Pressurised metered dose inhalers containing solutions of beta-2 agonists

Abstract

The present invention relates to a pharmaceutical formulation for use in the administration of 2(1H)-quinolinone derivatives long-acting β 2 -agonists by inhalation. In particular this invention relates to a chemically stable highly efficient TA 2005 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 which comprises an active ingredient selected from a 2(1H)-quinolinone derivative long acting β 2 -agonist of formula (I):  
       
         
           
           
               
               
           
         
       
       wherein the formulation is administratable by pressurized metered dose inhalers, R 1  is methyl and R 2  is hydrogen or R 1  and R 2  form a methylene bridge (CH 2 ) n  
 n is 1 or 2  
 R 3 , R 4 , R 5  and R 6  are each independently hydrogen, hydroxyl, C 1 -C 4  straight chain or branched alkyl, C 1 -C 4  straight chain or branched alkyl substituted by one or more halogen and/or hydroxyl, halogen, C 1 -C 4  straight chain or branched alkoxy, a stereoisomer, physiologically acceptable salt and solvate thereof, in a solution of a liquefied HFA propellant, a co-solvent, and optionally an amount of water up to 5% on the total weight of the formulation.  
 
     
     
         2 . The 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, relaive to the total amount of the fine particle dose collected in the stages S3-AF of the impactor.  
     
     
         3 . The pharmaceutical formulation according to  claim 1 , wherein the fraction of particles equal to or less than 1.1 μm delivered on actuation of the inhaler is higher than 40%.  
     
     
         4 . The pharmaceutical formulation according to  claim 1 , wherein the active ingredient is 8-hydroxy 5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxy-phenyl)-1-methylethyl]amino]ethyl]-2(1H)-quinolinone, a physiologically acceptable salt or a solvate thereof.  
     
     
         5 . The pharmaceutical formulation according to  claim 1 , wherein the active ingredient is 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxy-phenyl)-1-methylethyl]amino]ethyl]-2(1H)-quinolinone hydrochloride.  
     
     
         6 . The pharmaceutical formulation according to  claim 5  wherein the active ingredient is in a concentration comprised between 0.0005 and 0.024% w/v.  
     
     
         7 . The pharmaceutical formulation according to  claim 5  wherein the active ingredient is in a concentration comprised between 0.001 and 0.008% w/v.  
     
     
         8 . The pharmaceutical formulation according to  claim 1 , wherein the apparent pH is comprised between 2.5 and 5.0.  
     
     
         9 . The pharmaceutical formulation according to  claim 1 , wherein the apparent pH is comprised between 2.8 and 4.0.  
     
     
         10 . The pharmaceutical formulation according to  claim 8  wherein the pH is adjusted by adding a mineral acid.  
     
     
         11 . The pharmaceutical formulation according to  claim 10 , wherein the mineral acid is selected from the group consisting of hydrochloric, nitric and phosphoric acid.  
     
     
         12 . The pharmaceutical formulation according to  claim 1 , wherein the propellant comprises one or more hydrofluoroalkanes (HFAs) selected from the group consisting of HFA 134a and HFA 227.  
     
     
         13 . The pharmaceutical formulation according to  claim 1 , wherein the co-solvent is selected from the group consisting of C 1 -C 4 alkyl alcohols, polyols, polyalkylene glycols, (poly)alkoxy derivatives and mixtures thereof.  
     
     
         14 . The pharmaceutical formulation according to  claim 13  wherein the co-solvent is ethanol.  
     
     
         15 . The pharmaceutical formulation according to  claim 14  wherein the ethanol is present from 5 to 30% by weight.  
     
     
         16 . The pharmaceutical formulation according to  claim 15 , wherein the ethanol is present from 10 to 20% by weight.  
     
     
         17 . The pharmaceutical formulation according to  claim 1 , filled in a canister having part or all of internal metallic surfaces of the canister lined with an inert organic coating.  
     
     
         18 . The pharmaceutical formulation according to  claim 17 , wherein the canister is lined with an inert organic coating selected from the group consisting of epoxy-phenol resins, perfluoroalkoxyalkane, perfluoroalkoxyalkylene, perfluoroalkylenes, polyether sulfone, a copolymer fluorinated-ethylene-propylene polyether sulfone and mixtures thereof.  
     
     
         19 . The pharmaceutical formulation according to  claim 18  wherein the inert organic coating is polytetrafluoroethylene (Teflon).  
     
     
         20 . The pharmaceutical formulation according to  claim 1  further comprising at least one additional active ingredient selected from steroids or anticholinergic atropine-like derivatives.  
     
     
         21 . A method of preparing the formulation of  claim 1 , the method comprising: 
 a) preparing a solution of one or more active ingredients in one or more co-solvents;    b) optionally adding a pre-determined amount of water and/or adjusting the pH of the solution;    c) filling the inhaler with said solution;    d) crimping with valves and gassing;    e) adding a propellant comprising a hydrofluoroalkane (HFA).    
     
     
         22 . The pharmaceutical formulation according to  claim 9  wherein the pH is adjusted by adding a mineral acid.  
     
     
         23 . A method of treating respiratory diseases comprising 
 administering the formulation according to  claim 1  with a pressurized metered dose inhaler to a patient in need thereof.