METHODS AND DOSAGE FORMS FOR CONTROLLED DELIVERY OF PALIPERIDONE AND RISPERIDONE

• US 20090202631A1
• Filed: 04/22/2009
• Published: 08/13/2009
• Est. Priority Date: 07/29/2002
• Status: Active Grant

• Current Assignee: Atul D. Ayer, Gayatri Sathyan, Iran Reyes, Julie Lee, Nipun Davar, Nyomi V. Yam, Sonya Seroff, Suneel K. Gupta
• Original Assignee: Atul D. Ayer, Gayatri Sathyan, Iran Reyes, Julie Lee, Nipun Davar, Nyomi V. Yam, Sonya Seroff, Suneel K. Gupta
• Inventors: Yam, Nyomi V., Sathyan, Gayatri, Seroff, Sonya, Ayer, Atul D., Lee, Julie, Reyes, Iran, Davar, Nipun, Gupta, Suneel K.
• Granted Patent: US 9,393,192 B2
• Time in Patent Office: Days
• US Class Current: 424/464
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/2086 Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer

Abstract

Dosage forms and methods for providing a substantially ascending rate of release of paliperidone or risperidone are provided. The sustained release dosage forms provide therapeutically effective average steady-state plasma paliperidone or risperidone concentrations when administered once per day. This once-a-day dosing regimen results in only one peak plasma paliperidone or risperidone concentration occurrence in each 24 hour period. In addition, the peak plasma paliperidone or risperidone concentration occurs at a later time following dose administration and exhibits a lesser magnitude than the peak plasma paliperidone or risperidone concentration that occurs following administration of paliperidone or risperidone in an immediate-release dosage form.

Claims

1. A method for treating a condition responsive to paliperidone or risperidone comprising orally administering a dosage form containing an active agent selected from the group consisting of paliperidone, risperidone and pharmaceutically acceptable addition salts thereof wherein the dosage form releases the active agent at a substantially ascending release rate for a prolonged period of time.

2. A method for administering an active agent to a subject comprising:

administering a dosage from to the subject wherein the dosage form comprises;

(a) a core comprising a plurality of layers wherein a drug composition contains an active agent in at least one layer and at least one other layer comprises a suitable fluid-expandable polymer;

(b) a semipermeable membrane surrounding the core to form a compartment having an osmotic gradient to drive fluid from an external fluid environment contacting the semipermeable membrane into the compartment; and

(c) an orifice formed through the semipermeable membrane and into the core to permit the active agent to be released from within the compartment into the external fluid environment;

wherein the dosage form releases the active agent at a substantially ascending release rate for a prolonged period of time.

3. The method of claim 2 for administering an active agent to a subject wherein the core is a capsule shaped tablet.

4. The method according to claim 2 wherein the active agent is paliperidone.

5. The method according to claim 2 wherein the active agent is risperidone.

6. The method according to claim 2 wherein at least a first drug composition layer comprises an osmagent and a second drug composition layer does not comprise an osmagent.

7. The method according to claim 6 wherein the osmagent is sodium chloride salt.

8. The method according to claim 7 wherein the osmagent is at least 20% of the first layer drug composition.

9. The method according to claim 6 wherein the first drug composition layer is proximal to the exit orifice.

10. The method according to claim 2, wherein the capsule shaped tablet core comprises two layers and the paliperidone is contained within a first layer and the fluid-expandable polymer is contained within a second layer and the orifice is formed through the semipermeable membrane adjacent the first layer.

11. The method according to claim 2, wherein the capsule shaped tablet core comprises three layers and a portion of the active agent is contained within a first drug composition layer and the remaining portion of the active agent is contained within a second drug composition layer, wherein the portion of active agent contained within the first layer is less than the portion of active agent contained within the second layer, and wherein the fluid-expandable polymer is contained within a third layer and the orifice is formed through the semipermeable membrane adjacent the first layer.

12. The method according to claim 11 characterized by producing a substantially ascending blood plasma concentration of active agent.

13. The method according to claim 12 wherein a C_max occurs after about 14 hours after administration to the subject.

14. The method according to claim 12 wherein a C_max occurs between about 16 hours and about 22 hours after administration to the subject.

15. The method according to claim 12 wherein a C_max occurs between about 18 hours and about 21 hours after administration to the subject.

16. The method according to claim 10, wherein the proportion of active agent contained within the first layer to the active agent contained within the second layer is less than 1.0.

17. The method according to claim 10, wherein the proportion of active agent contained within the first layer to the active agent contained within the second layer is less than about 0.33.

18. The method according to claim 10 wherein the concentration of active agent in the first drug layer to the concentration of active agent in the second drug layer is less than 0.44.

19. The method according to claim 10 wherein the concentration of active agent in the first drug layer to the concentration of active agent in the second drug layer is less than 0.33.

20. The method according to claim 11, wherein the first layer comprises an osmagent and the second layer comprises no osmagent.

21. The method of claim 20 wherein the osmagent is at least 20% of the first layer.

22. A method for delivering an active agent, the method comprising orally administering to a subject a capsule shaped tablet dosage form containing an active agent selected from the group consisting of paliperidone, risperidone and pharmaceutically acceptable addition salt thereof wherein the dosage form releases the active agent from the dosage form at a substantially ascending release rate for a prolonged period of time.

23. The method of claim 22 wherein the active agent is paliperidone.

24. The method of claim 22 wherein the active agent is risperidone

25. The method according to claim 23, wherein the dosage form comprises:

(a) a core containing a plurality of layers wherein the active agent is contained in at least one layer and at least one other layer comprises a suitable fluid-expandable polymer;

(b) a semipermeable membrane surrounding the core to form a compartment having an osmotic gradient to drive fluid from an external fluid environment contacting the semipermeable membrane into the compartment; and

(c) an orifice formed through the semipermeable membrane and into the core to permit the active agent to be released from the compartment into the external fluid environment.

26. The method according to claim 25, wherein the capsule shaped tablet core comprises two layers and the active agent is contained within a first layer and the fluid-expandable polymer is contained within a second layer and the orifice is formed through the semipermeable membrane adjacent to the first layer.

27. The method according to claim 25, wherein the core comprises three layers and a portion of the active agent is contained within a first layer and the remaining portion of the active agent is contained within a second layer, wherein the portion of active agent contained within the first layer is less than the portion of active agent contained within the second layer, and wherein the fluid-expandable polymer is contained within a third layer and the orifice is formed through the semipermeable membrane adjacent the first layer.

28. The method according to claim 27, wherein the proportion of active agent contained within the first layer to the active agent contained within the second layer is less than 1.0.

29. The method according to claim 27, wherein the proportion of active agent contained within the first layer to the active agent contained within the second layer is less than about 0.33.

30. The method according to claim 27 wherein the concentration of active agent in the first drug layer to the concentration of active agent in the second drug layer is less than 0.44.

31. The method according to claim 27 wherein the concentration of active agent in the first drug layer to the concentration of active agent in the second drug layer is less than 0.33.

32. The method according to claim 27, wherein the first layer comprises an osmagent and the second layer comprises no osmagent.

33. The method of claim 32 wherein the osmagent is at least 20% of the first layer.

35. The dosage form of claim 33 wherein the active agent is paliperidone.

36. The dosage form of claim 33 wherein the active agent is risperidone.

39. The dosage form according to claim 35, wherein the capsule shaped tablet core comprises three layers and a portion of the active agent is contained within a first layer and the remaining portion of the paliperidone is contained within a second layer, wherein the portion of active agent contained within first layer is less than the portion of active agent contained within the second layer, and wherein the fluid-expandable polymer is contained within a third layer and the orifice is formed through the semipermeable membrane adjacent the first layer.

50. The dosage form according to claim 35 further comprising a subcoat for reducing the rate of degradation of the active agent paliperidone, which subcoat comprises a hydroxyalkylcellulose polymer possessing a 8,500 to 4,000,000 molecular weight that at least partially surrounds the core and is positioned between an inside surface of the semipermeable membrane and the core.

51. The dosage form according to claim 35 further comprising a subcoat for reducing the rate of degradation of the active agent paliperidone which subcoat comprises a mixture of hydroxypropyl cellulose and providone prepared in ethanol that at least partially surrounds the core and is positioned between an inside surface of the semipermeable membrane and the core.

34. A capsule shaped tablet dosage form comprising a drug layer composition having an active agent wherein the dosage form, following oral administration to a subject, releases the active agent from the dosage form at a substantially ascending release rate for a prolonged period of time.

37. The dosage form according to claim 34 comprising:

(a) a capsule shaped tablet core containing a plurality of layers wherein the paliperidone is contained in at least one layer and at least one other layer comprises a suitable fluid-expandable polymer;

(b) a semipermeable membrane surrounding the capsule shaped tablet core to form a compartment having an osmotic gradient to drive fluid from an external fluid environment contacting the semipermeable membrane into the compartment; and

(c) an orifice formed through the semipermeable membrane and into the capsule shaped tablet core to permit paliperidone to be released from within the compartment into the external fluid environment.

38. The dosage form according to claim 37, wherein the capsule shaped tablet core comprises two layers and the active agent is contained within a first layer and the fluid-expandable polymer is contained within a second layer and the orifice is formed through the semipermeable membrane adjacent the first layer.

40. The dosage form according to claim 37, wherein the proportion of active agent contained within the first layer to the active agent contained within the second layer is less than 1.0.

41. The dosage form according to claim 37, wherein the proportion of active agent contained within the first layer to the active agent contained within the second layer is less than about 0.33.

42. The dosage form according to claim 37 wherein the concentration of active agent in the first drug layer to the concentration of active agent in the second drug layer is less than 0.44.

43. The dosage form according to claim 37 wherein the concentration of active agent in the first layer to the concentration of active agent in the second drug layer is less than 0.33.

44. The dosage form according to claim 37, wherein the first layer comprises an osmagent and the second layer comprises no osmagent.

45. The dosage form of claim 37 wherein the osmagent is at least 20% of the first layer.

46. The dosage form of claim 37 characterized by releasing the active agent from the dosage form at a substantially ascending rate of release for about 10 hours to about 14 hours.

47. The dosage form of claim 37 characterized by releasing the active agent from the dosage form at a substantially ascending rate of release for about 14 hours to about 18 hours.

48. The dosage form of claim 37 characterized by releasing the active agent from the dosage form at a substantially ascending rate of release for about 18 hours to about 20 hours.

49. The dosage form of claim 37 characterized by having a T₉₀ from the core occurring at about 20 hours.