Controlled release hydrocodone formulations

1. A solid oral controlled-release dosage form suitable for 24 hour dosing of an active agent in a human patient comprising a pharmaceutically acceptable matrix comprising an analgesically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof and controlled release material; said dosage form after administration to a human patient, providing a C 24 /C max ratio of 0.55 to about 0.85; a therapeutic effect for at least about 24 hours and a dissolution release rate in-vitro of the hydrocodone or salt thereof, when measured by the USP Basket Method at 100 rpm in 700 ml Simulated Gastric Fluid (SGF) at 37° C. for 1 hour and thereafter switching to 900 ml with Phosphate Buffer at a pH of 7.5 at 37° C., wherein at least 20% by weight hydrocodone or salt thereof is released at 4 hours, from about 20% to about 65% by weight hydrocodone or salt thereof is released at 8 hours, from about 45% to about 85% by weight hydrocodone or salt thereof is released at 12 hours, and at least 80% by weight hydrocodone or salt thereof is released at 24 hours.

2. The dosage form of claim 1 , which provides a C 24 /C max ratio of 0.55 to 0.75.

3. The dosage form of claim 1 , wherein said matrix is a plurality of multiparticulate matrices.

4. The dosage form of claim 3 , wherein said multiparticulate matrices are compressed into a tablet.

5. The dosage form of claim 3 , wherein said multiparticulate matrices are disposed in a pharmaceutically acceptable capsule.

6. The dosage form of claim 1 which provides a C 24 /C max ratio of 0.60 to 0.70.

7. The dosage form of claim 1 which provides a dissolution release rate in-vitro of the hydrocodone when measured by the USP Basket method at 100 rpm in 700 ml aqueous buffer at a pH of 1.2 at 37° C. is at least 10% to about 45% by weight hydrocodone or salt thereof released at 1 hour.

8. The dosage form of claim 1 , which provides a time to maximum plasma concentration (T max ) of hydrocodone at about 4 to about 14 hours after oral administration of the dosage form.

9. The dosage form of claim 1 , which provides a time to maximum plasma concentration (T max ) of hydrocodone at about 6 to about 12 hours after oral administration of the dosage form.

10. The dosage form of claim 1 , which provides a C max of hydrocodone which is less than 60% of the C max of an equivalent dose of an immediate release hydrocodone reference formulation.

11. The dosage form of claim 1 , wherein said administration is first administration.

12. The dosage form of claim 1 , wherein said administration is steady state administration.

13. The dosage form of claim 1 , wherein said ratio is obtained from a population of patients.

14. A solid oral controlled-release dosage form suitable for 24 hour dosing of an active agent in a human patient comprising a plurality of pharmaceutically acceptable beads coated with an analgesically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof and overcoated with a pH-independent hydrophobic material comprising an acrylic polymer, said dosage form providing an in-vitro release rate, of hydrocodone 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 35% at 1 hour, from about 10% to about 70% at 4 hours, from about 20% to about 75% at 8 hours, from about 30% to about 80% at 12 hours, from about 40% to about 90% at 18 hours, and greater than about 60% at 24 hours; the in-vitro release rate being substantially independent of pH in that a difference, at any given time, between an amount of opioid released at one pH and an amount released at any other pH, when measured in-vitro using the USP Paddle Method of U.S. Pharmacopeia XXII (1990) at 100 rpm in 900 ml aqueous buffer, is no greater than 10%; said dosage form providing a C 24 /C max ratio of 0.55 to about 0.85; and a therapeutic effect for at least 24 hours, after oral administration to a human patient.

15. The dosage form of claim 14 , which provides a C 24 /C max ratio of 0.55 to 0.75.

16. The dosage form of claim 14 , which provides a time to maximum plasma concentration (T max ) of hydrocodone at about 4 to about 14 hours after oral administration of the dosage form.

17. The dosage form of claim 14 , which provides a time to maximum plasma concentration (T max ) of hydrocodone at about 6 to about 12 hours after oral administration of the dosage form.

18. The dosage form of claim 14 , which provides a C max of hydrocodone which is less than 60% of the C max of an equivalent dose of an immediate release hydrocodone reference formulation.

19. The dosage form of claim 14 , wherein said administration is first administration.

20. The dosage form of claim 14 , wherein said administration is steady state administration.

21. The dosage form of claim 14 , wherein said ratio is obtained from a population of patients.

22. A method of providing effective analgesia in a human patient for at least about 24 hours comprising orally administering a dosage form of claim 14 to a human patient.

23. A sustained release oral dosage form comprising:

(a) a bilayer core comprising:

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

(ii) a displacement layer comprising an osmopolymer; and

(b) a semipermeable wall comprising a hydrophobic material selected from the group consisting of a cellulosic polymer, an acrylic polymer and a combination thereof surrounding the bilayer core and having a passageway disposed therein for the release of said hydrocodone or pharmaceutically acceptable salt thereof; said dosage form providing a C 24 /C max ratio of 0.55 to about 0.85; a therapeutic effect for at least about 24 hours after oral administration to a human patient and a dissolution release rate in-vitro of the hydrocodone or salt thereof, when measured by the USP Basket Method at 100 rpm in 700 ml Simulated Gastric Fluid (SGF) at 37° C. for 1 hour and thereafter switching to 900 ml with Phosphate Buffer at a pH of 7.5 at 37° C., wherein at least 20% by weight hydrocodone or salt thereof is released at 4 hours, from about 20% to about 65% by weight hydrocodone or salt thereof is released at 8 hours, from about 45% to about 85% by weight hydrocodone or salt thereof is released at 12 hours, and at least 80% by weight hydrocodone or salt thereof is released at 24 hours.

24. The dosage form of claim 23 , which provides a C 24 /C max ratio of 0.55 to 0.75.

25. The dosage form of claim 23 , which provides a time to maximum plasma concentration (T max ) of hydrocodone at about 4 to about 14 hours after oral administration of the dosage form.

26. The dosage form of claim 23 , which provides a time to maximum plasma concentration (T max ) of hydrocodone at about 6 to about 12 hours after oral administration of the dosage form.

27. The dosage form of claim 23 , which provides a C max of hydrocodone which is less than 60% of the C max of an equivalent dose of an immediate release hydrocodone reference formulation.

28. The dosage form of claim 23 , wherein said administration is first administration.

29. The dosage form of claim 23 , wherein said administration is steady state administration.

30. The dosage form of claim 23 , wherein said ratio is obtained from a population of patients.

31. A sustained release oral dosage form comprising:

(a) a bilayer core comprising:

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

(ii) a displacement layer comprising an osmopolymer; and

(b) a semipermeable wall comprising a hydrophobic material selected from the group consisting of a cellulosic polymer, an acrylic polymer and a combination thereof surrounding the bilayer core and having a passageway disposed therein for the release of said hydrocodone or pharmaceutically acceptable salt thereof; said dosage form providing an in-vitro release rate, of hydrocodone 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 35% at 1 hour, from about 10% to about 70% at 4 hours, from about 20% to about 75% at 8 hours, from about 30% to about 80% at 12 hours, from about 40% to about 90% at 18 hours, and greater than about 60% at 24 hours; the in-vitro release rate being substantially independent of pH in that a difference, at any given time, between an amount of opioid released at one pH and an amount released at any other pH, when measured in-vitro using the USP Paddle Method of U.S. Pharmacopoeia XXII (1990) at 100 rpm in 900 ml aqueous buffer, is no greater than 10%.

32. A method of providing effective analgesia in a human patient for at least about 24 hours comprising orally administering a dosage form of claim 31 to a human patient.

33. The dosage form of claim 1 , further comprising a non-opioid drug.

34. The dosage form of claim 33 , wherein the non-opioid drug is selected from the group consisting of a non-steroidal anti-inflammatory agent, an NMDA receptor antagonist, acetaminophen, aspirin, a neuro-active steroid and a non-opioid analgesic, their mixtures and pharmaceutically acceptable salts thereof.

35. The dosage form of claim 14 , further comprising a non-opioid drug.

36. The dosage form of claim 35 , wherein the non-opioid drug is selected from the group consisting of a non-steroidal anti-inflammatory agent, an NMDA receptor antagonist, acetaminophen, aspirin, a neuro-active steroid and a non-opioid analgesic, their mixtures and pharmaceutically acceptable salts thereof.

37. The dosage form of claim 23 further comprising a non-opioid drug.

38. The dosage form of claim 37 , wherein the non-opioid drug is selected from the group consisting of a non-steroidal anti-inflammatory agent, an NMDA receptor antagonist, acetaminophen, aspirin, a neuro-active steroid and a non-opioid analgesic, their mixtures and pharmaceutically acceptable salts thereof.

39. The dosage form of claim 31 , further comprising a non-opioid drug.

40. The dosage form of claim 39 , wherein the non-opioid drug is selected from the group consisting of a non-steroidal anti-inflammatory agent, an NMDA receptor antagonist, acetaminophen, aspirin, a neuro-active steroid and a non-opioid analgesic, their mixtures and pharmaceutically acceptable salts thereof.

41. The method of claim 32 , wherein the dosage form , also contains a non-opioid drug.

42. The method of claim 41 , wherein the non-opioid drug is selected from the group consisting of a non-steroidal anti-inflammatory agent, an NMDA receptor antagonist, acetaminophen, aspirin, a neuro-active steroid and a non-opioid analgesic, their mixtures and pharmaceutically acceptable salts thereof.