Methods for producing aripiprazole suspension and freeze-dried formulation

Abstract

Disclosed are a method for producing an aripiprazole suspension, wherein the aripiprazole has a mean particle size of 1 to 10 ?m, the method comprising the steps of: (a) combining bulk aripiprazole and a vehicle to form a primary suspension; (b) subjecting the primary suspension to first pulverization using e.g., a high shear pulverizing machine, a dispersion machine that applies shear force to a material to be processed, a colloid mill, an ultrasonic dispersion machine, or a high-pressure jet type emulsifying dispersion machine to form a secondary suspension; and (c) subjecting the secondary suspension to second pulverization using e.g., a high-pressure jet type emulsifying dispersion machine to form a sterile final suspension; and a method for producing a freeze-dried formulation from the aripiprazole suspension.

1 . A method for producing an aripiprazole suspension comprising the steps of:
 (a) combining bulk aripiprazole and a vehicle to form a primary suspension;   (b) subjecting the primary suspension to first pulverization to form a secondary suspension; and   (c) subjecting the secondary suspension to second pulverization to form a final suspension.   
     
     
         2 . The method according to  claim 1 , wherein
 in the first pulverization of step (b), the secondary suspension is formed by pulverizing the primary suspension using a high shear pulverizing machine, a dispersion machine that applies shear force to a material to be processed, a colloid mill, an ultrasonic dispersion machine, or a high-pressure jet type emulsifying dispersion machine, and   in the second pulverization of step (c), the final suspension is formed by pulverizing the secondary suspension using a high-pressure jet type emulsifying dispersion machine.   
     
     
         3 . The method according to  claim 1 , wherein in the first pulverization of step (b), the secondary suspension is formed by pulverizing the primary suspension using a high shear pulverizing machine or a dispersion machine that applies shear force to a material to be processed, and in the second pulverization of step (c), the final suspension is formed by pulverizing the secondary suspension using a high-pressure homogenizer. 
     
     
         4 . The method according to  claim 3 , wherein in step (c), the high-pressure homogenizer is used at a pulverization pressure of 300 to 1000 bar. 
     
     
         5 . The method according to  claim 3 , wherein in step (c), the high-pressure homogenizer is used at a pulverization pressure of 300 to 600 bar. 
     
     
         6 . The method according to  claim 3 , wherein in step (c), the high-pressure homogenizer is used at an inlet temperature of 1 to 70° C. 
     
     
         7 . The method according to  claim 1 , wherein in the first pulverization of step (b), the secondary suspension is formed by pulverizing the primary suspension using a high-pressure homogenizer, and in the second pulverization of step (c), the final suspension is formed by pulverizing the secondary suspension using a high-pressure homogenizer. 
     
     
         8 . The method according to  claim 7 , wherein in the first pulverization of step (b), the secondary suspension is formed by pulverizing the primary suspension using a high-pressure homogenizer at a pulverization pressure of 50 to 200 bar, and in the second pulverization of step (c), the final suspension is formed by pulverizing the secondary suspension using a high-pressure homogenizer at a pulverization pressure of 200 to 1000 bar, wherein the difference between the pulverization pressure in step (b) and the pulverization pressure in step (c) is 100 to 900 bar. 
     
     
         9 . The method according to Item 8, wherein in step (b), the pulverization pressure of the high-pressure homogenizer is in the range of 50 to 200 bar, and in step (c), the pulverization is carried out plural times and the pulverization pressure is raised stepwise within the range of 200 to 1000 bar. 
     
     
         10 . The method according to  claim 9 , wherein in step (c), the final pulverization pressure of the high-pressure homogenizer is 300 to 600 bar. 
     
     
         11 . The method according to  claim 7 , wherein in steps (b) and (c), the high-pressure homogenizer is used at an inlet temperature of 1 to 50° C. 
     
     
         12 . The method according to  claim 1 , wherein the vehicle contains at least one suspending agent selected from the group consisting of carboxymethyl cellulose, carboxymethyl cellulose salts, hydroxypropyl cellulose, hydroxypropylethyl cellulose, hydroxypropylmethyl cellulose and polyvinyl pyrrolidone. 
     
     
         13 . The method according to  claim 1 , wherein the bulk aripiprazole contains aripiprazole particles with a particle size of 100 μm or more in an amount of 10% or more, and has a mean particle size of 20 μm to 1000 μm. 
     
     
         14 . The method according to  claim 1 , wherein the bulk aripiprazole has a mean particle size of more than 100 μm. 
     
     
         15 . The method according to  claim 1 , wherein the bulk aripiprazole has a mean particle size of 110 μm to 1000 μm. 
     
     
         16 . The method according to  claim 1 , wherein the bulk aripiprazole has a mean particle size of 200 μm to 400 μm. 
     
     
         17 . The method according to  claim 1 , wherein the aripiprazole in the aripiprazole suspension has a mean particle size of 1 to 10 μm. 
     
     
         18 . The method according to  claim 1 , wherein the aripiprazole in the aripiprazole suspension has a mean particle size of 1 to 5 μm. 
     
     
         19 . The method according to  claim 1 , wherein the aripiprazole in the aripiprazole suspension has a mean particle size of 2 to 4 μm. 
     
     
         20 . The method according to  claim 1 , wherein the aripiprazole in the aripiprazole suspension has a mean particle size of 2 to 3 μm. 
     
     
         21 . The method according to  claim 1 , comprising the steps of:
 (I) combining sterile bulk aripiprazole with a mean particle size of 200 μm to 400 μm and a sterile vehicle to form a sterile primary suspension;   (II) subjecting the sterile primary suspension to first pulverization using a high shear pulverizing machine or a dispersion machine that applies shear force to a material to be processed, to form a sterile secondary suspension; and   (III) subjecting the sterile secondary suspension to second pulverization using a high-pressure homogenizer to form a sterile final suspension;   
       wherein the aripiprazole in the sterile final suspension has a mean particle size of 1 to 10 μm. 
     
     
         22 . The method according to  claim 1 , wherein the bulk aripiprazole is in the form selected from the group consisting of monohydrate and Anhydride Crystals B. 
     
     
         23 . The method according to  claim 1 , further comprising the step of filtering the final suspension with a filter having a nominal filtration rating of 10 to 225 μm. 
     
     
         24 . A method for producing a freeze-dried formulation of Aripiprazole Hydrate A, the method comprising the steps of: cooling the suspension produced by the method according to  claim 1  and containing Aripiprazole Hydrate A, to −20 to −55° C. to freeze the suspension; and subsequently performing drying at below about 0° C. 
     
     
         25 . A method for producing a freeze-dried formulation containing aripiprazole in anhydrous form, the method comprising the steps of:
 (1) cooling the aripiprazole suspension produced by the method according to  claim 1  using bulk aripiprazole in the form of a monohydrate or anhydrous crystals to −20 to −55° C. to freeze the suspension;   (2) performing primary drying at below about 0° C.; and   (3) performing secondary drying at above about 0° C.