Pharmaceutical formulation containing opioid agonist, opioid antagonist and bittering agent

• US 7,144,587 B2
• Filed: 08/06/2002
• Issued: 12/05/2006
• Est. Priority Date: 08/06/2001
• Status: Expired due to Term

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Euroceltique SA
• Inventors: Wright, Curtis, Oshlack, Benjamin, Breder, Christopher, Colucci, Robert
• Primary Examiner(s): TRAN, SUSAN T
• Application Number:
  US10/213,921
• Publication Number:
  US 20030124185A1
• Time in Patent Office: 1,582 Days
• Field of Search: 424/451, 424/452, 424/464, 424/465, 424/468, 424/484, 424/489
• US Class Current: 424/490
• 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 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/205 Polysaccharides, e.g. alginate, gums; Cyclodextrin
• CPC Class Codes: A61K 9/2081 with microcapsules or coated microparticles according to A61K9/50
• CPC Class Codes: A61K 9/5078 with drug-free core

Abstract

Disclosed in certain embodiments is an oral dosage form comprising a therapeutically effective amount of an opioid analgesic; an opioid antagonist; and a bittering agent in an effective amount to impart a bitter taste to an abuser upon administration of the dosage form after tampering.

Claims

1. An oral dosage form comprising:

a therapeutically effective amount of an opioid analgesic;

a sequestered opioid antagonist; and

a sequestered bittering agent, which bittering agent and opioid antagonist are substantially released only upon tampering of the dosage form in an amount sufficient to impart a bitter taste to an abuser upon oral administration of said tampered dosage form.

2. The oral dosage form of claim 1, wherein the bittering agent is selected from the group consisting of flavor oils;

flavoring aromatics;

oleoresins;

extracts derived from plants;

sucrose derivatives;

chlorosucrose derivatives;

quinine sulphate;

denatonium benzoate; and

combinations thereof.

3. The oral dosage form of claim 1, wherein the bittering agent is a flavor oil selected from the group consisting of spearmint oil, peppermint oil, eucalyptus oil, oil of nutmeg, allspice, mace, oil of bitter almonds, menthol and combinations thereof.

4. The oral dosage form of claim 1, wherein the bittering agent is a fruit flavor selected from the group consisting of lemon, orange, lime, grapefruit, and mixtures thereof.

5. The oral dosage form of claim 1, wherein the bittering agent is denatonium benzoate.

6. The oral dosage form of claim 1, wherein said bittering agent is in an amount of less than about 50% by weight of the dosage form.

7. The oral dosage form of claim 1, wherein said bittering agent is in an amount of less than about 10% by weight of the dosage form.

8. The oral dosage form of claim 1, wherein said bittering agent is in an amount of less than about 5% by weight of the dosage form.

9. The oral dosage form of claim 1, wherein said bittering agent is in an amount of from about 0.1 to 1.0 percent by weight of the dosage form.

10. The oral dosage form of claim 1, further comprising a pharmaceutically acceptable excipient.

11. The oral dosage form of claim 10, wherein said excipient is a sustained release excipient.

12. The oral dosage form of claim 11, said dosage form providing an analgesic effect for at least about 12 hours after oral administration to a human patient.

13. The oral dosage form of claim 1 wherein said bittering agent is at least partially interdispersed with the opioid analgesic.

14. The oral dosage form of claim 1 having a ratio of opioid antagonist to opioid agonist that is analgesically effective when the combination is administered orally, but which is aversive in physically dependent human subjects when administered to physically dependent human subjects at the same amount or at a higher amount than said therapeutically effective amount.

15. The oral dosage form of claim 14 wherein said ratio of opioid antagonist to opioid agonist maintains an analgesic effect but does not increase analgesic efficacy of the opioid agonist relative to the same therapeutic amount of opioid analgesic when administered to human patients without said opioid antagonist.

16. The oral dosage form of claim 1, wherein the antagonist is in an amount effective to attenuate a side effect of said opioid agonist selected from the group consisting of anti-analgesia, hyperalgesia, hyperexcitability, physical dependence, tolerance, and a combination of any of the foregoing.

17. The oral dosage form of claim 1, wherein the amount of antagonist released during the dosing interval enhances the analgesic potency of the opioid agonist.

18. A method of treating pain comprising administering to a patient an oral dosage form of claim 1.

21. The oral dosage form of claim 1, wherein said bittering agent is present in multiparticulates individually coated with a material that prevents substantial release of the bittering agent.

22. The oral dosage form of claim 1, wherein said bittering agent is dispersed in a matrix comprising a sequestering material that prevents substantial release of the bittering agent.

19. A method of preparing a pharmaceutical oral dosage form comprising combining a therapeutically effective amount of an opioid analgesic and a sequestered opioid antagonist into an oral dosage form with a sequestered bittering agent, which sequestered bittering agent and sequestered opiod antagonist are substantially released only upon tampering of the oral dosage form in an amount sufficient to impart a bitter taste to an abuser upon oral administration of said tampered dosage form.

20. The method of claim 19, wherein said bittering agent is at least partially interdispersed with the opioid analgesic.