Matrix for sustained, invariant and independent release of active compounds

• US 20050245483A1
• Filed: 04/04/2003
• Published: 11/03/2005
• Est. Priority Date: 04/05/2002
• Status: Abandoned Application

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Purdue Pharma L.P.
• Inventors: Spitzley, Christof, Muhlau, Silke, Brogmann, Bianca
• Application Number:
  US10/510,673
• Publication Number:
  US 20050245483A1
• Time in Patent Office: Days
• US Class Current: 514/57
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/2095 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 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/70 Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug hollow drug-filled fibres A61K9/0092
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/10 Laxatives
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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

The invention concerns a storage stable pharmaceutical formulation comprising preferably two active compounds in a non-swellable diffusion matrix, whereby the compounds are released from the matrix in a sustained, invariant and, if several compounds are present, independent manner and the matrix is determined with respect to its substantial release characteristics by ethylcellulose and at least one fatty alcohol. The invention also concerns methods for producing such pharmaceutical formulations.

Claims

1. Storage stable pharmaceutical formulation comprising at least two pharmaceutically active compounds in a diffusion matrix, characterized in that the matrix is determined with respect to its essential release characteristics by ethylcellulose or an ethylcellulose-based polymer and at least one fatty alcohol and that the active compounds are released from the substantially non-swellable diffusion matrix in a sustained, invariant and independent manner.

2. Pharmaceutical formulation to claim 1, characterized in that the fatty alcohol comprises lauryl, myristyl, stearyl, cetylstearyl, ceryl and/or cetylalcohol.

3. Pharmaceutical formulation to claim 2, characterized in that the formulation comprises ethylcellulose.

4. Pharmaceutical formulation according to claim 3, characterized in that the formulation does not comprise relevant amounts of alkaline and/or water-swellable substances.

5. Pharmaceutical formulation according to claim 4, characterized in that the formulation comprises fillers, lubricants, flowing agents and/or plasticizers.

6. Pharmaceutical formulation according to claim 5, characterized in that the fillers are selected from the group comprising sugars, starches and hydrolysates thereof, sugar alcohols, poorly soluble calcium salts and/or povidone.

7. Pharmaceutical formulation according to claim 5, characterized in that it comprises magnesium stearate, calcium stearate and/or calcium laureate and/or fatty acids.

8. Pharmaceutical formulation according to claim 5, characterized in that it comprises a flowing agent selected from the group consisting of highly dispersed silica, talcum, corn starch, magnesium oxide, magnesium and calciumstearate.

9. Pharmaceutical formulation according to claim 5, characterized in that it comprises dibutyl sebacate as a plasticizer.

10. Pharmaceutical preparation according to claim 5, characterized in that the formulation can be stored over a period of at least two years under standard conditions (60% relative humidity, 25°

C.) in accordance with admission guidelines.

11. Pharmaceutical preparation according to claim 5, characterized in that it comprises as the pharmaceutically active compounds at least one opioid analgesic selected from the group comprising morphine, oxycodone, hydromorphone, propoxyphene, nicomorphine, dihydrocodeine, diamorphine, papaveretum, codeine, ethylmorphine, phenylpiperidine and derivatives thereof, methadone, dextropropoxyphene, buprenorphine, pentazocin, tilidine, tramadol and hydrocodone and at least one opioid antagonist, selected from the group comprising naltrexone, naloxone, nalmefene, nalorphine, nalbuphin, naloxonazinene, methylnaltrexone, ketylcyclazocine, norbinaltorphimine, naltrindol, 6-β

-naloxol and 6-β

-naltrexol.

12. Pharmaceutical formulation according to claim 11, characterized in that the opioid analgesic and the antagonist are present in the form of their pharmaceutically acceptable and equally active derivatives, free base, salts and the like.

13. Pharmaceutical formulation according to claim 12, characterized in that the formulation comprises oxycodone and naloxone, and wherein oxycodone is present in an amount raging from about 10 mg to about 150 mg, and naloxone is present in an amount ranging from about 1 mg to about 50 mg per unit dosage.

14. Pharmaceutical formulation according to claim 13, characterized in that it comprises oxycodone and naloxone in a weight ratio ranging from about 25:

1, to about 1;

1.

15. Pharmaceutical formulation according to claim 12, characterized in that it contains oxycodone and naloxone with oxycodone being present in an amount ranging from about 10 Mg to about 150 mg, and naloxone is present in an amount ranging from about 1 mg to about 50 mg.

16. Pharmaceutical formulation according to claim 13, characterized in that the formulation is in the form of a tablet, preferably a multi-layered tablet, a capsule, a dragè

e, a granulate and/or a powder.

17. Pharmaceutical formulation according to claim 16, characterized in that the pharmaceutical preparation is suitable for oral, nasal and/or rectal application.

18. Pharmaceutical formulation according to claim 16, characterized in that the formulation is produced by build-up and/or break-down granulation.

19. Pharmaceutical formulation according to claim 17, characterized in that the formulation is produced by extrusion.

33. Method of producing a pharmaceutical dosage form for the treatment of opioid-induced side effects, characterized in that the pharmaceutical dosage form comprises a pharmaceutical formulation according to claim 5.

34. Method according to claim 33, characterized in that the preparation is used for treatment of opioid-induced obstipation.

35. Method of producing a pharmaceutical dosage form for the treatment of idiopathic syndromes, characterized in that the pharmaceutical dosage form comprises a pharmaceutical formulation according to claim 5.

36. Method according to claim 35, characterized in that the preparation is used for treatment of irritable bowel syndrome, treatment of idiopathic pruritus or pruritus due to cholestasia and/or renal dysfunction.

37. Method according to 33, characterized in that the matrix is a substantially non-swellable diffusion matrix whose release characteristics are determined by amounts of ethylcellulose or an ethylcellulose-based polymer and of at least one fatty alcohol.

38. Method according to 37, characterized in that the preparation comprises from about 1 mg to about 50 mg naloxone.

39. Method according to claim 38, characterized in that naloxone is present in the form selected from the pharmaceutically acceptable and equally active derivatives the free base, salts and the like.

40. Method according to claim 39, characterized in that the matrix is produced by extrusion.

41. A pharmaceutical formulation according to claim 4, characterized in that the formulation does not comprise relevant amounts of derivatives of acrylic acid and/or hydroxyalkylcelluloses.

42. A pharmaceutical formulation according to claim 6, characterized in that the fillers are selected from the group comprising lactose, glucose, saccharose, micro-crystalline cellulose, cellactose, sorbitol, mannitol, calcium hydrogenphosphate, dicalciumphosphate, tricalciumphosphate and povidone.

43. A pharmaceutical formulation according to claim 7, characterized in that it comprises stearic acid.

44. A pharmaceutical formulation according to claim 12, characterized in that the opioid analgesic and the antagonist are present in the form of the hydrochloride, sulfate, bisulfate, tartrate, nitrate, citrate, bitartrate, phosphate, malate, maleate, hydrobromide, hydroiodide, fumarate or succinate.

45. A pharmaceutical formulation according to claim 13, characterized in that the formulation comprises oxycodone and naloxone, and wherein oxycodone is present in an amount raging from about 10 mg to about 80 mg and naloxone is present in an amount ranging from about 1 mg to about 50 mg per unit dosage.

46. A pharmaceutical formulation according to claim 14, characterized in that it comprises oxycodone and naloxone in a weight ratio ranging from about 5:

1 to about 1;

1.

52. The method according to claim 34, characterized in that the preparation is used for treatment of opioid-induced pruritus.

53. The method according to 38, characterized in that the preparation comprises from about 5 mg to about 20 mg naloxone.

54. The method according to claim 39, characterized in that naloxone is present in the form of the hydrochloride, sulfate, bisulfate, tartrate, nitrate, citrate, bitartrate, phosphate, malate, maleate, hydrobromide, hydroiodide, fumarate or succinate.

20. Storage stable pharmaceutical formulation comprising at least two active compounds in a sustained release matrix, characterized in that the matrix is a substantially non-swellable diffusion matrix whose release characteristics are determined by amounts of ethylcellulose or an ethylcellulose-based polymer and at least one fatty alcohol as matrix components, and by extrusion or granulation of the matrix materials together with the amount of the active compounds for formulation of an active compound-containing matrix.

21. Storage stable pharmaceutical formulation according to claim 20, wherein the diffusion matrix is a substantially non-erosive matrix.

22. Storage stable pharmaceutical formulation according to claim 20, wherein the matrix material contains ethylcellulose.

23. Storage stable pharmaceutical formulation according to claim 20, wherein the matrix is formed by extrusion.

47. A storage stable pharmaceutical formulation according to claim 23, wherein the matrix is formed by melt extrusion.

24. Storage stable pharmaceutical formulation having an effective amount of an opioid agonist and an opioid antagonist in a substantially non-swellable and non-erosive diffusion matrix, whose release characteristics are determined by amounts of ethylcellulose or an ethylcellulose-based polymer and at least one fatty alcohol.

25. Storage stable pharmaceutical formulation according to claim 24 having an effective amount of oxycodone and naloxone, with oxycodone being present in an amount ranging from about 10 mg to about 150 mg, and naloxone is present in an amount ranging from about 1 mg to about 50 mg per unit dosage.

26. Storage stable pharmaceutical formulation according to claim 24 having an effective amount of oxycodone and naloxone, wherein oxycodone and naloxone are present in a weight ratio ranging from about 25:

1, to about 1;

1.

27. Method for producing a formulation according to claim 26, characterized in that production is effected by granulation, preferably build-up and/or break-down granulation.

28. Method for producing a formulation according to claim 26, being an extrusion method, wherein counter-rotating or co-rotating single or multiple screw extruders with/without kneading elements are used.

29. Method according to claim 28, being an extrusion method wherein counter-rotating twin-screw extruders are used.

30. Method according to claim 28, characterized in that the temperature of the heating zones of the extruders is from about 20°

to about 120°

C.

31. Method according to claim 28, characterized in that the diameter of the nozzle on the extruder is between about 1 mm to about 10 mm.

32. Method according to claim 28, characterized in that the resulting temperature in the extruder does not influence the stability of the active compounds.

48. A storage stable pharmaceutical formulation according to claim 25 having an effective amount of oxycodone and naloxone, with oxycodone being present in an amount ranging from about 10 mg to about 80 mg and naloxone being present in an amount ranging from about 1 mg to about 50 mg per unit dosage.

49. A storage stable pharmaceutical formulation according to claim 26 having an effective amount of oxycodone and naloxone, wherein oxycodone and naloxone are present in a weight ratio ranging from about 5:

1 to about 1;

1.

50. The method according to claim 30, characterized in that the temperature of the heating zones of the extruders is from about 50°

to about 70°

C.

51. The method according to claim 31, characterized in that the diameter of the nozzle on the extruder is between about 3 mm to about 5 mm.