Pressurized metered dose inhalers and pharmaceutical aerosol fomulations

Abstract

Provided are pressurized metered dose inhalers containing stable formulations of a β-agonist drug in suspension or solution. Also provided are aerosol formulations suitable for inhalation therapy containing a β-agonist drug in suspension or solution.

1 . A pressurized metered dose inhaler comprising a container equipped with a metering valve and containing a pressurized aerosol formulation formulated from a composition comprising: 
 a β-agonist drug;    at least one fluoroalkane propellant; and    greater than 5% by weight, based on total weight of said aerosol formulation, of a solvent that is capable of solubilizing or dissolving said β-agonist drug.    
     
     
         2 . A pressurized metered dose inhaler according to  claim 1 , wherein said metering valve is constructed and arranged to provide metered doses of said β-agonist drug in an amount that is thereapuetically effective.  
     
     
         3 . A pressurized metered dose inhaler according to  claim 1 , wherein said metering valve is constructed and arranged to provide metered doses of said β-agonist drug in an amount of about 12 μg per actuation of said meterering valve.  
     
     
         4 . A pressurized metered dose inhaler according to  claim 1 , wherein said fluoroalkane comprises 1,1,1,2-tetrafluoroethane.  
     
     
         5 . A pressurized metered dose inhaler according to  claim 1 , wherein said formulation is substantially free of chlorofluorocarbons.  
     
     
         6 . A pressurized metered dose inhaler according to  claim 1 , wherein said propellant is present in an amount of from about 70 to about 94% by weight.  
     
     
         7 . A pressurized metered dose inhaler according to  claim 1 , wherein said solvent is present in an amount of at least 10% by weight.  
     
     
         8 . A pressurized metered dose inhaler according to  claim 1 , wherein said solvent is present in an amount of at least 15% by weight.  
     
     
         9 . A pressurized metered dose inhaler according to  claim 1 , wherein said solvent is present in an amount in the range of from greater than 5% to about 30% by weight, based on the total weight of said aerosol formulation.  
     
     
         10 . A pressurized metered dose inhaler according to  claim 1 , wherein said solvent is selected from the group consisting of ethers and alcohols.  
     
     
         11 . A pressurized metered dose inhaler according to  claim 1 , wherein said solvent comprises an aliphatic alcohol having from 1 to about 6 carbon atoms.  
     
     
         12 . A pressurized metered dose inhaler according to  claim 1 , wherein said solvent comprises ethanol.  
     
     
         13 . A pressurized metered dose inhaler according to  claim 1 , wherein said solvent is more polar than said propellant.  
     
     
         14 . A pressurized metered dose inhaler according to  claim 1 , wherein said β-agonist drug comprises formoterol.  
     
     
         15 . A pressurized metered dose inhaler according to  claim 14 , wherein said formoterol is present in an amount of about 1% by weight or less, based on the total weight of said aerosol formulation.  
     
     
         16 . A pressurized metered dose inhaler according to  claim 14 , wherein said formoterol is present in an amount of about 0.01 to about 0.02% by weight, based on the total weight of said aerosol formulation.  
     
     
         17 . A pressurized metered dose inhaler according to  claim 14 , wherein said formoterol comprises formoterol fumarate.  
     
     
         18 . A pressurized metered dose inhaler according to  claim 1 , wherein said aerosol formulation is substantially free of a surfactant.  
     
     
         19 . A pressurized metered dose inhaler according to  claim 14 , wherein said formoterol comprises formoterol fumarate in an amount of up to about 1% by weight, said solvent comprises ethanol in an amount of greater than 5% to about 30% by weight, and said propellant is present in an amount of from about 70% to about 94% by weight, all weights based on the total weight of said aerosol formulation.  
     
     
         20 . A pressurized metered dose inhaler according to  claim 1 , wherein said aerosol formulation is adapted to be stable under conditions up to about 40° C. and about 75% relative humidity for at least about four weeks.  
     
     
         21 . A pressurized metered dose inhaler comprising a container equipped with a metering valve and containing a pressurized aerosol formulation formulated from a composition comprising: 
 particles of a β-agonist drug;    at least one fluoroalkane propellant; and    a surfactant that is capable of forming a suspension of said particles of β-agonist drug.    
     
     
         22 . A pressurized metered dose inhaler according to  claim 21 , wherein said metering valve is constructed and arranged to provide metered doses of said β-agonist drug in an amount that is therapeutically effective.  
     
     
         23 . A pressurized metered dose inhaler according to  claim 21 , wherein said metering valve is constructed and arranged to provide metered doses of said β-agonist drug in an amount of about 12 μg per actuation of said metering valve.  
     
     
         24 . A pressurized metered dose inhaler according to  claim 21 , wherein said fluoroalkane comprises 1,1,1,2-tetrafluoroethane.  
     
     
         25 . A pressurized metered dose inhaler according to  claim 21 , wherein said formulation is substantially free of chlorofluorocarbons.  
     
     
         26 . A pressurized metered dose inhaler according to  claim 21 , wherein said propellant is present in an amount up to about 99.9% by weight.  
     
     
         27 . A pressurized metered dose inhaler according to  claim 21 , wherein said β-agonist drug comprises formoterol.  
     
     
         28 . A pressurized metered dose inhaler according to  claim 27 , wherein said formoterol has an average particle size of less than about 100 μm.  
     
     
         29 . A pressurized metered dose inhaler according to  claim 27 , wherein said formoterol has an average particle size of less than about 20 μm.  
     
     
         30 . A pressurized metered dose inhaler according to  claim 27 , wherein said formoterol has an average particle size of from about 1 μm to about 10 μm.  
     
     
         31 . A pressurized metered dose inhaler according to  claim 21 , wherein said aerosol formulation is substantially free of a solvent.  
     
     
         32 . A pressurized metered dose inhaler according to  claim 27 , wherein said formoterol is present in an amount of about 1% by weight or less, based on the total weight of said aerosol formulation.  
     
     
         33 . A pressurized metered dose inhaler according to  claim 27 , wherein said formoterol is present in an amount of about 0.01 to about 0.02% by weight, based on the total weight of said aerosol formulation.  
     
     
         34 . A pressurized metered dose inhaler according to  claim 27 , wherein said formoterol comprises formoterol fumarate.  
     
     
         35 . A pressurized metered dose inhaler according to  claim 21 , wherein said surfactant is present in an of at least about 0.002% by weight, based on the total weight of said aerosol composition.  
     
     
         36 . A pressurized metered dose inhaler according to  claim 21 , wherein said surfactant is present in an of about 1% by weight or less, based on the total weight of said aerosol composition.  
     
     
         37 . A pressurized metered dose inhaler according to  claim 21 , wherein said surfactant is at least one selected from the group consisting of polyalcohols.  
     
     
         38 . A pressurized metered dose inhaler according to  claim 21 , wherein said surfactant comprises at least one selected from the group consisting of polyethylene glycol, diethylene glycol monoethyl ether, polyoxyethylene(20) sorbital monolaurate or monooleate; and polyoxyethylene 4-lauryl ether.  
     
     
         39 . A pressurized metered dose inhaler according to  claim 21 , wherein said surfactant comprises polyoxyethylene 4-lauryl ether.  
     
     
         40 . A pressurized metered dose inhaler according to  claim 27 , wherein said formoterol comprises formoterol fumarate in an amount of up to about 1% by weight, said surfactant comprises polyoxyethylene 4-lauryl ether in an amount of about 1% by weight or less, and said propellant is present in an amount 99.9% by weight, all weights based on the total weight of said aerosol formulation.  
     
     
         41 . A pressurized metered dose inhaler according to  claim 21 , wherein said aerosol formulation is adapted to be stable under conditions up to about 40° C. and about 75% relative humidity for at least about four weeks.  
     
     
         42 . An aerosol formulation adapted for use in a pressurized aerosol container, said aerosol formulation being formulated from a composition comprising: 
 a β-agonist drug;    at least one fluoroalkane propellant; and    greater than 5% by weight, based on total weight of said aerosol formulation, of a solvent that is capable of solubilizing or dissolving said β-agonist drug.    
     
     
         43 . An aerosol formulation according to  claim 42 , wherein said fluoroalkane comprises 1,1,1,2-tetrafluoroethane.  
     
     
         44 . An aerosol formulation according to  claim 42 , wherein said formulation is substantially free of chlorofluorocarbons.  
     
     
         45 . An aerosol formulation according to  claim 42 , wherein said propellant is present in an amount of from about 70 to about 94% by weight.  
     
     
         46 . An aerosol formulation according to  claim 42 , wherein said solvent is present in an amount of at least 10% by weight.  
     
     
         47 . An aerosol formulation according to  claim 42 , wherein said solvent is present in an amount of at least 15% by weight.  
     
     
         48 . An aerosol formulation according to  claim 42 , wherein said solvent is present in an amount in the range of from greater than 5% to about 30% by weight, based on the total weight of said aerosol formulation.  
     
     
         49 . An aerosol formulation according to  claim 42 , wherein said solvent is selected from the group consisting of ethers and alcohols.  
     
     
         50 . An aerosol formulation according to  claim 42 , wherein said solvent comprises an aliphatic alcohol having from 1 to about 6 carbon atoms.  
     
     
         51 . An aerosol formulation according to  claim 42 , wherein said solvent comprises ethanol.  
     
     
         52 . An aerosol formulation according to  claim 42 , wherein said solvent is more polar than said propellant.  
     
     
         53 . An aerosol formulation according to  claim 42 , wherein said β-agonist drug comprises formoterol.  
     
     
         54 . An aerosol formulation according to  claim 53 , wherein said formoterol is present in an amount of about 1% by weight or less, based on the total weight of said aerosol formulation.  
     
     
         55 . An aerosol formulation according to  claim 53 , wherein said formoterol is present in an amount of about 0.01 to about 0.02% by weight, based on the total weight of said aerosol formulation.  
     
     
         56 . An aerosol formulation according to  claim 53 , wherein said formoterol comprises formoterol fumarate.  
     
     
         57 . An aerosol formulation according to  claim 42 , wherein said aerosol formulation is substantially free of a surfactant.  
     
     
         58 . An aerosol formulation according to  claim 53 , wherein said formoterol comprises formoterol fumarate in an amount of up to about 1% by weight, said solvent comprises ethanol in an amount of greater than 5% to about 30% by weight, and said propellant is present in an amount of from about 70% to about 94% by weight, all weights based on the total weight of said aerosol formulation.  
     
     
         59 . An aerosol formulation according to  claim 42 , wherein said aerosol formulation is adapted to be stable under conditions up to about 40° C. and about 75% relative humidity for at least about four weeks.  
     
     
         60 . An aerosol formulation adapted for use in a pressurized aerosol container, said aerosol formulation being formulated from a composition comprising: 
 particles of a β-agonist drug;    at least one fluoroalkane propellant; and    a surfactant that is capable of forming a suspension of said particles of β-agonist drug.    
     
     
         61 . An aerosol formulation according to  claim 60 , wherein said fluoroalkane comprises 1,1,1,2-tetrafluoroethane.  
     
     
         62 . An aerosol formulation according to  claim 60 , wherein said formulation is substantially free of chlorofluorocarbons.  
     
     
         63 . An aerosol formulation according to  claim 60 , wherein said propellant is present in an amount up to about 99.9% by weight.  
     
     
         64 . An aerosol formulation according to  claim 60 , wherein said β-agonist drug comprises formoterol.  
     
     
         65 . An aerosol formulation according to  claim 64 , wherein said formoterol has an average particle size of less than about 100 μm.  
     
     
         66 . An aerosol formulation according to  claim 64 , wherein said formoterol has an average particle size of less than about 20 μm.  
     
     
         67 . An aerosol formulation according to  claim 64 , wherein said formoterol has an average particle size of from about 1 μm to about 10 μm.  
     
     
         68 . An aerosol formulation according to  claim 60 , wherein said aerosol formulation is substantially free of a solvent.  
     
     
         69 . An aerosol formulation according to  claim 64 , wherein said formoterol is present in an amount of about 1% by weight or less, based on the total weight of said aerosol formulation.  
     
     
         70 . An aerosol formulation according to  claim 64 , wherein said formoterol is present in an amount of about 0.01 to about 0.02% by weight, based on the total weight of said aerosol formulation.  
     
     
         71 . An aerosol formulation according to  claim 64 , wherein said formoterol comprises formoterol fumarate.  
     
     
         72 . An aerosol formulation according to  claim 60 , wherein said surfactant is present in an of at least about 0.002% by weight, based on the total weight of said aerosol composition.  
     
     
         73 . An aerosol formulation according to  claim 60 , wherein said surfactant is present in an of about 1% by weight or less, based on the total weight of said aerosol composition.  
     
     
         74 . An aerosol formulation according to  claim 60 , wherein said surfactant is at least one selected from the group consisting of polyalcohols.  
     
     
         75 . An aerosol formulation according to  claim 60 , wherein said surfactant comprises at least one selected from the group consisting of polyethylene glycol, diethylene glycol monoethyl ether, polyoxyethylene(20) sorbital monolaurate or monooleate; and polyoxyethylene 4-lauryl ether.  
     
     
         76 . An aerosol formulation according to  claim 60 , wherein said surfactant comprises polyoxyethylene 4-lauryl ether.  
     
     
         77 . An aerosol formulation according to  claim 64 , wherein said formoterol comprises formoterol fumarate in an amount of up to about 1% by weight, said surfactant comprises polyoxyethylene 4-lauryl ether in an amount of about 1% by weight or less, and said propellant is present in an amount 99.9% by weight, all weights based on the total weight of said aerosol formulation.  
     
     
         78 . An aerosol formulation according to  claim 60 , wherein said aerosol formulation is adapted to be stable under conditions up to about 40° C. and about 75% relative humidity for at least about four weeks.