Diuretic aerosols and methods of making and using them

• US 7,981,401 B2
• Filed: 02/02/2007
• Issued: 07/19/2011
• Est. Priority Date: 11/26/2002
• Status: Active Grant

• Current Assignee: Alexza Pharmaceuticals Inc. (Grupo Ferrer Internacional SA)
• Original Assignee: Alexza Pharmaceuticals Inc. (Grupo Ferrer Internacional SA)
• Inventors: Every, Nathan R., Lu, Amy T., Hale, Ron L., Rabinowitz, Joshua D.
• Primary Examiner(s): ALSTRUM ACEVEDO, JAMES HENRY
• Application Number:
  US11/670,892
• Publication Number:
  US 20070140982A1
• Time in Patent Office: 1,628 Days
• Field of Search: 424/43, 424/45, 514/173.249, 514/263.34, 514/404, 514/416, 514/560, 514/601, 514/736, 514/737
• US Class Current: 424/43
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 9/007 Pulmonary tract; Aromatherapy
• CPC Class Codes: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M

Abstract

Described herein are diuretic condensation aerosols and methods of making and using them. Kits for delivering a condensation aerosol are also described. The diuretic aerosols typically comprise diuretic condensation aerosol particles that comprise a diuretic compound. In some variations the diuretic compound is selected from the group consisting of bumetanide, ethacrynic acid, furosemide, muzolimine, spironolactone, torsemide, triamterene, tripamide, BG 9928, and BG 9719. Methods of treating edema using the described aerosols are also provided. In general, the methods typically comprise the step of administering a therapeutically effective amount of diuretic condensation aerosol to a person with edema. The diuretic condensation aerosol may be administered in a single inhalation, or may be administered in more than one inhalation. Methods of forming a diuretic condensation aerosol are also described. The methods typically comprise the steps of providing a diuretic composition, vaporizing the composition to form a vapor, and then condensing the diuretic composition vapor.

Claims

1. A condensation aerosol for delivery wherein the condensation aerosol is formed by heating a film containing a drug, to produce a vapor of the drug, and condensing the vapor to form a condensation aerosol characterized by less than 10% drug degradation products by weight, and a MMAD of less than 5 microns, wherein the drug is selected from the group consisting of bumetanide, ethacrynic acid, furosemide, muzolimine, spironolactone, torsemide, triamterene, tripamide, BG 9928 and BG 9719.

2. The condensation aerosol of claim 1, wherein the film has a thickness between 0.05 and 20 microns.

3. The condensation aerosol of claim 2, wherein the film has a thickness between 0.2 and 10 microns.

4. The condensation aerosol of claim 1, wherein the condensation aerosol is characterized by a MMAD of less than 3 microns.

5. The condensation aerosol of claim 1, wherein the condensation aerosol is characterized by a MMAD of 1 to 3.5 microns.

6. The condensation aerosol of claim 1, wherein the condensation aerosol is characterized by less than 5% drug degradation products by weight.

7. The condensation aerosol of claim 6, wherein the condensation aerosol is characterized by less than 2.5% drug degradation products by weight.

8. The condensation aerosol of claim 6, wherein the condensation aerosol is characterized by an MMAD of 1 to 3.5 microns and wherein the drug is bumetanide.

9. The condensation aerosol of claim 1, wherein the solid support is a metal foil.

10. The condensation aerosol of claim 1, wherein the drug is bumetanide.

11. The condensation aerosol of claim 1, wherein the drug is ethacrynic acid.

12. The condensation aerosol of claim 1, wherein the drug is furosemide.

13. The condensation aerosol of claim 1, wherein the drug is muzolimine.

14. The condensation aerosol of claim 1, wherein the drug is spironolactone.

15. The condensation aerosol of claim 1, wherein the drug is torsemide.

16. The condensation aerosol of claim 1, wherein the drug is triamterene.

17. The condensation aerosol of claim 1, wherein the drug is tripamide.

18. The condensation aerosol of claim 1, wherein the drug is BG 9928.

19. The condensation aerosol of claim 1, wherein the drug is BG 9719.

20. A method of producing a drug in an aerosol form comprising:

a. heating a film containing the drug to produce a vapor of the drug, and

b. providing an air flow through the vapor to form a condensation aerosol characterized by less than 10% drug degradation products by weight, and a MMAD of less than 5 microns, wherein the drug is selected from the group consisting of bumetanide, ethacrynic acid, furosemide, muzolimine, spironolactone, torsemide, triamterene, tripamide, BG 9928 and BG 9719.

21. The method of claim 20, wherein the condensation aerosol is formed at a rate greater than 10⁹ particles per second.

22. The method of claim 21, wherein the condensation aerosol is formed at a rate greater than 10¹⁰ particles per second.

23. The method of claim 20, wherein the condensation aerosol is characterized by a MMAD of less than 3 microns.

24. The method of claim 20, wherein the condensation aerosol is characterized by a MMAD of 1 to 3.5 microns.

25. The method of claim 20, wherein the condensation aerosol is characterized by less than 5% drug degradation products by weight.

26. The method of claim 25, wherein the condensation aerosol is characterized by less than 2.5% drug degradation products by weight.

27. The method of claim 25, wherein the condensation aerosol is characterized by a MMAD of 1 to 3.5 microns and wherein the drug is bumetanide.

28. The method of claim 24, wherein the solid support is a metal foil.

29. The method of claim 24, wherein the drug is bumetanide.

30. The method of claim 24, wherein the drug is ethacrynic acid.

31. The method of claim 24, wherein the drug is furosemide.

32. The method of claim 24, wherein the drug is muzolimine.

33. The method of claim 24, wherein the drug is spironolactone.

34. The method of claim 24, wherein the drug is torsemide.

35. The method of claim 24, wherein the drug is triamterene.

36. The method of claim 24, wherein the drug is tripamide.

37. The method of claim 24, wherein the drug is BG 9928.

38. The method of claim 24, wherein the drug is BG 9719.

39. The method of claim 20, wherein the film has a thickness between 0.05 and 20 microns.

40. The method of claim 39, wherein the film has a thickness between 0.2 and 10 microns.

41. A method of treating edema in a patient comprising administering to the patient a therapeutic amount of a drug condensation aerosol by inhalation, wherein the condensation aerosol is formed by heating a film containing the drug to produce a vapor of the drug, and condensing the vapor to form a condensation aerosol characterized by less than 10% drug degradation products by weight, and a MMAD of less than 5 microns, wherein the drug is selected from the group consisting of bumetanide, ethacrynic acid, furosemide, muzolimine, spironolactone, torsemide, triamterene, tripamide, BG 9928 and BG 9719.

42. The method of claim 41, wherein the condensation aerosol is characterized by a MMAD of less than 3 microns.

43. The method of claim 41, wherein the condensation aerosol is characterized by a MMAD of 1 to 3.5 microns.

44. The method of claim 41, wherein the condensation aerosol is characterized by less than 5% drug degradation products be weight and wherein the drug is bumetanide.

45. The method of claim 41, wherein peak plasma drug concentration is reached in less than 0.1 hours.

46. The method of claim 41, wherein the condensation aerosol is formed at a rate greater than 0.5 mg/second.

47. The method of claim 41, wherein at least 50% by weight of the condensation aerosol is amorphous in form.

48. The method of claim 41, wherein the therapeutic amount of a drug condensation aerosol comprises between 0.1 mg and 10 mg of bumetanide delivered in a single inspiration.

49. The method of claim 41, wherein the therapeutic amount of a drug condensation aerosol comprises between 10 mg and 100 mg of ethacrynic acid delivered in a single inspiration.

50. The method of claim 41, wherein the therapeutic amount of a drug condensation aerosol comprises between 10 mg and 200 mg of muzolimine delivered in a single inspiration.

51. The method of claim 41, wherein the therapeutic amount of a drug condensation aerosol comprises between 1 mg and 150 mg of torsemide delivered in a single inspiration.

52. The method of claim 41, wherein the therapeutic amount of a drug condensation aerosol comprises between 1 mg and 25 mg of tripamide delivered in a single inspiration.

53. The method of claim 41, wherein the therapeutic amount of a drug condensation aerosol comprises between 1 mg and 25 mg of delivered in a single inspiration.

54. The method of claim 41, wherein the film has a thickness between 0.05 and 20 microns.

55. The method of claim 54, wherein the film has a thickness between 0.2 and 10 microns.

56. A method of treating congestive heart failure in a patient comprising administering to the patient a therapeutic amount of a drug condensation aerosol by inhalation, wherein the condensation aerosol is formed by heating a film containing the drug to produce a vapor of the drug, and condensing the vapor to form a condensation aerosol characterized by less than 10% drug degradation products by weight, and a MMAD of less than 5 microns, wherein the drug is selected from the group consisting of bumetanide, ethacrynic acid, furosemide and torsemide.

57. The method of claim 56, wherein the condensation aerosol is characterized by a MMAD of less than 3 microns.

58. The method of claim 56, wherein the condensation aerosol is characterized by a MMAD of 1 to 3.5 microns.

59. The method of claim 58, wherein the condensation aerosol is characterized by less than 5% drug degradation products by weight and wherein the drug is bumetanide.

60. The method of claim 56, wherein peak plasma drug concentration is reached in less than 0.1 hours.

61. The method of claim 56, wherein the condensation aerosol is formed at a rate greater than 0.5 mg/second.

62. The method of claim 56, wherein at least 50% by weight of the condensation aerosol is amorphous in form.

63. The method of claim 56, wherein the therapeutic amount of a drug condensation aerosol comprises between 0.1 mg and 10 mg of bumetanide delivered in a single inspiration.

64. The method of claim 56, wherein the therapeutic amount of a drug condensation aerosol comprises between 10 mg and 100 mg of ethacrynic acid delivered in a single inspiration.

65. The method of claim 56, wherein the therapeutic amount of a drug condensation aerosol comprises between 10 mg and 200 mg of muzolimine delivered in a single inspiration.

66. The method of claim 56, wherein the therapeutic amount of a drug condensation aerosol comprises between 1 mg and 150 mg of torsemide delivered in a single inspiration.

67. The method of claim 56, wherein the therapeutic amount of a drug condensation aerosol comprises between 1 mg and 25 mg of triamterene delivered in a single inspiration.

68. The method of claim 56, wherein the film has a thickness between 0.05 and 20 microns.

69. The method of claim 68, wherein the film has a thickness between 0.2 and 10 microns.

70. A method of administering a drug to a patient comprising administering to the patient a therapeutic amount of a drug condensation aerosol by inhalation, wherein the drug condensation aerosol is formed by heating a film containing the drug to produce a vapor of the drug, and condensing the vapor to form a condensation aerosol characterized by less than 10% drug degradation products by weight, and a MMAD of less than 5 microns, wherein the drug is selected from the group consisting of bumetanide, ethacrynic acid, furosemide, muzolimine, spironolactone, torsemide, triamterene, tripamide, BG 9928 and BG 9719.

71. The method of claim 70, wherein the drug is bumetanide.

72. The method of claim 70, wherein the drug is ethacrynic acid.

73. The method of claim 70, wherein the drug is furosemide.

74. The method of claim 70, wherein the drug is muzolimine.

75. The method of claim 70, wherein the drug is spironolactone.

76. The method of claim 70, wherein the drug is torsemide.

77. The method of claim 70, wherein the drug is triamterene.

78. The method of claim 70, wherein the drug is tripamide.

79. The method of claim 70, wherein the drug is BG 9928.

80. The method of claim 70, wherein the drug is BG 9719.

81. The method of claim 70, wherein the film has a thickness between 0.05 and 20 microns.

82. The method of claim 81, wherein the film has a thickness between 0.2 and 10 microns.

83. A kit for delivering a drug condensation aerosol comprising:

a. a film containing the drug, wherein the drug is selected from the group consisting of bumetanide, ethacrynic acid, furosemide, muzolimine, spironolactone, torsemide, triamterene, tripamide, BG 9928 and BG 9719, and

b. a device for providing the condensation aerosol, wherein the condensation aerosol is formed by heating the film to produce a vapor of the drug, and condensing the vapor to form a condensation aerosol characterized by less than 10% drug degradation products by weight, and a MMAD of less than 5 microns.

84. The kit of claim 83, wherein the device comprises:

a. a flow through enclosure containing the solid support,

b. a power source that can be activated to heat the solid support, and

c. at least one portal through which air can be drawn by inhalation,

wherein activation of the power source is effective to produce a vapor of the drug, and drawing air through the enclosure is effective to condense the vapor to form the condensation aerosol.

85. The kit of claim 84, wherein the heat for heating the solid support is generated by an exothermic chemical reaction.

86. The kit of claim 85, wherein the exothermic chemical reaction is oxidation of combustible materials.

87. The kit of claim 84, wherein the heat for heating the solid support is generated by passage of current through an electrical resistance element.

88. The kit of claim 84, wherein the solid support has a surface area dimensioned to accommodate a therapeutic dose of the drug.

89. The kit of claim 83, wherein peak plasma drug concentration is reached in less than 0.1 hours.

90. The kit of claim 83, further including instructions for use.

91. The kit of claim 83, wherein the condensation aerosol is characterized by a MMAD of less than 3 microns.

92. The kit of claim 83, wherein the condensation aerosol is characterized by a MMAD of 1 to 3.5 microns.

93. The kit of claim 83, wherein the condensation aerosol is characterized by less than 5% drug degradation products be weight and wherein the drug is bumetanide.

94. The kit of claim 83, wherein the drug is bumetanide.

95. The kit of claim 83, wherein the drug is ethacrynic acid.

96. The kit of claim 83, wherein the drug is furosemide.

97. The kit of claim 83, wherein the drug is muzolimine.

98. The kit of claim 83, wherein the drug is spironolactone.

99. The kit of claim 83, wherein the drug is torsemide.

100. The kit of claim 83, wherein the drug is triamterene.

101. The kit of claim 83, wherein the drug is tripamide.

102. The kit of claim 83, wherein the drug is BG 9928.

103. The kit of claim 83, wherein the drug is BG 9719.

104. The kit of claim 83, wherein the solid support has a surface to mass ratio of greater than 1 cm² per gram.

105. The kit of claim 83, wherein the solid support has a surface to volume ratio of greater than 100 per meter.

106. The kit of claim 83, wherein the solid support is a metal foil.

107. The kit of claim 106, wherein the metal foil has a thickness of less than 0.25 mm.

108. The kit of claim 83, wherein the film has a thickness between 0.05 and 20 microns.

109. The kit of claim 108, wherein the film has a thickness between 0.2 and 10 microns.