Pharmaceutical compositions of calcitonin drug-oligomer conjugates and methods of treating diseases therewith

• US 6,770,625 B2
• Filed: 09/05/2002
• Issued: 08/03/2004
• Est. Priority Date: 09/07/2001
• Status: Expired due to Term

• Current Assignee: Biocon Limited (Biocon Incorporated)
• Original Assignee: Nobex Corporation (Biocon Incorporated)
• Inventors: Opawale, Foyeke, Hickey, Anthony, Soltero, Richard, Bovet, Li Li, Rehlaender, Bruce, Ekwuribe, Nnochiri N.
• Primary Examiner(s): RUSSEL, JEFFREY E
• Application Number:
  US10/235,284
• Publication Number:
  US 20030069170A1
• Time in Patent Office: 698 Days
• Field of Search: 424/450, 514/2, 514/3, 514/4, 514/12, 514/21, 514/784, 514/808, 530/303, 530/304, 530/305, 530/307, 530/345, 530/408, 530/409, 530/410, 530/411
• US Class Current: 514/11.9
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61K 47/554 the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics

Abstract

Pharmaceutical compositions that include a drug-oligomer conjugate, a fatty acid component, and a bile salt component are described. The drug is covalently coupled to an oligomeric moiety. The fatty acid component and the bile salt component are present in a weight-to-weight ratio of between 1:5 and 5:1. Methods of treating diseases in a subject in need of such treatment using such pharmaceutical compositions are also provided, as are methods of providing such pharmaceutical compositions.

Claims

1. A pharmaceutical composition comprising:

a drug-oligomer conjugate comprising a drug covalently coupled to an oligomeric moiety and wherein the drug is a calcitonin polypeptide;

a fatty acid component comprising a fatty acid; and

a bile salt component comprising a bile salt;

wherein the fatty acid component and the bile salt component are present in a weight-to-weight ratio of between 1;

5 and 5;

1, wherein the fatty acid component is present in an amount sufficient to lower the precipitation point of the bile salt compared to a precipitation point of the bile salt if the fatty acid component were not present in the pharmaceutical composition, and wherein the bile salt component is present in an amount sufficient to lower the solubility point of the fatty acid compared to a solubility point of the fatty acid if the bile salt were not present in the pharmaceutical composition.

2. The pharmaceutical composition of claim 1, wherein the fatty acid component is present in an amount sufficient to lower the precipitation point of the bile salt by at least 1.0 pH units.

3. The pharmaceutical composition of claim 1, wherein the bile salt component is present in an amount sufficient to lower the solubility point of the fatty acid by at least 0.5 pH units.

4. The pharmaceutical composition of claim 1, wherein the bile salt component is present in an amount such that the fatty acid is soluble at a pH of 8.2, and wherein the fatty acid component is present in an amount such that the bile salt remains in solution at a pH of 5.5.

5. The pharmaceutical composition of claim 1, wherein the fatty acid component and the bile salt component are present in a weight ratio of between 1:

2 and 2;

1.

6. The pharmaceutical composition of claim 1, wherein the bile salt component comprises a pharmaceutically acceptable salt of cholic acid.

7. The pharmaceutical composition of claim 1, wherein the bile salt component is sodium cholate.

8. The pharmaceutical composition of claim 1, wherein the fatty acid component comprises a medium-chain fatty acid and a long-chain fatty acid.

9. The pharmaceutical composition of claim 8, wherein the medium-chain fatty acid is selected from the group consisting of lauric acid, capric acid, and mixtures thereof, and the long-chain fatty acid is oleic acid.

10. The pharmaceutical composition of claim 1, wherein the pH of the composition is between 6.2 and 9.0.

11. The pharmaceutical composition of claim 1, further comprising a buffering component.

12. The pharmaceutical composition of claim 11, wherein the buffering component comprises tris-base or trolamine.

13. The pharmaceutical composition of claim 11, wherein the pharmaceutical composition is a liquid pharmaceutical composition.

14. The pharmaceutical composition of claim 13, wherein the liquid pharmaceutical composition is suitable for oral administration.

15. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a solid dosage pharmaceutical composition.

16. The pharmaceutical composition of claim 1, wherein the calcitonin polypeptide is salmon calcitonin.

17. The pharmaceutical composition of claim 16, wherein the drug-oligomer moiety comprises salmon calcitonin coupled to two oligomeric moieties, wherein one oligomeric moiety is coupled to the lysine at the 11 position of the salmon calcitonin, and wherein one oligomeric moiety is coupled to the lysine at the 18 position of the salmon calcitonin.

18. The pharmaceutical composition of claim 17, wherein the oligomeric moiety coupled to the lysine at the 11 position comprises the structure CH₃O(C₂H₄O)₇—

(CH₂)₇—

C(O)— and

wherein the oligomeric moiety coupled to the lysine at the 18 position of the salmon calcitonin comprises the structure CH₃O(C₂H₄O)₇—

(CH₂)₇—

C(O)—

.

19. The pharmaceutical composition of claim 1, wherein the drug-oligomer conjugate is present as a substantially monodispersed mixture.

20. The pharmaceutical composition of claim 1, wherein the drug-oligomer conjugate is present as a monodispersed mixture.

21. The pharmaceutical composition of claim 1, wherein the drug-oligomer conjugate is amphiphilically balanced.

22. The pharmaceutical composition of claim 1, wherein the oligomeric moiety comprises a hydrophilic moiety and a lipophilic moiety.

37. The pharmaceutical composition of claim 1, wherein the calcitonin polypeptide is salmon calcitonin.

38. The pharmaceutical composition of claim 37, wherein the drug-oligomer moiety comprises salmon calcitonin coupled to two oligomeric moieties, wherein one oligomeric moiety is coupled to the lysine at the 11 position of the salmon calcitonin, and wherein one oligomeric moiety is coupled to the lysine at the 18 position of the salmon calcitonin.

39. The pharmaceutical composition of claim 38, wherein the oligomeric moiety coupled to the lysine at the 11 position comprises the structure CH₃O(C₂H₄O)₇—

(CH₂)₇—

C(O)— and

wherein the oligomeric moiety coupled to the lysine at the 18 position of the salmon calcitonin comprises the structure CH₃O(C₂H₄O)₇—

(CH₂)₇—

C(O)—

.

23. A pharmaceutical composition comprising:

a drug-oligomer conjugate comprising a drug covalently coupled to an oligomeric moiety and wherein the drug is a calcitonin polypeptide;

a bile salt component comprising a bile salt; and

a fatty acid component comprising a fatty acid, wherein the fatty acid component and the bile salt component are present in a weight-to-weight ratio of between 1;

5 and 5;

1, and wherein the fatty acid component is present in a first amount such that, at the precipitation point of the bile salt, the bile salt precipitates as first bile salt particles that, upon a return to a pH above the precipitation point of the bile salt, re-solubilize more quickly than second bile salt particles that would have precipitated if the fatty acid component were not present in the composition.

24. The pharmaceutical composition of claim 23, wherein the precipitation point of the bile salt is at or below a pH of 5.5.

25. The pharmaceutical composition of claim 23, wherein the first bile salt particles are able to re-solubilize in less than 75% of the time it would have taken for the second bile salt particles to re-solubilize.

26. The pharmaceutical composition of claim 23, wherein the fatty acid component and the bile salt component are present in a weight ratio of between 1:

2 and 2;

1.

27. The pharmaceutical composition of claim 23, wherein the bile salt component comprises a pharmaceutically acceptable salt of cholic acid.

28. The pharmaceutical composition of claim 23, wherein the bile salt component is sodium cholate.

29. The pharmaceutical composition of claim 23, wherein the fatty acid component comprises a medium-chain fatty acid and a long-chain fatty acid.

30. The pharmaceutical composition of claim 29, wherein the medium-chain fatty acid is selected from the group consisting of lauric acid, capric acid, and mixtures thereof, and the long-chain fatty acid is oleic acid.

31. The pharmaceutical composition of claim 23, wherein the pH of the composition is between 6.2 and 9.0.

32. The pharmaceutical composition of claim 23, further comprising a buffering component.

33. The pharmaceutical composition of claim 32, wherein the buffering component comprises tris-base or trolamine.

34. The pharmaceutical composition of claim 32, wherein the pharmaceutical composition is a liquid pharmaceutical composition.

35. The pharmaceutical composition of claim 34, wherein the liquid pharmaceutical composition is suitable for oral administration.

36. The pharmaceutical composition of claim 23, wherein the pharmaceutical composition is a solid dosage pharmaceutical composition.

40. The pharmaceutical composition of claim 23, wherein the drug-oligomer conjugate is present as a substantially monodispersed mixture.

41. The pharmaceutical composition of claim 23, wherein the drug-oligomer conjugate is present as a monodispersed mixture.

42. The pharmaceutical composition of claim 23, wherein the drug-oligomer conjugate is amphiphilically balanced.

43. The pharmaceutical composition of claim 23, wherein the oligomeric moiety comprises a hydrophilic moiety and a lipophilic moiety.

44. A pharmaceutical composition comprising:

a drug-oligomer conjugate comprising a drug and an oligomeric moiety and wherein the drug is a calcitonin polypeptide;

between 0.1 and 15% (w/v) of a fatty acid component; and

between 0.1 and 15% (w/v) of a bile salt component;

wherein the fatty acid component and the bile salt component are present in a weight-to-weight ratio of between 1;

5 and 5;

1 and wherein the fatty acid component comprises a medium-chain fatty acid and a long-chain fatty acid.

45. The pharmaceutical composition claim 44, wherein the fatty acid component and the bile salt component are present in a weight ratio of between 1:

2 and 2;

1.

46. The pharmaceutical composition of claim 44, wherein the bile salt component comprises a pharmaceutically acceptable salt of cholic acid.

47. The pharmaceutical composition of claim 44, wherein the bile salt component is sodium cholate.

48. The pharmaceutical composition of claim 44, wherein the medium-chain fatty acid is selected from the group consisting of lauric acid, capric acid, and mixtures thereof, and the long-chain fatty acid is oleic acid.

49. The pharmaceutical composition of claim 44, wherein the pH of the composition between 6.2 and 9.0.

50. The pharmaceutical composition of claim 44, further comprising a buffering component.

51. The pharmaceutical composition of claim 50, wherein the buffering component comprises iris-base or trolamine.

52. The pharmaceutical composition of claim 50, wherein the pharmaceutical composition is a liquid pharmaceutical composition.

53. The pharmaceutical composition of claim 52, wherein the liquid pharmaceutical composition is suitable for oral administration.

54. The pharmaceutical composition of claim 44, wherein the pharmaceutical composition is a solid dosage pharmaceutical composition.

55. The pharmaceutical composition of claim 44, wherein the calcitonin polypeptide is salmon calcitonin.

56. The pharmaceutical composition of claim 55, wherein the drug-oligomer moiety comprises salmon calcitonin coupled to two oligomeric moieties, wherein one oligomeric moiety is coupled to the lysine at the 11 position of the salmon calcitonin, and wherein one oligomeric moiety is coupled to the lysine at the 18 position of the salmon calcitonin.

57. The pharmaceutical composition of claim 56, wherein the oligomeric moiety coupled to the lysine at the 11 position comprises the structure CH₃O(C₂H₄O)₇—

(CH₂)₇—

C(O)— and

wherein the oligomeric moiety coupled to the lysine at the 18 position of the salmon calcitonin comprises the structure CH₃O(C₂H₄O)₇—

(CH₂)₇—

C(O)—

.

58. The pharmaceutical composition of claim 44, wherein the drug-oligomer conjugate is present as a substantially monodispersed mixture.

59. The pharmaceutical composition of claim 44, wherein the drug-oligomer conjugate is present as a monodispersed mixture.

60. The pharmaceutical composition of claim 44, wherein the drug-oligomer conjugate is amphiphilically balanced.

61. The pharmaceutical composition of claim 44, wherein the oligomeric moiety comprises a hydrophilic moiety and a lipophilic moiety.

62. A method of treating a bone disorder in a subject in need of such treatment, said method comprising administering to the subject a pharmaceutical composition comprising (a) a therapeutically effective amount of a calcitonin drug-oligomer conjugate that comprises a calcitonin drug covalently coupled to an oligomeric moiety;

(b) a fatty acid component comprising a fatty acid; and

(c) a bile salt component comprising a bile salt, wherein the fatty acid component and the bile salt component are present in a weight ratio of between 1;

5 and 5;

1, wherein the fatty acid component is present in an amount sufficient to lower the precipitation point of the bile salt compared to a precipitation point of the bile salt if the fatty acid component were not present in the pharmaceutical composition, and wherein the fatty acid component is present in an amount sufficient to lower the solubility point of the fatty acid compared to a solubility point of the fatty acid if the bile salt were not present in the pharmaceutical composition.

63. The method of claim 62, wherein the fatty acid component is present in an amount sufficient to lower the precipitation point of the bile salt by at least 1.0 pH units.

64. The method of claim 62, wherein the bile salt component is present in an amount sufficient to lower the solubility point of the fatty acid by at least 0.5 pH units.

65. The method of claim 62, wherein the bile salt components is present in an amount such that the fatty acid is soluble at a pH of 8.2, and wherein the fatty acid component is present in an amount such that the bile salt remains in solution at a pH of 5.5.

66. The method of claim 62, wherein the fatty acid component and the bile salt component are present in a weight ratio of between 1:

2 and 2;

1.

67. The method of claim 62, wherein the bile salt component comprises a pharmaceutically acceptable salt of cholic acid.

68. The method of claim 62, wherein the bile salt component is sodium cholate.

69. The method of claim 62, wherein the fatty acid component comprises a medium-chain fatty acid and a long-chain fatty acid.

70. The method of claim 69, wherein the medium-chain fatty acid is selected from the group consisting of lauric acid, capric acid, and mixtures thereof, and the long-chain fatty acid is oleic acid.

71. The method of claim 62, wherein the pH of the composition is between 6.2 and 9.0.

72. The method of claim 62, further comprising a buffering component.

73. The method of claim 72, wherein the buffering component comprises tris-base or trolamine.

74. The method of claim 72, wherein the pharmaceutical composition is a liquid pharmaceutical composition.

75. The method of claim 72, wherein the pharmaceutical composition is a solid dosage pharmaceutical composition.

76. The method of claim 62, wherein the method comprises orally administering the pharmaceutical composition to the subject.

77. The method of claim 62, wherein the calcitonin drug is a calcitonin polypeptide.

78. The method of claim 77, wherein the calcitonin polypeptide is salmon calcitonin.

79. The method of claim 78, wherein the calcitonin drug-oligomer moiety comprises salmon calcitonin coupled to two oligomeric moieties, wherein one oligomeric moiety is coupled to the lysine at the 11 position of the salmon calcitonin, and wherein one oligomeric moiety is coupled to the lysine at the 18 position of the salmon calcitonin.

80. The method of claim 79, wherein the oligomeric moiety coupled to the lysine at the 11 position comprises the structure CH₃O(C₂H₄O)₇—

(CH₂)₇—

C(O)— and

wherein the oligomeric moiety coupled to the lysine at the 18 position of the salmon calcitonin comprises the structure CH₃O(C₂H₄O)₇—

(CH₂)₇—

C(O)—

.

81. The method of claim 62, wherein the calcitonin drug-oligomer conjugate is present as a substantially monodispersed mixture.

82. The method of claim 62, calcitonin drug-oligomer conjugate is present as a monodispersed mixture.

83. The method of claim 62, wherein the calcitonin drug-oligomer conjugate is amphiphilically balanced.

84. The method of claim 62, wherein the oligomeric moiety comprises a hydrophilic moiety and a lipophilic moiety.

85. A method of treating a bone disorder in a subject in need of such treatment, said method comprising administering to the subject a pharmaceutical composition comprising (a) a therapeutically effective amount of a calcitonin drug-oligomer conjugate that comprises a calcitonin drug covalently coupled to an oligomeric moiety;

(b) a bile salt component comprising a bile salt; and

(c) a fatty acid component comprising a fatty acid, wherein the fatty acid component and the bile salt component are present in a weight ratio of between 1;

5 and 5;

1, and wherein the fatty acid component is present in a first amount such that, at the precipitation point of the bile salt, the bile salt precipitates as first bile salt particles that, upon a return to a pH above the precipitation point of the bile salt, re-solubilize more quickly than second bile salt particles that would have precipitated if the fatty acid component were present in a second amount less than the first amount.

86. The method of claim 85, wherein the precipitation point of the bile salt is at or below a pH of 5.5.

87. The method of claim 85, wherein the first bile salt particles are able to re-solubilize in less than 75% of the time it would have taken for the second bile salt particles to re-solubilize.

88. The method of claim 85, wherein the fatty acid component and the bile salt component are present in a weight ratio of between 1:

2 and 2;

1.

89. The method of claim 85, wherein the bile salt component comprises a pharmaceutically acceptable salt of cholic acid.

90. The method of claim 85, wherein the bile salt component is sodium cholate.

91. The method of claim 85, wherein the fatty acid component comprises a medium-chain fatty acid and a long-chain fatty acid.

92. The method of claim 91, wherein the medium-chain fatty acid is selected from the group consisting of lauric acid, capric acid, and mixtures thereof, and the long-chain fatty acid is oleic acid.

93. The method of claim 85, wherein the pH of the composition is between 6.2 and 9.0.

94. The method of claim 85, further comprising a buffering component.

95. The method of claim 94, wherein the buffering component comprises tris-base or trolamine.

96. The method of claim 85, wherein the pharmaceutical composition is a liquid pharmaceutical composition.

97. The method of claim 85, wherein the pharmaceutical composition as a solid dosage pharmaceutical composition.

98. The method of claim 85, wherein the method comprises orally administering the pharmaceutical composition to the subject.

99. The method of claim 85, wherein the calcitonin drug is a calcitonin polypeptide.

100. The method of claim 99, wherein the calcitonin polypeptide is salmon calcitonin.

101. The method of claim 100, wherein the drug-oligomer moiety comprises salmon calcitonin coupled to two oligomeric moieties, wherein one oligomeric moiety is coupled to the lysine at the 11 position of the salmon calcitonin, and wherein one oligomeric moiety is coupled to the lysine at the 18 position of the salmon calcitonin.

102. The method of claim 101, wherein the oligomeric moiety coupled to the lysine at the 11 position comprises the structure CH₃O(C₂H₄O)₇—

(CH₂)₇—

C(O)— and

wherein the oligomeric moiety coupled to the lysine at the 18 position of the salmon calcitonin comprises the structure CH₃O(C₂H₄O)₇—

(CH₂)₇—

C(O)—

.

103. The method of claim 85, wherein the calcitonin drug-oligomer conjugate is present as a substantially monodispersed mixture.

104. The method of claim 85, wherein the calcitonin drug-oligomer conjugate is present as a monodispersed mixture.

105. The method of claim 85, wherein the calcitonin drug-oligomer conjugate is amphiphilically balanced.

106. The method of claim 85, wherein the oligomeric moiety comprises a hydrophilic moiety and a lipophilic moiety.

107. A method of treating a bone disorder in a subject in need of such treatment, said method comprising administering to the subject a pharmaceutical composition comprising (a) a therapeutically effective amount of a calcitonin drug-oligomer conjugate that comprises a calcitonin drug and an oligomeric moiety;

(b) between 0.1 and 15% (w/v) of a fatty acid component; and

(c) between 0.1 and 15% (w/v) of a bile salt component, wherein the fatty acid component and the bile salt component are present in a weight to weight ratio of between 1;

5 and 5;

1.

108. The method of claim 107, wherein the fatty acid component and the bile salt component are present in a weight ratio of between 1:

2 and 2;

1.

109. The method of claim 107, wherein the bile salt component comprises a pharmaceutically acceptable salt of cholic acid.

110. The method of claim 107, wherein the bile salt component is sodium cholate.

111. The method of claim 107, Wherein the fatty acid component comprises a medium-chain fatty acid and a long-chain fatty acid.

112. The method of claim 111, wherein the medium-chain fatty acid is selected from the group consisting of lauric acid, capric acid, and mixtures thereof, and the long-chain fatty acid is oleic acid.

113. The method of claim 107, wherein the pH of the composition is between 6.2 and 9.0.

114. The method of claim 107, further comprising a buffering component.

115. The method of claim 114, wherein the buffering component comprises tris-base or trolamine.

116. The method of claim 114, wherein the pharmaceutical composition is a liquid pharmaceutical composition.

117. The method of claim 107, wherein the pharmaceutical composition is a solid dosage pharmaceutical composition.

118. The method of claim 107, wherein the method comprises orally administering the pharmaceutical composition to the subject.

119. The method of claim 107, wherein the calcitonin drug is a calcitonin polypeptide.

120. The method of claim 119, wherein the calcitonin polypeptide is salmon calcitonin.

121. The method of claim 120, wherein the drug-oligomer moiety comprises salmon calcitonin coupled to two oligomeric moieties, wherein one oligomeric moiety is coupled to the lysine at the 11 position of the salmon calcitonin, and wherein one oligomeric moiety is coupled to the lysine at the 18 position of the salmon calcitonin.

122. The method of claim 121, wherein the oligomeric moiety coupled to the lysine at the 11 position comprises the structure CH₃O(C₂H₄O)₇—

(CH₂)₇—

C(O)— and

wherein the oligomeric moiety coupled to the lysine at the 18 position of the salmon calcitonin comprises the structure CH₃O(C₂H₄O)₇—

(CH₂)₇—

C(O)—

.

123. The method of claim 107, wherein the calcitonin drug-oligomer conjugate is present as a substantially monodispersed mixture.

124. The method of claim 107, wherein the calcitonin drug-oligomer conjugate is present as a monodispersed mixture.

125. The method of claim 107, wherein the calcitonin drug-oligomer conjugate is amphiphilically balanced.

126. The method of claim 107, wherein the oligomeric moiety comprises a hydrophilic moiety and a lipophilic moiety.

127. A pharmaceutical composition comprising:

a drug-oligomer conjugate comprising a drug and an oligomeric moiety and wherein the drug is a calcitonin polypeptide;

between 0.1 and 15% (w/v) of a fatty acid component; and

between 0.1 and 15% (w/v) of a bile salt component;

wherein the fatty acid component and the bile salt component are present in a weight-to-weight ratio of between 1;

5 and 5;

1 and

further comprising a buffering component comprising tris-base or trolamine.

128. The pharmaceutical composition of claim 127, wherein the pharmaceutical composition is a liquid pharmaceutical composition.

129. The pharmaceutical composition of claim 128, wherein the liquid pharmaceutical composition is suitable for oral administration.

130. A pharmaceutical composition comprising:

a drug-oligomer conjugate comprising a drug and an oligomeric moiety and wherein the drug is a calcitonin polypeptide;

between 0.1 and 15% (w/v) of a fatty acid component; and

between 0.1 and 15% (w/v) of a bile salt component;

wherein die fatty acid component and the bile salt component are present in a weight-to-weight ratio of between 1;

5 and 5;

1 and

wherein the pharmaceutical composition is a solid dosage pharmaceutical composition.