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 . An agent for preventing or treating prostate cancer, prostatomegaly, endometriosis, hysteromyoma, metrofibroma, precocious puberty, and dysmenorrhea, or a contraceptive, which comprises the sustained-release composition according to  claim 3 .  
     
     
         23 . An agent for preventing recurrence of breast cancer after the operation for premenopausal breast cancer, which comprises the sustained-release composition according to  claim 3 .  
     
     
         24 . 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 .  
     
     
         25 . 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 .  
     
     
         26 . A process for producing 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, which comprises adding water to an organic solvent containing a lactic acid-glycolic acid polymer having weight average molecular weight of about 5,000 to 15,000 at a ratio of less than about 5 to 50 (ratio by volume) relative to 100 of the organic solvent.  
     
     
         27 . The process for producing a polymer according to  claim 26 , wherein the organic solvent is hydrophilic.  
     
     
         28 . The process for producing a polymer according to  claim 27 , wherein the hydrophilic organic solvent is acetone.  
     
     
         29 . The process for producing a polymer according to  claim 26 , wherein the ratio of water relative to 100 of the organic solvent is about 10 to about 45 (ratio by volume).  
     
     
         30 . The process for producing a polymer according to  claim 26 , wherein the ratio of water relative to 100 of the organic solvent is about 40 (ratio by volume).  
     
     
         31 . 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.  
     
     
         32 . Use of lactic acid-glycolic acid polymer or salt thereof according to  claim 31  for producing the sustained-release composition which does not include gelatin.  
     
     
         33 . A microsphere containing a lactic acid-glycolic acid polymer having weight average molecular weight of about 11,600 to about 14,000 or a salt thereof, and a LH-RH derivative or a salt thereof, and not containing gelatin.  
     
     
         34 . The microsphere according to  claim 33 , wherein the LH-RH derivative or a salt thereof 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.    
     
     
         35 . The microsphere according to  claim 33 , wherein the LH-RH derivative or a salt thereof 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.    
     
     
         36 . The microsphere according to  claim 33 , wherein the LH-RH derivative or a salt thereof is contained at about 5% (w/w) to about 24% (w/w).  
     
     
         37 . The microsphere according to  claim 33 , which is a microcapsule.  
     
     
         38 . The microsphere according to  claim 33 , wherein the LH-RH derivative or a salt thereof is released during at least more than 2 weeks.  
     
     
         39 . An agent for preventing or treating prostate cancer, prostatomegaly, endometriosis, hysteromyoma, metrofibroma, precocious puberty and dysmenorrhea, or a contraceptive, which comprises the microsphere according to  claim 33 .  
     
     
         40 . An agent for preventing recurrence of breast cancer after the operation for premenopausal breast cancer, which comprises the microsphere according to  claim 33 .  
     
     
         41 . 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 microsphere according to  claim 33 .  
     
     
         42 . 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 microsphere according to  claim 33.