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Composition and method for treatment of otitis media

Imported: 24 Feb '17 | Published: 13 Jan '04

Alan J. Mautone

USPTO - Utility Patents

Abstract

A process, composition and method for increasing and enhancing mammalian eustachian tube lumen patency and pressure equalization performance is disclosed wherein 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 sterols, lipids, fatty acids, cholesteryl esters, phospholipids, carbohydrates, and proteins, in powder form, and one or more propellants, in which the lipid surfactants and spreading agents are not soluble, are administered through a mammalian airway orifice. Upon administration, the propellant(s) are evaporated from the mixture and the lipid crystals are deposited within 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. In an alternate preferred embodiment, the afore-mentioned reduction of surface tension and delivery of therapeutically active agents is provided by a mixture of lipid crystals comprised of surfactant(s), therapeutically active agents and a propellant in which such other components are not soluble.

Claims

1. A method of increasing and enhancing mammalian eustachian tube lumen patency and pressure equalization performance comprising administering a dose of a mixture of lipid crystals, as an aerosol, through an external airway of a mammal, said mixture being comprised of at least one lipid surfactant in an amount effective in lowering surface tension of an air/liquid interface resident upon epithelial tissue lining said lumen, at least one spreading agent in an amount effective in distributing said surfactant within said lumen and at least one propellant in which said surfactants and spreading agents are not soluble, said surfactants and said spreading agents being selected from the group consisting of sterols, lipids, fatty acids, cholesteryl esters, phospholipids, carbohydrates, and proteins, all in powder form;

2. The method of claim 1 wherein said amount of lipid surfactant is selected to be present in an amount of from about 50 to about 99.99 weight percent and wherein said spreading agent is selected to be present in an amount of from about 0.01 to about 50 weight percent.

3. The method of claim 1 wherein said lipid surfactant is selected to be present in an amount of from about 80 to about 99.5 weight percent and wherein said spreading agent is selected to be present in an amount of from about 0.5 to about 20 weight percent.

4. The method of claim 1 wherein a metered dose inhalation device is filled with said mixture of lipid crystals and thereafter said device is utilized to administer a metered dose of said mixture through an external nasal orifice of said mammal.

5. The method of claim 1 wherein a metered dose inhalation device is filled with said mixture of lipid crystals and thereafter said device is utilized to administer a metered dose of said mixture via oral inhalation.

6. The method of claim 1 wherein the sterols are cholesterol, ergosterol, cholecalciferol and mixtures thereof.

7. The method of claim 1 wherein the fatty acids are palmitic acid, oleic acid and mixtures thereof.

8. The method of claim 1 wherein the lipids are phospholipids, neutral lipids and mixtures thereof.

9. The method of claim 8 wherein the phospholipids are any of a class known as phosphatidylcholines.

10. The method of claim 9 wherein the phosphatidylcholine is any fully saturated diacyl phosphatidylcholine.

11. The method of claim 10 wherein the fully saturated diacyl phosphatidylcholine is 1,2 dipalmitoyl phosphatidylcholine.

12. The method of claim 8 wherein the phospholipid is a diacylphosphatidylglycerol, diacylphosphatidylethanolamime, diacylphosphatidylserine, diacylphosphatidylinositol, sphingomelin, Cardiolipin, lysophospholipid, plasmalogen, diether phosphonolipid, dialkylphospholipid, and a mixture thereof.

13. The method of claim 1 wherein the carbohydrates are glucose, fructose, galactose, pneumogalactan, dextrose and mixtures thereof.

14. The method of claim 1 wherein the protein is selected from albumin and pulmonary surfactant specific proteins A or B or C or D and mixtures thereof.

15. The method of claim 1 wherein the cholesteryl ester is cholesteryl palmitate, cholesteryl oleate, cholesteryl stearate and mixtures thereof.

16. The method of claim 1 wherein the propellants are fluorocarbons.

17. The method of claim 16 wherein the fluorocarbon is a chlorofluorocarbon, hydrofluorocarbon and mixtures thereof.

18. The method of claim 1 wherein the propellant is carbon dioxide.

19. The method of claim 1 wherein the propellant is any pharmaceutical grade hypo-allergenic propellant in which neither the surfactant or spreading agent are soluble.

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

21. A method of administering therapeutic agents, effective in the treatment of otitis media, directly to mammalian eustachian tube and middle ear tissues while simultaneously increasing and enhancing eustachian tube lumen patency and pressure equalization performance comprising administering a dose of a mixture of lipid crystals in combination with said therapeutic agents, as an aerosol, through an external airway of a mammal, said mixture being comprised of at least one lipid surfactant in an amount effective in lowering surface tension of an air/liquid interface resident upon epithelial tissue lining said lumen, at least one spreading agent in an amount effective in distributing said surfactants upon said interface within said lumen, at least one therapeutically active agent effective in the treatment of otitis media and at least one propellants, said surfactants and said spreading agents being selected from the group consisting of sterols, lipids, fatty acids, cholesteryl esters, phospholipids, carbohydrates, and proteins, said surfactants, spreading agents and therapeutically active agents all being in powder form and insoluble in the propellants,

22. The method of claim 21 wherein said lipid surfactant is selected to be present in an amount of from about 50 to about 99.99 weight percent and wherein said spreading agent is selected to be present in an amount of from about 0.01 to about 50 weight percent.

23. The method of claim 21 wherein said lipid surfactant is selected to be present in an amount of from about 80 to about 99.5 weight percent and wherein said spreading agent is selected to be present in an amount of from about 0.5 to about 20 weight percent.

24. The method of claim 21 wherein a metered dose inhalation device is filled with said mixture of lipid crystals in combination with said therapeutically active agent and thereafter said device is utilized to administer a metered dose of said mixture through an external nasal orifice of said mammal.

25. The method of claim 21 wherein a metered dose inhalation device is filled with said mixture of lipid crystals in combination with said therapeutically active agent and thereafter said device is utilized to administer a metered dose of said mixture by means of oral inhalation.

26. The method of claim 21 wherein the sterols are cholesterol, ergosterol, cholecalciferol and mixtures thereof.

27. The method of claim 21 wherein the fatty acids are palmitic acid, oleic acid and mixtures thereof.

28. The method of claim 21 wherein the lipids are phospholipids, neutral lipids and mixtures thereof.

29. The method of claim 28 wherein the phospholipids are any of a class known as phosphatidylcholines.

30. The method of claim 29 wherein the phosphatidylcholine is any fully saturated diacyl phosphatidylcholine.

31. The method of claim 30 wherein the fully saturated diacyl phosphatidylcholine is 1,2 dipalmitoyl phosphatidylcholine.

32. The method of claim 28 wherein the phospholipid is a diacylphosphatidylglycerol, diacylphosphatidylethanolamime, diacylphosphatidylserine, diacylphosphatidylinositol, sphingomelin, Cardiolipin, lysophospholipid, plasmalogen, diether phosphonolipid, dialkylphospholipid, and a mixture thereof.

33. The method of claim 21 wherein the carbohydrates are glucose, fructose, galactose, pneumogalactan, dextrose and mixtures thereof.

34. The method of claim 21 wherein the protein is selected from albumin and pulmonary surfactant specific proteins A or B or C or D and mixtures thereof.

35. The method of claim 21 wherein the cholesteryl ester is cholesteryl palmitate, cholesteryl oleate, cholesteryl stearate and mixture thereof.

36. The method of claim 21 wherein said therapeutically active agent is an anti-inflammatory, antibiotic, decongestant and gene therapy agent.

37. The method of claim 36 wherein said anti-inflammatory agent is betamethasone.

38. The method of claim 36 wherein said antibioitic is erythromycin, amoxicillin, zythromax and amoxicillia/elavalanste potassium.

39. The method of claim 36 wherein said decongestant is phenylephrine.

40. The method of claim 21 wherein the propellants are fluorocarbons.

41. The method of claim 40 wherein the fluorocarbon is a chlorofluorocarbon, hydrofluorocarbon and mixtures thereof.

42. The method of claim 21 wherein the propellant is carbon dioxide.

43. The method of claim 21 wherein the propellant is any pharmaceutical grade, hypo-allergenic propellant in which neither the surfactant, spreading agent or therapeutically active agent are soluble.

44. The method of claim 21 wherein 95 percent of said crystals and a particle size no greater than 4 microns in diameter.

45. A method of administering therapeutic agents, effective in the treatment of otitis media, directly to mammalian eustachian tube and middle ear tissues while simultaneously increasing and enhancing eustachian tube lumen patency and pressure equalization performance comprising administering a dose of a mixture of lipid crystals in combination with said therapeutic agents, as an aerosolized mixture of lipid crystals, through an external airway of a mammal, said mixture being comprised of at least one lipid surfactant in an amount effective in lowering surface tension of an air/liquid interface resident upon epithelial tissue lining said lumen, at least one therapeutically active agent effective in the treatment of otitis media and at least one propellant, said lipid surfactants being selected from the group consisting of sterols, lipids, fatty acids, cholesteryl esters, phospholipids, carbohydrates, and proteins, said surfactants and therapeutically active agents all being in powder form and insoluble in the propellants,

46. The method of claim 45 wherein said lipid surfactant is selected to be present in an amount of from about 50 to about 99.99 weight percent and wherein said therapeutically active agent is selected to be present in an amount of from about 0.01 to about 50 weight percent.

47. The method of claim 45 wherein said lipid surfactant is selected to be present in an amount of from about 80 to about 99.5 weight percent and wherein said therapeutically active agent is selected to be present in an amount of from about 0.5 to about 20 weight percent.

48. The method of claim 45 wherein a metered dose inhalation device is filled with said mixture of lipid crystals in combination with said therapeutically active agent and thereafter said device is utilized to administer a metered dose of said mixture through an external nasal orifice of said mammal.

49. The method of claim 45 wherein a metered dose inhalation device is filled with said mixture of lipid crystals in combination with said therapeutically active agent and thereafter said device is utilized to administer a metered dose of said mixture by means of oral inhalation.

50. The method of claim 45 wherein the sterols are cholesterol, ergosterol, cholecalciferol and mixtures thereof.

51. The method of claim 45 wherein the fatty acids are palmitic acid, oleic acid and mixtures thereof.

52. The method of claim 45 wherein the lipids are phospholipids, neutral lipids and mixtures thereof.

53. The method of claim 52 wherein the phospholipids are any of a class known as phosphatidylcholines.

54. The method of claim 53 wherein the phosphatidylcholine is any fully saturated diacyl phosphatidylcholine.

55. The method of claim 54 wherein the fully saturated diacyl phosphatidylcholine is 1,2 dipalmitoyl phosphatidylcholine.

56. The method of claim 52 wherein the phospholipid is a diacylphosphatidylglycerol, diacylphosphatidylethanolamime, diacylphosphatidylserine, diacylphosphatidylinositol, sphingomelin, Cardiolipin, lysophospholipid, plasmalogen, diether phosphonolipid, dialkylphospholipid, and a mixture thereof.

57. The method of claim 45 wherein the carbohydrates are glucose, fructose, galactose, pneumogalactan, dextrose and mixtures thereof.

58. The method of claim 45 wherein the protein is selected from albumin and pulmonary surfactant specific proteins A or B or C or D and mixtures thereof.

59. The method of claim 45 wherein the cholesteryl ester is cholesteryl palmitate, cholesteryl oleate, cholesteryl stearate and mixture thereof.

60. The method of claim 45 wherein said therapeutically active agent is an anti-inflammatory, antibiotic, decongestant or gene therapy agent.

61. The method of claim 60 wherein said anti-inflammatory agent is betamethasone.

62. The method of claim 60 wherein said antibiotic is erythromycin, amoxicillin, zythromax and amoxicillia/elavalanste potassium.

63. The method of claim 60 wherein said decongestant is phenylephrine.

64. The method of claim 45 wherein the propellants are fluorocarbons.

65. The method of claim 64 wherein the fluorocarbon is a chlorofluorocarbon, hydrofluorocarbon and mixtures thereof.

66. The method of claim 45 wherein the propellant is carbon dioxide.

67. The method of claim 45 wherein the propellant is selected to be any pharmaceutical grade, hypo-allergenic propellant in which neither the at least one surfactant or therapeutically active agent are soluble.

68. The method of claim 45 wherein the therapeutic agent is selected from the group consisting of sterols, lipids, fatty acids, cholesteryl esters, phospholipids, carbohydrates, and proteins.