Stable pressurized aerosol solution composition of glycopyrronium bromide and formoterol combination
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; and 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 (DP3) 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.
2. 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.
3. A pharmaceutical aerosol solution composition according to claim 2 , wherein said mineral acid is present in an amount of acid equivalent to 0.22 μg/μl of 1M hydrochloric acid.
4. A pharmaceutical aerosol solution composition according to claim 1 , wherein said co-solvent is ethanol.
5. A pharmaceutical aerosol solution composition according to claim 1 , wherein said formoterol salt is formoterol fumarate.
6. A pharmaceutical aerosol solution composition according to claim 1 , wherein said solvate form of said formoterol salt is formoterol fumarate dihydrate.
7. 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.
8. A pharmaceutical aerosol solution composition according to claim 7 , 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.
9. A pharmaceutical aerosol solution composition according to claim 8 , wherein said inhalation corticosteroid is beclometasone dipropionate which is present in an amount of 50 to 250 μg per actuation.
10. A pharmaceutical aerosol solution composition according to claim 8 , wherein said inhalation corticosteroid is budesonide which is present in an amount of 50 to 250 μg per actuation.
11. 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.
12. A pharmaceutical aerosol solution composition according to claim 11 , 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.
13. 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; and 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 (DP3) 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.
14. A method for the 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.
15. The aerosol can according to claim 13 , wherein the metering valve comprises a chlorobutyl rubber gasket or a bromobutyl rubber gasket.