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1. WO2020115709 - MODIFIED RELEASE PHARMACEUTICAL COMPOSITION

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[ EN ]

CLAIMS:

What Is Claimed Is:

1. A pharmaceutical composition comprising a mixture of:

immediate release particles, each immediate release particle comprising: an active ingredient selected from methylphenidate, dexmethylphenidate, structural analogs of methylphenidate or dexmethylphenidate, pharmaceutical salts thereof, and mixtures thereof; and a taste-masking coating, wherein the taste-masking coating comprises a taste-masking polymer and a plasticizer; and modified release particles, each modified release particle comprising: the active ingredient; and a modified release coating, wherein the modified release coating comprises a mixture of polymer A and delayed release polymer B.

2. The pharmaceutical composition of claim 1 , wherein the composition is an orally disintegrating tablet.

3. The pharmaceutical composition of claim 1 , wherein the composition is a

chewable tablet.

4. The pharmaceutical composition of any one of the preceding claims, wherein the active ingredient is dexmethylphenidate HCI.

5. The pharmaceutical composition of any one of the preceding claims, wherein each of the immediate release particles further comprises an inert core and a drug layer covering the inert core, wherein the drug layer comprises a binder and the active ingredient.

6. The pharmaceutical composition of claim 5, wherein the taste-masking coating covers the drug layer.

7. The pharmaceutical composition of claim 5, wherein the inert core in each of the immediate release particles is a microcrystalline cellulose sphere.

8. The pharmaceutical composition of any one of the preceding claims, wherein each of the modified release particles further comprises an inert core and a drug layer covering the inert core, wherein the drug layer comprises a binder and the active ingredient.

9. The pharmaceutical composition of claim 8, wherein the modified release coating covers the drug layer.

10. The pharmaceutical composition of claim 8, wherein the inert core in the modified release particles is a microcrystalline cellulose sphere.

1 1. The pharmaceutical composition of any one of claims 5-10, wherein the binder is selected from the group consisting of hydrophilic polymers, low molecular weight hydroxypropyl cellulose, low molecular weight hydroxypropyl methylcellulose, low molecular weight methylcellulose, low molecular weight polyvinyl pyrrolidone, vinyl pyrrolidone and vinyl acetate copolymer, dextrose, pregelatinized starch, maltodextrin, and combinations thereof.

12. The pharmaceutical composition of claim 1 1 , wherein the binder is low molecular weight hydroxypropyl cellulose.

13. The pharmaceutical composition of any one of claims 5-12, wherein the binder is about 0% to about 12% by weight of the drug layer of the immediate release particles or the modified release particles.

14. The pharmaceutical composition of any one of the preceding claims, wherein the active ingredient is dexmethylphenidate HCI and is about 88% to about 100% by weight of the drug layer of each of the immediate release particles or each of the modified release particles.

15. The pharmaceutical composition of any one of claims 5-14, wherein the drug layers of each of the immediate release and the modified release particles each comprises about 10% hydroxy propyl cellulose and about 90%

dexmethylphenidate HCI.

16. The pharmaceutical composition of any one of the preceding claims, wherein the taste-masking polymer is cellulose acetate.

17. The pharmaceutical composition of any one of the preceding claims, wherein the plasticizer in the taste-masking coating is triethyl citrate.

18. The pharmaceutical composition of any one of the preceding claims, wherein the plasticizer is about 8% to about 12% by weight of the taste-masking coating.

19. The pharmaceutical composition of any one of the preceding claims, wherein the taste-masking polymer is about 88% to about 92% by weight of the taste- masking coating.

20. The pharmaceutical composition of any one of the preceding claims, wherein the taste-masking coating comprises about 10% triethyl citrate and about 90% cellulose acetate.

21. The pharmaceutical composition of any one of the preceding claims, wherein the modified release coating further comprises a plasticizer.

22. The pharmaceutical composition of any one of the preceding claims, wherein the polymer A comprises a polymer insoluble in gastrointestinal fluids.

23. The pharmaceutical composition of any one of the preceding claims, wherein the polymer A is selected from ethylcellulose, cellulose acetate butyrate, or cellulose acetate.

24. The pharmaceutical composition of any one of the preceding claims, wherein the delayed release polymer B is a polymer carrying free carboxylic groups ionized at pH 7.5.

25. The pharmaceutical composition of any one of the preceding claims, wherein the delayed release polymer B comprises a pH-dependent enteric polymer.

26. The pharmaceutical composition of any one of claims 1 -24, wherein the delayed release polymer B is selected from (meth)acrylic acid/alkyl (e.g. methyl)

(meth)acrylate copolymers or methacrylic acid copolymers type A, B or C, cellulose derivatives, preferably cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, carboxymethylethyl cellulose, cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetate phthalate, zein, shellac, alginate and mixtures thereof.

27. The pharmaceutical composition of any one the preceding claims, wherein the modified release coating is a combination of cellulose acetate butyrate, Eudragit L100 (methacrylic acid - methylmethacrylate copolymer (1 :1 ) or methacrylic acid copolymer Type A), and Eudragit S100 (methacrylic acid - methylmethacrylate copolymer (1 :2) or methacrylic acid copolymer Type B).

28. The pharmaceutical composition of any one of the preceding claims, wherein plasticizer in the modified release coating is castor oil.

29. The pharmaceutical composition of any one of the preceding claims, wherein the mixture of polymer A and delayed release polymer B is about 80% to about 90% by weight of the modified release coating.

30. The pharmaceutical composition of any one of the preceding claims, wherein the plasticizer is about 10% to about 20% by weight of the modified release coating.

31. The pharmaceutical composition of any one of the preceding claims, wherein the modified release coating comprises about 60% cellulose acetate butyrate, about 15% Eudragit L100, about 10% Eudragit S100, and about 15% castor oil.

32. The pharmaceutical composition of any one of claims 5-31 , wherein the inert core is about 25% to about 35% by weight of each of the immediate release particles.

33. The pharmaceutical composition of claim 32, wherein the inert core is about 32% by weight of each of the immediate release particles.

34. The pharmaceutical composition of any one of claims 8-33, wherein the inert core is about 20% to about 35% by weight of each of the modified release particles.

35. The pharmaceutical composition of claim 34, wherein the inert core is about 28% of each of the modified release particles.

36. The pharmaceutical composition of any one of claims 5-35, wherein the drug layer is about 40% to about 50% by weight of each of the immediate release particles.

37. The pharmaceutical composition of claim 36, wherein the drug layer of the

immediate release particle is about 48% by weight of each of the immediate release particles.

38. The pharmaceutical composition of any one of claims 8-37, wherein the drug layer is about 35% to about 50% by weight of each of the modified release particles.

39. The pharmaceutical composition of claim 38, wherein the drug layer of the

modified release particle is about 48% by weight of each of the modified release particles.

40. The pharmaceutical composition of any one of the preceding claims, wherein the taste-masking coating is about 15% to about 25% by weight of each of the immediate release particles.

41. The pharmaceutical composition of claim 40, wherein the taste-masking coating is about 20% by weight of each of the immediate release particles.

42. The pharmaceutical composition of any one of the preceding claims, wherein the modified release coating is about 15% to about 35% by weight of each of the modified release particles.

43. The pharmaceutical composition of claim 42, wherein the modified release

coating is about 20% by weight of each of the modified release particles.

44. The pharmaceutical composition of any one of claims 8-43, wherein a ratio of the drug layer to the inert core in the modified release particles is about 0.1 to about 9.

45. The pharmaceutical composition of claim 44, wherein the ratio of the drug layer to the inert core in each of the modified release particles is about 1.5.

46. The pharmaceutical composition of any one of the preceding claims, wherein a ratio of immediate release particles to modified release particles is about 1 :1.

47. The pharmaceutical composition of any one of the preceding claims, wherein the mixture of immediate release particles and modified release particles is about 20% to about 25% by weight of the pharmaceutical composition.

48. The pharmaceutical composition of claim 47, further comprising a sugar alcohol.

49. The pharmaceutical composition of claim 47, further comprising a disintegrant.

50. The pharmaceutical composition of claim 47, further comprising an excipient.

51. The pharmaceutical composition of claim 47, further comprising a sugar alcohol, a disintegrant, and an excipient.

52. The pharmaceutical composition of claim 48 or 51 , wherein the sugar alcohol is selected from mannitol and xylitol.

53. The pharmaceutical composition of any one of claims 48, 51 , and 52, wherein the sugar alcohol is present in an amount of about 30% to about 75% by weight of the pharmaceutical composition.

54. The pharmaceutical composition of claim 49 or 51 , wherein the disintegrant is selected from crospovidone, croscarmellose sodium, and sodium starch glycolate.

55. The pharmaceutical composition of any one of claims 49, 51 , and 54, wherein the disintegrant is present in an amount of about 2% to about 10% by weight of the pharmaceutical composition.

56. The pharmaceutical composition of any one of claims 50 or 51 , further

comprising an excipient selected from a lubricant, a gliding agent, a tacking agent, and combinations thereof.

57. The pharmaceutical composition of claim 56, wherein the excipient selected from magnesium stearate, colloidal silica, talc, and combinations thereof.

58. The pharmaceutical composition of any one of claims 47-57, further comprising a filler selected from microcrystalline cellulose, spray-processed lactose, dicalcium phosphate dehydrate, and spray-dried sucrose.

59. The pharmaceutical composition of claim 58, wherein the filler is present in an amount of about 30% to about 35% by weight of the composition.

60. The pharmaceutical composition of any one of claims 47-59, further comprising a gum selected from xanthan gum, guar gum, and a mixture of guar gum and microcrystalline cellulose.

61. The pharmaceutical composition of claim 60, wherein the gum is present in an amount of about 0.25% to about 1 % by weight of the composition.

62. The pharmaceutical composition of any one of claims 47-61 , wherein the active ingredient is dexmethylphenidate HCI and is present in an amount of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg.

63. The pharmaceutical composition of any one of claims 47-62, wherein 85% of the active ingredient in the immediate release particles is released at 1 hour when tested in a dissolution apparatus 2 according to USP 38 <71 1 > in 900 ml_ of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm.

64. The pharmaceutical composition of any one of claims 47-62, wherein release of the active ingredient from the modified release particles is triggered by a change in pH.

65. The pharmaceutical composition of any one of claims 47-61 , wherein release of the active ingredient from the modified release particles in vitro is delayed in an acidic pH and more than 80% of the active ingredient from the modified release particles is released at 4 hours when tested in a dissolution apparatus 2 according to USP 38 <71 1 > in 900ml of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37°C and a paddle speed of 75 rpm.

66. The pharmaceutical composition of any one of claims 47-61 , wherein release of the active ingredient from the modified release particles in vitro is delayed in an acidic pH and more than 80% of the active ingredient from the modified release particles is released at 6 hours when tested in a dissolution apparatus 2 according to USP 38 <71 1 > in 900ml of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37°C and a paddle speed of 75 rpm.

67. The pharmaceutical composition of any one of claims 47-61 , wherein release of the active ingredient from the modified release particles in vitro is delayed in an acidic pH and more than 80% of the active ingredient from the modified release particles is released at 16 hours when tested in a dissolution apparatus 2

according to USP 38 <71 1 > in 900ml of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37°C and a paddle speed of 75 rpm.

68. The pharmaceutical composition of any one of claims 65-67, wherein the

modified release particles release less than 20% of the active ingredient at 2 hours when tested in a dissolution apparatus 2 according to USP 38 <71 1 > in 900 ml_ of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm.

69. The pharmaceutical composition of any one of claims 65-67, wherein the

modified release particles release less than 20% of the active ingredient at 1 hour when tested in a dissolution apparatus 2 according to USP 38 <71 1 > in 900ml of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37°C and a paddle speed of 75 rpm.

70. The pharmaceutical composition of any one of claims 1 -69, wherein the

immediate release particles have a mean diameter of 250 pm to 450pm.

71. The pharmaceutical composition of any one of claims 1 -69, wherein the modified release particles have a mean diameter of 250 pm to 450pm.

72. A method for treating a patient in need thereof, the method comprising

administering to the patient a therapeutically effective amount of the

pharmaceutical composition of any one of the preceding claims.

73. The method of claim 72, wherein the therapeutically effective amount

administered to the patient treats attention deficit hyperactivity disorder.

74. The method of claims 72 or 73, wherein the pharmaceutical composition is

administered once daily.

75. The method of any one of claims 72-74, wherein the pharmaceutical composition is bioequivalent to FOCALIN® XR.