Sustained-release preparation

Abstract

A sustained-release preparation which comprises a physiologically active peptide of general formula wherein X represents an acyl group; R 1 , R 2 and R 4 each represents an aromatic cyclic group; R 3 represents a D-amino acid residue or a group of the formula wherein R 3 ′ is a heterocyclic group; R 5 represents a group of the formula —(CH 2 ) n —R 5 ′ wherein n is 2 or 3, and R 5 ′ is an amino group which may optionally be substituted, an aromatic cyclic group or an O-glycosyl group; R 6 represents a group of the formula —(CH 2 ) n —R 6 ′ wherein n is 2 or 3, and R 6 ′ is an amino group which may optionally be substituted; R 7 represents a D-amino acid residue or an azaglycyl residue; and Q represents hydrogen or a lower alkyl group, or a salt thereof and a biodegradable polymer having a terminal carboxyl group. The sustained-release preparation shows a constant release of the peptide over a long time and is substantially free from an initial burst.

What is claimed is:  
     
         1 . A sustained-release preparation which comprises a physiologically active peptide of the general formula  
       
         
           
           
               
               
           
         
       
       wherein 
 X represents an acyl group;  
 R 1 , R 2  and R 4  each represents an aromatic cyclic group;  
 R 3  represents a D-amino acid residue or a group of the formula  
                     
 wherein  
 R 3 ′ is a heterocyclic group;  
 R 5  represents a group of the formula —(CH 2 ) n —R 5 ′ wherein n is 2 or 3 and R 5 ′ is an amino group which may optionally be substituted, an aromatic cyclic group or an O-glycosyl group;  
 R 6  represents a group of the formula —(CH 2 ) n —R 6 ′ wherein n is 2 or 3 and R 6 ′ is an amino group which may optionally be substituted;  
 R 7  represents a D-amino acid residue or an azaglycyl residue; and  
 Q represents hydrogen or a lower alkyl group, or a salt thereof and a biodegradable polymer having a terminal carboxyl group.  
 
     
     
         2 . The sustained-release preparation according to  claim 1 , wherein X is a C 2-7  alkanoyl group which may optionally be substituted by a 5- or 6-membered heterocyclic carboxamido group.  
     
     
         3 . The sustained-release preparation according to  claim 2 , wherein X is a C 2-4  alkanoyl group which may optionally be substituted by a tetrahydrofurylcarboxamide group.  
     
     
         4 . The sustained-release preparation according to  claim 1 , wherein X is acetyl.  
     
     
         5 . The sustained-release preparation according to  claim 1 , wherein the biodegradable polymer is a mixture of (A) a copolymer of glycolic acid and a hydroxycarboxylic acid of the general formula  
       
         
           
           
               
               
           
         
       
       wherein R represents an alkyl group of 2 to 8 carbon atoms and (B) a polylactic acid.  
     
     
         6 . The sustained-release preparation according to  claim 1 , wherein X is acetyl, and the biodegradable polymer is a mixture of (A) a copolymer of glycolic acid and a hydroxycarboxylic acid of the general formula  
       
         
           
           
               
               
           
         
       
       wherein R represents an alkyl group of 2 to 8 carbon atoms and (B) a polylactic acid.  
     
     
         7 . The sustained-release preparation according to  claim 5 , wherein the copolymer has a weight average molecular weight of about 2,000 to 50,000, as determined by GPC.  
     
     
         8 . The sustained-release preparation according to  claim 5 , wherein the copolymer has a dispersion value of about 1.2 to 4.0.  
     
     
         9 . The sustained-release preparation according to  claim 5 , wherein the polylactic acid has a weight average molecular weight of about 1,500 to 30,000 as determined by GPC.  
     
     
         10 . The sustained-release preparation according to  claim 5 , wherein the polylactic acid has a dispersion value of about 1.2 to 4.0.  
     
     
         11 . The sustained-release preparation according to  claim 1 , wherein the biodegradable polymer is a copolymer of lactic acid and glycolic acid.  
     
     
         12 . The sustained-release preparation according to  claim 11 , wherein the copolymer has a weight average molecular weight of about 5,000 to 25,000, as determined by GPC.  
     
     
         13 . The sustained-release preparation according to  claim 11 , wherein the copolymer has a dispersion value of about 1.2 to 4.0.  
     
     
         14 . The sustained-release preparation according to  claim 1 , wherein the proportion of the physiologically active peptide ranges from about 0.01 to 50% (w/w) based on the biodegradable polymer.  
     
     
         15 . The sustained-release preparation according to  claim 1 , wherein the physiologically active peptide is a LH-RH antagonist.  
     
     
         16 . The sustained-release preparation according to  claim 1 , wherein the physiologically active peptide is  
       
         
           
           
               
               
           
         
       
       or its acetate.  
     
     
         17 . The sustained-release preparation according to  claim 1 , wherein the physiologically active peptide is NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-Lys(Nisp)-Pro-DAlaNH 2  or its acetate.  
     
     
         18 . The sustained-release preparation according to  claim 1 , wherein the physiologically active peptide is NAcD2Nal-D4ClPhe-D3Pal-Ser-Tyr-DhArg(Et 2 )-Leu-hArg(Et 2 )-Pro-DAlaNH 2  or its acetate.  
     
     
         19 . A method of producing a sustained-release preparation which comprises dissolving a physiologically active peptide of the general formula  
       
         
           
           
               
               
           
         
       
       wherein 
 X represents an acyl group;  
 R 1 , R 2  and R 4  each represents an aromatic cyclic group;  
 R 3  represents a D-amino acid residue or a group of the formula  
                     
 wherein  
 R 3 ′ is a heterocyclic group;  
 R 5  represents a group of the formula —(CH 2 ) n —R 5 ′ wherein n is 2 or 3, and R 5 ′ is an amino group which may optionally be substituted, an aromatic cyclic group or an O-glycosyl group;  
 R 6  represents a group of the formula —(CH 2 ) n —R 6 ′ wherein n is 2 or 3, and R 6 ′ is an amino group which may optionally be substituted;  
 R 7  represents a D-amino acid residue or an azaglycyl residue; and  
 Q represents hydrogen or a lower alkyl group or a salt thereof and a biodegradable polymer having a terminal carboxyl group in a solvent which is substantially immiscible with water and then removing said solvent.  
 
     
     
         20 . The method according to  claim 19 , wherein the biodegradable polymer is a mixture of (A) a copolymer of glycolic acid and a hydroxycarboxylic acid of the general formula  
       
         
           
           
               
               
           
         
       
       wherein R represents an alkyl group of 2 to 8 carbon atoms and (B) a polylactic acid.  
     
     
         21 . The method according to  claim 19 , wherein X is acetyl, and the biodegradable polymer is a mixture of (A) a copolymer of glycolic acid and a hydroxycarboxylic acid of the general formula  
       
         
           
           
               
               
           
         
       
       wherein R represents an alkyl group of 2 to 8 carbon atoms and (B) a polylactic acid.  
     
     
         22 . The method according to  claim 19 , wherein the biodegradable polymer is a copolymer of lactic acid and glycolic acid.  
     
     
         23 . A method according to  claim 19 , which comprises dissolving the biodegradable polymer and the physiologically active peptide in a solvent which is substantially immiscible with water and adding the resulting solution to an aqueous medium to provide an O/W emulsion.  
     
     
         24 . A method of producing a sustained-release preparation which comprises dissolving a biodegradable polymer comprising a mixture of (A) a copolymer of glycolic acid and a hydroxycarboxylic acid of the general formula  
       
         
           
           
               
               
           
         
       
       wherein R represents an alkyl group of 2 to 8 carbon atoms and (B) a polylactic acid and a substantially water-insoluble physiologically active peptide or a salt thereof in a solvent which is substantially immiscible with water and then removing said solvent.  
     
     
         25 . A method according to  claim 24 , which further comprises after dissolving the biodegradable polymer and the substantially water-insoluble peptide or salt thereof in the solvent adding the resulting solution to an aqueous medium to provide an O/W emulsion.