Stable pharmaceutical solution formulations for pressurised metered dose inhalers

Abstract

An aerosol solution composition for use in an aerosol inhaler comprises an active material, a propellant containing a hydrofluoroalkane, a cosolvent and optionally a low volatility component to increase the mass median aerodynamic diameter (MMAD) of the aerosol particles on actuation of the inhaler. The composition is stabilized by using a small amount of mineral acid and a suitable can having part or all of its internal metallic surfaces made of stainless steel, anodized aluminium or lined with an inert organic coating.

1 . An aerosol composition which comprises a β 2 -agonist drug of the phenylalkylamino class bearing a functional group sensitive to oxidative and/or hydrolytic reaction in a solution of a liquefied HFA propellant, a co-solvent selected from pharmaceutically acceptable alcohols, wherein the pH of the solution -is comprised between 2.5 and 5.0 by addition of small amounts of a mineral acid such as hydrochloric, nitric or phosphoric acid.  
   
   
       2 . A composition according to  claim 1  wherein the active ingredient is a β 2 -agonist selected from salbutamol, formoterol, salmeterol and TA-2005, salts thereof or their combination with steroid such as beclomethasone dipropionate, fluticasone propionate, budesonide and its 22R-epimer or an anticholinergic atropine-like derivative such as ipratropium bromide, oxitropium bromide, tiotropium bromide  
   
   
       3 . A composition according to claims  1 - 2  filled in a container having part or all of its internal metallic surfaces made of stainless steel, anodised aluminium or lined with an inert organic coating.  
   
   
       4 . A composition according to claims  1 - 3 , wherein the container is lined with an inert organic coating selected from epoxy-phenol resins, perfluoroalkoxyalkane, perfluoroalkoxyalkylene, perfluoroalkylenes such as polytetrafluoroethylene, fluorinated-ethylene-propylene, polyether sulfone and a copolymer fluorinated-ethylene-propylene polyether sulfone  
   
   
       5 . A composition according to claims  1 - 4 , wherein the active ingredient is formoterol fumarate and the pH of the solution -is comprised between 3.0 and 3.5.  
   
   
       6 . A composition according to claims  1 - 5 , wherein the solution includes a low volatility component with a vapour pressure at 25° C. not more than 0.1 kPa, preferably not more than 0.05 kPa.  
   
   
       7 . A composition according to any preceding claim, wherein the solution includes at least 0.2% by weight of the low volatility component and not more than 10% by weight.  
   
   
       8 . A composition according to claims  6 - 7 , wherein the low volatility component is selected from a glycol or an ester of long-chain fatty acids.  
   
   
       9 . A composition according to claims - 6 - 8 , wherein the low volatility component is isopropyl myristate.  
   
   
       10 . A composition according to any preceding claim, wherein the propellant includes one or more HFAs selected from the group comprising HFA 134a and HFA 227.  
   
   
       11 . A composition according to any preceding claims, wherein the cosolvent is an alcohol, preferably ethanol.  
   
   
       12 . A method of preparing the formulations of claims  1 - 10 , the method comprising: 
 (a) preparation of a solution of one or more active ingredients in one or more co-solvents optionally containing an appropriate amount of a low volatility component;    (b) filling the device with said solution;    (c) adding a pre-determined amount of a strong mineral acid;    (d) adding a propellant containing a hydrofluoroalkane (HFA);    (e) crimping with valves and gassing.