Aerosol Formulations Comprising Formoterol Fumarate Dihydrate

Abstract

The invention provides a method of producing a highly stable pharmaceutical aerosol suspension formulation suitable for use in a metered dose inhaler, the formulation comprising formoterol fumarate di-hydrate in suspension, a steroid in suspension, a propellant and ethanol, the method comprising the steps of drying the formoterol fumarate di-hydrate to a water content of 4.8 to 4.28%.

1 - 27 . (canceled) 
     
     
         28 . A method of producing a highly stable pharmaceutical aerosol suspension formulation comprising formoterol fumarate di-hydrate in suspension, a steroid in suspension, a propellant and ethanol, the method comprising the steps of
 drying the formoterol fumarate di-hydrate to a water content of 4.8 to 4.28% at a temperature between 10 and 70 Celsius and a pressure of 10 to 400 mbar,   mixing the dried formoterol fumarate di-hydrate with a steroid,   introducing a pre-mix of propellant and ethanol into the vial under pressure through the valve, and   forming suspension of the formoterol fumarate di-hydrate and the steroid in the propellant and ethanol,   
       wherein the water content of the formoterol fumarate di-hydrate is measured according to the Karl Fischer Method, and 
       wherein the formulation is capable of being dispensed from a metered dose inhaler (MDI) to provide a Delivered dose formoterol fumarate di-hydrate that has a variance of no more than +/−25% of the mean Delivered dose when the formulation is stored at 40° C. and 75% relative humidity for up to 6 months. 
     
     
         29 . The method of  claim 28 , wherein the steroid is selected from the group consisting of budesonide, ciclesonide, mometasone, fluticasone, beclomethasone, flunisolide, loteprednol, triamcinolone, amiloride, rofleponide or a pharmaceutically acceptable salt or derivative of these active compounds, selected from mometasone furoate, fluticasone propionate, beclomethasone dipropionate, triamcinolone acetonide and flunisolide acetate. 
     
     
         30 . The method of  claim 29 , wherein the steroid is fluticasone propionate. 
     
     
         31 . The method of  claim 30 , wherein the fluticasone proprionate is present in an amount of 0.05 to 2% by weight of the formulation. 
     
     
         32 . The method of  claim 28 , wherein the formoterol fumarate di-hydrate is present in an amount of 0.001 to 0.1% by weight of the formulation. 
     
     
         33 . The method of  claim 28 , further comprising a step of drying a cromone selected from the group consisting of a pharmaceutically acceptable salt of cromoglycinic acid, nedocromil, and mixtures thereof, and mixing the cromone with the dried formoterol fumarate di-hydrate and the steroid. 
     
     
         34 . The method of  claim 33 , wherein the cromone is present in the formulation in an amount of 0.001 to 1%. 
     
     
         35 . The method of  claim 28 , wherein the propellant is a hydrofluoroalkane of the general formula: CxHyFz in which x is the number 1, 2 or 3, y and z are each an integer greater than or equal to (≧) 1, and y+z=2x+2. 
     
     
         36 . The method of  claim 35 , wherein the propellant is HFA 134a or HFA 227 or a mixture thereof. 
     
     
         37 . The method of  claim 28 , wherein the propellant is employed in an amount of greater than 90% by weight. 
     
     
         38 . The method of  claim 28 , wherein the ethanol is present in amounts of less than 2.5% by weight. 
     
     
         39 . The method of  claim 28 , wherein the vial is in the form of an aluminum, uncoated container. 
     
     
         40 . The method of  claim 39 , wherein the vial is adapted to be placed in a metered dose inhaler and each dose of the plurality of doses contains 3 to 15 micrograms of formoterol fumarate di-hydrate. 
     
     
         41 . The method of  claim 40 , wherein each dose of the plurality of doses contains 50 to 500 micrograms of fluticasone proprionate. 
     
     
         42 . The method of  claim 28 , wherein the mixing step is performed prior to introducing the dried formoterol fumarate di-hydrate and steroid into an aerosol vial. 
     
     
         43 . The method of  claim 28 , wherein the dried formoterol fumarate di-hydrate and steroid are mixed in an aerosol vial. 
     
     
         44 . The method of  claim 42  or  43  wherein the amount of dried formoterol fumarate dihydrate and steroid is sufficient to provide a plurality of dosages. 
     
     
         54 . The method of  claim 42 ,  43 , or  44 , wherein the vial comprises or is adapted to comprise a metered dose valve.