Claims for Patent: 4,464,378

Summary for Patent: 4,464,378

Title:	Method of administering narcotic antagonists and analgesics and novel dosage forms containing same
Abstract:	The invention provides a novel method of administering narcotic antagonists, narcotic analgesics and related compounds, and novel dosage forms containing those compounds which are adapted for nasal administration. The nasal dosage forms disclosed include solutions, suspensions, gels and ointments. Especially preferred compounds which can be advantageously administered in accordance with the invention include naloxone, naltrexone, nalbuphine, levorphanol, buprenorphine, butorphanol, .DELTA..sup.9 -tetrahydrocannabinol (THC), cannabidiol (CBD) and levonantradol.
Inventor(s):	Hussain; Anwar A. (Lexington, KY)
Assignee:	University of Kentucky Research Foundation (Lexington, KY)
Application Number:	06/258,308
Patent Claims:	1. A method for eliciting an analgesic or narcotic antagonist response in a warm-blooded animal, which comprises nasally administering to said animal: (a) to elicit an analgesic response, an analgesically effective amount of morphine, hydromorphone, metopon, oxymorphone, desomorphine, dihydromorphine, levorphanol, cyclazocine, phenazocine, levallorphan, 3-hydroxy-N-methylmorphinan, levophenacylmorphan, metazocine, norlevorphanol, phenomorphan, nalorphine, nalbuphine, buprenorphine, butorphanol or pentazocine, or a nontoxic pharmaceutically acceptable acid addition salt thereof; or (b) to elicit a narcotic antagonist response, a narcotic antagonist effective amount of naloxone, naltrexone, diprenorphine, nalmexone, cyprenorphine, levallorphan, alazocine, oxilorphan, cyclorphan, nalorphine, nalbuphine, buprenorphine, butorphanol, cyclazocine or pentazocine, or a nontoxic pharmaceutically acceptable acid addition salt thereof. 2. A method according to claim 1 for eliciting a narcotic antagonist response in a warm-blooded animal, which comprises nasally administering to said animal a narcotic antagonist effective amount of naxolone, naltrexone, diprenorphine, nalmexone, cyprenorphine, levallorphan, alazocine, oxilorphan, cyclorphan, nalorphine, nalbuphine, buprenorphine, butorphanol, cyclazocine or pentazocine, or a nontoxic pharmaceutically acceptable acid addition salt thereof. 3. The method according to claim 2 wherein the compound administered is naloxone, naltrexone, nalorphine, nalbuphine, buprenorphine, diprenorphine, nalmexone or cyprenorphine, or a nontoxic pharmaceutically acceptable acid addition salt thereof. 4. The method according to claim 2 wherein the compound administered is in the form of a long-chain carboxylic acid salt, the carboxylic acid portion of the salt containing from 10 to 20 carbon atoms. 5. The method according to claim 4 wherein the long chain carboxylic acid salt is a stearate, palmitate or myristate. 6. The method according to claim 3 wherein the compound administered is naloxone or a nontoxic pharmaceutically acceptable acid addition salt thereof. 7. The method according to claim 3 wherein the compound administered is naltrexone or a nontoxic pharmaceutically acceptable acid addition salt thereof. 8. The method according to claim 3 wherein the compound administered is nalorphine or a nontoxic pharmaceutically acceptable acid addition salt thereof. 9. The method according to claim 3 wherein the compound administered is nalbuphine or a nontoxic pharmaceutically acceptable acid addition salt thereof. 10. The method according to claim 3 wherein the compound administered is buprenorphine or a nontoxic pharmaceutically acceptable acid addition salt thereof. 11. A method according to claim 1 for eliciting an analgesic response in a warm-blooded animal which comprises nasally administering to said animal an analgesically effective amount of nalorphine, nalbuphine, buprenorphine, butorphanol, cyclazocine, levallorphan or pentazocine, or a nontoxic pharmaceutically acceptable acid addition salt thereof. 12. The method according to claim 11 wherein the compound administered is in the form of a long chain carboxylic acid salt, the carboxylic acid portion of the salt containing from 10 to 20 carbon atoms. 13. The method according to claim 12 wherein the long chain carboxylic acid salt is a stearate, palmitate or myristate. 14. The method according to claim 11 wherein the compound administered is buprenorphine or a nontoxic pharmaceutically acceptable acid addition salt thereof. 15. A method according to claim 1 for eliciting an analgesic response in a warm-blooded animal, which comprises nasally administering to said animal an analgesically effective amount of morphine, hydromorphone, metopon, oxymorphone, desomorphine, dihydromorphine, levorphanol, phenazocine, 3-hydroxy-N-methylmorphinan, levophenacylmorphan, metazocine, norlevorphanol or phenormorphan, or a nontoxic pharmaceutically acceptable acid addition salt thereof. 16. The method according to claim 15 wherein morphine is administered, in the form of the free base or a nontoxic pharmaceutically acceptable acid addition salt thereof. 17. The method according to claim 15 wherein hydromorphone, metopon, oxymorphone, desomorphine, dihydromorphine, levorphanol, phenazocine, 3-hydroxy-N-methylmorphinan, levophenacylmorphan, metazocine, norlevorphanol or phenomorphan is administered, in the form of the free base or a nontoxic pharmaceutically acceptable acid addition salt thereof. 18. The method according to claim 17 wherein the compound administered is hydromorphone, metopon or oxymorphone, or a nontoxic pharmaceutically acceptable acid addition salt thereof. 19. The method according to claim 15 wherein the compound administered is in the form of a long chain carboxylic acid salt, the carboxylic acid portion of the salt containing from 10 to 20 carbon atoms. 20. A method according to claim 2 wherein the compound administered is butorphanol, pentazocine, cyclazocine or oxilorphan, or a nontoxic pharmaceutically acceptable acid addition salt thereof. 21. The method according to claim 20 wherein the compound administered is butorphanol or a nontoxic pharmaceutically acceptable acid addition salt thereof. 22. A method according to claim 11 wherein the compound administered is butorphanol, cyclazocine or pentazocine, or a nontoxic pharmaceutically acceptable acid addition salt thereof. 23. The method according to claim 17 wherein the compound administered is levorphanol or a nontoxic pharmaceutically acceptable acid addition salt thereof. 24. The method according to claim 1 wherein the compound administered is morphine, oxymorphone, buprenorphine, naloxone, nalorphine, nalbuphine, naltrexone, hydromorphone, metopon, nalmexone, cyprenorphine or diprenorphine, or a nontoxic pharmaceutically acceptable acid addition salt thereof. 25. The method according to claim 24 wherein the compound is in the form of a long-chain carboxylic acid salt, the carboxylic acid portion of the salt containing from 10 to 20 carbon atoms. 26. The method according to claim 25 wherein the long-chain carboxylic acid salt is a stearate, palmitate or myristate. 27. The method according to claim 1 wherein the compound administered is levorphanol, cyclazocine, phenazocine, butorphanol, pentazocine or oxilorphan, or a nontoxic pharmaceutically acceptable acid addition salt thereof. 28. The method according to claim 27 wherein the compound is in the form of a long-chain carboxylic acid salt, the carboxylic acid portion of the salt containing from 10 to 20 carbon atoms. 29. The method according to claim 28 wherein the long-chain carboxylic acid salt is a stearate, palmitate or myristate. 30. A pharmaceutically acceptable nasal dosage form for eliciting an analgesic response in a warm-blooded animal, which comprises (i) an analgesically effective amount of morphine, hydromorphone, metopon, oxymorphone, desomorphine, dihydromorphine, levorphanol, cyclazocine, phenazocine, 3-hydroxy-N-methylmorphinan, levophenacylmorphan, metazocine, norlevorphanol, phenomorphan, nalorphine, nalbuphine, buprenorphine, butorphanol, levallorphan or pentazocine, or a nontoxic pharmaceutically acceptable acid addition salt thereof, and (ii) a nontoxic pharmaceutically acceptable nasal carrier therefor, said nasal dosage form comprising a nasal ointment or a nasal gel. 31. A dosage form according to claim 30, said dosage form comprising a nasal ointment. 32. A dosage form according to claim 30, said dosage form comprising a nasal gel. 33. A dosage form according to claim 32, said dosage form comprising a sustained release nasal gel. 34. A dosage form according to claim 30, wherein (i) comprises an analgesically effective amount of morphine or buprenorphine, or of a nontoxic pharmaceutically acceptable acid addition salt of morphine or buprenorphine. 35. A dosage form according to claim 30, wherein the compound administered is in the form of a long chain carboxylic acid salt, the carboxylic acid portion of the salt containing from 10 to 20 carbon atoms. 36. A pharmaceutically acceptable nasal dosage form for eliciting a narcotic antagonist response in a warm-blooded animal, which comprises (i) a narcotic antagonist effective amount of naloxone, naltrexone, diprenorphine, nalmexone, cyprenorphine, levallorphan, alazocine, oxilorphan, cyclorphan, nalorphine, nalbuphine, buprenorphine, butorphanol, cyclazocine or pentazocine, or a nontoxic pharmaceutically acceptable acid addition salt thereof, and (ii) a nontoxic pharmaceutically acceptable nasal carrier therefor, said nasal dosage form comprising a nasal ointment or a nasal gel. 37. A dosage form according to claim 36, said dosage form comprising a nasal ointment. 38. A dosage form according to claim 36, said dosage form comprising a nasal gel. 39. A dosage form according to claim 38, said dosage form comprising a sustained release nasal gel. 40. A dosage form according to claim 36, wherein (i) comprises a narcotic antagonist effective amount of naloxone, naltrexone, nalorphine, nalbuphine or buprenorphine, or of a nontoxic pharmaceutically acceptable acid addition salt of naloxone, naltrexone, nalorphine, nalbuphine or buprenorphine. 41. A dosage form according to claim 36, wherein the compound administered is in the form of a long chain carboxylic acid salt, the carboxylic acid portion of the salt containing from 10 to 20 carbon atoms. 42. A pharmaceutically acceptable sustained release nasal dosage form for nasally delivering systemic therapeutic levels of drug to a warm-blooded animal which comprises (i) a systemically therapeutically effective amount of a long chain carboxylic acid salt of morphine, hydromorphone, metopon, oxymorphone, desomorphine, dihydromorphine, levorphanol, cyclazocine, phenazocine, 3-hydroxy-N-methylmorphinan, levophenacylmorphan, metazocine, norlevorphanol, phenomorphan, nalorphine, nalbuphine, buprenorphine, butorphanol, pentazocine, naloxone, naltrexone, diprenorphine, nalmexone, cyprenorphine, levallorphan, alazocine, oxilorphan or cyclorphan, and (ii) a nontoxic pharmaceutically acceptable nasal carrier therefor. 43. A dosage form according to claim 42, wherein (i) comprises a systemically therapeutically effective amount of a long chain carboxylic acid salt of naloxone, naltrexone, nalorphine, nalbuphine or buprenorphine. 44. A dosage form according to claim 42, wherein the carboxylic acid portion of said salt contains 10 to 20 carbon atoms. 45. A dosage form according to claim 44, wherein said salt is a stearate, palmitate or myristate. 46. A dosage form according to claim 42, said dosage form comprising a nasal solution, nasal suspension, nasal ointment or nasal gel. 47. A dosage form according to claim 42, wherein (i) comprises a systemically therapeutically effective amount of a long chain carboxylic acid salt of levorphanol, cyclazocine, phenazocine, butorphanol, pentazocine or oxilorphan. 48. A method for eliciting an analgesic response in a warm-blooded animal, which comprises nasally administering to said animal an analgesically effective amount of a pharmaceutically acceptable nasal dosage form as claimed in claim 30. 49. A method for eliciting a narcotic antagonist response in a warm-blooded animal, which comprises nasally administering to said animal a narcotic antagonist effective amount of a pharmaceutically acceptable nasal dosage form as claimed in claim 36. 50. A dosage form according to claim 36, wherein (i) comprises a narcotic antagonist effective amount of butorphanol, pentazocine, cyclazocine or oxilorphan, or of a nontoxic pharmaceutically acceptable acid addition salt of butorphanol, pentazocine, cyclazocine or oxilorphan. 51. A dosage form according to claim 30, wherein (i) comprises an analgesically effective amount of levorphanol, cyclazocine, phenazocine, butorphanol or pentazocine, or of a nontoxic pharmaceutically acceptable acid addition salt of levorphanol, cyclazocine, phenazocine, butorphanol or pentazocine.