Multiparticulates

• US 20080260815A1
• Filed: 08/31/2005
• Published: 10/23/2008
• Est. Priority Date: 08/31/2004
• Status: Active Grant

• Current Assignee: Euroceltique SA
• Original Assignee: Euroceltique SA
• Inventors: Tamber, Harjit, Hayes, Geoffrey Gerard, Walden, Malcolm, Martinelli, Vincenzo, Mohammad, Hassan, Whitelock, Steve
• Granted Patent: US 9,259,872 B2
• Time in Patent Office: Days
• US Class Current: 424/455
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/146 with organic macromolecular 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: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/02 without antiinflammatory effect
• CPC Class Codes: B29C 48/04 Particle-shaped making granules B29B9/00
• CPC Class Codes: B29C 48/63 having sections without mixing elements or threads, i.e. having cylinder shaped sections

Abstract

Extrusion of a mix containing a pharmaceutically active agent can be achieved using a plasticising excipient in an amount sufficient to act as plasticiser and also act as lubricant, thereby avoiding the need for inclusion of a lubricant. The invention provides multiparticulates with controlled release properties, substantially free of lubricant. The present invention is preferably directed to extruded multiparticulates containing an opioid such as oxycodone, an ammonium methacrylate copolymer such as Eudragit® RSPO, a plasticising excipient such as preferably stearyl alcohol and a water permeability modifier such as preferably Eudragit® RLPO. The obtained multiparticulates show a release rate profile which is pH-independent.

Claims

1. A method of preparing an extruded pharmaceutical composition which comprises selecting a plasticising excipient that provides plasticising and lubricating properties, and extruding a mix including a pharmaceutically active agent and the plasticising excipient, said plasticising excipient being employed in an amount effective to act as a plasticiser for the mix and to act as a lubricant for the mix.

2. A method according to claim 1, wherein the mix is substantially free of further excipient acting to lubricate the mix.

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18. A process for preparing multiparticulates containing a pharmaceutically active agent, which comprises extrusion of an extrudable blend of active agent, ammonium methacrylate copolymer, plasticiser which also acts as lubricant, and water permeability modifier.

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21. A pharmaceutical composition comprising multiparticulates, wherein said multiparticulates comprise a pharmaceutically active agent and a plasticising excipient with lubricating properties, and are substantially free of further lubricant.

22. Multiparticulates according to claim 21, comprising a pharmaceutically active agent, ammonium methacrylate copolymer, plasticising excipient with lubricating properties, and water permeability modifier.

24. Multiparticulates according to claim 21 wherein the pharmaceutically active agent is an opioid.

25. Multiparticulates according to claim 24 wherein the pharmaceutically active agent is oxycodone free base or a pharmaceutically acceptable salt thereof.

26. Multiparticulates according to claim 22, wherein the ammonium methacrylate copolymer is Eudragit RS PO.

27. Multiparticulates according to claim 21, wherein the plasticising excipient is chosen from water insoluble solids such as cetyl alcohol, stearyl alcohol and cetostearyl alcohol;

water soluble solids such as sorbitol and sucrose and high molecular weight polyethylene glycol;

water insoluble liquids such as dibutyl sebacate and tributyl citrate and water soluble liquids such as triethyl citrate, propylene glycol and low molecular weight polyethylene glycol.

28. Multiparticulates according to claim 22, wherein the water permeability modifier is chosen from an insoluble hydrophilic wicking agent such as microcrystalline cellulose, a gelling agent which hydrates to form a gel to control the water movement, a high molecular weight polyethylene glycol such as PEG 6000, or a water permeable ammonium methacrylate copolymer, also referred to as an ammonio methacrylate copolymer, such as Eudragit RL PO or Eudragit RL 100.

29. Multiparticulates according to claim 22, which contains on a w/w basis 3 to 50% pharmaceutically active agent, 25 to 85% insoluble ammonium methacrylate copolymer, 1 to 30% non-dominating plasticiser, and 1 to 30% water permeability modifier.

30. A unit dose form comprising multiparticulates according to claim 21.

31. A unit dose form according to claim 30, which contains 5 to 400 mg of oxycodone hydrochloride.

32. A unit dose form according to claim 30, suited for administration once daily.

33. A unit dose form according to claim 30, suited for administration twice daily.

34. A unit dose form according to claim 30 comprising a capsule with a fill of the multiparticulates.

35. A unit dose form according to claim 30, wherein the pharmaceutically active agent is oxycodone, and wherein the unit dose form further comprises an oxycodone antagonist.

36. The use of an analgesic pharmaceutically active agent in the preparation of a unit dose form for a method of providing analgesia to a patient, which method comprises administering an effective amount of a controlled release formulation comprising multiparticulates according to claim 30 wherein the pharmaceutically active agent is an analgesic.

37. A method of providing analgesia to a patient which comprises administering an effective amount of a controlled release formulation comprising multiparticulates according to claim 30 wherein the pharmaceutically active agent is an analgesic.

38. A unit dose form according to claim 31, suited for administration once daily.

39. A unit dose form according to claim 31, suited for administration twice daily.

40. A unit dose form according to claim 31 comprising a capsule with a fill of the multiparticulates.

41. A unit dose form according to claim 31, wherein the pharmaceutically active agent is oxycodone and the unit dose form further comprises an oxycodone antagonist.

42. The use of an analgesic pharmaceutically active agent in the preparation of a unit dose form for a method of providing analgesia to a patient, which method comprises administering an effective amount of a controlled release formulation comprising multiparticulates according to claim 31 wherein the pharmaceutically active agent is an analgesic.

43. A method of providing analgesia to a patient which comprises administering an effective amount of a controlled release formulation comprising multiparticulates according to claim 31 wherein the pharmaceutically active agent is an analgesic.

23. A pharmaceutical composition comprising multiparticulates, wherein said multiparticulates consist essentially of a pharmaceutically active agent, ammonium methacrylate copolymer, plasticising excipient with lubricating properties, and water permeability modifier.