Stable pressurised aerosol solution composition of glycopyrronium bromide and formoterol combination

Patent metadata

Field	Value
Publication number	US-10596149-B2
Application number	US-201615379924-A
Country	US
Kind code	B2
Filing date	Dec 15, 2016
Priority date	Dec 30, 2013
Publication date	Mar 24, 2020
Grant date	Mar 24, 2020

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.

First claim

The invention claimed is:

1. 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.

2. A method according to claim 1 , 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.

3. A method according to claim 1 , 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.

4. A method according to claim 1 , wherein the HFA propellant is at least one member selected from the group consisting of HFA 134a (1,1,1,2-tetrafluoroethane), HFA 227 (1,1,1,2,3,3,3-heptafluoropropane, and mixtures thereof, and HFA 134a (1,1,1,2-tetrafluoroethane).

5. A method according to claim 1 , wherein:
the co-solvent is ethanol or anhydrous ethanol; and
the co-solvent is present in the composition at a concentration of 8 to 25% (w/w).

6. A method according to claim 1 , wherein:
the co-solvent is ethanol or anhydrous ethanol; and
the co-solvent is present in the composition at a concentration of 10 to 15% (w/w).

7. A method according to claim 1 , wherein:
the co-solvent is ethanol or anhydrous ethanol; and
the co-solvent is present in the composition at a concentration of about 12% (w/w).

8. A method according to claim 1 , wherein:
the mineral acid is 1M hydrochloric acid; and
the stabilizing amount of the mineral acid in the composition is 0.15 to 0.28 μg/μl.

9. A method according to claim 1 , wherein:
the mineral acid is 1M hydrochloric acid; and
the stabilizing amount of the mineral acid in the composition is 0.18 to 0.26 μg/μl.

10. A method according to claim 1 , wherein:
the mineral acid is 1M hydrochloric acid; and
the stabilizing amount of the mineral acid in the composition is 0.224 μg/μl.

11. A method according to claim 1 , wherein:
the inhalation corticosteroid is present in the composition; and
the inhalation corticosteroid is at least one member selected from the group consisting of beclometasone dipropionate and budesonide.

12. A method according to claim 1 , wherein the composition comprises:
glycopyrronium bromide in an amount sufficient to provide a dosage of 6 to 25 μg per actuation of the pressurized metered dose inhaler;
formoterol fumarate dihydrate in an amount sufficient to provide a dosage of 6 to 12 μg per actuation of the pressurized metered dose inhaler; and
beclometasone dipropionate or budesonide in an amount sufficient to provide a dosage of from 20 to 1000 μg per actuation of the pressurized metered dose inhaler.

13. A method according to claim 1 , wherein the composition comprises:
glycopyrronium bromide in an amount sufficient to provide a dosage of 6, 12, or 25 μg per actuation of the pressurized metered dose inhaler;
formoterol fumarate dihydrate in an amount sufficient to provide a dosage of 6 or 12 μg per actuation of the pressurized metered dose inhaler; and
beclometasone dipropionate or budesonide in an amount sufficient to provide a dosage of from 50 to 250 μg per actuation of the pressurized metered dose inhaler.

14. A method according to claim 1 , wherein the amount of the degradation product N-(3-bromo)- [2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxypheny propan-2-ylamino]ethyl] phenyl]formamide formed, when the composition is stored in accelerated conditions at 25° C. and 60% relative humidity (RH) for at least 6 months, is lowered to less than 0.10% w/w, with respect to the theoretical formoterol fumarate content of 6 μg/actuation.

Assignees

• Chiesi Farm Spa

Inventors

• Bonelli Sauro
• Copelli Diego
• Alberi Massimiliano Dagli
• Usberti Francesca
• Zambelli Enrico

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K47/02

  Inorganic compounds · CPC title

• A61K31/40 Primary

  having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil · CPC title

• A61M15/009

  using medicine packages with incorporated spraying means, e.g. aerosol cans (pocket atomiser of the injector type A61M11/08) · CPC title

• A61M15/0071

  having a display or indicator · CPC title