Main agent uniformly dispersed microsphere and a sustained release formulation comprising the same

Abstract

The present application provides a microsphere in which a main agent is uniformly dispersed in a polymer matrix, wherein an average volume-based particle diameter of the microsphere is 1 μm or more and 150 μm or less, and a variation coefficient of area ratios in four regions is 0.35 or less, wherein the area ratios in four regions are calculated by (s/A)×100 (%) wherein the four regions are prepared by preparing a cross section observation sample obtained by cutting the microsphere; observing the cross section observation sample with an electron microscope at a magnification capable of confirming the main agent in the microsphere or a higher magnification; and dividing the electron microscope observation image into four regions; and A is an area of a respective divided region, and s is a sum of cross section areas of the main agent included in the respective divided region. The microsphere of the present invention can appropriately control the initial release amount of the main agent and its release rate during a subsequent release period, and can continuously release the main agent for a predetermined period of time.

1 . A microsphere in which a main agent is uniformly dispersed in a polymer matrix,
 wherein an average volume-based particle diameter of the microsphere is 1 μm or more and 150 μm or less, and   a variation coefficient of area ratios in four regions is 0.25 or less, wherein the area ratios in four regions are calculated by (s/A)×100(%) wherein the four regions are prepared by preparing a cross section observation sample obtained by cutting the microsphere; observing the cross section observation sample with an electron microscope at a magnification capable of confirming the main agent in the microsphere or a higher magnification; and dividing the electron microscope observation image into four regions, and A is an area of a respective divided region, and s is a sum of cross section areas of the main agent included in the respective divided region.   
     
     
         2 . The microsphere according to  claim 1 , wherein the main agent is a lipophilic substance. 
     
     
         3 . The microsphere according to  claim 1 , wherein an average particle diameter of the dispersed main agent is 5 nm to 500 nm. 
     
     
         4 . The microsphere according to  claim 1 , wherein a content of the main agent in the microsphere is 0.10 to 50% by mass relative to the total amount of the microsphere. 
     
     
         5 . The microsphere according to  claim 1 , wherein the polymer is a biodegradable polymer. 
     
     
         6 . A sustained release formulation comprising the microsphere according to  claim 1 . 
     
     
         7 . A sustained release formulation comprising the microsphere according to  claim 2 . 
     
     
         8 . A sustained release formulation comprising the microsphere according to  claim 3 . 
     
     
         9 . A sustained release formulation comprising the microsphere according to  claim 4 . 
     
     
         10 . A sustained release formulation comprising the microsphere according to  claim 5 . 
     
     
         11 . A method of producing a microsphere in which a main agent is uniformly dispersed in a polymer matrix, comprising:
 a step of continuously feeding to a pulverizing apparatus a solution of the polymer and the main agent obtained by dissolving or dispersing the polymer and the main agent in a good solvent of the polymer, and a solution containing a poor solvent of the polymer to prepare emulsified particles; and removing the good solvent from the prepared emulsified particles to precipitate the microsphere;   wherein an average volume-based particle diameter of the microsphere is 1 μm or more and 150 μm or less, and   a variation coefficient of area ratios in four regions is 0.25 or less, wherein the area ratios in four regions are calculated by (s/A)×100(%) wherein the four regions are prepared by preparing a cross section observation sample obtained by cutting the microsphere; observing the cross section observation sample with an electron microscope at a magnification capable of confirming the main agent in the microsphere or a higher magnification; and dividing the electron microscope observation image into four regions; and A is an area of a respective divided region, and s is a sum of cross section areas of the main agent included in the respective divided region.