MXPA99010107A - Biodegradable compositions comprising poly(cycloaliphatic phosphoester) compounds, articles, and methods for using the same - Google Patents

Abstract

Biodegradable, flowable or flexible polymer compositions are described comprising a polymer having the recurring monomeric units shown in formula (I), wherein:each of R and R'is independently straight or branched alkylene, either unsubstituted or substituted with one or more non-interfering substituents;L is a divalent cycloaliphatic group;R''is selected from the group consisting of H, alkyl, alkoxy, aryl, aryloxy, heterocyclic or heterocycloxy;and n is 5 to 1,000, wherein said biodegradable polymer is biocompatible before and upon biodegradation. In one embodiment, one or more of R, R'or R''is a biologically active substance. Amorphous compositions containing a biologically active substance, in addition to the polymer, and methods for controllably releasing biologically active substances using the compositions, are also described.

Description

BIODEGRADABLE COMPOSITIONS CONTAINING POLYPHOSFOESTER COMPOUNDS CICLOAUFATICQ), ARTICLES AND METHODS FOR USING THEMSELVES BACKGROUND OF THE INVENTION FIELD OF THE INVENTION The present invention relates to biodegradable compositions of poly (phosphoester) which are degraded in vivo in non-toxic waste, in particular to those containing a cycloaliphatic structure in the base structure of the polymer. The compositions of the invention are particularly useful as flexible or flowable materials for controlled and localized drug delivery systems.

DESCRIPTION OF THE BACKGROUND TECHNIQUE Biocompatible polymeric materials have been used extensively in the therapeutic delivery of drugs and in medical applications of implants. If a medical implant is designed to be used as a drug supply or other controlled release system, using a biodegradable polymeric vehicle is an effective means of delivering the therapeutic agent locally and in a controlled manner, see Langer et al. , "Chemical and Physical Structures of Polymers as Carriers for Controlled Relay of Bioactive Agents", J. Macro. Science, Rev. Macro. Chem. Phys., C23 (1), 61-126 (1983). As a result, a smaller amount of total drug is required, and side effects can be minimized. The polymers have been used for some time as carriers of therapeutic agents to effect a sustained and localized release see Leong et al., "Polymeric Controlled Drug Delivery", Advanced Drug Delivery Rev., 1: 199-233 (1987); Langer, "New Methods of Drug Delivery", Science, 249: 1527-33 (1990) and Chien et al., Novel Drug Delivery Systems (1982). Such delivery systems offer the potential for improved therapeutic efficacy and reduced overall toxicity. When a matrix based on non-biodegradable polymer is used, the steps leading to the release of the therapeutic agent are diffusion of water into the matrix, dissolution of the therapeutic agent and diffusion of the therapeutic agent outward through the channels of the matrix. As a consequence, the average residence time of the therapeutic agent that exists in the soluble state is normally greater for a non-biodegradable matrix than for a biodegradable matrix, for which the passage through the matrix channels is no longer required, while I presented. Since the half-life for many pharmaceutical compounds is short, the therapeutic agents can be broken down or inactivated within the non-biodegradable matrix before they are released. This aspect is particularly significant for many bio-macromolecules, for example, smaller proteins and polypeptides, since these molecules are generally hydrolytically unstable and have markedly low permeabilities through most polymer matrices. Even in non-biodegradable matrices, many bio-macromolecules begin to aggregate and precipitate from the solution, blocking the very necessary channels for diffusion outside the vehicle matrix. These problems are solved a little using a rigid biodegradable matrix which, in addition to allowing some diffusion release, allows mainly the controlled release of the therapeutic agent by degradation of the solid polymer matrix. Examples of classes of synthetic polymers that have been studied as possible solid biodegradable materials include polyesters (Pitt et al., "Biodegradable Drug Delivery Systems Based on Aliphatic Polyesters: Applications to Contraceptives and Narcotic Antagonists", Controlled Relay of Bioactive Materials, 19-44. (Richard Baker ed., 1980), poly (amino acids) and pseudo-poly (amino acids) (Pulapura et al. "Trends in the Development of Bioresorbable Polymers for Medical Applications", J. Biomaterials Appl., 6: 1 216-50 (1992); polyurethanes (Bruin et al., "Biodegradable Lysine Diisocyanate-based Poly (Glycolide-co-e Caprolactone) -Urethane Network in Artificial Skin", Biomaterials, 1 1: 4, 291-95 (1990); polyorthoesters (Heller et al., "Relay of Norethindrone from poly (Ortho Esters)", Polymer Engineering Sci., 21: 11, 727-31 (1981); and polyanhydrides (Leong et al., "Polyanhydrides for Controlled Relase of Bioactive Agents ", Biomaterials 7: 5, 364-71 (1986) Polymers having phosphate bonds, referred to as poly (phosphates), poly (phosphonates) and poly (phosphites), are known .. See Penczek et al., Handbook of Polymer Synthesis, Chapter 17: "Phosphorus-Containing Polymers", (Hans R. Kricheldorf ed., 1992) The respective structures of these three classes of compounds, each having a different side chain connected to the phosphorus atom, are as follows: Polyphosphate Polyphosphonate Polyphosphite The versatility of these polymers comes from the versatility of the phosphorus atom, which is known for a multiplicity of reactions. Their link may involve 3p orbitals or various 3s-3p hybrids; spd hybrids are also possible due to accessible d orbitals. Therefore, the physicochemical properties of the poly (phosphoesters) can be easily changed by varying either the R group or the R 'group. The biodegradability of the polymer is mainly due to the physiologically labile phosphoester bond in the base structure of the polymer. A wide range of biodegradation rates can be achieved by manipulating the base structure or the side chain.

An additional feature of poly (phosphoesters) is the availability of side functional groups. Since phosphorus can be pentavalent, drug molecules or other biologically active substances can be chemically bound to the polymer. For example, drugs with -O-carboxy groups can be coupled to phosphorus via a phosphoester linkage, which is hydrolysable. See Leong, U.S. Patent Nos. 5,194,581 and 5,256,765. The P-O-C group in the base structure also lowers the glass transition temperature of the polymer and, importantly, confers solubility in the common organic solvents, which is desirable for easy characterization and processing. However, the drug delivery systems that use most known biodegradable polymers, including those based on phosphoesters, have been rigid materials. In such cases, the drug is incorporated into the polymer, and the mixture is shaped into a certain shape, such as a cylinder, disc or fiber for implantation. However, proteins and other large biomolecules are still difficult to supply from rigid biodegradable polymers because these larger molecules are particularly unstable and typically degrade together with the vehicle of the solid polymeric matrix. More specifically, when a polymer begins to degrade after administration, the decomposition byproducts of the polymer create a highly concentrated microenvironment as the polymer is ionized, protonated or hydrolyzed. The proteins are denatured or easily degraded under these conditions and therefore are not useful for therapeutic purposes. In addition, during the process of preparing rigid drug delivery systems, biologically active substances such as proteins are normally exposed to extreme adverse situations. The necessary manufacturing steps may include excessive exposure to heat, extreme pH conditions, large amounts of organic solvents, cross-linking agents, freezing and drying. After manufacture or preparation, drug delivery systems must be stored for a somewhat prolonged period prior to administration, and little information is available on the long-term stability of proteins within supply systems. biodegradable solids. Rigid polymers can be inserted into the body in the form of small particles, such as microspheres or microcapsules, with a syringe or catheter. However, because these are still solid particles, they do not form the continuous and nearly homogeneous monolithic matrix that is sometimes needed for the preferred release profiles. In addition, sometimes microspheres or microcapsules, prepared from these polymers and containing biologically active substances that are to be released into the body, are difficult to produce on a large scale. Most microencapsulation procedures involve high temperatures and contact with organic solvents, steps that tend to damage the biological activity of proteins. Moreover, their storage frequently presents problems and, after injecting them, their granulated nature can cause blockages in the injection devices and / or irritation of the soft tissues in which the small particles are injected. Dunn et al., Patents E.U.A Nos. 5,278,201; 5,278,202 and 5,340,849, describe a thermoplastic drug delivery system in which a solid, biodegradable, straight-chain polymer or copolymer is dissolved in a solvent to form a liquid solution. Once the polymer solution is placed in the body, where there is enough water, the solvent dissipates or diffuses away from the polymer allowing it to coagulate or solidify as a solid substance. However, the system requires the presence of a solvent, and it is difficult to find an organic solvent that is sufficiently non-toxic to obtain an acceptable biocompatibility. Therefore, there is a need for a composition and method for delivering a flexible or flowable biodegradable composition that can be used in vivo to release a variety of biologically active substances. different, including hydrophobic drugs and even large and bulky biological macromolecules, such as therapeutically useful proteins, which, preferably, do not require the presence of significant amounts of organic solvent. There is also a continuing need for biodegradable polymer compositions that can deliver controlled release so that trauma to the surrounding soft tissue can be minimized. Coover et al., U.S. Patent No. 3,271, 329, describe organophosphorus polymers prepared from dialkyl or diaryl biphosphites and certain diol compounds, such as 1,4-cyclohexanedimethanol. See column 1, lines 24-31. Vandenberg et al., U.S. Patent No. 3,655,585, describe phosphorus polymers having at least one recurring unit having the formula: wherein R can be alkyl and Z can be alkylene such as cyclohexylene. See column 1, lines 28-55. Herwig et al., U.S. Patent No. 3,875,263, describe diphosphinic acid esters having a cyclic alkylene moiety, for example, 1,4-methylene cyclohexane. See column 1, lines 18-37 and column 2, line 13. However, all these patents suggest that such compounds and polymeric compositions made from such compounds must be extruded or molded to form articles or spun into fibers ( Coover et al.); used as additives for lubricating oils, gasoline and synthetic resins or other polymers (Vandenberg et al., and Herwig et al.); or used as coating compounds (Herwig et al.). These compounds are known to those skilled in the art primarily because they confer high flame resistance and fire-proof characteristics (Coover et al., And Herwig et al.) Or increased stability to oxidation and heat and improved impact resistance ( Vandenberg et al.).

BRIEF DESCRIPTION OF THE INVENTION It has now been discovered that polymer compositions made with poly (cycloaliphatic phosphoester) compounds provide conveniently flexible or flowable vehicles for even large and / or bulky bio-macromolecules, including hydrophobic drugs and even large and bulky bio-macromolecules, such as as the therapeutically useful proteins. The biodegradable polymer composition of the invention consists of a polymer having the recurring monomer units shown in Figure 1: O - O - R - L R '- O P I R " wherein: each of R and R 'is independently a straight or branched aliphatic group, either unsubstituted or substituted with one or more non-interfering substituents; L is a divalent cycloaliphatic group; R "is selected from the group consisting of H, alkyl, alkoxy, aryl, aryloxy, heterocyclic or heterocycloxy, and n is from 5 to 1, 000 wherein the biodegradable polymer composition is biocompatible both before and after biodegradation. Particularly preferred embodiment, one or more than one R, R 'and R "is a biologically active substance in a form that can be released in a physiological medium. The invention also comprises a flexible article useful for implantation, injection or otherwise placed totally or partially within the body, the article consisting of a biodegradable, flexible or flowable polymer composition, consisting of a polymer having the units recurrent monomers shown in formula I wherein R, R ', R ", L and n are as defined above, Even in another embodiment of the invention, a method is provided for the controlled release of a biologically active substance consisting of steps of: (a) combining the biologically active substance with a biodegradable polymer having the recurring monomer units shown in formula I: wherein R, R ', L, R "and n are as defined above, to form a polymer composition that can be implanted or injected; (b) placing the polymer composition formed in step (a) either partially or totally within the body at a preselected site in vivo, such that the polymer composition is at least in partial contact with a biological fluid. Because the compositions of the invention are preferably viscous, "gel-like" materials that can flow or flexible materials, these can be used to deliver a wide variety of drugs, for example, from hydrophobic drugs such as paclitaxel to soluble large macromolecules. in water such as proteins. Even though they can not flow, the compositions of the invention remain flexible and allow the large proteins, at least partially, to diffuse through the matrix before the protein degrades. Therefore, the invention provides a delivery system that is both convenient to be used and to allow the delivery of large bio-macromolecules in an effective manner.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the structure of P (frans-CHDM-HOP) as determined by 31 P-NMR and 1 H-NMR.

Figure 2 shows the chromatogram and the molecular weight distribution for P (c / s- / fra # 7s-CHDM-HOP). Figure 3A graphically represents the active energy as a function of the frequency of P (rans-CHDM-HOP), and Figure 3B shows the dependence of the corresponding viscosity with the temperature. Figure 4A shows HEK293 cells grown on a P surface (CHDM-HOP) after 72 hours of incubation, and Figure 4B shows HEK293 cells grown on a TCPS surface after 72 hours of incubation. Figure 5 graphically depicts the effect of the side chain structure on the in vitro degradation rate of 3 poly (phosphoesters) of the invention in a phosphate-based buffer. Figure 6 shows the release curves of the FITC-BSA bio-macromolecule from polymer P (CHDM-HOP) with a charge of 33%. Figure 7 graphically depicts the in vitro release kinetics of FITC-BSA as a function of loading levels of 30%, 10% and 1%. Figure 8 graphically depicts the in vitro effect of the structure of the side chain on the release kinetics of the FITC-BSA protein at a loading level of 10%.

Figure 9 shows the release of low molecular weight drugs (doxorubicin, cisplatin and 5-f luorouracil) from P (CHDM-HOP). Figure 10 graphically depicts the simultaneous release of cisplatin and doxorubicin from a matrix of P (CHDM-HOP). Figure 11 graphically represents the cumulative percentage of IL-2 released from the P (CHDM-HOP) matrix in phosphate-based buffer as a function of time. Figure 12 shows the calibration curves for the cumulative percentage of release of IL-2 from a matrix of P (CHDM-HOP) in a phosphate-based buffer. Figure 13 compares the pharmacokinetics of IL-2 administered as a subcutaneous bolus or dispersed in a matrix of P (CHDM-HOP). Figure 14 shows the results of a histological examination of a subcutaneous injection site in a Balb / c mouse. Figure 15 shows the distribution of tumor sizes in mice four weeks after tumor implantation in a melanoma-like tumor model in vivo. Figure 16 shows the tumor size distribution in mice six weeks after tumor implantation in a melanoma-like tumor model in vivo.

Figure 17 shows the percentage of survival as a function of time for four different treatment groups in a melanoma-like tumor model in vivo. Figure 18 shows the release curves of two polymer compositions of the invention, one consisting of the chemotherapeutic agent paclitaxel in the polymer P (CHDM-EOP) and the other consisting of paclitaxel in the polymer P (CHDM-HOP). Figure 19 shows the in vitro release curves of lidocaine from three different samples of mixture P (CHDM-HOP) / lidocaine. Figure 20A shows the accumulated amount of lidocaine released in vitro as a function of the incubation time, and Figure 20B shows the release of lidocaine as a function of the square root of time. Figure 21 is a graph of maximum nociceptive effect percentage versus time after in vivo injection of 25 mg lidocaine in P (CHDM-HOP) or in saline. Figure 22 is a graph of the percentage of maximum motor function effect versus time after injection of 25 mg of lidocaine in P (CHDM-HOP) or in saline. Figure 23 shows the concentration of lidocaine in plasma after the injection of 25 mg of lidocaine in saline, 25 mg of lidocaine in P (CHDM-HOP) and 50 mg of lidocaine in P (CHDM-HOP).

DETAILED DESCRIPTION OF THE INVENTION Polymer compositions of the invention As used herein, the term "aliphatic" refers to a linear, branched or cyclic alkane, alkene or alkyne. Preferred linear or branched aliphatic groups in the poly (cycloaliphatic phosphoester) composition of the invention have from 1 to 20 carbon atoms. Preferred cycloaliphatic groups may have one or more sites of unsaturation, ie, double or triple bonds, but they are not aromatic in nature. As used herein, the term "aryl" refers to a cyclic carbon compound unsaturated with 4n + 2 p-electrons. As used herein, the term "heterocyclic" refers to a saturated or unsaturated ring compound having one or more atoms other than the carbon in the ring, for example, nitrogen, oxygen or sulfur. As used herein, the term "non-interfering substituent" means a substituent that does not react with the monomers; that does not catalyze, terminate or otherwise interfere with the polymerization reaction; and that does not react with the resulting polymer chain by intra- or inter-molecular reactions. The biodegradable and injectable polymer composition of the invention consists of a polymer having the recurring monomer units shown in formula I: O - Ì O - R - L - R '- O - P R " wherein each of R and R 'is independently a linear or branched aliphatic group, which is unsubstituted or substituted by one or more non-interfering substituents. Each of R and R 'can be any aliphatic portion so long as the portion does not undesirably interfere with the polymerization or biodegradation reactions of the polymer. Preferably, R and R 'have from 1-20 carbon atoms.

For example, each of R and R 'can be an alkylene group, such as methylene, ethylene, 1,2-dimethylethylene, n-propylene, isopropylene, 2-methylpropylene, 2,2-dimethylpropylene or tert-butylene, n- pentylene, ter-pentylene, n-hexylene, n-heptylene and the like; alkenylene, such as ethynylene, propenylene, dodecenylene, and the like; alkynylene, such as propynylene, hexinylene, octadeceninylene, and the like; an aliphatic group substituted with a non-interfering substituent, for example, an aliphatic group substituted with hydroxy-, halogen or nitrogen. However, preferably, each of R and R 'is a branched or straight-chain alkylene group and, even more preferred, an alkylene group having from 1 to 7 carbon atoms. More preferred, R is a methylene or ethylene group. In one embodiment of the invention, any of R, R 'or both R and R' can be a biologically active substance in a form that can be released in a physiological medium. When the biologically active substance is part of the base structure of poly (phosphoester) in this manner, it is released as the polymer matrix formed by the composition of the invention degrades. Generally speaking, the biologically active substance of the invention can vary widely for the purpose of the composition. The term "biologically active substance" includes, without limitation, drugs; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or condition; substances that affect the structure or function of the body; or prodrugs, which become biologically active or are more active after they have been placed in a predetermined physiological environment. The active substance or active substances can be described as an individual entity or as a combination of entities. Non-limiting examples of broad categories of biologically active substances include the following expanded therapeutic categories: β-adrenergic blocking agents, anabolic agents, androgenic steroids, antacids, antiasthmatic agents, anti-allergenic materials, anti-cholesterole and antilipide agents, anticholinergic and sympathomimetics, anticoagulants, anticonvulsants , antidiarrheals, antiemetics, antihypertensive agents, anti-infective agents, anti-inflammatory agents such as steroids, non-steroidal anti-inflammatory agents, antimalarials, antimanic agents, antinausea agents, antineoplastic agents, anti-obesity agents, antiparkinson agents, antipyretic and analgesic agents, antispasmodic agents, antithrombotic agents, anti-inflammatory agents, antianginal agents, antihistamine agents, antitussives, appetite suppressants, benzophenanthridine alkaloids, biological products, agents steroids, brain dilators, coronary dilators, decongestants, diuretics, diagnostic agents, erythropoietic agents, estrogens, expectorants, gastrointestinal sedatives, humoral agents, hyperglycemic agents, hypnotic agents, hypoglycemic agents, ion exchange resins, laxatives, mineral supplements, miotics, mucolytic agents, neuromuscular drugs, nutritional substances, peripheral vasodilators, progestational agents, prostaglandins, psychic energizers, psychotropics, sedatives, stimulants, thyroid and antithyroid agents, tranquilizers, uterine relaxants, vitamins, antigenic materials and prodrugs. Specific examples of useful biologically active substances from the above categories include: (a) antineoplastic agents such as androgen inhibitors, antimetabolites, cytotoxic agents and immunomodulators; (b) antitussives such as dextromethorphan, dextromethorphan bromohydrate, noscapine, carbetapentane citrate and chlorphedianol hydrochloride; (c) antihistamines such as chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate and phenyltoloxamine citrate; (d) decongestants such as phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride and ephedrine; (e) various alkaloids such as codeine phosphate, codeine sulfate and morphine; (f) mineral supplements such as potassium chloride, zinc chloride, calcium carbonate, magnesium oxide and other alkali metal and alkaline earth metal salts; (g) ion exchange resins such as cholestyramine; (h) antiarrhythmics such as N-acetylprocainamide; (i) antipyretics and analgesics such as acetaminophen, aspirin and ibuprofen; ) appetite suppressants such as phenylpropanolamine hydrochloride or caffeine; (k) expectorants such as guafenesin; (I) antacids such as aluminum hydroxide and magnesium hydroxide; (m) biological products such as peptides, polypeptides, proteins and amino acids, hormones, interferons or cytokines and other bioactive peptide compounds, such as hGH, tPA, calcitomin, ANF, EPO and insulin; (n) anti-infective agents such as antifungals, antivirals, antiseptics and antibiotics and (or) desensitizing agents and antigenic materials such as those useful for vaccine applications. More specifically, the non-limiting examples of useful biologically active substances include the following therapeutic categories: analgesics, such as non-steroidal anti-inflammatory drugs, opiate agonists and salicylates; antihistamines such as Hi blockers and H2 blockers; anti-infective agents such as anthelmintics, antianaerobic agents, antibiotics, aminoglycoside antibiotics, antifungal antibiotics, cephalosporin antibiotics, macrolide antibiotics, various ß-lactam antibiotics, penicillin antibiotics, quinolone antibiotics, sulfonamide antibiotics, tetracycline antibiotics, antimycobacterials, antimicrobial antituberculosis, antiprotozoa, antimalarial antimalarials, antiviral agents, antiretroviral agents, scabicides, and urinary anti-infectives; neoplastic agents, such as alkylating agents, nitrogenous mustard alkylating agents, nitrosourea alkylating agents, antimetabolites, purine analog antimetabolites, pyrimidine analog antimetabolites, hormonal antineoplastic agents, natural antineoplastic agents, natural antibiotic antineoplastic agents, and natural alkaloid antineoplastic agents of vinca; autonomic agents, such as anticholinergics, anticholinergic antimuscarinics, ergot alkaloids, parasympathomimetics, parasympathomimetic cholinergic agonists, parasympathomimetic cholinesterase inhibitors, sympatholytics, sympatholytics-blockers, sympatholytics ß-blockers, sympathomimetics, and sympathomimetics adrenergic agonists; cardiovascular agents, such as antianginal, antianginal ß-blockers, antianginal calcium channel blockers, antianginal nitrate-based, antiarrhythmics, cardiac glycoside antiarrhythmics, class I antiarrhythmics, class II antiarrhythmics, class III antiarrhythmics, class IV antiarrhythmics, antihypertensive agents, antihypertensive agents, antihypertensive blockers, angiotensin convertase enzyme inhibitors (ACE inhibitor), anti-hypertensive agents, blockers, calcium channel blocker antihypertensives, central nervous system antihypertensive drugs, antihypertensive agents, diuretics , antihypertensive peripheral vasodilators, antilipidemic agents, antilipidemic bile acid sequestrants, antilipidemic inhibitors of HMG-CoA reductase, inotropes, cardiac inotropes of glycoside and thrombolytic agents; dermatological agents, such as antihistamines, anti-inflammatory agents, anti-inflammatory agents based on corticosteroids, antipruritics / local anesthetics, topical anti-infectives, topical anti-fungal antifungal agents, topical anti-viral antiviral and topical antineoplastic agents; electrolytic and renal agents, such as acidifying agents, alkalizing agents, diuretics, carbonic anhydrase inhibitor diuretics, loop-level diuretics, osmotic diuretics, potassium-sparing diuretics, thiazide-based diuretics, electrolyte replacements, and uricosuric agents; enzymes such as pancreatic enzymes and thrombolytic enzymes; gastrointestinal agents such as antidiarrheals, antiemetics, gastrointestinal antiinflammatory agents, salicylate-based gastrointestinal antiinflammatory agents, antacid antiulcer agents, gastric acid pump inhibitor antiulcer agents, gastric mucosal antiulcer agents, H2 blockers antiulcer agents, colelitolytic agents, digestive, emetic, laxative and stool softeners and prokinetic agents; general anesthetics such as anesthetics by inhalation, halogenated anesthetics by inhalation, intravenous anesthetics, intravenous anesthetics based on barbiturates, intravenous anesthetics based on banzodiazepine and intravenous anesthetics opiate agonists, hematological agents such as antianemic agents, hematopoietic antianemic agents, coagulation agents , anticoagulants, hemostatic coagulation agents, platelet inhibiting coagulation agents, thrombolytic enzyme coagulation agents and plasma volume expanders; hormones and hormone modifiers such as abortion inducers, adrenal agents, adrenal corticosteroid agents, androgens, antiandrogens, antidiabetic agents, antibiabetic agents based on sulfonylurea, antihipoglycemic agents, oral contraceptives, progestin contraceptives, estrogens, fertility agents, oxytocics , parathyroid agents, pituitary hormones, progestins, antithyroid agents, thyroid and tocolytic hormones; immunobiological agents such as immunoglobulin, immunosuppressants, toxoids and vaccines; local anesthetics such as local anesthetics based on amide and local anesthetics on ester bases; musculoskeletal agents such as anti-gout anti-inflammatory agents, anti-inflammatory agents based on corticosteroids, anti-inflammatory agents based on gold compounds, anti-inflammatory immunosuppressive agents, nonsteroidal anti-inflammatory drugs (NSAIDs), anti-inflammatory agents based on salicylate, skeletal muscle relaxants, muscle relaxants, skeletal muscle neuromuscular and muscle relaxant blockers of reverse neuromuscular blockers; neurogenic agents such as anticonvulsants, barbiturate-based anticonvulsants, benzodiazepine-based anticonvulsants, antimigraine agents, antiparkinson agents, antimalarial agents, opioid agonists and opiate antagonists, ophthalmic agents such as anti-glaucoma agents, anti-glaucoma-blocking agents, miotic antiglaucoma agents, mydriatics, mydriatics, adrenergic agonists, antimuscarinic mydriatics, ophthalmic anesthetics, ophthalmic antiinfectives, aminoglycoside-based ophthalmic antiinfectives, macrolide-based ophthalmic antiinfectives, quinolone-based ophthalmic antiinfectives, sulfonamide-based ophthalmic antiinfectives, tetracycline-based ophthalmic anti-infectives, anti-inflammatory ophthalmic agents, anti-inflammatory ophthalmic agents based on corticosteroids and non-steroidal anti-inflammatory ophthalmic drugs (NSAIDs); psychotropic agents, such as antidepressants, heterocyclic antidepressants, monoamine oxidase inhibitors (MAOI), selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants, antimanyatics, antipsychotics, phenothiazine-based antipsychotics, anxiolytics, sedatives and hypnotics, sedatives and hypnotics based on barbiturate, anxiolytics, sedatives and hypnotics based on benzodiazepine, and psychostimulants; respiratory agents such as antitussives, bronchodilators, adrenergic agonist bronchodilators, muscarinic bronchodilator agents, expectorants, mucolytic agents, anti-inflammatory respiratory agents and anti-inflammatory respiratory agents based on corticosteroids; toxicological agents such as antidotes, heavy metal antagonists / chelators, substance abuse agents, substance abuse prevention agents and agents for substance abuse abstinence syndrome; minerals and vitamins such as vitamin A, vitamin B, vitamin C, vitamin D, vitamin E and vitamin K. Preferred classes of useful biologically active substances from the above categories include: (1) nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics such as diclofenac, ibuprofen, ketoprofen and naproxen; (2) analgesic opioid agonists, such as codeine, fentanyl, hydromorphone and morphine; (3) salicylate-based analgesics, such as aspirin (ASA) (ASA with enteric coating); (4) anti-histamine H-i blockers, such as clemastine and terfenadine; (5) H2-blocking antihistamines, such as cimetidine, famotidine, nizadine and ranitidine; (6) anti-infective agents, such as mupirocin; (7) antianaerobic anti-infective agents such as chloramphenicol and clindamycin; (8) antifungal antibiotic anti-infective agents such as amphotericin b, clotrimazole, fluconazole and ketoconazole; (9) macrolide antibiotic anti-infective agents, such as azithromycin and erythromycin; (10) Anti-infectives of different deoß-lactam antibiotics, such as aztreonam and imipenema; (1 1) anti-infectives of penicillin antibiotics, such as nafcillin, oxacillin, penicillin G, and penicillin V; (12) anti-infectious quinolone antibiotics such as ciprofloxacin and norfloxacin; (13) anti-infectives of tetracycline antibiotics, such as doxycycline, minocycline and tetracycline; (14) antimicrobial anti-tuberculosis drugs such as isoniazid (INH), and rifampin; (15) antiprotozoal antiinfective agents such as atovaquone and dapsone; (16) anti-malarial antiprotozoal antimalarial agents, such as chloroquine and pyrimethamine; (17) antiretroviral anti-infective agents such as ritonavir and zidovudine; (18) antiviral antiinfective agents such as acyclovir, ganciclovir, interferon alfa and rimantadine; (19) alkylating antineoplastic agents such as carboplatin and cisplatin; (20) alkylating nitrosourea based antineoplastic agents, such as carmustine (BCNU); (21) anti-metabolite antineoplastic agents such as methotrexate; (22) pyrimidine-like antimetabolite antimetabolite agents such as fluorouracil (5-FU) and gemcitabine; (23) hormonal antineoplastic agents such as goserelin, leuprolide and tamoxifen; (24) natural antineoplastic agents such as aldesleukin, interleukin-2, docetaxel, etoposide (VP-16), interferon alpha, paclitaxel, and tretinoin (ATRA); (25) natural antineoplastic agents of antibiotic type such as bleomycin, dactinomycin, daunorubicin, doxorubicin and mitomycin; (26) natural vinca alkaloid antineoplastic agents, such as vinblastine and vincristine; (27) autonomic agents such as nicotine; (28) anticholinergic autonomic agents such as benzotropin and trihexyphenidyl; (29) anticholinergic anticholinergic autonomic agents such as atropine and oxybutynin; (30) autonomic ergot alkaloid agents such as bromocriptine; (31) parasympathomimetic cholinergic agonists such as pilocarpine; (32) parasympathomimetic cholinesterase inhibitors such as pyridostigmine; (33) sympatholytic α-blockers such as prazosin; (34) ß-blocker sympatholytics such as atenolol; (35) sympathomimetic adrenergic agonists, such as albuterol and dobutamine; (36) cardiovascular agents such as aspirin (ASA) (ASA with enteric coating); (37) antianginal β-blockers such as atenolol and propranolol; (38) antianginal calcium channel blockers such as niferipine and verapamil; (39) nitrate-based antiaginous agents such as isosorbide dinitrate (ISDN); (40) cardiac antiarrhythmics based on glycoside such as digoxin; (41) class I antiarrhythmics such as lidocaine, mexiletine, phenytoin, procainamide, and quinidine; (42) Class II antiarrhythmics, such as atenolor, metoprolor, propranolol, and timolol; (43) class III atiarrhythmics such as amiodarone; (44) class IV antiarrhythmics, such as diltiazem and verapamil; (45) antihypertensives to blockers such as prazosin; (46) hypertensive angiotensin convertase enzyme inhibitors (ACE inhibitor), such as captopril and enalapril; (47) β-blocker antihypertensives such as atenolol, metoprolol, nadolol and propanolol; (48) hypertensive agents blocking the calcium channel, such as diltiazem and nifedipine; (49) adrenergic antihypertensives that act on the central nervous system, such as clonidine and methyldopa; (50) diuretic antihypertensive agents such as amiloride, furosemide and hydrochlorothiazide (HCTZ) and spironolactone; (51) Peripheral vasodilator antihypertensive drugs such as hydralazine and minoxidil; (52) antilipidemic agents such as gemfibrozil and probucol; (53) antilipidemic bile acid sequestrants such as cholestyramide; (54) antilipidemic HMG-CoA reductase inhibitors, such as lovastatin and pravastatin; (55) inotropes such as amrinone, dobutamine, and dopamine; (56) cardiac glycoside inotropes, such digoxin; (57) thrombolytic agents such as alteplase (TPA), anistreplase, streptokinase and urokinase; (58) dermatological agents such as colchicine, isotretinoin, methotrexate, minoxidil, tretinoin (ATRA); (59) dermatological anti-inflammatory agents based on corticosteroid, such as betamethasone and dexamethasone; (60) topical anti-fungal anti-infectives such as amphotericin B, clotrimazole, miconazole and nystatin; (61) topical antiviral anti-infectives such as acyclovir; (62) topical antineoplastic agents such as fluorouracil (5-FU); (63) electrolytic and renal agents such as lactulose; (64) loop level diuretics such as furosemide; (65) Potassium-conserving diuretics such as triamterene; (66) thiazide-based diuretics such as hydrochlorothiazide (HCTZ); (67) uricosuric agents such as probenecid; (68) enzymes such as RNase and DNase; (69) thrombolytic enzymes such as alteplase, anistreplase, streptokinase and urokinase; (70) antiemetics such as prochlorperazine; (71) Salicylate-based gastrointestinal anti-inflammatory agents, such as sulfasalazine; (72) anti-ulcer agents inhibiting the gastric acid pump, such as omeprazole; (73) H2-blocking anti-ulcer agents such as cimetidine, famotidine, nizatidine and ranitidine; (74) digestives such as pancrelipase; (75) prokinetic agents such as erythromycin; (76) intravenous anesthetic agents opiate agonists such as fentanyl; (77) hematopoietic anti-anemic agents such as erythropoietin, filgrastim (G-CSF), and sargramostima (GM-CSF); (78) coagulation agents such as antihemophilic factors 1-10 (AHF 1-10); (79) anticoagulant agents such as warfarin; (80) thrombolytic enzyme coagulation agents such as alteplase, anistreplase, streptokinase and urokinase; 881) hormones and hormone modifiers such as bromocriptine; (82) abortion inducers such as methotrexate; (83) antidiabetic agents such as insulin; (84) oral contraceptives such as estrogen and progestin; (85) progestin-based contraceptives such as levonorgestrel and norgestrel; (86) estrogens such as conjugated estrogens, diethylstilbestrol (DES), estrogens (estradiol, estrone, and estropipate); (87) fertility agents such as clomiphene, human chorionic gonadotropin (HCG), and menotropins; (88) parathyroid agents such as calcitonin; (89) pituitary hormones such as desmopressin, goserelin, oxytocin and vasopressin (ADH); (90) progestins such as medroxyprogesterone, noretrindrone and progesterone; (91) thyroid hormones, such as levothyroxine; (92) immunobiological agents such as interferon beta-1 b and interferon gamma-1 b; (93) immunoglobulins, such as IM immunoglobulins, IMIG, IGIM and immunoglobulins IV, IVIG, IGIV; (94) local anesthetics based on amides such as lidocaine; (95) local anesthetics based on ester such as benzocaine and procaine; (96) anti-inflammatory agents based on musculoskeletal corticosteroids such as beclomethasone, betamethasone, cortisone, dexamethasone, hydrocortisone and prednisone; (97) musculoskeletal anti-inflammatory immunosuppressants such as azathioprine, cyclophosphamide and methotrexate; (98) nonsteroidal musculoskeletal anti-inflammatory drugs (NSAIDs), such as diclofenac, buprofen, ketoprofen, ketorolac and naproxen; (99) skeletal muscle relaxant such as baclofen, cyclobenzaprine and diazepam; (100) Inverted neuromuscular blocker skeletal muscle relaxants such as pyridostigmine; (101) neurogenic agents such as nimodipine, riluzole, tacrine and ticlopidine; (102) anticonvulsants such as carbamazepine, gabapentin, lamotrigine, phenytoin and valproic acid; (103) anticonvulsants based on barbiturates such as phenobarbital and primidone; (104) benzodiazepine-based anticonvulsants such as clonazepam, diazepam and lorazepam; (105) Antiparkinsonian agents such as bromocriptine, levodopa, carbidopa and pergolide; (106) anti-aging agents such as meclizine; (107) opioid agonists such as codeine, fentanyl, hydromorphone, methadone and morphine; (108) opioid antagonists such as naloxone; (109) β-blocker antiglaucoma agents such as timolol; (1 10) miotic antiglaucoma agents such as pilocarpine; (111) aminoglycoside-based ophthalmic antiinfectives such as gentamicin, neomycin and tobramycin; (12) quinolone ophthalmic antiinfectives such as ciprofloxacin, norfloxacin and ofloxacin; (13) ophthalmic anti-inflammatory agents based on corticosteroids such as dexamethasone and prednisolone; (114) Non-steroidal ophthalmic anti-inflammatory drugs (NSAIDs), such as diclofenac; (15) antipsychotics such as clozapine, haloperidol and risperidone; (116) sedative and hypnotic anxiolytics based on benzodiazepine such as clonazepam, diazepam, lorazepam, oxazepam and prazepam; (117) psychostimulants such as methylphenidate and pemoline; (118) antitussives such as codeine; (119) bronchodilators such as theophylline; (120) adrenergic agonist bronchodilators such as albuterol; (121) corticosteroid respiratory antiinflammatory agents, such as dexamethasone; (122) antidotes such as flumazenil and naloxone; (123) heavy metal antagonist / chelating agents such as penicillamine; (124) agents to prevent substance abuse, such as disulfiram, naltrexone and nicotine; (125) agents for abstinence syndrome from substance abuse such as bromocriptine; (126) minerals such as iron, calcium and magnesium; (127) vitamin B compounds, such as cyanocobalamin, (vitamin B-12) and niacin (vitamin B3); (128) vitamin C compounds, such as ascorbic acid; e (129) vitamin D compounds such as calcitriol. In addition to the above, the following less common drugs may also be used: chlorhexidine; oestradiol cypionate in oil; estradiol valerate in oil; flurbiprofen, flurbiprofen sodium; ivermectin; levodopa; nafarelin and somatropin. In addition, the following new drugs can also be used: recombinant beta-glucan; bovine immunoglobulin concentrate; bovine superoxide dismutase; The formulation consists of fluorouracil, epinephrine and bovine collagen; hirudin (r-Hir) recombinant, HIV-1 immunogen; anti-CT antibody from human; recombinant human growth hormone (r-hGH); hemoglobin (r-Hb) of recombinant human; mercasermin (r-IGF-1) of recombinant human; recombinant beta-1 a interferon; lenograstim (G-CSF); olanzapine; recombinant thyroid stimulating hormone (r-TSH); and topotecano. Additionally, the following intravenous products may be used: acyclovir sodium; aldesleukin; atenolol; bleomycin sulfate, human calcitonin; salmon calcitonin; carboplatin; carmustine; dactinomycin, daunorubicin hydrochloride; docetaxel; Doxorubicin hydrochloride; epoetin alfa; etoposide (VP-16); flurouracil (5-FU); ganciclovir sodium; gentamicin sulfate; interferon alfa; leuprolide acetate; meperidine HCl; methadone HCl; sodium methotrexate; paclitaxel; ranitidine hydrochloride; vinblastine sulfate; and zidovudine (AZT). Also, the following list of peptides, proteins and other large molecules can be used, such as interleukins 1 to 18, including mutants and analogues; interferons a, ß, and?; luteinizing hormone-releasing hormone (LHRH) and its analogues, gonadotropin releasing hormone (GnRH), transforming growth factor-β (TGF-β); fibroblast growth factor (FGF); tumor necrosis factor-a and ß (TNF-a and ß); nerve growth factor (VGF); growth hormone releasing factor (GHRF); epidermal growth factor (EGF); homologous factors of fibroblast growth factor (FGFHF); hepatocyte growth factor (HGF); insulin growth factor (IGF); platelet-derived growth factor (PDGF); invasion inhibition factor-2 (I I F-2); bone morphogenetic proteins 1-7 (BMP 1-7); somatostatin; thymosin-a-1; ?-globulin; superoxide dismutase (SOD); and complement factors. Alternatively, the biologically active substance can be nucleic acids consisting of nucleotides attached to polynucleotide chains with base structures consisting of alternating series of pentose sugars and phosphate residues. One way to avoid the complications of systems based on cell development for delivering genes to patients in gene therapy is to deliver retroviral vectors directly to the target cells. For example, this technique has been used to infect endothelial cells in the walls of blood vessels. The polymers and the composition of the invention can be used for the direct delivery of such retroviral vectors and / or genetic materials related to other sites in vivo, for example, to the lungs to treat diseases in the lungs, such as cystic fibrosis, or to treat tumors in any localized portion of the body. Preferably, the biologically active substance is selected from the group consisting of peptides, polypeptides, proteins, amino acids, polysaccharides, growth factors, hormones, anti-angiogenesis factors, interferons or cytokines, antigenic materials, and prodrugs. In a particularly preferred embodiment, the biologically active substance is a therapeutic drug or prodrug, more preferably a drug that is selected from the group consisting of chemotherapeutic agents and other antineoplastic agents such as paclitaxel, antibiotics, antivirals, antifungals, anti-inflammatories, and anticoagulants, useful antigens for vaccine applications or the corresponding prodrugs. Various forms of the biologically active agents can be used. These include, without limitation, forms such as uncharged molecules, molecular complexes, salts, ethers, esters, amides and the like, which are biologically activated when implanted, injected or otherwise placed in the body. L in the polymer composition of the invention can be any divalent cycloaliphatic group insofar as it does not interfere with the polymerization or biodegradation reactions of the polymer of the composition. Specific examples of useful L groups include unsubstituted and substituted cycloalkylene groups, such as cyclopentylene, 2-methyl-cyclopentylene, cyclohexylene, 2-chlorocyclohexylene and the like; cycloalkylene groups having additional ring structures bridged or fused on one or more sides, such as tetralinylene, decalinylene, and norpinanylene; or similar. R "in the polymer composition of the invention is an alkyl, alkoxy, aryl, aryloxy, heterocyclic or heterocycloxy residue Examples of useful R" alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, -C8H17, and similar groups; alkyl substituted with a non-interfering substituent, such as a halogen group; the corresponding alkoxy groups and alkyl which is conjugated with a biologically active substance to form a pendant drug delivery system. When R "is alkyl or alkoxy, it preferably contains from 2 to about 20 carbon atoms, even more preferred from 6 to 15 carbon atoms When R" is aryl or the corresponding aryloxy group, it typically contains from 5 to 14. carbon atoms, preferably from 5 to 12 carbon atoms and, optionally, may contain one or more rings that are fused to one another. Examples of particularly suitable aromatic groups include phenyl, phenoxy, naphthyl, anthracenyl, phenanthrenyl and the like. When R "is a heterocyclic or heterocycloxy group, it typically contains from 5 to 14 ring atoms, preferably from 5 to 12 ring atoms and one or more heterogeneous atoms Examples of suitable hetocyclic groups include furan, thiophene, pyrrole, isopyrrole, 3-isopyrrole, pyrazole, 2-isoimidazoI, 2-isoimidazole, 1, 2,3-triazole, 1, 2,4-triazole, oxazole, thiazole, isothiazole, 1,2,3-oxadiazole 1, 2,4-oxadiozole, 1, 2,5-oxadiazole, 1,4-oxadiazole, 1, 2,3,4-oxatriazole, 1, 2,3,5-oxatriazole, 1, 2,3 - dioxazole, 1,4-dioxazole, 1,2-d-oxazole, 1,3-d-dioxazole, 1, 2,5-oxatriazole, 1,3-oxathiol, 1,2-pyran, 1,4-pyran, 1,2-pyrone, 1,4-pyrone, 1,2-dioxin, 1,3-dioxin, pyridine, N-alkylpyridinium, pyridazine, pyrimidine, pyrazine, 1,3-triazine, 1, 2,4-triazine, 1, 2,3-triazine, 1, 2,4-oxazine, 1,2-oxazine, 1, 3,5-oxazine, 1,4-oxazine, o-isoxazine, p-isoxazine, 1, 2,5-oxathiazine, 1, 2,6-oxathiazine, 1, 4, 2-oxadiazine, 1, 3,5,2-oxadiazine, azepine, oxepine, tiepine, 1, 2, 4- d azepine, indene, soindene, benzofuran, isobenzofuran, thionaphthene, 1,4-pyrindine, pyrazo [3,4-b] -pyrrole, isoindazole, indoxazine, benzoxazole, anthranil, 1,2-benzopyran, 1-2. benzopyrone, 1,4-benzopyrone, 2,1-benzopyrone, 2,3-benzopi Rona, quinoline, isoquinoline, 12-benzodiazine, 1,3-benzodiazine, napthyridine, pyrido [3,4-bjpyridine, 1, 3,2-benzoxazine, 1,4-benzoxazine, 1,4-benzisoxazine, 3 , 1,4-benzoxazine, 1,2-benzisoxazine, 1,4-benzisoxazine, carbazole, xanthrene, acridine, purine, and the like. Preferably, when R "is heterocyclic or heterocycloxy, it is selected from the group consisting of furan, pyridine, N-alkylpyridine, 1, 2,3- and 1, 2,4-triazoles, indene, anthracene, and purine rings. In a particularly preferred embodiment, R "is an alkyl group, an alkoxy group, a phenyl group, a phenoxy group, or a heterocycloxy group and, even more preferably, an alkoxy group having from 1 to 10 carbon atoms. More preferred, R "is an ethoxy or hexyloxy group Alternatively, the side chain R" may be a biologically active substance that is attached in a pendant manner to the base structure of the polymer, for example by ionic or covalent binding. In this hanging system, the biologically active substance is released as the bond that connects R "with the phosphorus atom is broken under physiological conditions.The number" n "can vary quite a lot depending on the capacity of biodegradation and the characteristics of desired release in the polymer, but typically ranges from 5 to 1000. Preferably, n ranges from 5 to 500 and, more preferably, from 5 to about 200.

The polymer molecular weight used in the composition of the invention can vary widely, but must remain low enough for the polymer to maintain its flowable or flexible state. For example, the weight average molecular weights (Mw) typically range from 2000 to about 400,000 daltons, preferably from about 2000 to about 200,000 daltons and more preferably, from 2000 to 50,000 daltons. The number average molecular weight (Mn) can also vary widely, but generally falls in the range of about 1000 to 200,000 daltons, preferably from 1000 to about 100,000 daltons and more preferably, from 1000 to about 25,000 daltons. Biodegradable polymers differ from non-biodegradable polymers in the sense that they can be degraded during in vivo therapy. This generally involves the breakdown of the polymer in its monomeric subunits. In principle, the final products of the hydrolytic cleavage of the polymer used in the invention are a cycloaliphatic diol, an aliphatic alcohol and phosphate. All these degradation products are potentially non-toxic. However, the intermediate oligomeric products of the hydrolysis may have different properties. Therefore, the toxicology of a biodegradable polymer designed for injection or to place it totally or partially within the body, even one that is synthesized from seemingly innocuous monomeric structures, is typically determined after one or more toxicology analyzes.

There are different ways of testing the toxicity and / or biocompatibility known to those skilled in the art. A typical test for in vitro toxicity, however, should be performed with live carcinoma cells, such as the GT3TKB tumor cells, as follows: Two hundred microliters of various concentrations of the degraded polymer products are placed in culture plates of tissue from 96 cavities seeded with human gastric carcinoma cells (GT # TKB) at a density of 10 / cavity. The degraded polymer products are incubated with the GT3TKB cells for 48 hours. The results can be plotted as% relative growth versus concentration of degraded polymer in the cavity of tissue cultures. Polymers that are used in medical applications, such as drug delivery systems, can also be evaluated by well-known in vivo biocompatibility tests, such as by subcutaneous implantation or injection in rats to confirm that the system hydrolyzes without significant levels of irritation or inflammation at the insertion site. The biodegradable polymer used in the invention is preferably sufficiently pure to be biocompatible with itself and remain biocompatible after biodegradation. By the term "biocompatible" it is meant that the biodegradation products of the polymer itself are non-toxic and result in only minimal tissue irritation when injected or placed in intimate contact with vascularized tissues. The requirement for biocompatibility is more readily achieved due to the presence of an organic solvent that is not required in the composition of the polymer of the invention. However, the polymer used in the invention is preferably soluble in one or more common organic solvents for ease of synthesis, purification and handling. Common organic solvents include solvents such as ethanol, chloroform, dichloromethane, acetone, ethyl acetate, DMAC, N-methyl pyrrolidone, dimethylformamide and dimethyl sulfoxide. The polymer is preferably soluble in at least one of the above solvents. The polymer of the invention may also consist of additional biocompatible monomer units so long as they do not interfere with the desired biodegradable characteristics and flow characteristics of the invention. Such additional monomer units can even offer greater flexibility in the design of the desired precise release profile for the delivery of target drugs or the precise rate of biodegradation desired for other applications. When such additional monomer units are used, however, these must be used in amounts small enough to ensure the production of a biodegradable copolymer having the desired physical characteristics, such as viscosity, flowability, flexibility or morphology. Example of such additional biocompatible monomers include the recurring units found in other poly (phosphoesters), poly (Iactida), poly (glycolides), poly (caprolactone), poly (anhydrides), poly (amides), poly (urethanes), poly ( steramides), poly (orthoesters), poly (dioxanone), poly (acetals), poly (ketals), poly (carbonates), poly (orthocarbonates), poly (phosphazenes), poly (hydroxybutyrates), poly (hydroxyvalerate), poly ( alkylenoxalates), poly (alkylene succinates), poly (malic acid), poly (amino acids), poly (vinylpyrrolidone), poly (ethylene glycol), poly (hydroxycellulose), chitin, chitosan, and copolymers, terpolymers or combinations or mixtures of the above materials . When additional monomer units are used, those that have a lower degree of crystallization and that are more hydrophobic are preferred. Especially preferred recurring units with the desired physical characteristics are those obtained from poly (lactides), poly (caprolactones), and copolymers thereof with glycolides in which there are more amorphous regions.

Synthesis of poly (cycloaliphatic phosphoester) polymers The most common general reaction for preparing poly (phosphates) is a dehydrochlorination between a phosphorus dichlorhidate and a diol according to the following equation: O II n Cl-P-Cl n HO- R- OH P- O- R- O 2n HCl II OR 'OR' Most pol i (phosphonates) are also obtained by condensation between appropriately substituted dichlorides and diols . Poly (phosphites) have been prepared from glycols in a two step condensation reaction. A molar excess of 20% of a dimethyl phosphite is used to make it react with the glycol, followed by the removal of the end groups methoxyphosphils in the oligomers by high temperature. An advantage of the polycondensation in the molten state is that it avoids the use of solvents and large amounts of other additives, thus making the purification more straight. It can also supply reasonably high molecular weight polymers. However, a little stringent conditions are frequently required and can lead to acidification of the chain (or hydrolysis if water is present). Thermally induced undesired side reactions, such as crosslinking reactions, may also occur if the base structure of the polymer is susceptible to subtraction of the hydrogen atom or oxidation with subsequent recombination of macro radicals. To minimize these secondary reactions, the polymerization can also be carried out in solution. Polycondensation in solution requires that both the prepolymer and the phosphorus component be soluble in a common solvent. Typically, a chlorinated organic solvent, such as chloroform, dichloromethane or dichloroethane, is used.

The solution polymerization is preferably run in the presence of equimolar amounts of the reactants and a stoichiometric amount of an acid acceptor, usually a tertiary amine such as pyridine or triethylamine. The product is then isolated from the solution typically by precipitation in a non-solvent and purified to remove the hydrochloride salt by conventional techniques known to those skilled in the art, such as by washing with an aqueous acid solution, for example diluted HCl. The reaction times tend to be prolonged with the polymerization in solution than with the polymerization in the molten state. However, because milder overall reaction conditions can be used, side reactions are minimized, and more sensitive functional groups can be incorporated into the polymer. In addition, obtaining undesirably high molecular weights is less likely with solution polymerization. The interfacial polycondensation can be used when high reaction rates are desired. The mild conditions used minimize the side reactions and there is no need for a stoichiometric equivalence between the diol and the dichlorhidate starting materials as in the solution methods. However, hydrolysis of the acid chloride may occur in the alkaline aqueous phase. Sensitive diclohidates that have a little solubility in water are generally subjected to hydrolysis instead of polymerization. Phase transfer catalysts, such as crown ethers or tertiary ammonium chloride can be used to bring the ionized diol to the interface to facilitate the polycondensation reaction. The yield and molecular weight of the resulting polymer after inter-face polycondensation are affected by the reaction time, the molar ratio of the monomers, the volume ratio of the immiscible solvents, the type of acid acceptor, and the type and concentration of the phase transfer catalyst. In a preferred embodiment of the invention, the biodegradable polymer of formula I is prepared by a process comprising the step of reacting a diol having the formula: HO-RL-R'-OH wherein R, R 'and L they are as defined above, with a phosphorodihalidate of formula II: OR II halo - P - halo R " wherein "halo" is Br, Cl or I, and R "is as defined above, to form the polymer of formula I. The diol HO-RL-R'-OH can be prepared by standard chemistry procedures, and many such compounds can be obtained on a commercial basis.

When either R or R 'is a biologically active substance, the biologically active substance is preferably the diol itself, for example, a steroid such as an estradiol. Alternatively, the biologically active substance can be a diamino compound that is reacted with the carboxyl group of a carboxylic acid to produce terminal hydroxyl groups that can be used to form the poly (phosphoester) structure. The purpose of the polymerization reaction is to form a polymer consisting of (i) recurrent cycloaliphatic units and (ii) recurrent phosphoester units. The result can be a homopolymer, a relatively homogeneous copolymer, or a block copolymer having a little heterogeneous microcrystalline structure. Any of these three modalities are appropriate to be used as a controlled release means. The process used to make the polymers used in the invention can be carried out at temperatures that vary widely, depending on whether a solvent is used or not, and also what is used; the desired molecular weight; the desired solubility; the susceptibility of the reagents to form secondary reactions and the presence of a catalyst. Preferably, however, the process is carried out at a temperature ranging from 0 to approximately + 235 ° C for the conditions in the molten state. Slightly lower temperatures, for example, from minus 50 to about 100 ° C, may be possible with polymerization in solution or using a cationic or anionic catalyst. The time required for the process can also vary widely, depending on the type of reaction being used, the molecular weight desired and, in general, the need to use more or less stringent conditions for the reaction to proceed to the desired degree of completion. Typically, however, the process is carried out for a time between 30 minutes and 4 days. While the process may be in volume, in solution, by interfacial polycondensation, or any other convenient polymerization method, preferably, the process is carried out under solution conditions. Particularly useful solvents include methylene chloride, chloroform, tetrahydrofuran, dimethyl formamide, dimethyl sulfoxide, toluene or any of a wide variety of other inert organic solvents. When the solution polymerization reaction is particularly used, an acid acceptor is advantageously present during the polymerization reaction. A particularly suitable class of acid acceptors consists of tertiary amines such as pyridine, trimethyl amine, triethyl amine, substituted aniline and substituted aminopyridine. The most preferred acid acceptor is the substituted aminopyridine 4-dimethylaminopyridine ("DMAP"). The addition sequence for the solution polymerization can vary significantly depending on the relative reactivities of the diol; the phosphorodihalidate of the formula II; the purity of these reagents; the temperature at which the polymerization reaction is carried out; the degree of agitation used in the polymerization reaction and the like. Preferably, however, the diol is combined with a solvent and an acid acceptor, and then the phosphorus dihalidate is added slowly. For example, a solution of the phosphorus dihalidate in a solvent can be drained in, or added dropwise to the cooled reaction mixture of the diol, solvent and acid acceptor, to control the speed of the polymerization reaction. The polymer of formula I is isolated from the reaction mixture by conventional techniques, such as by precipitation, extraction with an immiscible solvent, evaporation, filtration, crystallization and the like. However, typically the polymer of formula I is either isolated or purified by quenching a solution of the polymer with a non-solvent or partial solvent, such as diethyl ether or petroleum ether.

Biodegradability and Release Characteristics The polymer of formula I is usually characterized by a rate of biodegradation that is controlled at least in part as a function of the hydrolysis of the phosphoester linkage of the polymer. Other factors are also important. For example, the lifetime of a biodegradable polymer in vivo also depends on its molecular weight, crystallinity, biostability and the degree of crosslinking. In general, the higher the molecular weight, the greater the degree of crystallinity, and the greater the biostability, the lower the biodegradation. In addition, the degradation rate of the polymer can be further controlled by choosing a side chain of different lengths. Accordingly, the degradation times can vary widely, preferably from less than one day to several months. Accordingly, the structure of the secondary chain can influence the release behavior of the compositions consisting of a biologically active substance. For example, it is expected that the conversion of the secondary chain of phosphate to a lipophilic, more hydrophobic or bulky group would decrease the degradation process. Therefore, the release is usually faster from polymer compositions with a minor chain of aliphatic group than with a voluminous aromatic secondary chain. Further, when R and / or R 'in the portion of the base structure of formula I are themselves biologically active substances, the rate of release of the biologically active substance in vivo is governed primarily by the rate of biodegradation. When the biologically active substance to be released is conjugated to the phosphorus secondary chain R "to form a pendant drug delivery system, the release profile is governed to a significant degree by the brittleness of the phosphorus bond / R". The mechanical properties of the polymer are also important with respect to the flowability or flexibility of the composition containing the polymer. For example, the glass transition temperature is preferably low enough to keep the composition of the invention fluid at body temperature. Even more preferred, the glass transition temperature of the polymer used in the invention is from about 0 to 37 ° C, and more preferably, from 0 to about 25 ° C.

Polymer compositions The polymer composition of the invention can be a flexible or flowable material. By "can flow" is meant the ability to assume, over time, the shape of the space that contains it at body temperature. This includes, for example, liquid compositions that are capable of being sprayed on a site; injected with a manually operated syringe adapted with, for example, a 23 gauge needle; or delivered through a catheter. Also included by the term "can flow", however, are the highly viscous "gel-like" materials at room temperature that can be supplied to the desired site by decanting, squashing a tube, or being injected with any of the commercially available injection systems that provide higher injection pressures than those that could be exerted by manual means alone for highly viscous materials that are still fluid. When the polymer used is itself fluid, the polymer composition of the invention, even when it is viscous, need not include a biocompatible solvent to be fluidized, although trace or residual amounts of biocompatible solvents may still be present. The viscosity of the polymer can be adjusted by the molecular weight of the polymer, as well as by mixing the cis- and trans- isomers of the cyclohexanedimethanol in the base structure of the polymer. Even without the presence of a biologically active substance, the polymer composition of the invention can be used for a variety of medical applications. For example, it can be injected to form, after injection, a temporary biomechanical barrier to coat or encapsulate internal organs or tissues, such as barriers used to prevent adhesions after abdominal surgery. The polymer composition of the invention can also be used to produce bone waxes and fillers to repair damage to bones or connective tissue, such as temporary internal "bandages" to prevent further internal damage or promote healing of internal wounds, or coatings for solid devices that can be implanted. The biodegradable composition can even be injected subcutaneously to accumulate tissue or to fill the defects. The injected polymer composition will slowly biodegrade within the body and allow the natural tissue to develop and replace the polymer matrix as it disappears. Therefore, when the material is injected into a soft tissue defect, it will fill the defect and provide a scaffold for the natural collagen tissue to grow. This collagen-based fabric will gradually replace the biodegradable polymer. However, preferably, the polymer composition of the invention consists of a biologically active substance and provides controllable and effective release of the biologically active substance over time, and even in the case of large biomacromolecules. Therefore, in a preferred embodiment, the biodegradable polymer composition comprises both: a) at least one biologically active substance and b) the polymer having the recurring monomer units shown in formula I wherein R, R ', L , R "and n are as defined above The biologically active substances are used in amounts that are therapeutically effective, which vary widely depending mainly on the particular biologically active substance that is being used The amount of biologically active substance incorporated into the composition it also depends on the desired release profile, the concentration of the substance required for a biological effect, and the length of time in which the biologically active substance has to be released for treatment.Preferably, the biologically active substance can be easily mixed with the polymer matrix of the invention at different load levels, at room temperature and without the need for an organic solvent. However, it is also possible to use a solvent during the mixing procedure for faster or complete mixing, and then evaporate the solvent when the mixing is complete. There is no critical upper limit of the amount of biologically active substance incorporated except for that of an acceptable solution or dispersion viscosity to maintain the physical characteristics desired for the composition. The lower limit of the substance incorporated in the delivery system depends on the activity of the drug and the length of time necessary for the treatment. Therefore, the amount of the biologically active substance must not be so small that it fails to produce the desired physiological effect, nor so large that the active substance is released in an uncontrollable manner. Typically, within these limits, the amounts of the biologically active substance range from 1% to about 65% and can be incorporated into the present delivery systems. However, smaller amounts can be used to achieve effective treatment levels for biologically active substances that are particularly potent. In addition, the polymer composition of the invention may consist of blends of the polymer of the invention with other biocompatible polymers or copolymers, so long as the additional polymers or copolymers do not undesirably interfere with the biodegradation or mechanical characteristics of the composition. Mixtures of the polymers of the invention with such other polymers can offer even greater flexibility in designing the desired precise release profile for the target drug delivery or the precise rate of biodegradability desired. Examples of such additional biocompatible polymers include other poly (phosphoesters), poly (carbonates), poly (esters), poly (orthoesters), poly (phosphazenes), poly (amides), poly (urethanes), poly (imino-carbonates), and poly (anhydrides). The pharmaceutically acceptable polymer carriers can also consist of a wide range of additional materials. Without being limited thereto, such materials may include diluents, binders and adhesives, lubricants, disintegrants, colorants, bodily agents, flavors, sweeteners and various materials such as buffer solutions and adsorbents, to properly prepare a particular medicated composition, with the condition that none of these additional materials will interfere with the biocompatibility, biodegradability and flowability or flexibility of the polymer compositions of the invention. For the delivery of a biologically active substance, the biologically active substance is added to the polymer composition. The biologically active substance is dissolved to form a homogeneous solution of a reasonably constant concentration in the polymer composition, or dispersed to form a suspension or dispersion within the polymer composition at a desired level of "charge" (grams of substance biologically active by grams of the total composition including the biologically active substance, usually expressed as a percentage). While it is possible that the biodegradable polymer or the biologically active agent can be dissolved in a small amount of a solvent that is not toxic to more efficiently produce a homogeneous, monolithic distribution or a fine dispersion of the biologically active agent in the flexible or fluid composition , it is an advantage of the invention that, in a preferred embodiment, no solvent is needed to form a fluid composition. Furthermore, the use of solvents is preferably avoided because, once the composition of the polymer containing the solvent is totally or partially placed inside the body, the solvent dissipates or diffuses away from the polymer and must be processed and eliminated. by the body, placing an extra load on the cleansing capacity of the body at a time when the disease or damage was adversely affected. However, when a solvent is used to facilitate mixing to maintain the flowability of the polymer composition of the invention, it must be non-toxic, or otherwise biocompatible, and must be used in minimal amounts. Solvents that are toxic should clearly not be used in any material to be placed even partially within a living body. Such solvent should also not cause tissue irritation or necrosis at the site of administration.

Examples of suitable biocompatible solvents, when used, include N-methyl-2-pyrrolidone, 2-pyrrolidone, ethanol, propylene glycol, acetone, methyl acetate, ethyl acetate, methylethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, oleic acid, or 1-dodecylazacycloheptan-2-one. Preferred solvents include N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethyl sulfoxide, and acetone because of their solvation ability and biocompatibility.

Flowable or flexible supply systems In its simplest form, a biodegradable therapeutic agent delivery system consists of a solution or dispersion of a biologically active substance in a polymer matrix that has an unstable (biodegradable) bond incorporated in the base structure of the polymer. The cleavage of the bond converts a water insoluble polymer into water-soluble, low molecular weight polymer fragments, which can be excreted from the body. The biologically active substance is typically released from the polymer matrix at least as rapidly as the matrix is biodegraded in vivo. With some biologically active substances, the substance will be released only after the polymer has been degraded to a point where a non-diffusing substance has been exposed to body fluids. As the polymer begins to degrade, the biologically active substance that was completely surrounded by the polymer matrix begins to be released. However, with this mechanism, a long peptide chain that is physically entangled in a rigid solid implant structure may tend to degrade together with the matrix and separate from the rest of the peptide chain, thereby releasing incomplete fragments of molecules. With the polymer composition of the present invention, however, the polymer will typically degrade after the peptide or protein has been partially released. In a particularly preferred mechanism, when a peptide chain is being released from the composition of the invention, the composition remains flexible and allows a large molecule protein, at least partially, to diffuse through the polymer matrix before its own degradation or that of the polymer. The rate of initial release of proteins from the composition is therefore generally diffusion controlled through channels in the matrix structure, the rate of which is inversely proportional to the molecular weight of the protein. Once the degradation of the polymer begins, however, the protein that remains in the matrix can also be released by the erosion forces. Amorphous biodegradable matrices of the invention typically contain polymer chains that are associated with other chains.

These associations can be created by a simple entanglement of polymer chains within the matrix, as opposed to hydrogen bonding or van der Vaals interactions or between crystalline regions of the polymer or interactions that are ionic in nature. Alternatively, the synthesis of block copolymers or the mixture of two different polymers can be used to create viscous, "plasta-like" materials with a wide variation in physical and mechanical properties. When the biologically active substance is a protein, the interactions between specific proteins and polymeric materials often also affect the characteristics of the composition. Important factors include: (i) the molecular weight of the protein, which is an important parameter in relation to diffusion characteristics; (ii) the isoelectric point of the protein, which governs charge-charge interactions; (iii) the presence of cisterns on the protein, which can participate in the formation of intermolecular disulfide bonds; (iv) the primary amino acid sequence of the protein, which may be susceptible to chemical modification in association with a polymeric material; (v) the presence or absence of carbohydrates on the protein, which can improve or avoid interaction with polymeric materials; (vi) the relative hydrophobicity of a protein, which can interact with hydrophobic sites on a polymer; and (vii) the heterogeneity of the protein, which often exists when proteins are produced by recombinant methods; In a particularly preferred embodiment, the composition of the invention is sufficiently flowable to be injected into the body.

It is particularly important that the injected composition results in minimal tissue irritation after injection or that it is placed in direct contact with vascularized tissues. The biologically active substance of the composition and the polymer of the invention can form a homogeneous matrix, or the biologically active substance can be encapsulated in some way within the polymer. For example, the biologically active substance can be first encapsulated in a microsphere and then combined with the polymer in such a way that at least a portion of the microsphere structure is maintained. Alternatively, the biologically active substance can be sufficiently immiscible in the polymer of the invention so that it is dispersed in small droplets, rather than being dissolved, in the polymer. Any form is acceptable, but it is preferred that, considering the homogeneity of the composition, a significant portion of the biologically active substance be released in vivo prior to the biodegradation of the polymer by hydrolysis of the phosphoester linkage. In one embodiment, the polymer composition of the invention is used to form a soft drug delivery "reservoir" that can be administered as a liquid, for example, by injection, but which remains sufficiently viscous to maintain the drug within the area located around the injection site. The degradation time of the deposit thus formed can be varied from several days to a few years, depending on the selected polymer and its molecular weight. By using a polymer composition in flowable form, still the need to make an incision can be eliminated. In any case, the "reservoir" of flexible or flowable supply will adjust to the shape of the space it occupies within the body with a minimum of trauma to the tissues that surround it. The flexible or flowable polymer composition of the invention can be placed anywhere within the body, including soft tissue such as muscle or fat; hard tissue such as bone or cartilage; a cavity such as the periodontal, oral, vaginal, rectal or nasal cavity; or a sac like a periodontal sac or the cul-de-sac of the eye. The composition can also be sprinkled on or poured into open wounds or used as a delivery system to the site during surgery. When it is flowable, the composition of the invention can be injected into deeper wounds, such as burn wounds, to avoid the formation of deep scars. The composition can also be used to act as a temporary barrier to prevent direct adhesion of different tissue types to one another, for example, after abdominal surgery, due to its ability to encapsulate tissues, organs and prosthetic devices. In gene therapy, the flexible or flowable composition of the invention may be useful to provide a means to deliver genes to patients without involving a cell-based system. In particular, the composition of the invention can be injected to sites that would otherwise be inaccessible for direct delivery of gene vectors. In addition, depending on the need for continuous gene therapy, the sustained release ability of the biologically active substance of the composition of the invention would eliminate the need for repeated invasion procedures to re-introduce the gene vector to the site involved. In orthopedic applications, the flowable or flexible composition of the invention may be useful for repairing bone defects and connective tissue injury. For example, the biodegradable composition can be loaded with morphogenetic bone proteins to form a bone graft useful even for large segmentation defects, when the bone can be immobilized and supported. The composition can also be injected into a suitable orthopedic space to facilitate adhesion and cell proliferation before the polymer matrix is degraded to non-toxic waste. Once injected, the polymer composition of the invention must remain in at least partial contact with a biological fluid, such as blood, secretions of internal organ, mucous membranes, cerebrospinal fluid and the like. For drug delivery systems, the imped or injected composition will release the biologically active substance contained within its matrix at a controlled rate until the substance is exhausted, following the general rules for diffusion or dissolution of a biologically active substance from a polymer matrix. biodegradable. The following examples are illustrative of preferred embodiments of the invention and should not be considered as limiting to the same invention. All polymer molecular weights are average molecular weights. All percentages are based on the percentage by weight of the final supply system or formulation being prepared unless otherwise indicated, and all totals equal to 100% by weight.

EXAMPLES EXAMPLE 1 Synthesis of Polyphosphoester P (trans-CHDM-HOP) O N- CHo O ~ CH2OH II CI-P-Cl (NMM) HOCH 0 (CH2) 5CH3 (DMAP) O -CH O- P- -f? CH2 0 (CH2) 5CH3 P (CHDM / HOP) Under a stream of argon, 10 g of trans- ~ 4-cyclohexane dimethanol (CHDM), 1794 g of 4-dimethylaminopyridine (DMAP), 15.25 ml (14.03 g) of N-methyl morpholine (NMM), and 50 ml of methylene chloride were transferred to a 250 ml flask equipped with a funnel. The solution in the flask was cooled to -15 ° C with stirring, and a solution of 15.19 g of exophyl phosphorodichloride (HOP) in 30 ml of methylene chloride were added through the funnel. The temperature of the reaction mixture was raised to the boiling point gradually and maintained at reflux temperature overnight. The reaction mixture was filtered, and the filtrate was evaporated to dryness. The residue was redissolved in 100 ml of chloroform. This solution was washed with a 0.1 M solution of a mixture of HCL and NaCl, dried over anhydrous Na2SO4 and quenched into 500 mL of ether. The resulting flowable precipitate was combined and dried under vacuum to form a pale yellow light gel polymer with the flow characteristics of a viscous syrup. The yield for this polymer was 70-80%. The structure of P (íraps-CHDM-HOP) was measured by the spectrum of 31 P-NMR and 1 H-NMR, as shown in figure 1, and by the FT-IR spectrum. The molecular weights, (Pm = 8584; Nm = 3076) were determined by gel permeation chromatography (GPC) as shown in Figure 2, using polystyrene as a calibration standard.

EXAMPLE 2 Synthesis of Polv (phosphoester) P icis & IRAIS-CHDM-HOP Poly (phosphoester) P (cis / trans - ', 4-cyclohexanedimethanolhexyl phosphate) was prepared following the procedure described above in example 1 except that a mixture of cis- and trans-1,4-cyclohexanedimethanol was used as the material of departure. As expected, the cis- / trans -P (CHDM-HOP) product was less viscous than the trans-isomer obtained in Example 1.

EXAMPLE 3: Synthesis of P (CHDM-HOP) of low molecular weight.

Under a stream of argon, 10 g of Ips-1,4-cyclohexane dimethanol (CHDM), 15.25 ml (14.03 g) of N-methyl morpholine (NMM), and 50 ml of methylene chloride were transferred into a glass flask. 250 ml equipped with a funnel. The solution in the flask was cooled to -40 ° C with stirring. A solution of 15.19 g of hexyl phosphorodichlorhydrate (HOP) in 20 ml of methylene chloride was added through the funnel, and an additional 10 ml of methylene chloride were used to wash the funnel. The mixture was then brought to room temperature gradually and kept stirring for 4 hours.

The reaction mixture was filtered, and the filtrate was evaporated to dryness. The residue was redissolved in 100 ml of chloroform. This solution was washed with a mixture of 0.5 M HCl-NaCl solution, washed with saturated NaCl solution, dried over anhydrous Na 2 S 4, and quenched in a 1: 5 mixture of ether oil. The resulting oily precipitate was combined and dried under vacuum to form a light pale yellow viscous material. The structure of the product was confirmed by 1 H-NMR, 31 P-NMR and FT-IR spectra.

EXAMPLE 4: Synthesis of Poly (phosphoester) Pltrans-CHDM-BOP) O N- CH 3 O -CH 2 OH II CI-P-Cl (NMM) HOCH 2 - 0 (CH 2) 3 CH 3, P (CHDM-BOP) Under a stream of argon, 10 g of rapes-1,4-cyclohexane dimethanol (CHDM), 0.424 g (5%) of 4-dimethylamino-pyridine (DAMP), 15.25 ml (14.03 g) of N-methylmorpholine (NMM) and 50 ml of methylene chloride were transferred to a 250 ml flask equipped with a funnel. The solution in the funnel was cooled to minus 40 ° C with stirring. A solution of 13.24 g of butyl phosphorus dichloridate (BOP) in 20 ml of methylene chloride was added through the funnel with an additional 10 ml of methylene chloride being used to wash the funnel. The mixture was heated to the boiling point gradually, and it was refluxed for 4 hours. The reaction mixture was filtered, and the filtrate was evaporated to dryness, taking care to keep the temperature below 60 ° C. The residue was redissolved in 100 ml of chloroform. The formed solution was washed with 0.5 M HCl-NaCl solution and saturated NaCl solution, dried over anhydrous Na 2 SO 4, and quenched in a 1: 5 mixture of ether oil. The resulting oily precipitate was combined and dried under vacuum to produce a light pale yellow viscous material.

EXAMPLE 5: Synthesis of Poly (phosphoester) P (frans-CHDM-EOP) P (CHDM-EOP) The polymer p (CHDM-EOP) was prepared by the method of Example 1 using, as starting materials, rans-1, 4-cyclohexane dimethanol (CHDM) and phosphorus-ethyl dihydrochloride (EOP).

EXAMPLE 6: Rheological properties of P (fr-ans-CHDM-HQP) P (trans-CHDM-HOP) remained in a gel-like fluid state at room temperature. The polymer exhibited a fixed viscosity of 327 Pa-s at 25 ° C (shown in Figure 3B), and an active flow energy of 67.5 KJ / mol (shown in Figure 3A).

EXAMPLE 7: In vitro cytotoxicity of Pítrans-CHDM-HOP) Covers objects were coated with P (trans -CHDM-HOP) by a rotary coating method. Coated coated objects were then dried and sterilized by UV irradiation overnight under a cover. A coated objects cover of P (íraps-CHDM-HOP) was placed in the bottom of each cavity of a plate of 6 cavities. 5x105 HEK293 cells (from human embryonic kidney) were placed on plates in each cavity and cultured for 72 hours at 37 ° C. The resulting cell morphology was examined, using tissue culture polystyrene (TCPS) as a positive control. Cells grown on the surface P (CHDM-HOP) proliferated at a slightly slower rate. However, the morphology of cells cultured on the polymer surface was similar to the morphology of cells grown on the TCPS surface. See Figure 4A for the morphology of HEK293 cells cultured on the polymer surface and Figure 4B for the morphology of HEK293 cells grown on a TCPS surface, both after 72 hours of incubation.

EXAMPLE 8 In vitro degradation of P (CHDM-Alkyl Phosphate) Each of the following poly (phosphate) s was prepared as described above: TABLE I A sample of 50 mg of each polymer was incubated in 5 mL of 0.1 M, pH 7.4 saline phosphate pH regulator (PBS) at 37 ° C. At various points in time, the supernatant was poured off, and the polymer samples were washed 3 times with distilled water. The polymer samples were then extracted with chloroform and the chloroform solution was evaporated to dryness. The residue was analyzed for weight loss compared to the original 50 mg sample. Figure 5 graphically depicts the effect of the side chain structure on the rate of in vitro degradation of poly (phosphates) in PBS.

EXAMPLE 9 In vitro release profile of protein by P (CHDM-HOP) The polymer P (CHDM-HOP) was mixed with the FITC-BSA protein (serum albumin coil, a protein, labeled with the FITC fluorescent label, "FITC-BSA") at a ratio of 2: 1 (w / w) (33% charge). The measured amounts (66 mg or 104 mg) of the polymer-protein mixture were placed in 10 ml of PBS (0.1 M, pH 7.4), a phosphate pH regulator. At regular intervals (scarcely every day) the samples were centrifuged, the regulator pH supernatant was removed and subjected to absorption spectroscopy (501 nm), and fresh amounts of pH regulator were added to the samples. The resulting release curve, which describes the cumulative percentage of FITC-BSA released against time, is represented graphically in Figure 6. The level of loading of the protein in both cases was 33% by weight.

EXAMPLE 10 Protein release profile in vitro at various loading levels FITC-BSA was mixed with P (CHDM-HOP) at different loading levels (1%, 10% and 30%) at room temperature until the mixture formed a homogeneous paste. 60 mg of the protein loaded polymer paste were placed in 6 mL of 0.1 M phosphate buffer and stirred constantly at 37 ° C. At various points in time, the samples were centrifuged, and the supernatant was replaced with a fresh pH regulator. The FITC-BSA released in the supernatant was measured by UV spectrophotometry at 501 nm. Figure 7 graphically depicts in vitro release kinetics of FITC-BSA as a function of loading level.

EXAMPLE 11 Effect of the side chain structure on the in vitro protein release kinetics of FITC-BSA The following three polymers were prepared as described above: P (CHDM-EOP) P (CHDM-BOP) YP (CHDM-HOP) FITC-BSA was mixed with each polymer at a loading level of 10% at room temperature to form a homogeneous paste. 60 mg of the protein loaded polymer paste were placed in 6 mL of 0.1 M phosphate buffer with constant agitation at 37 ° C. At several time intervals, the samples were centrifuged, and the supernatant was replaced with fresh pH regulator. The FITC-BSA released in the supernatant was measured by UV spectrophotometry at 501 nm, Figure 8 graphically depicts the in vitro effect of side chain variations on the FITC-BSA protein release kinetics at the loading level from 10%.

EXAMPLE 12 Release of small molecular weight drug in vitro from P (CHDM-HOP) A paste of P (CHDM-HOP) containing doxorubicin, cisplatin, or 5-fluorouracil was prepared by mixing 100 mg of P (CHDM-HOP) with 1 mg of the desired drug at room temperature respectively. An aliquot of 60 mg of the drug-laden paste was placed in 6 mL of pH buffer of 0.1 M phosphate at 37 ° C with constant agitation, with 3 samples being made for each drug being tested. At several time points, the supernatant was replaced with fresh pH buffer. The levels of doxorubicin and 5-fluorouracil in the supernatant were quantified by UV spectrophotometry at 484 nm and 280 nm, respectively. The level of cisplatin was measured with an atomic absorbance spectrophotometer. Figure 9 shows the release of these low molecular weight drugs from P (CHDM-HOP).

EXAMPLE 13 In vitro simultaneous release profile of doxorubicin and cisplatin from P (CHDM-HOP) A paste was made by mixing 300 mg of P (CHDM-HOP) with 6 mg of doxorubicin and 6 mg of cisplatin at room temperature to form a uniform dispersion. A 100 mg sample of the paste was incubated in 10 mL of phosphate buffer (pH 7.4) at 37 ° C with shaking. At different time points, the samples were centrifuged, 9 mL of the supernatant was removed and replaced with fresh pH regulator. The supernatant removed was analyzed spectrophotometrically at 484 nm to determine the amount of doxorubicin released in the removed supernatant, and the release of cisplatin was measured by atomic absorbance spectrophotometer. Figure 10 graphically depicts the simultaneous release of cisplatin and doxorubicin from P (CHDM-HOP).

EXAMPLE 14 Release of In vitro Interleukin-2 from P (CHDM-HOP) A paste was prepared by mixing, with a spatula, 300 mg of P (CHDM-HOP) with 3 mg of IL-2 at room temperature to form a uniform dispersion. A sample of 95 mg of paste P (CHDM-HOP) / IL-2 was placed in 5 mL of 0.1 M phosphate buffer (pH 7.4) at 37 ° C.

At several time points, the sample was centrifuged and 4 mL of the 4 mL supernatant was removed and replaced. The supernatant removed was analyzed for IL-2 by using CTLL-2 culture, as described above. The cumulative percentage of released IL-2 was calculated based on the initial amount of IL-2 mixed in the paste. At the last time point, there was IL-2 still left in the sample. Figure 1 1 graphically represents the cumulative percentage of IL-2 released from matrix P (CHDM-HOP) against time in days.

EXAMPLE 15 In vitro lnterleucin-2 release of P (CHDM-HOP) in tissue culture A paste was prepared by mixing, with a spatula, interleukin-2 ("IL-2", 18x106 IU) lyophilized human with 240 mg of P (CHDM-HOP) at room temperature until it was homogeneous. Three samples of 80 mg of paste P (CHDM-HOP) / IL-2 were incubated with 1.5 mL of tissue culture (RPM medium 11640 containing 10% FCS) at 37 ° C with constant agitation. At several time points, the samples were centrifuged, and the supernatant was removed and replaced with fresh medium. The amount of IL-2 in the removed supernatant samples was determined by an ELISA assay.

The amount of biologically active IL-2 released was analyzed by the following CTLL cell culture method: CTLL cells were plated in a 96 well plate at a density of 2x104 cells per well and incubated with an aliquot of the cell. supernatant removed. After two days of incubation, the cell growth rate was evaluated by the WST-1 assay. A calibration curve was constructed in parallel for the determination of IL-2 release of P (CHDM-HOP) in tissue culture medium. Figure 12 shows the calibration curves constructed by the sustained release of IL-2. The complete data establishes that more than 30% of the bioactivity was retained at all points in time.

EXAMPLE 16 In vivo Release of Interleukin-2 from P (CHDM-HOP) A sample of P (CHDM-HOP) was sterilized by irradiation? to 2.5 MRads and aseptically mixed with IL-2 in the same manner as described above in Example 15. Six female Balb / c mice, 6-8 weeks old, were injected subcutaneously with 50 mg of the IL-2 polymer paste sample containing 3.5x105 lU of lL-2. Two additional mice received the same dose of IL-2 as a bolus injection, and two additional mice received a blank P (CHDM-HOP) injection as a control.

At several points in time, 50 μl of blood samples were collected from the tail vein. Blood samples from each group were combined and diluted with HBSS supplemented with 1% BSA. The serum was separated and analyzed for IL-2 as described above. Sustained release of IL-2 was achieved in vivo, with detectable levels of IL-2 present in the serum, for up to 3 weeks after injection of the P-loaded paste (CHDM-HOP) / IL-2. In contrast, IL-2 levels were undetectable after 48 hours in mice injected with the bolus of IL-2. The figure 13 graphically compares the pharmacokinetics of IL-2 administered either as a bolus or dispersed in a matrix of P (CHDM-HOP). The figure 14 describes the histological examination of a subcutaneous injection site from this in vivo experiment.

EXAMPLE 17 In vivo biocompatibility of P (rans-CHDM-HOP) The polymer P (frans-CHDM-HOP) was synthesized as described in Example 1. To facilitate the injection, ethyl alcohol was added to the polymer at levels of 10% and 20% by volume to reduce the viscosity. Samples of 25 μl of the polymer alone, 25 μl of the polymer containing 10% alcohol and 25 μl of the polymer containing 20% alcohol were injected into the posterior muscles of Sprague Dawley rats. The tissues at the injection sites were harvested at either 3 or 30 days after injection, processed for paraffin histology, marked with hematoxylin, eosin ink and analyzed. Medical-grade silicone oil was injected into the rats of the control group. Histological examination of the posterior muscle sections of the rats injected with the polymer diluted with ethanol showed that there was no acute inflammatory response. The level of presence of macrophage was comparable to that of the control group, which had been injected with medical-grade silicone oil, and neutrophils were not present in any of the samples taken on either the third or the thirtieth day.

EXAMPLE 18 Drug sensitivity in an in vitro tumor model In vitro studies were done on the B16 / F10 melanoma cell line using, as the drug, doxorubicin ("DOX"), cisplatin, or 5-fluorouracil ("5-FU"). B16 / F10 cells were cultured in the presence of different concentrations of DOX, cisplatin and 5-FU. According to the data, DOX showed the strongest inhibitory effect on cell culture, even at 0.1 μg / ml.

EXAMPLE 19 Controlled Delivery of Interleukin-2 and Doxorubicin from P (CHDM-HOP) in a Tumor Model in vivo Interleukin-2 ("IL-2") freeze-dried from Chiron, mouse? -interferon ("mlFN-?") Was obtained from Boehringer Mannheim, and doxorubicin hydrochloride ("DOX") was obtained from Sigma. C57BL / 6 mice, 6-8 weeks old, were obtained from Charles River. The aggressive melanoma cell line B16 / I10 was used to cause tumors in the mice, and the cells were maintained by passages in weekly steps. The polymer P (CHDM-HOP) was synthesized as described in example 1. The mice were randomly placed in groups as shown in Table 2. The day of tumor injection with cells of the cell line Melanoma was denoted as day 0. Each mouse received a subcutaneous injection of 50 μl (105) tumor cells in a phosphate buffer (PBS) exit solution on the left flank. On day 3 or day 7, the mice that had tumors were selectively injected into the right flank with one of the following formulations: (1) a bolus of IL-2, (2) a bolus of DOX, (3) an IL-2 polymer paste, (4) a DOX polymer paste, (5) a polymer paste containing LL-2 and DOX, or (6) a polymer paste containing IL-2 and mlFN- ? A control group and a negative control group did not receive additional injections on day 3 or day 7.

The bolus preparation of IL-2 or DOX was prepared by dissolving an appropriate amount of IL-2 or DOX in 50 μl of isotonic solution just before injection. The polymer paste formulations of 1L-2, DOX, a mixture of IL-2 and DOX or a mixture of IL-2 and mlFN-? were prepared by mixing 50 μl of sterilized P (CHDM-HOP) with the drug (s) until homogeneous.

TABLE 2 Placement of groups of mice for tumor model in vivo On day 28 and day 42 of tumor growth, the tumor sizes of the different mice were measured. The results are shown below in Table 3, which shows the numerical data for the growth of tumor volumes on day 28 and day 42 and the number of mice that survived the experiment per drug group. The volume of the tumor was calculated as half the product of the length and the square of the width, according to the procedure of Osieka et al., 1981.

TABLE III CHDM-HOP polymer as vehicle for cytokine and drug delivery in melanoma model Standard error of the principal Based on these measurements, the distribution of tumor sizes was graphically represented in figure 15 for day 28 (four weeks after tumor implantation) and in figure 16 for day 42 (six weeks after tumor implantation). The graphs were subdivided into planes according to the different treatments given to the mice that had tumor. The results on day 28 showed that, compared to the control group (tumor without treatment) and the bolus injection of IL-2, the group of mice that received an injection of polymer / IL-2 paste successfully delayed the growth of the tumor. However, for the group of mice that did not receive the polymer / IL-2 paste injection until day 7, the tumor had already become substantial in size by day 7 and, accordingly, no significant reduction in tumor size. Excellent tumor reduction was obtained with the combination of IL-2 and DOX. The average size of a tumor treated with an injection of a polymer paste containing IL-2 and DOX was significantly smaller than the tumor in the control group. Specifically, the average tumor size for mice receiving the IL-2 and DOX / polymer paste on day 3 was 657.3 mm3, as opposed to 2458 mm3 for the control group. Even when the treatment was delayed until day 7 of tumor growth, a therapeutic effect could still be observed with the polymer paste formulation containing IL-2 and DOX.

The results on day 42 of tumor growth also confirmed that day 3 injection of polymer paste containing IL-2 and DOX gave the best result in retarding tumor growth. The combined therapy of IL-2 and DOX in a polymer paste of the invention resulted in the occurrence of tumors of smaller size in more than the test animals. According to the distribution data shown in figure 15, there were four mice with tumors of less than 1000 mm3 in the case of combined IL-2 and DOX polymer paste therapy, compared to only one mouse within that scale for injection of DOX polymer paste alone. It was also clear that IL-2 alone did not provide the most desirable effect, as assessed at the 42nd day of tumor growth. Despite the good distribution of small tumor sizes on day 28, the long-term survival data appeared to be adversely affected, not only by the progression of tumor growth at that point, but also by the lack of supply continuous, controlled IL-2 over a longer period of time. With the polymer paste formulation of IL-2 and DOX, the polymer degraded more slowly, allowing a gradual decrease in the rate of diffusion of the therapeutic agent over time. However, due to the significant difference in the distribution of tumor sizes within each group, the average tumor size in Table III did not provide a complete picture. A more complete appreciation of the meaning of the treatments of the invention can be obtained by comparing the data of the distribution graph of Figure 16, which shows the dispersity in tumor sizes six weeks after tumor implantation, with the survival curve shown in Figure 17, which shows the mass death of mice in all groups before the measurement of day 42, except for groups of animals that had received on the third day the injection of either DOX-containing paste alone or the combination of IL-2 and DOX. Therefore, the data, taken as a whole, show that the combined therapy of IL-2 and DOX in the paste significantly delayed tumor growth and extended life. The initial deaths around 3-4 days after injections of the polymer paste containing DOX were thought to be due, at least in part, to the toxic effect of DOX that causes the deaths of the weakest animals. The corresponding injections of DOX bolus produced no initial death, probably due to the rapid distribution and evacuation of the body of the DOX injected in bolus.

EXAMPLE 20 Incorporation of paclitaxel into P (CHDM-HOP) or P (CHDM-EOP) 100 mg of each of the polymers of example 1, p (CHDM-HOP), and of example 5, p (CHDM-EOP), were dissolved in ethanol at a concentration of 50%. After the polymer was completely dissolved, 5 mg of paclitaxel powder (a chemotherapeutic drug) were added to the solution and stirred until the powder was completely dissolved. This solution was then poured into ice water to precipitate the polymer composition. The resulting suspension was centrifuged, decanted, and lyophilized overnight to obtain a viscous gel-like product.

EXAMPLE 21 In vitro release of paclitaxel from P (CHDM-HOP) v P (CHDM-EOP) In a 1.7 mL tube of microcentrifuge plastic, 5 mg of the paclitaxel polymer formulations of Example 20 to be tested were incubated with 1 mL of a pH buffer of 80% PBS and 20% PEG 400 at 37 ° C. Four samples of each formulation to be evaluated were prepared. At specific time points, approximately every day, the pH buffer solution PBS: PEG was poured out for paclitaxel analysis by HPLC, and fresh pH regulator was added to the microcentrifuge tube. The release study was completed on day 26, at which point the remaining paclitaxel in the polymer was extracted with a solvent to make a mass balance on paclitaxel. The resulting release curves for the release of paclitaxel from both polymers are shown in Figure 18. The total recovery of paclitaxel was 65% for formulation P (CHDM-HOP) and 75% for formulation P (CHDM-EOP).

EXAMPLE 22 Preparation of P-paste (CHDM-HOP) / Lidocaine / A paste of P (CHDM-HOP) and lidocaine (base, Sigma, catalog # L-7757) was prepared by mechanically mixing as follows: 60 mg of P (CHDM-HOP) and 16 mg of lidocaine were weighed on a glass carries samples of microscope. The polymer and the lidocaine drug were thoroughly mixed with a spatula until a uniform mixture was obtained. The resulting lidocaine / polymer mixture formed a lidocaine paste of 24% w / w with the lidocaine remaining as a solid.

EXAMPLE 23 In vitro release of P lidocaine (CHDM-HOP) Approximately 10 mg of the lidocaine / polymer mixture prepared above in example 22 were placed in 2.0 mL of phosphate buffer (PBS) (0.1 M, pH 7.4) at 37 ° C on a shaker. The pH regulator was placed at specific time points, and the samples were removed. The lidocaine released from the polymer in the samples was analyzed by HLPC. The results of the three different samples of the lidocaine / polymer mixture are depicted graphically in Figure 19. Figure 20A shows the cumulative amount of lidocaine released as a function of incubation time and Figure 20B shows the cumulative amount of lidocaine released over the square root of time, showing that approximately 90% of the drug was released within a week. The linear relationship between the amount of lidocaine released and the square root of time indicated that the mechanism of drug release was mainly through diffusion during the test period.

EXAMPLE 24 Release of P lidocaine (CHDM-HOP) in a rat sciatic nerve model in vivo Simple jugular catheters were inserted into male Sprague-Dawley rats, approximately 150-200 g in weight. The rats were anesthetized by i.p. with almost 0.3-0.4 ml of an anesthetic cocktail (25 mg / ml ketamine, 2.5 mg / ml xylazine and 14.5% ethanol 200 degrees). The sciatic nerve of the animal was identified. Each animal received a single injection of either 25 mg or 50 mg of lidocaine in either P (CHDM-HOP) or as a saline solution in their sciatic nerve to block the nerve. The rats in the control group received an equivalent amount of white polymer injected into their sciatic nerves. Rats were observed over time, and points were assigned for motor and nociceptive responses as follows: Response and motor function normal motor function = 0, light foot drag = 1, moderate foot drag = 2, no motor function = 3; Response and nociceptive function normal nociceptive response = 0, slightly delayed nociceptive response = 1, delayed nociceptive response = 2, and no nociceptive response = 3. Blood samples were also collected at specific time points, and plasma concentration of lidocaine was calculated by HLPC. Figure 22 shows the plane of percentage of effect of maximum motor function against time after injection with 25 mg of lidocaine in P (CHDM-HOP) or in saline. A maximum percentage effect of 10% on this graph represents a score of "3" for "no motor response". All rats injected with preparations containing lidocaine exhibited complete motor block during the first hour after injection. Table 4 below summarizes the duration of the blocking effect of lidocaine after injection of lidocaine in saline or in P (CHDM-HOP).

TABLE IV Duration of lidocaine reaction after injection of lidocaine in saline or in P (CHDM-HOP) The duration of motor function blockade of lidocaine in P (CHDM-HOP) was clearly longer than that achieved by saline with lidocaine. However, the degree of motor function block was only partial, in which a rat could still move its leg with a slight drag. It was also observed that the increase in complete motor blockade was minimal even at the highest lidocaine concentration of 50 mg lidocaine. Table 5 below shows the percentage of rats that exhibited complete blocking of the nociceptive response following the administration of 25 mg of lidocaine either as a saline solution or in P (CHDM-HOP).

TABLE V Percentage of rats with complete nociceptive response Compared with lidocaine / saline, the lidocaine / P formulation (CHDM-HOP) prolonged the sensory blocking effect of lidocaine significantly.

Figure 21 describes the percentage of maximum nociceptive effect against time after injection with 25 mg of lidocaine in either P (CHDM-HOP) or saline. The maximum percentage effect of 100% on this graph represented a rating of "3", that is, "no nociceptive response". Again, compared to the data of lidocaine in saline, a significantly prolonged local anesthetic effect was observed in the lidocaine / P (CHDM-HOP) group. It was observed that the recovery of the motor block occurred well after the complete recovery of the sensory block in the formulations of lidocaine / saline and the lidocaine / P (CHDM-HOP). Rats were often able to move with their hind legs and still exhibit no apparent response to pain stimulation. Because the complete response to nociception was well recovered after recovery of motor function, the pharmaceutical compositions of the invention are believed to be well suited for the clinical administration of local anesthetics and the management of chronic pain. Figure 23 shows the concentration of lidocaine in plasma after the injection of 25 mg of lidocaine in saline, 25 mg of lidocaine in P (CHDM-HOP) and 50 mg of lidocaine in P (CHDM-HOP). By increasing the concentration of lidocaine in the polymer formulation, the duration of the aesthetic function was extended with a minimum increase in the concentration of lidocaine in the systemic circulation, indicating that the diffusion of most of the drug was restricted to the local area.

The invention being described in this manner, it will be apparent that it can be varied in many ways. Such variations should not be considered as departing from the spirit and scope of the invention, and all these modifications are designed to be included within the scope of the following claims.

Claims (59)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A biodegradable, flowable or flexible polymer composition consisting of a polymer having the recurring monomer units shown in formula I: wherein each of R and R 'is independently direct or branched aliphatic, whether substituted or unsubstituted with one or more substituents that do not interfere; L is a divalent cycloaliphatic group; R "is selected from the group consisting of H, alkyl, alkoxy, aryl, aryloxy, heterocyclic or heterocycloxy, and n is 5 to 1, 000, wherein said biodegradable polymer composition is biocompatible both before and with biodegradation. polymer composition according to claim 1, wherein each of R and R 'is a branched or straight-chain alkylene group having from 1 to 7 carbon atoms 3.- The polymer composition according to the claim 1, wherein each of R and R 'is a methylene group or an ethylene group. 4. - The polymer composition according to claim 1, wherein R "is an alkyl group, an alkoxy group, a phenyl group, a phenoxy group, or a heterocycloxy group 5.- The polymer composition according to the claim 1, wherein R "is an alkoxy group. 6. The polymer composition according to claim 1, wherein n is from 5 to 500. 7. The polymer composition according to claim 1, wherein L is a cycloaliphatic group, either unsubstituted or replaced with a substituent that does not interfere. 8. The polymer composition according to claim 7, wherein L is cyclohexylene. 9. The polymer composition according to claim 1, wherein said polymer comprises additional biocompatible monomer units or is mixed with other biocompatible polymers. 10. The polymer composition according to claim 1, wherein the molecular weight (Pm) of said polymer is from 2,000 to 400,000 daltons. 11. The polymer composition according to claim 1, wherein said composition also comprises at least one biologically active substance. 12. - The polymer composition according to claim 1, wherein said biologically active substance is selected from the group consisting of peptides, polypeptides, proteins, amino acids, polysaccharides, growth factors, hormones, antiangiogenesis factors, interferons or cytokines, antigenic materials , and prodrugs of these substances. 13. The polymer composition according to claim 1, wherein said biologically active substance is a therapeutic drug or prodrug. 14. The polymer composition according to claim 13, wherein said drug is selected from the group consisting of antineoplastic agents, local anesthetics, antibiotics, antivirals, antifungals, anti-inflammatories, anticoagulants, antigenic materials suitable for vaccine applications, and prodrugs of those substances. 15. The polymer composition according to claim 1, wherein said biologically active substance and said polymer form an amorphous, monolithic matrix. 16. The polymer composition according to claim 1, wherein said polymer composition is non-toxic and results in minimal tissue irritation when injected or otherwise placed in intimate contact with vascularized tissues. 17. - A temporary barrier film to prevent adhesion of one tissue to another or to encapsulate an organ or tissue, wherein said film barrier consists of the polymer composition according to claim 1. 18.- A biodegradable polymer composition , flowable or flexible consisting of a polymer having the recurring mohomeric units shown in formula I: or - (O-R-L-R- O-P-) n- R " wherein each of R and R 'is independently direct or branched aliphatic, either unsubstituted or substituted with one or more substituents that do not interfere; L is a divalent cycloaliphatic group; R "is selected from the group consisting of H, alkyl, alkoxy, aryl, aryloxy, heterocyclic or heterocycloxy, and n is 5 to 1, 000, wherein said biodegradable polymer composition is biocompatible both after and with biodegradation; or more than R, R 'and R "is a biologically active substance in a form capable of being released in a physiological environment. 19. The polymer composition according to claim 18, wherein each of R and R 'is a branched or straight chain alkylene group having from 1 to 7 carbon atoms. 20. - The polymer composition according to claim 18, wherein each of R and R 'is a methylene group or an ethylene group. 21. The polymer composition according to claim 18, wherein R "is an alkyl group, an alkoxy group, a phenyl group, a phenoxy group, or a heterocycloxy group 22. The polymer composition according to Claim 18, wherein R "is an alkoxy group. 23. The polymer composition according to claim 18, wherein n is from 5 to 500. 24.- The polymer composition according to claim 18, wherein L is a cycloaliphatic group, either unsubstituted or replaced with a substituent that does not interfere. 25. The polymer composition according to claim 24, wherein L is cyclohexylene. 26. The polymer composition according to claim 18, wherein said polymer comprises additional biocompatible monomer units or is mixed with other biocompatible polymers. 27. The polymer composition according to claim 18, wherein the molecular weight (Pm) of said polymer is from 2,000 to 400,000 daltons. 28. - The polymer composition according to claim 18, wherein R "is a biologically active substance 29. The polymer composition according to claim 18, wherein either R or R 'is a biologically active substance. 30. The polymer composition according to claim 18, wherein said biologically active substance is selected from the group consisting of peptides, polypeptides, proteins, amino acids, polysaccharides, growth factors, hormones, anti-angiogenesis factors, interferons or cytokines, materials 31.- The polymer composition according to claim 18, wherein said biologically active substance is a therapeutic drug or prodrug 32.- The polymer composition according to claim 31, wherein said antiviral agent is a prodrug. wherein said drug is selected from the group consisting of antineoplastic agents, anesthetics local icos, antibiotics, antiviral, antifungal, anti-inflammatory, anticoagulants, antigenic materials suitable for vaccine applications, and prodrugs of these substances. 33. The polymer composition according to claim 18, wherein said polymer composition is non-toxic and results in minimal tissue irritation when injected or otherwise placed in intimate contact with vascularized tissues. 34.- A flexible article useful for implantation, injection, or otherwise placed totally or partially within the body, said article consists of a biodegradable, flowable or flexible polymer composition consisting of a polymer having the recurring monomer units shown in the formula I: wherein each of R and R 'is independently direct or branched aliphatic, either unsubstituted or substituted with one or more substituents that do not interfere; L is a divalent cycloaliphatic group; R "is selected from the group consisting of H, alkyl, alkoxy, aryl, aryloxy, heterocyclic or heterocycloxy, and n is from 5 to 1, 000, wherein said biodegradable polymer composition is biocompatible both after and with biodegradation; The article according to claim 34, wherein each of R and R 'is a straight or branched chain alkylene group having from 1 to 20 carbon atoms, The article according to claim 34, in where R "is an alkoxy group. 37. - The article according to claim 34, wherein L is a cycloaliphatic group having from 1 to 20 carbon atoms, either unsubstituted or substituted with a substituent that does not interfere. 38.- The article according to claim 34, wherein n is from 5 to 500. 39.- The article according to claim 34, wherein said polymer consists of biocompatible monomer units or said polymer composition consists of one or more additional biocompatible polymers. 40. The article according to claim 34, wherein said biologically active substance is selected from the group consisting of peptides, polypeptides, proteins, amino acids, polysaccharides, growth factors, hormones, anti-angiogenesis factors, and other antineoplastic agents, interferons or cytokines, antigenic materials, and prodrugs of these substances. 41. The article according to claim 34, wherein said biologically active substance is a therapeutic drug or prodrug. 42. The article according to claim 41, wherein said drug is selected from the group consisting of chemotherapeutic agents, local anesthetics, antibiotics, antivirals, antifungals, anti-inflammatories, anticoagulants, antigenic materials suitable for vaccine applications, and prodrugs thereof substances 43. - The article according to claim 34, wherein said biologically active substance and said polymer form an amorphous, monolithic matrix. 44. The article according to claim 34, wherein said composition is non-toxic and results in minimal tissue irritation when injected or placed in some other way in intimate contact with vascularized tissues. 45.- A method for the controlled release of a biologically active substance that consists of the steps of: a) combining the biologically active substance with a biodegradable polymer having the recurring monomer units shown in formula I: O - (O - R - L - R '- O - n - R " wherein each of R and R 'is independently direct or branched aliphatic, either unsubstituted or substituted with one or more substituents that do not interfere; L is a divalent cycloaliphatic group; R "is selected from the group consisting of H, alkyl, alkoxy, aryl, aryloxy, heterocyclic or heterocycloxy, and n is from 5 to 1, 000, wherein said biodegradable polymer is biocompatible before and with biodegradation, to form a polymer composition flowable or flexible, and b) placing said polymer composition partially or totally within a preselected site in vivo, such that the polymer composition is in at least partial contact with a biological fluid. claim 45, wherein each of R and R 'is a branched or straight-chain alkylene group having from 1 to 20 carbon atoms 47. The method according to claim 45, wherein R "is a group alkoxy 48. The method according to claim 45, wherein L is a cycloaliphatic group having from 1 to 20 carbon atoms, either unsubstituted or substituted with a substituent that does not interfere. 49.- The method according to claim 45, wherein the n is from 5 to 500. 50.- The method according to claim 45, wherein said polymer consists of additional biocompatible monomer units or said polymer composition comprises of one or more additional biocompatible polymers. 51. The method according to claim 45, wherein said biologically active substance is selected from the group consisting of peptides, polypeptides, proteins, amino acids, polysaccharides, growth factors, hormones, anti-angiogenesis factors and other antineoplastic agents, interferons or cytokines. , antigenic materials, and prodrugs of these substances. 52. - The method according to claim 45, wherein said biologically active substance is a therapeutic drug or prodrug. 53. The method according to claim 52, wherein said drug is selected from the group consisting of chemotherapeutic agents, local anesthetics, antibiotics, antivirals, antifungals, anti-inflammatories, anticoagulants, antigenic materials suitable for vaccine applications, and prodrugs thereof. substances 54. The method according to claim 45, wherein said biologically active substance and said polymer form an amorphous, monolithic matrix. 55. The method according to claim 45, wherein said composition is non-toxic and results in minimal tissue irritation when injected or otherwise placed in intimate contact with inflamed tissues. 56.- The polymer composition according to claim 13 wherein said drug is selected from the group consisting of β-adrenergic blocking agents, anabolic agents, androgenic steroids, antacids, antiasthmatic agents, anti-allergenic materials, antiarrhythmics, anti-cholesterolemic agents and anti-lipids , anticholinergic and sympathomimetics, anticonvulsants, antidiarrheals, antiemetics, antihypertensive agents, anti-infective agents, antimalarials. antimamic agents, antinauseants, antiobesity agents, antiparkinson agents, antipyretic and analgesic agents, antispasmodic agents, antithrombotic agents, antiuricemic agents, antianginal agents, antihistamines, antitussives, appetite suppressants, benzophenanthridine alkaloids, biological products, cardioactive agents, cerebral dilators, coronary dilators, decongestants, diuretics, agents of diagnosis, erythropoietic agents, estrogens, expectorants, gastrointestinal sedatives, humoral agents, hyperglycemic agents, hypnotics, hypoglycemic agents, ion exchange agents, laxatives, mineral supplements, miotics, mucolytic agents, neuromuscular drugs, nutritional substances, peripheral vasodilators, agents progestational, prostaglandins, psychic energizers, psychotropics, sedatives, stimulants, thyroid and antithyroid agents, tranquilizers, uterine relaxants, vitamins, and prodrugs of these substances. 57.- The polymer composition according to claim 31 wherein said drug is selected from the group consisting of β-adrenergic blocking agents, anabolic agents, androgenic steroids, antacids, antiasthmatic agents, anti-allergenic materials, antiarrhythmics, anti-cholesterolemic agents and anti-lipids , anticholinergic and sympathomimetics, anticonvulsants, antidiarrheals, antiemetics, antihypertensive agents, anti-infective agents, antimalarials, antimalarial agents, anti-nausea agents, anti-obesity agents, antiparkinson agents, antipyretic and analgesic agents, antispasmodic agents, antithrombotic agents, antichuriemic agents, antianginal agents, antihistamines, antitussives , appetite suppressants, benzophenanthridine alkaloids, biological products, cardioactive agents, cerebral dilators, coronary dilators, decongestants, diuretics, diagnostic agents, erythropoietic agents, estrogen ogenos, expectorants, gastrointestinal sedatives, humoral agents, hyperglycemic agents, hypnotics, hypoglycemic agents, ion exchange agents, laxatives, mineral supplements, miotics, mucolytic agents, neuromuscular drugs, nutritional substances, peripheral vasodilators, progestational agents, prostaglandins, psychic energetizers , psychotropic, sedatives, stimulants, thyroid and antithyroid agents, tranquilizers, uterine relaxants, vitamins, and prodrugs of these substances. 58.- The polymer composition according to claim 41 wherein said drug is selected from the group consisting of β-adrenergic blocking agents, anabolic agents, androgenic steroids, antacids, antiasthmatic agents, anti-allergenic materials, antiarrhythmics, anti-cholesterolemic agents and anti-lipids , anticholinergic and sympathomimetics, anticonvulsants, antidiarrheals, antiemetics, antihypertensive agents, anti-infective agents, antimalarials, antimalarial agents, anti-nausea agents, anti-obesity agents, antiparkinson agents, antipyretic and analgesic agents, antispasmodic agents, antithrombotic agents, anti-inflammatory agents, anti-anginal agents, antihistamines, antitussives , appetite suppressants, benzophenanthridine alkaloids, biological products, cardioactive agents, cerebral dilators, coronary dilators, decongestants, diuretics, diagnostic agents, erythropoietic agents, and strigogens, expectorants, gastrointestinal sedatives, humoral agents, hyperglycemic agents, hypnotics, hypoglycemic agents, ion exchange agents, laxatives, mineral supplements, miotics, mucolytic agents, neuromuscular drugs, nutritional substances, peripheral vasodilators, progestational agents, prostaglandins, psychic energetizers , psychotropic, sedatives, stimulants, thyroid and antithyroid agents, tranquilizers, uterine relaxants, vitamins, and prodrugs of these substances. 59.- The polymer composition according to claim 52 wherein said drug is selected from the group consisting of β-adrenergic blocking agents., anabolic agents, androgenic steroids, antacids, antiasthmatic agents, antiallergenic materials, antiarrhythmics, anticolesterolémicos and antilípidos agents, anticholinergic and sympathomimetics, anticonvulsants, antidiarrheals, antiemetics, antihypertensive agents, antiinfective agents, antimalarials, antimamic agents, antinauseants, antiobesity agents, antiparkinsonian agents , antipyretic and analgesic agents, antispasmodic agents, antithrombotic agents, antiuricemic agents, antianginal agents, antihistamines, antitussives, appetite suppressants, benzophenanthridine alkaloids, biological products, cardioactive agents, cerebral dilators, coronary dilators, decongestants, diuretics, diagnostic agents, erythropoietic agents, estrogens, expectorants, gastrointestinal sedatives, humoral agents, hyperglycemic agents, hypnotics, hypoglycemic agents, ion exchange agents, lax before, mineral supplements, miotics, mucolytic agents, neuromuscular drugs, nutritional substances, peripheral vasodilators, progestational agents, prostaglandins, psychic energetizers, psychotropics, sedatives, stimulants, thyroid and antithyroid agents, tranquilizers, uterine relaxants, vitamins, and prodrugs of these substances .