Formoterol superfine formulation

Abstract

The present invention relates to a pharmaceutical formulation for use in the administration of a long-acting β 2 -agonist by inhalation. In particular this invention relates to a chemically stable highly efficient formoterol HFA solution formulation to be administered by pressurised metered dose inhalers (pMDIs) characterized by a deep lung penetration. The invention also relates to methods for the preparation of said formulation and to its use in respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD).

1 . A pharmaceutical aerosol formulation to be administered by a pressurized metered dose inhaler which comprises an active ingredient selected from formoterol or a stereoisomer, physiologically acceptable salt and solvate thereof, in a solution of a liquefied HFA propellant and a co-solvent, characterized in that the amount of residual water is less than 1500 ppm on the total weight of the formulation.  
     
     
         2 . A pharmaceutical formulation according to  claim 1  wherein the amount of residual water is less than 1000 ppm.  
     
     
         3 . A pharmaceutical formulation according to  claim 1  wherein the amount of residual water is less than 500 ppm.  
     
     
         4 . A pharmaceutical formulation according to  claim 1  wherein the fraction of particles equal or less than 1.1 μm delivered on actuation of the inhaler is higher or equal than 30% as defined by the content of the stages S6-AF of an Andersen Cascade Impactor, relatively to the content of the stages S6-AF, according to the method referred to in the description on page 17 lines 4 to 12.  
     
     
         5 . A pharmaceutical formulation according to  claim 1  wherein the superfine fraction is higher than 50%.  
     
     
         6 . A pharmaceutical formulation according to  claim 1  wherein the active ingredient is (R,R)-(±)-formoterol fumarate in a concentration comprised between 0.003 and 0.192% w/v.  
     
     
         7 . A pharmaceutical formulation according to  claim 6  wherein the active ingredient is in a concentration comprised between 0.006 and 0.048% w/v.  
     
     
         8 . A pharmaceutical formulation according to  claim 1  wherein the pH is comprised between 2.5 and 5.0.  
     
     
         9 . A pharmaceutical formulation according to  claim 8  wherein the pH is comprised between 3.5 and 4.0.  
     
     
         10 . A pharmaceutical formulation according to  claim 8  wherein the pH is adjusted by adding hydrochloric acid.  
     
     
         11 . A pharmaceutical formulation according to  claim 1 , wherein the propellant includes one or more hydrofluoroalkanes [HFAs] selected from the group comprising HFA 134a and HFA 227.  
     
     
         12 . A pharmaceutical formulation according to  claim 1 , wherein the co-solvent is selected from the group of lower alkyl (C 1 -C 4 ) alcohols, polyols, polyalkylene glycols, (poly)alkoxy derivatives and their combinations.  
     
     
         13 . A pharmaceutical formulation according to  claim 12  wherein the co-solvent is ethanol.  
     
     
         14 . A pharmaceutical formulation according to  claim 13  wherein ethanol is in anhydrous form.  
     
     
         15 . A pharmaceutical formulation according to  claim 13  wherein the concentration of ethanol is comprised between 10 and 20% w/w.  
     
     
         16 . A pharmaceutical formulation according to  claim 1  filled in a canister having part or all of its internal metallic surfaces made of standard aluminium, stainless steel, anodized aluminium or lined with an inert organic coating.  
     
     
         17 . A pharmaceutical formulation according to  claim 15  comprising 0.012-0.048% w/v formoterol fumarate, 12% w/w anhydrous ethanol, 0.037% w/w HCl 1 M and HFA 134a.  
     
     
         18 . A pharmaceutical formulation according to  claim 15  comprising 0.006-0.024% w/v formoterol fumarate, 12% w/w anhydrous ethanol, 0.023% w/w HCl 1 M and HFA 134a.  
     
     
         19 . A pharmaceutical formulation according to  claim 1  comprising a further active ingredient selected from the class of steroids such as beclomethasone dipropionate, fluticasone propionate, ciclesonide, budesonide and its 22R-epimer or anticholinergic atropine-like derivatives such as ipratropium bromide, oxitropium bromide, tiotropium bromide.  
     
     
         20 . A pharmaceutical formulation according to  claim 1  filled in a pressurized metered dose inhaler overwrapped in a package capable of resisting water ingress.  
     
     
         21 . A pharmaceutical formulation according to  claim 20  wherein the package further incorporates a material able to adsorb any propellant and co-solvent which may leak from the canister such as a molecular sieve.  
     
     
         22 . A method of preparing the pharmaceutical formulations of  claim 1 , the method comprising: 
 (a) preparing of a solution of one or more active ingredients in one or more co-solvents;    (b) optionally adjusting the pH of the solution;    (c) filling of the inhaler with said solution;    (d) crimping with valves and gassing;    (e) adding a propellant containing a hydrofluoroalkane (HFA).    
     
     
         23 . A pharmaceutical formulation according to  claim 9  wherein the pH is adjusted by adding hydrochloric acid.  
     
     
         24 . A pharmaceutical formulation according to  claim 14  wherein the concentration of ethanol is comprised between 10 and 20% w/w.