Polymeric coupling agents and pharmaceutically-active polymers made therefrom

Abstract

A pharmaceutically-active polymeric compound of the general formula (I), Y−[Y n −LINK B−X] m −LINK B  (I) wherein (i) X is a coupled biological coupling agent of the general formula (II) Bio −LINK A−Bio   (II) wherein Bio is a biologically active agent fragment or precursor thereof linked to LINK A through a hydrolysable covalent bond; and LINK A is a coupled central flexible linear first segment of <2000 theoretical molecular weight linked to each of said Bio fragments; (ii) Y is LINK B-OLIGO; wherein (a) LINK B is a coupled second segment linking one OLIGO to another OLIGO and an OLIGO to X or precursor thereof; and (b) OLIGO is a short length of polymer segment having a molecular weight of less than 5,000 and comprising less than 100 monomeric repeating units; (iii) m is 1-40; and (iv) n is selected from 2-50. The compounds are useful as biomaterials, particularly, providing antibacterial a.i. in vivo. Also provided are biological coupling agents useful as intermediates in the preparation of the pharmaceutically-active polymeric compounds.

1 . A pharmaceutically-active polymeric compound of the general formula (I),  
         Y−[Y   n −LINK  B−X]   m −LINK  B   (I)  wherein (i) X is a coupled biological coupling agent of the general formula (II)        Bio −LINK  A−Bio   (II)    wherein Bio is a biologically active agent fragment or precursor thereof linked to LINK A through a hydrolysable covalent bond;    and LINK A is a coupled central flexible linear first segment of <2000 theoretical molecular weight linked to each of said Bio fragments;    (ii) Y is LINK B-OLIGO; wherein    (a) LINK B is a coupled second segment linking one OLIGO to another OLIGO and an OLIGO to X or precursor thereof; and    (b) OLIGO is a short length of polymer segment having a molecular weight of less than 5,000 and comprising less than 100 monomeric repeating units;    (iii) m is 1-40; and    (iv) n is selected from 2-50.    
   
   
       2 . A compound as defined in  claim 1  wherein LINK A is linked to Bio by carboxylic ester, amide or sulfonamide links.  
   
   
       3 . A compound as defined in  claim 1  wherein LINK A contains within itself polyalkyl, polyethylene oxide, polyalkylene oxide, polyamides, polyester, polyvinyl, polycarbonate, polyanhydrides or polysiloxanes.  
   
   
       4 . A compound as defined in  claim 1  wherein LINK A has a molecular weight selected from 60-700  
   
   
       5 . A compound as defined in  claim 1  wherein Y n  has a molecular weight of less than 15,000 theoretical molecular weight.  
   
   
       6 . A compound as defined in  claim 5  wherein Y n  has a molecular weight of <10,000.  
   
   
       7 . A compound as defined in  claim 6  wherein Y n  has a molecular weight of <5,000.  
   
   
       8 . A compound as defined in  claim 1  wherein LINK B has a molecular weight selected from 60-2000.  
   
   
       9 . A compound as defined in  claim 8  wherein LINK B has a molecular weight selected from 60-700.  
   
   
       10 . A compound as defined in  claim 1  wherein LINK B is linked to other segments via urethanes, esters, ureas, sulfonamides, carbonates, anhydrides or amides.  
   
   
       11 . A compound as defined in  claim 1  having at least two Bio fragments or precursors thereof of different biological activities.  
   
   
       12 . A compound as defined in  claim 1  wherein said Bio is a biologically-active entity selected from an anti-coagulant, an anti-inflammatory agent, an proliferative agent, an antibacterial agent, and a hydrolysable precursor fragment thereof.  
   
   
       13 . A compound as defined in  claim 12  having at least two of said Bio entities and/or said hydrolysable precursor fragment thereof.  
   
   
       14 . A compound as defined in  claim 1  wherein said Bio is an antibacterial or hydrolysable precursor fragment thereof.  
   
   
       15 . A compound as defined in  claim 1  wherein said Bio has a molecular weight of <4000.  
   
   
       16 . A compound as defined in  claim 1  wherein said Bio has a molecular weight of <2000.  
   
   
       17 . A biological coupling agent of the general formula (III)  
         PBio −LINK  A−PBio   (III)  wherein PBio is a biologically active agent fragment or precursor thereof linked to LINK A through a hydrolysable covalent bond and having at least one functional group to permit step growth polymerization;    and LINK A is a coupled central flexible linear first segment of <2000 theoretical molecular weight linked to each of said PBio fragments.    
   
   
       18 . A compound as defined in  claim 17  wherein LINK A is linked to Bio by carboxylic ester, amide or sulfonamide links.  
   
   
       19 . A compound as defined in  claim 15  wherein LINK A has a molecular weight selected from 40-700  
   
   
       20 . A pharmaceutically-active polymeric composition comprising a pharmaceutically-active polymeric compound as defined in  claim 1  in admixture with a compatible base polymer.  
   
   
       21 . A composition as defined in  claim 20  wherein said base polymer is selected from the group consisting of polyurethanes, polysulfones, polycarbonates, polyesters, polyethylene, polypropylene, polystyrene, polysilicone, poly(acrylonitrile-butadienestyrene), polybutadiene, polyisoprene, polymethylmethacrylate, polyamine, polyvinylacetate, polyacrylonitrile, polyvinyl chloride, polyethylene, terephthalate, cellulose and other polysacharides.  
   
   
       22 . A composition as defined in  claim 21  wherein said base polymer is a segmented polyurethane, a polyester, a polycarbonate, polysaccharide or polyamide or polysilicone.  
   
   
       23 . A composition as defined in  claim 20  in the form of a shaped article.  
   
   
       24 . A shaped article as defined in  claim 23  in the form of an implantable medical device, self-supporting film, or fiber.