Once-a-day oxycodone formulations

• US 20040170680A1
• Filed: 04/15/2004
• Published: 09/02/2004
• Est. Priority Date: 05/02/2001
• Status: Active Grant

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Euroceltique SA
• Inventors: Wright, Curtis, Oshlack, Benjamin, Prater, Derek
• Granted Patent: US 7,846,476 B2
• Time in Patent Office: Days
• US Class Current: 424/457
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/02 without antiinflammatory effect

Abstract

The invention is directed to sustained release formulations containing oxycodone or a pharmaceutically acceptable salt thereof which provide a mean C₂₄/C_max oxycodone ratio of 0.6 to 1.0 or 0.7 to 1 after oral administration at steady state to patients and methods thereof.

Claims

1. A sustained-release oral dosage form for once-a-day administration comprising:

a pharmaceutically acceptable matrix comprising an analgesically effective amount of oxycodone or a pharmaceutically acceptable salt thereof and a sustained release material, said dosage form providing an analgesic effect for at least about 24 hours after oral administration at steady state to human patients; and

said dosage form providing a mean C₂₄/C_max oxycodone ratio of 0.6 to 1.0 after steady state oral administration to said patients.

2. The dosage form of claim 1, which provides a mean T_max of oxycodone at about 2 to about 17 hours after administration at steady state to said patients.

3. The dosage form of claim 1, which provides a mean T_max of oxycodone at about 8 to about 16 hours after administration at steady state to said patients.

4. The dosage form of claim 1, which provides a mean W₅₀ for the oxycodone of between 4 and 24 hours after administration at steady state to said patients.

5. The dosage form of claim 4, which provides a mean W₅₀ for the oxycodone of at least 12 hours after administration at steady state to said patients.

6. The dosage form of claim 1, wherein the matrix is substantially homogeneous.

7. The dosage form of claim 1, wherein said matrix is contained within a gelatin capsule.

8. The dosage form of claim 1, wherein said matrix is formulated into a tablet.

9. The dosage form of claim 1, which provides a mean T_max at about 12 to about 16 hours after administration at steady state to said patients.

10. The dosage form of claim 1, wherein said oxycodone or pharmaceutically acceptable salt thereof is an amount from about 5 to about 640 mg.

11. The dosage form of claim 1, wherein said pharmaceutically acceptable salt of oxycodone is oxycodone hydrochloride.

12. The dosage form of claim 1, which provides a mean C₂₄/C_max ratio of 0.7 to 0.99 after administration at steady state to said patients.

13. The dosage form of claim 1, which provides a mean C₂₄/C_max ratio of 0.8 to 0.95 after administration at steady state to said patients.

14. The dosage form of claim 1, which provides an in-vitro release rate, of oxycodone or a pharmaceutically acceptable salt thereof, when measured by the USP Basket Method at 100 rpm in 900 ml aqueous buffer at a pH of between 1.6 and 7.2 at 37°

C. of from 0% to about 40% at 1 hour, from about 8% to about 70% at 4 hours, from about 20% to about 80% at 8 hours, from about 30% to about 95% at 12 hours, from about 35% to about 95% at 18 hrs, and greater than about 50% at 24 hours.

15. A method of treating pain in patients comprising:

orally administering to human patients on a once a day basis, a sustained release dosage form comprising a pharmaceutically acceptable matrix comprising oxycodone or a pharmaceutically acceptable salt thereof and a sustained release material, to provide an analgesic effect for at least about 24 hours and a mean C₂₄/C_max oxycodone ratio of 0.6 to 1.0 after administration at steady state to said patients.

16. The method of claim 15 which provides a mean T_max of oxycodone at about 2 to about 17 hours after administration at steady state to said patients.

17. The method of claim 15 which provides a mean T_max of oxycodone at about 8 to about 16 hours after administration at steady state to said patients.

18. The method of claim 15, which provides a mean W₅₀ of the oxycodone of between 4 and 24 hours after administration at steady state to said patients.

19. The method of claim 18, which provides a mean W₅₀ of the oxycodone of at least 12 hours after administration at steady state to said patients.

20. The method of claim 15, which provides a mean C₂₄/C_max ratio of 0.7 to 0.99 after administration at steady state to said patients.

21. The method of claim 15, which provides a mean C₂₄/C_max ratio of 0.8 to 0.95 after administration at steady state to said patients.

22. The method of claim 15, wherein said dosage form provides an in-vitro release rate, of oxycodone or a pharmaceutically acceptable salt thereof, when measured by the USP Basket Method at 100 rpm in 900 ml aqueous buffer at a pH of between 1.6 and 7.2 at 37°

C. of from 0% to about 40% at 1 hour, from about 8% to about 70% at 4 hours, from about 20% to about 80% at 8 hours, from about 30% to about 95% at 12 hours, from about 35% to about 95% at 18 hrs, and greater than about 50% at 24 hours.

23. A sustained release oral dosage form comprising:

(a) a bilayer core comprising;

(i) a drug layer comprising an analgesically effective amount of oxycodone or a pharmaceutically acceptable salt thereof; and

(ii) a displacement layer comprising an osmopolymer; and

(b) a semipermeable wall surrounding the bilayer core having a passageway disposed therein for the release of said oxycodone or pharmaceutically acceptable salt thereof;

said dosage form providing an analgesic effect for at least about 24 hours after steady-state oral administration to human patients; and

said dosage form providing a mean C₂₄/C_max oxycodone ratio of 0.6 to 1.0 after oral administration at steady state to said patients.

24. The dosage form of claim 23, which provides a mean T_max of oxycodone in about 2 to about 17 hours after administration at steady state to said patients.

25. The dosage form of claim 23, which provides a mean T_max of oxycodone in about 8 to about 16 hours after administration at steady state to said patients.

26. The dosage form of claim 23, which provides a mean W₅₀ of the oxycodone of between 4 and 24 hours after administration at steady state to said patients.

27. The dosage form of claim 23, which provides a W₅₀ of the oxycodone of at least 12 hours after administration at steady state to said patients.

28. The dosage form of claim 23, wherein said displacement layer further comprises an osmagent.

29. The dosage form of claim 28, wherein said osmagent is selected from the group consisting of osmotic salts and osmotic carbohydrates.

30. The dosage form of claim 23, wherein said pharmaceutically acceptable salt of oxycodone is oxycodone hydrochloride.

31. The dosage form of claim 23, wherein said oxycodone or pharmaceutically acceptable salt thereof is in an amount of from about 5 to about 640 mg.

32. The dosage form of claim 23, which provides a mean T_max of oxycodone which occurs at about 12 to about 16 hours after administration at steady state to said patients.

33. The dosage form of claim 23, which provides a mean C₂₄/C_max ratio of 0.7 to 0.99 after administration at steady state to said patients.

34. The dosage form of claim 23, which provides a mean C₂₄/C_max ratio of 0.8 to 0.95 after administration at steady state to said patients.

35. The dosage form of claim 23, which provides an in-vitro release rate, of oxycodone or a pharmaceutically acceptable salt thereof, when measured by the USP Basket Method at 100 rpm in 900 ml aqueous buffer at a pH of between 1.6 and 7.2 at 37°

C. of from 0% to about 40% at 1 hour, from about 8% to about 70% at 4 hours, from about 20% to about 80% at 8 hours, from about 30% to about 95% at 12 hours, from about 35% to about 95% at 18 hrs, and greater than about 50% at 24 hours.

36. A method of treating pain in patients comprising:

orally administering to human patients a sustained release oral dosage form comprising

(a) a bilayer core comprising;

(i) a drug layer comprising an analgesically effective amount of oxycodone or a pharmaceutically acceptable salt thereof; and

(ii) a displacement layer comprising an osmopolymer; and

(b) a semipermeable wall surrounding the bilayer core having a passageway disposed therein for the release of said oxycodone or pharmaceutically acceptable salt thereof;

to provide an analgesic effect at least about 24 hours after oral administration at steady state to human patients; and

to provide a mean C₂₄/C_max oxycodone ratio of 0.6 to 1.0 after oral administration at steady state to said patients.

37. The method of claim 36, which provides a mean T_max of oxycodone at about 2 to about 17 hours after administration at steady state to said patients.

38. The method of claim 36, which provides a mean T_max of oxycodone at about 8 to about 16 hours after administration at steady state to said patients.

39. The method of claim 36, which provides a W₅₀ of the oxycodone of between 4 and 24 hours after administration at steady state to said patients.

40. The method of claim 39, which provides a W₅₀ of the oxycodone of at least 12 hours after administration at steady state to said patients.

41. The method of claim 36, which provides a mean C₂₄/C_max ratio of 0.7 to 0.99 after administration at steady state to said patients.

42. The method of claim 36, which provides a mean C₂₄/C_max ratio of 0.8 to 0.95 after administration at steady state to said patients.

43. The method of claim 36, wherein said dosage form provides an in-vitro release rate of oxycodone or a pharmaceutically acceptable salt thereof, when measured by the USP Basket Method at 100 rpm in 900 ml aqueous buffer at a pH of between 1.6 and 7.2 at 37°

C. of from 0% to about 40% at 1 hour, from about 8% to about 70% at 4 hours, from about 20% to about 80% at 8 hours, from about 30% to about 95% at 12 hours, from about 35% to about 95% at 18 hrs, and greater than about 50% at 24 hours.

44. A sustained-release oral dosage form for once-a-day administration comprising:

a plurality of pharmaceutically acceptable matrices comprising an analgesically effective amount of oxycodone or a salt thereof and a sustained release material,

said dosage form providing an analgesic effect for at least about 24 hours after oral administration at steady state to human patients; and

said dosage form providing a mean C₂₄/C_max oxycodone ratio of 0.6 to 1.0 after oral administration at steady state to said patients.

45. The dosage form of claim 44, which provides a mean T_max of oxycodone at about 2 to about 17 hours after administration at steady state to said patients.

46. The dosage form of claim 44, which provides a mean T_max of oxycodone at about 8 to about 16 hours after administration at steady state to said patients.

47. The dosage form of claim 44, which provides a W₅₀ of the oxycodone of between 4 and 24 hours after administration at steady state to said patients.

48. The dosage form of claim 47, which provides a W₅₀ of the oxycodone of at least 12 hours after administration at steady state to said patients.

49. The dosage form of claim 44, wherein said plurality of matrices is contained within a gelatin capsule.

50. The dosage form of claim 44, wherein said plurality of matrices is formulated into a tablet.

51. The dosage form of claim 44, which provides a mean T_max at about 12 to about 16 hours after administration at steady state to said patients.

52. The dosage form of claim 44, wherein said oxycodone or pharmaceutically acceptable salt thereof is an amount from about 5 to about 640 mg.

53. The dosage form of claim 44, wherein said pharmaceutically acceptable salt of oxycodone is oxycodone hydrochloride.

54. The dosage form of claim 44, which provides a mean C₂₄/C_max ratio of 0.7 to 0.99 after administration at steady state to said patients.

55. The dosage form of claim 44, which provides a mean C₂₄/C_max ratio of 0.8 to 0.95 after administration at steady state to said patients.

56. The dosage form of claim 44, which provides an in-vitro release rate, of oxycodone or a pharmaceutically acceptable salt thereof, when measured by the USP Basket Method at 100 rpm in 900 ml aqueous buffer at a pH of between 1.6 and 7.2 at 37°

C. of from 0% to about 40% at 1 hour, from about 8% to about 70% at 4 hours, from about 20% to about 80% at 8 hours, from about 30% to about 95% at 12 hours, from about 35% to about 95% at 18 hrs, and greater than about 50% at 24 hours.

57. A method of treating pain in a patient comprising:

orally administering to a patient on a once-a-day basis a sustained release dosage form comprising a plurality of sustained release matrices comprising oxycodone or a pharmaceutically acceptable salt thereof and a sustained release material,

to provide an analgesic effect for at least about 24 hours after oral administration at steady state to human patients; and

to provide a mean C₂₄/C_max oxycodone ratio of 0.6 to 1.0 after oral administration at steady state to said patients.

58. The method of claim 57, which provides a mean T_max of oxycodone at about 2 to about 17 hours after administration at steady state to said patients.

59. The method of claim 57, which provides a mean T_max of oxycodone at about 8 to about 16 hours after administration at steady state to said patients.

60. The method of claim 57, which provides a W₅₀ of the oxycodone of between 4 and 24 hours after administration at steady state to said patients.

61. The method of claim 57, which provides a W₅₀ of the oxycodone of at least 12 hours after administration at steady state to said patients.

62. The method of claim 57, which provides a mean C₂₄/C_max ratio of 0.7 to 0.99 after administration at steady state to said patients.

63. The method of claim 57, which provides a mean C₂₄/C_max ratio of 0.8 to 0.95 after administration at steady state to said patients.

64. The method of claim 57, wherein said dosage form provides an in-vitro release rate of oxycodone or a pharmaceutically acceptable salt thereof, when measured by the USP Basket Method at 100 rpm in 900 ml aqueous buffer at a pH of between 1.6 and 7.2 at 37°

C. of from 0% to about 40% at 1 hour, from about 8% to about 70% at 4 hours, from about 20% to about 80% at 8 hours, from about 30% to about 95% at 12 hours, from about 35% to about 95% at 18 hrs, and greater than about 50% at 24 hours.

65. A sustained-release oral dosage form for once-a-day administration comprising:

a pharmaceutically acceptable matrix comprising an analgesically effective amount of oxycodone or a pharmaceutically acceptable salt thereof and a sustained release material,

said dosage form providing an analgesic effect for at least about 24 hours after oral administration at steady state to human patients; and

said dosage form providing a mean C₂₄/C_max oxycodone ratio of 0.6 to 1.0 and a T_max of oxycodone at greater than 6 to about 17 hours after oral administration at steady state to said patients.

66. A sustained-release oral dosage form for once-a-day administration comprising:

a pharmaceutically acceptable matrix comprising an analgesically effective amount of oxycodone or a pharmaceutically acceptable salt thereof and a sustained release material,

said dosage form providing an analgesic effect for at least about 24 hours after oral administration at steady state to human patients; and

said dosage form providing a mean C₂₄/C_max oxycodone ratio of 0.7 to 1.0 after oral administration at steady state to said patients.

67. A sustained-release oral dosage form for once-a-day administration comprising:

a plurality of pharmaceutically acceptable matrices comprising an analgesically effective amount of oxycodone or a pharmaceutically acceptable salt thereof and a sustained release material,

said dosage form providing an analgesic effect for at least about 24 hours after oral administration at steady state to human patients; and

said dosage form providing a mean C₂₄/C_max oxycodone ratio of 0.6 to 1.0 and a T_max of oxycodone at greater than 6 to about 17 hours after oral administration at steady state to said patients.

68. A sustained-release oral dosage form for once-a-day administration comprising:

a plurality of pharmaceutically acceptable matrices comprising an analgesically effective amount of oxycodone or a pharmaceutically acceptable salt thereof and a sustained release material,

said dosage form providing an analgesic effect for at least about 24 hours after oral administration at steady state to human patients; and

said dosage form providing a mean C₂₄/C_max oxycodone ratio of 0.7 to 1.0 after oral administration at steady state to said patients.

69. The use of a sustained release dosage form comprising a pharmaceutically acceptable matrix comprising oxycodone or a pharmaceutically acceptable salt thereof and a sustained release material in the production of an analgesic preparation for oral administration to human patients on a once a day basis, to provide an analgesic effect for at least about 24 hours and a mean C₂₄/C_max oxycodone ratio of 0.6 to 1.0 after administration at steady state to said patients.

70. The use of a sustained release oral dosage form comprising

(a) a bilayer core comprising:

(i) a drug layer comprising an analgesically effective amount of oxycodone or a pharmaceutically acceptable salt thereof; and

(ii) a displacement layer comprising an osmopolymer; and

(b) a semipermeable wall surrounding the bilayer core having a passageway disposed therein for the release of said oxycodone or pharmaceutically acceptable salt thereof;

in the production of an analgesic preparation for oral administration to human patients to provide an analgesic effect at least about 24 hours after oral administration at steady state to human patients; and

to provide a mean C₂₄/C_max oxycodone ratio of 0.6 to 1.0 after administration at steady state to said patients.

71. The use of a sustained release dosage form comprising a plurality of sustained release matrices comprising oxycodone or a pharmaceutically acceptable salt thereof and a sustained release material, in the production of an analgesic preparation for oral administration to a patient on a once-a-day basis, to provide an analgesic effect for at least 24 hours after oral administration at steady state to human patients;

and to provide a mean C₂₄/C_max oxycodone ration of 0.6 to 1.0 after oral administration at steady state to said patients.