Liquid delivery compositions

0001It Various approaches have been designed to provide the continuous, sustained release of drugs to allow in a subject. These controlled release systems are designed so that they before the drug prior to delivery protect the environment, while they controlled release of the drug in a targeted area allow. All currently available suffer approaches However, under one or more disadvantages or limitations.

0002A number of conventional Controlled release systems are based on microstructures, such as as lipospheres, Liposomes, microcapsules, microparticles or nanoparticles. The Microstructures are typically in the form of a dispersion in the body of a subject introduced. While microstructure dispersions for many applications useful are able these systems are not used to form a continuous film barrier or a solid implant with the structural integrity, for prosthetic Applications is required to form. In addition, microstructures when them into a body cavity be used, in which a considerable liquid flow occurs, z. B. the mouth or the eye, due to their small size and discontinuous Nature poorly retained will. Another limitation Such microstructures based systems is the lack of reversibility the establishment without extensive and complex surgical intervention. If complications arise after their release, are systems based on microstructures considerably more difficult from the body of remove subject than a solid implant.

0003Conventional Systems for the controlled delivery may as macrostructures be prepared. An active agent such as a drug, can be mixed with a polymer. The mixture is then for implantation in a special shape such as cylinder, disc or fiber form brought. Alternatively, a solid porous implant, which consists of a biodegradable polymer is formed as a container for Holding one of the microsystems for controlled described above serve release in place in a subject. By both these approaches will Festimplantat- the drug delivery system typically through an incision in the body used. These incisions are often larger than desired and can lead to the subject a Such treatment reluctantly accepted.

0004Out Polymer-drug conjugates can be both Microstructures and macrostructures of conventional Systems are preparing controlled release. As such they have the same drawbacks as those above for similar Structures of other conventional Systems have been described controlled release. Furthermore can preparing polymer-drug conjugates of water-soluble polymers , so that this not be recovered if required can. Because polymer-drug conjugates, a number of drug release mechanisms, such as hydrolysis, enzymatic cleavage, or cleaved by light, offer and a higher Degree of control over allow the release rates, it would be desirable if this without those mentioned above Disadvantages could be prepared.

0005The Disadvantages of the systems described above were able to partially the development of drug delivery systems are overcome, in the form a liquid (Z. B. over a syringe) can be administered and subsequently in situ be converted into a solid implant. Liquid polymeric compositions for use as biodegradable delivery systems with controlled Release are described in US Patent Nos. 4,938,763, 5,278,201 and 5,278,202 described. These compositions are the body in a liquid state administered. Once it is in the body, coagulates or cures the composition to form a solid. Such polymeric Composition comprises a water-soluble dissolved in a solvent non-reactive thermoplastic polymer or copolymer. This polymeric solution is in the body z. B. introduced through a syringe, whereby it upon dissipation or diffusion of the solvent in the surrounding body fluids "corroborated". The other injectable polymeric composition based on a thermosetting system of prepolymers, the cured in situ can be. This polymeric system includes reactive liquid oligomeric prepolymers, which cure by cross-linking to form solids, usually using a curing agent.

0006These injectable liquid polymeric systems have a number of special advantages. While they the need for an incision prevent allow the liquid delivery systems the formation of an implant with structural integrity, sufficient to allow it as a prosthetic device or as a continuous film barrier can be used. Because a solid implant is formed, avoid this liquid Systems, the problems of dissipation, which with dispersions observed microstructures in those regions of the body, in where considerable Liquid flow occurs. Despite these advantages, the lack currently the in situ formation of implants available liquid Delivery systems certain desirable characteristics.

0007If a liquid Delivery system comprising a biodegradable polymer and a water-soluble in a solvent resolved comprising active agent in contact with an aqueous medium, such as a Body fluid, arrives, the solvent dissipates or diffused into the aqueous Medium. If the polymer precipitates or coagulates to form a solid matrix, the active means everywhere trapped or encapsulated in the polymeric matrix. The release of the active agent then follows the general rules for the dissolution or diffusion of a drug from a polymeric matrix out. The education the solid matrix from the liquid Delivery system is, however, not immediately, but typically occurs over a On period of several hours. During initial this Period, the rate of diffusion of the active agent significantly be faster than the release rate associated with the sequence in the formed solid matrix occurs. This initial burst effect (ie the amount of active agent that is released in the first 24 hours) may for from loss or release of a large amount of the active agent cause the formation of the solid matrix. Whom the active agent is particularly toxic, this initial leads Release or this initial impact likely to toxic side effects and may cause damage to adjacent tissue structures.

0008The Development of liquid Delivery systems, which permit the in situ formation of an implant would, while they initial the same impact effect reduce or eliminate, would a represent significant progress. Such Abgabesy systems would allow, that higher safely incorporated concentrations of an active agent in an implant could become. The efficiency of such systems would also be improved, as a larger percentage of the active agent remain in the implant for sustained release dignity and not while the initial shock would be lost. Optimally, would the liquid Delivery system a number of ways to control the release of an active agent from the system offer. These benefits would the applications extend such treatments and the possibility of toxic side effects reduce. Therefore, there remains need for systems with controlled Release, which in liquid form can be used, by in situ to form a solid implant, and that the delayed release of an active agent into the body facilitate a subject without an initial burst of the active generating agent.

SUMMARY THE INVENTION

0009The present invention provides liquid compositions the for the delivery of active agents in vivo are useful and allow, the initial impact of control active agent more effectively than was previously possible. This can, for example, by incorporating the active agent in a controlled release component and combining the Controlled release component with the liquid polymer systems, those described in U.S. Patent Nos. 4,938,763, 5,278,201 and 5,278,202 will take place. The controlled release component , a microstructure (z. B. a microcapsule) or Makrostruktur- (Z. B. a film or fiber) controlled release system, a molecular controlled release system (eg. as a Polymer / drug conjugate) or combinations thereof include. The resulting liquid Delivery compositions can either liquid or dissolved Formulations of a biocompatible prepolymer, polymer or copolymer in combination with the controlled release component lock in. These liquid Delivery compositions can in the body of a subject in liquid Form are introduced. The liquid Composition solidifies or cures in situ to form then an implant with kontrollierer release.

0010The for the in situ formation of the controlled release implant Formulation used can be a liquid delivery composition be that a biocompatible polymer in a aqueous insoluble medium is essentially is an organic solvent, the with an aqueous medium miscible or dispersible in this is, and the component having includes controlled release. The biocompatible polymer is substantially dissolved in the organic solvent. The component Controlled release may be either dissolved, dispersed or in the entrained polymer / solvent solution be. In a preferred embodiment the biocompatible polymer is biodegradable and / or biologically erodible.

0011The liquid The delivery composition can be used to form a solid implant controlled release both inside and outside the body of the to form the subject. In one embodiment of the invention, the liquid Delivery composition in an implant site in the subject introduced, where the composition when in contact with a body fluid to form the implant solidifies controlled release. In a further embodiment the invention, a solid implant formed outside the subject be by the liquid Composition with an aqueous Medium is brought into contact. The solid implant can Dame in an implantation site are used in the subject.

0012In yet another embodiment, of the present invention, the liquid Abgabezucomposition be used to provide a film dressing on a tissue of a subject to form. An amount (effective to form a film dressing) of liquid Composition is dispensed onto the fabric, for example by spraying, Brushing or spraying, and the film dressing is on the fabric formed by the liquid brought delivery composition with an aqueous medium in contact is.

0013The Invention also includes a method for treating a subject with an active agent by administering the liquid delivery composition to an implant site in a subject to form a solid implant to form a controlled release in situ. The treatment of a subject with the active agent can also be carried out, by tion a solid implant sustained liberates in the subject is used, the outside is formed of the subject by the liquid delivery composition with an aqueous medium is brought into contact. The present invention extends to a method, which is one of the treatment of a fabric Subject (eg. B. injured tissue) by applying to the formation a film dressing on the tissue effective amount of the liquid composition includes.

0014In a further embodiment the invention, the controlled release component, which incorporates the active agent, as part of a liquid delivery composition, which a liquid, comprises a biocompatible prepolymer is introduced into the body of a subject will. The liquid Prepolymer has at least one polymerizable ethylenically unsaturated group (Z. B. a Acrylesterterminiertes prepolymer) on. If a curing agent is employed, the curing agent is to this composition typically just before use added. The prepolymer remains after the introduction of the curing agent for a short Period a liquid. During this Period, the liquid Delivery composition z. B. introduced by syringe into a body will. The mixture then solidifies in situ to form a solid implant. Other embodiments of the liquid delivery system can also the prepolymer and the controlled release component and a pore-forming agent or an organic solvent which with an aqueous dispersible medium miscible or in this, included. alternative can the pore forming agent or the organic solvent to the liquid prepolymer composition together with or be added directly after the addition of the curing agent. When a liquid Delivery composition is used, the pore-forming agent or the organic solvent includes in combination with the prepolymer, comprises the implant, formed a solid microporous polymer matrix, in which the component is embedded with controlled release.

0015A another embodiment of the present invention is directed to a method for treating a Subject with the active agent from, which comprises introducing the liquid prepolymer composition includes in the subject. Yet another embodiment of the invention provides the treatment of injured tissue of a subject in front of which applying an effective amount to form a film dressing the liquid comprises prepolymer composition.

0016On Another method for creating liquid compositions that For in vivo delivery active agents useful are and more effective control of the initial impact of the active agent as previously allow, is the active agent with a water-insoluble conjugating biocompatible polymer and the resultant polymer / drug conjugate in a biocompatible solvent dissolve, a liquid similar polymer system that described in U.S. Patent Nos. 4,938,763, 5,278,201 and 5,278,202 to form. The water-insoluble biocompatible polymers can those which are described in the aforementioned patents, or be related copolymers. About that addition, the liquid Polymer system and a water-insoluble biocompatible polymer lock in, which is not conjugated to the active agent. In one embodiment, the invention can this liquid Compositions in liquid Form in the body of a subject are introduced. solidifying the liquid composition itself or coagulates in situ to form an implant controlled release in which the active agent with is conjugated to the solid matrix polymer. In a further embodiment the invention, a solid implant formed outside the subject be by the liquid Composition with an aqueous Medium is brought into contact. The solid implant may then in an implantation site are used in the subject. In yet a further embodiment of the present invention, the liquid delivery composition used to form a film dressing on a tissue of a subject will.

SHORT DESCRIPTION THE DRAWINGS

0017<figref idrefs="S40">1</figref> shows the cumulative amount of naltrexone, which in from formulations of N-methyl-2-pyrrolidone (NMP) dissolved 75/25 poly (D, L-lactide-co-glycolide) (PLG) has been released. The Formulations included either free naltrexone or merger of naltrexone and Poly (D, L-lactide) (PLA) prepared microparticles on. Each of the formulations contained 5.0% by weight of naltrexone (Relative to the free drug).

0018<figref idrefs="S41">2</figref> shows the cumulative amount of an antipsychotic drug (APD) who was released from formulations dissolved in NMP 75/25 PLG. The formulations included either free APD or poly (vinyl pyrrolidinone) ( "PVP") having high molecular weight encapsulated APD. Each of the formulations contained 5.0 to Weight APD (on a free drug).

0019<figref idrefs="S42">3</figref> shows the cumulative amount of chlorin e₆, the released from formulations dissolved in DMSO 75/25 PLG has been. The formulations included both free chlorin e₆ and covalently attached to a (N-2-hydroxypropyl) -methacrylamide) / N-methacryloylglycine copolymer bound chlorin e₆ on. Each of the formulations contained 0.5% by weight of chlorin e₆ (based on a free drug basis).

DETAILED DESCRIPTION OF THE INVENTION

0020The present invention provides biocompatible liquid delivery compositions, the to form solid structures may be used, which the delivery of an active agent in a continuous, controlled permit manner. The compositions are typically in liquid form administered. After setting solidify or cure ( "confirm"), the compositions to form a solid or gelatinous matrix ( "implant"), which is substantially insoluble in aqueous Media, such as body fluids is. Based on the relative distribution characteristics of the active Agent in a given formulation, an initial observed release of a comparatively large amount of the active agent will. In some cases Like this initial Release not be problematic; For example, the active Means a drug with a broad therapeutic window be. In other cases , the initial Release but damage on adjacent tissues or cause toxic side effects to lead.

Liquid polymer system with a Controlled release component

0021Of the initial impact can be reduced or prevented by the physical state of the active is means modified z. B. by incorporating the active Agent into a controlled release component, which then in the liquid delivery composition dissolved, is dispersed or entrained. For example, the component controlled release microstructures, macrostructures, Conjugates, complexes or salts with low water solubility lock in. In principle allows it additional Time to release the active agent from the component is required controlled release of the formulation, without the initial Loss of a considerable Amount of active agent to solidify into a solid implant. Thus, the present compositions are useful for delivery of active agents in vivo and permit the initial burst of the active Means to control more effectively than was previously possible.

0022Examples suitable controlled release components include microstructures such as microparticles, nanoparticles, cyclodextrins, microcapsules, Micelles and liposomes a. The controlled release component can also macro structures such as fibers, rods, films, discs or Include cylinder. Suitable controlled release components also include Salts of the active agent having low water solubility and complexes or A conjugates in which the active agent is operatively associated with a carrier molecule. Also included in the definition of the component with controlled Release are combinations of the above approaches. For example, the Controlled release component is a microstructure, such as be about one microcapsule containing the active agent as part of a Complex conjugate or salt with low water solubility includes.

0023If the liquid introduced delivery composition into the subject by injection to be, is the size of the microcapsules or microparticles, typically to no more than 500 microns, and preferably not greater than 150 microns limited. Microstructures larger than 500 microns are syringes or rubber hoses can be difficult to administer and unpleasant or irritating effect on adjacent tissue. In other Applications, the controlled release component, however, a macrostructure such as a fiber, a film or a larger polymer beads lock in. these can with the liquid Proportion of liquid Delivery composition dispersed, be entrained or associated, so that the composition solidifies to form a matrix, in which the macrostructure embedded therein. Alternatively came liquid act as an adhesive proportion to the macrostructure at an implantation site in the body to keep the subject in position. The macrostructures are larger than 500 microns. The upper limit for the size of the macrostructures depends on the special application.

0024As soon as It was formed into a solid matrix, creates the resulting Implant at least two modes for controlling the release of active Agent - a first mode based on the release rate of the active Agent from the controlled release component and a second mode based on the release from the implant matrix. The second mode is the rate of biodegradation and / or bioerosion of the implant material is determined and can also the diffusion to be determined, where the implant is a microporous matrix is. The release rate from the controlled component Release can also by the rate of biodegradation and / or bioerosion of a polymer matrix to be determined, eg. as there where the controlled release component is a polymeric microparticle or a polymeric microcapsule. The release rate may also depend a number of other processes depend, for example then, if the controlled release component is a conjugate of a carrier molecule and the active agents including. The release rate of the active agent of the conjugate may also be determined by the decay rate of the conjugate.

0025The Selection of a particular controlled release component depends on the physical properties of the active agent (eg., solubility, stability etc.) and the desired Properties of the liquid Composition and the resulting implant from. The component Controlled release may be one or more of any number Include materials. The controlled release component may be a polymer, z. B. than the matrix of a microparticle, as the coating a microcapsule, or as the carrier molecule of a conjugate with a active agents include. The controlled release component may also include a hydrophobic Include counterion such as as when the active agent as a low water solubility salt present. The controlled release component may also include combinations of the compounds mentioned, such For example, if the controlled release component as the active agent in a polymer coating encapsulated Conjugate includes.

0026The Controlled release component may include a plurality of include microstructures such as microparticles, microcapsules or nanoparticles. The Microparticles or microcapsules typically have a size between 1 and 500 microns, although smaller particles used can be (Z. B. nanoparticles of the order of 10 nanometers to 1000 nanometers). Microcapsules in this context defined as reservoir systems in which a simple reservoir of Material including the active agent, by a membrane envelope surrounded. The stock can contain only the active agent or it can also be other materials such as a polymer matrix or include a means for modifying the release rate. alternative came the stock, the active agent as part of a conjugate of built complex or a salt with low water solubility include. microparticles are small monolithic entities in which the active agent throughout the particle matrix is ​​typically distributed in a random arrangement. In these two definitions, however, covers many practical formulations. For example, Microcapsules during the method of microencapsulation agglomerate. In other examples, the size of the in a "microcapsule" system contained Particles of the active agent in the same order of magnitude as the microcapsules itself. For the purpose of this invention, the term "microstructure" is defined such that it Mikropartike1, Nanoparticles, microcapsules or any related intermediate forms thereof. Various physical and chemical processes for preparing these microstructures have been developed and the technology is well established and well documented. See, for example Patrick V. Deasy; "Microencapsulation and Related Drug Processes, "Marcel Dekker Inc., New York (1984). A number of exemplary methods for the preparation of microcapsules and microparticles are known (see ., E.g., U.S. Patents No. 4,061,254, 4,818,542, 5,019,400 and 5,271,961. and Wakiyama et al., Chem. Pharm Bull., 29, 3363-68 (1981)). Depending on the wished chemical and physical properties, a number of these Methods are used to microcapsules or microparticles to prepare.

0027The Microparticles can in the form of lipospheres present. In this example, the microparticles include a phospholipid and optionally in a solid inert material such as a wax, on. lipospheres are solid, insoluble in water Microparticles embedded a layer of the phospholipid on the surface thereof have. The core of the lipospheres contain either a solid active agent or an active agent that is inert in the solid material is dispersed (see, eg., US Patent 5,188,837).

0028liposomes, containing the active agent, are typically prepared by a well-known method (see, eg., US Patent 5,049,386) in an aqueous solution educated. The composition containing the liposomes aqueous solution may in the compositions of the present invention, for example by forming a water-in-oil emulsion this solution in a liquid be incorporated prepolymer. After curing, a polymer matrix formed with embedded liposomes.

0029nanoparticles are carriers for drugs or other active molecules, in the nanometer order (10 nm-1000 nm) are prepared. Drugs can in under Nanopartike1 Veruse colloidal coacervation of polymers, absorption on the surface solid gel polymer carriers, Coating of the particles by polymerization, polycondensation, or coacervation, solidifying spherical micelles under Nanokompartmentation by polymerization or polycondensation, and interface polymerization be incorporated using the Elektrokapillar emulsification.

0030The nanoparticles can for example nanospheres comprise as, in Gref et al., Science, 263, 1600-1602 (1994) to be discribed. The nanospheres can be formed from diblock polymers, the lipophilic and a exhibit hydrophilic block. The active agent is within the entire nanosphere and is typically distributed as a molecular dispersion within the lipophilic core of the nanospheres before. When in high dosage in the nanospheres is present, however, a phase separation of the active agent may occur which the formation of agglomerates, or crystals of active agent leads.

0031The liquid Delivery compositions can a number of macrostructures such as fibers, rods, films, Include disks or cylinders. These macrostructures can from stock systems in which the active agent by a membrane is surrounded, which controls the rate of release, or monolithic Systems exist in which the active agent within the entire Macrostructure matrix is ​​distributed.

0032The present liquid Delivery compositions offer the advantage of safe, sustained release an active agent without an initial burst effect. In another Ausfürungsform the invention can be done by incorporating the active agent (Eg., A drug) in a controlled release component, which comprises a conjugate, can be achieved. Conjugates are in this context refers to a component with controlled Release in which the active agent covalently bonded to a carrier molecule is. By covalently bonding the active agent to the carrier molecule the solubility changing and transport properties of the active agent. Preferably has the carrier molecule itself no biological activity and came biodegrade easily. The carrier molecule is typically a polymer, but came also be a smaller organic molecule. For example, the active agent through an ester or amide linkage covalently bonded to a small molecule such as stearic acid bound be, whereby the water solubility the active agent is reduced.

0033The Polymers used to prepare drug conjugates may be water, z., polyethylene glycol, poly-L-aspartic acid, poly (glutamic acid), polylysine, Poly (malic acid), dextran, and copolymers of (N- (2-hydroxypropyl) methacrylamide) (HPMA). The preparation for Polymers used in drug conjugates may also water insoluble Polymers such as polyglycolide, poly (D, L-lactide) (PLA), polycaprolactone (PCL), Polyorthoesters, polycarbonates, polyamides, polyanhydrides, polyurethanes, Polyesteramides, polyphosphazenes, polyhydroxybutyrate, polyhydroxyvalerates, Polyalkylene oxalates, and copolymers, terpolymers, or combinations or mixtures thereof include. Some polymers or copolymers may be either water soluble or insoluble in water be dependent built on their molecular weight and the ratio in the copolymer Monomers, for. Example, poly (lactide-co-lysine) and poly (lactide-co-malolactonic acid). In order to a drug with these polymers can be conjugated, they must reactive groups such as hydroxyl, carboxyl, or amino groups, exhibit. These reactive groups may be either at the terminal groups the polymers or lying on side chains of the main polymer structure. When the reactive groups in terminal position are, the molecular weight of the polymer may need to be low be enough to sufficiently End groups to achieve the desired to have drug dosage. There are a number of ways to a with reactive groups to bind drug to polymers. These include the Formation of activated ester groups such as p-nitrophenyl esters, hydroxysuccinimide esters, as well as the use of dicyclohexylcarbodiimide (DCC) a. The Polymer-drug conjugates can in the liquid Polymer compositions as either microstructures or as Macrostructures are incorporated. You can also just in the liquid polymer compositions disbanded or dispersed.

0034A Series of polymers such as poly (amino acids), poly (amino acid ester), Poly (carboxylic acids), Poly (hydroxycarboxylic) Polyorthoesters, polyphosphazenes, and related Polyallcylenglycole Copolymers was in the preparation of polymer / drug conjugates used. For example, of poly (amino acids) such as poly-L-aspartic acid, poly (lysine) and poly (glutamic acid) used in the preparation of polymer / drug conjugates. Related copolymers such as poly (lactic acid-co-lysine) (PLA / Lys) and a poly (ethylene glycol) -poly (aspartic acid) block copolymer have also been employed. Other polymers for use in the preparation of polymer / drug conjugates are suitable include Dextran and copolymers of N- (2-hydroxypropyl) methacrylamide (HPMA copolymers) on. The polymers used to prepare drug conjugates can water soluble be, for. example, polyethylene glycol, poly-L-aspartic acid and poly (lysine) or alternatively a water-insoluble Polymer such as poly (lactide-co-glycolide) (PLG) may be. Some of the employed Copolymers, for. Example, PLA / Lys, may either water soluble be insoluble in water or, dependent of the relationship to incorporated into the copolymer monomer. Other examples of thermoplastic Polymers employed as the carrier molecule can be, conclude Poly (glycolide), poly (D, L-lactide) (PLA), poly (caprolactone) (PLC) and copolymers of malolactonic acid and D, L-lactide (PLA / MLA) a.

0035The liquid The delivery composition can also be only one organic solvent and a conjugate made, in the covalent attachment of the active agent a thermoplastic polymer is attached, which essentially insoluble in an aqueous Medium is, z. B. PLA or PLG with low molecular weight. alternative the composition may comprise the thermoplastic polymer in unbound Form and comprise bound to the active agent.

0036In a further embodiment of the present invention, the component with controlled Release include a complex in which a Trägermole-molecule operatively with the active agent is associated. The complex may also operationally active with the Agent and the carrier molecule assoziertes include metal cation. The complex can be a biodegradable polymer with carboxyl groups include. The carboxyl groups on the polymer can have a coordinated complex with a drug and a metal such as zinc, magnesium make or calcium. These complexes can upon contact with water disintegrate. The fact that the drug is part of a complex is, however, may prevent the drug from the implant diffused as rapidly as the corresponding free drug.

0037The Controlled release component may include a salt, such as a salt of the active agent having low water solubility. For the purposes of this invention, the term "low water solubility salt" is defined as a Salt, the solubility of a of not more than 25 mg / l (25 ppm) has. solubility the salt with low water solubility is hereby defined as the amount of salt that can be measured in the solution can be, if the salt of in distilled water at a temperature of not four hours more- than 40 ° C dispersed or stirred is. The low water solubility salt typically includes a non-toxic, water-insoluble carboxylate anion as a counter ion for the active agent (eg. as the anionic form of pamoic acid, tannic acid or Stearic acid). This method of reducing the initial burst effect is particularly useful where the active agent is a water-soluble biologically active agent such as a peptide (see, for. example, U.S. Pat. No. 5,192,741). The low water solubility salt the active agent may be in the liquid delivery compositions according to the present Invention be dispersed. Alternatively, the salt with low Water before incorporation into the liquid Delivery composition in the polymeric matrix of a microparticle be microencapsulated or dispersed.

0038The present controlled release components may be prepared from Polymers or materials are prepared, which finished in the liquid Delivery composition either soluble or insoluble are, that is, in the organic solvent or liquid prepolymer soluble or insoluble. The polymer or materials used in the manufacture are insoluble, the compositions may prepared as dispersions, eg. B. microparticles or microcapsules and stored. When the polymer or material in the liquid composition as a whole soluble is, the component can directly in front of controlled release be of use to the composition added and mixed. The exact time window during which such compositions are used can, depends on the dissolution rate of the polymer or material in the particular composition. For example, if the polymer or material of the component with controlled Release in the whole composition is only slightly soluble, it may be possible, the composition as a dispersion or mixture for a limited Period to lay. Alternatively, if the component with controlled release of the active agent is a conjugate, the liquid in the Total composition soluble is, all components of the composition are mixed together, the liquid Composition already longer form prior to use.

0039In one embodiment the invention, the controlled release component in a solution formulation a polymer or copolymer dissolved, dispersed or entrained are to the liquid form delivery composition. The liquid delivery composition typically includes a biodegradable and / or biologically erodible, biocompatible polymer or copolymer in a non-toxic organic solvents dissolved is. The solvent is with an aqueous Medium, such as body fluids, miscible or dispersible in this. This liquid composition can injected into an implant site of the body of a subject or are used. Upon contact with body fluids in the adjacent Tissues solidifies the liquid Composition in situ to form an implant with controlled Release. The controlled release implant isa solid polymer matrix in which the component with controlled Release is embedded.

0040alternative , the controlled release component in a liquid formulation resolved a prepolymer or be dispersed to the liquid delivery composition to form. After injection or insertion into an implant site the prepolymer is cured, to form a solid polymeric matrix, in which the component with controlled release is embedded. The step of curing may by means of a curing agent or by other known methods, eg., by exposing the Polymers of electromagnetic radiation occur. When a used curing agent is, so a mixture is formed which prepolymer the and comprising the controlled release component. The curing agent typically just prior to injection to this mixture added, a liquid to form Prepolymerzubereitung.

0041In one embodiment of the present invention, the controlled release component, which includes the active agent as part of a liquid composition in the body of a Subject are introduced. The liquid composition comprises a biocompatible polymer which is substantially insoluble in an aqueous Medium is, in combination with an organic solvent, and the controlled release component. The organic solvent is with an aqueous Medium miscible or dispersible in this. Preferably, the biocompatible polymer biodegradable and / or bioerodable. The Polymerist typically a thermoplastic polymer such as about a polylactide, a polycaprolactone or a polyglycolide. The active agent may be a bioactive agent or a diagnostic his agent. As used herein, the term "biologically active Means "drug Drug or some other substance, which in effect a body can cause. The term "diagnostic Agent "means as used herein, a substance, such as an imaging agent, that the capture or monitoring a physiological condition or a physiological function allowed. The liquid The delivery composition can be used in an implantation site in the body of the are injected or incorporated subject. Upon contact with a aqueous Medium, such as body fluids in the adjacent tissues, the liquid delivery composition solidifies in situ to form a controlled release implant. The organic solvents the liquid Composition dissipates into the liquid of the surrounding tissue and the polymer coagulates to form a solid implant. The implant is a solid polymer matrix in which the component embedded controlled release. The implant allows the controlled release of active agents such as drugs, Drugs, diagnostic agents and the like.

0042The liquid Composition can be also used to implant precursor outside of the body to form. The structure of the implant precursor is composed of an outer bag and a liquid Filling. After introduction of the implant precursor in the body the subject leads the contact with a body fluid for the in situ formation of the controlled release implant. The implant precursor comprising a mixture of a biocompatible Polymer, which in an aqueous medium is substantially insoluble, the controlled release component, which active the Includes means and an organic solvent, which with an aqueous dispersible medium miscible or in this.

0043So As used herein, the term "implant site" include a location in or The implant formed in which controlled release or is to be applied, such as a soft tissue such as muscle or fat, or a hard tissue such as Bone tissue. examples for Close implantation sites Tissue defects such as job is regenerating tissue; cavities such as a Peridontaltasche, a surgical incision or otherwise shaped pockets and cavities; a natural Cavity such as the oral, vaginal, rectal or nasal cavities, or the conjunctival sac of the eye, and the like; and other bodies, in or on which the liquid placed delivery composition or implant precursor and can be formed into a solid implant.

0044The present liquid Delivery composition, a biocompatible polymer or copolymer in combination with a controlled release component and an organic solvent lock in. As disclosed in US Pat. No. 4,938,763, the disclosure of is incorporated by reference into this application, the organic solvent biocompatible and with an aqueous Medium miscible or dispersible in this. The liquid composition may optionally include a pore-forming agent and / or a physiologically including acceptable means for modifying the release rate. The liquid Composition and the resulting implant precursor and / or the solid implant are biocompatible in so far as neither the polymer, yet, the solvent nor the controlled release component nor the polymer matrix substantial tissue irritation or necrosis at the implant site cause.

0045The Polymers or copolymers are substantially in an aqueous Medium z. B. body fluids, insoluble and are within the body an animal biodegradable and bioerodable and / or bioabsorbable. The term "biologically degradable "means that the polymer and / or polymer matrix of the implant with time by type before enzymes, by hydrolytic activity and / or by other similar Mechanisms in the human body are degraded. By "biologically erodible "is meant that the implant matrix with time, at least partially due to contact with substances in the liquid present surrounding tissue, cellular activity and the like eroded, or is degraded. By "bioabsorbable," it is meant that the polymer matrix within the human body, for example, by a Cell, a tissue, and the like degraded and absorbed.

Thermoplastic polymers.

0046Thermoplastic Polymers in the liquid Delivery composition useful are close a biocompatible polymers biodegradable and / or biologically erodible and bioabsorbable are, and be soft when they be exposed Flitze, but return to their original state, when they cooled are. The thermoplastic polymers are capable of organic in a solvent essentially dissolve. The thermoplastic poly mers are also able, after the dissipation of the solvent component from the polymer solution and coagulate the contact of the polymer with an aqueous medium or precipitate to form an outer membrane and to form an inner core consisting of a solid microporous matrix consists.

0047Thermoplastic Polymers which are suitable for use in the polymer solution generally include every one that the aforementioned have properties. Examples are polylactides, polyglycolides, Polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, Polyorthoesters, polydioxanone, polyacetals, polyketals, polycarbonates, Polyphosphazenes, polyhydroxybutyrate, polyhydroxyvalerates, polyalkylene oxalates, Polyalkylene succinates, poly (amino acids), poly (methyl vinyl ether), Poly (maleic anhydride), Chitin, chitosan, and copolymers, terpolymers, or combinations or mixtures thereof. PLA, PCL, polyglycolides and copolymers thereof are particularly preferred thermoplastic Polymers.

0048The thermoplastic polymer with a suitable organic solvent combined to a solution to form. solubility or miscibility of a polymer in a particular solvent varies depending on factors such as crystallinity, Hydrophilicity, capacity of hydrogen bonding, and molecular weight of the polymer. consequently are the molecular weight and the concentration of the polymer in the solvent adjusted to the desired solubility to reach. Preferably, the thermoplastic polymers a low degree of crystallization, a low degree of Hydrogen bonding, low solubility in water, and a high solubility in organic solvents.

Solvent.

0049Suitable solvent are for use in the present liquid delivery composition those who biocompatible, pharmaceutically acceptable, with the polymer component and an aqueous Medium miscible, and are able to diffuse into an aqueous medium, such as in tissue fluids, surrounding the implant site such as blood serum, lymph, cerebrospinal fluid (CSF), saliva and the like. In addition, the solvent preferably biocompatible. Typically, the solvent a Hildebrand solubility from about 9 to about 13 (cal / cm³)^1/2 on. The degree of polarity of the solvent should for at least about 10% solubility in water and the dissolution the polymer component be sufficient.

0050Solvents, in the liquid Delivery composition useful are, for example, include N-methyl-2-pyrrolidone; 2-pyrrolidone; aliphatic alcohols having from two to eight carbon atoms; propylene glycol; glycerol; tetraglycol; glycerol; solketal; alkyl esters such as as ethyl acetate, ethyl lactate, ethyl butyrate, dibutyl malonate, tributyl citrate, Tri-N-hexylacetylcitrat, diethyl succinate, diethyl glutarate, diethyl malonate, and triethylcitrate; triacetin; tributyrin; diethyl carbonate; propylene carbonate; aliphatic ketones such as acetone and methyl ethyl ketone; dialkylamides such as dimethylacetamide and dimethylformamide; cyclic alkyl amides such as caprolactam; dimethyl sulfoxide; dimethyl; decylmethylsulfoxide; Oleic acid; aromatic Amides such as N, N-diethyl-m-toluamide; 1-dodecylazacycloheptan-2-one, and 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone and dergleichen.-Preferred solvents according to the present close invention N-methyl-2-pyrrolidone (NMP), 2-pyrrolidone, ethyl lactate, dimethyl sulfoxide (DMSO), and propylene carbonate.

0051A Mixture of solvents, that for a variable degree of solubility for the Polymer components provides, can be used to determine the coagulation rate of polymers, a slow coagulation or solidification rate have to increase. For example, the polymer can with a combined solvent mixture be that a good solvent (Ie, a solvent, in which the polymer is very soluble) and a poor Solvent (d. h., a solvent, in which the polymer has a low degree of solubility) or a nonsolvent (Ie, one in which the polymer is not soluble) includes. Preferably contains the solvent mixture a poor solvent or a non-solvent and an effective amount of a good solvent, in admixture such that the polymer remains soluble, while it in solution is present, but upon dissipation of the solvent in a Surrounding aqueous Medium z. B. tissue fluid at the implant site, coagulated and precipitates.

0052The Concentration of polymer in the liquid composition allows generally a rapid and effective dissipation of the solvent and coagulation or precipitation of the polymer. This concentration may range from about 0.01 gram of polymer per ml of solvent up to a saturated in about Concentration range, preferably from about 0.1 grams / ml up to a roughly saturated Concentration, and more preferably from about 0.2 gram / ml to about 0.7 gram / ml.

The thermosetting polymers.

0053On formed in situ biodegradable implant can also Crosslinking appropriately functionalized biodegradable Prepolymers are constructed. The liquid thermosetting systems of the present close invention the controlled release component and reactive, liquid prepolymers on. The liquid cure prepolymers in situ to form a solid matrix, usually with the aid of a Curing catalyst. In general, any biocompatible oligomer are used, which can be attached to a polymerizable functional group, to form a biocompatible prepolymer. Although each of the herein described biodegradable thermoplastic polymers can be used can, is the limiting Criterion that the oligomers of these polymers of low molecular weight liquids be and must specify at least one functional group with a derivatizing agent that is a polymerizable functional containing group, can be implemented. Suitable liquid prepolymers include oligomers with pendant Hydroxyl groups which have been reacted with a derivatizing agent, to a prepolymer having at least one polymerizable ethylenically unsaturated to form group. For example, a polylactide of low Molecular weight, a terminal having hydroxyl, are reacted with acryloyl chloride to a endverschlossenes with an acrylic ester to Polylactidoligomer produce. The ethylenically unsaturated Groups on the prepolymers may then by addition of a curing catalyst, such as a free radical initiator or by exposure to electromagnetic radiation are polymerized.

0054There the prepolymer after addition of a curing agent for a short Period liquid remains, a mixture of the liquid prepolymer with a can Controlled release component and a curing agent optionally processed, z. B. into a syringe and into the body of a Subject to be injected. The mixture then forms an in situ solid implant, thereby bypassing the need for a Inizision is. As with systems based on thermoplastic polymers, is the release rate of ak tive agent through the diffusion rates influence of the agent out of the implant. In some cases, the rate of release by the biodegradation and / or bioerosion the polymeric matrix implant determined. In other cases, the release rate of the release rate of the active agent from the component intended controlled release.

Active agent.

0055The liquid Delivery compositions of the present invention include active agent, such as a biologically active agent or a a diagnostic agent, either singly or in combination, so that the implant or film dressing of a delivery system of the active agent to adjacent or distant tissues and organs creates in the subject. Bioactive agents which alone or in Combination used in the implant precursor and implant can be, close to Example, a drug, a drug, or other suitable biologically, physiologically, or pharmaceutically active substance a, which is a local or systemic biological, physiological or therapeutic effect in the body an animal, including a mammal deploy and adjacent from the solid implant matrix into the liquid or surrounding tissue can be released. Diagnostic agents, which can be used, conclude imaging agents, such as radiodiagnostic agents a.

0056The active agent may be soluble in the polymer solution to form a homogeneous to form mixture, or insoluble in the polymer solution to prepare a suspension to form or dispersion. After implantation, the active Means preferably embedded within the implant matrix. While the Matrix degrades over time, is the active agent from the matrix in the liquid of adjacent tissue, preferably at a controlled rate, released. The release of the active agent from the matrix may for example, via solubility of the active agent in an aqueous Medium, the distribution the agent within the matrix, the size, shape, porosity, solubility and biodegradability of the implant matrix, and the like be varied.

0057The liquid The delivery composition includes the biologically active agent in a Amount that is effective to achieve the desired level of biological, physiological, pharmacological and therapeutic effect in provide animal. There is generally no critical upper limit for the amount of biologically active agent in the liquid delivery composition may be included, apart from that, the pharmacological through the dictated characteristics of the particular biologically active agent is. The lower limit for the Amount of biologically active agent incorporated into the polymer solution will depend on the activity of biologically active agent and the desired for the treatment Time period from.

0058The biologically active agent can be a biological or physiological activity stimulate the animal. For example, the agent may act to it promotes cell growth and tissue regeneration, function in the Birth control exercises, nerve stimulation or bone growth caused, and the like more. Examples of useful include biologically active agent a substance, or metabolic precursor thereof, which is capable of growth and survival of cells and tissues to promote or to improve the function of cells, such as a Substance that promotes the nerve growth, such as a ganglioside, a nerve growth factor, and the like; an agent which the growth of hard or soft tissue promoting, such as fibronectin (FN), human growth hormone (HGH), protein growth factor interleukin-1 (IL-1), and the like; a substance which is the bone growth promotes, such as hydroxyapatite, tricalcium phosphate, and the like; and a substance that the prevention of infections in Implant site useful is, for example, an antiviral agent such as vidarabine or Acyclovir, an antibacterial agent such as a penicillin or Tetracycline, an antiparasitic agent such as quinacrine or Chloroqum.

0059Suitable biologically active agents for use in the invention also include anti-inflammatory agents such as hydrocortisone, prednisone and the like; antibacterial agents such as penicillin, cephalosporins, bacitracin and the same; antiparasitic agents such as quinacrine, chloroquine and the same; antifungal agents such as nystatin, gentamicin, and the same; antiviral agents such as acyclovir, ribarivin, Interferons and the like; antineoplastic agents such as methotrexate, 5-fluorouracil, adriamycin, tumor-specific antibodies, which are conjugated to toxins, tumor necrosis factor and the like; analgesic agents such as salicylic acid, acetaminophen, ibuprofen, Flurbiprofen, morphine and the like; Lokalanästheti ka such as lidocaine, Bupivacaine, benzocaine and the like; Vaccines such as hepatitis, Influenza, measles, rubella, tetanus, polio, rabies and the like; Agents acting on the central nervous system, such as a tranquilizer, B-adrenergic blocking agent, dopamine and the like; growth factors such as colony stimulating factor, platelet-derived growth factor (PDGF), Fibroblast growth factor, transforming growth factor B, human growth hormone, morphogenetic Bone proteins, insulin-like Growth factor and the like; Hormones such as progesterone, follicle Hormone, insulin, somatotropins and the like; Antihistamines such as as diphenhydramine, chlorphencramine and the like; cardiovascular agents such as digitalis, nitroglycerine, papaverine, streptokinase and like; Anti-ulcer agents such as cimetidine hydrochloride, isopropamide iodide, and the same; Bronchodilators such as Metaproternalsulfate, Aminophylline and the like; Vasodilators such as theophylline, Niacin, minoxidil, and the like; and other similar substances. The biologically active agent may also be an antihypertensive agent, an anticoagulant, be an antispasmodic agent, or an antipsychotic agent. For additional Examples of biologically active agents, the present invention in the may be used see the corresponding US patent application of the applicant under the Serial No. 07 / 783.512, filed October 28, 1991, the Disclosure is incorporated by reference into this application.

0060Accordingly the implant can be formed as a delivery system for drugs, Drugs, other biologically active agents, and diagnostic agents to the implantation site adjacent to or distant from the Tissue function. The active agent is in the controlled release component incorporated. In a further embodiment of the invention, the active agent directly into the polymeric matrix, the component its surrounds controlled release incorporated.

Liquid polymer-drug conjugates.

0061Of the initial shock at Drug from the liquid Polymer systems described in U.S. Patent Nos. 4,938,763, 5,278,201 and 5,278,202 describes may also reduce or prevent are, by the active agent is insoluble in water directly to a biodegradable polymer is conjugated and the resulting Polymer-drug conjugate is dissolved in a biocompatible solvent a liquid similar polymer system the form described in the aforementioned patents. The insoluble in water biokompapatible polymers can be as those described in these patents, or related copolymers. Thus, Polyglycolide, poly (D, L-lactide), polycaprolactone, polyorthoesters, Polycarbonates, polyamides, polyanhydrides, polyurethanes, polyesteramides, Polyphosphazenes, polyhydroxybutyrate, polyhydroxyvalerates, polyalkylene oxalates, and copolymers, terpolymers, or combinations or mixtures of thereof having molecular weights which are sufficiently low to the desired To achieve drug dosage used. also related Copolymers or terpolymers such as poly (lactide-co-malolactonic acid), or Combinations or blends of the above polymers with other polymers can be used to form a solid implant in which the active agent is conjugated directly to the polymer matrix.

0062The Monomer ratios (D, L-lactide to malolactonic acid) can be varied to a balance between the specific for an application desired insolubility to achieve in water and the carboxyl group. In some make it may be advantageous, other combinations of monomers to use to obtain a copolymer having the desired properties. To the Example MLABE polymerized with glycolide or caprolactone in order to remove the benzyl protecting groups by hydrogenation each poly (glycolide-co-malolactonic acid) or poly (caprolactone-co-malolactonic acid) to receive. Terpolymers such as poly (D, L-lactide / glycolide / malolactonic acid) may also are produced by the same process.

Pore ​​structure.

0063The using the present liquid delivery compositions Close formed implants preferably a microporous inner Core and a microporous outer membrane a. Typically, the pores of the inner core are substantially uniform and the membrane of the solid implant is essentially non-porous compared with the porous Nature of the core. Preferably, the outer membrane of the implant includes Pores with considerable smaller diameters than the pores in the inner core, z. B. the ratio the average pore size in the core to the average pore size in the membrane is at about 2/1 to about 100/1, and preferably from about 2/1 to etwa_10 / 1st

0064pore can are formed in the matrix of the implant in several ways. The dissipation, dispersion or diffusion of the solvent out of the solidifying Polymer matrix in the liquid of adjacent tissue can pores, including pore channels, in produce the polymer matrix. The dissipation of the solvent from the coagulating mass creates pores within the solid implant. The Size of the pores of the solid implant is in the range of about 1-1000 microns, preferably the size of the pores the membrane layer is about 3-500 microns. The solid microporous implant has a porosity in the range of about 5-95%. Preferably, the membrane has a porosity of 5 % To about 10% and the core has a porosity of about 40% to about 60 %.

0065Optional can be included in the polymer solution, a pore-forming agent to additional pores to produce in the polymer matrix. This approach is comprehensive described in US Application Serial No. 07 / 283.512, the disclosure of which is incorporated by reference into this application. Suitable pore-forming agents include a sugar, a salt, a water-soluble Polymer, and a water-insoluble Substance that decays quickly to a water soluble substance, a.

Means for modifying the release rate.

0066The polymer solution may include a means for modifying the release rate to a controlled, delayed Release of a biologically active agent from the solid implant matrix provide. Suitable means for release rate modification conclude an ester of a monocarboxylic acid, an ester of a dicarboxylic acid, an ester of a tricarboxylic acid, a polyhydric alcohol, a fatty acid, a triester of glycerol, a sterol, an alcohol, and combinations thereof.

0067The present invention will now be described with reference to the following Examples closer described.

example 1

Naltrexone / PLA microparticles in PLG / NMP.

0068A Melt / fusion mixture in the ratio of 1: 1 was on a prepared Teflon film by poly (D, L-lactide) (PLA; approx 2.000 MW; Boehringer-Ingelheim; Resomer L104) melted and the same Volume naltrexone base was added. The melt was allowed to Lady cool, to obtain a molten solid. The molten solid was separated from the Teflon film and ground to a fine powder. A formulation with five Percent (by weight) of naltrexone was prepared by adding 30 mg the melted / fused naltrexone / PLA powder to 300 mg a solution of poly (D, L-lactide-co-glycolide) (PLG) in N-methylpyrrolidone (NMP) added were. A 5% (by weight) control formulation of naltrexone was prepared by adding 15 mg of unprocessed naltrexone base to 300 mg of PLG / NMP solution added were. The in-vitro release of naltrexone from each of the formulations was evaluated by adding a drop of formulation to an aliquot of of five ml phosphate buffered saline (PBS) in a vial added with 10 ml has been. The amount of released naltrexone was supporting the Vial at 37 ° C and monitoring the absorbance at 280 nm determined as a function of time. The Results (in <figref idrefs="S40">1</figref> shown) indicate that those formulation which the microparticles of melted / fused Naltrexone / PLA in the PLG / NMP solution dispersed contained, the initial Release of naltrexone (in comparison with the control solution of Naltrexone significantly decreased in PLG / NMP).

example 2

Ganirelix microparticles in PLG / NMP.

0069ganirelix acetate (A GnRH antagonist for the treatment of endometriosis and prostate cancer suitable) was in microparticles of a solvent-insoluble, rapidly biodegradable polymer incorporated. This served to the solubility to reduce of ganirelix in the polymer / solvent formulation and the dispersion properties of Ganirelixacetats in this improve formulation. Ganirelix acetate (6 gm) and poly (sebacic acid) (4 gm; "PSA") were mixed, to form a homogeneous powder mixture. The powder mixture was on a stove at 80 ° C melted and mixed until the ganirelix acetate in the PSA melt was homogeneously dispersed. The ganirelix acetate / PSA melt was allowed to Cool to room temperature, to form a solid which then for in a Cryo-Mill one minute was ground to a fine powder. The powder was sieved to collect the particles of less than 60 microns. A solution of PLA in ethyl lactate in the ratio 50:50 was prepared by dissolving an equal amount of PLA in ethyl lactate using a Sonicator at 45 ° C produced. The final formulation was prepared by adding 1.14 gm of the ganirelix acetate / PSA microparticles to 4 ml of the prepared PLA / ethyl lactate solution. The resulting mixture was mixed well by shaking, could through a 20-gauge needle be administered. was due to the solubility of PSA in ethyl lactate this formulation within one hour after mixing verwendet.-A relatively strong shock effect is observed with formulations where ganirelix easy the PLA / NMP solution disbanded is (> 10% on the first Day after administration). This initial surge of ganirelix can local cause tissue irritation and is clinically unacceptable. experiments In vitro and in vivo, that the liquid composition with the Ganirelix acetate / PSA microparticles the high initial release of ganirelix (<3% on the first Day after administration) removed.

example 3

Microcapsules of porcine Somatotrophin in PLA / NMP.

0070A stock solution PLA / NMP is prepared by PLA (2000 MW) in an equal amount of N-methylpyrrolidone dissolved is (50:50 PLA ​​/ NMP). A liquid Composition, the microcapsules of porcine somatotropin (PST) contains, is adding 0.2 g of microcapsules containing 41 wt .-% PST in a matrix of carboxymethylcellulose, prepares to 2.0 g of PLA / NMP solution. A similar Formulation is prepared by mixing microcapsules containing PST in a contain gelatin matrix, are added to the 50:50 PLA ​​/ NMP solution. The in vitro release of PST from these formulations by dispensing the formulation (150-300 microliters) through a 20-gauge needle checked directly in 10 ml phosphate buffered saline. The release rate from the microcapsule formulations is significantly lower than the initial Release of PST from the microcapsules alone.

example 4

Microencapsulated antipsychotic Drug in PLG / NMP.

0071Seventeen (17.0) grams of antipsychotic (APD) drug Benzisoazolpyrimidinon can an aqueous solution (17.0 g polymer in 300 ml of water) of water-soluble, biodegradable Polymer poly (vinyl pyrrolidinone) ( "PVP"; MW added 100,000) will. The resulting preparation is a well dispersed suspension. These Suspension is measured using a Büchi 190 mini spray drier spray-dried with the following parameters: -Heizrate 11, extraction rate 20, Compressed air pressure 80 psi, air flow 800 NL / hr, nozzle opening 0.7 mm, inlet temperature 167 ° C, and discharge temperature 103 ° C. After 75 min of processing under the conditions mentioned were yield 3.2 g of fine powder of encapsulated in PVP APD. A 5 % Strength (by weight) of the formulation dispersed in polymer solution APD can be prepared by mixing 27 mg of the PVP-encapsulated particles to a solution of poly (D, L-lactide-co-glycolide) (60% 75/25 PLG (12:11)) in NMP added will. A control formulation was prepared by mixing untreated APD (13.5 mg) was added to the same 60% PLG / NMP solution. The in-vitro release of APD from these formulations may be evaluated by adding a drop of the particular formulation respectively to an aliquot of 5.0 ml of a buffer solution (in added vials of 10 ml) and then at 37 ° C is stored. The absorbance at 280 nm as a function the time monitored. The Results indicate that coating the solid APD particles with a water soluble Polymer of high molecular weight, the initial release of APD reduced (see <figref idrefs="S41">2</figref>).

example 5

Polymer bound chlorine <u>e</u>₆ in PLG / DMSO.

0072On Conjugate of chlorin <u>e</u>₆Covalently bound to an N- (2-hydroxypropyl) -methacrylamide / N-Methacryloylglycm copolymer (HPMA copolymer) containing glycyl side chains, bonded, was in accordance with the . Krinick, Ph.D. Dissertation: Combination Polymeric Drugs as Anticancer Agents, University of Utah (1992), procedures described prepares. The containing conjugate 11 wt .-% chlorine <u>e</u>₆ and 89 wt .-% HMPA copolymer. The chlorin<u>e</u>₆ was the carboxyl groups of the pendant glycine residues to the HPMA copolymer bound. Two formulations were prepared, each of 0.5 wt .-% chlorin <u>e</u>₆(based contained on a free drug basis). One of the formulations contained 53 wt .-% PLG (iv = 0.11 dl / g), 46.5 wt .-% DMSO and 0.5 Wt .-% of free chlorine <u>e</u>₆, The second formulation contained 51 wt .-% PLG, 44.75 wt .-% DMSO and 4.25 wt .-% of chlorine <u>e</u>₆/ HMPA copolymer conjugate. drops the two formulations were precipitated into 5 ml phosphate buffered saline and the samples were incubated at 37 ° C placed in a shaking incubator. The concentration of chlorin <u>e</u>₆ in the solution was as a function of time using UV-VIS spectroscopy (.lambda.max = 650 nm) monitored. The cumulative percentage of drug released is in <figref idrefs="S42">3</figref> shown. The results indicated that chlorin <u>e</u>₆ from the formulation chlorin the <u>e</u>₆/ HMPA copolymer conjugate contains, is released much more slowly. In addition, no burst effect was from the formulation with the chlorine <u>e</u>₆/ HMPA copolymer conjugate observed.

example 6

PLA / MLA-p-doxorubicin in PLG / NMP.

0073On water-soluble Copolymer of D, L-lactide with malolactonic (PLA / MLA) is prepared by first adding D, L-lactide with malolactonic acid monobenzyl ester- (MLABE) is copolymerized. The benzyl protecting groups are from the resulting copolymer removed by hydrogenation, a copolymer (PLA / MLA) with free carboxyl groups pendent to obtain. The free carboxyl groups are with dicyclohexylcarbodiimide and p-nitrophenol were reacted to obtain a PLA / MLA copolymer with pendant p-nitrophenol ester groups. Doxorubicin is to the PLA / MLA copolymer via an aminolysis attached to to obtain a PLA / MLA-p-doxorubicin copolymer.

0074A sufficient amount of PLA / MLA-p-doxorubicin is a 60: 40 added PLG / NMP stock solution to a liquid Composition with 2.0 wt .-% doxorubicin (relative to free doxorubicin) to form. A control formulation with free doxorubicin is by adding 20 mg of doxorubicin to 980mg of 60 40 PLG / NMP stock solution is preparing. The in-vitro release of doxorubicin from each of the formulations is evaluated by adding a drop of formulation to an aliquot of five ml phosphate buffered saline (PBS) is added in a 10 ml vial. The formulation with free doxorubicin shows a considerable initial impact of Drug. In essence, over a period of 3 days, no Doxorubicin released from a sample which includes the PLA / MLA-p-doxorubicin. The in vitro determination is repeated by adding a drop of formulation to an aliquot of five ml of rabbit peritoneal fluid is added in a 10 ml vial. The formulation with free doxorubicin shows a substantial initial burst of doxorubicin. The PLA / MLA-p-doxorubicin containing composition does not show a surge and the rate of release of doxorubicin is well below the free for the formulation with Doxorubicin observed rate.

example 7

PLG-t-doxorubicin in PLG / NMP.

0075Poly (D, L-lactide-co-glycolide) (PLG) with low molecular weight and carboxyl-terminated is reacted with dicyclohexylcarbodiimide and p-nitrophenol a PLG copolymer with terminal p-nitrophenol ester groups to obtain. The doxorubicin is then reacted with the p-nitrophenol ester groups, to obtain a PLG copolymer, wherein the doxorubicin to the terminated attached carboxyl groups of the copolymer (PLG-t-doxorubicin).

0076The PLG-t-doxorubicin conjugate is then to 60: added 40 PLG / NMP stock solution to a liquid Composition with 2.0 wt .-% doxorubicin (relative to free doxorubicin) to form. The rate of release of doxorubicin in PBS and rabbit peritoneal fluid is determined using standard procedures. As with the PLA / MA-p-doxorubicin composition observed is substantially over a period of 3 days from the addition of a sample which includes the PLG-t-doxorubicin to PBS no doxorubicin released. From the addition of a drop of the PLG-t-doxorubicin composition to Kaninchen-peritoneal is not a shock effect to observe. Again, the release rate of doxorubicin is from the PLG-t-doxorubicin composition to rabbit peritoneal fluid-chen significantly lower than for the free doxorubicin formulation observed rate.

0077all Publications and patent applications in this specification have the current State of the art in the art out on which these Invention relates. All cited publications and patent applications herein are incorporated herein by reference as if each individual publication individually or patent application and of itself herein by reference would have been included.

0078The Invention has been described with reference to various specific and Preferred embodiments and techniques described. However, it is understood that many Variations and modifications are possible are, without departing from the spirit and scope of the invention.