Levothyroxine compositions and methods

• US 20030203968A1
• Filed: 04/28/2003
• Published: 10/30/2003
• Est. Priority Date: 02/15/2001
• Status: Abandoned Application

• Current Assignee: Elaine A. Strauss, Franz G. Andrew, Philip A. Dimenna, Rocco L. Gemma
• Original Assignee: Elaine A. Strauss, Franz G. Andrew, Philip A. Dimenna, Rocco L. Gemma
• Inventors: Franz, G. Andrew, Gemma, Rocco L., Strauss, Elaine A., DiMenna, Philip A.
• Application Number:
  US10/425,008
• Publication Number:
  US 20030203968A1
• Time in Patent Office: Days
• US Class Current: 514/567
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2072 characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms A61K9/0004, A61K9/0056, A61K9/0065 take precedence
• CPC Class Codes: B01F 23/60 Mixing solids with solids
• CPC Class Codes: B01F 25/433 Mixing tubes wherein the shape of the tube influences the mixing, e.g. mixing tubes with varying cross-section or provided with inwardly extending profiles
• CPC Class Codes: B01F 25/4334 Mixers with a converging cross-section
• CPC Class Codes: B01F 25/82 uniting flows of material taken from different parts of a receptacle or from a set of different receptacles

Abstract

The present invention generally relates to stable pharmaceutical compositions, and methods of making and administering such compositions. In one aspect, the invention features stabilized pharmaceutical compositions that include pharmaceutically active ingredients such as levothyroxine (T4) sodium and liothyronine (T3) sodium (thyroid hormone drugs), preferably in an immediate release solid dosage form. Also provided are methods for making and using such immediate release and stabilized compositions.

Claims

1. An immediate release pharmaceutical composition comprising a levothyroxine salt.

2. The composition of claim 1, wherein at least about 85% of the levothyroxine dissolves in aqueous solution in less than about 30 minutes as determined by a standard dissolution test.

3. The composition of claims 1, wherein at least about 85% of the levothyroxine dissolves in aqueous solution by about 10 to about 15 minutes as determined by the standard dissolution test.

4. The composition of claims 2, wherein at least about 85% of the levothyroxine dissolves in aqueous solution by about 10 to about 15 minutes as determined by the standard dissolution test.

5. The composition of claims 1, wherein the composition exhibits a levothyroxine (T4) plasma Cmax of between from about 10 μ

g/dL to about 20 μ

g/dL as determined by a standard Cmax test.

6. The composition of claims 2, wherein the composition exhibits a levothyroxine (T4) plasma Cmax of between from about 10 μ

g/dL to about 20 μ

g/dL as determined by a standard Cmax test.

7. The composition of claims 3, wherein the composition exhibits a levothyroxine (T4) plasma Cmax of between from about 10 μ

g/dL to about 20 μ

g/dL as determined by a standard Cmax test.

8. The composition of claim 4, wherein the composition exhibits a levothyroxine (T4) plasma Cmax of between from about 12 μ

g/dL to about 16 μ

g/dL as determined by the standard Cmax test.

9. The composition of claims 4, wherein the In(Cmax) of the levothyroxine (T4) plasma level is between from about 1 to about 3.

10. The composition of claims 5, wherein the In(Cmax) of the levothyroxine (T4) plasma level is between from about 1 to about 3.

11. The composition of claims 1, wherein the composition exhibits a triiodothyronine (T3) plasma Cmax of between from about 0.1 ng/mL to about 10 ng/mL as determined by the standard Cmax test.

12. The composition of claim 1, wherein the composition exhibits a triiodothyronine (T3) plasma Cmax of between from about 0.5 ng/mL to about 2 ng/mL as determined by the standard Cmax test.

13. The composition of claims 1, wherein the In(Cmax) is between from about 0.01 to about 5.

14. The composition of claims 1, wherein the composition exhibits a levothyroxine (T4) plasma Tmax of between from about 0.5 hours to about 5 hours as determined by a standard Tmax test.

15. The composition of claim 1, wherein the composition exhibits a levothyroxine (T4) plasma Tmax of between from about 1 hour to about 3 hours as determined by the standard Tmax test.

16. The composition of claims 1, wherein the composition exhibits a triiodothyronine (T3) plasma Tmax of between from about 10 hours to about 20 hours as determined by the standard Tmax test.

17. The composition of claim 1, wherein the composition exhibits a triiodothyronine (T3) plasma Tmax of between from about 12 hours to about 16 hours as determined by the standard Tmax test.

18. The composition of claims 1, wherein the composition features a levothyroxine (T4) plasma AUC (0-t) of between from about 450 μ

g-hour/dL to about 600 μ

g-hour/dL.

19. The composition of claim 1, wherein the composition features a levothyroxine (T4) AUC (0-t) of between from about 500 μ

g-hour/dL to about 550 μ

g-hour/dL.

20. The composition of claims 1, wherein the In[AUC(0-t)] is between from about 1 to about 10.

21. The composition of claims 1, wherein the composition features a triiodothyronine (T3) AUC (0-t) of between from about 10 ng-hour/mL to about 100 ng-hour/mL.

22. The composition of claim 1, wherein the composition features a triiodothyronine (T3) AUC (0-t) of between from about 20 ng-hour/mL to about 60 ng-hour/mL.

23. The composition of claims 1, wherein the ln[AUC(0-t)] is between from about 1 to about 5.

24. The composition of claims 1, wherein the composition is essentially sugar free.

25. The composition of claims 1, wherein the composition is essentially non-granular.

26. The composition of claims 1, wherein the composition further comprises microcrystalline β

-cellulose.

27. The composition of claim 26, wherein the microcrystalline β

-cellulose has a bulk density of between from about 0.10 g/cm³ to about 0.35 g/cm³.

28. The composition of claims 26, wherein the microcrystalline β

-cellulose has a bulk density of between from about 0.15 g/cm³ to about 0.25 g/cm³.

29. The composition of claims 26, wherein the microcrystalline β

-cellulose has a bulk density of between from about 0.17 g/cm³ to about 0.23 g/cm³.

30. The composition of claims 26, wherein the microcrystalline β

-cellulose has a bulk density of between from about 0.19 g/cm³ to about 0.21 g/cm³.

31. The composition of claims 26, wherein the microcrystalline β

-cellulose has a conductivity of less than about 200 μ

S/cm.

32. The composition of claim 26, wherein the microcrystalline β

-cellulose has a conductivity of less than about 75 μ

S/cm.

33. The composition of claims 26, wherein the microcrystalline β

-cellulose has a conductivity of between from about 0.5 μ

S/cm to 50 μ

S/cm.

34. The composition of claims 26, wherein the microcrystalline β

-cellulose has a conductivity of between from about 15 μ

S/cm to 30 μ

S/cm.

35. The composition of claims 1, wherein the composition has a post-packaging potency of between from about 95% to about 120% as determined by a standard potency test.

36. The composition of claim 35, wherein the composition has a post-packaging potency of between from about 98% to about 110% as determined by the standard potency test.

38. The composition of claims 1, wherein the composition is formulated as a tablet.

39. The composition of claim 38, wherein the tablet has a total hardness of between from about 1 to about 30 KP as determined by a standard hardness test.

40. The composition of claim 38, wherein tablet has a total hardness of between from about 5 to about 15 KP as determined by a standard hardness test.

41. The composition of claims 38, wherein the tablet is configured to increase heat transfer away from the tablet.

42. The composition of claim 38, wherein the tablet has a surface area of between from about 0.9 in.² to about 0.15 in.².

43. The composition of claim 38, wherein the tablet has a surface area of about 0.115 in.².

44. The composition of claims 38, wherein the tablet is beveled.

45. The composition of claim 38, wherein the tablet further comprises a score.

46. The composition of claims 38, wherein the tablet has a raised violin configuration.

47. The composition of claims 1, wherein the composition features less than about 10% total impurities as determined by a standard impurity test.

48. The composition of claim 1, wherein the composition features less than about 5% total impurities as determined by the standard impurity test.

49. The composition of claims 47, wherein the impurities comprise at least one of diiodothyronine (T2), triiodothyronine (T3), triiodothyroacetic acid amide, triiodothyroethylamine, triiodothyroacetic acid, triiodothyroethyl alcohol, tetraiodothyroacetic acid amide, tetraiodothyroacetic acid, triiodothyroethane, and tetraiodothyroethane.

50. The composition of claims 48, wherein the impurities comprise at least one of diiodothyronine (T2), triiodothyronine (T3), triiodothyroacetic acid amide, triiodothyroethylamine, triiodothyroacetic acid, triiodothyroethyl alcohol, tetraiodothyroacetic acid amide, tetraiodothyroacetic acid, triiodothyroethane, and tetraiodothyroethane.

51. The composition of claims 47, wherein the impurities detected in the assay consist of diiodothyronine (T2), triiodothyronine (T3), triiodothyroacetic acid, and tetraiodothyroacetic acid.

52. The composition of claims 48, wherein the impurities detected in the assay consist of diiodothyronine (T2), triiodothyronine (T3), triiodothyroacetic acid, and tetraiodothyroacetic acid.

53. The composition of claims 1, wherein the composition further comprises a pharmaceutically acceptable croscarmellose salt.

54. The composition of claims 1, wherein the composition further comprises a pharmaceutically acceptable magnesium salt.

55. The composition of claims 53, wherein the composition further comprises a pharmaceutically acceptable magnesium salt.

58. An aqueous solution comprising at a composition of claim 1.

60. The aqueous solution of claim 58, wherein the solution is adapted for child or infant use.

65. The method of claim 58, wherein the tablet has a raised violin configuration.

89. A composition of claim 1, wherein at least about 80% of the levothyroxine dissolves in aqueous solution by about 15 minutes as determined by the standard dissolution test.

56. An immediate release pharmaceutical composition in tablet form comprising levothyroxine sodium, the composition comprising:

a) between from about 0.01 mg/tablet to about 500 mg/tablet levothyroxine sodium (USP);

b) between from about 100 mg/tablet to about 110 mg/tablet of microcrystalline β

-cellulose, NF (Ceolus®

) having a bulk density of between from about 0.10 g/cm³ to about 0.35 g/cm³;

c) between from about 25 mg/tablet to about 50 mg/tablet of croscarmellose sodium, NF (Ac-di-sol); and

d) between from about 0.5 mg/tablet to about 5 mg/tablet of magnesium stearate, NF.

57. The composition of claim 56, wherein the composition further comprises at least one pharmaceutically acceptable coloring agent.

59. An aqueous solution comprising at a composition of claim 56.

61. A method of making an immediate release pharmaceutical composition comprising a levothyroxine salt, the method comprising

a) mixing a levothyroxine salt with microcrystalline β

-cellulose and a croscarmellose salt to make a blend; and

b) compressing the blend in a ratio of initial volume to final volume of between from about 2;

1 to about 5;

1 to make the composition.

62. The method of claim 61, wherein the ratio of initial volume to final volume is about 4:

1.

63. The method of claims 61, wherein the composition features less than about 5% total impurities as determined by the standard impurity test.

64. The method of claims 61, wherein the method further comprises forming a tablet.

66. A method of making a stabilized pharmaceutical composition comprising a levothyroxine salt, the method comprising

a) mixing a levothyroxine salt with microcrystalline β

-cellulose and a croscarmellose salt to make a blend; and

b) compressing the blend in a ratio of initial volume to final volume of between from about 2;

1 to about 5;

1 to make the composition.

67. The method of claim 66, wherein the ratio of initial volume to final volume is about 4:

1.

68. The method of claims 66, wherein the composition features less than about 5% total impurities as determined by the standard impurity test.

69. The method of claims 66, wherein the method further comprises forming a tablet.

70. The method of claim 66, wherein the tablet has a raised violin configuration.

71. A stabilized, immediate release pharmaceutical composition comprising a levothyroxine.

72. A method of preparing a stabilized, immediate release pharmaceutical composition of claim 71 comprising

(a) forming a blend by blending the levothyroxine and β

-sheet form of microcrystalline cellulose, and

(b) forming therefrom a solid dosage.

73. A method of claim 72, wherein the solid dosage is formed by compressing the blend in a tableting machine.

74. A method of claim 72, wherein the blend is compressed in a ratio of initial volume to final volume from 3.3:

1 to 4.0;

1.

75. A method of claim 72, wherein the levothyroxine is levothyroxine sodium.

76. A method of claim 72, wherein the stabilized, immediate release pharmaceutical composition further includes liothyronine.

77. A method of claim 76, wherein the liothyronine is liothyronine sodium.

78. A stabilized pharmaceutical composition comprising levothyroxine, wherein the composition exhibits a levothyroxine (T4) plasma Cmax of between from about 10 μ

g/dl to about 20 μ

g/dl as determined by a standard Cmax test.

79. A composition of claim 78, wherein the composition exhibits a levothyroxine (T4) plasma Cmax of between from about 12 μ

g/dl to about 16 μ

g/dl as determined by the standard Cmax test.

80. A composition of claims 78, wherein the In(Cmax) of the levothyroxine (T4) plasma level is between from about 1 to about 3.

81. A composition of claims 79, wherein the In(Cmax) of the levothyroxine (T4) plasma level is between from about 1 to about 3.

82. A stabilized pharmaceutical composition comprising levothyroxine, wherein the composition exhibits a triiodothyronine (T3) plasma Tmax of between from about 10 hours to about 20 hours as determined by the standard Tmax test.

83. A composition of claim 82, wherein the composition exhibits a triiodothyronine (T3) plasma Tmax of between from about 12 hours to about 16 hours as determined by the standard Tmax test.

84. A stabilized immediate release pharmaceutical composition comprising levothyroxine, wherein the composition exhibits a levothyroxine (T4) plasma Tmax of between from about 0.5 hours to about 5 hours as determined by a standard Tmax test.

85. A composition of claim 85, wherein the composition exhibits a levothyroxine (T4) plasma Tmax of between from about 1 hour to about 3 hours as determined by the standard Tmax test.

86. A pharmaceutical composition, comprising the product of dissolution of a preparation comprising levothyroxine, cross-linked sodium carboxymethylcellulose, and β

-form microcrystalline cellulose, in an aqueous medium.

87. A composition of claim 86, wherein the preparation comprises about 0.001 to 1% by weight levothyroxine, about 5 to about 40% by weight cross-linked sodium carboxymethylcellulose, and at least about 50% by weight of 1-form microcrystalline cellulose.

88. An immediate release pharmaceutical composition comprising levothyroxine, wherein at least about 85% of the levothyroxine dissolves in aqueous solution in less than about 20 minutes as determined by a standard dissolution test.

90. A stabilized pharmaceutical composition comprising levothyroxine, wherein at least about 85% of the levothyroxine dissolves in aqueous solution in less than about 20 minutes as determined by a standard dissolution test.

91. A composition of claim 90, wherein at least about 80% of the levothyroxine dissolves in aqueous solution by about 15 minutes as determined by the standard dissolution test.

92. An immediate release pharmaceutical composition comprising levothyroxine, wherein the composition is essentially sugar free.

93. A stabilized pharmaceutical composition comprising levothyroxine, wherein the composition is essentially sugar free.

94. An immediate release pharmaceutical composition comprising levothyroxine, wherein the composition is essentially non-granular.

95. A stabilized pharmaceutical composition comprising levothyroxine, wherein the composition is essentially non-granular.

96. An immediate release pharmaceutical composition comprising levothyroxine, wherein the composition has a post-packaging potency of between from about 95% to about 120% as determined by a standard potency test.

97. A composition of claim 96, wherein the composition has a post-packaging potency of between from about 98% to about 110% as determined by the standard potency test.

99. A composition of claim 96, wherein the composition has a post-packaging potency of between from about 98% to about 110% as determined by the standard potency test.

98. A stabilized pharmaceutical composition comprising levothyroxine, wherein the composition has a post-packaging potency of between from about 95% to about 120% as determined by a standard potency test.

100. An immediate release pharmaceutical composition comprising levothyroxine, wherein the composition is formulated as a tablet.

101. A composition of claim 100, wherein the tablet has a total hardness of between from about 1 to about 30 KP as determined by a standard hardness test.

102. A composition of claim 100, wherein tablet has a total hardness of between from about 5 to about 15 KP as determined by a standard hardness test.

103. A stabilized pharmaceutical composition comprising levothyroxine, wherein the composition is formulated as a tablet.

104. A composition of claim 103, wherein the tablet has a total hardness of between from about 1 to about 30 KP as determined by a standard hardness test.

105. A composition of claim 103, wherein tablet has a total hardness of between from about 5 to about 15 KP as determined by a standard hardness test.

106. An immediate release pharmaceutical composition comprising levothyroxine, wherein the tablet is configured to increase heat transfer away from the tablet.

107. A composition of claim 106, wherein the tablet has a surface area of between from about 0.9 in.² to about 0.15 in.².

108. A composition of claims 106, wherein the tablet is beveled.

109. A composition of claim 106, wherein the tablet is scored.

110. A composition of claims 106, wherein the tablet has a raised violin configuration.

112. A composition of claim 106, wherein the tablet has a surface area of between from about 0.9 in.² to about 0.15 in.².

113. A composition of claims 106, wherein the tablet is beveled.

114. A composition of claim 106, wherein the tablet is scored.

115. A composition of claims 106, wherein the tablet has a raised violin configuration.

111. A stabilized pharmaceutical composition comprising levothyroxine, wherein the tablet is configured to increase heat transfer away from the tablet.

116. A method of instructing a human to take an immediate release pharmaceutical composition in tablet form comprising levothyroxine for reduced or absent thyroid function, said method comprising:

instructing the human to take a certain number of the immediate release pharmaceutical levothyroxine tablets a selected number of times daily to treat reduced or absent thyroid function.

117. A method according to claim 116, wherein said reduced or absent thyroid function is caused by an etiology selected from the group consisting of myxedema, cretinism and obesity.

118. A method of instructing a human to take a stabilized, immediate release pharmaceutical composition in tablet form comprising levothyroxine for reduced or absent thyroid function, said method comprising:

instructing the human to take a certain number of the immediate release pharmaceutical levothyroxine tablets a selected number of times daily to treat reduced or absent thyroid function.

119. A method according to claim 118, wherein said reduced or absent thyroid function is caused by an etiology selected from the group consisting of myxedema, cretinism and obesity.

120. A method of instructing a human to take an effective amount of an immediate release pharmaceutical composition in tablet form comprising levothyroxine to treat a thyroid indication selected from the group consisting of replacement or supplemental therapy in hypothyroidism, suppression of pituitary TSH secretion, prevention of euthyroid goiters and adjunctive therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer said method comprising

administering to the human an effective number of the immediate release pharmaceutical levothyroxine tablets a selected number of times daily to treat said thyroid indication.

121. A method of instructing a human to take an effective amount of a stabilized, immediate release pharmaceutical composition in tablet form comprising levothyroxine to treat a thyroid indication selected from the group consisting of replacement or supplemental therapy in hypothyroidism, suppression of pituitary TSH secretion, prevention of euthyroid goiters and adjunctive therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer, said method comprising

administering to the human an effective number of the stabilized, immediate release pharmaceutical levothyroxine tablets a selected number of times daily to treat said thyroid indication.

122. A method of treating a human with an immediate release pharmaceutical composition in tablet form comprising levothyroxine for reduced or absent thyroid function, said method comprising:

administering to the human an effective number of the immediate release pharmaceutical levothyroxine tablets a selected number of times daily to treat reduced or absent thyroid function.

123. A method according to claim 122, wherein said reduced or absent thyroid function is caused by an etiology selected from the group consisting of myxedema, cretinism and obesity.

124. A method of treating a human with a stabilized, immediate release pharmaceutical composition in tablet form comprising levothyroxine for reduced or absent thyroid function, said method comprising:

administering to the human an effective number of the immediate release pharmaceutical levothyroxine tablets a selected number of times daily to treat reduced or absent thyroid function.

125. A method according to claim 124, wherein said reduced or absent thyroid function is caused by an etiology selected from the group consisting of myxedema, cretinism and obesity.

126. A method of treating a human with an effective amount of an immediate release pharmaceutical composition in tablet form comprising levothyroxine for a thyroid indication selected from the group consisting of replacement or supplemental therapy in hypothyroidism, suppression of pituitary TSH secretion, prevention of euthyroid goiters and adjunctive therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer, said method comprising

administering to the human an effective number of the immediate release pharmaceutical levothyroxine tablets a selected number of times daily to treat said thyroid indication.

127. A method of treating a human with an effective amount of a stabilized, immediate release pharmaceutical composition in tablet form comprising levothyroxine to treat a thyroid indication selected from the group consisting of replacement or supplemental therapy in hypothyroidism, suppression of pituitary TSH secretion, prevention of euthyroid goiters and adjunctive therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer, said method comprising:

administering to the human an effective number of the stabilized, immediate release pharmaceutical levothyroxine tablets a selected number of times daily to treat said thyroid indication.