Stable pressurized aerosol solution composition of glycopyrronium bromide and formoterol combination

Patent metadata

Field	Value
Publication number	US-10617669-B2
Application number	US-201615196253-A
Country	US
Kind code	B2
Filing date	Jun 29, 2016
Priority date	Dec 30, 2013
Publication date	Apr 14, 2020
Grant date	Apr 14, 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 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.

Assignees

• Chiesi Farm Spa

Inventors

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

Classifications

• A61M15/0071

  having a display or indicator · CPC title

• A61K31/573

  substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone · CPC title

• A61K47/10

  Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers · CPC title

• A61K9/008 Primary

  comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI] · CPC title

• A61K47/02

  Inorganic compounds · CPC title