MXPA99009127A - Biodegradable terephthalate polyester-poly(phosphate) polymers, compositions, articles, and methods for making and using the same - Google Patents

Abstract

Biodegradable terephthalate polymers are described comprising the recurring monomeric units shown in formula (I):wherein R is a divalent organic moiety;R'is an aliphatic, aromatic or heterocyclic residue;x is=1;and n is 0-5,000, wherein the biodegradable polymer is biocompatible before and upon biodegradation. Processes for preparing the polymers, compositions containing the polymers and biologically active substances, articles useful for implantation or injection into the body fabricated from the compositions, and methods for controllably releasing biologically active substances using the polymers, are also described.

Description

BIODEGRADABLE POLYMERS OF TERTIKTALATE-POLKPHOSPHATE POLYESTER), COMPOSITIONS, ARTICLES AND METHODS FOR DEVELOPING AND USING THEM1. FIELD OF THE INVENTIONThe present invention relates to biodegradable compositions of homopolymer and block copolymer, in particular those containing ester linkages of both phosphate and terephthalate in the polymer backbone,that degrade in vivo in non-toxic waste. The polymers of the invention are particularly useful as implantable medical devices and drug delivery systems.2. BACKGROUND OF THE INVENTION 15 Biocompatible polymeric materials have been used extensively in therapeutic applications of drug delivery and medical implant devices. Sometimes, it is also convenient that these polymers are not only biocompatible, but also biodegradable,to eliminate the need to remove the polymer once its therapeutic value has been exhausted. In many cases, conventional methods of drug delivery such as frequent periodic dosing are not ideal. For example, with very toxic drugs, conventional frequent dosingcan cause high initial levels of drug at the time of dosing, often at near-toxic levels, which is followed by low drug levels between doses that may be below their therapeutic value. However, with the controlled release of the drug, drug levels can be maintained more easily at therapeutic but non-toxic levels; this through a predictable controlled release over a longer period. If a biodegradable medical device is intended to be used as a drug delivery system or other controlled release system, the use of a polymeric vehicle is an effective means to release the therapeutic agent locally and in a controlled manner; see Langer et al., "Chemical and physical structures of polymers as vehicles for controlled release of bioactive agents", J. Macro. Science, Rev. Macro. Chem. Phys., C23: 1, 61-126 (1983). As a result, less total drug is required and toxic side effects can be reduced. The polymers have been used as carriers of therapeutic agents to effect a localized and sustained release. See Leong et al., "Controlled release of drugs with polymers," Advanced Drug Delivery Reviews, 1: 199-233 (1987); Langer, "New methods of drug delivery", Science, 249: 1527-33 (1990); and Chien et al., Novel Drug Delivery Systems (1982). These delivery systems offer the potential for greater therapeutic efficacy and lower overall toxicity. For a non-biodegradable matrix, the steps leading to release of the therapeutic agent are the diffusion of water to the matrix, dissolution of the therapeutic agent and diffusion of the therapeutic agent outward through the channels of the matrix. As a consequence, the average residence time in which the therapeutic agent exists in a soluble state is greater for a non-biodegradable matrix than for a biodegradable matrix, therefore the passage through the matrix channels, although it may occur, It is no longer necessary. Since many pharmaceutical agents have short half-lives, the therapeutic agents can be decomposed or inactivated within the non-biodegradable matrix before being released. This question is particularly significant for many smaller bio-macromolecules and polypeptides, since these molecules are usually hydrolyticallyV unstable and have low permeability from one side to the other of the polymer matrix. In fact, in a non-biodegradable matrix, many bio-macromolecules aggregate with each other and precipitate, blocking the channels necessary for their diffusion outside the vehicle matrix. These problems are reduced by using a biodegradable matrix which, in addition to some release by diffusion, also allows the controlled release of the therapeutic agent by degradation of the polymer matrix. Examples of the classes of synthetic polymers that arehave studied as possible biodegradable materials, include polyesters* (Pitt et al., "Biodegradable Drug Release Systems Based on Aliphatic Polyesters: Application to Contraceptives and Narcotics Antagonists," Controlled Relase of Bioactive Materials, 19-44 (Richard Baker ed., 1980); poly (amino acids); pseudo-poly (amino acids) (Pulapura and others,"Trends in the development of bioresorbable polymers for medical applications", J. of Biomaterials Appi), 6: 1, 216-50 (1992); polyurethanes (Bruin et al., "Poly (glycolide-co-epsilon-caprolactone) biodegradable network based on potassium diisocyanate", Biomaterials, 11: 4, 291-95 (1990), polyorthoesters (Heller et al, "Release of norethindrone from poly (ortho-esters) ", PolymerEngineering Sci.), 21: 11, 727-31 (1981); and polyanhydrides (Leong et al., "P.Alianhydrides for the controlled release of bioactive agents", Biomaterials 7: 5, 364-71 (1986)). Specific examples of biodegradable materials that are used as medical implant materials are polylactide, polyglucolide, polydioxanone, poly (lactide-co-giicolda), poly (glycolide-co-polydioxanone), polyanhydrides, poly (glycolide-co-trimethylene carbonate). ), and poly (glycolide-co-caprolactone). Polymers are known to have phosphate bonds, called poly (phosphates), poly (phosphonates) and poly (phosphites). See Penczek et al., Handbook of Polymer Synthesis, Chapter 17: "Polymers containing phosphorus", (Hans R. Kricheldorf, ed., 1992). The respective structures of these three classes of compounds, each having a different side chain connected to the phosphorus atom, are as follows:O O O '- (- P- O- R- CHrr - (- P' i - O- R- CHrr - ^ / P ?? - O- R- CHp- O -R 'R' H Polyphosphate Polyphosphonate PolyphosphiteThe versatility of these polymers comes from the versatility of the phosphorus atom, of which a multitude of reactions are known. Your links may include 3p orbitals or several 3s-3p hybrids; spd hybrids are also possible by accessible d orbitals. In this way, the physicochemical properties of the poly (phosphoesters) can be easily changed by varying either the R group or the R 'group. The biodegradability of the polymer is mainly due to the physiologically labile phosphoester bond in the polymer backbone. By manipulating the skeleton or side chain, a wide range of biodegradation rates can be obtained.

An additional feature of poly (phosphoesters) is the availability of functional side groups. Since phosphorus can be pentavalent, drug molecules or other biologically active substances can be chemically bound to the polymer. For example, drugs with -O-carboxy groups can be coupled to phosphorus via an ester linkage that is hydrolysable. The P-O-C group in the skeleton also reduces the glass transition temperature of the polymer and, importantly, confers solubility in common organic solvents, which is convenient for easy characterization and processing. Login and others, in the Patents of E.U. Nos. 4,259,222; 4,315,847; and 4,315,969, describe 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. Kadiyala et al., Biomedical Applications of Synthetic Biodegradable Polymers, Chapter 3: "Poly (Phosphoesters): Synthesis, Physicochemical Characterization and Biological Response", 33-57 (Jeffrey O. Hollinger ed., 1995) on page 40, describe the synthesis of bis (2-hydroxyethyl) terephthalate (BHET) and its subsequent reaction with dimethyl phosphite to form the corresponding poly (phosphite):Various other patents describe flame retardants having a recurring unit of pore-bound terephthalate and may also have a repeating unit of poii (phosphonate) having a side chain -PR 'in which a R' group has replaced the hydrogen atom of a poly (phosphite), but lacks the oxygen that intervenes in a poly (phosphate). See, for example, Desitter et al., Patent of E.U.A. No. 3,927,231, and Reader, patent of E.U.A. No. 3,932,566. Starck et al., Patent of E.U.A. No. 597,473, disclose side chains which may be substituted with many types of groups, including an alkoxy group, but the document generally makes it clear that poly (phosphonates) rather than poly (phosphates) are contemplated. (See column 2, lines 28-40). Engelhardt et al., Patent of E.U.A. No. 5,530,093, discloses a multitude of finished textile compositions having a wide variety of polycondensed structures with recurring phosphoester units, including some with recurring terephthalate units, but give no guidance to indicate that poly (phosphates) should be selected more than the other two kinds of phosphoester polymers to make the biodegradable materials. Therefore, there remains a need for materials such as the poly terephthalate-poly (phosphate) polymers of the invention, which are particularly well suited for making biodegradable materials and for other biomedical applications.

BRIEF DESCRIPTION OF THE INVENTIONThe biodegradable terephthalate polymers of the present invention comprise the recurring monomer units shown in formula I:wherein: R is a divalent organic moiety; R 'is an aliphatic, aromatic or heterocyclic residue; x is > 1; and n is 0-5000, wherein the biodegradable polymer is sufficiently pure to be biocompatible and degrades into biocompatible waste after its biodegradation. In another embodiment, the invention contemplates a process for preparing a biodegradable terephthalate homopolymer, comprising the step of polymerizing p moles of a diol compound having the formula II:where R is as defined above, with q moles of a phosphorus-dichioridate of formula III: II O Cl-P-Cl I O-R 'where R 'is as defined above, and p > q, to form q moles of a homopolymer of formula IV, shown below:IVwhere R, R 'and X are as defined above. The invention also contemplates a process for preparing a biodegradable block copolymer, comprising the steps of: (a) the polymerization step described above; and (b) subsequently reacting the homopolymer of formula IV and excess of the diol of formula II with (p-q) moles of terephthaloyl chloride having the formula V: Vto form a block copolymer of formula I. In another embodiment, the invention comprises a biodegradable terephthalate polymer composition comprising: (a) at least one biologically active substance, and (b) a polymer having the recurring monomer units. shown in the formula I. In another embodiment of the invention, an article useful for implantation, injection, or to be placed in another form either partially or totally within the body, comprises the biodegradable terephthalate polymer of formula I, or the composition of polymer described above. In another embodiment of the invention, a method for the controlled release of a biologically active substance is provided, comprising the steps of: (a) combining the biologically active substance with a biodegradable terephthalate polymer having the recurring monomer units shown in the Formula I, to form a mixture; (b) converting the mixture into a solid article with form; and (c) implanting or injecting the solid article in vivo at a predetermined site, such that the implanted or injected solid article is at least in partial contact with a biological fluid.

BRIEF DESCRIPTION OF THE DRAWINGSFigure 1A shows the DSC curve of P (BHET-EOP / TC, 80/20), and Figure 1 B shows the DSC curve of P (BHET-EOP / TC, 50/50). Figure 2A shows the 1H-NMR spectrum, and Figure 2B shows the 31 P-NMR spectrum for P (BHET-EOP / TC, 80/20). Figure 3 shows the FT-IR spectrum for P (BHET-EOP / TC,80/20).

Figure 4 shows the GPC chromatogram for P (BHET-EOP / TC, 80/20). Figure 5 shows the molecular weights and the elementary analyzes for P (BHET-EOP / TC, 80/20) and P (BHET-HOP / TC, 90/10). Figure 6 shows the storage stability ofP (BHET-EOP / TC, 80/20) and P (BHET-EOP / TC, 85/15). Figures 7A and 7B show in vitro degradation data for P (BHET-EOP / TC, 80/20) and P (BHET-EOP / TC, 85/15). Figure 8 shows the molecular weight change of poly (phosphoesters) P (BHDPT-EOP) and P (BHDPT-EOP / TC) during their in vitro degradation. Figure 9 shows the in vivo degradation of P (BHET-EOP / TC, 80/20) in terms of weight loss. Figure 10 shows a photograph of electron microscopy of P microspheres (BHET-EOP / TC, 80/20) containing FITC-BSA. Figure 11 shows the effect of the loading level on the release kinetics of FITC-BSA from microspheres. Figure 12 shows the release of lidocaine from polymer microspheres BHDPT-EOP and BHDPT-HOP. Figure 13 shows the release of lidocaine from P-copolymer microspheres (BHDPT-EOPZTC). Figure 14 shows the cytotoxicity of P microspheres (BHET-EOP TC, 80/20). Figure 15 shows a graph of relative cell growth toxicity assay (%) against the concentration of degraded polymer in a tissue culture well (mg / ml) for four separate polymers.

Figure 16 shows a graph of cell toxicity assay for two microspheres and their respective monomers.

DETAILED DESCRIPTION OF THE INVENTIONPolymers of the Invention As used herein, the term "aliphatic" refers to a linear, branched or cyclic alkane, alkene or alkyne. Preferred aliphatic groups in the poly (phosphate) polymer of the invention are linear or branched alkanes having from 1 to 10 carbons, with linear alkane groups having from 1 to 7 carbon atoms being preferable. As used herein, the term "aromatic" refers to a cyclic carbon compound unsaturated 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 carbon in the ring, eg, nitrogen, oxygen or sulfur. The biodegradable terephthalate polymer of the invention comprises the recurring monomer units 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 polymer. Specifically, R can be an aliphatic group, for example, alkylene such as ethylene, 1,2-dimethylethylene, n-propylene, isopropylene, 2-methyl-propylene, 2,2'-dimethyl-propylene or tert-butylene, ter-pentylene, n-hexylene, n-heptylene and the like; alkenylene such as ethenylene, propenylene, dodecenylene and the like; alkynylene such as propynylene, hexinylene, octadecenylene and the like; an aliphatic group substituted with a non-intervening substituent, for example hydroxy-, halogen-, or aliphatic group substituted with nitrogen; or a cycloaliphatic group such as cyclopentylene, 2-methyl-cyclopentylene, 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-intervening substituent. In addition, R can be a divalent heterocyclic group such as pyrrolylene, furanylene, thiophenylene, alkylene-pyrrolylene-alkylene, pyridylene, pyridinylene, pyrimidinylene and the like, or can be any of these, substituted with a non-intervening substituent. However, preferably R is an alkylene group, a cycloaliphatic group, a phenylene group or a divalent group having the formula:wherein X is oxygen, nitrogen or sulfur, and n is from 1 to 3. Preferably, R is an alkylene group having from 1 to 7 carbon atoms and, most preferably, R is an ethylene group, a 2-methyl group -propylene, or a 2,2'-dimethyl-propylene group. R 'in the polymer of the invention is an aliphatic, aromatic or heterocyclic residue. When R 'is aliphatic, it is preferably alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -C 8 H 17, and the like; alkyl substituted with a non-intervening substituent such as halogen, alkoxy or nitro; or alkyl conjugated to a biologically active substance to form a pendant drug delivery system. When R 'is aromatic, it typically contains about 5 to 14 carbon atoms, preferably about 5 to 12 carbon atoms and, optionally, may contain one or more rings that may be 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 about 5 to 14 ring atoms, preferably about 5 to 12 ring atoms, and one or more heteroatoms. Examples of suitable heterocyclic groups include furan, thiophene, pyrrole, isopyrrole, 3-pyrrole, pyrazole, 2-isoimidazole, 1,2,3-triazole, 1,4-triazole, oxazole, thiazole, isothiazole, 1, 2,3-oxadiazole, 1,4-oxadiazole, 1, 2,5-oxadiazole, 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-oxathiol, 1,2-pyran, 1-4-pyran, 1 -2-pyrone, 1,4-pyrone, 1,2-dioxin, 1,3-dioxin, pyridine, N-alkyl-pyridinium, 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, 1,2,2-oxadiazine, 1, 3,5,2-oxadiazine, azepine, oxepine, tiepine, 1,4-diazepine, indene, isoindene , benzofuran, sobenzofuran, thionaphthene, isothionaphthene, indole, indolenyl, 2-benzezole, 1-4-pyrindine, pyrazo [3,4-b] -pyrrole, sodazole, indoxazine, benzoxazole, anthranil, 1,2-benzopyran , 1,2-benzopyrone, 1,4-benzopyrona, 2,1-benzopyrone, 2,3-benzopyrone, quinoline, isoquinoline, 1,2-benzodiazine, 1,3-benzodiazine, naphthyridine, pyrido [3,4-b] ] - pyridine, pyrid [3,2-b] -pyridine, pyridine [4,3-b] pyridine, 1,2-benzoxazine, 1,4-benzoxazine, 2 , 3,1-benzoxazine, 3,1, 4-benzoxazi na, 1,2-benzisoxazine, 1,4-benzizoxazine, 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 a particularly preferred embodiment, R 'is an alkyl group or a phenyl group and, most preferably, an alkyl group having from 1 to 7 carbon atoms. Preferably, R 'is an ethyl group. The value of x can vary widely, depending on the desired solubility of the polymer, the desired Tg, the desired polymer stability, the desired stiffness of the final polymers and the biodegradability and desired release characteristics in the polymer. However, usually x is >; 1 and, typically varies between 1 and 40, approximately. Preferably, x is about 1 to 30, preferably about 1 to 20 and most preferably about 2 to 20. The most common way to control the value of x is to vary the loading ratio of the "x" portion. in relation to the other monomer. For example, in the case of preparing the polymer:Widely variable loading ratios of phosphorus-dichioridate "x" reagent ("EOP") can be used with the terephthaloyl chloride ("TC") reagent.

The proportions of EOP 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 EOP / TC charge ratio ranges from about 90:10 to about 50:50; preferably from about 85:15 to 50:50, and most preferably from about 80:20 to about 50:50. The number n can vary widely depending on the biodegradability and the desired release characteristics in the polymer, but typically ranges from 0 to about 5,000, preferably from about 2 to about 500. It is preferred that n be from about 5 to 300, and preferably from about 5 to 200. Biodegradable polymers differ from non-biodegradable polymers in that they can be degraded during in vivo therapy. This usually involves breaking the polymer into its monomer subunits. In principle, the final products of the hydrolytic cleavage of a poly (phosphate) are phosphate, 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 made for implantation or injection, even synthesized from seemingly innocuous monomeric structures, is typically determined after one or more in vitro toxicity analyzes. Preferably, the biodegradable polymer of the invention is sufficiently pure to be biocompatible on its own and can remain biocompatible by biodegradation. By "biocompatible" it is understood that neither the biodegradation products nor the polymer are toxic and cause only minimal tissue irritation when implanted or injected into vascularized tissue.

The polymer of the invention is preferably soluble in one or more common organic solvents for ease of manufacture and processing. Common organic solvents include solvents such as chloroform, dichloromethane, acetone, ethyl acetate, DMAC, N-methyl-pyrrolidone, dimethylformamide and dimethyl sulfoxide. Preferably, the polymer is soluble 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 degree of branching of the diols used to prepare the polymer, the relative proportion of phosphorus-containing monomer used to make the polymer, and the like. However, preferably the Tg is within the range of about -10 ° C to 80 ° C, and preferably between 0 and 50 ° C approximately. Synthesis of Polyester Polymers (Phosphate) The most common general reaction in the preparation of poly (phosphates) is a dehydrochlorination between a phosphorus-dichioridate and a diol, according to the following equation:O OII n C - P - Cl n HO - R - OH * - -, P - - O - R - i + 2nHCI I O - R 'O - RA Friedel-Crafts reaction can also be used to synthesize poly (phosphates). The polymerization is typically carried out by reacting any bis (chloromethyl) compound with aromatic hydrocarbons or chloromethylated diphenyl ether, with triaryl phosphates. Poly (phosphates) can also be obtained by mass condensation between phosphorus diimidazolides and talus aromatic diols such as resorcinol and quinoline, usually under nitrogen or some other inert gas. One advantage of mass polycondensation is that it avoids the use of solvents and large amounts of other additives, thus making the purification more direct. It can also provide reasonably high molecular weight polymers. However, a little stringent conditions are often required and can cause chain acidolysis (or hydrolysis if water is present). Thermally undesirable side reactions such as entanglement reactions may also occur if the polymer backbone is susceptible to separation of hydrogen atoms or oxidation with subsequent recombination of macroradicals. To reduce these side reactions, the polymerization is preferably carried out in solution. Polycondensation in solution requires that both 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 receptor, usually a tertiary amine such as pyridine or triethylamine. Then, the product is typically isolated from the solution by means of precipitation with a non-solvent and purified to remove the hydrochloride salt by conventional techniques known to those of average skill in the art, such as washing with an aqueous acid solution, by example, dilute HCl. Reaction times tend to be longer in the solution polymerization than in the polymerization! mass. However, since milder reaction conditions can be used, side reactions can be reduced, and more sensitive functional groups can be incorporated into the polymer. The disadvantages of solution polymerization are that it is less likely to reach high molecular weights, such as an Mw greater than 20,000. Interfacial polycondensation can be used when high molecular weight polymers are desired at high reaction rates. The mild conditions reduce the side reactions. The dependence of the high molecular weight on the stoichiometric equivalence between the diol and the dichloridate, which is inherent for the methods in solution, is also eliminated. However, hydrolysis of the acid chloride in the alkaline aqueous phase may occur. Sensitive dichloridates that have a certain solubility in water are generally subject to hydrolysis instead of polymerization. Phase transfer catalysts such as crown ethers or tertiary ammonium chloride can be used to bring the ionized diol to the interface and facilitate the polycondensation reaction. The yield and molecular weight of the resultant 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 receptor, and the type and concentration of the phase transfer catalyst. In a preferred embodiment of the invention, the process for the preparation of a biodegradable terephthalate homopolymer of formula I comprises the step of polymerizing p moles of a diol compound having formula II:where R is as defined above, with q moles of a phosphorus-dichioridate of formula III:O II Cr- P- Cl I O- R 'wherein R 'is as defined above, and p > q, to form q moles of a homopolymer of formula IV, shown below:rvwhere R, R 'and x are as defined above. The homopolymer thus formed can be isolated, purified and used as such. Alternatively, the homopolymer, isolated or not, can be used to prepare a block copolymer of the invention by means of: (a) polymerization as described above; and (b) subsequent reaction of the homopolymer of formula IV and excess of diol of formula II with (p-q) moles of terephthaloyl chloride having the formula V: Vto form the 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 homopolymer. The polymerization step (a) can be carried out at widely varying temperatures, depending on the solvent used, the desired molecular weight, the desired solubility and the susceptibility of the reactants to form side reactions. Preferably, however, the polymerization step (a) takes place at temperatures of about -40 to + 160 ° C for solution polymerization, preferably around 0 to 65 ° C; In mass polymerization, temperatures on the scale of about + 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 about 30 minutes and about 24 hours. Although the polymerization step (a) may be in bulk, in solution, by means of interfacial polycondensation, or any other convenient polymerization method, preferably the polymerization step (a) is a solution polymerization reaction. Particularly when the solution polymerization reaction is used, an acid receptor will conveniently be present during the polymerization step (a). A particularly suitable class of acid receptor comprises tertiary amines such as pyridine, trimethylamine, triethylamine, substituted anilines and substituted aminopyridines. The preferred acid receptor is the substituted aminopyridine 4-dimethylaminopyridine ("DMAP").

The addition sequence for the polymerization step (a) can vary significantly depending on the relative reactivity of the diol of formula II, the phosphorus-dichioridate of formula III and the homopolymer of formula IV; the purity of these reagents; the temperature at which the polymerization reaction is carried out; the degree of agitation used in the polymerization reaction; and similar. Preferably, however, the diol of formula II is combined with a solvent and an acid receptor, and then phosphorus dichloridate is added slowly. For example, a phosphorus dichioridate solution in a solvent can be drained or added dropwise to the cooled reaction mixture of the diol, solvent and acid receptor to control the speed of the polymerization reaction. The purpose of the copolymerization of step (b) is to form a block copolymer comprising (i) the phosphorylated homopolymer chains produced as a result of the polymerization step (a), and (ii) interconnecting polyester units. The result is a block copolymer having a microcrystalline structure particularly well suited for use as a controlled release medium. The copolymerization step (b) of the invention usually takes place at a temperature slightly higher than the temperature of the polymerization step (a), but can also vary widely, depending on the type of copolymerization reaction used, the presence of one or more catalysts, the desired molecular weight, the desired solubility and the susceptibility of the reagents to undesirable side reactions. However, when the copolymerization step (b) is carried out as a solution polymerization reaction, it typically takes place 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 co-polymerization of step (b) can also vary widely, depending on the molecular weight of the desired material and, in general, on the need to use more or less stringent conditions for the reaction to proceed to the desired degree of termination. Typically, however, the copolymerization step (b) takes place for a time from about 30 minutes to 24 hours. The addition sequence for the copolymerization step (b) can vary significantly depending on the relative reactivities of the homopolymer of formula IV and the terephthaloyl chloride of formula V; the purity of these reagents; the temperature at which the copolymerization reaction is carried out; the degree of agitation used in the copolymerization reaction; and similar. Preferably, however, the terephthaloyl chloride of formula V is added slowly to the reaction mixture, instead of vice versa. For example, a solution of terephthaloyl chloride in a solvent can be drained or added dropwise to the cooled reaction or at room temperature to control the speed of the copolymerization reaction. The polymer of formula I, either a homopolymer (where and isO) or a block copolymer (where Y is greater than O), is isolated from the reaction mixture by conventional techniques such as precipitation separation, extraction with an immiscible solvent, evaporation, filtration, crystallization and the like. Typically, however, the polymer of formula I is isolated and purified by cooling a solution of said polymer with a non-solvent or a partial solvent such as diethyl ether or petroleum ether.

When the polymer of the invention is synthesized by a two-step polycondensation in solution to produce a block copolymer, the addition sequence of the reactive chlorides and the reaction temperatures in each step are preferably optimized to obtain the molecular weight combination desired with good solubility in common organic solvents. Preferably, the additive sequence comprises dissolving the bis-terephthalate starting material with an acid receptor in a solvent in which both are soluble, cooling the solution with stirring, slowly adding an equimolar amount of the phosphorus-dichioridate (dissolved in the same solvent) to the solution, allow to react at room temperature for a while, slowly add an appropriate amount of terephthaloyl chloride, which is also dissolved in the same solvent, and increase the temperature to about 50 ° C before refluxing during the night.

Biodegradability and Release Characteristics The polymer of formula I is usually characterized by a rate of release of the biologically active substance in vivo that is controlled, at least in part, as a function of the hydrolysis of the phosphoester linkage of the polymer during biodegradation. Additionally, the biologically active substance to be administered can be conjugated to the phosphorus side chain R 'to form a pendant drug delivery system. In addition, the structure of the side chain can influence the release behavior of the polymer. For example, it is expected that conversion of the side chain to a more lipophilic, more hydrophobic or bulky group would retard the degradation process. Thus, for example, the release is usually faster from polymer compositions with a small aliphatic group side chain, than with a voluminous aromatic side chain. The in vivo duration of a biodegradable polymer also depends on its molecular weight, crystallinity, biostability, and the degree of entanglement. In general, the higher the molecular weight, the greater the degree of crystallinity, and the higher the biostability, the slower the biodegradation. Consequently, the degradation times can vary widely, preferably from less than one day to several months.

Polymer Compositions The polymer of formula I can be used either alone or as a composition containing, in addition, a biologically active substance, to form a variety of useful biodegradable materials. For example, the polymer of formula I can be used to produce a bioabsorbable suture, an orthopedic tool or bone cement to repair damage to bone or connective tissue, a laminate for degradable or non-degradable fabrics, or a liner for an implantable device. , even without the presence of a biologically active substance. Preferably, however, the biodegradable terephthalate polymer composition comprises: (a) at least one biologically active substance, and (b) the polymer having the recurring monomer units in the formula I, wherein R, R '. x and n are as defined above.

The biologically active substance of the invention can vary widely for the purpose of the composition. The active substance or substances can be described as a single entity or a combination of entities. The delivery system is designed to be used with biologically active substances that have high solubility in water, as well as those having low water solubility, to produce a delivery system having controlled release rates. The term "biologically active substance" includes, without limitation, medications; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of diseases or discomforts; 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 medium. Non-limiting examples of broad categories of useful biologically active substances include the following therapeutic categories: anabolic agents, antacids, antiasthmatic agents, anti-cholesterol and anti-lipid agents, anticoagulants, anticonvulsants, antidiarrheals, antiemetics, anti-infective agents, anti-inflammatory agents, antimalarial agents, anti-nausea agents , antineoplastic agents, anti-obesity agents, antipyretic and analgesic agents, antispasmodics, antithrombotic agents, anti-calcemic agents, anti-angina agents, antihistamines, antitussives, appetite suppressants, biological agents, cerebral dilators, coronary dilators, decongestants, diuretics, diagnostic agents, agents erythropoietic, expectorants, gastrointestinal sedatives, anti-hyperglycemic agents, hypnotics, hypoglycaemic agents, ion exchange resins, laxatives, mineral supplements, mucolytic agents, neuromuscular rmacos, peripheral vasodilators, psychotropics, sedatives, stimulants, thyroid and antithyroid, uterine relaxants, vitamins, and prodrugs agents. More specifically, non-limiting examples of useful biologically active substances include the following therapeutic categories: analgesics such as non-steroidal anti-inflammatory drugs, opiate agonists and salicylates; antihistamines such as Hi blockers and H2 blockers; anti-infective agents such as anthelmintics, antianaerobes, antibiotics, aminoglycoside antibiotics, antifungal antibiotics, cephalosporin antibiotics, macrolide antibiotics, various β-lactam antibiotics, penicillin antibiotics, quinolone antibiotics, sulfonamide antibiotics, tetracycline antibiotics, antimycobacterials, antimicrobial antituberculosis drugs , antiprotozoa, antiprotozoa against malaria, antiviral agents, antiretroviral agents, scabicides and urinary anti-infectives; antineoplastic agents such as alkylating agents, nitrogen mustard alkylating agents, nitrosourea alkylating agents, antimetabolites, purine analog antimetabolites, pyrimidine analog antimetabolites, hormonal antineoplastics, natural antineoplastics, natural antineoplastic antibiotics, and natural vinca alkaloid antineoplastic agents; autonomic agents such as anticholinergic, antimuscarinic antimuscarinics, ergot alkaloids, parasympathomimetics, cholinergic agonist parasympathomimetics, cholinesterase inhibitor parasympathomimetics, sympatholytics, sympatholytic a-blockers, sympatholytic ß blockers, sympathomimetics, and sympathomimetics adrenergic agonists; cardiovascular agents such as antianginal, antianginal ß-blockers, antianginal calcium channel blockers, antianginal nitrate, antiarrhythmics, antiarrhythmic cardiac glycosides, class I antiarrhythmics, class II antiarrhythmics, class 5 antiarrhythmics, class IV antiarrhythmics, antihypertensive agents, anti-hypertensive agents a-blockers, antihypertensive drugs inhibitors of angiotensin-converting enzyme (ACE inhibitor), anti-hypertensive β-blockers, antihypertensive agents blocking the cleft channel, central action adrenergic antihypertensives, antihypertensive agents 10 diuretics, peripheral hypertensive antihypertensive vasodilators, antilipémicos, antilipemic bile acid sequestrants, antilipemic inhibitors of HMG-CoA reductase, inotropes, inotropic cardiac glycosides, and thrombolytic agents; Dermatological agents such as antihistamines, anti-inflammatory agents, anti-inflammatory agents, corticosteroids, anestheticslocal / antipruritic, topical anti-infectives, topical anti-fungal antifungal agents, antiviral topical anti-infectives, and topical antineoplastic agents;^ p electrolytic and renal agents such as acidifying agents, alkalizing agents, diuretics, diuretics, carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics,thiazide diuretics, electrolyte replacements and uricosuric agents; enzymes such as pancreatic enzymes and thrombolytic enzymes; gastrointestinal agents such as antidiarrheals, antiemetics, gastrointestinal anti-inflammatory agents, salicylate gastrointestinal anti-inflammatory agents, antacid anti-ulcer agents, agentsanti-ulcer gastric acid pump inhibitors, anti-ulcer agents of the gastric mucosa, anti-ulcer agents blockers H2, colelitolytic agents, digestive, emetics, laxatives and stool softeners and prokinetic agents; general anesthetics such as inhalation anesthetics, halogenated inhalation anesthetics, intravenous anesthetics, intravenous barbiturate anesthetics, intravenous benzodiazepine anesthetics, and intravenous anesthetics opiate agonists; hematological agents such as anti-anemia agents, hematopoietic antianemic agents, coagulation agents, anticoagulants, hemostatic coagulation agents, platelet inhibiting coagulation agents, thrombolytic enzyme coagulation agents, and plasma volume expanders; Hormones and hormone modifiers such as abortifacients, adrenal agents, adrenal agents, corticosteroids, androgens, antiandrogens, antidiabetic agents, antidiabetic agents of sulfonylurea, anti-hypoglycaemic agents, oral contraceptives, progestin contraceptives, estrogens, fertility agents, oxytocics, parathyroid agents, hormones pituitary, 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-gout anti-inflammatory agents, anti-inflammatory agents corticosteroids, anti-inflammatory agents of gold compounds, anti-inflammatory immunosuppressive agents, nonsteroidal anti-inflammatory drugs (NSAIDs), salicylate antiinflammatory agents, skeletal muscle relaxants, muscle relaxants, neuromuscular blocking agents, and relaxants of skeletal muscle reverse neuromuscular blockers; neurological agents such as anticonvulsants, barbiturate anticonvulsants, benzodiazepine anticonvulsants, anti-migraine agents, antiparkinson agents, antiviral agents, opiate agonists and opiate antagonists; ophthalmic agents such as antiglaucoma agents, anti-glaucoma agents beta-blockers, antiglaucoma agents miotics, mydriatics, mydriatics, adrenergic agonists, mydriatics, antimuscarinic agents, ophthalmic anesthetics, anti-infective ophthalmic agents, anti-infective aminoglycoside ophthalmic agents, anti-infective macrolide ophthalmic agents, quinolone ophthalmic antiinfectives, anti-infective sulfonamide anti-infective ophthalmic agents of tetracycline ophthalmic, ophthalmic antiinflammatory agents, anti-inflammatory agents ophthalmic corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) ophthalmic; psychotropic agents such as antidepressants, heterocyclic antidepressants, monoamine oxidase inhibitors (MAOIs), selective inhibitors of serotonin incorporation (ISISs), tricyclic antidepressants, antimaniacs, antipsychotics, phenothiazine antipsychotics, anxiolytics, sedatives and hypnotics, sedatives and hypnotics barbiturates, anxiolytics, sedatives and hypnotics of benzodiazepine, and psychostimulants; Respiratory agents such as antitussives, brincodilators, adrenergic agonist bronchodilators, antimuscarinic bronchodilators, expectorants, mucolytic agents, respiratory antiinflammatory agents and respiratory anti-inflammatory agents corticosteroids; toxicological agents such as antidotes, heavy metal antagonists / chelating agents, agents against substance abuse, deterrents against substance abuse and anti-abstinence agents for substances of abuse; minerals; and vitamins such as vitamin A, vitamin B, vitamin C, vitamin D, vitamin E and vitamin K.

Preferred classes of useful biologically active substances of the above categories include: (1) non-steroidal anti-inflammatory analgesics (NSAIDs) such as diclofenac, ibuprofen, ketoprofen and naproxen; (2) opiate agonist analgesics such as codeine, fentanyl, hydromorphone and morphine; (3) analgesic salicylates such as aspirin (ASA) (ASA with enteric coating); (4) antihistamine blockers Hi such as cimetidine and terfenadine; (5) antihistamines H2 blockers such as cimetidine, famotidine, nizadine and ranitidine; (6) anti-infective agents such as mupirocin; (7) antianaerobic antiinfectives such as chloramphenicol and clindamycin; (8) anti-infectious antifungal antibiotics such as amphotericin B, clotrimazole, fluconazole and ketoconazole; (9) anti-infective macrolide antibiotics such as azithromycin and erythromycin; (10) various anti-infective ß-lactam antibiotics such as aztreonam and mypenem; (11) anti-infective penicillin antibiotics such as nafcillin, oxacillin, penicillin G and penicillin V; (12) antiinfective quinolone antibiotics such as ciprofloxacin and norfloxacin; (13) anti-infective tetracycline antibiotics such as doxycycline, minocycline and tetracycline; (14) antimicrobial anti-tuberculosis drugs such as isoniazid (INH) and rifampicin; (15) antiprotozoal antiinfectives such as atovaquone and dapsone; (16) antiprotozoal anti-malarial anti-malaria drugs such as chloroquine and pyrimethamine; (17) antiretroviral anti-infectives such as ritonavir and zidovudine; (18) anti-viral antiviral agents such as acyclovir, ganciclovir, interferon alfa and rimantadine; (19) alkylating antineoplastic agents such as carboplatin and cisplatin; (20) nitrosoureas alkylating antineoplastic agents such as carmustine (BCNU); (21) Antimetabolite antineoplastic agents such as methotrexate; (22) pyrimidine-like antimetabolite antimetabolite agents such as fluorouracil (5-FU) and gemcitabine; (23) hormonal antineoplastic drugs such as goserelin, leuprolide and tamoxifen; (24) natural antineoplastics such as aldesleukin, interleukin 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 benztropine and trihexylphenidyl; (29) anticholinergic anticholinergic autonomic agents such as atropine and oxybutynin; (30) autonomic alkaloid agents of rye ergot such as bromocriptine; (31) parasympathomimetic cholinergic agonists such as pilocarpine; (32) cholinesterase inhibitor parasympathomimetics such as pyridostigmine; (33) sympatholytic β-blockers such as prazosin; (34) ß-blocker sympatholytics such as atenolol; (35) sympathomimetic adrenergic agonists such as albuterol and dobutamine; (36) cardiovascular agents such as aspirin (ASA) (ASA with enteric coating); (37) antianginal β-blockers such as atenolol and propranolol; (38) antianginal calcium channel blockers such as nifedipine and verapamil; (39) antianginal nitrate such as isosorbide dinitrate (ISDN); (40) antiarrhythmic cardiac glycosides such as digoxin; (41) class I antiarrhythmics such as lidocaine, mexiletine, phenytoin, procainimide and quinidine; (42) class II antiarrhythmics such as atenolol, metoprolol, propranolol and timolol; (43) class III antiarrhythmics such as amiodarone; (44) Class IV antiarrhythmics such as diltiazem and verapamil; (45) anti-hypertensive a-blockers such as prasozine; (46) Angiotensin-converting enzyme inhibitors (ACE inhibitors) antihypertensives such as captopril and enalapril; (47) β-blocker antihypertensives such as atenolol, metoprolol, nadolol and propanolol; (48) calcium channel blocking antihypertensive agents such as diltiazem and nifedipine; (49) centrally acting adrenergic antihypertensives such as clonidine and methyldopa; (50) diuretic antihypertensive agents such as amiloride, furosemide, hydrochlorothiazide (HCTZ) and spironolactone; (51) Peripheral vasodilator antihypertensive drugs such as hydralazine and minoxidil; (52) antilipémicos such as gemfibrozil and probucol; (53) anti-lipemic bile acid sequestrants such as cholestyramine; (54) antilipemic HMG-CoA reductase inhibitors such as lovastatin and pravastin; (55) nitropos such as amrinone, dobutamine and dopamine; (56) inotropic cardiac glycosides 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-infectives such as amphotericin B, clotrimazole, miconazole and nystatin; (61) topical antiviral anti-infectives such as acyclovir; (62) topical antineoplastic agents such as fluorouracil (5-FU); (63) electrolytic and renal agents such as lactulose; (64) loop diuretics such as furosemide; (65) potassium-sparing diuretics 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) anti-ulcer agents inhibiting the gastric acid pump such as omeprazole; (73) H2-blocking anti-ulcer agents such as cimetidine, famotidine, nizatidine and ranitidine; (74) digestives such as pancrealipase; (75) prokinetic agents such as erythromycin; (76) intravenous anesthetics opiate agonists such as fentanyl; (77) hematopoietic antianemic agents such as erythropoietin, f? Grastim (G-CSF) and sargramostim (GM-CSF); (78) coagulation agents such as antihemophilic 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) abortifains such as methotrexate; (83) antidiabetic agents such as insulin; (84) oral contraceptives such as estrogen and progestin; (85) progestin contraceptives such as levonorgestrel and norgestrei; (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) toroid hormones such as levothyroxine; (92) immunobiological agents such as interferon beta-1 b and interferon gamma-1b; (93) immunoglobulins such as IM immunoglobulin, IMIG, IGIM and immunoglobulin IV, IVIG, IGIV; (94) local amide anesthetics such as lidocaine; (95) local ester anesthetics such as benzocaine and procaine; (96) musculoskeletal corticosteroid anti-inflammatory agents such as beclomethasone, betamethasone, cortisone, dexamethasone, hydrocortisone and prednisone; (97) musculoskeletal anti-inflammatory immunosuppressants such as azathioprine, cyclophosphamide and methotrexate; (98) musculoskeletal non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac, ibuprofen, ketoprofen, ketorolac and naproxen; (99) skeletal muscle relaxants such as baclofßno, cyclobenzaprine and diazepam; (100) skeletal muscle reagents neuromuscular reverse 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) barbituric anticonvulsants such as phenobarbital and primodone; (104) benzodiazepine anticonvulsants such as clonazepam, diazepam and lorazepam; (105) antiparkinson agents such as bromocriptine, levodopa, carbidopa and pergolide; (106) anti-vertigo agents such as meclizine; (107) opiate agonists such as codeine, fentanyl, hydromorphone, methadone and morphine; (108) opiate antagonists such as naloxone; (109) β-blocking agents against glaucoma such as timolol; (110) miotic agents against glaucoma such as pilocarpine; (111) anti-infective aminoglycoside ophthalmic agents such as gentamcin, neomycin and tobramycin; (112) quinolone ophthalmic antiinfectives such as ciprofloxacin, norfloxacin and ofloxacin; (113) Ophthalmic corticosteroid anti-inflammatory agents such as dexamethasone and prednisolone; (114) ophthalmic nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac; (115) antipsychotics such as clozapine, haloperidol and risperidone; (116) anxiolytics, sedatives and hypnotics of benzodiazepine such as clonazepam, diazepam, lorazepam, oxazepam and prazepam; (117) psychostimulants such as methylphenidate and pemolin; (118) antitussives such as codeine; (119) bronchodilators such as theophylline; (120) adrenergic agonist bronchodilators such as albuterol; (121) respiratory anti-inflammatory agents corticosteroids such as dexamethasone; (122) antidotes such as flumazenil and naloxone; (123) antagonists / heavy metal chelating agents such as penicillamine; (124) deterrents against the abuse of substances such as disulfiram, naltrexone and nicotine; (125) anti-abstinence agents such as bromocriptine; (126) minerals such as iron, calcium and magnesium; (127) vitamin B compounds such as cyanocobalamin (vitamin B12) V niacin (vitamin B3); (128) vitamin C compounds such as ascorbic acid; and (129) vitamin D compounds such as calciferol. In addition to the above, the following less common drugs may also be used: chlorhexidine; oestradiol cypionate in oil; estradiol valerate in oil; flurbiprofen; sodium flurbiprofen; ivermectin; levodopa; nafarelin; and somatropin. In addition, the following new drugs can also be used: recombinant beta-glucan; bovine immunoglobulin concentrate; bovine superoxide dismutase; the formulation 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 mecasermin (r-IGF-1); Recombinant beta-1a interferon; lenograstim (G-CSF); olanzapine; recombinant thyroid stimulating hormone (r-TSH); and topotecan. The following intravenous products can also be used: sodium acyclovir; aldesleukin; atenolo; bleomycin sulfate, human calcitonin; salmon calcitonin; carboplatin; carmustine; dactinomycin, daunorubicin hydrochloride; docetaxel; Doxorubicin hydrochloride; epoetin alfa; etoposide (VP-16); fluorouracil (5-FU); sodium ganciclovir; gentamicin sulfate; interferon alfa; leuprolide acetate; meperidine hydrochloride; methadone hydrochloride; sodium methotrexate; paclitaxel; ranitidine hydrochloride; vinblastine sulfate; and zidovudine (AZT). Additional specific examples of biologically active substances useful 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 chlorphedianol hydrochloride; (c) antihistamines such as chlorpheniramine maleate, phenindamine tartate, 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 metal and alkaline earth metal salts; (g) ion exchange resins such as cholestyramine; (h) antiarrhythmics such as N-acetylprocainamide; (i) antipyretics and analgesics such as acetaminophen, aspirin and ibuprofen; (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 intyrieucins 1-18, including mutants and analogs, RNase, DNase, luteinizing hormone-releasing hormone (LHRH) ) and analogous, gonadotropin-releasing hormone (GnRH), growth-transforming factor-ß (TGF-ß), fibroblast growth factor (FGF), tumor necrosis factor-ß (TNF-a and ß), growth factor of nerve (NGF), growth hormone releasing factor (GHRF), epidermal growth factor (EGF), fibroblast growth factor homologous factor (FGFHF), hepatocyte growth factor (HGF), growth factor of insulin (TGF), factor 2 of invasion inhibition (IIF-2), bone morphogenetic proteins 1-7 (BMP 1 -7), somatostatin, thymosin a-1, gamma-globulin, superoxide dismutase (SOD), factors of complement, hGH, tP A, calcitonin, ANF, EPO and insulin; and (n) anti-infective agents such as antifungals, antivirals, antiseptics and antibiotics. Alternatively, the biologically active substance may be a radiosensitizer such as metoclopramide, sensamide or neusensamide (manufactured by Oxigene); profiromycin (made by Vion); RSR13 (made by Altas); Thymitaq (made by Agouron), etanidazoi or lobenguan (manufactured by Nycomed); gadolinium texafrin (made by Pharmacyclics); BuDR / Broxine (made by NeoPharm); IPdR (made by Sparta); CR2412 (made by Cell Therapeutic); L1X (made by Terrapin); or similar. Preferably, the biologically active substance is selected from the group consisting of peptides, polypeptides, proteins, amino acids, polysaccharides, growth factors, hormones, anti-angiogenesis factors, interferons or cytokines and prodrugs. In a particularly preferred embodiment, the biologically active substance is a drug or prodrug, preferably a drug selected from the group consisting of chemotherapeutic agents and other antineoplastics such as paclitaxel, antibiotics, antivirals, antifungals, anti-inflammatories and anticoagulants. The biologically active substances are used in amounts that are therapeutically effective. Although the effective amount of a biologically active substance will depend on the particular material used, amounts of the biologically active substance of about 1% to 65% have been readily incorporated into the present delivery systems, achieving controlled release. Smaller amounts may be used to achieve effective treatment levels for certain biologically active substances. Pharmaceutically acceptable carriers can be prepared from a wide variety of materials. Without being limited thereto, such materials include diluents, binders and adhesives, lubricants, disintegrants, colorants, fillers, flavors, sweeteners and various materials such as buffers and adsorbents, to prepare a particular medicinal composition.

Implants and Administration Systems Designed for Invention In its simplest form, a biodegradable therapeutic agent delivery system consists of a dispersion of the therapeutic agent in a polymer matrix. The therapeutic agent is typically released as the polymer matrix is biodegraded in vivo in soluble products that can be absorbed by the body and ultimately excreted therefrom. In a particularly preferred embodiment, an article is used for implantation, injection or to be otherwise positioned either partially or totally within the body, the article comprising 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, first the biologically active substance can be encapsulated in a microsphere and then combined with the polymer in such a way that at least a portion of the microsphere structure is maintained. Alternatively, the biologically active substance may be sufficiently immiscible in the polymer of the invention to be dispersed as small droplets, instead of being dissolved in the polymer. Any form is acceptable, but it is preferred that, regardless of the homogeneity of the composition, the release rate of the biologically active substance in vivo remains controlled, at least partially, as a function of the hydrolysis of the phosphoester linkage of the polymer by biodegradation . In a preferred embodiment, the article of the invention is designed for implantation or injection into the body of an animal. It is particularly important that said article cause minimal tissue irritation when implanted or injected into the vascularized tissue. As a structural medical device, the polymer compositions of the invention provide a physical form having specific chemical, physical and mechanical properties sufficient for the application, in addition to being a composition that degrades in vivo in non-toxic waste. Typical structural medical articles include implants such as orthopedic fixation devices, ventricular shunts, degradable fabric laminates, drug vehicles, bioabsorbable sutures, burn dressings, overlays for placing on other implant devices, and the like. In orthopedic articles, the composition of the invention may be useful for repairing damage to bone and connective tissue. For example, a biodegradable porous material with bone morphogenetic proteins can be loaded to form a bone implant useful even for large segmental defects. In vascular graft applications a biodegradable material may be used in the form of woven fabric to promote internal tissue growth. The polymer composition of the invention can be used as a temporary barrier to prevent adhesion of tissue, for example, after abdominal surgery. On the other hand, in nerve regeneration articles, the presence of a biodegradable support matrix can be used to facilitate the adhesion and proliferation of cells. When manufacturing the polymer composition as a nerve generation tube, for example, the tubular article can also serve as a geometric guide for axonal elongation in the direction of functional recovery. As a drug delivery device, the polymer compositions of the invention provide a polymer matrix capable of sequestering a biologically active substance and providing controlled, predictable release of the substance. The polymer matrix is then degraded into non-toxic waste. Implantable medical devices and biodegradable drug release products can be prepared in several ways. The polymer can be processed molten using conventional extrusion or injection techniques, or these products can be prepared by dissolving the polymer in an appropriate solvent, followed by the formation of the device, and subsequent removal of the solvent by evaporation or extraction. With these methods, polymers can be formed into drug delivery systems of almost any desired size or shape, for example, solid wafers or wafers or injectable rods, microspheres or other microparticles. Once an implant medical article is in position, it must remain in at least partial contact with a biological fluid such as blood, internal secretions of the organs, mucous membranes, cerebrospinal fluid and the like. The following examples are illustrative of preferred embodiments of the invention and are not constructed to be limiting of the invention. All the molecular weights of the polymers are average molecular weights. All percentages are based on the weight percent of the system or final administration formulation that is prepared, unless otherwise indicated, and all totals are equal to 100% by weight.

EXAMPLESEXAMPLE 1 Preparation of bis (2-hydroxyethyl) terephthalate monomer ("BHET")Ca (Ac) 2 (H20)?O OHOCH2CH20, - C r 11 - / W - r C 11 - 1 OCH2CH2OH(BHET)1.4 moles of dimethyl terephthalate (277 g) and 7.2 moles of ethylene glycol (445 g) were weighed into a 1 liter round bottom flask 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 slight vacuum. The reaction ended after 18 hours. While still melted, the mixture was emptied in cold water. The formed precipitate was collected, dried under vacuum and redissolved in warm methanol. The sediment (composed mainly of oligomers) was separated by filtration. 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 product "BHET".

Alternatively, BHET can be prepared with excellent purity according to the following reaction scheme:The BHT is also commercially available.

EXAMPLE 2 Synthesis of PÍBHET-EOP / TC copolymer. 80/20)(BHET)poly (BHET / EOP) (TC)poly (BHET / EOP / TC) In a 250 ml flask equipped with a funnel, 10 g of 1,4-bis (hydroxyethyl) terephthalate (BHET) prepared as described above were placed under a stream of argon. Example 1, 9.61 g of 4-dimethylamino pyridine (DMAP), and 70 ml of methylene chloride. The solution in the flask was cooled to -40 ° C with stirring, and a solution of 5.13 g of ethyl phosphorus dichloridate (EOP) (distilled before use) in 20 ml of chloride was added dropwise through the funnel. of methylene. After the addition was complete, the mixture was stirred at room temperature for four hours to form the BHET-EOP homopolymer. A solution of 1.60 g of terephthaloyl chloride (TC) (obtained from Aldrich Chemical Company and recrystallized with hexane before use) in 20 ml of methylene chloride was then added dropwise. The temperature was gradually brought to about 45-50 ° C, and the reaction mixture was refluxed overnight to complete the copolymerization of the homopolymer P (BHET-EOP) with the additional monomer TC to form the copolymer P (BHET- EOP / TC). The solvent was then evaporated and the residue was redissolved in approximately 100-200 ml of chloroform. The chloroform solution was washed three times with a saturated solution of NaCl, dried over anhydrous Na 2 S 4, and cooled in ether. The resulting precipitate was redissolved in chloroform and cooled again in ether. The leathery, off-white solid precipitate was separated by filtration and dried under vacuum. The yield was 82%. The structure of P (BHET-EOP / TC, 80/20) was determined by means of spectra of ^ H NMR, 31 p NMR and FT IR, as shown in figures 2 and 3. The structure was confirmed by means of elemental analysis, which was closely correlated with the theoretical proportions. The results of the elemental analysis are shown in Figure 5. The molecular weight of P (BHET-EOP / TC, 80/20) was first measured by gel permeation chromatography (CPG) with polystyrene as the calibration standard. The resulting graph established a weight average molecular weight (Mw) of about 6100 and a number average molecular weight (Mn) of about 2200, as shown in Figure 4. The vapor pressure osmometry ("VPO") for this polymer gave an Mn value of about 7900. The results of these molecular weight studies are also shown in Figure 5.

EXAMPLE 3 Variations in the charge ratio of P.BHET-EOP / TC, 80/20)A series of other P (BHET-EOP TC) copolymers of the invention was prepared following the procedure described above in Example 2, except that the charge ratio of EOP to TC used during the initial polymerization step and the step of copolymerization respectively. The results are shown later in Table 1. From the loading ratio of EOP TC, the value of "x" of the formula shown below can be calculated. For example, in P (BHET-EOP / TC, 80/20), prepared as in Example 2, x is 8.

TABLE 1 Variation of the charge ratio of EOP to TC in P.BHET-EOP / TC)* Charge ratio of ethyl phosphorus dichioridate to terephthaloyl chloride.

EXAMPLE 4 Synthesis of PÍBHET-HOP / TC copolymers. 80/20 v 90:10)The phosphoester P (BHET-HOP / TC, 80/20) and P (BHET-HOP / TC, 90/10) copolymers were prepared by the procedure described above in Example 2, except that it was replaced with hexyl phosphorus dichioridate.

("HOP") the ethyl phosphorus dichioridate monomer (EOP) during the initial polymerization step, and the loading ratio was varied. For P (BHET-HOPTC, 90/10), the elemental analysis was determined, the Mw / Mn value determined by CPG, and the Mn determined by OPV, and are shown in Figure 5.

EXAMPLE 5 Preparation of the bis-3-hydroxy-2,2'-dimethylpropyl terephthalate monomer ("BHDPT")Bis (3-hydroxy-2,2'-dimethylpropyl) terephthalate (BHDPT) was synthesized by reacting terephthaloyl chloride (TC) with an excess of the 2,2'-dimethyl-1,3-propanediol diol in 2-butanone with K2CO3 as the acid receptor.

EXAMPLE 6 Synthesis and isolation of homopolymer P (BHDPT-EOP)The monomer BHDPT prepared in Example 5 above and the 4-dimethyl-aminopyridine acid receptor (DMAP) were dissolved in methylene chloride. The resulting solution was cooled to -70 ° C using a dry ice / acetone bath, and an equimolar amount of ethyl phosphorus dichioridate (EOP) was added slowly. The reaction mixture was then heated and refluxed overnight. The salt formed in the polymerization was removed by filtration. The remaining polymer solution (filtrate) was washed three times with a saturated solution of NaCl and the homopolymer was precipitated in diethyl ether.

EXAMPLE 7 Synthesis of copolymer P.BHDPT-EOP / TC)EOP, DMAPCopolymers of P (BHDPT-EOP) were synthesized with CT by means of the two step solution copolymerization shown above. After the reaction between BHDPT and EOP proceeded at room temperature for one hour, the reaction flask was cooled in a dry ice / acetone bath. An appropriate amount of TC was slowly added to the flask (the number of moles of TC and EOP combined equaled the number of moles of BHDPT). The reaction mixture was then heated and refluxed overnight. The salt formed in the polymerization was removed by filtration. The remaining copolymer solution (filtrate) was washed three times with a saturated solution of NaCl, and the copolymer was precipitated in diethyl ether.

EXAMPLE 8 Variations of charge ratio for P (BHDPT-EOP / TC)A series of other P (BHDPT-EOP / TC) copolymers of the invention was prepared following the procedure described above in Example 7, except that the charge ratio of EOP to TC was varied which was used during the initial polymerization step and the copolymerization step respectively. The results are shown later in table 2. From the loading ratio of EOP / TC, the value of x of the formula shown below can be calculated. For example, in P (BHDPT-EOP TC, 80/20), the value of x is 8.

TABLE 2* Charge ratio of ethyl phosphorus dichioridate to terephthaloyl chloride.

EXAMPLE 9 Synthesis and isolation of the homopolymer Pf BHDPT-HOP)The monomer BHDPT prepared in Example 5 above and the 4-dimethyl-aminopyridine acid receptor (DMAP) were dissolved in methylene chloride. The resulting solution was cooled to -70 ° C using a dry ice / acetone bath, and an equimolar amount of hexyl phosphorus dichioridate (HOP) was added slowly. The reaction mixture was then heated and refluxed overnight. The salt formed in the polymerization was removed by filtration. The remaining polymer solution (filtrate) was washed three times with a saturated solution of NaCl and the homopolymer was precipitated in diethyl ether.

EXAMPLE 10 Synthesis of poly. phosphoester) P.BHPPT-HOP / TC)Copolymers of P (BHDPT-HOP) were synthesized with TC by means of a two step solution polymerization. After the reaction between BHDPT and HOP proceeded at room temperature for one hourThe reaction flask was cooled in a dry ice / acetone bath. An appropriate amount of TC was slowly added to the flask (the number of moles of TC and HOP combined equaled the number of moles of BHDPT). The reaction mixture was then heated and refluxed overnight. The salt formed during the copolymerization was removed by filtration. The remaining copolymer solution (filtrate) was washed three times with a saturated solution of NaCl, and the copolymer was precipitated in diethyl ether.

EXAMPLE 11 Other variations of diolDiol terephthalates that are structurally related to BHET and BHDPT were synthesized in a manner similar to that used in Example 5, by reacting TC with n-propylene diol or with 2-methylpropylene diol, the structures of which are shown below, to form the diol terephthalate. correspondent.

These diol terephthalates were then reacted withEOP to form the corresponding homopolymers. The homopolymers thus formed were then used to produce the copolymers of the invention in a second reaction with TC, as described above in Example 7.

EXAMPLE 12 Glass transition temperatures for copolymers P.BHET-EOP / TC)By means of differential scanning calorimetry (DSC), it was determined that the glass transition temperatures (Tgs) of P (BHET-EOP / TC, 80/20) and P (BHET-EOP / TC, 50/50), they were 24.5 ° C and 62.2X, respectively. Figure 1 shows the DSC curves for these two polymers. The Tgs of four additional copolymers of P (BHET-EOP / TC) of different proportions of charge EOP TC were determined and their results were tabulated as shown in table 3 below:TABLE 3 Polymer glass transition temperatures (Tgs) (BHET-EOP TC)* Ratio of ethyl phosphorodichloride to terephthaloyl chloride The Tg increased as the proportion of EOP decreased and the proportion of TC increased.

EXAMPLE 14 Glass transition temperatures for P copolymers (BHDPT-EOP / TC)We also conducted a study of the influence of an increasing proportion of terephthaloyl chloride (TC) on the Tgs of polymers P (BHDPT-EOP / TC). The results are shown below in table 4.

TABLE 4 Influence of the EOP / TC ratio on the Tg of P BHDPT-EOP / TC)* The total molar amount of Te and EOP equaled the molar amount of BHDPT.

EXAMPLE 15 Glass transition temperatures for several R groupsA study was also conducted showing the effect on the glass transition temperature (Tg) for copolymers made from the following series of diols having variable R groups:wherein R is -CH2CH2-; -CH2CH2CH2-; -CH2CH (CH3) CH2-; and -CH2CH (CH3) 2CH2-. The results are shown below in table 5:TABLE 5 Influence of the change of the "R" group on the Tg of the polymerAs shown in Table 5, the Tg increased as the size and degree of branching of the R group increased. In addition, the polymers changed their physical condition as the Tg changed.

Specifically, as the Tg increased, the polymers changed from rubber consistency to fine powders.

EXAMPLE 16 Solubilities of the polymers of the inventionThe solubility in organic solvents of the homopolymer P (BHET-EOP, 100/0) and for the following block copolymers was determined: P (BHET-EOP / TC, 95/5) P (BHET-EOP / TC, 90/10 ) P (BHET-EOP / TC, 85/15) P (BHET-EOP / TC, 80/20) and P (BHET-EOP / TC, 50/50).

The organic solvents used for the test were chloroform, methylene chloride, N-methyl-pyrrolidone (NMP), dimethylformamide (DMF) and dimethyl sulfoxide (DMSO). The results of these solubility tests are summarized below in Table 6.

BOX ßThe results showed that the solubility of these polymers in organic solvents increased as the EOP / TC ratio increased.

EXAMPLE 16 Viscosities of polymersThe intrinsic viscosities of a series of polymers P (BHET-EOP / TC) of different charge ratios in chloroform (CH3CI) at 40 ° C in a Ubbeiohde viscometer were measured. The results are shown below in table 7.

TABLE 7 Intrinsic viscosities of polymers PÍBHET-EOP / TC)* Charge ratio of ethyl phosphorus dichioridate to terephthaloyl chloride. + The intrinsic viscosity of P (BHET-EOP / TC, 50/50) was not determined because it was not soluble in chloroform.

EXAMPLE 17 Physical propertiesFilm sheets were prepared by solvent casting of a series of P (BHET-EOP / TC) copolymers having varying loading ratios. Both copolymer P (BHET-EOP / TC, 80/20) and P (BHET-EOP / TC, 85/15) exhibited good film-forming properties. Also, fibers of the molten copolymer at 160 ° C were successfully pulled with both copolymers.

EXAMPLE 18 Stability testsThe copolymers (BHET-EOP / TC) of the invention were placed in a desiccator at room temperature and their stability was monitored by intrinsic viscosity and GPC. The copolymers were stable under these conditions without the need to store under inert gas. Samples of P (BHET-EOP / TC, 80/20) were also saved andP (BHET-EOP TC, 85/15) for one month at the ambient atmosphere and temperature. The stability was tested by intrinsic viscosity at the end of a period of one month, and the results are plotted in Figure 6.

EXAMPLE 19 In vitro degradationP films (BHET-EOP / TC, 80/20) and P (BHET-EOP / TC, 85/15) were made by solution casting methods, as prepared in Example 18, and dried under vacuum for 2 hours. Discs 1 mm thick and 6 mm in diameter were cut from these film sheets. Three disks of each copolymer were placed in 4 ml of phosphate buffered saline (PBS) (0.1 M, pH 7.4) at 37 ° C. The discs were taken from the PBS at different time points, washed with distilled water and dried overnight. Samples were analyzed to determine molecular weight changes and weight loss over time, as shown in Figures 7A and 7B. The weight average molecular weight of P (BHET-EOP / TC, 80/20) was reduced by approximately 20% in three days. After 18 days, the P disks (BHET-EOP / TC, 85/15) and P (BHET-EOP / TC, 80/20) lost approximately 40% and 20% by mass, respectively. These data demonstrated the feasibility of finely adjusting the degradation rate of the copolymers and confirmed that the copolymers became hydrolytically more labile as the phosphate component (EOP) increases. The same procedure was repeated for the polymers ofP (BHDPT-EOP) synthesized in Examples 6-8 above, including copolymers with different loading ratios from EOP to TC. Figure 8 is a diagrammatic representation of the degree of degradation of homopolymer P (BHDPT-EOP) and the following block copolymers, as measured by molecular weight change over time: P (BHDPT-EOP / TC, 85/15 ), P (BHDPT-EOP / TC, 75/25), and P (BHDPT-EOP / TC, 50/50).

EXAMPLE 20 In vivo degradation of the copolymer P (BHET-EOP / TC)Figure 9 shows the in vivo degradation of P (BHET-EOP / TC,80/20), measured by weight loss.

EXAMPLE 21 In Vitro Biocompatibility / Cytotoxicity of P (BHET-EOP / TC, 80/20)The cytotoxicity of the copolymer P (BHET-EOP / TC, 80/20) was determined by culturing human embryonic kidney (HEK) cells on a coverslip that had been coated with the copolymer P (BHET-EOP / TC, 80/20). HEK cells were also cultured on a coverslip coated with TCPS. Cells grown on the copolymer coated coverslip exhibited normal morphology at all times and proliferated significantly at 72 days, compared to a considerably smaller amount when identical HEK cells were grown on TCPS.

EXAMPLE 22 In vivo biocompatibility of P (BHET-EOP / TC, 80/20)A 100 mg wafer of P-polymer (BHET-EOP / TC, 80/20) was formed and, as a reference, a copolymer of lactic and glycolic acid ("PLGA", 75/25), known to be biocompatible. These wafers were inserted between muscle layers of the right foot of adult Sprague-Dawley SPF rats under anesthesia. The wafers were recovered at specific times and the surrounding tissues were prepared for histopathological analysis by a certified pathologist using the following punctuation:Score Irritation level 0 No irritation 0-200 Very slight irritation 200-400 Mild irritation 400-600 Moderate irritation More than 600 Severe irritationThe results of the histopathological analysis are shown below in table 8.

TABLE 8 Inflammatory response at the implantation site (i.m.)It was observed that the phosphoester copolymer P (BHET-EOP TC, 80/20) has an acceptable biocompatibility similar to that exhibited by the PLGA reference wafer.

EXAMPLE 23 Preparation of P-microspheres (BHET-EOP / TC 80/20) by encapsulating FITC-BSAMicrospheres were prepared by a double emulsion / solvent extraction method using FITC-labeled bovine serum albumin (FITC-BSA) as a model protein drug. 100 μl of a FITC-BSA solution (10 mg / ml) was added to a solution of 100 mg of P (BHET-EOP / TC, 80/20) in 1 ml of methylene chloride, and emulsified by sonication for 15 minutes. seconds on ice. The resulting emulsion was immediately emptied into 5 ml of an aqueous solution vortexed in 1% polyvinyl alcohol (PVA) and 5% NaCl. The vortex was held for one minute. The resulting emulsion was emptied into 20 ml of an aqueous solution of 0.3% PVA and 5% NaCl, which was stirred vigorously. 25 ml of a 2% isopropanol solution was added and the mixture was kept stirred for one hour to ensure complete extraction. The resulting microspheres were harvested by centrifugation at 3000 X g, washed three times with water and lyophilized. Empty microspheres were prepared in the same way but using water as the internal aqueous phase. These preparation conditions have been optimized to increase the encapsulation efficiency, improve the morphology of the microspheres and reduce the burst release. The resulting microspheres were mainly of a diameter between 5 and 20 μm and exhibited a smooth surface morphology. Figure 10 shows the size and smoothness of the microspheres, demonstrated by electron microscopy. The loading level of FITC-BSA was determined by analyzing FITC after hydrolyzing the microspheres in a 0.5 N NaOH solution overnight. The loading levels were determined by comparison with a standard curve generated by making a series of FITC-BSA solutions in 0.5 N NaOH. Protein loading levels of 1.5, 14.1 and 22.8% by weight were easily obtained. The encapsulation efficiency of FITC-BSA was determined by the microspheres at different loading levels, comparing the trapped amount of FITC-BSA with the initial amount in solution by fluorometry. As shown later in Table 9, encapsulation efficiencies of 84.6 and 99.6% were obtained. These results showed that encapsulation efficiencies of 70-90% can easily be obtained.

TABLE 9 Encapsulation efficiency and loading level of FITC-BSA in P (BHET-EOP / TC, 80/20)In addition, it was determined by observation with confocal fluorescence microscopy that the encapsulated FITC-BSA was evenly distributed within the microspheres.

EXAMPLE 24 Preparation of P-microspheres (BHDPT-EOP / TC, 50/50) containing lidocaineAn aqueous solution of polyvinyl alcohol (PVA) 0.5% w / v was prepared in a 600 ml flask combining 1.35 g of PVA with 270 ml of deionized water. The solution was stirred for one hour and filtered. A copolymer / drug solution was prepared by combining 900 mg of copolymer P (BHDPT-EOP / TC, 50/50) and 100 mg of lidocaine in 9 ml of methylene chloride and mixed with vortex. While stirring the PVA solution at 800 rpm with a mixer above, the polymer / drug mixture was added. The combination was stirred for an hour and measured. The microspheres thus formed were then filtered, washed with deionized water and lyophilized overnight.

The experiment produced 625 mg of microspheres loaded with 3.7% w / w of lidocaine. Microspheres containing lidocaine were also prepared from P (BHDPT-HOP TC, 50/50) by the same procedure. This experiment produced 676 mg of microspheres loaded with 5.3% w / w of lidocaine.

EXAMPLE 25 In vitro release kinetics of microspheres prepared from P-copolymers (BHET-EOP / TC, 80/20)Five mg of P (BHET-EOP / TC, 80/20) microspheres containing FITC-BSA were suspended in one ml of phosphate buffer saline (PBS) at pH 7.4 and placed on a heated stirrer at a temperature of 37 ° C. At various time points the suspension was rotated at 3000 X g for 10 minutes and 500 μl samples of the supernatant fluid were removed and replaced with fresh PBS. The release of FITC-BSA from the microspheres was followed by measuring the fluorescence intensity of the samples extracted at 519 nm. Climbing upwards, 50 mg of P microspheres (BHET-EOP / TC, 80/20) were suspended in flasks containing 10 ml of phosphate buffer saline (PBS). The flasks were heated in an incubator at a temperature of 37 ° C and shaken at 220 rpm. Samples were removed from the supernatant and replaced at various time points, and the amount of FITC-BSA released in the samples was analyzed by spectrophotometry at 492 nm.

The results indicated that more than 80% of the encapsulated FITC-BSA was released over the course of the first two days, with an additional amount released of approximately 5% after 10 days in PBS at 37 ° C. The release kinetics of FITC-BSA from P microspheres (BHET-EOP / TC, 80/20) at different loading levels, is shown in Figure 11.

EXAMPLE 26 Kinetics of In Vitro Release of Microspheres Prepared from Copolymers P (BHDPT-EOP / TC, 50/50)Approximately 10 mg of P (BHDPT-EOPTC, 50/50) microspheres loaded with lidocaine were placed in PBS (0.1 M, pH 7.4) at 37 ° C on a shaker. Samples of the incubation solution were periodically removed and the amount of lidocaine released in the samples was determined by HPLC. Figures 12 and 13 show the resulting release kinetics. The same procedure was followed for microspheres prepared from P (BHDPT-HOP / TC, 50/50). Figures 12 and 13 also show the kinetics of lidocaine release from these microspheres.

EXAMPLE 27 In vitro cytotoxicity test of the copolymer on cellsP-microspheres (BHET-EOP / TC, 80/20) were added to 96-well tissue culture plates at different concentrations. Subsequently, wells were harvested with human gastric carcinoma cells (GT3TKB) at a density of 10 4 cells / well. The cells were incubated with the microspheres for 48 hours at 37 ° C. The resulting proliferation rate of the cells was analyzed by MTT test and plotted as percentage of relative growth against concentration of copolymer microspheres in the tissue culture well. The results are shown in figure 14.

EXAMPLE 28 Toxicity test of polymer degradation products on tumor cells GT3TKBThe degradation of approximately 100-150 mg of each of the following polymers was separately caused in 20 ml of 1M NaOH at 37 ° C for 1-2 days:PLLA (Mw = 14,000) P (BHET-EOP) PCPP: SA (20:80) Poly (L-lysine) (Mw = 88,000)Complete degradation of all polymers was observed.

The solution was then neutralized with 20 ml of 1 M HCl. Approximately 200 μl of the degradation products of the polymers at different concentrations were placed in 96-well tissue culture plates and seeded with human gastric carcinoma cells (GT3TKB) at a density of 104 / well. The degradation products of the polymer were incubated with GT3TKB cells for 48 hours.

The results of the test were graded as% relative growth versus concentration of degraded polymer in the tissue culture well and are shown in Figure 15. An additional toxicity test was performed with microspheres prepared from BHET monomer and BHET-homopolymer. EOP, and compared with microspheres prepared from LA and PLLA. The results of the test were plotted as% relative growth against the concentration of the polymers or microspheres in a tissue culture well and are shown in Figure 16. Having described the invention, it will be obvious that it can be varied in many ways. It is considered that such variations do not deviate from the spirit and scope of the invention, and it is intended that all these modifications are included within the scope of the following claims.

Claims (114)

NOVELTY OF THE INVENTION CLAIMS

1. - A biodegradable terephthalate polymer comprising the recurring monomer units shown in formula I: wherein R is a divalent organic moiety; R 'is an aliphatic, aromatic or heterocyclic residue; x is > 1; and n is 0 - 5,000; wherein said biodegradable polymer is biocompatible before and after its degradation.

2. The polymer 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: wherein X is oxygen, nitrogen or sulfur, and n is from 1 to 3.

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

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

5. - The polymer according to claim 1, further characterized in that R is an n-propylene group.

6. The polymer according to claim 1, further characterized in that R is 2-methyl-propylene.

7. The polymer according to claim 1, further characterized in that R is 2,2'-dimethyl-propylene.

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

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

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

11. The polymer according to claim 1, further characterized in that x is from about 1 to about 30.

12. The polymer according to claim 1, further characterized in that x is from about 1 to about 20.

13. - The polymer according to claim 1, further characterized in that x is from about 2 to about 20.

14. The polymer according to claim 1, further characterized in that said polymer is prepared by solution polymerization.

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

16. The polymer according to claim 1. further characterized in that said polymer is soluble in at least one solvent selected from the group consisting of acetone, dimethylene chloride. chloroform, ethyl acetate, DMAC, N-methyl-pyrrolidone, dimethylformamide and dimethyl sulfoxide.

17. A process for the preparation of a biodegradable terephthalate homopolymer comprising the recurring monomer units of the formula I: wherein R is a divalent organic moiety; R 'is an aliphatic, aromatic or heterocyclic residue; x is es = 1; and n is 0 - 5,000; wherein said biodegradable polymer is biocompatible before and after its biodegradation; said process comprises the step of polymerizing p moles of a diol compound having the formula II: wherein R is as defined above, with g moles of a phosphorus-dichioridate of formula III: Or II Cl- P- Cl I o- re where R 'is as defined above, and p > q. to form q moles of a homopolymer of formula IV, shown below: IV where R, R 'and x are as defined above.

18. The process according to claim 17, further characterized in that R is an alkylene group having 1 to 7 carbon atoms.

19. The process according to claim 17, further characterized in that R is an ethylene group.

20. The process according to claim 17. further characterized in that R is a n-propylene group.

21. The process according to claim 17, further characterized in that R is 2-methyl-propylene.

22. The process according to claim 17, further characterized in that R is 2,2'-dimethyl-propylene.

23. The process according to claim 17, further characterized in that R 'is an alkyl group having from 1 to 7 carbon atoms.

24. The process according to claim 17, further characterized in that R 'is an ethyl group.

25. The process according to claim 17, further characterized in that x is from about 1 to about 40.

26.- The method according to claim 17, further characterized in that said polymerization reaction is carried out at a temperature of about -40 to approximately + 160 ° C.

27. The method according to claim 17, further characterized in that the temperature of the polymerization varies approximately from 0 to 65 ° C.

28. The method according to claim 17, further characterized in that said polymerization is carried out for a time of between 30 minutes and 24 hours approximately.

29. The process according to claim 17, further characterized in that said polymerization is a solution polymerization reaction.

30. The method according to claim 17, further characterized in that an acid receptor is present.

31. The process according to claim 17, further characterized in that the acid receptor is a tertiary amine.

32. A process for the preparation of a biodegradable terephthalate polymer comprising the recurring monomer units of formula I: wherein R is a divalent organic moiety; R 'is an aliphatic, aromatic or heterocyclic residue; x is es > 1; and n is 0 - 5,000; wherein said biodegradable polymer is biocompatible before and after its biodegradation; said method comprises the steps of: (a) polymerizing p moles of a compound dio! which has the formula II: where R is as defined above, with q moles of a phosphorus-dichioridate of formula III: where R 'is as defined above, and p > q, to form q moles of a polymer of formula IV, shown below: IV where R, R 'and x are as defined above; and (b) subsequently reacting said polymer of formula IV and excess diol of formula II with (p-q) moles of terephthaloyl chloride having the formula V: V 5 to form said polymer of formula I.

33.- The process according to claim 32, ) further characterized in that R is an alkylene group having from 1 to 7 carbon atoms.

34. The process according to claim 32, further characterized in that R is an ethylene group.

35. The process according to claim 32, further characterized in that R is an n-propylene group.

36. The process according to claim 32, further characterized in that R is 2-methylpropylene.

37. The process according to claim 32, further characterized in that R is 2,2'-di-methyl-propylene.

38.- The process according to claim 32, further characterized in that R 'is an alkyl group having from 1 to 7 carbon atoms.

39. The method according to claim 32, further characterized in that R1 is an ethyl group.

40.- The method according to claim 32, further characterized in that x is approximately 1 to 30.

41. The method according to claim 32, characterized in that x is approximately 2 to 20.

42. - The method according to claim 32, further characterized in that said step (a) of the polymerization reaction is carried out at a temperature of about -40 to about + 160 ° C.

43.- The method according to claim 32, further characterized in that the temperature of the polymerization step (a) varies approximately from 0 to 65 ° C.

44.- The method according to claim 32, further characterized in that said step (a) of the polymerization is carried out for a time of between 30 minutes and 24 hours approximately.

45.- The procedure according to claim 32, further characterized in that said step (a) of the polymerization is a solution polymerization reaction.

46.- The method according to claim 32, further characterized in that an acid receptor is present during said polymerization step (a).

47. The method according to claim 32, further characterized in that the acid receptor is a tertiary amine.

48. The method according to claim 32, further characterized in that said step (b) of copolymerization is carried out at a temperature between -40 and 100 ° C approximately.

49.- The method according to claim 32, further characterized in that said step (b) of copolymerization is carried out for a time of approximately 30 minutes to 24 hours.

50.- The process according to claim 32, further characterized in that said polymer of formula I is purified by cooling a solution of said polymer with a non-solvent or a partial solvent.

51. A bioabsorbable suture comprising the polymer of claim 1.

52. A brace, bone cement or bone wax for repairing damage to bone and connective tissue, comprising the polymer of i and claim 1.

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

54.- A coating for an implantable device comprising the polymer of claim 1.

55.- A biodegradable terephthalate polymer composition comprising (a) at least one biologically active substance, and (b) a polymer having the recurrent monomer units shown in formula I: Wherein R is a divalent organic moiety; R 'is an aliphatic, aromatic or heterocyclic residue; x is es = 1; and n is 0 - 5,000; and said polymer is biocompatible before and after its biodegradation.

56.- The polymer composition according to claim 55, further characterized in that R is an alkylene group, a cycloaliphatic group, a phenylene group, or a divalent group having the formula: wherein X is oxygen, nitrogen or sulfur , and n is from 1 to 3. 5

57. The polymer composition according to claim 55, further characterized in that R is an ethylene group.

58. The polymer composition according to claim 55, further characterized in that R is an n-propylene group.

59. The polymer composition according to claim 55, further characterized in that R is 2-methyl-propiieno.

60.- The polymer composition according to claim 55, further characterized in that R is 2,2'-dimethyl-propylene.

61- The polymer composition according to claim 55, further characterized in that R 'is an alkyl group or a phenyl group.

62.- The polymer composition according to claim 55, further characterized in that R 'is an ethyl group.

63.- The polymer composition according to claim 55, further characterized in that x is from about 1 to 20 about 30.

64.- The polymer composition according to claim 55, further characterized in that said copolymer is prepared by polymerization in solution.

65.- The polymer composition according to claim 55, further characterized in that said polymer comprises additional biocompatible monomer units.

66. - The polymer composition according to claim 55, further characterized in that said polymer is soluble in at least one solvent selected from the group consisting of acetone, dimethylene chloride, chloroform, ethyl acetate, DMAC, N-methyl-pyrrolidone , dimethylformamide and dimethyl sulfoxide.

67.- The polymer composition according to claim 55, 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 these substances.

68.- The polymer composition according to claim 55, further characterized in that said biologically active substance is a therapeutic drug or prodrug.

69.- The polymer composition according to claim 68, characterized in that said drug is selected from the group consisting of antineoplastic, antibiotic, antiviral, antifungal, anti-inflammatory and anticoagulant agents.

70. The polymer composition according to claim 55, further characterized in that said biologically active substance and said polymer form a homogeneous matrix.

71.- The polymer composition according to claim 55, further characterized in that it has an in vivo release rate of the biologically active substance, which is controlled at least partially as a function of the hydrolysis of the phosphoester linkage of the polymer during its biodegradation

72. - A useful article for implantation, injection or to be placed in another way totally or partially inside the body; said article comprises a biodegradable terephthalate polymer composition consisting of: (a) at least one biologically active substance, and (b) a polymer having the recurring monomer units shown in Figure I: Wherein R is a divalent organic moiety; R 'is an aliphatic, aromatic or heterocyclic residue; x is es > 1; and n is 0 - 5,000; wherein said polymer is sufficiently pure to render the biocompatible biodegradable composition after its biodegradation. 15.

The article according to claim 72, further characterized in that R is an alkylene group, a cycloalkylene group, a phenylene group or a divalent group having the formula: wherein X is oxygen, nitrogen or sulfur, and n is from 1 to 3.

The article according to claim 72, further characterized in that R is an ethylene group.

75.- The article according to claim 72, 25 further characterized in that R is an n-propylene group.

76. - The article according to claim 72, further characterized in that R is 2-methyl-propylene.

77. The article according to claim 72, further characterized in that R is 2,2'-dimethyl-propylene.

78. The article according to claim 72, further characterized in that R 'is an alkyl group or a phenyl group.

79. The article according to claim 72, further characterized in that R 'is an ethyl group.

80.- The article according to claim 72, further characterized in that x is from about 1 to about 30.

81.- The article according to claim 72, further characterized in that x is approximately 2 to 20.

82.- The article according to claim 72, further characterized in that said polymer is prepared by solution polymerization.

83. The article according to claim 72, further characterized in that said polymer comprises additional biocompatible monomer units.

84. The article according to claim 72, further characterized in that said polymer is soluble in at least one solvent selected from the group consisting of acetone, dimethylene chloride, chloroform, ethyl acetate, DMAC, N-methyl-pyrrolidone , dimethylformamide and dimethyl sulfoxide.

85.- The article according to claim 72, 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 these substances.

86.- The article according to claim 72, further characterized in that said biologically active substance is a therapeutic drug or prodrug.

87. The article according to claim 86, characterized in that said biologically active substance is selected from the group consisting of anti-neoplastic, antibiotic, antiviral, antifungal, anti-inflammatory, anticoagulant and prodrug agents of these substances.

88.- The article according to claim 72, further characterized in that said biologically active substance and said polymer form a homogeneous matrix.

89. The article according to claim 72, further characterized in that said biologically active substance is encapsulated within said polymer.

90.- The article according to claim 72, characterized in that said polymer has an in vivo release rate of the biologically active substance, which is controlled at least partially as a function of the hydrolysis of the phosphoester bond of the polymer by its biodegradation .

91. The article according to claim 72, further characterized in that said article is adapted for implantation or injection into the body of an animal.

92. - The article according to claim 72, further characterized in that said article causes minimal tissue irritation when implanted or injected into vascularized tissue.

93. The article according to claim 72, further characterized in that said article is in the form of a laminate for degradable fabric.

94. The article according to claim 72, further characterized in that said article is in the form of a bioabsorbable suture, a material for repairing bone damage, or a coating on an implant device.

95.- A method for the controlled release of a biologically active substance, comprising the steps of: (a) combining the biologically active substance with a biodegradable terephthalate polymer having the recurring monomer units shown in formula I: wherein R is a divalent organic moiety; R 'is an aliphatic, aromatic or heterocyclic residue; x is > 1; and n is 0 - 5,000; wherein said polymer is biocompatible before and after its biodegradation, to form a mixture; (b) forming said mixture into a solid article with form; and (c) implanting or injecting said solid article in vivo at a preselected site so that the implanted or injected solid matrix is at least in partial contact with a biological fluid.

96. - The method according to claim 95, further characterized in that R is an ethylene group.

97. The method according to claim 96, further characterized in that R is an n-propylene group.

The method according to claim 96, further characterized in that R is 2-methyl-propylene.

99. The method according to claim 96, further characterized in that R is 2,2'-dimethylpropyiene.

100. The method according to claim 96, further characterized in that R 'is an ethyl group.

101. The method according to claim 96, further characterized in that x is from about 1 to about 30.

102. The method according to claim 96, further characterized in that the ratio is from about 10: 1 to about 1. :1.

103. The method according to claim 96, further characterized in that said polymer comprises additional biocompatible monomer units.

104. The method according to claim 96, 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 these substances.

105. - The method according to claim 96, further characterized in that said biologically active substance is a therapeutic drug or prodrug.

106. The method according to claim 96, further characterized in that said drug is selected from the group consisting of chemotherapeutic agents, antibiotics, antivirals, antifungals, anti-inflammatories and anticoagulants.

107. The method according to claim 96, further characterized in that said biologically active substance and said polymer form a homogeneous matrix.

108. The method according to claim 96, further characterized in that it comprises encapsulating said biologically active substance within said polymer.

109. The method according to claim 96, further characterized in that said polymer has an in vivo release rate of the biologically active substance that is controlled at least partially as a function of the hydrolysis of the phosphoester linkage of the polymer by its degradation. .

110. The method according to claim 96, further characterized in that said article is non-toxic and causes minimal tissue irritation when implanted or injected into vascularized tissue.

111. The method according to claim 96, further characterized in that said article is in the form of a laminate for degradable fabric.

112. - The method according to claim 96, further characterized in that said polymer composition is used as a coating for an implant.

113. The method according to claim 96, further characterized in that the polymer composition is used as a barrier to prevent adhesion.

114. The method according to claim 96, further characterized in that said polymer composition is manufactured as a tube for the generation of rib.