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|Title:||Controlled release sterile injectable aripiprazole formulation 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 thereof, 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.|
|Inventor(s):||Kostanski; Janusz W. (Princeton, NJ), Matsuda; Takakuni (Tokushima, JP), Nerurkar; Manoj (Bangalore, IN), Naringrekar; Vijay H. (Princeton, NJ)|
|Assignee:||Otsuka Pharmaceutical Co., Ltd. (Tokyo, JP)|
|Filing Date:||Oct 06, 2014|
|Claims:||1. A method for preparing a controlled release sterile aripiprazole injectable formulation, prepared by mixing a freeze-dried composition with water for injection, wherein the freeze-dried composition comprises: (a) aripiprazole having a mean particle size of about 1 to 10 microns, and (b) one or more suspending agents, wherein said aripiprazole is present in an amount of about 0.1 to about 400 mg per 1 mL, and wherein said formulation is a homogenous aqueous suspension and upon injection into a subject, said formulation releases aripiprazole over a period of at least about two weeks from the date of administration, wherein said method comprises the steps of: (a) preparing sterile bulk aripiprazole having a desired particle size distribution, (b) preparing a sterile vehicle comprising one or more suspending agents for the sterile bulk aripiprazole, (c) combining said sterile aripiprazole and said sterile vehicle comprising one or more suspending agents to form a sterile primary suspension, (d) reducing the mean particle size of the aripiprazole in said sterile primary suspension to within the range from about 1 to about 10 microns to form a sterile final suspension containing from about 0.1 to about 400 mg of aripiprazole per mL, (e) freeze-drying said sterile final suspension to form a freeze-dried product, and (f) adding water to the resulting freeze-dried product. |
2. The method as defined in claim 1, wherein the step of reducing the mean particle size of the aripiprazole in said sterile primary suspension is carried out employing wet milling.
3. The method as defined in claim 2, wherein the wet milling comprises wet ball milling.
4. The method as defined in claim 1, wherein said freeze drying step is carried out by cooling the sterile final suspension to about -40.degree. C. and drying the resulting cooled sterile final suspension at below about 0.degree. C., to form freeze dried aripiprazole in the form of its monohydrate.
5. The method as defined in claim 1, wherein the freeze drying step is carried out in three phases: (1) a freezing phase which includes cooling of the sterile final suspension at about -40.degree. C., (2) a primary drying phase which is performed at below about 0.degree. C., and (3) a secondary drying phase which is performed at above about 0.degree. C., to form aripiprazole in the form of anhydrous crystals.
6. The method of claim 1, wherein said formulation comprises: (a) aripiprazole having a mean particle size of about 1 to 10 microns, (b) carboxymethyl cellulose or its sodium salt, (c) mannitol, (d) sodium phosphate to adjust pH to about 7, optionally sodium hydroxide to adjust pH to about 7, wherein upon injection into a subject, said formulation releases aripiprazole over a period of at least about three weeks from the date of administration.
7. The method as defined in claim 6, wherein the formulation is administered intramuscularly or subcutaneously.