Process for producing sustained-release preparation

Abstract

The present invention is to provide sustained-release microcapsules which contains high amount of a drug, suppresses initial release and shows stable release, and the production method of which comprises adding a physiologically active substance to biodegradable polymer in an organic solvent containing a fat and oil (in particular, vitamin E) and dispersing and emulsifying the mixture.

What is claimed is:  
     
         1 . A process for producing a sustained-release microcapsule of a water-soluble physiologically active substance, which comprises forming a w/o type emulsion comprising a solution containing a water-soluble physiologically active substance as an inner aqueous phase and an uniform organic solvent solution containing a biodegradable polymer and a fat and oil as an oil phase, and removing the organic solvent.  
     
     
         2 . A process according to    claim 1   , wherein the w/o type emulsion is dispersed in an aqueous phase, and the organic solvent is removed by in-water drying.  
     
     
         3 . A process according to    claim 1   , wherein the inner aqueous phase is a solution containing a water-soluble physiologically active substance and a basic substance.  
     
     
         4 . A process according to    claim 1   , wherein the water-soluble physiologically active substance is a polypeptide the molecular weight of which ranges from about 200 to about 80,000.  
     
     
         5 . A process according to    claim 1   , wherein the water-soluble physiologically active substance is an integrin antagonist.  
     
     
         6 . A process according to    claim 5   , wherein the integrin antagonist is a GPIIb/IIIa antagonist.  
     
     
         7 . A process according to    claim 6   , wherein the GPIIb/IIIa antagonist is a 2-piperazinone-1-acetic acid derivative represented by the formula (I):  
                   
       wherein A 1  and A 2  are independently a proton-accepting group or a group convertible into a proton-accepting group, D is a spacer having a 2- to 6-atomic chain optionally bonded through a hetero atom and/or a 5- or 6-membered ring (provided that the 5- or 6-membered ring is counted as 2- or 3-atomic chain, depending on its bonding position), R 1  is a hydrogen atom or hydrocarbon group, R 2  is a hydrogen atom or a residual group formed by removing —CH(NH 2 )COOH from an α-amino acid, or R 1  and R 2  may be combined to form a 5- or 6-membered ring, P is a spacer having a 1- to 10-atomic chain optionally bonded through a hetero atom and/or a 5- or 6-membered ring (provided that the 5- or 6-membered ring is counted as 2- or 3-atomic chain, depending on its bonding position), Y is an optionally esterified or amidated carboxyl group, and n is an integer of 0-8; or a salt thereof.  
     
     
         8 . A process according to    claim 7   , wherein the 2-piperazinone-1-acetic acid derivative (I) is (S)-4-(4-guanidinobenzoylamino)acetyl-3-[3-(4-guanidinobenzoylamino)]propyl-2-oxopiperazine-1-acetic acid or a salt thereof.  
     
     
         9 . A process according to    claim 7   , wherein the 2-piperazinone-1-acetic acid derivative (I) is (S)-4-(4-guanidinobenzoylamino)acetyl-3-[3-(4-guanidinobenzoylamino) ]propyl-2-oxopiperazine-1-acetic acid hydrochloride.  
     
     
         10 . A process according to    claim 7   , wherein the 2-piperazinone-1-acetic acid derivative (I) is (S)-4-(4-guanidinobenzoylamino)acetyl-3-[3-(4-guanidinobenzoylamino) ]propyl-2-oxopiperazine-1-acetic acid dihydrochloride.  
     
     
         11 . A process according to    claim 1   , wherein the biodegradable polymer is an aliphatic polyester.  
     
     
         12 . A process according to    claim 11   , wherein the aliphatic polyester is a lactic acid/glycolic acid copolymer.  
     
     
         13 . A process according to    claim 1   , wherein the fat and oil is an oil soluble vitamin.  
     
     
         14 . A process according to    claim 13   , wherein the oil soluble vitamin is α-tocopherol.  
     
     
         15 . A process according to    claim 1   , wherein the final concentration of the fat and oil in a whole content of the sustained-release microcapsule is about 3% to about 30% (w/w).  
     
     
         16 . A process according to    claim 1   , wherein the W/O type emulsion comprising a solution containing a water-soluble physiologically active substance and a basic substance as an inner aqueous phase and an uniform organic solvent solution containing a biodegradable polymer and a fat and oil as an oil phase is dispersed in an aqueous phase to form a W/O/W type emulsion, and the organic solvent is removed by in-water drying.  
     
     
         17 . A process according to    claim 3    or    16   , wherein the basic substance is a basic amino acid.  
     
     
         18 . A process according to    claim 17   , wherein the basic amino acid is L-arginine.  
     
     
         19 . A process according to    claim 3    or    16   , wherein the final concentration of the basic substance in a whole content of the sustained-release microcapsule is about 1% to about 8% (w/w).  
     
     
         20 . A process for producing a sustained-release microcapsule, which comprises removing an organic solvent from a S/O type dispersion where a metal complex of a water-soluble physiologically active peptide is dispersed in an uniform organic solvent solution containing a biodegradable polymer and a fat and oil.  
     
     
         21 . A process according to    claim 20   , wherein the S/O type dispersion is dispersed in an aqueous phase to form a S/O/W type emulsion, and the organic solvent is removed by in-water drying.  
     
     
         22 . A process according to    claim 20   , wherein the water-soluble physiologically active peptide is human growth hormone.  
     
     
         23 . A process according to    claim 20   , wherein the metal complex of the water-soluble physiologically active peptide is a zinc complex of human growth hormone.  
     
     
         24 . A sustained-release microcapsule produced by the process according to    claim 1   .  
     
     
         25 . A sustained-release microcapsule produced by the process according to    claim 20   .  
     
     
         26 . Use of a fat and oil for the manufacture of a sustained-release microcapsule of a water-soluble physiologically active substance, said microcapsule being produced by forming a w/o type emulsion comprising a solution containing the water-soluble physiologically active substance as an inner aqueous phase and an organic solvent solution containing a biodegradable polymer as an oil phase, and removing the organic solvent.  
     
     
         27 . Use of a fat and oil for the manufacture of a sustained-release microcapsule of a metal complex of a water-soluble physiologically active peptide.