Derivatisation of Insulin with Polysaccharides

Abstract

The present invention relates to a composition comprising a population of polysaccharide derivatives of a protein, wherein the protein is insulin or an insulin-like protein and the polysaccharide is anionic and comprises between 2 and 125 saccharide units, and wherein the population consists of substantially only N-terminal derivatives of the protein. Typically, the polysaccharide is PSA. The present invention also relates to pharmaceutical compositions comprising the novel compounds, and methods for making the novel compounds.

1 . A composition comprising a population of polysaccharide derivatives of a protein, wherein the protein is insulin or an insulin-like protein and the polysaccharide is anionic and comprises between 2 and 125 saccharide units, and wherein the population consists substantially only of N-terminal derivatives of the protein. 
     
     
         2 . The composition according to  claim 1  wherein the polysaccharide is selected from polysialic acid, heparin, hyaluronic acid or chondroitin sulphate. 
     
     
         3 . The composition according to  claim 2  wherein the polysaccharide is polysialic acid, preferably consisting substantially only of sialic acid units. 
     
     
         4 . The composition according to any preceding claim wherein the insulin or insulin-like protein is derivatised by the polysaccharide at the reducing terminal unit of the polysaccharide. 
     
     
         5 . The composition according to any of  claims 1 - 3  wherein the polysaccharide derivatives are of general formula (I) 
       
         
           
           
               
               
           
         
         wherein m is at least one; 
         HNB is derived from B—NH 2  which is the N-terminus insulin or an insulin-like protein; 
         L is a bond, a linking group, or comprises a polypeptide or a synthetic digomer; 
         GlyO is an anionic saccharide unit; 
         wherein the linking group, if present, is of general formula —Y—C(O)—R 1 —C(O)—; 
         wherein Y is NR 2  or NR 2 —NR 2 ; R 1  is a difunctional organic radical selected from the group consisting of alkanediyl, arylene, alkarylene, heteroarylene and alkylheteroarylene, any of which may substituted and/or interrupted by carbonyl, ester, sulfide, ether, amide and/or amine linkages; 
         and R 2  is H or C 1-6  alkyl. 
       
     
     
         6 . The composition according to  claim 5  wherein L is a bond or is a group 
       
         
           
           
               
               
           
         
       
     
     
         7 . A composition according to any preceding claim wherein the polysaccharides comprise 10-80 sialic acid units, more preferably 20-60 sialic acid units, most preferably 40-50 sialic acid units. 
     
     
         8 . A composition according to any preceding claim wherein the polydispersity of the anionic polysaccharide is less than 1.3, preferably less than 1.2, most preferably less than 1.1. 
     
     
         9 . A composition according to any preceding claim which is a pharmaceutical composition and comprises one or more pharmaceutically acceptable excipients. 
     
     
         10 . A composition according to any of  claims 1 - 8  for use in therapy.