Novel Block Copolymer, Micelle Preparation, And Anticancer Agent Containing The Same As Active Ingredient

Abstract

A medicinal preparation is desired which has no harmful side effects such as hypersensitive reaction, heightens the water solubility of a sparingly water-soluble anticancer agent, maintains a high drug concentration in the blood, accumulates a drug in a tumor tissue at a high concentration, heightens the pharmacological effect of the sparingly water-soluble anticancer agent, and diminishes the side effects of the anticancer agent. Provided are: a novel block copolymer which can be a drug carrier having no harmful side effects such as hypersensitive reaction; a micelle preparation in which micelles are formed and which contains a sparingly water-soluble anticancer agent, especially paclitaxel, incorporated in the micelles in an amount necessary for a disease treatment without bonding it to the block copolymer and which can heighten the solubility of the drug in water; and an anticancer agent which comprises the micelle preparation as a medical ingredient, maintains a high concentration in the blood, has more potent drug activity, and is reduced in toxicity.

1 . A block copolymer obtained by reacting a compound represented by the following general formula (1): 
       
         
           
           
               
               
           
         
       
       wherein R1 represents a hydrogen atom or a (C1 to C5) alkyl group, R2 represents a (C1 to C5) alkylene group, R3 represents a methylene group or an ethylene group, R4 represents a hydrogen atom or a (C1 to C4) acyl group, R5 represents a hydroxyl group, an optionally substituted aryl (C1 to C8) alkoxy group or —N(R6)-CO—NHR7, R6 and R7 may be the same or different and each represents a (C3 to C6) cyclic alkyl group or a (C1 to C5) alkyl group optionally substituted with a tertiary amino group; n represents 5 to 1000, m represents 2 to 300, x represents 0 to 300 and y represents 0 to 300, provided that the sum of x and y is 1 or more to m or less; and R5 is a hydroxyl group at a ratio of 1-99% relative to m, an optionally substituted aryl (C1 to C8) alkoxy group at a ratio of 1-99% relative to m, and —N(R6)-CO—NHR7 at a ratio of 0-10% relative to m, 
       with a carbodiimide compound in an amount of m to 5 m equivalents relative to the compound represented by the general formula (1) in a solvent at 30 to 60° C. for 2 to 48 hours. 
     
     
         2 . A block copolymer obtained by reacting a compound represented by the following general formula (2): 
       
         
           
           
               
               
           
         
       
       wherein R1 represents a hydrogen atom or a (C1 to C5) alkyl group, R2 represents a (C1 to C5) alkylene group, R3 represents a methylene group or an ethylene group, R4 represents a hydrogen atom or a (C1 to C4) acyl group, n represents 5 to 1000, x represents 0 to 300 and y represents 0 to 300 provided that the sum of x and y is 2 to 300, 
       with an optionally substituted aryl (C1 to C8) alkyl alcohol or an optionally substituted aryl (C1 to C8) alkyl halide to give a product which is partially esterified in the carboxylic acid side chains, followed by reacting the product with a carbodiimide compound in an amount of (x+y) to 5(x+y) equivalents relative to the compound represented by the general formula (2) in a solvent at 30 to 60° C. for 2 to 48 hours. 
     
     
         3 . The block copolymer according to  claim 1  or  2 , wherein R1 is a methyl group, R2 is a trimethylene group, R3 is a methylene group, R4 is an acetyl group, n is 20 to 500, m is 10 to 100, x is 0 to 100, and y is 0 to 100. 
     
     
         4 . The block copolymer according to any of  claims 1  to  3 , wherein the carbodiimide compound is diethyl carbodiimide, diisopropyl carbodiimide, dicyclohexyl carbodiimide or 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide or an inorganic salt thereof. 
     
     
         5 . The block copolymer according to any of  claims 1  to  3 , wherein the carbodiimide compound is diisopropyl carbodiimide. 
     
     
         6 . A block copolymer represented by the following general formula (3): 
       
         
           
           
               
               
           
         
       
       wherein R1 represents a hydrogen atom or a (C1 to C5) alkyl group, R2 represents a (C1 to C5) alkylene group, R3 represents a methylene group or an ethylene group, R4 represents a hydrogen atom or a (C1 to C4) acyl group, R5 represents a hydroxyl group, an optionally substituted aryl (C1 to C8) alkoxy group or —N(R6)-CO—NHR7, R6 and R7 may be the same or different and each represents a (C3 to C6) cyclic alkyl group or a (C1 to C5) alkyl group optionally substituted with a tertiary amino group; n represents 5 to 1000, m represents 2 to 300, x′ represents 0 to 300 and y′ represents 0 to 300, provided that the sum of x′ and y′ is 1 or more to m or less; and R5 is a hydroxyl group at a ratio of 0-88% relative to m, an optionally substituted aryl (C1 to C8) alkoxy group at a ratio of 1-89% relative to m, and —N(R6)-CO—NHR7 at a ratio of 11-30% relative to m. 
     
     
         7 . The block copolymer according to  claim 6 , wherein R1 is a methyl group, R2 is a trimethylene group, R3 is a methylene group, R4 is an acetyl group, the optionally substituted aryl (C1 to C8) alkoxy group represented by R5 is a benzyloxy group or a 4-phenyl-1-butoxy group, each of R6 and R7 is an isopropyl group, n is 20 to 500, m is 10 to 100, x′ is 0 to 100, and y′ is 0 to 100. 
     
     
         8 . The block copolymer according to  claim 6  or  7 , wherein R5 is a hydroxyl group at a ratio of 0-75% relative to m, an optionally substituted aryl (C1 to C8) alkoxy group at a ratio of 10-80% relative to m, and —N(R6)CO—NHR7 at a ratio of 11-30% relative to m. 
     
     
         9 . The block copolymer according to  claim 8 , wherein R5 is a hydroxyl group at a ratio of 0% relative to m. 
     
     
         10 . A micelle preparation formed from the block copolymer of any of  claims 1  to  9  and a sparingly water-soluble anticancer agent. 
     
     
         11 . The micelle preparation according to  claim 10 , wherein the sparingly water-soluble anticancer agent is a taxane-based anticancer agent. 
     
     
         12 . The micelle preparation according to  claim 11 , wherein the taxane-based anticancer agent is paclitaxel. 
     
     
         13 . An anticancer agent comprising the micelle preparation of any of  claims 10  to  12  as an active ingredient.