Dual controlled release osmotic device

• US 8,241,667 B2
• Filed: 12/29/2005
• Issued: 08/14/2012
• Est. Priority Date: 11/06/2001
• Status: Active Grant

• Current Assignee: Acella Holdings LLC
• Original Assignee: Osmotica Kereskedelmi Es Szolgaltato Kft (Osmotica Pharmaceuticals Plc)
• Inventors: Vergez, Juan A., Ricci, Marcelo A.
• Primary Examiner(s): Blanchard, David J
• Assistant Examiner(s): Kassa, Tigabu
• Application Number:
  US11/321,736
• Publication Number:
  US 20060177510A1
• Time in Patent Office: 2,420 Days
• Field of Search: None
• US Class Current: 424/473
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system

Abstract

A pharmaceutical composition and dosage form for the treatment of incontinence with oxybutynin and a second drug is provided. The second drug can be darifenacin or tolterodine. Depending upon the route of administration, the dosage form used, and the second drug used, the dosage form may independently include therapeutic or sub-therapeutic amounts of the oxybutynin and the second drug. Particular embodiments include a dosage form that provides a controlled release of oxybutynin and the second drug to maintain therapeutically effective levels oxybutynin and/or the second in a mammal for an extended period of time. An osmotic device containing a bi-layered core is provided. The osmotic device provides a dual controlled release of both drugs from the core. A method of treating urinary (stress or urge) incontinence with the pharmaceutical composition and dosage form is provided. Together, oxybutynin and the second drug provide an overall improved therapeutic benefit over either agent alone when administered at approximately the same dose.

Claims

1. A dual controlled release osmotic device consisting essentially of:

a bi-layered core consisting essentially of a controlled release active agent-containing first layer and a controlled release active agent-containing second layer, wherein the first and second layers are in intimate contact with one another and in stacked arrangement, and the osmotic device excludes a partition between the first layer and the second layer and excludes a push-layer; and

a membrane enveloping the core, wherein the membrane comprises at least one preformed passageway in communication with at least one of the first and second active agent-containing layers;

whereby the osmotic device provides a controlled release of the first active agent through at least one preformed passageway according to a first release profile and the second layer provides a controlled release of the second active agent through at least one preformed passageway according to a second release profile.

2. The osmotic device of claim 1, wherein the osmotic device comprises at least one first preformed passageway in communication with the first layer and at least one second preformed passageway in communication with the second layer.

3. The osmotic device of claim 2, wherein at least one of the two preformed passageways is plugged with a water soluble and/or water erodible material.

4. The osmotic device of claim 2, wherein both of the preformed passageways are plugged with a water soluble and/or water erodible material, and the material plugging the first passageway is the same as the material plugging the second passageway.

5. The osmotic device of claim 2, wherein both of the preformed passageways are plugged with a water soluble and/or water erodible material, and the material plugging the first passageway is different than the material plugging the second passageway.

6. The osmotic device of claim 1, wherein the membrane comprises at least one preformed passageway in communication with both the first and second layers.

7. The osmotic device of claim 1 further comprising at least one external coat exterior to the membrane.

8. The osmotic device of claim 7, wherein the external coat is independently selected at each occurrence from water soluble and/or water erodible.

9. The osmotic device of claim 7, wherein the external coat is independently selected at each occurrence from microporous, permeable, semipermeable and impermeable.

10. The osmotic device of claim 7, wherein the external coat is independently selected at each occurrence from inert and drug-containing.

11. The osmotic device of claim 10, wherein the external coat provides a rapid release of drug.

12. The osmotic device of claim 7, wherein the membrane comprises at least a first preformed passageway and at least a second preformed passageway, wherein the first passageway has been formed after application of the external coat to the membrane, and the second passageway has been formed before application of the external coat to the membrane such that the second passageway is plugged by the external coat, and release of the second active agent begins after release of the first active agent has started.

13. The osmotic device of claim 7, wherein the membrane comprises at least a first preformed passageway and at least a second preformed passageway, wherein the first and second passageways have been formed before application of the external coat to the membrane;

and the first and second passageways are plugged by the external coat.

14. The osmotic device of claim 1 further comprising at least one internal coat interposed the core and the membrane.

15. The osmotic device of claim 14, wherein the internal coat is independently selected at each occurrence from water soluble and/or water erodible.

16. The osmotic device of claim 14, wherein the internal coat is independently selected at each occurrence from inert and drug-containing.

17. The osmotic device of claim 14, wherein the internal coat is independently selected at each occurrence from microporous, permeable, semipermeable and impermeable.

18. The osmotic device of claim 1, wherein the first active agent and the second active agent are released from the core sequentially or in an overlapping manner when the osmotic device is exposed to an aqueous environment.

19. The osmotic device of claim 1, wherein each active agent is independently released from the core according to a timed, targeted, pseudo-first order, first order, pseudo-zero order, zero-order, sustained, slow, extended, pulsatile and/or delayed release profile.

20. The osmotic device of claim 1, wherein initial release of the first active agent and the second active agent is delayed for a period of time after exposure to an aqueous environment.

21. The osmotic device of claim 20, wherein each active agent is independently released from the core according to a timed, targeted, pseudo-first order, first order, pseudo-zero order, zero-order, sustained, slow, extended, and/or pulsatile release profile.

22. The osmotic device of claim 1 comprising:

a bi-layered core consisting essentially of a controlled release first layer comprising a first drug and at least one pharmaceutical excipient, and a different controlled release second layer comprising a second drug and at least one pharmaceutical excipient, wherein the first and second layers are in intimate contact with one another and in stacked arrangement, and the core excludes a partition between the first layer and the second layer and excludes a push-layer; and

a membrane enveloping the core and having at least two preformed passageways to permit a controlled release of the first and second drugs from the core when the osmotic device is exposed to an aqueous environment, wherein at least one first passageway is in communication with the first layer and at least one second passageway is in communication with the second layer.

23. The osmotic device of claim 22, wherein the membrane is semipermeable.

24. The osmotic device of claim 22, wherein each drug is independently released from the core according to a timed, targeted, pseudo-first order, first order, pseudo-zero order, zero-order, sustained, slow, extended, pulsatile and/or delayed release profile.

25. The osmotic device of claim 22, wherein the first drug and the second drug are released from the core sequentially or in an overlapping manner when the osmotic device is exposed to an aqueous environment.

26. The osmotic device of claim 22 further comprising at least one external coat exterior to the membrane.

27. The osmotic device of claim 26, wherein the external coat is independently selected at each occurrence from water soluble and/or water erodible.

28. The osmotic device of claim 26, wherein the external coat is independently selected at each occurrence from microporous, permeable, semipermeable and impermeable.

29. The osmotic device of claim 26, wherein the external coat is independently selected at each occurrence from inert and drug-containing.

30. The osmotic device of claim 29, wherein the external coat provides a rapid release of drug.

31. The osmotic device of claim 26, wherein the first passageway has been formed after application of the external coat to the semipermeable membrane and the second passageway has been formed before application of the external coat to the semipermeable membrane such that the second passageway is plugged by the external coat and release of the second drug begins after release of the first drug has started.

32. The osmotic device of claim 26, wherein the first and second passageways have been formed before application of the external coat to the semipermeable membrane;

the first and second passageways are plugged by the external coat; and

release of the first drug and the second drug is delayed for a period of time after exposure to an aqueous environment.

33. The osmotic device of claim 22 further comprising at least one internal coat interposed the core and the membrane.

34. The osmotic device of claim 33, wherein the internal coat is independently selected at each occurrence from water soluble and/or water erodible.

35. The osmotic device of claim 33, wherein the internal coat is independently selected at each occurrence from inert and drug-containing.

36. The osmotic device of claim 33, wherein the internal coat is independently selected at each occurrence from microporous, permeable, semipermeable and impermeable.

37. The osmotic device of claim 22, wherein the first drug and the second drug are released sequentially or in an overlapping manner when the osmotic device is exposed to an aqueous environment.

38. The osmotic device of claim 1 comprising:

a bi-layered core consisting essentially of a controlled release active agent-containing first layer and a controlled release active agent-containing second layer, wherein the first and second layers are in intimate contact with one another, and the layers are in stacked arrangement, and the core excludes a partition between the first layer and the second layer and excludes a push-layer; and

a semipermeable membrane enveloping the core, wherein the membrane comprises at least one preformed passageway in communication with at least one of the first and second active agent-containing layers;

whereby the osmotic device provides a controlled release of the first active agent through at least one preformed passageway according to a first release profile and the second layer provides a controlled release of the second active through at least one preformed passageway according to a second release profile, and each drug is independently released from the core according to a timed, targeted, pseudo-first order, first order, pseudo-zero order, zero-order, sustained, slow, extended, pulsatile and/or delayed release profile.

39. The osmotic device of claim 38 further comprising at least one external coat exterior to the membrane.

40. The osmotic device of claim 39, wherein the external coat is independently selected at each occurrence from water soluble and/or water erodible.

41. The osmotic device of claim 39, wherein the external coat is independently selected at each occurrence from microporous, permeable, semipermeable and impermeable.

42. The osmotic device of claim 39, wherein the external coat is independently selected at each occurrence from inert and drug-containing.

43. The osmotic device of claim 42, wherein the external coat provides a rapid release of drug.

44. The osmotic device of claim 39, wherein the first passageway has been formed after application of the external coat to the semipermeable membrane and the second passageway has been formed before application of the external coat to the semipermeable membrane such that the second passageway is plugged by the external coat and release of the second active agent begins after release of the first active agent has started.

45. The osmotic device of claim 39, wherein the first and second passageways have been formed before application of the external coat to the semipermeable membrane;

the first and second passageways are plugged by the external coat; and

release of the first active agent and the second active agent is delayed for a period of time after exposure to an aqueous environment.

46. The osmotic device of claim 38 further comprising at least one internal coat interposed the core and the membrane.

47. The osmotic device of claim 46, wherein the internal coat is independently selected at each occurrence from water soluble and/or water erodible.

48. The osmotic device of claim 46, wherein the internal coat is independently selected at each occurrence from microporous, permeable, semipermeable and impermeable.

49. The osmotic device of claim 46, wherein the internal coat is independently selected at each occurrence from inert and drug-containing.

50. The osmotic device of claim 38, wherein the first active agent and the second active agent are released sequentially or in an overlapping manner when the osmotic device is exposed to an aqueous environment.

51. The osmotic device of claim 1, 22 or 38, wherein the first release profile and the second release profile are different.