Freeze-dried aripiprazole formulation

Abstract

An object of the present invention is to provide a freeze-dried aripiprazole powder formulation that exhibits good dispersibility and is easily dispersed into a homogenous suspension when reconstituted with water. The present invention provides a freeze-dried aripiprazole formulation obtained by a process comprising the steps of spraying for freezing an aripiprazole suspension containing (I) aripiprazole, (II) a vehicle for the aripiprazole, and (III) water for injection, and drying

1 . A freeze-dried aripiprazole formulation obtained by a process comprising the steps of spraying for freezing an aripiprazole suspension containing
 (I) aripiprazole,   (II) a vehicle for the aripiprazole, and   (III) water for injection; and   drying.   
     
     
         2 . The freeze-dried formulation according to  claim 1 , consisting essentially of particles with a particle size of substantially 30 μm or more. 
     
     
         3 . The freeze-dried formulation according to  claim 1 , comprising aripiprazole in an amount of 50 w/w % or more. 
     
     
         4 . The freeze-dried formulation according to  claim 1 , which has a bulk density of about 0.05 to about 0.5 g/mL. 
     
     
         5 . The freeze-dried formulation according to  claim 1  wherein the aripiprazole has a mean particle size of about 1 to about 10 microns. 
     
     
         6 . The freeze-dried formulation according to  claim 5  wherein the aripiprazole has a mean particle size of about 2.5 microns. 
     
     
         7 . The freeze-dried formulation according to  claim 1 , comprising at least one member selected from the group consisting of suspending agents, bulking agents, and buffers. 
     
     
         8 . The freeze-dried formulation according to  claim 1 , comprising
 (II-a) one or more suspending agents,   (II-b) one or more bulking agents, and   (II-c) one or more buffers.   
     
     
         9 . The freeze-dried formulation according to  claim 1 , comprising
 (II-a) carboxymethyl cellulose or a salt thereof,   (II-b) mannitol, and   (II-c) sodium phosphate.   
     
     
         10 . The freeze-dried formulation according to  claim 1 , further comprising (IV) a pH adjusting agent. 
     
     
         11 . The freeze-dried formulation according to  claim 10 , wherein the pH adjusting agent is sodium hydroxide. 
     
     
         12 . The freeze-dried formulation according to  claim 1 , comprising
 (I) aripiprazole,   (II-a) carboxymethyl cellulose or a sodium salt thereof,   (II-b) mannitol,   (II-c) sodium phosphate, and optionally   (IV) sodium hydroxide.   
     
     
         13 . The freeze-dried formulation according to  claim 1 , wherein the aripiprazole is in the form of a monohydrate. 
     
     
         14 . A process for producing a freeze-dried aripiprazole formulation comprising the steps of
 (e′-1) spray-freezing an aripiprazole suspension having a mean particle size in the range of about 1 to about 10 microns to obtain spray-frozen particles; and   (e′-2) drying the spray-frozen particles to obtain spray-freeze-dried particles.   
     
     
         15 . The process for producing a freeze-dried aripiprazole formulation according to  claim 14 , comprising the steps of
 (d′) reducing the mean particle size of aripiprazole in a primary suspension formed by mixing aripiprazole, a vehicle for the aripiprazole, and water to the range of about 1 to about 10 microns to form a final suspension;   (e′-1) spray-freezing the aripiprazole suspension having a mean particle size of about 1 to about 10 microns to obtain spray-frozen particles; and   (e′-2) drying the spray-frozen particles to obtain spray-freeze-dried particles.   
     
     
         16 . The process according to  claim 15 , wherein the reduction of the mean particle size of aripiprazole in the sterile primary suspension is carried out by wet milling. 
     
     
         17 . The process according to  claim 14 , wherein the spraying in step (e′-1) is either spraying at a low temperature for freezing or spraying under reduced pressure for freezing. 
     
     
         18 . The process according to  claim 14 , further comprising selecting particles with a particle size of substantially 30 μm or more. 
     
     
         19 . The freeze-dried formulation according to  claim 1 , which exhibits good dispersibility and forms a homogenous aripiprazole suspension upon reconstitution with water. 
     
     
         20 . The freeze-dried formulation according to  claim 1 , comprising particles with a particle size of less than 75 μm in an amount of 15 w/w % or less.