MXPA01003418A - Biodegradable terephthalate polyester-poly(phosphonate) and polyester-poly(phosphite) compositions, articles, and methods of using them - Google Patents

Abstract

The invention comprises biodegradable terephthalate polymers comprising the recurring monomeric units shown in formula (I), wherein R is a divalent organic moiety;R'is hydrogen, an aliphatic, aromatic or heterocyclic residue;x is=1;and n is 3-7,500, where the biodegradable polymer is sufficiently pure to be biocompatible and is capable of forming biocompatible residues upon biodegradation. Medical and drug delivery devices comprising the polymers and a biologically active substance, articles useful for implantation or injection into the body, fabricated using the polymers, and methods for controlled release of biologically active substances using the polymers, are also described.

Description

BIODEGRADABLE COMPOSITIONS OF PO IESTER TEREFTALATE- POLKPHOSPHONATE) AND POLYESTER-POLYPHOSPHITE). ARTICLES AND METHODS FOR USING THEM BACKGROUND OF THE INVENTION FIELD OF THE INVENTION The invention relates to biodegradable compositions of block homopolymers and copolymers, in particular those containing phosphite and terephthalate ester linkages, or both phosphonate and terephthalate ester linkages in the polymer base structure, which is degraded in vivo in waste. non-toxic The copolymers of the invention are particularly useful as implantable medical devices, essentially non-osteoconductive, non-porous, and as drug delivery systems.

DESCRIPTION OF THE RELATED TECHNIQUE Biocompatible polymeric materials have been used extensively in therapeutic drug delivery applications and medical implant devices. Sometimes, it is also desirable that such polymers be not only biocompatible, but also biodegradable to eliminate the need to remove the polymer once its therapeutic value has been exhausted. Conventional methods for drug delivery, such as frequent periodic dosing, are not ideal in many cases. For example, with highly toxic drugs, frequent conventional dosing may result in high initial drug levels at the time of dosing, often near toxic levels, followed by low drug levels between doses that may be below the level of the drug. therapeutic value. However, with controlled drug delivery, drug levels can be more easily maintained at therapeutic, but non-toxic levels, by controlled release in a predictable manner over a long term. If a biodegradable medical device is designed to be used as a drug delivery system or other controlled release system, the use of a polymeric carrier is an effective means to deliver the therapeutic agent locally and in a controlled manner, see Langer et, " Chemical and Physical Structures of Polymers as Carriers for Controlled Relay of Bioactive Agents ", J. Macro. Science, Rev. Macro. Chem. Phyes., C23: 1 61-126 (1983). As a result, less total drug is required, and toxic side effects can be minimized. The polymers have been used as carriers of therapeutic agents to effect a localized and sustained release. See Leong et al., "Polymeric Controlled Drug Delivery", Advanced Drug Delivery Reviews, 1: 199-233 (1987) and Langer; "New Methods of Drug Delivery", Science, 249: 1527-33 (1990); and Chien et al., Novel Drug Delivery Systems (1982). Such delivery systems offer the potential for improved therapeutic efficacy and reduced total toxicity. For a non-biodegradable matrix, the steps leading to the release of the therapeutic agent are diffusion of water into the matrix, dissolution of the therapeutic agent, and diffusion of the therapeutic agent out through the channels of the matrix. As a consequence, the mean residence time of the therapeutic agent leaving in the soluble state is longer for a non-biodegradable matrix than for a biodegradable matrix, for which the passage through the matrix channels, although it may occur, is no longer is required. Because many pharmacists have short average lifetimes, the therapeutic agents can decompose or become inactive within the non-biodegradable matrix before they are released. This problem is particularly significant for many smaller biomacromolecules and polypeptides, because those molecules are generally hydrolytically unstable and have low permeability through a polymer matrix. In fact, in a non-biodegradable matrix, many biomacromolecules aggregate and precipitate, blocking the necessary channels for diffusion outside the carrier matrix. These problems are solved using a biodegradable matrix that, in addition to some diffusion release, also allows the controlled release of the therapeutic agent by degradation of the polymer matrix. The use of a biodegradable polymer matrix also eliminates the need for the polymer to form a highly porous material because the release of the therapeutic agent is no longer conditioned solely by diffusion through the pores of the polymer matrix. Examples of classes of synthetic polymers that have been studied as possible biodegradable materials include polyesters (Pitt et al., "Biodegradable Drug Delivery Systems Based on Alipathic Polyesters: Application to Contraceptives and Narcotic Antagonists," Controlled Relase of Bioactive Materials, 19-44 ( Richard Baker ed., 1980); poly (amino acids) and pseudo-poly (amino acids) (Pulapura et al., "Trends in the Development of Bioresorbable Polymers for Medical Applications," J. of Biomaterials Appl. 6: 1, 216-60 (1992); polyurethanes (Bruin et al., "Biodegradable Lysine Diisocyanate-based Poly- (Glycolide-co-e Caprolactone) -Uretahane Network in Artificial Skin," Biomaterials, 11: 4, 291-95 (1990); polyorthoesters (Heller et al. ., "Reread of Norethindrone from Poly (Ortho Esters)," Polymer Enginnerring Sci., 21: 11, 727-31 (1981), and polyanhydrides (Leong et al., "Polyanhydrides for Controlled Relays of Bioactive Agents," Biomaterials, 7: 5, 364-71 (1986) Specific examples of biodegradable materials that are used as medical implant materials are polylactide, polyglycolide, polydioxanone, poly (lactide-co-glycolide), poly (glycolide-co-polydioxanone), polyanhydrides. , poly (glycolide-co-trimethylene carbonate), and poly (glycolide-co-caprolactone) .The injectable polyphosphazenes, has also been n described as useful for forming biodegradable solid implants in situ. See Dunn et al, in the patents of E.U.A. Nos. 5,340,849; 5,324,519; 5,278,202 and 5,278.201. Polymers having phosphoester linkages, called poly (phosphates), poly (phosphonates) and poly (phosphites), are known. See Penczek et al, Handbook of Polymer Synthesis, Chapter 17: "Phosphorus-Containing Polymers," 1077-1132 (Hans R. Kricheldorf ed., 1992). The respective structures of each of these three classes of compounds, each having a different side chain connected to the phosphorus atom, is as follows: O O O -O- R- O -) - P- O- R- O -) - P- O- R- O -) - O- R 'R' H Polyphosphate Polyphosphonate Polyphosphite Phosphorus adds versatility to polymers by allowing a multiplicity of reactions. The phosphorus binding can involve the 3p orbits or several 3s-3p hybrids; Spd hybrids are also possible due to accessible orbits. In this way, the physicochemical properties of the poly (phosphoesters) can be easily changed by varying either the R or R group. The biodegradability of the polymer is mainly due to the physiologically unstable phosphoester bond in the polymer base structure. By manipulating the base structure or the side chain, a broad scale of biodegradation ratios can be obtained. Kadiyala et al, Biomedical Applications of Synthetic Biodegradable Polymers, Chapter 3: "Poly (phosphoesters): Synthesis, Physicochemical Characterization and Biological Response," 33-57, 34-5 (Jeffrey O. Hollinger ed., 1995). See also the published PCT application WO 98/44021 (U.S.A. Series No. 09 / 053,648) for a discussion of poly (phosphate) terephthalate polymers useful as biodegradable materials. An additional feature of poly (phosphoesters) is the availability of functional side groups. Because phosphorus can be pentavalent, drug molecules or other biologically active substances can be chemically bound to the polymer, as well as physically dissolved in the polymer, before forming the polymer in its final form. For example, drugs with O-carboxy groups can be coupled to phosphorus through an ester linkage, which is hydrolysable. The P-O-C group in the polymer base structure also lowers the glass transition temperature of the polymer and, importantly, confers solubility in common organic solvents, which is desirable for easy characterization and processing. Kadiyala et al, on page 35. Specifically, EP 386 757 discloses the use of poly (phosphate) esters as prosthetic vehicles and the delivery of therapeutic agents, recognizing that the polymers are biodegradable due to the hydrolysable phosphoester linkage in the base structure. With phosphorus in the trivalent state, the polymers can be polyphosphates or polyphosphonates having the general formula: wherein R and R 'are organic or metallic organ portions, and n is from 10 to 105. Similarly, EP 057 116 discloses biocompatible polyphosphate esters with difunctional oligomers linked by phosphate bridge-forming structures of the general formula I: where n > 2; OL is an oligomer, preferably selected from the group comprising polyethylene terephthalate and polybutylene terephthalate; Y and Z are the two functional groups of the oligomer, such as OH; and R can be an unsubstituted or substituted alkyl, aryl or aralkyl group. These compounds are described as allowing easy adjustment of biodegradability. Poly (phosphite) esters have been known for some time. Specifically, Coover al, of the US patent. No. 3,271, 329, describes the production of polymers from dialkyl or diaryl hydrogen phosphites and certain glycolic or dihydroxy aromatic hydrocarbons. It was found that the resulting polymers of high molecular weight are highly flame resistant. Similarly, Friedman, of the U.S. patent. No. 3,422,982, describes polyphosphites of 2,2-dimethyl-3-hydroxypropyl-2-dimethyl-3-hydroxypropionate. It was found that the resulting compounds are remarkably stable towards hydrolysis, heat and light, and were therefore thought to be useful as stabilizers for other polymers. Kadiyala et al, describes the loading of a biodegradable porous material with morphogenic bone proteins to make a bone graft for defects of long segments. Kadiyala et al also discloses reacting bis (2-hydroxyethyl) terephthalate with dimethylphosphite to form the following biodegradable poly (phosphite).

The lyophilized pellets of a powder of the above polymer, abbreviated as "PPET", were implanted subcutaneously in rats to test soft tissue response and compression-molded bone connections were implanted in rabbits. No inflammatory response was observed. However, the polymer suffered rapid decomposition and structural rigidity was lost. The corresponding poly (phosphate) terephthalate materials have been described as biodegradable materials in WO 98/44021 (E.U.A. series No. 09 / 053,648, filed April 2, 1998). Login et al, in the patents of E.U.A. Nos. 4,259,222, 4,315,847 and 4,315,969, discloses a poly (phosphate) -polyester polymer having a recurring unit of halogenated terephthalate useful in flame retardant materials, but without a phosphor having a side chain. A number of other US patents describes poly (phosphothane) compounds that are useful for their flame retardant qualities, such as Ko et al, U.S. No. 5,399,654; Besecke et al, patents of E.U.A. Nos. 4,463,159 and 4,472,570; Login et al, patents of E.U.A. Us. 4,259,222, 4,315,847, and 4,315,969; Okamato et al, patents of E.U.A. Us. 4,072,658 and 4,156,663; Schmidt et al, patents of E.U.A. No. 4,328,174 and 4,374,971; and Hechenbleikner, patent of E.U.A. No. 4,082,897, or for its dirt release effects, such as Engelhardt et al, of the U.S. patent. No. 5,530,093. Certain poly (phosphonate) terephthalate compounds are described as flame retardants by Desitter et al, U.S. Pat.

No. 3,927,231; Reader, patent of E.U.A. No. 3,932,566; and Starck et al, and Canadian Patent No. 597, 473. It is described by the use of the above biodegradable poly (phosphite), poly [bis (2-ethoxy) terephthalate hydrophosphonic] (PPET), as a macroporous, biodegradable structure and suggests uses in bone graft applications. Bone implant studies are said to suggest good body tolerance of the material. However, no new bone formation was observed, possibly due to the rapid rate of degradation in vivo. Hungnan Lo, "Synthesis of Biodegradable Polymers and Porous Grafts for Orthopedic Applications" (dissertation of Ph. D. 1995, The Johns Hopkins University, Baltimore, MD). However, neither Kadiyala et al, nor describe pol (phosphites) terephthalate that do not have a pending side chain, specifically as they are particularly well suited to manufacture biodegradable drug delivery systems. In this way, a need remains for additional materials that are particularly well suited for manufacturing medical devices and biodegradable drug delivery systems.

BRIEF DESCRIPTION OF THE INVENTION Applicants have now discovered that medical or drug delivery devices can be advantageously manufactured from a composition comprising a biodegradable terephthalate copolymer comprising the recurring monomer units as shown in formula I: in R is a divalent organic portion; x is > 1; n is 3-7,500; and R 'is hydrogen, an aliphatic, aromatic, or hetercyclic residue. The compositions or devices may advantageously comprise at least one biologically active substance. Typically, the biodegradable polymer is sufficiently pure to be biocompatible and is capable of forming biocompatible residues with biodegradation. In one embodiment, the invention comprises medical devices or essentially non-osteoconductive drug delivery devices comprising the polymer described above, especially where R 'is hydrogen. Preferably, the device of the invention is non-porous and is adapted for implantation or injection into the body of an animal. In preferred embodiments of the composition or device, or any embodiment comprising the copolymer of formula I or the use of that copolymer, the variable groups can be defined more specifically. For example, R in the formula is an alkylene group, a cycloaliphatic group, a phenylene group, or comprises a divalent group having the formula: wherein Y is oxygen, nitrogen or sulfur and m is 1 to 3. Preferably, R can also be an alkylene group having from 1 to 7 carbon atoms, or an ethylene group. The R 'in the formula I can preferably be an alkyl group, a phenyl group, an alkyl group having from 1 to 7 carbon atoms, an ethyl group. The x in formula I can preferably be from 1 to 30, or from 1 to 20, or from 2 to 20. In preferred embodiments of the composition or device, or any embodiment comprising the copolymer of formula I or the use of that copolymer , the copolymer is prepared by solution polymerization or may comprise additional biocompatible monomer units. Additionally, the copolymer can be soluble in at least one of the solvents selected from the group consisting of acetone, dichloromethane, chloroform, ethyl acetate, DMAC, N-methylpyrrolidone, dimethylformamide and dimethyl sulfoxide. In embodiments of the composition or device, or any modality comprising the copolymer of formula I or the use of that copolymer, comprising a biologically active substance, the biologically active substance can preferably be selected from the group consisting of peptides, polypeptides, proteins, amino acids, polysaccharides, growth factors, hormones, anti-angiogenesis factors, interferons, or cytokines, and prodrugs of those substances. The biologically active substance can also be a therapeutic drug or prodrug, such as any anti-neoplastic agent, antibiotic, antiviral agent, antifungal agent, anti-inflammatory agent, anticoagulant, or prodrugs of those substances. In especially preferred embodiments the biologically active substance is paclitaxel. Additionally, the biologically active substance and the copolymer can form a homogeneous matrix or the biologically active substance can be capped within the copolymer. The composition, device or method for using them can also be characterized by a rate of release of the biologically active substance in vivo. The rate of release can be partially controlled by hydrolysis of the phosphoester linkage of the polymer with biodegradation. The composition, device, or method for using them can also be adapted for implantation or injection into the body of an animal. Preferably, the selected composition results in minimal tissue irritation when implanted or injected into vascular tissue. The specific modalities of the composition, device or the same to use them will use them as being able to be a bioabsorbable suture, a brace, or a bone cement bone wax to repair injuries to bones and connective tissue. Alternatively, they will use a laminated body to be used as a degradable or non-degradable fabric, or they can be manufactured as a tube for nerve regeneration. In other embodiments, the composition or device is implantable and comprises a coating comprising the polymer of formula I. The copolymer can also be used as a coating on other structures or as a barrier to prevent adhesion onto implantable or injectable compositions or devices. . In another embodiment of the invention, the composition or device comprising a polymer of formula I can be used in methods for delivering at least one biologically active substance, such as one or more of the biologically active substances noted above. By selecting the appropriate polymer or combination of polymer-biologically active substance, one or more biologically active substances can be released in a controlled manner. Thus, the invention specifically includes a method for the controlled release of at least one biologically active substance comprising the steps of: (a) combining one or more biologically active substances with a biodegradable terephthalate polymer having the monomeric units recurrent ones that are shown in formula I to form a mixture; (b) forming the mixture in a solid article, formed; and (c) implanting or injecting the solid article in vivo at a preselected site, so that the solid article, implanted or injected, is at least in partial contact with a biological fluid. All of the foregoing modalities and preferred embodiments noted above can be combined or selected for use with this method.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows a GPC chromatogram for poly (BHET-EP) as prepared in Example 2A. Figure 2 shows a GPC chromatogram for poly (BHET-EP / TC) as prepared in Example 3A.

DETAILED DESCRIPTION OF THE INVENTION Polymers of the invention As used herein, the term "aliphatic" refers to a linear, branched or cyclic alkane, alkene, or alkylene. Preferred aliphatic groups in the polymers of the invention are linear or branched alkanes having 1 to 10 carbons, preferably being linear alkane groups of 1 to 7 carbon atoms. As used herein, the term "aromatic" refers to a cyclic carbon compound not saturated with 4n + 2p electrons. As used herein, the term "heterocyclic" refers to a saturated or unsaturated ring compound having one or more atoms other than the carbon in the ring, for example, nitrogen, oxygen or sulfur. The biodegradable terephthalate copolymer composition of the invention comprises the recurring monomer units as shown in formula I: wherein R is a divalent organic moiety. R can be any divalent organic portion as long as it does not interfere with the polymerization, copolymerization, or biodegradation reactions of the copolymer. Thus, specific R can be an aliphatic group, for example, alkylene, such as ethylene, 1,2-dimethylethylene, n-propylene, isopropylene, 2-methylpropylene, 2,2-dimethylpropylene, or tert-butylene, tert-pentylene , n-hexylene, n-heptylene and the like; alkenylene, such as ethenylene, propenylene, dodecenylene and the like; alkynylene such as propynylene, hexinylene, octadecylene, and the like, an aliphatic group substituted with a non-interfering substituent, for example, an aliphatic group substituted with hydroxy, halogen or nitrogen; or a cycloaliphatic group such as cyclopentylene, 2-methylcyclopentylene, cyclohexylene, cyclohexenylene and the like. R may also be a divalent aromatic group, such as phenylene, benzylene, naphthalene, phenanthrenylene, and the like, or a divalent aromatic group substituted with a non-interfering substituent. In addition, R can also be a divalent heterocyclic group, such as pyrrolylene, furanylene, thiophenylene, alkylene-pyrrolylene-alkylene, pyridylene, pyridinylene, pyridinylene, pyrimidinylene and the like, or can be any of those substituted with a substituent that does not interfere. Preferably, however, R is an alkylene group, a cycloaliphatic group, a phenylene group, or a divalent group having the formula: wherein Y is oxygen, nitrogen, or sulfur and m is from 1 to 3. More preferably, R is an alkylene group having 1 to 7 carbon atoms and, more preferably, R is an ethylene group. R 'in the polymer of the invention is hydrogen, an aliphatic, aromatic or heterocyclic residue. When R 'is aliphatic, it is preferably: alkyl such as methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, -C 8 H 7, and the like; or alkyl substituted with a non-interfering substituent, such as halogen, alkoxy or nitro. When R 'is aromatic, it typically contains from 5 to 14 carbon atoms, preferably from 5 to 12 carbon atoms and, optionally, may contain one or more rings that are fused to one another. Examples of particularly suitable aromatic groups include phenyl, naphthyl, anthracenyl, phenanthrenyl and the like. When R 'is heterocyclic, it typically contains from 5 to 14 ring atoms, preferably from 5 to 12 ring atoms, and one or more heteroatoms. Examples of suitable heterocyclic groups include furan, thiophene, pyrrole, isopyralla, 3-pyrrolol, pyrazole, 2-isoimidazole, 1,2,3-triazole, 1,4-triazole, oxazole, thiazole, isothiazole, 1,2 , 3-oxadiazole, 1, 2,4-oxadiazole, 1,2,5-oxadizole, 1,4-oxadiazole, 1, 2,3,4-oxatriazole, 1, 2,3,5-oxatriazole, 1 , 2,3-dioxazole, 1, 2,4-dioxazole, 1,2-dioxazole, 1,4-dioxazole, 1, 2,5-oxatriazole, 1,3-oxathiola, 1,2-pyran, 1,4-pyran , 1,2-pyrone, 1,4-pyrone, 1,2-dioxin, 1,3-dioxin, pyridine, N-alkylpyridinium, pyridazine, pyrimidine, pyrazine, 1,3-triazine, 1, 2,4 -triazine, 1, 2,3-triazine, 1, 2,4-oxazine, 1,2-oxazine, 1, 3,5-oxazine, 1,4-oxazine, o-isoxazine, p-isoxazine, 1 , 2,5-oxathiazine, 1, 2,6-oxathiazine, 1,4-oxadiazine, 1, 3,5,2-oxadiazine, azepine, oxepine, tiepine, 1,2,4-diazepine, indene, isoindene , benzofuran, isobenzofuran, thionaphthene, isothionaphthene, indole, indolenine, 2-sobenzazole, 1,4-pyrindine, pyrazole- [3,4-b] -pyrrole, soindazole, indoxazine, benzoxazole, anthranyl, 1,2-benzopyran , 1, 2- benzcpirone, 1,4-benzopyrone, 2,1-benzopyrone, 2,3-benzopyrone, quinoline, - isoquinoline, 1,2-benzo-diazine, 1,3-benzodiazine, naphthyridine, pyrido- [3,4-b] -pyridine, pyrido [3,2-b] -pyridine, pyrido- [4,3-b] ] pyridine, 1,2-benzoxazine, 1, 4,2-benzoxazine, 2,3,1-bezoxazine, 3,1, 4-benzoxazine, 1,2-benzisoxazine, 1,4-benzisoxazine, carbazole , xanthrene, acridine, purine, and the like. Preferably, when R 'is heterocyclic, it is selected from the group consisting of furan, pyridine, N-alkylpyridine, 1, 2,3- and 1, 2,4-triazoles, indene, anthracene and purine. In particularly preferred embodiments, R 'is hydrogen or an alkyl group or a phenyl group and, even more preferably, an alkyl group having from 1 to 7 carbon atoms. More preferably, R 'is an ethyl group.

The value of x may vary depending on the desired solubility of the polymer, the desired Tg, the desired polymer stability, the desired stiffness of the final polymers, and the desired biodegradability and release characteristics in the polymer. However, x is usually > 1 and, typically, ranges from 1 to 40. Preferably, x is from 1 to 30, more preferably, from 1 to 20, and more preferably from 2 to 20. The most common way to control the value of x is to vary the ratio of the "x" portion in relation to the monomer. For example, the case to manufacture the polymer: by varying widely the feed ratios of the "x" reagent of dialkyl phosphite can be used with the diol reagent. The feed ratios of the reagents can easily vary from 99: 1 to 1:99, for example, 95: 5, 90:10, 85:15, 80:20, 75:25, 70:30, 65:35, 60:40, 55:45, 50:50, 45:55, 20:80, 15:85, and similar. Preferably, the feed ratio between the dialkyl phosphite reagent and the diol reagent ranges from 90:10 to 50:50; even more preferably from 85:15 to 50:50; and more preferably from 80:20 to 50:50. Similarly, in the case of polymer manufacture: By varying widely the feed ratios of the "x" dichloroethylphosphonic reagent ("EP") can be used with the terphataloyl chloride reagent ("TC"). Feeding ratios from EP to TC can easily vary from 99: 1 to 1: 99, for example, 95: 5, 90:10, 85:15, 80:20, 75:25, 70:30, 65:35 , 60:40, 55:45, 50:50, 45:55, 20:80, 15:85 and similar. Preferably, the feed ratio between the phosphonic dichloride reagent and the TC reagent ranges from 90:10 to 50:50; even more preferably, from 85:15 to 50:50; and more preferably from 80:20 to 50:50. The number n can vary greatly depending on the biodegradability and the desired release characteristics in the polymer, but typically ranges from 3 to 7,500, preferably from 5 to 5,000. More preferably, n is from 5 to 300 and more preferably from 5 to 200. The polymer of the invention may also comprise additional biocompatible monomer units so long as they do not interfere with the desired biodegradable characteristics. Said additional monomeric units can offer even greater flexibility to design the desired precise release profile for the target drug delivery or the precise rate of biodegradability desired for the structural implants. Examples of said additional biocompatible monomers include the recurring units found in polycarbonates, polyorthoesters, polyamides; polyurethanes; poly (iminocarbonates) and polyanhydrides. Biodegradable polymers differ from non-biodegradable polymers in that they can be degraded during in vivo therapy. This usually involves decomposition of the polymer in its monomeric subunits. In principle, the final hydrolytic decomposition products of a poly (phosphite) are phosphite, alcohol and diol, all of which are potentially non-toxic. The intermediate oligomeric products of hydrolysis may have different properties, but the toxicology of a biodegradable polymer designed for implant or injection, even one synthesized from seemingly harmless monomeric structures, is typically determined after one or more in vitro toxicity analyzes. The biodegradable polymer composition of the invention is preferably pure enough to be compatible with itself and remains biocompatible with biodegradation. By "biocompatible" it is meant that the biodegradation products or the polymer are non-toxic and result in only minimal tissue irritation when implanted or injected into vascular tissue. The polymer of the invention is preferably soluble in one or more common organic solvents for ease of manufacture and processing. Common organic solvents include solvents such as chloroform, dichloromethane, acetone, ethyl acetate, DMAC, N-methylpyrrolidone, dimethylformamide and dimethyl sulfoxide. The polymer is preferably in at least one of the above Solvents. The glass transition temperature (Tg) of the polymer of the invention can vary widely depending on the branching of the diols that are used to prepare the polymer, the relative proportion of the phosphorus-containing monomer used to make the polymer, and the like. However, preferably, the Tg is within the range of -10 ° C to 100 ° C and, even more preferably, between 0 and 50 ° C.

Non-osteoconductivity of the polymer The polymers of the present invention, especially where R 'in the formula I is hydrogen (poly (phosphite) polymer, are preferably non-osteoconductive.) An osteoconductive material is one that facilitates the growth of bone in an area of the body where bone growth, instead of soft tissue growth, would be expected.An osteoconductive material generally acts as a scaffold in which bone filaments grow without the formation of fibrous tissue of separation, as often happens when objects are implanted In the body, for this reason, osteoconductive materials are often porous materials having a pore diameter of at least one tenth of a millimeter (100 microns) wide to provide ease of tissue and bone growth.

One method to measure the pore size and porosity of a material is to record the volume of mercury intrusion into the material at different pressures with a Porosity Model 30K-A1 porosity meter (Porous Materials, Inc., Ithaca, NY) . The porosimeter analyzes a material to determine the properties such as the pore surface area, the total pore volume and the average pore size. The porosimeter is capable of measuring pores on the scale of 35 Angstroms to 500 microns. Pore size is an important measurement to consider when determining whether a material is osteoconductive or not. Alternatively, especially where R 'is not hydrogen, the polymer compositions and devices of the present invention may not be osteoconductive and therefore need not be porous. Preferably, they are non-porous, have pore diameters of less than 100 microns, or have only a very small number of pore diameters of more than 100 microns. In any case, the poly (phosphonate) polymers of the invention do not promote bone growth and, accordingly, do not need to provide a structure adequate to support a network of bone filaments. In this manner, the polymers of the present invention are advantageously suitable for controlled rates of biodegradation and concomitant release of biologically active materials. Synthesis of poly (terephthalate-poly (phosphite) polymers) The most common general reaction for preparing a poly (phosphite) is a condensation of a diol with a dialkyl or diaryl phosphite according to the following equation: n R- O- + 2n ROH Poly (phosphites) can also be obtained by using tetraalkyldiamides of phosphoric acid as condensation agents, according to the following equation: o O n Rj- N- P- N- R2 + n HO- R'-OH - P-O-R'-O ^ Tr + 2n R2NH H H The above polymerization reactions can be in volumetric or solution polymerization. One advantage of volumetric polycondensation is that it avoids the use of solvents and large amounts of other additives, making the purification more direct. It can also provide reasonably high molecular weight polymers. However, conditions that are somewhat stringent are often required, and can lead to chain acidolysis (or hydrolysis if water is present). Undesired, thermally induced side reactions, such as entanglement reactions, may also occur if the base structure of the polymer is susceptible to hydrogen atom abstraction or oxidation with subsequent macroradical recombination. To minimize these side reactions, the polymerization is preferably carried out in solution. Solution polycondensation requires that the diol and the phosphorus component be soluble in a common solvent. Typically, a chlorinated organic solvent, such as chloroform, dichloromethane, or dichloroethane, is used. The solution polymerization is preferably 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 the solution by precipitation with a non-solvent and purified to remove the hydrochloride salt by conventional techniques known to those skilled in the art., such as washing with an aqueous acid solution, for example, dilute HCl. Reaction times tend to be longer with solution copolymerization than with volumetric polymerization. However, because milder total reaction conditions can be used, side reactions are minimized, and more sensitive functional groups can be incorporated into the polymer. The disadvantages of solution polymerization are that obtaining high molecular weights, such as PM greater than 20,000, is less likely. The interfacial polycondensation can be used when high molecular weight polymers are desired at high reaction rates. The average conditions minimize lateral reactions. The dependence of high molecular weight on the stoichiometric equivalence between the diol and the inherent phosphite in solution methods is also eliminated. However, hydrolysis of the acid chloride can occur in the alkaline aqueous phase. Phase transfer catalysts, such as crown ethers or tertiary ammonium chloride, can be used to bring the ionized diol to the interface to facilitate the polycondensation reaction. The production and molecular weight of the resulting polymer after interfacial polycondensation are affected by the reaction time, the molar ratio of the monomers, the volume ratio of the immiscible solvents, the type of acid acceptor, and the type and concentration of the catalyst of phase transfer. The polymer of formula I, either a homopolymer or a block polymer, is isolated from the reaction mixture by conventional techniques, such as by precipitation, extraction with an immiscible solvent, evaporation, filtration, crystallization and the like. However, typically, the polymer of formula I is isolated and purified by quenching a solution of said polymer with a non-solvent or a partial solvent, such as diethyl ether or petroleum ether.

Synthesis of polyester-poly (phosphonate) polymers The most common general reaction for preparing a poly (phosphonate) is a dehydrochlorination between a phosphonic dichloride and a diol according to the following equation: O O 11 Cl- P- Cl + n HO-R-OH - (- P- O-R- ^ j- + 2n HCl 1 R H A Friedel-Crafts reaction can also be used to synthesize polyphosphonates. The polymerization is typically carried out by reacting bis (chloro-methyl) compounds with aromatic hydrocarbons or chloromethylated diphenyl ether with triaryl phosphonates. Poly (phosphonates) can also be obtained by volumetric condensation between phosphorus diimidazoles and aromatic diols, such as resorcinol and quinoline, usually under nitrogen or some other inert gas. One advantage of volumetric polycondensation is that it avoids the use of solvents and large amounts of other additives, making the purification more direct. It can also provide reasonably high molecular weight polymers. However, conditions that are somewhat stringent are often required, and can lead to chain acidolysis (or hydrolysis if water is present). Negative, thermally induced side reactions, such as entanglement reactions, can also occur if the base structure of the polymer is susceptible to hydrogen atom abstraction or oxidation with subsequent macroradical recombination. To minimize these side reactions, the polymerization is preferably carried out in solution. Solution polycondensation requires that the diol and the phosphorus component be soluble in a common solvent. Typically, a chlorinated organic solvent, such as chloroform, dichloromethane, or dichloroethane, is used. The solution polymerization is preferably 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 the solution by precipitation with a non-solvent and purified to remove the hydrochloride salt by conventional techniques known to those skilled in the art, such as washing with an aqueous acid solution, for example, dilute HCl. Reaction times tend to be longer with solution copolymerization than with volumetric polymerization. However, because milder total reaction conditions can be used, side reactions are minimized, and more sensitive functional groups can be incorporated into the polymer. The disadvantages of solution polymerization are that obtaining high molecular weights, such as PM greater than 20,000, is less likely. The interfacial pollcondensation can be used when high molecular weight polymers are desired at high reaction rates. The average conditions minimize lateral reactions. The dependence of high molecular weight on the stoichiometric equivalence between the diol and the inherent phosphite in solution methods is also eliminated. However, hydrolysis of the acid chloride can occur in the alkaline aqueous phase. Sensitive dichlorides that have some solubility in water are generally subject to hydrolysis rather than to polymerization. Phase transfer catalysts, such as crown ethers or tertiary ammonium chloride, can be used to bring the ionized diol to the interface to facilitate the polycondensation reaction. The production and molecular weight of the resulting polymer after interfacial polycondensation are affected by the reaction time, the molar ratio of the monomers, the volume ratio of the immiscible solvents, the type of acid acceptor, and the type and concentration of the catalyst of phase transfer. In a preferred embodiment of the invention, the biodegradable terephthalate polymer of formula I can be produced by a method comprising the steps of polymerizing p moles of a diol compound having formula II: wherein R is a as defined above, with q moles of a phosphonic dichloride of formula III: or q moles of a dialkyl or diaryl of formula Illa: Illa O R 2 ^ - O- P | - O- R 2o R ' wherein R2 is H, Cl, halogenide or an organic portion, wherein R 'is defined as above, and p > q, to form q moles of a polymer of formula IV, as shown below: IV wherein R, R 'and x are as defined above. The polymer formed in this way can be isolated, purified and used as is. Alternatively, the polymer, insulated or not, can be used to prepare a copolymer composition of the invention by: (a) polymerization as described above; and (b) further reacting the polymer of formula IV and excess diol of formula II with (p-q) moles of terephthaloyl chloride having the formula V: V to form a polymer of formula I.

The function of the polymerization reaction of step (a) is to phosphorylate the diester starting material and then polymerize it to form the polymer. The polymerization step (a) can take place at temperatures that vary widely, depending on the solvent used, the desired solubility, the desired molecular weight and the susceptibility of the reagents to form side reactions. Preferably, however, the polymerization step (a) takes place at a temperature of -40 to + 160 ° C for solution polymerization, preferably 0 to 65 ° C; In volumetric, temperatures in the scale of + 150 ° C are generally used. The time required for the polymerization step (a) can also vary widely, depending on the type of polymerization used and the desired molecular weight. Preferably, however, the polymerization step (a) takes place for a time between 30 minutes and 24 hours. While the polymerization step (a) may be in volumetric, in solution, by interfacial polycondensation, or any other convenient polymerization method, preferably, the polymerization step (a) is a solution polymerization reaction. In particular, when the solution polymerization reaction is employed, an acid acceptor is conveniently present during the polymerization step (a). A suitable particular class of acid acceptor comprises tertiary amines, such as pyridine, trimethylamine, triethylamine, substituted anilines and substituted aminopyridines. The most preferred acid acceptor is the substituted aminopyridine 4-dimethyl-aminopyridine ("DMAP"). The addition sequence for the polymerization step (a) can vary significantly, depending on the relative reactivities of the diol of formula II, the phosphonic dichloride of formula III, and the polymer of formula IV; the purity of these reagents, the ambient temperature at which the polymerization reaction is carried out; the degree of agitation employed in the polymerization reaction, and the like. Preferably, however, the diol of formula II is combined with a solvent and an acid acceptor, and then the phosphonic dichloride is slowly added. For example, a solution of the phosphonic dichloride in a solvent can be distilled in or added dropwise to the cold reaction mixture of diol, solvent and acid acceptor, to control the speed of the polymerization reaction. The purpose of the step copolymerization (b) is to form a copolymer comprising (i) the phosphorylated polymer chains produced as a result of the polymerization step (a), and (ii) interconnecting the polyester units. The result is a copolymer having a particular microcrystalline structure suitable for use with a controlled release medium. The copolymerization step (b) of the invention usually occurs at a slightly higher temperature than the temperature of the polymerization step (A), but can also vary greatly, depending on the type of copolymerization reaction employed, the presence of one or more catalysts, the desired molecular weight, the desired solubility and the susceptibility of the reagents to the unwanted side reaction. However, when the copolymerization step (b) is carried out as a solution polymerization reaction, it almost always occurs at a temperature between about -40 and 100 ° C. Typical solvents include methylene chloride, chloroform or any of a wide variety of inert organic solvents. The time required for the step copolymerization (b) can also vary widely, depending on the molecular weight of the desired material and, in general, the need to employ more or less stringent conditions for the reaction to proceed to the desired degree of completion. Almost always, however, the copolymerization step (b) occurs during its approximate time of 30 minutes to 24 hours. When the polymer of the invention is synthesized by a polycondensation of two-step solution to produce a copolymer, the addition sequence of the reactive chlorides and the reaction temperatures in each step are preferably optimized to obtain the desired molecular weight combination with good solubility in common organic solvents. Preferably, the additive sequence comprises the dissolution of the bis-terephthalate starting material with an acid acceptor in a solvent in which both are soluble, cooling the solution with stirring, slowly adding an equal molar amount of the phosphonic dichloride (dissolved in the same solvent) to the solution, to allow the reaction to proceed at room temperature for a period, slowly adding an appropriate amount of terephthaloyl chloride which also dissolves in the same solvent, and increasing the temperature to about 50 ° C before under reflux overnight. The polymer of formula I, be it a homopolymer, block copolymer or other copolymer, is isolated from the reaction mixture by conventional techniques, such as precipitate, extraction with an immiscible solvent, evaporation, filtration, crystallization and the like. Almost always, however, the polymer of formula I is isolated and purified by quenching a solution of said polymer with a partial or non-solvent solvent, such as diethyl ether or petroleum ether.

Biodegradable capacity and release characteristics The lifetime of a biodegradable polymer in vivo also depends in part on its molecular weight, crystallinity, biostability and e! degree of interlacing. In general, biodegradation will be slower at higher molecular weight, higher degree of crystallinity and greater biostability. By working with poly (phosphates) and poly (phosphonates), the structure of the side chain can influence the release behavior of the polymer and the biodegradable capacity. For example, it is generally expected that with these classes of poly (phosphoesters), the conversion of the phosphorus side chain to a more lipophilic, more hydrophobic or bulky group would slow down the degradation process. For example, the release would usually be faster from copolymer compositions with a side chain of the small aliphatic group than with a bulky aromatic side chain. The poly (phosphites) and poly (phosphonates) of terephthalate of formula I are usually characterized by a rate of release of the biologically active substance in vivo which is controlled at least in part as a function of hydrolysis of the phosphoester linkage of the polymer during the biodegradation However, poly (phosphites) do not have a side chain that can be manipulated to influence the rate of biodegradation. Therefore, it has been somewhat surprising to discover that the lifetime of a biodegradable terephthalate poly (phosphite) polymer in vivo depends sufficiently on its molecular weight, crystallinity, biostability, and the degree of entanglement to achieve even higher speeds. of acceptable degradation. In general, the higher the molecular weight, the greater the degree of crystallinity and the higher the biostability, the slower the biodegradation.

Biologically active substances In general, the polymer of formula I is preferably employed as a composition that contains, in addition to the polymer, a biologically active substance to form a variety of useful biodegradable materials. However, the polymer of formula I can be used as a medical device in the form of a bioabsorbable suture, a brace or bone cement to repair injuries to bone or connective tissue, a laminate for degradable or non-degradable fabrics, or a coating for an implantable device, even without the presence of a biologically active substance. Preferably, the composition of the biodegradable terephthalate polymer comprises: (a) at least one biologically active substance and (b) the polymer with the recurring monomer units illustrated in formula I, wherein R, R ', x and y are as defined with anteriority. The polymer of formula I, especially where R 'is hydrogen, may also be employed as a non-osteoconductive, non-porous composition which contains in addition to the polymer a biologically active substance to form a variety of useful biodegradable materials. The biologically active substance of the invention can vary widely with the purpose for the composition. The active substance (s) can be described as a single entity or a combination of entities. The delivery system is designed to be used with biologically active substances that have a high water solubility, as well as those that have a low solubility in water to produce a delivery system having controlled release rates. The term "biologically active substance" includes, without limitation, drugs; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease; or substances that affect the structure or function of the body; or prodrugs, which become biologically active or more active after being placed in a predetermined physiological environment. Non-limiting examples of broad categories of useful biologically active substances include the following expanded therapeutic categories: anabolic agents, antacids, asthmatic agents, anticolesterol and antilipid agents, anticoagulants, anticonvulsants, antidiarrheals, antiemetics, anti-infective agents, anti-inflammatory agents, antimalarial agents, antinausea agents, antineoplastic agents, antiobesity agents, antipyretic and analgesic agents, antispasmodic agents, antithrombotic agents, anti-inflammatory agents, antianginal agents, antistamines, antitussives, appetite suppressants, biological agents, cerebral dilators, coronary dilators, decongestants, diuretics, diagnostic agents, erythropoietic agents, expectorants, gastrointestinal sedatives, hyperglycemic agents, hypnotics, hypoglycemic agents, exchange resins ionics, laxatives, mineral supplements, mucolytic agents, neuromuscular drugs, peripheral vasodilators, psychotropics, sedatives, stimulants, thyroid and antithyroid agents, relaxants, urethins, vitamins and prodrugs. Specific examples of biologically active substances from the above categories include: (a) antineoplastics, such as androgen inhibitors, antimetabolites, cytotoxic agents and immunomodulators; (b) antitussives, such as dextromethorphan, dextromethorphan hydrobromide, noscapine, carbetapentane citrate and clofedianol hydrochloride; (c) anthistamines, such as chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, and phenyltoloxamine citrate: (d) decongestants, such as phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, and ephedrine; (e) various alkaloids, such as codeine phosphate, codeine sulfate and morphine; (f) mineral supplements, such as potassium chloride, zinc chloride, calcium carbonates, magnesium oxide and other alkali metals and alkaline earth metal salts; (g) ion exchange resin, such as cholestriramine; (h) antiarrhythmics, such as N-acetylprocainamide; (i) antipyretics and analgesics, such as acetaminophen, aspirin and ibuprofen; (j) appetite suppressants, such as phenylpropanolamine hydrochloride or caffeine; (k) expectorants, such as guaifenesin; (I) antacids, such as aluminum hydroxide and magnesium hydroxide; (m) biological agents, such as peptides, polypeptides, proteins and amino acids, hormones, interferons or cytokines and other bioactive peptide compounds, such as hGH, tPA, calcitonin, ANF, EPO and insulin; and (n) anti-infective agents, such as antifungals, antivirals, antiseptics and antibiotics. Non-limiting examples of useful biologically active substances include the following therapeutic categories: analgesics, such as non-steroidal anti-inflammatory drugs, opiate agonists and salicylates; antihistamines, such as Hi-blockers and H2-blockers; anti-infective agents, such as anthelmintic, antianaerobic, antibiotics, aminoglycoside antibiotics, antifungal antibiotics, cephalosporin antibiotics, macrolide antibiotics, miscellaneous β-lactam antibiotics, penicillin antibiotics, quinoline antibiotics, sulfonamide antibiotics, tetracycline antibiotics, antimycobacterials, antimicrobial agents for antituberculosis, antiprotozoa, antimalarial antimalarials, antiviral agents, antiretroviral agents, scabicides and urinary anti-infectives; antineoplastic agents, such as alkylating agents, nitrogenous mustard alkylation agents, nitrosourea alkylation agents, antimetabolites, purine analogue antimetabolites, pyrimidine analog antimetabolites, hormonal antineoplastics, natural antineoplastic agents, natural antineoplastic antibiotics, and natural alkaloid antineoplastic agents - from vinca; automic agents such as anticholinergic, anticholinergic antimuscarinics, ergot alkaloids, parasympathomimetics, parasympathomimetics of cholinergic agonist, cholinesterase inhibitor parasympathomimetics, sympatholytics, a-blocker sympatholytics, ß-blocker sympatholytics, sympathomimetics, and sympathomimetics of adrenergic agonist; cardiovascular agents, such as antianginal, ß-blocker antianginal, calcium channel blocker antianginal, nitrate antianginal, antiarrhythmic, cardiac glycoside antiarrhythmics, class I antiarrhythmics, class II antiarrhythmics, class III antiarrhythmics, class IV antiarrhythmics, antihypertensive agents anti-hypertension agents a-blockers, angiotensin-converting enzyme inhibitor antihypertensive agents (ACE inhibitor), anti-hypertensive agents β-blockers, antihypertensive agents calcium channel blockers, central acting adrenergic antihypertensive agents, antihypertensive agents diuretics, peripheral vasodilator antihypertensive agents, antilipémicos, anti-lipemic bile acid sequestrants, HMG-CoA reductase inhibitor antilipémicos, inotropes, inotropes of cardiac glycosides, and thrombolytic agents, dermatological agents, such as antihistamines, agonists anti-inflammatory agents, corticosteroid anti-inflammatory agents, antipruritics / local anesthetics, topical anti-infective agents, antifungal topical anti-infective agents, topical antiviral anti-infective agents, and topical antineoplastic agents; electrolytic and renal agents, such as acidifying agents, alkalizing agents, diuretics, carbonic anhydrase inhibitor diuretics, loop diuretics, osmotic diuretics, potassium shortage diuretics, thiazide diuretics, electrolyte replacements, and uricosuric agents; enzymes, such as pancreatic enzymes and thrombolytic enzymes, gastrointestinal agents, such as antidiarrheals, antiemetics, gastrointestinal antiinflammatory agents, salicylate gastrointestinal antiinflammatory agents, antiulcer agents with antacids, gastric acid puff inhibitor anti-ulcer agents, gastric mucosal anti-ulcer agents, anti-ulcer agents H2-blockers, colelitolytic agents, digestives, emetics, laxatives and stool softeners, and prokinetic agents, general anesthetics, such as inhalation anesthetics, halogenated inhalation anesthetics, intravenous anesthetics, intravenous anesthetics of barbiturate, intravenous anesthetics of benzodiazepine, and intravenous anesthetics of opiate agonists, haematological agents, as antianemia agents, hematopoietic antianemia agents, coagulation agents, anticoagulants, hemostatic coagulation agents, inhibitory coagulation agents s of platelets, strombolytic enzyme coagulation agents and plasma volume expanders; hormones and hormone modifiers, such as abortifacients, adrenal agents, adrenal corticosteroid agents, androgens, antiandrogens, antidiabetic agents, sulfonylurea antidiabetic agents, agents Antibiotics, oral contraceptives, progestin contraceptives, estrogens, fertility agents, oxytoxics, parathyroid agents, , pituitary hormones, progestins, antithyroid agents, thyroid hormones, and tocolytics, immunobiological agents, such as immunoglobulins, immunosuppressants, toxoids, and vaccines; local anesthetics, such as local amide anesthetics, and local ester anesthetics; musculoskeletal agents, such as anti-inflammatory anti-inflammatory agents, corticosteroid antiinflammatory agents, anti-inflammatory agents with gold compound, anti-inflammatory agents, immunosuppressants, nonsteroidal anti-inflammatory drugs (NSAIDs), salicylate anti-inflammatory agents, skeletal muscle relaxants, muscle-skeletal relaxants of neuromuscular blocker, and muscle-skeletal relaxants of reverse neuromuscular blocker; neurological agents, such as barbiturate anticonvulsants, benzodiazepine anticonvulsants, antimigraine agents, anti-parkinsonian agents, antiviral agents, opiate agonists, opiate antagonists, and PARP inhibitors; ophthalmic agents, such as anti-glaucoma agents, ß-blocking anti-glaucoma agents, miotic anti-glaucoma agents, mydriatics, adrenergic agonist mydriatics, antimuscarinic mydriatics, ophthalmic anesthetics, ophthalmic antiinfectives, ophthalmic aminoglycoside antiinfectives, ophthalmic macrolide antiinfectives, antiinfectives of quinolone ophthalmic, sulfonamide ophthalmic antiinfectives, tetracycline ophthalmic antiinfectives, ophthalmic antiinflammatory agents, agents • anti-inflammatory drugs of ophthalmic corticosteroids, non-inflammatory anti-inflammatory drugs "Ophthalmic steroids (NSAIDs); psychotropic agents, such as antidepressants, heterocyclic antidepressants, monoamine oxidase inhibitors (MAOI), selective serotonin reuptake inhibitors (SRI), tricyclic antidepressants, antimanic agents, antipsychotics, phenothiazine antipsychotics, anxiolytics, sedatives, and hypnotics, sedatives of barbiturates and hypnotics, anxiolytics of benzodiazepine, sedatives, and hypnotics, and psychostimulants, respiratory agents, such as antitussives, bronchodilators, adrenergic agonist bronchodilators, antimuscarinic bronchodilators, expectorants, mucolytic agents, respiratory anti-inflammatory agents, anti-inflammatory agents of corticosteroids Respiratory agents, toxicological agents, such as antidotes, heavy metal antagonists / chelating agents, substance abuse agents, deterrent substance abuse agents, abstinence agents, minerals, and vitamins, such as tamin A, vitamin B, vitamin C, vitamin D, vitamin E, and vitamin K. Preferred classes of biologically active substances useful from the above categories include: (1) analgesics of nonsteroidal anti-inflammatory drugs (NSAIDs), such as diclofenac, ibuprofen , ketoprofen, and naproxen; (2) analgesics of opiate agonists, such as codeine, fentanyl, hydromorphone, and morphine; (3) salicylate analgesics, such as aspirin (ASA) (enteric coated ASA); (4) antihistamine H blockers, such as clemastine and terfenadine; (5) H2-blockers antihistamines, such as cimetidine, famotidine, nizadine, and ranitidine; (6) anti-infective agents, such as mupirocin; (7) antianaredobic anti-infective agents, such as chloramphenicol and clindamycin; (8) antimicotic antibiotic anti-infective agents, such as amphotericin b, clotrimazole, fluconazole, and ketoconazole; (9) anti-infective agents macrolide antibiotics such as azithromycin and erythromycin; (10) miscellaneous anti-infective agents of β-lactam antibiotics, such as aztreonam and imipenem; (11) penicillin antibiotic anti-infective agents, such as nafcillin, oxacillin, penicillin G, and penicillin V; (12) anti-infective quinolone antibiotics, such as ciprofloxacin and norfloxacin; (13) tetracycline antibiotic anti-infective agents, such as doxycycline, minocycline, and tetracycline; (14) antimicrobial antimicrobial anti-tuberculosis agents, such as isoniazid (INH), and rifampin; (15) anti-infectives with antiprotozoal agents, such as atovaquone and dapsone; (16) anti-malarial antimalarial agents with antiprotozoal agents, such as chloroquine and pyrimethamine; (17) Anti-retroviral anti-infective agents, such as ritonavir and zidovudine; (18) antiviral anti-infective agents, such as acyclovir, ganciclovir, interferon alfa, and rimantadine; (19) antineoplastic alkylation agents, such as carboplatin and cisplatin; (20) nitrosourea alkylation antineoplastic agents, such as carmustine (BCNU); (21) antimetabolite antineoplastic agents, such as methotrexate; (22) Antimicrobial antimetabolite analogous pyrimidine agents, such as fluorouracil (5-FU) and gemcitabine; (23) hormonal antineoplastic drugs such as goserelin, leuprolide, and tamoxifen; (24) natural antineoplastics, such as aldesleukin, interieucin-2, docetaxel, etoposide (VP-16), interferon alpha, paclitaxel, and tretinoin (ATRA); (25) natural antineoplastic antibiotics, such as bleomycin, dactinomycin, daunorubicin, doxorubicin, and mitomycin; (26) natural vinca alkaloid antineoplastic drugs such as vinblastine and vincristine; (27) autonomic agents, such as nicotine; (28) anticholinergic autonomic agents, such as benzotropin and trihexyphenidyl; (29) anticholinergic anticholinergic agents, such as atropine and oxybutynin; (30) autonomic agents of ergot alkaloid, such as bromocriptine; (31) parasympathomimetics, of cholinergic agonists, such as pilocarpine; (32) parasympathomimetics of cholinesterase inhibitor, such as pyridostigmine; (33) a-blocker sympatholytics, such as prazosin; (34) sympatholytics of β-blockers, such as atenolol; (35) slickerticomimetics of adrenergic agonists, such as albuterol and dobutamine; (36) cardiovascular agents, such as aspirin (ASA) (enteric coating ASA); (37) antianginal ß-blockers, such as atenolol and propranolol; (38) antianginal calcium channel blockers, such as nifedipine and verapamil; (39) nitrate antianginals, such as isosorbide dinitrate (ISDN); (40) cardiac glycoside antiarrhythmics, such as digoxin; (41) class I antiarrhythmics, such as lidocaine, mexiletine, phenytoin, procainamide, and quinilidine; (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) α-blocker antihypertensive agents, such as prazosin; (46) angiotensin-converting enzyme inhibitor (ACE inhibitor) antihypertensive agents, such as captopril and enalapril) (47) ß-blocker antihypertensive agents such as atenolol, metoprolol, nanodol, and propranolol; (48) calcium channel blocking antihypertensive agents, such as diltiazem and nifedipine; (49) centrally acting adrenergic antihypertensive agents, such as clonidine and methyldopa; (50) diuretic antihypertensive agents, such as amiloride, furosemide, hydrochlorothiazide (HCTZ), and spironolactone; (51) peripheral vasodilator antihypertensive agents, such as hydrazine and minoxidil; (52) antilipemic, such as gemfibrozil and probucol; (53) antilipemic bile acid sequestrants, such as cholestyramine; (54) anti-lipemic HMG-CoA reductase inhibitor, such as lavostatin and pravastatin; (55) inotropes, such as amrinone, dobutamine, and dopamine; (56) cardiac glycoside inotropes, such as digoxin; (57) thrombolytic agents, such as alteplase (TPA), anistreplase, streptokinase, and urokinase; (58) Dermatological agents, such as colchicine, isotretinoin, methotrexate, minoxidil, tretinoin (ATRA); (59) Dermatological corticosteroid anti-inflammatory agents, such as betamethasone and dexamethasone; (60) topical anti-fungal anti-infective agents, such as amphotericin B, clotrimazole, miconazole, and nlstatin; (61) antiviral topical anti-infective agents, such as acyclovir; (62) topical antineoplastic agents, such as fluorouracil (5-FU); (63) electrolytic and renal agents, such as lactulose; (64) loop diuretics, such as, furosemide; (65) diuretics of potassium deficiency, such as triamterene; (66) thiazide diuretics, such as hydrochlorothiazide (HCTZ); (67) uricosuric agents, such as probenecid; (68) enzymes, such as, RNase and DNase; (69) thrombolytic enzymes, such as alteplase, anistreplase, streptokinase and urokinase; (70) antiemetics, such as prochlorperazine; (71) salicylate gastrointestinal antiinflammatory agents, such as sulfasalazine; (72) antiulcer agents of gastric acid pump inhibitors, such as omeprazole; (73) anti-ulcer agents H2-blockers, such as omeprazole; (73) H2-blocking anti-ulcer agents, such as cimetidine, famotidine, nizatidine, and ranitidine; (74) digestives, such as pancrelipase; (75) prokinetic agents, such as erythromycin; (76) intravenous anesthetics opiate agonists, such as fentanyl; (77) hematopoietic antianemia agents, such as erythropoietin, filgrastim (G-CSF), and sargramostim (GM-CSF); (78) coagulation agents, such as anti-hemophilic factors 1-10 (AHF 1-10); (79) anticoagulants, such as warfarin; (80) thrombolytic enzyme coagulation agents, such as alteplase, anistreplase, streptokinase and urokinase; (81) hormones and hormone modifiers, such as bromocriptine; (82) abortifacient, such as methotrexate; (83) antidiabetic agents, such as insulin; (84) oral contraceptives, such as estrogen and progestin; (85) progestin contraceptives, such as levonorgestrel and norgestrel; (86) estrogens, such as conjugated estrogens, diethylstilbestrol (DES), estrogen (estradiol, estrone, and estropipate); (87) fertility agents, such as clomiphene, human chorionic gonadotropin (HCG), and menotropins; (88) parathyroid agents, such as 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) immunobiological agents, such as interferon beta-1b and interferon gamma-1 b; (93) immunoglobulins, such as IM immunoglobulin, IMIG, IGIM and immunoglobulin IV, IVIG, IGIV; (94) local amide anesthetics, such as lidocaine; (95) local anesthetics of ester, such as benzocaine and procaine; (96) anti-inflammatory agents with muscle-skeletal corticosteroids, such as beclomethasone, betamethasone, costisone, dexamethasone, hydrocortisone, and prednisone; (97) muscle-skeletal anti-inflammatory immunosuppressants, such as azathioprine, cyclophosphamide, and methotrexate; (98) tarameos non-steroidal musculoskeletal anti-inflammatories (NSAIDs) such as diclofenac, ibuprofen, ketoprofen, quetorlac, and naproxen; (99) skeletal muscle relaxants, such as baclofen, cyclobenzaprine, and diazephan; (100) muscle-skeletal relaxants of reverse neuromuscular blockers, such as pyridostigmine; (101) neurological agents, such as nimodipine, riluzole, tacrine and ticlopidine; (102) anticonvulsants, such as carbamazepine, gabapentin, lamotrigine, phenytoin, and valproic acid; (103) barbiturate anticonvulsants, such as phenobarbital and primidone; (104) benzodiazepine anticonvulsants, such as clonazepam, diazepam, and lorazepam; (105) antiparkinson agents, such as bromocriptine, levodopa, carbidopa, and pergolide; (106) antiviral agents, such as meclizine; (107) opiate agonists, such as codeine, fent, hydromphone, methadone, and morphine; (108) opiate antagonists, such as naloxone; (109) ß-blocker antiglaucoma agents, such as timolol; (110) miotic antiglaucoma agents, such as pilocarpine; (111) anti-infective agents of aminiglucoside ophthalmic agents, such as gentamicin, neomycin, and tobramycin; (12) quinolone ophthalmic antiinfective agents, such as cyprofloxacin, norfloxacin and ofloxacin; (113) anti-inflammatory agents of ophthalmic corticosteroids, such as dexamethasone and prednisolone; (114) non-steroidal ophthalmic anti-inflammatory drugs (NSAIDs), such as diclofenac; (115) antipsychotics, such as clozapine, haloperidol, and risperidone; (116) benzodiazepine anxiolytics, sedatives and hypnotics; as clonazepán, diazepán, lorazepán, oxazepán, and prazepán; (117) psychostimulants, such as methylphenidate and pemoline; (118) antitussives, such as codeine; (119) bronchodilators, such as theophylline; (120) bronchodilators of adrenergic agonists, such as albuterol; (121) anti-inflammatory agents of respiratory corticosteroids, such as dexamethasone; (122) antidotes, such as flumazenil and naloxone; (123) heavy metal antagonists / chelating agents, such as penicillamine; (124) agents of abuse of deterrents, such as disulfiram, naltrexone and nicotine; (125) abstaining substance abuse agents, such as bromocriptine; (126) minerals, such as iron, calcium and magnesium; (127) vitamin B compounds, such as cyanocobalamin (vitamin B12) and niacin (vitamin B); (128) Vitamin C compounds, such as ascorbic acid; and (129) vitamin D compounds, such as calcitriol. In addition to the above, the following less common drugs may also be used: chlorhexidine; oestradiol cypionate in oil, estradiol valerate in oil, flurbiprofen, flurbiprofen sodium, ivermectin, levodopa, nafarelin and somatropin. In addition, the following new drugs can also be used: recombinant beta-glucan; bovine immunoglobulin concentrate; bovine superoxide dismutase; a mixture comprising fluorouracil, epinephrine, and bovine collagen; recombinant hirudin (r-Hir), HIV-1 immunogen; anti-human CT antibody; recombinant human growth hormone (r-hGH); recombinant human hemoglobin (r-Hb); recombinant human mecarsermin (r-IGF-1); recombinant interferon beta-1a; lenograstim (G-CSF); olanzapine; recombinant thyroid stimulating hormone (r-TSH) and topotecan. In addition, the following intravenous products may be used: sodium-acyclovir, aldesleukin, atenolol, bleomycin sulfate, human calcitonin, salmon calcitonin, carboplatin, carmustine, dactinomycin, daunorubicin HCl, docetaxel, doxorubicin HCl, alpha epoetin, etoposide (VP -16), fluorouracil (5-FU), sodium-ganciclovir, gentamicin sulfate, alpha interferon, leuprolide acetate, meperidine HCl, methadone HCl, methotrexate sodium, paclitaxel, ranitidine HCl, vinblastine sulfate, and zidovudine ( AZT). Even the following list of peptides, proteins and other large molecules can also be used, such as interleukins 1 to 18, including mutants and analogs; interferons a, ß, and?; Luteinizing hormone releasing hormone (LHRH) and analogues, gonadotropin releasing hormone (GnRH) and transforming growth factor-β (TGF-β) fibroblast growth factor (FGF), factor-a & ß of tumor necrosis (TNF-a &ß); nerve growth factor (NGF); growth hormone releasing factor (GHRF); epidermal growth factor (EGF); homologous factor of fibroblast growth factor (FGFHF); hepatocyte growth factor (HGF); insulin growth factor (IGF); invasion inhibition factor-2 (IIF-2); somatostatin; thymosin-a-1; ?-globulin; superoxide dismutase (SOD); and complementary factors. Preferably, the biologically active substance is selected from the group consisting of peptides, polypeptides, proteins, amino acids, polysaccharides, growth factors, hormones, antiangiogenesis factors, nteferons or cytokines, and prodrugs. In a particular preferred embodiment, the biologically active substance is a therapeutic drug or prodrug, more preferably a drug selected from the group consisting of chemotherapeutic agents and other antineoplastic agents (such as paclitaxel), antibiotics, antivirals, antinomycotes, antiinflammatories, anticoagulants, and prodrugs of these substances. Biologically active substances are used in amounts that are therapeutically effective. While the effective amount of a biologically active substance will depend on the particular material being used, the amounts of the biologically active substance from about 1% to about 65% have been easily incorporated into the present delivery systems, while achieving at the same time the controlled release. Smaller amounts may be used to achieve effective levels of treatment for certain biologically active substances. Pharmaceutically acceptable carriers can be prepared from a wide range of materials. Without being limited thereto, such materials include diluents, binders and adhesives, lubricants, disintegrants, colorants, bulking agents, sweeteners and miscellaneous materials, such as pH regulators and adsorbents for preparing a particular medicated composition.

Implants and delivery systems designed for injection In its simplest form, a delivery system of biodegradable therapeutic agents consists of a dispersion of the therapeutic agent in a polymer matrix. The therapeutic agent is almost always released when the polymer matrix biodegrades in vivo in soluble products that can be absorbed and finally excreted from the body. In a particular preferred embodiment of the invention, an article is used for implantation, injection, or else it is placed totally or partially within the body, the article comprises the biodegradable terephthalate polymer composition of the invention. The biologically active substance of the composition and the polymer of the invention can form a homogeneous matrix or the biologically active substance can be encapsulated in some way within the polymer. For example, the biologically active substance can first be encapsulated in a microsphere and then combined with the polymer so that at least a portion of the microsphere structure is retained. The composition, especially where R 'is hydrogen in formula 1, can be employed in a non-osteoconductive medical device essentially in the form of a bioabsorbable suture, a laminate for degradable and non-degradable fabrics, or a coating for an implantable device. In its simplest form, a biodegradable delivery system for a biologically active substance consists of a physical dispersion of the therapeutic agent in a polymer matrix. The therapeutic agent is almost always released when the polymer matrix biodegrades in vivo in soluble products that can be absorbed and finally excreted from the body.

In a particular preferred embodiment, the non-osteoconductive biodegradable composition in essence of the invention is used to make an article useful for implantation, injection or otherwise placed totally or partially within the body. The biologically active substance of the composition and polymer of the invention can form a homogeneous matrix or the biologically active substance can be encapsulated in some way within the polymer. For example, the biologically active substance can first be encapsulated in a microsphere and then combined with the polymer so that at least a portion of the microsphere structure is retained. The biologically active substance may be sufficiently immiscible in the polymer of the invention to disperse as small droplets, instead of dissolving in the polymer. Any form is acceptable, but it is preferred that, regardless of the homogeneity of the composition, the rate of release of the biologically active substance in vivo remains under control, at least partially as a function of hydrolysis of the phosphoester linkage of the polymer in biodegradation. In a preferred embodiment the article of the invention is adapted for implantation or injection into the body of an animal. In particular, it is important that said article results in minimal tissue irritation when implanted or injected into vascular tissue. As all or part of a non-osteoconductive medical device in essence, the copolymer compositions of the invention provide a physical form having specific and sufficient chemical, physical and mechanical properties for the application and a composition that degrades in vivo in non-toxic waste. . Typical structural medical articles include such implants as ventricular shunts, laminates for degradable or non-degradable fabrics, drug-vehicles, bioabsorbable sutures, bandages for burns, coatings to be placed on other implant devices and the like. As a structural medical device, the copolymer compositions of the invention provide a physical form having specific and sufficient chemical, physical and mechanical properties for the application and a composition that degrades in vivo in non-toxic waste. Typical structural medical items include implants, such as orthopedic fixation devices, ventricular leads, laminates for degradable or non-degradable fabrics, drug-vehicles, bioabsorbable sutures, bandages for burns, coatings that will be placed on other implant devices and the like. In orthopedic appliances, the composition of the invention may be a bone wax, bone cement or other material useful for repairing bone and connective tissue injuries. For example, a biodegradable porous material can be loaded with bone morphogenetic proteins to form a bone graft useful for defects of larger segments. In vascular graft applications, a biodegradable material in the form of a woven fabric can be used to promote the internal growth of tissue. The composition of the copolymer of the invention can be used as a temporary barrier to prevent adhesion of the tissue, for example, following abdominal surgery. On the other hand, in nerve regeneration articles, the presence of a biodegradable support matrix can be used to facilitate cell adhesion and proliferation. When the composition of the copolymer is manufactured as a tube for nerve generation, for example, the tubular article can also serve as a geometric guide for elongation of the axon in the direction of functional recovery. As a drug delivery device, the composition of the copolymer of the invention provides a polymer matrix capable of sequestering a biologically active substance and providing controlled and predictable delivery of the substance. The polymer matrix is then degraded to non-toxic waste. The biodegradable medical implant devices and drug delivery products can be prepared in various ways. The copolymer can be melted using conventional extrusion or injection molding techniques, or these products can be prepared by dissolving in an appropriate solvent, followed by formation of the device, and subsequent removal of the solvent by evaporation or extraction. Through these methods, the polymers can be formed in drug delivery systems of almost any desired size or shape, for example, implantable solid wafers or wafers or injectable sticks, microspheres or other microparticles. Once a medical implant article is in place, it must remain at least in partial contact with a biological fluid, such as blood, internal organic secretions, mucous membranes, cerebrospinal fluid and the like. The following examples are illustrative of preferred embodiments of the invention and are not intended to be a limitation thereof. All molecular weights of the polymer are average molecular weights. All percentages are based on the percentage by weight of the final supply system or formulation being prepared, unless otherwise indicated, and all totals equal 100% by weight.

ILLUSTRATIVE EXAMPLES EXAMPLE 1 Preparation of Bis (2-hydroxyethyl) terephthalate Co (Ac) 2 (H20) (BHET) 1.4 moles of dimethylterephthalate (277 g) and 7.2 moles of ethylene glycol (445 g) were weighed into a 1 liter beaker connected to a vacuum line. A catalytic amount of cobalt (II) acetate tetrahydrate (180 mg, 0.5 mole) and hydrated calcium acetate (90 mg, 0.4 mole) was added. The reaction mixture was heated to 160 ° C in an oil bath under a gentle vacuum. After 18 hours, the reaction was concluded. While it was still molten, the mixture was poured into cold water. The formed precipitate was collected, dried under vacuum and redissolved in hot methanol. The sediment (composed largely of oligomers) was filtered. The filtrate was cooled to -20 ° C to form a precipitate, which was recrystallized from methanol and ethyl acetate to produce a white powder, the "BHET" product. Alternatively, BHET having an excellent purity can be prepared according to the following reaction scheme: BHET is also available in the market.

EXAMPLE 2 Synthesis of polyrbis (2-ethoxy) -hydrophosphonic terephthalate (PPET) H3CO- Poly (bis (2-ethoxy) hydrophosphonic] terephthalate (PPET) is synthesized by voluminous condensation of dimethylphosphite (DMP) or diethylphosphite and bis (2-hydroxyethyl) terephthalate (BHET). 1.0 grams (4 mmoles) of BHET are added to a flask equipped with a magnetic stirrer, a thermometer, and a condenser that can be attached to a vacuum line. 0.433 grams (4 mmoles) of DMP are added to the BHET and a solution of sodium methoxide in methanol is added to raise the basic character of the reaction mixture. The higher pH prevents transesterification of the final hydroxyl group of BHET. The mixture is heated at 100 ° C for 48 hours and then brought to 120 ° C for 8 hours by applying high vacuum at 0.01 mm Hg.

EXAMPLE 2 A Synthesis of polifBHET EP) To a 100 ml three neck round flask were added 9.27 g of 1,4-bis (2-hydroxyethyl) terephthalate (BHET), 8.91 g of dimethylaminopyridine (DAMAP), and 30 ml of dry dichloromethane, subsequently under protection of dry nitrogen gas. The mixture was stirred with a magnetic stir bar until a clear solution was obtained. The flask was cooled in a dry ice / acetone bath for 10 minutes and 5.47 g of ethylphosphonic dichloride (EP) in 10 ml of dichloromethane was added through a funnel over a period of 1 hour. The reaction mixture was gradually heated under reflux conditions with a heating mantle and kept under reflux overnight (about 18 hours). After being refluxed overnight, about 25 ml of dichloromethane was distilled off, and the remaining viscous mixture was heated to about 90 ° C with an oil bath to produce second stage polymerization. After two hours, the remaining dichloromethane was vented and 145 ml of chloroform was added to the flask. The resulting solution was washed three times with saturated NaCl solution, dried over anhydrous MgSO 4, and poured into 500 ml of diethyl ether to precipitate the polymer product. The polymer product was collected by filtration and dried in a vacuum oven.

The GPC chromatogram illustrated in Figure 1 indicated that the polymer product had a mass molecular weight of approximately 11.3 KD.

EXAMPLE 3 Synthesis of other poly (phosphite) polymers Other poly (phosphite) esters of the invention can be prepared by the process described in Example 2 above, except that other diols are substituted by the bis (2-hydroxyethyl) terephthalate, during the initial polymerization step. For example, bis (3-hydroxypropyl) terephthalate, bis (3-hydroxy-2-methyl-propyl) terephthalate, bis (3-hydroxy-2,2-dimethyl-poryl) terephthalate, and bis (6-hydroxyhexyl) can be used. terephthalate EXAMPLE 3 A Synthesis of poly (BHET-EP / TC 80/20) DMAP To a 100 ml three neck round flask were added 9.87 g of 1, 4, bis (2-hydroxyethyl) terephthalate (BHET), 9.03 g of dimethylaminopyridine (DMAP), and 40 ml of dry dichloromethane, subsequently under protection of dry nitrogen gas. The mixture was stirred with a magnetic stir bar until a clear solution was obtained. The flask containing the solution was cooled in a dry ice / acetone bath for 10 minutes, and then 4.34 g of ethylphosphonic dichloride in 15 ml of dichloromethane was added through a funnel over a period of 35 minutes. The reaction mixture was allowed to warm gradually to room temperature and was stirred for half an hour. The reaction mixture was cooled in a dry ice / acetone bath and 1.5 grams of terephthalic chloride (TC) in 15 ml of dichloromethane was added over a period of 40 minutes. After completing the addition of TC, the reaction mixture was gradually heated under reflux with a heating mantle. After being refluxed overnight (about 18 hours) about 30 ml of dichloromethane were distilled. The remaining viscous mixture was heated to about 90 ° C in an oil bath to initiate the second stage polymerization. After two hours, the remaining dichloromethane was vented, and 150 ml of chloroform was added to the flask. The polymer solution was then washed 3 times with saturated NaCl solution, dried with MgSO, anhydrous, and precipitated in 500 ml of diethyl ether. The resulting polymer was collected and dried in a vacuum oven. The GPC chromatogram illustrated in Figure 2 indicated that the polymer had a PMp of 11.2 KD.

EXAMPLE 4 Preparation of PPET microspheres that encapsulate FITC-BSA The microspheres are prepared by a double emulsion method / solvent extraction using FITC-labeled bovine serum albumin (FITC-BSA) as a model protein drug. One hundred μl of FITC-BSA solution (10 mg / ml) was added to a 100 mg solution of PPET, in 1 ml of methylene chloride, and emulsified by sound treatment for 15 seconds on ice. The resulting emulsion was immediately poured into 5 ml swirling aqueous solution of 1% polyvinyl alcohol (PVA) and NaC. The swirl action was maintained for approximately 1 minute, the resulting emulsion was poured into 20 ml of an aqueous solution of PVA at 0.3% NaCl at 5% with strong agitation. 25 ml of 2% isopropanol solution was added and the mixture was continued to stir for 1 hour to ensure complete extraction. The resulting microspheres were collected by centrifugation at 3000 Xg, washed 3 times with water, and lyophilized. The empty microspheres are prepared in the same way, except that the water is used as the internal aqueous phase. The resulting microspheres are largely between 5 and 20 μm in diameter and generally have a smooth surface morphology. It is determined by observation with a confocal fluorescence microscope that the encapsulated FITC-BSA is distributed uniformly within the microspheres. The loading level of FITC-BSA is determined by performing tests for FITC after hydrolyzing the microspheres in 0.5N NaOH solution. The loading levels are determined by comparison of a standard curve that is generated by making a series of solutions of FITC-BSA in 0.5 N NaOH. The protein loading levels of approximately 15% by weight of about 59% are easily obtained. The efficiency of the encapsulation of FITC-BSA by the microspheres is determined at different loading levels by comparing the amount of FITC-BSA entrapped with the initial amount of solution by fluoromotria. Encapsulation efficiencies of approximately 70% to almost 100% can be obtained.

EXAMPLE 4A Synthesis of copolymers P (BHET-HP / TC 80:20 v 90:10) The phosphoester P (BHET-HP / TC, 80:20) and P (BHET-HP / TC, 90:10) copolymers can also be prepared by the procedure described above in Example 2A, except that hexyl phosphonic dichloride (HP) ) is substituted for the monomer ethylphosphonic dichloride (EP) during the initial polymerization step. In addition, the feeding ratio may vary.

EXEMPJ-O 5 Preparation of PPET microspheres containing lidocaine An aqueous solution of 5% polyvinyl alcohol in volume (PVA) is prepared in a 600 ml beaker by combining 1.35 g of PA with 270 ml of deionized water. The solution is stirred for 1 hour and filtered. A copolymer / drug solution is prepared by combining 900 mg of PPET copolymer and 100 ml of lidocaine in 9 ml of methylene chloride and mixing with vortex. While the PVA solution is being stirred at 500-1000 rpm with a top mixer, the polymer / drug mixture is added dropwise. The combination is stirred for about 1 hour and a half. The microspheres thus formed are then filtered, washed with deionized water and lyophilized overnight. The experiment produced microspheres loaded with about 3.5-4.0% w / w of idocaine. Microspheres containing lidocaine are also prepared from other poly (phosphite) s by the same procedure. This experiment produces microspheres loaded with approximately 5.0-5.5% w / w lidocaine.

EXAMPLE 5 A Preparation of P microspheres (BHET-EP / TC, 80/20) microspheres encapsulating FITC-BSA The microspheres are prepared through a double emulsion / solvent extraction method using FITC-labeled bovine serum albumin (FITC-BSA) as a model protein drug. 100 μL of a solution of FITC-BSA (10 mg / mL) is added to a solution of (100 mg of P (BHET-EP / TC, 80/20) in 1 mL of methylene chloride, and emulsified by sound treatment for 15 seconds on ice. The resulting emulsion is immediately poured into 5 mL of a swirling aqueous solution of 1% polyvinyl alcohol (PVA) 5% NaCl. The whirling action is maintained for approximately one minute. The resulting emulsion is poured into 20 mL of an aqueous solution of 0.3% PVA and 5% NaCl with vigorous stirring. 25 ml of a 2% isopropanol solution is added, and the mixture is kept under stirring for one hour to ensure complete extraction. The resulting microspheres are collected by centrifugation at 3000 X g, washed three times with water, and lyophilized. The empty microspheres are prepared in the same manner, except that the water is used in the internal aqueous phase. The resulting microspheres are largely between 5 and 20 μm in diameter, and in general have a smooth surface morphology. It is determined by observation with a confocal fluorescence microscope that the encapsulated FITC-BSA is distributed uniformly within the microspheres. The loading level of FITC-BSA is determined by titrating for FITC after hydrolyzing the microspheres in a 0.5 N NaOH solution overnight. The loading levels are determined by comparison with a standard curve, which is generated by making a series of solutions of FITC-BSA in 0.5 N NaOH. The protein loading levels of about 1 59 around 25% by weight are obtained with ease. The encapsulation efficiency of FITC-BSA by the microspheres is determined at different loading levels by comparing the amount of FITC-BSA entrapped with the initial amount in solution by fluorometry. Encapsulation efficiencies of approximately 70% to almost 100% can be obtained.

EXAMPLE 6 In vitro release kinetics of microspheres prepared from PPET polymers Five milligrams of PPET microspheres containing FITC-BSA are suspended in one milliliter of phosphate buffer saline (PBS) at pH 7.4 and placed on a stirrer which is heated to a temperature of about 37 ° C. At various time points, the suspension is rotated at 3000 X g for 10 minutes, and 500 μl samples of the supernatant fluid, and replaced with fresh PBS, the release of FITC-BSA from the microspheres can be followed with the measurement of the fluorescence intensity of the samples removed at 519 nm. In progressive increase, about 50 mg of PPET microspheres are suspended in containers containing 10 mL of pH phosphate buffer (PBS). The containers are heated in an incubator at a temperature of about 37 ° C and then stirred at about 220 rpm. Samples of the supernatant are removed and replaced at various time points, and the amount of FIC-BSA released in the samples is analyzed by spectrophotometry at 492 nm. The results generally indicate satisfactory release rates.

EXAMPLE 6 A Preparation of P microspheres (BHDPT-EP TC 50/50) containing lidocaine An aqueous solution of 0.5% polyvinyl alcohol by volume (PVA) is prepared in a 600 ml beaker by combining 1.35 g of PVA with 270 ml of deionized water. The solution is stirred for one hour and filtered. A copolymer / drug solution is prepared by combining 900 mg of P copolymer (BHDPT-EP / TC, 50/50) and 100 mg of lidocaine in 9 ml of methylene chloride and swirling. While the PVA solution is being stirred at 500-1000 rpm with a top mixer, the polymer / drug mixture is added dropwise. The combination is stirred for about one and a half hours. The microspheres thus formed are then filtered, washed with deionized water and lyophilized overnight. The experiment produces microspheres loaded with 3.5-4.0% w / w lidocaine. Microspheres containing lidocaine are also prepared from P (BHDPT-HP / TC, 50/50) by the same procedure. This procedure produces microspheres loaded with approximately 5.0-5.5% w / w lidocaine.

EXAMPLE 7 In vitro release kinetics of microspheres prepared from PPET polymers Approximately 10 mg of PPET microspheres loaded with lidocaine are placed in PBS (0.1 M, pH 7.4) at 37 ° C in a shaker. Samples of the incubated solution are periodically removed, and the amount of lidocaine released in the samples is tested by HPLC. The same procedure can be followed to test the microspheres prepared from other poly (phosphite) s.

EXAMPLE 7A Kinetics of in vitro release of microspheres prepared from copolymers of P (PHET-EP / TC, 80/20) Five mg of P-microspheres (PHET-EP / TC, 80/20) containing FITC-BSA are suspended in one mL of phosphate buffer pH (PBS) at pH 7.4 and placed on a shaker that is heated at a temperature of approximately 37 ° C. At various time points, the suspension is stirred at 3000 X g for 10 minutes, and 500 μl samples of the supernatant fluid are removed and replaced with fresh PBS. The release of TITC-BSA from the microspheres can be followed by measurement of the fluorescence intensity of the samples removed at 519 nm. In progressive increase, about 50 mg of P microspheres (PHET-EP / TC, 80/20) are suspended in containers containing 10 mL of pH phosphate buffer (PBS). The containers are heated in an incubator at a temperature of about 37 ° C, and then stirred around 220 rpm. The supernatant samples are removed and replaced at various time points, and the amount of FITC-BSA released in the samples is analyzed by spectrophotometry at 492 nm. The results generally indicate satisfactory release rates.

EXAMPLE 8 Kinetics of in vitro release of microspheres prepared from copolymers of P (PHET-EP / TC, 80/20) Five mg of P-microspheres (PHET-EP / TC, 80/20) containing FITC-BSA are suspended in one mL of phosphate buffer saline (PBS) at pH 7.4 and placed on a shaker that is heated to a temperature approximately 37 ° C. At various time points, the suspension is stirred at 3000 X g for 10 minutes, and 500 μl samples of the supernatant fluid are removed and replaced with fresh PBS. The release of FITC-BSA from the microspheres can be followed by measurement of the fluorescence intensity of the samples removed at 519 nm. In progressive increase, about 50 mg of P microspheres (PHET-EP / TC, 80/20) are suspended in containers containing 10 mL of pH phosphate buffer (PBS). The containers are heated in an incubator at a temperature of about 37 ° C, and then stirred at about 220 rpm. The supernatant samples are removed and replaced at various time points and the amount of FITC-BSA released in the samples is analyzed by spectrophotometry at 492 nm. The results generally indicate satisfactory release rates. In this way the invention is described, and it will be apparent that it can be varied in many ways. Said variations are not considered to be far from the spirit and scope of the invention, and all these modifications are intended to be included within the scope of the following claims.

Claims (75)

7 NOVELTY OF THE INVENTION CLAIMS

1. - A medical or drug delivery device comprising a biodegradable terephthalate polymer comprising the recurring monomer units shown in formula I: wherein R is a divalent organic moiety; R 'is hydrogen, an aliphatic, aromatic or heterocyclic residue; x is > 1 and N is 3-7,500, wherein the biodegradable polymer is sufficiently pure to be biocompatible and is capable of forming biocompatible residues with biodegradation.

2. The device according to claim 1, further characterized in that R is an alkylene group, a cycloaliphatic group, a phenylene group or a divalent group having the formula: in which Y is oxygen, nitrogen, or sulfur and m is from 1 to 3.

3. - The device according to claim 1, further characterized in that R is an alkylene group having from 1 to 7 carbon atoms.

4. The device according to claim 1, further characterized in that R is an ethylene group.

5. The device according to claim 1, further characterized in that R 'is an alkyl group or a phenyl group.

6. The device according to claim 1, further characterized in that R 'is an alkyl group having from 1 to 7 carbon atoms.

7. The device according to claim 1, further characterized in that R 'is an ethyl group.

8. The device according to claim 1, further characterized in that x is from 1 to 30.

9. The device according to claim 1, further characterized in that x is from 1 to 20.

10. The device of according to claim 1, further characterized in that x is from 2 to 20.

11. The device according to claim 1, further characterized in that said copolymer is prepared by solution polymerization.

12. - The device according to claim 1, further characterized in that said polymer comprises additional biocompatible monomer units.

13. The device according to claim 1, further characterized in that said copolymer is soluble in at least one of the solvents selected from the group consisting of acetone, dichloromethane, chloroform, ethyl acetate, DMAC, N-methylpyrrolidone, dimethylformamide and sodium sulfoxide. dimethyl.

14. The device according to claim 1, further characterized in that said device comprises a biologically active substance.

15. The device according to claim 14, further characterized in that said biologically active substance is selected from the group consisting of peptides, polypeptides, proteins, amino acids, polysaccharides, growth factors, hormones, anti-angiogenesis factors, interferons or cytokines, and prodrugs of those substances.

16. The device according to claim 14, further characterized in that said biologically active substance is a drug or therapeutic prodrug.

17. The device according to claim 14, further characterized in that said biologically active substance is selected from the group consisting of antineoplastic, antibiotic, antiviral, antifungal, anti-inflammatory, anticoagulant, and prodrugs of these substances.

18. The device according to claim 14, further characterized in that said biologically active substance is paclitaxel.

19. The device according to claim 14, further characterized in that said biologically active substance and said polymer form a homogeneous matrix.

20. The device according to claim 14, further characterized in that said biologically active substance is encapsulated within said polymer.

21. The device according to claim 14, further characterized in that said polymer is characterized by a rate of release of the biologically active substance in vivo partially controlled as a function of hydrolysis of the phosphoester linkage of the polymer with biodegradation.

22. The device according to claim 14, further characterized in that said device is adapted for implantation or injection into the body of an animal.

23. The device according to claim 14, further characterized in that said device results in minimal tissue irritation when implanted or injected into vascular tissue.

24. - The device according to claim 1, further characterized in that said device is a bioabsorbable suture.

25. The device according to claim 1, further characterized in that said device is an orthopedic apparatus, bone cement, or bone wax to repair injuries to bones and connective tissue.

26. The device according to claim 1, further characterized in that said device is a laminate for degradable or non-degradable fabrics or is manufactured as a tube for nerve regeneration.

27. The device according to claim 1, further characterized in that said device is implantable and comprises a coating comprising said polymer or used as a barrier to prevent adhesion.

28. A biodegradable terephthalate copolymer composition comprising: a) at least one biologically active substance and b) a copolymer having the recurring monomer units shown in formula 1: wherein R is a divalent organic moiety; R 'is hydrogen, an aliphatic, aromatic or heterocyclic residue; x is > 1; and n is 3-7,500, wherein the biodegradable polymer is sufficiently pure to be biocompatible and is capable of forming biocompatible residues with biodegradation.

29. The copolymer composition according to claim 28, further characterized in that R is an alkylene group, a cycloaliphatic group, a phenylene group, or a divalent group having the formula: wherein Y is oxygen, nitrogen or sulfur and m is from 1 to 3.

30.- The copolymer composition according to claim 28, further characterized in that R is an alkylene group having from 1 to 7 carbon atoms.

31. The copolymer composition according to claim 28, further characterized in that R 'is an alkyl group or a phenyl group.

32. The copolymer composition according to claim 28, further characterized in that R 'is an alkyl group having from 1 to 7 carbon atoms.

33. The copolymer composition according to claim 28, further characterized in that x is from 1 to 30.

34. - The copolymer composition according to claim 28, further characterized in that said copolymer is prepared by solution polymerization.

35. The copolymer composition according to claim 28, further characterized in that said polymer comprises additional biocompatible monomer units.

36. The copolymer composition according to claim 28, further characterized in that said copolymer is soluble in at least one of the solvents selected from the group consisting of acetone, dichloromethane, chloroform, ethyl acetate, DMAC, N-methylpyrrolidone, dimethylformamide and dimethyl sulfoxide.

37.- The copolymer composition according to claim 28, further characterized in that said biologically active substance is selected from the group consisting of peptides, polypeptides, proteins, amino acids, polysaccharides, growth factors, hormones, anti-angiogenesis factors, interferons or cytokines, and prodrugs of those substances.

38.- The copolymer composition according to claim 28, further characterized in that said biologically active substance is a therapeutic drug or prodrug.

39. The copolymer composition according to claim 38, further characterized in that said biologically active substance is selected from the group consisting of antineoplastic, antibiotic, antiviral, antifungal, anti-inflammatory, anticoagulant, and prodrugs of those substances.

40.- The copolymer composition according to claim 38, further characterized in that said biologically active substance is paclitaxel.

41. The copolymer composition according to claim 28, further characterized in that said biologically active substance and said polymer form a homogeneous matrix.

42.- The copolymer composition according to claim 28, further characterized in that said polymer is characterizedA rate of release of the biologically active substance in vivo partially controlled as a function of hydrolysis of the phosphoester linkage -of the polymer during biodegradation.

43.- A method for the controlled release of a biologically active substance comprising the steps of: a) combining the biologically active substance with a biodegradable copolymer of terephthalate comprising the recurring monomer units shown in formula I: wherein R is a divalent organic moiety; R 'is hydrogen, an aliphatic, aromatic or heterocyclic residue; x is > 1 and n is 3-7,500, wherein the biodegradable polymer is sufficiently pure to be biocompatible and is capable of forming biocompatible residues with biodegradation, to form a mixture; b) forming said mixture in a formed, solid product; and c) implanting or injecting said solid article in vivo at a preselected site in an animal so that the implanted or injected solid matrix is in at least partial contact with a biological fluid.

44. The method according to claim 43, further characterized in that R is an alkylene group having from 1 to 7 carbon atoms.

45.- The method of compliance with \? > claim 43, further characterized in that R 'is an alkyl group having from 1 to 7 carbon atoms.

46. The method according to claim 43, further characterized in that x is from 1 to 30.

47. The method according to claim 43, further characterized in that said copolymer comprises additional biocompatible monomer units.

48. The method according to claim 43, further characterized in that said biologically active substance is selected from the group consisting of peptides, polypeptides, proteins, amino acids, polysaccharides, growth factors, hormones, anti-angiogenesis factors, and other antineoplastic agents. , Interferons or cytokines, and prodrugs of those substances.

49. The method according to claim 43, further characterized in that said biologically active substance is a therapeutic drug or prodrug.

50. The method according to claim 43, further characterized in that said drug is selected from the group consisting of chemotherapeutic, antibiotic, antiviral, antifungal, anti-inflammatory and anticoagulant agents.

51.- The method according to claim 43, -characterized in addition because said biologically active substance is paclitaxel.

52. The method according to claim 43, further characterized in that said biologically active substance and said copolymer form a homogeneous matrix.

53. The method according to claim 43, further characterized in that it comprises encapsulating said biologically active substance within said polymer.

The method according to claim 43, further characterized in that said copolymer is characterized by a rate of release of the biologically active substance in vivo partially controlled as a function of hydrolysis of the phosphoester linkage of the copolymer with biodegradation.

55. The method according to claim 43, further characterized in that said device results in minimal tissue irritation when implanted or injected into vascular tissue.

56.- The method according to claim 43, further characterized in that said device is a bioabsorbable suture.

57. The method according to claim 43, further characterized in that said device is a laminate for degradable or non-degradable fabrics or is manufactured as a tube for nerve regeneration.

58. The method according to claim 43, further characterized in that said article is an orthopedic apparatus, bone cement, or bone wax for repairing injuries to bones or connective tissue.

59.- The method according to claim 43, further characterized in that said copolymer composition is used as a coating for an implant, or is used as a barrier to prevent adhesion.

60.- A composition of biodegradable terephthalate copolymer, essentially non-osteoconductive, comprising at least one biologically active substance and a copolymer having the recurring monomer units shown in formula I: wherein R is a divalent organic moiety; R 'is hydrogen, an aliphatic, aromatic or heterocyclic residue; x is > 1 and n is 3-7,500, wherein the biodegradable polymer is sufficiently pure to be biocompatible and is capable of forming biocompatible residues with biodegradation.

61.- A medical or drug delivery device comprising a copolymer composition according to claim 60.

62.- The copolymer composition according to claim 60, further characterized in that R is an alkylene group, a cycloaliphatic group , a phenylene group, or a divalent group having the formula: wherein Y is oxygen, nitrogen or sulfur and m is 1 to 3.

63. The copolymer composition according to claim 60, further characterized in that R is an alkylene group having from 1 to 7 carbon atoms.

64. - The copolymer composition according to claim 60, further characterized in that R 'is an alkyl group or a phenyl group.

65. The copolymer composition according to claim 60, further characterized in that R 'is an alkyl group having from 1 to 7 carbon atoms.

66. The copolymer composition according to claim 60, further characterized in that x is from 1 to 30.

67. The copolymer composition according to claim 60, further characterized in that said copolymer is prepared by solution polymerization.

68.- The copolymer composition in accordance with the - claim 60, further characterized in that said copolymer comprises additional biocompatible monomer units.

69. The copolymer composition according to claim 60, further characterized in that said copolymer is soluble in at least one of the solvents selected from the group consisting of acetone, dimethylene chloride, chloroform, ethyl acetate, DMAC, N-methylpyrrolidone, dimethylformamide and dimethyl sulfoxide.

70. The copolymer composition according to claim 60, further characterized in that said biologically active substance is selected from the group consisting of peptides, polypeptides, proteins, amino acids, polysaccharides, growth factors, hormones, anti-angiogenesis factors, interferons. or cytokines, and prodrugs of those substances.

71. The copolymer composition according to claim 60, further characterized in that said biologically active substance is a therapeutic drug or prodrug.

72. The copolymer composition according to claim 60, further characterized in that said biologically active substance is selected from the group consisting of antineoplastic, antibiotic, antiviral, antifungal, anti-inflammatory and anticoagulant agents.

73 - The copolymer composition according to claim 60, further characterized in that said drug is paclitaxel.

74.- The copolymer composition according to claim 60, further characterized in that said biologically active substance and said copolymer form a homogeneous matrix.

75. The copolymer composition according to claim 60, further characterized in that said polymer is characterized by a rate of release of the biologically active substance in vivo partially controlled as a function of hydrolysis of the phosphoester linkage of the polymer during biodegradation.