Hyaluronic acid derivative and drug containing the same

Abstract

A hyaluronic acid derivative in which an anti-inflammatory drug is bound to hyaluronic acid through a covalent bond via a spacer having a biodegradable region, and a production process thereof.

1 . A hyaluronic acid compound in which a non-steroidal anti-inflammatory drug is bound to hyaluronic acid through a covalent bond, wherein a partial structure of hyaluronic acid disaccharide unit into which the anti-inflammatory drug is introduced is represented by the following formula (1):
   Y—CO—NH—R 1 —(O—R 2 ) n   (1)
   wherein Y—CO— represents the glucuronic acid residue of the hyaluronic acid disaccharide unit;   R 2  represents a hydrogen atom or a non-steroidal anti-inflammatory drug residue, and at least one R 2  is a non-steroidal anti-inflammatory drug residue;   —NH—R 1 —(O—) n , represents a spacer residue in a spacer compound represented by H 2 N—R 1 —(OH) n  having n numbers of a hydroxyl group;   R 1  represents a linear or branched hydrocarbon group having from 2 to 12 carbon atoms which may have a substituent;   —CO—NH— represents an amide bond of a carboxyl group in the glucuronic acid as a constituting saccharide of the hyaluronic acid with an amino group in the spacer compound;   wherein a hydroxyl group in the spacer compound forms an ester bond with a carboxyl group in the non-steroidal anti-inflammatory drug residue; and   n is an integer of from 1 to 3, and   wherein a carbonyl group in a hyaluronic acid residue constituting the hyaluronic acid compound is present as an amide bond participating in the binding with the spacer-binding anti-inflammatory drug residue or as a free carboxyl group not participating therein.   
     
     
         2 . The hyaluronic acid compound according to  claim 1 , wherein non-steroidal anti-inflammatory drug is selected from the group consisting of ketoprofen, naproxen, ibuprofen, flurbiprofen, acetylsalicylic acid, felbinac, fenbufen, mefenamic acid, diclofenac and etodolac. 
     
     
         3 . The hyaluronic acid compound according to  claim 1 , wherein the non-steroidal anti-inflammatory drug is a compound represented by the following formula (2): 
       
         
           
           
               
               
           
         
         wherein, 
         R 3  represents a substituent selected from the group consisting of a lower alkyl group, a lower alkoxyl group and a hydrogen atom; 
         R 4 , R 5  and R 6  each independently represents a substituent selected from the group consisting of lower alkyl group, a lower alkoxyl group, a hydroxyl group, a halogen atom, and a hydrogen atom; and 
         each X is the same or different and each represents a substituent selected from the group consisting of a lower alkyl group, a trifluoromethyl group, and a halogen atom, wherein at least one of X is a halogen atom. 
       
     
     
         4 . The hyaluronic acid compound according to  claim 3 , wherein the non-steroidal anti-inflammatory drug is a compound represented by the following formula (7): 
       
         
           
           
               
               
           
         
         wherein R 8  represents a substituent selected from the group consisting of a lower alkyl group, a lower alkoxyl group, and a hydrogen atom; and 
         X 1  and X 2  each independently represents a substituent selected from the group consisting of a lower alkyl groups, a trifluoromethyl group, and a halogen atom, wherein at least one of X 1  and X 2  represents a halogen atom. 
       
     
     
         5 . The hyaluronic acid compound according to  claim 1 , wherein the non-steroidal anti-inflammatory drug is represented by the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The hyaluronic acid compound according to  claim 1 , wherein the hyaluronic acid has a weight average molecular weight of from 500,000 to 3,000,000. 
     
     
         7 . The hyaluronic acid compound according to  claim 1 , wherein the hyaluronic acid compound has a degree of substitution of the non-steroidal anti-inflammatory drug of from 0.1 to 80 mol % per repeating disaccharide unit of hyaluronic acid. 
     
     
         8 . The hyaluronic acid compound according to  claim 1 , wherein R 1  in formula (1) is selected from the group consisting of an ethylene group, a trimethylene group and a propylene group, which may have one or more substituents. 
     
     
         9 . The hyaluronic acid compound according to  claim 1 , which is obtainable by a method comprising reacting hyaluronic acid with a spacer-bound non-steroidal anti-inflammatory drug, or reacting a spacer-bound hyaluronic acid with a non-steroidal anti-inflammatory drug, and adjusting the reaction solution to alkaline conditions. 
     
     
         10 . The hyaluronic acid compound according to  claim 1 , wherein a solution obtained by dissolving the hyaluronic acid compound in an aqueous medium to a concentration of 1.0% by weight is capable of passing through a porous filter having a pore size of 0.45 μm and a diameter of 25 mm, at a ratio of 2 mL per minute or more at a temperature of 24° C. under a pressure of 5.0 kg/cm 2 . 
     
     
         11 . The hyaluronic acid compound according to  claim 1 , wherein a solution obtained by dissolving the hyaluronic acid compound in an aqueous medium to a concentration of 1.0% by weight is capable of passing through a porous filter having a pore size of 0.22 μm and a diameter of 25 mm, at a ratio of 2 mL per minute or more at a temperature of 24° C. under a pressure of 5.0 kg/cm 2 . 
     
     
         12 . A hyaluronic acid compound solution which is capable of being pushed out from an injector and which comprises the hyaluronic acid compound according to any one of  claims 1  to  11  dissolved in an aqueous medium. 
     
     
         13 . The hyaluronic acid compound solution according to  claim 12 , wherein the aqueous medium is an aqueous medium selected from the group consisting of phosphate buffered saline, saline and water for injection. 
     
     
         14 . The hyaluronic acid compound solution according to  claim 12 , which is sterilized through a filter. 
     
     
         15 . A pharmaceutical composition which comprises the hyaluronic acid compound according to  claim 1  as an active ingredient and a pharmaceutically acceptable carrier. 
     
     
         16 . The pharmaceutical composition according to  claim 15 , which is an arthritis treating agent, an anti-inflammatory medicament or an analgesic. 
     
     
         17 . The pharmaceutical composition according to  claim 15 , which is useful for parenteral administration. 
     
     
         18 . The pharmaceutical composition according to  claim 17 , which is an injection useful for topical administration. 
     
     
         19 . The pharmaceutical composition according to  claim 17 , which is an injection useful for intra-articular administration. 
     
     
         20 . A pharmaceutical composition which is capable of being pushed out from an injector and which comprises a solution in which the hyaluronic acid compound according to  claim 1 , as an active ingredient, is dissolved in an aqueous medium. 
     
     
         21 . A kit for injection of a hyaluronic acid compound, which comprises the hyaluronic acid compound solution according to  claim 12  which is filled in an injector capable of pushing out the solution. 
     
     
         22 . The kit according to  claim 21 , wherein the filled solution is a pharmaceutical composition which comprises a hyaluronic acid compound as an active ingredient and a pharmaceutically acceptable carrier,
 wherein the hyaluronic acid compound is a hyaluronic acid compound in which a non-steroidal anti-inflammatory drug is bound to hyaluronic acid through a covalent bond, wherein a partial structure of hyaluronic acid disaccharide unit into which the anti-inflammatory drug is introduced is represented by the following formula (1):
   Y—CO—NH—R 1 —(O—R 2 ) n   (1)
 
   wherein Y—CO— represents the glucuronic acid residue of the hyaluronic acid disaccharide unit;   R 2  represents a hydrogen atom or a non-steroidal anti-inflammatory drug residue, and at least one R 2  is a nonsteroidal anti-inflammatory drug residue;   —NH—R 1 —(O—) n  represents a spacer residue in a spacer compound represented by H 2 N—R 1 —(OH) n  having n numbers of a hydroxyl group;   R 1  represents a linear or branched hydrocarbon group having from 2 to 12 carbon atoms which may have a substituent;   —CO—NH— represents an amide bond of a carboxyl group in glucuronic acid as a constituting saccharide of the hyaluronic acid with an amino group in the spacer compound;   wherein a hydroxyl group in the spacer compound forms an ester bond with a carboxyl group in the non-steroidal anti-inflammatory drug residue; and   n is an integer of from 1 to 3; and   wherein a carbonyl group in a hyaluronic acid residue constituting the hyaluronic acid compound is present as an amide bond participating in the binding with the spacer-binding anti-inflammatory drug residue or as a free carboxyl group not participating therein.   
     
     
         23 . A medical injection kit which is sealed with a plunger for medicament extrusion in such a manner that it can be slid and which comprises a syringe filled with a solution in which the hyaluronic acid compound according to  claim 1  is dissolved in pharmaceutically acceptable phosphate buffered saline, saline or water for injection.