Conjugate of polyethylene glycol and chitosan

Abstract

PEG-chitosan conjugates comprising chitosan and polyethylene glycol moieties or derivatives thereof which are bonded together and their use in medicine is described. In one embodiment, the conjugate comprises a chitosan moiety or a derivative thereof and a polyethylene glycol moiety or a derivative thereof which are bonded together via the amino function on the chitosan by the use of an activated chitosan species. In another embodiment, the conjugate comprises a chitosan moiety or a derivative thereof and a polyethylene glycol moiety or a derivative thereof which are bonded together, the chitosan portion of the conjugate having a molecular weight in the range of from 10 kilodaltons to 1000 kilodaltons.

We claim:  
     
         1 . A composition for the controlled release of a drug comprising a polyethylene glycol- chitosan conjugate, wherein the polyethylene glycol-chitosan conjugate comprises a chitosan or chitosan derivative moiety and a polyethylene glycol or a polyethylene glycol derivative moiety, and the composition is formulated for delivery to a mucosal membrane.  
     
     
         2 . The composition of  claim 1 , wherein the chitosan or chitosan derivative moiety has a molecular weight of 10 kD to 1000 kD.  
     
     
         3 . The composition of  claim 1  , wherein the chitosan or chitosan derivative moiety has a molecular weight of 20 kD to 500 kD.  
     
     
         4 . The composition of  claim 1 , wherein the chitosan or chitosan derivative moiety has a molecular weight of 100 kD to 300 kD.  
     
     
         5 . The composition of  claim 1 , wherein the polyethylene glycol-chitosan conjugate is represented by the formula (I):  
       —[ m —NR 1   2 ] p —  (I)  
       wherein C m  is a remainder of a monomeric unit of a chitosan or a chitosan derivative moiety; p is an integer of 50 to 6000;  
       R 1  is independently selected from a hydrogen atom and  
       
         
           
           
               
               
           
         
       
       wherein R 2  is selected from a bond and a first divalent organic group; X is selected from an oxygen atom, a sulfur atom, and the group —NR 3 —, wherein R 3  is selected from a hydrogen atom and a monovalent organic group; and [PEG] is a polyethylene glycol or polyethylene glycol derivative moiety,  
       provided that 1% to 99% of the groups represented by R 1  is  
       
         
           
           
               
               
           
         
       
     
     
         6 . The composition of  claim 5 , wherein C m  is the remainder of the monomeric unit of chitosan.  
     
     
         7 . The composition of  claim 5 , wherein p is an integer of 150 to 2,000.  
     
     
         8 . The composition of  claim 5 , wherein [PEG] is —R 4 —(OCH 2 CH 2 ) n —, and R 4  is a hydrocarbon group selected from the group consisting of an aliphatic hydrocarbon, an alicyclic hydrocarbon, and an aromatic hydrocarbon, and n is an integer of 10 to 1,000.  
     
     
         9 . The composition of  claim 8 , wherein R 4  is an alkyl group.  
     
     
         10 . The composition of  claim 8 , wherein R 4  is a methyl group.  
     
     
         11 . The composition of  claim 5 , wherein R 2  is  
       
         
           
           
               
               
           
         
       
       wherein R 5  is a divalent organic group that is bonded to the carbonyl group of R 1 .  
     
     
         12 . The composition of  claim 5 , wherein R 2  is  
       
         
           
           
               
               
           
         
       
       and R 6  is independently selected from a linear or a branched alkyl group having one to four carbon atoms and R 7  is a divalent organic group.  
     
     
         13 . The composition of  claim 11 , wherein R 5  is selected from the group consisting of  
       
         
           
           
               
               
           
         
       
       wherein R 6  is independently selected from a linear or a branched alkyl group, and R 7  is a divalent organic group; and  
       
         
           
           
               
               
           
         
       
       wherein each of R 8 , R 9 , R 10 , and R 11  is independently selected from a hydrogen atom and a linear or branched alkyl group having one to three carbon atoms.  
     
     
         14 . The composition of  claim 1 , which has been prepared by compression and is intended for delivery to the gastrointestinal tract.  
     
     
         15 . The composition of  claim 1 , which is in the form of microspheres, microparticles or matrices.  
     
     
         16 . The composition of  claim 1  for administration to the nasal cavity, the buccal cavity or the vaginal cavity.  
     
     
         17 . A method for the preparation of a composition for the controlled release of a drug across a mucosal membrane comprising a polyethylene glycol-chitosan conjugate, the method comprising preparing the polyethylene glycol-chitosan conjugate by bonding the amino function of an activated chitosan species to a polyethylene glycol or polyethylene glycol derivative moiety.  
     
     
         18 . The method of  claim 17 , wherein the activated chitosan species is prepared using bis(acrylamide).