MXPA99009126A - Biodegradable polymers chain-extended by phosphates, compositions, articles and methods for making and using the same - Google Patents

Abstract

Biodegradable polymers are described comprising the recurring monomeric units shown in formula (I) or (II) wherein X is -O- or -NR'-, where R'is H or alkyl;L is a branched or straight chain aliphatic group having from 1-20 carbon atoms;M1 and M2 are each independently (1) a branched or straight chain aliphatic group having from 1-20 carbon atoms;or (2) a branched or straight chain, oxy-, carboxy- or amino-aliphatic group having from 1-20 carbon atoms;Y is -O-, -S- or -NR'-, where R'is H or alkyl;R is H, alkyl, alkoxy, aryl, aryloxy, heterocyclic or heterocycloxy;the molar ratio of x:y is about 1;the molar ratio n:(x or y) is between about 200:1 and 1:200;and the molar ratio q:r is between about 1:99 and 99:1;wherein said biodegradable polymer is biocompatible before and upon biodegradation. Processes for preparing the polymers, compositions containing the polymers and biologically active substances, articles useful for implantation or injection into the body fabricated from the compositions, and methods for controllably releasing biologically active substances using the polymers, are also described.

Description

BIODEGRADABLE POLYMERS BY CHAIN EXTENDED BY PHOSPHATES, COMPOSITIONS, ARTICLES AND METHODS TO PREPARE AND USE THEMSELVES.

BACKGROUND OF THE INVENTION 1.- FIELD OF THE INVENTION The present invention relates to biodegradable polymer compositions, in particular to those containing phosphate and ester linkages in the base structure of the polymer and which are degraded in vivo in non-toxic waste. The polymers of the invention are particularly useful as implantable medical devices and drug delivery systems. 2. - DESCRIPTION OF THE PREVIOUS TECHNIQUE Biocompatible polymeric materials have been used extensively in therapeutic applications of drug delivery and medical implant devices. Sometimes, it is also desirable that such polymers be not only biocompatible, but also biodegradable to obviate the need to remove the polymer once its therapeutic value has been exhausted. Conventional drug delivery methods, such as frequent periodic dosing, are not ideal in many cases. For example, with highly toxic drugs, frequent conventional dosing can result in high initial drug levels, followed by low levels between doses that may be below their therapeutic value. However, with controlled drug delivery, drug levels can be maintained more closely at therapeutic, non-toxic levels, by controlled release in a predictable manner over a long term. If a biodegradable medical device is designed to be used as a drug supply or other controlled release system, using a polymeric vehicle is an effective means of delivering the therapeutic agent in a local and controlled manner, see Langer et al., "Chemical and Physicai Structures of Polymers as Carriers for Controled Relase of Bioactive Agents ", J. Macro Science, Rev. Macro. Chem. Phys., C23 (1), 61-126 (1983). As a result, less drug is required, and the toxic side effects can be minimized. The polymers have been used as vehicles of therapeutic agents to effect a localized and sustained release. See Long et al., "Polymeric Controlled Drug Delivery," Advanced Drug Delivery Reviews, 1: 199-233 (1987); Langer et al., "New methods of Drug Delivery", Science, 249: 1527-33 (1990); and Chien et al., Nobel Drug Delivery Systems (1982). Such delivery systems offer the potential for improved therapeutic efficacy and reduced total toxicity.

For a non-biodegradable matrix, 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 longer for a non-biodegradable matrix than for a biodegradable matrix, for which the passage through the matrix channels, although it may occur, already it is not required. Because many pharmaceutical products have short half-lives, the therapeutic agents can be broken down or inactivated within the non-biodegradable matrix before being released. This aspect is particularly important for many smaller bio-macromolecules and polypeptides, because those molecules are generally hydrolytically unstable and have low permeability through a polymer matrix. In fact, in a non-biodegradable matrix, many bio-macromolecules aggregate and precipitate, blocking the channels necessary for diffusion outside the vehicle matrix. These problems are solved using a biodegradable matrix which, in addition to some diffusional release, also allows controlled release of the therapeutic agent by degradation of the polymer matrix. Examples of classes of synthetic polymers that have been studied as possible biodegradable materials include polyesters (Pitt et al., "Biodegradable Drug Delivery Systems Based on Aliphatic Polyesters: Application to Contraceptives and Narcotic Antagonists", Controlled Relase of Bioactive Materials, 19-44 ( Richard Baker et al., Ed. 1980)); poly (amino acids) and pseudo-poly (amino acids) (Pulapura et al., "Trends in the Development of Bioresorbable Polymers for Medical Applications", Journal of Biomaterials Applications, 6 (1), 216-50 (1992)); polyurethanes (Bruin et al., "Biodegradabie Lysine Diisocyanate-based Poly (glycolide-co-e-caprolactone) -urethane Network in Artificial Skin", Biomaterials, 11 (4), 291-95 (1990), polyorthoesters (Heller et al. "Relay of Norethindrone from Poly (OrthoEsters)", Polymer Engineering and Science, 21 (11), 727-31 (1981)), and polyanhydrides (Leong et al., "Poiyanhydrides for Controlled Relay of Bioactive Agents" Biomaterials 7 (5) , 364-71 (1986) 9. Specific examples of materials that are used as medical implant materials are polylactides, polyglycides, polydioxanone, poly (lactide-co-glycoido), poly (glycolide-co-polydioxanone), polyanhydrides, poly ( glycolide-co-trimethylene carbonate), and poiy (glycolide-co-caprolactone) Polymers that have phosphate bonds, called poly (phosphates), poly (phosphonates) and poly (phosphites), are known, see Penczek et al. " Phosphorus-Containing Polymers ", Handbook of Polymer Synthesis, Part B, Chapter 17, 1077-1132 (Hans R Kricheldorf ed. 1992). The respective structures of these three classes of compounds, each having a different chain of materials connected to the phosphorus atom, are as follows: -R- O- -i- p- -R- -o- i-? P- - R 0- F. H Polyphosphate Polyphosphonate Polyphosphite The versatility of these polymers comes from the versatility of the phosphorus atom, which is known for a multiplicity of reactions. Your link may involve the 3p orbits or several 3s-3p hybrids; Spd hybrids are also possible due to accessible orbits. Therefore, the physico-chemical properties of the poly (phosphonates) can be easily changed by varying the group R or the R '. The biodegradability of the polymer is mainly due to the physiologically labile phosphoester bond in the polymer base structure. By manipulating the base structure or the side chain, a wide range of biodegradation rates are obtainable. Kadiyaia et al., "Poly (Phosphoesters): Synthesis, Psychochemical Characterization and Biological! Respons", Biomedical Applications of Synthetic Biodegradable Polymers, Chapter 3: 33-57 (Jeffrey o.Hollinger ed., 1995). An additional feature of poly (phosphoesters) is the availability of functional side groups. Because 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 through an ester linkage, which is hydrolysable. The P-O-C group in the base structure also lowers the glass transition temperature of the polymer and, importantly, confers solubility in common organic solvents, which is desirable for easy characterization and processing. Friedman, of the patent of E.U.A. No. 3,442,982, describes a poii polymer (phosphoester-co-ester) having, in its ester portion, the following asymmetric group: Friedman polymers are noted as being stable to hydrolysis, heat and light. (Column 1, row 42-44 and column 3, lines 74-75). Starck et al., Of Canadian Patent No. 597,473, discloses poly (phosphonates), and the incorporation of phosphorus is said to render the resultant polymers non-combustible (Column 6, row 1-2). Engelhardt et al., Patent of E.U.A. No. 5,530,093 discloses a multitude of textile finishing compositions having a wide variety of polycondensate structures with recurring ester and phosphoester units. The ester portions of Starck et al. And Engelhardt et al. Are oriented as follows: -O-CO-R3-CO-O There remains a need for materials such as the poly (phosphoester-co-ester) compounds of the invention, which are particularly well suited for the manufacture of biodegradable materials and other biomedical applications.

BRIEF DESCRIPTION OF THE INVENTION The biodegradable polymers of the invention consist of the recurring monomer units shown in formula I or II: O O O II frX- Mi -Gfcr -Y- - Y (-C - Mi - X-fe 11 1 Wherein: X is -O- or -NR'-, wherein R'es H or alkyl; M-i and M2 are independently (1) a straight or branched chain aliphatic group having 1-20 carbon atoms; or (2) an oxy-, carboxy-, or amino-aliophane group having from 1-20 carbon atoms; And it is -O-, -S- or -NR'-; L is a branched or straight chain aliphatic group having 1-20 carbon atoms; R is H, alkyl, alkoxy, aryl, aryloxy, heterocyclic or heterocycloxy; The molar ratio of x: y is approximately 1; The molar ratio of n: (x or y) is between 200: 1 and 1: 200; and The molar ratio of q: r is between 1: 99 and 99: 1. These biodegradable polymers are biocompatible before and with biodegradation. In another embodiment, the composition consists of polymer compositions consisting of: (a) at least one biologically active substance and (b) a polymer having the recurring monomer units shown in Formula I or II. In yet another embodiment of the invention, an article useful for implantation, injection or to be otherwise placed in whole or in part within the body, consists of the biodegradable polymer of formula I or II or of the polymer compositions described above. In a further embodiment, the invention contemplates a process for preparing a biodegradable polymer comprising the steps of: (a) reacting a heterocyclic ring having the formula III, IV or V: V Where Mi, M2 and X are as defined above, with an initiator having the formula: H-Y-L-Y-H, where Y and L are as defined above, to form a prepolymer of formula VI or VII, shown below: (VI) OR O -f-X- M - G - -Y- L- Y- • fO- Mi - X? - (V) O O O O II II - [r (X- M2- G ») q e - i - G I ') J i- Y- L-Y- iC- M- X) p-tC- M2- X ?? - Where X, Mi, M2, Y, L, x, y, q and r are as defined previously; and (b) further reacting said prepolymer of formula I, IV or V with a phosphorodialidate of formula VIII: V I H Or halo- -halo R where "halo" is Br, Cl, or I; and R is how it is defined above, to form said polymer of formula I or II. In another embodiment of the invention, there is provided a method for the controlled release of a biologically active substance consisting of the steps of: (a) combining the biologically active substance with a biodegradable polymer having the monomeric units recurring ones shown in formula I or II to form a mixture; (b) forming the mixture in a formed solid article; and (c) implanting or injecting the solid article in vivo at a pre-site determined, in such a way that the solid article implanted or injected is at least in partial contact with a fluid biological.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the results of a GPC analysis of a polymer of the invention in graphic form. Figures 2 A and 2B show differential evaluation calorimetry data for two polymers of the present invention. Figures 3 A and 3B show the weight loss (3 A) and the change in Pm (weight) (3B) for discs made of two polymers of the invention over a period of eight days in PBS at 37 ° C. Figure 4 shows the change in Pm (weight) of two polymers of the invention after having been exposed to air at room temperature for one month. Figure 5 shows the 1 H NMR spectrum of a polymer of the invention, P (LAEG-EOP). Figure 6 shows the 31P NMR spectrum of a polymer of the invention, P (LAEG-EOP). Figure 7 shows the shelf stability data for a polymer of the invention at room temperature. Figure 8 shows the cytotoxicity data for microspheres of a polymer of the invention, P (LAEG-EOP). Figures 9 A and 9B show the weight loss (9 A) and the change in Pm (weight) (9B) for discs made of two polymers of the invention in vitro.

Figures 10A and 10B show the weight loss (10A) and the change in Pm (weight) (10B) for discs made of the polymer of the invention in vivo. Figure 11 shows the biocompatibility data for polymers of the invention. Figure 12 shows the effect of the manufacturing method on the release rate of microspheres of a polymer of the invention. Figure 13 shows the release rate of lidocaine and cisplatin from microspheres of a polymer of the invention. Figure 14 shows the appearance of P (LAEG-EOP) microspheres containing FITC-BSA. Figure 15 shows the release rate of lidocaine from microspheres of a polymer of the invention. Figure 16 shows the release rate of iidocaine and cisplatin from microspheres of a polymer of the invention.

POLYMERS OF THE INVENTION As used herein, the term "aliphatic" refers to a linear, branched alkane, alkene or cyclic alkyne. The preferred aliphatic groups in the polymer poii (phosphoester-co-ester) of the invention are linear or branched and have from 1 to 10 carbons, preferably being linear groups having from 1 to 7 carbon atoms.

As used herein, the term "arite" refers to a cyclic carbon compound not saturated with 4n + 2 p electrons. As used herein, the term "heterocyclic" refers to a saturated or unsaturated ring compound having one or m. { atoms other than carbon in the ring, for example, nitrogen, oxygen or sulfur. The biodegradable polymer of the invention consists of the recurring monomer units shown in formula I or II: i Where X is -O- or -NR'- wherein R 'is H or alkyl. L can be any direct or branched chain divalent aliphatic group having 1-20 carbon atoms, as long as it does not interfere with the polymerization or biodegradation reactions of the polymer. Specifically, L may be an alkylene group, such as methylene, ethylene, 1,2-dimethyl-ethylene, n-propylene, isopropylene, 2,2-dimethylpropylene, or tert-butylene, n-pentylene, tert-pentyne, n -exylene, n-heptylene, and the like; an alkylene substituted with a non-interfering substituent, for example, alkylene substituted by hydroxy-, halogen- or nitrogen; an alkenylene group such as ethenylene, propenylene, 2- (3-propenyl) -dodecylene, and an alkynylene group such as ethynylene, propynylene, 1- (4-butynyl) -3-methylidecyiene; and similar. Preferably, however, L is independently a branched or straight chain alkylene group, more preferably, an alkylene group having from 1 to 7 carbon atoms. Even more preferably, L is an ethylene group or a methylene group substituted by methyl, and more preferably L is an ethylene group. Mi and M2 in the formula are each independently either (1) a straight or branched chain aliphatic group having 1-20 carbon atoms or (2) an oxy-, carboxy-, or amino-aliphatic group having 1 -20 carbon atoms. In any case, the straight or branched chain aliphatic group can be any divalent aliphatic portion having 1-20 carbon atoms, more preferably 1-7 carbon atoms, which does not interfere with the polymerization, copolymerization or biodegradation reactions of the polymers. Specifically, when either Mi and M2 is a branched or straight chain aiiphatic group having 1-20 carbon atoms, it can be, for example, an alkyiene group, such as methylene, ethylene, 1-methylethylene, 1-2. dimethylethylene, n-propylene, trimethylene, isopropylene, 2,2-dimethylpropylene, tert-butylene, n-pentylene, tert-pentylene, n-exylene, n-heptylene, n-octylene, n-nonylene, n-decylene, n- undecyniene, n-dodecyiene, and the like; an aikylene group, such as n-propenylene, 2-vinylpropyne, n-butylene, 3-ethenyiibutiene, n-pentenylene, 4- (3-propenyl) hexyiene, n-octenylene, 1- (4-butenyl) -3-methyldecylene, 2- (3-propenyl) dodecylene, hexadecenene, and the like; an aikylene group, such as ethynylene, propynylene, 3- (2-ethynyl) pentylene, n-hexynylene, 2- (2-propynyl) decylene, and the like; or an alkylene, alkenylene or alkynylene group substituted with a non-interfering substituent, such as, for example, a hydroxy, halogen or nitrogen group, such as 2-chloro-n-decylene, 1-hydroxy-3-ethenylbutylene, 2-propyl-6 -nitro-10-dodeciniieno, and the like. When either Mi and M2 is a direct or branched chain oxy-aliphatic group having 1-20 carbon atoms, it can be, for example, a divalent alkoxyiene group, such as ethoxylene, 2-methylethoxylene, propoxylene, butoxyiene, pentoxylene, dodecyanoxy , hexadecyloxylene and the like. When either Mi and M2 is a straight or branched chain oxy-aliphatic group, preferably, it has the formula -O- (CH2) a- where a is from 1 to 7. When either Mi or M2 is an oxy-aliphatic group branched or direct chain having 1-20 carbon atoms, can also be, for example, a dioxyalkylene group such as dioxymethylene, dioxyethylene, 1,3-dioxypropylene, 2-methoxy-1,3-dioxypropylene, 1,3-dioxy -2-methylpropylene, dioxy-n-pentylene, dioxy-n-octadecylene, methoxyne-methoxylene, ethoxy-methylene, ethoxy-ethoxy, ethoxy-1-propoxylene, butoxy-n-propoxylene, pentadecyloxylene-methoxy- ene, and the like. When Mi or M2 is a branched or direct dioxo-aiiphatic group, preferably, it has the formula -O- (CH2) aO- or -O- (CH2) aO- (CH2) b- where each of a and b is from 1 to 7.

When either Mi or M2 is a branched or straight-chain carboxy-aiiphatic group having 1-20 carbon atoms, it can also be, for example, a divalent carboxylic acid ester as the divalent radical of methyl formate, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, ethyl propionate, allyl propionate, acrylate t-butyl, n-butyl butyrate, vinyl chloroacetate, 2-methoxy-carbonyl-cyclohexanone, 2-acetoxycyclohexanone, and the like. When either Mi or M2 is a branched or straight chain carboxy-aliphatic group preferably, it has the formula -O-CHR2-CO-O-CHR3-, wherein R2 and R3 are each independently H, alkyl, alkoxy, aryi, Aryoxy, heterocyclic or heterocycloxy. When either Mi or M2 is a branched or straight chain amino-aliphatic group having 1-20 carbon atoms, it can be a divalent amine such as -CH2NH-, - (CH2) 2N-, -CH2 (C2H5) N-, -n-C4H9NH-, -t-C4H9NH-, -CH2 (C3H7) N-, -C2H5 (C3H7) N-, -CH2 (C8H? 7) N-, and the like. When either Mi or M2 is a branched or straight chain amino-aliphatic group it preferably has the formula - (CH2) a-NR'- where R 'is H or a lower alkyl. Preferably, Mi and / or M2 is an alkylene group having the formula -O- (CH2) a- wherein a is 1 to 7 and, more preferably, it is a divalent ethylene group. In a particularly preferred embodiment, Mi and M2 are both present; Mi and M2 are not the same chemical entity; and Mi and M2 are n-pentylene and the divalent radical of methyl acetate respectively.

R in the polymer of the invention is H, alkyl, akoxy, aryl, aryloxy, heterocyclic residue or heterocycloxy. Examples of useful R'alkyl groups include methyl, ethyl, n-propyium, i-propyl, n-butyl, tert-butyl, -C8H17, and similar groups; alkyl substituted with a non-interfering substituent, such as idroxy, halogen, alkoxy or nitro; corresponding alkoxy groups; and conjugated alkyl to a biologically active substance to form a pending drug delivery system. When R is arid 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 together. Examples of particularly suitable aromatic groups include phenyl, phenoxy, naphthyl, anthracenium, phenanthrenium and the like. When R is heterocyclic or heterocycloxy, it typically contains from 5 to 14 carbon atoms, preferably from 5 to 12 carbon atoms, and one or more heteroatoms. Examples of suitable heterocyclic groups include furan, thiophene, pyrrole, isopyralla, 3-isopyralla, pyrazole, 2-isoimidazole, 1,2,3-triazole, 1,4-triazole, oxazole, thiazole, siazole, 1, 2,3-oxadiazole, 1, 2,4-oxadiazole, 1, 2,5-oxadiazole, 1, 3,4-oxadiazole, 1, 2,3,4-oxatriazole, 1, 2,3,5-oxatriazole, 1, 2,3-dioxazole, 1,4-dioxazole, 1,2-dioxazole, 1,4-dioxazole, 1, 2,5-oxatriazole, 1,3-oxathioia, 1,2- pyran, 1,4-pyran, 1,2-pyrone, 1,4-pyrone, 1,2-dioxin, 1,3-dioxin, pyridine, N-alkyipyridinium, pyridazine, pyrimidine, pyrazine, 1, 3,5- triazine, 1,4-triazine, 1,2,3-triazine, 1,4-oxazine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, or- isoxazine, p-isoxazine, or 1, 2,5-oxathiazine, 1, 2,6-oxathiazine, 1, 4,2-oxadiazine, 1, 3,5,2-oxadiazine, azepine, oxepine, tiepine, 1, 2 , 4-diazepine, indene, isoindene, benzofuran, isobenzofuran, thionaphthene, isothionephtene, indole, indoienine, 2-isobenzasole, 1,4-pyrindine, pyrazole (3,4-b) -pyrrole, isoindazole, indoxazine, benzoxazole, anthranil, 1,2-benzopyran, 1,2-benzopyrone, 1,4-benzopyrone, 2,1-benzopyrone, 2,3-benzopyrone, quinoline, isoquinoline, 12-benzodiazine, 1,3-benzodiazine , naphthyridine, pyrido (3,4-b) -pyridine, pyrido (3,2-b) -pyridine, pyrido (4,3-b) -pyridine, 1,2-benzoxazine, 1,4 2-benzoxazine, 2,3,1-benzoxazine, 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, and 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, more preferably, an alkoxy group having from 1 to 7 carbon atoms. More significantly, R is an ethoxy group. The molar ratio of n: (x or y) can vary greatly depending on the biodegradability and the desired release characteristics in the polymer, but typically ranges between 200: 1 and 1: 200. Preferably, the ratio x: y is from 100: 1 to 1: 100 and, more preferably, from 50: 1 to 1: 50.

The molar ratio of q: r can vary greatly depending on the biodegradability and the desired release characteristics in the polymer, but typically varies between 1: 200 and 200: 1. Preferably, the ratio q: r is from 1: 150 to 150: 1 and, more preferably, from 1: 99 to 99: 1. The molar ratio of x: y can also vary greatly depending on the biodegradability and the desired release characteristics in the polymer, but typically it is about 1. Biodegradable polymers differ from non-biodegradable polymers in that they can be degraded during in vivo therapy. This generally involves the decomposition of the polymer into monomer subunits. In principle, the final products of hydrolytic decomposition of a poly (phosphoester) are phosphate, alcohol, and diol, all of which are potently non-toxic. The intermediate oligomeric products of hydrolysis may have different properties, but the toxicology of a biodegradable polymer designed for implantation or injection, even one synthesized from seemingly harmless monomeric structures, is typically determined after one or more in vitro toxicity analyzes. A typical toxicity analysis would be performed with live carcinoma cells, such as GT3TKB tumor cells, as follows: Approximately 100-150 mg of the sample polymer are degraded in 20 ml of 1 M NaOH at 37 ° C for 1 -2 days, or until complete degradation is observed. The solution is then neutralized with 20 ml of 1 M HCl. Approximately 200 μL of various concentrations of degraded polymer products are placed in 96-well tissue culture plates and seeded with human gastric carcicoma cells (GT3TKB) at a density of 104 / cavity. The degraded polymer products are incubated with the GT3TKB cells for 48 hours. The results of the analysis can be plotted as% relative growth vs. Concentration of degraded polymer in the tissue culture cavity. The biodegradable polymer of the invention is preferably sufficiently pure to be biocompatible per se and remains biocompatible with degradation. By "biocompatible" it means that the biodegradation products or the polymer itself are non-toxic and result only in minimal tissue irritation when implanted or injected into vascularized tissue. • The polymer of the invention is preferably soluble in one or more common organic solvents for ease of manufacture and processing. Common organic solvents include solvents such as chloroform, dichloromethane, acetone, ethyl acetate, DMAC, N-methyl pyrrolidone, dimethylformamide, and dimethylsulfoxide. The polymer is preferably soluble in at least one of the above solvents.

Synthesis of Polymers (phosphoester-co-ester) The most common general reaction to prepare poly (phosphates) is a dehydrochlorination between a phosphorodichlorhydrate and a diol according to the following equation: n + 2n HCl Most poii (phosphonates) are also obtained by condensation between dichlorides and suitably substituted diols. The poly (phosphites) have been prepared from glycols in a two step condensation reaction. A 20% molar excess of a dimethylphosphite is used to react with the glycol, followed by the removal of the methoxyphosphonium end groups in the oligomers by high temperature. One advantage of polycondensation casting is that it avoids the use of solvents and large amounts of other additives, thus making the purification more direct. It can also provide polymers of reasonably high molecular weight. However, a little stringent conditions are often required and can lead to chain acidoiysis (or hydrolysis if water is present). Undesired lateral reactions, thermally induced, may also occur as inter-chain reactions, if the base structure of the polymer is susceptible to hydrogen atom abstraction or to oxidation with subsequent macroradicai recombination. To minimize these side reactions, the polymerization can also be carried out in solution. Polycondensation in solution requires that 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 must be run in the presence of equimolar amounts of the reagents and a stoichiometric amount of an acid acceptor, usually a tertiary amine such as pyridine or triethiamine. The product is typically isolated from the solution by precipitation in a non-solvent and purified to remove the hydrochloride salt by conventional techniques known to those of skill in the art, such as washing with an aqueous acid solution, for example diluted HCl. The reaction times tend to be longer in the solution polymerization than with the melt polymerization. However, because milder reaction conditions can be used in general, side reactions are minimized, and more sensitive functional groups can be incorporated into the polymer. The disadvantages of solution polymerization are that obtaining high molecular weights, such as a Pm (Mw) greater than 20,000, is unlikely.

Interfacial polycondensation can be used when high molecular weight polymers are desired at high reaction rates. Soft conditions minimize side effects. In addition, the dependence of high molecular weight on the stoichiometric equivalence between dioi and inherent dihydrochloride in the solution methods is removed. However, hydrolysis of the acid chloride in the alkaline aqueous phase may occur. Sensitive dihydrochlorides that have some solubility in water are subject to hydrolysis rather than 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 ration. The yield and the molecular weight of the resulting polymer after the interfacial polycondensation are affected by the reaction time, the molar ratio of the monomers, the volume ratio of the non-miscible 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 I or II is manufactured by a process consisting of the steps of: (a) reacting at least one heterocyclic ring compound having the formula III, IV or V: IV V Where: Mi, M2 and X are as defined above, with an initiator having the formula: H-Y-L-Y-H Where Y and L are as defined above, to form a prepolymer of formula VI or VII, shown below: SAW Vil - M2- X q} and Where X, Mi, M2, Y, L, R, x, y, q and r are as defined above; and (b) further reacting said prepolymer of formula III, or IV or V with a phosphorodidaidate of formula HIV.

VIII OR II halo - P - halo I R Where "halo" is Br, Cl or I; and R is as defined above, to form said polymer of formula I or 11. The function of the first reaction step (a) is to use the initiator to open the ring of the heterocyclic ring compound of formula III, IV or V.

Examples of useful heterocyclic compounds of formula III, IV or V include caproiactones, caprolactams, amino acid anhydrides such as glycine anhydride, cycloalkylene carbonates, dioxanones, glycolides, lactides and the like. When the compound of the invention has the formula I, only one heterocyclic ring compound of the formula i 11, which contains Mi, can be used to prepare the prepoiimer of formula VI in step (to). When the compound of the invention has the formula II, then a combination of a heterocyclic compound of the formula III, which contains Mi, and a heterocyclic compound of the formula IV, which contains M2, can be used in step (a). Alternatively, when the compound of the invention has the formula II, a single heterocyclic compound of formula V, which contains M.}. and M2, can be used in step (a). Examples of suitable initiators include a wide variety of compounds having at least two active hydrogens (HYLYH) wherein L is a chaining group and defined above, and Y can be -O-, -S- or NR ", wherein R "is as defined above. The linker group L is can be a straight chain group, for example alkylene, but can also be substituted with one or more additional groups containing active hydrogen. For example, L can be a straight-chain aikylene group substituted with one or more additional alkyl groups, each carrying a portion of activated hydrogen, such as -OH, -SH, or NH2. In this way, several branched polymers can be prepared using the branched active hydrogen initiators to design the resulting polymer in such a way that it has the desired properties. However, when branched polymers are reacted with acid chlorides, interlinked polymers will result. The reaction step (a) can take place at temperatures that vary widely, depending on the solvent used, the molecular weight desired, the susceptibility of the reactants to form side reactions, and the presence of a catalyst. Preferably, however, the reaction step (a) takes place at a temperature from 0 to about + 235 ° C for casting conditions. Somewhat lower temperatures may be possible with the use of a cationic or anionic catalyst.

The time required for the reaction step (a) can also vary widely, depending on the type of reaction being used, and the desired molecular weight. Preferably, however, the reaction step (a) takes place for a time between 1 hour and 7 days. Although the reaction step (a) may be in bulk, in solution, by interfacial polycondensation, or any other convenient polymerization method, preferably, the reaction step (a) takes place under melting conditions. Examples of particularly useful prepolymers of formula V include: (i) OH-terminated prepolymer derived from poiicaprolactone. H- [-0 (CH2) 5 -CO-] - O-CH2-CH2-O - [- CO- (CH2) 5 -O-V-H; (ii) prepolymer terminated in NH-derivative of polycaproiactam (Nylon 6). H- [-NH- (CH 2) 5 -CO-] x -NH-CH 2 -CH 2 -NH - [- CO- (CH 2) 5 -NH-] and-H; (Ii) OH-terminated prepolymer polylactide derivative H - [- OCH- (CH 3) -CO -] - O-CH 2 -CH 2 -O - [- CO-CH (CH 3) -O-] y-H; and (iv) OH-terminated prepolymer of polytrimethylene carbonate H - [- O (CH 2) 3 -O-CO -] - O-CH 2 -CH 2 -O - [- CO-O- (CH 2) 3 - O-] yH. Examples of particularly useful prepoiomers of formula VI include: (i) OH-terminated copolymer of iactide and glycolide: O O O O H - [(-OCH-C-OCH-C-) - (OCH2-C-OCH2-C) r]? -0-CH2CH2 - O-ff CH. CH.

O O O O // - [(C-CH20-C-CH20) r- (C-CHO-C-CHO-)] -H CH. CH. (ii) OH-terminated copolymer derived from lactide and caprolactone: O O or H - C -) q- (OC5H10 - C) r]? -0-CH2CH2 - O - // O O O // - [(C - C5H10O) r- (C - -) q] y-H (iii) OH-terminated copolymer derived from glycolide and caprolactone: O O O II II II H - [(-OCH2-C-OCH2-C) - (OC H10-C) ^ -O- CH2CH2- O - // O O O // - [(C-C5H1QO) (C - CH20 - C - CH2O - ^ -H The object of the polymerization step (b) is to form a polymer consisting of (i) the prepolymer produced as a result of step (a) and (i) phosphorylated units that are interconnected. The result can be a cloque copolymer having a microcrystalline structure that is particularly well suited for use as a controlled release medium. The polymerization step (b) of the invention normally takes place at a slightly lower temperature than the temperature of step (a), but can also vary widely, depending on the type of polymerization reaction used, the presence of one or more catalysts , the desired molecular weight, and the susceptibility of the reactants to undesirable side reaction. When melting conditions are used, the temperature can vary from 0-150 ° C. However, when the polymerization step (b) is carried out in a solution polymerization reaction, it typically takes place at a temperature between -40 and 100 ° C. Typical solvents include methylene chloride, chloroform, and any of a wide variety of inert organic solvents.

The time required for the polymerization of step (b) may also vary widely, depending on the molecular weight of the desired material 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 polymerization step (b) takes place for a time of 30 minutes to 48 hours. Particularly when a solution polymerization reaction is used, an acid acceptor is advantageously present during the polymerization step (a). A particularly suitable acid acceptor compound consists of tertiary amines, such as pyridine, trimethiamine, triethylamine, substituted anilines and substituted aminopyridines. The most preferred acid acceptor is the substituted aminopyridine 4-dimethyl-aminopyridine ("DMAP"). The polymers of formula I and II are isolated from the reaction mixture by conventional techniques, such as precipitation out, extraction with a non-miscible solvent, evaporation, filtration, crystallization and the like. Typically, however, the polymers of formulas I and II are isolated and purified by quenching a solution of said polymer with a non-solvent or a partial solvent such as diethyl ether or petroleum ether.

Characteristics of Biodegradability and Release The polymers of formulas I and II are typically characterized by a rate of release of the biologically active substance in vivo which is controlled at least in part as a function of hydrolysis of the phosphoester linkage of the polymer during biodegradation. Additionally, the biologically active substance to be released can be conjugated to the phosphorus side chain R 'to form a pending drug delivery system. In addition, other factors are also important. The life of a biodegradable polymer in vivo also depends on its molecular weight, crystallinity, biostability, and the degree of chaining. In general, the higher the molecular weight, the higher the degree of crystallinity, and the greater the biostability, the biodegradation will be slower. Accordingly, the structure of the side chain can influence the release behavior of compositions consisting of the biologically active substance. For example, it is expected that the conversion of the phosphate side chain to a more lipophilic, more hydrophobic or bulky group would slow down the degradation process. Thus, the release is normally faster from polymer compositions with a small aliphatic group side chain than with a bulky aromatic side chain.

Polymer Compositions The polymers of formulas I and li can be used alone or as a composition that also contains a biologically active substance to form a variety of useful biodegradable materials. For example, the polymers of formulas I and 11 can be used to produce a bioabsorbable suture, orthopedic apparatus or bone cement to repair injuries to bone or connective tissue, a laminate for degradable or non-degradable fabrics, or a coating for a device of implant, even without the presence of a biologically active substance. Preferably, however, the biodegradable polymer composition consists of both: (a) at least one biologically active substance and (b) the polymer having the recurring monomer units shown in formula I or II wherein X, Mi, M2, L, R, Y, x, y, q, r, and n are as defined above. The biologically active substance of the invention can vary widely for the purpose of the composition. The biologically active substance (s) can be described as a single entity or a combination of entities. The delivery system is designed to be used with biologically active substances that have high solubility in water as well as those that have low solubility in water to produce a delivery system having controlled release rates. The term "biologically active substance" includes, without limitation, drugs; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of diseases or conditions; or substances that affect the structure or functioning of the body; or pro-drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment. Non-limiting examples of broad categories of useful biologically active substances include the following expanded therapeutic categories: anabolic agents, antacids, anti-asthmatic agents, anti-cholemic and anti-lipid agents, anti-coagulants, anti-convulsants, anti-diarrheals, anti -emetics, anti-infective agents, anti-inflammatory agents, anti-manic agents, anti-nauseants, anti-neoplastic agents, anti-obesity agents, anti-pyretic and analgesic agents, anti-spasmodic agents, anti-thrombotic agents, agents anti-uricémics, anti-anginal agents, antihistamines, antitussives, appetite suppressants, biological materials, brain dilators, coronary dilators, decongestants, diuretics, diagnostic agents, erythropoietic agents, expectorants, gastrointestinal sedatives, hyperglycemic agents, hypnotics, hypoglycemic agents, ion exchange resins, laxatives, mineral supplements, age mucolytics, neuromuscular drugs, peripheral vasodilators, psychotropics, sedatives, stimulants, thyroid and antithyroid agents, uterine relaxants, vitamins and prodrugs. Specific examples of useful biologically active substances of the above categories include: (a) anti-neopiastic as androgen inhibitors, antimetabolites, cytotoxic agents, immunomodulators; (b) anti-tusives such as dextromethorphan, dextromethorphan hydrobromide, noscapine, carbetapentane citrate, and ciorfedianol hydrochloride; (c) antihistamines such as chlorpheniramine malate, fenindamine tartrate, pyrilamine maleate, doxylamine succinate, and phenytoioloxamine citrate; (d) decongestants such as phenylephrine hydrochloride, feniipropanolamine hydrochloride, pseudoephedrine hydrochloride, and ephedrine; (e) several alkaloids such as codeine phosphate, codeine sulfate and morphine; (f) mineral supplements such as potassium chloride, zinc chloride, calcium carbonates, magnesium oxide, and other alkali metal or alkaline earth metal salts; (g) ion exchange resins such as cholestyramine; (h) anti-arrhythmics such as N-acetylprocainamide; (i) antipyretics and analgesics such as acetaminophen, aspirin and ibuprofen; (j) appetite suppressants such as phenylpropanolamine hydrochloride or caffeine; (k) expectorants such as guaifenesin; (I) antacids such as aluminum hydroxide and magnesium hydroxide; (m) biological materials such as peptides, protein and amino acid polypeptides, hormones, interferons or cytokines and other bioactive peptide compounds, such as hGH, tPA, calcitonin, ANF, EPO and insulin; and (n) anti-infectious agents such as anti-fungal, anti-viral, antiseptic and antibiotic. Preferably, the biologically active substance is selected from the group consisting of poiisaccharides, growth factors, hormones, anti-angiogenesis factors, interferons or cytokines, and pro-drugs. More specifically, 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, as H blockers and H2- blockers; anti-infective agents such as anthelmintics, antianaerobic, antibiotics, aminoglycoside antibiotics, antifungal antibiotics, cephalosporin antibiotics, macrolide antibiotics, various ß-lactam antibiotics, penicillin antibiotics, quinoline antibiotics, sulfonamide antibiotics, tetracycline antibiotics, antimycobacterials , antimicrobial antituberculosis, antiprotoazoles, antimalarial antiprotoazoles, antiviral agents, antiretroviral agents, scabicides, and urinary anti-infectives; antineoplastic agents, such as alkylating agents, nitrogen mustard alkylating agents, nitrosourea alkylating agents, antimetabolites, purine analog antimetabolites, pyrimidine analog antimetabolites, hormonal antineoplastics, natural antineoplastic agents, natural antibiotic antineoplastic agents, and natural vinca vinca alkaloid antineoplastic agents; autonomic agents, such as anticoiinergics, anticholinergic antimuscarinics, alkaloids of the deceased, parasympathomimetics, parasympathomimetics, cholinergic agonists, parasympathomimetic cholinesterase inhibitors, sympatholytics, a-blocker sympatholytics, ß-blocker sympatholytics, sympathomimetics, and sympathomimetic adrenergic agonists; cardiovascular agents, such as antianginal, antianginal ß-blocker, antianginal calcium channel blocker, antianginal nitrate, antiarrhythmics, cardiac glycoside antiarrhythmics, class I antiarrhythmics, class II antiarrhythmics, class III antiarrhythmics, class IV antiarrhythmics, antihypertensive agents, antihypertensive agents -blockers, angiotensin-converting enzyme inhibitors, (ACE inhibitor), β-blocker antihypertensives, calcium channel blocker antihypertensive agents, centrally acting adrenergic antihypertensives, diuretic antihypertensive agents, peripheral hypertensive antihypertensive drugs, antilipemic agents, antilipemic bile acid sequestrants, inhibitors of HMG-CoA reductase inhibitors, inotropes, inotropes cardiac glycosides, and thrombolytic agents; dermatological agents, such as antihistamines, anti-inflammatory agents, anti-inflammatory agents of corticosteroids, antipruritic / local anesthetics, topical anti-infectives, antifungal topical antifungal, anti-infective topical antiviral, and topical anti-neoplastic; electrolytic and renal agents, such as acidifying agents, alkalizing agents, diuretics, carbonic anhydrase inhibitor diuretics, loop diuretics, osmotic diuretics, low potassium diuretics, thiazide diuretics, electrolyte replacements, and uricosuric agents; enzymes, such as pancreatic enzymes and thrombolytic enzymes; gastrointestinal agents, such as antidiarrheals, anti-emetics, gastrointestinal anti-inflammatory agents, salicylate anti-inflammatory agents, anti-ulcer agents antacids, anti-ulcer agents of gastric acid pump inhibitor, anti-ulcer agents of gastric mucosa, anti-inflammatory agents -blood of H2 blocker, colelitoiíticos agents, digestive, emetics, laxatives and stool softeners, and prokinetic agents; general anesthetics, such as inhalation anesthetics, halogenated inhalation anesthetics, intravenous anesthetics, intravenous barbiturate anesthetics, intravenous benzodiazepine anesthetics, and intravenous anesthetics opiate agonists; hematological agents, such as antianemia agents, hematopoietic antianemia agents, coagulation agents, anticoagulants, hemostatic coagulation agents, platelet inhibitor coagulation agents, thrombolytic enzyme coagulation agents, and plasma volume expanders; hormones and hormone modifiers, such as abortifacients, adrenal agents, adrenal corticosteroid agents, androgens, anti-androgens, antidiabetic agents, antidiabetic agents of sulfonylurea, antihipoglycemic agents, oral contraceptives, progestin contraceptives, estrogens, fertility agents, oxytocics, agents parathyroid, pituitary hormones, progestins, antithyroid agents, thyroid and tocolytic hormones; immunobiological agents, such as immunoglobulins, immunosuppressants, toxoids, and vaccines; local anesthetics, such as local amide anesthetics, and local ester anesthetics, musculoskeletal agents, anti-gout anti-inflammatory agents, corticosteroid anti-inflammatory agents, gold compound anti-inflammatory agents, anti-inflammatory immunosuppressive agents, anti-inflammatory drugs -non-steroidal inflammatories (NSAIDs), anti-inflammatory agents of saiicilate, skeletal muscle relaxants, skeletal muscle relaxants of neuromuscular blocker, and skeletal muscle relaxants of reverse neuromuscular biochemist; neurological agents, such as anticonvulsants, barbiturate anticonvulsants, benzodiazepine anticonvulsants, antimigraine agents, anti-parkinsonian agents, anti-vertigo agents, opiate agonists, and opiate antagonists, ophthalmic agents, such as anti-giaucoma agents, anti-glaucoma agents, β-blocker, miotic anti-glaucoma agents, mydriatics, mydriatic adrenergic agonists, antimuscarinic mydriatics, ophthalmic anesthetics, ophthalmic anti-infectives, aminoglycoside ophthalmic anti-infectives, macrolide anti-infective ophthalmic agents, anti-quinolone ophthalmic anti-infectives, anti- sulfonamide ophthalmic infectious agents, tetracycline ophthalmic antiinfectives, ophthalmic anti-inflammatory agents, ophthalmic corticosteroid anti-inflammatory agents, and non-steroidal ophthalmic anti-inflammatory drugs (NSAIDs); psychotropic agents, such as antidepressants, monoamine oxidase inhibitors (MAOls), selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, antimalarials, antipsychotics, phenothiazine antipsychotics, anxioiíticos, sedatives, and hypnotics, sedatives and hypnotics of barbiturates, anxiolytics, sedatives, and benzodiazepine hypnotics, and psychostimulants; respiratory agents, such as antitussives, bronchodilators, bronchodilators, adrenergic agonists, antimuscarinic bronchodilators, expectorants, mucolytic agents, respiratory anti-inflammatory agents, respiratory anti-inflammatory agents of corticosteroids; toxicosis agents, such as antidotes, heavy metal antagonists / chelating agents, substance abuse agents, substance abuse deterrents, and substance abuse withholding agents; minerals and vitamins, such as vitamin A, vitamin B, vitamin C, vitamin D, vitamin E, and vitamin K. Preferred types of biologically active substances useful from the above categories include (1) analgesics of nonsteroidal anti-inflammatory drugs (NSAIDs) ), such as diclofenac, ibuprofen, ketoprofen, and naproxen; (2) opiate agonist analgesics, such as codeine, fentanyl, hydromorphone, and morphine; (3) salicylate analgesics, such as aspirin (ASA) (enteric coating ASA)); (4) antihistamines of H-blocker, such as clemastine and terfenadine; (5) antihistamines of H2 blocker such as cimetidine, famotidine, nizadine, and ranitidine; (6) anti-infective agents, such as mupirocin; (7) anti-anaesthobic anti-infectives, such as chloramphenicol and cyandamicin; (8) anti-infective antifungal antibiotics, such as amphotericin b, clotrimazole, fluconazole, and ketoconazole; (9) anti-infective macrolide antibiotics, such as azithromycin, and erythromycin; (10) anti-infective ß-lactam antibiotics, such as aztreone and mipenem; (11) anti-infective penicillin antibiotics, such as nafcillin, oxacycin, penicillin G, and penicillin V; (12) anti-infective quinoline antibiotics, such as ciprofloxazine and norfloxazine; (13) anti-infective tetracycline antibiotics, such as doxycycline, minocycline and tetracycline; (14) antimicrobial anti-tuberculosis drugs such as isoniazid (INH), and rifampin; (15) antiprotozoal anti-infectives such as atovaquone and dapsone; (16) Anti-infective antiprotozoa antimalarials, such as chloroquine and pyrimethamine; (17) antiretroviral anti-infectives, such as ritonavir and zidovudine; (18) antiviral anti-infective agents such as acyclovir, ganciclovir, alpha interferon, and rimantadine; (19) antineoplastic alkylating agents, such as carboplatin and cisplatin; (20) antineoplastic nitrosourea alkylating agents, such as carmustine (BCNU); (21) antimetabolite antineoplastic agents such as methotrexate; (22) antimicrobial antimetaboite agents pyrimidine analogs, such as fiuorouracii (5-FU) and gemcitabine; (23) hormonal antineoplastics, such as goselerin, leuprolide and tamoxifen; (24) natural antineoplastics, such as aldesleukin, interleukin-2, docetaxei, etoposide (VP-16), alpha interferon, paclitaxcel, and trethionine (ATRA); (25) natural antineoplastic antibiotics, such as bleomycin, dactinomycin, daunorubicin, doxorubicin, and mitomycin; (26) natural vinca alkaloid antineoplastic drugs such as vinbiastine and vincristine; (27) autonomic agents, such as nicotine; (28) anticholinergic autonomic agents, such as benztropine and trihexyphenidyl; (29) anticholinergic anticholinergic agents, such as atropine and oxybutynin; (30) autonomic agents of ergot alkaloid, such as bromocriptine; (31) parasympathomimetics cholinergic agonists such as pilocarpine; (32) parasympathetic cholinesterase inhibitor, such as pyridostigmine; (33) a-blocker sympatholytics, such as prazosin; (34) β-blocker sympatholytics such as atenoiol; (35) sympathomimetic adrenergic agonists, such as albuterol and dobutamine; (36) cardiovascular agents, such as aspirin (ASA) (ASA with enteric coating); (37) antianginal ß-blocker, such as atenoiol and propranolol; (38) Antianginal calcium channel blocker, such as nifedipine and verapamil; (39) antianginal nitrate, such as isosorbide dinitrate (ISDN); (40) cardiac glycoside antiarrhythmics, such as digoxin; (41) class I antiarrhythmics, such as lidocaine, mexiietine, phenotoin, procainamide, and quinidine; (42) class II antiarrhythmics, such as atenoiol, metoprolol, propranolol, and timolol; (43) class III antiarrhythmics, such as amiodarone; (44) class IV antiarrhythmics, such as diltiazema and verapamil; (45) anti-hypertensive a-blocker, such as prasozine; (46) antihypertensive angiotensin-converting enzyme inhibitor (ACE inhibitor), such as captopril and enalapril; (47) ß-blocker antihypertensive agents, such as atenolol, metoprolol, nadolol and propranoiol; (48) calcium channel blocker antihypertensive agents, such as diltiazem and nifedipine; (49) centrally acting adrenergic antihypertensives, such as clonidine and methyldopa; (50) diuretic antihypertensive agents, such as amiloride, furosemide, hydrochlorothiazide (HCTZ), and spironolactone; (51) peripheral hypertensive vasodilators, such as hydralazine and minoxidil; (52) antilipemic, such as gemfibrosii and probucoi; (53) antilipemic bile acid sequestrants such as coytyramine; (54) antilipemic HMG-CoA reductase inhibitor, such as lovastatin and pravastatin; (55) Inotropes, such as amrinone, dobutamine, and dopamine; (56) cardiac glycoside inotropes such as digoxin; (57) thrombolytic agents, such as alteplase (TPA), anistreplase, streptokinase, and urokinase; (58) Dermatological agents, such as colchicine, isotrethionine, methotrexate, minoxidium, tretinoin (ATRA); (59) Dermatological corticosteroid anti-inflammatory agents, 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 drugs, such as fluorouracil (5-FU); (63) electrolytic and renal agents, such as lactulose; (64) loop diuretics, such as furosemide; (65) potassium diuretics such as triamterene; (66) thiazide diuretics, such as hydrochlorothiazide (HCTZ); (67) uricosuric agents, such as probenecid; (68) enzymes such as RNase and Dnasa; (69) thrombolytic enzymes, such as alteplase, anistreplase, streptokinase and urokinase; (70) antiemetics, such as prochlorperazine; (71) gastrointestinal anti-inflammatory agents of saicycylate, such as sulfasalazine; (72) anti-ulcer agents gastric acid pump inhibitor, such as omeprazoia; (73) anti-ulcer agents H1 -blocker; as cimetidine, famotidine, nizatidine, and ranitidine; (74) digestives, such as pancrelipase; (75) prokinetic agents, such as erythromycin; (76) intravenous anesthetics opiate agonists such as fentanyl; (77) ematopoietic anti-anemia agents, such as erythropoietin, filgrastim (G-CSF), and sargramostim (GM-CSF); (78) coagulation agents, such as anti-hemophilic factors 1-10 (AHF 1-10); (79) anticoagulants, such as warfarin; (80) thrombolytic enzyme coagulation agents, such as alteplase, anistreplase, streptokinase and urokinase; (81) hormones and hormone modifiers, such as bromocriptine; (82) abortifacients, such as methotrexate; (83) antidiabetic agents, such as insulin; (84) oral contraceptives, such as estrogen and progestin; (85) progestin contraceptives, such as levonorgestrel and norgestrel; (86) estrogens such as conjugated estrogens, diethylstilbestrol (DES), estrogen (estradiol, estrone, and estropipate); (87) fertility agents such as clomiphene, human chorionic gonadotropin (HCG), and menotropins; (88) parathyroid agents such as caicitonin; (89) pituitary hormones, such as desmopressin, goserelin, oxytocin, and vasopressin (ADH); (90) progestins, such as medroxyprogesterone, norethindrone, and progesterone; (91) thyroid hormones, such as levothyroxine; (92) immunobiological agents, such as beta-1 b interferon and gamma-1 b interferon; (93) immunoglobulins, such as IM immuno globulin, IMIG, IGIM, and immunoglobulin IV, IVIG, IGIV; (94) local amide anesthetics, such as lidocaine; (95) local anesthetics of ester, such as benzocaine and procaine; (96) skeletal muscle corticosteroid anti-inflammatory agents, such as beclomethasone, betamethasone, cortisone, dexamethasone, hydrocortisone, and prednisone; (97) musculoskeletal anti-inflammatory immunosuppressants, such as azathioprine, cyclophosphamide, and methotrexate; (98) non-steroidal musculoskeletal anti-inflammatory drugs (NSAIDs), such as diclofenac, ibuprofen, ketoprofen, cetorlac, and naproxen; (99) musculoskeletal relaxants, such as baciofen, ciciobenzaprine, and diazepam; (100) Musculoskeletal relaxants of reversed neuromuscular blocker, such as pyridostigmine; (101) neurological agents, such as nimodipine, riluzole, tacrine and ticlopidine; (102) anticonvulsants such as carbamazepine, gabapentin, lamotrigine, phenytoin, and valproic acid; (103) barbiturate anticonvulsants, such as phenobarbital and primidone; (104) benzodiazepine anticonvulsants, such as clonazepam, diazepam, and lorazepam; (105) anti-parkinsonian agents, such as bromocriptine, levodopa, carbidopa, and pergolide; (106) anti-vertigo agents, such as meciizine; (107) opiate agonists such as chain, fentanyl. hydromorphone. methadone and morphine; (108) opiate agonists such as naloxone; (109) β-blocker anti-glaucoma agents, such as thymol; (110) miotic anti-glaucoma agents, such as piiocarpine: (111) aminoglycoside ophthalmic anti-infectives, such as gentamicin. neomycin. and trobamycin: (112) quinolone ophthalmic antiinfectives, such as ciprofloxacin, norfloxacin, and ofioxacin: (113) ophthalmic corticosteroid anti-inflammatory agents, such as dexamethasone and prednisolone; (114) non-steroidal ophthalmic anti-inflammatory drugs (NSAIDs), such as diclofenac: (115) antipsychotics. comoclozapine, haloperidol, and risperidone; (116) benzodiazepine anjiolytics. soothing and hypnotic, such as clonazepam. diazepam lorazepan, oxazepan, and prazepan; (117) psychostimulants, such as methylphenidate and femolin; (118) antitussives, such as codeine: (119) bronchodilators such as theophylline; (120) adrenergic agonist bronchodilators, such as albuterol; (121) respiratory anti-inflammatory agents corticosteroids such as dexamethasone; (122) antidotes, such as flumazenii and naloxone; (123) heavy metal antagonists / chelating agents. as peniciamine: (124) dissuasive agents of substance abuse, such as disulfiram, naltrexone, and nicotine; (125) abstinence-abusing agents, such as bromocriptine: (126 minerals, such as iron, calcium, and magnesium; (127) vitamin B compound, such as cyanocobalamin (vitamin B? 2), and niacin (vitamin B3); 128) vitamin C compounds, such as ascorbic acid, and (129) vitamin D compounds, such as calcitrol.

In addition to those mentioned above, the following less common drugs may also be used: chlorhexidine; estradiol cypionate in oil; estradiol valerate in oil; flurbiprofen; sodium flurbiprofen; ivermectin; levodopa; nafarelin; and somatropin. Additionally, the following new drugs may also be used: recombinant beta-glucan, bovine immunoglobulin concentrate; bovine dismutase superoxide, the formulation consisting of fluorouracil, epinephrine, and bovine collagen; hirudin immunogen (r-Hir), recombinant HIV-1, human anti-TAC antibody; recombinant human growth hormone (r-hGH); recombinant human hemoglobin (r-Hb); Recombinant human mecasermin (r-IGF-1); beta-1 to recombinant interferon; lenograstim (G-CSF); olanzapine; recombinant thyroid stimulating hormone (r-TSH); and topotecan. Additionally, the following intravenous products may be used: sodium acyclovir; aidesleucine; atenolol; bleomycin sulfate, human caicyonin; saiton calcitonin; carboplatin; carmustine; Dactinomycin; daurubicin (HCl); docetaxei; doxorubicin HCl; alpha epoetin; etoposide (VP-16); fiuorouracii (5-FU), ganciclovir sodium; gentamicin sulfate; alpha interferon; leuproiido acetate; meperidine HCl; methadone HCl; sodium methotrexate; pacñitaxel; ranitidine HCl; vinblastine sulfate; and zidovudine (AZT). Moreover, the following list of peptides, proteins and other large molecules, such as interleukins 1 to 18, including mutants and analogues; a, ß, and? interferons, hormone that releases luteinizing hormone (LHRH) and analogues, gonadotropin releasing hormone (GnRH), transforming growth factor (TGF-β); fibroblast growth factor (FGF); epidermal growth factor (EGF); homologous fibroblast growth factor factor (FGFHF); hepatocyte growth factor (HGF); insulin growth factor (IGF); Inhibitory factor-2 inhibitor (IIF-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 may be a radiosensitizer, such as metoclopramide, sensamide or neusensamide (manufactured by Oxigene); profiromycin (manufactured by Vion); RSR13 (manufactured by Allos); Thymitac (manufactured by Agouron), etanidazole or lobenguan (manufactured by Nycomed); gadolinium texaprin (manufactured by Pharmacyciics); BuDR / Broxina (manufactured by NeoPharm); IpdR (manufactured by Sparta); CR2412 (manufactured by Cell Therapeutic); L1X (manufactured by Terrapin); or similar. In a particularly preferred embodiment, the biologically active substance is a therapeutic drug or prodrug, more preferably a drug selected from the group consisting of chemotherapeutic and other antineoplastic, antibiotic, anti-viral, anti-fungal, anti-inflammatory and anticoagulant agents. More preferably, the biologically active substance is paclitaxel.

Bio-active substances are used in amounts that are therapeutically effective. Although the effective amount of a bio-active substance will depend on the particular material being used, amounts of the biologically active substance have been easily incorporated from 1% to 65% in the present delivery systems while controlled release is achieved. Lower amounts can be used to achieve effective treatment levels for certain bio-active substances. Pharmaceutically acceptable vehicles can be prepared from a wide range of materials. Without being limited thereto, such materials include diluents, binders and adhesives, lubricants, disintegrants, colorants, bulking agents, flavorings, sweeteners, and various materials such as pH regulators and adsorbents for the purpose of preparing a particular medical composition.

Implants and Delivery Systems Designed for Invention In its simplest form, a biodegradable therapeutic agent delivery system consists of a dispersion of the therapeutic agent in a polymer matrix. The therapeutic agent is typically released as the polymer matrix degrades in vivo in soluble products that can be excreted from the body.

In a particularly preferred embodiment, an article is used for implanting, injecting or otherwise placing totally or partially within the body, the article comprising the biodegradable polymer composition of the invention. 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 structure of the microsphere is maintained. Alternatively, the biologically active substance may be non-miscible in the polymer of the invention enough to disperse as small droplets, rather than dissolve, in the polymer. . Any form is acceptable, but it is preferred that, regardless of the homogeneity of the composition, the rate of release of the biologically active substance in vivo remains controlled, at least partially, as a function of hydrolysis of the phosphoester linkage of the polymer with biodegradation. In a preferred embodiment, the article of the invention is designed for implantation or injection into the body of an animal. It is particularly important that said article results in minimal tissue irritation when implanted or injected into vascularized tissue. As a structural medical device, the polymer compositions of the invention provide a physical form that has sufficient chemical, physical and mechanical properties for the application and a composition that degrades in vivo in non-toxic waste. Typical structural medical articles include implants such as orthopedic fixation devices, ventricular shunts, laminates for degradable fabrics, drug vehicles, bioabsorbable sutures, burn coatings, coatings to be placed on other implant devices, and the like. In orthopedic articles, the composition of the invention may be useful for repairing bone and connective tissue injuries. For example, a biodegradable porous material can be loaded with bone morogenetic proteins to form a bone graft useful even for large segmentation defects. In vascular graft applications, a biodegradable material in the form of a woven fabric can be used to promote tissue ingrowth. The polymer composition of the invention can be used as a temporary barrier to prevent adhesion of tissue, for example, after abdominal surgery. On the other hand, in nerve regeneration articles, the presence of a biodegradable support matrix can be used to facilitate adhesion and cell proliferation. When the polymer composition is manufactured as a rib generation tube, for example, the tubular article can also serve as a geometric guide for axonal elongation in the direction of functional recovery.

As a drug delivery device, the polymer compositions of the invention provide a polymer matrix capable of sequestering a biologically active substance and providing a predictable, controllable supply of the substance. The polymer matrix is then degraded to non-toxic waste. Biodegradable medical implant devices and drug delivery products can be prepared in different ways. The polymer can be processed in casting using conventional injection or extrusion molding techniques, or those products can be prepared by dissolving in a suitable solvent, followed by formation of the device, and the subsequent removal of the solvent by evaporation or extraction. Once a medical implant article is placed, it must remain at least in partial contact with a biological fluid such as blood, secretions from internal organs, mucous membranes, cerebrospinal fluid and the like.

EXAMPLES EXAMPLE 1 Synthesis of Poly (L-lactide-co-ethyl-phosphate) T Poly (LAEG-EOP) 1 P (LAEG-EOP) g (0.139 moles of (3S) -cis-3,6-dimetii-1,4-dioane-2,5-dione (L-lactide) (obtained from Aldrich Chemical Company, recrystallized with ethyl acetate, sublimated, and recrystallized with ethyl acetate again) and 0.432 g (6.94 mmoles) of ethylene glycol (99.8%, anhydride, from Aldrich) were placed in a 250 ml round bottom flask rinsed with dry argon.The flask was closed under vacuum and placed in an oven heated to 140 ° C. The flask was kept at that temperature for 48 hours with occasional stirring.

The flask was then filled with dry argon and placed in an oil bath at 135 ° C. Under a stream of argon, 1.13 g of ethyl phosphorodichlorhydrate were added with stirring. After one hour of agitation, a low vacuum (approximately 20 mm Hg) was applied to the system, and allowed to stand overnight. One hour before the treatment, a high vacuum was applied. After cooling, the polymer was dissolved in 200 ml of chloroform and quenched in one liter of ether twice to an off-white precipitate, which was dried under vacuum. It was confirmed by NMR spectroscopy that the polymer obtained was the desired product, poly (L-lactide-co-ethyl-phosphate) [Poly (LAEG-EOP)], as shown in Figures 5 and 6.

EXAMPLE 2 Properties of P (LAEG-EOP) A polymer of P (LAEG-EOP) wherein (x or y) / n = 10: 1 was prepared as described in example 1 above. The resulting poly (phosphoester-co-ester) polymer was analyzed by GPC using polystyrene as a standard, and the resulting graph established a MW (weight) of 33,000 and an NM (number) of 4,800, as shown in Figure 6 The viscosity was measured in chloroform (CH3CI) at 40 ° C and determined to be 0.315 di / g. The polymer was soluble in ethyl acetate, acetone, acetonitrile, chloroform, dichloromethane, tetrahydrofuran, N-methylpyrrolidone, dimethylformamide, and dimethyl sulfoxide. The polymer formed a brittle film, and the Tg determined by DSC was 51.5 ° C, as shown in Figures 2A and 2B.

EXAMPLE 3 Synthesis of Poly (L-lactide-co-hexyl-phosphate) T Poli.LAEG-HOPVl A second poly (L-lactide-phosphate) having the following structure: it was also prepared by the method described in example 1, except that the hexyium phosphorodichlorhydrate ("HOP") was replaced by EOP (ethyl phosphorodicihydrate).

EXAMPLE 4 Properties of P (LAEG-EOP) v PÍLAEG-HOP) The average weight of the molecular weight (MW (weight) of the phosphoester-co-ester polymer of Example 1, P (LAEG-EOP), and the polymer of Example 3, P (LAEG-HOP), were determined first by gel permeation (GPC) with polystyrene as the calibration standard, as shown in figure 1. Samples of each were allowed to remain then exposed to air at room temperature to test the room storage capacity, without protection. one month, the PM (weight) was again determined for each polymer.The results (plotted in figure 4) showed that, although the PM (weight) for P (LAEG-EOP) was reduced by approximately one third after one month of ambient conditions without protection, the PM (weight) for P (LAEG-HOP) remained relatively constant, showing even a slight increase See also figure 7. Discs were then manufactured for degradation studies from each polymer by molding by compression at 50 ° C and at a pressure of 200 MPa. The discs were 4 mm in diameter, 1.5 mm thick, and 40 mg in weight. The degradation studies were conducted by placing the discs in 4 ml of 0.1 M phosphate buffered saline (PBS) (pH 7.4) at 37 ° C. Identical samples were removed at different time points of up to 8 days, washed with distilled water, and dried under vacuum overnight. The samples were analyzed for weight loss and molecular weight change (GPC), and the results are shown in Figures 3 A, 3B, 9 A and 9B. Both polymers P (LAEG-EOP) and P (LAEG-HOP), demonstrated favorable degradation profiles.

EXAMPLE 5 In vivo biocompatibility of P (LAEG-EOP) A 100 mg polymer wafer was formed from P (LAEG-EOP) and, as a reference, a copolymer of lactic and glycolic acid ["PLGA (RG755")] which is known to be biocompatible. These wafers were inserted between muscle layers of the right posterior paw of adult Sraf-Dawley SPF rats under anesthesia. The wafers were removed at specific times, and the surrounding tissues were prepared for histological analysis by a certified pathologist using the following qualification: Rating Irritation Level 0 No irritation 0-200 Light irritation 200-400 Soft Irritation 400-600 Moderate Irritation More than 600 Severe irritation The results of the histopathological analysis are shown in Table 8 below.

TABLE 8 Inflammatory response at the Implantation site (i.m.) See also Figure 11. The phosphoester P (LAEG-EOP) copolymer showed that it has an acceptable biocompatibility similar to that exhibited by the reference PLGA wafer.

EXAMPLE 6 Preparation of Microspheres Microspheres were made from P (LAEG-EOP) by a solvent evaporation method (double emulsion) using methylene chloride as a solvent.

EXAMPLE 7 Preparation of copolymer microspheres containing FITC-BSA solution with 10% theoretical loading level One hundred ml of FITC-BSA solution (100 mg / ml dissolved in water) were added to a solution of 100 mg of P (LAEG-EOP) in 1 ml of methylene chloride, and emulsified by sonification for 15 seconds on ice . The resulting emulsion was immediately poured into 5 ml of a 1% solution of polyvinyl alcohol (PVA) in 5% NaCl ai with swirl formation, and vortex formation was maintained for one minute. The emulsion formed in this way was then poured into 20 ml of a 0.3% PVA solution in 5% NaCl, which was vigorously stirred. Twenty-five ml of a 2% isopropanol solution were added, and the mixture was kept under stirring for one hour to ensure complete extraction. The resulting microspheres were collected by centrifugation at 3000 X g, washed 3 times with water, and freeze-dried. Different formulations of microspheres were made using as the second aqueous phase a 5% solution of NaCl or a 5% solution of NaCl containing also 1% of PEG 8000. Yet another technique was used in the evaporation of the solvent by stirring the mixture during the overnight, thereby forming microspheres by evaporation of solvent.

EXAMPLE 8 Estimation of encapsulation efficiency and load level The loading level of FITC-BSA was determined by FITC analysis after hydrolyzing the microspheres with 0.5 N NaOH overnight. The amount of FITC-BSA was compared with a standard curve that was generated by making a series of FITC-BSA solutions in 0.5 N NaOH. The encapsulation efficiency of the microspheres was determined by comparing the amount of FITC-BSA entrapped with the initial amount in solution by fluorometry. The encapsulation efficiency (%) and loading level (%) of FITC-BSA are shown in Table 1 below.

TABLE 1 Encapsulation efficiency and load level of FITC-BSA Example 9 Cytotoxicity of the Copolymer Microspheres containing P (LAEG-EOP) were added to tissue culture plates of 96 cavities at different concentrations. Human gastric carcicoma cells (GT3TKB) were then seeded at a rate of 104 cells / well. The cells were then incubated with the microspheres in the wells for 48 hours at 37 ° C. The speed of cell proliferation was analyzed by an. { MTT analysis. and the results were plotted as% relative growth vs. Concentration of copolymer microspheres in the tissue culture cavity, as shown in Figure 8.

EXAMPLE 10 Effect of the manufacturing method on the release of FITC-BSA from the microspheres Fifty mg of microspheres of a polymer of the invention were suspended in ampules containing 10 ml of PBS, and the ampules were shaken in an incubator at 37 ° C and at a speed of 220 rpm. The superfluous fluid was replaced at several time intervals, and the amount of FITC-BSA released was analyzed by spectrophotometry at 492 nm. The results were plotted as% cumulative release of FITC-BSA from the microspheres vs time in hours, as shown in Figure 12.

EXAMPLE 11 Preparation of P (LAEG-EOP) microspheres containing lidocaine using polyvinyl alcohol as the non-solvent phase A 0.5% w / v solution of polyvinyl alcohol. { Ionic (PVA) in deionized water solution was prepared in a 600 ml beaker by combining 1.05 g of PVA with 210 ml of deionized water. The solution was stirred for one hour and filtered. A polymer / drug solution was prepared by combining 630 mg of polymer and 70 mg of lidocaine in 7 ml of methylene chloride and mixing by swirling. The PVA solution was mixed at 500 rpm with top mixer, and the polymer / drug solution was added by dripping. After 30 minutes of mixing, 200 ml of cold deionized water was added to the PVA solution by stirring. The resulting mixture was stirred for a total of 3.5 hours. The formed microspheres were filtered, washed with deionized water and lyophilized overnight. In this way, microspheres loaded with 4.2% w / w of lidocaine were obtained. Approximately 10 mg of microspheres were placed in phosphate buffered saline (0.1 M, pH 7.4) at 37 ° C on a shaker and samples were taken regularly. The results were plotted as% of released lidocaine vs time in days, as shown in figure 15.

EXAMPLE 12 Preparation of P (DAEG-EOP) The racemic mixture d, l of poly (L-lactide-co-ethyl-phosphate) ["P (DAEG-EOP")] was prepared in the same manner as P (LAEG-EOP), as described in Example 1 .

EXAMPLE 13 Preparation of P (DAEG-EOP) microspheres with lidocaine using silicon oil as the non-solvent phase Two percent sorbitan trioleate, which is commercially available from Aldrich under the trade name Span-85, in silicon oil, was prepared in a 400 ml beaker by combining 3 ml Span-85 with 150 ml oil. silicon and mixing with a top mixer set at 500 rpm. A solution of polymer P (DAEG-EOP) / drug was prepared by dissolving 400 mg of the polymer prepared above in Example 9, and 100 mg of lidocaine in 4.5 ml of methylene chloride. The resulting polymer / drug solution was added dropwise to the silicon oil / Span mixture with stirring. The mixture was stirred for one hour and 15 minutes. The microspheres thus formed were filtered and washed with petroleum ether to remove the silicon oil / Span mixture. and it was lyophilized overnight. 450 mg of microspheres loaded with 7.6% w / w of lidocaine were obtained in this way. Approximately 10 mg of microspheres were placed in phosphate buffered saline (0.1 M, pH 7.4) at 37 ° C on a shaker and samples were collected regularly. The results were plotted as% of released lidocaine vs. time in days, as shown in figure 16.

EXAMPLE 14 Biocompatibility of Poly (phosphoester) microspheres in mouse peritoneal cavity The biocompatibility of biodegradable poly (phosphoester) microspheres of the invention was measured as follows: Three 30 mg / ml samples of poly (L-lactide-co-etii-phosphate) microspheres were prepared, the first having larger diameters of 75 microns, the second having diameters on the scale of 75-125 microns, and the third having diameters on the scale of 125-250 microns. Each sample was injected intraperitoneally in a group of 18 female CD-1 mice having a starting body weight of 25 g. The animals in each group were weighed, sacrificed and they were necropsied at 2, 7 and 14 days, and at 1, 2 and 3 months. Any lesions detected during the necropsy were graded on a scale of 0 to 4, with 0 indicating no response to treatment and 4 indicating a severe response to treatment. Inflammatory lesions were observed to be restricted to an association with the microspheres on peripheral surfaces or within fatty tissue, and were compatible with isolation and encapsulation of foreign body. Staphylococcal peritoneal stasis to muitifocai with mesothelial hyperplasia was observed at 2-7 days, but resolved gradually by macrophage infiltration, the formation of c. { giant inflammatory cells, and the fibrous encapsulation of the microspheres in subsequent sacrifices. The occasional adhesion of the microspheres to the liver and the diaphragm with associated inflammatory reaction was also observed. No injuries related to the microspheres in abdominal or thoracic organs were observed. The microspheres that were detected throughout the duration of the study, appeared transparent in the initial sacrifices but, later, they developed crystalline material internally. No effects on body growth were observed. The peritoneal reaction was observed as limited to areas directly adjacent to the microspheres without obvious detrimental effects on major thoracic or abdominal organs. The invention being described in this way, it will be apparent that it can vary in many ways. Such variations should not be considered as separate from the spirit and scope of the invention and all such modifications are designed to be included within the scope of the following claims.

Claims (1)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A biodegradable polymer consisting of the recurring monomer units shown in formula I or II: O O or II -fex-M- c} ? - -Y- L- Y- 4ci? - -M «-x-h -P Wherein: X is -O- or -NR'-, wherein R'es H or alkyl; Mi and M2 are independently (1) a straight or branched chain aliphatic group having 1-20 carbon atoms; or (2) an oxy-, carboxy-, or amino-aliphatic group having 1-20 carbon atoms: Y is -O-, -S- or -NR'-; L is a straight or branched chain aliphatic group having 1-20 carbon atoms, R is H, alkyl, akoxy, ary, aryloxy, heterocyclic or heterocycloxy; The molar ratio of x: y is approximately 1. The molar ratio of n: (x or y) is between 200: 1 and 1: 200; and the molar ratio of q: r is between 1: 99 and 99: 1. Where said biodegradable polymer is biocompatible before and with biodegradation. 2. - The polymer according to claim 1, wherein each of Mi and L are a straight or branched chain alkylene group. 3. The polymer according to claim 1, wherein each of Mi and L have from 1 to 7 carbon atoms. 4. The polymer according to claim 1, wherein Mi is an ethylene group or a methylene group substituted by methyl, and L is an ethylene group. 5. The polymer according to claim 1, wherein R is an alkyl group, an alkoxy group, a fenium group, a phenoxy group, or a heterocycloxy group. 6. The polymer according to claim 1, wherein R is an alkoxy group having from 1 to 7 carbon atoms. 7. The polymer according to claim 1, wherein R is an ethoxy group. 8. The polymer according to claim 1, wherein each of M and M2 is a straight or branched chain alkyiene group. 9. The polymer according to claim 1, wherein at least one of Mi and M2 is an alkyiene or alkoxylene group having a formula selected from the group consisting of - (CH2) a-, - (CH2) aO-, and - (CH2) aO- (CH2) b-. in which each of a and b is 1-7. 10. The polymer according to claim 1, wherein at least one of Mi and M2 has the formula: -CHR2-CO-O-CHR3-, wherein R2 and R3 are each independently H, alkyl, alkoxy , aryl, aryloxy, heterocyclic or heterocycloxy. 1. The polymer according to claim 1, wherein each of Mi and M2 have from 1 to 7 carbon atoms. 12. The polymer according to claim 1, wherein X is -O-. 13. The polymer according to claim 1, wherein X is -NR'-. 14. The polymer according to claim 1, wherein: Mi and M2 are each an alkylene or alkoxy- ene group; L is an alkylene group; X is -O-; and R is an alkoxy group. 15. The polymer according to claim 1, wherein the molar ratio x: y is 1. 16. The polymer according to claim 1, wherein the molar ratio q: r is 1: 99 and 99: 1. 17. The polymer according to claim 1, wherein each of x and y is from 1 to 1, 000. 18. The polymer according to claim 1, wherein the molar ratio n: (x or Y) is between 100: 1 and 1: 100. 19. The polymer according to claim 1, wherein said polymer is prepared by melt polymerization. 20. - The polymer according to claim 1, wherein said polymer consists of biocompatible monomer units • additional. 21. The polymer according to claim 1, in Wherein said polymer is soluble in at least one of the solvents selected from the group consisting of acetone, dimethylene chloride, chloroform, ethyl acetate, DMAC, N-methylpyrrolidone, dimethylformamide and dimethisufuoxide. 22. A process for preparing a biodegradable polymer 10 comprising the recurring monomer units of formula I or II: Where: X is -O- or - NR'-, where R'es H or alkyl; Mi and M2 are independently (1) a straight or branched chain aliphatic group having 1-20 carbon atoms; or (2) an oxy-, carboxy-, or amino-aliphatic group having 1-20 carbon atoms; Y is -O-, -S- or -NR'-; L is a branched or straight chain aliphatic group having 1-20 carbon atoms, R is H, alkyl, akoxy, aryl, aryloxy, heterocyclic or heterocycloxy; The molar ratio of x: y is approximately 1. The molar ratio of n: (x or y) is between 200: 1 and 1: 200; and the molar ratio of q: r is between 1: 99 and 99: 1. Wherein said biodegradable polymer is biocompatible before and with biodegradation; wherein said biodegradable polymer is biocompatible before and with biodegradation, said process consists of the steps of: (a) reacting a heterocyclic ring having the formula III, IV or V: IV V Where Mi, M2 and X are as defined above, with an initiator having the formula: H - Y - L - Y - H, wherein Y and L are as defined above, to form a prepolymer of formula VI or Vil, shown immediately: VI O O II x II -i-X-M1 - C -)? - Y- L- Y (-C-M - X-) and- VII 2 - X) c Where X, Mi, M2, Y, L, x, y, q and r are as defined above; and (b) further reacting said polymer of formula III, IV or V with a phosphorodialidate of formula VIII: VIII OR II halo - P - halo I R where "halo" is Br, Cl, or I; and R is as defined above, to form said polymer of formula I or II. 23. - The method according to claim 22, in where each of Mi and L is a straight or branched chain aikylene group which has 1 to 7 carbon atoms. 24. The method according to claim 22, in where Mi is an ethylene group or a methylene group substituted by methyl, and L is an ethylene group. 25. - The process according to claim 22, wherein R is an alkoxy group having from 1 to 7 carbon atoms. 26. The process according to claim 22, wherein R is an ethoxy group. 27. The method according to claim 22 in where each of Mi and M2 is a straight or branched chain alkylene group. 28. - The process according to claim 22, wherein at least one of Mi and M2 is an alkylene or alkoxylene group having a formula selected from the group consisting of - (CH2) a-, - (CH2) aO-, and - (CH2) aO- (CH2) b-, in which each of a and b is 1 -7. 29. The process according to claim 22, wherein at least one of Mi and M2 has the formula: -CHR2-CO-O-CHR3-, wherein R2 and R3 are each independently H, alkyl, alkoxy , aryio, aryioxy, heterocyclic or heterocycloxy. 30. The method according to claim 22, wherein each of M and M2 have from 1 to 7 carbon atoms. 31. The method according to claim 22, wherein X is -O-. 32. The method according to claim 22, wherein X is -NR'-. 33. The process according to claim 22, wherein: Mi and M2 are each an alkylene or alkoxylene group; L is an alkylene group; X is -O-; and R is an alkoxy group. 34. The method according to claim 22, wherein the molar ratio x: y is 1. 35.- The method according to claim 22, wherein the molar ratio q: r is 1: 99 and 99: 1. 36.- The procedure according to claim 22, wherein each of x and y is from 1 to 1, 000. 37. - The method according to claim 22, wherein the molar ratio n: (x or y) is between 100: 1 and 1: 100. 38.- The method according to claim 22, wherein said reaction step (a) takes place at a temperature of or at + 235 ° C. 39.- The method according to claim 22, wherein said reaction step (a) takes place for a time between 1 hour to seven days. The method according to claim 22, wherein, in said initiator, L is substituted with one or more additional substituents containing Y-H-, in which Y is as defined above. 41. The process according to claim 22, wherein a catalyst is present during the reaction step (a). 42. The process according to claim 22, wherein during the polymerization step (b), an acid acceptor is present. 43.- The method according to claim 22, wherein said polymerization step (b) takes place at a temperature between -40 and 150 ° C. 44. The method according to claim 22, wherein said polymerization step (b) takes place for a time of 30 minutes to 24 hours. 45. - The procedure according to claim 22, wherein said polymer of formula I or II is purified by quenching a solution of said polymer with a non-solvent or partial solvent. 46.- A bioabsorbent suture consisting of the polymer according to claim 1. 47.- An orthopedic article, bone cement or bone wax to repair injuries to bones and connector tissue consisting of the polymer according to claim 1. 48.- A laminate for degradable or non-degradable fabrics consisting of the polymer according to claim 1. 49.- A coating for a implantable device consisting of the polymer according to claim 1. 50.- A polymer composition biodegradable consisting of: (a) at least one biologically active substance and (b) a polymer consisting of the recurring monomer units shown in formula I or II: Wherein: X is -O- or -NR'-, wherein R'es H or alkyl; Mi and M2 are independently (1) a straight or branched chain aliphatic group having 1-20 carbon atoms; or (2) an oxy-, carboxy-, or amino-aliphatic group having from 1-20 carbon atoms; And it is -O-, -S- or -NR'-; L is a branched or straight chain aliphatic group having 1-20 carbon atoms; R is H, alkyl, alkoxy, aryl, aryloxy, heterocyclic or heterocycloxy; the molar relation of x: y is approximately 1; the molar relation of n: (x or y) is between 200: 1 and 1: 200; and the molar relation of q: r is between 1: 99 and 99: 1; wherein said biodegradable polymer is biocompatible before and with biodegradation. 51. The polymer composition according to claim 50, wherein each of Mi and L are a straight or branched chain alkylene group. 52. The polymer composition according to claim 50, wherein Mi is an ethylene group or a methylene group substituted by methyl, and L is an ethylene group. 53. The polymer composition according to claim 50, wherein R is an alkyl group, an alkoxy group, a phenyl group, a phenoxy group, or a heterocycloxy group. 54.- The polymer composition according to claim 50, wherein R is an alkoxy group. 55. - The polymer composition according to claim 50, wherein each of Mi and M2 is a straight or branched chain alkylene group. 56.- The polymer composition according to claim 50, wherein at least one of Mi and M2 is an alkylene or alkoxylene group having a formula selected from the group consisting of - (CH2) a-, - (CH2) a -0-, and - (CH2) a-0- (CH2) b-, in which each of a and b is 1-7. 57.- The polymer compositions according to claim 50, wherein at least one of Mi and M2 has the formula: -CHR2-CO-O-CHR3-, wherein R2 and R3 are each independently H, alkyl , alkoxy, aryio, aryioxy, heterocyclic or heterocyclic. 58.- The polymer compositions according to claim 50, wherein each of Mi and M2 have from 1 to 7 carbon atoms. 59.- The polymer compositions according to claim 50, wherein X is -O-. 60.- The polymer compositions according to claim 50, wherein X is -NR'-. 61.- The polymer compositions according to claim 50, wherein: Mi and M2 are each an alkylene or alkoxylene group; L is an alkylene group; X is -O-; and R is an alkoxy group. 62.- The polymer compositions according to claim 50, wherein the molar ratio x: y is 1. 63. - The polymer compositions according to claim 50, wherein the molar ratio q: r is 1: 99 and 99: 1. 64.- The polymer composition according to claim 50, wherein each of x and y is from 1 to 1, 000. 65.- The polymer composition according to claim 50, wherein the molar ratio n: (x or y) is between 100: 1 and 1: 100. 66.- The polymer composition according to claim 50, wherein said polymer is prepared by melt polymerization. 67.- The polymer composition according to claim 50, wherein said polymer comprises additional biocompatible monomer units. 68.- The polymer composition according to claim 50, wherein said polymer is soluble in at least one of the solvents selected from the group consisting of acetone, dimethylene chloride, chloroform, ethyl acetate, DMAC, N-methylpyrrolidone, dimethylformamide and dimethylsulfoxide. 69.- The polymer composition according to claim 50, wherein said biologically active substance is selected from the group consisting of polysaccharides, growth factors, hormones, anti-angiogenesis factors, interferons or cytokines, and pro-drugs of those substances . 70. - The polymer composition according to claim 50, wherein said bio-active substance is a therapeutic drug or pro-drug. 71.- The polymer composition according to claim 70, wherein said biologically active substance is selected from the group consisting of antineoplastic, antibiotic, antiviral, antifungal, anti-inflammatory, and anticoagulant agents. 72. The polymer composition according to claim 71, wherein the antineoplastic agent is paciitaxel. 73.- The polymer composition according to claim 50, wherein said biologically active substance and said polymer form a homogeneous matrix. The polymer composition according to claim 50, wherein said polymer is characterized by a release rate of the biologically active substance in vivo controlled at least partially as a function of hydrolysis of the phosphoester linkage of the polymer during biodegradation. 75.- A useful article for implantation, injection or to be placed otherwise totally or partially within the body, said article consisting of a polymer composition consisting of (a) at least one biologically active substance and (b) a polymer which has the recurring monomer units shown in formula I or II: Wherein: X is -O- or -NR'-, wherein R'es H or alkyl; Mi and M2 are independently (1) a straight or branched chain aliphatic group having 1-20 carbon atoms; or (2) an oxy-, carboxy-, or amino-aliphatic group having 1-20 carbon atoms; And it is -O-, -S- or -NR'-; L is a branched or straight chain aliphatic group having 1-20 carbon atoms; R is H, alkyl, alkoxy, aryl, aryloxy, heterocyclic or heterocycloxy: the molar ratio of x: y is about 1; the molar ratio of n: (x or y) is between 200: 1 and 1: 200; and the molar ratio of q: r is between 1: 99 and 99: 1: wherein said biodegradable polymer is biocompatible before and with biodegradation. 76. The article according to claim 75, wherein each of Mi and L is a straight or branched chain alkylene group. 77. The article according to claim 75, wherein each of Mi and L have from 1 to 7 carbon atoms. 78. - The article according to claim 75, wherein R is an alkyl group, an akoxy group, a phenyl group, a phenoxy group, or a heterocycloxy group. 79.- The article according to claim 75, wherein R is an alkoxy group. 80. The article according to claim 75, wherein each of Mi and M2 is a straight or branched chain alkylene group. 81. The article according to claim 75, wherein at least one of Mi and M2 is an alkylene or akoxyiene group having a formula selected from the group consisting of - (CH2) a-, - (CH2) aO-, and - (CH2) a-0- (CH2) b-, in which each of a and b is 1-7. 82. The article according to claim 75, wherein at least one of Mi and M2 has the formula: -CHR2-CO-O-CHR3-, wherein R2 and R3 are each independently H, alkyl, alkoxy , aryl, aryloxy, heterocyclic or heterocycloxy. 83. The article according to claim 75, wherein each of Mi and M2 have from 1 to 7 carbon atoms. 84.- The article according to claim 75, wherein X is -O-. 85.- The article according to claim 75, wherein X is -NR'-. 86. - The article according to claim 75, wherein: M-i and M2 are each an alkylene or alkoxylene group; L is an alkylene group; X is -O-; and R is an alkoxy group. 87. The article according to claim 75, wherein the molar ratio x: y is 1. 88. The article according to claim 75, wherein the molar ratio q: r is 1: 99 and 99: 1. 89.- The article according to claim 75, wherein each of x and y is from 1 to 1, 000. 90. The article according to claim 75, wherein the molar ratio n: (x or y) is between 100: 1 and 1: 100. 91. The article according to claim 75, wherein said polymer is prepared by melt polymerization. 92. The article according to claim 75, wherein said polymer comprises additional biocompatible monomer units. 93. The article according to claim 75, wherein said polymer is soluble in at least one of the solvents selected from the group consisting of acetone, dimethylene chloride, chloroform, ethyl acetate, DMAC, N-methylpyrrolidone, dimethylformamide and dimethylsulfoxide. 94. The article according to claim 75, wherein said biologically active substance is selected from the group consisting of polysaccharides, growth factors, hormones, anti-angiogenesis factors, interferons or cytokines, and pro-drugs of those substances. 95. - The article according to claim 75, wherein said biologically active substance is a therapeutic drug or pro-drug. 96. The article according to claim 75, wherein said biologically active substance is selected from the group consisting of antineoplastic, antibiotic, antiviral, antifungal, anti-inflammatory agents., and anticoagulants. 97.- The article according to claim 75, wherein the antineoplastic agent is paciitaxel. 98.- The article according to claim 75, wherein said biologically active substance and said polymer form a homogeneous matrix. The article according to claim 75, wherein said biologically active substance is encapsulated within said polymer 100. The article according to claim 75, wherein said polymer is characterized by a rate of release of the substance. biologically active in vivo controlled at least partially as a function of hydrolysis of the phosphoester linkage of the polymer during biodegradation. 101. The article according to claim 75, wherein said article is adapted for implantation or injection into the body of an animal. 102. - The article according to claim 75, wherein said article is a microsphere. 103. The article according to claim 75, wherein said article results in minimal tissue irritation when implanted or injected into vascularized tissue. 104. The article according to claim 75, wherein said article is in the form of a laminate for degradable fabric. 105. The article according to claim 75, wherein said article is in the form of a bioabsorbent suture, a material for repairing bone lesions, or a coating on an implant device. 106.- 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 monomeric units shown in Formula I or II: Wherein: X is -O- or -NR'-, wherein R'es H or alkyl; M and M2 are independently (1) a straight or branched chain aliphatic group having 1-20 carbon atoms; or (2) an oxy-, carboxy-, or amino-aiiphatic group having from 1-20 carbon atoms; And it is -O-, -S- or -NR'-; L is a branched or straight chain aliphatic group having 1-20 carbon atoms; R is H, alkyl, akoxy, aryl, aryloxy, heterocyclic or heterocycloxy; the molar ratio of x: y is approximately 1; the molar relation of n: (x or y) is between 200: 1 and 1: 200; and the molar ratio of q: r is between 1: 99 and 99: 1; wherein said biodegradable polymer is biocompatible before and with biodegradation, to form a mixture; (b) forming said mixture in a solid article or microsphere formed; and (c) implanting or injecting said invivo solid article or microsphere into a preselected site, such that the implanted or injected solid matrix is at least in partial contact with a biological fluid. 107. The method according to claim 106, wherein each of R and L is a straight or branched chain alkylene group. 108. The method according to claim 106, wherein R 'is an alkoxy group. 109. The method according to claim 106, wherein each of Mi and M2 is a straight or branched chain alkylene group. The method according to claim 106, wherein at least one of Mi and M2 is an alkylene or alkoxylene group having a formula selected from the group consisting of - (CH2) a-, - (CH2) aO-, and - (CH2) aO- (CH2) b-, in which each of a and b is 1-7. 1. The method according to claim 106, wherein at least one of Mi and M2 has the formula: -CHR2-CO-O-CHR3-, wherein R2 and R3 are each independently H, alkyl , alkoxy, aryl, aryloxy, heterocyclic or heterocycloxy. 12. The method according to claim 106, wherein each of Mi and M2 have from 1 to 7 carbon atoms. 13. The method according to claim 106, wherein X is -O-. 114. The method according to claim 106, wherein X is -NR'-. 15. The method according to claim 106, wherein: Mi and M2 are each an alkylene or alkoxylene group; L is an alkylene group; X is -O-; and R is an alkoxy group. 116. The method according to claim 106, wherein the molar ratio x: y is 1. 117. The method according to claim 106, wherein the molar ratio q: r is 1: 99 and 99: 1. 1 18. The method according to claim 106, wherein each of x and y is from 1 to 1, 000. 119. The method according to claim 106, wherein the molar ratio n: (x or y) is between 100: 1 and 1: 100. 120. - The method according to claim 106, wherein said polymer comprises additional biocompatible monomer units. 121. The method according to claim 106, wherein said biologically active substance is selected from the group consisting of polysaccharides, growth factors, hormones, anti-angiogenesis factors, and other anti-neoplastic agents, interferons or cytokines, and pro-drugs of those substances. 122. The method according to claim 106, wherein the anti-neopia agent is paciitaxel. 123. The method according to claim 106, wherein said biologically active substance is a therapeutic drug or pro-drug. 124. The method according to claim 106, wherein said drug is selected from the group consisting of chemotherapeutic, antibiotic, antiviral, antifungal, anti-inflammatory, and anticoagulant agents. 125. The method according to claim 106, wherein said biologically active substance and said polymer form a homogeneous matrix. 126. The method according to claim 106, which additionally consists of encapsulating said biologically active substance within said polymer 127. The method according to claim 106, wherein said polymer is characterized by a rate of release of the biologically active substance in vivo controlled at least partially as a function of hydrolysis of the phosphoester linkage of the polymer during biodegradation. 128. The method according to claim 106, wherein said article is non-toxic and results in minimal tissue irritation when implanted or injected into vascularized tissue. 129.- The method according to claim 106, wherein said article is in the form of microspheres. 130. The method according to claim 106, wherein said article is in the form of a laminate for degradable fabric. 131. The method according to claim 106, wherein said polymer composition is used as a coating for an implant. 132. The method according to claim 106, wherein the polymer composition is used as a barrier for adhesion prevention. 133. The method according to claim 106, wherein said polymer composition is manufactured as a tube for nerve regeneration. SUMMARY OF THE INVENTION Biodegradable polymers are described which consist of the recurring monomer units shown in formula (I) or in the formula (H) Where X is -O- or -NR'-, where R'es H or alkyl: L is a straight or branched chain aliphatic group having 1-20 carbon atoms: Mi and M2 are each independently a straight or branched chain aliphatic group having 1-20 carbon atoms; or a straight or branched chain oxy-, carboxy- or amino-aliphatic group having 1-20 carbon atoms; And it is -O-, -S- or -NR'-; wherein R 'is H or alkyl; R is H, alkyl, alkoxy, aryl, aryloxy, heterocyclic or heterocycloxy; the molar ratio of x: y is approximately 1; the ratio n: (x or y) is between approximately 200: 1 and 1: 200; and the molar ratio q: r is between about 1: 99 and 99: 1; wherein said biodegradable polymer is biocompatible prior to biodegradation; also described are methods for preparing the polymers, compositions containing the polymers and biologically active substances, articles useful for implantation or injection into the body manufactured from the compositions and methods for controllably releasing biologically active substances which use Polymers. SR / cgt * P99 / 1333F