Orally administrable opioid formulations having extended duration of effect

• US 5,968,551 A
• Filed: 07/27/1995
• Issued: 10/19/1999
• Est. Priority Date: 12/24/1991
• Status: Expired due to Term

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Purdue Pharma L.P.
• Inventors: Oshlack, Benjamin, Chasin, Mark
• Primary Examiner(s): Spear, James M.
• Application Number:
  US08/508,246
• Time in Patent Office: 1,545 Days
• Field of Search: 424/456, 424/457, 424/458, 424/461, 424/462, 424/451, 424/460, 424/496, 424/484, 424/489, 424/491, 424/494, 424/497, 424/498
• US Class Current: 424/456
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• 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 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2072 characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms A61K9/0004, A61K9/0056, A61K9/0065 take precedence
• 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: A61K 9/2846 Poly(meth)acrylates
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5047 Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Sustained release oral solid dosage forms of opioid analgesics are provided as multiparticulate systems which are bioavailable and which provide effective blood levels of the opioid analgesic for at least about 24 hours. A unit dose of the opioid analgesic contains a plurality of substrates including the opioid analgesic in sustained release form. The substrates have a diameter from about 0.1 mm to about 3 mm.

Claims

1. A bioavailable sustained-release oral analgesic dosage form for once-a-day administration, comprising:

a unit dose comprising a plurality of pharmaceutically acceptable matrices comprising an analgesically effective amount of an opioid analgesic or a salt thereof and a hydrophobic material, each of said matrices having a diameter from about 0.1 mm to about 3 mm, said dosage form being bioavailable and providing a therapeutic effect for about 24 hours or more after oral administration to a human patient.

2. The dosage form of claim 1, wherein said matrices are selected from the group consisting of spheroids, pellets, ion-exchange resin beads, granules, and mixtures thereof.

4. The dosage form of claim 1 wherein said matrices comprise a substantially uniform mixture of said opioid analgesic or salt thereof and said hydrophobic material.

5. The dosage form of claim 1, wherein said opioid analgesic is selected form the group consisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone, oxymorphone, dihydrocodeine, dihydromorphine, and mixtures thereof.

6. The dosage form of claim 1, wherein said opioid analgesic is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, 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, 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.

7. The dosage form of claim 1, wherein said opioid analgesic or salt thereof consists of from about 2 mg to about 64 mg hydromorphone.

8. The dosage form of claim 1, wherein said opioid analgesic or salt thereof consists of from about 5 mg to about 800 mg morphine.

9. The dosage form of claim 1, wherein said opioid analgesic or salt thereof consists of from about 5 mg to about 400 mg oxycodone.

12. The dosage form of claim 1, wherein said hydrophobic material is selected from the group consisting of an acrylic polymer, an alkylcellulose, shellac, zein, hydrogenated vegetable oil, hydrogenated castor oil, and mixtures of any of the foregoing.

14. The dosage form of claim 1, wherein said matrices are contained in a hard gelatin capsule.

15. The dosage form of claim 1, wherein each of said matrices has a diameter of from about 0.5 mm to about 2 mm.

17. The dosage form of claim 1, further comprising a release-modifying agent.

18. The dosage form of claim 1, further comprising a non-opioid drug.

19. The dosage form of claim 18, wherein the said non-opioid drug is a non-steroidal anti-inflammatory agent.

20. The dosage form of claim 19, wherein said non-steroidal anti-inflammatory agent is selected from the group consisting of ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, and mixtures of any of the foregoing.

39. The dosage form of claim 18, wherein said non-opioid drug is selected from the group consisting of acetaminophen and aspirin.

43. The dosage form of claim 17, wherein said release modifying agent comprises a hydrophilic polymer.

44. The dosage form of claim 43, wherein said hydrophilic polymer comprises hydroxypropylmethylcellulose.

3. A method for preparing a bioavailable sustained-release opioid analgesic dosage form for once-a-day oral administration, comprising preparing a unit dose comprising a plurality of inert beads coated with an opioid analgesic or a salt thereof and a sustained-release coating comprising a hydrophobic material, such that each of said beads has a diameter from about 0.1 to about 3 mm and such that said dosage form provides an in-vitro dissolution indicative of a once-a-day oral dosage form, is bioavailable, and provides a therapeutic effect for about 24 hours or more after oral administration to a human patient.

10. The method of claim 3, further comprising incorporating said unit dose within a hard gelatin capsule.

13. The method of claim 3, further comprising incorporating a therapeutically effective amount of a non-opioid drug into said unit dose.

16. The dosage form of claim 3, wherein each of said beads is from about a 8 mesh bead to about 50 mesh bead.

25. The method of claim 13, wherein the said non-opioid drug is a non-steroidal anti-inflammatory agent.

41. The method of claim 13, wherein said non-opioid drug is selected from the group consisting of acetaminophen and aspirin.

45. The method of claim 3, wherein said opioid analgesic is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, 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, 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.

52. The method of claim 25, wherein said non-steroidal anti-inflammatory drug is selected from the group consisting of ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, and mixtures of any of the foregoing.

11. A bioavailable sustained-release dosage form for once-a-day oral administration of morphine, comprising

a unit dose of inert pharmaceutically acceptable beads having a diameter from about 0.1 mm to about 3 mm coated with an analgesically effective amount of morphine or a salt thereof, said beads further comprising a sustained-release overcoat comprising an effective amount of a hydrophobic material selected from an acrylic polymer, an alkyl cellulose, and mixtures thereof, said unit dose being bioavailable and providing a therapeutic effect for about 24 hours or more after oral administration.

21. A bioavailable sustained-release opioid analgesic dosage form for once-a-day oral administration, consisting essentially of

a unit dose of inert pharmaceutically acceptable beads coated with an analgesically effective amount of an opioid analgesic or a salt thereof, said beads further comprising a sustained-release overcoat comprising an effective amount of a hydrophobic material selected from the group consisting of an acrylic polymer, an alkylcellulose, shellac, zein, hydrogenated vegetable oil, hydrogenated castor oil, and mixtures of any of the foregoing, and said coated beads having a diameter from about 0.1 mm to about 3 mm, said dosage form being bioavailable and providing a therapeutic effect for about 24 hours or more after oral administration to a human patient.

22. The dosage form of claim 21, wherein said opioid analgesic or salt thereof consists of from about 2 mg to about 64 mg hydromorphone.

23. The dosage form of claim 21, wherein said opioid analgesic or salt thereof consists of from about 5 mg to about 800 mg morphine.

24. The dosage form of claim 21, wherein said opioid analgesic or salt thereof consists of from about 5 mg to about 400 mg oxycodone.

26. The dosage form of claim 21, wherein said unit dose of said beads are contained within a hard gelatin capsule.

27. The dosage form of claim 21, wherein each of said beads has a diameter from about 0.5 to about 2 mm.

28. The dosage form of claim 21, wherein each of said beads is from about 8 mesh to about 50 mesh.

29. The dosage form of claim 21, wherein said opioid analgesic is selected form the group consisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone, oxymorphone, dihydrocodeine, dihydromorphine, and mixtures thereof.

30. A dosage form of claim 29, further comprising a non-opioid drug.

31. The dosage form of claim 30, wherein the said non-opioid drug is a non-steroidal anti-inflammatory agent.

32. The dosage form of claim 31, wherein said non-steroidal anti-inflammatory agent is selected from the group consisting of ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, and mixtures of any of the foregoing.

40. The dosage form of claim 30, wherein said non-opioid drug is selected from the group consisting of acetaminophen and aspirin.

33. A method of treating a patient for moderate to severe pain with a bioavailable sustained-release opioid analgesic dosage form for once-a-day oral administration, comprising orally administering to a patient on a once-a-day basis a unit dose of an oral opioid analgesic consisting essentially of a plurality of inert pharmaceutically acceptable beads coated with an analgesically effective amount of an opioid analgesic or a salt thereof and overcoated with a hydrophobic material, such that each of said heads has a diameter from about 0.1 mm to about 3 mm, said unit dose being bioavailable and manufactured in a sustained-release form to provide therapeutically effective blood plasma levels of said opioid analgesic for about 24 hours or more.

34. The method of claim 33, further said unit dose is prepared by coating said inert pharmaceutically acceptable beads with said opioid analgesic, and thereafter overcoating with a hydrophobic material selected from the group consisting of an acrylic polymer, an alkyl cellulose, shellac, zein, hydrogenated vegetable oil, hydrogenated castor oil, and mixtures of any of the foregoing.

35. The method of claim 33, further comprising incorporating a therapeutically effective amount of a non-steroidal anti-inflammatory agent into said unit dose.

36. The method of claim 33, further comprising preparing said coated beads such that said unit dose provides a peak plasma level of said opioid in-vivo from about 3 to about 10 hours after administration.

37. The method of claim 33, further comprising preparing said coated beads such that said unit dose provides a peak plasma level of said opioid in-vivo from about 2 to about 4 hours after administration.

38. The method of claim 33, further comprising incorporating said unit dose within a hard gelatin capsule.

42. The method of claim 33, further comprising incorporating a therapeutically effective amount of aspirin or acetaminophen into said unit dose.

46. A bioavailable sustained-release opioid analgesic dosage form for once-a-day oral administration, comprising

inert pharmaceutically acceptable beads having a diameter from about 0.1 mm to about 3 mm coated with an analgesically effective amount of an opioid analgesic or a salt thereof, said beads further comprising a sustained-release overcoat comprising an effective amount of a hydrophobic material in an amount sufficient to provide a sustained-release of said opioid analgesic such that said dosage form provides a therepeutic effect for about 24 hours or more after oral administration to a human patient.

47. The dosage form of claim 46, wherein said opioid analgesic or salt thereof consists of from about 2 mg to about 64 mg hydromorphone.

48. The dosage form of claim 46, wherein said opioid analgesic or salt thereof consists of from about 5 mg to about 800 mg morphine.

49. The dosage form of claim 46, wherein said opioid analgesic or salt thereof consists of from about 5 mg to about 400 mg oxycodone.

50. The dosage form of claim 46, wherein said hydrophobic material is selected from the group consisting of an acrylic polymer, an alkyl cellulose, and mixtures thereof.

51. The dosage form of claim 46, wherein said opioid analgesic is morphine sulfate and said hydrophobic material is selected from the group consisting of an acrylic polymer, an alkyl cellulose, and mixtures thereof.