Stable pressurised aerosol solution composition of glycopyrronium bromide and formoterol combination

Abstract

Aerosol solution compositions intended for use with a pressurized metered dose inhaler, comprising glycopyrronium bromide and formoterol, or a salt thereof, optionally in combination with one or more additional active ingredients, and stabilized by a selected amount of a mineral acid, exhibit improved stability when contained in an aerosol can provided with a metering valve having at least a butyl rubber gasket.

1 . A pharmaceutical aerosol solution composition, for use in a pressurized metered dose inhaler, comprising:
 (a) glycopyrronium bromide at a dosage in the range of from 5 to 26 μg per actuation;   (b) formoterol, or a salt thereof or a solvate of said salt, at a dosage in the range of from 1 to 25 μg per actuation;   (c) a HFA propellant;   (d) a co-solvent;   (e) a stabilizing amount of a mineral acid;   wherein said composition is contained in an aerosol can provided with a metering valve having at least a butyl rubber gasket.   
     
     
         2 . A pharmaceutical aerosol solution composition according to  claim 1 , wherein the amount of the degradation product N-(3-bromo)-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyl]formamide formed, when said composition is stored in accelerated conditions at 25° C. and 60% relative humidity (RH) for at least 6 months, is lower than 0.10% w/w, with respect to the theoretical formoterol fumarate content of 6 μg/actuation. 
     
     
         3 . A pharmaceutical aerosol solution composition according to  claim 1 , wherein said mineral acid is present in an amount equivalent to 0.15 to 0.28 μg/μl of 1M hydrochloric acid. 
     
     
         4 . A pharmaceutical aerosol solution composition according to  claim 3 , wherein said mineral acid is present in an amount of acid equivalent to 0.22 μg/μl of 1M hydrochloric acid. 
     
     
         5 . A pharmaceutical aerosol solution composition according to  claim 1 , wherein said co-solvent is ethanol. 
     
     
         6 . A pharmaceutical aerosol solution composition according to  claim 1 , wherein said formoterol salt is formoterol fumarate. 
     
     
         7 . A pharmaceutical aerosol solution composition according to  claim 1 , wherein said solvate form of said formoterol salt is formoterol fumarate dihydrate. 
     
     
         8 . A pharmaceutical aerosol solution composition according to  claim 1 , further comprising one or more pharmaceutically active ingredients selected from the group consisting of a beta-2 agonist, an inhalation corticosteroid, an antimuscarinic agent, and a phosphodiesterase-4 inhibitor. 
     
     
         9 . A pharmaceutical aerosol solution composition according to  claim 8 , wherein said inhalation corticosteroid is beclometasone dipropionate, budesonide or its 22R-epimer, ciclesonide, flunisolide, fluticasone propionate, fluticasone furoate, mometasone furoate, butixocort, triamcinolone acetonide, triamcinolone, methylprednisolone, prednisone, loteprednol, or rofleponide. 
     
     
         10 . A pharmaceutical aerosol solution composition according to  claim 9 , wherein said inhalation corticosteroid is beclometasone dipropionate which is present in an amount of 50 to 250 μg per actuation. 
     
     
         11 . A pharmaceutical aerosol solution composition according to  claim 9 , wherein said inhalation corticosteroid is budesonide which is present in an amount of 50 to 250 μg per actuation. 
     
     
         12 . A pharmaceutical aerosol solution composition according to  claim 1 , wherein the level of formoterol degradation products formed, when said composition is stored in accelerated conditions at 25° C. and 60% relative humidity (RH) for at least 6 months, is lower than 10% w/w with respect to the theoretical formoterol fumarate content of 6 μg/actuation, and wherein the residual level of formoterol fumarate, when said composition is stored in accelerated conditions at 25° C. and 60% relative humidity (RH) for at least 6 months, is higher than 90% w/w with respect to its initial content. 
     
     
         13 . A pharmaceutical aerosol solution composition according to  claim 12 , wherein the overall level of formoterol degradation products formed, when said composition is stored in accelerated conditions at 25° C. and 60% relative humidity (RH) for at least 6 months, is lower than 2% w/w with respect to the theoretical formoterol fumarate content of 6 μg/actuation, and wherein the residual level of the formoterol fumarate, when said composition is stored in accelerated conditions at 25° C. and 60% relative humidity (RH) for at least 6 months, is higher than 95% w/w with respect to its initial content. 
     
     
         14 . An aerosol can, comprising a metering valve having at least a butyl rubber gasket and containing a pharmaceutical aerosol solution composition comprising:
 (a) glycopyrronium bromide at a dosage in the range of from 5 to 26 μg per actuation;   (b) formoterol, or a salt thereof or a solvate of said salt, at a dosage in the range of from 1 to 25 μg per actuation;   (c) a HFA propellant;   (d) a co-solvent;   (e) a stabilizing amount of a mineral acid; and,   (f) optionally, an inhalation corticosteroid.   
     
     
         15 . A method to lower the amount of degradation product N-(3-bromo)-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyl]formamide (DP3) formed during the shelf-life of a pharmaceutical aerosol solution composition intended for use in a pressurized metered dose inhaler comprising:
 (a) glycopyrronium bromide at a dosage in the range of from 5 to 26 μg per actuation;   (b) formoterol, or a salt thereof or a solvate of said salt, at a dosage in the range of from 1 to 25 μg per actuation;   (c) a HFA propellant;   (d) a co-solvent;   (e) a stabilizing amount of a mineral acid; and   (f) optionally, an inhalation corticosteroid   said method comprising containing the above composition in an aerosol can provided with a metering valve having at least a butyl rubber gasket.   
     
     
         16 . A method according to  claim 15 , wherein the overall level of formoterol degradation products formed, when said composition is stored in accelerated conditions at 25° C. and 60% relative humidity (RH) for at least 6 months, is lower than 10% w/w with respect to the theoretical formoterol fumarate content of 6 μg/actuation, and wherein the residual level of formoterol fumarate, when said composition is stored in accelerated conditions at 25° C. and 60% relative humidity (RH) for at least 6 months, is higher than 90% w/w with respect to its initial content. 
     
     
         17 . A method according to  claim 15 , wherein the overall level of formoterol degradation products formed, when said composition is stored in accelerated conditions at 25° C. and 60% relative humidity (RH) for at least 6 months, is lower than 2% w/w with respect to the theoretical formoterol fumarate content of 6 μg/actuation, and wherein the residual level of the formoterol fumarate, when said composition is stored in accelerated conditions at 25° C. and 60% relative humidity (RH) for at least 6 months, is higher than 95% w/w with respect to its initial content. 
     
     
         18 . A method for the prevention and/or treatment of an obstructive respiratory disorder selected from the group consisting of asthma and COPD, comprising administering an effective amount of a pharmaceutical aerosol solution composition according to  claim 1  to a subject in need thereof.