Controlled release nanoparticulate compositions

• US 20080124393A1
• Filed: 10/31/2007
• Published: 05/29/2008
• Est. Priority Date: 10/01/1998
• Status: Abandoned Application

• Current Assignee: Elan Pharma International Limited (Perrigo Company PLC)
• Original Assignee: Elan Pharma International Limited (Perrigo Company PLC)
• Inventors: Hontz, Robert, Devane, John G., Jain, Rajeev A., Clancy, Maurice Joseph Anthony, Cumming, Kenneth Iain, Swanson, Jon, Codd, Janet Elizabeth
• Application Number:
  US11/979,231
• Publication Number:
  US 20080124393A1
• Time in Patent Office: Days
• US Class Current: 424/465
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection

Abstract

Described are controlled release nanoparticulate formulations comprising a nanoparticulate agent to be administered and a rate-controlling polymer which functions to prolong the release of the agent following administration. The novel compositions release the agent following administration for a time period ranging from about 2 to about 24 hours or longer.

Claims

1. A controlled release nanoparticulate clozapine composition comprising

(a) clozapine particles having an effective average particle size of less than about 1000 nm;

(b) at least one surface stabilizer adsorbed on the surface of the clozapine particles, and

(c) at least one pharmaceutically acceptable rate-controlling polymer, wherein the clozapine composition provides controlled release of the clozapine for a time period ranging from about 2 to about 24 hours or longer.

2. The composition of claim 1, wherein the effective average particle size of the clozapine particles is selected from the group consisting of less than about 800 nm, less than about 600 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 100 nm, and less than about 50 nm.

3. The composition of claim 1, wherein the concentration of the polymer is from about 5 to about 95% (w/w).

4. The composition of claim 3, wherein the concentration of the polymer is from about 10 to about 65% (w/w).

5. The composition of claim 1 additionally comprising a binder agent in an amount of from about 0.1 to about 10% (w/w).

6. The composition of claim 1 additionally comprising a lubricant in an amount of from about 0.1 to about 10% (w/w).

7. The composition of claim 6, wherein the lubricant is selected from the group consisting of magnesium stearate, hydrogenated vegetable oil, and stearic acid.

8. The composition of claim 1, wherein the composition is a wet granulation.

9. The composition of claim 8 formed as a wet granulation, wherein water is added to the nanoparticulate clozapine, surface stabilizer, and polymer to form granules prior to forming the solid dose of the controlled release formulation.

10. The composition of claim 1, wherein the rate-controlling polymer is selected from the group consisting of gum arabic, agar, guar gum, cereal gums, dextran, casein, gelatin, pectin, carrageenan, waxes, shellac, hydrogenated vegetable oils, polyvinylpyrrolidone, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropyl methylcelluose (HPMC), sodium carboxymethylcellulose (CMC), poly(ethylene) oxide, alkyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydrophilic cellulose derivatives, polyethylene glycol, polyvinylpyrrolidone, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, polyvinyl acetaldiethylamino acetate, poly(alkylmethacrylate), poly(vinyl acetate), polymers derived from acrylic or methacrylic acid and their respective esters, and copolymers derived from acrylic or methacrylic acid and their respective esters.

11. The composition of claim 10, wherein the rate-controlling polymer is HPMC.

12. The composition of claim 10, wherein the rate-controlling polymer is a polymer derived from acrylic or methacrylic acid and their respective esters or copolymers derived from acrylic or methacrylic acid and their respective esters.

13. The composition of claim 1, wherein the clozapine is present in an amount of from about 1 μ

g to about 800 mg.

14. A dosage form comprising a controlled release nanoparticulate clozapine composition according to claim 1, wherein the dosage form is in tablet form or in multiparticulate form.

15. The dosage form of claim 14 further comprising at least one auxiliary excipient, wherein the clozapine and at least one auxiliary excipient are compressed into tablet form prior to coating with a rate controlling polymer.

16. The dosage form of claim 14, wherein the clozapine, the rate controlling polymer and at least one auxiliary excipient are in the form of a controlled release matrix tablet.

17. The dosage form of claim 16, wherein the controlled release matrix is coated with a rate controlling polymer.

18. The dosage form of claim 14, wherein the tablet is a multilayer tablet comprising the nanoparticulate clozapine and at least one auxiliary excipient, and wherein the multilayer tablet is coated with a rate controlling polymer.

19. The dosage form of claim 14, wherein the tablet is a multilayer tablet comprising the nanoparticulate clozapine and the rate controlling polymer material.

20. The dosage form of claim 19, wherein the multilayer tablet is coated with an additional rate controlling polymer.

36. The dosage form according to claim 14, wherein the nanoparticulate clozapine, at least one auxiliary excipient, and the rate controlling polymer material are combined into a multiparticulate form.

37. The dosage form according to claim 36, wherein the multiparticulate form comprises discrete pellets, minitablets, or combinations thereof having a size larger than the nanoparticulate clozapine particles.

38. The dosage form according to claim 36, wherein the multiparticulate is encapsulated in hard or soft gelatin capsules.

39. The dosage form according to claim 36, wherein the multiparticulate is incorporated into a sachet.

40. The dosage form according to claim 37, wherein the discrete pellets or minitablets are compressed into tablet form.

41. The dosage form according to claim 40, wherein the tablet form is coated with a rate controlling polymer material.

42. The dosage form according to claim 37 wherein the discrete pellets or minitablets are compressed into a multilayer tablet.

43. The dosage form according to claim 42 wherein the multilayer tablet is coated with a rate controlling material.

44. The dosage form according to claim 14, wherein the dosage form is a tablet, and wherein the composition further comprises an osmagent and a semi-permeable membrane, wherein the semi-permeable membrane surrounds the tablet, is permeable to aqueous media, but impermeable to the nanoparticulate clozapine, and the semi-permeable membrane also defines an orifice therein.

21-35. -35. (canceled)

45. A method of preparing a solid dose controlled release clozapine nanoparticulate formulation comprising:

(a) combining a nanoparticulate clozapine composition having an effective average particle size of less than about 1000 nm and at least one surface stabilizer adsorbed on the surface of the nanoparticulate clozapine with at least one suitable rate-controlling polymer; and

(b) forming a solid dose of the combination of step (a), wherein the solid dose releases the nanoparticulate clozapine following oral administration to a patient for a time period ranging from about 2 to about 24 hours or longer.

46. The method of claim 45, wherein the effective average particle size is selected from the group consisting of less than about 800 nm, less than about 600 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 100 nm, and less than about 50 nm.

47. The method of claim 45, wherein the concentration of the polymer is from about 5 to about 95% (w/w).

48. The method of claim 47, wherein the concentration of the polymer is from about 10 to about 65% (w/w).

49. The method of claim 45, comprising adding water to the nanoparticulate clozapine, surface stabilizer, and rate-controlling polymer to form granules prior to step (b).

50. A method of treating a mammal comprising:

(a) administering to the mammal an effective amount of a solid dose controlled release nanoparticulate clozapine composition comprising particles of clozapine having an effective average particle size of less than about 1000 nm and at least one surface stabilizer adsorbed on the surface of the clozapine particles; and

(b) releasing the clozapine particles to the mammal following administration for a time period ranging from about 2 to about 24 hours or longer.