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Claims for Patent: 6,103,219

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Claims for Patent: 6,103,219

Title: Pharmaceutical excipient having improved compressibility
Abstract:A microcrystalline cellulose-based excipient having improved compressibility, whether utilized in direct compression, dry granulation or wet granulation formulations, is disclosed. The excipient is an agglomerate of microcrystalline cellulose particles and from about 0.1% to about 20% silicon dioxide particles, by weight of the microcrystalline cellulose, wherein the microcrystalline cellulose and silicon dioxide are in intimate association with each other. The silicon dioxide utilized in the novel excipient has a particle size from about 1 nanometer to about 100 microns. Most preferably, the silicon dioxide is a grade of colloidal silicon dioxide.
Inventor(s): Sherwood; Bob E. (Amenia, NY), Staniforth; John H. (Bath, GB), Hunter; Edward A. (Glenham, NY)
Assignee: Edward Mendell Co., Inc. (Patterson, NY)
Application Number:08/992,073
Patent Claims: 1. An aqueous slurry useful in the preparation of a compressible pharmaceutical excipient, comprising a mixture of microcrystalline cellulose in the form of a wet cake and from about 0.1 % to about 20% by weight silicon dioxide based on the weight of said microcrystalline cellulose, said silicon dioxide having an average primary particle size from about 1 nm to about 100 .mu.m, the solids content of said aqueous slurry being from about 0.5% to about 25% by weight, said silicon dioxide being present in an amount from about 0.5% to about 10%, by weight, based on the weight of said microcrystalline cellulose.

2. The slurry of claim 1, wherein said silicon dioxide is present in an amount from about 1.25% to about 5%, by weight, based on the weight of said microcrystalline cellulose.

3. The slurry of claim 1, which has a solid content from about 15% to about 20%.

4. The slurry of claim 3, which has a solid content from about 17% to about 19%.

5. The Slurry of claim 1, which has been pH-adjusted with a member of the group consisting of ammonium hydroxide, sodium hydroxide and mixtures thereof.

6. The slurry of claim 1, further comprising a member of the group consisting of non-silicon metal oxides, starches, starch derivatives, surfactants, polyalkylene oxides, celluloses, cellulose ethers, cellulose esters and mixtures thereof.

7. A method of enhancing the compressibility of microcrystalline cellulose in wet granulation products, comprising:

(i) forming an aqueous slurry containing a mixture of microcrystalline cellulose in the form of a wet cake and silicon dioxide having an average primary particle size from about 1 nm to about 100 .mu.m, the amount of silicon dioxide being from about 0.1% to about 20% relative to the amount of microcrystalline cellulose, by weight, wherein said slurry comprises from about 0.5% to about 25% by weight microcrystalline cellulose; and

(ii) drying said slurry to obtain an excipient comprising a plurality of agglomerated particles of microcrystalline cellulose in intimate association with said silicon dioxide.

8. The method of claim 7, wherein said slurry contains from about 15% to about 20% microcrystalline cellulose.

9. The method of claim 7, wherein said slurry contains from about 17% to

about 19% microcrystalline cellulose.

10. The method of claim 7, wherein said silicon dioxide is colloidal silicon dioxide.

11. The method of claim 7, further comprising drying said slurry of microcrystalline cellulose and silicon dioxide by a method selected from the group consisting of flash drying, ring drying, spray drying, and micron drying.

12. The method of claim 7, further comprising drying said slurry of microcrystalline cellulose and silicon dioxide by spray drying.

13. The method of claim 7, further comprising drying said slurry such that the resultant excipient particles have an average particle size from about 10 .mu.m to about 1,000 .mu.m.

14. The method of claim 7, further comprising drying said slurry such that the resultant excipient particles have a particle size of from about 10 .mu.m to about 500 .mu.m.

15. The method of claim 12, further comprising drying said slurry such that the resultant excipient particles have a particle size of from about 30 .mu.m to about 250 .mu.m.

16. The method of claim 7, further comprising drying said slurry such that the resultant excipient particles have a moisture content of from about 0.5 to about 15%.

17. The method of claim 7, wherein said slurry further comprises a member of the group consisting of non-silicon metal oxides, starches, starch derivatives, surfactants, polyalkylene oxides, cellulose, celluloses, celluloses ethers, and mixtures thereof.

18. The microcrystalline cellulose-based excipient particles prepared by the process of claim 7.

19. The microcrystalline cellulose-based excipient particles prepared by the process of claim 15.

20. A method of preparing a solid dosage form, comprising:

(a) forming an aqueous slurry containing a mixture of microcrystalline cellulose in the form of a wet cake and silicon dioxide having a particle size from about 1 nm to about 100 .mu.m, the amount of silicon dioxide being from about 0.1% to about 20% relative to the amount of microcrystalline cellulose, by weight;

(b) drying said slurry to obtain an excipient comprising a plurality of agglomerated particles of microcrystalline cellulose in intimate association with said silicon dioxide;

(c) mixing an active ingredient with said excipient in a ratio from about 1:99 to about 99:1;

(d) incorporating said mixture obtained in step (c) into a plurality of solid unit doses.

21. The method of claim 20, wherein said silicon dioxide is colloidal silicon dioxide, further comprising wet granulating said mixture obtained in step (c) prior to incorporating said mixture into said solid unit doses.

22. The method of claim 22, wherein said aqueous slurry prepared in step (a) comprises from about 0.5% to about 25% by weight microcrystalline cellulose.

23. The method of claim 20, wherein said drying of step (b) is accomplished by spray drying such that the resultant excipient particles have an average particle size from about 10 .mu.m to about 1,000 .mu.m.

24. The method of claim 20, wherein said drying of step (b) is accomplished by spray drying such that the resultant excipient particles have an average particle size from about 30 .mu.m to about 250 .mu.m.

25. The method of claim 20, wherein the resultant excipient particles have a bulk density from about 0.2 g/ml to about 0.6 g/ml.

26. The method of claim 21, wherein the resultant excipient particles have a bulk density of from about 0.35 g/ml to about 0.55 g/ml.

27. The method of claim 21, further comprising wet granulating the mixture of step (c), adding a further amount of excipient obtained in step (b) to said granulation, and thereafter incorporating the mixture into a solid dosage form.

28. The method of claim 21, further comprising wet granulating the mixture of step (b) prior to mixing said excipient with said active ingredient in step (c).

29. The method of claim 28, further comprising adding a further amount of excipient obtained in step (b) to the mixture of said granulation and said active ingredient, and thereafter compressing the mixture into a solid dosage form.

30. The method of claim 21, further comprising wet granulating the mixture of step (c), adding a further amount of a pharmaceutically acceptable excipient to said granulation, and thereafter compressing the mixture into a solid dosage form.

31. The method of claim 28, further comprising adding a further amount of pharmaceutically acceptable excipient to the mixture of said granulation and said active ingredient, and thereafter compressing the mixture into a solid dosage form.

32. A solid dosage form of a compressed mixture of from about 1% to about 99% of an excipient comprising a particulate agglomerate of coprocessed microcrystalline cellulose and from about 0.1% to about 20% by weight silicon dioxide, the microcrystalline cellulose and silicon dioxide being in intimate association with each other, said silicon dioxide portion of said agglomerate being derived from a silicon dioxide having an average primary particle size from about 1 nm to about 100 .mu.m, and from about 99% to about 1% of a systemically active therapeutic agent.

33. The solid dosage form of claim 32, wherein the active agent is an antihistamine.

34. The solid dosage form of claim 33, wherein the antihistamine is selected from the group consisting of dimenhydrinate, dimenhydramine, chlorpheniramine, and dexchlorpheniramine.

35. The solid dosage form of claim 32, wherein the active agent is an analgesic.

36. The solid dosage form of claim 32, wherein the analgesic is selected from the group consisting of aspirin, codene, morphene, dihydromorphone, and oxycodone.

37. The solid dosage form of claim 32, wherein the active agent is a non-steroidal anti-inflammatory agent.

38. The solid dosage form of claim 37, wherein the non-steroidal anti-inflammatory agent is selected form the group consisting of naproxyn, diclofenac, indomethacin, ibuprofen, and sulindac.

39. The solid dosage form of claim 32, wherein the active agent is an anti-emetic.

40. The solid dosage form of claim 39, wherein the anti-emetic is metoclopramide.

41. The solid dosage form of claim 32, wherein the active agent is an anti-epileptic.

42. The solid dosage form of claim 41, wherein the anti-epileptic is selected from the group consisting of phenytoin, meprobamate and nitrezepam.

43. The solid dosage form of claim 32, wherein the active agent is a vasodilator.

44. The solid dosage form of claim 43, wherein the vasodilator is selected from the group consisting of nifedipine, papaverine, diltiazem and nicardirine.

45. The solid dosage form of claim 32, wherein the active agent is an anti-tussive agent.

46. The solid dosage form of claim 32, wherein the active agent is an expectorant.

47. The solid dosage form of claim 32, wherein the active agent is an anti-asthmatic.

48. The solid dosage form of claim 32, wherein the active agent is an antacid.

49. The solid dosage form of claim 32, wherein the active agent is an anti-spasmodic.

50. The solid dosage form of claim 32, wherein the active agent is an antidiabetic.

51. The solid dosage form of claim 32, wherein the active agent is a diuretic.

52. The solid dosage form of claim 32, wherein the active agent is an antihypotensive.

53. The solid dosage form of claim 32, wherein the active agent is an antihypertensive.

54. The solid dosage form of claim 32, wherein the active agent is a bronchodilator.

55. The solid dosage form of claim 32, wherein the active agent is a steroid.

56. The solid dosage form of claim 55, wherein the steroid is selected from the group consisting of hydrocortisone, triamcinolone, and prednisone.

57. The solid dosage form of claim 32, wherein the active agent is an antibiotic.

58. The solid dosage form of claim 32, wherein the active agent is selected from the group consisting of antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, vitamins, and stimulants.

59. The solid dosage form of claim 32, prepared by a process comprising the steps of

(a) forming an aqueous slurry containing a mixture of microcrystalline cellulose in the form of a wet cake and silicon dioxide having a particle size from about 1 nm to about 100 .mu.m, the amount of silicon dioxide being from about 0.1% to about 20% relative to the amount of microcrystalline cellulose, by weight;

(b) drying said slurry to obtain an excipient comprising a plurality of agglomerated particles of microcrystalline cellulose in intimate association with said silicon dioxide;

(c) mixing the active agent with said excipient in a ratio from about 1:99 to about 99:1;

(d) incorporating said mixture obtained in step (c) into a plurality of solid dosage forms.

60. The solid dosage form of claim 32, wherein the solid dosage form provides a sustained-release of the systemically active therapeutic agent.

61. The solid dosage form of claim 32, the solid dosage form provides a sustained-release of the systemically active therapeutic agent over a period of at least 12 hours.

62. The solid dosage form of claim 32, wherein the solid dosage form provides an immediate release of the systemically active therapeutic agent.

63. The solid dosage form of claim 32, further comprising a coating of a hydrophobic polymer.

64. The solid dosage form of claim 63, wherein the solid dosage form includes a sufficient amount of the hydrophobic polymer coating to provide a sustained release of the active agent over a predetermined period.

65. The solid dosage form of claim 63, wherein the coating further includes an enteric coating material.

66. The solid dosage form of claim 32, further comprising a coating of an enteric coating material.

67. The solid dosage form of claim 66, wherein the enteric coating material is selected from a group consisting of cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinylacetate phthalate, methacrylic acid copolymer, shellac, hydroxypropylmethylcellulose succinate, cellulose acetate trimellitate, and mixtures thereof.

68. The solid dosage form of claim 63, wherein the coating further includes a hydrophilic material.

69. The solid dosage form of claim 32, further comprising a coating of a hydrophilic material.

70. The solid dosage form of claim 66, wherein the solid dosage form includes a sufficient amount of the coating to provide a sustained release of the active agent over a predetermined period.

71. The solid dosage form of claim 64, wherein the predetermined period is

12 hours.

72. The solid dosage form of claim 64, wherein the predetermined period is 24 hours.

73. The solid dosage form of claim 69, wherein the hydrophilic material is hydroxypropylmethylcellulose.

74. The solid dosage form of claims 32, further comprising a coating of an additional amount of the active agent.

75. The solid dosage form of claim 63, wherein the coating further includes an additional amount of the active agent.

76. The solid dosage form of claim 32, further comprising at least a partial coating of a support platform.

77. A solid dosage form of a compressed mixture of from about 1% to about 99% of an excipient comprising a particulate agglomerate of coprocessed microcrystalline cellulose and from about 0.1% to about 20% by weight silicon dioxide, the microcrystalline cellulose and silicon dioxide being in intimate association with each other, said silicon dioxide portion of said agglomerate being derived from a silicon dioxide having an average primary particle size from about 1 nm to about 100 .mu.m, and from about 99% to about 1% of a locally active therapeutic agent.

78. The solid dosage form of claim 77, wherein the locally active therapeutic agent is selected from a group consisting of antifungal agents, antibiotic agents, antiviral agents, breath fresheners, antitussive agents, anti-cariogenic compounds, analgesic agents, local anesthetics, oral antiseptics, anti-flammatory agents, hormonal agents, antiplaque agents, acidity reducing agents, and tooth desensitizers.

79. The solid dosage form of claim 77, wherein the solid dosage form provides a sustained-release of the locally active therapeutic agent.

80. The solid dosage form of claims 69, wherein the solid dosage form includes a sufficient amount of the coating to provide a sustained release of the active agent over a predetermined period.

81. The solid dosage form of claim 70, wherein the predetermined period is 12 hours.

82. The solid dosage form of claim 70, wherein the predetermined period is 24 hours.

83. The solid dosage form of claim 66, wherein the coating further includes an additional amount of the active agent.
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