MICROSPHERES HAVING CORE/SHELL STRUCTURE

• US 20100203151A1
• Filed: 06/09/2008
• Published: 08/12/2010
• Est. Priority Date: 06/25/2007
• Status: Active Grant

• Current Assignee: Otsuka Pharmaceutical Company Limited (Otsuka Holdings Company Limited)
• Original Assignee: Otsuka Pharmaceutical Company Limited (Otsuka Holdings Company Limited)
• Inventors: Hiraoka, Shogo
• Granted Patent: US 10,632,079 B2
• Time in Patent Office: Days
• US Class Current: 424/497
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/5031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5089 Processes
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Abstract

Disclosed are microspheres having a core/shell structure and a spherical shape, wherein (a) the core comprises solid-state aripiprazole, and (b) the shell coats all or most of the surface of the core, and the shell comprises a biodegradable polymer; a process for producing the microspheres; and an injectable aqueous suspension formulation containing the microspheres; and the like.

Claims

1. Microspheres having a core/shell structure and a spherical shape,

(a) the core comprising solid-state aripiprazole;

and

(b) the shell coating all or most of the surface of the core, and the shell comprising a biodegradable polymer.

2. Microspheres according to claim 1, wherein the aripiprazole content is 55 to 95% by weight of the total weight of the microsphere.

3. Microspheres according to claim 1 or 2, having a mean particle size of 20 to 150 μ

m.

4. Microspheres according to claim 1 or 2, wherein the shell has an average thickness of 0.5 to 20 μ

m.

5. Microspheres according to claim 1 or 2, wherein the biodegradable polymer is at least one member selected from the group consisting of polylactic acids and lactic acid-glycolic acid copolymers.

6. Microspheres according to claim 5, wherein the polylactic acids or the lactic acid-glycolic acid copolymers have a molecular weight of 5000 to 200000.

7. An injectable aqueous suspension formulation comprising the microspheres according to claim 1, a vehicle therefor, and water for injection.

8. An injectable aqueous suspension formulation according to claim 7, which upon injection releases aripiprazole over a period of at least one month.

9. An injectable aqueous suspension formulation according to claim 7 or 8, wherein the vehicle comprises:

(1) one or more suspending agents,

(2) one or more isotonic agents, and

(3) optionally one or more pH adjusting agents.

10. A process for producing microspheres having a core/shell structure and a spherical shape according to claim 1, the process comprising:

(i) preparing a solution containing aripiprazole, a biodegradable polymer, and an organic solvent;

(ii) mixing the solution obtained in step (i) with water to obtain an O/W emulsion, under conditions effective for suppressing evaporation of the organic solvent; and

(iii) removing the organic solvent at least partially from the O/W emulsion under conditions effective for allowing the aripiprazole to precipitate in the form of spherical particles.

11. A process according to claim 10, wherein the organic solvent used in step (i) is a water-immiscible organic solvent.

12. A process according to claim 10, wherein the water used in step (ii) contains an emulsifier.

13. A process according to claim 10, wherein step (ii) comprises the substeps of (a) dispersing the solution obtained in step (i) in water in the presence or absence of an emulsifier to form an O/W emulsion and (b) dispersing the O/W emulsion obtained in substep (a) in water in the presence or absence of an emulsifier to form an O/W emulsion.

14. A process according to claim 10, wherein, in step (ii), the O/W emulsion is produced under low-temperature conditions effective for suppressing evaporation of the organic solvent, and in step (iii), the low temperature emulsion obtained in step (ii) is stirred in an open system at room temperature to allow the organic solvent to volatilize.

15. A method for treating schizophrenia, comprising administering an injectable aqueous suspension formulation according to claim 7 to a patient in need of such treatment.

16. Use of an injectable aqueous suspension formulation according to claim 7 for production of a medicament for treating schizophrenia.

17. An injectable aqueous suspension formulation according to claim 7 for use in treating schizophrenia.