Stable pharmaceutical compositions for pressurized metered dose inhalers

Abstract

The present invention provides a stable pharmaceutical composition to be used with pressurized metered dose inhalers comprising a beta 2 agonist, a corticosteroid, a muscarinic antagonist, HFO propellant, a co-solvent, an organic acid(s) and optionally water. The invention further provides a specific container and a valve system comprising internally coated canister and a valve for storing the composition. The invention also provides a pharmaceutical composition comprising a beta 2 agonist, a corticosteroid, a muscarinic antagonist for the treatment or prophylaxis of asthma, chronic obstructive pulmonary disease (COPD), rhinitis or as adjunct therapy for cystic fibrosis, non-cystic fibrosis bronchiectasis, lung infections or pulmonary fibrosis.

Description

[0001] FIELD OF THE INVENTION

[0002]

[0001] The present invention provides a stable pharmaceutical composition comprising a beta 2 agonist, a corticosteroid, a muscarinic antagonist, a HFO propellant, a co-solvent, an organic acid(s) and optionally water; wherein the composition is provided in an internally coated canister having a specific valve.

[0003] BACKGROUND OF THE INVENTION

[0004]

[0002] Metered dose inhalers (MDIs) are important and well known devices used to deliver appropriate therapy for a growing number of respiratory diseases. MDIs are a convenient, inexpensive delivery system and are widely used. Today, there are many different metered dose inhaler based products on the market to deliver active pharmaceutical ingredients (APIs) for local and / or systemic therapy.

[0005]

[0003] MDIs when actuated create propellant droplets containing the pharmaceutical product for delivery to the respiratory tract as an aerosol. Formulations for aerosol administration via MDIs can be solutions or suspensions. Solution formulations offer the advantage of being homogeneous, with the active ingredient and excipients completely dissolved in the propellant vehicle or its mixture with suitable co-solvents such as ethanol. Solution formulations also obviate physical stability problems of micronized particles associated with suspension formulations so assuring more consistent and uniform dosage administration. Since solution formulations provide smaller mass median aerodynamic diameters (MMADs) they facilitate delivery to the entire lung including the alveolar regions. The mass median aerodynamic diameter is generally measured with a cascade impactor.

[0006]

[0004] However, a significant challenge associated with solution formulations is the chemical stability of the active ingredients. The loss of active substance content should be minimized during the shelf-life and the appearance of degradative product should be diminished so that the medicament can be used with its effectiveness and safety. It means, the physical and chemical stability as well as the maintenance of the quality parameters during the shelf-life of the aerosol are of essential importance for its practical medical use.

[0005] There has been a common challenge in preparing solution formulations containing beta 2- agonist; they are often chemically unstable especially in the presence of co-solvents such as ethanol which are necessary to formulate the solutions. Thus, the investigations have been directed vastly to avoid the degradation of beta 2-agonist.

[0007]

[0006] Increase in global temperature is already having a significant impact on our climate. The hydrofluorocarbon (HFC) propellants used today in pressurized MDI have a global warming potential (GWP) many times that of carbon dioxide. Thus, there is a clear requirement for developing the pressurized MDI with alternative propellants having lower GWP and the only two potential alternate propellants currently available with a significantly lower GWP are HFO 1234ze and HFC 152a.

[0008]

[0007] EP 1787639 Bl discloses an aerosol solution composition which comprises a beta 2- agonist drug of the phenyl alkyl ami no class bearing a functional group sensitive to oxidative and / or hydrolytic reaction in a solution of a liquefied HFA propellant, a co-solvent selected from pharmaceutically acceptable alcohols, wherein the apparent pH of the solution is comprised between 2.5 and 5.0 by addition of small amounts of a mineral acid selected from hydrochloric, nitric and phosphoric acid, wherein the active ingredient is formoterol as p2-agonist drug or a salt thereof in combination with a steroid selected from beclometasone dipropionate, fluticasone propionate, budesonide and its 22R-epimer or an anticholinergic atropine like derivative selected from ipratropium bromide, oxitropium bromide and tiotropium bromide.

[0009]

[0008] EP 2223682 Bl discloses an aerosol composition which consists of formoterol fumarate dihydrate in combination with beclometasone dipropri onate in a solution of a liquefied HFA 134a propellant and 12% w / w ethanol as a co-solvent, and hydrochloric acid in an amount such that the solution has an apparent pH between 3.0 and 3.5.

[0010]

[0009] EP 2010190 Bl discloses a pressurized solution formulation for a metered dose inhaler comprising formoterol fumarate dihydrate in combination with beclometasone dipropionate as active substances dissolved in a mixture consisting of HFA134a propellant and an amount of ethanol of 12% w / w as a co-solvent and 0.024% w / w hydrochloric acid (IM) for use in the prevention and / or treatment of a severe broncho-pulmonary disease selected from severe persistent asthma or severe or very severe chronic obstructive pulmonary disease (COPD), wherein, upon actuation of said inhaler, 50 pl of said solution comprising formoterol fumarate at a dose per actuation of 6 pg and beclometasone dipropionate at a dose of 100 pg per actuation are metered for delivery.

[0011]

[0010] US 2006 / 0140873 discloses a composition for use in a metered dose inhaler (MDI), the composition comprising predetermined amounts of an active pharmaceutical ingredient (API) insoluble in the composition, a propellant comprising a hydrofluoroalkane (HFA), and a pharmaceutically acceptable non-aminated Cl -6 organic acid that increases post-shaking suspension time of the API in the composition to at least 30 seconds to provide uniform dosing of the API from the inhaler over at least 30 seconds post-shaking.

[0012]

[0011] WO 2015 / 101576 discloses an aerosol solution composition intended for use with a pressurised metered dose inhaler using HFA propellant, comprising glycopyrronium bromide and formoterol stabilized by a selected amount of a mineral acid and wherein the amount of the degradation product N-(3-bromo)-[2-hydroxy-5-[l-hydroxy-2-[l-(4-methoxyphenyl) propan-2- ylamino]ethyl] phenyl]formamide is lower than the limit of quantification, when stored in accelerated conditions at 25°C and 60% relative humidity (RH) for 6 months in a can internally coated by a resin comprising a fluorinated ethylene propylene (FEP) polymer. The degradation product N-(3-bromo)-[2-hydroxy-5-[l-hydroxy-2-[l-(4-methoxyphenyl) propan-2 - ylamino]ethyl]phenyl]formamide, is formed by interaction of formoterol and glycopyrronium bromide, when the composition is stored in accelerated conditions at 25°C and 60% relative humidity (RH) for at least 6 months.

[0013]

[0012] WO 2019 / 236559 discloses a stable pharmaceutical composition to be used with pressurized metered dose inhalers and comprises a beta 2 agonist, a propellant, a co-solvent, an organic acid(s) and optionally water.

[0014]

[0013] WO 2021 / 165348 discloses a can for use in a pMDI device, said can containing a formulation comprising at least a corticosteroid, a LABA agent, a LAMA agent and a HFA 152a or HFO propellant, being said can internally coated.

[0015]

[0014] The present invention discloses a stable pharmaceutical composition comprising to be used with pressurized metered dose inhalers and comprises beta 2 agonist, a corticosteroid, a muscarinic antagonist, a HFO propellant, a co-solvent, an organic acid(s) and optionally water, wherein the composition is provided in an internally coated canister having a metering valve with 3 gaskets, wherein the neck gasket is made of cycloolefin copolymer (COC), along with two stem gaskets that are made of EPDM (ethylene propylene diene monomer) and a corrosion resistant spring. SUMMARY OF THE INVENTION

[0016]

[0015] According to one aspect of the present invention there is provided a pharmaceutical composition comprising a beta 2-agonist, a corticosteroid, a muscarinic antagonist, HFO propellant, a co-solvent and an organic acid(s). The composition is to be used with pressurized metered dose inhalers wherein the composition is provided in an internally coated canister having a metering valve with 3 gaskets, wherein the neck gasket is made of cycloolefm copolymer (COC), along with two stem gaskets that are made of EPDM (ethylene propylene diene monomer).

[0017]

[0016] According to one aspect of the present invention there is provided a pharmaceutical composition comprising a beta 2-agonist, a corticosteroid, a muscarinic antagonist, HFO propellant, a co-solvent and an organic acid(s). The composition is to be used with pressurized metered dose inhalers wherein the composition is provided in an internally coated canister having a metering valve with 3 gaskets, wherein the neck gasket of the metering valve is made of cycloolefm copolymer (COC) and two stem gaskets that are made of EPDM (ethylene propylene diene monomer), wherein the metering valve has a corrosion resistant spring.

[0018]

[0017] According to one aspect of the present invention there is provided a pharmaceutical composition comprising a beta 2-agonist, a corticosteroid, a muscarinic antagonist, HFO propellant, a co-solvent, an organic acid(s) and water. The composition is to be used with pressurized metered dose inhalers wherein the composition is provided in an internally coated canister having a metering valve with 3 gaskets, wherein the neck gasket of the metering valve is made of cycloolefm copolymer (COC) and two stem gaskets that are made of EPDM (ethylene propylene diene monomer), wherein the metering valve has a corrosion resistant spring.

[0019]

[0018] According to one aspect of the present invention there is provided a pharmaceutical composition comprising long acting a beta 2-agonist (LABA), a corticosteroid (ICS), a long acting muscarinic antagonist (LAMA), HFO propellant, a co-solvent and an organic acid(s). The composition is to be used with pressurized metered dose inhalers wherein the composition is provided in an internally coated canister having a metering valve with 3 gaskets, wherein the neck gasket of the metering valve is made of cycloolefm copolymer (COC), along with two stem gaskets that are made of EPDM (ethylene propylene diene monomer) and a corrosion resistant spring.

[0020]

[0019] According to one aspect of the present invention there is provided a pharmaceutical composition comprising a short acting beta 2-agonist (SABA), a corticosteroid (ICS), a long acting muscarinic antagonist (LAMA), HFO propellant, a co-solvent and an organic acid(s). The composition is to be used with pressurized metered dose inhalers wherein the composition is provided in an internally coated canister having a metering valve with 3 gaskets, wherein the neck gasket of the metering valve is made of cycloolefin copolymer (COC) and two stem gaskets that are made of EPDM (ethylene propylene diene monomer), wherein the metering valve comprises a corrosion resistant spring.

[0021]

[0020] According to one aspect of the present invention there is provided a pharmaceutical composition comprising a long acting beta 2-agonist (LABA), a corticosteroid (ICS), a long acting muscarinic antagonist (LAMA), HFO propellant, a co-solvent, an organic acid(s) and water. The composition is to be used with pressurized metered dose inhalers wherein the composition is provided in an internally coated canister having a metering valve with 3 gaskets, wherein the neck gasket of the metering valve is made of cycloolefin copolymer (COC) and two stem gaskets that are made of EPDM (ethylene propylene diene monomer), wherein the metering valve comprises a corrosion resistant spring.

[0022]

[0021] According to one aspect of the present invention there is provided a pharmaceutical composition comprising a short acting beta 2-agonist (SABA), a corticosteroid (ICS), a long acting muscarinic antagonist (LAMA), HFO propellant, a co-solvent, an organic acid(s) and water. The composition is to be used with pressurized metered dose inhalers wherein the composition is provided in an internally coated canister having a metering valve with 3 gaskets, wherein the neck gasket of the metering valve is made of cycloolefin copolymer (COC) and two stem gaskets that are made of EPDM (ethylene propylene diene monomer), wherein the metering valve comprises a corrosion resistant spring.

[0023]

[0022] According to one aspect of the present invention there is provided a pharmaceutical composition comprising a short acting beta 2-agonist (SABA), a corticosteroid (ICS), a long acting muscarinic antagonist (LAMA), HFO 1234ze, a co-solvent, an organic acid(s) and water. The composition is to be used with pressurized metered dose inhalers wherein the composition is provided in an internally coated canister having a metering valve with 3 gaskets, wherein the neck gasket of the metering valve is made of cycloolefin copolymer (COC) and two stem gaskets that are made of EPDM (ethylene propylene diene monomer), wherein the metering valve comprises a corrosion resistant spring.

[0023] According to one aspect of the present invention there is provided a pharmaceutical composition comprising formoterol fumarate, beclometasone dipropionate, glycopyrronium bromide, HFO 1234ze, ethanol, and maleic acid. The composition is to be used with pressurized metered dose inhalers wherein the composition is provided in an internally coated canister having a metering valve with 3 gaskets, wherein the neck gasket of the metering valve is made of cycloolefin copolymer (COC) and two stem gaskets that are made of EPDM (ethylene propylene diene monomer).

[0024]

[0024] According to one aspect of the present invention there is provided a pharmaceutical composition comprising formoterol fumarate, beclometasone dipropionate, glycopyrronium bromide, HFO 1234ze, ethanol, and maleic acid. The composition is to be used with pressurized metered dose inhalers wherein the composition is provided in an internally coated canister having a metering valve with 3 gaskets, wherein the neck gasket of the metering valve is made of cycloolefin copolymer (COC) and two stem gaskets that are made of EPDM (ethylene propylene diene monomer), wherein the metering valve comprises a corrosion resistant spring.

[0025]

[0025] According to one aspect of the present invention there is provided a pharmaceutical composition comprising formoterol fumarate, beclometasone dipropionate, glycopyrronium bromide, HFO 1234ze, ethanol, maleic acid and water. The composition is to be used with pressurized metered dose inhalers wherein the composition is provided in an internally coated canister having a metering valve with 3 gaskets, wherein the neck gasket of the metering valve is made of cycloolefin copolymer (COC) and two stem gaskets that are made of EPDM (ethylene propylene diene monomer).

[0026]

[0026] According to one aspect of the present invention there is provided a pharmaceutical composition comprising formoterol fumarate dihydrate, beclometasone dipropionate, glycopyrronium bromide, HFO 1234ze, ethanol, maleic acid and water. The composition is to be used with pressurized metered dose inhalers wherein composition is provided in an internally coated canister having a metering valve with 3 gaskets, wherein the neck gasket of the metering valve is made of cycloolefin copolymer (COC) and two stem gaskets that are made of EPDM (ethylene propylene diene monomer), wherein the metering valve comprises a corrosion resistant spring. DETAILED DESCRIPTION

[0027]

[0027] The present invention relates to a pharmaceutical composition comprising a beta 2-agonist, a corticosteroid, a long acting muscarinic antagonist, a HFO propellant, a co-solvent, an organic acid(s) and optionally water. The pharmaceutical composition is a solution or a suspension, preferably a solution.

[0028]

[0028] The aerosol medicinal products are very important as pharmaceutical dosage forms for drug administration by pulmonary route. The physical and chemical stability as well as the maintenance of the quality parameters, during the shelf-life of the aerosol, are of essential importance for its practical medical use.

[0029]

[0029] Solution compositions eliminate the typical concerns around physical stability of micronized particles required for lung delivery and ensure that a consistent particle size is achieved throughout the shelf-life of the product. Solution compositions also provide smaller Mass Median Aerodynamic Diameter (MMAD) and therefore facilitate drug delivery to the entire lung including the alveolar regions.

[0030]

[0030] There has been a common challenge in preparing stable solution compositions containing a combination of three different actives, particularly a solution of beta 2 agonist as one of the actives because they are often chemically unstable especially in the presence of co-solvents such as ethanol which are necessary to formulate the solutions. Further, it was known that in the presence of glycopyrronium bromide a portion of the formoterol component undergoes degradation to form N-(3-bromo)-[2-hydroxy-5-[l-hydroxy-2-[l-(4-methoxyphenyl)propan-2- ylamino]ethyl] phenyl] formamide (DP3). Thus, the investigations have been directed vastly to avoid the degradation and / or reactions of beta 2 agonist in the composition.

[0031]

[0031] The preparation of stable solution formulations is even more vital when bronchodilator beta 2-agonists having benzylic hydroxyl group, like formoterol, albuterol, and others, may suffer from inherent chemical stability due to their susceptibility to substitution by nucleophilic species in the formulation via SN1 or SN2 reactions. Ethanol can satisfy the role of a nucleophile and cause degradation of beta 2 agonists having benzylic hydroxyl group.

[0032]

[0032] Surprisingly, it has been found that the organic acids such as maleic acid, which have much weaker proton donating ability, can stabilize beta 2 agonist in solution formulations containing cosolvent such as ethanol for delivery using pressurized metered dose inhalers. Further, unexpectedly, it has been found that when such formulation is stored in an internally coated canister having a specific valve there was further enhancement in the stability of the formulation.

[0033] As used herein, internally coated canister, means canister anodized or coated with an inert organic or inorganic coating preferably comprising ethylene -tetrafluoroethylene co-polymer (ETFE), a perfluorinated polymer, a perfluoroalkoxyalkane polymer, a per- fluoroalkoxyalkylene polymer (PF A), a perfluoroalkylene polymer, fluorinated-ethylene-propylene polymer (FEP), poly ether sulfone polymer (PES), a fluorinated-ethylene-propylene polyether sulfone polymer (FEP- PES), fluorinated plasma coating (FCP), plasma or combinations thereof. Preferably the canister is coated with FEP polymer, FCP or plasma.

[0033]

[0034] As used herein, specific valve, means a metering valve with 3 gaskets, wherein the neck gasket of the metering valve is made of cycloolefin copolymer (COC), along with two stem gaskets that are made of EPDM (ethylene propylene diene monomer) and optionally the valve has a very high corrosion resistant spring.

[0034]

[0035] The present invention provides a stable pharmaceutical composition comprising a beta 2- agonist, a corticosteroid, a long acting muscarinic antagonist, a HFO propellant, a co-solvent, an organic acid(s) and optionally water; wherein composition is provided in an internally coated canister having a valve using 3 gaskets, wherein the neck gasket is made of cycloolefin copolymer (COC), along with two stem gaskets that are made of EPDM (ethylene propylene diene monomer) and a corrosion resistant spring. When water is present in the pharmaceutical compositions, it may be present up to 5 %w / w, more preferably up to 3 %w / w, and the most preferably up to 1 %w / w of the composition.

[0035]

[0036] In accordance with the invention, a beta 2-agonist is present in the composition in an amount between approximately 0.001 %w / w and 1 %w / w of composition, more preferably between 0.001 % w / w and 0.04 % w / w of the composition. The beta 2-agonist of the invention include, but not limited to, albuterol, levalbuterol, formoterol, arformoterol, vilanterol, indacaterol, salmeterol, and Olodaterol or pharmaceutically acceptable salts thereof. Preferably the beta 2- agonist is formoterol or formoterol fumarate. The invention is formulated to provide the dose of 4pg to 50 pg of formoterol per actuation.

[0036]

[0037] In accordance with the invention, a corticosteroid is present in the composition in an amount between approximately 0.005 %w / w and 1 %w / w, more preferably between 0.05 % w / w and 0.40 % w / w of the composition. The corticosteroid of the invention include, but not limited to, beclometasone or beclometasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone propionate, fluticasone furoate, mometasone furoate, triamcinolone acetate, or prednisolone. Preferably the corticosteroid is beclometasone or beclometasone dipropionate. The invention is formulated to provide the dose of 50pg to 300 pg of beclometasone per actuation.

[0038] In accordance with the invention, a long acting muscarinic antagonist is present in the composition in an amount between approximately 0.001 %w / w and 1 %w / w, more preferably between 0.05 % w / w and 0.30 % w / w of the composition. The long acting muscarinic receptor antagonist of the invention include, but not limited to, umeclidinium, aclidinium, glycopyrronium, ipratropium, oxitropium, tiotropium or pharmaceutically acceptable salts thereof. Preferably the long acting muscarinic receptor antagonist is glycopyrronium or glycopyrronium bromide. The invention is formulated to provide the dose of 5pg to 30 pg of glycopyrronium per actuation.

[0037]

[0039] In accordance with the invention, the propellant of the invention is HFO propellant selected from 2,3,3,3-tetrafluoropropene (HFO-1234yf) and 1,3,3,3-tetrafluoropropene (HFO-1234ze) or mixtures thereof. Preferably, the propellant is HFO-1234ze(E).

[0038]

[0040] The co-solvent of the invention include, but not limited to dichloromethane, chloroform, ethylacetate, N-methyl pyrrolidone, benzylalcohol, isopropylacetate, acetonitrile, tetrahydrofuran, isopropanol, methanol, ethanol or mixtures thereof. Preferably the co-solvent is ethanol; and it is present in an amount between approximately 1 %w / w and 40 %w / w, more preferably between 4 %w / w and 20 %w / w by weight of the composition.

[0039]

[0041] In accordance with the invention, “organic acid” term refers to any organic compound with acidic properties. An organic acid is different from an inorganic acid (or mineral acid) that is derived from one or more inorganic compounds. Organic acids tend to have weaker proton donating ability than inorganic acids. The organic acid of the invention include, but are not limited to, maleic acid, fumaric acid, citric acid, acetic acid, xinafoic acid, oxalic acid, lactic acid, 2-methyl propionic acid, malic acid, butanoic acid, tartaric acid, propionic acid, pentanoic acid, succinic acid, glycolic acid, hexanoic acid, malonic acid, glutaric acid, formic acid, adipic acid, ascorbic acid, benzoic acid, glucuronic acid, pyruvic acid, oxaloacetic acid, dihydroxyfumaric acid or mixtures thereof.

[0040]

[0042] Preferably the organic acid is maleic acid; and it is present in an amount between approximately 0.001 and 1 % w / w, more preferably between 0.001 % w / w and 0.10 %w / w of the composition.

[0043] Another embodiment provides the use of pharmaceutical composition comprising a beta 2- agonist, a corticosteroid, a long acting muscarinic antagonist, a HFO propellant, a co-solvent, an organic acid(s) and optionally water for the treatment or prophylaxis of asthma, COPD, rhinitis or as adjunct therapy for cystic fibrosis, non-cystic fibrosis bronchiectasis, lung infections or pulmonary fibrosis.

[0041]

[0044] Another embodiment provides the use of pharmaceutical composition comprising a beta 2- agonist, a corticosteroid, a long acting muscarinic antagonist, a HFO propellant, a co-solvent, an organic acid(s) and water for the treatment or prophylaxis of asthma, COPD, rhinitis or as adjunct therapy for cystic fibrosis, non-cystic fibrosis bronchiectasis, lung infections or pulmonary fibrosis.

[0042]

[0045] In accordance with the present invention, compositions of the present invention are less prone to hydrolytic and / or oxidative degradation. Thus, the most physically and chemically stable formulations of the invention have a significant decrease in total degradation of product. In addition to the economic advantages, the formulations in accordance with the present invention remain stable at the range of temperatures to which these medicaments are normally exposed. The person having ordinary skill in the art can also easily determine the presence of hydrolytic and / or oxidative degradation products, for example, by HPLC analysis. The use of internally coated containers along with the specified valve has been found to confer an additional protection not only for the chemical stabilization of active substance but also for the absence of corrosion or other unacceptable signs of deterioration of the container and valve material by contact with the product.

[0046] According to one aspect of the present invention there is provided a stable pharmaceutical composition comprising beclometasone dipropionate in an amount from about 0.13-0.327 %w / w, formoterol fumarate dihydrate in an amount from about 0.006-0.01 %w / w, glycopyrronium bromide in an amount from about 0.015-0.025 %w / w, maleic acid in an amount from about 0.002- 0.003 %w / w, ethanol in an amount from about 11-18 %w / w, water in an amount from about 0.2- 0.6 %w / w and HFO-1234ze in quantities sufficient to make up the volume. All amounts are based on total weight of the composition. This composition is provided in an internally coated canister filled under pressure fitted with a metering valve having 3 gaskets, wherein the neck gasket of the metering valve is made of cycloolefin copolymer (COC) and two stem gaskets that are made of EPDM (ethylene propylene diene monomer), wherein the metering valve comprises a corrosion resistant spring and having a 25 pL, 50 pL or 63 pL nominal metering chamber volume.

[0047] According to one aspect of the present invention there is provided a stable pharmaceutical composition in the form of a solution comprising beclometasone dipropionate in an amount from about 0.13-0.327 %w / w, formoterol fumarate dihydrate in an amount from about 0.006-0.01 %w / w, glycopyrronium bromide in an amount from about 0.015-0.025 %w / w, maleic acid in an amount from about 0.002-0.003 %w / w, ethanol in an amount from about 11-18 %w / w, water in an amount from about 0.2- 0.6 %w / w and HFO-1234ze in quantities sufficient to make up the volume. All amounts are based on total weight of the composition. This composition is provided in an internally coated canister filled under pressure fitted with a metering valve having 3 gaskets, wherein the neck gasket of the metering valve is made of cycloolefin copolymer (COC) and two stem gaskets that are made of EPDM (ethylene propylene diene monomer), wherein the metering valve comprises a corrosion resistant spring and having a 25 pL, 50 pL or 63 pL nominal metering chamber volume. The formulations does not exhibit a total impurity greater than 0.5% w / w when tested under accelerated storage conditions at 25°C and 60% relative humidity for one month in valve down position or the formulation does not exhibit a total impurity greater than 5% w / w when tested under accelerated storage conditions at 25°C and 60% relative humidity for six month in valve down position.

[0043]

[0048] According to one aspect of the present invention there is provided a stable pharmaceutical composition in the form of a solution comprising beclometasone dipropionate in an amount from about 0.13-0.327 %w / w, formoterol fumarate dihydrate in an amount from about 0.006-0.01 %w / w, glycopyrronium bromide in an amount from about 0.015-0.025 %w / w, maleic acid in an amount from about 0.002-0.003 %w / w, ethanol in an amount from about 11-15 %w / w, water in an amount from about 0.2- 0.6 %w / w and HFO-1234ze in quantities sufficient to make up the volume. All amounts are based on total weight of the composition. This composition is provided in an internally coated canister filled under pressure fitted with a metering valve having 3 gaskets, wherein the neck gasket of the metering valve is made of cycloolefin copolymer (COC) and two stem gaskets that are made of EPDM (ethylene propylene diene monomer), wherein the metering valve comprises a corrosion resistant spring and having a 25 pL, 50 pL or 63 pL metering chamber.

[0049] According to one aspect of the present invention there is provided a stable pharmaceutical composition in the form of a solution comprising beclometasone dipropionate in an amount from about 0.1303-0.172 %w / w, formoterol fumarate dihydrate in an amount from about 0.006-0.01 %w / w, glycopyrronium bromide in an amount from about 0.0161-0.022 %w / w, maleic acid in an amount from about 0.0023-0.003 %w / w, ethanol in an amount from about 11 .5-16.5 %w / w, water in an amount from about 0.4-0.5 %w / w and HFO-1234ze in quantities sufficient to make up the volume. All amounts are based on total weight of the composition. This composition is provided in an internally coated canister filled under pressure fitted with a metering valve having 3 gaskets, wherein the neck gasket of the metering valve is made of cycloolefin copolymer (COC) and two stem gaskets that are made of EPDM (ethylene propylene diene monomer), wherein the metering valve comprises a corrosion resistant spring and having a 25 pL, 50 pL or 63 pL metering chamber.

[0050] According to one aspect of the present invention there is provided a stable pharmaceutical composition in the form of a solution comprising beclometasone dipropionate in an amount from about 0.1303-0.172 %w / w, formoterol fumarate dihydrate in an amount from about 0.006-0.01 %w / w, glycopyrronium bromide in an amount from about 0.0161-0.022 %w / w, maleic acid in an amount from about 0.0023-0.003 %w / w, ethanol in an amount from about 11.5-12.5 %w / w, water in an amount from about 0.4-0.5 %w / w and HFO-1234ze in quantities sufficient to make up the volume. All amounts are based on total weight of the composition. This composition is provided in an internally coated canister filled under pressure fitted with a metering valve having 3 gaskets, wherein the neck gasket of the metering valve is made of cycloolefin copolymer (COC) and two stem gaskets that are made of EPDM (ethylene propylene diene monomer), wherein the metering valve comprises a corrosion resistant spring and having a 25 pL, 50 pL or 63 pL metering chamber.

[0051] In another aspect of the present invention there is provided a stable pharmaceutical composition in the form of solution comprising beclometasone dipropionate in an amount 0.260- 0.277 %w / w, formoterol fumarate dihydrate in an amount of 0.0076-0.0085 %w / w, glycopyrronium bromide in an amount of 0.0161-0.0190 %w / w, maleic acid in an amount of 0.0023-0.003 %w / w, ethanol in an amount from about 11.5-16.5 %w / w, water in an amount from about 0.4-0.5 %w / w and HFO-1234ze in quantities sufficient to make up the volume. All amounts are based on total weight of the composition. This composition is provided in an internally coated canister filled under pressure fitted with a metering valve having 3 gaskets, wherein the neck gasket of the metering valve is made of cycloolefin copolymer (COC) and two stem gaskets that are made of EPDM (ethylene propylene diene monomer), wherein the metering valve comprises a corrosion resistant spring and having a 25 pL, 50 pL or 63 pL metering chamber.

[0044]

[0052] In another aspect of the present invention there is provided a stable pharmaceutical composition in the form of solution comprising beclometasone dipropionate in an amount 0.261- 0.277 %w / w, formoterol fumarate dihydrate in an amount of 0.0076-0.0085 %w / w, glycopyrronium bromide in an amount of 0.0161-0.0190 %w / w, maleic acid in an amount of 0.0023-0.003 %w / w, ethanol in an amount from about 11.5-12 %w / w, water in an amount from about 0.4-0.5 %w / w and HFO-1234ze(E) in quantities sufficient to make up the volume. All amounts are based on total weight of the composition. This composition is provided in an internally coated canister filled under pressure fitted with a metering valve having 3 gaskets, wherein the neck gasket of the metering valve is made of cycloolefin copolymer (COC) and two stem gaskets that are made of EPDM (ethylene propylene diene monomer), wherein the metering valve comprises a corrosion resistant spring and having a 25 pL, 50 pL or 63 pL metering chamber.

[0045]

[0053] According to one aspect of the present invention there is provided a stable pharmaceutical composition in the form of a solution comprising beclometasone dipropionate in an amount from about 0.1303-0.172 %w / w, formoterol fumarate dihydrate in an amount from about 0.006-0.01 %w / w, glycopyrronium bromide in an amount from about 0.0161-0.022 %w / w, maleic acid in an amount from about 0.0023-0.0028 %w / w, ethanol in an amount from about 14-16 %w / w, water in an amount from about 0.4-0.5 %w / w and HFO-1234ze(E) in quantities sufficient to make up the volume. All amounts are based on total weight of the composition. This composition is provided in an internally coated canister filled under pressure fitted with a metering valve having 3 gaskets, wherein the neck gasket of the metering valve is made of cycloolefin copolymer (COC) and two stem gaskets that are made of EPDM (ethylene propylene diene monomer), wherein the metering valve comprises a corrosion resistant spring and having a 25 pL, 50 pL or 63 pL metering chamber.

[0054] In another aspect of the present invention there is provided a stable pharmaceutical composition in the form of solution comprising beclometasone dipropionate in an amount 0.261- 0.277 %w / w, formoterol fumarate dihydrate in an amount of 0.0076-0.0085 %w / w, glycopyrronium bromide in an amount of 0.0161-0.0188 %w / w, maleic acid in an amount of 0.0023-0.0028 %w / w, ethanol in an amount from about 14-16 %w / w, water in an amount from about 0.4-0.5 %w / w and HFO-1234ze(E) in quantities sufficient to make up the volume. All amounts are based on total weight of the composition. This composition is provided in an internally coated canister filled under pressure fitted with a metering valve having 3 gaskets, wherein the neck gasket of the metering valve is made of cycloolefin copolymer (COC) and two stem gaskets that are made of EPDM (ethylene propylene diene monomer), wherein the metering valve comprises a corrosion resistant spring and having a 25 pL, 50 pL or 63 pL metering chamber.

[0055] Manufacturing Process

[0046]

[0056] The composition of the present invention may be manufactured by any of the processes as described below:

[0047]

[0057] Manufacturing Process 1 :

[0048]

[0058] Step 1. Weigh the quantity of beclometasone dipropionate, formoterol fumarate dihydrate and glycopyrronium bromide and dissolve in between 30-70% ethanol. Stir till a clear solution is obtained.

[0049]

[0059] Step 2. Weigh the quantity of maleic acid and dissolve in the remaining ethanol and water (if present). Stir till a clear solution is obtained.

[0050]

[0060] Step 3. Mix the solution of step 1 with the solution of step 2 in the batching vessel.

[0051]

[0061] Step 4. Charge part of the HFO-1234ze propellant into the batching vessel and stir to homogenize.

[0052]

[0062] Step 5. Fill the concentrate into the internally coated canisters crimped with valves. Make the volume with HFO propellant.

[0053]

[0063] Manufacturing Process 2:

[0054]

[0064] Step 1. Weigh the quantity of beclometasone dipropionate, formoterol fumarate dihydrate and glycopyrronium bromide and dissolve in between 30-70% ethanol. Stir till a clear solution is obtained.

[0055]

[0065] Step 2. Weigh the quantity of maleic acid and dissolve in the remaining ethanol and water (if present). Stir till a clear solution is obtained.

[0056]

[0066] Step 3. Mix the solution of step 1 with the solution of step 2 and stir to homogenize.

[0057]

[0067] Step 4. Fill the concentrate into the internally coated canisters.

[0058]

[0068] Step 5. Make the volume with HFO propellant.

[0059]

[0069] The formulations according to present invention does not exhibit a total impurity greater than 1% w / w when tested under accelerated storage conditions at 25°C and 60% relative humidity for one month in valve down position or the formulation does not exhibit a total impurity greater than 7% w / w when tested under accelerated storage conditions at 25°C and 60% relative humidity for six month in valve down position.

[0070] The following examples are included to demonstrate particular embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventors to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

[0060] EXAMPLE 1

[0061]

[0071] An aerosol formulation may be prepared with the following composition:

[0062] Table 1

[0063]

[0072] This solution formulation is filled under pressure into the 14 mL FCP coated canister fitted with a metering valve having 3 gaskets, wherein the neck gasket is made of cycloolefin copolymer (COC), along with two stem gaskets that are made of EPDM (ethylene propylene diene monomer) and corrosion resistant spring.

[0064]

[0073] Manufacturing Process:

[0065]

[0074] Step 1. Weighed quantity of beclometasone dipropionate, formoterol fumarate dihydrate and Glycopyrronium bromide were dissolved in between 30-70% ethanol. Stirred till a clear solution was obtained.

[0075] Step 2. Weighed quantity of maleic acid was dissolved in water and the remaining ethanol. Solution was stirred.

[0066]

[0076] Step 3. The solution of step 1 was mixed with solution of step 2 and the mixture was stirred to homogenize.

[0067]

[0077] Step 4. The concentrate was filled into FCP coated canisters.

[0068]

[0078] Step 5. Volume was made up with HFO-1234ze(E).

[0069]

[0079] Brief Procedure for Determination of Assay / Total Degradation Product

[0070]

[0080] Assay and related substances determinations are carried out using a Liquid Chromatograph (LC) by recovering the drug substances from the canisters with appropriate diluent systems composed of water and organic solvents. The test samples are run on the LC using a C18 column with a suitable organic: aqueous mobile phase. Peak identification and quantitation is carried out from the resulting chromatography.

[0071]

[0081] Assay Data

[0072]

[0082] As evident from Table 2, the Assay data demonstrates the stability of the pharmaceutical composition of formoterol in the presence of organic acid and use of internally coated canister fitted with a specified metering valve.

[0073] Table 2

[0074] VD- Valve down

[0075]

[0083] Aerodynamic Particle Size Distribution (APSD) using Next Generation Impactor.

[0076]

[0084] The APSD of the particles delivered from a pMDI device plays a key role in determining the amount and region of drug deposition in the lung and thereby the efficacy of the inhaler. As evident from Table 3, the data demonstrates the stability of the pharmaceutical composition in terms of maintaining ASPD over the time.

[0077] Table 3

[0078] 085] BDP=Beclometasone dipropionate, FFD=Formoterol fumarate dihydrate, GPB= Glycopyrronium Bromide, %LC= % Percent Label Claim EXAMPLE 2

[0079]

[0086] Following aerosol formulations were prepared using the manufacturing process as described in example 1.

[0080] Table 4

[0081] BDP=Beclometasone dipropionate, FFD=Formoterol fumarate dihydrate, GPB= Glycopyrronium

[0082] Bromide, q.s=quantity sufficient, HC1- Hydrochloric acid

[0083]

[0087] Total Impurity Data (Formoterol Fumarate Dihydrate):

[0084]

[0088] The formulations F2-F6 were subjected to a various storage conditions to evaluate the chemical stability of these compositions. The accelerated storage condition (ACC) is the harshest, with the samples being subjected to 25° C and 60% Relative Humidity. Data after 1 month storage at the ACC condition is a good indicator of stability of the composition.

[0089] As evident from Table 5, the ACC data demonstrates that the composition having a solution of formoterol in the presence of an organic acid, specifically maleic acid was found to be stable in comparison to a composition having a solution of formoterol without organic acid viz., due to significant reduction in the total degradation of the composition with organic acid. Further, the composition, additionally having water, surprisingly demonstrates added benefit in reducing the total degradation of formoterol.

[0085]

[0090] Further, it has been observed that the composition having a solution of formoterol in the presence of an organic acid, specifically maleic acid was found to be stable due to significant reduction in the total degradation of the composition with organic acid and use of specified valve. In addition, the data further demonstrate the surprising added benefit of water to form a stable pharmaceutical composition.

[0086] Tablet 5

[0087] BRT= Below Reporting Threshold

[0088] VD= Valve Down

[0089] N / A=Not Available

[0090] ND- Not Detected

[0091]

[0091] The samples of the on-market product, i.e., the reference product (Trimbow®), were also analyzed, and Table 6 shows the formoterol fumarate dihydrate impurity profde of the reference product at different ages.

[0092] Table 6

[0093] EXAMPLE 3

[0094]

[0092] Following aerosol formulations were prepared using the manufacturing process as described in example 1.

[0095] Tablet 7.

[0096]

[0093] BDP=Beclometasone dipropionate, FFD=Formoterol fumarate dihydrate, GPB= Glycopyrronium Bromide.

Claims

Claims:Claim 1. A stable pharmaceutical composition comprising a beta 2-agonist, a corticosteroid, a long acting muscarinic antagonist, a HFO propellant, a co-solvent, an organic acid(s) and water; wherein composition is provided in an internally coated canister having a metering valve having 3 gaskets, wherein the neck gasket of the metering valve is made of cycloolefin copolymer (COC) and two stem gaskets that are made of EPDM (ethylene propylene diene monomer).Claim 2. The stable pharmaceutical composition according to claim 1, wherein the beta 2-agonist is selected from a group consisting of albuterol, levalbuterol, formoterol, arformoterol, vilanterol, indacaterol, salmeterol, and olodaterol or pharmaceutically acceptable salts thereof.Claim 3. The stable pharmaceutical composition according to claim 1, wherein the corticosteroid is selected from a group consisting of beclometasone or beclometasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone propionate, fluticasone furoate, mometasone furoate, triamcinolone acetate, or prednisolone.Claim 4. The stable pharmaceutical composition according to claim 1, wherein the long acting muscarinic antagonist is selected from a group consisting of umeclidinium, aclidinium, glycopyrronium, ipratropium, oxitropium, tiotropium or pharmaceutically acceptable salts thereof.Claim 5. The stable pharmaceutical composition according to claim 1, wherein the HFO propellant is selected from a group consisting of 2,3,3,3-tetrafluoropropene (HFO-1234yf) and 1, 3,3,3- tetrafluoropropene (HFO-1234ze) or mixtures thereof.Claim 6. The stable pharmaceutical composition according to claim 1, wherein the co-solvent is selected from a group consisting of dichloromethane, chloroform, ethylacetate, N-methyl pyrrolidone, benzyl alcohol, isopropylacetate, acetonitrile, tetrahydrofuran, isopropanol, methanol, ethanol or mixtures thereof.Claim 7. The stable pharmaceutical composition according to claim 1, wherein the organic acid is selected from a group consisting of maleic acid, fumaric acid, citric acid, acetic acid, xinafoic acid,oxalic acid, lactic acid, 2-methyl propionic acid, malic acid, butanoic acid, tartaric acid, propionic acid, pentanoic acid, succinic acid, glycolic acid, hexanoic acid, malonic acid, glutaric acid, formic acid, adipic acid, ascorbic acid, benzoic acid, glucuronic acid, pyruvic acid, oxaloacetic acid, dihydroxyfumaric acid or mixtures thereof.Claim 8. The stable pharmaceutical composition according to claim 1, wherein the beta 2-agonist is formoterol fumarate dihydrate, a corticosteroid is beclometasone dipropionate and a long acting muscarinic antagonist is glycopyrronium bromide.Claim 9. The stable pharmaceutical composition according to claim 1, wherein the HFO propellant is HFO-1234ze, the co-solvent is ethanol and the organic acid is maleic acid.Claim 10. The stable pharmaceutical composition according to claim 8, wherein the HFO propellant is HFO-1234ze, the co-solvent is ethanol and the organic acid is maleic acid.Claim 11. The stable pharmaceutical composition according to claim 10, wherein the metering valve comprises a corrosion resistant spring.Claim 12. The stable pharmaceutical composition according to claim 1, wherein the composition is in the form of a solution or a suspension.Claim 13. A stable pharmaceutical composition in the form of a solution comprising beclometasone dipropionate in an amount from about 0.13-0.327 %w / w, formoterol fumarate dihydrate in an amount from about 0.006-0.01 %w / w, glycopyrronium bromide in an amount from about 0.015-0.025 %w / w, maleic acid in an amount from about 0.002-0.003 %w / w, ethanol in an amount from about 11-18 %w / w, water in an amount from about 0.2-0.6 %w / w and HFO-1234ze, wherein the composition is provided in an internally coated canister fdled under a pressure fitted with a metering valve having 3 gaskets, wherein the neck gasket of the metering valve is made of cycloolefin copolymer (COC), along with two stem gaskets that are made of EPDM (ethylene propylene diene monomer).Claim 14. The stable pharmaceutical composition according to claim 13, wherein the metering valve comprises a corrosion resistant spring.

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