US2018243238A1PendingUtilityA1

Rapid dissolution formulation of a calcium receptor-active compound

Assignee: AMGEN INCPriority: Sep 12, 2003Filed: Apr 30, 2018Published: Aug 30, 2018

Est. expirySep 12, 2023(expired)· nominal 20-yr term from priority

Inventors:Glen Gary Lawrence Francisco Alvarez Hung-Ren H. Lin Tzuchi R. Ju

A61P 43/00A61P 5/20A61P 5/18A61P 5/00A61P 3/00A61P 3/14A61K 31/00A61K 31/135A61K 9/2077A61K 9/2866A61K 31/137A61K 9/20

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References

Claims

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

exact text as granted — not AI-modified

What is claimed is:

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

wherein:
X 1 and X 2 , which may be identical or different, are each a radical chosen from CH 3 , CH 3 O, CH 3 CH 2 O, Br, Cl, F, CF 3 , CHF 2 , CH 2 F, CF 3 O, CH 3 S, OH, CH 2 OH, CONH 2 , CN, NO 2 , CH 3 CH 2 , propyl, isopropyl, butyl, isobutyl, t-butyl, acetoxy, and acetyl radicals, or two of X 1 may together form an entity chosen from fused cycloaliphatic rings, fused aromatic rings, and a methylene dioxy radical, or two of X 2 may together form an entity chosen from fused cycloaliphatic rings, fused aromatic rings, and a methylene dioxy radical; provided that X 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

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 50 of the cinacalcet HCl particles is less than or equal to about 50 μm.

15 . The composition according to claim 12 , wherein the cinacalcet HCl particles have a particle D 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 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 50 measured using a sieve analysis ranging from about 50 μm to about 150 μm.

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

21 . The composition according to claim 17 , wherein the granules have a granule D 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 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 50 of the cinacalcet HCl particles is less than or equal to about 50 μm.

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 50 measured using a sieve analysis ranging from about 50 μm to about 150 μm.

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

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

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