DOSAGE FORM

• US 20120135075A1
• Filed: 06/07/2010
• Published: 05/31/2012
• Est. Priority Date: 06/05/2009
• Status: Active Grant

• Current Assignee: Euroceltique SA
• Original Assignee: Euroceltique SA
• Inventors: Mohammad, Hassan
• Granted Patent: US 9,814,679 B2
• Time in Patent Office: Days
• US Class Current: 424/464
• 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 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• CPC Class Codes: A61K 9/205 Polysaccharides, e.g. alginate, gums; Cyclodextrin
• 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: A61P 25/04 Centrally acting analgesics, e.g. opioids

Abstract

The present invention provides a dosage form, particularly a tamper resistant dosage form, comprising: melt-extruded particulates comprising a drug; and a matrix; wherein said melt-extruded particulates are present as a discontinuous phase in said matrix.

Claims

1. A dosage form comprising:

melt-extruded particulates comprising a drug; and

a matrix;

wherein said melt-extruded particulates are present as a discontinuous phase in said matrix.

2. A dosage form as claimed in claim 1, wherein said particulates are stretched particulates.

3. A dosage form as claimed in claim 1, which comprises 15-80% wt of said particulates, based on the total weight of the dosage form.

4. A dosage form as claimed in claim 1, which comprises 20-85% wt of said matrix, based on the total weight of the dosage form.

5. A dosage form as claimed in claim 1, wherein said matrix comprises a continuous phase comprising a gel-forming agent, particularly a curable gel-forming agent.

6. A dosage form as claimed in claim 1 in the form of a tablet.

7. A dosage form as claimed in claim 1, wherein said dosage form is tamper resistant.

8. A dosage form as claimed in claim 1, wherein the amount of drug released from the dosage form at 0.5 hour when measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) with 40% ethanol at 37°

C., is within ±

20% of the amount of drug released from the dosage form at 0.5 hour when measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) with 0% ethanol at 37°

C.

9. A dosage form as claimed in claim 1, wherein said particulates have a breaking strength of at least 350 Newtons.

10. A dosage form as claimed in claim 1, wherein said particulates are microparticulates.

11. A dosage form as claimed in claim 1, wherein said melt-extruded particulates have a diameter of less than about 1000 μ

m.

12. A dosage form as claimed in claim 1, wherein said melt-extruded particulates have a length of less than about 1000 μ

m.

13. A dosage form as claimed in claim 1, wherein said drug is a drug susceptible to abuse.

14. A dosage form as claimed in claim 1, wherein said drug is an opioid agonist, a tranquilizer, a CNS depressant, a CNS stimulant or a sedative hypnotic.

15. A dosage form as claimed in claim 1, wherein said drug is an opioid agonist.

16. A dosage form as claimed in claim 15, wherein said opioid agonist is selected from the group consisting of oxycodone, oxymorphone, hydrocodone, hydromorphone, morphine, codeine, buprenorphine, fentanyl, tramadol, tapentadol and pharmaceutically acceptable salts thereof.

17. A dosage form as claimed in claim 1, wherein said particulates comprise 3 to 50% wt of drug, based on the total weight of a particulate.

18. A dosage form as claimed in claim 1, further comprising one or more additional active ingredients.

19. A dosage form as claimed in claim 1, wherein said particulates further comprise a polymer conferring crush resistance.

20. A dosage form as claimed in claim 1, wherein said particulates further comprise a polymer selected from an acrylic polymer, a methacrylic polymer or mixtures thereof.

21. A dosage form as claimed in claim 20, wherein said acrylic and methacrylic polymers are selected from the group consisting of methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.

22. A dosage form as claimed in claim 20, wherein said acrylic and methacrylic polymers are selected from the group consisting of acrylic acid alkyl esters and methacrylic acid alkyl esters.

23. A dosage form as claimed in claim 19, wherein said particulates comprise 10 to 50% wt of polymer conferring crush resistance, based on the total weight of a particulate.

24. A dosage form as claimed in claim 1, wherein said particulates further comprise a rate controlling or modifying agent.

25. A dosage form as claimed in claim 24, wherein said rate controlling or modifying agent is an alkyl cellulose.

26. A dosage form as claimed in claim 24, wherein said particulates comprise 20 to 50% wt of rate controlling or modifying agent, based on the total weight of the particulate.

27. A dosage form as claimed in claim 1, wherein said particulates further comprise a lubricant.

28. A dosage form as claimed in claim 1, wherein said particulates further comprise a plasticiser.

29. A dosage form as claimed in claim 1, wherein said particulates comprise oxycodone or hydromorphone, an ethyl acrylate and methyl methacrylate copolymer, ethyl cellulose as rate controlling or modifying agent, stearyl alcohol and/or triethyl citrate as plasticiser, glyceryl dibehenate as lubricant and optionally an opioid antagonist.

30. A dosage form as claimed in claim 1, wherein said particulates comprise an opioid agonist and further comprise an opioid antagonist.

31. A dosage form as claimed in claim 1, wherein said matrix comprises a silicone and/or a gel-forming agent.

32. A dosage form as claimed in claim 31, wherein said matrix comprises said gel-forming agent that is selected from polyethylene oxide, polyvinyl alcohol, hydroxypropyl methyl cellulose, carbomers, poly(uronic) acids or mixtures thereof.

33. A dosage form as claimed in claim 31, wherein said silicone or gel-forming agent is curable.

34. A dosage form as claimed in claim 33, wherein said dosage form can be flattened without breaking to a thickness of less than about 60% of the thickness of the dosage form before flattening.

35. A process for preparing a dosage form as claimed in claim 1, comprising:

mixing melt-extruded particulates comprising a drug with a matrix material so that said particulates form a discontinuous phase in said matrix and forming said mixture into a dosage form.

36. A process for preparing a dosage form as claimed in claim 1, comprising:

mixing melt-extruded particulates with a matrix material so that said particulates form a discontinuous phase in said matrix and forming said mixture into a dosage form, wherein said melt-extruded particulates are optionally prepared by stretching and cutting a melt extrudate comprising a drug.

37. A process for preparing a dosage form as claimed in claim 1 comprising:

i) melt extruding a composition comprising said drug to form a melt extrudate;

ii) optionally stretching said melt extrudate to form an optionally stretched extrudate;

iii) cutting said optionally stretched extrudate to form particulates;

iv) mixing said particulates with a matrix material so that said particulates form a discontinuous phase in said matrix; and

forming said mixture into a dosage form.

38. A process as claimed in claim 35, wherein said particulates are melt extruded at a temperature of 100°

C. or less.

39. A process as claimed in claim 35, further comprising curing said matrix.

47. A method of treating or managing pain, comprising treating or managing the pain with the dosage form of claim 1.

49. A method of treating a subject in need of pain relief comprising administering to said subject in need of pain relief the dosage form as claimed in claim 1.

40. A melt extrudate comprising a drug, wherein said extrudate has a diameter of less than about 1 mm.

41. An extrudate as claimed in claim 40, wherein said extrudate is a stretched extrudate.

42. Particulates comprising a drug, wherein said particulates have a diameter and/or length of less than about 1 mm.

43. Particulates as claimed in claim 42, wherein said particulates are melt-extruded particulates.

44. Particulates as claimed in claim 43, wherein said particulates are stretched particulates.

46. A method of treating or managing pain, comprising treating or managing the'"'"'pain with the particulates of claim 42.

45. Particulates comprising a drug, wherein said particulates are obtainable by i) melt extruding a composition comprising said drug to form a melt extrudate;

ii) optionally stretching said melt extrudate to form an optionally stretched extrudate; and

iii) cutting said optionally stretched extrudate to form particulates.

48. (canceled)