Method of manufacturing corticosteriod containing foam compositions

Abstract

The present invention provides a method of manufacturing foamable, corticosteroid containing compositions as well as methods for treating various skin diseases.

What is claimed is: 
     
         1 . A method for single-stream manufacture of a foamable composition including a corticosteroid, the method comprising:
 a) forming a homogenous solution comprising: i) an aliphatic alcohol; ii) a can corrosion inhibitor; iii) a polyol; iv) at least one foam structuring agent comprising one or more fatty alcohols, non-ionic surfactants, or combinations thereof; and v) water, wherein the solution is formed in a single batch vessel at a temperature of between about 55° to 75° C. while minimizing the evaporative losses;   b) cooling the homogenous solution of step (a) to a temperature of between about 40° to 55° C.;   c) adding a corticosteroid, or a pharmaceutically acceptable salt, ester, or solvate thereof, to the cooled solution of step (b) and forming a homogenous solution while maintaining a temperature of between about 40° to 55° C.;   d) filling an aerosol canister with the solution of step (c) while the solution is maintained at a temperature of between about 40° to 50° C.; and   e) charging the canister with a propellant thereby forming a single-phase foamable composition.   
     
     
         2 . The method of  claim 1 , wherein the aliphatic alcohol and can corrosion inhibitor are combined before adding the polyol, one or more foam structuring agents and water. 
     
     
         3 . The method of  claim 2 , wherein the can corrosion inhibitor is added to the aliphatic alcohol which is heated to at least about 55° C. before addition of the can corrosion inhibitor. 
     
     
         4 . The method of  claim 1 , wherein the solution of step (a) is maintained at a temperature of between about 65° to 70° C. 
     
     
         5 . The method of  claim 1 , wherein the solution of step (a) is cooled to a temperature of between about 45° to 50° C. before step (c). 
     
     
         6 . The method of  claim 1 , wherein the homogenous solution of step (c) is formed while maintaining a temperature of between about 45° to 50° C. 
     
     
         7 . The method of  claim 1 , wherein filling is performed while maintaining the solution at a temperature of between about 42° to 48° C. 
     
     
         8 . The method of  claim 1 , wherein the solution of step (a) is prepared in a suitable vessel to keep evaporative losses below 0.25% w/w during compounding. 
     
     
         9 . The method of  claim 1 , wherein the corticosteroid is selected from the group consisting of methylprednisolone, hydrocortisone, prednisolone, clobetasone, hydrocortisone butyrate, flumetasone, fluocortin, fluperolone, fluorometholone, fluprednidene, desonide, triamcinolone, alclometasone, hydrocortisone buteprate, dexamethasone, clocortolone, betamethasone, fluclorolone, desoximetasone, fluocinolone acetonide, fluocortolone, diflucortolone, fludroxycortide, fluocinonide, budesonide, diflorasone, amcinonide, halometasone, mometasone furoate, methylprednisolone aceponate, beclometasone, hydrocortisone aceponate, fluticasone, prednicarbate, difluprednate, halobetasol, resocortol butyrate, clobetasol and halcinonide. 
     
     
         10 . The method of  claim 9 , wherein the halobetasol is halobetasol propionate. 
     
     
         11 . The method of  claim 1 , wherein the aliphatic alcohol is methyl, ethyl, isopropyl or butyl alcohol, or a combination thereof. 
     
     
         12 . The method of  claim 1 , wherein the aliphatic alcohol is ethyl alcohol. 
     
     
         13 . The method of  claim 1 , wherein the fatty alcohol is selected from the group consisting of lauryl alcohol, myristyl alcohol, cetyl alcohol, lauryl alcohol, stearyl alcohol, octyldodecanol, and combinations thereof. 
     
     
         14 . The method of  claim 1 , wherein the fatty alcohol is a mixture of cetyl alcohol and stearyl alcohol. 
     
     
         15 . The method of  claim 1 , wherein the polyol is selected from the group consisting of glycerin, propylene glycol, butylene glycol, dipropylene glycol, pentylene glycol, hexylene glycol, polyethylene glycol and combinations thereof. 
     
     
         16 . The method of  claim 1 , wherein the polyol is propylene glycol. 
     
     
         17 . The method of  claim 1 , wherein the at least one foam structuring agent comprises an ethoxylated alcohol. 
     
     
         18 . The method of  claim 17 , wherein the ethoxylated alcohol is polyoxyl 20 cetostearyl ether. 
     
     
         19 . The method of  claim 1 , wherein the at least one foam structuring agent is a combination of one or more of cetyl alcohol, stearyl alcohol, and an ethoxylated alcohol. 
     
     
         20 . The method of  claim 1 , wherein the at least one foam structuring agent is Emulsifying Wax, NF. 
     
     
         21 . The method of  claim 1 , wherein the can corrosion inhibitor is less than approximately 0.005%, 0.001% or 0.0005% w/w of benzoic acid. 
     
     
         22 . The method of  claim 1 , wherein the composition has a pH of about 4.0 to 6.3. 
     
     
         23 . The method of  claim 1 , wherein the propellant is selected from propane, n-butane, isobutane, n-pentane, isopentane, dichloro difluoro methane, dichloro tetrafluoro ethane, octafluoro cyclobutane, 1,1,1,2-tetrafluoroethane, 1,1-difluoroethane, 1,1,1,2,3,3,3-heptafluoropropane and mixtures of two or more thereof. 
     
     
         24 . The method of  claim 1 , wherein the foam exhibits traditional rigid (mousse-like) and thermolabile (quick-break) characteristics. 
     
     
         25 . The method of  claim 1 , wherein the foamable composition is void of a buffer. 
     
     
         26 . The method of  claim 1 , wherein the corticosteroid remains stable for at least six months at 40° C. 
     
     
         27 . The method of  claim 1 , wherein the composition has an acceptable shelf-life of greater than about 24, 27, 30, 33, 36, 39, 42, 45 or 48 months. 
     
     
         28 . The method of  claim 27 , wherein the composition has an acceptable shelf-life of greater than about 36 months. 
     
     
         29 . The method of  claim 28 , wherein the shelf-life is determined at International Conference on Harmonisation (ICH) long-term storage condition by:
 a) the 95% one-sided lower confidence interval of the linear regression of the assay for halobetasol or its pharmaceutically acceptable salts, esters, and solvates;   b) the 95% one-sided upper confidence interval of the linear regression of the degradant products for halobetasol or its pharmaceutically acceptable salts, esters, and solvates; or   c) the pH stability of the composition.   
     
     
         30 . A storage stable, foamable composition produced by the method of  claim 1 .