Details for Patent: 7,514,100

Title:	Controlled release hydrocodone formulations
Abstract:	A solid oral controlled-release dosage form of hydrocodone is disclosed, the dosage form comprising an analgesically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof, and controlled release material.
Inventor(s):	Oshlack; Benjamin (New York, NY), Huang; Hua-Pin (Englewood Cliffs, NJ), Masselink; John K. (Old Tappan, NJ), Tonelli; Alfred P. (Congers, NY)
Assignee:	Purdue Pharma L.P. (Stamford, CT)
Filing Date:	Sep 11, 2003
Application Number:	10/660,349
Claims:	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.sub.24/C.sub.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.degree. C. for 1 hour and thereafter switching to 900 ml with Phosphate Buffer at a pH of 7.5 at 37.degree. 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.sub.24/C.sub.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.sub.24/C.sub.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.degree. 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.sub.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.sub.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.sub.max of hydrocodone which is less than 60% of the C.sub.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.degree. 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.sub.24/C.sub.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.sub.24/C.sub.max ratio of 0.55 to 0.75. 16. The dosage form of claim 14, which provides a time to maximum plasma concentration (T.sub.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.sub.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.sub.max of hydrocodone which is less than 60% of the C.sub.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.sub.24/C.sub.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.degree. C. for 1 hour and thereafter switching to 900 ml with Phosphate Buffer at a pH of 7.5 at 37.degree. 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.sub.24/C.sub.max ratio of 0.55 to 0.75. 25. The dosage form of claim 23, which provides a time to maximum plasma concentration (T.sub.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.sub.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.sub.max of hydrocodone which is less than 60% of the C.sub.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.degree. 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.