Sustained-release composition and process for producing the same

Abstract

Present invention is to provide a sustained-release composition which contains a physiologically active substance in high content even when gelatin is not included, and suppresses its initial excessive release and, thus, can achieve a stable release rate over about one month. A sustained-release composition containing a lactic acid-glycolic acid polymer having a ratio or weight average molecular weight and number average molecular weight of about 1.90 or lower, or a salt thereof, and a physiologically active substance.

1 . A sustained-release composition containing a lactic acid-glycolic acid polymer having a ratio of weight average molecular weight to number average molecular weight of about 1.90 or lower, or a salt thereof, and a physiologically active substance. 
     
     
         2 . The sustained-release composition according to  claim 1 , wherein the physiologically active substance is a physiologically active peptide. 
     
     
         3 . The sustained-release composition according to  claim 2 , wherein the physiologically active substance is an LH-RH derivative. 
     
     
         4 . The sustained-release composition according to  claim 1 , wherein weight average molecular weight of said lactic acid-glycolic acid polymer is about 3,000 to about 100,000. 
     
     
         5 . The sustained-release composition according to  claim 4 , wherein weight average molecular weight of lactic acid-glycolic acid polymer is about 8,000 to about 15,000. 
     
     
         6 . The sustained-release composition according to  claim 1 , wherein the ratio of the low molecular weight fraction of molecular weight of lactic acid-glycolic acid polymer of about 3,000 or smaller is about 9% or lower. 
     
     
         7 . The sustained-release composition according to  claim 6 , wherein the ratio of the low molecular weight fraction of molecular weight of lactic acid-glycolic acid polymer of about 3,000 or smaller is about 3% to about 9%. 
     
     
         8 . The sustained-release composition according to  claim 1 , wherein said polymer has a molar ratio of lactic acid to glycolic acid of from 100:0 to 40:60. 
     
     
         9 . The sustained-release composition according to  claim 1 , wherein said polymer has a molar ratio of lactic acid to glycolic acid of from 70:30 to 80:20. 
     
     
         10 . The sustained-release composition according to  claim 3 , wherein the LH-RH derivative is a peptide represented by the formula:
   5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z   wherein Y denotes DLeu, DAla, DTrp, DSer(tBu), D2Nal or DHis(ImBzl), and Z denotes HN-C 2 H 5  or Gly-NH 2 , or a salt thereof.   
     
     
         11 . The sustained-release composition according to  claim 3 , wherein the LH-RH derivative is a peptide represented by the formula:
   5-oxo-Pro-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH-C 2 H 5 ,   or acetate thereof.   
     
     
         12 . The sustained-release composition according to  claim 3 , wherein the LH-RH derivative or a salt thereof is contained at about 5% (w/w) to about 24% (w/w) in the sustained-release composition. 
     
     
         13 . The sustained-release composition according to  claim 1 , wherein the physiologically active substance or a salt thereof is slightly water-soluble or water-soluble. 
     
     
         14 . The sustained-release composition according to  claim 1 , which is for injection. 
     
     
         15 . The sustained-release composition according to  claim 1 , which releases a physiologically active substance or a salt thereof over at least two weeks. 
     
     
         16 . The sustained-release composition according to  claim 1 , which does not contain a drug retaining substance. 
     
     
         17 . The sustained-release composition according to  claim 1 , which does not contain gelatin. 
     
     
         18 . A process for producing the sustained-release composition according to  claim 1 , which comprises removing a solvent from a mixed solution containing a physiologically active substance or a salt thereof and a lactic acid-glycolic acid polymer having a ratio of weight average molecular weight to number average molecular weight of about 1.90 or lower, or a salt thereof. 
     
     
         19 . The process according to  claim 18 , which comprises mixing and dispersing a physiologically active substance or a salt thereof in an organic solvent solution containing a lactic acid-glycolic acid polymer having a ratio of weight average molecular weight to number average molecular weight of about 1.90 or lower or a salt thereof, and removing the organic solvent. 
     
     
         20 . The process according to  claim 19 , wherein the physiologically active substance or a salt thereof is used as an aqueous solution containing the physiologically active substance or a salt thereof. 
     
     
         21 . A pharmaceutical comprising the sustained-release composition according to  claim 1 . 
     
     
         22 . A method for preventing or treating prostate cancer, prostatomegaly, endometriosis, hysteromyoma, metrofibroma, precocious puberty and dysmenorrhea, or a contraceptive, which comprises administering to a mammal an effective dose of the sustained-release composition according to  claim 3 . 
     
     
         23 . A method for preventing recurrence of breast cancer after the operation for premenopausal breast cancer, which comprises administering to a mammal an effective dose of the sustained-release composition according to  claim 3 . 
     
     
         24 . A lactic acid-glycolic acid polymer having weight average molecular weight of about 8,000 to about 15,000 and having a ratio of weight average molecular weight to number average molecular weight of about 1.90 or lower, or a salt thereof.