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Claims for Patent: 6,706,281

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Claims for Patent: 6,706,281

Title: Melt-extrusion multiparticulates
Abstract:A unit dose sustained-release oral dosage form containing a plurality of melt-extruded particles, each consisting essentially of a therapeutically active agent, one or more retardants, and an optional water-insoluble binder is disclosed. The particles have a length of from about 0.1 to about 12 mm and can be of varying diameters and each unit dose provides a release of therapeutically active agents over at least about 8 hours. Methods of preparing the unit doses as well as extrusion processes and methods of treatment are also 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:10/038,867
Patent Claims: 1. A unit dose sustained-release oral dosage form comprising a plurality of melt extruded particles, each of said particles comprising: (a) an opioid analgesic selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, 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, metophon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, proheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, salts thereof and mixtures thereof; (b) one or more retardants; and (c) an optional water insoluble binder, said particles having a (length) size from about 0.1 mm to about 12 mm, said unit dose providing a release of said opioid analgesic over at least about 6 hours.

2. The dosage form of claim 1, wherein said opioid analgesic is morphine or pharmaceutically acceptable salts thereof.

3. The dosage form of claim 1, wherein said opioid analgesic is codeine or pharmaceutically acceptable salts thereof.

4. The dosage form of claim 1, wherein said opioid analgesic is hydromorphone or pharmaceutically acceptable salts thereof.

5. The dosage form of claim 1, wherein said opioid analgesic is hydrocodone or pharmaceutically acceptable salts thereof.

6. The dosage form of claim 1, wherein said opioid analgesic is oxycodone or pharmaceutically acceptable salts thereof.

7. The dosage form of claim 1, wherein said retardant is selected from the group consisting of acrylic polymers, hydroxyalkylcelluloses and mixtures thereof.

8. The dosage form of claim 1, wherein said acrylic polymer is comprised of monomers selected from the group consisting of an ester of acrylic acid, an ester of methacrylic acid, an alkyl ester of acrylic acid, an alkyl ester of methacrylic acid, and mixtures of any of the foregoing.

9. The dosage form of claim 1, wherein said water insoluble binder is selected from the group consisting of hydrogenated vegetable or castor oil, paraffin, higher aliphatic alcohols, higher aliphatic acids, long chain fatty acids, fatty acid esters, and mixtures thereof.

10. The dosage form of claim 1, wherein said binder is selected from the group consisting of higher aliphatic alcohols and water-insoluble waxes.

11. The dosage form of claim 1, wherein said particles have a diameter from about 0.1 to about 5 mm.

12. The dosage form of claim 1, wherein each of said particles comprise from about 1% to about 99% of said retardant.

13. The dosage form of claim 1, wherein each of said particles comprise from about 5% to about 95% of said retardant.

14. A unit dose sustained-release oral dosage form comprising a plurality of melt extruded particles, each of said particles comprising: (a) an opioid analgesic; (b) one or more retardants; and (c) an optional water insoluble binder; said particles having a (length) size from about 0.1 mm to about 12 mm, said unit dose providing a release of said opioid analgesic over at least about 6 hours.

15. A method of preparing a multiparticulate sustained release oral dosage form, comprising: (a) mixing together a therapeutically active agent, a water-insoluble retardant, and an optional binder to obtain a homogeneous mixture, the ratio of said water insoluble retardant to said therapeutically active agent in said mixture being sufficient to impart a release of said therapeutically active agent from said particles over a time period of at least about 4 hours when said particle is exposed to an aqueous fluid; (b) heating said homogenous mixture; (c) extruding said homogenous mixture to thereby form strands; (d) cooling said strands containing said homogeneous mixture; and (e) cutting said strands into particles having a size from about 0.1 mm to about 12 mm; and (f) dividing said particles into unit doses.

16. The method of claim 15, wherein said unit doses are placed into gelatin capsules.

17. The method of claim 15, wherein said homogenous mixture is heated to a temperature from about 30.degree. C. to about 200.degree. C. prior to extrusion.

18. The method of claim 15, wherein said therapeutically active agent is selected from the group consisting of systemically active therapeutic agents, locally active therapeutic agents, disinfecting agents, chemical impregnants, cleansing agents, deodorants, fragrances, dyes, animal repellents, insect repellents, fertilizing agents, a pesticides, herbicides, fungicides, and plant growth stimulants.

19. The method of claim 18, wherein said therapeutically active agent is an opioid analgesic selected from the group consisting of alfentanil, allyiprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethyithiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacyl morphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metophon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, proheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, salts thereof and mixtures thereof.

20. The method of claim 19, wherein said opioid analgesic is morphine or pharmaceutically acceptable salts thereof.

21. The method of claim 19, wherein said opioid analgesic is codeine or pharmaceutically acceptable salts thereof.

22. The method of claim 19, wherein said opioid analgesic is hydromorphone or pharmaceutically acceptable salts thereof.

23. The method of claim 19, wherein said opioid analgesic is hydrocodone or pharmaceutically acceptable salts thereof.

24. The method of claim 15, wherein said retardant is selected from the group consisting of acrylic polymers, hydroxyalkylcelluloses and mixtures thereof.

25. The method of claim 15, wherein said acrylic polymer is comprised of monomers selected from the group consisting of an ester of acrylic acid, an ester of methacrylic acid, an alkyl ester of acrylic acid, an alkyl ester of methacrylic acid, and mixtures of any of the foregoing.

26. The method of claim 15, wherein said water insoluble binder is selected from the group consisting of hydrogenated vegetable or castor oil, paraffin, higher aliphatic alcohols, higher aliphatic acids, long chain fatty acids, fatty acid esters, and mixtures thereof.

27. The method of claim 15, wherein said binder is selected from the group consisting of higher aliphatic alcohols and water-insoluble waxes.

28. The method of claim 15, further comprising adjusting the aperture and aperture shape of the extruder to obtain a strand having a diameter from about 0.1 mm to about 3 cm.

29. A sustained release unit dose formulation comprising the particles prepared according to the method of claim 15.

30. A method of treating a patient with a sustained release multiparticulate formulation of a therapeutically active agent, comprising: (a) mixing together a therapeutically active agent, a water-insoluble retardant, and an optional binder to obtain a homogeneous mixture, the ratio of said water insoluble retardant to said therapeutically active agent in said mixture being sufficient to impart a release of said therapeutically active agent from said particles over a time period of at least about 4 hours when said particle is exposed to an aqueous fluid; (b) heating said homogenous mixture; (c) extruding said homogenous mixture to thereby form strands; (d) cooling said strands containing said homogeneous mixture; and (e) cutting said strands into particles having a size from about 0.1 mm to about 12 mm; (f) dividing said particles into unit doses; and (g) administering said unit dose to a patient.

31. A method of preparing a multiparticulate sustained release oral dosage form, comprising: (a) directly metering into an extruder a water-insoluble retardant, a therapeutically active agent, and an optional binder; (b) heating said homogenous mixture; (c) extruding said homogenous mixture to thereby form strands; (d) cooling said strands containing said homogeneous mixture; and (e) cutting said strands into particles having a size from about 0.1 mm to about 12 mm; and (f) dividing said particles into unit doses.

32. The method of claim 15, wherein the diameter of said particles is from about 0.1 mm to about 3 cm.

33. The method of claim 15, wherein said therapeutically active agent is an opioid and said retardant is an acrylic polymer.

34. The method of claim 15, wherein said therapeutically active agent is an opioid and said retardant is a hydroxyalkylcellulose.

35. An opioid unit dose sustained-release oral dosage form having substantially no feeding-fasting effect, comprising a plurality of melt extruded particles, each of said particles comprising: (a) an opioid analgesic; (b) one or more retardants; and (c) an optional water insoluble binder; said particles having a (length) size from about 0.1 mm to about 12 mm, said unit dose providing a release of said therapeutically active agent over at least about 12-24 hours.

36. An opioid unit dose sustained-release oral dosage form having substantially no feeding-fasting effect, comprising a plurality of melt extruded particles, each of said particles comprising: (a) an opioid analgesic; (b) one or more retardants; and (c) an optional water insoluble binder; said particles having a (length) size from about 0.1 mm to about 12 mm, said unit dose providing a release of said therapeutically active agent over at least about 6 hours.

37. The dosage form of claim 35, wherein said therapeutically active agent is an opioid and said retardant is an acrylic polymer.

38. The dosage form of claim 36, wherein said therapeutically active agent is an opioid and said retardant is a hydroxyalkylcellulose.

39. The method of claim 19, wherein said opioid analgesic is oxycodone or pharmaceutically acceptable salts thereof.
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