Process for making chemically stable C-17/21 OH 20-ketosteroid aerosol products

Abstract

A medicinal aerosol steroid solution formulation product with enhanced chemical stability. The steroid is a 20-ketosteroid having an OH group at the C-17 or C-21 position and the aerosol container has a non-metal interior surface which has been found to reduce chemical degradation of such steroids.

1 . A medicinal aerosol steroid solution formulation product with enhanced chemical stability, including: 
 an aerosol container equipped with a dispensing valve and containing a medicinal aerosol formulation having a 20-ketosteroid drug dissolved therein;    said 20-ketosteroid having an OH group at the C-17 or C-21 position or both, provided that said 20-ketosteroid is other than flunisolide; and    wherein said container is provided with a non-metal interior surface so as to reduce chemical degradation of the 20-ketosteroid.    
     
     
         2 . The product of  claim 1 , wherein said container is made of aluminum having an inert interior coating.  
     
     
         3 . The product of  claim 2 , wherein the interior coating is an epoxy-phenolic lacquer.  
     
     
         4 . The product of  claim 1 , wherein said dispensing valve is a metered dose valve.  
     
     
         5 . The product of  claim 1 , wherein said medicinal aerosol formulation includes a hydrogen-containing propellant.  
     
     
         6 . The product of  claim 5 , wherein the hydrogen-containing propellant is a hydrofluorocarbon.  
     
     
         7 . The product of  claim 6 , wherein the hydrofluorocarbon propellant is selected from the group consisting of 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, and mixtures thereof.  
     
     
         8 . The product of  claim 1 , wherein said medicinal aerosol formulation includes ethanol.  
     
     
         9 . The product of  claim 1 , wherein said 20-ketosteroid has an OH group at the C-17 position, but not at the C-21 position.  
     
     
         10 . The product of  claim 1 , wherein said 20-ketosteroid has an OH group at the C-21 position, but not at the C-17 position.  
     
     
         11 . The product of  claim 1 , wherein said 20-ketosteroid has an OH group at both the C-17 and C-21 positions.  
     
     
         12 . The product of  claim 1 , wherein the 20-ketosteroid is a corticosteroid selected from the group consisting of budesonide, triamcinolone acetonide, desonide, fluocinolone acetonide, alclometasone, beclomethasone, beclomethasone 17-monopropionate, betamethasone, betamethasone 17-valerate, clocortolone, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone 21-isonicotinate, diflorasone, flumethasone, methylprednisolone, paramethasone, prednisolone, triamcinolone, clobetasol, and fluorometholone.  
     
     
         13 . The product of  claim 1 , wherein the 20-ketosteroid is budesonide.  
     
     
         14 . The product of  claim 1 , wherein the 20-ketosteroid is triamcinolone acetonide.  
     
     
         15 . The product of  claim 1 , wherein the 20-ketosteroid is dexamethasone.  
     
     
         16 . The product of  claim 1 , wherein the 20-ketosteroid is betamethasone 17-valerate.  
     
     
         17 . The product of any preceeding claim wherein the container and/or the valve has a coating applied by vapor deposition.  
     
     
         18 . The product of  claim 17 , wherein metal valve components have a coating applied by vapor deposition.  
     
     
         19 . The product of claims  17  or  18 , wherein the coating is a glass.  
     
     
         20 . The product of  claim 19 , wherein the coating is applied by the Silcosteel process.  
     
     
         21 . A method of reducing the chemical degradation of a medicinal 20-ketosteroid dissolved in a formulation contained in a metal container, said 20-ketosteroid being other than flunisolide and having an OH group at the C-17 position or C-21 position or both, comprising the step of providing a coating of inert material on the interior surface of the metal container so as to reduce reaction of the 20-ketosteroid with metal oxides from the container.  
     
     
         22 . A process for making a chemically stable steroid solution aerosol product by filling into a container an aerosol formulation comprising a dissolved 20-ketosteroid other than flunisolide, said 20-ketosteroid having an OH group at the C-17 position or C-21 position or both, and said container having an inert non-metal interior surface so as to avoid chemical degradation of the 20-ketosteroid due to interaction with the container.  
     
     
         23 . An aerosol valve having a non-metal coating applied to one or more metal surfaces by vapor deposition.  
     
     
         24 . The valve of  claim 23  wherein the coating is fused silica.  
     
     
         25 . A medicinal aerosol product equipped with a metering valve and containing a medicinal aerosol formulation, said product comprising a layer of fused silica material applied on an internal surface of said product in contact with the formulation.  
     
     
         26 . The product of  claim 25 , wherein said layer is on at least one component of the metering valve.  
     
     
         27 . The product of  claim 25 , wherein said layer is sub-micron in thickness.  
     
     
         28 . A method of making an improved metered dose medicinal aerosol product containing a medicinal aerosol formulation, comprising the step of coating an internal surface of said product, that is to be in contact with the formulation, with a layer of fused silica.  
     
     
         29 . (New) A medicinal aerosol steroid solution formulation metered dose inhaler product with enhanced chemical stability, including: 
 an aerosol container equipped with a metered dose dispensing valve and containing a medicinal aerosol formulation including a hydrofluoroalkane propellant selected from the group consisting of 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, and mixtures thereof, and having a 20-ketosteroid drug dissolved therein, which drug has an OH group at the C-21 position.    
     
     
         30 . (New) The product of  claim 29 , wherein said 20-ketosteroid has an OH group at the C-21 position, but not at the C-17 position.  
     
     
         31 . (New) The product of  claim 29 , wherein said 20-ketosteroid has an OH group at both the C-17 and C-21 positions.  
     
     
         32 . (New) The product of  claim 29 , wherein the 20-ketosteroid is dexamethasone.  
     
     
         33 . (New) The product of  claim 29 , wherein the 20-ketosteroid is betamethasone 17-valerate.  
     
     
         34 . (New) The product of any preceding claim wherein the container and/or the valve has a coating applied by vapor deposition.  
     
     
         35 . (New) The product of  claim 34 , wherein metal valve components have a coating applied by vapor deposition.  
     
     
         36 . (New) The product of claims  34  or  35 , wherein the coating is a glass.  
     
     
         37 . (New) The product of  claim 36 , wherein the coating is applied by the Silcosteel process.