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Last Updated: March 19, 2024

Claims for Patent: 6,696,066


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Summary for Patent: 6,696,066
Title: Opioid agonist/antagonist combinations
Abstract:The invention is directed in part to oral dosage forms comprising a combination of an orally analgesically effective amount of an opioid agonist and an orally active opioid antagonist, the opioid antagonist being included in a ratio to the opioid agonist to provide a combination product which is analgesically effective when the combination is administered orally, but which is aversive in a physically dependent subject. Preferably, the amount of opioid antagonist included in the combination product provides at least a mildly negative, "aversive" experience in physically dependent addicts (e.g., precipitated abstinence syndrome).
Inventor(s): Kaiko; Robert F. (Weston, CT), Colucci; Robert D. (Newton, CT)
Assignee: Euro-Celtique S.A. (Luxembourg, LU)
Application Number:10/244,783
Patent Claims: 1. A sustained release oral dosage form, comprising an orally therapeutically effective dose of an opioid agonist, an opioid antagonist, and a sustained release carrier, said dosage form having a ratio of opioid antagonist to opioid agonist that provides a combination product which is analgesically effective when the combination is administered orally, but which (i) is aversive in physically dependent human subjects when administered at the same dose or at a higher dose than said therapeutically effective dose; and (ii) maintains an analgesic effect but does not increase analgesic efficacy of the opioid agonist relative to the same therapeutic dose of opioid analgesic when administered to human patients without said opioid antagonist; such that the dosage form is administrable on a twice-a-day or on a once-a-day basis.

2. The sustained release oral dosage form of claim 1, wherein the amount of antagonist included in the oral dosage form causes an aversive experience in a physically dependent addict taking about 2-3 times said therapeutically effective dose.

3. The sustained release oral dosage form of claim 1, wherein the opioid agonist is hydrocodone and the antagonist is naltrexone.

4. The sustained release oral dosage form of claim 3, wherein the ratio of naltrexone to hydrocodone is from about 0.03:1 to about 0.27:1.

5. The sustained release oral dosage form of claim 3, wherein the ratio of naltrexone to hydrocodone is from about 0.05:1 to about 0.20:1.

6. The sustained release oral dosage form of claim 1, wherein the opioid agonist is selected from the group consisting of morphine, hydromorphone, hydrocodone, oxycodone, codeine, levorphanol, meperidine, methadone, and mixtures thereof.

7. The sustained release oral dosage form of claim 1, further comprising an additional non-opioid drug selected from the group consisting of an NSAID, a COX-2 inhibitor, acetaminophen, aspirin, an NMDA receptor antagonist, a drug that blocks a major intracellular consequence of NMDA-receptor activation, an antitussive, an expectorant, a decongestant, an antihistamine and mixtures thereof.

8. The sustained release oral dosage form of claim 1, further comprising one or more pharmaceutically acceptable inert excipients.

9. The sustained release oral dosage form of claim 6, wherein said opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, cyclazocine, levallorphan, and mixtures thereof.

10. The sustained release oral dosage form of claim 6, wherein said opioid antagonist is naltrexone.

11. The sustained release oral dosage form of claim 1, wherein said opioid antagonist is naltrexone and said opioid agonist is oxycodone, wherein the ratio of naltrexone to oxycodone is from about 0.037:1 to about 0.296:1.

12. The sustained release oral dosage form of claim 1, wherein said opioid antagonist is naltrexone and said opioid agonist is codeine, wherein the ratio of naltrexone to codeine is from about 0.005:1 to about 0.044:1.

13. The sustained release oral dosage form of claim 1, wherein said opioid antagonist is naltrexone and said opioid agonist is hydromorphone, wherein the ratio of naltrexone to hydromorphone is from about 0.148:2 to about 1.185:1.

14. The sustained release oral dosage form of claim 1, wherein said opioid antagonist is naltrexone and said opioid agonist is levorphanol, wherein the ratio of naltrexone to levorphanol is from about 0.278:1 to about 2.222:1.

15. The sustained release oral dosage form of claim 1, wherein said opioid antagonist is naltrexone and said opioid agonist is meperidine, wherein the ratio of naltrexone to meperidine is from about 0.0037:1 to about 0.0296:1.

16. The sustained release oral dosage form of claim 1, wherein said opioid antagonist is naltrexone and said opioid agonist is methadone, wherein the ratio of naltrexone to methadone is from about 0.056:1 to about 0.444:1.

17. The sustained release oral dosage form of claim 1, wherein said opioid antagonist is naltrexone and said opioid agonist is morphine, wherein the ratio of naltrexone to morphine is from about 0.018:1 to about 0.148:1.

18. The sustained release oral dosage form of claim 1, wherein said opioid antagonist is naltrexone and said opioid agonist is oxycodone, wherein the ratio of naltrexone to oxycodone is from about 0.056:1 to about 0.222:1.

19. The sustained release oral dosage form of claim 1, wherein said opioid antagonist is naltrexone and said opioid agonist is codeine, wherein the ratio of naltrexone to codeine is from about 0.0083:1 to about 0.033:1.

20. The sustained release oral dosage form of claim 1, wherein said opioid antagonist is naltrexone and said opioid agonist is hydromorphone, wherein the ratio of naltrexone to hydromorphone is from about 0.222:1 to about 0.889:1.

21. The sustained release oral dosage form of claim 1, wherein said opioid antagonist is naltrexone and said opioid agonist is levorphanol, wherein the ratio of naltrexone to levorphanol is from about 0.417:1 to about 1.667:1.

22. The sustained release oral dosage form of claim 1, wherein said opioid antagonist is naltrexone and said opioid agonist is meperidine, wherein the ratio of naltrexone to meperidine is from about 0.0056:1 to about 0.022:1.

23. The sustained release oral dosage form of claim 1, wherein said opioid antagonist is naltrexone and said opioid agonist is methadone, wherein the ratio of naltrexone to methadone is from about 0.083: to about 0.333:1.

24. The sustained release oral dosage form of claim 1, wherein said opioid antagonist is naltrexone and said opioid agonist is morphine, wherein the ratio of naltrexone to morphine is from about 0.028:1 to about 0.111:1.

25. The sustained release oral dosage form of claim 1, wherein said dosage form provides a release of said opioid agonist for about 12 to about 24 hours.

26. The sustained release oral dosage form of claim 1, wherein said opioid agonist and opioid antagonist are incorporated in a matrix formulation.

27. The sustained release oral dosage form of claim 26, wherein said sustained release carrier is incorporated in said matrix formulation with said opioid agonist and opioid antagonist.

28. The sustained release oral dosage form of claim 26, wherein said sustained release carrier is coated onto said matrix formulation.

29. The sustained release oral dosage form of claim 26, wherein said sustained release carrier is incorporated in said matrix formulation with said opioid agonist and is coated onto said matrix formulation.

30. A method of treating oral abuse of an oral opioid formulation, comprising preparing a sustained release oral dosage form which comprises a therapeutically effective dose of an opioid agonist and a sustained release carrier and incorporating therein an opioid antagonist in a ratio to said opioid agonist such that the oral dosage form is analgesically effective when administered orally, but (i) is aversive in physically dependent human subjects when administered at the same dose or at a higher dose than said therapeutically effective dose; and (ii) maintains an analgesic effect but does not increase analgesic efficacy of the opioid agonist relative to the same therapeutic dose of opioid analgesic when administered to human patients without said opioid antagonist.

31. The method of claim 30, wherein the amount of antagonist included in the sustained release oral dosage form causes an aversive experience in physically dependent addicts taking about 2-3 times said therapeutically effective dose of the opioid.

32. The method of claim 30, wherein the opioid agonist is hydrocodone and the antagonist is naltrexone.

33. The method of claim 32, wherein the ratio of naltrexone to hydrocodone is from about 0.03:1 to about 0.27:1.

34. The method of claim 32, wherein the ratio of naltrexone to hydrocodone is from about 0.05:1 to about 0.20:1.

35. The method of claim 30, wherein the opioid agonist or analgesic is selected from the group consisting of morphine, hydromorphone, hydrocodone, oxycodone, codeine, levorphanol, meperidine, methadone, and mixtures thereof and the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, cyclazocine, levallorphan, and mixtures thereof.

36. The method of claim 30, wherein the opioid antagonist is naltrexone and the opioid agonist is oxycodone in a naltrexone/oxycodone ratio from about 0.037:1 to about 0.296:1.

37. The method of claim 30, wherein the opioid antagonist is naltrexone and the opioid agonist is oxycodone in a naltrexone/oxycodone ratio from about 0.056:1 to about 0.222:1.

38. The method of claim 30, further comprising incorporating into said oral dosage form an additional non-opioid drug selected from the group consisting of an NSAID, a COX-2 inhibitor, acetaminophen, aspirin, an NMDA receptor antagonist, a drug that blocks a major intracellular consequence of NMDA-receptor activation, an antitussive, an expectorant, a decongestant, an antihistamine and mixtures thereof.

39. The method of claim 30, wherein the opioid antagonist is naltrexone and the opioid agonist is codeine in a naltrexone/codeine ratio from about 0.005:1 to about 0.044:1.

40. The method of claim 30, wherein the opioid antagonist is naltrexone and the opioid agonist is hydromorphone in a naltrexone/hydromorphone ratio from about 0.148:1 to about 1.185:1.

41. The method of claim 30, wherein the opioid antagonist is naltrexone and the opioid agonist is levorphanol in a naltrexone/levorphanol ratio from about 0.278:1 to about 2.222:1.

42. The method of claim 30, wherein the opioid antagonist is naltrexone and the opioid agonist is meperidine in a naltrexone/meperidine ratio from about 0.0037:1 to about 0.0296:1.

43. The method of claim 30, wherein the opioid antagonist is naltrexone and the opioid agonist is methadone in a naltrexone/methadone ratio from about 0.056:1 to about 0.444:1.

44. The method of claim 30, wherein the opioid antagonist is naltrexone and the opioid agonist is morphine in a naltrexone/morphine ratio from about 0.018:1 to about 0.148:1.

45. The method of claim 30, wherein the opioid antagonist is naltrexone and the opioid agonist is codeine in analtrexone/codeine ratio from about 0.0083:1 to about 0.033:1.

46. The method of claim 30, wherein the opioid antagonist is naltrexone and the opioid agonist is hydromorphone in a naltrexone/hydromorphone ratio from about 0.222:1 to about 0.889:1.

47. The method of claim 30, wherein the opioid antagonist is naltrexone and the opioid agonist is levorphanol in a naltrexone/levorphanol ratio from about 0.417:1 to about 1.667:1.

48. The method of claim 30, wherein the opioid antagonist is naltrexone and the opioid agonist is meperidine in a naltrexone/meperidine ratio from about 0.0056:1 to about 0.022:1.

49. The method of claim 30, wherein the opioid antagonist is naltrexone and the opioid agonist is methadone in a naltrexone/methadone ratio from about 0.083:1 to about 0.333:1.

50. The method of claim 30, wherein the opioid antagonist is naltrexone and the opioid agonist is and morphine in a naltrexone/morphine ratio from about 0.028:1 to about 0.111:1.

51. The method of claim 30, wherein said dosage form provides a release of said opioid agonist for about 12 to about 24 hours.

52. The method of claim 30, wherein said opioid agonist and opioid antagonist are incorporated in a matrix formulation.

53. The method of claim 52, wherein said sustained release carrier is incorporated in said matrix formulation with said opioid agonist and opioid antagonist.

54. The method of claim 52, wherein said sustained release carrier is coated onto said matrix formulation.

55. The method of claim 52, wherein said sustained release carrier is incorporated in said matrix formulation with said opioid agonist and is coated onto said matrix formulation.

56. The oral dosage form of claim 2, wherein said combination decreases analgesia as assessed by direct measurement in patients or by use of one or more surrogate measures of opioid effect in human subjects.

57. The method of claim 30, wherein said ratio of opioid antagonist to opioid agonist decreases analgesia as assessed by direct measurement in patients or by use of one or more surrogate measures of opioid effect in human subjects.

58. A sustained release oral dosage form, comprising an orally therapeutically effective dose of an opioid agonist, an opioid antagonist, and a sustained release carrier, said dosage form having a ratio of opioid antagonist to opioid agonist that provides a combination product which is analgesically effective when the combination is administered orally, but which (i) is aversive in physically dependent human subjects when administered at the same dose or at a higher dose than said therapeutically effective dose; and (ii) maintains or decreases analgesic efficacy of the opioid agonist relative to the same therapeutic dose of opioid analgesic when administered to human patients without said opioid antagonist; such that the dosage form is administrable on a once-a-day basis.

59. The sustained release oral dosage form of claim 58, wherein said dosage form provides a release of said opioid agonist for about 12 to about 24 hours.

60. The sustained release oral dosage form of claim 58, wherein said opioid agonist and opioid antagonist are incorporated in a matrix formulation.

61. The sustained release oral dosage form of claim 60, wherein said sustained release carrier is incorporated in said matrix formulation with said opioid agonist and opioid antagonist.

62. The sustained release oral dosage form of claim 60, wherein said sustained release carrier is coated onto said matrix formulation.

63. The sustained release oral dosage of claim 60, wherein said sustained release carrier is incorporated in said matrix formulation with said opioid agonist and is coated onto said matrix formulation.

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