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Details for Patent: 6,375,957

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Details for Patent: 6,375,957

Title: Opioid agonist/opioid antagonist/acetaminophen combinations
Abstract:The invention is directed in part to oral dosage forms comprising a combination of an opioid agonist, acetaminophen 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. (Newtown, CT)
Assignee: Euro-Celtique, S.A. (Luxembourg, LU)
Filing Date:Feb 11, 2000
Application Number:09/503,020
Claims:1. An oral dosage form, comprising

an orally therapeutically effective amount of

(A) an opioid agonist;

(B) acetaminophen; and

(C) an opioid antagonist;

the dosage form having a ratio of opioid antagonist to opioid agonist to acetaminophen 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 in the same amount or in a higher amount than said therapeutically effective amount; and (ii) maintains an analgesic effect but does not increase analgesic efficacy of the opioid agonist together with the acetaminophen relative to the same therapeutic amount of opioid analgesic together with the acetaminophen when administered to human patients without said opioid antagonist.

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

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

4. The 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 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 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, oxymorphone, dihydrocodeine, tramadol, pharmaceutically acceptable salts thereof, and mixtures thereof.

7. The oral dosage form of claim 1, further comprising an additional non-opioid drug selected from the group consisting of an NSAID, an NMDA receptor antagonist, a drug that blocks a major intracellular consequence of NMDA-receptor activation, dimenhydrinate or a pharmaceutically acceptable salt thereof, an antitussive, an expectorant, a decongestant, an antihistamine and mixtures thereof.

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

9. The 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 oral dosage form of claim 6, wherein said opioid antagonist is naltrexone.

11. The oral dosage form of claim 1, further comprising a sustained release carrier that causes said opioid agonist to be released over a time period of about 8 to about 24 hours when orally administered to a human patient.

12. The 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.

13. The 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.

14. The 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 0.148:1 to about 1.185:1.

15. The 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.

16. The 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.

17. The 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.

18. The 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.

19. The oral dosage form of claim 11, wherein the sustained release carrier further causes said opioid antagonist to be released over a time period of about 8 to about 24 hours when orally administered to a human patient.

20. The oral dosage form of claim 19, wherein the sustained release carrier further causes the acetaminophen to be released over a time period of about 8 to about 24 hours when orally administered to a human patient.

21. The oral dosage form of claim 1, wherein the opioid agonist would be subtherapeutic if administered without the acetaminophen.

22. The oral dosage form of claim 1, wherein the acetaminophen would be subtherapeutic if administered without the opioid agonist.

23. The oral dosage form of claim 1, wherein the dosage form comprises from about 10 mg to about 2000 mg of acetaminophen.

24. The oral dosage form of claim 1, wherein the dosage form comprises from about 25 mg to about 1000 mg of acetaminophen.

25. The oral dosage form of claim 1, wherein the dosage form comprises from about 325 mg to about 1000 mg of acetaminophen.

26. The oral dosage form of claim 1, wherein the opioid agonist and the acetaminophen would each be subtherapeutic if not used in combination with each other.

27. The oral dosage form of claim 1, further comprising a sustained release carrier which causes the drugs to be released from the dosage form over a time period from about 8 hours to about 24 hours when the dosage form is orally administered to a human patient.

28. The oral dosage form of claim 27, wherein the opioid agonist is selected from the group consisting of morphine, hydromorphone, hydrocodone, oxycodone, codeine, levorphanol, meperidine, methadone, oxymorphone, dihydrocodeine, tramadol, pharmaceutically acceptable salts thereof, and mixtures thereof.

29. The oral dosage form of claim 28, wherein said opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, cyclazocine, levallorphan, and mixtures thereof.

30. The oral dosage form of claim 29, wherein the dosage form comprises from about 10 mg to about 2000 mg of acetaminophen.

31. The oral dosage form of claim 27, wherein either or both the opioid agonist and the acetaminophen would be subtherapeutic if not used in combination with each other.

32. A method of treating pain, comprising:

administering an oral dosage form which contains a therapeutically effective amount of

(A) an opioid agonist;

(B) acetaminophen; and

(C) an opioid antagonist;

the dosage form having a ratio of opioid antagonist to opioid agonist to acetaminophen that provides a combination product which is analgesically effective when the combination is administered orally, but (i) is aversive in physically dependent human subjects when administered in the same amount or a higher amount than said therapeutically effective amount; and (ii) maintains an analgesic effect but does not increase analgesic efficacy of the opioid analgesic together with the acetaminophen relative to the same therapeutic amount of opioid analgesic together with the acetaminophen when administered to human patients without said opioid antagonist.

33. The method of claim 32, wherein the antagonist included in the oral dosage form causes an aversive experience in physically dependent addicts taking about 2-3 times said therapeutically effective amount.

34. The method of claim 32, wherein the opioid agonist is selected from the group consisting of morphine, hydromorphone, hydrocodone, oxycodone, codeine, levorphanol, meperidine, methadone, oxymorphone, dihydrocodeine, tramadol, pharmaceutically acceptable salts thereof, and mixtures thereof and the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, cyclazocine, levallorphan, and mixtures thereof.

35. The method of claim 34, further comprising preparing said oral dosage form with a sustained release carrier such that the dosage form is administrable on a twice-a-day or on a once-a-day basis.

36. The method of claim 32, wherein the dosage form comprises from about 10 mg to about 2000 mg of acetaminophen.

37. The 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.

38. The 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.

39. The 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.

40. The 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.

41. The 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.

42. The 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 0.083:1 to about 0.333:1.

43. The 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.

44. The oral dosage form of claim 1, further comprising an additional non-opioid drug selected from the group consisting of a COX-2 inhibitor and aspirin.

45. The method of claim 26, 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.

46. The method of claim 26, 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.

47. The method of claim 26, 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.

48. The method of claim 26, 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.

49. The method of claim 26, 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.

50. The method of claim 26, wherein said opioid antagonist is naltrexone and said opioid agonist is methadone, wherein the ratio of naltrexone to methadone is from about 0.083:1 to about 0.333:1.

51. The method of claim 26, 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.

52. The oral dosage form of claim 1, 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.

53. The method of claim 26, 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.

54. A method of preventing oral abuse of an oral opioid formulation, comprising:

preparing an oral dosage form which comprises a therapeutically effective amount of

(A) an opioid agonist;

(B) acetaminophen; and

(C) an opioid antagonist;

the dosage form having a ratio of opioid antagonist to opioid agonist to acetaminophen that provides a combination product which is analgesically effective when the combination is administered orally, but (i) is aversive in physically dependent human subjects when administered in the same amount or a higher amount than said therapeutically effective amount; and (ii) maintains an analgesic effect but does not increase analgesic efficacy of the opioid analgesic together with the acetaminophen relative to the same therapeutic amount of opioid analgesic together with the acetaminophen when administered to human patients without said opioid antagonist.

55. An oral dosage form, comprising:

an orally therapeutically effective amount of

(A) an opioid agonist;

(B) acetaminophen; and

(C) an opioid antagonist;

the dosage form having a ratio of opioid antagonist to opioid agonist to acetaminophen 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 in the same amount or a higher amount than said therapeutically effective amount; and (ii) maintains or decreases analgesic efficacy of the opioid agonist together with the acetaminophen relative to the same therapeutic amount of opioid analgesic together with the acetaminophen when administered to human patients without said opioid antagonist.
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