Polyanhydride polymers and their uses in biomedical devices

Abstract

A biocompatible, bioerodable polyanhydride polymer having a Young's modulus between about 1.5 and 3 and a selected rate of surface degradation, and methods of forming and using the polymer, are disclosed. The polymer is formed of a polyester prepolymer having a preferred molecular weight of greater than 5 and less than 7.5 Kdaltons, and a selected number of anhydride linkages between 5 and about 30.

1 . A polyanhydride polymer having the structure:  
     
       
         
         
             
             
         
       
     
     wherein,  
     
       
         
         
             
             
         
       
       where E is a para ester or an meta or para ether linkage, and the pre-polymer is an α-ω,-dihydroxy terminated polyester or polyether polymer having a molecular weight in a selected range between 1 to 10 Kdaltons;  
       x=80% to 98% by weight, y=20% to 2% by weight, n=2 to 4, m=2 to 10; and the average total number of anhydride linkages is a selected number in the range between 5-30.  
     
   
   
       2 . The polymer of  claim 1 , the linked phenoxy structure in the polymer is 1,3-bis(p-carboxyphenoxy)propane anhydride, and is present in the polymer in at least 2% by weight.  
   
   
       3 . The polymer of  claim 1 , wherein the pre-polymer has an average molecular weight greater than 5 Kdaltons and less than 10 Kdaltons, and the polymer has an average total number of anhydride linkages between 8 and 12.  
   
   
       4 . The polymer of  claim 1 , wherein the pre-polymer is an α-ω,-dihydroxy terminated polylactide, polyε-caprolactone or polyglycolide polymer.  
   
   
       5 . The polymer of  claim 4 , wherein the pre-polymer includes a polyethylene glycol group.  
   
   
       6 . The polymer of  claim 1 , which is joined at one of its ends to a branched alcohol, forming a branched polyanhydride polymer.  
   
   
       7 . A method of producing a biodegradable, polyanhydride polymer having a selected Young's modulus between 1.5-3 GPa, comprising 
 (i) selecting a polylactide, polycaprolactone or polyglycolide α-ω,-dihydroxy polymer whose polymer chains having an average polymer-chain molecular weight greater than 5 Kdaltons and less than 10 Kdaltons, where lower Young's modulus values are attained by selecting an average polymer-chain molecular weight greater than 5 Kdaltons and less than about 10 Kdaltons,    (ii) converting the selected polymer chains to α-ω,-dianhydride chains, and    (iii) polymerizing the α-ω,-dianhydride chains under time and temperature conditions effective to produce a polylactide-based polyanhydride polymer having a selected average number of anhydride linkages in the range between 5 and 25, where lower Young's modulus values are attained with a lower average total number of anhydride linkages.    
   
   
       8 . The method of  claim 7 , wherein the α-ω,-dihydroxy polymer chains selected in step (i) are polylactide, polyε-caprolactone, or polyglycolide chains having an average molecular weight greater than 5 and less than 7.5 Kdaltons, and the total number of anhydride linkages is between 8-12.  
   
   
       9 . The method of  claim 7 , for use in producing a biodegradable, polyanhydride polymer having a rate of surface degradation that is effective to fully erode a bar of the polymer having dimensions of 50 microns×50 microns×2 mm, when incubated in phosphate buffered saline at 37° C., within a selected period of 5-180 days, wherein the α-ω,-dianhydride chains are polymerized in step (iii) under conditions effective to produce a selected rate of surface degradation, where a higher rate of surface degradation is achieved with a greater average total number of anhydride linkages.  
   
   
       10 . The method of  claim 7 , wherein step (ii) includes reacting the α-ω,-dihydroxy chains with succinic or glutaric anhydride under conditions effective to convert the α-ω,-dianhydride chains to α-ω,-dicarboxylic acid chains, removing unreacted anhydride, and reacting the α-ω,-dicarboxylic acid chains with acetic anhydride under conditions effective to achieve the selected average number of anhydride linkages in the anhydride polymer.  
   
   
       11 . The method of  claim 9 , wherein step (iii) is carried out in the presence of a dicarboxy phenoxy alkyl dianhydride compound of the form:  
     
       
         
         
             
             
         
       
       and the polyanhydride polymer formed has the structure:  
       
         
           
           
               
               
           
         
       
       where E is a para ester linkage or a para or meta ether linkage, and the pre-polymer is an α-ω,-dihydroxy terminated polyester or polyether polymer having a molecular weight in a selected range between 1 to 10 Kdaltons;  
       x=80% to 98% by weight, y=20% to 2% by weight, n=2 to 4, m=2 to 10; and the average total number of anhydride linkages is a selected number in the range between 5-25.  
     
   
   
       12 . A biodegradable polyester-based polyanhydride polymer having, as a repeating polymer unit, a polylactide, polycaprolactone or polyglycolide α-ω,-dianhydride chain having an average molecular weight greater than 5 and less than 10 Kdaltons, and between 8-12 anhydride linkages, and characterized by: 
 (i) a Young's modulus between 1.5-3 GPa, and (ii) a rate of surface degradation that is effective to fully erode a bar of the polymer having dimensions of 50 microns×50 microns×2 mm, when incubated in phosphate buffered saline at 37° C., within a selected period of 5-365 days.    
   
   
       13 . The polymer of  claim 12 , wherein the rate of surface degradation is effective to fully erode a bar of the polymer having dimensions of 50 microns×50 microns×2 mm, when incubated in phosphate buffered saline at 37° C., within a selected period of 5-180 days.  
   
   
       14 . The polymer of  claim 13 , formed as an expandable, biodegradable intravascular stent.  
   
   
       15 . The polymer of  claim 14 , having a drug embedded within the polymer, for release therefrom, as the polymer is bioeroded.  
   
   
       16 . An expandable, biodegradable stent comprising a biodegradable, polyanhydride polymer having, as a repeating polymer unit, the dianhydride of a polylactide, polycaprolactone or polyglycolide α-ω,-dihydroxy polymer having an average molecular weight greater than 5 and less than 10 Kdaltons, a selected Young's modulus between 1.5 and 3, and a selected average number of anhydride linkages in the range between 5 and 30.  
   
   
       17 . The stent of  claim 16 , wherein the polyanhydride polymer forms a biodegradable stent core, and the core is coated, on its exterior surface(s), with a polymer coating composed of a second biodegradable polyanhydride having a Young's modulus greater than 3, and a drug embedded therein.