RAPID DISSOLUTION FORMULATION OF A CALCIUM RECEPTOR-ACTIVE COMPOUND

Abstract

The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a calcium receptor-active compound and at least one pharmaceutically acceptable excipient, wherein the composition has a controlled dissolution profile. The present invention further relates to a method of manufacturing the pharmaceutical composition, as well as a method of treating a disease using the pharmaceutical composition.

Claims

1. A pharmaceutical composition comprising an effective dosage amount of a calcium receptor-active compound and at least one pharmaceutically acceptable excipient, wherein at least one dosage unit of the composition has a dissolution profile in 0.05 N HCl, measured according to a dissolution test conducted in a USP 2 apparatus at a temperature of about 37? C., and at a rotation speed of about 75 r.p.m., which comprises from about 50% to about 125% of a target amount of the calcium receptor-active compound being released from the composition no later than about 30 minutes from the start of the test.

2. The composition according to claim 1, wherein the calcium receptor-active compound is chosen from calcimimetic compounds and calcilytic compounds.

3. The composition according to claim 2, wherein the calcimimetic compounds and calcilytic compounds are chosen from compounds of formula (I) and pharmaceutically acceptable salts and forms thereof ##STR00002## wherein: X.sub.1 and X.sub.2, which may be identical or different, are each a radical chosen from CH.sub.3, CH.sub.3O, CH.sub.3CH.sub.2O, Br, Cl, F, CF.sub.3, CHF.sub.2, CH.sub.2F, CF.sub.3O, CH.sub.3S, OH, CH.sub.2OH, CONH.sub.2, CN, NO.sub.2, CH.sub.3CH.sub.2, propyl, isopropyl, butyl, isobutyl, t-butyl, acetoxy, and acetyl radicals, or two of X.sub.1 may together form an entity chosen from fused cycloaliphatic rings, fused aromatic rings, and a methylene dioxy radical, or two of X.sub.2 may together form an entity chosen from fused cycloaliphatic rings, fused aromatic rings, and a methylene dioxy radical; provided that X.sub.2 is not a 3-t-butyl radical; n ranges from 0 to 5; m ranges from 1 to 5; and the alkyl radical is chosen from C1-C3 alkyl radicals, which are optionally substituted with at least one group chosen from saturated and unsaturated, linear, branched, and cyclic C1-C9 alkyl groups, dihydroindolyl and thiodihydroindolyl groups, and 2-, 3-, and 4-piperid(in)yl groups; and the stereoisomers thereof.

4. The composition according to claim 3, wherein the calcimimetic compounds and calcilytic compounds are chosen from compounds of formula (II) and pharmaceutically acceptable salts and forms thereof ##STR00003## wherein: X.sub.1 and X.sub.2, which may be identical or different, are each a radical chosen from CH.sub.3, CH.sub.3O, CH.sub.3CH.sub.2O, Br, Cl, F, CF.sub.3, CHF.sub.2, CH.sub.2F, CF.sub.3O, CH.sub.3S, OH, CH.sub.2OH, CONH.sub.2, CN, NO.sub.2, CH.sub.3CH.sub.2, propyl, isopropyl, butyl, isobutyl, t-butyl, acetoxy, and acetyl radicals, or two of X.sub.1 may together form an entity chosen from fused cycloaliphatic rings, fused aromatic rings, and a methylene dioxy radical, or two of X.sub.2 may together form an entity chosen from fused cycloaliphatic rings, fused aromatic rings, and a methylene dioxy radical; provided that X.sub.2 is not a 3-t-butyl radical; n ranges from 0 to 5; and m ranges from 1 to 5.

5. The composition according to claim 4, wherein the pharmaceutically acceptable salts and forms thereof are chosen from salts of hydrochloric acid and salts of methanesulfonic acid.

6. The composition according to claim 4, wherein the calcimimetic compounds are chosen from cinacalcet, cinacalcet HCl, and cinacalcet methanesulfonate.

7. The composition according to claim 1, wherein the dissolution profile comprises from about 70% to about 110% of the target amount of the calcium receptor-active compound being released from the composition no later than about 30 minutes from the start of the test.

8. The composition according to claim 7, wherein the dissolution profile comprises at least about 75% of the target amount of the calcium receptor-active compound being released from the composition no later than about 30 minutes from the start of the test.

9. The composition according to claim 6, wherein the dissolution profile comprises from about 70% to about 110% of the target amount of the cinacalcet HCl being released from the composition no later than about 30 minutes from the start of the test.

10. The composition according to claim 9, wherein the dissolution profile comprises at least about 75% of the target amount of the cinacalcet HCl being released from the composition no later than about 30 minutes from the start of the test.

11. The composition according to claim 6, wherein the cinacalcet HCl and cinacalcet methanesulfonate are in a form chosen from amorphous powders, crystalline particles and mixtures thereof.

12. The composition according to claim 1, wherein the calcium receptor-active compound is cinacalcet HCl.

13. The composition according to claim 12, wherein the cinacalcet HCl is in a form chosen from needle-shape particles, rod-shape particles, plate-shaped particles, and mixtures of any of the foregoing.

14. The composition according to claim 12, wherein the particle D.sub.50 of the cinacalcet HCl particles is less than or equal to about 50 ?m.

15. The composition according to claim 12, wherein the cinacalcet HCl particles have a particle D.sub.50 effective to release from about 70% to about 110% of the target amount of the cinacalcet HCl from the composition no later than about 30 minutes from the start of the test in 0.05 N HCl.

16. The composition according to claim 15, wherein the cinacalcet HCl particles have a particle D.sub.50 effective to release at least about 75% of the target amount of the cinacalcet HCl from the composition no later than about 30 minutes from the start of the test in 0.05 N HCl.

17. The composition according to claim 1, wherein the composition is in the form of granules.

18. The composition according to claim 1, wherein the composition is in a form chosen from tablets, capsules, and powders.

19. The composition according to claim 17, wherein the granules have a granule D.sub.50 measured using a sieve analysis ranging from about 50 ?m to about 150 ?m.

20. The composition according to claim 19, wherein the granules have a granule D.sub.50 measured using a sieve analysis ranging from about 80 ?m to about 130 ?m.

21. The composition according to claim 17, wherein the granules have a granule D.sub.50 effective to release from about 70% to about 110% of the target amount of the calcium-receptor active compound from the composition no later than about 30 minutes from the start of the test in 0.05 N HCl.

22. The composition according to claim 21, wherein the granules have a granule D.sub.50 effective to release at least about 75% of the target amount of the calcium-receptor active compound from the composition no later than about 30 minutes from the start of the test in 0.05 N HCl.

23. The composition according to claim 12, wherein the cinacalcet HCl is present in a therapeutically effective amount for the treatment of at least one of hyperparathyroidism, hyperphosphonia, hypercalcemia, and elevated calcium phosphorus product.

24. The composition according to claim 12, wherein the cinacalcet HCl is present in an effective dosage amount for the treatment of at least one of hyperparathyroidism, hyperphosphonia, hypercalcemia, and elevated calcium phosphorus product.

25. The composition according to claim 23, wherein the hyperparathyroidism is chosen from primary hyperparathyroidism and secondary hyperparathyroidism.

26. The composition according to claim 24, wherein the hyperparathyroidism is chosen from primary hyperparathyroidism and secondary hyperparathyroidism.

27. The composition according to claim 12, wherein the cinacalcet HCl is present in an amount ranging from about 1% to about 70%? by weight relative to the total weight of the composition.

28. The composition according to claim 27, wherein the cinacalcet HCl is present in an amount ranging from about 5% to about 40% by weight relative to the total weight of the composition.

29. The composition according to claim 28, wherein the cinacalcet HCl is present in an amount ranging from about 15% to about 20% by weight relative to the total weight of the composition.

30. The composition according to claim 1, wherein the at least one pharmaceutically acceptable excipient is chosen from non-cellulose and cellulose diluents, binders, and disintegrants.

31. The composition according to claim 1, wherein the at least one pharmaceutically acceptable excipient is chosen from microcystalline cellulose, starch, talc, povidone, crospovidone, magnesium stearate, colloidal silicon dioxide, and sodium dodecyl sulfate and any combination thereof.

32. The composition according to claim 31, wherein crospovidone is present intergranularly, intragranularly, or a combination thereof.

33. The composition according to claim 31, wherein crospovidone is present intergranularly.

34. The composition according to claim 31, wherein crospovidone is present intragranularly.

35. The composition according to claim 1, wherein the composition comprises microcystalline cellulose and starch in a weight ratio ranging from about 1:1 to about 15:1.

36. The composition according to claim 35, wherein the composition comprises microcystalline cellulose and starch in a weight ratio of about 10:1.

37. The composition according to claim 1, wherein the granules within the composition comprises microcystalline cellulose and starch in a weight ratio ranging from about 1:1 to about 10:1.

38. The composition according to claim 37, wherein the weight ratio between the microcystalline cellulose and the starch in the granules with the composition is about 5:1.

39. The composition according to claim 31, wherein the microcystalline cellulose is present in an amount ranging from about 25% to about 85% by weight relative to the total weight of the composition.

40. The composition according to claim 31, wherein the starch is present in an amount ranging from about 5% to about 35% by weight relative to the total weight of the composition.

41. The composition according to claim 31, wherein the povidone is present in an amount ranging from about 1% to about 5% by weight relative to the total weight of the composition.

42. The composition according to claim 31, wherein the crospovidone is present in an amount ranging from about 1% to about 10% by weight relative to the total weight of the composition.

43. The composition according to claim 1 comprising: (a) from about 10% to about 40% by weight of cinacalcet HCl or cinacalcet methanesulfonate; (b) from about 45% to about 85% by weight of at least one diluent; (c) from about 1% to about 5% by weight of at least one binder; (d) from about 1% to about 10% by weight of at least one disintegrant; and (e) from about 0.05% to about 5% of at least one additive chosen from glidants, lubricants, and adherents; wherein the percentage by weight is relative to the total weight of the composition.

44. The composition according to claim 43 comprising from about 0.05% to about 1.5% by weight of at least one glidant relative to the total weight of the composition.

45. The composition according to claim 43 comprising from about 0.05% to about 1.5% by weight of adherent relative to the total weight of the composition.

46. The composition according to claim 43, further comprising at least one ingredient chosen from lubricants and clear and color coating materials.

47. The composition according to claim 43 further comprising from about 1% to about 6% by weight of at least one coating material chosen from clear and color coating materials relative to the total weight of the composition.

48. The composition according to claim 43 comprising (a) from about 10% to about 40% by weight of cinacalcet HCl; (b) from about 5% to about 10% by weight of starch; (c) from about 40% to about 75% by weight of microcrystalline cellulose; (d) from about 1% to about 5% by weight of povidone; and (e) from about 1% to about 10% by weight of crospovidone; wherein the percentage by weight is relative to the total weight of the composition.

49. The composition according to claim 48 further comprising from about 0.05% to about 1.5% by weight of colloidal silicon dioxide relative to the total weight of the composition.

50. The composition according to claim 48 further comprising from about 0.05%? to about 1.5% by weight of magnesium stearate relative to the total weight of the composition.

51. The composition according to claim 48 further comprising from about 1% to about 6% by weight of at least one coating material chosen from clear and color coating materials relative to the total weight of the composition.

52. The composition according to claim 12, wherein the effective dosage amount of cinacalcet HCl ranges from about 1 mg to about 360 mg.

53. The composition according to claim 52, wherein the effective dosage amount of cinacalcet HCl ranges from about 5 mg to about 240 mg.

54. The composition according to claim 52, wherein the effective dosage amount of cinacalcet HCl ranges from about 20 mg to about 100 mg.

55. The composition according to claim 52, wherein the effective dosage amount of cinacalcet HCl is chosen from about 5 mg, about 15, mg, about 30 mg, about 50 mg, about 60 mg, about 75 mg, about 90 mg, about 120 mg, about 150 mg, about 180 mg, about 210 mg, about 240 mg, about 300 mg, and about 360 mg.

56. The composition according to claim 12, wherein the therapeutically effective amount of cinacalcet HCl ranges from about 1 mg to about 360 mg.

57. The composition according to claim 56, wherein the therapeutically effective amount of cinacalcet HCl ranges from about 5 mg to about 240 mg.

58. The composition according to claim 56, wherein the therapeutically effective amount of cinacalcet HCl ranges from 20 mg to 100 mg.

59. The composition according to claim 56, wherein the therapeutically effective amount of cinacalcet HCl is chosen from about 5 mg, about 15, mg, about 30 mg, about 50 mg, about 60 mg, about 75 mg, about 90 mg, about 120 mg, about 150 mg, about 180 mg, about 210 mg, about 240 mg, about 300 mg, and about 360 mg.

60. A pharmaceutical composition comprising an effective dosage amount of a calcium receptor-active compound and at least one pharmaceutically acceptable excipient, wherein at least one dosage unit of the composition has a dissolution profile in 0.05 N HCl, measured according to a dissolution test conducted in a USP 2 apparatus at a temperature of 37? C.?0.5? C., and at a rotation speed of 75 r.p.m., which comprises from 50% to 125% of a target amount of the calcium receptor-active compound being released from the composition no later than 30 minutes from the start of the test.

61. A method of making a pharmaceutical composition comprising: (a) forming a granule comprising an effective dosage amount of a calcium receptor-active compound and at least one pharmaceutically acceptable excipient; and (b) controlling the particle size of the granule such that from about 50% to about 125% of a target amount of the calcium receptor-active compound is released from the composition no later than about 30 minutes from the start of a test in 0.05 N HCl according to a dissolution test conducted in a USP 2 apparatus at a temperature of about 37 ? C., and a rotation speed of about 75 r.p.m.

62. A method of making a pharmaceutical composition comprising: (a) forming a granule comprising an effective dosage amount of a calcium receptor-active compound and at least one pharmaceutically acceptable excipient; and (b) controlling the particle size of the granule such that from about 50% to about 125% of a target amount of the calcium receptor-active compound is released from the composition no later than about 30 minutes from the start of a test in 0.05 N HCl according to a dissolution test conducted in a USP 2 apparatus at a temperature of 37? C.?0.5? C., and a rotation speed of 75 r.p.m.

63. A method of making a pharmaceutical composition comprising: (a) forming a composition comprising an effective dosage amount of particles of a calcium receptor-active compound and at least one pharmaceutically acceptable excipient; and (b) controlling the particle size of the calcium receptor-active compound such that from about 50% to about 125% of a target amount of the calcium receptor-active compound is released from the composition no later than about 30 minutes from the start of a test in 0.05 N HCl according to a dissolution test conducted in a USP 2 apparatus at a temperature of about 37? C., and a rotation speed of about 75 r.p.m.

64. A method of making a pharmaceutical composition comprising: (a) forming a composition comprising an effective dosage amount of particles of a calcium receptor-active compound and at least one pharmaceutically acceptable excipient; and (b) controlling the particle size of the calcium receptor-active compound such that from about 50% to about 125% of a target amount of the calcium receptor-active compound is released from the composition no later than about 30 minutes from the start of a test in 0.05 N HCl according to a dissolution test conducted in a USP 2 apparatus at a temperature of 37? C.?(0.5)? C., and a rotation speed of 75 r.p.m.

65. A method of making a pharmaceutical composition comprising forming a granule comprising an effective dosage amount of a calcium receptor-active compound and at least one pharmaceutically acceptable excipient in a granulator, wherein the granulator has a volume ranging from about 1 L to about 2000 L, and wherein the granulator contains water in a granulation level ranging from about 10% to about 50% relative to the weight of the dry powders in the granulator,

66. The method according to claim 65, wherein the granulator has a volume ranging from about 65 L to about 1200 L.

67. The method according to claim 65, wherein the granulator has a volume ranging from about 300 L to about 800 L.

68. The method according to claim 65, wherein the water is in a granulation level ranging from about 20% to about 40% relative to the weight of the dry powders in the granulator.

69. The method according to claim 65, wherein the water is in a granulation level ranging from about 30% to about 36% relative to the weight of the dry powders in the granulator.

70. The method according to claim 65, wherein the granulator has a impeller, whose tip speed ranges from about 5 m/s to about 10 m/s.

71. The method according to claim 70, wherein the impeller tip speed ranges from about 7 m/s to about 9 m/s.

72. A method for the treatment of at least one disease chosen from hyperparathyroidism, hyperphosphonia, hypercalcemia, and elevated calcium phosphorus product, comprising administering to a patient in need thereof a pharmaceutical composition comprising an effective dosage amount of a calcium receptor-active compound and at least one pharmaceutically acceptable excipient, wherein the composition has a dissolution profile in 0.05 N HCl, measured according to a dissolution test conducted in a USP 2 apparatus at a temperature of about 37? C., and at a rotation speed of about 75 r.p.m., which comprises from about 50% to about 125% of a target amount of the calcium receptor-active compound being released from the composition in no later than about 30 minutes from the start of the test.

73. The method according to claim 72, wherein the patient is human.

74. The method according to claim 72, wherein an effective dosage amount of the pharmaceutical composition is chosen from about 5 mg, about 15 mg, about 30 mg, about 50 mg, about 60 mg, about 75 mg, about 90 mg, about 120 mg, about 150 mg, about 180 mg, about 210 mg, about 240 mg, about 300 mg, and about 360 mg.

75. A method for the treatment of at least one disease chosen from hyperparathyroidism, hyperphosphonia, hypercalcemia, and elevated calcium phosphorus product, comprising administering to a patient in need thereof a pharmaceutical composition comprising an effective dosage amount of a calcium receptor-active compound and at least one pharmaceutically acceptable excipient, wherein the composition has a dissolution profile in 0.05 N HCl, measured according to a dissolution test conducted in a USP 2 apparatus at a temperature of 37? C.?0.5? C., and at a rotation speed of 75 r.p.m., which comprises from about 50% to about 125% of a target amount of the calcium receptor-active compound being released from the composition in no later than about 30 minutes from the start of the test.

76. The method according to claim 75, wherein the patient is human.

77. The method according to claim 75, wherein an effective dosage amount of the pharmaceutical composition is chosen from about 5 mg, about 15 mg, about 30 mg, about 50 mg, about 60 mg, about 75 mg, about 90 mg, about 120 mg, about 150 mg, about 180 mg, about 210 mg, about 240 mg, about 300 mg, and about 360 mg.

78. A pharmaceutical composition comprising (a) from about 10% to about 40% by weight of cinacalcet HCl; (b) from about 45% to about 85% by weight of at least one diluent; and (c) from about 1% to about 5% by weight of at least one binder; wherein the percentage by weight is relative to the total weight of the composition.

79. The composition according to claim 78 further comprising from about 1% to about 10% by weight of at least one disintegrant, wherein the percentage by weight is relative to the total weight of the composition.

80. The composition according to claim 78 further comprising from about 0.05% to about 5% of at least one additive chosen from glidants, lubricants, and adherents, wherein the percentage by weight is relative to the total weight of the composition.

81. The composition according to claim 80 comprising from about 0.05% to about 1.5% by weight of at least one glidant.

82. The composition according to claim 80 comprising from about 0.05% to about 1.5% by weight of adherent.

83. The composition according to claim 78 further comprising at least one ingredient chosen from lubricants and clear and color coating materials.

84. The composition according to claim 78 further comprising from about 1% to about 6% by weight of at least one coating material chosen from clear and color coating materials relative to the total weight of the composition.

85. The composition according to claim 78, wherein the cinacalcet HCl is in a form chosen from amorphous powders, crystalline particles, matrix particles, and mixtures of any of the foregoing.

86. The composition according to claim 78, wherein the cinacalcet HCl is in a form chosen from needle-shape particles, rod-shape particles, plate-shaped particles, and mixtures of any of the foregoing.

87. The composition according to claim 78, wherein the particle D.sub.50 of the cinacalcet HCl particles is less than or equal to about 50 ?m.

88. The composition according to claim 78, wherein the composition is in the form of granules.

89. The composition according to claim 78, wherein the composition is in a form chosen from tablets, capsules, and powders.

90. The composition according to claim 88, wherein the granules have a granule D.sub.50 measured using a sieve analysis ranging from about 50 ?m to about 150 ?m.

91. The composition according to claim 90, wherein the granules have a granule D.sub.50 measured using a sieve analysis ranging from about 80 ?m to about 130 ?m.

92. The composition according to claim 78, wherein the cinacalcet HCl is present in a therapeutically effective amount for the treatment of at least one of hyperparathyroidism, hyperphosphonia, hypercalcemia, and elevated calcium phosphorus product.

93. The composition according to claim 78, wherein the cinacalcet HCl is present in an effective dosage amount for the treatment of at least one of hyperparathyroidism, hyperphosphonia, hypercalcemia, and elevated calcium phosphorus product.

94. The composition according to claim 92, wherein the hyperparathyroidism is chosen from primary hyperparathyroidism and secondary hyperparathyroidism.

95. The composition according to claim 93, wherein the hyperparathyroidism is chosen from primary hyperparathyroidism and secondary hyperparathyroidism.

96. The composition according to claim 78, wherein the cinacalcet HCl is present in an amount ranging from about 10% to about 30% by weight relative to the total weight of the composition.

97. The composition according to claim 96, wherein the cinacalcet HCl is present in an amount ranging from about 15% to about 20% by weight relative to the total weight of the composition.

98. The composition according to claim 78, wherein the at least one diluent is chosen from microcystalline cellulose, starch, and mixtures thereof.

99. The composition according to claim 98, wherein the microcrystalline cellulose is present in an amount ranging from about 40% to about 75% by weight, and the starch is present in an amount ranging from about 5% to about 10% by weight, relative to the total weight of the composition.

100. The composition according to claim 78, wherein the at least one binder is povidone.

101. The composition according to claim 100, wherein the povidone is present in an amount ranging from about 1% to about 5% by weight, relative to the total weight of the composition.

102. The composition according to claim 78, wherein the at least one disintegrant is crospovidone.

103. The composition according to claim 102, wherein crospovidone is present intergranularly, intragranularly, or a combination thereof.

104. The composition according to claim 102, wherein crospovidone is present intergranularly.

105. The composition according to claim 102, wherein crospovidone is present intragranularly.

106. The composition according to claim 98, wherein the composition comprises microcystalline cellulose and starch in a weight ratio ranging from about 1:1 to about 15:1.

107. The composition according to claim 106, wherein the composition comprises microcystalline cellulose and starch in a weight ratio of about 10:1.

108. The composition according to claim 98, wherein the granules within the composition comprises microcystalline cellulose and starch in a weight ratio ranging from about 11 to about 10:1.

109. The composition according to claim 108, wherein the weight ratio between the microcystalline cellulose and the starch in the granules with the composition is about 5:1.

110. The composition according to claim 78 comprising (a) from about 10% to about 40% by weight of cinacalcet HCl; (b) from about 5% to about 10% by weight of starch; (c) from about 40% to about 75% by weight of microcrystalline cellulose; (d) from about 1% to about 5% by weight of povidone; and (e) from about 1% to about 10% by weight of crospovidone; wherein the percentage by weight is relative to the total weight of the composition.

111. The composition according to claim 110 further comprising from about 0.05% to about 1.5% by weight of colloidal silicon dioxide relative to the total weight of the composition.

112. The composition according to claim 110 further comprising from about 0.05% to about 1.5% by weight of magnesium stearate relative to the total weight of the composition.

113. A method of controlling the dissolution rate of a formulation comprising an effective dosage amount of a calcium receptor-active compound and at least one pharmaceutically acceptable excipient, the method comprising producing the formulation in a granulator which has a volume ranging from about 1 L to about 2000 L, and contains water in a granulation level ranging from about 10% to 50% relative to the amount of dry powders in the granulator.

114. The method according to claim 113, herein the calcium receptor-active compound is cinacalcet HCl.

115. The method according to claim 113, wherein the granulator has a volume ranging from about 65 L to about 1200 L.

116. The method according to claim 113, wherein the granulator has a volume ranging from about 300 L to about 800 L.

117. The method according to claim 113, wherein the water is in a granulation level ranging from about 20% to about 40% relative to the weight of the dry powders in the granulator.

118. The method according to claim 117, wherein the water is in a granulation level ranging from about 30% to about 36% relative to the weight of the dry powders in the granula

Description

EXAMPLES

[0085] Three pharmaceutical formulations with target amounts of 30 mg, 80 mg, and 90 mg active pharmaceutical ingredient with the following components were prepared:

TABLE-US-00003 30 mg 60 mg 90 mg Tablet Tablet Tablet Weight % Amount Amount Amount (w/w) (mg) (mg) (mg) Cinacalcet HCl 18.367 33.06 66.12 99.18 Pregelatinized starch 33.378 60.08 120.16 180.24 (Starch 1500) Microcrystalline cellulose 6.678 12.02 24.04 36.06 (Avicel PH102) Povidone (Plasdone 2.044 3.68 7.36 11.04 K29/32) Crospovidone 1.233 2.22 4.44 6.66 (Polyplasdone XL) Purified Water.sup.1 Microcrystalline cellulose 34.300 61.74 123.48 185.22 (Avicel PH102) Magnesium stearate 0.500 0.90 1.80 2.70 Colloidal silicon dioxide 0.500 0.90 1.80 2.70 (Colloidal anhydrous silica) (Cab-O-Sil M5P) Crospovidone 3.000 5.40 10.80 16.20 (Polyplasdone XL) Core Tablet 100.000 180.00 360.00 540.00 Purified Water.sup.1 Opadry? II (colored 4.000 7.20 14.40 21.60 film former) Purified Water.sup.1 Opadry? Clear (clear 1.500 2.70 5.40 8.10 film former) Carnauba Wax Powder 0.010 0.018 0.036 0.054 Opacode? Ink (Black).sup.2 .sup.1The purified Water was removed during processing. .sup.2Trace quantities of ink were applied to the coated tablet.

[0086] The 30-, 60- and 90-mg tablets were made according to the process flow diagram depicted below.

[0087] The wet granulation process was conducted in a PMA 800 L high-shear granulator with water serving as the granulation fluid. The cinacalcet HCl and the intra-granulation excipients (pregelatinized starch, microcrystalline cellulose, povidone, and crospovidone) were dry-mixed for 1 to 2 minutes with an impeller speed set point at 116?10 rpm, followed by granulation with 30.0% to 36.0% w/w water (based on intra-granular lot size; target was 34.9% w/w) with an impeller speed set point at 116?10 rpm and at a slow or fast chopper speed (target was slow speed). During the granulation process water was delivered at 9.8?0.5 kg/min.

[0088] Following granulation, the mixture was wet-milled using an in-line Comil equipped with a 0.375 (0.953 cm) opening screen and an impeller speed set point at 1400?50 rpm. The mixture was then discharged into a fluid-bed dryer.

[0089] After completion of the wet-milling process, the granulation mixture was dried in an Aeromatic MP6 fluid bed dryer with an inlet temperature set point at 70??5? C. When the outlet temperature reached 37? C. to 41? C., samples were taken to determine moisture levels by loss on drying (LOD). The granules were dried until the average moisture levels reached 1.0% to 2.5%.

[0090] The dried granulation mixture was milled through a Quadro Mill 196S (Comil) equipped with a 0.055 (0.140 cm) opening screen at an impeller speed of 1650?50 rpm into a 1000 L Gallay tote.

[0091] Except for magnesium stearate, the extra-granular excipients were blended in a 650 L Gallay tote blender for 7?1 minutes at 12?1 rpm. This mixture was further blended with the dry-milled granulation in a 1000 L Galley tote blender for 15?5 minutes at 12?1 rpm, and then for 6?1 minutes at 12?1 rpm after magnesium stearate was added for lubrication.

[0092] The final lubricated blend was compressed into tablets containing 30-, 60-, or 90 mg of the free base equivalent of active cinacalcet HCl using a Unipress 27 tablet press set to a speed of 2000 ?300 tablets per minute and equipped with a force feeder. Throughout the compression operation, individual tablet weights (target weights of 180, 360, and 540 mg for 30-, 60-, and 90-mg tablets, respectively), the average weight of 10 tablets, tablet hardness and thickness were monitored at pre-determined intervals.

[0093] The color-coating suspension and clear-coating solution were prepared by slowly adding either the Opadry? II (green) or Opadry? Clear into purified water while mixing until uniform (?45 minutes). The color suspension and clear solution deaerated for ?45 minutes before the spraying process began, and were used within a pre-determined time limit.

[0094] Each lot was film-coated with color and clear coats in a Vector Hi-Coater 48 pan. The color-coating suspension was applied onto a moving core tablet bed (pan speed=4 to 7 rpm) and a spray rate of 250?50 grams per minute per 3 guns. The distance between the spray guns and the tablet bed was approximately 8 (20 cm) to 11 (28 cm), and the air volume was 600?200 ft.sup.3 per minute (17.1?5.7 m.sup.3 per minute) with a pan pressure differential maintained between ?0.1 (?0.25 cm) to ?0.3 (?0.76 cm) of water. Supply air temperature was adjusted to 80?10? C. to maintain an exhaust temperature of 41?3? C.

[0095] When the clear-coating application was completed, the heater and the air supply was turned off and the wax was spread evenly over the moving tablet bed (after it reached ?37? C.) with a pan speed of 4 to 7 rpm. The tablets were rotated for 5?1 minutes, and after the supply air and exhaust fan were turned on, the tablets were rotated for an additional 5?1 minutes with a pan speed of 4 to 7 rpm and supply air of 600?200 ft.sup.3 per minute (17.1?5.7 m.sup.3 per minute). The pan was jogged until the tablet bed temperature reached ?30? C.

[0096] An Ackley ink-based offset printer was used to produce 2-sided printed tablets.

[0097] The dissolution profile of the three formulations were measured according the dissolution protocol described in the USP 26/NF 21, chapter 711 using a USP 2 apparatus at a temperature of about 37? C., and at a rotation speed of about 75 r.p.m. The dissolution profile of the formulations in which at least about 75% of the cinacalcet HCl was released from the composition in no later than about 30 minutes from the start of the test is set forth in Table 2.

TABLE-US-00004 TABLE 2 Time (min) 30 mg Tablet 60 mg Tablet 90 mg Tablet 15 85.3 81.9 80.8 30 95.2 93.8 93.4 45 97.7 97.7 97.9 60 98.7 98.8 99.8

[0098] The content uniformity of the three formulations were measured in accordance with USP 26/NF 21, chapter 905, described in detail above. The content uniformity and for each of the three formulations is set forth in Table 3.

TABLE-US-00005 TABLE 3 30 mg Tablet 60 mg Tablet 90 mg Tablet Mean % Mean % Mean % Container (10 tablets) RSD (10 tablets) RSD (10 tablets) RSD 1 (beg.) 98.5 0.8 96.7 1.6 99.7 1.2 5 98.8 0.8 98.5 0.8 100.7 0.9 11 98.5 0.6 98.3 1.0 99.9 0.7 16 98.3 0.8 97.6 1.3 99.9 0.5 22 98.3 1.0 96.3 1.8 100.7 0.9 end 98.0 0.6 95.8 1.9 99.3 0.8