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US-12616654-B2 - Stainless steel can for pressurised metered dose inhalers

US12616654B2US 12616654 B2US12616654 B2US 12616654B2US-12616654-B2

Abstract

The invention generally refers to a stainless steel can for use in a metered dose inhaler device, containing an aerosol formulation, comprising glycopyrronium bromide and formoterol, or a salt or a solvate thereof, optionally in combination with one or more additional active ingredient, endowed with a high stability.

Inventors

  • Enrico Zambelli
  • Sauro BONELLI
  • Diego COPELLI
  • MASSIMILIANO DAGLI ALBERI
  • Francesca Usberti

Assignees

  • CHIESI FARMACEUTICI S.P.A.

Dates

Publication Date
20260505
Application Date
20191202

Claims (20)

  1. 1 . A pharmaceutical aerosol solution formulation contained in an aerosol can made of stainless steel, wherein the solution formulation comprises: (a) glycopyrronium bromide at a dosage in the range of from 5 to 26 μg per actuation; (b) formoterol, or a salt or a solvate thereof, at a dosage in the range of from 1 to 25 μg per actuation; (c) a HFA propellant; (d) a co-solvent; (e) a mineral acid; and optionally (f) an inhalation corticosteroid; wherein the stainless steel is selected from grade 904L, 316, 316L, 305, 304, 304L, 6Mo, or 2205.
  2. 2 . The pharmaceutical aerosol solution formulation according to claim 1 , wherein said glycopyrronium bromide is present in an amount from 6 to 25 μg per actuation.
  3. 3 . The pharmaceutical aerosol solution formulation according to claim 1 , wherein said formoterol, or a salt or a solvate thereof is present in an amount from 6 to 12 μg per actuation.
  4. 4 . The pharmaceutical aerosol solution formulation according to claim 1 wherein the HFA propellant is HFA134a, HFA 227, HFA152a or a mixture thereof.
  5. 5 . The pharmaceutical aerosol solution formulation according to claim 1 , wherein the co-solvent is a (C1-C4) alkyl alcohol.
  6. 6 . The pharmaceutical aerosol solution formulation according to claim 5 , wherein the co-solvent is ethanol in a concentration suitable to completely dissolve the active ingredients in the formulation.
  7. 7 . The pharmaceutical aerosol solution formulation according to claim 6 , wherein ethanol is anhydrous ethanol at a concentration comprised from 5 to 30% w/w on the total weight of the formulation.
  8. 8 . The pharmaceutical aerosol solution formulation according to claim 1 , wherein the mineral acid is a pharmaceutically acceptable monoprotic or polyprotic acid.
  9. 9 . The pharmaceutical aerosol solution formulation according to claim 8 , wherein the mineral acid is hydrochloric acid.
  10. 10 . The pharmaceutical aerosol solution formulation according to claim 9 , wherein the mineral acid is 1M hydrochloric acid in an amount in the range from 0.1 to 0.3 μg/μl of the formulation.
  11. 11 . A pharmaceutical aerosol solution formulation according to claim 1 , characterised in that the amount of the degradation product N-(3-bromo)-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl) propan-2-ylamino]ethyl]phenyl]formamide is lower than 0.10% w/w with respect to the theoretical formoterol fumarate content of 6 μg/actuation when stored in accelerated conditions at 25° C. and 60% relative humidity (RH) for at least 3 months.
  12. 12 . A pharmaceutical aerosol solution formulation according to claim 1 , wherein the formoterol salt is formoterol fumarate.
  13. 13 . A pharmaceutical aerosol solution formulation according to claim 1 , wherein the solvate form of the formoterol salt is formoterol fumarate dihydrate.
  14. 14 . A pharmaceutical aerosol solution formulation according to claim 1 , wherein the inhalation corticosteroid is selected from the group of beclometasone dipropionate, budesonide or its 22R-epimer, ciclesonide, flunisolide, fluticasone propionate, fluticasone furoate, mometasone furoate, butixocort, triamcinolone acetonide, triamcinolone, methylprednisolone, prednisone, loteprednol and rofleponide.
  15. 15 . A pharmaceutical aerosol solution formulation according to claim 14 wherein the inhalation corticosteroid is beclometasone dipropionate.
  16. 16 . A pharmaceutical aerosol solution formulation according to claim 15 , wherein the beclometasone dipropionate is present in an amount in the range from 50 to 250 μg per actuation.
  17. 17 . A pharmaceutical aerosol solution formulation according to claim 16 , wherein the beclometasone dipropionate is present in the amount of 100 or 200 μg per actuation.
  18. 18 . A pharmaceutical aerosol solution formulation according to claim 1 , wherein the overall formoterol degradation products level is lower than 10% w/w with respect to the theoretical formoterol fumarate content of 6 μg/actuation and the residual level of formoterol fumarate is higher than 90% w/w with respect to its initial content.
  19. 19 . A pharmaceutical aerosol solution formulation according to claim 1 , wherein the overall formoterol degradation products level is lower than 2% w/w with respect to the theoretical formoterol fumarate content of 6 μg/actuation and the residual level of the formoterol fumarate is higher than 95% w/w with respect to its initial content.
  20. 20 . An aerosol can made of stainless steel selected from grade 904L, 316, 316L, 305, 304, 304L, 6Mo, or 2205 containing a pharmaceutical aerosol solution formulation according to claim 1 , suitable for use in a pressurised metered dose inhaler.

Description

FIELD OF THE INVENTION The present invention relates to an aerosol solution formulation intended for use with a pressurised metered dose inhaler (pMDI), comprising glycopyrronium bromide and formoterol, or a salt thereof or a solvate of said salt, optionally in combination with an inhalation corticosteroid (ICS), stabilised by a selected amount of a mineral acid, the said formulation being contained in a can made of stainless steel. The invention further relates to the use of such pressurised metered dose inhaler comprising said formulation in a stainless steel can, in the prevention and therapy of airway diseases. BACKGROUND OF THE INVENTION Glycopyrronium bromide (also known as glycopyrrolate) is a muscarinic M3 anticholinergic agent used to reduce salivation associated with administration of certain anaesthetics, and as adjunctive therapy for peptic ulcers. It has also been reported to be effective in the treatment of asthmatic symptoms (Hansel et al., Chest 2005; 128:1974-1979). WO 2005/107873 relates to the use of glycopyrrolate for the treatment of childhood asthma. WO 01/76575 discloses a controlled release formulation for pulmonary delivery of glycopyrrolate, intended for use in the treatment of respiratory diseases, in particular of chronic obstructive pulmonary disease (COPD). WO 01/76575 focuses, essentially, on dry powder formulations suitable for delivery by means of a dry powder inhaler (DPI). WO 2005/074918 discloses combinations of glycopyrrolate with glucocorticoid drugs and their use for treating diseases of the respiratory tract. WO 2005/110402 refers to combinations of glycopyrrolate with abeta-2 agonist of the class of indane or of benzothiazole-2-one derivatives for the treatment of inflammatory or of obstructive airway diseases. WO 2006/105401 refers to combinations of an anticholinergic, a corticosteroid and a long-acting beta-2 agonist for the prevention and treatment of respiratory, inflammatory or obstructive airway diseases; glycopyrrolate is among the optional anticholinergic agents. According to WO 2007/057223 and WO 2007/057222, combinations of glycopyrronium bromide with an anti-inflammatory steroid, particularly mometasone furoate, are reported to provide a therapeutic benefit in the treatment of inflammatory and obstructive airways diseases. WO 2007/057221 and WO 2007/057219 respectively refer to combinations of a glycopyrronium salt with an indanyl derivative beta-2 agonist (or analogue) or with an anti-inflammatory steroid, particularly mometasone furoate. WO 00/07567 discloses, in example 4, a suspension aerosol formulation wherein to a mixture of micronized actives, namely formoterol fumarate, glycopyrronium bromide and disodium cromoglycate, a propellant mixture of HFA and dinitrogen monoxide, together with 2% by weight of ethanol, are added. The “Martindale. The complete drug reference”, January 2002, monograph on glycopyrronium bromide (page 467) shows that in investigations on compatibility of this substance with aqueous infusion solutions for injections and additives, the stability of glycopyrronium bromide is questionable above a pH 6, owing to ester hydrolysis. US 2002/025299 discloses pressurised aerosol solution formulations of different active ingredients among which is formoterol or its combinations with a steroid such as beclometasone dipropionate, or with an anticholinergic atropine-like derivative such as ipratropium bromide, oxitropium bromide, tiotropium bromide, further acidified by HCl and stored in given cans such as stainless steel or anodised aluminium, or even lined with an inert organic coating. WO 2005/074900 discloses an inhalable combination of an anticholinergic agent with a beta-2 mimetic agent for the treatment of inflammatory or obstructive respiratory diseases, the examples show formulations of the (R, R)-enantiomer of glycopyrronium bromide in combination with formoterol, either as DPI formulation or pMDI suspension. US 2006/0257324 discloses the delivery of a combination of two or more dissolved drugs in a HFA propellant-cosolvent system, substantially having the same particle size distribution and thus allowing for their co-deposition in the same lung region. The therein described formulations comprise a beta-2 agonist (formoterol or carmoterol being exemplified) and a corticosteroid (beclometasone dipropionate being exemplified), or an anticholinegic agent such as ipratropium, oxitropium, tiotropium or glycopyrronium bromide, these latter being only generically cited in the description. Formoterol is a beta-2 adrenergic agonist drug capable of relaxing smooth muscle in the bronchi and opening the airways to reduce wheezing conditions. It is commonly used as formoterol fumarate in the management of asthma and other respiratory conditions. It is known that aerosol solutions of formoterol fumarate are relatively unstable and have a short shelf-life when stored under suboptimal conditions. In WO 2011/076843 the applicant further disclosed