Composition and method for treatment of otitis media

• US 6,616,913 B1
• Filed: 08/16/2000
• Issued: 09/09/2003
• Est. Priority Date: 11/28/1999
• Status: Expired due to Term

• Current Assignee: Scientific Development and Research Incorporated
• Original Assignee: Scientific Development and Research Incorporated
• Inventors: Mautone, Alan J.
• Primary Examiner(s): Krass, Frederick
• Assistant Examiner(s): JAGOE, DONNA A
• Application Number:
  US09/639,682
• Time in Patent Office: 1,119 Days
• Field of Search: 514/951, 514/958, 514/975, 424/45, 424/46, 128/200.23
• US Class Current: 424/45
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/0046 Ear
• CPC Class Codes: A61K 9/1274 Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases, cochleates; Sponge phases
• CPC Class Codes: A61P 27/16 Otologicals

Abstract

The present invention discloses a method of increasing and enhancing mammalian eustachian tube lumen patency and pressure equalization performance by administering an aerosolized mixture of lipid crystals comprised of a mixture of one or more lipids surfactants and one or more spreading agents selected from the group consisting of cholesteryl esters, phospholipids, carbohydrates, and proteins, in powder form, and one or more fluorocarbon propellants through a mammalian nasal orifice. Upon administration, the propellant(s) are evaporated from the mixture and the lipid crystals are deposited at a subject mammalian eustachian tube whereupon said lipid crystals come into contact with lumen surfaces of the tube forming an amorphous spread film thereupon substantially decreasing the opening pressure of the lumen. In a second preferred embodiment, a therapeutically active agent effective in the treatment of otitis media is added to the mixture of lipid crystals and upon administration of said aerosol mixture, the amorphous spread film formed thereby carries said therapeutically active agent through the eustachian tube to the tissues of the middle ear.

Claims

1. A method of treating otitis media comprising administering a dose of a mixture of lipid crystals, as an aerosol, through an external nasal airway of a mammal, said mixture being comprised of:

one or more lipid surfactant, one or more spreading agent and at least one propellant in which said surfactants and spreading agents are not soluble, said surfactants and spreading agents being selected from the group consisting of cholesteryl esters, phospholipids, carbohydrates, and proteins, all in powder form and said surfactants being present in an amount of from about 80 to about 95.5 weight percent and said spreading agents being present in an amount of from about 20 to about 0.5 weight percent based upon total weight of said lipid surfactants and spreading agents in said mixture, wherein when said propellants are evaporated therefrom, said aerosolized mixture of lipid crystals is provided.

2. The method of claim 1 wherein a metered dose inhalation device is utilized to administer said mixture through an external nasal orifice of said mammal.

3. The method of claim 1 wherein the lipids are selected from the group consisting of phospholipids, neutral lipids and mixtures thereof.

4. The method of claim 3 wherein the phospholipids are any of a class known as phosphatidylcholines.

5. The method of claim 4 wherein the phosphatidylcholine is any fully saturated diacyl phosphatidylcholine.

6. The method of claim 5 wherein the fully saturated diacylphosphatidylcholine is 1,2 dipalmitoyl phosphatidylcholine.

7. The method of claim 3 wherein the phospholipid is diacylphosphatidylglycerol.

8. The method of claim 3 wherein the phospholipid is diacylphosphatidylethanolamine.

9. The method of claim 3 wherein the phospholipid is diacylphosphatidylserine.

10. The method of claim 3 wherein the phospholipid is diacylphosphatidylinositol.

11. The method of claim 3 wherein the phospholipid is a sphingomyelin.

12. The method of claim 3 wherein the phospholipid is Cardiolipin.

13. The method of claim 3 wherein the phospholipid is a lysophospholipid.

14. The method of claim 3 wherein the phospholipid is plasmalogen.

15. The method of claim 3 wherein the phospholipid is a diether phosphonolipid.

16. The method of claim 3 wherein the phospholipid is a dialkylphospholipid.

17. The method of claim 1 wherein the carbohydrates are selected from the group consisting of glucose, fructose, galactose, pneumogalactan and dextrose.

18. The method of claim 1 wherein the protein is selected from the group consisting of albumin and pulmonary surfactant specific proteins A and B and C and D, their synthetic analogs and mixtures thereof.

19. The method of claim 1 wherein the cholesteryl ester is selected from the group consisting of cholesteryl palmitate, cholesteryl oleate and cholesteryl stearate.

20. The method of claim 1 wherein the propellant is a fluorocarbon propellant.

21. The method of claim 19 wherein said fluorocarbon propellant is selected from the group consisting of a chlorofluorocarbon, hydrofluorocarbon and mixtures thereof.

22. The method of claim 1 wherein said propellant is carbon dioxide.

23. The method of claim 1 wherein 95 percent of said lipid crystals demonstrate a particle size no greater than 4 microns in diameter.

24. A method of treating otitis media comprising administering a dose of a mixture of lipid crystals in combination with at least one therapeutically active agent effective in the treatment of otitis media, as an aerosol, through an external nasal airway of a mammal, said mixture being comprised of:

one or more lipid surfactant, one or more spreading agent, one or more therapeutically active agent and at least one propellant in which said surfactants, spreading agents and therapeutic agent are not soluble, said surfactants and spreading agents being selected from the group consisting of cholesteryl esters, phospholipids, carbohydrates, and proteins, all in powder form and said surfactants being present in an amount of from about 80 to about 95.5 percent by weight and said spreading agents being present in an amount of from about 20 to about 0.5 weight percent based upon total weight of said lipid surfactants and spreading agents in said mixture wherein when said propellants are evaporated therefrom, said aerosolized mixture of lipid crystals in combination with at least one therapeutically active agent is provided.

25. The method of claim 24 wherein a metered dose inhalation device is utilized to administer said mixture of lipid crystals in combination with said therapeutically active agent.

26. The method of claim 24 wherein the lipids are selected from the group consisting of phospholipids, neutral lipids and mixtures thereof.

27. The method of claim 26 wherein the phospholipids are any of a class known as phosphatidylcholines.

28. The method of claim 27 wherein the phosphatidylcholine is any fully saturated diacyl phosphatidylcholine.

29. The method of claim 28 wherein the fully saturated diacyl phosphatidylcholine is 1,2, dipalmitoyl phosphatidylcholine.

30. The method of claim 26 wherein the phospholipid is diacylphosphatidylglycerol.

31. The method of claim 26 wherein the phospholipid is diacylphosphatidylethanolamine.

32. The method of claim 26 wherein the phospholipid is diacylphosphatidylserine.

33. The method of claim 26 wherein the phospholipid is diacylphosphatidylinositol.

34. The method of claim 26 wherein the phospholipid is a sphingomyelin.

35. The method of claim 26 wherein the phospholipid is Cardiolipin.

36. The method of claim 26 wherein the phospholipid is a lysophospholipid.

37. The method of claim 26 wherein the phospholipid is plasmalogen.

38. The method of claim 26 wherein the phospholipid is a diether phosphonolipid.

39. The method of claim 26 wherein the phospholipid is a dialkylphospholipid.

40. The method of claim 24 wherein the carbohydrates are selected from the group consisting of glucose, fructose, galactose, pneumogalactan and dextrose.

41. The method of claim 24 wherein the protein is selected from the group consisting of albumin and pulmonary surfactant specific proteins A and B and C and D, their synthetic analogs and mixtures thereof.

42. The method of claim 24 wherein the cholesteryl ester is selected from the group consisting of cholesteryl palmitate, cholesteryl oleate and cholesteryl stearate.

43. The method of claim 24 wherein said therapeutically active agent is an anti-inflammatory agent.

44. The method of claim 43 wherein said anti-inflammatory agent is betamethasone.

45. The method of claim 44 wherein said betamethasone is selected from the group consisting of betamethasone dipropionate, betamethasone valerate and mixtures thereof.

46. The method of claim 24 wherein said therapeutically active agent is antibiotic.

47. The method of claim 46 wherein said antibiotic is selected from the group consisting of erythromycin, amoxicillin, azithromycin clavulanic acid and mixtures thereof.

48. The method of claim 24 wherein said therapeutically active agent is a decongestant.

49. The method of claim 48 wherein said decongestant is phenylephrine.

50. The method of claim 49 wherein said phenylephrine is selected from the group consisting of phenylephrine HCl, phenylephrine bitartrate and mixtures thereof.

51. The method of claim 24 wherein the propellant is a fluorocarbon.

52. The method of claim 51 wherein the fluorocarbon propellant is selected from the group consisting of a chlorofluorocarbon, hydrofluorocarbon and mixtures thereof.

53. The method of claim 24 wherein the propellant is carbon dioxide.

54. The method of claim 24 wherein 95 percent of said lipid crystals demonstrate a particle size no greater than 4 microns in diameter.

63. The process of claim 52 wherein the phospholipid is diacylphosphatidylserine.

55. A process for preparing a eustachian tube lumen patency enhancing medicament comprising:

combining one or more lipid surfactants, one or more spreading agents and one or more propellants to form a mixture, said lipids and said spreading, agents being selected from the group consisting of cholesteryl esters, phospholipids, carbohydrates, and proteins, all in powder form, said lipids and said spreading agents being insoluble in the propellants, said lipid surfactants being selected to be present in an amount of from about 80 to about 99.5 weight percent and said spreading agents are selected to be present in an amount of from about 20 to about 0.5 weight percent, based upon total weight of said lipid surfactants and spreading agents in said mixture,

wherein when said propellants are evaporated therefrom, a mixture of aerosolized lipid crystals is released for se as the medicament.

56. The process of claim 55 wherein said mixture is bottled in a metered dose device.

57. The process of claim 55 wherein the lipids are selected from the group consisting of phospholipids, neutral lipids and mixtures thereof.

58. The process of claim 57 wherein the phospholipids are any of a class known as phosphatidylcholines.

59. The process of claim 58 wherein the phosphatidylcholine is any fully saturated diacyl phosphatidylcholine.

60. The process of claim 59 wherein said fully saturated diacyl phosphatidylcholine is 1,2, dipalmitoyl phosphatidylcholine.

61. The process of claim 57 wherein the phospholipid is diacylphosphatidylglycerol.

62. The process of claim 57 wherein the phospholipid is diacylphosphatidylethanolamine.

64. The process of claim 57 wherein the phospholipid is diacylphosphatidylinositol.

65. The process of claim 57 wherein the phospholipid is a sphingomyelin.

66. The process of claim 57 wherein the phospholipid is Cardiolipin.

67. The process of claim 57 wherein the phospholipid is a lysophospholipid.

68. The process of claim 57 wherein the phospholipid is plasmalogen.

69. The process of claim 57 wherein the phospholipid is a diether phosphonolipid.

70. The process of claim 57 wherein the phospholipid is a dialkylphospholipid.

71. The process of claim 55 wherein the carbohydrates are selected from the group consisting of glucose, fructose, galactose, pneumogalactan and dextrose.

72. The process of claim 55 wherein the protein is selected from the group consisting of albumin and pulmonary surfactant specific proteins A and B and C and D, their synthetic analogs and mixtures thereof.

73. The process of claim 55 wherein the cholesteryl ester is selected from the group consisting of cholesteryl palmitate, cholesteryl oleate and cholesteryl stearate.

74. The process of claim 55 wherein the propellant is a fluorocarbon.

75. The process of claim 74 wherein the fluorocarbon propellant is selected from the group consisting of a chlorofluorocarbon, hydrofluorocarbon and mixtures thereof.

76. The process of claim 55 wherein the propellant is carbon dioxide.

77. The process of claim 55 wherein 95 percent of said lipid crystals demonstrate a particle size no greater than 4 microns in diameter.

78. A process for preparing an otitis media medicament comprising:

combining one or more lipid surfactants, one or more spreading agents, one or more therapeutically active agent effective in the treatment of otitis media and one or more propellant to form a mixture, said lipids and said spreading agents being selected from the group consisting of cholesteryl esters, phospholipids, carbohydrates, and proteins, all in powder form, wherein said lipids, said spreading agents and said therapeutically active agents are insoluble in the propellants, said lipid surfactants are selected to be present in an amount of from about 80 to about 99.5 weight percent and said spreading agents are selected to be present in an amount of from about 20 to about 0.5 weight percent, based upon total weight of said lipid surfactants and spreading agents in said mixture; and

wherein when said propellants are evaporated therefrom, a mixture of aerosolized lipid crystals is released for use as the medicament.

79. The process of claim 78 wherein said mixture is bottled in a metered dose device.

80. The process of claim 78 wherein the lipids are selected from the group consisting of phospholipids, neutral and mixtures thereof.

81. The process of claim 80 wherein the phospholipids are any of a class known as phosphatidylcholines.

82. The process of claim 81 wherein the phosphatidylcholine is any fully saturated diacyl phosphatidylcholine.

83. The process of claim 82 wherein the fully saturated diacyl phosphatidylcholine is 1,2 dipalmitoyl phosphatidylcholine.

84. The process of claim 80 wherein the phospholipid is diacylphosphatidylglycerol.

85. The process of claim 80 wherein the phospholipid is diacylphosphatidylethanolamine.

86. The process of claim 80 wherein the phospholipid is diacylphosphatidylserine.

87. The process of claim 80 wherein tithe phospholipid is diacylphosphatidylinositol.

88. The process of claim 80 wherein the phospholipid is a sphingomyelin.

89. The process of claim 80 wherein the phospholipid is Cardiolipin.

90. The process of claim 80 wherein the phospholipid is a lysophospholipid.

91. The process of claim 80 wherein the phospholipid is plasmalogen.

92. The process of claim 80 wherein the phospholipid is a diether phosphonolipid.

93. The process of claim 80 wherein the phospholipid is a dialkylphospholipid.

94. The process of claim 78 wherein the carbohydrates are selected from the group consisting of glucose, fructose, galactose, pneumogalactan and dextrose.

95. The process of claim 78 wherein the protein is selected from the group consisting of albumin and pulmonary surfactant specific proteins A and B and C and D, their synthetic analogs and mixtures thereof.

96. The process of claim 78 wherein the cholesteryl ester is selected from the group consisting of cholesteryl palmitate, cholesteryl oleate and cholesteryl stearate.

97. The process of claim 78 wherein said therapeutically active agent is an anti-inflammatory agent.

98. The process of claim 97 wherein said anti-inflammatory agent is betamethasone.

99. The process of claim 98 wherein said betamethasone is selected from the group consisting of betamethasone dipropionate, betamethasone valerate and mixtures thereof.

100. The process of claim 78 wherein said therapeutically active agent is an antibiotic.

101. The process of claim 100 wherein said antibioitic is selected from the croup consisting of erythromycin, amoxicillin, azithromycin, clavulanic acid, and mixtures thereof.

102. The process of claim 78 wherein said therapeutically active agent is a decongestant.

103. The process of claim 102 wherein said decongestant is phenylephrine.

104. The process of claim 103 wherein said phenylephrine is selected from the group consisting of phenylephrine HCl, phenylephrine bitartrate and mixtures thereof.

105. The process of claim 78 wherein the propellant is a fluorocarbon.

106. The process of claim 105 wherein the fluorocarbon propellant is selected from the group consisting of a chlorofluorocarbons hydrofluorocarbon and mixtures thereof.

107. The process of claim 78 wherein the propellant is carbon dioxide.

108. The process of claim 78 wherein 95 percent of said lipid crystals demonstrate a particle size no greater than 4 microns in diameter.