Claims for Patent: 6,743,442

Summary for Patent: 6,743,442

Title:	Melt-extruded orally administrable opioid formulations
Abstract:	Bioavailable sustained release oral opioid analgesic dosage forms, comprising a plurality of multiparticulates produced via melt extrusion techniques are disclosed.
Inventor(s):	Oshlack; Benjamin (New York, NY), Chasin; Mark (Manalapan, NJ), Huang; Hua-Pin (Englewood Cliffs, NJ), Sackler; David (Greenwich, CT)
Assignee:	Euro-Celtique, S.A. (Luxembourg, LU)
Application Number:	09/777,616
Patent Claims:	1. A sustained-release pharmaceutical formulation comprising an extruded blend of a therapeutically active agent, one or more hydrophobic materials selected from the group consisting of alkylcelluloses, acrylic polymers, and mixtures thereof; and one or more hydrophobic fusible carriers having a melting point from about 30.degree. to about 200.degree. C. and selected from the group consisting of natural or synthetic waxes, fatty acids, fatty alcohols, and mixtures thereof, said extruded blend divided into a unit dose containing an effective amount of said therapeutically active agent to render a desired therapeutic effect and providing a sustained-release of said therapeutically active agent for a time period of from about 8 to about 24 hours, said extruded blend being formed by mixing the therapeutically active agent, the one or more hydrophobic materials, and the one or more hydrophobic fusible carriers in an extruder to form said blend and extruding said blend through the extruder. 2. The formulation of claim 1, wherein said extrudate comprises a strand-shaped matrix cut into multi-particulates having a length of from about 0.1 to about 5 mm in length. 3. The formulation of claim 1, wherein said extrudate has a diameter of from about 0.1 to about 5 mm. 4. The formulation of claim 1, wherein said therapeutically active agent is an opioid analgesic or a pharmaceutically acceptable salt thereof. 5. The formulation of claim 4, wherein said opioid analgesic is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, bupernorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dexocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl, butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, pharmaceutically acceptable salts thereof and mixtures thereof. 6. The extrudate of claim 5 wherein said opioid analgesic is selected from the group consisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone, oxymorphone, dihydrocodeine, dihydromorphine, tramadol, pharmaceutically acceptable salts thereof and mixtures thereof. 7. The formulation of claim 2, wherein a unit dose comprising an effective amount of said multiparticulates to render a therapeutic effect is contained within a gelatin capsule. 8. The formulation of claim 2, wherein a unit dose comprising an effective amount of said multiparticulates to render a therapeutic effect is compressed into a tablet. 9. The formulation of claim 8, wherein said therapeutically active agent is tramadol or a pharmaceutically acceptable salt thereof. 10. The formulation of claim 7 wherein said therapeutically active agent is an opioid analgesic selected from the group consisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone, oxymorphone, dihydrocodeine, dihydromorphine, tramadol, pharmaceutically acceptable salts thereof and mixtures thereof. 11. The formulation of claim 10, which provides an in-vitro release (when assessed by the USP Paddle or Basket Method at 100 prm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37.degree. C. from about 1 to about 42.5% opioid released after one hour, from about 5 to about 65% opioid released after 2 hours, from about 15 to about 85% opioid released after 4 hours, from about 20 to about 90% opioid released after 6 hours, from about 35 to about 95% opioid released after 12 hours, from about 45 to about 100% opioid released after 18 hours, and from about 55 to about 100% opioid released after 24 hours, by weight. 12. The formulation of claim 10 which provides a peak plasma level at from about 2 to about 8 hours after oral administration. 13. The formulation of claim 10, which provides a W.sub.50 from about 4 to about 12 hours. 14. The formulation of claim 10, which provides a rapid rate of initial rise in the plasma concentration of the opioid after oral administration, such that the peak plasma level obtained in-vivo occurs from about 2 to about 8 hours after oral administration. 15. The formulation of claim 10, which provides a rapid rate of initial rise in the plasma concentration of the opioid after oral administration, such that the absorption half-life is from about 1 to about 8 hours after oral administration (in the fasted state). 16. The formulation of claim 10, which provides an in-vitro release (when assessed by the USP Paddle or Basket Method at 100 prm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37.degree. C. from about 12.5 to about 42.5% opioid released after one hour, from about 25 to about 65% opioid released after 2 hours, from about 45 to about 85% opioid released after 4 hours, and greater than about 60% opioid released after 8 hours, by weight. 17. A method of preparing a sustained-release pharmaceutical extrudate suitable for oral administration, comprising: blending in an extruder, a therapeutically active agent together with (1) a hydrophobic material selected from the group consisting of alkylcelluloses, acrylic polymers, and mixtures thereof and (2) a hydrophobic fusible carrier selected from the group consisting of natural or synthetic waxes, fatty acids, fatty alcohols, and mixtures thereof, said retardant material having a melting point between 30-200.degree. C. and being included in an amount sufficient to further slow the release of the therapeutically active agent, heating said blend to a temperature sufficient to soften the mixture sufficiently to extrude the same; extruding said heated mixture as a strand having a diameter of from 0.1-3 mm; cooling said strand; and dividing said strand to form non-spheroidal multi-particulates of said extrudate having a length from 0.1-5 mm; and dividing said non-spheroidal multi-particulates into unit doses containing an effective amount of said therapeutically active agent, said unit dose providing a sustained-release of said therapeutically active agent for a time period of from about 8 to about 24 hours. 18. The method of claim 17, wherein said therapeutically active agent is an opioid analgesic is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, bupernorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dexocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, pharmaceutically acceptable salts thereof and mixtures thereof. 19. The method of claim 17, further comprising containing said unit dose of said multiparticulates within a gelatin capsule. 20. The formulation of claim 1, further comprising a plasticizer. 21. The formulation of claim 1, further comprising a lubricant. 22. The formulation of claim 20, wherein said plasticizer is selected from the group consisting of diethyl phthalate, tributyl citrate, triacetin, and mixtures thereof. 23. The formulation of claim 21, wherein said lubricant is selected from the group consisting of magnesium stearate, stearic acid, talc, and mixtures thereof. 24. The dosage form of claim 6, wherein said opioid analgesic is hydromorphone or a pharmaceutically acceptable salt thereof and the unit dose comprises from about 4 mg to about 64 mg of hydromorphone or a pharmaceutically acceptable salt thereof. 25. The dosage form of claim 6, wherein said opioid analgesic is morphine or a pharmaceutically acceptable salt thereof and the unit dose comprises from about 5 mg to about 800 mg of morphine or a pharmaceutically acceptable salt thereof. 26. The dosage form of claim 6, wherein said opioid analgesic is oxycodone or a pharmaceutically acceptable salt thereof and the unit dose comprises from about 5 mg to about 400 mg of oxycodone or a pharmaceutically acceptable salt thereof. 27. The method of claim 18, further comprising blending a plasticizer with said therapeutically active agent, said hydrophobic material, and said hydrophobic fusible carrier prior to heating said blend. 28. The method of claim 32, wherein said plasticizer is selected from the group consisting of diethyl phthalate, tributyl citrate, triacetin, and mixtures thereof. 29. The method of claim 19, wherein said opioid analgesic is hydromorphone or a pharmaceutically acceptable salt thereof and the unit dose comprises from about 4 mg to about 64 mg of hydromorphone or a pharmaceutically acceptable salt thereof. 30. The method of claim 19, wherein said opioid analgesic is morphine or a pharmaceutically acceptable salt thereof and the unit dose comprises from about 5 mg to about 800 mg of morphine or a pharmaceutically acceptable salt thereof. 31. The method of claim 19, wherein said opioid analgesic is oxycodone or a pharmaceutically acceptable salt thereof and the unit dose comprises from about 5 mg to about 400 mg of oxycodone or a pharmaceutically acceptable salt thereof. 32. The dosage from claim 6, wherein said opioid analgesic hydromorphone or a pharmaceutically acceptable salt thereof and the unit dose comprises from about 4 mg to about 64 mg of hydromorphone or a pharmaceutically acceptable salt thereof. 33. The dosage from claim 6, wherein said opioid analgesic is morphine or a pharmaceutically acceptable salt thereof and wherein said unit dose comprises from about 5 mg to about 800 mg of morphine or a pharmaceutically acceptable salt thereof. 34. The dosage form of claim 6, wherein said opioid analgesic is oxycodone or a pharmaceutically acceptable salt thereof and wherein said unit dose comprises from about 5 mg to about 400 mg of oxycodone or a pharmaceutically acceptable salt thereof.