Controlled release sterile injectable aripiprazole formulaton and method

Abstract

A controlled release sterile freeze-dried aripiprazole formulation is provided which is formed of aripiprazole of a desired mean particle size and a vehicle therefor, which upon constitution with water and intramuscular injection releases aripiprazole over a period of at least about one week and up to about eight weeks. A method for preparing the controlled release freeze-dried aripiprazole formulation, and a method for treating schizophrenia employing the above formulation are also provided.

32 . A controlled release sterile aripiprazole injectable formulation which upon injection releases aripiprazole over a period of at least one week, which comprises:
 (a) aripiprazole,   (b) a vehicle therefor, and   (c) water for injection.   
     
     
         33 . The formulation as defined in  claim 32 , wherein said vehicle comprises one or more suspending agents. 
     
     
         34 . A controlled release aripiprazole injectable formulation which upon injection releases aripiprazole over a period of at least one week, which comprises:
 (a) aripiprazole, and   (b) a vehicle therefor, said vehicle comprising:
 (1) one or more suspending agents, 
 (2) optionally one or more bulking agents, and 
 (3) optionally one or more buffering agents, and 
   (c) water for injection.   
     
     
         35 . The formulation as defined in  claim 34 , further including a pH adjusting agent. 
     
     
         36 . The formulation as defined in  claim 34 , in the form of a sterile suspension. 
     
     
         37 . The formulation as defined in  claim 34 , in the form of a sterile suspension containing solids having a mean particle size within the range from about 1 to about 30 microns. 
     
     
         38 . The formulation as defined in  claim 34 , in the form of a sterile suspension containing solids having a mean particle size within the range from about 1 to about 20 microns. 
     
     
         39 . The formulation as defined in  claim 38 , wherein the solids have a mean particle size from about 1 to about 10 microns. 
     
     
         40 . The formulation as defined in  claim 34 , designed to release aripiprazole at a controlled rate over a two week to four week period. 
     
     
         41 . The formulation as defined in  claim 34 , in the form of a suspension where:
 (a) the aripiprazole is present in an amount within the range from about 1 to about 40%,   (b) the suspending agent is present in an amount within the range from 0.2 to about 10%,   (c) the bulking agent is present in an amount within the range from about 2 to about 10%,   (d) the buffer is present in an amount within the range from about 0.02 to about 2% to adjust the pH of the suspension within the range from about 6 to about 7.5,   all of the above % being % by weight/volume % based on the volume of suspension.   
     
     
         42 . The formulation as defined in  claim 34 , wherein the suspending agent is carboxymethylcellulose or its sodium-salt, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropylethyl cellulose, hydroxypropylmethyl cellulose, or polyvinylpyrrolidone, the bulking agent is mannitol, sucrose, maltose, lactose, xylitol or sorbitol, and the buffer is sodium phosphate, potassium phosphate or TRIS buffer. 
     
     
         43 . The formulation as defined in  claim 34 , which upon injection releases aripiprazole over a two to four week period comprising:
 (a) aripiprazole,   (b) carboxymethyl cellulose or its sodium salt,   (c) mannitol,   (d) sodium phosphate to adjust pH to about 7,   (e) optionally sodium hydroxide to adjust pH to about 7, and   (f) water for injection.   
     
     
         44 . The formulation as defined in  claim 42 , comprising 
       
         
           
                 
                 
                 
                 
                 
                 
                 
                 
               
                     
                     
                 
                     
                   aripiprazole 
                   100 
                   mg 
                   200 
                   mg 
                   400 
                   mg 
                 
                     
                   carboxymethyl 
                   9 
                   mg 
                   9 
                   mg 
                   9 
                   mg 
                 
                     
                   cellulose 
                 
                     
                   mannitol 
                   45 
                   mg 
                   45 
                   mg 
                   45 
                   mg 
                 
                     
                   Na phosphate 
                   0.8 
                   mg 
                   0.8 
                   mg 
                   0.8 
                   mg 
                 
                 
                 
                 
                 
                 
               
                     
                   sodium 
                   qs to adjust 
                   qs to adjust 
                   qs to adjust 
                 
                     
                   hydroxide 
                   pH to 7 
                   pH to 7 
                   pH to 7 
                 
                 
                 
                 
                 
                 
                 
                 
                 
               
                     
                   water for 
                   qs to 1 
                   mL 
                   qs to 1 
                   mL 
                   qs to 1 
                   mL 
                 
                     
                   injection 
                 
                     
                     
                 
             
                
               
               
                
                
                
                
                
               
            
             
                
                
               
            
             
                
                
                
               
            
           
         
       
     
     
         45 . The formulation as defined in  claim 35 , which permits delivery of from about 0.1 to about 600 mg of aripiprazole per 1 mL of suspension. 
     
     
         46 . The formulation as defined in  claim 32 , wherein the aripiprazole is in anhydrous form or in the form of a monohydrate. 
     
     
         47 . The formulation as defined in  claim 46 , wherein the aripiprazole is in the form of Aripiprazole Anhydride Crystals B or Aripiprazole Hydrate A. 
     
     
         48 . A sterile freeze-dried controlled release aripiprazole formulation which comprises:
 (a) aripiprazole, and   (b) a vehicle therefor,   
       which formulation upon constitution with water forms a sterile injectable formulation which upon injection releases aripiprazole over a period of at least about two weeks. 
     
     
         49 . The freeze-dried formulation as defined in  claim 48 , having a mean particle size within the range from about 1 to about 10 microns which upon constitution with water for injection releases aripiprazole over a period of at least about three weeks. 
     
     
         50 . The freeze-dried formulation as defined in  claim 49 , having a mean particle size of about 2.5 microns. 
     
     
         51 . The freeze-dried formulation as defined in  claim 49 , wherein said vehicle comprises:
 (a) one or more suspending agents,   (b) one or more bulking agents, and   (c) one or more buffering agents.   
     
     
         52 . The freeze-dried formulation as defined in  claim 51 , further including a pH adjusting agent. 
     
     
         53 . The freeze-dried formulation as defined in  claim 51 , which upon constitution with water and injection releases aripiprazole over at least about a three week period, comprising:
 (a) aripiprazole,   (b) carboxymethyl cellulose or its sodium salt,   (c) mannitol,   (d) sodium phosphate to adjust pH to about 7, and   (e) optionally sodium hydroxide to adjust pH to about 7.   
     
     
         54 . The freeze-dried formulation as defined in  claim 53 , which upon reconstitution with water and injection releases aripiprazole over about a four week period. 
     
     
         55 . The freeze-dried formulation as defined in  claim 54 , wherein the aripiprazole is the form of anhydrous crystals or is in the form of a monohydrate. 
     
     
         56 . A method for preparing the sterile freeze-dried formulation as defined in  claim 48 , which comprises the steps of:
 (a) preparing sterile bulk aripiprazole having a desired particle size distribution,   (b) preparing a sterile vehicle for the sterile bulk aripiprazole,   (c) combining said sterile aripiprazole and said sterile vehicle to form a sterile primary suspension which includes a sterile mixture of solids,   (d) reducing the mean particle size of said sterile mixture of solids in said sterile primary suspension to within the range from about 1 to about 10 microns to form a sterile final suspension, and   (e) freeze drying said sterile final suspension to form the freeze-dried formulation.   
     
     
         57 . The method as defined in  claim 56 , wherein the step of reducing the mean particle size of the sterile mixture of solids in said sterile primary suspension is carried out employing wet milling. 
     
     
         58 . The method as defined in  claim 57 , wherein the wet milling comprises wet ball milling. 
     
     
         59 . The method as defined in  claim 56 , wherein said freeze drying step is carried out by cooling the sterile final suspension to about -40° and drying said cooled sterile final suspension at below about 0° C., to form freeze-dried aripiprazole in the form of its monohydrate. 
     
     
         60 . The method as defined in  claim 56 , where the freeze drying step of the sterile final suspension is carried out in three phases: (1) a freezing phase which includes cooling of the sterile final suspension at about −40° C., (2) a primary drying phase which is performed at below about 0° C., and (3) a secondary drying phase which is performed at above about 0° C., to form aripiprazole in anhydrous form. 
     
     
         61 . A method of treating schizophrenia, which comprises administering to a patient in need of treatment the formulation as defined in  claim 34 . 
     
     
         62 . The method as defined in  claim 61 , wherein the formulation is administered intramuscularly or subcutaneously.