High-molecular weight conjugate of steroids

Abstract

Enzymes in the body vary among different species, and also vary among individuals of the same species. Thus, it has been demanded to develop a novel steroid-containing pharmaceutical preparation which can release a drug in a manner independent of the enzymes present in the body, and which is expected to have an efficacious therapeutic effect. Disclosed is a high-molecular weight conjugate of a steroid, comprising a structure in which a carboxylic acid group of a polymer having a polyethylene glycol moiety and a succinic acid monoamide moiety having two or more succinic acid monoamide units is ester-bonded to a hydroxy group in the steroid.

The invention claimed is: 
     
       1. A high-molecular weight conjugate of steroids, comprising a structure in which a carboxylic acid group of a block copolymer having a polyethylene glycol moiety and polyaspartic acid is ester-bonded to an alcoholic hydroxy group in the steroids, and
 wherein the conjugate is represented by formula (I) 
 
       
         
           
           
               
               
           
         
         wherein R1 represents a (C1-C6) alkyl group; R2 represents a (C2-C6) alkylene group; R3 represents a (C1-C6) acyl group; R4 —OR4 represents an alcoholic hydroxy group of said steroids; R5 represents a group selected from the group consisting of a (C1-C30) alkoxy group, a (C7-C30) aralkyloxy group, a (C1-C30) alkylamino group, a di(C1-C30) alkylamino group, an amino acid with a protected carboxy group and —N(R6)CONH(R7) wherein R6 and R7, which may be identical or different from each other, represent a (C3-C6) cyclic alkyl group or a (C1-C5) alkyl group which may be substituted with a tertiary amine group; t represents an integer from 100 to 300; and d, e, f, g, h, i or j each independently represents an integer from 0 to 100; provided that d+e represents an integer from 1 to 100, d+e+f+g+h+i+j represents an integer from 6 to 100; and respective units of the polyaspartic acid are bonded in any order. 
       
     
     
       2. The high-molecular weight conjugate of steroids according to  claim 1 , wherein R1 represents a (C1-C3) alkyl group, R2 represents a (C2-C4) alkylene group, R3 represents a (C1-C3) acyl group, t represents an integer from 100 to 300, and d, e, f, g, h, i or j each independently represents an integer from 0 to 90, provided that d+e represents an integer from 1 to 90 and d+e+f+g+h+i+j represents an integer from 15 to 90. 
     
     
       3. The high-molecular weight conjugate of steroids according to  claim 1  or  2 , in which the steroids are prednisolone, methyl prednisolone, dexamethasone, betamethasone, clobetasol, diflorasone, diflucortolone, fluocinolone acetonide, hydrocortisone, difluprednate, beclometasone, triamcinolone or alclometasone. 
     
     
       4. A method of manufacturing the high-molecular weight conjugate of steroids described in  claim 1 , the method comprising ester-bonding a carboxylic acid group of a block copolymer having a polyethylene glycol moiety and polyaspartic acid to an alcoholic hydroxy group of the steroids, by using a dehydrating condensation agent in an organic solvent. 
     
     
       5. A pharmaceutical composition comprising as an active ingredient the high-molecular weight conjugate of steroids according to  claim 1 . 
     
     
       6. An anti-inflammatory agent comprising as an active ingredient the high-molecular weight conjugate of steroids according to  claim 1 . 
     
     
       7. An anti-rheumatism agent comprising as an active ingredient the high-molecular weight conjugate of steroids according to  claim 1 . 
     
     
       8. An agent for treating collagen disease comprising as an active ingredient the high-molecular weight conjugate of steroids according to  claim 1 . 
     
     
       9. An anti-allergy agent comprising as an active ingredient the high-molecular weight conjugate of steroids according to  claim 1 . 
     
     
       10. The high-molecular weight conjugate of steroids according to claim 2, in which the steroids are prednisolone, methyl prednisolone, dexamethasone, betamethasone, clobetasol, diflorasone, diflucortolone, fluocinolone acetonide, hydrocortisone, difluprednate, beclometasone, triamcinolone or alclometasone.