Abuse-resistant opioid dosage form

• US 20030004177A1
• Filed: 05/10/2002
• Published: 01/02/2003
• Est. Priority Date: 05/11/2001
• Status: Abandoned Application

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Endo Pharmaceuticals Incorporated (Endo International PLC)
• Inventors: Zeng, Yadi, Jim, Fai, Howard-Sparks, Michelle, Kao, Huai-Hung
• Application Number:
  US10/143,140
• Publication Number:
  US 20030004177A1
• Time in Patent Office: Days
• 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 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61K 9/282 Organic compounds, e.g. fats
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention pertains to a pharmaceutical dosage form comprising an opioid agonist and one or more opioid antagonists contained in a matrix separate from the opioid agonist. The separate matrix for the opioid antagonist allows independent release rates to be achieved for the opioid and opioid antagonist(s). The antagonist(s) can be released slowly or fully contained when the tablet is taken orally. Crushing the tablet allows full release of the antagonist(s), deterring abuse. The abuse deterring antagonist(s) may be an opioid antagonist, an irritant, another appropriate antagonist(s), or a combination thereof. The invention also allows variable release of the opioid and antagonist(s).

Claims

1. An abuse resistant oral pharmaceutical dosage form comprising:

a first matrix including a first opioid antagonist;

a second matrix including an opioid agonist; and

a coating including a second opioid antagonist;

wherein said tablet, when intact, is adapted to release at least about 30% of the total opioid antagonist in the first hour based on dissolution according to USP XXIV Apparatus I, basket method at 100 rpm using 0.1 N HCl as dissolution medium at 37.5°

C.

2. The abuse resistant oral pharmaceutical dosage form of claim 1 wherein when said tablet is adapted to release, when crushed, at least about 75% of the total opioid antagonist in the first hour based on dissolution according to USP XXIV Apparatus I, Basket method at 100 rpm using 0.1 N HCl as dissolution medium at 37.5°

C.

3. The abuse resistant oral pharmaceutical dosage form of claim 1 wherein said second opioid antagonist is different from said first opioid antagonist.

4. The abuse resistant oral pharmaceutical dosage form of claim 1 wherein said first and second opioid antagonists are the same.

5. The abuse resistant oral pharmaceutical dosage form of claim 3 wherein said first opioid antagonist is naltrexone and said second opioid antagonist is naloxone.

6. The abuse resistant oral pharmaceutical dosage form of claim 1 wherein said tablet is adapted to release at least about 50% of the total antagonist in the first hour.

7. The abuse resistant oral pharmaceutical dosage form of claim 1 wherein said first matrix is dispersed in said second matrix.

8. The abuse resistant oral pharmaceutical dosage form of claim 7, wherein said first matrix is coated to prevent release of said first opioid antagonist.

9. The abuse resistant oral pharmaceutical dosage form of claim 1 wherein said opioid agonist is selected from the group consisting of codeine, dihydrocodeine, hydrocodone, hydromorphone, levorphanol, meperidine, buprenorphine, fentanyl, fentanyl derivatives, dipipanone, heroin, tramadol, etorphine, dihydroetorphine, butorphanol, methadone, morphine, and propoxyphene and pharmaceutically acceptable salts thereof.

10. The abuse resistant oral pharmaceutical dosage form of claim 9 wherein said opioid agonist is selected from the group consisting of oxycodone, oxymorphone, and morphine.

11. The abuse resistant oral pharmaceutical dosage form of claim 10 wherein at least one of said opioid antagonists is selected from the group consisting of naloxone and naltrexone.

12. The abuse resistant oral pharmaceutical dosage form of claim 1 wherein said coating includes an additional opioid antagonist.

13. The abuse resistant oral pharmaceutical dosage form of claim 1 wherein said tablet, when intact, is adapted to release at least about 30% of the total opioid antagonist in the first hour, and not more than about 75% in 12 hours, based on dissolution according to USP XXIV Apparatus I, basket method at 100 rpm using 0.1 N HCl as dissolution medium at 37.5°

C.

15. The abuse resistant oral pharmaceutical dosage form of claim 14 wherein said first matrix is dispersed in said second matrix.

16. The abuse resistant oral pharmaceutical dosage form of claim 15, wherein said first matrix is coated to prevent release of said first opioid antagonist.

17. The abuse resistant oral pharmaceutical dosage form of claim 14 wherein when said tablet is adapted to release, when crushed, at least about 75% of the total opioid antagonist in the first hour based on dissolution according to USP XXIV Apparatus I, Basket method at 100 rpm using 0.1 N HCl as dissolution medium at 37.5°

C.

18. The abuse resistant oral pharmaceutical dosage form of claim 14 wherein said first and second opioid antagonists are the same.

19. The abuse resistant oral pharmaceutical dosage form of claim 14 wherein said first opioid antagonist is naltrexone and said second opioid antagonist is naloxone.

20. The abuse resistant oral pharmaceutical dosage form of claim 14 wherein said opioid agonist is selected from the group consisting of oxycodone, oxymorphone, and morphine.

21. The abuse resistant oral pharmaceutical dosage form of claim 20 wherein at least one of said opioid antagonists is selected from the group consisting of naloxone and naltrexone.

22. The abuse resistant oral pharmaceutical dosage form of claim 14 wherein said coating includes an additional opioid antagonist.

23. The abuse resistant oral pharmaceutical dosage form of claim 14 wherein said tablet, when intact, is adapted to release at least about 30% of the total opioid antagonist in the first hour, and not more than about 75% in 12 hours, based on dissolution according to USP XXIV Apparatus I, basket method at 100 rpm using 0.1 N HCl as dissolution medium at 37.5°

C.

25. The abuse resistant oral pharmaceutical dosage form of claim 24 wherein when said tablet is adapted to release, when crushed, at least about 75% of the total opioid antagonist in the first hour based on dissolution according to USP XXIV Apparatus I, Basket method at 100 rpm using 0.1 N HCl as dissolution medium at 37.5°

C.

26. The abuse resistant oral pharmaceutical dosage form of claim 24 wherein said first and second opioid antagonists are the same.

27. The abuse resistant oral pharmaceutical dosage form of claim 24 wherein said opioid agonist is selected from the group consisting of oxycodone, oxymorphone, and morphine.

28. The abuse resistant oral pharmaceutical dosage form of claim 24 wherein at least one of said opioid antagonists is selected from the group consisting of naloxone and naltrexone.

29. The abuse resistant oral pharmaceutical dosage form of claim 24 wherein said coating includes an additional opioid antagonist.

30. The abuse resistant oral pharmaceutical dosage form of claim 26 wherein said coating includes an additional opioid antagonist.

14. An abuse resistant oral pharmaceutical dosage form comprising:

a first matrix including a first opioid antagonist;

a second matrix including an opioid agonist; and

a third matrix including a second opioid antagonist;

wherein said tablet, when intact, is adapted to release at least about 30% of the total opioid antagonist in the first hour based on dissolution according to USP XXIV Apparatus I, Basket method at 100 rpm using 0.1 N HCl as dissolution medium at 37.5°

C.

24. An abuse resistant oral pharmaceutical dosage form comprising:

a first matrix including a first opioid antagonist;

a second matrix including an opioid agonist; and

a coating including a second opioid antagonist;

wherein said tablet, when intact, is adapted to release at least about 0.3 mg of said second opioid antagonist in the first hour based on dissolution according to USP XXIV Apparatus I, Basket method at 100 rpm using 0.1 N HCl as dissolution medium at 37.5°

C.

31. An abuse resistant oral pharmaceutical dosage form comprising:

a first matrix including a first opioid antagonist; and

a second matrix including an opioid agonist; and

a third matrix including a second opioid antagonist;

wherein said tablet, when intact, is adapted to release at least about 0.3 mg of said second opioid antagonist in the first hour based on dissolution according to USP XXIV Apparatus I, Basket method at 100 rpm using 0.1 N HCl as dissolution medium at 37.5°

C.

32. The abuse resistant oral pharmaceutical dosage form of claim 31 wherein when said tablet is adapted to release, when crushed, at least about 75% of the total opioid antagonist in the first hour based on dissolution according to USP XXIV Apparatus I, Basket method at 100 rpm using 0.1 N HCl as dissolution medium at 37.5°

C.

33. The abuse resistant oral pharmaceutical dosage form of claim 31 wherein said first and second opioid antagonists are the same.

34. The abuse resistant oral pharmaceutical dosage form of claim 31 wherein said opioid agonist is selected from the group consisting of codeine, dihydrocodeine, hydrocodone, hydromorphone, levorphanol, meperidine, buprenorphine, fentanyl, fentanyl derivatives, dipipanone, heroin, tramadol, etorphine, dihydroetorphine, butorphanol, methadone, morphine, and propoxyphene.

35. The abuse resistant oral pharmaceutical dosage form of claim 34 wherein said opioid agonist is selected from the group consisting of oxycodone, oxymorphone, and morphine.

36. The abuse resistant oral pharmaceutical dosage form of claim 31 wherein at least one of said opioid antagonists is selected from the group consisting of naloxone, naltrexone, nalorphine, diprenorphine, levallorphan, pentazocine, metazocine, cyclazocine, etazocine, N-cyclopropylmethyl-7,8-dihydro-14-hydroxynormorphinone, and 21-cyclopropyl z, -(1-hydroxy-1-methylethyl)-6,14-endo-ethano-tetrahydrooripavine (or diphenorphine).

37. The abuse resistant oral pharmaceutical dosage form of claim 31 wherein at least one of said opioid antagonists is selected from the group consisting of naloxone and naltrexone.

38. The abuse resistant oral pharmaceutical dosage form of claim 31 wherein said coating includes an additional opioid antagonist.

39. The abuse resistant oral pharmaceutical dosage form of claim 33 wherein said coating includes an additional opioid antagonist.

40. An abuse resistant oral pharmaceutical dosage form comprising an opioid agonist and an opioid antagonist, wherein said tablet, when intact, is adapted to release at least about 30% of the total opioid antagonist in the first hour, and not more than about 75% in 12 hours, based on dissolution according to USP XXIV Apparatus I, basket method at 100 rpm using 0.1 N HCl as dissolution medium at 37.5°

C.

41. The abuse resistant oral pharmaceutical dosage form of claim 40 wherein when said tablet, when intact, is adapted to release at least about 40% of the total opioid antagonist in the first hour, and not more than 65% in 12 hours.

42. The abuse resistant oral pharmaceutical dosage form of claim 40 wherein when said tablet is adapted to release, when crushed, at least about 75% of the total opioid antagonist in the first hour based on dissolution according to USP XXIV Apparatus I, Basket method at 100 rpm using 0.1 N HCl as dissolution medium at 37.5°

C.

43. The abuse resistant oral pharmaceutical dosage form of claim 40 wherein said tablet includes two opioid antagonists.

44. The abuse resistant oral pharmaceutical dosage form of claim 40 wherein said opioid agonist is selected from the group consisting of oxycodone, oxymorphone, and morphine.

45. The abuse resistant oral pharmaceutical dosage form of claim 43 wherein at least one of said opioid antagonists is selected from the group consisting of naloxone and naltrexone.

47. The abuse resistant oral pharmaceutical dosage form of claim 46 wherein said first and second opioid antagonists are the same.

48. The abuse resistant oral pharmaceutical dosage form of claim 46 wherein said coating includes two different opioid antagonists.

49. The abuse resistant oral pharmaceutical dosage form of claim 47 wherein said coating includes two different opioid antagonists.

50. The abuse resistant oral pharmaceutical dosage form of claim 48 wherein said antagonists are selected from the group consisting of naloxone, naltrexone, nalorphine, diprenorphine, levallorphan, pentazocine, metazocine, cyclazocine, etazocine, N-cyclopropylmethyl-7,8-dihydro-14-hydroxynormorphinone, and 21-cyclopropyl z, -(1-hydroxy-1-methylethyl)-6,14-endo-ethano-tetrahydrooripavine (or diphenorphine).

51. The abuse resistant oral pharmaceutical dosage form of claim 50 wherein said antagonists are naloxone and naltrexone.

46. An abuse resistant oral pharmaceutical dosage form comprising a first matrix including a first opioid antagonist, a second matrix including an opioid agonist, and a coating including a second opioid antagonist.

52. An abuse resistant oral pharmaceutical dosage form comprising a first matrix including a first opioid antagonist, a second matrix including an opioid agonist, and a third matrix including a second opioid antagonist.

53. The abuse resistant oral pharmaceutical dosage form of claim 52 wherein said first and second opioid antagonists are the same.

54. The abuse resistant oral pharmaceutical dosage form of claim 52 wherein said coating includes two different opioid antagonists.

55. The abuse resistant oral pharmaceutical dosage form of claim 53 wherein said coating includes two different opioid antagonists.

56. The abuse resistant oral pharmaceutical dosage form of claim 54 wherein said antagonists are selected from the group consisting of naloxone, naltrexone, nalorphine, diprenorphine, levallorphan, pentazocine, metazocine, cyclazocine, etazocine, N-cyclopropylmethyl-7,8-dihydro-14-hydroxynormorphinone, and 21-cyclopropyl z, -(1-hydroxy-1-methylethyl)-6,14-endo-ethano-tetrahydrooripavine (or diphenorphine).

57. The abuse resistant oral pharmaceutical dosage form of claim 56 wherein said antagonists are naloxone and naltrexone.