CN1901850A - Injectable sustained release implant having a bioerodible matrix core and a bioerodible skin - Google Patents

Abstract

An injectable drug delivery device includes a core containing one or more drugs and one or more polymers. The core may be surrounded by one or more polymer outer layers (referred to herein as ''coatings,'' ''skins,'' or ''outer layers''). In certain embodiments, the device is formed by extruding or otherwise preforming a polymeric skin for a drug core. The drug core may be co-extruded with the skin, or inserted into the skin after the skin has been extruded, and possibly cured. In other embodiments, the drug core may be coated with one or more polymer coatings. These techniques may be usefully applied to fabricate devices having a wide array of drug formulations and skins that can be selected to control the release rate profile and various other properties of the drugs in the drug core in a form suitable for injection using standard or non-standard gauge needles. The device may be formed by combining at least one polymer, at least one drug, and at least one liquid solvent to form a liquid suspension or solution wherein, upon injection, such suspension or solution under goes a phase change and forms a gel. The configuration may provide for controlled release of the drug(s) for an extended period.

Description

But Injectable sustained release implant with a bioerodible matrix core and bioerosion skin

Invention field

The present invention relates to the Injectable sustained release drug delivery systems and be used to prepare the method for these devices.

Description of Related Art

The United States Patent (USP) of Hong Guo etc. is described some drug delivery systems for the 6th, 375, No. 972, this patent by reference and integral body is attached to herein, these devices use various combinations of drug cores and polymer coating to implant living tissue drug delivery rate with control.Although these devices have significant advantage, as the part of common product development cycle, dwindling of these plant bulks may make that the preparation of device is difficult more.Described in ' 972 patents, drug-reservoir can form in the pipe by many distinct methods supports, comprises drug matrices is injected the preforming pipe.More tacky along with Guan Gengxiao and drug matrices material, this technology becomes increasingly difficult.

Kajihara etc. are published in Journal of Controlled Release, and 73, the article among the pp.279-291 (2001) discloses a kind of method that addresses this problem, and describes in the literary composition and uses the slow releasing preparation of siloxanes as the preparing carriers pharmaceutical grade protein.The content of this article integral body by reference is attached to herein.

The another kind of method of dwindling the sustained release drug delivery systems size is disclosed in No. the 10/428th, 214, the U.S. Patent application of submitting on May 2nd, 2003.Although disclosure is not limited to the device of any specific dimensions, wherein disclosed coextrusion technology is applicable to the preparation of dingus.

Although have inherent difficulty in the preparation of little, sustained release drug delivery device, these devices have begun to approach the device injection and have become possible size.Yet, still need improved Injectable sustained release delivery system and the technology for preparing this system.

Summary of the invention

The injectable drug delivery device that comprises the core that contains one or more medicines and one or more polymer.This core can be centered on by one or more polymeric outer layers (this paper is called " coating ", " skin " or " skin ").In certain embodiments, device is by extrusion molding or make the polymer sheath preforming of drug core.Drug core can with the skin coextrusion, perhaps extrude the back and insert in the skin, and may solidify at skin.In other embodiments, drug core can apply one or more polymer coatings.Can use these technology effectively, to be applicable to the form of use standard or non-standard number (gauge) pin injection, preparation has the device of wide region pharmaceutical preparation and skin, can select skin release rate profile and various other characteristics with control drug core Chinese medicine.This device can be by forming at least a polymer, at least a medicine and at least a liquid flux mixing formation liquid suspension or solution, and after the injection, wherein this suspension or solution experience phase change and forms gel.This structure can provide the medicine sustained release of time expand.

In the embodiment of using skin, micromicro is to medicine or the liquid environment infiltration that may expose device, semi-permeable or impermeable.Drug core can comprise not can the appreciable impact drug release rate polymeric matrix.Perhaps, this polymeric matrix can influence drug release rate.The polymeric matrix of skin, drug core or both all can be biological erodible.Device can be prepared into the prolongation block (mass) that is partitioned into drug delivery systems, it can keep and not apply so that all faces of drug core or (when using skin) each section (segment) ends exposed, perhaps coat, but for example to the layer of drug osmotic, or bioerosion semi-permeable, impermeable to medicine.

The accompanying drawing summary

Be explained in more detail referring now to the invention of accompanying drawing to the application, wherein same contrast numeral is meant identical or corresponding element:

Fig. 1 shows the equipment that is used for the coextrusion drug delivery systems;

Fig. 2-5 shows the different rates of release of extruding preparation;

Fig. 6 shows the equipment that is used to extrude the drug delivery systems skin;

Fig. 7 is the method flow diagram of preparation injectable drug delivery device;

Fig. 8 shows injectable drug delivery device;

Fig. 9 shows the injection delivery system; And

Figure 10 shows the rate of release of some device;

Figure 11 shows the speed that FA discharges from device;

The comparison rate of release of Figure 12 display device and prior art device;

Figure 13-15 shows the before speed that has technique device to discharge of some drugs.

Detailed Description Of The Invention

For complete understanding the present invention, now some exemplary embodiment will be described, comprise the system and method for the Injectable sustained release drug delivery systems that uses the extrusion molding preparation with cylindrical cross-section.Yet, should understand system and method described herein and can be effectively applied to many different devices, if any the geometric device of different cross section or the device of the different activities drug core of two or more concentric arrangement or non-concentric arrangement is arranged.Also will recognize arbitrary medicine described herein and outer field various combination, or this paper other drug or the skin specifically do not mentioned, in the scope of the present disclosure, and can be effectively applied to injectable drug delivery device of the present invention.In going back other embodiments, the present invention can use gelling preparation and other transfer devices such as liquid suspension by original position, and easily is fit to the injection transmission of medicine.All these embodiments will fall in the scope of the invention described herein.

Fig. 1 shows the equipment that is used for the coextrusion drug delivery systems.As shown in fig. 1, system 100 can comprise co-extrusion device 102, and 102 comprise first extruder 104 and second extruder 106 at least, and both are connected to die head (diehead) 108 in the mode of extruding those skilled in the art and knowing.Die head 108 has outlet 110, is extruded out from exporting 110 from the coextrusion material of extruder 104,106.Die head 108 and/or export 110 and can establish the cross sectional shape of extruding material.Suitable commercially available extruder as extruder 104,106 comprises Randcastle type RCP-0250 Microtruder (Randcastle Extrusion Systems, Cedar Grove, the New Jersey) and relevant heater, controller and related hardware.For example at United States Patent (USP) the 5th, 569, No. 429, the 5th, 518, No. 672 and the 5th, 486, exemplary extruder is also disclosed in No. 328.

Extruder 104,106 can form compositions coextrusion product 112,112 and break away from from die head 108 in outlet 110 in a known way through die head 108 extruded materials.Each extruder 104,106 can be extruded greater than a kind of material to form compositions coextrusion product 112 through die head 108.System 100 also can have above two extruders and is used to extrude, for example contiguous or drug matrices or other skins with one heart.Product 112 can comprise skin 114 and core 116.As described in more detail, skin 114 can be the device 312 of medicine impermeability pipe 112,212 (or its precursor) and/or above-mentioned ' 972 patent ', and core 116 can be the device 314 of bank 114,214 (or its precursor) and/or ' 972 patent '.

Generally speaking, coextrusion product 112 can have the size range of being applicable to be about No. 30 to about No. 12 pin, or internal diameter is about 0.0055 inch external diameter that uses to about 0.0850 inch pin.Should understand coextrusion product 112 and can apply one or more other layers, and initial size can be like this: promptly the external diameter of coating unit is corresponding to concrete pin size.Also should understand the pin size and only play the example effect, system described herein can be used for preparing the injection device that uses than the above-mentioned specific greater or lesser pin of pin.Will also be understood that the not strict injection device that refers to only use above-mentioned hypodermic needle size of term used herein " injection device ".On the contrary, but this term can comprise the device through arthroscope, conduit or other medical apparatus administrations with broad understanding.Similarly, term " injection " and " through injection " refer to comprise than through hypodermic needle mode widely, as through arthroscope, conduit or other medical apparatus administrations.In certain embodiments, device can be injected with ophthalmic or periocular injections mode near patient's eye.

In extrusion method, may command is extruded parameter such as hydraulic pressure, flow velocity and is extruded the temperature of material.Can select suitable extruder, so that can form under the pressure and flow velocity of product 112 in the die head 108 and the outlet 110 that are enough in each size, discharge the coextrusion material, die head and outlet can form the product that can be injected to the patient after cutting apart.Term used herein " patient " refers to people or inhuman animal.As described in greater detail, also can influence extrusion through the selection of extruder 104,106 extruded materials, and relate to other parameters and the whole system 100 of extrusion.

System 100 can comprise the material of extruding through extruder 104,106 and/or extrude other processing unit (plant)s that product 112 provides further processing.As an example and unrestricted, system 100 also can comprise curing station (station) 118, when product 112 is cured up to small part through these stations.These curing station 118 curable skins 114, core 116 or the two, and when extruding product 112 through curing stations 118, can operate this product continuously, or when intermittence, coordinate to use the passage of extruded material.Curing station 118 can be used heat, ultraviolet radiation or be applicable to some other energy of polymer in the cured product 112.Should understand and in skin 114 and/or core 116, to use corresponding curable polymer, as heat curing copolymer or radiation curable polymer.Generally speaking, state of cure can be controlled by the amount of control curing station 118 applied energies.

Cutting apart station 120 can provide and product 112 cut apart or cut into the shorter product 112 of series _ICut apart station 120 and can use cutting to extrude any appropriate technology of product 112, whether it can solidify according to product 112, uncured or partly solidified the variation.For example, cut apart station 120 and can adopt pincers, shearing, cutting knife or any other technology.Cutting apart the technology of using at station 120 can change according to the required structure of product 112 each cutting part.For example, when the open end need add dispersion membrane or other functional coats, cut mode may be suitable.Yet,, can use pincers when cutting when needing sealing respectively to hold.When each end or shorter product 112 _IDo not need different cutting on the same group the time, multiple cutting equipment can be provided.

Use suitable material 122,124 to have many respectively with co-extrusion device 102 to form skin 114 and core 116.In this, ' 972 patents are described the many suitable materials that form implantable drug delivery systems, and these materials more specificity are used for injectable drug delivery device.Preferred selection can through system 100 extrude and material that can negative effect material special properties as material 122,124.For example, for those to the impervious material of core 116 Chinese medicines, can select through extrusion device processing just for or still keep impermeable material.Similarly, when drug delivery systems makes up fully, can select biocompatible materials as the material that contacts with patient biological tissue.Suitable polymers as material 122,124 includes but not limited to polycaprolactone (PCL), ethylene vinyl acetate polymer (EVA), Polyethylene Glycol (PEG), polyvinyl acetate (PVA), polylactic acid (PLA), polyglycolic acid (PGA), lactic acid-ethanol copolymer (PLGA), Polyalkylcyanoacrylanano (polyalkyl cyanoacralate), polyurethane, nylon or its copolymer.In comprising the polymer of lactic acid monomer, lactic acid can be any mixture of D-, L-or D-and L-isomer.

Except that polymer, non-aqueous solvent such as PEG can be used as material 122,124 and use effectively in preparation core 116.For example, can use the nonaqueous solvent of used polymer in the dissolving core 116 effectively, it causes the phase change of core 116, or extrudes (for example, by bigger operating temperature range is provided) easily or be easy to carry out its processing of base of product 112.

Some is extruded parameter and can set or advise by the selection of material 124, and material 124 is placed in the extruder 104 to form internal drug core 116.Those skilled in the art can recognize easily that extrusion device generally comprises one or more heaters and one or more screw actuator, piston or other Pressure generators.Improve the temperature be extruded material, hydraulic pressure or both can be the purpose of extruder.When the pharmaceutical active medicine is included in the rapidoprint and when extruder 104 was extruded, this may have difficulties.Active medicine may be heated and/or be exposed under the high pressure of its effect of negative effect.When medicine itself was present in the polymeric matrix, difficulty can be solved, and therefore also polymeric material was mixed, heated and/or pressurize in extruder 104 with medicine.Can select material 124 so that when by injection, the activity of core 116 Chinese medicines of product 112 is enough to produce ideal effect.In addition, in order to form the substrate of extruding in the core 116, when with medicine and polymer mixed, the polymeric material of selecting to form substrate preferably can make substrate can not make the medicine loss of stability.Can select host material to make diffusion couple medicine almost not have influence or not have influence from the speed of substrate release through substrate.Also can select the granularity of used one or more medicines in the substrate to produce control action with stripping to medicine.

Can be chosen in the material 122,124 of the stable coextrusion product 112 of the deenergized period of drug delivery systems.Can choose wantonly and select these materials, so that after drug delivery systems was measured the release medicine in the scheduled time, drug delivery systems was corroded by original position, gets final product bioerosion.Also can select these materials to make material stable in the required life-span, can't significantly weather, and the material aperture not change at transfer device.Can choose wantonly select one of material 122,124 or both with given pace by bioerosion, this bioerosion speed may command or help to control the rate of release of any active medicine.Other material can be recognized,, their bioerosion characteristic can be selected similarly as the other coating on some or all devices.

Therefore on the one hand, this paper has described the method that is used for being chosen in the coextrusion method material therefor for preparing injectable drug delivery device.Generally speaking, for material 122,124, select the method for material to carry out according to the following steps: (1) selects one or more medicines; (2) but select an a kind of extruded material or a class material; (3) estimate this material or such material, determine whether and how material influences the speed that selected one or more medicines discharge from this material or such material; (4) estimate the stability and the physicochemical properties of this material or such material; (5) estimate the stability of medicine in the substrate of this material or such material; And (6) estimate this material or such material, determine when forming substrate with selected one or more medicines, this material or such material whether prevent that biomolecule (as protein material) from migrating in the substrate and with one or more drug interactions.Therefore, internal material has two kinds of functions at least: allow the coextrusion of core or extrude; With the erosion or the degraded that suppress or prevent the core Chinese medicine.The advantage of this system is to control the difference between medicine is released into varying environment such as histological types or various disease condition from transfer device speed.

Material 122,124 can comprise one or more medical active medicines, matrix-forming polymer, any biomaterial such as lipid (comprising long-chain fatty acid) and wax, antioxidant and (in some cases) release regulator (for example water or surfactant).These materials can be biocompatible, and keep stable in extrusion.Under processing conditions, the blend of active medicine and polymer should be extrudable.Any biomaterial of matrix-forming polymer or use can carry one or more active medicines of q.s, so that produce the treatment useful effect in the required time.The material that yet is preferably used as pharmaceutical carrier does not have adverse effect to pharmaceutically active, or does not have significant adverse effect.

The polymer that uses in skin 114 and the core 116 or add to skin 114 and/or the coating of core 116 can be considered the permeability of one or more medicines in the core 116 is selected.Permeability need be a relative term.Term used herein " permeable " refers to permeable or permeable basically to material, and unless otherwise indicated, material is generally the medicine (for example, biofluid permeates in the film environment that transmission enters to device) that device transmits.Term used herein " impermeable " refers to impermeable or impermeable basically to material, and unless otherwise indicated, material is generally the medicine (for example, biofluid is impervious in the film environment that transmission enters to device) that device transmits.Term " semi-permeable " refers to some material rather than the infiltration of other matter selectives.Can recognize that in some cases film is to permeable drug, also control drug diffusion basically or see through the speed of film.So permeable membrane also can be rate of release restriction film or rate of release controlling diaphragm, in some environment, this permeability of the membrane is one of most important characteristics of control device rate of release.Therefore, if the device part applied by permeable coating, and the device remainder applied by impermeable coating, even the expectation certain medicine can pass impermeable coating, medicine will be mainly by only partly being discharged by permeable coating coated apparatus.

Can select polymer or other biological material, so that determine the rate of release of medicine from carrier by the physicochemical properties of medicine self rather than the character of pharmaceutical carrier as active drug carrier.Also can select release regulator as active drug carrier, perhaps can add release regulator to adjust rate of release.For example, organic acid such as citric acid and tartaric acid can be used for promoting that weakly basic drugs passes through the diffusion of release medium, and adding amine such as triethanolamine can promote the diffusion of weak acidic drug.The rate of release that tool polymer acid or alkaline pH value also can be used for promoting or slowing down active medicine.For example, PLGA can provide acidic micro-environment in substrate, because it has acid ph value after hydrolysis.For hydrophobic drug, can comprise hydrophilizing agent to increase its rate of release.

In the material that forms core 116, also can use surfactant to change its character.In substrate, pass through in some way in conjunction with suitable chemical compound the electric charge of any polymeric matrix, lipophile or hydrophilic in the scalable core 116.For example, can use surfactant to improve the wettability of the bad or hydrophobic composition of dissolubility.The example of suitable surfactant comprises dextran, polysorbate and sodium lauryl sulphate.More general character and the purposes of knowing surfactant, some is passed in the core 116 of medicine application preferably they can be added to the present invention.

Discuss the machined parameters of coextrusion now in more detail.

Temperature: processing temperature (extrusion temperature) should be less than active medicine, polymer and the release regulator decomposition temperature of (if existence).Can keep this temperature so that matrix-forming polymer can hold the active medicine of q.s, thereby reach required drug loading.For example, when the drug-polymer blend when extruding for 100 ℃, PLGA can load the most nearly 55% fluocinolone acetonide (FA), reaches 65% and load when extruding for 120 ℃.Medicine-blend polymer should demonstrate good flowability under processing temperature, with the homogeneity of guaranteeing end product and reach ideal draw ratio, can control the size of end product so preferably.

Screw speed: can set the screw speed of two extruders in the coextrusion system, under this speed, with the polymer sheath 114 of scheduled volume and medicine-core 116 material coextrusion of respective amount, to reach the desired thickness of polymer sheath 114.For example: have at extruder 104 and 106 under the condition of identical screw size,, can make 10% (weight) PCL skin 114 and 90% (weight) FA/PCL drug core 116 by speed operation extruder 106 with extruder 104 speed 1/9th.Also can use different screw sizes, and suitably regulate its speed.

By with polymer dissolution in solvent, can be with medicine or other chemical compounds and polymer mixed.Merge this solution that contains medicine or other chemical compound, on demand said composition is processed so that extrudable paste to be provided.Also can adopt the fusing-granulation technique and the technology well known to those skilled in the art that comprise solvent-free fusing-granulation, medicine and polymer are added to and can extrude in the paste.

Fig. 2-5 shows the various rates of release of extruding preparation.FA all shows two-phase release mode from the speed that the FA/PCL of no coextrusion polymer sheath (for example 75/25) or FA/PLGA (for example 60/40) core substrate discharges: prominent releasing mutually (seen Fig. 2 and 3) mutually with slow release.When the FA level (loading) in the PCL substrate is reduced to 60% or 40% when (Fig. 2 and Fig. 3-5 relatively), prominent releasing mutually not clearly from 75%.Look back the data that provide among Fig. 3 and 4, show that coextrusion preparation (medicine is in the polymeric matrix with PLGA skin) reaches nearly zero level and discharges the used time much shorter of preparation that used time ratio does not have the PLGA cortex.As shown in Figures 4 and 5, the coextrusion FA/ polymer core substrate with PLGA cortex can significantly make and prominently release effect and minimize.

The drug delivery systems of cutting apart can at one end stay opening, and drug core is exposed.Can select coextrusion to form material 124 and coextrusion heat and the pressure and the curing station 118 of the drug core 116 of product 112, so that the host material of drug core suppresses or prevents that enzyme, protein and other materials from entering drug core, had an opportunity before device release at medicine, entering of these materials can dissolved substance.When core became empty, substrate can die down and break.Skin 114 can expose degraded because of the effect of outside and the inside water and enzyme then.The technology of using United States Patent (USP) to describe for the 6th, 051, No. 576 can link the conjugate with higher deliquescent medicine formation low-solubility, can further discuss below; Perhaps, medicine can be linked together and form the molecule that enough can be retained in greatly in the substrate.

The material 122 that forms skin 114 can be selected to solidify through nonthermal source.As mentioned above, some medicines can be subjected to pyritous negative effect.Therefore, this system relates in one aspect to the selection of material and extrudes, and this material can solidify by the method except that heating, includes but not limited to catalysis, radiation and evaporation.Be limited as an example and not, can use can be through the solidified material of electromagnetic wave (EM) radiation (as visible or near visible range, as ultraviolet or indigo plant (blue) wavelength), and perhaps these materials are included in the material 122.In this example, when product 112 advanced by curing station 118, curing station 118 can comprise the corresponding EM radiation source of one or more curing materials, as intense light source, tuning laser etc.As an example but be not limited, curable can be used as material 122 based on acrylic acid binding agent and use.

Other parameters can influence the rate of release of medicine from the drug core 116 of injectable drug delivery device, as the pH of core substrate.The material 124 of drug core can comprise pH buffer agent etc., regulating the pH of substrate, thereby further is adjusted in the drug release rate in the end product 112.For example, can use organic acid such as citric acid, tartaric acid and succinic acid to set up acid pH microenvironment in the substrate.The low pH value that continues can promote the aperture diffusion that weakly basic drugs produces when the medicine stripping.Under the situation of weak acidic drug, can use amine such as triethanolamine to promote release rate of drugs.Also can use polymer as pH dependent release regulator.For example, PLGA can provide acidic micro-environment in substrate, because have acid ph value after its hydrolysis.

In material 124, can comprise greater than a kind of medicine, therefore also like this in the core 116 of product 112.These medicines can have identical or different rate of release.For example, 5-fluorouracil (5-FU) is a high water soluble, is difficult to keep the controlled release of medicine.On the other hand, steroid class such as triamcinolone acetonide (TA) are the height lipotropy, and elution profiles can be provided.When the mixture of 5-FU and TA formed piller (by compression or coextrusion), this piller provided the controlled release of 5-FU effect of drugs instant to obtain, short-term in 5 days, and the controlled release of TA is provided in the longer time simultaneously.Therefore, the mixture of 5-FU and TA, and/or their common medicine (codrug) or prodrug can be extruded separately or extrude with other drug and/or component of polymer and to form core 116.

Except the embodiment that exemplifies above, those skilled in the art can understand arbitrary these devices and preparation all can adopt, and use with system described herein.Core can comprise bio-compatible liquid or the oil with bio-compatible solid (but as bioerodible polymer) combination, and active medicine.In certain embodiments, inner core can the gel transmission, and in certain other embodiments, and inner core can be worked as granule or the liquid transfer that contact water or physiological fluid are transformed into gel.The example of the type system for example, has been described in No. the 60/501st, 947, U.S. Provisional Application that JIUYUE in 2003 was submitted on the 11st.Should ' 947 application the transmission of injection liquid also is provided, inversion of phases takes place in these liquid when injection, in-situ transesterification changes into gel transmission solvent.These liquid can use with injection device described herein.

Injection in-situ gelling compositions can be used with system described herein, comprises the polymer of medical substance, biocompatible solvents (for example Polyethylene Glycol (PEG)) and bio-compatible and bioerosion.Some embodiment of said preparation may be especially suitable, as dissolving is provided, is dispersed or suspended in the embodiment of the particulate injection of solid drugs among the PEG and will contains the embodiment of polymeric medicine gel injection to the patient.The U.S. Provisional Application No.60/482 that the example of injection in-situ gelling compositions can be submitted on June 26th, 2003 finds in 677.

Term used herein " medicine " will comprise all provide part or whole body physiology or pharmacological action when giving mammal material, certain drug of mentioning in including but not limited to be described below and their analog, derivant, pharmaceutically acceptable salt, ester, prodrug, common medicine and protection form.

Many different medicines can be added in the device described herein.For example; suitable medicine comprises steroid; the α receptor stimulating agent; the beta receptor antagonist; carbonic anhydrase inhibitors; adrenergic; physiologically active peptide and/or protein; antineoplastic agent; antibiotic; analgesics; anti-inflammatory agent; muscle relaxant; antuepileptic; antiulcerative; antiallergic agent; cardiac tonic; anti-arrhythmic; vasodilator; antihypertensive; antidiabetic drug; antihyperlipidemics; anticoagulant; hemolytic agent; antitubercular agent; hormone; narcotic antagonists; the osteoclast inhibitor; skeletonization promoter (osteogenic promoters); angiogenesis inhibitor; antimicrobial drug; NSAID (non-steroidal anti-inflammatory drug) (NSAID); glucocorticoid or other antiphlogistic corticoid; alkaloid analgesics such as opium kind analgesics; antiviral agents such as ucleosides antiviral agents or non-nucleoside antiviral agents; anti-benign prostatic hyperplasia (BPH) medicine; antifungal compound; anti-proliferative compounds; the glaucoma chemical compound; immunomodulatory compounds; cell traffic/migration stops medicine; the cytokine pegylated medicament; the α receptor blocking agent; antiandrogen; anticholinergic; purine energy medicine; the dopaminergic medicine; local anesthetic; Rhizoma et radix valerianae element (vanilloids) inhibitor; nitric oxide inhibitor; anti-apoptosis medicine; macrophage activation inhibitor; antimetabolite; neuroprotective; calcium channel blocker; γ-An Jidingsuan (GABA) antagonist; the α receptor stimulating agent; tranquilizer; tyrosine kinase inhibitor; nucleoside compound and nucleotide compound, and their analog; derivant; pharmaceutically acceptable salt; ester; prodrug; be total to medicine and protection form.

Suitable NSAID comprises diclofenac, etoldolac, fenoprofen, floctafenine, flurbiprofen, ibuprofen, indoprofen, ketoprofen, ketorolac, lornoxicam, morazone, naproxen, perisoxal, pirprofen, pranoprofen, suprofen, suxibuzone, tropesin, ximoprofen, Zaltoprofen, zileuton and zomepirac, and their analog, derivant, pharmaceutically acceptable salt, ester, prodrug, common medicine and protection form.

Suitable carbonic anhydrase inhibitors comprises brinzolamide, acetazolamide, methazolamide, diclofenamide (dichlorphenamide), ethoxzolamide and dorzolamide, and their analog, derivant, pharmaceutically acceptable salt, ester, prodrug, common medicine and protection form.

Suitable adrenergic comprises brimonidine, apraclonidine, bunazosin, levobetaxolol, levobunalol, carteolol, isoproterenol, fenoterol, metipranolol and clenbuterol, and their analog, derivant, pharmaceutically acceptable salt, ester, prodrug, common medicine and protection form.

Suitable α receptor stimulating agent comprises brimonidine and analog, derivant, pharmaceutically acceptable salt, ester, prodrug, is total to medicine and protection form.

Suitable beta receptor antagonist comprises betaxolol and timolol, and their analog, derivant, pharmaceutically acceptable salt, ester, prodrug, common medicine and protection form.

Suitable antiviral agents comprises nevirapine (neviripine) and analog, derivant, pharmaceutically acceptable salt, ester, prodrug, is total to medicine and protection form.

Suitable alkaloid analgesic comprises desmorphine; dezocine; paramorphan (dihydromorphine); eptazocine; ethylmorphine; glafenine; hydromorphone; isoladol; ketobemidone (ketobenidone); p-lactophetide; levorphanol; moptazinol; metazosin; metopon; morphine; nalbuphine; nalmefene; nalorphine; naloxone; norlevorphanol; normorphine; oxmorphone; pentazocine; phenperidine; fenyramidol (phenylramidol); tramadol and viminol, and their analog; the antiperspirant biology; pharmaceutically acceptable salt; ester; prodrug; be total to medicine and protection form.

Suitable glucocorticoid comprises the 21-prebediolone acetate; alclometasone; algestone; NSC 24345 (anaortave); amcinonide; beclometasone; betamethasone; budesonide; chloroprednisone; clobetasol; clobetasone butyrate; clocortolone; cloprednol; corticosterone; cortisone; cortivazol; the ground fluorine can be special; ground Suo Naide; desoximetasone; diflorasone; diflucortolone; difuprednate; enoxolone; Fluazacort; flucloronide; two dexamethasone; flunisolide; fluocinolone acetonide; fluocinonide; flucloronide; two dexamethasone; flunisolide; fluocortin butyl; fluocortolone; fluorometholone; fluperolone acetate; fluprednisolone; flurandrenolide; FLUTICASONE PROPIONATE; hydrocortamate; hydrocortisone; meprednisone; methylprednisolone; paramethasone; prednisolone; prednisolone 21-diethyl amino yl acetate; fluprednidene acetate; formocortal; loteprednol etabonate; medrysone; mometasone furoate; prednicarbate; prednisolone; prednisolone 25-diethyl amino yl acetate; Inflamase; prednisone; prednival; prednylidene; triamcinolone; triamcinolone acetonide; triamcinolone benetonide and triamcinolone hexacetonide, and their analog; derivant; pharmaceutically acceptable salt; ester; prodrug; be total to medicine and protection form.

Other suitable steroid comprises halcinonide, propanoic acid ulobetasol (halbetasolpropionate), halometasone, halopredone acetate, isoflupredone acetate, loteprednol etabonate, mazipredone, rimexolone and tixocortol, and their analog, derivant, pharmaceutically acceptable salt, ester, prodrug, common medicine and protection form.

Suitable BPH medicated bag is drawn together Finasteride and osaterone, and their analog, derivant, pharmaceutically acceptable salt, ester, prodrug, common medicine and protection form.

Suitable antitumoral compounds comprises alitretinoin (9-cis-retinoic acid); Bleomycin comprises bleomycin A; Capecitabine (5 '-deoxidation-5-fluoro-cytidine); Carubicin; Chlorozotocin, chromomycin comprise chromomycin A ₃, cladribine; Colchicine, cytosine arabinoside; Daunorubicin; Demecolcine, 9,10-dimethylpteroylglutamic acid, docetaxel, doxyifluridine, doxorubicin; Drostanolone, she beats Qu Sha, enocitabine, epirubicin, epitiostanol, estramustine; Etoposide; Floxuridine, fludarabine, 5-fluorouracil, Formestane, gemcitabine; Irinotecan; Lentinan, lonidamine, melengestrol, melphalan; Menogaril, methotrexate; Mitolactol; Nogalamycin; Nordihydroguaiaretic acid, Olivomycin such as Olivomycin A, paclitaxel; Spray Si Tating; Pirarubicin, plicamycin, porfiromycin, prednimustine, puromycin; Ranimustine, ristomycin are as ristomycin A; The temozolomide; Teniposide; Raltitrexed; Topotecan; Tuberculin, ubenimax, valrubicin (N-TFA base amycin-14-valerate), vinorelbine, vinblastine, vindesine, vinorelbine and zorubicin, and their analog, derivant, pharmaceutically acceptable salt, ester, prodrug, common medicine and protection form.

Suitable antimicrobial compound comprises capreomycin, comprises Capreomycin I A, Capreomycin I B, Capreomycin II A and Capreomycin II B; Carbomycin comprises carbomycin A; Carumonam; Cefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone, cefazolin sodium, cefbuperazone, Method of cefcapene pivoxil, cefclidin, cefdinir, cefditoren, cefixime (cefime), cefetamet (ceftamet), cefmenoxime, cefmetzole, cefminox, Cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotetan, cefotiam, cefoxitin, cefpimizole, cefpiramide, cefpirome, cefprozil, cefroxadine, cefsulodin, ceftazidime, cefteram, ceftezole, ceftibuten, ceftiofur, ceftizoxime, ceftriaxone, cefuroxime, cefuzonam, cefalexin, cefaloglycin, cefaloridine, cephalosporin, cefalotin, cefapirin, cephamycin such as cephamycin C, cefradine, chlortetracycline; Clarithromycin; clindamycin; clometocillin; clomocycline; cloxacillin; the ciclacillin; the Dan Nuosha star; demeclocycline; Destomycin A; dicloxacillin; dicloxacillin; dirithromycin; doxycycline; epicillin; Erythromycin A; ethambutol (ethanbutol); fenbenicillin; 6315-S; florfenicol; flucloxacillin; flumequine; fortimicin A; fortimicin B; forfomycin; foraltadone; fusidinic acid; gentamycin; glyconiazid; guamecycline; the hetacillin; idarubicin; Primaxin; isepamicin; josamycin; kanamycin; eumycin (leumycin) is as eumycin A1; lincomycin; lomefloxacin; Loracarbef; lymecycline; Meropenem (meropenam); the metampicillin; metacycline; the methicillin; the mezlocillin; micronaomicin; midecamycin such as midecamycin a1; mikamycin; minocycline; mitomycin such as ametycin; latamoxef; mupirocin; nafcillin; netilmicin; norcardian such as norcardian A; oleandomycin; oxytetracycline; panipenem (panipenam); Pazufloxacin; penamecillin; penicillin such as benzylpenicillin; penicillin N and penicillin; penillic acid; amyl penicillin (pentylpenicillin); peplomycin; the phenethicillin; pipacycline; piperacillin; pirlimycin; pivampicillin; pivcefalexin; porfiromycin; propiallin; quinacillin; the core Saccharocin; rifabutin; rifamide; rifampicin; Rifamycin Sodium; rifapentine; rifaximin; ritipenem acoxil; rekitamycin; Rolitetracycline; rosamicin; Roxithromycin; Sancycline; sisomicin; Sparfloxacin; spectinomycin; chain urea star; the sulbenicillin; sultamicillin; talampicillin; teicoplanin; temocillin; tetracycline; thostrepton; taimulin; ticarcillin; tigemonam; tilmicosin; tobramycin; tropospectromycin; trovafloxacin; tylosin and vancomycin, and their analog; derivant; pharmaceutically acceptable salt; ester; prodrug; be total to medicine and protection form.

Antiproliferative/antimitotic drug and prodrug comprise natural product such as vinca alkaloids (for example vinblastine, vincristine and vinorelbine), paclitaxel, epipodophyllotoxin (for example etoposide, teniposide), antibiotic (for example D actinomycin D, daunorubicin, doxorubicin and idarubicin), anthracycline (anthracyclines), mitoxantrone, bleomycin, plicamycin (mithramycin) and mitomycin, enzyme (for example altheine enzyme); The antiplatelet prodrug; Antiproliferative/resisting mitosis alkylation prodrug such as chlormethine (chlormethine, cyclophosphamide and analog, melphalan, chlorambucil), second diimine and methylmelamine (altretamine and thiophene are for group), alkyl sulfonate esters-busulfan, nitroso ureas (carmustine (BCNU) and analog, chain urea assistant star), triazenes, dacarbazine (DTIC); Antiproliferative/antimitotic antimetabolite such as folacin (methotrexate), pyrimidine analogue (fluorouracil, floxuridine and cytosine arabinoside), purine analogue and relevant inhibitor (mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine (cladribine); Platinum coordination complex (cisplatin, carboplatin), methylbenzyl hydrazine, hydroxyurea, mitotane, aminoglutethimide; Hormone (for example estrogen, progestogen); Anticoagulant (for example heparin, synthetic heparinate and other thrombin inhibitor); Fibrinolysis prodrug such as tissue plasmin activator, streptokinase and urokinase, aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab; Anti-migration medicine; Antisecretory drug (breveldin); Anti-inflammatory agent such as corticosteroid (hydrocortisone, cortisone, fludrocortisone, fluocinolone acetonide, prednisone, prednisolone, methylprednisolone, omcilon, betamethasone and dexamethasone), NSAIDS (salicylic acid and derivant, aspirin, acetaminophen, indole and indeneacetic acid (indomethacin, sulindac and etodolac), heteroaryl acetic acid (tolmetin, diclofenac and ketorolac), arylpropionic acid (for example ibuprofen and derivant), amino benzoic Acid (mefenamic acid and meclofenamic acid), bmap acid (piroxicam, tenoxicam, Phenylbutazone and oxyphenthatrazone), nabumetone, gold compound (auranofin, aurothioglucose, sodium aurothiomalate); Immunosuppressant (for example ciclosporin, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine and mycophenolate mofetil); Angiogenesis medicine such as VEGF (VEGF), fibroblast growth factor (FGF); Angiotensin receptor blocker; Nitric oxide donors; Antisense oligonucleotide and combination thereof; Cell cycle inhibitor, mTOR inhibitor, growth factor signal conversion inhibitors of kinases, neovascularization inhibitor, angiogenesis inhibitor and inhibitors of apoptosis, and their analog, derivant, pharmaceutically acceptable salt, ester, prodrug, common medicine and protection form.

System described herein can be effective to the administration of antiviral drugs.Therefore, on the one hand, this paper openly treats or reduces the method for retrovirus or slow virus infection danger, and this method comprises that the patient infusion to the needs treatment contains the sustained release drug delivery systems of antiviral agents, and the dosage of wherein said medicine discharges at least 7 days.This system provides treatment on the other hand or reduces the method for retrovirus or slow virus infection danger, this method comprises that the patient infusion to the needs treatment contains the sustained release drug delivery systems of antiviral agents, and being released in of wherein said medicine kept required described drug level at least 7 days in the blood plasma.

In certain embodiments, system reduces viral infection transmission danger between mother child.The example of viral infection comprises HIV, bowenoid papulosis (bowenoid papulosis), chickenpox, child HIV disease, people's cowpox, C type hepatitis, dengue fever, enterovirus, epidermodysplasia verruciformis, infectious erythema (erythema infectiosum), Buschke-Lowenstein epimegetic condyloma acuminatum; Hands, foot, stomatosis; Herpes simplex, 6 type herpesviruss, herpes zoster, varicelliform eruption, measles, milker, molluscum contagiosum, monkeypox, sheep pox, roseola infantum, rubella, variola, viral hemorrhagic fever, genital wart and non-genital wart.

In some embodiments, antiviral agents is selected from azidouridine, anasmycin, amantadine, bromo vinyl BrdU (bromovinyldeoxusidine), chlorovinyl BrdU (chlorovinyldeoxusidine), cytosine arabinoside, didanosine, deoxynojirimycin, zalcitabine (dideoxycitidine), didanosine, di-deoxynucleoside, desciclovir, deoxidation acyclovir (deoxyacyclovir), edoxudine, enviroxime, fiacitabine, foscamet, fialuridine, fluorothymidine, floxuridine, hypericin, interferon, interleukin, isethionate, nevirapine, pentamidine, ribavirin, rimantadine, stavudine, Sargramostim (sargramostin), suramin, trichosanthin, the tribromo thymidine, the trichlorine thymidine, vidarabine, zidoviridine, zalcitabine and 3-azido-3-deoxyribosylthymine.In certain embodiments, antiviral agents is selected from nevirapine, dilazep Wei Ding and efavirenz.In preferred embodiments, antiviral agents is a nevirapine.

In other embodiments, antiviral agents is selected from 2 ', 3 '-DIDEOXYADENOSINE (ddA), 2 ', 3 '-dideoxy guanosine (ddG), 2 ', 3 '-zalcitabine (ddC), 2 ', 3 '-Didansine (ddT), 2 ', 3 '-dideoxy-Didansine (d4T), 2 '-deoxidation-3 '-sulfo--cytosine (3TC or lamivudine), 2 ', 3 '-dideoxy-2 '-the fluorine adenosine, 2 ', 3 '-dideoxy-2 '-the fluorine inosine, 2 ', 3 '-dideoxy-2 '-fluorothymidine, 2 ', 3 '-dideoxy-2 '-flucytosine, 2 ', 3 '-dideoxy-2 ', 3 '-two dehydrogenations-2 '-fluorothymidine (Fd4T), 2 ', 3 '-dideoxy-2 '-β-fluorine adenosine (F-ddA), 2 ', 3 '-dideoxy-2 '-β-fluoro-inosine (F-ddI) and 2 ', 3 '-dideoxy-2 '-β-flucytosine (F-ddC).

In some embodiments, antiviral agents be selected from mono phosphoric acid ester formic acid trisodium, ganciclovir, trifluorothymidine, acyclovir, 3 '-azido-3 '-thymidine (AZT), didanosine (ddI), idoxuridine.

Exemplary antiviral agents comprises and is selected from following chemical compound: acyclovir, azidouridine, anasmycin, amantadine, the bromo vinyl BrdU, the chlorovinyl BrdU, cytosine arabinoside, didanosine, deoxynojirimycin, zalcitabine, didanosine, di-deoxynucleoside, desciclovir, the deoxidation acyclovir, edoxudine, enviroxime, fiacitabine, foscamet, fialuridine, fluorothymidine, floxuridine, ganciclovir, hypericin, interferon, interleukin, isethionate, idoxuridine, nevirapine, pentamidine, ribavirin, rimantadine, stavudine, Sargramostim, suramin, trichosanthin, trifluorothymidine, the tribromo thymidine, the trichlorine thymidine, mono phosphoric acid ester formic acid trisodium, vidarabine, zidoviridine, zalcitabine and 3-azido-3-deoxyribosylthymine.

In certain embodiments, antiviral agents is for suppressing or reduce the medicine of HIV infection or HIV susceptible tendency.Preferred non-nucleoside is thing seemingly, and comprises some chemical compounds such as nevirapine, dilazep Wei Ding and the efavirenz that exemplifies.Yet, although nucleoside derivates is less preferred, but also can use, comprise chemical compound as 3 '-azido-3 '-thymidine (AZT), didanosine (ddI), 2 ', 3 '-DIDEOXYADENOSINE (ddA), 2 ', 3 '-dideoxy guanosine (ddG), 2 ', 3 '-zalcitabine (ddC), 2 ', 3 '-Didansine (ddT), 2 ', 3 '-dideoxy-Didansine (d4T) and 2 '-deoxidation-3 '-thia-cytosine (3TC or lamivudine).Also can use the halogenation nucleoside derivates, for example comprise 2 ', 3 '-dideoxy-2 '-the fluorine nucleoside as 2 ', 3 '-dideoxy-2 '-fluorine adenosine, 2 ', 3 '-dideoxy-2 '-fluorine inosine, 2 ', 3 '-dideoxy-2 '-fluorothymidine, 2 ', 3 '-dideoxy-2 '-flucytosine; With 2 ', 3 '-dideoxy-2 ', 3 '-two dehydrogenation-2 ＇-fluorine nucleoside, include but not limited to 2 ', 3 '-dideoxy-2 ', 3 '-two dehydrogenations-2 '-fluorothymidine (Fd4T), 2 ', 3 '-dideoxy-2 '-β-fluorine adenosine (F-ddA), 2 ', 3 '-dideoxy-2 '-β-fluoro-inosine (F-ddI) and 2 ' 3 '-dideoxy-2 '-β-flucytosine (F-ddC).

In practice of the present invention, can use any pharmaceutically acceptable form of this compounds, just its free alkali or pharmaceutically acceptable salt or ester.For example, pharmaceutically acceptable salt comprises sulfate, lactate, acetate, stearate, hydrochlorate, tartrate, maleate etc.

Phrase used herein " pharmaceutically acceptable carrier " refers to pharmaceutically acceptable material, compositions or medium, as liquid or solid filler, diluent, excipient or envelope capsule material, relate to an organ or a part of another organ or part of carrying or being transported to health of theme antagonist from health.Each carrier is necessary for " acceptable ", implication for other composition of preparation be compatible, and patient harm not.Some example that can be used as the material of pharmaceutically acceptable carrier comprises: (1) sugar, as lactose, dextrose plus saccharose; (2) starch is as corn starch and potato starch; (3) cellulose and derivant thereof are as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdery tragacanth; (5) Fructus Hordei Germinatus; (6) gelatin; (7) Pulvis Talci; (8) excipient is as cupu oil and suppository wax; (9) oil is as Oleum Arachidis hypogaeae semen, cottonseed oil, safflower oil, Oleum sesami, olive oil, Semen Maydis oil and soybean oil; (10) glycol is as propylene glycol; (11) polyhydric alcohol is as glycerol, sorbitol, mannitol and Polyethylene Glycol; (12) ester is as ethyl oleate and ethyl laurate; (13) agar; (14) buffer agent is as magnesium hydroxide and aluminium hydroxide; (15) alginic acid; (16) the nontoxic compatible material of other that uses in the pharmaceutical preparation.

Can use common medicine or prodrug to discharge medicine with continuous fashion.In certain embodiments, can adopt common medicine or prodrug to be used for the core 116 or the skin 114 of aforementioned drug delivery systems.Example of slow-released system uses can be at United States Patent (USP) the 6th, 051, the common medicine and the prodrug that find in No. 576.This list of references by reference and integral body is attached to herein.In other embodiments, medicine or prodrug can be included in gelling, suspension and other embodiment described herein altogether.

Term used herein " medicine altogether " refers to that the first ingredient chemistry is connected at least a other ingredient identical or different with first ingredient.Each ingredient is reformulated to its pharmaceutically active form or its common medicine, puts together then.Each ingredient can link together through reversible covalent bonds such as ester, amide, carbamate, carbonic ester, ring ketal, thioester, thioamides, thiocarbamate, sulfocarbonate, xanthate and phosphate ester ester bond, thereby they in vivo must the position dissociate and produce the activity form of each medical compounds again.

Term used herein " ingredient " refers to that one of two or more pharmaceutically active parts connect to form medicine altogether of the present invention described herein.In some embodiments of the present invention, the combination of bimolecular same composition part forms dimer (this dimer can have or not have symmetrical plane).In mentioning free, the non-context of puting together form part, term " ingredient " refer to it combine with the other medicines active part form altogether medicine before, or drug hydrolysis is removed and is connected pharmaceutically active part afterwards between two or more ingredients altogether.In such situation, before puting together, each ingredient and its pharmaceutically active form or its common medicine are chemically identical.

Term " prodrug " will be included in the chemical compound that changes into therapeutic activity agent of the present invention under the physiological condition.The commonsense method of preparation prodrug will comprise the part such as the ester of selection, under physiological condition the prodrug hydrolysis will be converted into biologically-active moiety.In other embodiments, prodrug transforms through the enzymatic activity of host animal.Prodrug is generally formed by the chemical modification of biologically-active moiety.For example at Design of Prodrugs, H.Bundgaard edits, and Elsevier has described the conventional method of selecting and prepare suitable prodrug derivant in 1985.

In the context that relates to medicine altogether of the present invention, term " residue of ingredient " refers to be derived from the structure the common drug moiety away from the ingredient of functional group, is connected to another ingredient by this part of this functional group.For example, wherein functional group is-NH ₂, form amide (NH-CO-) key, then the residue of this ingredient be to comprise amide groups-NH-but the part that do not comprise the ingredient of hydrogen (H) (this hydrogen loses) when the formation amido link and form group and another ingredient.On this meaning, the implication of amino acid whose residue employed " residue " is similar in term used herein " residue " and the peptide mentioned in peptide and protein chemistry.

Altogether medicine can directly or through linking group be linked together and forms with covalent bond by two or more ingredients.Covalent bond between residue comprises following keyed jointing structure:

Wherein Z be O, N ,-CH ₂-,-CH ₂-O-or-CH ₂-S-, Y are O or N, and X is O or S.The dissociation rate of each ingredient can be by the selection of the type of key, ingredient and/or the physical form control of medicine altogether.The unstability of selected key type can be enzyme spcificity.In some embodiments, the key selectivity is unstable in the presence of esterase.In other embodiment of the present invention, key is a chemically unstable, for example by acid or alkali catalyzed hydrolysis.In some embodiments, linking group does not comprise sugar, reducing sugar, pyrophosphate or phosphate-based.

The unstable linking group of physiology can be unsettled any linking group under the condition that occurs in being similar to physiological fluid.Linking group can be straight key (for example ester, amide, carbamate, carbonic ester, ring ketal, thioester, thioamides, thiocarbamate, sulfocarbonate, xanthate, phosphate ester, sulphonic acid ester or sulfamic acid ester bond) or can be linking group (C for example ₁-C ₁₂Glycol, C ₁-C ₁₂Hydroxyl alkane acid, C ₁-C ₁₂Hydroxy alkyl amine, C ₁-C ₁₂Diacid, C ₁-C ₁₂Aminoacid or C ₁-C ₁₂Diamidogen).Especially preferred linking group is direct amide, ester, carbonic ester, carbamate and sulfamate linking group and through succinic acid, salicylic acid, diglycolic acid, oxyacid, oxygen methylene (oxamethylene) and halid linking group thereof.These linking groups are unstable under physiological condition, and physiological condition refers generally to pH about 6 to about 8.Whether the unstability of these linking groups depends on the accurate pH and the ionic strength of particular type, physiological fluid of linking group and the existence that trends towards the enzyme of catalytic hydrolysis reaction in the body.Generally speaking, unstability is measured with respect to the stability of this linking group when common medicine also is not dissolved in the physiological fluid in the body of linking group.Therefore, although some common medicines can be metastable in some physiological fluids, but, with respect to them for pure or be dissolved in the non-physiological fluid (for example nonaqueous solvent such as acetone), they are (or external, no matter be in mimic physiological fluid when being dissolved in that natural birth survives) relatively easy hydrolysis in vivo.Therefore, unsettled linking group reacts the linking group that the formation hydrolyzate comprises the ingredient that proposes previously for when being total to medicine dissolution in aqueous solution.

The common medicine that is used for preparing the drug delivery systems that uses with system described herein can be synthetic with the method for one of following synthesis flow explanation.Generally speaking, first kind and second kind of ingredient are connected directly, and first and second portion are being fit to be formed on condensation under the condition of labile bond under the physiological condition.In some situation, need be at some reactive groups of sealing on, another or two parts.Wherein each ingredient carry out through linking group such as oxygen methylene, succinic acid or diglycolic acid covalently bound, preferably at first condensation first ingredient and linking group.In some cases, be preferably in appropriate catalyst as comprising that (DDC: carbodiimide dicyclohexylcarbodiimide) exists down for EDCI (1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide) and DDC, or, in suitable solvent such as acetonitrile, react being applicable under the condition of removing water that condensation produces or other product (as refluxing or molecular sieve) or its two or more combinations.After first ingredient and linking group condensation, bonded first ingredient and linking group then can with the second ingredient condensation.In addition, in some cases, being preferably in appropriate catalyst exists down as the carbodiimide that comprises EDCI and DDC, or, in suitable solvent such as acetonitrile, react being applicable under the condition of removing water that condensation produces or other product (as refluxing or molecular sieve) or its two or more combinations.Wherein one or more active groups are closed, and preferably can remove blocking groups under the condition of selecting, but also preferably can remove the active group of deblocking in blocking groups hydrolyzate and this blocking groups are situation favourable on the physiology.

One skilled in the art will recognize that, be suitable linking group although describe diacid, glycol, aminoacid etc., expects that other linking group also within the scope of the present invention.For example, although the hydrolyzate of altogether medicine described herein can comprise diacid, the real reaction thing that is used to prepare linking group can be for example carboxylic acid halides such as succinyl dichloride..One skilled in the art will recognize that, also can use other possibility acid, alcohol, amino, sulfate group and sulfamoyl derivant to prepare corresponding linking group as reactant.

When first and second ingredient when covalent bond directly connects, carry out identical process basically, difference is not need to add in this case the step of linking group.First and second ingredient only is being applicable to combination under the condition that forms covalent bond.In some situation, may need to seal one, some active groups of another or two ingredients.In some situation, may need to use suitable solvent, as acetonitrile; Be applicable to the catalyst that forms straight key,, comprise EDCI and DCC as carbodiimide; Or be used to remove the water of condensation (as refluxing) or the condition of other byproduct of reaction.

Though in some situation, first and second ingredient can their primitive form directly connect, for active group, possible derivatization is to strengthen their reactivity.For example, when first is alcohol (free hydroxyl group is just arranged) for sour and second portion, but first's derivatization forms corresponding carboxylic acid halides, as acyl chlorides or acylbromide.One skilled in the art will realize that for by using conventional derivatization feedstock production medicine altogether described herein medicine altogether described herein increases productive rate, reduce production costs, improve purity etc. exists other probabilities.

First and second ingredients of common medicine can be any medicine, comprise any medicine of listing above, and their analog, derivant, pharmaceutically acceptable salt, ester, prodrug, common medicine and protection form.In certain embodiments, first and second ingredients are different medicines; In other embodiments, they are identical.

In some common medicine embodiment, first ingredient is NSAID.In some embodiment, second ingredient is a corticosteroid.In certain embodiments, first ingredient is 5-FU and second ingredient is TA.In certain embodiments, first ingredient is beta-lactam antibiotic such as amoxicillin, and second ingredient is beta lactamase restrainer such as Clavulanate (ester).

Following flow process 1-4 has illustrated according to exemplary reaction process of the present invention.These reaction process generally can directly or through pharmaceutically acceptable linking group replace the therapeutic agent that other has at least one functional group indirectly, and described functional group can have the therapeutic agent of similar or different functional groups to form covalent bond to another.Those skilled in the art will appreciate that also these reaction process generally can use other suitable linking group.

Flow process 1

R ₁-COOH+R ₂-OH→R ₁-COO-R ₂＝R ₁-L-R ₂

Wherein L is ester linking group-COO-, R ₁And R ₂Be respectively the residue of first and second ingredients or pharmacology part.

Flow process 2

R ₁-COOH+R ₂-NH ₂→R ₁-CONH-R ₂＝R ₁-L-R ₂

Wherein L is amide linking group-CONH-, R ₁And R ₂Have and top identical implication.

Flow process 3

Step 1:R ₁-COOH+HO-L-CO-Prot → R ₁-COO-L-CO-Prot

Wherein Prot is suitable reversible blocking group.

Step 2:R ₁-COO-L-CO-Prot → R ₁-COO-L-COOH

Step 3:R ₁-COO-L-COOH+R ₂-OH → R ₁-COO-L-COOR ₂

R wherein ₁, L and R ₂Have and top identical implication.

Flow process 4

R wherein ₁And R ₂Have and top identical implication, G is straight key, C ₁-C ₄Alkylidene, C ₂-C ₄Alkenylene, C ₂-C ₄Alkynylene or 1, the 2-condensed ring, and G forms cyclic anhydride with the acid anhydride base.Suitable acid anhydride comprises succinic anhydrides, glutaric anhydride, maleic anhydride, anhydride diethylene glycol and phthalic anhydride.

As mentioned above, medicine can be included in the material 122, and thereby is bonded to and extrudes product section 112 _ISkin 114 in.Can provide the biphase release of initial burst like this, thereby when this system placed in the body first, the major part of total drug release discharged from skin 114.Subsequently, more the multiple medicines thing discharges from core 116.One or more medicines that are included in the skin 114 can be identical with the medicine in the core 116.Perhaps, the medicine that is included in the skin 114 can be different with one or more medicines that core 116 comprises.For example, core 116 can comprise 5-FU, and skin 114 can comprise TA or loteprednol etabonate.

Described in top some example, can recognize that multiple material can be used for skin 114, to obtain different release rate profile.For example, discuss in aforementioned ' 972 patents, outer (as skin 114) can be centered on by other layer, and layer in addition is infiltration, semi-permeable or impervious (in ' 972 patents, element number is 110,210 and 310), or itself is formed by permeable or semipermeable materials.Therefore, the co-extrusion device technology and the material that can use ' fully describe in 972 patents provides with one or more layers.For example, three kinds of materials can the co-extrusion device of disposable coextrusion in, these other layers can provide the 3rd, coextrusion material with one heart.By these permeabilitys or semipermeable materials, active medicine can various control speed discharge in the core.In addition under some environment, even think that impervious material can allow core 116 Chinese medicines or other activating agent to discharge.Therefore, the permeability of skin 114 can help activating agent rate of release in time, and can be used as and control in time the parameter of rate of release and be used for launching (deploy) device.

In addition, the continuous block of coextrusion product 112 may be partitioned into the device 112 that for example centers on the impermeable skin 114 of core 116 _I, every section also applies semi-permeable layer or permeable formation with the rate of release of control through its exposed ends.Similarly, skin 114 its one or more layers or around the layer of device can given rate by bioerosion so that core material is along some or whole length of pipe, or its one or both ends exposed after a certain period.

Therefore can recognize,, can use the rate of release of different control of material expanding units, to obtain different release rate profile for skin 114 with around other one or more layers of co-extrusion device.

Product 112 extrude and more especially coextrusion allow very accurate product dimensional tolerance (tolerances).The key factor of having found to influence the speed that medicine discharges from the device that product 112 forms is the internal diameter of skin 114, and it relates to the total surface area that (initial at least) can be used for drug diffusion.Therefore, by keeping the close tolerance of skin 114 internal diameters, can reduce the rate variation that discharges from the drug core of each batch device.The external diameter of transfer device also can be controlled by changing machined parameters such as transporting velocity and die diameter.

Embodiment

By two little extruders of Randcastle, with one heart the co-extrusion outlet formed of coextrusion die head and conveyer can be used for preparing the injection transfer device of FA.The micronised powder of FA can be made granule with following matrix-forming material: medicine carrying level 40% or 60% PCL or polyvinyl acetate (PVAC).The gained mixture can with or do not have PLGA or EVA coextrusion as outer coating, form the tubular product of compositions.Can use pH 7.4 phosphate buffers to carry out release in vitro research, to estimate the feature that FA never discharges with transfer device.

By mixing the FA granule that 100g FA powder and 375g and 167g 40%PCL formulations prepared from solutions are used to form drug core, to prepare 40% and 60% drug load formulations respectively.After 2 hours, can or use cryogenic mill to grind to form 20 order sizes in 55 ℃ of oven dryings with granule craft.Gained drug/polymer mixture can be used as material 124 and uses, and available two little extruders of RandcastleRCP-0250 type, with the PLGA coextrusion as material 122, forms the tubular product 112 of compositions coextrusion.

Shown in Fig. 2-5, the preparation of Miao Shuing can provide the long-term slow release of FA in the above-described embodiments.From these figure as can be seen, FA is faster when the release ratio of the PCL substrate of no polymeric outer layer coating has the PLGA skin.Demonstrate biphase release mode: the prominent slow release phase then of releasing mutually.On the other hand, have the preparation of PLGA coating to give FA linear release, no matter levels of drugs, the persistent period is at least 5 months.The PLGA coating obviously can will be dashed forward and be released effect and obviously minimize.It is proportional also to can be observed in the rate of release of FA and the substrate medicine carrying level.Than PLGA, EVA has delayed the release of FA greatly.Can recognize the difference except rate of release, different polymer also can have the different physical characteristics of extruding.

In the coextrusion injectable drug delivery device, the release of medicine such as steroid can weaken by the various combination that uses internal matrix moulding material and outer polymer material.This just makes these devices be applicable to wherein needs the various application of medicine (comprising steroid) controlled release and slow release.As described below, also can use simply and extrude, just extruding of homogenous material or mixture extruded skin, then this skin solidified, and fills the drug core mixture with non-extrusion method.

Fig. 6 shows the equipment of extruding the drug delivery systems skin.As shown in the figure, system 600 can comprise extrusion device 602, and it has extruder 604, is connected with die head 608 to extrude the method that those skilled in the art know.Die head 608 can have outlet 610, is squeezed out from this outlet from the raw material of extruder 604.Die head 608 and/or export 610 and can establish the cross sectional shape that is extruded material.The commercially available extruder that can be used as extruder 604 comprises the little extruder of Randcastle RCP-0250 type (Randcastle Extrusion Systems, Cedar Grove, New Jersey), and relevant heater, controller etc.For example, United States Patent (USP) the 5th, 569 also discloses exemplary extruder in 429,5,518,672 and 5,486,328.Generally speaking, system 600 can be above system in conjunction with Fig. 1 description, and difference is not have central cores and skin 614 coextrusion, stays hollow area 622.

Curing station 618 also can be provided and cut apart station 620, and can describe in conjunction with Fig. 1 as above.Can recognize that can there be the tendency of subsiding under the gravity central area 622.In one embodiment, extruded material 612 can vertically be extruded, so that it can be cured and/or cut apart, and causes taking place 622 adhesions of undesirable central area and closure because of gravity subsides skin 614 walls.Extruded material 612 can 620 be divided into many sections 612 cutting apart the station _I, it can form the skin of sustained release drug delivery device.

Can recognize and to use other technology to form pipe or bar (straw) in advance, be used to prepare injectable drug delivery device described herein.A kind of technology of success use is dipped in uncured polyimides or other suitable polymers for tinsel such as nitinol with suitable external diameter.Curable then this polyimides.Tinsel can be extracted out from polyimides then, so that polymer pipe to be provided, this pipe can be injected or insert to required pharmaceutical preparation.This technology has been used for for example constructing the device that following Figure 10 describes.

Similarly, the injection device can use the core of pre-formation medicine or drug matrices material to make up.Can be by extruding, compress or other method forming core, be coated with the material membrane of suitable character then through spraying or other method.No matter be with the core of section preparation or with the core of the continuous length material of cutting into chunks, can be in uncured polymer or other suitable material dip coating, in the time of suitably, curable to form the drug delivery systems of suitable dimension.

Form howsoever, according to the type and the required release rate profile of device of core, polymeric outer layer can be infiltration, non-infiltration or part infiltration.Skin also can comprise one or more apertures, and the approach of going out of activating agent in the route of entry of biofluid or water and the core is provided.But skin is bioerosion or abiotic erosion also.But the skin of bioerosion can speed faster than the erosion rate of core or slow (or identical) corrode, but this core bioerosion itself or abiotic erosion.Be used for outer field suitable material and comprise any biocompatible polymer, include but not limited to PCL, EVA, PEG, PVA, PLA, PGA, PLGA, polyimides, Polyalkylcyanoacrylanano, polyurethane, nylon or their copolymer.In comprising the polymer of lactic acid monomer, lactic acid can be any mixture of D-, L-or D-and L-isomer.All these skins can be suitable for any injection device described herein.

In certain embodiments, use for example above-mentioned extruding or compress technique, core can form the drug matrices of one or more release rate of drugs in the independent control core.In these embodiments, polymeric outer layer can be omitted fully, or core can be coated with the layer that influences other character of injection device, comprises lubricant or binding agent.

Fig. 7 is the method flow diagram of preparation injectable drug delivery device.This method 700 can be by using extruder extruder as above described in conjunction with Figure 6, extruded polymer skin 704 and beginning.Can use any suitable polymers, but comprise the polymer of bioerosion or required infiltrative polymer is arranged, as to being transmitted impermeable, the semi-permeable or infiltration of the medicine biofluid that maybe this device placed.Can be according to biotic environment, selective etching and the permeability of the required medicine (and dissolubility) of above-mentioned extensive discussions, required rate of release and expectation.A kind ofly be applicable to that ophthalmic and the polymer of using near the eyes are polyimides.

As shown in step 706, bulk is extruded each section that micromicro is divided into hollow area continuously.For example, can use the above stations of cutting apart to cut apart in conjunction with Fig. 1 and 6 descriptions.

Shown in step 708, medicine can be inserted by extruding in the section that the skin block is cut into.This medicine can be any said medicine and pharmaceutical preparation, and can comprise rate of release control preparation, as be applicable to by biocompatible gel, mixture, polymer substrate, granular medicament chemical compound or any other preparation in injection or other technology insertion section.A kind of appropriate formulation is the slurry of PVA and FA, and this slurry can the section of being pressed into and curing.

As shown in step 710, can provide the rate of release of diffusion barrier with the limit drug core.This diffusion barrier can flow out drug core by it by for example confined liquid inflow drug core or limit drug and work.Can carry out other treatment step.For example, the section of curing and drug loading in the step 708 can be inserted in the polymer pipe such as polyimide tube of other wide slightly and long slightly size.This other pipe can provide the storage storehouse in its one or both ends, and the diffusion barrier that one or both ends can be for example installed in this storage storehouse is full of.

As shown in step 712, anchor (anchor) can be connected to device.Term used herein " anchor " refers to be used for fixing anything of the interior a certain position of body device, is formed expansion line or flexible material, the binding agent etc. that sting hand-hole as the ommatidium of accepting seam, the pin that blocks by injection device.Be applicable in any mechanism of its predetermined position fixture and be applicable to that any mechanism that uses can be used as anchor and uses in injectable drug delivery device.In one embodiment, the storage storehouse that storage storehouse such as above integrating step 710 are described can be full of curable adhesive, as UV curable adhesives.The part of anchor can be inserted this binding agent, and this binding agent can solidify, as by using solidified by ultraviolet ray radiation, so that anchor can be fixed to device.

Shown in step 714, this device can be packed, and as suitable number pin of pre-assembling device, and should make up and enclose in the suitable package to be transported to the end user.Shown in step 716, packages sealed can further be sterilized in any suitable manner.

Can recognize that in different embodiments, some above-mentioned steps can be omitted, changes or rearrange, condition is that employed these steps form the Injectable sustained release drug delivery systems.For example, the step that adds diffusion barrier 710 can be omitted fully, maybe can replace by the step of applying suitable character polymer coating for whole device.In another embodiment, one section institute's extruded polymer micromicro is filled drug core, curable subsequently whole block (if suitable), and be cut to many sections.Also can understand some step such as curing and extrude the skin step, applicable concrete preparation method as partly solidified skin in a step, is carried out other curing in subsequent process steps.All these changes all fall in this description scope, and condition is that they cause Injectable sustained release drug delivery systems described herein.

Fig. 8 shows injectable drug delivery device.Device 800 can comprise the skin 804 of drug core 802, one or more layers polymeric layer and be connected to the anchor 806 of device 800.Drug core 802, skin 804 and anchor 806 can be any core as herein described, Pi Hemao.In some structure, rate of release mainly can be by the core 802 surface areas decision at device 800 ends, and continuing of release mainly can be by the length decision of device 800.

The injectable drug delivery device that also can recognize suitable dimension and drug release characteristics can otherwise form.For example, for no skin 804 or influence the use of other coating of rate of release, the substrate formed solid of drug/polymer, compressor can have suitable release characteristics.Compressor can form the cylindrical block thing that the extruder that for example uses Fig. 6 is extruded, and is solidified into solid mass (before or after cutting apart) then.The device of compression also can be by in the preforming mould of suitable dimension, independent or form alternative with the blended drug particles of other material of compression.

The remarkable advantage that can recognize many methods of above-mentioned preparation injection device is the stability that can control and/or improve medicine itself.For example, in the time of in being included in core, can protect medicine, avoid degradable in the external environment condition or change the influence of its active strength in preparation, storage or when using.Substrate in drug core and/or one or more layers cortex can provide protective measure.Therefore, for example, when device comprised drug core, endothelium and crust, interior micromicro was made up of ultraviolet absorbable material (for example polyimides).If during preparation use the ultraviolet curing skin, then interior micromicro prevents the medicine in the ultraviolet radiation contact core.Therefore, medicine may be degraded during cured hardly.One or more skins and core substrate also can protect medicine to avoid chemical degradation and metabolism in biofluid by the interaction of control and limit drug and liquid.This mechanism also can help the medicine in the duration of storage stabilising arrangement by limit drug and air or moist the interaction.

Fig. 9 shows the injection delivery system.In use, pin 902 can puncture the wall of biomaterial 904.Pin 902 can be pre-installed injectable drug delivery device 906, and this device injectable and orders about as normal saline and enters in the Biomedia 908 through store liquid 910 in the storehouse at pin to the Biomedia 908 on wall 904 opposites as biofluid or tissue.Pin can carry out different storings at the different depth of Biomedia 908, and this depends on whether anchor is included in the device 906 and whether anchor connects biological wall 904.

Figure 10 shows the rate of release of some device.Use the above-mentioned tinsel method of soaking, preparation 0.0115 inch of internal diameter and external diameter is 0.0125 inch a preforming polyimide tube is to measure rate of release.Stick with paste to the preforming pipe by injection FA/PVA (ratio is 90: 10) then, form drug delivery systems.The pipe that to fill is cut into the section of 3mm again, and dry under environmental condition, then these sections is solidified 2 hours in 135 ℃.This reaches each total drug loading that installs about 26 μ g/mm.In these devices some are stayed two open ends.Other device seals with silicone adhesive at the one end.As can be seen from Figure 10, the device that two open ends are arranged discharges medicine (after initial a large amount of prominent releasing) with about 0.4 μ g/ days speed, and the device that an open end arranged discharges medicine (also after initial burst) with about 0.2 μ g/ days speed.

Figure 11-15 further specifies the experiment rate of release result of the injection device of type described herein.These results also illustrate the purposes of the injection device of type described in the U. S. application 10/714549, and the disclosure of this application by reference and integral body is attached to herein.Extrude the injection device sample (the about 0.8mm of external diameter) that contains medicine FA, and mix with pH 7.4 0.1m phosphate buffers external.Sample is placed a couple of days and measure FA burst size (μ g).Also contain the implantation usefulness device sample of drug sample (with trade mark Retisert in external preparation ^TMDevelop), and measure release amount of medicine (μ g).The results are shown in Figure 11-15.

Figure 11 is presented at greater than in 20 days time, and FA is from the release in vitro curve of type injection device described herein.

Figure 12 show FA from type injection device described herein with from trade mark Retisert ^TMThe more external curve that the implantation of exploitation discharges with device.

Figure 13 shows that loteprednol etabonate (LE) is from trade mark Retisert ^TMThe implantation of the following exploitation release in vitro curve of device.

Figure 14 shows that diclofenamide (dichlorphenamide) (2.2mg) is from trade mark Retisert ^TMThe implantation of the following exploitation release in vitro curve of device.

Figure 15 shows that brimonidine (2.2mg) is from trade mark Retisert ^TMThe implantation of the following exploitation release in vitro curve of device.

Although the present invention describes in detail in conjunction with its preferred embodiment, to those skilled in the art, can carry out various variations and can use equivalent, be conspicuous and do not deviate from the scope of the invention.Therefore, the present invention who proposes in claims should explain with the broad sense that allows legally.Each above-mentioned list of references and publish file by reference and integral body is attached to herein.

Claims (84)

1. the drug delivery systems of injection shape and size, described device comprises:

The core that comprises one or more medicines; And

Polymer sheath to small part around this core, this suitcase contains one or more first polymer.

2. the device of claim 1, wherein said core comprise substrate and one or more second polymer of one or more medicines.

3. the device of claim 2, but at least a bioerosion in wherein said one or more second polymer.

4. the device of claim 2, wherein said one or more second polymer comprise at least a following polymer: polyvinyl acetate (PVAC), polycaprolactone (PCL), Polyethylene Glycol (PEG), dl-lactide-glycolide copolymer (PLGA), ethylene vinyl acetate polymer (EVA), polyvinyl acetate (PVA), polylactic acid (PLA), polyglycolic acid (PGA), Polyalkylcyanoacrylanano, polyurethane or nylon or its copolymer.

5. the device of claim 1, wherein said one or more medicines comprise at least a medicine or prodrug altogether.

6. the device of claim 1, wherein said core comprises biocompatible gelling preparation.

7. the device of claim 1, wherein said one or more medicines comprise steroid.

8. the device of claim 7, wherein said steroid comprises at least a following medicine: loteprednol etabonate, triamcinolone acetonide (TA), fluocinolone acetonide or NSC 24345.

9. the device of claim 1, at least a antimetabolite that comprises in wherein said one or more medicines.

10. the device of claim 9, wherein said antimetabolite comprises 5-fluorouracil (5-FU).

11. the device of claim 1, at least a adrenergic that comprises in wherein said one or more medicines.

12. the device of claim 11, wherein said adrenergic comprises brimonidine.

13. the device of claim 1, at least a carbonic anhydrase inhibitors that comprises in wherein said one or more medicines.

14. the device of claim 13, wherein said carbonic anhydrase inhibitors comprise at least a following medicine: acetazolamide, methazolamide, ethoxzolamide, diclofenamide (dichlorphenamide), dorzolamide or brinzolamide.

15. the device of claim 1, at least a antiviral agents that comprises in wherein said one or more medicines.

16. the device of claim 15, wherein said antiviral agents comprises nevirapine.

17. the device of claim 1, wherein said polymer sheath be a kind of in described one or more medicines at least a impermeable, semi-permeable or the infiltration skin.

18. the device of claim 1, wherein said polymer sheath comprise at least a following material: PVAC, PCL, PEG, PLGA, EVA, PVA, PLA, PGA, Polyalkylcyanoacrylanano, polyurethane or nylon or its copolymer.

19. the device of claim 2, but at least a bioerosion in wherein said one or more first polymer and described one or more second polymer.

20. the device of claim 2, at least a radiation-hardenable in wherein said one or more first polymer and described one or more second polymer.

21. the device of claim 2, at least a thermal curable in wherein said one or more first polymer and described one or more second polymer.

22. the device of claim 2 at least aly in wherein said one or more first polymer and described one or more second polymer evaporates curing.

23. the device of claim 2, at least a in wherein said one or more first polymer and described one or more second polymer can be through catalytic curing.

24. the device of claim 1, wherein said polymer sheath also comprises at least a medicine.

25. the device of claim 1, described device also comprises anchor, and described device is used for being of a size of about No. 30 extremely about No. 15 pins or being of a size of about No. 30 extremely about No. 15 intubate injections through at least a on shape and size.

26. the device of claim 1, described device are used for being of a size of about No. 30 extremely about No. 15 intubate or being of a size of about No. 30 extremely about No. 15 pins injections through at least a on shape and size.

27. the device of claim 1, described device are used on shape and size near the eyes or intraocular injection is at least a.

28. the device of claim 1, described device also comprise the anchor of fixing this device after being used to inject.

29. the device of claim 1, described device provides the slow release of described one or more medicines when being exposed to Biomedia.

30. the device of claim 2, described device also comprises second polymer sheath.

31. the device of claim 30, wherein said polymer sheath is compared with second polymer sheath, and described one or more medicines are had different permeabilitys, and described core is covered fully by the combination of this polymer sheath and second polymer sheath.

32. the device of claim 30, but at least a bioerosion in the wherein said polymer sheath or second polymer sheath.

33. the device of claim 32, at least a rate of release is subjected at least a corrosive effect in the described polymer sheath or second polymer sheath in wherein said one or more medicines.

34. the device of claim 32, in wherein said one or more medicines at least a rate of release and the described polymer sheath or second polymer sheath at least a erosion irrelevant.

35. the device of claim 31, but wherein said core, described polymer sheath and the bioerosion separately of second polymer sheath.

36. the device of claim 31, at least a rate of release is by the surface area control of second polymer sheath at least a permeability at least a in these one or more medicines and the core that do not covered by described polymer sheath in wherein said one or more medicines.

37. the device of claim 31, at least a direct interaction that prevents biological fluid and described core in the wherein said polymer sheath and second polymer sheath.

38. the device of claim 31, rate of release at least a in wherein said one or more medicines is controlled by the surface area of described core.

39. the device of claim 31, at least a rate of release is not subjected to described at least a medicine by described core diffusion influence basically in wherein said one or more medicines.

40. the device of claim 31, at least a rate of release is subjected to the appreciable impact of described at least a kind of medicine by described core diffusion in wherein said one or more medicines.

41. the device of claim 31, at least a rate of release is subjected to the appreciable impact of at least a medicine dissolution in the described core in wherein said one or more medicines.

42. the device of claim 31, in wherein said one or more medicines at least a in this device than more stable in Biomedia.

43. the device of claim 31, described device is at least a solidification process stability that increase is provided in described one or more medicines.

44. the device of claim 31, described device is at least a storage-stable that increase is provided in described one or more medicines.

45. the device of claim 31, described device also comprises anchor.

46. a method, described method comprises:

The extruded polymer skin;

In this polymer sheath, extrude the core that contains one or more medicines, so that the block of the coextrusion with the core that comprises described one or more medicines to be provided; With

Described coextrusion block is shaped to the drug delivery systems of at least a injection shape and size.

47. the method for claim 46, wherein said polymer sheath comprises at least a curable polymer, and described method also comprises partly solidified at least this polymer sheath.

48. the method for claim 47, wherein said at least a curable polymer radiation-hardenable, described method also comprises radiation is applied to described polymer sheath.

49. the method for claim 47, wherein said polymer sheath is solidified in curing station.

50. the method for claim 46, the molding of wherein said coextrusion block comprise this coextrusion block is divided into many sections.

51. the method for claim 50, described method also comprise apply described many sections one or more layers, comprise the layer that at least one is following: but to the layer of described one or more drug osmotics, to semi permeable layer of described one or more medicines or bioerosion layer.

52. also comprising, the method for claim 50, described method use in dip-coating or the film coated described many sections of at least a coating.

53. the method for claim 50 wherein is provided for cutting apart the station of cutting apart of described coextrusion block.

54. the method for claim 46, the molding of wherein said coextrusion block comprise described coextrusion block is divided into many tubular sections.

55. the method for claim 46, wherein said polymer sheath comprises at least a medicine.

56. the method for claim 46, described method also comprise anchor is connected to one of described at least a drug delivery systems, this anchor is fixed this drug delivery systems after being applicable to injection.

57. the method for claim 56 wherein connects anchor and comprises:

UV curable adhesives is applied to described drug delivery systems;

Make described anchor touch this UV curable adhesives; And

Make this UV curable adhesives be exposed to ultraviolet radiation.

58. a device, described device comprises:

The drug core that contains one or more medicines, this drug core have the cylindrical basically of band sidewall, first end and second end;

It is outer to form the polymer sheath in storage storehouse also to extend to drug core first end at least around this drug core sidewall;

Binding agent in the described storage storehouse; And

Be applicable to the anchor of fixing this device after the injection, described anchor is partially embedded in the described binding agent.

59. the device of claim 58, wherein said binding agent are curable adhesive.

60. the device of claim 59, wherein said binding agent are radiation curable adhesive.

61. the device of claim 59, wherein said binding agent are UV curable adhesives.

62. a method that forms injectable drug delivery device, described method comprises:

Formation has the polymer sheath of interior zone;

Mixture is inserted the interior zone of this polymer sheath, and described mixture comprises at least a medicine;

This polymer sheath and mixture are divided into one or more snippets, the one or more drug cores that have first end and second end separately are provided;

One of this class drug core is inserted in the polymer sleeve pipe, and it is outer so that the storage storehouse to be provided that described polymer sleeve pipe extends to this drug core second end at least; And

Set up diffusion barrier on first end of this drug core, this diffusion barrier is to described at least a permeable drug.

63. the method for claim 62, described method also comprises:

Curable adhesive is inserted in the storage storehouse of described drug core second end;

The first of anchor is inserted in the described curable adhesive, and the second portion of this anchor is applicable in vivo fixedly drug delivery systems; And

This curable adhesive is solidified.

64. the method for claim 62, described method also comprise described drug delivery systems sterilization.

65. the method for claim 62, described method also comprise described drug delivery systems packing so that transportation.

66. a method, described method comprises:

Extrude polymer sheath with interior zone;

One or more medicines are inserted this interior zone, the cylindrical basically block thing with the core that comprises described one or more medicines is provided; And

This cylindrical block thing is shaped to the drug delivery systems of at least a injection shape and size.

, the method for claim 66, described method insert before one or more medicines partly solidified at least described polymer sheath 67. also being included in.

, the method for claim 66, described method form before the described cylindrical block thing partly solidified at least this cylindrical block thing 68. also being included in.

69. the method for claim 66, described method also comprise described at least a drug delivery systems is applied polymer layer.

70. a method, described method comprises:

Tinsel is inserted in the uncured polymer;

Solidify this polymer;

From this polymer, extract tinsel out, obtain around the polymer sheath of this tinsel part;

Remove polymer sheath down from this tinsel;

One or more medicines are inserted the interior zone of this polymer sheath, cylindrical basically block thing is provided, this block has the core that comprises one or more medicines; And

This cylindrical block thing is shaped at least a drug delivery systems of injection shape and size.

71. the method for claim 70, wherein said polymer are polyimides.

72. the method for claim 70, wherein said tinsel are the nitinol silk.

73. the method for claim 70, wherein said one or more medicines comprise the drug matrices of at least a medicine and at least a polymer.

74. the method for the treatment of or reducing retrovirus or slow virus infection danger, described method comprise that the patient infusion to the needs treatment contains the sustained release drug delivery systems of antiviral drugs, the dosage of wherein said medicine discharges at least 7 days.

75. method for the treatment of or reducing retrovirus or slow virus infection danger, described method comprises that the patient infusion to the needs treatment contains the sustained release drug delivery systems of antiviral drugs, and the release of wherein said medicine was kept the desired concn of described medicine in blood plasma at least 7 days.

76. a method, described method comprises:

Formation comprises the core of medicine;

Apply this core with polymer sheath; And

This core and polymer sheath are shaped to the device of injection shape and size.

77. the method for claim 76, wherein said core comprises many medicines.

78. the method for claim 76 wherein forms described core and comprises and extrude this core.

79. the method for claim 76 wherein forms described core and comprises that the mixture that will comprise medicine is compressed into the shape of this core.

80. the method for claim 76 wherein applies described core and comprises described polymer sheath is sprayed onto on this core.

81. the method for claim 76 wherein applies described core and is included in this core of dip-coating in the uncured polymer.

82. the method for claim 76 wherein applies described core and comprises that at least one surface that stays this core does not apply.

83. the method for claim 76, wherein said device are cylindrical.

84. the method for claim 76, described method also comprise anchor is connected to this device.

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