Melt-extrusion multiparticulates

• US 6,335,033 B2
• Filed: 07/22/1999
• Issued: 01/01/2002
• Est. Priority Date: 11/04/1994
• Status: Expired due to Term

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Euroceltique SA
• Inventors: Oshlack, Benjamin, Huang, Hua-Pin, Chasin, Mark
• Primary Examiner(s): Spear, James M.
• Application Number:
  US09/358,828
• Publication Number:
  US 20010033865A1
• Time in Patent Office: 894 Days
• Field of Search: 424/457, 424/458, 424/489, 424/456, 424/468, 424/451, 424/452, 424/486, 424/487, 424/488
• US Class Current: 424/457
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/2081 with microcapsules or coated microparticles according to A61K9/50
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: B29B 9/06 in the form of filamentary material, e.g. combined with extrusion

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.

Claims

1. A unit dose sustained-release oral dosage form comprising a plurality of extruded particles, each of said particles comprising:

an opioid analgesic dispersed in a matrix comprising

one or more hydrophobic materials selected from the group consisting of acrylic polymers and alkylcelluloses;

said particles being non-spheroidal and having a size 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 and the one or more hydrophobic materials 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. The unit dose of claim 1, wherein said opioid analgesic is selected from the group consisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone, oxymorphone, dihydrocodeine, dihydromorphine, pharmaceutically acceptable salts thereof and mixtures thereof.

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, pharmaceutically acceptable salts thereof and mixtures thereof.

5. The dosage form of claim 3, wherein said opioid analgesic consists of from about 2 mg to about 64 mg hydromorphone.

6. The dosage form of claim 3, wherein said opioid analgesic consists of from about 5 mg to about 800 mg morphine.

7. The dosage form of claim 3, wherein said opioid analgesic consists of from about 5 mg to about 400 mg oxycodone.

9. The unit dose 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.

10. The unit dose of claim 1, further comprising a water insoluble binder.

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

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

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

18. The unit dose of claim 1, wherein the diameter of said particles is from about 0.1 mm to about 3 cm.

38. The unit dose of claim 4 wherein said opioid analgesic is tramadol or a pharmaceutically acceptable salt thereof.

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

(a) mixing together an opioid analgesic, and a hydrophobic material in an extruder to obtain a homogeneous mixture, the ratio of said hydrophobic material to said opioid analgesic in said mixture being sufficient to impart a release of said opioid analgesic 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 homogeneous mixture in the extruder;

(c) extruding said homogeneous mixture with the extruder 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; and

administering said unit dose to a patient.

30. The method of claim 2, further comprising mixing a water insoluble binder with said opioid analgesic and said hydrophobic material in said extruder to obtain a homogeneous mixture.

31. The method of claim 30, wherein said binder is selected from the group consisting of stearyl alcohol, stearic acid, water insoluble waxes, fatty alcohols, hydrogenated fats, fatty acid esters, fatty acid glycerides, hydrophobic and hydrophilic polymers having hydrocarbon backbones and mixtures thereof.

40. The method of claim 2 wherein said opioid analgesic is tramadol or a pharmaceutically acceptable salt thereof.

8. A method of preparing a multiparticulate sustained release oral dosage form, comprising:

(a) directly metering into an extruder a hydrophobic material and an opioid analgesic;

(b) heating said homogeneous mixture in the extruder;

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

(d) cooling said strands containing said homogeneous mixture; and

(e) cutting said strands into particles having a size of from about 0.1 mm to about 12 mm; and

(f) dividing said particles into unit doses.

32. The method of claim 8, further comprising mixing a water insoluble binder with said opioid analgesic and said hydrophobic material in said extruder to obtain a homogeneous mixture.

33. The method of claim 32, wherein said binder is selected from the group consisting of stearyl alcohol, stearic acid, water insoluble waxes, fatty alcohols, hydrogenated fats, fatty acid esters, fatty acid glycerides, hydrophobic and hydrophilic polymers having hydrocarbon backbones and mixtures thereof.

41. The method of claim 8 wherein said opioid analgesic is tramadol or a pharmaceutically acceptable salt thereof.

12. 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:

an opioid analgesic dispersed in a matrix comprising;

one or more hydrophobic materials selected from the group consisting of acrylic polymers and alkylcelluloses;

said particles having a size 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 and the one or more hydrophobic materials in an extruder to form said matrix, extruding the matrix in the extruder to form strands, and cutting said strands into said extruded particles.

34. The opioid unit dose of claim 12, further comprising a water insoluble binder.

35. The opioid unit dose of claim 34, wherein said binder is selected from the group consisting of stearyl alcohol, stearic acid, water insoluble waxes, fatty alcohols, hydrogenated fats, fatty acid esters, fatty acid glycerides, hydrophobic and hydrophilic polymers having hydrocarbon backbones and mixtures thereof.

42. The unit dose of claim 12 wherein said opioid analgesic is tramadol or a pharmaceutically acceptable salt thereof.

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

(a) mixing together an opioid analgesic and one or more hydrophobic materials in an extruder to obtain a homogeneous mixture, the ratio of said one or more hydrophobic materials to said opioid analgesic in said mixture being sufficient to impart a release of said opioid analgesic 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 homogeneous mixture in the extruder;

(c) extruding said homogeneous mixture with the extruder 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°

C. to about 200°

C. prior to extrusion.

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

20. The method of claim 15, 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, pharmaceutically acceptable salts thereof and mixtures thereof.

21. The method of claim 15, wherein said opioid analgesic consists of from about 2 mg to about 64 mg hydromorphone or a pharmaceutically acceptable salt thereof.

22. The method of claim 15, wherein said opioid analgesic consists of from about 5 mg to about 800 mg morphine or a pharmaceutically acceptable salt thereof.

23. The method of claim 15, wherein said opioid analgesic consists of from about 5 mg to about 400 mg oxycodone or a pharmaceutically acceptable salt thereof.

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

25. The method of claim 15, wherein at least one of said one or more hydrophobic materials is an acrylic polymer 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, further comprising mixing a water insoluble binder with said opioid analgesic and said hydrophobic material in said extruder to obtain a homogeneous mixture.

27. The method of claim 26, wherein said binder is selected from the group consisting of stearyl alcohol, stearic acid water insoluble waxes fatty alcohols. hydrogenated fats, fatty acid esters, fatty acid glycerides, hydrocarbons, waxes, and hydrophobic and hydrophilic polymers having hydrocarbon backbones and mixtures thereof.

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.

39. The method of claim 20 wherein said opioid analgesic is tramadol or a pharmaceutically acceptable salt thereof.

29. 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:

an opioid analgesic dispersed in a matrix;

one or more hydrophobic materials selected from the group consisting of acrylic polymers. alkylcelluloses;

said particles having a size 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 6 hours said particles being formed by mixing the opioid analgesic, and the one or more hydrophobic materials in an extruder to form said matrix, extruding the matrix in the extruder to form strands, and cutting said strands into said extruded particles.

36. The opioid unit dose of claim 29, further comprising a water insoluble binder.

37. The opioid unit dose of claim 36, wherein said binder is selected from the group consisting of stearyl alcohol, stearic acid, water insoluble waxes, fatty alcohols, hydrogenated fats, fatty acid esters, fatty acid glycerides, hydrophobic and hydrophilic polymers having hydrocarbon backbones and mixtures thereof.

43. The unit dose of claim 29 wherein said opioid analgesic is tramadol or a pharmaceutically acceptable salt thereof.