Title of Invention

"A PROCESS FOR THE PREPARATION OF ENZYMATICALLY DEGRADABLE POLYMERS"

Abstract

A process for the preparation of enzymatically degradable polymers by reacting diester of poly (oxyalkylene glycol) and hydrochloride of trifunctional amino acid with a dicarboxylic acid in the presence of a condensing agent in a solvent at a temperature in the range of 0°C to room temperature for a period ranging between 1 hr to 24 hrs, neutralizing the hydrochloride salt by base followed by reacting the free ammo groups in the side chain of the polymer with the drug molecule containing carboxyl groups to obtain the desired enzymatically degradable polymer.

Full Text

This invention relates to a process of preparation of enzymatically degradable polymers. This invention particularly relates to a process for preparation of poly (ester) prodrugs by polycondensation of dicarboxylic acids with diesters of poly (oxyalkylene glycol) and trifunctional amino acid hydrochloride, in the presence of a condensing agent. More particularly, it relates to the process for the preparation of enzymatically degradable polymeric prodrugs having repeating structural unit according to formula I in the drawing accompanying this specification ,wherein, X is selected from phenoilc -OH of tyrosine, -OH of serine and threonine and -SH of cysteine, Y is pendant group selected from drug molecules containing carboxyl groups, R is hydrogen, methyl or mixture of hydrogen and methyl on the individual molecule, N is an integer of from 0 to about 100 and m is an integer of from 0 to 10. Water soluble polymeric prodrugs have been extensively investigated as they can provide site specific drug delivery, longevity in blood circulation, lower drug dosage levels, bicompatibility and biodegradability (R. Duncan, J. Kopecek, Adv. Polym. Sci. 57, 51 (1984), P. Sinko and J. Kohn, "Polymeric Drug Delivery Systems" In: Polymeric Delivery Systems, M.A. El-Nokaly, D.M. Piatt, B.A. Charpentier, Eds. ACS Symposium series 520, American Chemical Society, Washington, DC, P. 18-42 (1993)). Due to immunogenic nature of poly (α amino acid)s researchers have developed various synthetic polymeric prodrugs as alternatives. These can broadly be classified into two types, 1) biocompatible prodrugs and 2) biodegradable prodrugs. Some of the biocompatible polymeric prodrug systems developed are poly (methacrylic acid -co - 2(methyl sulfinyl) ethyl methacrylate) (P. Moltz, Int J. Biol. Macromol. 2, 245 (1980)), poly (methacrylic acid -co - N-2 (hydroxypropyl) methacrylamide) and poly (N-vinyl pyrrolidone -co - vinyl amine) (V. Hoffman, H. Ringsdorf, A. Seganova, Macromol. Chem. 180, 837 (1979), R. Duncan, J. Kopecek, P. Rajmanova, J.B. Lloyed, Biochim. Biophys. Acta 755, 518 (1983)). Various drug molecules such as chlorambucil, daunomycin, bis (2 chloroethyl) amine etc. were chemically linked to these polymers and prodrugs so synthesized were evaluated. Prodrugs based on high molecular weight poly (ethylene glycol)s and poly (oxyethylene dicarboxylic acid)s have also been developed (T. Ouchi, Y. Hagihara, K. Takahashi, Y. Takano, I. Igarashi, Drug Design and Discovery 9, 93 (1992), R.B. Greenwald, C.W. Gilbert, A. Pendri, CD. Conover, J. Xia, A. Martinez, J. Med. Chem. 39, 424 (1996)). Although these polymers are biocompatible they are not biodegradable. Thus they tend to accumulate in body after the delivery of attached drug molecule (R. Duncan, J. Kopecek Adv. Polym. Sci. 57, 51 (1984). Therefore biodegradable prodrugs are preferred over biocompatible ones. Polymers based on low molecular weight poly (ethylene glycol) and various trifunctional amino acids are being investigated as biodegradable prodrugs because the pendant functional groups in such polymers can be used for chemical linkage of drug molecules. Kohn et al (1992) reported water-soluble poly (ether -urethane) based on L-lysine and poly (ethylene glycol). The polymer was synthesized by the reaction of L-lysine ethyl ester with bis (succjuimidyl) carbonate derivative poly (ethylene glycol). The polymer so synthesized was treated with sodium hydroxide in order to de-block the side chain carboxyl groups of L-lysine and make them available for drug linkage. (A. Nathan, D. Bolikal, N. Vyavahare, S. Zalipsky, J. Kohn, Macromolecules 25, 4476 (1992)). Ulbrich et al (1997) reported a prodrug system based on poly (oxyalkylene glycol) and L-glutamic acid. This polymer was synthesized by connecting two blocks of monomethoxy poly (oxyethylene) carboxylic acid via biodegradable oligopeptide-1,4 bis(Y-para-nitroanilido glutamido) ethylene diamide (M. Pechar, J. Strohalm, K. Ulbrich, Macromol. Chem. 198, 1009 (1997)). The oligopeptide was synthesized following standard procedures of blocking and de-blocking of -NH2 and -COOH groups of amino acid. Won et al (1998) reported a polymer based on poly (ethylene glycol) and L-aspartic acid. In this, N-benzyloxylcarbonyl L-aspartic acid (N-cbz-L-aspartic acid) was converted into N-cbz-aspartic anhydride by the reaction of thionyl chloride. Subsequently, N-cbz-aspartic anhydride was reacted with poly (ethylene glycol) to obtain a polymer with blocked -NH2 groups. This polymer was treated with 1,4 cyclohexadiene and Palladium /activated charcoal in order to de-block -NH2 groups and make them available for drug linkage (C-Y Won, C-C Chu, J.D. Lee, J. Polym. Sci. Chem. Ed. 36, 2949 (1998). Thus, due to such tedious blocking and de-blocking procedures of -NH2 and -COOH groups, very few examples (mentioned herein above) of prodrugs based on trifunctional amino acids and poly (ethylene glycol) are reported so far. It is therefore an object of the present invention to provide a simpler process for the preparation of novel water soluble polymeric prodrug systems based on poly (oxyalkylene glycol) and trifunctional amino acids, which will eliminate the conventional blocking and de-blocking chemistry of -NH2 group. It is also an object of the present invention that such a process be applicable to various trifunctional amino acids. Another object of the present invention is to provide enzymatically degradable polymers. Such polymers are stable and degrade only in the presence of certain enzymes, depending upon the amino acid present in the polymer. This provides means of developing site specific drag delivery systems. Polymers based on poly (oxyalkylene glycol) and amino acids are suitable for this purpose. The inventors of the present invention have recently found that hydrochloride salts of various a amino acids can be directly esterified with poly (oxyalkylene glycol)s using a carbodiimide as condensing agent wherein, hydrochloride acts as amino protecting group (B.S. Lele, M.A. Gore, M.G. Kulkarni, Synthetic Communications (1998, In Press). Accordingly, the present invention provides a novel process for the preparation of condensation polymers based on dicarboxylic acids and diesters of poly (oxyalkylene glycol) and amino acid hydrochlorides. The main advantage of this novel process over the conventional processes is that it eliminates the use of -NH2 blocking groups namely N-benzyloxycarbonyl (N-cbz) and N-tertiarybutyloxycarbonyl (N-tboc) and the subsequent tedious procedures of deblocking viz. hydrogenation or reaction with 1,4 cyclohexadiene /Palladium/Charcoal and the acid hydrolysis respectively . The drug linkage to the polymers synthesized by following the process of the present invention is much simpler as this involves only the neutralization of hydrochloride salts by the treatment of commonly used bases. Also, the polymers synthesized by following the process of the present invention are novel. Accordingly, the present invention provides a process for the preparation of enzymatically degradable polymers, having repeating structural unit according to formula I in the drawing accompanying this specification wherein X is selected from phenolic -OH of tyrosine, -OH of serine and threonine and -SH of cysteine, Y is pendant group selected from drug molecules containing carboxyl groups, R is hydrogen, methyl or mixture of hydrogen and methyl on the individual molecule, n is an integer of from 0 to 100 and m is an integer of from 0 to 10, which comprises reacting diester of poly (oxyalkylene glycol) and hydrochloride of trifunctional amino acid with a dicarboxylic acid in the presence of a condensing agent such as herein described in a solvent at a temperature in the range of 25 to 30°C for a period ranging between 3 hrs to 24 hrs, neutralizing the hydrochloride salt by base followed by reacting the free amino groups in the side chain of the polymer with the drug molecule containing carboxyl groups to obtain the desired enzymatically degradable polymer. In an embodiment of the present invention poly (oxyalkylene glycol) may be such as compounds of the formula HOCH2-CHR-(CH2-CHR-O-)n-CH2-CHR-OH wherein R is hydrogen, methyl or mixture of hydrogen and methyl on the individual molecule, n is an integer which represents the average number of oxyalkylene groups, preferably from 0 to 100. In an another embodiment amino acid may be such as trifunctional amino acids like tyrosine, serine, threonine, cysteine etc. and their hydrochlorides may be prepared by treating the amino acid with hydrochloric acid. In yet another embodiment the dicarboxylic acid may be such as compound of the formula HOOC-(CH2-)m-COOH wherein m is an integer from 0 to 10. In still another embodiment the condensing agent may be such as carbodiimides like dicyclohexyl carbodiimde, diisopropyl carbodiimde. In an another embodiment the solvent used may be such as acetonitrile, tetrahydrofuran, dioxane, dimethyl formamide. In an another embodiment the base used for neutralization of hydrochloride salt may be such as triethylamine, tributylamine, sodium bicarbonate. In an another embodiment the pendant group Y may be such as drug molecules containing carboxyl group such as e.g. benzoic acid, methotrexate. In a feature of the present invention, the process is typically carried out under mild conditions. Stoichiometric amounts of poly (oxyalkylene glycol) and amino acid hydrochloride are dissolved in a solvent and the stoichiometric amount of a carbodiimde is added and the reaction mixture is stirred at room temperature for 12 hrs. After this, the reaction mixture is filtered to remove the urea salts formed due to condensation reaction. The clear solution containing diester of poly (oxyalkylene glycol) and amino acid hydrochloride is then poured into another solvent which is a nonsolvent for the diester. Precipitated diester is then isolated. In an another feature of the present invention, appropriate amounts of the diester so synthesized and a dicarboxylic acid are dissolved in a solvent and appropriate amount of a carbodiimde is added. The reaction mixture is stirred at room temperature for 12 hrs and filtered to remove urea salts. Clear solution containing the polymer is then poured into another solvent which is a nonsolvent for the polymer. Precipitated polymer is then isolated. In an another feature of the present invention, the polymer so synthesized is dissolved in a solvent and protected amino groups in the polymer are then freed from hydrochloride by the treatment of a base. Then acid chloride of a drug molecule is added and the reaction mixture is stirred at room temperature for 12 hrs for chemical linkage of drug molecules with pendant amino groups. The reaction mixture is then filtered to remove salts and the clear solution containing prodrug is poured into another solvent which is a nonsolvent for the prodrug. Precipitated prodrug is then isolated. The ranges and limitations provided in the instant specification and claims are those which are believed to particularly point out and distinctly claim the present invention. It is however understood that other ranges and limitations which perform substantially the same function in the same or substantially the same manner to obtain the same or substantially the same results are intended to be within the scope of the instant invention as defined by the instant specification and claims. The process of the instant invention will be further described by the following embodiments which are provided for illustration and are not to be construed as limiting the invention. EXAMPLE 1 This example describes the process for the preparation of polymer based on poly (ethylene glycol) and tyrosine and containing a drug in the side chain. Preparation of poly (ethylene glycol) 6000 - bis tyrosyl hydrochloride diester (PEG 6000 - bis Tyr.HCl) (diester) In a 100 ml capacity conical flask, 12 g PEG 6000 (0.002 M), 0.87 g (0.004 M) Tyr.HCl, and 20 ml DMF were taken. The contents of the flask were gently heated to dissolve the solids and obtain a clear solution. To this solution, 0.824 g DCC (0.004 M) dissolved in 10 ml DMF was added in a single portion. The reaction mixture was stirred at room temperature (25°C) for 24 hours. It was then filtered to separate out dicyclohexyl urea (DCU) formed and the clear solution was poured in 200 ml diethyl ether to precipitate out white powdery product. The product was isolated and purified by reprecipitation from THF into petroleum ether. Yield (78%). Preparation of poly (PEG 6000 - bis Tyr.HCl - sebacate) (polymer) In a 100 ml capacity conical flask 5 g PEG 6000 - bis Tyr.HCl (containing 0.00148 moles of Tyr-OH groups), 0.15 g sebacic acid (containing 0.00148 moles of-COOH groups) and 10 ml DMF were placed. Contents of the flask were gently heated to obtain clear solution. To this solution 0.30 g DCC (0. 00148 M) was added and the reaction mixture was stirred at room temperature for 24 hours. It was then filtered to remove DCU and the clear solution was poured in 100 ml diethyl ether to precipitate out the polymer. The polymer was purified by reprecipitation from DMF into diethyl ether. Yield (68 %). Preparation of poly (PEG 6000 - bis N-benzoyl tyrosyl - sebacate) (yrodrus) In a 100 ml capacity round bottom flask, 2.5 g poly (PEG 6000 - bis Tyr.HCl -sebacate) (containing 0.00063 moles of-NH2 groups) and 20'ml THF was placed and stirred with magnetic needle. To this suspension 0.18 ml triethylamine (0.00126 M) was added. After stirring for few minutes, 0.073 ml benzoyl chloride (0.00063 M) dissolved in 5 ml THF was added and the reaction mixture was stirred 3 hours at room temperature. It was then filtered to remove triethylamine.hydrochloride and the clear solution was poured in 200 ml petroleum ether to precipitate out the polymer. Polymer was purified by reprecipitation from THF into petroleum ether. Yield (77%). EXAMPLE 2 This example describes the process for the preparation of polymer based on poly (ethylene glycol) and cysteine and containing a drug in the side chain. Preparation of poly (ethylene glycol) 6000 - bis cystyl hydrochloride diester (PEG 6000 - bis Cyst.HCl) (diester) In a 100 ml capacity conical flask, 12 g PEG 6000 (0.002 M), 0.62 g (0.004 M) Cyst.HCl, and 20 ml DMF were taken. The contents of the flask were gently heated to dissolve the solids and obtain a clear solution. To this solution, 0.824 g DCC (0.004 M) dissolved in 10 ml DMF was added in a single portion. The reaction mixture was stirred at room temperature (25°C) for 24 hours. It was then filtered to separate out dicyclohexyl urea (DCU) formed and the clear solution was poured in 200 ml diethyl ether to precipitate out white powdery product. The product was isolated and purified by reprecipitation from THF into petroleum ether. Yield (80%). Preparation of poly (PEG 6000 - bis Cyst.HCl - sebacate) (polymer) In a 100 ml capacity conical flask 5 g PEG 6000 - bis Cyst.HCl (containing 0.002 moles of Cyst-SH groups), 0.20 g sebacic acid (containing 0.002 moles of-COOH groups) and 10 ml DMF were placed. Contents of the flask were gently heated to obtain clear solution. To this solution 0.412 g DCC (0. 002 M) was added and the reaction mixture was stirred at room temperature for 24 hours. It was then filtered to remove DCU and the clear solution was poured in 100 ml diethyl ether to precipitate out the polymer. The polymer was purified by reprecipitation from DMF into diethyl ether. Yield (67%). Preparation of poly (PEG 6000 - bis N-benzoyl cystyl - sebacate) (prodrug) In a 100 ml capacity round bottom flask, 2.5 g poly (PEG 6000 - bis Cyst.HCl -sebacate) (containing 0.0007 moles of -NH2 groups) and 20 ml THF was placed and stirred with magnetic needle. To this suspension 0.19 ml tiiethylamine (0.0014 M) was added. After stirring for few minutes, 0.081 ml benzoyl chloride (0.0007 M) dissolved in 5 ml THF was added and the reaction mixture was stirred 3 hours at room temperature. It was then filtered to remove triethylamine.hydrochloride and the clear solution was poured in 200 ml petroleum ether to precipitate out the polymer. Polymer was purified by reprecipitation from THF into petroleum ether. Yield (72%). EXAMPLE 3 This example describes the process for the preparation of polymer based on poly (ethylene glycol) and serine and containing a drug in the side chain. Preparation of poly (ethylene glycol) 6000 - bis seryl hydrochloride diester (PEG 6000 - bis Ser.HCl) (diester) In a 100 ml capacity conical flask, 12 g PEG 6000 (0.002 M), 0.56 g (0.004 M) Ser.HCl, and 20 ml DMF were taken. The contents of the flask were gently heated to dissolve the solids and obtain a clear solution. To this solution, 0.824 g DCC (0.004 M) dissolved in 10 ml DMF was added in a single portion. The reaction mixture was stirred at room temperature (25°C) for 24 hours. It was then filtered to separate out dicyclohexyl urea (DCU) formed and the clear solution was poured in 200 ml diethyl ether to precipitate out white powdery product. The product was isolated and purified by reprecipitation from THF into petroleum ether. Yield (88%). Preparation of poly (PEG 6000 - bis Ser.HCl - sebacate) (polymer) In a 100 ml capacity conical flask 5 g PEG 6000 - bis Ser.HCl (containing 0.00152 moles of Ser-OH groups), 0.15 g sebacic acid (containing 0.00152 moles of-COOH groups) and 10 ml DMF were placed. Contents of the flask were gently heated to obtain clear solution. To this solution 0.313 g DCC (0. 00152 M) was added and the reaction mixture was stirred at room temperature for 24 hours. It was then filtered to remove DCU and the clear solution was poured in 100 ml diethyl ether to precipitate out the polymer. The polymer was purified by reprecipitation from DMF into diethyl ether. Yield (81%). Preparation of poly (PEG 6000 - bis N-benzoyl seryl - sebacate) (yrodrus) In a 100 ml capacity round bottom flask, 2.5 g poly (PEG 6000 - bis Ser.HCl -sebacate) (containing 0.0005 moles of -NH2 groups) and 20 ml THF was placed and stirred with magnetic needle. To this suspension 0.14 ml triethylamine (0.001 M) was added. After stirring for few minutes, 0.057 ml benzoyl chloride (0.0005 M) dissolved in 5 ml THF was added and the reaction mixture was stirred 3 hours at room temperature. It was then filtered to remove triethylamine.hydrochloride and the clear solution was poured in 200 ml petroleum ether to precipitate out the polymer. Polymer was purified by reprecipitation from THF into petroleum ether. Yield (83 %). EXAMPLE 4 This example describes the process for the preparation of polymer based on poly (ethylene glycol) and threonine and containing a drug in the side chain. Preparation of poly (ethylene glycol) 6000 - bis threonyl hydrochloride diester (PEG 6000 - bis Thre.HCl) (diester) In a 100 ml capacity conical flask, 12 g PEG 6000 (0.002 M), 0.57 g (0.004 M) Thre.HCl, and 20 ml DMF were taken. The contents of the flask were gently heated to dissolve the solids and obtain a clear solution. To this solution, 0.824 g DCC (0.004 M) dissolved in 10 ml DMF was added in a single portion. The reaction mixture was stirred at room temperature (25°C) for 24 hours. It was then filtered to separate out dicyclohexyl urea (DCU) formed and the clear solution was poured in 200 ml diethyl ether to precipitate out white powdery product. The product was isolated and purified by reprecipitation from THF into petroleum ether. Yield (84%). Preparation of poly (PEG 6000 - bis Ser.HCl - sebacate) (polymer) In a 100 ml capacity conical flask 5 g PEG 6000 - bis Thre.HCl (containing 0.00178 moles of Ser-OH groups), 0.179 g sebacic acid (containing 0.00178 moles of-COOH groups) and 10 ml DMF were placed. Contents of the flask were gently heated to obtain clear solution. To this solution 0.366 g DCC (0. 00178 M) was added and the reaction mixture was stirred at room temperature for 24 hours. It was then filtered to remove DCU and the clear solution was poured in 100 ml diethyl ether to precipitate out the polymer. The polymer was purified by reprecipitation from DMF into diethyl ether. Yield (81 %). Preparation of poly (PEG 6000 - bis N-benzoyI threonyl - sebacate) (prodrug) In a 100 ml capacity round bottom flask, 2.5 g poly (PEG 6000 - bis Thre.HCl -sebacate) (containing 0.00053 moles of-NH2 groups) and 20 ml THF was placed and stirred with magnetic needle. To this suspension 0.15 ml triethylamine (0.0016 M) was added. After stirring for few minutes, 0.061 ml benzoyl chloride (0.00053 M) dissolved in 5 ml THF was added and the reaction mixture was stirred 3 hours at room temperature. It was then filtered to remove triethylamine.hydrochloride and the clear solution was poured in 200 ml petroleum ether to precipitate out the polymer. Polymer was purified by reprecipitation from THF into petroleum ether. Yield (76 %). EXAMPLE 5 This example describes the process for the preparation of polymer based on poly (ethylene glycol), tyrosine and itaconic acid and containing a drug in the side chain. Preparation of poly (ethylene glycol) 6000 - bis tyrosyl hydrochloride diester (PEG 6000 - bis Tyr.HCl) (diester) Same as described in the Example 1. Preparation of poly (PEG 6000 - bis Tyr.HCl - itaconate) (polymer) In a 100 ml capacity conical flask 5 g PEG 6000 - bis Tyr.HCl (containing 0.00148 moles of Tyr-OH groups), 0.085 g itaconic acid (containing 0.00148 moles of-COOH groups) and 10 ml DMF were placed. Contents of the flask were gently heated to obtain clear solution. To this solution 0.30 g DCC (0. 00148 M) was added and the reaction mixture was stirred at room temperature for 24 hours. It was then filtered to remove DCU and the clear solution was poured in 100 ml diethyl ether to precipitate out the polymer. The polymer was purified by reprecipitation from DMF into diethyl ether. Yield (60%). Preparation of poly (PEG 6000 - bis N-benzoyl tyrosyl -itaconate) (prodrug) In a 100 ml capacity round bottom flask, 2.5 g poly (PEG 6000 - bis Tyr.HCl -itaconate) (containing 0.0008 moles of -NH2 groups) and 20 ml THF was placed and stirred with magnetic needle. To this suspension 0.22 ml triethylamine (0.0016 M) was added. After stirring for few minutes, 0.092 ml benzoyl chloride (0.0008 M) dissolved in 5 ml THF was added and the reaction mixture was stirred 3 hours at room temperature. It was then filtered to remove triethylamine.hydrochloride and the clear solution was poured in 200 ml petroleum ether to precipitate out the polymer. Polymer was purified by reprecipitation from THF into petroleum ether. Yield (75 %). DEGRADATION STUDIES In a stoppered test tube lg prodrug was dissolved in 10 ml 0.01 M phosphate buffer of pH 7.4. To this solution 0.1 g oc chymotrypsin was added and the solution was kept at 37 °C for 7 days. After every 24 hours 1ml aliquot of the solution was taken out and Ninhydrin test was performed on it in order to estimate the amount of free amino acid liberated out due to polymer degradation. Ninhydrin test was validated by performing two control tests. In one control only prodrug and in the second control only chymotrypsin was assayed for Ninhydrin test. In both the controls the test was negative. Only in the case of the solution of prodrug and chymotrypsin positive Ninhydrin test is observed. This shows that the polymer degradation is truly enzymatic. Graph of free amino acids vs. time for all four examples is shown in Figure 1. It is well known that only free amino acids give Ninhydrin test. Data shown in Figure 1 show that chymotrypsin catalyzed the hydrolysis of ester bonds between PEG and amino acid, ester bond between amino acid and sebacic acid and amide bonds between benzoic acid and amino acid. Thus chymotrypsin exhibited pendant chain drug release as well as polymer backbone degradation for all the four examples. Table 1, Enzymatic degradation studies (Table Removed) Data for these degradation studies are shown in Table 1. The degradation products of these polymers are poly (ethylene glycol), sebacic acid, amino acid and the drug molecule, which are known to be biocompatible. Therefore, these polymers have potential advantages in drug delivery system. Also, due to the enzymatic mode of degradation, depending upon the amino acid present in the polymer, the degradation of polymers will vary with the specificity of enzymes. Thus, these polymers additionally could provide site specific drug delivery system. Advantages of the present invention are as follows; 1) The process of the present invention completely eliminates the use of conventional -NH2 group blocking reagents such as benzylchloroformate and tertiary butyloxycarbonyl chloride. The process of the present invention uses commonly available hydrochloride salts of amino acids for the protection of -NH2 groups. Thus, the drug linkage to the amino groups in the side chain of the polymers can be easily effected by neutralization of the hydrochloride salt. This is certainly advantageous over the conventional de-blocking method of hydrogenation or the reaction of the -Ncbz groups containing polymer with 1,4 cyclohexadiene and Palladium /activated charcoal. 2) The process of the present invention is generally applicable for the synthesis of polymers based on various amino acids as can be seen from the examples listed herein above. 3) Degradation products of the polymers so synthesized are known to be biocompatible. We claim : 1) A process for the preparation of enzymatically degradable polymers, having repeating structural unit according to formula I in the drawing accompanying this specification wherein X is selected from phenolic -OH of tyrosine, -OH of serine and threonine and -SH of cysteine, Y is pendant group selected from drug molecules containing carboxyl groups, R is hydrogen, methyl or mixture of hydrogen and methyl on the individual molecule, n is an integer of from 0 to 100 and m is an integer of from 0 to 10, which comprises reacting diester of poly (oxyalkylene glycol) and hydrochloride of trifunctional amino acid with a dicarboxylic acid in the presence of a condensing agent such as herein described in a solvent at a temperature in the range of 25 to 30°C for a period ranging between 3 hrs to 24 hrs, neutralizing the hydrochloride salt by base followed by reacting the free amino groups in the side chain of the polymer with the drug molecule containing carboxyl groups to obtain the desired enzymatically degradable polymer. 2) A process as claimed in claim 1 wherein poly (oxyalkylene glycol) is selected from the compounds of the formula HO-CH2-CHR-O-(CH2-CHR-O)-CH2-CHR-OH wherein n is an integer which represents the average number of oxyethylene groups preferably from 0 to 100. 3) A process as claimed in claims 1 to 2 wherein, the amino acid used is trifunctional amino acids selected from tyrosine, serine, threonine, cysteine and their hydrochlorides. 4) A process as claimed in claims 1 to 3 wherein, the dicarboxylic acid used is compound of the formula HOOC-(CH2)m-COOH wherein m is an integer from Oto 10. 5) A process as claimed in claims 1 to 4 wherein dicarboxylic acid used is itacoinc acid. 6) A process as claimed in claims 1 to 5 wherein, the condensing agent used is dicyclohexyl carbodiimide, diisopropyl carbodiimide. 7) A process as claimed in claims 1 to 6 wherein, the solvent used is acetonitrile, tetrahydrofuran, dioxane, dimethylformamide. 8) A process as claimed in claim 1 to 7 wherein, the base used for neutralization of hydrochloride salt is triethylamine, tributylamine, sodium bicarbonate. 9) A process as claimed in claims 1 to 8 wherein, the pendant Y group is such as drug molecules containing carboxyl group selected from benzoic acid, methotrexate. 10) A process for the preparation of enzymatically degradable polymers, as substantially described herein before with reference to the examples.

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101-del-1999-abstract.pdf

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