Details for Patent: 9,474,750

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. (Newton, CT)
Assignee:	Purdue Pharma L.P. (Stamford, CT)
Filing Date:	Aug 15, 2014
Application Number:	14/461,127
Claims:	1. A sustained release oral dosage form, comprising: (A) an orally therapeutically effective dose of an opioid agonist selected from oxycodone and pharmaceutically acceptable salts thereof; (B) an opioid antagonist selected from naltrexone, naloxone, nalmephene, cyclazocine, levallorphan, and mixtures thereof, and pharmaceutically acceptable salts thereof; and (C) a sustained release carrier that contains said opioid agonist and said opioid antagonist; said dosage form having a ratio of said opioid antagonist to said opioid agonist that provides a combination product which is analgesically effective when the combination is administered orally, but which is aversive in physically dependent human subjects when abused at a higher dose than said therapeutically effective dose. 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, further comprising an additional non-opioid drug selected from the group consisting of an NSAID, a COX-2 inhibitor, aspirin, 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. 4. The oral dosage form of claim 1, further comprising one or more pharmaceutically acceptable inert excipients. 5. The oral dosage form of claim 1, wherein said opioid antagonist is naloxone or a pharmaceutically acceptable salt thereof. 6. The oral dosage form of claim 1, wherein said sustained release carrier 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. 7. The oral dosage form of claim 1, wherein said opioid antagonist is naloxone or a pharmaceutically acceptable salt thereof present in an amount that corresponds to an equiantagonistic amount of naltrexone or a pharmaceutically acceptable salt thereof, and wherein the ratio of the equiantagonistic amount of naltrexone or pharmaceutically acceptable salt thereof to oxycodone or pharmaceutically acceptable salt thereof is from about 0.037:1 to about 0.296:1. 8. The oral dosage form of claim 7, wherein the ratio of the equiantagonistic amount of naltrexone or pharmaceutically acceptable salt thereof to oxycodone or pharmaceutically acceptable salt thereof is from about 0.056:1 to about 0.222:1. 9. The oral dosage form of claim 6, 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. 10. The oral dosage form of claim 1, wherein the dosage form is formulated for twice-a-day or once-a-day administration. 11. The oral dosage form of claim 1, wherein the oxycodone or pharmaceutically acceptable salt thereof is present in the dosage form in an amount of about 2.5 mg to about 800 mg. 12. The oral dosage form of claim 11, wherein said opioid antagonist is naloxone or a pharmaceutically acceptable salt thereof. 13. The oral dosage form of claim 1, wherein the oxycodone or pharmaceutically acceptable salt thereof is present in the dosage form in an amount that is equianalgesic to about 8 mg to about 50 mg hydrocodone or a pharmaceutically acceptable salt thereof. 14. The oral dosage form of claim 13, wherein said opioid antagonist is naloxone or a pharmaceutically acceptable salt thereof. 15. The oral dosage form of claim 1, wherein the oxycodone or pharmaceutically acceptable salt thereof is present in the dosage form in an amount that is equianalgesic to about 2 mg to about 64 mg hydromorphone hydrochloride. 16. The oral dosage form of claim 15, wherein said opioid antagonist is naloxone or a pharmaceutically acceptable salt thereof. 17. The oral dosage form of claim 1, wherein the oxycodone or pharmaceutically acceptable salt thereof is present in the dosage form in an amount that is equianalgesic to about 2.5 mg to about 800 mg morphine or a pharmaceutically acceptable salt thereof. 18. The oral dosage form of claim 17, wherein said opioid antagonist is naloxone or a pharmaceutically acceptable salt thereof. 19. The oral dosage form of claim 1, wherein the oxycodone or pharmaceutically acceptable salt thereof is present in the dosage form in an amount that is equianalgesic to about 25 mg to about 800 mg tramadol or a pharmaceutically acceptable salt thereof. 20. The oral dosage form of claim 19, wherein said opioid antagonist is naloxone or a pharmaceutically acceptable salt thereof. 21. The oral dosage form of claim 1, wherein the combination product is aversive in physically dependent human subjects when orally abused at a higher dose than said therapeutically effective dose. 22. The oral dosage form of claim 21, wherein the combination product is aversive in physically dependent human subjects when orally abused at about 2-3 times said therapeutically effective dose. 23. The oral dosage form of claim 1, wherein the combination product is aversive in physically dependent human subjects when parenterally abused at a higher dose than said therapeutically effective dose. 24. The oral dosage form of claim 23, wherein the combination product is aversive in physically dependent human subjects when parenterally abused at about 2-3 times said therapeutically effective dose. 25. A method of treating pain comprising administering to a subject in need thereof the oral dosage form of claim 1. 26. A method of preventing oral abuse of an oral opioid formulation by a subject, the method comprising providing to the subject the oral dosage form of claim 1.