Claims for Patent: 5,958,452

Summary for Patent: 5,958,452

Title:	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)
Assignee:	Euro-Celtique, S.A. (Luxembourg, LU)
Application Number:	08/833,948
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 and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, 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 extending 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. 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. 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, levophenacyl morphan, 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, salts thereof and mixtures thereof. 6. The extrudate of claim 4 wherein said opioid analgesic is selected from the group consisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone, oxymorphone, dihydrocodeine, dihydromorphine, tramadol 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. 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 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 release 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 sustained-release pharmaceutical formulation comprising an extruded blend of oxycodone, one or more hydrophobic materials selected from the group consisting of alkylcelluloses, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, 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, said formulation providing an in-vitro release when assessed by the USP Paddle or Basket Method at 100 rpm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37.degree. C. from about 1 to about 42.5% oxycodone released after one hour, from about 5 to about 65% oxycodone released after 2 hours, from about 15 to about 85% oxycodone released after 4 hours, from about 20 to about 90% oxycodone released after 6 hours, from about 35 to about 95% oxycodone released after 12 hours, from about 45 to about 100% oxycodone released after 18 hours, and from about 55 to about 100% oxycodone released after 24 hours, by weight. 18. A method of preparing a sustained-release pharmaceutical extrudate suitable for oral administration, comprising: blending a therapeutically active agent together with (1) a hydrophobic material selected from the group consisting of alkylcelluloses, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, 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. 19. The method of claim 18, 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, levophenacyl morphan, 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, salts thereof and mixtures thereof. 20. The method of claim 18, further comprising containing said unit dose of said multiparticulates within a gelatin capsule. 21. The method of claim 18, further comprising compressing said unit dose of multi-particulates into a tablet. 22. The method of claim 18, further comprising extruding said heated mixture under vacuum conditions to provide a substantially non-porous extrudate. 23. A sustained-release pharmaceutical formulation comprising an extruded blend of an opiod analgesic, one or more hydrophobic materials selected from the group consisting of alkylcellulose, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, 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. 24. The extrudate of claim 23, wherein said opioid analgesic is selected from the group consisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone, oxymorphone, dihydrocodeine, hydromorphine, tramadol and mixtures thereof. 25. The formulation of claim 17 which provides an in-vitro dissolution from about 12.5 to about 42.5% oxycodone released after one hour, from about 25 to about 65% oxycodone released after 2 hours, from about 45 to about 85% oxycodone released after 4 hours, and greater than about 60% oxycodone released after 8 hours, by weight. 26. The sustained-release pharmaceutical formulation of claim 1 wherein said therapeutically active agent, the one or more hydrophobic materials, and the one or more hydrophobic fusible carriers enter said extruder in powder form. 27. The sustained-release pharmaceutical formulation of claim 23 wherein said opioid analgesic, the one or more hydrophobic materials, and the one or more hydrophobic fusible carriers enter said extruder in powder form. 28. The sustained-release pharmaceutical formulation of claim 26 wherein said therapeutically active agent, the one or more hydrophobic materials, and the one or more hydrophobic fusible carriers, all in powder form, are mixed to form a powder mixture prior to entering the extruder. 29. The sustained-release pharmaceutical formulation of claim 27 wherein said opioid analgesic, the one or more hydrophobic materials, and the one or more hydrophobic fusible carriers, all in powder form, are mixed to form a powder mixture prior to entering the extruder. 30. The formulation of claim 10 which said provides a peak plasma level at from about 4 to about 6 hours after oral administration. 31. The sustained-release formulation of claim 1 wherein the blend is subjected to sufficient amount of heat to at least soften said blend during the extrusion process. 32. The sustained-release formulation of claim 1 wherein an effective amount of said extrudate is compressed into a tablet. 33. A sustained-release pharmaceutical formulation comprising an extruded blend of tramadol, one or more hydrophobic materials selected from the group consisting of alkylcelluloses, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, 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, said formulation providing an in-vitro release when assessed by the USP Paddle or Basket Method at 100 rpm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37.degree. C. from about 1 to about 42.5% tramadol released after one hour, from about 5 to about 65% tramadol released after 2 hours, from about 15 to about 85% tramadol released after 4 hours, from about 20 to about 90% tramadol released after 6 hours, from about 35 to about 95% tramadol released after 12 hours, from about 45 to about 100% tramadol released after 18 hours, and from about 55 to about 100% tramadol released after 24 hours, by weight. 34. The sustained-release formulation of claim 33 wherein the blend is subjected to a sufficient amount of heat to at least soften said blend during the extrusion process. 35. The sustained-release formulation of claim 33 wherein an effective amount of said extrudate is compressed into a tablet. 36. The formulation of claim 33, which provides a peak plasma level at from about 2 to about 8 hours after oral administration. 37. The formulation of claim 33, which provides a W.sub.50 from about 4 to about 12 hours. 38. The formulation of claim 33, which provides a rapid rate of initial rise in the plasma concentration of tramadol after oral administration, such that the absorption half-life is from about 1 to about 8 hours after oral administration in the fasted state. 39. The formulation of claim 33, which provides an in-vitro release when assessed by the USP Paddle or Basket Method at 100 rpm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37.degree. C. from about 12.5 to about 42.5% tramadol released after one hour, from about 25 to about 65% tramadol released after 2 hours, from about 45 to about 85% tramadol released after 4 hours, and greater than about 60% tramadol released after 8 hours, by weight. 40. The formulation of claim 33 which provide an in-vitro dissolution from about 12.5 to about 42.5% tramadol released after one hour, from about 25 to about 65% tramadol released after 2 hours, from about 45 to about 85% tramadol released after 4 hours, and greater than about 60% tramadol released after 8 hours, by weight. 41. A sustained-release pharmaceutical formulation comprising an extruded blend of hydromorophone, one or more hydrophobic materials selected from the group consisting of alkylcelluloses, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, 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, said formulation providing an in-vitro release when assessed by the USP Paddle or Basket Method at 100 rpm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37.degree. C. from about 1 to about 42.5% hydromorphone released after one hour, from about 5 to about 65% hydromorphone released after 2 hours, from about 15 to about 85% hydromorphone released after 4 hours, from about 20 to about 90% hydromorphone released after 6 hours, from about 35 to about 95% hydromorphone released after 12 hours, from about 45 to about 100% hydromorphone released after 18 hours, and from about 55 to about 100% hydromorphone released after 24 hours, by weight. 42. The sustained-release formulation of claim 41 wherein the blend is subjected to a sufficient amount of heat to at least soften said blend during the extrusion process. 43. The formulation of claim 41, wherein said extrudate comprises a strand-shaped matrix cut into multi-particulates having a length of from about 0.1 to about 5 mm and a diameter of from about 0.1 to about 5 mm. 44. The formulation of claim 43, wherein a unit dose comprising an effective amount of said multi-particulates to render a therapeutic effect is contained within a gelatin capsule. 45. The formulation of claim 41, which provides a peak plasma level at from about 2 to about 8 hours after oral administration. 46. The formulation of claim 41, which provides a W.sub.50 from about 4 to about 12 hours. 47. The formulation of claim 41 wherein the absorption half-life is from about 1 to about 8 hours after oral administration. 48. The formulation of claim 41, which provides an in-vitro release when assessed by the USP Paddle or Basket Method at 100 rpm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37.degree. C. from about 12.5 to about 42.5% hydromorphone released after one hour, from about 25 to about 65% hydromorphone released after 2 hours, from about 45 to about 85% hydromorphone released after 4 hours, and greater than about 60% hydromorphone released after 8 hours, by weight. 49. The formulation of claim 41 which provide an in-vitro dissolution from about 12.5 to about 42.5% hydromorphone released after one hour, from about 25 to about 65% hydromorphone released after 2 hours, from about 45 to about 85% hydromorphone released after 4 hours, and greater than about 60% hydromorphone released after 8 hours, by weight. 50. The formulation of claim 41 which contains about 10% hydromorphone, from about 60% to about 66% hydrophobic material and from about 24% to about 30% hydrophobic fusible material. 51. A sustained-release pharmaceutical formulation comprising an extruded blend of morphone, one or more hydrophobic materials selected from the group consisting of alkylcelluloses, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, 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, said formulation providing an in-vitro release when assessed by the USP Paddle or Basket Method at 100 rpm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37.degree. C. from about 1 to about 42.5% morphine released after one hour, from about 5 to about 65% morphine released after 2 hours, from about 15 to about 85% morphine released after 4 hours, from about 20 to about 90% morphine released after 6 hours, from about 35 to about 95% morphine released after 12 hours, from about 45 to about 100% morphine released after 18 hours, and from about 55 to about 100% morphine released after 24 hours, by weight. 52. The sustained-release formulation of claim 51 wherein the blend is subjected to a sufficient amount of heat to at least soften said blend during the extrusion process. 53. The formulation of claim 51, which provides a peak plasma level at from about 2 to about 8 hours after oral administration. 54. The formulation of claim 51, wherein said extrudate comprises a strand-shaped matrix cut into multi-particulates having a length of from about 0.1 to about 5 mm and a diameter of from about 0.1 to about 5 mm. 55. The formulation of claim 52, wherein a unit dose comprising an effective amount of said multi-particulates to render a therapeutic effect is contained within a gelatin capsule. 56. The formulation of claim 52, which provides a peak plasma level at from about 4 to about 6 hours after administration. 57. The formulation of claim 51, which provides a W.sub.50 from about 4 to about 12 hours. 58. The formulation of claim 51, which provides a rapid rate of initial rise in the plasma concentration of morphine after oral administration, such that the absorption half-life is from about 1 to about 8 hours after oral administration in the fasted state. 59. The formulation of claim 51, which provides an in-vitro release when assessed by the USP Paddle or Basket Method at 100 rpm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37.degree. C. from about 12.5 to about 42.5% morphine released after one hour, from about 25 to about 65% morphine released after 2 hours, from about 45 to about 85% morphine released after 4 hours, and greater than about 60% morphine released after 8 hours, by weight. 60. The formulation of claim 51 which provides an in-vitro dissolution from about 12.5 to about 42.5% morphine release after one hour, from about 25 to about 65% morphine released after 2 hours, from about 45 to about 85% morphine released after 4 hours, and greater than about 60% morphine released after 8 hours, by weight. 61. The formulation of claim 51 which contains about 50% morphine, about 35% hydrophobic material and about 15% hydrophobic fusible material. 62. The formulation of claim 1 wherein said hydrophobic fusible carrier has a melting point from about 45.degree. C. to about 90.degree. C. 63. The sustained-release formulation of claim 17 wherein the blend is subjected to a sufficient amount of heat to at least soften said blend during the extrusion process. 64. The formulation of claim 17, wherein said extrudate comprises a strand-shaped matrix cut into multi-particulates having a length of from about 0.1 to about 5 mm and a diameter of from about 0.1 to about 5 mm. 65. The formulation of claim 63, wherein a unit dose comprising an effective amount of said multi-particulates to render a therapeutic effect is contained within a gelatin capsule. 66. The formulation of claim 17, which provides a peak plasma level at from about 2 to about 8 hours after oral administration. 67. The formulation of claim 17, which provides a W.sub.50 from about 4 to about 12 hours. 68. The formulation of claim 17 which provides an absorption half-life from about 1 to about 8 hours after oral administration. 69. The formulation of claim 17, which provides an in-vitro release when assessed by the USP Paddle or Basket Method at 100 rpm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37.degree. C. from about 12.5 to about 42.5% oxycodone released after one hour, from about 25 to about 65% oxycodone released after 2 hours, from about 45 to about 85% oxycodone released after 4 hours, and greater than about 60% oxycodone released after 8 hours, by weight.