Process for producing water-soluble hyaluronic acid modification

Abstract

The present invention provides a water-soluble modified HA practically used as a drug carrier and a production method thereof. The present invention provides: a water-soluble modified hyaluronic acid, the residence time in blood of which is elongated to a practical level, which is produced by introducing a substituent into the carboxy group of the glucuronic acid of hyaluronic acid or a derivative thereof, via an amide bond, at a lower limit of an introduction ratio of 5 mole % or more, using a BOP condensing agent in an aprotic polar solvent; and a production method thereof. Moreover, by cross-linking the modified hyaluronic acid, the present invention provides a hyaluronic acid gel capable of extremely long drug sustained-release even at the same cross-linking functional group introduction ratio as that of the conventionally known gel.

1 . A hyaluronic acid gel, which is obtainable by cross-linking the modified hyaluronic acid,
 wherein the modified hyaluronic acid is obtainable by a process, which comprises a step of converting a carboxy group contained in the glucuronic acid portion of hyaluronic acid or a derivative thereof to a substituted amide group at a modification ratio of 5 mole % or more in an aprotic polar solvent, using a condensing agent represented by the following formula (II):   
       
         
           
           
               
               
           
         
         wherein each of R 10 , R 11 , R 12 , R 13 , R 14 , and R 15  is independently selected from a C 1-6  alkyl group, or each of R 10  and R 11 , R 12  and R 13 , and R 14  and R 15  may independently form a nitrogen-containing heterocycle together with a nitrogen atom to which they are attached; ring B represents a monocyclic or condensed ring nitrogen-containing heterocyclic group that may be substituted; and X −  represents an anion; 
         wherein the substituted amide group is formed by allowing hyaluronic acid or a derivative thereof to react with one or more compounds selected from the following formulas:
   H 2 N—CH 2 —(CHR 5 ) m-2 —CH 2 —NH 2 ;
 
   H 2 N—CH 2 —CH 2 —(Y 1 —CH 2 —CH 2 ) n —NH 2 ;
 
   H 2 N—CH 2 —(CHR 6 ) p-2 —CH 2 —OH;
 
   H 2 N—CH 2 —CH 2 —(Y 2 —CH 2 —CH 2 ) r —OH;
 
   H 2 N—(CH 2 ) j —SR 7 ;
 
   H 2 N—CH 2 —CH 2 —(Y 3 —CH 2 —CH 2 ) z —SR 8 ;
 
   H 2 N—(CH 2 ) l —O—CO—C(R 16 )═CH 2 ;
 
   H 2 N—(CH 2 ) q —NHCO—C(R 17 )═CH 2 ;
 
   H 2 N—CH 2 —CH 2 —(Y 4 —CH 2 —CH 2 ) t —NHCO—C(R 18 )═CH 2 ; or
 
   H 2 N—CH 2 —CH 2 —(Y 5 —CH 2 —CH 2 ) y —O—CO—C(R 19 )═CH 2  
 
 
       
       wherein each of m, l, p, j, and q independently represents an integer selected from 2 to 10; each of n, r, z, t, and y independently represents an integer selected from 1 to 200; each of R 5  and R 6  independently represents a hydrogen atom or a hydroxyl group; R 7  represents a hydrogen atom, a protective group, or —S—(CH 2 )—NH 2 ; R 8  represents a hydrogen atom, a protective group, or —S—(CH 2 —CH 2 —Y 3 ) z —CH 2 —CH 2 —NH 2 ; each of R 16 , R 17 , R 18 , and R 19  independently represents a hydrogen atom or a methyl group; and each of Y 1 , Y 2 , Y 3 , Y 4 , and Y 5  independently represents an oxygen atom or —NH—. 
     
     
         2 . The hyaluronic acid gel according to  claim 1 , which is used for encapsulation of a drug. 
     
     
         3 . The hyaluronic acid gel according to  claim 1 , wherein a drug which can be encapsulated is a conjugate consisting of a polymer and a drug. 
     
     
         4 . A pharmaceutical composition, which comprises the hyaluronic acid gel according to  claim 1 . 
     
     
         5 . A hyaluronic acid gel, which is obtainable by drying the hyaluronic acid gel according to  claim 1 . 
     
     
         6 . The hyaluronic acid gel according to  claim 5 , which is used for encapsulation of a drug. 
     
     
         7 . The hyaluronic acid gel according to  claim 5 , wherein a drug which can be encapsulated is a conjugate consisting of a polymer and a drug. 
     
     
         8 . A pharmaceutical composition, which comprises the hyaluronic acid gel according to  claim 5 .