Solid Dosage Form of Wetted Heparin

• US 20070224262A1
• Filed: 05/06/2005
• Published: 09/27/2007
• Est. Priority Date: 05/06/2004
• Status: Active Grant

• Current Assignee: NOVO Nordisk North America Operations A/S (Novo Nordisk A/S)
• Original Assignee: Emisphere Technologies, Inc. (Novo Nordisk A/S)
• Inventors: Majuru, Shingai, Singh, Brahma, Dhoot, Nikhil
• Granted Patent: US 8,039,018 B2
• Time in Patent Office: Days
• US Class Current: 424/456
• CPC Class Codes: A61K 31/727 Heparin; Heparan
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Abstract

The present invention relates to a solid pharmaceutical composition (such as a solid dosage form) comprising a delivery agent and wetted heparin. The inclusion of wetted heparin rather than un-wetted heparin in the solid pharmaceutical composition results in increased delivery of the heparin. Without being bound by any particular theory, applicants believe that because the polymer chain of the wetted heparin is already in an “open” form, while un-wetted heparin is not, less of the wetted heparin is broken down in the gastrointestinal tract and is more readily absorbed in the stomach.

Claims

1. A solid pharmaceutical composition comprising:

(a) a delivery agent; and

(b) wetted heparin.

2. The solid pharmaceutical composition of claim 1, wherein the delivery agent is

3. The solid pharmaceutical composition of claim 2, wherein the delivery agent is selected from N-(8-[2-hydroxybenzoyl]-amino)caprylic acid, N-(10-[2-hydroxybenzoyl]amino)decanoic acid, 8-(N-2-hydroxy-5-chlorobenzoyl)aminocaprylic acid, 8-(N-2-Hydroxy-4-methoxybenzoyl)aminocaprylic acid, 4-[(4-chloro, 2-hydroxybenzoyl)-amino]butanoic acid, pharmaceutically acceptable salts thereof, and mixtures thereof.

4. The solid pharmaceutical composition of claim 3, wherein the delivery agent is N-[8-(2-hydroxybenzoyl)amino]caprylic acid or a pharmaceutically acceptable salt thereof.

5. The solid pharmaceutical composition of claim 4, wherein the delivery agent is monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate.

6. The solid pharmaceutical composition of claim 4, wherein the delivery agent is N-(10-[2-hydroxybenzoyl]amino)decanoic acid, or a pharmaceutically acceptable salt thereof.

7. The solid pharmaceutical composition of claim 2, wherein the heparin in the wetted heparin is selected from unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin, ultra low molecular weight heparin, and mixtures thereof.

8. The solid pharmaceutical composition of claim 2, wherein the heparin in the wetted heparin is unfractionated heparin.

9. The solid pharmaceutical composition of claim 2, wherein the heparin in the wetted heparin is low molecular weight heparin.

10. The solid dosage form of claim 2, wherein the heparin in the wetted heparin is very low molecular weight heparin.

11. The solid pharmaceutical composition of claim 2, wherein the heparin in the wetted heparin is ultra low molecular weight heparin.

12. The solid pharmaceutical composition of claim 2, wherein the ratio of the delivery agent to the heparin (mg to USP heparin units) in the wetted heparin ranges from about 1:

20 to about 1;

400.

13. The solid pharmaceutical composition of claim 2, wherein the delivery agent and wetted heparin are gelled together.

14. The solid pharmaceutical composition of claim 2, further comprising a gelling agent.

15. The solid pharmaceutical composition of claim 2, wherein the solid pharmaceutical composition comprises a sufficient amount of delivery agent to cause gelling of the delivery agent and wetted heparin.

16. The solid pharmaceutical composition of claim 2, wherein the wetted heparin comprises heparin and a wetting agent.

17. The solid pharmaceutical composition of claim 16, wherein the delivery agent is partially solubilized by the wetting agent.

18. A solid dosage form comprising the solid pharmaceutical composition of claim 2.

19. The solid dosage form of claim 18, wherein the solid dosage form is a tablet.

20. The solid dosage form of claim 18, wherein the solid dosage form is a capsule.

21. The solid dosage form of claim 20, wherein the solid dosage form is a soft gelatin capsule.

22. The solid dosage form of claim 20, wherein the solid dosage form is a hard gelatin capsule.

23. The solid pharmaceutical composition of claim 2 wherein the dosage of heparin is greater than about 150,000 IU.

24. The solid pharmaceutical composition of claim 23 wherein the dosage of heparin is about 15,000 IU to about 150,000 IU.

25. The solid pharmaceutical composition of claim 24 wherein the dosage of heparin is about 25,000 IU to about 90,000 IU.

26. The solid pharmaceutical composition of claim 25 wherein the dosage of heparin is about 30,000 IU to about 80,000 IU.

27. The solid pharmaceutical composition of claim 26 wherein the dosage of heparin is about 37,500 IU to about 75,000 IU.

28. The solid pharmaceutical composition of claim 27 wherein the dosage of heparin is about 37,500 IU.

29. The solid pharmaceutical composition of claim 27 wherein the dosage of heparin is about 40,000 IU.

30. The solid pharmaceutical composition of claim 27 wherein the dosage of heparin is about 50,000 IU.

31. The solid pharmaceutical composition of claim 27 wherein the dosage of heparin is about 60,000 IU.

32. The solid pharmaceutical composition of claim 27 wherein the dosage of heparin is about 75,000 IU.

33. The solid pharmaceutical composition of claim 2 wherein the dosage of SNAC is less than about 2.4 g.

34. The solid pharmaceutical composition of claim 33 wherein the dosage of SNAC is less than about 2.2 g.

35. The solid pharmaceutical composition of claim 34 wherein the dosage of SNAC is less than about 1.8 g.

36. The solid pharmaceutical composition of claim 35 wherein the dosage of SNAC is less than about 1.2 g.

37. The solid pharmaceutical composition of claim 36 wherein the dosage of SNAC is less than about 1 g.

38. The solid pharmaceutical composition of claim 37 wherein the dosage of SNAC is less than about 0.9 g.

39. The solid pharmaceutical composition of claim 38 wherein the dosage of SNAC is less than about 0.8 g.

40. The solid pharmaceutical composition of claim 39 wherein the dosage of SNAC is less than about 0.7 g.

41. The solid pharmaceutical composition of claim 40 wherein the dosage of SNAC is less than about 0.6 g.

42. The solid pharmaceutical composition of claim 41 wherein the dosage of SNAC is less than or equal to about 0.5 g.

43. The solid pharmaceutical composition of claim 1 wherein the dosage of SNAC is about 50 mg to about 2.4 g.

44. The solid pharmaceutical composition of claim 43 wherein the dosage of SNAC is about 100 mg to about 1.2 g.

45. The solid pharmaceutical composition of claim 44 wherein the dosage of SNAC is about 900 mg to about 1.2 g.

46. The solid pharmaceutical composition of claim 45 wherein the dosage of SNAC is about 1.15 g.

47. The solid pharmaceutical composition of claim 44 wherein the dosage of SNAC is about 125 mg to about 1 g.

48. The solid pharmaceutical composition of claim 47 wherein the dosage of SNAC is about 250 mg to about 750 mg.

49. The solid pharmaceutical composition of claim 48 wherein the dosage of SNAC is about 400 mg to about 600 mg.

50. The solid pharmaceutical composition of claim 49 wherein the dosage of SNAC is about 500 mg.

51. A method for administering heparin to an animal comprising the step of administering the solid pharmaceutical composition or dosage form of claim 2.

52. A method of treating or preventing thrombosis in an animal comprising orally administering an anti-thrombosis effective amount of the solid pharmaceutical composition or dosage form of claim 2.

53. The method of claim 52, wherein the thrombosis is deep vein thrombosis or pulmonary embolism.

54. The method of claim 51 wherein said effective amount is sufficient to increase the aPTT by at least about 100% as compared to an untreated state of the same subject.

55. The method of claim 54 wherein said effective amount is sufficient to increase the aPTT by at least about 150% as compared to an untreated state of the same subject.

56. The method of claim 55 wherein said effective amount is sufficient to increase the aPTT by at least about 165% as compared to an untreated state of the same subject.

57. The method of claim 56 wherein said effective amount is sufficient to increase the aPTT by at least about 200% as compared to an untreated state of the same subject.

58. The method of claim 51 wherein said effective amount is sufficient to increase the AntiFactor Xa to about 0.05 to about 0.4 IU/ml.

59. The method of claim 58 wherein said effective amount is sufficient to increase the AntiFactor Xa to about 0.15 to about 0.35 IU/ml.

60. The method of claim 59 wherein said effective amount is sufficient to increase the AntiFactor Xa to about 0.15 to about 0.20 IU/ml.

61. The method of claim 60 wherein said effective amount is sufficient to increase the AntiFactor Xa to about 0.2 IU/ml.

62. The method of claim 51 wherein said effective amount is sufficient to increase the AntiFactor Xa to greater than about 0.05 IU/ml.

63. The method of claim 62 wherein said effective amount is sufficient to increase the AntiFactor Xa to greater than about 0.1 IU/ml.

64. The method of claim 63 wherein said effective amount is sufficient to increase the AntiFactor Xa to greater than about 0.15 IU/ml.

77. A method of preventing thrombosis in an animal comprising orally administering an anti-thrombosis effective amount of the solid pharmaceutical composition or dosage form of any of claim 2.

78. The method of claim 77, wherein the thrombosis is deep vein thrombosis or pulmonary embolism.

79. The method of claim 77 wherein said effective amount is sufficient to increase the aPTT by less than or equal to about 10% as compared to an untreated state of the same patient.

80. The method of claim 79 wherein said effective amount is sufficient to increase the aPTT by about 10%.

81. The method of claim 80 wherein no or a decreased number of thrombosis is seen as compared to an untreated patient.

82. The method of claim 77 wherein said effective amount is sufficient to increase the aPTT by more than about 10% as compared to an untreated state of the same patient.

83. The method of claim 77 wherein said effective amount is sufficient to increase the AntiFactor Xa to about 0.05 to about 0.4 IU/ml.

84. The method of claim 83 wherein said effective amount is sufficient to increase the AntiFactor Xa to about 0.15 to about 0.35 IU/ml.

85. The method of claim 84 wherein said effective amount is sufficient to increase the AntiFactor Xa to about 0.25 IU/ml.

86. The method of treating thrombosis in an animal of claim 2 wherein said animal is a mammal.

87. The method of treating thrombosis in a mammal of claim 86 wherein said mammal is a human.

88. The method of preventing thrombosis in an animal of claim 2 wherein said animal is a mammal.

89. The method of preventing thrombosis in a mammal of claim 88 wherein said mammal is a human.

104. The solid pharmaceutical composition of claim 81, wherein the human exhibits an Emax for anti-factor IIa of at least about 0.4 IU/ml.

65. A method of preparing a solid dosage form of wetted heparin comprising the steps of:

(a) blending a delivery agent and heparin;

(b) adding the delivery agent and heparin to a wetting agent to obtain a composition containing wetted heparin.

66. The method of claim 65, wherein the heparin in the wetted heparin is selected from unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin, ultra low molecular weight heparin, and mixtures thereof.

67. The method of claim 65, wherein the heparin in the wetted heparin is unfractionated heparin.

68. The method of claim 65, wherein the heparin in the wetted heparin is low molecular weight heparin.

69. The solid dosage form of claim 65, wherein the heparin in the wetted heparin is very low molecular weight heparin.

70. The method of claim 65, wherein the heparin in the wetted heparin is ultra low molecular weight heparin.

71. A method of improving the bioavailability of a solid heparin dosage form containing unwetted heparin, comprising the step of:

(a) substituting the unwetted heparin in the dosage form with wetted heparin.

72. The method of claim 71, wherein the heparin in the wetted heparin is selected from unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin, ultra low molecular weight heparin, and mixtures thereof.

73. The method of claim 71, wherein the heparin in the wetted heparin is unfractionated heparin.

74. The method of claim 71, wherein the heparin in the wetted heparin is low molecular weight heparin.

75. The method of claim 71, wherein the heparin in the wetted heparin is very low molecular weight heparin.

76. The method of claim 71, wherein the heparin in the wetted heparin is ultra low molecular weight heparin.

90. A solid pharmaceutical composition comprising:

(a) SNAC, and

(b) wetted heparin,

wherein;

(1) 120 minutes after oral administration of the solid pharmaceutical composition to a human, the human exhibits a plasma aPTT, an anti-factor IIa plasma concentration, an anti-factor Xa plasma concentration, or any combination of the foregoing that are statistically significantly greater than that 120 minutes after oral administration of an identical composition containing unwetted heparin instead of wetted heparin, or

(2) after oral administration of the solid pharmaceutical composition to a human, the human exhibits an Emax for aPTT, EAUC(0-inf) for aPTT, Emax for anti-factor IIa, EAUC(0-inf) for anti-factor IIa, Emax for anti-factor Xa, EAUC(0-inf) for anti-factor Xa, or any combination of the foregoing that are statistically significantly greater than after oral administration of an identical composition containing unwetted heparin instead of wetted heparin, or

(3) both.

91. The solid pharmaceutical composition of claim 90, wherein the heparin in the wetted heparin is selected from unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin, ultra low molecular weight heparin, and mixtures thereof.

92. The solid pharmaceutical composition of claim 90, wherein the heparin in the wetted heparin is unfractionated heparin.

93. The solid pharmaceutical composition of claim 90, wherein the heparin in the wetted heparin is low molecular weight heparin.

94. The solid pharmaceutical composition of claim 90, wherein the heparin in the wetted heparin is very low molecular weight heparin.

95. The solid pharmaceutical composition of claim 90, wherein the heparin in the wetted heparin is ultra low molecular weight heparin.

96. A solid pharmaceutical composition comprising:

(a) SNAC, and

(b) wetted heparin,

wherein;

(1) 120 minutes after oral administration of the solid pharmaceutical composition to a human, the human exhibits one or more of the following;

(i) a plasma aPTT of at least about 38 seconds,

(ii) an anti-factor IIa plasma concentration of at least 0.11 IU/ml, or

(iii) an anti-factor Xa plasma concentration of at least 0.1 IU/ml,

(2) after oral administration of the solid pharmaceutical composition to a human, the human exhibits one or more of the following;

(i) an Emax for aPTT of at least about 50 IU/ml,

(ii) an EAUC(0-inf) for aPTT of at least about 80 IU*hr/ml,

(iii) an Emax for anti-factor IIa of at least about 0.35 IU/ml,

(iv) an EAUC(0-inf) for anti-factor IIa of at least about 0.7 IU*hr/ml,

(v) an Emax for anti-factor Xa of at least about 0.35 IU/ml,

(vi) an EAUC(0-inf) for anti-factor Xa of at least about 0.68 IU*hr/ml, or

(3) both.

97. The solid pharmaceutical composition of claim 96, wherein the human exhibits a plasma aPTT of at least about 39 seconds.

98. The solid pharmaceutical composition of claim 96, wherein the human exhibits a plasma aPTT of at least about 50 seconds.

99. The solid pharmaceutical composition of claim 96, wherein the human exhibits an anti-factor IIa plasma concentration of at least about 0.2 IU/ml.

100. The solid pharmaceutical composition of claim 96, wherein the human exhibits an anti-factor Xa plasma concentration of at least about 0.2 IU/ml.

101. The solid pharmaceutical composition of claim 96, wherein the human exhibits an EAUC(0-inf) for aPTT of at least about 100 IU*hr/ml.

102. The solid pharmaceutical composition of claim 96, wherein the human exhibits an EAUC(0-inf) for aPTT of at least about 150 IU*hr/ml.

103. The solid pharmaceutical composition of claim 96, wherein the human exhibits an EAUC(0-inf) for aPTT of at least about 180 IU*hr/ml.

105. The solid pharmaceutical composition of claim 96, wherein the human exhibits an EAUC(0-inf) for anti-factor IIa of at least about 1.0 IU*hr/ml.

106. The solid pharmaceutical composition of claim 96, wherein the human exhibits an Emax for anti-factor Xa of at least about 0.4 IU/ml.

107. The solid pharmaceutical composition of claim 96, wherein the human exhibits an EAUC(0-inf) for anti-factor Xa of at least about 1.0 IU*hr/ml.

108. The solid pharmaceutical composition of claim 96, wherein the heparin in the wetted heparin is selected from unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin, ultra low molecular weight heparin, and mixtures thereof.

109. The solid pharmaceutical composition of claim 96, wherein the heparin in the wetted heparin is unfractionated heparin.

110. The solid pharmaceutical composition of claim 96, wherein the heparin in the wetted heparin is low molecular weight heparin.

111. The solid dosage form of claim 96, wherein the heparin in the wetted heparin is very low molecular weight heparin.

112. The solid pharmaceutical composition of claim 96, wherein the heparin in the wetted heparin is ultra low molecular weight heparin.

113. A method of treating or preventing DVT in a human in need thereof, the method comprising orally administering one or more solid pharmaceutical compositions comprising SNAC and wetted heparin, wherein

(1) 120 minutes after oral administration of the solid pharmaceutical composition to a human, the human exhibits one or more of the following:

(i) a plasma aPTT of at least about 38 seconds,

(ii) an anti-factor IIa plasma concentration of at least about 0.11 IU/ml, or

(iii) an anti-factor Xa plasma concentration of at least about 0.1 IU/ml,

(2) after oral administration of the solid pharmaceutical composition to a human, the human exhibits one or more of the following;

(i) an Emax for aPTT of at least about 50 IU/ml,

(ii) an EAUC(0-inf) for aPTT of at least 80 IU*hr/ml,

(iii) an Emax for anti-factor IIa of at least about 0.35 IU/ml,

(iv) an EAUC(0-inf) for anti-factor IIa of at least about 0.7 IU*hr/ml,

(v) an Emax for anti-factor Xa of at least about 0.35 IU/ml,

(vi) an EAUC(0-inf) for anti-factor Xa of at least about 0.68 IU*hr/ml, or

(3) both.

114. The method of claim 113, wherein the human exhibits a plasma aPTT of at least about 39 seconds.

115. The method of claim 113, wherein the human exhibits a plasma aPTT of at least about 50 seconds.

116. The method of claim 113, wherein the human exhibits an anti-factor IIa plasma concentration of at least about 0.2 IU/ml.

117. The method of claim 113, wherein the human exhibits an anti-factor Xa plasma concentration of at least about 0.2 IU/ml.

118. The method of claim 113, wherein the human exhibits an EAUC(0-inf) for aPTT of at least about 100 IU*hr/ml.

119. The method of claim 113, wherein the human exhibits an EAUC(0-inf) for aPTT of at least about 150 IU*hr/ml.

120. The method of claim 113, wherein the human exhibits an EAUC(0-inf) for aPTT of at least about 180 IU*hr/ml.

121. The method of claim 113, wherein the human exhibits an Emax for anti-factor IIa of at least about 0.4 IU/ml.

122. The method of claim 113, wherein the human exhibits an EAUC(0-inf) for anti-factor IIa of at least about 1.0 IU*hr/ml.

123. The method of claim 113, wherein the human exhibits an Emax for anti-factor Xa of at least about 0.4 IU/ml.

124. The method of claim 113, wherein the human exhibits an EAUC(0-inf) for anti-factor Xa of at least about 1.0 IU*hr/ml.

125. The method of claim 113, wherein the heparin in the wetted heparin is selected from unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin, ultra low molecular weight heparin, and mixtures thereof.

126. The method of claim 113, wherein the heparin in the wetted heparin is unfractionated heparin.

127. The method of claim 113, wherein the heparin in the wetted heparin is low molecular weight heparin.

128. The method of claim 113, wherein the heparin in the wetted heparin is very low molecular weight heparin.

129. The method of claim 113, wherein the heparin in the wetted heparin is ultra low molecular weight heparin.