Rapidly disintegrating solid oral dosage form

• US 6,316,029 B1
• Filed: 05/18/2000
• Issued: 11/13/2001
• Est. Priority Date: 05/18/2000
• Status: Expired due to Fees

• Current Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Original Assignee: FLAK Pharma International Limited
• Inventors: Jain, Rajeev A., Cumming, Kenneth Iain, Ruddy, Stephen B., Clancy, Maurice Joseph Anthony, Codd, Janet Elizabeth
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): FUBARA, BLESSING M
• Application Number:
  US09/572,961
• Time in Patent Office: 544 Days
• Field of Search: 424/501, 424/439, 424/489, 424/494, 424/484, 424/442, 424/485, 424/488, 424/400, 424/426, 424/486, 424/428, 424/429
• US Class Current: 424/484
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• 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 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• 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 9/2081 with microcapsules or coated microparticles according to A61K9/50
• CPC Class Codes: A61K 9/5161 Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
• CPC Class Codes: A61K 9/5192 Processes
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: Y10S 977/906 Drug delivery

Abstract

Disclosed is a rapidly disintegrating solid oral dosage form of a poorly soluble active ingredient and at least one pharmaceutically acceptable water-soluble or water-dispersible excipient, wherein the poorly soluble active ingredient particles have an average diameter, prior to inclusion in the dosage form, of less than about 2000 nm. The dosage form of the invention has the advantage of combining rapid presentation and rapid dissolution of the active ingredient in the oral cavity.

Claims

1. An oral solid dose rapidly disintegrating nanoparticulate formulation comprising:

(a) a solid dose matrix comprising at least one pharmaceutically acceptable water-soluble or water-dispersible excipient, and

(b) within the solid dose matrix a nanoparticulate active agent composition comprising;

(i) a poorly soluble active agent having an effective average particle size of less than about 2000 nm prior to inclusion in the dosage form; and

(ii) at least one surface stabilizer adsorbed on the surface of the active agent;

wherein the solid dose matrix surrounding the nanoparticulate active agent and at least one surface stabilizer substantially completely disintegrates or dissolves upon contact with saliva is less than about 3 minutes.

2. The composition of claim 1, wherein the effective average particle size of the active agent particles is less than about 1500 nm.

3. The composition of claim 1, wherein the solid dose matrix substantially completely disintegrates or dissolves upon contact with saliva in a time period selected from the group consisting of less than about 2 minutes, less than about 90 seconds, less than about 60 seconds, less than about 45 seconds, less than about 30 seconds, less than about 20 seconds, less than about 15 seconds, less than about 10 seconds, and less than about 5 seconds.

4. The composition of claim 1, wherein the concentration of the active agent is from about 0.1% to about 99.9% (w/w).

5. The composition of claim 4, wherein the concentration of the active agent is from about 5% to about 70% (w/w).

6. The composition of claim 5, wherein the concentration of the active agent is from about 15% to about 40% (w/w).

7. The composition of claim 1, wherein the concentration of the pharmaceutically acceptable water-soluble or water-dispersible excipient is from about 99.9% to about 0.1% (w/w).

8. The composition of claim 7, wherein the concentration of the pharmaceutically acceptable water-soluble or water-dispersible excipient is from about 95% to about 30% (w/w).

9. The composition of claim 8, wherein the concentration of the pharmaceutically acceptable water-soluble or water-dispersible excipient is from about 85% to about 60% (w/w).

10. The composition of claim 1, wherein said at least one pharmaceutically acceptable water-soluble or water-dispersible excipient is selected from the group consisting of a sugar, a sugar alcohol, a starch, a natural gum, a natural polymer, a synthetic derivative of a natural polymer, a synthetic polymer, and mixtures thereof.

11. The composition of claim 10, wherein said at least one pharmaceutically acceptable water-soluble or water-dispersible excipient is selected from the group consisting of lactose, glucose, mannose, mannitol, sorbitol, xylitol, erythritol, lactitol, maltitol, corn starch, potato starch, maize starch, gelatin, carrageenin, acacia, xanthan gum, an alginate, dextran, maltodextran, polyethylene glycol, polyvinylpyrrolidone, polyvinylalcohol, polyoxyethylene copolymers, polyoxypropylene copolymers, polyethyleneoxide, and a mixture thereof.

12. The composition of claim 10, wherein said excipient is selected from the group consisting of a direct compression material and a non-direct compression material.

13. The composition of claim 12, wherein said excipient is selected from the group consisting of a spray-dried mannitol and spray-dried lactose.

14. The composition of claim 1, wherein the solid dose formulation is made by fluid bed granulation.

15. The composition of claim 1 further comprising at least one effervescent agent.

16. The composition of claim 1, wherein said composition has been lyophilized.

17. The composition of claim 1, wherein the poorly soluble active agent is in the form of crystalline particles, semi-crystalline particles, amorphous particles, or a mixture thereof.

18. The composition of claim 1, wherein the effective average particle size of the active agent particles is less than about 1000 nm.

19. The composition of claim 1, wherein the effective average particle size of the active agent particles is less than about 600 nm.

20. The composition of claim 1, wherein the effective average particle size of the active agent particles is less than about 400 nm.

21. The composition of claim 1, wherein the effective average particle size of the active agent particles is less than about 300 nm.

22. The composition of claim 1, wherein the effective average particle size of the active agent particles is less than about 250 nm.

23. The composition of claim 1, wherein the effective average particle size of the active agent particles is less than about 100 nm.

24. The composition of claim 1, wherein the effective average particle size of the active agent particles is less than about 50 nm.

25. A method of preparing an oral solid dose rapidly disintegrating nanoparticulate formulation comprising:

(a) combining (i) a nanoparticulate composition of a poorly soluble active agent and at least one surface stabilizer adsorbed to the surface thereof, wherein the active agent has an effective average particle size of less than about 2000 nm, and (ii) at least one pharmaceutically acceptable water-dispersible or water-soluble excipient, which forms a solid dose matrix surrounding the nanoparticulate composition; and

(b) forming a solid dose formulation, wherein the solid dose matrix surrounding the nanoparticulate active agent and surface stabilizer substantially completely disintegrates or dissolves upon contact with saliva in less than about 3 minutes.

26. The method of claim 25, wherein the effective average particle size of the active agent particles is less than about 1500 nm.

27. The method of claim 25, wherein the solid dose matrix substantially completely disintegrates or dissolves upon contact with saliva in a time period selected from the group consisting of less than about 2 minutes, less than about 90 seconds, less than about 60 seconds, less than about 45 seconds, less than about 30 seconds, less than about 20 seconds, less than about 15 seconds, less than about 10 seconds, and less than about 5 seconds.

28. The method of claim 25, wherein the nanoparticulate composition and the at least one water-dispersible or pharmaceutically acceptable water-soluble excipient are combined in step (a) using fluid bed granulation to form granules of the nanoparticulate composition and at least one water-soluble or water-dispersible excipient, which are then compressed in step (b) to form a solid dose formulation.

29. The method of claim 28, comprising adding additional pharmaceutically acceptable water-soluble or water-dispersible excipient to the granules formed by fluid bed granulation in step (a) prior to compression of the granules in step (b) to form a solid dose formulation.

30. The method of claim 25 wherein step (b) comprises compression of the composition formed in step (a).

31. The method of claim 25 wherein step (b) comprises lyophilization of the composition formed in step (a).

32. The method of claim 25 additionally comprising adding at least one effervescent agent to the composition prior to step (b).

33. The method of claim 25, wherein the effective average particle size of the active agent particles is less than about 1000 nm.

34. The method of claim 25, wherein the effective average particle size of the active agent particles is less than about 600 nm.

35. The method of claim 25, wherein the effective average particle size of the active agent particles is less than about 400 nm.

36. The method of claim 25, wherein the effective average particle size of the active agent particles is less than about 300 nm.

37. The method of claim 25, wherein the effective average particle size of the active agent particles is less than about 250 nm.

38. The method of claim 25, wherein the effective average particle size of the active agent particles is less than about 100 nm.

39. The method of claim 25, wherein the effective average particle size of the active agent particles is less than about 50 nm.

40. The method of claim 25, wherein the concentration of the active agent is from about 0.1% to about 99.9% (w/w).

41. The method of claim 40, wherein the concentration of the active agent is from about 5% to about 70% (w/w).

42. The method of claim 41, wherein the concentration of the active agent is from about 15% to about 40% (w/w).

43. The method of claim 25, wherein the concentration of the pharmaceutically acceptable water-soluble or water-dispersible excipient is from about 99.9% to about 0.1% (w/w).

44. The method of claim 43, wherein the concentration of the pharmaceutically acceptable water-soluble or water-dispersible excipient is from about 95% to about 30% (w/w).

45. The method of claim 44, wherein the concentration of the pharmaceutically acceptable water-soluble or water-dispersible excipient is from about 85% to about 60% (w/w).

46. The method of claim 25, wherein said at least one pharmaceutically acceptable water-soluble or water-dispersible excipient is selected from the group consisting of a sugar, a sugar alcohol, a starch, a natural gum, a natural polymer, a synthetic derivative of a natural polymer, a synthetic polymer, and mixtures thereof.

47. The method of claim 46, wherein said at least one pharmaceutically acceptable water-soluble or water-dispersible excipient is selected from the group consisting of lactose, glucose, mannose, mannitol, sorbitol, xylitol, erythritol, lactitol, maltitol, corn starch, potato starch, maize starch, gelatin, carrageenin, acacia, xanthan gum, an alginate, dextran, maltodextran, polyethylene glycol, polyvinylpyrrolidone, polyvinylalcohol, polyoxyethylene copolymers, polyoxypropylene copolymers, polyethyleneoxide, and a mixture thereof.

48. The method of claim 46, wherein said excipient is selected from the group consisting of a direct compression material and a non-direct compression material.

49. The method of claim 48, wherein said excipient is selected from the group consisting of a spray-dried mannitol and spray-dried lactose.

50. The method of claim 25, wherein the poorly soluble active agent is in the form of crystalline particles, semi-crystalline particles, amorphous particles, or a mixture thereof.

51. A method of treating a mammal comprising administering to the mammal an effective amount of a solid dose rapidly disintegrating nanoparticulate formulation wherein:

(a) the formulation comprises a solid dose matrix comprising at least one pharmaceutically acceptable water-soluble or water-dispersible excipient, and

(b) within the solid dose matrix a nanoparticulate active agent composition comprising;

(i) a poorly soluble active agent having an effective average particle size of less than about 2000 nm prior to inclusion in the dosage form; and

(ii) at least one surface stabilizer adsorbed on the surface of the active agent;

wherein the solid dose matrix surrounding the nanoparticulate active agent and surface stabilizer substantially completely disintegrates or dissolves upon contact with saliva in less than about 3 minutes.

52. The method of claim 51, wherein the effective average particle size of the active agent particles is less than about 1500 nm.

53. The method of claim 51, wherein the effective average particle size of the active agent particles is less than about 1000 nm.

54. The method of claim 51, wherein the effective average particle size of the active agent particles is less than about 600 nm.

55. The method of claim 51, wherein the effective average particle size of the active agent particles is less than about 400 nm.

56. The method of claim 51, wherein the effective average particle size of the active agent particles is less than about 300 nm.

57. The method of claim 51, wherein the effective average particle size of the active agent particles is less than about 250 nm.

58. The method of claim 51, wherein the effective average particle size of the active agent particles is less than about 100 nm.

59. The method of claim 51, wherein the effective average particle size of the active agent particles is less than about 50 nm.

60. The method of claim 51, wherein the concentration of the active agent is from about 0.1% to about 99.9% (w/w).

61. The method of claim 60, wherein the concentration of the active agent is from about 5% to about 70% (w/w).

62. The method of claim 61, wherein the concentration of the active agent is from about 15% to about 40% (w/w).

63. The method of claim 51, wherein the concentration of the pharmaceutically acceptable water-soluble or water-dispersible excipient is from about 99.9% to about 0.1% (w/w).

64. The method of claim 63, wherein the concentration of the pharmaceutically acceptable water-soluble or water-dispersible excipient is from about 95% to about 30% (w/w).

65. The method of claim 64, wherein the concentration of the pharmaceutically acceptable water-soluble or water-dispersible excipient is from about 85% to about 60% (w/w).

66. The method of claim 51, wherein said at least one pharmaceutically acceptable water-soluble or water-dispersible excipient is selected from the group consisting of a sugar, a sugar alcohol, a starch, a natural gum, a natural polymer, a synthetic derivative of a natural polymer, a synthetic polymer, and mixtures thereof.

67. The method of claim 66, wherein said at least one pharmaceutically acceptable water-soluble or water-dispersible excipient is selected from the group consisting of lactose, glucose, mannose, mannitol, sorbitol, xylitol, erythritol, lactitol, maltitol, corn starch, potato starch, maize starch, gelatin, carrageenin, acacia, xanthan gum, an alginate, dextran, maltodextran, polyethylene glycol, polyvinylpyrrolidone, polyvinylalcohol, polyoxyethylene copolymers, polyoxypropylene copolymers, polyethyleneoxide, and a mixture thereof.

68. The method of claim 66, wherein said excipient is selected from the group consisting of a direct compression material and a non-direct compression material.

69. The method of claim 68, wherein said excipient is selected from the group consisting of a spray-dried mannitol and spray-dried lactose.

70. The method of claim 51, wherein the poorly soluble active agent is in the form of crystalline particles, semi-crystalline particles, amorphous particles, or a mixture thereof.