent from the composition in an effective concentration Release; apparatus comprises about 0.01μg to about 10μg anti-scarring agent; apparatus comprises approximately 10μg to About 10mg anti-scarring agent; apparatus comprises about 10mg to about 250mg anti-scarring agent; Unit contains about 250mg to about 1000mg anti-scarring agent; devices to contain about 1000mg Approximately 2500mg anti-scarring agent; surface of the device comprises less than about 0.01μg anti-scarring agent / mm ...²The apparatus surface of anti-scarring agent application; The surface of device comprises approximately 0.01 μ g and arrives approximately 1 μ g anti-scarring agent/mm²The apparatus surface of anti-scarring agent application; The surface of device comprises approximately 1 μ g and arrives approximately 10 μ g anti-scarring agent/mm²The apparatus surface of anti-scarring agent application; The surface of device comprises approximately 10 μ g and arrives approximately 250 μ g anti-scarring agent/mm²The apparatus surface of anti-scarring agent application; The surface of device comprises approximately 250 μ g and arrives approximately 1000 μ g anti-scarring agent/mm²The apparatus surface of anti-scarring agent application; The surface of device comprises approximately 1000 μ g and arrives approximately 2500 μ g anti-scarring agent/mm²The apparatus surface of anti-scarring agent application; By directly being attached to sensor, medicament or composition make up; By being sprayed to sensor, medicament or component make up; By medicament or composition electron spray are made up to sensor; By sensor is immersed in the solution that comprises described medicament or composition and makes up; By being covalently bound to sensor, medicament or composition make up; By medicament or the non-covalent sensor that is attached to of composition are made up; The material coating sensor that contains described medicament or composition by use makes up; The material coating sensor that absorbs described medicament by use makes up; By using that form by described medicament or composition or line that be coated with described medicament or composition interweaves and makes up; The complete covering sensor of sleeve that contains described medicament or composition by use makes up; A part that contains the sleeve covering sensor of described medicament or composition by use makes up; The complete covering sensor of covering that contains described medicament or composition by use makes up; A part that contains the covering covering sensor of described medicament or composition by use makes up; The complete covering sensor of electrostatic spinning fabric that contains described medicament or composition by use makes up; A part that contains the electrostatic spinning fabric covering sensor of described medicament or composition by use makes up; The complete covering sensor of mesh that contains described medicament or composition by use makes up; A part that contains the mesh covered sensor of described medicament or composition by use makes up; By with described medicament or composition structure sensor, making up; By with described medicament or composition dipping sensor, making up; A part that discharges the degradable polymer structure sensor of described medicament by use makes up; Make up by sensor being immersed the solution that contains described medicament and be used for the atent solvent of described sensor; Make up by sensor being immersed the solution comprise described medicament and will rinse the solvent of described sensor; Make up by sensor being immersed the solution comprise described medicament and will dissolve the solvent of described sensor; Make up by sensor being immersed the solution that comprises described medicament, polymer and be used for the atent solvent of described sensor; Make up by sensor being immersed the solution comprise described medicament, polymer and will rinse the solvent of described sensor; Make up by sensor being immersed the solution comprise described medicament, polymer and will dissolve the solvent of described sensor; Make up by sensor being sprayed to the solution that comprises described medicament and be used for the atent solvent of sensor; Make up by sensor being sprayed to the solvent that comprises described medicament and will rinse sensor; Make up by sensor being sprayed to the solution that comprises described medicament and will dissolve the solvent of sensor; Make up by sensor being sprayed to the solution that comprises described medicament, polymer and be used for the atent solvent of sensor; Make up by sensor being sprayed to the solution that comprises described medicament, polymer and will rinse the solvent of sensor; Make up by sensor being sprayed to the solution that comprises described medicament, polymer and will dissolve the solvent of sensor.

With the relevant other feature of method of making pump

The method of manufacturing the pump as described above can also be one, two or more of the following characteristics set Yi: the agent inhibits cell regeneration; the agent inhibiting angiogenesis; the pharmaceutical inhibition of fibroblast Migration; the pharmaceutical inhibition of fibroblast proliferation; the agent inhibiting deposition of extracellular matrix; the agent Inhibition of tissue reconstruction; the agent is an angiogenesis inhibitor; the agent is a 5 - lipoxygenase inhibitors Or antagonists; the agent is a chemokine receptor antagonist; the agent is a cell cycle inhibitor; The agent is a taxane; the agent is an anti-microtubule agents; the agent is taxol; the agent is not paclitaxel Alcohol, the agent is paclitaxel analogue or derivative; the agent is a vinca alkaloid; drug Agent is camptothecin or an analogue or derivative thereof; the agent is podophyllotoxin; the agent is podophyllotoxin, Wherein the podophyllotoxin is etoposide or an analogue or derivative thereof; the agent is anthracyclines; drug Agent is an anthracycline, wherein anthracycline is doxorubicin or an analogue or derivative thereof; the agent is Anthracyclines, wherein anthracycline is mitoxantrone or an analogue or derivative thereof; the agent is a platinum-based Compounds; The agent is a nitrosourea; The agent is imidazole nitrate; the agent is folic acid antagonists; drug Agent is a cytidine analogue; the agent is a pyrimidine analogs; the agent is a fluoropyrimidine analogues; the agent Is a purine analogues; the agent is a nitrogen mustard or an analogue or derivative thereof; the agent is hydroxyurea; the Agent mitomycin C or an analogue or derivative thereof; the agent is an alkyl sulfonate; the agent is Benzamide or an analogue or derivative thereof; the agent is a nicotinamide or an analogue or derivative thereof; the Pharmacy halogenated sugar or an analogue or derivative thereof; the agent is a DNA alkylating agent; the agent is Anti-microtubule agent; the agent is a topoisomerase inhibitor; The agent is a DNA cleaving agent; the agent Is an anti-metabolite; the pharmaceutical inhibition of adenosine deaminase; the pharmaceutical synthesis inhibiting purine ring; the agent is Nucleotide interconversion inhibitor; dihydrofolate reductase inhibition of the agent; agents blocking the thymidine monophosphate; The agent causes DNA damage; the agent is a DNA intercalating agent; the pharmaceutical inhibition of RNA synthesis Agent; the agent is a pyrimidine synthesis inhibitor; the pharmaceutical inhibition of ribonucleotide synthesis or function; drug Inhibits synthesis of thymidine monophosphate, or feature; the agent to inhibit DNA synthesis; the agent causes DNA Adduct formation; the agent inhibits protein synthesis; the pharmaceutical inhibition of microtubule function; the agent is a thin Cell cycle-dependent protein kinase inhibitor protein; the agent is a kinase inhibitor of epidermal growth factor Agent; the pharmaceutical elastase inhibitors; the agent is a factor Xa inhibitor; the agent is a method It acyltransferase inhibitors; the agent is a fibrinogen antagonist; the agent is of guanylate Enzyme irritants; the agent is a heat shock protein 90 antagonists; the agent is a heat shock protein 90 antagonist Agent, wherein the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof; drug Agent is a guanylate cyclase stimulating agent; the agent is a HMGCoA reductase inhibitor; the agent is HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or class Analogs or derivatives thereof; whey the agent is a hydroxy acid dehydrogenase inhibitor; The agent is inhibited IKK2 Agent; the agent is IL-1 antagonist; the agent is ICE antagonists; the agent is IRAK antagonist; The agent is IL-4 agonists; The agent is immunomodulatory agents; the agent is sirolimus or similar Objects or derivatives; the agent is not sirolimus; the agent is everolimus or an analogue or derivative Matter; the agent is tacrolimus or an analogue or derivative thereof; the agent is not tacrolimus; drug Agent is biolmus or an analogue or derivative thereof; This is a song Peimo pharmaceutical company or an analogue or derivative Thereof; the agent is auranofin or an analogue or derivative thereof; the agent is 27-0 - demethyl rapamycin Or an analogue or derivative thereof; the agent is guanidine stand Secretary Mo or an analogue or derivative thereof; the agent is Pimecrolimus or an analogue or derivative thereof; the agent is ABT-578 or an analogue or derivative thereof; The agent is inosine monophosphate dehydrogenase (IMPDH) inhibitor; the medicine is IMPDH inhibitors, Which IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof; the agent is IMPDH Inhibitors, which IMPDH inhibitor is 1-α-25 dihydroxyvitamin D3 or an analogue or derivative Biological; the agent is a leukotriene inhibitor; the agent is MCP-1 antagonists; the agent is MMP Inhibitors; The agent is NF κ B inhibitor; The agent is NF κ B inhibitor, wherein NF κ B Inhibitor is Bay 11-7082; The agent is NO antagonists; This is a p38 MAP kinase inhibitor drug Agent; the agent is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB 202190; the agent is a phosphodiesterase inhibitor; the agent is a TGF β inhibitor; the agent is Thromboxane A2 antagonist; the agent is TNFa antagonist; the agent is TACE inhibitors; the Tyrosine kinase inhibitor agent; the agent is a vitronectin inhibitor; the pharmaceutical is fibroblasts Cell growth factor inhibitors; the agent is a protein kinase inhibitor; the agent is PDGF receptor kinase Inhibitors; The agent is endothelial growth factor receptor kinase inhibitor; The agent is retinoic acid receptor antagonists Antagonist; The agent is platelet-derived growth factor receptor kinase inhibitor; The agent is fibrin Original antagonist; the agent is an anti-fungal agent, wherein the antifungal agent itraconazole is sulfur; the agent is a diphosphonic acid Salts; the agent is a phospholipase A1 inhibitor; the agent is histamine H1/H2/H3 receptor antagonist; The agent is a macrolide antibiotic; The agent is GP IIb / IIIa receptor antagonists; the agent is Endothelin receptor antagonist; The agent is peroxisome proliferator-activated receptor agonists; the Pharmaceutical agents are estrogen receptor; the agent is a somatostatin analogue; the agent is a neurokinin Peptide-1 antagonist; the agent is a neurokinin 3 antagonist; the agent is a VLA-4 antagonists; the Pharmacy osteoclasts inhibitors; the agent is a DNA topoisomerase inhibitor of ATP hydrolysis; the Agents are angiotensin I converting enzyme inhibitor; the agent is an angiotensin II antagonist; the Pharmacy is enkephalinase inhibitors; The agent is a peroxisome proliferator-activated receptor γ agonists Insulin sensitizers; The agent is protein kinase C inhibitor; The agent is a ROCK (rho-related Kinase) inhibitor; The agent is CXCR3 inhibitor; The agent is Itk inhibitors; the agent Is a cytosolic phospholipase A2-α inhibitors; The agent is a PPAR agonist; This is immunosuppressive agents Agent; the agent is Erb inhibitors; the agent is programmed cell death inhibitor; the agent is a lipid Cortical protein agonists; the agent is a VCAM-1 antagonist; the agent is a collagen antagonist; drug Agent is α2 integrin antagonists; the agent is a TNFα inhibitor; the agent is a nitric oxide inhibition Preparations; The agent is cathepsin inhibitors; the agent is not anti-inflammatory agents; This is not a steroid drug Alcohol; The agent is not a glucocorticosteroid; the agent is not dexamethasone; chlorine meter times the agent is not Song; The agent is not dipropionate; the agent is not anti-infective agents; the agent is not antibiotics; the The ingredient is not an antifungal agent; composition comprising a polymer; composition comprising a polymer carrier; anti-scarring Inhibits the formation of the device implanted device and the adhesion between the host; the device will be anti-scarring agent Locally delivered to tissue near the device; means comprises an anti-scarring agent having a coating; apparatus includes That contain the drug and the surface coating of the pump; including the pharmaceutical and device has a direct Contact with the pump coating; devices have included indirect contact with the drug and coating pump; devices have Including the pharmaceutical and partially cover the pump coating; devices have contained the drug and is fully covered Pump cover coating; the apparatus has a uniform coating; the device has a non-uniform coating; the apparatus has Discontinuous coating; the device has a patterned coating; the device has a coating having A thickness of 100μm or smaller; the device has a coating, wherein the coating has a thickness of 10μm or smaller Degrees; The device has coating and the coating adhesion when the device is deployed to the device surface; the apparatus A coating, and the coating is stable at room temperature for 1 year; the device has a coating layer, and wherein the anti-scar Mark forming agent is from about 0.0001% by weight to about 1% by weight present in the coating; the apparatus has Coatings, and anti-scarring agent is about 1% by weight to about 10% by weight present in the coating; The device has a coating, wherein the anti-scarring agent is about 10% by weight to about 25 percent by weight of In the coating; the device has a coating, wherein the anti-scarring agent is from about 25% by weight to about 70% of the amount present in the coating; the device has a coating, wherein the coating having a polymer; the apparatus Having a first composition having a first coating layer having a second composition and a second coating layer; The device has a first composition having a first coating layer having a second composition and a second Seed Coating, wherein the first composition and the second composition are different; the composition comprising a polymer; The composition comprises a polymeric carrier; the composition comprises a polymer carrier, wherein the polymeric carrier package Containing copolymer; the composition comprises a polymer carrier, wherein the polymeric carrier includes a block copolymer; The composition comprises a polymeric carrier, wherein the polymeric carrier comprises a random copolymer; the composition comprises Polymer-containing carrier, wherein the polymeric carrier comprises a biodegradable polymer; the composition contains Polymeric carrier, wherein the polymeric carrier comprises a non-biodegradable polymer; the composition contains Polymeric carrier, wherein the polymeric carrier comprises a hydrophilic polymer; the composition comprises a polymer containing , Wherein the polymeric carrier comprises a hydrophobic polymer; the composition comprises a polymer carrier, wherein Polymeric carrier comprises a polymer having a hydrophilic region; the composition comprises a polymer carrier, wherein Polymeric carrier comprises a polymer having a hydrophobic region; the composition comprises a polymer carrier, wherein Polymeric carrier comprises a non-conductive polymer; the composition comprises a polymer carrier, wherein the polymer Vectors containing elastomer; the composition comprises a polymer carrier, wherein the polymeric carrier includes a hydrogel; The composition comprises a polymeric carrier, wherein the polymeric carrier comprises a silicone polymer; the composition Comprises a polymer carrier, wherein the polymeric carrier comprising a hydrocarbon polymer; the composition comprises a polymer containing , Wherein the polymeric carrier comprises a polymer of styrene derivatives; the composition comprises a polymer carrier, Wherein the polymeric carrier comprises a polymer derived from butadiene; the composition comprises a polymer carrier, which The polymeric carrier comprises macromer; the composition comprises a polymer carrier, wherein the polymer contains Body comprises poly (ethylene glycol) polymer; the composition comprises a polymer carrier, wherein the polymeric carrier package Containing amorphous polymer; The apparatus includes a smooth coating, wherein the anti-scarring agent is positioned on the device Holes or cavities; anti-scarring agent is located in the apparatus of the channel, the cavity or divet; means includes The second pharmaceutically active agent; apparatus includes anti-inflammatory agents; apparatus comprises inhibiting infection Pharmacy; equipment package Inhibition of infection with agents, wherein the agent is anthracyclines; means includes inhibiting infection agents, Wherein the agent is doxorubicin; apparatus comprises inhibiting infection agent, wherein the agent is mitoxantrone Quinones; means includes inhibiting infection agent, wherein the agent is a fluoropyrimidine; means includes inhibiting infection The drug, wherein the agent is 5 - fluorouracil (5-FU); means includes inhibiting infection agents, which Folic acid antagonist in the pharmaceutical; means includes inhibiting infection agent, wherein the agent is methotrexate Methotrexate; apparatus comprises inhibiting infection agent, wherein the agent is podophyllotoxin; means includes a sense inhibition Dyeing agents, wherein the agent is etoposide; means includes inhibiting infection agent, wherein the drug Agent is camptothecin; means includes inhibiting infection agent, wherein the agent is hydroxyurea; means includes Inhibition of infection agent, wherein the agent is a platinum complex; means includes inhibiting infection agents, which In the pharmaceutical cisplatin; the method further comprises antithrombotic agents; This device contains a contrast agent; the device Containing contrast agents, wherein the contrast agent is a radiopaque material, wherein the radiopaque material comprises gold Genus, halogenated compound or a compound containing a barium; The apparatus includes contrast agent, wherein the contrast agent is Radiopaque material, wherein the radiopaque material comprises barium, tantalum or technetium; the apparatus comprising manufacturing Contrast agents, wherein the MRI contrast agent is responsive substance; The apparatus includes contrast agent, wherein the contrast agent Containing gadolinium chelates; The apparatus includes contrast agent, wherein the contrast agent comprises iron, magnesium, manganese, copper or Chromium; The apparatus includes contrast agent, wherein the contrast agent comprises a compound oxide; the apparatus comprising imaging Agent, wherein the contrast agent comprises a dye, a pigment or colorant; the apparatus comprising a material to produce echoes; The device contains a material to produce echoes, wherein the coating material produced in the form of echo; The device is Sterile; anti-scarring agent released after deployment of the device to the device surrounding tissues; Anti-shaped scar After deployment of the device into the agent released into the tissue surrounding the device, which is the connective tissue; anti scar Scarring agent released after deployment of the device to the device surrounding tissue, where tissue is muscle tissue; Anti-scarring agent released after deployment of the device to the device surrounding tissue, which is the nerve tissue group Weave; anti scarring agent released after deployment of the device to the device surrounding tissue, which is the organization Skin tissue; anti-scarring agent in the unit deployed to the period of approximately one year from the device to release an effective concentration Amp; anti-scarring agent in about a month to six month period to the effective concentration of the release from the device; resistance Scarring agent in the period of approximately 1-90 days from the device to the effective concentration of the release; anti-scarring agent is Effective concentration of a constant release rate from the device; anti-scarring agent is effective concentrations from the device to continuously Increase the rate of release; anti-scarring agent is an effective means for decreasing concentrations ranging from the rate of release Release; deployed from the unit during the period of about 90 days, anti-scarring agent by diffusion from the containing anti-scar Forming agent marks the effective concentration of the release composition; deployed from the device to about 90 days period, anti- Scarring agent through the erosion of the composition comprising an anti-scarring agent from the composition in an effective concentration Release; apparatus comprises about 0.01μg to about 10μg anti-scarring agent; apparatus comprises approximately 10μg to About 10mg anti-scarring agent; apparatus comprises about 10mg to about 250mg anti-scarring agent; Unit contains about 250mg to about 1000mg anti-scarring agent; devices to contain about 1000mg Approximately 2500mg anti-scarring agent; surface of the device comprises less than about 0.01μg anti-scarring agent / mm ...²The apparatus surface of anti-scarring agent application; The surface of device comprises approximately 0.01 μ g and arrives approximately 1 μ g anti-scarring agent/mm²The apparatus surface of anti-scarring agent application; The surface of device comprises approximately 1 μ g and arrives approximately 10 μ g anti-scarring agent/mm²The apparatus surface of anti-scarring agent application; The surface of device comprises approximately 10 μ g and arrives approximately 250 μ g anti-scarring agent/mm²The apparatus surface of anti-scarring agent application; The surface of device comprises approximately 250 μ g and arrives approximately 1000 μ g anti-scarring agent/mm²The apparatus surface of anti-scarring agent application; The surface of device comprises approximately 1000 μ g and arrives approximately 2500 μ g anti-scarring agent/mm²The apparatus surface of anti-scarring agent application; By directly being attached to pump, medicament or composition make up; By being sprayed to pump, medicament or component make up; By medicament or composition electron spray are made up to pump; By pump is immersed in the solution that comprises described medicament or composition and makes up; By being covalently bound to pump, medicament or composition make up; By medicament or the non-covalent pump that is attached to of composition are made up; The material coating pump that contains described medicament or composition by use makes up; The material coating pump that absorbs described medicament by use makes up; By using that form by described medicament or composition or line that be coated with described medicament or composition interweaves and makes up; The sleeve that contains described medicament or composition by use covers pump fully and makes up; A part that contains the sleeve covering pump of described medicament or composition by use makes up; The covering that contains described medicament or composition by use covers pump fully and makes up; A part that contains the covering covering pump of described medicament or composition by use makes up; The electrostatic spinning fabric that contains described medicament or composition by use covers pump fully and makes up; A part that contains the electrostatic spinning fabric covering pump of described medicament or composition by use makes up; The mesh that contains described medicament or composition by use covers pump fully and makes up; A part that contains the mesh covered pump of described medicament or composition by use makes up; By with described medicament or composition structure pump, making up; By with described medicament or composition dipping pump, making up; A part that discharges the degradable polymer structure pump of described medicament by use makes up; Make up by pump being immersed the solution that contains described medicament and be used for the atent solvent of described pump; Make up by pump being immersed the solution comprise described medicament and will rinse the solvent of (swill) described pump; Make up by pump being immersed the solution comprise described medicament and will dissolve the solvent of described pump; Make up by pump being immersed the solution that comprises described medicament, polymer and be used for the atent solvent of described pump; Make up by pump being immersed the solution comprise described medicament, polymer and will rinse the solvent of described pump; Make up by pump being immersed the solution comprise described medicament, polymer and will dissolve the solvent of described pump; Make up by pump being sprayed to the solution that comprises described medicament and be used for the atent solvent of pump; Comprise described medicament and the solvent of flushing pump is made up by pump is sprayed to; Make up by pump being sprayed to the solution that comprises described medicament and will dissolve the solvent of pump; Make up by pump being sprayed to the solution that comprises described medicament, polymer and be used for the atent solvent of pump; Comprise described medicament, polymer and the solution of the solvent of flushing pump is made up by pump is sprayed to; Make up by pump being sprayed to the solution that comprises described medicament, polymer and will dissolve the solvent of pump.

Provide the following examples to be used to illustrate, and not as restriction.

Embodiment

Embodiment 1

The parylene coating

By will install (for example, MiniMed 2007 implantable insulin pumps, Medtronic, Inc.) Zhao metal partly immerses the HPLC level isopropanol and washs.With the parylene coating machine (for example, PDS 2010 LABCOATER 2, from Cookson Electronics) and two-right-xylylene (PARYLENE N) or two chloro-two-right-xylylene (PARYLENE D) (all can be available from Specialty Coating Systems, Indianapolis, IN) as the coating feed material, (about 1 to 10um) is deposited on the device of cleaning with the parylene prime coat.

Embodiment 2

Paclitaxel coating-part coating

By being dissolved among the 5ml HPLC level THF, paclitaxel (5mg, 10mg, 50mg, 100mg, 200mg and 500mg) prepares paclitaxel solution.The device of parylene coating (as preparation at embodiment 1 for example) immersed paclitaxel/THF solution through coated portion.Selected incubation is after the time, withdrawing device and dry in forced air draft oven (50 ℃) from solution.Install dried overnight in vacuum drying oven then.Thereby changing the amount that the amount of the paclitaxel be used for every kind of solution and incubation time is coated on the paclitaxel on the device is 0.06 μ g/mm ²To 10 μ g/mm ²(μ g paclitaxel/mm ²Device, it places THF/ paclitaxel solution back to be coated with paclitaxel).Can modifier remain on the time in paclitaxel/THF solution, wherein long soak time provides more paclitaxels to be adsorbed onto on the device usually.In other example, replace paclitaxel with one of following representative compounds: mitoxantrone, doxorubicin, epithilone B, etoposide, taxotere, tubercidin, vinblastine, geldanamycin, simvastatin, sirolimus, everolimus, halofuginone (halifuginone), Mycophenolic Acid, mithramycin, pimecrolimus, 1-α-25 dihydroxyvitamin D ₃, Bay 11-7082, SB202190, and sulconazole.

Embodiment 3

Paclitaxel coating-coating fully

By being dissolved among the 5mlHPLC level THF, paclitaxel (5mg, 10mg, 50mg, 100mg, 200mg and 500mg) prepares paclitaxel solution.The device (as for example preparing among the embodiment 1) of whole parylene coatings is immersed paclitaxel/THF solution.Selected incubation is after the time, and withdrawing device is also dry in forced air draft oven (50 ℃).Install dried overnight in vacuum drying oven then.Thereby changing the amount that the amount of the paclitaxel be used for every kind of solution and incubation time is coated on the paclitaxel on the device is 0.06 μ g/mm ²To 10 μ g/mm ²In other example, replace paclitaxel with one of following representative compounds: mitoxantrone, doxorubicin, epithilone B, etoposide, taxotere, tubercidin, halofuginone, vinblastine, geldanamycin, simvastatin, sirolimus, everolimus, mithramycin, pimecrolimus, Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃, Bay11-7082, SB202190, and sulconazole.

Embodiment 4

The application of parylene external coating (overcoat)

The step that the device (as for example embodiment 2 or 3 preparations) of paclitaxel coating is placed the parylene coating machine and uses embodiment 1 to describe, with the other veneer of parylene on the device of paclitaxel coating.Select the coating persistent period so that parylene Topcoating thickness to be provided, it will cause device to have the desirable elution curve of paclitaxel.

Embodiment 5

The application of echogenic coating layer

DESMODUR (isocyanate prepolymer Bayer AG) (25%w/v) is dissolved in the 50:50 mixture of dimethyl sulfoxine and oxolane.Paclitaxel/parylene is immersed in the pre-polymer solution then as the device of external coating (as for example, embodiment 4 preparations).Selected incubation is after the time, withdrawing device from solution, and coating is at room temperature the dry 3-5 of part minute then.To install then and immerse in the beaker of water (room temperature) 3-5 minute to cause polyreaction to take place fast.Form the echo genetic horizon.

Embodiment 6

Paclitaxel/polymer coating-part coating

Preparation gathers (ethylene-co-vinyl acetate) { some 5% solution of EVA} (60% vinyl acetate) as solvent with THF.Paclitaxel (0.01%, 0.05%, 0.1%, 0.5%, 1%, 5%, 10%, 20%, 30% (w/w medicine and polymer) adding EVA solution with selected amount.Duct portion or its part of implantable pump installation are immersed in paclitaxel/EVA solution.From solution behind the withdrawing device, by device being placed 3 hours dry coatings of forced air draft oven (40 ℃).Then will be through the device of coating further dry 24 hours in a vacuum.This immersion coating process can repeat to be coated on increase the amount of the polymer/paclitaxel on the device.In addition, the amount that can use higher paclitaxel concentration in polymer/THF/ paclitaxel solution and/or longer soak time to be coated on the polymer/paclitaxel on the device with increase.In other example, can replace paclitaxel with one of following representative compounds: mitoxantrone, doxorubicin, epithilone B, etoposide, taxotere, tubercidin, vinblastine, geldanamycin, simvastatin, mithramycin, pimecrolimus, halofuginone, sirolimus, everolimus, Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃, Bay 11-7082, SB202190, and sulconazole.

Embodiment 7

Paclitaxel-heparin coating

Preparation gathers (ethylene-co-vinyl acetate) { some 5% solution of EVA} (60% vinyl acetate) as solvent with THF.Paclitaxel (every kind of EVA solution of solution adding of 0.01%, 0.05%, 0.1%, 0.5%, 1%, 5%, 10%, 20%, 30% (w/w medicine and polymer) and three (dodecyl) ammonio methacrylate-heparin complex (Po1ySciences) with selected amount.The all or part of immersion paclitaxel of the duct portion/EVA solution of device.From solution behind the withdrawing device, by device being placed 3 hours dry coatings of forced air draft oven (40 ℃).Then will be through the device of coating further dry 24 hours in a vacuum.This immersion coating process can repeat to be coated on increase the amount of the polymer/heparin complex on the device.In other example, can replace paclitaxel with one of following representative compounds: mitoxantrone, doxorubicin, epithilone B, etoposide, taxotere, tubercidin, halofuginone, vinblastine, geldanamycin, simvastatin, mithramycin, pimecrolimus, sirolimus, everolimus, Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃, Bay 11-7082, SB202190, and sulconazole.

Embodiment 8

Paclitaxel-heparin/heparin coating

The uncoated part of the device (as preparation among the embodiment 7) of paclitaxel-heparin coating is immersed three (dodecyl) ammonio methacrylate-heparin complex solution (PolySciences) (0.1% that contains selected amount, 0.5%, 1%, 2.5%, 5%, 10% (v/v)) in the 5%EVA/THF solution.From solution behind the withdrawing device, by device being placed 3 hours dry coatings of forced air draft oven (40 ℃).Then will be through the device of coating further dry 24 hours in a vacuum.This has paclitaxel/heparin coating and have heparin coating on one or more other parts of device for device provides on one or more parts of device.In other example, can replace paclitaxel with one of following representative compounds: mitoxantrone, doxorubicin, epithilone B, etoposide, mithramycin, pimecrolimus, taxotere, tubercidin, vinblastine, geldanamycin, halofuginone, simvastatin, sirolimus, everolimus, Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃, Bay 11-7082, SB202190, and sulconazole.

Embodiment 9

Paclitaxel/polymer coating-part coating

Use THF as solvent, preparation poly-(styrene-be total to-isobutene .-styrene) some 5% solution (SIBS).The paclitaxel that adds selected amount to every kind of SIBS solution.One or more parts of the duct portion of implantable pump installation are immersed paclitaxel/SIBS solution.From solution behind the withdrawing device, by device being placed 3 hours dry coatings of forced air draft oven (40 ℃).Then will be through the device of coating further dry 24 hours in a vacuum.This immersion coating process can repeat to be coated on increase the amount of the polymer/paclitaxel on the device.Can use the higher paclitaxel concentration of polymer/THF/ paclitaxel solution and/or longer soak time is coated on the polymer/paclitaxel on the device with increase amount.In other example, can replace paclitaxel with one of following representative compounds: mitoxantrone, doxorubicin, mithramycin, pimecrolimus, epithilone B, etoposide, taxotere, tubercidin, vinblastine, geldanamycin, simvastatin, sirolimus, everolimus, Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃, Bay 11-7082, SB202190, and sulconazole.

Embodiment 10

The external coating of paclitaxel/polymer coating-generation echo

The device that will be coated with as the paclitaxel of preparation among the embodiment 9 immerses DESMODUR solution (50%w/v) (the 50:50 mixture of dimethyl sulfoxine and oxolane).Withdrawing device and coating were at the dry 3-5 of room temperature part minute then.To install then and immerse in the beaker of water (room temperature) 3-5 minute to cause polyreaction to take place fast.Thereby form the echo genetic horizon.In other example, replace paclitaxel with one of following representative compounds: mitoxantrone, doxorubicin, epithilone B, mithramycin, pimecrolimus, etoposide, taxotere, tubercidin, vinblastine, geldanamycin, simvastatin, sirolimus, everolimus, Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃, Bay 11-7082, SB202190, and sulconazole.

Embodiment 11

The coating of polymer/generation echo

Use THF as solvent, preparation poly-(styrene-be total to-isobutene .-styrene) 5% solution (SIBS).The duct portion of implantable pump installation is immersed SIBS solution.Selected incubation is after the time, and withdrawing device from solution is by placing device 3 hours dry coatings of forced air draft oven (40 ℃).Then will be through the device of coating further dry 24 hours in a vacuum.

To immerse DESMODUR solution (50% w/v) (the 50:50 mixture of dimethyl sulfoxine and oxolane) through the device of coating.Withdrawing device and coating were at the dry 3-5 of room temperature part minute then.To install then and immerse in the beaker of water (room temperature) 3-5 minute to cause polyreaction to take place fast.Device drying at room temperature 24 hours under vacuum.Will be in all or part of immersion paclitaxel solution (5%w/v in the methanol) of device of coating.Remove this device and 40 ℃ of dryings 1 hour, vacuum drying was 24 hours then.

Can change the amount of the paclitaxel of polymer coating absorption by the solvent composition that changes paclitaxel concentration, immersion time and paclitaxel solution.In other example, can replace paclitaxel with one of following representative compounds: mitoxantrone, doxorubicin, epithilone B, etoposide, taxotere, mithramycin, pimecrolimus, tubercidin, vinblastine, geldanamycin, halofuginone, simvastatin, sirolimus, everolimus, Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃, Bay 11-7082, SB202190, and sulconazole.

Embodiment 12

Paclitaxel/silicon coating-part coating

By device being exposed to the gaseous state tetramethyl-ring tetrasiloxane, it is coated with the shell of implantable pump installation then by low-power plasma body polymerization polymerization on apparatus surface with siloxane layer.Can increase the thickness of siloxane layer by increasing the polymerization time.After the polymerization, will immerse paclitaxel/THF solution (5% w/v) then through the part of apparatus for coating and absorb in the silicon coating to allow paclitaxel selected period.Then from solution withdrawing device and in forced air draft oven 40 ℃ dry 2 hours down.To install then in a vacuum under the room temperature further dry 24 hours.Concentration by changing paclitaxel/THF solution and change the immersion time of installing in the paclitaxel THF solution and can change the amount that is coated on the paclitaxel on the device.In other example, can replace paclitaxel with one of following representative compounds: mitoxantrone, doxorubicin, epithilone B, etoposide, taxotere, tubercidin, mithramycin, pimecrolimus, vinblastine, geldanamycin, halofuginone, simvastatin, sirolimus, everolimus, Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃, Bay 11-7082, SB202190, and sulconazole.

Embodiment 13

Spray-dired device

As solvent, preparation gathers (styrene-be total to-isobutene .-styrene) some 2% solution (50ml) (SIBS) with THF.The paclitaxel (0.01%, 0.05%, 0.1%, 0.5%, 1%, 2.5%, 5%, 10% and 20% (with respect to polymer w/w)) that adds selected amount to every kind of solution.With the fixing implantable pump installation of pair of forceps, spray with one of paclitaxel/polymer solution with spray gun then.Air-dry apparatus then.With tweezers device is fixed on reposition and has second coating of the paclitaxel/polymer solution of same concentrations to this device application.To install air-dry dried overnight under the room temperature in a vacuum then.Can be by changing content of taxol in the solution and by increasing the total amount of using that the number of plies is come the paclitaxel that is coated with on the modifier that is coated with.In other example, can replace paclitaxel with one of following representative compounds: mitoxantrone, doxorubicin, epithilone B, etoposide, taxotere, tubercidin, mithramycin, pimecrolimus, vinblastine, geldanamycin, simvastatin, sirolimus, everolimus, Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃, Bay 11-7082, SB202190, and sulconazole.

Embodiment 14

The device of medicine coating-nondegradable

The duct portion of implantable pump installation is connected to the axle of rotation.Then with paclitaxel (5%w/w) at polyurethane (CHRONOFLEX 85A; CardioTech Biomaterials)/ solution spray auto levelizer outer surface in the THF solution (2.5% w/v) all or part of on.Not impaired or to guarantee device by the saturated speed spray solution of the solution of being sprayed.To install air-dry, dry 24 hours then at the vacuum chamber relaxing the bowels with purgatives of warm nature.In other example, can replace paclitaxel with one of following representative compounds: mitoxantrone, doxorubicin, epithilone B, etoposide, taxotere, tubercidin, mithramycin, pimecrolimus, vinblastine, geldanamycin, simvastatin, sirolimus, everolimus, Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃, Bay 11-7082, SB202190, and sulconazole.

Embodiment 15

The device of medicine coating-degradable

The duct portion of implantable pump installation is connected to the axle of rotation.Then with on the solution spray auto levelizer outer surface of paclitaxel (5%w/w) in PLGA/ ethyl acetate solution (2.5% w/v) all or part of.Not impaired or to guarantee device by the saturated speed spray solution of the solution of being sprayed.To install air-dry, dry 24 hours then at the vacuum chamber relaxing the bowels with purgatives of warm nature.In other example, can replace paclitaxel with one of following representative compounds: mitoxantrone, doxorubicin, epithilone B, etoposide, taxotere, tubercidin, vinblastine, geldanamycin, simvastatin, sirolimus, mithramycin, pimecrolimus, everolimus, Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃, Bay 11-7082, SB202190, and sulconazole.

Embodiment 16

Device-degradable the external coating of medicine coating

The duct portion that will be coated with as the medicine of the implantable pump installation of preparation among embodiment 14 or the embodiment 15 is connected to axle.PLGA/ ethyl acetate solution (2.5%w/v) is sprayed to all or part of on the outside of deivce face, thereby on first contains the coating of medicine, forms coating.Not impaired or to guarantee device by the saturated speed spray solution of the solution of being sprayed.To install air-dry, in a vacuum under the room temperature dry 24 hours then.

Embodiment 17

The microball preparation of drug loading

Paclitaxel (10% w/w) is added the solution of PLGA (50/50, Mw ≈ 54,000) in DCM (5% w/v).With the solution vortex and pour (agitator that the TEFLON of suspension type agitator and 3 blades is coated with) PVA aqueous solution (about 89% hydrolysis, Mw ≈ 13,000,2% w/v) then into through stirring.Agitating solution 6 hours, centrifugal solution is with the precipitation microsphere afterwards.Microsphere is resuspended in the water.Repeated centrifugation-ishing process 4 times.Final microspheres solution quick freezing in acetone/the dry ice bath.The refrigerated solution of lyophilization produces fine powder then.By changing the size that mixing speed and/or PVA solution concentration can change the microsphere of formation.Freeze dried powder can be resuspended in PBS or the saline and as incubation liquid or as the flushing liquor direct injection.In other example, can replace paclitaxel with one of following representative compounds: mitoxantrone, doxorubicin, epithilone B, etoposide, taxotere, mithramycin, pimecrolimus, tubercidin, vinblastine, geldanamycin, simvastatin, sirolimus, everolimus, Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃, Bay 11-7082, SB202190, and sulconazole.

Embodiment 18

The device (external skin) of medicine coating

All or part of immersion polyurethane (CHRONOFLEX 85A)/THF solution (2.5% w/v) with the duct portion of implantable pump installation.Air-dry 10 seconds of the device that permission is coated with.Install then and on unfolded thinly powdery paclitaxel on a slice release liner, rolling to provide with 0.1 device to the coating of 10mg paclitaxel.Carrying out rolling process in such a manner makes the paclitaxel powder mainly adhere to the outside of the device that is coated with.Installed air-dry 1 hour, then room temperature vacuum drying 24 hours.In other example, can replace paclitaxel with one of following representative compounds: mitoxantrone, doxorubicin, epithilone B, mithramycin, pimecrolimus, etoposide, taxotere, tubercidin, vinblastine, geldanamycin, simvastatin, sirolimus, everolimus, Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃, Bay 11-7082, SB202190, and sulconazole.

Embodiment 19

Device (external skin) with medicine coating of heparin coating

The device that will be coated with as the medicine of preparation among the embodiment 18 further is coated with heparin coating.To immerse heparin-benzalkonium chloride complex (1.5% (w/v) in the isopropyl alcohol, STS Biopolymers) solution as the device of preparation among the embodiment 18.Withdrawing device is also air-dry 1 hour from solution, and vacuum drying is 24 hours then.This process inner surface and outer surface of heparin apparatus for coating.

Embodiment 20

The part medication coat of device

The axle that the duct portion of implantable pump installation is connected rotation.Thereby the assembling shelter system only part of apparatus surface exposes.Then with the expose portion of the solution spray auto levelizer of paclitaxel (5% w/w) in polyurethane (CHRONOFLEX85A)/THF solution (2.5% w/v).Not impaired or to guarantee device by the saturated speed spray solution of the solution of being sprayed.To install air-dry, in a vacuum under the room temperature dry 24 hours then.In other example, can replace paclitaxel with one of following representative compounds: mitoxantrone, doxorubicin, epithilone B, etoposide, taxotere, tubercidin, vinblastine, geldanamycin, mithramycin, pimecrolimus, simvastatin, sirolimus, everolimus, Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃, Bay 11-7082, SB202190, and sulconazole.

Embodiment 21

The device of medicine-dexamethasone coating

Duct portion as the implantable pump installation of coating among the embodiment 20.Thereby reset the part of sheltering originally of shelter exposing device then.Use the expose portion of dexamethasone (10% w/w)/polyurethane (CHRONOFLEX 85A)/THF solution (2.5% w/v) sprayer unit then.This device is air-dry, and the vacuum chamber relaxing the bowels with purgatives of warm nature is dry 24 hours afterwards.In other example, can replace paclitaxel with one of following representative compounds: mitoxantrone, doxorubicin, epithilone B, etoposide, taxotere, tubercidin, vinblastine, mithramycin, pimecrolimus, geldanamycin, simvastatin, sirolimus, everolimus, Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃, Bay 11-7082, SB202190, and sulconazole.

Embodiment 22

The device of medicine-heparin coating

Duct portion as the implantable pump installation of coating among the embodiment 20.Thereby reset the only part of sheltering originally of exposing device of shelter then.Use the expose portion of heparin-benzalkonium chloride complex (1.5% (w/v) in the isopropyl alcohol (STS Biopolymers)) sprayer unit then.Sample is air-dry, and vacuum drying is 24 hours afterwards.In other example, can replace paclitaxel with one of following representative compounds: mitoxantrone, doxorubicin, epithilone B, etoposide, taxotere, tubercidin, vinblastine, geldanamycin, mithramycin, pimecrolimus, simvastatin, sirolimus, everolimus, Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃, Bay 11-7082, SB202190, and sulconazole.

Embodiment 23

The device of medicine-dexamethasone coating

The axle that the duct portion of implantable pump installation is connected rotation.The solution spray auto levelizer in PLGA (50/50, Mw ≈ 54,000)/ethyl acetate solution (2.5%w/v) all or part of with paclitaxel (5%w/w) and dexamethasone (5%w/w) then.Not impaired or to guarantee device by the saturated speed spray solution of the solution of being sprayed.To install air-dry, in a vacuum under the room temperature dry 24 hours then.In other example, can replace paclitaxel with one of following representative compounds: mitoxantrone, doxorubicin, epithilone B, etoposide, taxotere, tubercidin, vinblastine, geldanamycin, mithramycin, pimecrolimus, simvastatin, sirolimus, everolimus, Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃, Bay 11-7082, SB202190, and sulconazole.

Embodiment 24

The device of medicine-dexamethasone coating (order coating)

The axle that the duct portion of implantable pump installation is connected rotation.Then with the outer surface of the solution spray auto levelizer of paclitaxel (5% w/w) in PLGA (50/50, Mw ≈ 54,000)/ethyl acetate solution (2.5% w/v).Not impaired or to guarantee device by the saturated speed spray solution of the solution of being sprayed.Air-dry apparatus.Then the methanol solution of dexamethasone (2% w/v) is sprayed to device the surface (with guarantee device not impaired or by the saturated speed of the solution of being sprayed).The permission device is air-dry, at the vacuum chamber relaxing the bowels with purgatives of warm nature dry 24 hours afterwards.In other example, can replace paclitaxel with one of following representative compounds: mitoxantrone, doxorubicin, epithilone B, etoposide, mithramycin, pimecrolimus, taxotere, tubercidin, vinblastine, geldanamycin, simvastatin, sirolimus, everolimus, Mycophenolic Acid, 1-α-25 dihydroxyvitamin D ₃, Bay11-7082, SB202190, and sulconazole.

Embodiment 25

Medicine loads implantable glucose monitors-paclitaxel and immerses

By with 1mg, 5mg, 10mg, 20mg, 50mg, 75mg, 100mg, 200mg and 500mg paclitaxel are weighed to respectively and add HPLC level methanol in the glass scintillation pipe then and prepare the 10ml paclitaxel solution.Under the room temperature on the rail mounted shaking table gentle agitation of solutions 1 hour.(DexCom, sensing head Inc.) immerses the degree of depth of about 0.5cm in the 0.1mg/ml solution with implantable glucose sensor.After about 2 hours, take out the sensing head part and allow air-dry 6 hours from solution.Further dried electrode is 24 hours under vacuum.For the paclitaxel solution of all preparations, repeat this process with new pick off at every turn.

Embodiment 26

Preparation is used for the film-non-woven film of the drug loading of implantable glucose sensor

Add 353ml dimethyl acetylamide (DMAC) to 2 liters of glass beakers.To this solution add the 660g polyurethane solutions (CHRONOFLEX AR, 25% solid among the DMAC, CardioTechBiomaterials, Inc).Suspension type agitator device (Cole Palmer) agitating solution 15 minutes with paddle formula propeller-blade with coating TEFLON.Add poly-(vinylpyrrolidone) (the PLASDONE K-90D) of 62.5g to solution.Agitating solution dissolved up to polymer in 6 hours fully.Three group of 5 x 15g aliquot of polymer solution placed 20ml glass scintillation pipe.Add paclitaxel to one group of polymer solution, thereby obtain paclitaxel and polymer ratio is 0.1%, 0.5%, 1%, 10% and 20%.For second group of polymer solution, rapamycin obtains rapamycin and polymer ratio is 0.1%, 0.5%, 1%, 10% and 20% thereby add.For the 3rd group of polymer solution, add mithramycin (mythramycin) thus mithramycin and polymer ratio are 0.1%, 0.5%, 1%, 10% and 20%.Solution was rolled 3 hours with 20 rev/mins.Non-woven DACRON fiber filter film is placed on the PET release liner of silicone coating.Will be with casting cutter (0.006 ") from the film of every kind of polymer solution at filter membrane upper mold (cast).Allow at room temperature air-dry 1 hour of casting solution.With film 50 ℃ further dry 3 hours, afterwards with they under vacuum dry 24 hours.With each film cut to size should be arranged and use o-shape ring be mechanically secured to implantable glucose sensing device (DexCom, Inc).

Embodiment 27

Preparation is used for the film-perforated membrane of the drug loading of implantable glucose sensor

Add 353ml dimethyl acetylamide (DMAC) to the 2L glass beaker.Add 660g polyurethane solutions (CHRONOFLEX AR, 25% solid in DMAC) to solution.Suspension type agitator device (Cole Palmer) agitating solution 15 minutes with paddle formula propeller-blade with coating TEFLON.Add poly-(vinylpyrrolidone) (the PLASDONE K-90D) of 62.5g to solution.Agitating solution dissolved up to polymer in 6 hours fully.Three group of 5 x 15g aliquot of polymer solution placed 20ml glass scintillation pipe.Add paclitaxel to one group of polymer solution, thereby obtain paclitaxel and polymer ratio is 0.1%, 0.5%, 1%, 10% and 20%.For second group of polymer solution, rapamycin obtains rapamycin and polymer ratio is 0.1%, 0.5%, 1%, 10% and 20% thereby add.For the 3rd group of polymer solution, thereby adding mithramycin mithramycin and polymer ratio are 0.1%, 0.5%, 1%, 10% and 20%.Solution was rolled 3 hours with 20 rev/mins.With casting cutter (0.012 ") with the film of every kind of polymer solution PET release liner upper mold at the coating siloxanes.Allow at room temperature air-dry 1 hour of casting solution.With film 50 ℃ further dry 3 hours, afterwards with they under vacuum dry 24 hours.(Seare Biomatrix Systems Inc) goes up compacting at the porous silicon siloxane film with each film.Each laminate film cut to size should be arranged and use o-shape ring be mechanically secured to implantable glucose sensing device (DexCom, Inc).

Embodiment 28

Film-the paclitaxel that is used for the drug loading of implantable glucose monitors immerses

By with 1mg, 5mg, 10mg, 20mg, 50mg, 75mg, 100mg, 200mg and 500mg paclitaxel are weighed to respectively and add HPLC level methanol in the 20ml glass scintillation pipe then and prepare the 10ml paclitaxel solution.Under the room temperature on the rail mounted shaking table gentle agitation of solutions 1 hour.As (2.6:1w/w) solution of the CHRONOFLEX AR/PVP (Plasdone K-90D) among the embodiment 27 preparation DMAC.Non-woven DACRON fibrous filter membrane is placed on the PET release liner of silicone coating.With the casting cutter polymer solution film is cast on the filter membrane.Allow at room temperature air-dry 1 hour of casting solution.With film 50 ℃ further dry 3 hours, afterwards with they under vacuum dry 24 hours.Film was immersed in the 0.1mg paclitaxel solution 2 hours.Remove striping and air-dry 2 hours from solution at 45 ℃.The vacuum drying film is 2 hours then.Each film cut to size should be arranged and use o-shape ring be mechanically secured to implantable glucose sensing device (DexCom, Inc).Use the paclitaxel solution of all preparations to repeat this process.In other example, can replace paclitaxel with one of following representative compounds: rapamycin, mithramycin, everolimus, pimecrolimus, and halofuginone.

Embodiment 29

Film-paclitaxel the dipping that is used for the drug loading of implantable glucose monitors

By with 1mg, 5mg, 10mg, 20mg, 50mg, 75mg, 100mg, 200mg and 500mg paclitaxel are weighed to respectively and add HPLC level methanol in the 20ml glass scintillation pipe then and prepare the 10ml paclitaxel solution.Under the room temperature on the rail mounted shaking table gentle agitation of solutions 1 hour.(DexCom, CHRONOFLEX AR/PVP Inc) (Plasdone K-90D) (2.6:1w/w) film immersed in the 0.1mg paclitaxel solution 2 hours will to be used for implantable glucose monitoring arrangement.From solution, take out film and air-dry 2 hours at 45 ℃.The vacuum drying film is 24 hours then.Then each film is pressed into the porous silicon siloxane film (Seare Biomatrix Systems, Inc) on.Each laminate film cut to size should be arranged and use o-shape ring be mechanically secured to implantable glucose sensing device (DexCom, Inc).Use the paclitaxel solution of all preparations to repeat this process.In other example, can replace paclitaxel with one of following representative compounds: rapamycin, mithramycin, everolimus, pimecrolimus, and halofuginone.

Embodiment 30

Be coated with implantable glucose sensor

By 20g polyurethane being dissolved in preparation polyurethane solutions (CHRONOFLEX AL 85 A) in the 400ml oxolane (THF).The 15ml aliquot of this solution is placed 20ml glass scintillation pipe.In each bottle, add 1mg respectively, 5mg, 10mg, 20mg, 50mg, 75mg, 100mg and 200mg paclitaxel then.Then with 20 rev/mins of upset solution 3 hours.With the fixing implantable glucose sensing apparatus of clip (DexCom, Inc).Then clip is connected suspension type agitator (Cole Palmer) and mixing speed is arranged to 40 rev/mins.A kind of paclitaxel solution is placed the TLC sprayer unit (Aldrich) that connects nitrogen supply (NS).Spray this device up to obtaining shallow layer.Allow this to install air-dry 5 hours.From falling the clip of turnback withdrawing device and clamping once more.Repeat coating process then.With every kind of paclitaxel solution and repeat whole coating process with new device at every turn.In other example, can replace paclitaxel with one of following representative compounds: rapamycin, mithramycin, everolimus, pimecrolimus and halofuginone.

Embodiment 31

Duct portion-the immersion of the implantable pump of drug loading

By with 1mg, 5mg, 10mg, 20mg, 50mg, 75mg, 100mg, 200mg and 500mg paclitaxel are weighed to respectively and add HPLC level methanol in the 20ml glass scintillation pipe then and prepare the 10ml paclitaxel solution.Under the room temperature on the rail mounted shaking table gentle agitation of solutions 1 hour.The end portion of the duct portion of implantable pump (Medtronic) is immersed the 0.1mg/ml paclitaxel solution.After 2 hours, withdrawing device and air-dry 24 hours from solution at 37 ℃.With every kind of paclitaxel solution and repeat whole coating process with new device at every turn.In other example, can replace paclitaxel with one of following representative compounds: rapamycin, mithramycin, everolimus, pimecrolimus, and halofuginone.

Embodiment 32

Be coated with implantable pump

By 20g polyurethane being dissolved in preparation polyurethane solutions (CHRONOFLEX AL 85A) in the 400ml oxolane (THF).The 15ml aliquot of this solution is placed 20ml glass scintillation pipe.In each bottle, add 1mg respectively, 5mg, 10mg, 20mg, 50mg, 75mg, 100mg and 200mg paclitaxel then.Then with 20 rev/mins of upset solution 3 hours.With the fixing implantable glucose sensing apparatus of clip (DexCom, Inc).Then clip is connected suspension type agitator (Cole Palmer) and mixing speed is arranged to 40 rev/mins.A kind of paclitaxel solution is placed the TLC sprayer unit (Aldrich) that connects nitrogen supply (NS).Spray this device up to obtaining the scumbling layer of cloth.Allow this to install air-dry 5 hours.Remove device and clamp once more from falling the clip of turnback.Repeat coating process then.With every kind of paclitaxel solution and repeat whole coating process with new device at every turn.In other example, can replace paclitaxel with one of following representative compounds: rapamycin, mithramycin, everolimus, pimecrolimus and halofuginone.

Embodiment 33

Sensor section-the immersion of the cochlear implant of drug loading

By with 1mg, 5mg, 10mg, 20mg, 50mg, 75mg, 100mg, 200mg and 500mg paclitaxel are weighed to respectively and add HPLC level methanol in the 20ml glass scintillation pipe then and prepare the 10ml paclitaxel solution.Under the room temperature on the rail mounted shaking table gentle agitation of solutions 1 hour.The end portion of the Sensor section of cochlear implant is immersed the 0.1mg/ml paclitaxel solution.After 2 hours, withdrawing device and air-dry 24 hours from solution at 37 ℃.With every kind of paclitaxel solution and repeat whole coating process with new device at every turn.In other example, can replace paclitaxel with one of following representative compounds: rapamycin, mithramycin, everolimus, pimecrolimus, and halofuginone.

Embodiment 34

Be used to assess the Screening test method of multiple chemical compound to the influence of the nitric oxide production of macrophage

Mouse macrophage cell line RAW 264.7 usefulness pancreatin are handled to remove cell and bed board in each hole on 6 orifice plates from bottle.With about 2 x 10 ⁶Individual cell inoculation is in the 2mL culture medium that contains 5% heat-inactivated fetal bovine serum (FBS).In 37 ℃ of incubation RAW, 264.7 cells 1.5 hours to allow to be attached to plastics.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 mitoxantrone incubation cell.By the mitoxantrone DMSO storage liquid that directly adds 1/1000 dilution for preparing previously to every hole mitoxantrone is added cell.Contain IFN γ at 37 ℃ of incubations, add deduct 24 hours (Chem.Ber. (1879) 12:426 of flat board of mitoxantrone of LPS; J.AOAC (1977) 60-594; Ann.Rev.Biochem. (1994) 63:175).

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, 1.5mL H ₃PO ₄, 48.5mL ddH ₂O) and 50 μ l Greiss reagent B (0.05g N-(1-naphthyl)-ethylenediamine, 1.5mL H 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 absorbance mean deviation is obtained concentration value from nitrite standard curve (1 μ M is to 2mM).Determine 50% inhibition concentration (IC by average nitrite concentration and positive control (with IFN γ and LPS stimulated cells) ₅₀).Determine the IC of mitoxantrone with the meansigma methods of the duplicate experiment of n=4 ₅₀Value (is seen Fig. 2 (IC ₅₀=927nM)).Measure the IC of following other chemical compound with this algoscopy ₅₀Value: IC ₅₀(nM): paclitaxel, 7; CNI-1493,249; Halofuginone, 12; Geldanamycin, 51; Anisomycin, 68; 17-AAG, 840; Anisomycin, 769.

Embodiment 35

Be used to assess the Screening test method of multiple anti-scarring agent to the TNF-α production of macrophage

With human macrophage is that THP-1 paves plate and contains 1 X 10 among the 12 hole flat boards so that every hole in 2mL contains the culture medium of 10%FCS ⁶Cell.By 20mg zymosan A is resuspended in 2mL ddH ₂Among the O and the zymosan of homogenize after obtaining unit for uniform suspension to prepare conditioning.In the 250g precipitation and be resuspended in that to reach final concentration in the 4mL human serum be 5mg/mL, incubation 20 minutes is to allow opsonic action in 37 ℃ of water-baths with the zymosan of homogenize.Prepare Bay11-7082 in DMSO, concentration is 10 ^-2M, and serial dilution 10-is doubly to obtain a series of storage liquid concentration (10 ^-8M to 10 ^-2M) (J.Immunol. (2000) 165:411-418; J.Immunol. (2000) 164:4804-4811; 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.Dull and stereotyped 24 hours of 37 ℃ of incubations.

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 measure dull and stereotyped 1 hour of diluent (PBS, 10% FCS pH7.0) sealing with 200 μ l/ holes.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/mL.Sample supernatant and standard will and join with the dull and stereotyped back of capture antibody coating room temperature incubation 2 hours with triplicate mensuration.Washing dull and stereotyped 5 times and with 100 μ l operation detection agent (the anti-human TNF alpha detection of biotinylation antibody+avidin-HRP) was room temperature incubation 1 hour.Behind this incubation, add 100 μ l substrate solution (Substrate Solution) (tetramethyl benzidine, H with plate washing 7 times and to flat board ₂O ₂) and room temperature incubation 30 minutes.In the hole, add stop bath (Stop Solution) (2N H then ₂SO ₄) and under 450nm, read yellow reaction with the λ correction of 570nm.Determine mean light absorbency 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 Fig. 3; IC ₅₀=810nM)) and rapamycin (IC ₅₀=51nM; IC Fig. 4) ₅₀Value.Use this algoscopy to determine the following IC of chemical compound in addition 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 36

Be used for assessing the surgical operation adhesion model of rat fibre modification inhibitor

Fibrosis ability 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 is exposed and the proposition abdominal cavity.With the #10 scalpel 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 avoided serious tissue injury to produce petechial hemorrhage.With the withdrawal of the left side of abdominal part and turn up to expose peritoneal wall part near caecum.Excision muscle (transverses abdominis) top 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 stitching thread.Preparation is used on both sides and the peritoneum sidewall both sides through striking off at the caecum through swiping.Place the two other stitching thread by totally 4 stitching thread caecum is connected to injured sidewall and with two-layer closed abdominal incision.After 7 days, after death assess animal, the degree and the seriousness of adhesion quantitatively and are qualitatively given a mark.

Embodiment 37

Be used for assessing the surgical operation adhesion model of rabbit fibre modification inhibitor

The rabbit uterus angle model is used to assess anti--fibre modification ability in the body of preparation.White (NZW) doe of sophisticated New Zealand is disposed under general anesthesia.Use aseptic preventive measure, at center line with abdominal part with two layer opens to expose the uterus.Two cornua uteris are proposed from the abdominal cavity and assess size at the FrenchScale of conduit.On the French Scale between #8 and the #14 angle of (2.5-4.5mm diameter) be considered suitable for this model.Two cornua uteris wear and tear with 45 with the relative stomach wall blade with the #10 dissecting knife, and area is long 2.5cm, and wide 0.4cm is hemorrhage until observing speckle.The surface of tamponade wearing and tearing is hemorrhage until stopping.Then that single angle is relative with stomach wall and fix by two stitching thread, described stitching thread is positioned at 2mm outside the eroded area edge.Administered formulation and with three layers of closed abdominal part.After 14 days, after death assessing the degree and the seriousness of animal adhesion, quantitative and qualitative scoring.

Embodiment 38

Be used to assess the Screening test method of the influence of multiple 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 storage liquid 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.72 hours (In vitro toxicol. (1990) 3:219 of flat board that contain fibroblast and mitoxantrone at 37 ℃ of incubations; Biotech.Histochem. (1993) 68:29; Anal.Biochem. (1993) 213:426).

For stopping measuring, remove culture medium by the gentleness suction.Add CYQUANT 400X GR dye indicator (Molecular Probes to 1 * lysis (CellLysis) buffer; Eugene, 1/400 diluent OR), and in the hole of flat board, add 200 μ l mixture.At room temperature lucifuge incubation dull and stereotyped 3-5 minute.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=4 is determined IC ₅₀Value.Determine the IC of following chemical compound with this algoscopy ₅₀Value: IC ₅₀(nM): mitoxantrone, 20 (Fig. 5); Rapamycin, 19 (Fig. 6); Paclitaxel, 23 (Fig. 7); Mycophenolic Acid, 550; Second, 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 (-)-perillyl alcohol, 966; Celastrol, 271; Anacitabine, 225; Oxaliplatin, 380; Chromomycin A3,4; Vinorelbine, 4; Idarubicin, 34; Nogalamycin, 5; 17-DMAG, 5; Epothilone D, 2; Vinblastine, 2; Vincristine, 7; Cytosine arabinoside, 137.

Embodiment 39

The mesh that contains paclitaxel damages the example of the assessment of neointimal hyperplasia development in the carotid artery model as assessment fibre modification inhibitor to the rat air bag

The rat air bag is damaged carotid artery model be used to illustrate that the mesh system that contains paclitaxel is to settling the effect of neointimal hyperplasia development in back 14 days.

Matched group

To weigh the Wistar rat anesthesia of 400-500g with 1.5% halothane in the oxygen, left external carotid artery will be exposed.(Baxter, Irvine CA) are advanced to left common carotid artery until aorta by the arteriotomy in the external carotid artery with A2 French Fogarty air bag embolectomy conduit.With enough saline with airbag inflation to produce slight resistance (about 0.02ml), with twist motion it is retracted to carotid bifurcation.With air bag deflation, repetitive operation is twice more then.This technology produces the expansion of arterial wall and degrading of endothelium.After taking out conduit with ligation of external carotid artery.Right common carotid artery is less than damage and with comparing.

Taxol treatment around the local vascular

After left common carotid artery damage, immediately the long arterial distal section of 1cm is exposed and treat with the mesh (on the 10:90PLG mesh in the 50:50P LG coating 345 μ g paclitaxels) that 1 x 1cm contains paclitaxel.Closure of wound and animal kept 14 days then.

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 infusion.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.The dyeing of transverse section Mayer ' s hematoxylin and eosin is used for cell counting and use Movat ' s five colors dyeing to be used for morphometric analysis and to be used for extracellular matrix components assessing.

The result

From Fig. 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 40

The influence that paclitaxel and other anti-microtubule agent are produced matrix metalloproteinase

A. material and method

1.IL-1 the AP-1 transcriptional activity that stimulates is suppressed by paclitaxel

Construct transfection chondrocyte with containing the CAT reporter gene that AP-1 drives adds IL-1, and IL-1 (50ng/ml) stimulates, and incubation 24 hours in the existence of the paclitaxel of various concentration and not.Taxol treatment reduces CAT activity (meansigma methods ± SD) in the mode of concentration dependent.According to the t-check, the data and the inductive CAT activity of IL-1-of mark asterisk (*) have significance, P＜0.05.Shown in the result be the representative of three independent experiments.

2. Paclitaxel to the inductive AP-1DNA of IL-1 in conjunction with activity, the influence of AP-1DNA

Measure in conjunction with active with radiolabeled people AP-1 sequence probe and gel mobility shift assay.The paclitaxel (10 of in the future personal various concentration ^-7To 10 ^-5M) handle or the extract of the chondrocyte that the then IL-1 β (20ng/ml) of being untreated handles and excess probe incubation on ice 30 minutes, follow native gel electrophoresis." com " swimming lane contains excessive unlabelled AP-1 oligonucleotide.Shown in the result be the representative of three independent experiments.

3. Paclitaxel is to the influence of inductive MMP-1 of IL-1 and MMP-3mRNA expression

With the paclitaxel (10 of cell with variable concentrations ^-7To 10 ^-5M) handled cell 24 hours, in the presence of paclitaxel, handled other 18 hours then with IL-1 β (20ng/ml).Separate total RNA, measure the MMP-1mRNA level by rna blot analysis.Trace is scraped subsequently and uses ³²The radiolabeled rat GAPDH of P-cDNA surveys again, and described rat GAPDH cDNA is as house-keeping gene.Shown in the result be the representative of four independent experiments.Quantitative collagenase-1 and stromelysin-expression mRNA level.The GAPDH normalization of the expression of MMP-1 and MMP-3.

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 in the Ham ' s F12 culture medium of 5%FBS 37 ℃ and be incubated overnight.Cell hunger in the culture medium of serum-free is spent the night, handled 6 hours with the anti-microtubule agent of variable concentrations then.In each plate, add IL-1 (20ng/ml) then, with other 18 hours of dull and stereotyped incubation.Separate total RNA by acidify guanidinium isothiocyanate method, and on denaturant gel, carry out electrophoresis.Analyze degeneration RNA sample (15 μ g) by gel electrophoresis in 1% denaturant gel, transfer on the nylon membrane and usefulness ³²The collagenase cDNA probe hybridization of P-labelling.Will ³Be marked with in glyceraldehyde phosphate dehydratase (GAPDH) the cDNA conduct of 2P-labelling and guarantee roughly the same application of sample.The film smayned that exposes is also used the ImageQuant quantitative analysis.

B. result

1. The promoter of matrix metalloproteinase family

Figure 11 A 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 having established matrix metalloproteinase such as collagenase and molten stromatin well.Therefore, 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 Figure 11 B, IL-1 stimulates 5 times of AP-1 transcriptional activities.With paclitaxel the pretreatment of the chondrocyte of transient transfection has been reduced the inductive AP-1 reporter gene of IL-1 CAT activity.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 effective inhibitor of AP-1 in the chondrocyte.

3. Paclitaxel to AP-1DNA in conjunction with active influence

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 Figure 11 C, 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.It is closely related to the bonded minimizing of DNA with AP-1 that the paclitaxel of AP-1 transcriptional activity suppresses.

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 Figure 11 D, 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 expression of MMPs mRNA fully under the concentration similar to suppressing the AP-1 activity.

5. Other anti-microtubule agent is to the influence of collagenase expression

Figure 12 A-H illustrates anti-microtubule agent and suppresses collagenase expression.By adding the expression of proinflammatory cytokine IL-1 stimulation collagenase.With multiple anti-microtubule agent, particularly LY290181, hexanediol, deuterium oxide, glycine ethyl ester, ethylene glycol bis-(succinimido succinate), tubercidin, AIF ₃, and epithilone precincubation 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 metalloproteinase 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 angiogenesis.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, glycine ethyl ester, AIF ₃, tubercidin, epithilone and ethylene glycol bis-(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 41

Paclitaxel is to the inhibition of angiogenesis

A. Chicken chorio-allantois (" CAM ") is measured

With fertilization raise and train Embryo Gallus domesticus shell cultivate before incubation 3 days.In this process, be positioned at air-gap shell on every side by removal and make the ovum content turn.Separate the shell inner membrance then and make the content of ovum skid off from blunt end gently the perforation of the end opposite of shell.The ovum content is emptied in the aseptic glass bowl of round bottom also with the covering of culture dish lid.Then these are put into 90% relative humidity and 3% CO ₂Calorstat in and incubation 3 days.

(MI) 0.25,0.5, the concentration of 0.5% methylated cellulose aqueous solution of 1,5,10,30 μ g/10ul aliquots is mixed for Sigma, St.Louis with paclitaxel.Because paclitaxel is insoluble in water, use bead to produce subparticle.With this solution of 10 mul aliquots samples on parafilm dry 1 hour, forming diameter was the dish of 2mm.Then the exsiccant dish that contains paclitaxel carefully was placed on the growing edge of each CAM at the 6th day of incubation.Be placed on acquisition contrast on the CAM by the methylcellulose dish that in identical time-histories, will not contain paclitaxel.Exposed back (incubation the 8th day) by the stereoscopic microscope observing vascular system at 2 days.With Liposyn II, a kind of White-opalescent solution is expelled among the CAM to increase the observability of vascular details.Use the vascular system imaging of Zeiss stereoscopic microscope with undyed live embryo, (Dage-MTI Inc., Michigan City IN) connect for described Zeiss stereoscopic microscope and camera.These video signals are showed under the 160x amplification and use image analysis system (Vidas, Kontron then; Etching, Germany) catch.Then in graphic recorder (model 3000; Matrix Instruments, Orangeburg NY) goes up preparation image egative film.

Film with 2% glutaraldehyde submergence, 8 the biggest no shell embryos in the 0.1M sodium cacodylate buffer liquid; The other fixative of injection under CAM.After 10 minutes, take out CAM and put into fresh fixative room temperature 2 hours in position.To be organized in then to wash in the dimethyl arsenic acid buffer liquid that contains 6% sucrose and spend the night.With the target area in 1% Osmic acid. back 4 ℃ fix 1.5 hours.To be organized in then in the ethanol of gradient series and dewater, carry out solvent exchange with expoxy propane, and embedding in the Spurr resin.Cut slice with diamond knife, be placed on the copper mesh, dyeing, and under the Joel1200EX ultramicroscope, observe.Similarly, cutting 0.5mm cuts into slices and dyes to be used for light microscopy with C.I. 49410..

Growing the 11st day, Embryo Gallus domesticus is being used for corrosion casting (casting) technology.The hypodermic needle that uses 30-number is with Mercox resin (Ted Pella, Inc., Redding, CA) injection CAM vascular system.Founding materials is made up of 2.5g Mercox CL-2B polymer and 0.05g catalyst (55% benzoyl peroxide), has 5 minutes polymerization times.After injection, make plastics room temperature original position shelve 1 hour, in 65 ℃ of stoves, spend the night then.Then CAM is placed in 50% sodium hydrate aqueous solution to digest all organic components.With the extensively washing in distilled water of plastics casting mold, air-dry, with the coating of gold/palladium, and with Philips 501B smayning electron microscope observation.

Measurement result is as follows.Incubation the 6th day, embryo's centrally-located was to the network center of the radial expansion of blood vessel; CAM develops near the embryo.The blood vessel of these growths is positioned near surface and is easy to as seen, makes this system become the ideal model of research angiogenesis.Live, the imaging of undyed CAM blood capillary network with can using the non-invasion of stereoscopic microscope.

Transverse section by CAM shows the outside ectoderm of being made up of two cellular layers, the wider mesoderm that contains blood capillary, and adventitial cell and inner single endoderm cell's layer, described blood capillary is located immediately under the ectoderm.Under the ultramicroscope level, show the typical structure details of CAM blood capillary.Typically, the position of these vasculars and ectodermic inner cell layer tight association.

Being exposed to concentration is 0.25,0.5,1,5,10, or the paclitaxel of 30 μ g is after 48 hours, under condition of living body with each CAM of stereomicroscopy that is equipped with video/computer interface, so that the influence of assessment angiogenesis.Use this imaging device under the amplification of 160x, this amplification allows directly to show the hemocyte in the blood capillary; Blood flow in the target area can easily be assessed and record thus.For this research, the inhibition of angiogenesis is defined as the area (measuring diameter 2-6mm) of the CAM that lacks blood capillary network and vascular flow.By these experiments, (table 1) assessed in the avascular area territory on 4 no blood vessel gradients.This scale is represented total inhibition degree, and maximum inhibition is expressed as 3 on the no blood vessel gradient scale.Depend on its concentration, paclitaxel is very consistent and induce maximum avascular area territory (diameter 6mm or do not have on the blood vessel gradient scope be 3) in 48 hours.

Table 1

No blood vessel gradient

^*The positive angiogenesis inhibitor reaction of-expression

Table 2 shows the dose dependent experimental data of the paclitaxel effect of variable concentrations.

Table 2

Medicament Delivery vector Concentration Inhibition/n

Paclitaxel methylcellulose (10ul) 0.25 μ g 2/11

Methylcellulose (10ul) 0.5 μ g 6/11

Methylcellulose (10ul) 1 μ g 6/15

Methylcellulose (10ul) 5 μ g 20/27

Methylcellulose (10ul) 10 μ g 16/21

Methylcellulose (10ul) 30 μ g 31/31

The CAM of typical taxol treatment also shows that with transparent methylcellulose dish described methylcellulose dish centrally-located is in the avascular area territory of 6mm in diameter measurement.Under higher a little amplification, the periphery in these avascular area territories is obviously clear; Functional on every side vascular often is redirected away from the paclitaxel source.Never observe this angular reorientation of blood flow under normal operation.Another feature of paclitaxel effect is the formation of the blood island in the avascular area territory, the gathering of expression hemocyte.

In a word, this studies have shown that after paclitaxel is applied to CAM 48 hours, and angiogenesis is suppressed.Blood vessel suppresses to form the avascular area territory, and these three transition stages by the paclitaxel effect are represented.Disruptive blood capillary is contained in the most affected zone in avascular area territory, has the erythrocyte that exosmoses; The intercellular that this expression lacks between the endotheliocyte connects.Entoderm keeps their intercellular to be connected with ectodermic cell, and these germinal layers remain intact thus; Yet they are thickening a little.Because near the normal blood vessels zone, blood vessel keeps their connection complex and also is kept perfectly thus.Around the taxol treatment zone, other angiogenic growth is suppressed, and this redirects by typical blood vessel or " bend pipe " effect but significantly.

Embodiment 42

Be used to assess the Screening test of paclitaxel to the influence of smooth muscle cell migration

With former generation human smooth muscular cells before measuring in the smooth muscle cell minimal medium hungry serum 16 hours, contain insulin and human alkaline fibroblast growth factor (bFGF) in the described minimal medium.Measure for migration, the cell trypsinized to take out cell from flask, is diluted to 2-2.5 X 10 with the washing of migration culture medium and in the migration culture medium ⁵The concentration of cell/mL.The migration culture medium is formed by not containing Dulbecco ' s ModifiedEagle Medium phenol red, that contain 0.35% human serum albumin (DMEM).The top that the smooth muscle cell of 100 μ L volumes (about 20,000-25,000 cell) is added Boyden chamber component (Chemicon QCM Chemotaxis 96-hole migration plate).To base apertures, add chemoattractant, derivative growth factor of recombined human blood platelet (rhPDGF-BB), concentration is 10ng/mL, cumulative volume is 150 μ L.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).The paclitaxel DMSO for preparing previously that directly adds 1/1000 dilution by the cell in top chamber stores liquid, and paclitaxel is added cell.Incubation allowed cell migration in dull and stereotyped 4 hours.

When during 4 hours, finishing, abandon the cell in the top chamber and will adhere to smooth muscle cell below the filter in cell separation liquid (Chemicon) 37 ℃ separated 30 minutes.With the cracking in containing of the cell that moves in conjunction with the lysis buffer of the CYQUANT GR dyestuff of DNA, and room temperature incubation 15 minutes.In the minisize fluorescence plate reader～480nm excitation wavelength and～read fluorescence under the 520nm emission maximum.Behind subtracting background fluorescence (the contrast chamber that does not have chemoattractant), will average from the relative fluorescence unit in triplicate hole, obtain the average number of migrating cell from the standard curve of smooth muscle cell, described smooth muscle cell from 25,000 cells/well serial dilutions to 98 cells/well.Compare by the average and the positive control (in response to the smooth muscle cell chemotaxis of rhPDGF-BB) that will have the migrating cell under the paclitaxel, measure 50% inhibition concentration (IC ₅₀).Referring to Figure 13 (IC ₅₀=0.76nM).List of references: Biotechniques (2000) 29:81; J.ImmunolMethods (2001) 254:85.

Embodiment 43

Be used to assess of the Screening test of multiple chemical compound to the influence of the IL-1 β generation of macrophage

With human macrophage is that the THP-1 plating is in 12 hole flat boards, so that 1 X 10 is contained in every hole in 2mL contains the culture medium of 10%FCS ⁶Cell.By 20mg zymosan A is resuspended in 2mL ddH ₂Among the O and the zymosan of homogenize after obtaining unit for uniform suspension to prepare conditioning.In the 250g precipitation and be resuspended in that to reach final concentration in the 4mL human serum be 5mg/mL, incubation 20 minutes is to allow opsonic action in 37 ℃ of water-baths with the zymosan of homogenize.Prepare geldanamycin in DMSO, concentration is 10 ^-2M, and serial dilution 10-is doubly to obtain a series of storage liquid concentration (10 ^-8M to 10 ^-2M).

Stimulate the THP-1 cell to produce IL-1 β by the zymosan that adds the 1mg/mL conditioning.Add each hole by the direct DMSO storage liquid that will formerly prepare, geldanamycin is added the THP-1 cell with 1/1000 dilution.Every kind of drug level detects in triplicate hole.With flat board 37 ℃ of incubations 24 hours.

After stimulating in 24 hours, collect supernatant so that IL-1 β is produced quantitatively.By the IL-1 β concentration in the ELISA mensuration supernatant, use recombined human IL-1 β to obtain standard curve.Spent the night with 4 ℃ of bags of 100 μ L Anti-Human IL-1 β capture antibodies (Capture Antibody) 96 hole MaxiSorb are dull and stereotyped, described Anti-Human IL-1 β capture antibody be diluted in wrap be cushioned liquid (the 0.1M sodium carbonate, pH9.5) in.The dilution of used capture antibody is batch specific and measures by experience.Then with the capture antibody suction, with dull and stereotyped 3 times of lavation buffer solution (PBS, 0.05% tween 20) washing.Measuring diluent (PBS, 10% FCS pH7.0) with 200 μ L/ holes at room temperature sealed dull and stereotyped 1 hour.After sealing, with dull and stereotyped 3 times of lavation buffer solution washing.Be prepared as follows standard specimen and sample diluting liquid: (a) with sample supernatant dilution 1/4 and 1/8; (b) prepare recombined human IL-1 β with 1000pg/mL, and serial dilution, the standard curve of acquisition 15.6pg/mL to 1000pg/mL.Sample supernatant and standard specimen be with triplicate mensuration, and behind the flat board that adds capture antibody bag quilt incubation 2 hours at room temperature.Washing dull and stereotyped 5 times and with 100 μ L operation detection agent (biotinylation Anti-Human IL-1 β detects antibody+Avidin-HRP) room temperature incubation 1 hour.Behind this incubation, dull and stereotyped 7 times and of washing with 100 μ L substrate solution (tetramethyl benzidine, H ₂O ₂) add dull and stereotyped and room temperature incubation 30 minutes.Add stop bath (2N H to the hole then ₂SO ₄), read yellow reaction at 450nm, proofread and correct at 570nm λ.Measure mean light absorbency from triplicate data read, and deduct average background.Obtain IL-1 β concentration value from standard curve.By average IL-1 β concentration and positive control (with the THP-1 cell of the zymosan stimulation of nursing one's health) are relatively measured 50% inhibition concentration (IC ₅₀).The meansigma methods of use n=4 repeated experiments is measured the IC of geldanamycin ₅₀Value (IC ₅₀=20nM).See Figure 14.Use this to measure to determine the IC of following additional compounds ₅₀Value: IC ₅₀(nM): Mycophenolic Acid 2888nM); Anisomycin, 127; Hycamtin, 0.48; Halofuginone, 919; IDN-6556,642; Epirubicin hydrochloride, 774; Hycamtin, 509; Fascaplycin, 425; Daunorubicin, 517; Celastrol, 23; Oxaliplatin (oxalipatin), 107; Chromomycin A3,148.List of references: J.Immunol. (2000) 165:411-418; J.Immunol. (2000) 164:4804-4811; J.Immunol Meth. (2000) 235 (1-2): 33-40.

Embodiment 44

Be used to assess the Screening test of all cpds to the influence of the IL-8 production of macrophage

With human macrophage is that the THP-1 plating is in 12 hole flat boards, so that 1 X 10 is contained in every hole in 2mL contains the culture medium of 10%FCS ⁶Cell.By 20mg zymosan A is resuspended in 2mL ddH ₂Among the O and the zymosan of homogenize after obtaining unit for uniform suspension to prepare conditioning.In the 250g precipitation and be resuspended in that to reach final concentration in the 4mL human serum be 5mg/mL, incubation 20 minutes is to allow opsonic action in 37 ℃ of water-baths with the zymosan of homogenize.Prepare geldanamycin in DMSO, concentration is 10 ^-2M, and serial dilution 10-is doubly to obtain a series of storage liquid concentration (10 ^-8M to 10 ^-2M).

Stimulate the THP-1 cell to produce IL-8 by the zymosan that adds the 1mg/mL conditioning.Add each hole by the direct DMSO storage liquid that will formerly prepare, geldanamycin is added the THP-1 cell with 1/1000 dilution.Every kind of drug level detects in triplicate hole.With flat board 37 ℃ of incubations 24 hours.

After stimulating in 24 hours, collect supernatant so that IL-8 is produced quantitatively.By the IL-8 concentration in the ELISA mensuration supernatant, use recombined human IL-8 to obtain standard curve.Spent the night with 4 ℃ of bags of 100 μ L Anti-Human IL-8 capture antibodies (Capture Antibody) 96 hole MaxiSorb are dull and stereotyped, described Anti-Human IL-8 capture antibody be diluted in wrap be cushioned liquid (the 0.1M sodium carbonate, pH9.5) in.The dilution of used capture antibody is batch specific and measures by experience.Then with the capture antibody suction, with dull and stereotyped 3 times of lavation buffer solution (PBS, 0.05% tween 20) washing.Measuring diluent (PBS, 10% FCS pH7.0) with 200 μ L/ holes at room temperature sealed dull and stereotyped 1 hour.After sealing, with dull and stereotyped 3 times of lavation buffer solution washing.Be prepared as follows standard specimen and sample diluting liquid: (a) with sample supernatant dilution 1/100 and 1/1000; (b) prepare recombined human IL-8 with 200pg/mL, and serial dilution, the standard curve of acquisition 3.1pg/mL to 200pg/mL.Sample supernatant and standard specimen be with triplicate mensuration, and behind the flat board that adds capture antibody bag quilt incubation 2 hours at room temperature.Washing dull and stereotyped 5 times and with 100 μ L operation detection agent (biotinylation Anti-Human IL-8 detects antibody+Avidin-HRP) room temperature incubation 1 hour.Behind this incubation, dull and stereotyped 7 times and of washing with 100 μ L substrate solution (tetramethyl benzidine, H ₂O ₂) add dull and stereotyped and room temperature incubation 30 minutes.Add stop bath (2N H to the hole then ₂SO ₄), read yellow reaction at 450nm, proofread and correct at 570nm λ.Measure mean light absorbency from triplicate data read, and deduct average background.Obtain the IL-8 concentration value from standard curve.By average IL-8 concentration and positive control (with the THP-1 cell of the zymosan stimulation of nursing one's health) are relatively measured 50% inhibition concentration (IC ₅₀).The meansigma methods of use n=4 repeated experiments is measured the IC of geldanamycin ₅₀Value (IC ₅₀=27nM).See Figure 15.Use this to measure to determine the IC of following additional compounds 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: J.Immunol. (2000) 165:411-418; J.Immunol. (2000) 164:4804-4811; J.Immunol Meth. (2000) 235 (1-2): 33-40.

Embodiment 45

Be used to assess the Screening test of all cpds to the influence of the MCP-1 production of macrophage

With human macrophage is that the THP-1 plating is in 12 hole flat boards, so that 1 X 10 is contained in every hole in 2mL contains the culture medium of 10%FCS ⁶Cell.By 20mg zymosan A is resuspended in 2mL ddH ₂Among the O and the zymosan of homogenize after obtaining unit for uniform suspension to prepare conditioning.In the 250g precipitation and be resuspended in that to reach final concentration in the 4mL human serum be 5mg/mL, incubation 20 minutes is to allow opsonic action in 37 ℃ of water-baths with the zymosan of homogenize.Prepare geldanamycin in DMSO, concentration is 10 ^-2M, and serial dilution 10-is doubly to obtain a series of storage liquid concentration (10 ^-8M to 10 ^-2M).

Stimulate the THP-1 cell to produce MCP-1 by the zymosan that adds the 1mg/mL conditioning.Add each hole by the direct DMSO storage liquid that will formerly prepare, geldanamycin is added the THP-1 cell with 1/1000 dilution.Every kind of drug level detects in triplicate hole.With flat board 37 ℃ of incubations 24 hours.

After stimulating in 24 hours, collect supernatant so that MCP-1 is produced quantitatively.By the MCP-1 concentration in the ELISA mensuration supernatant, use recombined human MCP-1 to obtain standard curve.Spent the night with 4 ℃ of bags of 100 μ L Anti-Human MCP-1 capture antibodies (Capture Antibody) 96 hole MaxiSorb are dull and stereotyped, described Anti-Human MCP-1 capture antibody be diluted in wrap be cushioned liquid (the 0.1M sodium carbonate, pH9.5) in.The dilution of used capture antibody is batch specific and measures by experience.Then with the capture antibody suction, with dull and stereotyped 3 times of lavation buffer solution (PBS, 0.05% tween 20) washing.Measuring diluent (PBS, 10% FCS pH7.0) with 200 μ L/ holes at room temperature sealed dull and stereotyped 1 hour.After sealing, with dull and stereotyped 3 times of lavation buffer solution washing.Be prepared as follows standard specimen and sample diluting liquid: (a) with sample supernatant dilution 1/100 and 1/1000; (b) prepare recombined human MCP-1 with 500pg/mL, and serial dilution, the standard curve of acquisition 7.8pg/mL to 500pg/mL.Sample supernatant and standard specimen be with triplicate mensuration, and behind the flat board that adds capture antibody bag quilt incubation 2 hours at room temperature.Washing dull and stereotyped 5 times and with 100 μ L operation detection agent (biotinylation Anti-Human MCP-1 detects antibody+Avidin-HRP) room temperature incubation 1 hour.Behind this incubation, dull and stereotyped 7 times and of washing with 100 μ L substrate solution (tetramethyl benzidine, H ₂O ₂) add dull and stereotyped and room temperature incubation 30 minutes.Add stop bath (2N H to the hole then ₂SO ₄), read yellow reaction at 450nm, proofread and correct at 570nm λ.Measure mean light absorbency from triplicate data read, and deduct average background.Obtain the MCP-1 concentration value from standard curve.By average MCP-1 concentration and positive control (with the THP-1 cell of the zymosan stimulation of nursing one's health) are relatively measured 50% inhibition concentration (IC ₅₀).The meansigma methods of use n=4 repeated experiments is measured the IC of geldanamycin ₅₀Value (IC ₅₀=7nM).See Figure 16.Use this to measure to determine the IC of following additional compounds 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; Bay58-2667,216; 15-deoxidation prostaglandin J2,724; Rapamycin, 0.05; CNI-1493,0.02; BXT-51072,683; Halofuginone, 9; CYC 202,306; Hycamtin, 514; Fascaplycin, 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: J.Immunol. (2000) 165:411-418; J.Immunol. (2000) 164:4804-4811; J.Immunol Meth. (2000) 235 (1-2): 33-40.

Embodiment 46

Be used to assess the Screening test of paclitaxel for the influence of 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.Preparing concentration with DMSO is 10 ^-2The paclitaxel 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.The flat board 72 hours that contains cell and paclitaxel at 37 ℃ of incubations.

For stopping measuring, remove culture medium by the gentleness suction.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.At room temperature lucifuge incubation dull and stereotyped 3-5 minute.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 Figure 17 (IC ₅₀=7nm) determine the following IC of chemical compound in addition with this algoscopy 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; Epithilone D, 5; Tubercidin, 30; Vinblastine, 3; Vincristine, 9.

It is the influence of RAW264.7 to fibroblast and mouse macrophage that this mensuration can be used for assessing chemical compound.In Figure 18, shown and be used to assess the result (IC of paclitaxel the influence of Mus RAW 264.7 macrophage proliferations ₅₀=134nM).

List of references: In vitro toxicol. (1990) 3:219; Biotech.Histochem. (1993) 68:29; Anal.Biochem. (1993) 213:426.

Embodiment 47

Use to assess fibrotic inhibition around the blood vessel of paclitaxel

To weigh the WISTAR rat anesthesia of 250-300g by intramuscular injection Innovar (0.33ml/kg).In case calm, they are placed under the halothane anesthesia.In case set up general anesthesia, the fur of neck area is scraped off, skin is clamped and uses the povidone iodine wiping.On left neck artery, make a longitudinal cut, expose external carotid artery.Be placed on two ligation bands around the external carotid artery and carry out horizontal arteriotomy.Then 2# FRENCH FOGART balloon catheter is introduced carotid artery and is fed left common carotid artery, with saline with airbag inflation.Conduit is passed through carotid artery three times up and down.Take out conduit then, binder is tied a knot on left external carotid artery.

Then the paclitaxel (33%) in the ethane-acetic acid ethyenyl ester (EVA) is injected 10 rats in the circumference mode around the common carotid artery.Independent EVA is injected around the common carotid artery of other 10 rats.(paclitaxel also can be applied on the EVA film, and described film is placed in the circumference mode around the common carotid artery then) put to death every group of 5 rat at 14 days, at 28 days with last 5 execution.Observe that rat body weight alleviates or the sign of other general disease.After 14 or 28 days,, the mode of left neck artery with initial experiment exposed Animal Anesthesia.Separate carotid artery, with 10% buffered formaldehyde fixed and carry out histological examination.

As measured by the standard type determination and analysis, the statistics of neointimal hyperplasia degree reduces the drug-induced minimizing of display fibers reaction of degeneration significantly.

Embodiment 48

Be used to assess medicament and induce the interior evaluating of PU film around the blood vessel of silk coating of cicatrization ability

Described the rat carotid artery model and be used for determining whether a kind of material stimulates fibre modification.With the Wistar rat of the heavy 300g of halothane anesthesia to 400g.The skin of shaving neck regions and to skin degerming.On trachea, produce longitudinal incision and expose left neck artery.The polyurethane film that will cover with silk thread or contrast uncoated PU film parcel common carotid artery distal section.Sew up wound and animal rehabilitation.After 28 days, put to death rat with the pressure infusion of 100mmHg with carbon dioxide and 10% buffering formaldehyde.Gather in the crops two carotid artery and handle and be used for the histology.Can in handled left neck artery, cut continuous transverse section and in untreated right carotid, cut continuous transverse section by every 2mm with respective horizontal.To cut into slices and use H﹠amp; E and Movat ' s dyeing are with the growth of assessment carotid artery surrounding tissue.Area by the quantitative blood vessel perivascular granulation tissue of computer assisted morphometric analysis.The area of granulation tissue ratio in silk coating group is significantly higher in uncoated group of contrast.See Figure 19.

Embodiment 49

With the interior evaluating of PU film around the blood vessel of different silk suture material coating with the assessment cicatrization

Described the rat carotid artery model and be used for determining whether a kind of material stimulates fibre modification.With the Wistar rat of the heavy 300g of halothane anesthesia to 400g.The skin of shaving neck regions and to skin degerming.On trachea, produce longitudinal incision and expose left neck artery.To use silk stitching thread ((3-0Silk-Black Braided (Davis from three kinds of different manufacturers; Geck), 3-0SOFSILK (U.S.Surgical/Davis ﹠amp; Geck) and the polyurethane film parcel common carotid artery distal section that covers of 3-0Silk-Black Braided (LIGAPAK) (Ethicon, Inc.)).(polyurethane film can also be with other medicament coating to induce fibre modification.) sew up wound and the rehabilitation of permission animal.

After 28 days, put to death rat with the pressure infusion of 100mmHg with carbon dioxide and 10% buffering formaldehyde.Gather in the crops two carotid artery and handle and be used for the histology.Can in handled left neck artery, cut continuous transverse section and in untreated right carotid, cut continuous transverse section by every 2mm with respective horizontal.To cut into slices and use H﹠amp; E and Movat ' s dyeing are with the growth of assessment carotid artery surrounding tissue.Area by the quantitative blood vessel perivascular granulation tissue of computer assisted morphometric analysis.The thickness of granulation tissue with three groups in identical, show that thread stitching thread surrounding tissue propagation is independent of the generation method.See Figure 20.

Embodiment 50

Be used to assess medicament and induce the interior evaluating of silk powder around the blood vessel of synulotic ability

Described the rat carotid artery model and be used for determining whether a kind of material stimulates fibre modification.With the Wistar rat of the heavy 300g of halothane anesthesia to 400g.The skin of shaving neck regions and to skin degerming.On trachea, produce longitudinal incision and expose left neck artery.The silk powder is sprayed on the tremulous pulse of exposure and coats this tremulous pulse with the PU film then.The silk powder (not having contaminative protein) of natural silk powder or purification is used for the different animals group.Only the carotid artery that coats with the PU film is used as matched group.Sew up wound and the rehabilitation of permission animal.After 28 days, put to death rat with the pressure infusion of 100mmHg with carbon dioxide and 10% buffering formaldehyde.Gather in the crops two carotid artery and handle and be used for the histology.Can in handled left neck artery, cut continuous transverse section and in untreated right carotid, cut continuous transverse section by every 2mm with respective horizontal.To cut into slices and use H﹠amp; E and Movat ' s dyeing are with the growth of assessment carotid artery surrounding tissue.Area by the quantitative inner membrance of computer assisted morphometric analysis, middle film and blood vessel perivascular granulation tissue.

Natural silk causes serious cellular inflammation, and it mainly is made up of neutrophil cell and lymphocytic infiltration in the fibrin network, without any extracellular matrix or blood vessel.In addition, handled tremulous pulse is badly damaged, and has hypocellular middle film (media), fragmentation elastic layer and thick neointimal hyperplasia.Neointimal hyperplasia contains many inflammatory cells and is inaccessible in 2/6 example.This serious immunoreation may be caused by the antigen protein of fibroin in the coating said preparation.At the other end, regenerated silk powder only causes slight foreign body reaction around handled tremulous pulse.The feature that this tissue is replied is inflammatory cell, giant cell and the blood vessel in the extracellular matrix.Handled tremulous pulse is complete.These results show that removing coating protein from natural silk can prevent immunoreation and promote the benign tissue growth.Find the degraded of regenerated silk powder in some tissue slices, showing that tissue is replied may be ripe in time and heal.See Figure 21.

Embodiment 51

Be used to assess medicament and induce talcous interior evaluating around the blood vessel of synulotic ability

Described the rat carotid artery model and be used for determining whether a kind of material stimulates fibre modification.With the Wistar rat of the heavy 300g of halothane anesthesia to 400g.The skin of shaving neck regions and to skin degerming.On trachea, produce longitudinal incision and expose left neck artery.Pulvis Talci is sprayed on the tremulous pulse of exposure and coats this tremulous pulse with the PU film then.Only the carotid artery that coats with the PU film is used as matched group.Sew up wound and the rehabilitation of permission animal.After 1 to 3 months, put to death rat with the pressure infusion of 100mmHg with carbon dioxide and 10% buffering formaldehyde.Gather in the crops two carotid artery and handle and be used for the histology.Can in handled left neck artery, cut continuous transverse section and in untreated right carotid, cut continuous transverse section by every 2mm with respective horizontal.To cut into slices and use H﹠amp; E and Movat ' s dyeing are with the growth of assessment carotid artery surrounding tissue.Area by the quantitative inner membrance of computer assisted morphometric analysis, middle film and blood vessel perivascular granulation tissue.Histopathology result and morphometric analysis show 1st month with 3rd month to talcous identical local-acknowledgement.Practical site around blood vessel, big tissue reaction catches this Pulvis Talci.The feature of this tissue is a large amount of macrophages in thick extracellular matrix, does not almost have neutrophil cell, lymphocyte and blood vessel.The influence that handled blood vessel seems complete and is not subject to processing.In a word, this result shows that Pulvis Talci induces gentle secular fibre modification reaction, and it is subclinical in itself and does not injure any adjacent tissue.See Figure 22.

Embodiment 52

Carrying out MIC by microtitration meat soup dilution process measures

A. The MIC of various Gram-negatives and positive bacteria measures

Basic as Amsterdam, D.1996, " Susceptibility testing of antimicrobials inliquid media ", p.52-111, i nLoman, V., ed.Antibiotics in laboratory medicine, 4th ed.Williams and Wilkins, Baltimore, the MIC that carries out that describes among the MD measures.In brief, test antibacterial activity (the minimal inhibitory concentration mensuration of multiple chemical compound with MIC at Pseudomonas aeruginosa (P.aeruginosa), Klebsiella pneumonia (K.pneumoniae), escherichia coli (E.coli), staphylococcus epidermidis (S.epidermidis) and staphylococcus aureus (S.aureus), under anaerobic use 96 hole polystyrene microtitration plates (Falcon 1177) and Mueller Hinton culture fluid 37 ℃ of incubations 24 hours.(MHB is used for most tests, just C721 (streptococcus pyogenes (S.pyogenes) is used 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 various Gram-negatives 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	The gram leather San Shi 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 aforesaid MIC measured, tested the following chemical compound of multiple concentration: mitoxantrone, cisplatin, tubercidin, methotrexate, 5-fluorouracil, etoposide, 2-purinethol, doxorubicin, Ismipur, camptothecine, hydroxyurea and cytosine arabinoside were to the clinical separation strain of methicillin-resistant staphylococcus aureus and the antibacterial activity of resistance of vancomycin tablet coccus clinical separation strain.Demonstrate and suppress growth (MIC value＜1.0 x 10 ^-3) chemical compound comprise: mitoxantrone (two kinds of bacterial strains), methotrexate (vancomycin sheet coccus), 5-fluorouracil (two kinds of bacterial strains), etoposide (two kinds of bacterial strains) and 2-purinethol (vancomycin sheet coccus).

Embodiment 53

The preparation of buffer release liquid

By in beaker, adding 8.22g sodium chloride, 0.32g sodium dihydrogen phosphate (monohydrate) and 2.60g sodium hydrogen phosphate (anhydrous) preparation buffer release liquid.Add 1L hplc grade 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 54

Be used to measure the releasing research of therapeutic agent from the release profiles of the device of coating

The sample that loads the therapeutic agent conduit is placed the 15ml culture tube.Add 15ml buffer release liquid (embodiment 53) to culture tube.With the sealing of the screw-cap of effective TEFLON liner and place on 37 ℃ of baking oven swiveling wheels.Get buffer and replace from culture tube at a plurality of time points with fresh buffer.With HPLC getting buffer is analyzed the amount of contained therapeutic agent in this buffer then.

With mention in this manual and/or the request for data table in above listed all United States Patent (USP), U.S. Patent Application Publication, U.S. Patent application, foreign patent, foreign patent application and non-patent publications is complete quotes as a reference.

Content according to the front will be understood, although particular of the present invention has been described in explanation in this article for example, can make multiple modification and will not deviate from the spirit and scope of the invention.Therefore, the present invention only is subjected to the restriction of appended claim.

Claims (39)

1. device, the compositions that it comprises pick off and anti-scarring agent or comprises anti-scarring agent, wherein said medicament restraining device and implant cicatrization between the host of this device.

2. device, the compositions that it comprises blood or tissue glucose monitor (that is, pick off) and anti-scarring agent or comprises anti-scarring agent, wherein said medicament restraining device and implant cicatrization between the host of this device.

3. device, the compositions that it comprises pressure or tension pick-up and anti-scarring agent or comprises anti-scarring agent, wherein said medicament restraining device and implant cicatrization between the host of this device.

4. device, the compositions that it comprises cardiac sensor and anti-scarring agent or comprises anti-scarring agent, wherein said medicament restraining device and implant cicatrization between the host of this device.

5. device, the compositions that it comprises respiration pickup and anti-scarring agent or comprises anti-scarring agent, wherein said medicament restraining device and implant cicatrization between the host of this device.

6. device, the compositions that it comprises hearing transducer and anti-scarring agent or comprises anti-scarring agent, wherein said medicament restraining device and implant cicatrization between the host of this device.

7. device, the compositions that it comprises electrolyte or metabolite pick off and anti-scarring agent or comprises anti-scarring agent, wherein said medicament restraining device and implant cicatrization between the host of this device.

8. device, the compositions that it comprises pump and anti-scarring agent or comprises anti-scarring agent, wherein said medicament restraining device and implant cicatrization between the host of this device.

9. device, the compositions that it comprises implantable insulin pump and anti-scarring agent or comprises anti-scarring agent, wherein said medicament restraining device and implant cicatrization between the host of this device.

10. device, the compositions that it comprises drug delivery pump and anti-scarring agent in the sheath or comprises anti-scarring agent, wherein said medicament restraining device and implant cicatrization between the host of this device.

11. device, it comprises the compositions that is used for chemotherapeutic implantable drug delivery pump and anti-scarring agent or comprises anti-scarring agent, wherein said medicament restraining device and implant cicatrization between the host of this device.

12. device, it comprises the compositions that is used for the treatment of cardiopathic drug delivery pump and anti-scarring agent or comprises anti-scarring agent, wherein said medicament restraining device and implant cicatrization between the host of this device.

13. device, it comprises the compositions that medicine is sent implant (that is, pump) and anti-scarring agent or comprised anti-scarring agent, wherein said medicament restraining device and implant cicatrization between the host of this device.

14. suppress synulotic method, it comprises pick off and anti-scarring agent or the compositions that comprises anti-scarring agent is placed the animal reservoir that wherein said medicament suppresses cicatrization.

15. suppress synulotic method, it comprises blood or tissue glucose monitor (that is, pick off) and anti-scarring agent or the compositions that comprises anti-scarring agent is placed the animal reservoir that wherein said medicament suppresses cicatrization.

16. suppress synulotic method, it comprises pressure or tension pick-up and anti-scarring agent or the compositions that comprises anti-scarring agent is placed the animal reservoir that wherein said medicament suppresses cicatrization.

17. suppress synulotic method, it comprises cardiac sensor and anti-scarring agent or the compositions that comprises anti-scarring agent is placed the animal reservoir that wherein said medicament suppresses cicatrization.

18. suppress synulotic method, it comprises respiration pickup and anti-scarring agent or the compositions that comprises anti-scarring agent is placed the animal reservoir that wherein said medicament suppresses cicatrization.

19. suppress synulotic method, it comprises hearing transducer and anti-scarring agent or the compositions that comprises anti-scarring agent is placed the animal reservoir that wherein said medicament suppresses cicatrization.

20. suppress synulotic method, it comprises electrolyte or metabolite pick off and anti-scarring agent or the compositions that comprises anti-scarring agent is placed the animal reservoir that wherein said medicament suppresses cicatrization.

21. suppress synulotic method, it comprises pump and anti-scarring agent or the compositions that comprises anti-scarring agent is placed the animal reservoir that wherein said medicament suppresses cicatrization.

22. suppress synulotic method, it comprises implantable insulin pump and anti-scarring agent or the compositions that comprises anti-scarring agent is placed the animal reservoir that wherein said medicament suppresses cicatrization.

23. suppress synulotic method, it comprises pump in the sheath and anti-scarring agent or the compositions that comprises anti-scarring agent is placed the animal reservoir that wherein said medicament suppresses cicatrization.

24. suppress synulotic method, it comprises that the compositions that will be used for chemotherapeutic implantable drug delivery pump and anti-scarring agent or comprise anti-scarring agent places the animal reservoir, wherein said medicament suppresses cicatrization.

25. suppress synulotic method, it comprises that the compositions that will be used for the treatment of cardiopathic drug delivery pump and anti-scarring agent or comprise anti-scarring agent places the animal reservoir, wherein said medicament suppresses cicatrization.

26. suppress synulotic method, it comprises that the compositions of medicine being sent implant (that is, pump) and anti-scarring agent or comprising anti-scarring agent places the animal reservoir, wherein said medicament suppresses cicatrization.

27. the method for process units, it comprises: with pick off and anti-scarring agent or comprise the compositions combination of anti-scarring agent, and wherein said medicament restraining device and implant cicatrization between the host of this device.

28. the method for process units, it comprises: with blood or tissue glucose monitor (promptly, pick off) and anti-scarring agent or comprise the compositions combination of anti-scarring agent, wherein said medicament restraining device and implant cicatrization between the host of this device.

29. the method for process units, it comprises: with pressure or tension pick-up and anti-scarring agent or comprise the compositions combination of anti-scarring agent, and wherein said medicament restraining device and implant cicatrization between the host of this device.

30. the method for process units, it comprises: with cardiac sensor and anti-scarring agent or comprise the compositions combination of anti-scarring agent, and wherein said medicament restraining device and implant cicatrization between the host of this device.

31. the method for process units, it comprises: with respiration pickup and anti-scarring agent or comprise the compositions combination of anti-scarring agent, and wherein said medicament restraining device and implant cicatrization between the host of this device.

32. the method for process units, it comprises: with hearing transducer and anti-scarring agent or comprise the compositions combination of anti-scarring agent, and wherein said medicament restraining device and implant cicatrization between the host of this device.

33. the method for process units, it comprises: with electrolyte or metabolite pick off and anti-scarring agent or comprise the compositions combination of anti-scarring agent, and wherein said medicament restraining device and implant cicatrization between the host of this device.

34. the method for process units, it comprises: with pump and anti-scarring agent or comprise the compositions combination of anti-scarring agent, and wherein said medicament restraining device and implant cicatrization between the host of this device.

35. the method for process units, it comprises: with implantable insulin pump and anti-scarring agent or comprise the compositions combination of anti-scarring agent, and wherein said medicament restraining device and implant cicatrization between the host of this device.

36. the method for process units, it comprises: with drug delivery pump in the sheath and anti-scarring agent or comprise the compositions combination of anti-scarring agent, and wherein said medicament restraining device and implant cicatrization between the host of this device.

37. the method for process units, it comprises: will be used for chemotherapeutic implantable drug delivery pump and anti-scarring agent or comprise the compositions combination of anti-scarring agent, wherein said medicament restraining device and implant cicatrization between the host of this device.

38. the method for process units, it comprises: will be used for the treatment of cardiopathic drug delivery pump and anti-scarring agent or comprise the compositions combination of anti-scarring agent, wherein said medicament restraining device and implant cicatrization between the host of this device.

39. the method for process units, it comprises: with drug delivery pump and anti-scarring agent or comprise the compositions combination of anti-scarring agent, and wherein said medicament restraining device and implant cicatrization between the host of this device.

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