Claims for Patent: 8,722,679

Summary for Patent: 8,722,679

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 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.
Inventor(s):	Kostanski; Janusz W. (Princeton, NJ), Matsuda; Takakuni (Tokushima, JP), Nerurkar; Manoj (Monmouth Junction, NJ), Naringrekar; Vijay H. (Princeton, NJ)
Assignee:	Otsuka Pharmaceutical Co., Ltd. (Tokyo, JP)
Application Number:	11/979,145
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,722,679
Patent Claims:	1. 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) a vehicle therefor, wherein said formulation is a homogenous suspension and upon injection into a subject, said formulation releases aripiprazole over a period of at least one week. 2. 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. 3. The formulation as defined in claim 2, wherein upon injection into a subject, said formulation releases aripiprazole over a period of at least three weeks from the date of administration. 4. The formulation as defined in claim 2, wherein said aripiprazole has a mean particle size of about 2.5 microns. 5. The formulation as defined in claim 2, wherein said formulation further comprises (c) one or more bulking agents; and (d) one or more buffering agents. 6. The formulation as defined in claim 5, wherein said formulation further comprises (e) a pH adjusting agent. 7. The formulation as defined in claim 2, 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, and (e) optionally sodium hydroxide to adjust pH to about 7, and wherein upon injection into a subject, said formulation releases aripiprazole over a period of at least about three weeks from the date of administration. 8. The formulation as defined in claim 7, wherein upon injection into a subject, said formulation releases aripiprazole over a period of about three to four weeks from the date of administration. 9. The formulation as defined in any one of claims 2, 5 and 7, wherein upon injection into a subject, said formulation releases aripiprazole over a period of three or four weeks from the date of administration. 10. The formulation as defined in claim 7, wherein upon injection into a subject, said formulation releases aripiprazole over a period of about four weeks from the date of administration. 11. The formulation as defined in claim 2, wherein the aripiprazole is in the form of anhydrous crystals or in the form of a monohydrate. 12. The formulation as defined in claim 11, wherein the aripiprazole is in the form of Aripiprazole Anhydrous Crystals B or Aripiprazole Hydrate A. 13. The formulation as defined in claim 5, wherein the aripiprazole is in the form of anhydrous crystals or in the form of a monohydrate. 14. The formulation as defined in claim 13, wherein the aripiprazole is in the form of Aripiprazole Anhydrous Crystals B or Aripiprazole Hydrate A. 15. The formulation as defined in claim 7, wherein the aripiprazole is in the form of anhydrous crystals or in the form of a monohydrate. 16. The formulation as defined in claim 15, wherein the aripiprazole is in the form of Aripiprazole Anhydrous Crystals B or Aripiprazole Hydrate A. 17. The formulation as defined in claim 5, wherein said formulation comprises: (a) aripiprazole having a mean particle size of about 1 to about 10 microns in an amount within the range from about 1 to about 40%, (b) suspending agent in an amount within the range from 0.2 to about 10%, (c) bulking agent in an amount within the range from about 1 to about 10%, and (d) buffering agent 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, wherein all of the above % are % by weight/volume based on the total volume of the formulation. 18. The formulation as defined in claim 5, wherein the suspending agent is selected from the group consisting of carboxymethylcellulose or its sodium salt, hydroxypropyl cellulose, hydroxypropylethyl cellulose, hydroxypropylmethyl cellulose, and polyvinylpyrrolidone; the bulking agent is selected from the group consisting of mannitol, sucrose, maltose, lactose, xylitol and sorbitol; and the buffering agent is selected from the group consisting of sodium phosphate, potassium phosphate and TRIS buffer. 19. The formulation as defined in claim 7, wherein said formulation is selected from the group consisting of the following Formulations A, B and C: TABLE-US-00008 Formulation A Formulation B Formulation C Aripiprazole having a 100 mg 200 mg 400 mg mean particle size of about 1 to 10 microns Carboxy-methyl 9 mg 9 mg 9 mg cellulose Mannitol 45 mg 45 mg 45 mg Sodium 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 20. The formulation as defined in claim 5 or 7, wherein said aripiprazole has a mean particle size of about 2.5 microns. 21. The formulation as defined in claim 2, wherein said formulation comprises from about 100 to about 400 mg aripiprazole per 1 mL. 22. 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, wherein said aripiprazole is in the form a monohydrate, and (b) one or more suspending agents, wherein said aripiprazole is present in an amount of about 0.1 to about 600 mg per 1 mL, and wherein said formulation is a homogenous 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. 23. 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 600 mg per 1 mL, and wherein said formulation is a homogenous suspension and upon injection into a subject, said formulation releases aripiprazole over a period of at least about one week from the date of administration. 24. The formulation as defined in claim 23, wherein said formulation further comprises (c) one or more bulking agents; and (e) one or more buffering agents. 25. The formulation as defined in claim 24, 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, and (e) optionally sodium hydroxide to adjust pH to about 7. 26. The formulation as defined in claim 2, 5 or 7, wherein the aripiprazole has a mean particle size of about 2 to 4 microns. 27. A controlled release sterile aripiprazole injectable formulation as defined in claim 2 which is obtained by a process which 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 sterile 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 freeze-dried product. 28. The formulation as defined in claim 27, wherein the step of reducing the mean particle size of the aripiprazole in said sterile primary suspension is carried out employing wet milling. 29. The formulation as defined in claim 28, wherein the wet milling comprises wet ball milling. 30. The formulation as defined in claim 27, wherein freeze-drying is carried out by cooling the homogeneous suspension to about -40.degree. C. and drying the resulting cooled sterile final suspension at below about 0.degree. C. under vacuum, to form said freeze-dried product. 31. The formulation as defined in claim 17, wherein said formulation comprises: (a) aripiprazole having a mean particle size of about 1 to about 5 microns in an amount within the range from about 1 to about 40%, (b) suspending agent in an amount within the range from about 0.2 to about 10%, (c) bulking agent in an amount within the range from about 1 to about 10%, and (d) buffering agent 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, wherein all of the above % are % by weight/volume based on the total volume of the formulation. 32. The formulation as defined in claim 31, wherein said formulation comprises: (a) aripiprazole having a mean particle size of about 2.5 microns in an amount within the range from about 5 to about 20%, (b) suspending agent in an amount within the range from about 0.5 to about 5%, (c) bulking agent in an amount within the range from about 4 to about 5%, and (d) buffering agent in an amount within the range from about 0.03 to about 1% to adjust the pH of the suspension within the range from about 6 to about 7.5, wherein all of the above % are % by weight/volume based on the total volume of the formulation. 33. The formulation as defined in claim 4, wherein the aripiprazole having a mean particle size of about 2.5 microns has a particle size distribution as follows: 95%<20 microns 90%<15 microns 50%<10 microns 10%<2 microns. 34. The formulation as defined in claim 32, wherein the aripiprazole having a mean particle size of about 2.5 microns has a particle size distribution as follows: 95%<20 microns 90%<15 microns 50%<10 microns 10%<2 microns. 35. The formulation as defined in claim 2, wherein said formulation comprises from about 50 to about 400 mg aripiprazole per 2 mL. 36. The formulation as defined in claim 2, wherein said formulation comprises from about 100 to about 200 mg aripiprazole per 1 mL.