Stabilized thyroxine compounds

• US 6,627,660 B1
• Filed: 11/16/1999
• Issued: 09/30/2003
• Est. Priority Date: 11/16/1999
• Status: Expired due to Term

• Current Assignee: Shire LLC (Shire plc)
• Original Assignee: New River Pharmaceuticals Inc. (Shire plc)
• Inventors: LeClercq, Anne F., Piccariello, Thomas
• Primary Examiner(s): Travers, Russell
• Assistant Examiner(s): Sharareh, Shahnam
• Application Number:
  US09/440,635
• Time in Patent Office: 1,414 Days
• Field of Search: 514/109, 514/103, 514/114, 514/104, 514/140, 514/141, 514/567, 514/2, 530/324, 530/326, 530/327, 424/464, 424/465, 424/479, 424/451
• US Class Current: 514/567
• 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: A61P 5/14 of the thyroid hormones, e.g. T3, T4

Abstract

Throxinyldimethylphosphinate was invented as a prodrug to stabilize thyroxine, a drug widely used to treat hypothyroidism. The presence of the dimethylphosphinate group at the phenolic hydroxyl of thyroxine is key to preventing thyroxine from decomposing through the proposed pathway. The prodrug will be hydrolyzed in the stomach or the gut into thyroxine and the biologically inert dimethylphosphinic acid. Related products may be stabilized with the same or similar protecting groups.

Claims

1. A composition comprising thyroxine protected at a phenolic hydroxyl with a protecting group, wherein said protecting group is a dialkylphosphinate.

2. The composition of claim 1, wherein said dialkylphosphinate is dimethylphosphinate.

3. The composition of claim 1, wherein said dialkylphosphinate is diethylphosphinate.

4. A method of stabilizing and increasing the shelf life of a thyroid hormone comprising protecting thyroxine with a protecting group at a phenolic hydroxyl, wherein said protecting group is a dialkylphosphinate.

5. The method of claim 4, wherein said dialkylphosphinate is dimethylphosphinate.

6. The method of claim 4, wherein said dialkylphosphinate is diethylphosphinate.

7. A pharmaceutical composition comprising a thyroxine protected with a protecting group at a phenolic hydroxyl, wherein said protecting group is a dialkylphosphinate;

and a pharmaceutically acceptable excipient.

8. The pharmaceutical composition of claim 7, wherein said dialkylphosphinate is dimethylphosphinate.

9. The pharmaceutical composition of claim 7, wherein said dialkylphosphinate is diethylphosphinate.

10. The pharmaceutical composition of claim 7, 8, or 9 wherein said composition is in the form of an ingestible tablet.

11. The pharmaceutical composition of claim 7, 8, or 9 wherein said composition is in the form of an intravenous preparation.

12. The pharmaceutical composition of claim 7, 8, or 9 wherein said composition is in the form of an oral suspension.

13. A method of treating hypothyroidism comprising administering to a patient in need thereof a thyroxine protected at a phenolic hydroxyl, wherein said protecting group is a dialkylphosphinate.

14. The method of claim 13, wherein said dialkylphosphinate is dimethylphosphinate.

15. The method of claim 13, wherein said dialkylphosphinate is diethylphosphinate.

16. The method of claim 13, 14, or 15 wherein said thyroxine is administered in the form of an ingestible tablet.

17. The method of claim 13, 14, or 15 wherein said thyroxine is administered in the form of an intravenous preparation.

18. The method of claim 13, 14, or 15 wherein said thyroxine is administered in the form of an oral suspension.

19. A composition comprising thyroxine protected at a phenolic hydroxyl with a protecting group, wherein said protecting group is a dialkylphosphate.

20. The composition of claim 19, wherein said dialkylphosphate is dimethylphosphate.

21. The composition of claim 19, wherein said dialkylphosphate is diethylphosphate.

22. A method of stabilizing and increasing the shelf life of a thyroid hormone comprising protecting thyroxine with a protecting group at a phenolic hydroxyl, wherein said protecting group is a dialkylphosphate.

23. The method of claim 22, wherein said dialkylphosphate is dimethylphosphate.

24. The method of claim 22, wherein said dialkylphosphate is diethylphosphate.

25. A pharmaceutical composition comprising a thyroxine protected with a protecting group at a phenolic hydroxyl, wherein said protecting group is a dialkylphosphate;

and a pharmaceutically acceptable excipient.

26. The pharmaceutical composition of claim 25, wherein said dialkylphosphate is dimethylphosphate.

27. The pharmaceutical composition of claim 25, wherein said dialkylphosphate is diethylphosphate.

28. The pharmaceutical composition of claim 25, 26, or 27 wherein said composition is in the form of an ingestible tablet.

29. The pharmaceutical composition of claim 25, 26, or 27 wherein said composition is in the form of an intravenous preparation.

30. The pharmaceutical composition of claim 25, 26, or 27 wherein said composition is in the form of an oral suspension.

31. A method of treating hypothyroidism comprising administering to a patient in need thereof a thyroxine protected at a phenolic hydroxyl, wherein said protecting group is a dialkylphosphate.

32. The method of claim 31, wherein said dialkylphosphate is dimethylphosphate.

33. The method of claim 31, wherein said dialkylphosphate is diethylphosphate.

34. The method of claim 31, 32, or 33 wherein said thyroxine is administered in the form of an ingestible tablet.

35. The method of claim 31, 32, or 33 wherein said thyroxine is administered in the form of an intravenous preparation.

36. The method of claim 31, 32, or 33 wherein said thyroxine is administered in the form of an oral suspension.

37. A composition comprising iodotyrosine protected at a phenolic hydroxyl with a protecting group, wherein said protecting group is a dialkylphosphinate.

38. The composition of claim 37, wherein said dialkylphosphinate is dimethylphosphinate.

39. The composition of claim 37, wherein said dialkylphosphinate is diethylphosphinate.

40. A method of stabilizing and increasing the shelf life of a thyroid hormone comprising protecting iodotyrosine with a protecting group at a phenolic hydroxyl, wherein said protecting group is a dialkylphosphinate.

41. The method of claim 40, wherein said dialkylphosphinate is dimethylphosphinate.

42. The method of claim 40, wherein said dialkylphosphinate is diethylphosphinate.

43. A pharmaceutical composition comprising a iodotyrosine protected with a protecting group at a phenolic hydroxyl, wherein said protecting group is a dialkylphosphinate;

and a pharmaceutically acceptable excipient.

44. The pharmaceutical composition of claim 43, wherein said dialkylphosphinate is dimethylphosphinate.

45. The composition of claim 43, wherein said dialkylphospinate is diethylphosphinate.

46. The pharmaceutical composition of claim 43, 44, or 45 wherein said composition is in the form of an ingestible tablet.

47. The pharmaceutical composition of claim 43, 44 or 45 wherein said composition is in the form of an intravenous preparation.

48. The pharmaceutical composition of claim 43, 44, or 45 wherein said composition is in the form of an oral suspension.

49. A method of treating hypothyroidism comprising administering to a patient in need thereof an iodotyrosine protected at a phenolic hydroxyl, wherein said protecting group is a dialkylphosphinate.

50. The method of claim 49, wherein said dialkyphosphinate is dimethylphosphinate.

51. The method of claim 49, wherein said dialkylphosphinate is diethylphosphinate.

52. The method of claim 49, 50, or 51 wherein said iodotyrosine is administered in the form of an ingestible tablet.

53. The method of claim 49, 50 or 51 wherein said iodotyrosine is administered in the form of an intravenous preparation.

54. The method of claim 49, 50, or 51 wherein said iodotyrosine is administered in the form of an oral suspension.

55. A composition comprising iodotyrosine protected at a phenolic hydroxyl with a protecting group, wherein said protecting group is a dialkylphosphate.

56. The composition of claim 55, wherein said dialkylphosphate is dimethylphosphate.

57. The composition of claim 55, wherein said dialkylphosphate is diethylphosphate.

58. A method of stabilizing and increasing the shelf life of a thyroid hormone comprising protecting iodotyrosine with a protecting group at a phenolic hydroxyl, wherein said protecting group is a dialkylphosphate.

59. The method of claim 58, wherein said dialkylphosphate is dimethylphosphate.

60. The method of claim 58, wherein said dialkylphosphate is diethylphosphate.

61. A pharmaceutical composition comprising an iodotyrosine protected with a protecting group at a phenolic hydroxyl, wherein said protecting group is a dialkylphosphate;

and a pharmaceutically acceptable excipient.

62. The pharmaceutical composition of claim 61, wherein said dialkylphosphate is dimethylphosphate.

63. The pharmaceutical composition of claim 61, wherein said dialkylphosphate is diethylphosphate.

64. The pharmaceutical composition of claim 61, 62, or 63 wherein said composition is in the form of an ingestible tablet.

65. The pharmaceutical composition of claim 61, 62, or 63 wherein said composition is in the form of an intravenous preparation.

66. The pharmaceutical composition of claim 61, 62, or 63 wherein said composition is in the form of an oral suspension.

67. A method of treating hypothyroidism comprising administering to a patient in need thereof an iodotyrosine protected at a phenolic hydroxyl, wherein said protecting group is a dialkylphosphate.

68. The method of claim 67, wherein said dialkylphosphate is dimethylphosphate.

69. The method of claim 67, wherein said dialkylphosphate is a diethylphosphate.

70. The method of claim 67, 68, or 69 wherein said iodotyrosine is administered in the form of an ingestible tablet.

71. The method of claim 67, 68, or 69 wherein said iodotyrosine is administered in the form of an intravenous preparation.

72. The method of claim 67, 68, or 69 wherein said iodotyrosine is administered in the form of an oral suspension.

74. The composition of claim 72, wherein said dialkylphosphinate is dimethylphosphinate.

75. The composition of claim 72, wherein said dialkylphosphinate is diethylphosphinate.

73. A composition comprising diiodotyrosine protected at a phenolic hydroxyl with a protecting group, wherein said protecting group is a dialkylphosphinate.

76. A method of stabilizing and increasing the shelf life of a thyroid hormone comprising protecting diiodotyrosine with a protecting group at a phenolic hydroxyl, wherein said protecting group is a dialkylphosphinate.

77. The method of claim 76, wherein said dialkylphosphinate is dimethylphosphinate.

78. The method of claim 76, wherein said dialkylphosphinate is diethylphosphinate.

79. A pharmaceutical composition comprising a diiodotyrosine protected with a protecting group at a phenolic hydroxyl, wherein said protecting group is a dialkylphosphinate;

and a pharmaceutically acceptable excipient.

80. The pharmaceutical composition of claim 79, wherein said dialkylphosphinate is dimethylphosphinate.

81. The pharmaceutical composition of claim 79, wherein said dialkylphosphinate is diethylphosphinate.

82. The pharmaceutical composition of claim 79, 80, or 81 wherein said composition is in the form of an ingestible tablet.

83. The pharmaceutical composition of claim 79, 80, or 81 wherein said composition is in the form of an intravenous preparation.

84. The pharmaceutical composition of claim 79, 80 or 81 wherein said composition is in the form of an oral suspension.

85. A method of treating hypothyroidism comprising administering to a patient in need thereof a diiodotyrosine protected at a phenolic hydroxyl, wherein said protecting group is a dialkylphosphinate.

86. The method of claim 85, wherein said dialkylphosphinate is dimethylphosphinate.

87. The method of claim 85, wherein said dialkylphosphinate is diethylphosphinate.

88. The method of claim 85, 86, or 87 wherein said diiodotyrosine is administered in the form of an ingestible tablet.

89. The method of claim 85, 86, or 87 wherein said diiodotyrosine is administered in the form of an intravenous preparation.

90. The method of claim 85, 86, or 87 wherein said diiodotyrosine is administered in the form of an oral suspension.

91. A composition comprising diiodotyrosine protected at a phenolic hydroxyl with a protecting group, wherein said protecting group is a dialkylphosphate.

92. The method of claim 91, wherein said dialkylphosphate is dimethylphosphate.

93. The method of claim 91, wherein said dialkylphosphate is diethylphosphate.

94. A method of stabilizing and increasing the shelf life of a thyroid hormone comprising protecting diiodotyrosine with a protecting group at a phenolic hydroxyl, wherein said protecting group is a dialkylphosphate.

95. The pharmaceutical composition of claim 94, wherein said dialkylphosphate is dimethylphosphate.

96. The pharmaceutical composition of claim 94, wherein said dialkylphosphate is diethylphosphate.

97. A pharmaceutical composition comprising a diiodotyrosine protected with a protecting group at a phenolic hydroxyl, wherein said protecting group is a dialkylphosphate;

and a pharmaceutically acceptable excipient.

98. The pharmaceutical composition of claim 97, wherein said dialkylphosphate is dimethylphosphate.

99. The pharmaceutical composition of claim 97, wherein said dialkylphosphate is diethylphosphate.

100. The pharmaceutical composition of claim 97, 98, or 99 wherein said composition is in the form of an ingestible tablet.

101. The pharmaceutical composition of claim 97, 98, or 99 wherein said composition is in the form of an intravenous preparation.

102. The pharmaceutical composition of claim 97, 98, or 99 wherein said composition is in the form of an oral suspension.

103. A method of treating hypothyroidism comprising administering to a patient in need thereof a diiodotyrosine protected at a phenolic hydroxyl, wherein said protecting group is a dialkylphosphate.

104. The method of claim 103, wherein said dialkylphosphate is dimethylphosphate.

105. The method of claim 103, wherein said dialkylphosphate is diethylphosphate.

106. The method of claim 103, 104, or 105 wherein said diiodotyrosine is administered in the form of an ingestible tablet.

107. The method of claim 103, 104, or 105 wherein said diiodotyrosine is administered in the form of an intravenous preparation.

108. The method of claim 103, 104, or 105 wherein said diiodotyrosine is administered in the form of an oral suspension.