Pharmaceutical compositions

• US 20080233197A1
• Filed: 06/19/2007
• Published: 09/25/2008
• Est. Priority Date: 06/19/2006
• Status: Active Grant

• Current Assignee: Alfred Liang, Boehm Garth, Francis Joseph Matthews
• Original Assignee: Alpharma Pharmaceuticals LLC (Pfizer Inc.)
• Inventors: Liang, Alfred, Garth, Boehm, Matthews, Francis Joseph
• Granted Patent: US 8,158,156 B2
• Time in Patent Office: Days
• US Class Current: 424/490
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/16 Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction A61K9/20 takes precedence if the final form is a tablet; microspheres with drug-free outer coating, microcapsules A61K9/50; mixture of different granules, microcapsules, (coated) microparticles A61K9/5084; nanoparticles A61K9/51
• CPC Class Codes: A61K 9/167 with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface with further drug-free outer coating A61K9/5073
• CPC Class Codes: A61K 9/1676 having a drug-free core with discrete complete coating layer containing drug adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/50 Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals A61K9/2081 takes precedence; particles with a single coating comprising drug A61K9/167
• CPC Class Codes: A61K 9/5015 Organic compounds, e.g. fats, sugars
• 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 9/5073 having two or more different coatings optionally including drug-containing subcoatings
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/36 Opioid-abuse
• 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: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Provided herein is a pharmaceutical composition comprising an antagonist, an agonist, a seal coat, and a sequestering polymer, wherein the antagonist, agonist, seal coat and at least one sequestering polymer are all components of a single unit, and wherein the seal coat forms a layer physically separating the antagonist from the agonist from one another. Methods for manufacturing such a pharmaceutical composition are also provided.

Claims

1. A multi-layer pharmaceutical composition comprising an agonist and an antagonist thereof, wherein the agonist and antagonist are not in contact with one another in the intact form of the composition, wherein the agonist is substantially released and the antagonist is substantially sequestered upon administration to a human being.

2. A pharmaceutical composition of claim 1 wherein the agonist and antagonist are separated from one another by a seal coat comprising a sequestering polymer.

3. A pharmaceutical composition of claim 2 wherein the seal coat comprises a sequestering polymer hydrophobicity-enhancing additive.

4. A pharmaceutical composition of claim 2 wherein the seal coat further comprises a charge-neutralizing additive.

5. A pharmaceutical composition of claim 1 wherein the agonist and antagonist are separated from one another by seal coat comprising a sequestering polymer, a sequestering polymer hydrophobicity-enhancing additive, and a charge-neutralizing additive.

7. A pharmaceutical composition of claim 3 or 5 wherein the sequestering polymer hydrophobicity-enhancing additive is talc.

8. A pharmaceutical composition of claim 4 or 5 wherein the charge-neutralizing additive is sodium lauryl sulfate.

9. A pharmaceutical composition of claim 1 wherein the composition comprises at least a first layer comprising an agonist and a second layer comprising an antagonist thereof, and wherein the first and second layers are physically separated from one another by a third layer.

10. A pharmaceutical composition of claim 9 wherein the first layer is external to the second layer.

11. A pharmaceutical composition of claim 9 or 10 wherein the third layer includes at least one sequestering polymer, and optionally includes a sequestering polymer hydrophobicity-enhancing additive, a charge-neutralizing additive, or both, and wherein the weight-by-weight ratio of sequestering polymer hydrophobicity-enhancing additive or charge-neutralizing additive to the sequestering polymer in the third layer is such that no more than 10% of the antagonist is released from the composition as determined using the USP paddle method at 37°

C., 100 rpm, with incubation in a buffer containing a surfactant.

12. A pharmaceutical composition of claim 9 or 10 wherein the third layer includes at least one sequestering polymer, and optionally includes a sequestering polymer hydrophobicity-enhancing additive, a charge-neutralizing additive, or both, wherein the weight-by-weight ratio of sequestering polymer hydrophobicity-enhancing additive or charge-neutralizing additive to the sequestering polymer in the third layer is such that no more than approximately 10% of the antagonist is released from the composition in vivo following administration to a patient.

13. A pharmaceutical composition of claim 9 or 10 wherein the third layer includes at least one sequestering polymer, and optionally includes a sequestering polymer hydrophobicity-enhancing additive, a charge-neutralizing additive, or both, wherein the weight-by-weight ratio of sequestering polymer hydrophobicity-enhancing additive or charge-neutralizing additive to the sequestering polymer in the third layer is such that no more than approximately 10% of the antagonist is released from the composition in vivo following administration to a patient as determined by measuring plasma 6-beta naltrexol levels.

14. A pharmaceutical composition of any one of claim 9 or 10 wherein the third layer includes at least one sequestering polymer, and optionally includes a sequestering polymer hydrophobicity-enhancing additive, a charge-neutralizing additive, or both, wherein the weight-by-weight ratio of sequestering polymer hydrophobicity-enhancing additive or charge-neutralizing additive to the sequestering polymer in the third layer is such that no more than approximately 10% of the antagonist is released from the composition in vivo following administration to a patient in the fed state.

15. A pharmaceutical composition of any one of claim 9 wherein the third layer comprises a sequestering polymer and a charge-neutralizing additive present at less than approximately 4% on a weight-by-weight basis with respect to the sequestering polymer.

16. A pharmaceutical composition of claim 9 wherein the third layer comprises a sequestering polymer and a sequestering polymer hydrophobicity-enhancing additive present at approximately a 1:

1 ratio on a weight-by-weight basis with respect to the sequestering polymer.

17. A pharmaceutical composition of claim 9 wherein the third layer comprises a sequestering polymer, a charge-neutralizing additive and a sequestering polymer hydrophobicity-enhancing additive wherein the charge-neutralizing additive is present at less than approximately 4% on a weight-by-weight basis with respect to the sequestering polymer and the sequestering polymer hydrophobicity-enhancing additive is present at approximately a 1:

1 ratio on a weight-by-weight basis with respect to the sequestering polymer.

18. A pharmaceutical composition of claim 9 wherein the third layer comprises the charge-neutralizing additive sodium lauryl sulfate at less than approximately 4% on a weight-by-weight basis with respect to the first sequestering polymer.

19. A pharmaceutical composition of claim 9 wherein the third layer comprises the sequestering polymer hydrophobicity-enhancing additive talc at approximately a 1:

1 ratio on a weight-by-weight basis with respect to the sequestering polymer.

20. A pharmaceutical composition of claim 9 comprising an osmotic pressure regulating agent within the first layer.

21. A pharmaceutical composition of claim 20 wherein the osmotic pressure regulating agent is sodium chloride.

22. A pharmaceutical composition of claim 1 comprising a sustained release carrier which imparts sustained release properties to the agonist.

23. A pharmaceutical composition of claim 22 wherein the sustained release carrier is Eudragit L100-55.

29. A pharmaceutical composition of any one of claims 2, 24, 25, 26 or 27 wherein a charge-neutralizing additive is in admixture with the sequestering polymer in an amount sufficient to decrease the amount of antagonist released from the composition in vivo.

30. A pharmaceutical composition of claim 29 wherein the charge-neutralizing additive is sodium lauryl sulfate.

31. The pharmaceutical composition of claim 30 wherein the amount of charge-neutralizing additive relative to the amount of sequestering polymer on a weight-by-weight basis is approximately 1%, approximately 1.5%, approximately 2%, approximately 2.5%, approximately 3%, approximately 3.5%, approximately 4%, approximately 4.5%, approximately 5%, approximately 5.5%, approximately 1-2%, approximately 2-3%, approximately 3-4% or approximately 4-5%.

32. The pharmaceutical composition of claim 30 wherein the wherein the amount of charge-neutralizing additive relative to the amount of sequestering polymer is approximately 1 to approximately 3%.

33. The pharmaceutical composition of claim 30 wherein the wherein the amount of charge-neutralizing additive relative to the amount of sequestering polymer is approximately 3.2%.

34. The pharmaceutical composition of claim 30 wherein the wherein the amount of charge-neutralizing additive relative to the amount of sequestering polymer is approximately 3.4%.

35. The pharmaceutical composition of claim 1 further comprising a sequestering polymer hydrophobicity-enhancing additive in an amount sufficient to decrease the amount of antagonist released from the composition in vivo.

36. The pharmaceutical composition of claim 35 wherein sequestering polymer hydrophobicity-enhancing additive is present at greater than approximately 66% and less than approximately 150% of the amount of sequestering polymer on a weight-by-weight basis.

37. The pharmaceutical composition of claim 35 wherein sequestering polymer hydrophobicity-enhancing additive is present at approximately the same amount as the sequestering polymer on a weight-by-weight basis.

38. The pharmaceutical composition of any one of claims 35, 36 or 37 wherein the sequestering polymer hydrophobicity-enhancing additive is talc.

39. The pharmaceutical composition of claim 2 wherein both a charge-neutralizing additive and a sequestering polymer hydrophobicity-enhancing additive are present in an amount sufficient to decrease the amount of antagonist released from the composition in vivo.

40. The pharmaceutical composition of claim 2 wherein the sequestering polymer comprises Eudragit RS.

41. The pharmaceutical composition of claim 1 wherein the agonist is in a controlled-release form.

42. The pharmaceutical composition of claim 41 wherein the agonist is in contact with a sequestering polymer.

44. The pharmaceutical composition of claim 1 wherein the antagonist is not substantially released in vivo following administered to a patient in the fed state.

45. The pharmaceutical composition of claim 1 or 44 wherein less than approximately 10% of the antagonist is released.

46. The pharmaceutical composition of claim 1 or 44 wherein less than approximately 5% of the antagonist is released.

47. The pharmaceutical composition of claim 1 or 44 wherein less than approximately 3% of the antagonist is released.

48. The pharmaceutical composition of claim 1 or 44 wherein release of the antagonist is determined by measuring plasma levels of naltrexone.

49. The pharmaceutical composition of claim 1 or 44 wherein release of the antagonist is determined by measuring plasma levels of 6-beta-naltrexol.

50. The pharmaceutical composition of claim 1 wherein the antagonist is an opioid antagonist.

51. The pharmaceutical composition of claim 50 wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmefene, cyclazacine, and levallorphan.

52. The pharmaceutical composition of claim 50 wherein the opioid antagonist is naltrexone.

53. The pharmaceutical composition of claim 1 wherein the agonist is an opioid agonist.

54. The pharmaceutical composition of claim 53 wherein the opioid agonist is selected from the group consisting of morphine, hydromorphone, hydrocodone and oxycodone.

55. The pharmaceutical composition of claim 53 wherein the opioid agonist is morphine.

6. A pharmaceutical composition of wherein the sequestering polymer is Eudragit®

RS.

24. A pharmaceutical composition comprising an antagonist in direct contact with a seal coat, an agonist in direct contact with the seal coat and a sequestering polymer but not the antagonist, wherein the antagonist and agonist are present within a single multilayer pharmaceutical unit.

25. A pharmaceutical composition comprising a pharmaceutical dosing unit consisting essentially of a multilayer bead comprising an antagonist and an agonist that are not in direct contact with one another.

26. A pharmaceutical composition comprising a plurality of pharmaceutically active units wherein each unit comprises an antagonist, an agonist, a seal coat, and a sequestering polymer wherein the antagonist and the agonist are not in direct contact with one another.

27. A pharmaceutical composition comprising a pharmaceutically inert support material, an antagonist in direct contact with the support material, a seal coat in direct contact with the antagonist and an agonist, and a sequestering polymer in direct contact with the agonist.

28. A pharmaceutical composition comprising an antagonist indirectly and fixably bound to an agonist such that physical disruption of the intact dosage form causes the antagonist and agonist to be admixed together.

43. (canceled)

56-66. -66. (canceled)

67. A multiple layer pharmaceutical composition comprising an agonist and an antagonist within distinct layers of the composition, wherein at least 90% of the antagonist is sequestered for at least 24 hours following administration to a human being.

69. The composition of claim 67 or 68 wherein the antagonist is an opioid antagonist.

70. The composition of claim 69 wherein the antagonist is selected from the group consisting of naltrexone, naloxone, nalmefene, cyclazacine, levallorphan, derivatives or complexes thereof, and pharmaceutically acceptable salts thereof.

71. The composition of claim 67 or 68 wherein the antagonist is naltrexone.

72. The composition of either of claims 67 or 68 wherein the agonist is an opioid.

73. The composition of claim 72 wherein the opioid is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydroetorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papavereturn, pentazocine, phenadoxone, phenazocine, phenomorphan, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, derivatives thereof, complexes thereof, and pharmaceutically acceptable salts thereof.

74. The composition of claim 67 or 68 wherein the agonist is morphine.

75. The composition of either of claims 67 or 68 wherein the antagonist is an opioid antagonist and the agonist is an opioid.

76. The composition of claim 75 wherein the antagonist is naltrexone and the agonist is morphine.

68. A multiple layer pharmaceutical composition comprising an agonist and an antagonist within distinct layers of the composition, wherein at least 95% of the antagonist is sequestered for at least 24 hours following administration to a human being.

77. A pharmaceutical composition comprising naltrexone within a sequestering subunit and morphine in contact with the subunit but not the naltrexone, wherein administration of the composition to a human being results in the release of substantially all of the morphine from the composition but less than 10% of the naltrexone from the composition within 24 hours of administration.

79. The pharmaceutical composition of either of claims 77 or 78 wherein naltrexone release is determined by measuring the amount of 6-beta-naltrexone in the plasma of the human being.

78. A pharmaceutical composition comprising naltrexone within a sequestering subunit and morphine in contact with the subunit but not the naltrexone, wherein administration of the composition to a human being results in the release of substantially all of the morphine from the composition but less than 5% of the naltrexone from the composition within 24 hours of administration.