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Claims for Patent: 5,965,161

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Claims for Patent: 5,965,161

Title: Extruded multi-particulates
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:08/334,209
Patent Claims: 1. A unit dose sustained-release oral dosage form comprising a plurality of extruded particles, each of said particles consisting essentially of

an opioid analgesic dispersed in a matrix comprising

one or more retardants; and

a water insoluble binder;

said particles being non-spheroidal and having a length from about 0.1 mm to about 12 mm and a diameter from about 0.1 mm to about 5 mm, said unit dose providing a release of said opioid analgesic over at least about 6 hours, said particles being formed by mixing the opioid analgesic, the one or more retardants, and the water insoluble binder in an extruder to form said matrix, extruding the matrix in the extruder to form strands, and cutting said strands into said extruded particles.

2. A sustained-release particle comprising

an active agent selected from the group consisting of disinfecting agents, chemical impregnants, cleansing agents, deodorants, fragrances, dyes, animal repellants, insect repellents, fertilizing agents, pesticides, herbicides, fungicides and plant growth stimulants dispersed in a matrix comprising

at least one retardant; and

a water insoluble binder selected from the group consisting of fatty alcohols, hydrogenated fats, fatty acid glycerides, hydrocarbons, waxes, hydrophobic and hydrophilic polymers having hydrocarbon backbones, fatty acid esters and mixtures thereof;

said particle being non-spheroidal and having a length from about 0.1 mm to about 12 mm and a diameter from about 0.1 mm to about 5 mm and providing sustained release of said active agent, said particle being formed by mixing the active agent, the at least one retardant, and the water insoluble binder in an extruder to form said matrix, extruding the matrix in the extruder to form strands, and cutting said strands into said extruded particles.

3. A sustained-release formulation comprising

a plurality of extruded particles, each of said particles comprising

an opioid analgesic dispersed in a matrix comprising

one or more retardants selected from the group consisting of ethylcellulose and acrylic polymers; and

a water insoluble binder selected from the group consisting of fatty alcohols, hydrogenated fats, fatty acid glycerides, hydrocarbons, waxes, hydrophobic and hydrophilic polymers having hydrocarbon backbones, fatty acid esters and mixtures thereof;

said particles being non-spheroidal and having a length from about 0.1 mm to about 12 mm and a diameter from about 0.1 mm to about 5 mm and providing sustained release of the opioid analgesic over at least about 6 hours, said particles being formed by mixing the opioid analgesic, the one or more retardants, and the water insoluble binder in an extruder to form said matrix, extruding the matrix in the extruder to form strands, and cutting said strands into said extruded particles.

4. The unit dose of claim 1, wherein said opioid analgesic is 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.

5. The unit dose of claim 1, wherein said opioid analgesic consists of from about 2 mg to about 64 mg hydromorphone.

6. The unit dose of claim 1, wherein said opioid analgesic consists of from about 5 mg to about 800 mg morphine.

7. The unit dose of claim 1, wherein said opioid analgesic consists of from about 5 mg to about 400 mg oxycodone.

8. The unit dose of claim 1, wherein said retardant is selected from the group consisting of acrylic polymers, hydroxyalkylcelluloses and mixtures thereof.

9. The unit dose of claim 8, 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.

10. The unit dose of claim 1, wherein said water insoluble binder is selected from the group consisting of fatty alcohols, hydrogenated fats, fatty acid esters, fatty acid glycerides, hydrocarbons, waxes, stearic acid, stearyl alcohol, and hydrophobic and hydrophilic polymers having hydrocarbon backbones, and mixtures thereof.

11. The unit dose of claim 1, wherein said water insoluble binder is selected from the group consisting of stearyl alcohol, stearic acid, water-insoluble waxes, and mixtures thereof.

12. A unit dose comprising

a gelatin capsule containing a plurality of extruded particles, each of said particles comprising

an opioid analgesic dispersed in a matrix comprising

one or more retardants selected from the group consisting of ethylcellulose, acrylic polymers and mixtures thereof;

a water insoluble binder selected from the group consisting of stearic acid; and

a hydroxyalkycellulose;

said particles being non-spheroidal and having a length from about 0.1 mm to about 12 mm and a diameter from about 0.1 mm to about 5 mm, said formulation providing sustained release of the olpioid analgesic over at least about 6 hours, said particles being formed by mixing the opioid analgesic, the one or more retardants, and the water insoluble binder in an extruder to form said matrix, extruding the matrix in the extruder to form strands, and cutting said strands into said extruded particles.

13. The unit dose of claim 1, wherein each of said particles comprise from about 1% to about 99% of said one or more retardants.

14. The unit dose of claim 1, wherein each of said particles comprise from about 5% to about 95% of said one or more retardants.

15. A method of preparing a multiparticulate sustained release oral dosage form, comprising the steps of:

(a) feeding, in powder form, a therapeutically active agent, and a waterinsoluble retardant into an extruder;

(b) mixing together the therapeutically active agent and the water-insoluble retardant in the extruder to obtain a homogeneous mixture;

(c) heating said homogeneous mixture in the extruder;

(d) extruding said homogeneous mixture with the extruder to thereby form strands;

(e) cooling said strands containing said homogeneous mixture;

(f) cutting said strands into generally cylindrically-shaped particles having a length from about 0.1 mm to about 12 mm and a diameter of from about 0.1 mm to about 5 mm; and

(g) dividing said generally cylindrically-shaped particles into unit doses, 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 6 hours when said particles are exposed to an aqueous fluid.

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. A method of treating a patient with a sustained release multiparticulate formulation of a therapeutically active agent, comprising the steps of:

(a) feeding in powder form, a therapeutically active agent, and a waterinsoluble retardant into an extruder;

(b) mixing together the therapeutically active agent and the water-insoluble retardant in the extruder to obtain a homogeneous mixture;

(c) heating said homogeneous mixture in the extruder;

(d) extruding said homogeneous mixture with the extruder to thereby form strands;

(e) cooling said strands containing said homogeneous mixture;

(f) cutting said strands into generally cylindrically-shaped particles having a length of from about 0.1 mm to about 12 mm and a diameter of from about 0.1 mm to about 3 mm;

(g) dividing said generally cylindrically-shaped particles into unit doses; and

(h) administering said unit dose to a patient, 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 6 hours when said unit dose is administered to said patient.

19. The method of claim 15, wherein said therapeutically active agent is an opioid analgesic selected from the group consisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone, oxymorphone, dihydrocodeine, dihydromorphine, tramadol, salts thereof, and mixtures thereof.

20. The method of claim 15 wherein said therapeutically active agent is 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, metaphon, 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.

21. The method of claim 15, wherein said therapeutically active agent consists of from about 2 mg to about 64 mg hydromorphone.

22. The method of claim 15, wherein said therapeutically active agent consists of from about 5 mg to about 800 mg morphine.

23. The method of claim 15, wherein said therapeutically active agent consists of from about 5 mg to about 400 mg oxycodone.

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 water-insoluble retardant 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 step (a) further includes feeding a binder into the extruder, and wherein step (b) further includes mixing the binder with the therapeutically active agent, and the water-insoluble retardant to obtain the homogeneous mixture, and wherein said binder is water insoluble and is selected from the group consisting of fatty alcohols, hydrogenated fats, stearic acid, stearyl alcohol, fatty acid glycerides, hydrocarbons, waxes, hydrophobic and hydrophilic polymers having hydrocarbon backbones, fatty acid esters, and mixtures thereof.

27. A method of preparing a multiparticulate sustained release oral dosage form, comprising the steps of:

(a) directly metering into an extruder a water-insoluble retardant and a therapeutically active agent to obtain a homogeneous mixture;

(b) heating said homogeneous mixture;

(c) extruding said homogeneous mixture to thereby form strands;

(d) cooling said strands containing said homogeneous mixture;

(e) cutting said strands into generally cylindrically-shaped particles having a length of from about 0.1 mm to about 12 mm and a diameter of from about 0.1 mm to about 3 mm; and

(f) dividing said generally cylindrically-shaped particles into unit doses.

28. An opioid unit dose sustained-release oral dosage form having substantially no feeding-fasting effect, comprising a plurality of extruded particles, each of said particles comprising a matrix consisting essentially of

an opioid analgesic;

one or more retardants;

said particles having a length from about 0.1 mm to about 12 mm and a diameter of from about 0.1 mm to about 3 mm, said unit dose providing a release of said opioid analgesic over at least about 12-24 hours, said particles being formed by mixing the opioid analgesic, the one or more retardants, an optional water insoluble binder, and optional excipients in an extruder to form said matrix, extruding the matrix in the extruder to form strands, and cutting said strands into said extruded particles.

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

30. The method according to claim 27, wherein step (a) further includes directly metering a binder into the extruder.

31. The method according to claim 27, wherein step (a) further includes directly metering a pharmaceutical excipient into the extruder.

32. The unit dose of claim 10 wherein said hydrogenated fats are selected from the group consisting of hydrogenated vegetable oil and hydrogenated castor oil; and wherein said waxes are water-insoluble.

33. The unit dose of claim 1, wherein said one or more retardants is an acrylic polymer.

34. The unit dose of claim 1, wherein said one or more retardants is an hydroxyalkylcellulose.

35. The unit dose of claim 32, wherein said water-insoluble wax is paraffin.

36. The method of claim 26, wherein said hydrogenated fats are selected from the group consisting of hydrogenated vegetable oil and hydrogenated castor oil; and wherein said waxes are water-insoluble.

37. The dosage form of claim 28, wherein said one or more retardants is an acrylic polymer.

38. The dosage form of claim 28, wherein said one or more retardants is an hydroxyalkylcellulose.

39. The method of claim 15, further comprising the step of formulating said unit doses into tablets.

40. The method of claim 36, wherein said water-insoluble wax is paraffin.

41. The unit dose of claim 1, wherein said binder is stearic acid.

42. The unit dose of claim 41, wherein said one or more retardants is ethylcellulose.

43. The unit dose of claim 1, wherein said therapeutically active agent is tramadol.

44. The unit dose of claim 42, wherein said opioid analgesic is selected from the group consisting of hydromorphone, oxycodone, morphine, tramadol, salts thereof and mixtures thereof.

45. The unit dose of claim 1, wherein said binder is selected from the group consisting of stearic acid, stearyl alcohol, and mixtures thereof.

46. The unit dose of claim 1, wherein said opioid analgesic, said one or more retardants and said water insoluble binder are mixed together to obtain a homogeneous mixture.

47. The unit dose of claim 46, wherein said mixture is heated to a temperature sufficient to melt said mixture but below the temperature required to melt said one or more retardants.

48. The unit dose of claim 46, wherein said mixture further comprises a plasticizer.

49. The unit dose of claim 48, wherein said one or more retardants is selected from the group consisting of ethylcellulose, acrylic polymers, and mixtures thereof.

50. The unit dose of claim 49, wherein said mixture is heated to a temperature of from 85 to 105.degree. C.

51. The unit dose of claim 50, wherein said plasticizer is selected from the group consisting of diethyl phthalate, tributyl citrate and polyvinyl acetate phthalate.

52. The method of claim 15, wherein said water-insoluble retardant is ethylcellulose.

53. The method of claim 26, wherein said binder is stearic acid.

54. The method of claim 15, wherein said active agent is tramadol.

55. The sustained-release particle of claim 2, wherein said hydrogenated fats are selected from the group consisting of hydrogenated vegetable oil and hydrogenated castor oil; and wherein said wax is paraffin.

56. The sustained-release formulation of claim 3, wherein said hydrogenated fats are selected from the group consisting of hydrogenated vegetable oil and hydrogenated castor oil; and wherein said wax is paraffin.

57. The sustained release formulation of claim 28, wherein said opioid analgesic is selected from the group consisting of morphine, tramadol, oxycodone, hydromorphone, hydrocodone, oxymorphone, dihydrocodeine, dihydromorphine, salts thereof and mixtures thereof.

58. The oral dosage form of claim 28, further comprising a water insoluble binder.

59. The oral dosage form of claim 58, further comprising a pharmaceutical excipient.

60. The unit does of claim 4, wherein said opioid analgesic is selected from the group consisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone, oxymorphone, dihydrocodeine, dihydromorphine, tramadol, salts thereof and mixtures thereof.

61. The method according to claim 15, wherein step (a) further includes feeding a binder into the extruder, and wherein step (b) further includes mixing the binder with the therapeutically active agent, and the water-insoluble retardant to obtain the homogeneous mixture.

62. The method according to claim 61, wherein, prior to step (a), the therapeutically active agent and the binder are mixed together.

63. The method according to claim 61, wherein, prior to step (a), the therapeutically active agent, the water-insoluble retardant and the binder are mixed together.

64. The method according to claim 18, wherein step (a) further includes feeding a binder into the extruder, and wherein step (b) further includes mixing the binder with the therapeutically active agent, and the water-insoluble retardant to obtain the homogeneous mixture.

65. The method according to claim 64, wherein, prior to step (a), the therapeutically active agent and the binder are mixed together.

66. The method according to claim 65, wherein, prior to step (a), the therapeutically active agent, the water-insoluble retardant and the binder are mixed together.
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