Stable pressurized aerosol solution composition of glycopyrronium bromide and formoterol combination

Patent metadata

Field	Value
Publication number	US-10596113-B2
Application number	US-201414585533-A
Country	US
Kind code	B2
Filing date	Dec 30, 2014
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 or a solvate of said salt, 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 a can internally coated by a resin comprising a fluorinated ethylene propylene (FEP) polymer.

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 5 to 26 μg per actuation;
(b) formoterol, or a salt thereof or a solvate of said salt, at a dosage in the range 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 said composition in an aerosol can internally coated by a resin comprising a fluorinated ethylene propylene (FEP) polymer.

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 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 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 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 formoterol fumarate, when said composition is stored in accelerated conditions at 25° C. and 60% relative humidity 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 pharmaceutical aerosol solution composition comprises:
(a) glycopyrronium bromide in an amount sufficient to deliver 5 to 26 μg per actuation;
(b) formoterol fumarate in an amount sufficient to deliver 1 to 24 μg per actuation; and
(c) beclometasone dipropionate in an amount sufficient to deliver 50 to 250 μg per actuation;
dissolved in HFA-134a and ethanol, wherein:
the composition comprises hydrochloric acid in an amount equivalent to 0.18 to 0.26 μg/μl of 1M HCl;
the composition comprises ethanol in an amount of 10 to 15% w/w of the composition; and
the composition comprises HFA-134a in an amount of 85 to 90% w/w of the composition.

5. A method according to claim 4 , wherein:
when said composition is stored in accelerated conditions at 25° C. and 60% relative humidity for at least 6 months showed a N-(3-bromo)-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl) propan-2-ylamino]ethyl]phenyl]formamide level of less than 0.10% w/w with respect to a theoretical formoterol fumarate content of 6 μg/actuation; and
containing said composition in an aerosol can internally coated by a resin comprising a fluorinated ethylene propylene (FEP) polymer comprises performing an oxygen purging step by vacuum crimping.

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

• A61K9/008 Primary

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

• A61M2205/0238

  the material being a coating or protective layer · CPC title

• A61K31/167

  having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol · CPC title

• A61K9/124 Primary

  characterised by the propellant · CPC title