Biodegradable, anionic polymers derived from the amino acid l-tyrosine

Abstract

Polymers with a hydrolytically labile polymer backbones with non-toxic biocompatible diphenolic repeating units having the structure: wherein R 9 is an alkyl, aryl or alkylaryl group with up to 18 carbon atoms having a pendent carboxylic acid group or the benzyl ester thereof; and non-toxic biocompatible diphenolic repeating units having the structure: wherein R 12 is an alkyl, aryl or alkylaryl group with up to 18 carbon atoms having a pendent carboxylic acid ester group selected from straight and branched alkyl and alkylaryl esters containing up to 18 carbon atoms and ester derivatives of biologically and pharmaceutically active compounds covalently bonded to the polymer, provided that said ester group is not a benzyl group or a group that is removed by hydrogenolysis. Implantable medical devices and treatment methods using the polymers are also disclosed.

1 . A polymer with a hydrolytically labile polymer backbone comprising non-toxic biocompatible diphenolic repeating units having the structure: 
       
         
           
           
               
               
           
         
         wherein R 9  is an alkyl, aryl or alkylaryl group with up to 18 carbon atoms having a pendent carboxylic acid group or the benzyl ester thereof; and 
         non-toxic biocompatible diphenolic repeating units having the structure: 
       
       
         
           
           
               
               
           
         
         wherein R 12  is an alkyl, aryl or alkylaryl group with up to 18 carbon atoms having a pendent carboxylic acid ester group selected from the group consisting of straight and branched alkyl and alkylaryl esters containing up to 18 carbon atoms and ester derivatives of biologically and pharmaceutically active compounds covalently bonded to said polymer, provided that said ester group is not a benzyl group or a group that is removed by hydrogenolysis. 
       
     
     
         2 . The polymer of  claim 1 , characterized by said polymer having the structure: 
       
         
           
           
               
               
           
         
         wherein each R 7  is independently an alkylene group containing up to 4 carbon atoms; 
         A is a C═O group or a 
       
       
         
           
           
               
               
           
         
          group, wherein R is selected from the group consisting of saturated and unsaturated, substituted and unsubstituted alkyl, aryl and alkylaryl groups containing up to 18 carbon atoms; 
         k is between about 5 and about 3,000; and 
         x is greater than 0 and less than 1 and f ranges from 0 to less than 1. 
       
     
     
         3 . The implantable medical device of  claim 2 , wherein f is 0. 
     
     
         4 . The polymer of  claim 2 , wherein f ranges between about 0.05 and about 0.95. 
     
     
         5 . The polymer of  claim 2 , wherein k is between 2 and about 200. 
     
     
         6 . The polymer of  claim 2 , wherein x is between about 0.5 and about 0.75. 
     
     
         7 . The polymer of  claim 1  or  2 , wherein R 9  has a structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein R 2  is hydrogen or a benzyl group and a and b are independently 0, 1 or 2. 
       
     
     
         8 . The polymer of  claim 7 , where in R 9  has the structure: 
       
         
           
           
               
               
           
         
         wherein a is 2 and b is 1. 
       
     
     
         9 . The polymer of  claim 1  or  2 , wherein said pendent group of R 9  comprises a pendant benzyl carboxylate group. 
     
     
         10 . The polymer of  claim 1  or  2 , wherein said pendent group of R 9  comprises a pendant carboxylic acid group. 
     
     
         11 . The polymer of  claim 1  or  2 , wherein R 12  has a structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein R 2  is selected from the group consisting of straight and branched alkyl and alkylaryl groups containing up to 18 carbon atoms and derivatives of biologically and pharmaceutically active compounds covalently bonded to said polymer; and c and d are independently 0, 1 or 2. 
       
     
     
         12 . The polymer of  claim 11 , wherein R 12  has the structure: 
       
         
           
           
               
               
           
         
         wherein c is 2 and d is 1. 
       
     
     
         13 . The polymer of  claim 1  or  2 , wherein said ester group of said pendent carboxylic acid ester group of R 12  is a straight-chained alkyl group selected from the group consisting of ethyl, butyl, hexyl and octyl groups. 
     
     
         14 . A block copolymer comprising the polymer of  claim 1 , block copolymerized with poly(alkylene oxide) repeating units, each poly(alkylene oxide) repeating unit comprising between about 5 and about 3,000 alkylene oxide groups comprising an alkylene group containing up to 4 carbon atoms. 
     
     
         15 . The polymer of  claim 2  or  14 , wherein said alkylene group is ethylene. 
     
     
         16 . The polymer of  claim 14 , wherein each poly(alkylene oxide) repeating unit contains between about 20 and about 200 alkylene oxide groups. 
     
     
         17 . The polymer of  claim 2 , wherein A is a 
       
         
           
           
               
               
           
         
         group, wherein R 8  is selected from the group consisting of —CH 2 —C(═O)—, —CH 2 —CH 2 —C(═O)—, —CH═CH— and (—CH 2 —)z, wherein z is an integer between 2 and 8, inclusive. 
       
     
     
         18 . The polymer of  claim 17 , wherein R 8  is selected from the group consisting of substituted and unsubstituted aryl and alkylaryl groups containing from 6 to 12 carbon atoms. 
     
     
         19 . A medical device comprising the polymer of  claim 10 , adapted for implantation into the body of an animal. 
     
     
         20 . The medical device of  claim 19 , wherein the device is in the form of a suture, bone implant, vascular graft or stent. 
     
     
         21 . The medical device of  claim 19 , wherein the surface of said device is coated with said polymer. 
     
     
         22 . The medical device of  claim 19 , comprising a biologically or pharmaceutically active compound in combination with said polymer, wherein said active compound is present in an amount sufficient for therapeutically effective site-specific or systemic drug delivery. 
     
     
         23 . The medical device of  claim 22 , wherein said biologically or pharmaceutically active compound is covalently bonded to said polymer. 
     
     
         24 . An implantable medical device in the form of a sheet consisting essentially of the polymer of  claim 10  for use as a barrier for surgical adhesion prevention. 
     
     
         25 . A method for site-specific or systemic drug delivery comprising implanting in the body of a patient in need thereof an implantable drug delivery device comprising a therapeutically effective amount of a biologically or pharmaceutically active compound in combination with the polymer of  claim 10 . 
     
     
         26 . The method of  claim 25 , wherein said biologically or pharmaceutically active compound is covalently bonded to said polymer. 
     
     
         27 . The method of  claim 25 , wherein said biologically or pharmaceutically active compound is physically admixed with a biologically or pharmaceutically active agent. 
     
     
         28 . A method for preventing the formation of adhesions between injured tissues comprising inserting a barrier between said injured tissues a sheet consisting essentially of the polymer of  claim 10 . 
     
     
         29 . A controlled drug delivery system comprising a biologically or pharmaceutically active agent physically coated with the polymer of  claim 10 . 
     
     
         30 . A controlled drug delivery system comprising a biologically or pharmaceutically active agent physically embedded or dispersed into a polymeric matrix form from the polymer of  claim 10 . 
     
     
         31 . A controlled drug delivery system comprising a biologically or pharmaceutically active agent covalently bonded to the polymer of  claim 10 . 
     
     
         32 . A method of regulating cellular attachment, migration and proliferation on a polymeric substrate comprising contacting living cells, tissues or biological fluids containing living cells with the polymer of  claim 10 . 
     
     
         33 . The method of  claim 32 , wherein said polymer is in the form of a coating on a medical implant. 
     
     
         34 . The method of  claim 32 , wherein said polymer is in the form of a film. 
     
     
         35 . The method of  claim 32 , wherein said polymer is in the form of a polymeric tissue scaffold.