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.

1 - 25 . (canceled) 
   
   
       26 . A method of producing a plurality of microcapsules together constituting a sustained-release preparation of leuprorelin which comprises:
 (a) dissolving or suspending leuprorelin in an organic solvent solution comprising an organic solvent selected from the group consisting of halogenated hydrocarbons, alkyl ethers having three or more carbon atoms, alkyl esters of carboxylic acids wherein the alkyl group has four or more carbon atoms, aromatic hydrocarbons and mixtures thereof and a biodegradable polymer comprising a copolymer of lactic acid and glycolic acid or a polymer of lactic acid to form a mixture;   (b) adding the mixture to an aqueous medium to provide an O/W emulsion; and   (c) transforming the mixture into microcapsules by removal of the organic solvent, wherein the polymer has a terminal carboxyl group.   
   
   
       27 . The method of  claim 26  wherein said leuprorelin is in the form of leuprorelin acetate. 
   
   
       28 . The method of  claim 27  wherein the organic solvent of step (a) comprises dichloromethane. 
   
   
       29 . The method of  claim 28  wherein said aqueous medium of step (b) comprises polyvinyl alcohol in water. 
   
   
       30 . A method of producing a plurality of microcapsules together constituting a sustained-release preparation of leuprorelin which comprises
 (a) dissolving or suspending leuprorelin acetate in a dichloromethane solution of a biodegradable polymer comprising a copolymer of lactic acid and glycolic acid or a polymer of lactic acid to form a mixture;   (b) adding the mixture to an aqueous medium comprising polyvinyl alcohol in water to provide an O/W emulsion; and   (c) transforming the mixture into microcapsules by removal of the dichloromethane solvent, wherein the polymer has a terminal carboxyl group.   
   
   
       31 . A method of producing a sustained-release preparation which comprises:
 preparing an oil phase comprising (a) leuprorelin, (b) a biodegradable lactic acid-glycolic acid copolymer or a biodegradable lactic acid polymer and (c) at least one organic solvent selected from the group consisting of halogenated hydrocarbons, alkyl ethers having three or more carbon atoms, alkyl esters of carboxylic acids wherein the alkyl group has four or more carbon atoms, aromatic hydrocarbons and mixtures thereof;   providing an aqueous phase;   forming an O/W emulsion by emulsifying said oil phase in said aqueous phase; and   recovering the sustained-release preparation from said emulsion, wherein the polymer has a terminal carboxyl group.   
   
   
       32 . The method of  claim 31 , wherein said organic solvent is dichloromethane. 
   
   
       33 . The method of  claim 31 , wherein said leuprorelin is in the form of leuprorelin acetate. 
   
   
       34 . The method of  claim 31  or  claim 32 , wherein said oil phase is a homogeneous oil phase. 
   
   
       35 . The method of  claim 31  or  claim 32 , wherein the step of recovering includes a step of removing at least one organic solvent from the oil phase. 
   
   
       36 . The method of  claim 31  or  claim 32 , wherein said aqueous phase comprises polyvinyl alcohol and water. 
   
   
       37 . The method of  claim 31  or  claim 32 , wherein the lactic acid-glycolic acid copolymer or the lactic acid polymer has a number-average molecular weight determined by end group determination which is between about 0.4 and about 2.0 times a number-average molecular weight determined by gel permeation chromatography. 
   
   
       38 . A method of forming a sustained-release preparation comprising the steps of:
 forming an oil phase by adding leuprorelin to a solution comprising lactic acid-glycolic acid copolymer or lactic acid polymer and at least one organic solvent selected from the group consisting of halogenated hydrocarbons, alkyl ethers having three or more carbon atoms, alkyl esters of carboxylic acids wherein the alkyl group has four or more carbon atoms, aromatic hydrocarbons and mixtures thereof;   providing an aqueous phase;   forming an O/W emulsion by emulsifying said oil phase in said aqueous phase; and   recovering the sustained-release preparation from the emulsion, wherein the polymer has a terminal carboxyl group.   
   
   
       39 . The method of  claim 38 , wherein said organic solvent is dichloromethane. 
   
   
       40 . The method of  claim 38 , wherein said leuprorelin is in the form of leuprorelin acetate. 
   
   
       41 . The method of  claim 38  or  claim 39 , wherein the aqueous phase comprises polyvinyl alcohol and water. 
   
   
       42 . The method of  claim 38  or  claim 39 , wherein the lactic acid-glycolic acid copolymer or the lactic acid polymer has a number-average molecular weight determined by end group determination which is between about 0.4 and about 2.0 times a number-average molecular weight determined by gel permeation chromatography. 
   
   
       43 . The method of  claim 38  or  claim 39 , wherein the step of recovering includes a step of removing organic solvent from the oil phase. 
   
   
       44 . The method of  claim 38  or  39 , wherein said oil phase is a homogeneous oil phase.