Composition and method for treatment of otitis media

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.

I claim:  
     
         1 . A process for preparing a eustachian tube lumen patency and performance 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 sterols, lipids, fatty acids, cholesteryl esters, phospholipids, carbohydrates, and proteins, all in powder form, wherein said lipids and said spreading agents are insoluble in the propellants and said lipid surfactants are selected to be present in an amount effective in reducing surface tension of an air/liquid interface resident upon epithelial tissue lining the lumen of the eustachian tube and said spreading agents are selected to be present in an amount effective in distributing said surfactant within said lumen when said propellants are evaporated from said mixture to form a mixture of lipid crystals for use as the medicament.    
     
     
         2 . The process of  claim 1  wherein said lipid surfactant is selected to be present in an amount of from about 99.99 to about 50 weight percent and wherein said spreading agent is selected to be present in an amount of from about 50 to about 0.01 weight percent.  
     
     
         3 . The process 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 20 to about 0.5 weight percent.  
     
     
         4 . The process of  claim 1  further comprising bottling said mixture within a metered dose device  
     
     
         5 . The process of  claim 1  wherein the sterols are selected from the group consisting of cholesterol, ergosterol, cholecalciferol and mixtures thereof.  
     
     
         6 . The process of  claim 1  wherein the fatty acids are selected from the group consisting of palmitic acid, oleic acid and mixtures thereof.  
     
     
         7 . The process of  claim 1  wherein the lipids are selected from the group consisting of phospholipids, neutral lipids and mixtures thereof.  
     
     
         8 . The process of  claim 7  wherein the phospholipids are selected to be any of a class known as phosphatidylcholines.  
     
     
         9 . The process of  claim 8  wherein the phosphatidylcholine is selected to be any fully saturated diacyl phosphatidylcholine.  
     
     
         10 . The process of  claim 9  wherein the fully saturated diacyl phosphatidylcholine is selected to be 1,2 dipalmitoyl phosphatidylcholine.  
     
     
         11 . The process of  claim 7  wherein the phospholipid is selected from the group consisting of diacylphosphatidylglycerol, diacylphosphatidylethanolamime, diacylphosphatidylserine, diacylphosphatidylinositol, sphingomelin, Cardiolipin, lysophospholipid, plasmalogen, diether phosphonolipid, dialkylphospholipid, and mixtures thereof.  
     
     
         12 . The process of  claim 1  wherein the carbohydrates are selected from the group consisting of glucose, fructose, galactose, pneumogalactan, dextrose and mixtures thereof.  
     
     
         13 . The process of  claim 1  wherein the protein is selected from the group consisting of albumin and pulmonary surfactant specific proteins A, B, C, D and mixtures thereof.  
     
     
         14 . The process of  claim 1  wherein the cholesteryl ester is selected from the group consisting of cholesteryl palmitate, cholesteryl oleate, cholesteryl stearate and mixtures thereof.  
     
     
         15 . The process of  claim 1  wherein the propellants are selected to be fluorocarbons.  
     
     
         16 . The process of  claim 15  wherein the fluorocarbon is selected from the group consisting of chlorofluorocarbon, hydrofluorocarbon and mixtures thereof.  
     
     
         17 . The process of  claim 1  wherein the propellant is selected to be carbon dioxide.  
     
     
         18 . The process of  claim 1  wherein the propellant is selected to be any pharmaceutical grade hypo-allergenic propellant in which the at least one surfactant and spreading agent are not soluble.  
     
     
         19 . The process of  claim 1  wherein 95 percent of said crystals demonstrate a particle size no greater than 4 microns in diameter.  
     
     
         20 . A process for preparing an otitis media medicament comprising: 
 combining at least one lipid surfactant, at least one spreading agents, at least one therapeutically active agents effective in the treatment of otitis media and at least one propellants to form a mixture, said lipids 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, wherein said lipids, said spreading agents and said therapeutically active agents are insoluble in the propellants and said lipids are selected to be present in an amount effective in lowering surface tension of an air/liquid interface resident upon epithelial tissues lining mammalian eustachian tube and middle ear and said spreading agents being present in an amount effective in distributing said surfactant within said lining of the lumen and middle ear when said propellants are evaporated from said mixture to form a mixture of lipid crystals combined with said therapeutic agents for use as the medicament.    
     
     
         21 . The process of  claim 20  wherein said lipid surfactant is selected to be present in an amount of from about 99.99 to about 50 weight percent and wherein said spreading agent is selected to be present in an amount of from about 50 to about 0.01 weight percent.  
     
     
         22 . The process of  claim 20  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 20 to about 0.5 weight percent.  
     
     
         23 . The process of  claim 20  further comprising bottling said mixture within a metered dose device  
     
     
         24 . The process of  claim 20  wherein the sterols are selected from the group consisting of cholesterol, ergosterol, cholecalciferol and mixtures thereof.  
     
     
         25 . The process of  claim 20  wherein the fatty acids are selected from the group consisting of palmitic acid, oleic acid and mixtures thereof.  
     
     
         26 . The process of  claim 20  wherein the lipids are selected from the group consisting of phospholipids, neutral lipids and mixtures thereof.  
     
     
         27 . The process of  claim 26  wherein the phospholipids are selected to be any of a class known as phosphatidylcholines.  
     
     
         28 . The process of  claim 27  wherein the phosphatidylcholine is selected to be any fully saturated diacyl phosphatidylcholine.  
     
     
         29 . The process of  claim 28  wherein the fully saturated diacyl phosphatidylcholine is selected to be 1,2 dipalmitoyl phosphatidylcholine.  
     
     
         30 . The process of  claim 26  wherein the phospholipid is selected from the group consisting of diacylphosphatidylglycerol, diacylphosphatidylethanolamime, diacylphosphatidylserine, diacylphosphatidylinositol, sphingomelin, Cardiolipin, lysophospholipid, plasmalogen, diether phosphonolipid, dialkylphospholipid, and mixtures thereof.  
     
     
         31 . The process of  claim 20  wherein the carbohydrates are selected from the group consisting of glucose, fructose, galactose, pneumogalactan, dextrose and mixtures thereof.  
     
     
         32 . The process of  claim 20  wherein the protein is selected from the group consisting of albumin and pulmonary surfactant specific proteins A, B, C, D and mixtures thereof.  
     
     
         33 . The process of  claim 20  wherein the cholesteryl ester is selected from the group consisting of cholesteryl palmitate, cholesteryl oleate, cholesteryl stearate and mixtures thereof.  
     
     
         34 . The process of  claim 20  wherein said therapeutically active agent is selected from the group consisting of anti-inflammatory, antibiotic, decongestant and gene therapy agents.  
     
     
         35 . The process of  claim 34  wherein the anti-inflammatory agent is selected to be betamethasone.  
     
     
         36 . The process of  claim 34  wherein said antibiotic is selected from the group consisting of erythromycin, amoxicillin, zythromax, Augmentin and mixtures thereof.  
     
     
         37 . The process of  claim 34  wherein the decongestant is selected to be phenylephrine.  
     
     
         38 . The process of  claim 20  wherein the propellants are selected to be fluorocarbons.  
     
     
         39 . The process of  claim 38  wherein the fluorocarbon is selected from the group consisting of chlorofluorocarbons, hydrofluorocarbons and mixtures thereof.  
     
     
         40 . The process of  claim 20  wherein the propellant is selected to be carbon dioxide.  
     
     
         41 . The process of  claim 20  wherein the propellant is selected to be any hypo-allergenic, pharmaceutical grade propellant in which the neither the surfactant, spreading agent or therapeutically active agent are soluble.  
     
     
         42 . The process of  claim 20  wherein 95 percent of said crystals demonstrate a particle size no greater than 4 microns in diameter.  
     
     
         43 . A process for preparing an otitis media medicament comprising: 
 combining at least one lipid surfactant, at least one therapeutically active agent effective in the treatment of otitis media and at least one propellants to form a mixture, said lipid surfactants being selected from the group consisting of sterols, lipids, fatty acids, cholesteryl esters, phospholipids, carbohydrates, and proteins all in powder form, wherein said lipids and said therapeutically active agents are insoluble in the propellants and said lipids are selected to be present in an amount effective in lowering surface tension of an air/liquid interface resident upon epithelium lining said eustachian tube and middle ear and effective in distributing said surfactant within said lining of the lumen and middle ear when said propellants are evaporated to form an aerosolized mixture of lipid crystals combined with said therapeutic agents for use as the medicament.    
     
     
         44 . The process of  claim 43  wherein said lipid surfactant is selected to be present in an amount of from about 99.99 to about 50 weight percent and wherein said therapeutically active agent is selected to be present in an amount of from about 50 to about 0.01 weight percent.  
     
     
         45 . The process of  claim 43  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 20 to about 0.5 weight percent.  
     
     
         46 . The process of  claim 43  further comprising bottling said mixture within a metered dose administration device.  
     
     
         47 . The process of  claim 43  wherein the sterols are selected from the group consisting of cholesterol, ergosterol, cholecalciferol and mixtures thereof.  
     
     
         48 . The process of  claim 43  wherein the fatty acids are selected from the group consisting of palmitic acid, oleic acid and mixtures thereof.  
     
     
         49 . The process of  claim 43  wherein the lipids are selected from the group consisting of phospholipids, neutral lipids and mixtures thereof.  
     
     
         50 . The process of  claim 49  wherein the phospholipids are any of a class known as phosphatidylcholines.  
     
     
         51 . The process of  claim 50  wherein the phosphatidylcholine is any fully saturated diacyl phosphatidylcholine.  
     
     
         52 . The process of  claim 51  wherein the fully saturated diacyl phosphatidylcholine is 1,2 dipalmitoyl phosphatidylcholine.  
     
     
         53 . The process of  claim 49  wherein the phospholipid is selected from the group consisting of diacylphosphatidylglycerol, diacylphosphatidylethanolamime, diacylphosphatidylserine, diacylphosphatidylinositol, sphingomelin, Cardiolipin, lysophospholipid, plasmalogen, diether phosphonolipid, dialkylphospholipid, and mixtures thereof.  
     
     
         54 . The process of  claim 43  wherein the carbohydrates are selected from the group consisting of glucose, fructose, galactose, pneumogalactan, dextrose and mixtures thereof.  
     
     
         55 . The process of  claim 43  wherein the protein is selected from the group consisting of albumin and pulmonary surfactant specific proteins A, B, C, D and mixtures thereof.  
     
     
         56 . The process of  claim 43  wherein the cholesteryl ester is selected from the group consisting of cholesteryl palmitate, cholesteryl oleate, cholesteryl stearate and mixtures thereof.  
     
     
         57 . The process of  claim 43  wherein said therapeutically active agent is selected from the group consisting of anti-inflammatory, antibiotic, decongestant and gene therapy agents.  
     
     
         58 . The process of  claim 57  wherein said anti-inflammatory agent is betamethasone.  
     
     
         59 . The process of  claim 57  wherein said antibioitic is selected from the group consisting of erythromycin, amoxicillin, zythromax and Augmentin.  
     
     
         60 . The process of  claim 57  wherein said decongestant is phenylephrine.  
     
     
         61 . The process of  claim 43  wherein the propellants are fluorocarbons.  
     
     
         62 . The process of  claim 61  wherein the fluorocarbon is selected from the group consisting of chlorofluorocarbon, hydrofluorocarbon and mixtures thereof.  
     
     
         63 . The process of  claim 43  wherein the propellant is selected to be carbon dioxide.  
     
     
         64 . The process of  claim 43  wherein the propellant is selected to be any pharmaceutical grade, hypo-allergenic propellant in which neither the at least one surfactant or therapeutic agent are not soluble.