Opioid agonist/antagonist combinations

• US 6,277,384 B1
• Filed: 12/22/1998
• Issued: 08/21/2001
• Est. Priority Date: 12/22/1997
• Status: Expired due to Term

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Euroceltique SA
• Inventors: Colucci, Robert D., Kaiko, Robert F.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): WARE, TODD
• Application Number:
  US09/218,662
• Time in Patent Office: 973 Days
• Field of Search: 424/451, 424/464, 424/400, 514/282, 514/289, 514/810, 514/812
• US Class Current: 424/400
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/16 Amides, e.g. hydroxamic acids
• CPC Class Codes: A61K 31/451 having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/60 Salicylic acid; Derivatives thereof
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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).

Claims

1. An oral dosage form, comprising an orally therapeutically effective dose of an opioid agonist, and an opioid antagonist, the 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.

2. The 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 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, 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, 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 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 which imparts sustained release properties to said opioid agonist.

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 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.

20. 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.

21. 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.

22. 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.

23. 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.

24. 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.

25. 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.

48. 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.

26. A method of preventing oral abuse of an oral opioid formulation, comprising preparing an oral dosage form which comprises a therapeutically effective dose of an opioid agonist 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.

27. The method of claim 26, wherein the amount of antagonist included in the oral dosage form causes an aversive experience in physically dependent addicts taking about 2-3 times said therapeutically effective dose of the opioid.

28. The method of claim 26, wherein the opioid agonist is hydrocodone and the antagonist is naltrexone.

29. The method of claim 28, wherein the ration of naltrexone to hydrocodone is from about 0.03:

1 to about 0.27;

1.

30. The method of claim 28, wherein the ratio of naltrexone to hydrocodone is from about 0.05:

1 to about 0.20;

1.

31. The method of claim 26, 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.

32. The method of claim 26, 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.

33. The method of claim 26, 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.

34. The method of claim 26, 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.

35. The method of claim 26, wherein said oral dosage form further comprises 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 26, 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.

37. The method of claim 26, 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.

38. The method of claim 26, 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.

39. The method of claim 26, 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.

40. The method of claim 26, 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.

41. The method of claim 26, 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.

42. The method of claim 26, wherein the opioid antagonist is naltrexone and the opioid agonist is codeine in a naltrexone/codeine ratio from about 0.0083:

1 to about 0.033;

1.

43. The method of claim 26, 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.

44. The method of claim 26, 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.

45. The method of claim 26, 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.

46. The method of claim 26, 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.

47. The method of claim 26, wherein the opioid antagonist is naltrexone and the opioid agonist is and morphine in a naltrexonel/morphine ratio from about 0.028:

1 to about 0.111;

1.

49. 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.

50. An oral dosage form, comprising an orally therapeutically effective dose of an opioid agonist, and an opioid antagonist, the 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.