Method of preventing abuse of opioid dosage forms

• US 6,228,863 B1
• Filed: 12/22/1998
• Issued: 05/08/2001
• 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., Palermo, Philip J.
• Primary Examiner(s): Weddington, Kevin E.
• Application Number:
  US09/218,663
• Time in Patent Office: 868 Days
• Field of Search: 514/282, 514/289, 514/810, 514/812
• US Class Current: 514/282
• 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 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/34 Tobacco-abuse
• CPC Class Codes: A61P 25/36 Opioid-abuse

Abstract

The invention relates in part to a method of reducing the abuse potential of an oral dosage form of an opioid analgesic, wherein an analgesically effective amount of an orally active opioid agonist is combined with an opioid antagonist into an oral dosage form which would require at least a two-step extraction process to be separated from the opioid agonist, the amount of opioid antagonist including being sufficient to counteract opioid effects if extracted together with the opioid agonist and administered parenterally.

Claims

1. A method of reducing the abuse potential of an oral dosage form of an opioid analgesic, comprising

combining an analgesically effective amount of an orally active opioid agonist together with an opioid antagonist into an oral dosage form, said opioid agonist/antagonist combination being chosen such that the opioid agonist and opioid antagonist are only extractable from the dosage form together, and at least a two-step extraction process is required to separate the opioid antagonist from the opioid agonist, the amount of opioid antagonist including being sufficient to counteract opioid effects if extracted together from the oral dosage form together with the opioid agonist and administered parenterally, wherein the dose of said antagonist causes the opioid agonist/antagonist combination to provide an aversive effect in a physically dependent human subject when the dosage form is orally administered.

2. The method of claim 1, wherein said combination of said opioid agonist and said opioid antagonist require are only extractable from the dosage form together, and thereafter must be separated from each other in a separate extraction step.

3. The method of claim 2, wherein both said opioid agonist and said opioid antagonist are soluble in acid, and must be separated utilizing a high pH solution.

4. The method of claim 3, wherein said opioid agonist is hydrocodone bitartrate and said opioid antagonist is naltrexone hydrochloride, wherein both the hydrocodone and naltrexone dissolve at a pH less than 8 and about 80% of said hydrocodone and about 10% of said naltrexone are extractable at a high pH.

5. The method of claim 1 where the opioid agonist is hydromorphone hydrochloride and the opioid antagonist is naltrexone hydrochloride.

6. The method of claim 1 where the opioid agonist is oxycodone hydrochloride and the opioid antagonist is naltrexone hydrochloride.

7. The method of claim 1 where the opioid agonist is morphine sulfate and the opioid antagonist is naltrexone hydrochloride.

8. The method of claim 3, further comprising incorporating into the dosage form a further ingredient which makes separation of the opioid agonist from the opioid antagonist more difficult.

9. The method of claim 8, wherein said further ingredient is selected from the group consisting of gelling agents, waxes, and mixtures thereof.

10. The method of claim 8, further comprising incorporating into the preparation of the dosage form one or more processing steps which further impede the separation of the opioid agonist from the opioid antagonist.

11. A method of reducing the abuse potential of an oral dosage form of an opioid analgesic, comprising

combining into an oral dosage form (i) an analgesically effective amount of an opioid agonist selected from the group consisting of hydrocodone, hydromorphone, oxycodone, morphine, codeine, levorphanol, meperidine, methadone, and salts thereof together with (ii) an opioid antagonist or a pharmaceutically acceptable salt thereof, said opioid agonist/antagonist combination being chosen such that the opioid agonist and opioid antagonist are only extractable from the dosage form together, and at least a two-step extraction process is required to separate the opioid antagonist from the opioid agonist, the amount of opioid antagonist including being sufficient to counteract opioid effects if extracted together from the oral dosage form together with the opioid agonist and administered parenterally.

12. The method of claim 11, wherein said combination of said opioid agonist and said opioid antagonist are only extractable from the dosage form together, and thereafter must be separated from each other in a separate extraction step.

13. The method of claim 12, wherein both said opioid agonist and said opioid antagonist are soluble in acid, and must be separated utilizing a high pH solution.

14. The method of claim 13, wherein said opioid agonist is hydrocodone bitartrate and said opioid antagonist is naltrexone hydrochloride, wherein both the hydrocodone and naltrexone dissolve at a pH less than 8 and about 80% of said hydrocodone and about 10% of said naltrexone are extractable at a high pH.

15. The method of claim 11 where the opioid agonist is hydromorphone hydrochloride.

16. The method of claim 11 where the opioid agonist is oxycodone hydrochloride.

17. The method of claim 11 where the opioid agonist is morphine sulfate.

18. The method of claim 11 where the opioid agonist is hydrocodone bitartrate.

19. The method of claim 13, further comprising incorporating into the dosage form a further ingredient which makes separation of the opioid agonist from the opioid antagonist more difficult.

20. The method of claim 19, wherein said further ingredient is selected from the group consisting of gelling agents, waxes, and mixtures thereof.

21. The method of claim 11, wherein said opioid antagonist is naltrexone or a pharmaceutically acceptable salt thereof.

22. The method of claim 15, wherein said opioid antagonist is naltrexone or a pharmaceutically acceptable salt thereof, and the ratio of said naltrexone to said hydromorphone is from about 0.148:

1 to about 1.185;

1, by weight.

23. The method of claim 15, wherein said opioid antagonist is naltrexone or a pharmaceutically acceptable salt thereof, and the ratio of said naltrexone to said hydromorphone is from about 0.222:

1 to about 0.889;

1 by weight.

24. The method of claim 16, wherein said opioid antagonist is naltrexone or a pharmaceutically acceptable salt thereof, and the ratio of said naltrexone to said oxycodone is from about 0.037:

1 to about 0.296;

1 by weight.

25. The method of claim 16, wherein said opioid antagonist is naltrexone or a pharmaceutically acceptable salt thereof, and the ratio of said naltrexone to said oxycodone is from about 0.056:

1 to about 0.222;

1 by weight.

26. The method of claim 17, wherein said opioid antagonist is naltrexone or a pharmaceutically acceptable salt thereof and the ratio of said naltrexone to said morphine is from about 0.018:

1 to about 1.148;

1, by weight.

27. The method of claim 17, wherein said opioid antagonist is naltrexone or a pharmaceutically acceptable salt thereof and the ratio of said naltrexone to said morphine is from about 0.028:

1 to about 0.111;

1, by weight.

28. The method of claim 18, wherein said opioid antagonist is naltrexone or a pharmaceutically acceptable salt thereof, and the ratio of said naltrexone to said hydrocodone is from about 0.03:

1 to about 0.27;

1 by weight.

29. The method of claim 18, wherein said opioid antagonist is naltrexone or a pharmaceutically acceptable salt thereof, and the ratio of said naltrexone to said hydrocodone is from about 0.05:

1 to about 0.20;

1 by weight.

30. A method of reducing the abuse potential of an oral dosage form of an opioid analgesic, comprising

identifying an (i) opioid agonist selected from the group consisting of hydrocodone, hydromorphone, oxycodone, morphine, codeine, levorphanol, meperidine, methadone, or pharmaceutically acceptable salt thereof and (ii) an opioid antagonist or pharmaceutically acceptable salt thereof which when combined together in a solid dosage form along with pharmaceutical excipients are only extractable from the dosage form together, such that at least a two-step extraction process is required to separate the opioid antagonist from the opioid agonist;

and

preparing an oral solid dosage form comprising an analgesically effective amount of said opioid agonist, said opioid antagonist, and one or more pharmaceutical excipients, said opioid antagonist being included in an amount sufficient to counteract the analgesic effect of said opioid if extracted together with the opioid agonist and administered parenterally.

31. The method of claim 30, wherein said opioid agonist is hydrocodone bitartrate and said opioid antagonist is naltrexone hydrochloride.

32. The method of claim 30, further comprising incorporating into the dosage form a further ingredient which makes separation of the opioid agonist from the opioid antagonist more difficult, said further ingredient being selected from the group consisting of gelling agents, waxes, and mixtures thereof.

33. The method of claim 30, wherein said opioid antagonist is naltrexone or a pharmaceutically acceptable salt thereof.

34. The method of claim 30, wherein the dose of said antagonist causes the opioid agonist/antagonist combination to provide an aversive effect in a physically dependent human subject when the dosage form is orally administered.