Controlled release sterile injectable aripiprazole formulation and method

• US 8,030,313 B2
• Filed: 10/31/2007
• Issued: 10/04/2011
• Est. Priority Date: 10/23/2003
• Status: Active Grant

• Current Assignee: Otsuka Pharmaceutical Company Limited (Otsuka Holdings Company Limited)
• Original Assignee: Otsuka Pharmaceutical Company Limited (Otsuka Holdings Company Limited)
• Inventors: Matsuda, Takakuni, Naringrekar, Vijay H., Nerurkar, Manoj, Kostanski, Janusz W.
• Primary Examiner(s): CHONG, YONG SOO
• Application Number:
  US11/979,149
• Publication Number:
  US 20080112986A1
• Time in Patent Office: 1,434 Days
• Field of Search: 514/253.07, 514/253.03, 514/252.1
• US Class Current: 514/253.07
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/38 Cellulose; Derivatives thereof
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

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.

Claims

1. A method of treating schizophrenia, which comprises administering to a subject in need of treatment thereof, a sterile injectable formulation obtained by reconstitution of a homogeneous suspension from a sterile freeze-dried controlled release aripiprazole formulation which comprises:

(a) aripiprazole having a mean particle size of about 1 to 10 microns, and

(b) one or more suspending agents,

wherein said sterile freeze-dried controlled release aripiprazole formulation is in the form of a cake obtained by freeze-drying a homogeneous aqueous suspension comprising (a) and (b), and wherein upon reconstitution, which comprises adding water to said cake, the sterile injectable formulation is obtained which is a homogeneous suspension and which contains from about 0.1 to about 600 mg of aripiprazole per mL, and wherein upon injection into a subject, said sterile injectable formulation releases aripiprazole over a period of at least about two weeks from the date of administration.

2. The method as defined in claim 1, wherein the sterile injectable formulation is administered intramuscularly or subcutaneously.

3. The method of treating schizophrenia as defined in claim 1, wherein the sterile freeze-dried controlled release aripiprazole formulation further comprises:

(c) one or more bulking agents, and

(d) one or more buffering agents.

4. The method as defined in claim 3, wherein the sterile injectable formulation is administered intramuscularly or subcutaneously.

5. The method of treating schizophrenia as defined in claim 3, wherein the sterile freeze-dried controlled release aripiprazole 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,

wherein upon injection into a subject, said sterile injectable formulation releases aripiprazole over a period of at least about three weeks from the date of administration.

6. The method as defined in claim 5, wherein the sterile injectable formulation is administered intramuscularly or subcutaneously.

9. The method as defined in claim 1, wherein the sterile injectable formulation comprises from 100 to 400 mg aripiprazole/mL and is administered one to two times monthly.

10. The method as defined in claim 3, wherein the sterile injectable formulation comprises from 100 to 400 mg aripiprazole/mL and is administered one to two times monthly.

11. The method as defined in claim 5, wherein the sterile injectable formulation comprises from 100 to 400 mg aripiprazole/mL and is administered one to two times monthly.

13. The method as defined in claim 1, wherein the aripiprazole has a mean particle size of about 2 to about 4 microns.

14. The method as defined in claim 1, wherein the aripiprazole has a mean particle size of about 2.5 microns.

15. The method as defined in claim 1, wherein the aripiprazole is in the form of anhydrous crystals or in the form of a monohydrate.

16. The method as defined in claim 15, wherein the aripiprazole is in the form of Aripiprazole Anhydride Crystals B or Aripiprazole Hydrate A.

17. The method as defined in claim 3, wherein the aripiprazole is in the form of anhydrous crystals or in the form of a monohydrate.

18. The method as defined in claim 17, wherein the aripiprazole is in the form of Aripiprazole Anhydride Crystals B or Aripiprazole Hydrate A.

19. The method as defined in claim 5, wherein the aripiprazole is in the form of anhydrous crystals or in the form of a monohydrate.

20. The method as defined in claim 19, wherein the aripiprazole is in the form of Aripiprazole Anhydride Crystals B or Aripiprazole Hydrate A.

21. The method as defined in claim 3, wherein said sterile injectable 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 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 sterile injectable formulation within the range from about 6 to about 7.5,

wherein all of the above % are % by weight/volume based on the volume of the sterile injectable formulation.

22. The method as defined in claim 3, 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.

23. The method as defined in claim 5, wherein the sterile injectable formulation is selected from the group consisting of the following Formulations A, B and C:

24. The method as defined in claim 21, wherein the sterile injectable 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 sterile injectable formulation to about 6 to about 7.5,

wherein all of the above % are % by weight/volume based on the total volume of the sterile injectable formulation.

25. The method as defined in claim 24, wherein the sterile injectable 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 sterile injectable formulation to about 6 to about 7.5,

wherein all of the above % are % by weight/volume based on the total volume of the sterile injectable formulation.

26. The method as defined in claim 14, 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.

27. The method as defined in claim 25, 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.

28. The method as defined in claim 1, wherein the sterile injectable formulation contains from about 50 to about 400 mg of aripiprazole per 2 mL.

29. The method as defined in claim 1, wherein the sterile injectable formulation contains from about 100 to about 200 mg of aripiprazole per mL.

30. The method as defined in claim 3, wherein the sterile injectable formulation contains from about 50 to about 400 mg of aripiprazole per 2 mL.

31. The method as defined in claim 3, wherein the sterile injectable formulation contains from about 100 to about 200 mg of aripiprazole per mL.

32. The method as defined in claim 5, wherein the sterile injectable formulation contains from about 50 to about 400 mg of aripiprazole per 2 mL.

33. The method as defined in claim 5, wherein the sterile injectable formulation contains from about 100 to about 200 mg of aripiprazole per mL.

7. A method of treating schizophrenia, which comprises administering to a subject in need of treatment thereof, a sterile injectable formulation obtained by reconstitution of a homogeneous suspension from a sterile freeze-dried controlled release aripiprazole formulation which comprises:

(a) aripiprazole having a mean particle size of about 1 to 10 microns, and

(b) one or more suspending agents,

wherein said freeze-dried formulation is in the form of a cake obtained by freeze-drying a homogeneous aqueous suspension comprising (a) and (b), and wherein upon reconstitution, which comprises adding water to said cake, the sterile injectable formulation is obtained which is a homogeneous suspension and which contains from about 0.1 to about 600 mg of aripiprazole per mL, and wherein upon injection into a subject, said sterile injectable formulation releases aripiprazole over a period of at least about one week from the date of administration.

8. The method as defined in claim 7, wherein the sterile injectable formulation is administered intramuscularly or subcutaneously.

12. The method as defined in claim 7, wherein the sterile injectable formulation comprises from 100 to 400 mg aripiprazole/mL and is administered one to two times monthly.

34. The method as defined in claim 7, wherein the sterile injectable formulation contains from about 50 to about 400 mg of aripiprazole per 2 mL.

35. The method as defined in claim 7, wherein the sterile injectable formulation contains from about 100 to about 200 mg of aripiprazole per mL.