Pharmaceutical formulations for pressurized metered dose inhalers

Abstract

The present invention relates generally to pharmaceutical compositions comprising a LABA agent, a LAMA agent (optionally in combination with other active ingredients), a mixture of an acid and a chelating agent, a propellant, and a co-solvent. The present invention also provides pharmaceutical compositions for the treatment of respiratory diseases such as asthma and COPD.

Description

Technical Field

[0001] The present invention generally relates to pharmaceutical compositions comprising a LABA agent, a LAMA agent, a mixture of an acid and a chelating agent, a propellant and a cosolvent; the present invention further relates to the use of such pharmaceutical compositions in the treatment and prevention of respiratory diseases. Background of the Invention

[0002] A pressurized metered dose inhaler (pMDI) is a well-known device for administering a drug product to the respiratory tract by inhalation. The pMDI device typically has a canister (or "can" as described herein) containing the drug and an actuator housing with a mouthpiece. The canister is typically crimped with a metering valve assembly. Depending on the active ingredient and other components such as excipients, acids and the like, the final pMDI formulation may be in the form of a solution or suspension. As known in the art, solutions are typically intended to be substantially free of precipitates or particles, while suspensions typically refer to formulations with some undissolved material or precipitates. The pMDI device can use a propellant to discharge droplets containing the drug product as an aerosol into the respiratory tract.

[0003] Glycopyrronium bromide (also known as glycopyrrolate), classified as a long-acting muscarinic antagonist (LAMA), is a particularly effective bronchodilator for the treatment of respiratory diseases when combined with a LABA agent and a corticosteroid.

[0004] Aerosol inhalation compositions suitable for use in pMDI devices have been described in the literature comprising a combination of formoterol and glycopyrrolate.

[0005] WO 2011 / 076842 describes a pharmaceutical composition comprising glycopyrrolate dissolved in an HFA propellant and a co-solvent, containing an amount of 1 M hydrochloric acid (HCl), wherein the formulation exhibits a good stability profile.

[0006] WO2011 / 076843 describes a stable pharmaceutical composition comprising formoterol, glycopyrrolate dissolved in an HFA propellant and a co-solvent, wherein the formulation contains 1 M HCl in an amount ranging from 0.1-0.3 μg / μL.

[0007] WO2015 / 101576 describes a pMDI device that is particularly suitable for use with a solution of formoterol, beclomethasone dipropionate and glycopyrrolate contained in a FEP coated can. As disclosed therein, the formulation contained in the FEP coated can is endowed with improved stability and reduced amounts of degradation products, primarily N-(3-bromo)-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyl]formamide.

[0008] Chemical stability of active pharmaceutical ingredients (APIs) contained in pharmaceutical compositions is particularly desirable, especially in order to obtain formulations suitable for the market.

[0009] Although the above-mentioned prior art provides effective formulations and technical arrangements, there is still a need to find alternative aerosol formulations containing LABA agents (especially in combination with LAMA agents and corticosteroids) which are stable over a prolonged product life and have the possibility of using commercially available cans (e.g. made of aluminum or stainless steel).

[0010] We have surprisingly found that the inclusion of a mixture of an acid and a chelating agent in a formulation comprising a LAMA agent (optionally in combination with a LABA agent and / or a corticosteroid) substantially avoids degradation of the active ingredient, thereby keeping the formulation stable for an extended period of time even when the formulation is contained in an aluminum can.

[0011] Advantageously, the aerosol formulation comprising a mixture of an acid and a chelating agent as described herein, when formulated in a propellant, in the presence of a cosolvent, can be used in a pMDI device, in particular for the treatment of respiratory diseases, such as asthma and / or COPD, with excellent nebulization properties. SUMMARY OF THE INVENTION

[0012] In one aspect, the invention relates to a pharmaceutical composition comprising a LABA agent, a LAMA agent, a co-solvent, a propellant, and a mixture of an acid and a chelating agent.

[0013] In particular, the present invention relates to such formulations further comprising a corticosteroid agent.

[0014] In a further aspect, the present invention relates to the use of the pharmaceutical composition comprising a LABA agent, a LAMA agent, and optionally a corticosteroid agent, a co-solvent, a propellant, and a mixture of an acid and a chelating agent for use as a medicament.

[0015] In a further aspect, the present invention further relates to the use of a pharmaceutical composition comprising a LABA agent, a LAMA agent, a cosolvent, a propellant, and a mixture of an acid and a chelating agent for the treatment and / or prevention of respiratory disorders, in particular asthma and COPD.

[0016] In a further aspect, the present invention relates to a canister for a pMDI device containing a pharmaceutical composition according to the invention.

[0017] In a further aspect, the present invention relates to a pMDI device comprising the formulation as indicated above, preferably contained in a canister as described herein. DETAILED DESCRIPTION OF THE INVENTION

[0019] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

[0020] The "molar ratio" between formoterol or its salt or solvate of said salt and the acid is calculated taking into account the number of moles of formoterol or its salt or solvate of said salt in the formulation and the number of moles of the selected acid in the formulation.

[0021] Unless otherwise indicated, the term "LABA" or "LABA agent" includes within its meaning long-acting β2 agonists as known in the art, such as formoterol fumarate, arformoterol, or fenoterol.

[0022] Unless otherwise indicated, the term "formoterol fumarate" or "FF" refers to (R,R)-(±) formoterol fumarate or its dihydrate.

[0023] Unless otherwise indicated, the term "LAMA" or "LAMA agent" includes within its meaning long-acting muscarinic receptor antagonists known in the art, such as glycopyrronium, methscopolamine, ipratropium.

[0024] Glycopyrrolate, chemically defined as 3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide, has two chiral centers, corresponding to four potential different stereoisomers with configurations (3R, 2'R)-, (3S, 2'R)-, (3R, 2'S)- and (3S, 2'S)-. Glycopyrrolate in the form of any of these pure enantiomers or diastereomers or any combination thereof may be used in the practice of the present invention.

[0025] Unless otherwise indicated, the term "glycopyrronium bromide" refers to the racemic mixture of (3S,2'R), (3R,2'S)-3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide, also known as glycopyrrolate (US AN name).

[0026] Unless otherwise indicated, the term "EDTA" means ethylenediaminetetraacetic acid.

[0027] Unless otherwise indicated, the term "EDTANa4" or "tetrasodium EDTA" or "tetrasodium ethylenediaminetetraacetate" refers to the salt of ethylenediaminetetraacetic acid having four sodium atoms.

[0028] Unless otherwise indicated, the term "EDTANa2" or "disodium EDTA" or "disodium EDTA" refers to the salt of ethylenediaminetetraacetic acid having two sodium atoms.

[0029] Unless otherwise indicated, the term "EDTANa2Ca" or "sodium calcium EDTA" or "disodium EDTA calcium" refers to a salt of ethylenediaminetetraacetic acid having two sodium atoms and one calcium atom.

[0030] Unless otherwise indicated, the term "EDTACa" or "ethylenediaminetetraacetic acid monocalcium" refers to the salt of ethylenediaminetetraacetic acid having one calcium atom.

[0031] The term "% w / w" refers to the weight percentage of a component relative to the total weight of a formulation.

[0032] The term "% w / v" refers to the weight percentage of a component relative to the total volume of a formulation.

[0033] With respect to the term "apparent pH" as referred to herein, it is noted that the calculation of pH is generally characteristic of aqueous liquids, i.e., where water is the major component. In relatively aprotic solvents (e.g., the propellants used in the present invention, such as HFA or HFO systems), the protons are non-hydrated, and their activity coefficients may differ from those in aqueous solution. Although the Nerst equation (describing the potential of an electrochemical cell as a function of the concentration of the ions participating in the reaction) is applied with respect to an electromagnetic field (EMF), and the pH meter glass electrode system will produce a variable millivolt output depending on the proton concentration and carrier polarity, the pH meter reading represents the "apparent pH" according to the present invention. In this direction, the apparent pH according to the present invention can be measured by techniques known in the art, such as those specified in "Correlation between Apparent pH and Acid or Base Concentration in ASTM Medium" Orest Popovych, Analytical Chemistry 1964, 36, 4, 878-882; Analytical Standard Test Method (ASTM) D6423 - 19, "Standard Test Method for Determination of pH of Denatured Fuel Ethanol and Ethanol Fuel Blends".

[0034] The term "chelator" refers to an organic compound capable of linking metal ions together to form a complex ring structure called a chelate, as noted, for example, in the Handbook of Toxicology of Chemical Warfare Agents, 2009.

[0035] As described above, the present invention unexpectedly shows that the inclusion of a mixture of an acid and a chelating agent in a formulation comprising a LABA agent, optionally in combination with a LAMA agent and / or a corticosteroid, when contained in an aluminum can, stabilizes the formulation thus obtained, particularly when the formulation is in the form of a solution.

[0036] According to one embodiment, the formulation of the present invention is characterized in that it comprises a mixture of an acid selected from an organic acid, an inorganic acid or a mixture thereof and a chelating agent. According to the present invention, organic acids suitable for the formulation of the present invention are those described in, for example, WO2019 / 236559.

[0037] In a preferred embodiment, the formulation of the invention is characterized in that it comprises a mixture of an inorganic acid and a chelating agent.

[0038] In a further preferred embodiment, the formulation of the invention is characterized in that it comprises an inorganic acid selected from hydrochloric acid, nitric acid and phosphoric acid. Preferably, the inorganic acid is hydrochloric acid (HCl). Also preferred is a mixture of hydrochloric acid and phosphoric acid.

[0039] In one embodiment, the formulation of the invention is characterized in that it comprises a chelating agent selected from EDTA, EDTANa2, EDTANa2Ca, EDTACa. Preferably, the formulation comprises EDTANa4.

[0040] In a preferred embodiment, the formulation of the invention is characterized by comprising a mixture of an inorganic acid, preferably hydrochloric acid (HCl), and a chelating agent, preferably EDTANa4.

[0041] In a particularly preferred embodiment, the preparation of the present invention comprises a mixture of HCl and EDTANa4. In this regard, it has been surprisingly found that when a mixture of HCl and EDTANa4 is used, a preparation suitable for pMDI administration and comprising at least a LAMA agent and optionally comprising a LABA agent and / or a corticosteroid is particularly stable. From the data collected in the experimental section below, it can be seen that even when the preparation is contained in an aluminum can, the use of a mixture of HCl and EDTANa4 also provides an increase in stability. The mixture of HCl and EDTANa4 gives the preparation thus obtained a certain degree of stability in an aluminum can, which is comparable to the stability obtainable with the FEP technology.

[0042] In a preferred embodiment, the formulation of the invention is in the form of a solution.

[0043] As shown in the experimental part (Tables 2, 3, 5 and 6), the addition of a mixture of HCl and EDTANa4 to a solution formulation containing formoterol fumarate, glycopyrrolate and BDP in an aluminum can increases the stability of the formulation in terms of the residual % of active ingredients, particularly formoterol fumarate, relative to the corresponding formulation containing HCl not mixed with EDTA. It can be understood that the combination of an inorganic acid and a chelating agent is in fact capable of stabilizing not only formoterol fumarate, but also other active ingredients contained in the formulation, such as glycopyrrolate and beclomethasone dipropionate, to a degree comparable to the stability obtained by using the FEP technology.

[0044] The present invention brings several advantages to the prior art, such as increased stability of the formulation over time, good shelf life, good reproducibility of the final formulation, maintenance of optimal chemical conditions within commercially readily available cans, and consistent delivery and efficacy of the drug, especially when formulated as a solution for use in a pMDI device.

[0045] Even further, the mixture of inorganic acid and chelating agent may also avoid the use of FEP coated cans, thereby providing a simpler manufacturing process and final device system. As is known in the prior art and as described above, the formulation comprising formoterol and glycopyrrolate contained in a FEP coated can is actually endowed with improved stability, which is not achievable when the same formulation is contained in, for example, an aluminum can.

[0046] We have now found that a combination of a mineral acid and a chelating agent, in particular a mixture of HCl and EDTANa4, unexpectedly provides a degree of stability to the formulations of the invention when contained in aluminium cans which is comparable to that obtained using prior art FEP technology.

[0047] According to the present invention, the formulation is suitable for pMDI administration and comprises at least a LAMA agent and optionally a LABA agent and / or a corticosteroid, and a mixture of HCl and EDTANa4.

[0048] In one embodiment, the HCl is 1 M, ie a defined amount of an aqueous solution comprising 1 M HCl is added to the pharmaceutical formulation.

[0049] In another embodiment, the EDTANa4 is added to the formulation as an aqueous solution at a concentration of 1 to 5 mg / ml. Preferably, the concentration is 2 mg / ml to 3 mg / ml.

[0050] In one embodiment, the amount of 1M HCl included in the pharmaceutical formulation is in the range of 0.01 to 0.08% w / w. Preferably, the amount of 1M HCl is in the range of 0.010 to 0.035% w / w; more preferably, the amount of 1M HCl is in the range of 0.015 to 0.020% w / w; even more preferably, the amount of 1M HCl is 0.018% w / w.

[0051] In another embodiment, the amount of EDTANa4 included in the pharmaceutical preparation is in the range of 0.00002 to 0.002% w / w. Preferably, the amount of EDTANa4 is in the range of 0.0001 to 0.0009% w / w; more preferably, the amount of EDTANa4 is in the range of 0.0001 to 0.0005% w / w; more preferably, the amount of EDTANa4 is in the range of 0.0001 to 0.0003% w / w; even more preferably, the amount of EDTANa4 is 0.0002% w / w.

[0052] In a preferred embodiment, the amount of 1 M HCl contained in the pharmaceutical formulation is in the range of 0.01 to 0.08% w / w, and the amount of EDTANa4 is in the range of 0.00002 to 0.002% w / w.

[0053] More preferably, the amount of HCl is in the range of 0.015 to 0.035% w / w, and the amount of EDTANa4 is in the range of 0.0001 to 0.0009% w / w. Even more preferably, the amount of HCl is in the range of 0.015 to 0.025% w / w, and the amount of EDTANa4 is in the range of 0.0001 to 0.0005% w / w. Still more preferably, the amount of HCl is in the range of 0.015 to 0.025% w / w, and the amount of EDTANa4 is in the range of 0.0001 to 0.0003% w / w. Particularly more preferably, the amount of HCl is 0.018% w / w, and the amount of EDTANa4 is 0.0002% w / w.

[0054] In one embodiment, the formulation of the invention is a solution comprising a LABA agent, a LAMA agent, a mixture of an inorganic acid (preferably HCl) and a chelating agent (preferably EDTANa4), and a corticosteroid, in amounts according to the above embodiments.

[0055] In a preferred embodiment, the LABA agent in the formulation according to the present invention is selected from: fenoterol, formoterol fumarate, formoterol fumarate dihydrate, arformoterol, carmoterol (TA-2005), indacaterol, milvterol, bambuterol, clenbuterol, vilanterol, olodaterol, abetrol, terbutaline, salmeterol, its diastereoisomer mixture and pharmaceutically acceptable salt or its hydrate.

[0056] In a further preferred embodiment, the LABA is formoterol fumarate, preferably formoterol fumarate dihydrate.

[0057] In another embodiment, the formulation of the present invention comprises salbutamol or (R)-salbutamol (levosalbutamol) or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0058] Preferably, the amount of LABA according to the present invention is 0.0005-0.04% w / w, more preferably 0.001-0.03% w / w, even more preferably 0.005-0.02% w / w.

[0059] In one embodiment, the LAMA agent in the formulation according to the invention is selected from glycopyrronium, ipratropium, oxitropium, trospium, tiotropium, aclidinium and umeclidinium and any pharmaceutical counterions thereof.

[0060] A preferred LAMA agent is glycopyrrolate.

[0061] In one embodiment, the LAMA agent, preferably glycopyrrolate, is present in the formulation of the invention in an amount ranging from 0.005 to 0.14% (w / w), preferably 0.010 to 0.13% (w / w), more preferably 0.010 to 0.045% (w / w), wherein % (w / w) means the amount by weight of the component, expressed as a percentage relative to the total weight of the composition.

[0062] In one embodiment, the corticosteroid component of the formulation according to the invention is selected from the group consisting of budesonide, beclomethasone, e.g. as monopropionate or dipropionate, flunisolide, fluticasone, e.g. as propionate or furoate, ciclesonide, mometasone, e.g. as furoate, mometasone desonide, roflenide, hydrocortisone, prednisone, prednisolone, methylprednisolone, nafecort, deflazacort, halopednisolone acetate, fluocinolone acetonide, fluocinolone acetonide, clocortolone, tipredan, prednicarbate, alclometasone dipropionate, halometasone, rimexolone, deproton propionate, triamcinolone, betamethasone, fludrocortisone, deoxycorticosterone, roflenide, eprednolate.

[0063] Beclomethasone dipropionate (BDP) and budesonide are particularly preferred.

[0064] In a more preferred embodiment, the corticosteroid component is beclomethasone dipropionate (BDP).

[0065] According to another embodiment of the present invention, the amount of the corticosteroid component (preferably BDP) is 0.01-0.7% w / w, more preferably 0.05-0.5% w / w, even more preferably 0.08-0.35% w / w.

[0066] In one embodiment, the invention is directed to a formulation suitable for pMDI administration, preferably a solution, comprising: a LABA agent, a LAMA agent, a corticosteroid, and a mixture of an acid and a chelating agent.

[0067] In a preferred embodiment, the present invention is directed to a formulation suitable for pMDI administration, preferably a solution, comprising: a LABA agent, a LAMA agent, a corticosteroid, and a mixture of an inorganic acid and a chelating agent.

[0068] In a further preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising: a LABA agent, a LAMA agent, a corticosteroid, and a mixture of HCl and EDTANa4.

[0069] In a more preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising formoterol fumarate, glycopyrrolate, BDP, and a mixture of an inorganic acid and a chelating agent.

[0070] In a more preferred embodiment, the present invention relates to a formulation, preferably a solution, comprising: a mixture of glycopyrronium, formoterol, BDP, HCl and EDTANa4.

[0071] As mentioned above, the formulations of the present invention are particularly suitable for administration as pMDI solutions. In this regard, the formulations of the present invention further comprise a propellant and preferably a co-solvent, as described below.

[0072] The propellant in the formulation according to the invention is selected from hydrofluoroalkanes (HFAs) and hydrofluoroolefins (HFOs) and mixtures thereof.

[0073] In one embodiment, the hydrofluoroalkane propellant is selected from the group consisting of: HFA134a (1,1,1,2-tetrafluoroethane), HFA227 (1,1,1,2,3,3,3-heptafluoropropane), HFA152a (1,1-difluoroethane) and mixtures thereof.

[0074] In one embodiment, the HFO propellant in the formulation according to the invention is selected from: 1,3,3,3-tetrafluoropropene (HFO-1234ze) and 2,3,3,3-tetrafluoropropene (HFO-1234yf).

[0075] Preferably, the propellant is a HFA propellant, more preferably HFA134a.

[0076] In an equally preferred embodiment, the propellant is HFA152a.

[0077] The HFA or HFO may be present in the formulation in an amount of 75% to 95% (w / w), preferably 85% to 90% (w / w).

[0078] According to the above preferred embodiments, the present invention relates to a formulation as described in detail above, further comprising a co-solvent and optionally a low volatility component.

[0079] Preferably, the cosolvent is a polar compound capable of increasing the solubility of the component in the formulation. Preferred cosolvents are aliphatic alcohols having 1 to 4 carbon atoms, such as methanol, ethanol, propanol, isopropanol, etc., preferably ethanol, more preferably anhydrous ethanol.

[0080] When present, the co-solvent is used in an amount of 5% w / w to 20% w / w, more preferably 10 to 15% w / w.

[0081] Even in one embodiment, the preparation of the present invention is composed of the above-mentioned components, in other embodiments, the preparation of the present invention may optionally further comprise other components, such as excipients, additives or low volatility components. The addition of the components can be appropriately calibrated so as to adjust, for example, the chemical and physical properties of the preparation.

[0082] When present, the low volatility component is a compound characterized by a vapor pressure below 0.1 kPa, preferably below 0.05 kPa at 25° C. Preferred low volatility components are selected from glycols, propylene glycol, polyethylene glycol, glycerol or its esters, ascorbyl palmitate and isopropyl myristate, with isopropyl myristate and glycerol being particularly preferred.

[0083] In a further preferred embodiment, the present invention is directed to a formulation suitable for pMDI administration, preferably a solution, comprising, consisting of or consisting essentially of a LAMA agent, a LABA agent, and a corticosteroid, a mixture of an inorganic acid and a chelating agent, an HFA propellant, and an aliphatic alcohol having 1 to 4 carbon atoms, preferably ethanol.

[0084] In a particularly preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising, consisting of or consisting essentially of glycopyrrolate, formoterol fumarate, BDP, a mixture of HCl and EDTANa4, an HFA propellant, preferably HFA 134a or HFA 152a, and ethanol, more preferably anhydrous ethanol.

[0085] In a more particularly preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising, consisting of or consisting essentially of glycopyrrolate, formoterol fumarate, BDP, a mixture of HCl and EDTANa4, HFA 134a, and ethanol, preferably anhydrous ethanol.

[0086] In a likewise preferred embodiment, the invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising, consisting of or consisting essentially of glycopyrrolate, formoterol fumarate, BDP, a mixture of HCl and EDTANa4, HFA 152a, and ethanol, preferably anhydrous ethanol.

[0087] In one embodiment, the invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising, consisting of or consisting essentially of glycopyrrolate, formoterol fumarate, BDP, 1 M HCl in an amount ranging from 0.01 to 0.08% w / w, EDTANa4 in an amount ranging from 0.00002 to 0.002% w / w, a HFA propellant selected from HFA 134a and HFA 152a, ethanol, preferably anhydrous ethanol.

[0088] In a preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising, consisting of or consisting essentially of glycopyrrolate, formoterol fumarate, BDP, 1 M HCl in an amount ranging from 0.010 to 0.035% w / w, EDTANa4 in an amount ranging from 0.0001 to 0.0009% w / w, a HFA propellant selected from HFA 134a and HFA 152a, and ethanol, preferably anhydrous ethanol.

[0089] In a further preferred embodiment, the invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising, consisting of or consisting essentially of glycopyrrolate, formoterol fumarate, BDP, 1 M HCl in an amount ranging from 0.015 to 0.020% w / w, EDTANa4 in an amount ranging from 0.0001 to 0.0005% w / w, preferably 0.0001 to 0.0003% w / w, an HFA propellant selected from HFA 134a and HFA 152a, and ethanol, preferably anhydrous ethanol.

[0090] In a particularly preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising, consisting of or consisting essentially of formoterol fumarate, BDP, 1 M HCl in an amount of 0.024% w / w, EDTANa4 in an amount of 0.000025% w / w, HFA 134a, and ethanol, preferably anhydrous ethanol.

[0091] In a likewise preferred embodiment, the invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising, consisting of or consisting essentially of glycopyrrolate, formoterol fumarate, BDP, 1 M HCl in an amount of 0.018% w / w, EDTANa4 in an amount of 0.00002% w / w, HFA 152a, and ethanol, preferably anhydrous ethanol.

[0092] In some embodiments, the formulation does not contain other excipients except those explicitly defined above. For example, the formulation may not contain excipients except co-solvents, propellants, inorganic acids and chelating agents (e.g., HCl and EDTANa4).

[0093] According to the present invention, the preparation of the present invention may be a solution, a suspension or a system comprising a solution and a suspension.

[0094] In a preferred embodiment, the formulation of the present invention is a solution. Preferably, one or more, more preferably all, of the pharmaceutically active ingredients of the formulation, such as LABA, LAMA and / or corticosteroids, are completely and uniformly dissolved in the propellant and cosolvent.

[0095] With respect to cans or canisters, part or all of the canister of a pMDI device suitable for containing a formulation of the present invention may be made of metal, such as aluminum or a metal alloy, stainless steel or anodized aluminum, fluorine-passivated aluminum, etc. Alternatively, the canister may be a plastic canister or a plastic-coated glass bottle.

[0096] The metal can may have part or all of its interior surface lined with an inert organic coating.

[0097] The coating is typically applied to the interior surface of the can, thereby providing an interior layer that acts as an interface between the interior surface of the can and the formulation contained therein.

[0098] In this regard, suitable coated tanks of the present invention may have part or all of their inner surfaces coated with an inert organic or inorganic coating, which preferably comprises: epoxy phenol resin, perfluorinated polymer, perfluoroalkoxy alkane polymer, perfluoroalkoxy alkylene polymer (PFA), perfluoroalkylene polymer, poly-tetrafluoroethylene polymer (PTFE or Teflon), fluorinated-ethylene-propylene polymer (FEP), polyethersulfone polymer (PES), fluorinated-ethylene-propylene polyethersulfone polymer (FEP-PES), polyamide, polyimide, polyamideimide, polyphenylene sulfide, plasma, mixture or combination thereof.

[0099] In a preferred embodiment, the present invention relates to the above formulation contained in a pMDI can made of aluminum or stainless steel. Therefore, in one aspect, the present invention relates to a pMDI can made of aluminum or stainless steel, which is filled with the formulation of the present invention as described in detail above. Preferably an aluminum can.

[0100] The cannula of a pMDI device is typically crimped with a metered valve for delivering a therapeutically effective dose of the active ingredient.

[0101] The metering valve assembly comprises at least one rubber gasket seal made of a suitable elastomeric material selected from: low density polyethylene, butyl or halogenated butyl rubber, such as chlorobutyl or bromobutyl rubber (optionally halogenated copolymers of isobutylene and isoprene), butadiene-acrylonitrile, chloroprene rubber, EPDM (polymer of ethylene propylene diene monomer), TPE (thermoplastic elastomer), cyclic olefin copolymer (COC) or a combination thereof.

[0102] Metering valves according to the invention are typically capable of delivering a volume in the range of 25 μl to 150 μl, preferably in the range of 50 to 100 μl, and more preferably in the range of 50 μl to 70 μl per actuation; most preferred are 50, 63 and 100 μl per actuation. Suitable valves for use in the invention are commercially available.

[0103] According to another aspect of the invention, there is provided a method of filling an aerosol inhaler with a pharmaceutical composition of the invention. Conventional bulk production methods and machinery well known to those skilled in the art of pharmaceutical aerosol manufacture can be used to prepare large scale batches of canisters for commercial production filling.

[0104] As a general example, the method may include the following steps:

[0105] a) preparing a solution comprising formoterol fumarate, BDP, glycopyrrolate and ethanol;

[0106] b) adding a certain amount of 1M HCl to the ethanol solution and mixing the bulk solution;

[0107] c) adding a certain amount of EDTANa4 (as aqueous solution) and

[0108] d) filling a tank with the solution;

[0109] e) Crimp with valve and inflate with HFA propellant.

[0110] The packaged formulations of the present invention are stable for extended periods of time when stored under normal conditions of temperature and humidity.

[0111] The stability was evaluated by measuring the amount of residual active ingredient.

[0112] In a further aspect, the invention relates to a formulation as described above for use as a medicament. Accordingly, the invention relates to the use of a formulation as described herein for the preparation of a medicament.

[0113] Preferably, the formulations of the invention are used for prophylactic purposes or for the symptomatic relief of a wide range of respiratory disorders, such as all types of asthma and chronic obstructive pulmonary disease (COPD).

[0114] In a preferred embodiment, the invention relates to a formulation as described herein for use in the treatment and / or prevention of a breathing disorder, preferably for use in the treatment and / or prevention of asthma or COPD.

[0115] Other respiratory disorders for which the use of the pharmaceutical compositions of the invention may be beneficial are those characterized by peripheral airway obstruction due to inflammation and the presence of mucus, such as chronic obstructive bronchiolitis, chronic bronchitis, emphysema, acute lung injury (ALI), cystic fibrosis, rhinitis and adult or acute respiratory distress syndrome (ARDS).

[0116] As will be appreciated, all embodiments described herein are intended to be included within the scope of the present invention, also in any possible combination with all other preferred embodiments as set forth above and below.

[0117] The invention will now be described by way of the following non-limiting examples.

[0118] Experimental Section Example 1

[0119] A study was conducted to investigate the chemical stability of a formulation intended for pMDI administration comprising formoterol fumarate dihydrate (FF), glycopyrrolate (GB) and beclomethasone dipropionate (BDP). The formulation was a solution contained in an aluminum can (Al) or FEP coated can (FEP) crimped with a metering valve having a metering volume of 63 μl.

[0120] Certain amounts of HCl, either alone or mixed with EDTANa4, were added to the formulations to provide Formulations 1-2 as reported in Table 1.

[0121] Table 1

[0122] Formulations 1-2 were placed in an inverted position in a stability chamber at 40°C, 75% RH for 1 month, and the API assay and related degradation products were measured at T1 (1 month).

[0123] The formulations were also tested at different stability conditions at 25°C, 60% RH for 6 months, and the API assay and related degradation products were measured at T3 (3 months) and T6 (6 months). The % API residues are reported in Tables 2 and 3.

[0124] Table 2

[0125] Table 3

[0126] As can be observed from Tables 2 and 3, a significant improvement in the chemical stability of formoterol (FF), glycopyrrolate (GB) and beclomethasone dipropionate (BDP) was achieved when a mixture of HCl and EDTANa4 was added according to Formulation 1. It is noteworthy that even in aluminum cans, the %FF residual can reach values ​​above 90%, which is different from Formulation 2, where the %FF residual was significantly reduced after 3 months in aluminum cans.

[0127] Formulation 1 in aluminum cans showed significantly improved stability in terms of FF% residues, which was comparable to the stability of the formulation in FEP coated cans.

[0128] As is evident from Tables 2 and 3, the mixture of HCl and EDTANa4 according to the invention provides a comparable degree of stability in terms of residual % of API (particularly formoterol) to the high degree of stability obtainable using the FEP technique. Example 2

[0129] A second study was conducted to investigate the chemical stability of a formulation intended for pMDI administration comprising formoterol fumarate dihydrate (FF), glycopyrrolate (GB) and beclomethasone dipropionate (BDP) in HFA152a propellant. The formulation was a solution contained in an aluminum can (Al) or FEP coated can (FEP) crimped with a metering valve having a metering volume of 63 μl.

[0130] An amount of HCl mixed with EDTANa4 was added to the formulation to provide Formulation 3 as reported in Table 4.

[0131] Table 4

[0132] Formulation 3 was placed in a stability chamber in an inverted position at 40°C, 75% RH for 1 month and the API assay and related degradation products were measured at T1 (1 month).

[0133] The formulations were also tested under different stability conditions at 25°C, 60% RH for 3 months and the API assay and related degradation products were measured at T3 (3 months).

[0134] The % API residues are reported in Tables 5 and 6.

[0135] Table 5

[0136] Table 6

[0137] As can be observed from Tables 5 and 6, the best chemical stability of formoterol (FF), glycopyrrolate (GB) and beclomethasone dipropionate (BDP) was achieved when a mixture of HCl and EDTANa4 was added according to Formulation 3.

[0138] Formulation 3 in aluminum cans showed significantly improved stability in terms of FF% residues, which was comparable to the stability of the formulation in FEP coated cans, especially after 3 months in aluminum cans.

[0139] As can be seen from Tables 5 and 6, the mixture of HCl and EDTANa4 according to the present invention provides a comparable high degree of stability to that obtainable using FEP technology in terms of the residual % of the API, in particular formoterol.

Claims

1. A pharmaceutical composition comprising a LABA agent, a LAMA agent, a co-solvent, a propellant, and a mixture of an acid and a chelating agent.

2. The pharmaceutical composition of claim 1, wherein the LABA agent is selected from the group consisting of: fenoterol, formoterol fumarate, formoterol fumarate dihydrate, arformoterol, carmoterol (TA-2005), indacaterol, milvterol, bambuterol, clenbuterol, vilanterol, olodaterol, abetrol, terbutaline, salmeterol, diastereomeric mixtures thereof and pharmaceutically acceptable salts or hydrates thereof.

3. The pharmaceutical composition of claim 2, wherein the LABA agent is formoterol fumarate.

4. The pharmaceutical composition of claim 3, wherein the LABA agent is formoterol fumarate dihydrate.

5. The pharmaceutical composition according to any one of claims 1 to 4, further comprising a LAMA agent selected from the group consisting of glycopyrronium, ipratropium, oxitropium, trospium, tiotropium, aclidinium and umeclidinium and any pharmaceutical counterions thereof.

6. The pharmaceutical composition of claim 5, wherein the LAMA agent is glycopyrrolate.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the acid is selected from an inorganic acid, an organic acid or a mixture thereof.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the acid is an inorganic acid.

9. The pharmaceutical composition according to claim 8, wherein the inorganic acid is HCl.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the chelating agent is selected from EDTA, EDTANa2, EDTANa2Ca, EDTACa, preferably EDTANa4.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the mixture of acid and chelating agent is a mixture of HCl and EDTANa4.

12. The pharmaceutical composition according to any one of claims 1 to 9, wherein the amount of 1 M HCl ranges from 0.01 to 0.08% w / w.

13. The pharmaceutical composition according to claim 12, wherein the amount of 1 M HCl is in the range of 0.010 to 0.035% w / w.

14. The pharmaceutical composition according to claim 13, wherein the amount of 1 M HCl is in the range of 0.015 to 0.020% w / w.

15. A pharmaceutical composition according to any one of claims 1 to 11, wherein the amount of EDTANa4 is in the range of 0.00002 to 0.002% w / w.

16. The pharmaceutical composition according to claim 15, wherein the amount of EDTANa4 is in the range of 0.0001 to 0.0009% w / w.

17. The pharmaceutical composition according to claim 16, wherein the amount of EDTANa4 is in the range of 0.0001 to 0.0005% w / w.

18. The pharmaceutical composition according to claim 17, wherein the amount of EDTANa4 is in the range of 0.0001 to 0.0003% w / w.

19. The pharmaceutical composition according to any one of claims 1 to 18, wherein the amount of HCl is in the range of 0.01 to 0.08% w / w % w / w, and the amount of EDTANa4 is in the range of 0.00002 to 0.002% w / w.

20. The pharmaceutical composition according to claim 19, wherein the amount of HCl is in the range of 0.010 to 0.035% w / w % w / w and the amount of EDTANa4 is in the range of 0.0001 to 0.0009% w / w.

21. The pharmaceutical composition according to claim 20, wherein the amount of HCl is in the range of 0.015 to 0.020% w / w % w / w, and the amount of EDTANa4 is in the range of 0.0001 to 0.0005% w / w.

22. The pharmaceutical composition according to claim 21, wherein the amount of HCl is in the range of 0.015 to 0.020% w / w % w / w, and the amount of EDTANa4 is in the range of 0.0001 to 0.0003% w / w.

23. The pharmaceutical composition of claim 22, wherein the amount of HCl is 0.018% w / w % w / w and the amount of EDTANa4 is 0.0002% w / w.

24. A pharmaceutical composition according to any one of claims 1 to 23, further comprising a corticosteroid selected from the group consisting of budesonide, beclomethasone (BDP), e.g. as monopropionate or dipropionate, flunisolide, fluticasone, e.g. as propionate or furoate, ciclesonide, mometasone, e.g. as furoate, mometasone desonide, roflenide, hydrocortisone, prednisone, prednisolone, methylprednisolone, nafecort, deflazacort, halopednisolone acetate, fluocinolone acetonide, fluocinolone acetonide, clocortolone, tipredan, prednicarbate, alclomethasone dipropionate, halometasone, rimexolone, deproton propionate, triamcinolone, betamethasone, fludrocortisone, deoxycorticosterone, roflenide, eprednolate.

25. The pharmaceutical composition of claim 24, wherein the corticosteroid is budesonide or beclomethasone dipropionate (BDP).

26. The pharmaceutical composition of claim 25, wherein the corticosteroid is beclomethasone dipropionate (BDP).

27. A pharmaceutical composition according to any one of claims 1 to 26, wherein the co-solvent is an aliphatic alcohol having 1 to 4 carbon atoms.

28. The pharmaceutical composition of claim 27, wherein the co-solvent is ethanol.

29. The pharmaceutical composition according to any one of claims 1 to 28, wherein the propellant is selected from the group consisting of hydrofluoroalkanes (HFAs) and hydrofluoroolefins (HFOs) and mixtures thereof.

30. The pharmaceutical composition according to claim 29, wherein the propellant is selected from the group consisting of: HFA134a, HFA152a and mixtures thereof.

31. The pharmaceutical composition of claim 30, wherein the propellant is HFA134a.

32. The pharmaceutical composition of claim 30, wherein the propellant is HFA152a.

33. A pharmaceutical composition according to any one of claims 1 to 32, wherein the composition is a solution.

34. A pharmaceutical composition according to any one of claims 1 to 33, wherein the LABA agent is formoterol fumarate dihydrate, the corticosteroid is beclomethasone dipropionate (BDP), the LAMA agent is glycopyrrolate, the propellant is HFA134a, the inorganic acid is HCl, the chelating agent is EDTANa2, the cosolvent is ethanol, and the composition is a solution.

35. A pharmaceutical composition according to any one of claims 1 to 33, wherein the LABA agent is formoterol fumarate dihydrate, the corticosteroid is budesonide or beclomethasone dipropionate (BDP), the LAMA agent is glycopyrrolate, the propellant is HFA152a, the inorganic acid is HCl, the chelating agent is EDTANa2, the cosolvent is ethanol, and the composition is a solution.

36. A can containing the pharmaceutical composition according to any one of claims 1 to 35, wherein the can is made of aluminum, stainless steel, anodized aluminum and fluorine-passivated aluminum.

37. A canister for a pMDI device containing a pharmaceutical composition according to any one of claims 1 to 35.

38. A canister for a pMDI device according to claim 37, which is made of aluminium or stainless steel.

39. A pMDI device comprising a canister made of aluminium or stainless steel containing a pharmaceutical composition according to any one of claims 1 to 35.

40. A pharmaceutical composition according to any one of claims 1 to 35 for use as a medicament.

41. The pharmaceutical composition according to claim 40, for use in the treatment and / or prevention of respiratory disorders.

42. The pharmaceutical composition according to claim 41, for use in the treatment and / or prevention of asthma or COPD.

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