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 formulation, which comprises a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
       wherein 
       R 1  is methyl and R 2  is hydrogen or R 1  and R 2  form a methylene bridge (CH 2 ) n    
       wherein 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, in a solution of a liquefied HFA propellant, a co-solvent, and optionally an amount of water up to 5% based on the total weight of said formulation, 
       wherein said formulation is contained in a pressurized metered dose inhaler, 
       wherein a fraction of particles having a size equal to or less than 1.1 μm delivered on actuation of said metered dose inhaler is equal to or higher than 30% as defined by the content of stages S6-AF of an Andersen Cascade Imapctor, relative to the total amount of the fine particle dose collected in stages S3-AF of said Andersen impactor. 
     
   
   
       2 . The pharmaceutical formulation according to  claim 1 , wherein said fraction of particles equal to or less than 1.1 μm delivered on actuation of said metered dose inhaler is higher than 40%. 
   
   
       3 . The pharmaceutical formulation according to  claim 1 , wherein said formulation comprises 8-hydroxy 5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxy-phenyl)-1-methylethyl]amino]ethyl]-2(1H)-quinolinone or a pharmaceutically acceptable salt thereof. 
   
   
       4 . The pharmaceutical formulation according to  claim 1 , wherein said formulation comprises 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxy-phenyl)-1-methylethyl]amino]ethyl]-2(1H)-quinolinone hydrochloride. 
   
   
       5 . The pharmaceutical formulation according to  claim 4  wherein said compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof is present in a concentration between 0.0005 and 0.024% w/v. 
   
   
       6 . The pharmaceutical formulation according to  claim 4  wherein said compound, stereoisomer thereof or pharmaceutically acceptable salt thereof is present in a concentration between 0.001 and 0.008% w/v. 
   
   
       7 . The pharmaceutical formulation according to  claim 1 , which has an apparent pH between 2.5 and 5.0. 
   
   
       8 . The pharmaceutical formulation according to  claim 7  wherein said apparent pH is adjusted by adding a mineral acid. 
   
   
       9 . The pharmaceutical formulation according to  claim 8 , wherein said mineral acid is selected from the group consisting of hydrochloric acid, nitric acid, and phosphoric acid. 
   
   
       10 . The pharmaceutical formulation according to  claim 1 , which has an apparent pH between 2.8 and 4.0. 
   
   
       11 . The pharmaceutical formulation according to  claim 10  wherein said apparent pH is adjusted by adding a mineral acid. 
   
   
       12 . The pharmaceutical formulation according to  claim 1 , wherein said liquefied HFA propellant comprises one or more hydrofluoroalkanes selected from the group consisting of HFA 134a and HFA 227. 
   
   
       13 . The pharmaceutical formulation according to  claim 1 , wherein said co-solvent is selected from the group consisting of a C 1 -C 4  alkyl alcohol, a polyol, a polyalkylene glycol, a (poly)alkoxy alcohol, and mixtures thereof. 
   
   
       14 . The pharmaceutical formulation according to  claim 13  wherein said co-solvent is ethanol. 
   
   
       15 . The pharmaceutical formulation according to  claim 14  wherein said ethanol is present in an amount of from 5 to 30% by weight. 
   
   
       16 . The pharmaceutical formulation according to  claim 15 , wherein said ethanol is present in an amount of from 10 to 20% by weight. 
   
   
       17 . The pharmaceutical formulation according to  claim 1 , which is contained in a canister having part or all of internal metallic surfaces of said canister lined with an inert organic coating. 
   
   
       18 . The pharmaceutical formulation according to  claim 17 , wherein said canister is lined with an inert organic coating selected from the group consisting of an epoxy-phenol resin, a perfluoroalkoxyalkane polymer, a perfluoroalkoxyalkylene polymer, a perfluoroalkylene polymer, a polyether sulfone, a copolymer fluorinated-ethylene-propylene polyether sulfone, and mixtures thereof. 
   
   
       19 . The pharmaceutical formulation according to  claim 18 , wherein said inert organic coating is polytetrafluoroethylene. 
   
   
       20 . The pharmaceutical formulation according to  claim 1 , further comprising at least one additional active ingredient selected from the group consisting of a steroid, ipratropium bromide, oxitropium bromide, and tiotropium bromide. 
   
   
       21 . A method of preparing a formulation according to  claim 1 , said method comprising:
 a) preparing a solution of said compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof in one or more of said co-solvent;   b) optionally adding a pre-determined amount of water and/or adjusting the pH of said solution;   c) filling a metered dose inhaler with said solution; and   d) adding a propellant comprising a hydrofluoroalkane.   
   
   
       22 . A method of treating a respiratory disease, comprising administering an effective amount of a formulation according to  claim 1  with a pressurized metered dose inhaler to a patient in need thereof,
 wherein said disease is COPD or asthma.   
   
   
       23 . A pharmaceutical formulation, consisting essentially of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
       wherein 
       R 1  is methyl and R 2  is hydrogen or R 1  and R 2  form a methylene bridge (CH 2 ) n    
       wherein 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, in a solution of a liquefied HFA propellant, a co-solvent, and optionally an amount of water up to 5% based on the total weight of said formulation, 
       wherein said formulation is contained in a pressurized metered dose inhaler, 
       wherein a fraction of particles having a size equal to or less than 1.1 μm delivered on actuation of said metered dose inhaler is equal to or higher than 30% as defined by the content of stages S6-AF of an Andersen Cascade Imapctor, relative to the total amount of the fine particle dose collected in stages S3-AF of said Andersen impactor. 
     
   
   
       24 . The pharmaceutical formulation according to  claim 23 , wherein said fraction of particles equal to or less than 1.1 μm delivered on actuation of said metered dose inhaler is higher than 40%. 
   
   
       25 . The pharmaceutical formulation according to  claim 23 , wherein said formulation contains 8-hydroxy 5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxy-phenyl)-1-methylethyl]-amino]ethyl]-2(1H)-quinolinone or a pharmaceutically acceptable salt thereof. 
   
   
       26 . The pharmaceutical formulation according to  claim 23 , wherein said formulation contains 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxy-phenyl)-1-methylethyl]amino]ethyl]-2(1H)-quinolinone hydrochloride. 
   
   
       27 . The pharmaceutical formulation according to  claim 23 , wherein said compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof is present in a concentration between 0.0005 and 0.024% w/v. 
   
   
       28 . The pharmaceutical formulation according to  claim 27 , wherein said compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof is present in a concentration between 0.001 and 0.008% w/v. 
   
   
       29 . The pharmaceutical formulation according to  claim 23 , which has an apparent pH between 2.5 and 5.0. 
   
   
       30 . The pharmaceutical formulation according to  claim 29 , wherein said apparent pH is adjusted by adding a mineral acid. 
   
   
       31 . The pharmaceutical formulation according to  claim 30 , wherein said mineral acid is selected from the group consisting of hydrochloric acid, nitric acid, and phosphoric acid. 
   
   
       32 . The pharmaceutical formulation according to  claim 23 , which has an apparent pH between 2.8 and 4.0. 
   
   
       33 . The pharmaceutical formulation according to  claim 32 , wherein said apparent pH is adjusted by adding a mineral acid. 
   
   
       34 . The pharmaceutical formulation according to  claim 33 , wherein said mineral acid is selected from the group consisting of hydrochloric acid, nitric acid, and phosphoric acid. 
   
   
       35 . The pharmaceutical formulation according to  claim 23 , wherein said liquefied HFA propellant comprises one or more hydrofluoroalkanes selected from the group consisting of HFA 134a and HFA 227. 
   
   
       36 . The pharmaceutical formulation according to  claim 23 , wherein said co-solvent is selected from the group consisting of a C 1 -C 4  alkyl alcohol, a polyol, a polyalkylene glycol, a (poly)alkoxy alcohol, and mixtures thereof. 
   
   
       37 . The pharmaceutical formulation according to  claim 36 , wherein said co-solvent is ethanol. 
   
   
       38 . The pharmaceutical formulation according to  claim 37 , wherein said ethanol is present in an amount of from 5 to 30% by weight. 
   
   
       39 . The pharmaceutical formulation according to  claim 38 , wherein said ethanol is present in an amount of from 10 to 20% by weight. 
   
   
       40 . The pharmaceutical formulation according to  claim 23 , which is contained in a canister having part or all of internal metallic surfaces of said canister lined with an inert organic coating. 
   
   
       41 . The pharmaceutical formulation according to  claim 40 , wherein said canister is lined with an inert organic coating selected from the group consisting of an epoxy-phenol resin, a perfluoroalkoxyalkane polymer, a perfluoroalkoxyalkylene polymer, a perfluoroalkylene polymer, a polyether sulfone, a copolymer fluorinated-ethylene-propylene polyether sulfone, and mixtures thereof. 
   
   
       42 . The pharmaceutical formulation according to  claim 41 , wherein said inert organic coating is polytetrafluoroethylene. 
   
   
       43 . The pharmaceutical formulation according to  claim 23 , further consisting essentially of at least one additional active ingredient selected from the group consisting of a steroid, ipratropium bromide, oxitropium bromide, and tiotropium bromide. 
   
   
       44 . A method of treating a respiratory disease, comprising administering an effective amount of a formulation according to  claim 23  with a pressurized metered dose inhaler to a patient in need thereof,
 wherein said disease is COPD or asthma.   
   
   
       45 . A pharmaceutical aerosol formulation, which is contained in a pressurized metered dose inhaler and which comprises TA2005 in a solution consisting of a liquefied HFA propellant, a co-solvent, a mineral acid and optionally an amount of water up to 5% based on the total weight of said formulation,
 wherein a fraction of particles having a size equal to or less than 1.1 μm delivered on actuation of said metered dose inhaler is equal to or higher than 30% as defined by the content of stages S6-AF of an Andersen Cascade Imapctor, relative to the total amount of the fine particle dose collected in stages S3-AF of said Andersen impactor and wherein said TA2005 is present in said formulation in an amount of 0.001 to 0.008% w/v to deliver 1 to 2 μg of TA2005 per actuation of said inhaler.   
   
   
       46 . A method of treating a respiratory disease, comprising administering an effective amount of a formulation according to  claim 45  with a pressurized metered dose inhaler to a patient in need thereof,
 wherein said disease is COPD or asthma.