HK1027366B - Biodegradable polymers chain-extended by phosphates, compositions, articles and methods for making and using the same - Google Patents

Description

Biodegradable polymers, compositions, articles extended with phosphate esters and methods of making and using the same

Background

1. Field of the invention

The present invention relates to biodegradable polymer compositions, especially those comprising both phosphate and ester linkages in the polymer backbone and which degrade in vivo to non-toxic residues. The polymers of the present invention are particularly useful as implantable medical devices and drug delivery systems.

2. Description of the prior art

Biocompatible polymeric materials are widely used for therapeutic drug delivery and medical implant devices. It is also sometimes desirable that such polymers be not only biocompatible, but also biodegradable so as to eliminate the need to remove the polymer once its therapeutic value has been exhausted.

Conventional methods of drug release, such as frequent periodic administration, are not satisfactory in many cases. For example, for highly toxic drugs, frequent conventional administration may result in higher initial drug levels, often near toxic levels, when administered, followed by lower drug levels during the two administrations that may be below their therapeutic levels. The drug levels of the controlled drug release may be more closely maintained at therapeutic levels while being non-toxic and the release controlled in a predetermined manner over a longer period of time.

If biodegradable medical devices are used as drug delivery or other controlled release systems, the use of polymeric carriers is an effective means of delivering therapeutic agents in a locally controlled manner, see Langer et al, "chemical and physical Structure of polymers as carriers for controlled release bioactive agents", J.Macro Science, review of macromolecular chemistry and Physics (J.Macro Science, Rev.Macro.chem.Phys.), C23(1), 61-126 (1983). As a result, less total drug is required and toxic side effects are minimized. Polymers have been used as carriers for the local sustained release of therapeutic agents. See Leong et al, "polymer controlled Drug release", Advanced Drug release Reviews, 1: 199-; langer et al, "new methods of drug release", science 249: 1527-33 (1990); and Chien et al, Novel Drug delivery systems (Novel Drug delivery systems) (1982). Such delivery systems offer the potential to increase drug efficacy and reduce overall toxicity.

For a non-biodegradable matrix, the step of causing the therapeutic agent to be released is diffusion of water into the matrix, dissolution of the therapeutic agent, and subsequent diffusion of the therapeutic agent out through the channels of the matrix. As a result, the average residence time of the therapeutic agent in the soluble state in the non-biodegradable matrix is longer than in the biodegradable matrix, since in the former the therapeutic agent needs to pass through matrix channels, while in the latter there may be passage of the therapeutic agent through matrix channels, but this is no longer required. Because of the short half-life of many drugs, the therapeutic agent may be decomposed or inactivated in a non-biodegradable matrix before being released. This is particularly true for many biological macromolecules and smaller polypeptides, since these molecules are generally hydrolytically unstable and have low permeability to the polymer matrix. In fact, in non-biodegradable matrices, many biological macromolecules aggregate and precipitate, blocking the channels required for diffusion outside the carrier matrix.

These problems are alleviated by the use of biodegradable matrices, i.e. in addition to a certain degree of diffusional release, also allowing controlled release of the therapeutic agent by degradation of the polymer matrix. Examples of synthetic polymers studied as biodegradable materials include polyesters (Pitt et al, "biodegradable drug delivery systems based on aliphatic polyesters: use of contraceptives and narcotic antagonists", Controlled Release of bioactive substances (Controlled Release of bioactive materials), 19-44 (edited by Richard Baker et al, 1980), poly (amino acids) and pseudo-poly (amino acids) (Pulapura et al, "development trends in bioerodible polymers for medical applications", journal of biomaterial applications (journal of Biomaterials surfactants), 6(1), 216-50(1992)), polyurethanes (Bruin et al, "poly (glycolide-epsilon-caprolactone copolymers) for biodegrading lysine diisocyanate groups in artificial skin," Biomaterials (Biomaterials), 11(4), 291-95(1990), polyorthoesters (Heller et al, "Release of norethindrone from polyorthoester", Polymer Engineering and Science (Polymer Engineering and Science), 21(11), 727-31 (1981); polyanhydrides (Leong et al, "polyanhydrides for controlled release of biologically active agents", Biomaterials (Biomaterials), 7(5), 364-71 (1986)). Specific examples of biodegradable materials used as medical implant materials are polylactide, polyglycolide, polydioxanone (polydioxanone), lactide-glycolide copolymers, glycolide-dioxanone copolymers, polyanhydrides, glycolide-trimethylene carbonate copolymers and glycolide-caprolactone copolymers.

Polymers comprising phosphate linkages, known as polyphosphates, polyphosphonates, and polyphosphites, are known. See Penczek et al, "phosphorous-containing polymers", handbook of Polymer Synthesis (handbook of Polymer Synthesis), part B, Chapter 17, 1077-. The three types of compounds each have a different side chain attached to the phosphorus atom, and the respective structures are as follows:

polyphosphoester polyphosphonate polyphosphoester

The versatility of these polymers is due to the variability of the phosphorus atoms, which are well known for a variety of reactions. The binding may involve the 3p orbital or various 3s-3p hybrid orbitals; spd hybridization is also possible due to the accessibility of the d-orbitals. Thus, the physicochemical properties of poly (phosphoesters) can be readily altered by altering the R or R' groups. The biodegradability of polymers is mainly due to physiologically labile phosphate bonds in the polymer backbone. By controlling the backbone or side chains, a wide range of biodegradation rates can be achieved. Kadiyala et al, "polyphosphate: synthesis, physicochemical characteristics and biological reactions ", Biomedical Applications of synthetic biodegradable Polymers (Biomedical Applications of synthetic biodegradable Polymers), chapter 3: 33-57 (edited by Jeffrey O. Hollinger, 1995).

Another feature of polyphosphates is the availability of functional side chains. Since phosphorus can be pentavalent, drug molecules or other biologically active substances can be chemically bonded to the polymer. For example, a drug with an-O-carboxyl group may be coupled to a phosphorus via an ester linkage, which is hydrolyzable. The P-O-C groups in the backbone can also lower the glass transition temperature of the polymer and, more importantly, this gives the polymer its solubility in common organic solvents, which is desirable for ease of characterization and processing.

Friedman, U.S. patent 3442982, discloses poly (phosphate-ester) copolymers having as their ester moiety the following asymmetric groups:the polymers of Friedman are described therein as being stable to hydrolysis, heat and light (column 1, lines 42-44 and column 3, lines 74-75).

Canadian patent 597473 to Starck et al discloses polyphosphonates, and it is stated that the incorporation of phosphorus imparts non-flammability to the resulting polymer (column 6, lines 1-2). Engelhardt et al, U.S. patent 5530093, discloses various fabric finishing compositions having various polycondensate structures with phosphate and ester repeat units. The ester moieties of Starck et al and Engelhardt et al are arranged as follows:

-O-CO-R₃-CO-O-

there remains a need for poly (phosphate-ester) copolymer materials, such as those of the present invention, that are particularly well suited for the preparation of biodegradable materials and other biomedical applications.

Summary of the invention

The biodegradable polymer of the present invention comprises repeating monomer units represented by the following formula I or II:wherein:

x is-O-or-NR '-, wherein R' is H or alkyl;

M₁and M₂Each independently is (1) a branched or straight chain aliphatic group of 1 to 20 carbon atoms; or

(2) Branched or straight chain oxy-, carboxy-or amino-aliphatic groups of 1 to 20 carbon atoms

Clustering;

y is-O-, -S-or-NR' -;

l is a branched or straight chain aliphatic group of 1 to 20 carbon atoms;

r is H, alkyl, alkoxy, aryl, aryloxy, heterocyclyl or heterocycloxy;

the molar ratio of x to y is about 1;

the molar ratio of n to (x or y) is about 200: 1-1: 200; and is

The molar ratio of q to r is about 1: 99 to 99: 1.

These biodegradable polymers are biocompatible before and upon biodegradation.

In another embodiment, the present invention includes a polymer composition comprising:

(a) at least one biologically active substance and

(b) a polymer having repeating monomer units represented by formula I or II.

In another embodiment of the present invention, there is provided an article of manufacture for implantation, injection or otherwise wholly or partially implanted in a body, the article of manufacture comprising a biodegradable polymer of formula I or II or a polymer composition as described above.

In another embodiment, the present invention includes a method of making a biodegradable polymer, the method comprising the steps of: (a) reacting a heterocyclic compound of formula III, IV or V:

wherein M is₁、M₂And X is as defined above, with an initiator of the formula:

H-Y-L-Y-H

wherein Y and L are as defined above, to form a prepolymer of formula VI or VI I as shown below:

x, M therein₁、M₂、Y、L、x, y, q and r are as defined above; and

(b) and reacting the prepolymer of formula III, IV or V with a dihalophosphate (phosphorodihalate) of formula VIII:wherein halo is Br, Cl or I; and R is as defined above, to form the polymer of formula I or II.

In another embodiment of the present invention, there is provided a method for controlled release of a biologically active substance, the method comprising the steps of:

(a) mixing a biologically active substance with a biodegradable polymer having repeating monomer units represented by formula I or II to form a mixture;

(b) forming the mixture into a shaped solid article; and

(c) implanting or injecting the solid article in vivo at a preselected site such that the solid implanted or injected article is in at least partial contact with the biological fluid.

Brief Description of Drawings

FIG. 1 shows, in the form of a graph, the results of GPC analysis of the polymers of the invention.

FIGS. 2A and 2B show differential scanning calorimetry data for two polymers of the invention.

FIG. 3 shows the appearance of microspheres of a polymer of the invention prepared by a solvent evaporation process.

FIGS. 4A and 4B show the weight loss (4A) and the change in Mw (4B) after eight days in PBS at 37 ℃ for disks made from two polymers of the present invention.

FIG. 5 shows the change in Mw after 1 month of contact with air at room temperature for two polymers of the invention.

FIG. 6 shows the preparation of a polymer of the invention, P (LAEG-EOP)¹H-NMR spectrum.

FIG. 7 shows the preparation of a polymer of the invention, P (LAEG-EOP)³¹P-NMR spectrum.

FIG. 8 shows the storage stability data of the polymers of the invention at room temperature.

FIG. 9 shows cytotoxicity data for a polymer of the invention, P (LAEG-EOP) microspheres.

FIGS. 10A and 10B show the weight loss (10A) and Mw change (10B) in vitro for disks made from two polymers of the invention.

FIGS. 11A and 11B show the weight loss (11A) and Mw change (11B) in vivo for disks made from two polymers of the invention.

Fig. 12 shows biocompatibility data for the polymers of the present invention.

FIG. 13 shows the effect of manufacturing process on the release rate of polymeric microspheres of the present invention.

FIG. 14 shows the release rates of lidocaine and cisplatin from polymeric microspheres of the invention.

FIG. 15 shows the appearance of polymeric microspheres of the invention containing FITC-BSA.

FIG. 16 shows the rate of lidocaine release from polymeric microspheres of the invention.

FIG. 17 shows the rate of lidocaine release from polymeric microspheres of the invention.

Detailed DescriptionPolymers of the invention

The term "aliphatic" as used herein refers to straight chain, branched chain, cyclic alkanes, alkenes, or alkynes. Preferred aliphatic groups in the poly (phosphate-ester) copolymers of the present invention are straight or branched chain groups of 1 to 10 carbon atoms, preferably straight chain groups of 1 to 7 carbon atoms.

The term "aryl" as used herein refers to an unsaturated cyclic carbon compound having 4n +2 pi electrons.

The term "heterocycle" as used herein refers to a saturated or unsaturated cyclic compound having one or more non-carbon atoms in the ring, such as nitrogen, oxygen, or sulfur.

The biodegradable polymers of the present invention comprise repeating monomer units represented by formula I or II:wherein X is-O-or-NR '-, wherein R' is H or alkyl.

L may be any divalent branched or straight chain aliphatic group of 1 to 20 carbon atoms, provided that it does not interfere with the polymerization or biodegradation reactions of the polymer. Specifically, L may be an alkylene group such as a methylene group, an ethylene group, a 1, 2-dimethylethylene group, an n-propylene group, an isopropylene group, a 2, 2-dimethylpropylene group or a t-butylene group, an n-pentylene group, a t-pentylene group, an n-hexylene group, an n-heptylene group, etc.; alkylene substituted with non-interfering substituents, such as hydroxy, halogen or nitrogen substituted alkylene; alkenylene groups such as vinylene, propenylene, 2- (3-propenyl) -dodecylene; and alkynylenes such as ethynylene, propynyl, 1- (4-butynyl) -3-methyldecynyl and the like.

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 ethylene or methyl-substituted methylene, and most preferably L is ethylene.

M in the formula₁And M₂Each independently is (1) a branched or straight chain aliphatic group of 1 to 20 carbon atoms, or (2) a branched or straight chain oxy-, carboxy-, or amino-aliphatic group of 1 to 20 carbon atoms. In both cases, the branched or straight chain aliphatic group can be any divalent aliphatic moiety of 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms, that does not interfere with the polymerization, copolymerization or biodegradation reactions of the polymer. In particular, when M₁Or M₂When they are branched or straight-chain aliphatic radicals of 1 to 20 carbon atoms, they may be, for example, alkylene radicals, such as methylene, methyleneEthyl group, 1-methylethylene group, 1, 2-dimethylethylene group, n-propylene group, 1, 3-propylene group, isopropylene group, 2-dimethylpropylene group, t-butylene group, n-pentylene group, t-pentylene group, n-hexylene group, n-heptylene group, n-octylene group, n-nonylene group, n-decylene group, n-undecylene group, n-dodecylene group and the like; alkenylene groups such as n-propenylene, 2-vinylpropylene, n-butenylene, 3-vinylbutylene, n-pentenylene, 4- (3-propenyl) -hexylene, n-octenylene, 1- (4-butenyl) -3-methyldecylene, 2- (3-propenyl) dodecylene, hexadecenylene and the like; alkynylene groups such as ethynylene, propynyl, 3- (2-ethynyl) pentylene, n-hexylynyl, 2- (2-propynyl) decylene, and the like; or an alkylene, alkenylene or alkynylene group substituted with a non-interfering substituent such as hydroxyl, halogen or nitrogen, for example, 2-chloro-n-decylene, 1-hydroxy-3-vinylbutylene, 2-propyl-6-nitro-10-dodecynylene, and the like.

When M is₁Or M₂When it is a branched or straight chain oxy-aliphatic group of 1 to 20 carbon atoms, it may be, for example, a divalent alkyleneoxy group such as ethyleneoxy, 2-methylethyleneoxy, propyleneoxy, butyleneoxy, pentyleneoxy, dodecyleneoxy, hexadecyleneoxy, etc. When M is₁Or M₂When it is a branched or straight-chain oxy-aliphatic group, it preferably has the formula-O- (CH)₂)_a-, where a is 1 to 7.

When M is₁Or M₂When it is a branched or straight chain oxy-aliphatic group of 1 to 20 carbon atoms, it may also be, for example, an alkylenedioxy group such as methylenedioxy, ethylenedioxy, 1, 3-propylenedioxy, 2-methoxy-1, 3-propylenedioxy, 2-methyl-1, 3-propylenedioxy, n-pentylenedioxy, n-octadecylenedioxy, methyleneoxy-methyleneoxy, ethyleneoxy-ethyleneoxy, ethyleneoxy-1-propyleneoxy, butyleneoxy-n-propyleneoxy, pentadecyloxy-methyleneoxy, and the like. When M is₁Or M₂When it is a branched or straight-chain dioxo-aliphatic radical, it preferably has the formula-O- (CH)₂)_a-O-or-O-(CH₂)_a-O-(CH₂)_b-, where a and b are each 1 to 7.

When M is₁Or M₂When it is a branched or straight chain carboxy-aliphatic group of 1 to 20 carbon atoms, it may also be, for example, a divalent carboxylic acid ester such as the following divalent groups: methyl formate, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, ethyl propionate, allyl propionate, n-butyl acrylate, n-butyl butyrate, vinyl chloroacetate, 2-methoxycarbonyl cyclohexanone, 2-acetoxy cyclohexanone, and the like. When M is₁Or M₂When it is a branched or straight chain carboxy-aliphatic radical, it preferably has the formula-O-CHR²-CO-O-CHR³-, wherein R²And R³Each independently is H, alkyl, alkoxy, aryl, aryloxy, heterocyclyl or heterocycloxy.

When M is₁Or M₂When it is a branched or straight chain amino-aliphatic group of 1 to 20 carbon atoms, it may be a divalent amine, such as-CH₂NH-、-(CH₂)₂N-、-CH₂(C₂H₅)N-、-n-C₄H₉NH-、-t-C₄H₉NH-、-CH₂(C₃H₇)N-、-C₂H₅(C₃H₇)N-、-CH₂(C₈H₁₇) N-, etc. When M is₁Or M₂When it is a branched or straight chain amino-aliphatic group, it preferably has the formula- (CH)₂)_a-NR '-, wherein R' is H or lower alkyl.

M₁And/or M₂Preferably of the formula-O- (CH)₂)_aAlkylene of (a), wherein a is 1 to 7, most preferably a divalent ethylene group. In a particularly preferred embodiment, M₁And M₂Are both present; m₁And M₂Are not the same chemical group; and M₁And M₂Respectively n-pentylene and divalent methyl acetate groups.

R in the polymers of the invention is H, alkyl, alkaneOxy, aryl, aryloxy, heterocyclyl or heterocyclyloxy residues. Examples of useful alkyl radicals R' include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and-C₈H₁₇Etc.; alkyl substituted with a non-interfering substituent, such as hydroxy, halo, alkoxy, or nitro; the corresponding alkoxy group and the alkyl group which combines with the biologically active substance to form a pendant drug delivery system.

When R is aryl or the corresponding aryloxy group, it typically contains from about 5 to about 14 carbon atoms, preferably from about 5 to 12 carbon atoms, and may optionally contain one or more rings fused to each other. Examples of particularly suitable aryl groups include phenyl, phenoxy, naphthyl, anthryl, phenanthryl, and the like.

When R is heterocyclyl or heterocycloxy, it typically contains from about 5 to about 14 ring atoms, preferably from about 5 to about 12 ring atoms, and one or more heteroatoms. Examples of suitable heterocyclic groups include furan, thiophene, pyrrole, isoxazole, 3-isoxazole, pyrazole, 2-isoxazole, 1, 2, 3-triazole, 1, 2, 4-triazole, oxazole, thiazole, isothiazole, 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, 2, 4-dioxazole, 1, 3, 2-dioxazole, 1, 3, 4-dioxazole, 1, 2, 5-oxatriazole, 1, 3-oxathiophene (oxathiole), 1, 2-pyran, 1, 4-pyran, 1, 2-pyrone, 1, 4-pyrone, 2-imidazole, 1, 2, 3-triazole, 4-oxathiaole, 1, 2-oxathiaole, 1, 4-pyrone, 2-pyrone, 1, 2-dioxin, 1, 3-dioxin, pyridine, N-alkylpyridinium, pyridazine, pyrimidine, pyrazole, 1, 3, 5-triazine, 1, 2, 4-triazine, 1, 2, 3-triazine, 1, 2, 4-oxazine, 1, 3, 2-oxazine, 1, 3, 5-oxazine, 1, 4-oxazine, o-isoxazole, p-isoxazole, 1, 2, 5-oxathiazine, 1, 2, 6-oxathiazine, 1, 4, 2-oxadiazine, 1, 3, 5, 2-oxadiazine, oxaepine, thiazepin, 1, 2, 4-diazepine, indene, isoindole, benzofuran, isobenzofuran, thianaphthene, isothianaphthene, indole, indolenine, 2-isoindole, 1, 4-indolizine, pyrano [3, 4-b ] -pyrrole, isoindole, indoxazine, benzoxazole, phthalimide, 1, 2-benzopyran, 1, 2-benzopyrone, 1, 4-benzopyrone, 2, 1-benzopyrone, 2, 3-benzopyrone, quinoline, isoquinoline, 1, 2-benzodiazine, 1, 3-benzodiazine, 1, 5-naphthyridine, pyrido [3, 4-b ] -pyridine, pyrido [3, 2-b ] -pyridine, pyrido [4, 3-b ] -pyridine, 1, 3, 2-benzoxazine, 1, 4, 2-benzoxazine, 2, 3, 1-benzoxazine, 3, 4-benzoxazine, 1, 2-benzisoxazine, 1, 4-benzisoxazine, Carbazole, xanthene, acridine, purine, and the like. When R is a heterocyclic group or a heterocycloxy group, it is preferably selected from furan, pyridine, N-alkylpyridine, 1, 2, 3-triazole, 1, 2, 4-triazole, indene, anthracene and purine rings.

In a particularly preferred embodiment, R is alkyl, alkoxy, phenyl, phenoxy or heterocycloxy, even more preferably alkoxy having from 1 to 7 carbon atoms. R is most preferably ethoxy.

The molar ratio of n to (x or y) can vary over a wide range depending on the desired biodegradability and release characteristics of the polymer, but is typically from about 200: 1 to 1: 200. The ratio of x to y is preferably from about 100: 1 to about 1: 100, most preferably from about 50: 1 to about 1: 50.

The molar ratio q: r can vary widely depending on the desired biodegradability and release characteristics of the polymer, but is typically from about 1: 200 to 200: 1. The ratio q to r is preferably from about 1: 150 to 150: 1, most preferably from about 1: 99 to 99: 1.

The molar ratio of x to y can also vary within wide limits depending on the desired biodegradability and release characteristics of the polymer, but is typically about 1.

Biodegradable polymers are different from non-biodegradable polymers, i.e. they can be degraded during in vivo treatment. This process typically involves breaking the polymer into its monomeric subunits. In principle, the final hydrolytic cleavage products of polyphosphoesters are phosphate esters, alcohols and glycols, all of which are non-toxic. The hydrolyzed intermediate oligomeric products have different properties, but the toxicology of biodegradable polymers for implantation or infusion, even polymers synthesized from apparently non-toxic monomeric structures, is usually determined after one or more in vitro toxicity analyses. A typical toxicity assay is performed using hepatoma cells, such as GT3TKB tumor cells, in the following manner:

approximately 100-150mg of the polymer sample was degraded in 20ml of 1M sodium hydroxide at 37 ℃ for 1-2 days, or until complete degradation was observed. The solution was then neutralized with 20ml of 1M hydrochloric acid. Approximately 200. mu.l of each concentration of degraded polymer product was placed in 96-well tissue culture plates and seeded with human gastric carcinoma cells (GT3TKB) at a density of 104/well. The degraded polymer product was incubated with GT3TKB cells for 48 hours. The results of the analysis can be expressed as a plot of percent relative growth versus concentration of degraded polymer in the tissue culture wells.

The biodegradable polymers of the present invention are preferably sufficiently pure to be biocompatible themselves and remain biocompatible during biodegradation. By "biocompatible" is meant that the polymer itself or biodegradation products are non-toxic and produce only minimal tissue irritation when implanted or injected into vascular tissue.

The polymers of the present invention are preferably soluble in one or more common organic solvents to facilitate manufacture and processing. Common organic solvents include, for example, chloroform, dichloromethane, acetone, ethyl acetate, DMAC, N-methylpyrrolidone, dimethylformamide, and dimethylsulfoxide. The polymer is preferably soluble in at least one of the solvents mentioned above.Synthesis of Poly (phosphoester-co-ester) copolymer

In the preparation of polyphosphonates, the most common general reaction is the dehydrochlorination reaction between a phosphorodichloridate and a diol according to the following formula:

most polyphosphonates are also obtained by condensation reactions between appropriately substituted dichlorides and diols.

The polyphosphites can be prepared from diols using a two-step condensation reaction. Dimethyl phosphite was reacted with a 20% molar excess of diol and then the methoxyphosphonyl end groups were removed from the oligomers by high temperature.

The melt polycondensation reaction has the advantage that it avoids the use of solvents and large amounts of other additives, which results in a more convenient purification. It also makes it possible to obtain polymers of reasonably high molecular weight. But generally require more severe conditions to enable chain acidolysis (or hydrolysis in the presence of water). If the polymer backbone is susceptible to hydrogen atom abstraction or oxidation by subsequent large radical recombination, undesirable, thermally-induced side reactions, such as crosslinking reactions, may occur.

To minimize these side reactions, the polymerization reaction can also be carried out in solution. Solution polycondensation requires that both the prepolymer and the phosphorus component be dissolved in common solvents. Typically, a chlorinated organic solvent such as chloroform, dichloromethane or dichloroethane is used. The solution polymerization reaction must be carried out in the presence of equimolar amounts of the reactants and a stoichiometric amount of an acid acceptor, usually a tertiary amine such as pyridine or triethylamine. The product is then typically isolated from solution by precipitation in a non-solvent and purified from the hydrochloride salt by conventional techniques known to those of ordinary skill in the art, for example by washing with an acidic aqueous solution, such as dilute hydrochloric acid.

The reaction time required for the solution polymerization reaction is longer than that for the melt polymerization reaction. However, the reaction conditions employed are much milder, thereby minimizing side reactions and allowing the incorporation of more sensitive functional groups into the polymer. A disadvantage of solution polymerization is that it is not possible to obtain polymers of high molecular weight, for example Mw greater than 20000.

Interfacial polycondensation may be employed when it is desired to obtain high molecular weight polymers at high reaction rates. Mild reaction conditions minimize side reactions. The dependence of the high molecular weight inherent in the solution process on the stoichiometric equivalence between the diol and the dichloride (dichlorinate) is also eliminated. However, hydrolysis of the acid chloride can occur in the basic aqueous phase. Sensitive dichlorides which have some solubility in water are generally more susceptible to hydrolysis rather than polymerization. The ionized diol may be introduced to the interface using a phase transfer catalyst such as a crown ether or tertiary ammonium chloride to aid in the polycondensation reaction. The yield and molecular weight of the resulting polymer after interfacial polycondensation reaction are influenced by the reaction time, the molar ratio of the monomers, the volume ratio of the immiscible solvents, the type of acid acceptor, and the type and concentration of the phase transfer catalyst.

In a preferred embodiment of the present invention, the biodegradable polymer of formula I or II can be prepared by a process comprising the steps of: (a) reacting at least one heterocyclic compound of formula III, IV or V:wherein M is₁、M₂And X is as defined above, with an initiator of the formula:

H-Y-L-Y-H, wherein Y and L are as defined above, to form a prepolymer of formula VI or VII:x, M therein₁、M₂Y, L, R, x, Y, q and R are as defined above; and (b) further reacting the prepolymer of formula III, IV or V above with a dihalophosphate of formula VIII:wherein "halo" is Br, Cl or I; and R is as defined above, to form the polymer of formula I or II above.

The first reaction step (a) serves to open the ring of the heterocyclic compound of formula III, IV or V using an initiator. Examples of useful heterocyclic compounds of formula III, IV or V include caprolactone, caprolactam, amino acid anhydrides such as glycine anhydride, cycloalkylene carbonates, dioxanones, glycolides, lactides and the like.

When the compound of the present invention is a compound of formula I, only M-containing compounds may be used in step (a)₁The heterocyclic compound of formula III produces a prepolymer of formula VI. When the compound of the present invention is a compound of formula II, M-containing compounds may be used in step (a)₁Of the formula III and compounds containing M₂A mixture of heterocyclic compounds of formula IV. Alternatively, when the compound of the present invention is a compound of formula II, a compound containing M in combination may be used in step (a)₁And M₂A single heterocyclic compound of formula V.

Examples of suitable initiators include various compounds having at least two active hydrogens (H-Y-L-Y-H), where L is a linking group and is as defined above, and Y can be-O-, -S-, or-NR ", where R" is as defined above. The linking group L may be a straight chain group, such as an alkylene group, but may also be substituted with one or more additional active hydrogen-containing groups. For example, L may be one or more additional alkyl-substituted straight chain alkylene groups each bearing an active hydrogen moiety, such as-OH, -SH, or-NH₂. Thus, various branched polymers can be prepared using branched active hydrogen initiators to design polymers with desired characteristics. However, when these branched polymers are reacted with acid chlorides, crosslinked polymers will be obtained.

Reaction step (a) may be carried out at a variety of temperatures depending on the solvent used, the molecular weight desired, the sensitivity of the reactants to form side reactions and the presence of the catalyst. However, the reaction step (a) is preferably carried out at a melting temperature of about 0 to +235 ℃. In the case of using a cationic or anionic catalyst, a lower reaction temperature may be employed.

The reaction time required for reaction step (a) may vary widely depending on the type of reaction employed and the molecular weight desired. However, the reaction step (a) is preferably carried out for about 1 hour to 7 days.

When the reaction step (a) may be bulk polymerization, solution polymerization, interfacial polycondensation reaction or any other convenient polymerization method, the reaction step (a) is preferably carried out under melt conditions.

Examples of particularly useful prepolymers of formula V include:

(i) OH-terminated prepolymer derived from polycaprolactone: h- [ -O (CH)₂)₅-CO-]_x-O-CH₂-CH₂-O-[-CO-(CH₂)₅-O-]_y-H；

(ii) NH-terminated prepolymer derived from polycaprolactam (Nylon 6): h- [ -NH- (CH)₂)₅-CO-]_x-NH-CH₂-CH₂-NH-[-CO-(CH₂)₅-NH-]y-H；

(iii) OH-terminated prepolymer derived from polylactide: h- [ -OCH (CH)₃)-CO-]_x-O-CH₂-CH₂-O-[-CO-CH(CH₃)-O-]_y-H; and

(iv) OH-terminated prepolymer derived from polytrimethylene carbonate: h- [ -O (CH)₂)₃-O-CO-]_x-O-CH₂-CH₂-O-[-CO-O-(CH₂)₃-O-]_y-H。

Examples of particularly useful prepolymers of formula VI include:

(i) OH-terminated copolymers derived from lactide and glycolide:(ii) OH-terminated copolymers derived from lactide and caprolactone:and

(iii) OH-terminated copolymers derived from glycolide and caprolactone

The purpose of the polymerization reaction of step (b) is to form a polymer comprising (i) the prepolymer produced in step (a) and (ii) the phosphorylated units linked to each other. The result may be a block copolymer with a microcrystalline structure, which is particularly suitable for use as a controlled release medium.

The polymerization step (b) of the present invention is usually carried out at a slightly lower temperature than step (a), but the reaction temperature may also vary widely, depending on the type of polymerization reaction used, the presence of one or more catalysts, the molecular weight desired and the susceptibility of the reactants to undesirable side reactions. When melting conditions are used, the temperature change is about 0-150 ℃. However, when the polymerization step (b) is carried out under solution polymerization conditions, it is typically carried out at about-40 to 100 ℃. Typical solvents include dichloromethane, chloroform or any of a variety of inert organic solvents. The time required for the polymerization reaction of step (b) may also vary within wide limits, depending on the molecular weight of the material desired and generally also on the need to employ more or less severe conditions to bring the reaction to the desired degree of completeness. However, the polymerization step (b) is typically carried out for about 30 minutes to 48 hours.

The presence of an acid acceptor during the polymerisation step (a) is particularly beneficial when solution polymerisation conditions are employed. A particularly suitable class of acid acceptors includes tertiary amines, such as pyridine, trimethylamine, triethylamine, substituted anilines and substituted aminopyridines. The most preferred acid acceptor is substituted aminopyridine 4-dimethylaminopyridine ("DMAP").

The polymers of formula I and II can be isolated from the reaction mixture using conventional techniques, such as by precipitation, extraction with immiscible solvents, evaporation, filtration, and crystallization, among others. The polymers of formulae I and II are typically isolated and purified simultaneously by impregnating solutions of the above polymers with non-solvents or partially soluble solvents such as diethyl ether or petroleum ether.Biodegradability and Release characteristics

The polymers of formulae I and II are generally characterized by a rate of release of the biologically active substance in vivo which is at least partially controlled by hydrolysis of the phosphoester bond of the polymer during biodegradation. In addition, the bioactive agent being released may combine with the phosphorus side chain R' to form a pendant drug delivery system. Furthermore, other factors are also important.

The in vivo lifetime of a biodegradable polymer also depends on its molecular weight, crystallinity, biostability and degree of crosslinking. In general, the greater the molecular weight, the higher the crystallinity, and the greater the biostability, the slower the biodegradation.

Thus, the structure of the side chain may influence the release behavior of the composition comprising the biologically active substance. For example, it is expected that conversion of the phosphate side chain to a more lipophilic, more hydrophobic or more bulky group will slow the degradation process. Therefore, the slave band is smallerThe release is generally faster in polymer compositions having pendant aliphatic groups than in polymer compositions having larger aromatic side chains.Polymer composition

The polymers of formulae I and II can be used alone or as compositions additionally containing biologically active substances to form various biodegradable materials. Even in the absence of bioactive substances, for example, the polymers of formulae I and II can be used to produce bioerodible sutures, corrective devices or bone cements (bone cement) for repairing bone or connective tissue damage, laminates for degradable or non-degradable textiles, or the outer membrane (coating) of implant devices.

However, the biodegradable polymer composition preferably comprises both:

(a) at least one biologically active substance and

(b) a polymer having repeating monomer units represented by formula I or II wherein X, M₁、M₂L, R, Y, x, Y, q, R and n are as defined above.

The bioactive substances of the present invention can vary widely depending on the purpose of the composition. The active substance may be a single one or a mixture of more. The delivery system is designed to deliver biologically active substances of high water solubility as well as low water solubility to produce a delivery system with a controlled release rate. The term "biologically active substance" includes, but is not limited to, drugs; vitamin, mineral supplements; substances for the treatment, prevention, diagnosis, cure or alleviation of a disease or condition; or substances that affect body structure or function; or prodrugs which are biologically active or become more effective when placed in a predetermined physiological environment.

A wide range of non-limiting examples of biologically active substances that can be used include the following broad therapeutic agents: an anabolic agent, an antacid, an anti-asthmatic, an anticholesterolemic and an antilipidemic agent, an anticoagulant, an anticonvulsant, an antidiarrheal, an antiemetic, an anti-infective agent, an anti-inflammatory agent, an antimanic agent, an antiemetic, an antineoplastic agent, an antiobesity agent, an antipyretic analgesic, an antispasmodic agent, an antithrombotic agent, an anti-uricemic agent, an antianginal agent, an antihistamine, an antitussive agent, an appetite suppressant, a biological agent, cerebral vasodilators, coronary vasodilators, decongestants, diuretics, diagnostics, erythropoietics, expectorants, gastrointestinal inhibitors, hyperglycemic agents, hypnotics, hypoglycemic agents, ion exchange resins, laxatives, mineral supplements, mucolytics, neuromuscular drugs, peripheral vasodilators, psychotropic drugs (psychotropic drugs), sedatives, stimulants, thyroid and antithyroid drugs, uterine relaxants, vitamins and prodrugs.

Specific examples of the above classes of biologically active substances suitable for use include (a) antineoplastic agents, such as androgen inhibitors, antimetabolite agents, cytotoxic agents, immunomodulators; (b) antitussives such as dextromethorphan, dextromethorphan hydrobromide, narcotine, bitrex and chlorpheniolhydroxychloride; (c) antihistamines such as chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, phenicolamine succinate, and phentoloxamine citrate; (d) decongestants such as phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, and ephedrine; (e) various alkaloids, such as codeine phosphate, codeine sulfate, and morphine; (f) mineral supplements such as potassium chloride, zinc chloride, calcium carbonate, magnesium oxide, and other alkali and alkaline earth metal salts; (g) ion exchange resins such as cholestyramine; (h) antiarrhythmic agents, such as N-acetylprocainamide; (i) antipyretic analgesics such as acetaminophen, aspirin and ibuprofen; (j) appetite suppressants such as phenylpropanolamine hydrochloride or caffeine; (k) expectorants, such as guaifenesin; (l) Antacids such as aluminum hydroxide and magnesium hydroxide; (m) biologicals such as peptides, polypeptides, proteins and amino acids, hormones, interferons or cytokines and other biologically active peptidic compounds such as hGH, tPA, calcitonin, ANF, EPO and insulin; and (n) anti-infective agents, such as antifungal agents, antiviral agents, antiseptics, and antibiotics.

The biologically active substance is preferably selected from polysaccharides, growth factors, hormones, anti-angiogenic factors, interferons and cytokines, and pro-drugs. More specifically, non-limiting examples of useful bioactive substances include the following therapeutic categories: analgesics, such as non-steroidal anti-inflammatory drugs, opioid agonists, and salicylates; antihistamines, e.g. H₁-blocking agent and H₂-a blocking agent; anti-infective agents, such as anthelmintics, anti-anaerobes, antibiotics, aminoglycoside antibiotics, antifungal antibiotics, cephalosporin antibiotics, macrolide antibiotics, various beta-lactam antibiotics, penicillin antibiotics, quinolone antibiotics, sulfonamide antibiotics, tetracycline antibiotics, antimycobacterial agents, antinuclear mycorrhizal agents, antiprotozoal agents, antimalarial agents, antiviral agents, antiretroviral agents, sarcopticides, and anti-urethral infectives; antineoplastic agents, such as alkylating agents, nitrogen mustard alkylating agents, nitrosourea alkylating agents, antimetabolites, purine analog antimetabolites, pyrimidine analog antimetabolites, hormonal antineoplastic agents, natural antineoplastic agents, antibiotic natural antineoplastic agents, and vinca alkaloid natural antineoplastic agents; autonomic agents (autonomics) such as anticholinergics, antimuscarinic anticholinergics, ergot alkaloids, parasympathomimetics, cholinergic agonist parasympathomimetics, cholinesterase inhibitor parasympathomimetics, sympatholytics, alpha-blocker sympathomimetics, beta-blocker sympathomimetics, and adrenergic agonist sympathomimetics; cardiovascular agents, such as antianginals, beta-blockers, calcium channel blockers, nitrates, antiarrhythmics, cardiac glycosides, antiarrhythmics class I, antiarrhythmics class II, antiarrhythmics class III, antiarrhythmics class IV, antihypertensives, alpha-blockers, angiotensin converting enzyme inhibitors (ACE inhibitors), antihypertensives, beta-blockers, calcium channel blockers, centrally acting adrenergic antihypertensives, diuretics, peripheral vasodilators, antihypertensives, antilipemic agents, bile acid sequestrants, HMG-CoA reductase inhibitors, antihypertensivesLipid drugs, muscle contractants, cardiac glycoside muscle contractants, and thrombolytic agents; dermatological agents, such as antihistamines, anti-inflammatory agents, corticosteroid anti-inflammatory agents, antipruritic/local anesthetic agents, topical anti-infectives, antifungal topical anti-infectives, antiviral topical anti-infectives, and topical anti-neoplastic agents; electrolytes and renal drugs such as acidifying, alkalising, diuretic, carbonic anhydrase inhibitor diuretics, compensatory (loop) diuretics, osmotic diuretics, potassium deficiency diuretics, thiazide diuretics, electrolyte substitutes, and uricosuric drugs; enzymes such as pancreatin and thrombolytic enzyme; gastrointestinal agents, e.g. antidiarrheals, antiemetics, gastrointestinal anti-inflammatory agents, salicylates gastrointestinal anti-inflammatory agents, antacids anti-ulcer agents, gastric acid pump inhibitors anti-ulcer agents, gastric mucosa acting anti-ulcer agents, H₂-antiulcer agents of the blocker type, cholelitholytic agents, digestive agents, emetics, laxatives and stool softeners, and prokinetic agents; general anesthetics, such as inhalation anesthetics, halide-based inhalation anesthetics, intravenous anesthetics, barbiturate-based intravenous anesthetics, benzodiazepine-based intravenous anesthetics, and opioid agonist-based intravenous anesthetics; hematological agents such as antianemia agents, hematopoietic antianemia agents, coagulation agents, anticoagulant agents, hemostatic coagulation agents, platelet inhibitor coagulation agents, thrombolytic enzyme coagulation agents, and plasma volume expanders; hormones and hormone modulators, such as abortifacients, adrenal agents, corticosteroid adrenal agents, androgens, antiandrogens, antidiabetic agents, sulfonylurea antidiabetic agents, antihyperglycemic agents, oral contraceptives, progestin contraceptives, estrogens, anti-infertility agents, oxytocics, parathyroid agents, pituitary hormones, progestins, antithyroid agents, thyroid hormones, and tocolytics; immunological drugs such as immunoglobulins, immunosuppressants, toxoids and vaccines; local anesthetics, such as amide local anesthetics and ester local anesthetics; musculoskeletal agents, such as anti-gout anti-inflammatory agents, corticosteroid anti-inflammatory agents, gold compound anti-inflammatory agents, immunosuppressant anti-inflammatory agents, non-steroid anti-inflammatory agents (NSAIDs), salicylate anti-inflammatory agents, skeletal muscle relaxants, neuromuscular blocker skeletal muscle relaxants, and reverse neuromuscular blocker skeletal muscle relaxants; spirit of the inventionPharmacological agents such as anticonvulsants, barbiturates, benzodiazepines, antimigraines, antiparkinson, anti-vertigo, opioid agonists and opioid antagonists; ophthalmic agents, such as anti-glaucoma agents, beta-blocker anti-glaucoma agents, miotic anti-glaucoma agents, mydriatic agents, adrenergic agonist mydriatic agents, anti-muscarinic mydriatic agents, ophthalmic anesthetics, ophthalmic anti-infectives, ophthalmic aminoglycoside anti-infectives, ophthalmic macrolide anti-infectives, ophthalmic quinolone anti-infectives, ophthalmic sulfonamide anti-infectives, ophthalmic tetracycline anti-infectives, ophthalmic anti-inflammatories, ophthalmic corticosteroid anti-inflammatories, and ophthalmic non-steroidal anti-inflammatories (NSAIDs); psychotropic agents, such as antidepressants, heterocyclic antidepressants, monoamine oxidase inhibitors (MAOIs), Selective Serotonin Reuptake Inhibitors (SSRIs), tricyclic antidepressants, antimanics, antipsychotics, phenothiazine antipsychotics, anxiolytics, sedatives, hypnotics, barbiturate sedatives and oculogues, and psychostimulants; respiratory tract drugs such as antitussives, bronchodilators, adrenergic agonist bronchodilators, antimuscarinic bronchodilators, expectorants, mucolytics, respiratory tract anti-inflammatory drugs and respiratory tract corticosteroid anti-inflammatory drugs; toxicology agents, such as antidotes, heavy metal antagonists/chelators, narcotics (poison abstinence agents), poison deterrents (poison abstinence agents), and narcotics; a mineral; and vitamins such as vitamin a, vitamin B, vitamin C, vitamin D, vitamin E, and vitamin K.

Preferred classes of useful bioactive substances within the above-mentioned ranges include: (1) non-steroidal anti-inflammatory drug (NSAIDs) analgesics such as diclofenac, ibuprofen, ketoprofen, and naproxen; (2) opioid agonist analgesics such as codeine, fentanyl, hydromorphone, and morphine; (3) salicylate analgesics, such as aspirin (ASA) (enteric coated ASA); (4) h₁-blocker antihistamines such as clemastine and terfenadine; (5) h₂-blocker antihistamines such as cimetidine, famotidine, nizatidine and ranitidine;(6) anti-infective agents, such as mupirocin; (7) anti-anaerobe anti-infectives, such as chloramphenicol and clindamycin; (8) antifungal antibiotic anti-infectives, such as amphotericin B, clotrimazole, fluconazole, and ketoconazole; (9) macrolide antibiotic anti-infectives, such as azithromycin and erythromycin; (10) various beta-lactam antibiotic anti-infectives, such as aztreonam and imipenem; (11) penicillin antibiotic anti-infectives, such as nafcillin and oxacillin, penicillin G and penicillin V; (12) quinolone antibiotic anti-infectives, such as ciprofloxacin and norfloxacin; (13) tetracycline antibiotic anti-infectives, such as doxycycline, minocycline, and tetracycline; (14) anti-tubercle anti-infectives, such as Isoniazid (INH) and rifampicin; (15) antiprotozoal anti-infectives, such as atoquarone and dapsone; (16) antimalarial anti-infectives, chloroquine and pyrimethamine; (17) antiretroviral anti-infectives, such as ritonavir and zidovudine; (18) antiviral anti-infectives, such as acyclovir, ganciclovir, interferon alpha and rimantadine; (19) alkylating antineoplastic agents, such as carboplatin and cisplatin; (20) nitrosourea alkylating antineoplastic agents, such as carmustine (BCNU); (21) antimetabolite antineoplastic agents, such as methotrexate; (22) pyrimidine analog antimetabolite antineoplastic agents, such as fluorouracil (5-FU) and gemcitabine; (23) hormonal antineoplastics such as sexual riline, leuprolide, and tamoxifen; (24) natural antineoplastic agents, such as aldesleukin, interleukin-2, docetaxel, etoposide (VP-16), interferon alpha, paclitaxel, and tretinoin (ATRA); (25) antibiotic natural antineoplastic agents, such as bleomycin, actinomycin D, daunorubicin, doxorubicin and mitomycin; (26) vinca alkaloid natural antineoplastic agents, such as vinblastine and vincristine; (27) autonomic agents, such as nicotine; (28) anticholinergic autonomic agents such as benztropine and trihexyphenidyl; (29) antimuscarinic anticholinergic autonomic agents, such as atropine and oxybutynin; (30) ergot alkaloid autonomic agents, such as bromocriptine; (31) cholinergic agonist parasympathomimetics, such as pilocarpine; (32) cholinesterase inhibitor parasympathomimetics, such as pyridostigmine; (33) alpha-blockers sympatholyticDrugs such as prazosin; (34) beta-blocker sympathomimetic agents, such as atenolol; (35) adrenergic agonist sympathomimetics such as albuterol and dobutamine; (36) cardiovascular agents, such as aspirin (ASA) (enteric coated ASA); (37) beta-blockers anti-anginal drugs such as atenolol and propranolol; (38) calcium channel blockers such as nifedipine and verapamil; (39) nitrate anti-anginal drugs such as isosorbide dinitrate (ISDN); (40) cardiac glycoside antiarrhythmics, such as digoxin; (41) class I antiarrhythmics, such as lidocaine, mexiletine, phenytoin, procainamide, and quinidine; (42) class II antiarrhythmics, such as atenolol, metoprolol, propranolol, and timolol; (43) class III antiarrhythmics, such as amiodarone; (44) class IV antiarrhythmics, such as diltiazem and verapamil; (45) alpha-blockers, antihypertensive agents, such as prazosin; (46) angiotensin converting enzyme inhibitors (ACE inhibitors) antihypertensive agents such as captopril and enalapril; (47) beta-blockers antihypertensive drugs, atenolol, metoprolol, nadolol, and propranolol; (48) calcium channel blockers such as diltiazem and nifedipine; (49) centrally acting adrenergic antihypertensives such as clonidine and methyldopa; (50) diuretic antihypertensive agents such as amiloride and furosemide, Hydrochlorothiazide (HCTZ) and spironolactone; (51) peripheral vasodilator antihypertensives such as hydralazine and minoxidil; (52) antilipemics, such as gemfibrozil and probucol; (53) bile acid sequestrants antilipemics, such as cholestyramine; (54) HMG-CoA reductase inhibitors antilipemics, such as lovastatin and pravastatin; (55) muscle contractants, such as amphenium, dobutamine, and dopamine; (56) cardiac glycoside inotropic agents, such as digoxin; (57) thrombolytic agents, such as aktavas (TPA), anistreplase, streptokinase, and urokinase; (58) dermatological agents, such as colchicine, isotretinoin, methotrexate, minoxidil, tretinoin (ATRA); (59) dermatological corticosteroid anti-inflammatory agents, such as betamethasone and dexamethasone; (60) antifungal topical anti-infective agents, e.g. amphotericin B, clotrimazole, imidConazole and nystatin; (61) antiviral topical anti-infective agents, such as acyclovir; (62) topical antineoplastic agents, such as fluorouracil (5-FU); (63) electrolytes and renal drugs, such as lactulose; (64) compensatory diuretics, such as furosemide; (65) potassium-deficient diuretics, such as triamterene; (66) thiazide diuretics, such as Hydrochlorothiazide (HCTZ); (67) uricosuric agents, such as probenecid; (68) enzymes, such as rnases and dnases; (69) thrombolytic enzymes such as akvas, anistreplase, streptokinase, and urokinase; (70) antidiarrheal, chlorpromazine; (71) salicylates, gastrointestinal anti-inflammatory agents, such as sulfasalazine; (72) gastric acid pump inhibitors, such as omeprazole; (73) h₂Blockers such as cimetidine, famotidine, nizatidine and ranitidine; (74) digestive agents, such as pancreatic lipase; (75) prokinetic agents, such as erythromycin; (76) opioid agonist intravenous anesthetics, such as fentanyl; (77) hematopoietic antianemia agents, such as erythropoietin, filgrastim (G-CSF) and saras (GM-CSF); (78) clotting agents, such as antihemophilic factor 1-10(AHF 1-10); (79) anticoagulants, such as warfarin; (80) thrombolytic enzyme coagulants such as acrivasin (TPA), anistreplase, streptokinase, and urokinase; (81) hormones and hormone modulators, such as bromocriptine; (82) abortifacients, such as methotrexate; (83) antidiabetic agents, such as insulin; (84) oral contraceptives, such as estrogens and progestins; (85) progestin contraceptives, such as levonorgestrel and norgestrel; (86) estrogens, such as conjugated estrogens, e.g., Diethylstilbestrol (DES), estrogens (estradiol, estrone, and estropipate); (87) anti-infertility drugs, such as clomiphene, Human Chorionic Gonadotropin (HCG), and follicle stimulating hormone; (88) parathyroid agents, such as calcitonin; (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) immunobiologies such as interferon beta-1 b and interferon gamma-1 b; (93) immunoglobulins, such as immunoglobulin IM, IMIG, IGIM and immunoglobulin IV, IVIG, IGIV; (94) amide local anesthetics such as lidocaine; (95) local anesthetic of estersAgents such as benzocaine and procaine; (96) musculoskeletal corticosteroid anti-inflammatory agents such as beclomethasone, betamethasone, cortisone, dexamethasone, hydrocortisone, and prednisone; (97) musculoskeletal immunosuppressant anti-inflammatory drugs, such as azathioprine, cyclophosphamide, and methotrexate; (98) musculoskeletal non-steroidal anti-inflammatory drugs (NSAIDs), such as diclofenac, ibuprofen, ketoprofen, ketorolac, naproxen; (99) skeletal muscle relaxants, such as baclofen, cyclobenzaprine, and diazepam; (100) reverse neuromuscular blocking agents skeletal muscle relaxants, such as pyridostigmine; (101) neurological drugs such as nimodipine, riluzole, tacrine, and ticlopidine; (102) anticonvulsants such as carbamazepine, gabapentin, lamotrigine, phenytoin, and valproic acid; (103) barbiturates as anticonvulsants, such as phenobarbital and primidone; (104) benzodiazepine anticonvulsants, such as clonazepam, diazepam, and lorazepam; (105) anti-parkinson agents such as bromocriptine, levodopa, carbidopa, and pergolide; (106) anti-vertigo agents, such as meclizine; (107) opiate agonists such as codeine, fentanyl, hydromorphone, methadone, and morphine; (108) opioid antagonists, such as naloxone; (109) beta-blocker anti-glaucoma drugs such as timolol; (110) miotic anti-glaucoma agents such as pilocarpine; (111) ophthalmic aminoglycoside anti-infectives, such as gentamicin, neomycin, and tobramycin; (112) ophthalmic quinolone anti-infectives, such as ciprofloxacin, norfloxacin, and ofloxacin; (113) ophthalmic corticosteroid anti-inflammatory agents such as dexamethasone and prednisolone; (114) ophthalmic non-steroidal anti-inflammatory drugs (NSAIDs), such as diclofenac; (115) antipsychotics, such as clozapine, haloperidol, and risperidone; (116) benzodiazepines anxiolytics, sedatives and hypnotics, such as clonazepam, diazepam, lorazepam, oxazepam and pramazepam; (117) psychostimulants such as methylphenidate and pimoline; (118) antitussives, such as codeine; (119) bronchodilators, such as theophylline; (120) adrenergic agonist bronchodilators, such as salbutamol; (121) corticosteroid respiratory anti-inflammatory agents, such as dexamethasone; (122) antidotes, e.g.Flumazenil and naloxone; (123) heavy metal antagonists/chelators, such as penicillamine; (124) poison deterrents, such as disulfiram, naltrexone, and nicotine; (125) drug-withdrawal agents, such as bromocriptine; (126) minerals such as iron, calcium, and magnesium; (127) vitamin B compounds, e.g. cyanocobalamin (vitamin B)₁₂) And nicotinic acid (vitamin B)₃) (ii) a (128) Vitamin C compounds, such as ascorbic acid; and (129) vitamin D compounds, such as calcitriol.

In addition to the above, the following less commonly used drugs may also be used: oil solutions of chlorhexidine and estradiol cyclopropane; an oil solution of estradiol valerate; flurbiprofen; flurbiprofen sodium; ivermectin; levodopa; nafarelin and somatropin.

In addition, the following new drugs may also be used: recombinant beta-glucan; bovine immunoglobulin concentrate; bovine superoxide dismutase; a formulation comprising fluorouracil, epinephrine and bovine collagen; recombinant hirudin (r-Hir), HIV-1 immunogen; a human anti-TAC antibody; recombinant human growth hormone (r-hGH); recombinant human hemoglobin (r-Hb); recombinant human mecamylamine (r-IGF-1); recombinant interferon beta-1 a; filgrastim (G-CSF); olanzapine; recombinant thyroid stimulating hormone (r-TSH); and topotecan.

In addition, the following intravenously administered drugs may be used: acyclovir sodium; aldesleukin; atenolol; bleomycin sulfate, human calcitonin; salmon calcitonin; carboplatin; a carmustine; actinomycin D, daunorubicin hydrochloride; docetaxel; doxorubicin hydrochloride; epstein alpha; etoposide (VP-16); fluorouracil (5-FU); sodium ganciclovir; gentamicin sulfate; interferon alpha; leuprolide acetate; quenching with hydrochloric acid; methadone hydrochloride; methotrexate sodium; paclitaxel; ranitidine hydrochloride; vinblastine sulfate; and Zidovudine (AZT).

In addition, the following peptides, proteins and other macromolecular substances, such as interleukins 1-18, including mutants and analogues thereof; interferons α, β, and γ; luteinizing Hormone Releasing Hormone (LHRH) and analogs thereof; gonadotropin releasing hormone (GnRH), transforming growth factor-beta (TGF- β); fibroblast Growth Factor (FGF); tumor necrosis factor-alpha and beta (TNF-alpha and beta); nerve Growth Factor (NGF); growth Hormone Releasing Factor (GHRF); epidermal Growth Factor (EGF); fibroblast Growth Factor Homologous Factor (FGFHF); hepatocyte Growth Factor (HGF); insulin Growth Factor (IGF); invasion inhibitory factor-2 (IIF-2); bone morphogenetic protein 1-7(BMP 1-7); somatostatin; thymosin-alpha-1; gamma-globulin; superoxide dismutase (SOD); and complement factors.

Alternatively, the bioactive substance may be a radiosensitizer such as metoclopramide, sendamide, or neusense amide (manufactured by Oxigene); profiromycin (manufactured by Vion); RSR13 (manufactured by Allos); thymitaq (manufactured by Agouron); etanidazole or lobenguane (manufactured by nyomerd); gadolinium texaphrin (manufactured by pharmacophores); BuDR/Broxine (manufactured by Neopharma); IPdR (manufactured by Sparta); CR2412 (manufactured by Cell Therapeutic), LlX (manufactured by Terrapin), or the like.

In a particularly preferred embodiment, the biologically active substance is a therapeutic drug or prodrug, most preferably a drug selected from the following classes: chemotherapeutic agents and other antineoplastic, antibiotic, antiviral, antifungal, anti-inflammatory, and anticoagulant agents. Most preferably, the biologically active substance is paclitaxel.

The amount of biologically active substance is a therapeutically effective amount. The effective amount of biologically active substance depends on the particular material used and can be readily incorporated into the delivery system of the present invention to achieve a controlled release effect when the amount of biologically active substance is from about 1% to about 65%. For certain bioactive substances, a therapeutically effective level can be achieved with a lower dosage.

Pharmaceutically acceptable carriers can be prepared from a variety of materials. They are, for example, but not limited to, diluents, binders and adhesives, lubricants, disintegrants, colorants, fillers, flavoring agents, sweeteners, and various materials used in the preparation of particular pharmaceutical compositions, such as buffers and adsorbents.Implant and delivery system for injection

The simplest form of biodegradable therapeutic agent delivery system consists of a dispersion of the therapeutic agent in a polymer matrix. The therapeutic agent is released when the polymer matrix biodegrades in vivo to a soluble product that can be excreted from the body.

In a particularly preferred embodiment, the article is for implantation, injection or total or partial placement in the body, the article comprising the biodegradable polymer composition of the present invention. The biologically active substance and the polymer of the composition of the invention may form a homogeneous matrix or the biologically active substance may be encapsulated in the polymer in some manner. For example, the bioactive agent may be first encapsulated in the microspheres and then bound to the polymer in a manner that maintains at least a portion of the microsphere structure. Alternatively, the biologically active substance may be sufficiently immiscible in the polymer of the invention, i.e. dispersed in the polymer in the form of droplets, rather than dissolved in the polymer. Both forms are acceptable, but regardless of the homogeneity of the composition, it is preferred that the release rate of the biologically active substance in vivo is maintained at least partially controlled by hydrolysis of the phosphoester bond of the polymer during biodegradation.

In a preferred embodiment, the article of the invention is designed for implantation or injection into an animal. It is particularly important that such articles produce minimal tissue irritation when implanted or injected into vascular tissue.

As a structural medical device, the polymer composition of the present invention provides a physical form having specific chemical, physical and mechanical properties and a composition that degrades in vivo into a non-toxic residue. Typical structural medical articles include implants such as orthopedic fixation devices, ventricular shunts, laminates for degradable fabrics, drug carriers, bioerodible sutures, burn dressings, and coatings placed on other implant devices, and the like.

As an orthopedic article, the compositions of the present invention are useful for repairing bone and connective tissue injuries. For example, bone morphogenic proteins can be carried on biodegradable porous materials to form bone grafts for even large segmental defects. In vascular graft applications, biodegradable materials in the form of woven fabrics may be used to promote tissue ingrowth. The polymer composition of the invention can be used as a temporary barrier for preventing tissue adhesions, for example after abdominal surgery.

On the other hand, as a nerve regeneration article, the presence of a biodegradable support matrix aids cell adhesion and proliferation. When the polymer composition is formed into a tube for nerve generation, the tubular article may also serve as a geometric guide for axonal extension, for example, in functional recovery guidance.

As a drug delivery device, the polymer compositions of the present invention provide a polymer matrix that sequesters biologically active substances and allows for a predetermined controlled release of the substance. The polymer matrix then degrades into a non-toxic residue.

Biodegradable medical implant devices and drug delivery products can be prepared in several ways. The polymers may be melt processed using conventional extrusion or injection molding techniques, or these products may be prepared by dissolving the polymer in a suitable solvent to form a device, followed by removal of the solvent by evaporation or extraction.

Once the medical implant article is in place, it should remain at least partially in contact with biological fluids, such as blood, internal organ secretions, mucous membranes, and cerebrospinal fluid, among others.

Examples Example 1: poly (L-lactide-co-ethyl phosphate) [ poly (LAEG-EOP)]Synthesis of (2)

20g (0.139mol) of (3S) -cis-3, 6-dimethyl-1, 4-dioxane-2, 5-dione (L-lactide) (purchased from Aldrich Chemical Company, recrystallized from ethyl acetate, sublimed, and recrystallized again from ethyl acetate) and 0.432g (6.94mmol) of ethylene glycol (99.8%, anhydrous, purchased from Aldrich) were placed in a 250ml round bottom flask filled with dry argon. The flask was sealed under vacuum and placed in an oven heated to 140 ℃. The flask was held at this temperature for about 48 hours with intermittent shaking.

The flask was then filled with dry argon and placed in an oil bath heated to 135 ℃. Under a stream of argon and with stirring, 1.13g of ethyl dichlorophosphate was added. After stirring for 1 hour, a lower vacuum (about 20mmHg) was applied to the system and allowed to stand overnight. 1 hour before the post-treatment, a high vacuum was applied. After cooling, the polymer was dissolved in 200ml chloroform and quenched twice in one liter of ether to give a near white precipitate which was dried under vacuum.

It was confirmed by NMR spectrum that the obtained polymer was exactly the desired product, poly (L-lactide-co-ethyl phosphate) [ P (LAEG-EOP)]As shown in fig. 6 and 7.Example 2: properties of P (LAEG-EOP)

P (LAEG-EOP) polymer was prepared as in example 1, where (x or y)/n is 10: 1. The resulting poly (phosphate-ester) copolymer was analyzed by GPC using polystyrene as a standard, and the resulting graph showed Mw of 33000 and Mn of 4800, as shown in FIG. 7.

In Chloroform (CH)₃Cl) was found to have a viscosity of 0.315dL/g, measured at 40 ℃. The polymer is soluble in ethyl acetate, acetone, acetonitrile, chloroform, dichloromethane, tetrahydrofuran, N-methylpyrrolidone, dimethylformamide and dimethylsulfoxide. The polymer formed a brittle film with a Tg of 51.5 ℃ as measured by DSC as shown in figures 2A and 2B.Example 3: poly (L-lactide-co-hexyl phosphate) [ poly (LAEG-HOP)]Synthesis of (2)

A second poly (L-lactide-phosphate) copolymer having the structure:prepared as described in example 1, except that hexyl dichlorophosphate ("HOP") was used in place of EOP (ethyl dichlorophosphate).Example 4: properties of P (LAEG-EOP) and P (LAEG-HOP)

The weight average molecular weight (Mw) of the phosphate-ester copolymer of example 1, P (LAEG-EOP), and the polymer of example 3, P (LAEG-HOP), was first determined by Gel Permeation Chromatography (GPC) using polystyrene as calibration standards, as shown in FIG. 1. The various samples were then exposed to room temperature air to test their storage in an unprotected ambient environment. After one month, the Mw of each polymer was determined again. The results (plotted in FIG. 5) show that the Mw of P (LAEG-EOP) decreased by about one-third after one month in an unprotected ambient environment, but the Mw of P (LAEG-HOP) was fairly stable and increased even slightly. See fig. 8.

Discs for degradation studies were made from various polymers by compression moulding at 50 ℃ and a pressure of 200 MPa. The disks were 4mm in diameter, 1.5mm in thickness and 40mg in weight. Degradation studies were performed by placing the discs in 4ml of 0.1MPBS (pH7.4) at 37 ℃. At different time points over eight days, two samples were removed, rinsed with distilled water and dried under vacuum overnight. Samples were analyzed for weight loss and molecular weight change (GPC), and the results are shown in fig. 4A, 4B, 10A, and 10B. Both polymers, P (LAEG-EOP) and P (LAEG-HOP), have good degradation curves.Example 5: in vivo biocompatibility of P (LAEG-EOP)

A100 mg polymer sheet was formed with P (LAEG-EOP) using a copolymer of lactic and glycolic acids [ "PLGA (RG 755)" ] known to be biocompatible as a reference. These wafers were inserted between the muscle layers of the right limbs of adult SPF Sprague-Dawley rats under anesthesia. The slices were removed periodically and the surrounding tissue was histopathologically analyzed by a qualified pathologist using the following scoring criteria:

scoring Level of stimulation

0 has no irritation

0-200 mild stimulation

200-400 mild stimulation

400- & 600 moderate stimulation

Greater than 600 severe stimulation

The results of the histopathological analysis are shown in table 8.

TABLE 8

Stimulation response at the implantation site (i.m.)

Polymer and method of making same	Day 3	Day 7	Day 14	1 month	2 months old	3 months old
							P(LAEG-EOP)	130	123	180	198	106	99
PLGA(RG755)	148	98	137	105	94	43

Referring to fig. 12, the phosphate copolymer P (LAEG-EOP) showed acceptable biocompatibility similar to the PLGA reference flake.Example 6: preparation of microspheres

Microspheres were prepared from P (LAEG-EOP) by solvent evaporation (double emulsion) using dichloromethane as solvent. The results are shown in FIG. 3.Example 7: preparation of copolymer microspheres containing FITC-BSA at 10% of theoretical Loading level

100ml of FITC-BSA solution (100mg/ml in water) was added to 100mg of P (LAEG-EOP) in 1ml of dichloromethane and sonicated on ice for 15 seconds. The resulting emulsion was immediately poured into 5ml of vortexed 1% polyvinyl alcohol (PVA) in 5% sodium chloride solution and vortexing was continued for 1 minute. The emulsion formed was then poured into 20ml of 0.3% PVA in 5% sodium chloride solution, with vigorous stirring. 25ml of 2% isopropanol solution was added and the mixture was kept under stirring for 1 hour to ensure complete extraction. The resulting microspheres were collected by centrifugation at 3000Xg, washed 3 times with water and lyophilized.

Microspheres of different formulations were prepared by using 5% sodium chloride solution or 5% sodium chloride solution containing 1% PEG 8000 as the second aqueous phase. The solvent may be evaporated by another technique, i.e., by stirring the mixture overnight, such that microspheres are formed by solvent evaporation.Example 8: evaluation of encapsulation efficiency and load level

The loading level of FITC-BSA was determined by analyzing FITC after hydrolysis of the microspheres with 0.5N sodium hydroxide overnight. The amount of FITC-BSA was compared to a standard curve generated using a series of FITC-BSA in 0.5N sodium hydroxide solutions. Encapsulation efficiency of the microspheres was determined by fluorometric comparison of the amount of FITC-BSA entrapped with the initial amount in solution. The encapsulation efficiency (%) and loading level (%) of FITC-BSA are shown in Table 1 below.

TABLE 1

Encapsulation efficiency and Loading level of FITC-BSA

Carrier (%)	High load (24.98%)	Low load (1.5%)
			Encapsulation efficiency (%)	98.10	91.70

Example 9: cytotoxicity of the copolymers

Microspheres containing P (LAEG-EOP) were added to 96-well tissue culture plates at different concentrations. Human gastric cancer cells (GT3TKB) were then seeded at a density of 104 cells/well. The cells were then incubated with the microspheres at 37 ℃ for 48 hours. The cell proliferation rate was analyzed by MTT assay and the results are plotted as% relative growth versus concentration of copolymer microspheres in the tissue culture wells, as shown in fig. 9.Example 10: effect of manufacturing Process on Release of FITC-BSA from microspheres

50mg of the polymeric microspheres of the invention were suspended in a vial containing 10ml of PBS and the vial was shaken at 220rpm in an incubator at 37 ℃. The supernatants were removed at different time points and analyzed for release by spectrophotometry at 492nmThe amount of FITC-BSA placed. The results are plotted as% cumulative release of FITC-BSA from the microspheres versus time in hours, as shown in FIG. 13.Example 11: preparation of P (LAEG-EOP) microspheres containing lidocaine by using polyvinyl alcohol as non-solvent phase

A solution of 0.5% w/v polyvinyl alcohol (PVA) in deionized water was prepared by mixing 1.05g of PVA with 210ml of deionized water in a 600ml beaker. The solution was stirred for 1 hour and then filtered. The polymer/drug solution was prepared by vortex mixing 630mg of polymer and 70mg of lidocaine in 7ml of methylene chloride. The PVA solution was mixed with an overhead mixer at 500rpm and the polymer/drug solution was added dropwise. After mixing for 30 minutes, 200ml of cold deionized water was added to the stirred PVA solution. The resulting mixture was stirred for a total of 3.5 hours. The formed microspheres were filtered off, washed with deionized water and lyophilized overnight.

Microspheres loaded with 4.2% w/w lidocaine were thus obtained. Approximately 10mg of microspheres were placed in 37 ℃ phosphate buffered saline (0.1M, pH7.4) on a shaker and sampled regularly. Results are plotted as% lidocaine released versus time in days, as shown in fig. 16.Example 12: preparation of P (DAEG-EOP)

A d, 1-racemic mixture of poly (L-lactide-co-ethyl phosphate) copolymer [ "P (DAEG-EOP) ]was prepared in the same manner as described in example 1 for P (LAEG-EOP)"]。Example 13: preparation of P (DAEG-EOP) microspheres containing lidocaine by using silicone oil as non-solvent phase

A silicone oil solution of 2% sorbitan trioleate (commercially available from Aldrich under the trade name Span-85) was prepared in a 400ml beaker by mixing 3ml of Span-85 and 150ml of silicone oil with an overhead stirrer at 500 rpm. A P (DAEG-EOP) polymer/drug solution was prepared by dissolving 400mg of the polymer prepared in example 9 and 100mg of lidocaine in 4.5ml of methylene chloride. The resulting polymer/drug solution was added dropwise to the silicone oil/Span mixture with stirring. The mixture was stirred for 1 hour 15 minutes. The microspheres thus formed were filtered off, washed with petroleum ether to remove the silicone oil/Span mixture and then lyophilized overnight.

450mg of microspheres loaded with 7.6% w/w lidocaine were thus obtained. Approximately 10mg of microspheres were placed in 37 ℃ phosphate buffered saline (0.1M, pH7.4) on a shaker and sampled regularly. Results are plotted as% lidocaine released versus time in days, as shown in fig. 17.Example 14: biocompatibility of polyphosphate microspheres in mouse peritoneal cavity

The biocompatibility of the biodegradable polyphosphate microspheres of the present invention was tested as follows: three 30mg/ml samples of lyophilized poly (L-lactide-co-ethyl phosphate) microspheres were prepared, the first having a diameter greater than 75 microns, the second having a diameter between 75 and 125 microns, and the third having a diameter between 125 and 250 microns. Each sample was injected intraperitoneally into female CD-1 mice, 18 per group, with an initial body weight of 25 g. Animals in each group were weighed, sacrificed and necropsied on days 2, 7 and 14 and at 1, 2 and 3 months. Any lesions observed at necropsy were graded on a scale of 0-4, with 0 indicating no response to treatment and 4 indicating severe response to treatment.

The inflammatory lesions observed were limited to microspheres on the peritoneal surface or within the adipose tissue and were compatible with foreign body isolation and encapsulation. Lesions of mesothelial hyperplasia were observed on days 2-7 to multifocal supportive peritoneal steatitis, but this inflammation gradually subsided after sacrifice with infiltration of macrophages, formation of inflammatory giant cells and fibrous encapsulation of microspheres. The microspheres had intermittent adhesion to the liver and diaphragm and a concomitant inflammatory response was observed. In abdominal or thoracic organs, no microsphere-related damage was observed. Microspheres tested during the study were transparent at the beginning of sacrifice and at the later stages crystalline material was produced internally. No effect on the growth of the organism is observed. The peritoneal reaction observed was limited to the area immediately adjacent to the microspheres, but had no significant deleterious effect on major organs in the chest or abdomen.

It will be obvious that the invention described herein may be varied in a plurality of ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention, and it is intended that the scope of the appended claims be interpreted as including all such modifications.

Claims (145)

1. A biodegradable polymer comprising repeating monomer units represented by formula I or II:wherein:

x is-O-or-NR '-, wherein R' is H or alkyl;

M₁and M₂Each independently is (1) a branched or straight chain aliphatic group of 1 to 20 carbon atoms; or

(2) A branched or straight chain oxy-, carboxy-or amino-aliphatic group of 1 to 20 carbon atoms;

y is-O-, -S-or-NR' -;

l is a branched or straight chain aliphatic group of 1 to 20 carbon atoms;

r is H, alkyl, alkoxy, aryl, aryloxy, heterocyclyl or heterocycloxy;

the molar ratio of x to y is about 1;

the molar ratio of n to (x or y) is about 200: 1-1: 200; and is

The molar ratio of q to r is about 1: 99-99: 1; wherein the biodegradable polymer is biocompatible prior to and upon biodegradation.

2. The polymer of claim 1, wherein M is₁And each L is a branched or straight chain alkylene group.

3. The polymer of claim 1, wherein M is₁And each L has 1 to 7 carbon atoms.

4. The polymer of claim 1, wherein M is₁Is ethylene or methyl-substituted methylene, and L is ethylene.

5. The polymer of claim 1, wherein R is alkyl, alkoxy, phenyl, phenoxy, or heterocycloxy.

6. The polymer of claim 1, wherein R is an alkoxy group having 1 to 7 carbon atoms.

7. The polymer of claim 1, wherein R is ethoxy.

8. The polymer of claim 1, wherein M is₁And M₂Each is a branched or straight chain alkylene group.

9. The polymer of claim 1, wherein M is₁And M₂At least one is an alkylene group selected from the group consisting ofAlkylene oxide groups: - (CH)₂)_a-、-(CH₂)_a-O-and- (CH)₂)_a-O-(CH₂) b-, wherein a and b are each 1-7.

10. The polymer of claim 1, wherein M is₁And M₂Has the formula: -CHR₂-CO-O-CHR₃-, wherein R²And R³Each independently is H, alkyl, alkoxy, aryl, aryloxy, heterocyclyl or heterocycloxy.

11. The polymer of claim 1, wherein M is₁And M₂Each having 1 to 7 carbon atoms.

12. The polymer of claim 1, wherein X is-O-.

13. The polymer of claim 1 wherein X is-NR' -.

14. The polymer of claim 1, wherein:

M₁and M₂Each is alkylene or alkyleneoxy;

l is an alkylene group;

x is-O-; and is

R is an alkoxy group.

15. The polymer of claim 1, wherein the molar ratio of n to (x or y) y is from about 50: 1 to about 1: 50.

16. The polymer of claim 1 wherein the molar ratio of q: r is from about 1: 99 to about 99: 1.

17. The polymer of claim 1 wherein x and y are each from about 1 to about 1000.

18. The polymer of claim 1, wherein the molar ratio of n to (x or y) is from about 100: 1 to about 1: 100.

19. The polymer of claim 1, wherein the polymer is prepared by melt polymerization.

20. The polymer of claim 1, wherein the polymer comprises additional biocompatible monomeric units.

21. The polymer of claim 1, wherein the polymer is soluble in at least one solvent selected from the group consisting of: acetone, dichloromethane, chloroform, ethyl acetate, dimethylacetamide, N-methylpyrrolidone, dimethylformamide, and dimethylsulfoxide.

22. A method of making a biodegradable polymer comprising repeating monomer units of formula I or II:wherein:

x is-O-or-NR' -, wherein R is H or alkyl;

M₁and M₂Each independently is (1) a branched or straight chain aliphatic group of 1 to 20 carbon atoms; or

(2) A branched or straight chain oxy-, carboxy-or amino-aliphatic group of 1 to 20 carbon atoms;

y is-O-, -S-or-NR' -;

l is a branched or straight chain aliphatic group of 1 to 20 carbon atoms;

r is H, alkyl, alkoxy, aryl, aryloxy, heterocyclyl or heterocycloxy;

the molar ratio of x to y is about 1;

the molar ratio of n to (x or y) is about 200: 1-1: 200; and is

The molar ratio of q to r is about 1: 99-99: 1; wherein the biodegradable polymer is biocompatible prior to and upon biodegradation; the method comprises the following steps:

(a) reacting at least one heterocyclic compound of formula III, IV or V:wherein M is₁、M₂And X is as defined above, with an initiator of the formula:

H-Y-L-Y-H wherein Y and L are as defined above, to form a prepolymer of the formula VI or VII:x, M therein₁、M₂Y, L, R, x, Y, q and R are as defined above; and (b) further reacting the prepolymers VI and VII of formula III, IV or V above with a dihalophosphate of formula VIII:wherein "halo" is Br, Cl or I; and R is as defined above, to form the polymer of formula I or II above.

23. The method of claim 22, wherein M₁And each L is a branched or straight chain alkylene group having 1 to 7 carbon atoms.

24. The method of claim 22, wherein M₁Is ethylene or methyl-substituted methylene, and L is ethylene.

25. The method of claim 22, wherein R is an alkoxy group having 1 to 7 carbon atoms.

26. The method of claim 22, wherein R is ethoxy.

27. The method of claim 22, wherein M₁And M₂Each is a branched or straight chain alkylene group.

28. The method of claim 22, wherein M₁And M₂Is an alkylene or alkyleneoxy group selected from the group consisting of: - (CH)₂)_a-、-(CH₂)_a-O-and- (CH)₂)_a-O-(CH₂)_b-, where a and b are each 1 to 7.

29. The method of claim 22, wherein M₁And M₂Has the formula: -CHR²-CO-O-CHR³Wherein R is²And R³Each I is independently H, alkyl, alkoxy, aryl, aryloxy, heterocyclyl or heterocycloxy.

30. The method of claim 22, wherein M₁And M₂Each having 1 to 7 carbon atoms.

31. The method of claim 22, wherein X is-O-.

32. The method of claim 22, wherein X is-NR' -.

33. The method of claim 22, wherein:

M₁and M₂Each is alkylene or alkyleneoxy;

l is an alkylene group;

x is-O-; and is

R is an alkoxy group.

34. The method of claim 22, wherein the molar ratio of x to y is about 1.

35. The method of claim 22, wherein the molar ratio of q: r is from about 1: 99 to about 99: 1.

36. The method of claim 22, wherein the molar ratio of n to (x and y) is from about 50: 1 to about 1: 50, respectively.

37. The method of claim 22, wherein the molar ratio of n to (x or y) is from about 100: 1 to about 1: 100.

38. The process of claim 22, wherein the reacting step (a) is carried out at a temperature of 0 to +235 ℃.

39. The process of claim 22, wherein said reacting step (a) is completed in a time period of 1 hour to 7 days.

40. The process of claim 22 wherein in said initiator L is substituted with one or more additional Y-H-containing substituents wherein Y is as defined above.

41. The process of claim 22 wherein a catalyst is present in said reacting step (a).

42. The process of claim 22 wherein an acid acceptor is present during the polymerization step (b).

43. The process of claim 22, wherein the polymerization step (b) is carried out at a temperature of-40 to 150 ℃.

44. The process of claim 22, wherein said polymerization step (b) is completed in 30 minutes to 24 hours.

45. The method of claim 22, wherein the polymer of formula I or II is purified by impregnating a solution of the polymer with a non-solvent or partially dissolved solvent.

46. A bioerodible suture comprising the polymer of claim 1.

47. An orthotic device, bone cement or bone wax for repairing bone and connective tissue damage comprising the polymer of claim 1.

48. A laminate for degradable or non-degradable fabrics comprising the polymer of claim 1.

49. An outer film for an implantable article comprising the polymer of claim 1.

50. A biodegradable polymer composition comprising:

(a) at least one biologically active substance and

(b) a polymer having repeating monomer units represented by formula I or II:wherein:

x is-O-or-NR '-, wherein R' is H or alkyl;

M₁and M₂Each independently is (1) a branched or straight chain aliphatic group of 1 to 20 carbon atoms; or

(2) A branched or straight chain oxy-, carboxy-or amino-aliphatic group of 1 to 20 carbon atoms;

y is-O-, -S-or-NR' -;

l is a branched or straight chain aliphatic group of 1 to 20 carbon atoms;

r is H, alkyl, alkoxy, aryl, aryloxy, heterocyclyl or heterocycloxy;

the molar ratio of x to y is about 1;

the molar ratio of n to (x or y) is about 200: 1-1: 200; and is

The molar ratio of q to r is about 1: 99-99: 1; wherein the biodegradable polymer is biocompatible prior to and upon biodegradation.

51. The polymer composition of claim 50, wherein M₁And each L is a branched or straight chain alkylene group.

52. The polymer composition of claim 50, wherein M₁Is ethylene or methyl-substituted methylene, and L is ethylene.

53. The polymer composition of claim 50, wherein R is alkyl, alkoxy, phenyl, phenoxy, or heterocycloxy.

54. The polymer composition of claim 50, wherein R is alkoxy.

55. The polymer composition of claim 50, wherein M₁And M₂Each is a branched or straight chain alkylene group.

56. The polymer composition of claim 50, wherein M₁And M₂Is an alkylene or alkyleneoxy group selected from the group consisting of: - (CH)₂)_a-、-(CH₂)_a-O-and- (CH)₂)_a-O-(CH₂)_b-, where a and b are each 1 to 7.

57. The polymer composition of claim 50, wherein M₁And M₂Has the formula: -CHR²-CO-O-CHR³Wherein R is²And R³Each independently is H, alkyl, alkoxy, aryl, aryloxy, heterocyclyl or heterocycloxy.

58. The polymer composition of claim 50, wherein M₁And M₂Each having 1 to 7 carbon atoms.

59. The polymer composition of claim 50, wherein X is-O-.

60. The polymer composition of claim 50, wherein X is-NR' -.

61. The polymer composition of claim 50, wherein:

M₁and M₂Each is alkylene or alkyleneoxy;

l is an alkylene group;

x is-O-; and is

R is an alkoxy group.

62. The polymer composition of claim 50, wherein the molar ratio of n to (x and y) is from about 50: 1 to about 1: 50.

63. The polymer composition of claim 50, wherein the molar ratio of q: r is from about 1: 99 to about 99: 1.

64. The polymer composition of claim 50, wherein x and y are each about 1 to 1000.

65. The polymer composition of claim 50, wherein the molar ratio of n to (x or y) is from about 100: 1 to about 1: 100.

66. The polymer composition of claim 50, wherein the polymer is prepared by melt polymerization.

67. The polymer composition of claim 50, wherein the polymer comprises additional biocompatible monomeric units.

68. The polymer composition of claim 50, wherein the polymer is soluble in at least one solvent selected from the group consisting of: acetone, dichloromethane, chloroform, ethyl acetate, dimethylacetamide, N-methylpyrrolidone, dimethylformamide, and dimethylsulfoxide.

69. The polymer composition of claim 50 wherein said biologically active substance is selected from the group consisting of polysaccharides, growth factors, hormones, anti-angiogenic factors, interferons or cytokines, and prodrugs of such substances.

70. The polymer composition of claim 50 wherein said biologically active substance is a therapeutic drug or prodrug.

71. The polymer composition of claim 70 wherein said drug is selected from the group consisting of antineoplastic agents, antibiotics, antiviral agents, antifungal agents, anti-inflammatory agents, and anticoagulant agents.

72. The polymer composition of claim 71, wherein said antineoplastic agent is paclitaxel.

73. The polymer composition of claim 50, wherein the biologically active substance and the polymer form a homogeneous matrix.

74. The polymer composition of claim 50, wherein the polymer is characterized by a rate of release of the biologically active substance in vivo that is at least partially controlled by hydrolysis of a phosphoester bond of the polymer during biodegradation.

75. An article for implantation, injection or full or partial deployment in the body, said article comprising a biodegradable polymer composition comprising:

(a) at least one biologically active substance and

(b) a polymer having repeating monomer units represented by formula I or II:wherein:

x is-O-or-NR '-, wherein R' is H or alkyl;

M₁and M₂Each independently is (1) a branched or straight chain aliphatic group of 1 to 20 carbon atoms; or

(2) A branched or straight chain oxy-, carboxy-or amino-aliphatic group of 1 to 20 carbon atoms;

y is-O-, -S-or-NR' -;

l is a branched or straight chain aliphatic group of 1 to 20 carbon atoms;

r is H, alkyl, alkoxy, aryl, aryloxy, heterocyclyl or heterocycloxy;

the molar ratio of x to y is about 1;

the molar ratio of n to (x or y) is about 200: 1-1: 200; and is

The molar ratio of q to r is about 1: 99-99: 1; wherein the biodegradable polymer is biocompatible prior to and upon biodegradation.

76. The article of claim 75, wherein M is₁And each L is a branched or straight chain alkylene group.

77. The article of claim 75, wherein M is₁And each L has 1 to 7 carbon atoms.

78. The article of claim 75 wherein R is alkyl, alkoxy, phenyl, phenoxy, or heterocycloxy.

79. The article of claim 75, wherein R is alkoxy.

80. The article of claim 75, wherein M is₁And M₂Each is a branched or straight chain alkylene group.

81. The article of claim 75, wherein M is₁And M₂Is an alkylene or alkyleneoxy group selected from the group consisting of: - (CH)₂)_a-、-(CH₂)_a-O-and- (CH)₂)_a-O-(CH₂)_b-, where a and b are each 1 to 7.

82. The article of claim 75, wherein M is₁And M₂Has the formula: -CHR²-CO-O-CHR³Wherein R is₂And R₃Each independently is H, alkyl, alkoxy, aryl, aryloxy, heterocyclyl or heterocycloxy.

83. The article of claim 75, wherein M is₁And M₂Each having 1 to 7 carbon atoms.

84. The article of claim 75, wherein X is-O-.

85. The article of claim 75 wherein X is-NR' -.

86. The article of claim 75 wherein:

M₁and M₂Each is alkylene or alkyleneoxy;

l is an alkylene group;

x is-O-; and is

R is an alkoxy group.

87. The article of claim 75, wherein the molar ratio of n to (x and y) is from about 50: 1 to about 1: 50.

88. The article of claim 75, wherein the molar ratio of q: r is from about 1: 99 to about 99: 1.

89. The article of claim 75 wherein x and y are each about 1 to 1000.

90. The article of claim 75, wherein the molar ratio of n to (x or y) is from about 100: 1 to about 1: 100.

91. The article of claim 75 wherein said polymer is prepared by melt polymerization.

92. The article of claim 75 wherein said polymer comprises additional biocompatible monomeric units.

93. The article of claim 75 wherein said polymer is soluble in at least one solvent selected from the group consisting of: acetone, dichloromethane, chloroform, ethyl acetate, dimethylacetamide, N-methylpyrrolidone, dimethylformamide, and dimethylsulfoxide.

94. The article of claim 75 wherein said biologically active substance is selected from the group consisting of polysaccharides, growth factors, hormones, anti-angiogenic factors, interferons or cytokines, and prodrugs of such substances.

95. The article of manufacture of claim 75 wherein said biologically active substance is a therapeutic drug or prodrug.

96. The article of manufacture of claim 75 wherein said biologically active substance is selected from the group consisting of antineoplastic, antibiotic, antiviral, antifungal, anti-inflammatory, and anticoagulant agents, and prodrugs of such agents.

97. The article of manufacture of claim 96, wherein said anti-neoplastic agent is paclitaxel.

98. The article of claim 75 wherein said biologically active substance and said polymer form a homogeneous matrix.

99. The article of claim 75 wherein said biologically active substance is encapsulated in said polymer.

100. The article of claim 75 wherein said polymer is characterized by a rate of release of the biologically active substance in vivo which is at least partially controlled by hydrolysis of the phosphoester bond of the polymer during biodegradation.

101. The article of claim 75 wherein the article is suitable for implantation or injection into an animal.

102. The article of claim 75 wherein said article is a microsphere.

103. The article of claim 75 wherein said article produces minimal tissue irritation when implanted or injected into vascular tissue.

104. The article of claim 75, wherein the article is in the form of a laminate for a degradable fabric.

105. The article of claim 75, wherein the article is in the form of a bioerodible suture, a material for repairing bone damage, or an outer membrane of an implant device.

106. A method for controlled release of a biologically active substance, the method comprising the steps of:

(a) mixing a biologically active substance with a biodegradable polymer having repeating monomer units represented by formula I or II to form a mixture:wherein:

x is-O-or-NR '-, wherein R' is H or alkyl;

M₁and M₂Each independently is (1) a branched or straight chain aliphatic group of 1 to 20 carbon atoms; or

(2) A branched or straight chain oxy-, carboxy-or amino-aliphatic group of 1 to 20 carbon atoms;

y is-O-, -S-or-NR' -;

l is a branched or straight chain aliphatic group of 1 to 20 carbon atoms;

r is H, alkyl, alkoxy, aryl, aryloxy, heterocyclyl or heterocycloxy;

the molar ratio of x to y is about 1;

the molar ratio of n to (x or y) is about 200: 1-1: 200; and is

The molar ratio of q to r is about 1: 99-99: 1; wherein the biodegradable polymer is biocompatible prior to and upon biodegradation;

(b) forming the mixture into a shaped solid article or microsphere; and

(c) implanting or injecting the solid article or microsphere in vivo at a preselected site such that the implanted or injected solid matrix is in at least partial contact with the biological fluid.

107. The method of claim 106, wherein R and L are each a branched or straight chain alkylene.

108. The method of claim 106, wherein R' is alkoxy.

109. The method of claim 106, wherein M₁And M₂Each is a branched or straight chain alkylene group.

110. The method of claim 106, wherein M₁And M₂Is an alkylene or alkyleneoxy group selected from the group consisting of: - (CH)₂)_a-、-(CH₂)_a-O-and- (CH)₂)_a-O-(CH₂)_b-, where a and b are each 1 to 7.

111. The method of claim 106, wherein M₁And M₂Has the formula: -CHR²-CO-O-CHR³-, wherein R²And R³Each independently is H, alkyl, alkoxy, aryl, aryloxy, heterocyclyl or heterocycloxy.

112. The method of claim 106, wherein M₁And M₂Each having 1 to 7 carbon atoms.

113. The method of claim 106, wherein X is-O-.

114. The method of claim 106, wherein X is-NR' -.

115. The method of claim 106, wherein:

M₁and M₂Each is alkylene or alkyleneoxy;

l is an alkylene group;

x is-O-; and is

R is an alkoxy group.

116. The method of claim 106, wherein the molar ratio of n to (x and y) is from about 50: 1 to about 1: 50.

117. The method of claim 106, wherein the molar ratio of q: r is from about 1: 99 to about 99: 1.

118. The method of claim 106, wherein x and y are each about 1 to 1000.

119. The method of claim 106, wherein the molar ratio of n to (x or y) is from about 100: 1 to about 1: 100.

120. The method of claim 106, wherein the polymer comprises additional biocompatible monomeric units.

121. The method of claim 106 wherein said biologically active substance is selected from the group consisting of polysaccharides, growth factors, hormones, anti-angiogenic and other anti-neoplastic agents, interferons or cytokines, and prodrugs of such substances.

122. The method of claim 121 wherein the anti-neoplastic agent is paclitaxel.

123. The method of claim 106, wherein the biologically active substance is a therapeutic drug or prodrug.

124. The method of claim 106, wherein said drug is selected from the group consisting of chemotherapeutic agents, antibiotics, antivirals, antifungals, anti-inflammatories, and anticoagulants.

125. The method of claim 106, wherein the biologically active substance and the polymer form a homogeneous matrix.

126. The method of claim 106, further comprising encapsulating the bioactive agent within the polymer.

127. The method of claim 106, wherein the polymer is characterized by a release rate of the biologically active substance in vivo that is at least partially controlled due to hydrolysis of the phosphoester bond of the polymer during biodegradation.

128. The method of claim 106, wherein said article is non-toxic and produces minimal tissue irritation when implanted or injected into vascular tissue.

129. The method of claim 106, wherein the article is in the form of microspheres.

130. The method of claim 106, wherein the article is in the form of a laminate for a degradable fabric.

131. The method of claim 106, wherein the polymer composition is used as an outer membrane of an implant.

132. The method of claim 106, wherein the polymer composition is used as a barrier to prevent adhesions.

133. The method of claim 106, wherein the polymer composition is formed into a tube for nerve generation.

134. A polymer composition comprising a biodegradable polymer comprising repeating monomer units represented by the formula:wherein:

R₄is H or a branched or straight chain aliphatic group having 1 to 7 carbon atoms;

R₅is alkoxy or alkyl;

l is a branched or straight chain aliphatic group of 1 to 7 carbon atoms;

the molar ratio of x to y is about 1; and

the molar ratio of n to (x or y) is about 200: 1-1: 200;

wherein the biodegradable polymer is biocompatible prior to and upon biodegradation.

135. The polymer composition of claim 134, wherein R₄Is methyl.

136. The polymer composition of claim 134, wherein R₅is-OCH₂CH₃。

137. The polymer composition of claim 134, wherein R₄Is methyl and R₅is-OCH₂CH₃。

138. The polymer composition of claim 135 wherein each occurrence of a methyl-substituted tertiary carbon atom can be in the D or L configuration.

139. The polymer composition of claim 134, wherein the repeating monomer unit has the structure of formula:

140. the polymer composition of claim 134 or 139, further comprising a biologically active substance.

141. The polymer composition of claim 140, wherein the biologically active substance is an anti-neoplastic agent.

142. The polymer composition of claim 141, wherein the neoplastic agent is panitudinir.

143. The polymer composition of claim 140, wherein the biologically active substance is a local anesthetic.

144. The polymer composition of claim 143, wherein the local anesthetic is lidocaine.

145. The polymer composition of claim 140, wherein the biologically active substance is a radio-synergist.