Pharmaceutical preparation for a pressurized metered-dose inhaler

Abstract

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

Description

Technical Field

[0001] Field of the Invention 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 co-solvent; the present invention further relates to the use of such pharmaceutical compositions in the treatment and prevention of respiratory diseases.

Background Art

[0002] Background of the Invention A pressurized metered-dose inhaler (pMDI) is a well-known device for administering pharmaceuticals to the respiratory tract by inhalation. A pMDI device typically comprises a pharmaceutical-containing canister (or "can" as described herein) and an actuator housing having a mouthpiece. The can is usually crimped to a metering valve assembly. Depending on the active ingredient as well as further ingredients such as excipients, acids, the final pMDI formulation can take the form of a solution or a suspension. As is known in the art, a solution is generally intended to be substantially free of precipitates or particles, while a suspension typically refers to a formulation having a certain amount of insoluble material or precipitate. A pMDI device can use a propellant to eject droplets containing the pharmaceutical as an aerosol into the respiratory tract.

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

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

[0005] WO2011 / 076842 describes a pharmaceutical composition comprising glycopyrronium bromide dissolved in an HFA propellant and a co-solvent, containing a certain amount of 1M hydrochloric acid (HCl), which exhibits a good stability profile.

[0006] WO2011 / 076843 describes a stabilized pharmaceutical composition comprising formoterol, glycopyrronium bromide dissolved in an HFA propellant and a co-solvent, comprising 1M HCl in an amount in the range of 0.1 to 0.3 μg / μl.

[0007] WO2015 / 101576 describes a pMDI device suitable for use with a solution of formoterol, beclomethasone dipropionate and glycopyrronium bromide, especially contained in an FEP-coated can. As disclosed therein, the formulation contained in the FEP-coated can has improved stability and a reduced amount of degradation products mainly related to N-(3-bromo)-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyl]formamide.

[0008] The chemical stability of the active pharmaceutical ingredient (API) contained in a pharmaceutical composition is particularly desired to obtain a commercially suitable formulation.

Summary of the Invention

Problems to be Solved by the Invention

[0009] The above prior art provides effective formulations and technical preparations, but there is a need to find alternative aerosol formulations that are stable throughout the long product life and that can use commercially available cans such as those made of aluminum or stainless steel, especially LABA agents in combination with LAMA agents and corticosteroids.

[0010] The inventors have surprisingly found that by including 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, the degradation of the active ingredient is substantially avoided even when the formulation is contained in an aluminum canister, and thus the formulation is stably maintained over a long period of time.

[0011] Advantageously, the aerosol formulation containing the mixture of an acid and a chelating agent described herein can be used with excellent aerosolization performance in a pMDI device for the treatment of respiratory diseases such as asthma and / or COPD, especially when formulated in a propellant, in the presence of a co-solvent. **Means for Solving the Problems**

[0012] **Summary of the Invention** In one aspect, the present 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 a formulation that also contains 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 medicine.

[0015] In a further aspect, the present invention relates to the use of 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 for the treatment and / or prevention of respiratory disorders, especially asthma and COPD. **Modes for Carrying Out the Invention**

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

[0017] In still a further aspect, the present invention relates to a pMDI device comprising the above formulation, preferably contained in the canister described herein.

[0018] **Detailed Description of the Invention** Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0019] The "molar ratio" between formoterol or a salt thereof or a solvate of the salt and an acid is calculated taking into account the number of moles of formoterol or a salt thereof or a solvate of the salt in the formulation and the number of moles of the selected acid in the formulation.

[0020] Unless otherwise specified, the term "LABA" or "LABA agent" includes long-acting beta2 agonists known in the art such as formoterol fumarate, arformoterol or fenoterol in its meaning.

[0021] Unless otherwise specified, the term "formoterol fumarate" or "FF" refers to (R,R)-(±) formoterol fumarate or its dihydrate.

[0022] Unless otherwise specified, the term "LAMA" or "LAMA agent" includes long-acting muscarinic receptor antagonists such as glycopyrronium, methscopolamine, ipratropium, etc. as known in the art in its meaning.

[0023] Glycopyrronium bromide is chemically defined as 3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide and has two chiral centers corresponding to four possible different stereoisomers having configurations (3R,2’R)-, (3S,2’R)-, (3R,2’S)- and (3S,2’S)-. Glycopyrronium bromide in the form of any of these pure enantiomers or diastereomers or any combination thereof can be used in the practice of the present invention.

[0024] Unless otherwise specified, the term "glycopyrronium bromide" refers to the (3S,2’R),(3R,2’S)-3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide racemic mixture also known as glycopyrrolate (USAN name).

[0025] Unless otherwise specified, the term "EDTA" refers to ethylenediaminetetraacetic acid.

[0026] Unless otherwise specified, the term "EDTANa 4 ", or "tetrasodium EDTA", or "disodium ethylenediaminetetraacetate" refers to the salt of ethylenediaminetetraacetic acid having four sodium atoms.

[0027] Unless otherwise specified, the term "EDTANa 2 ", or "disodium EDTA", or "sodium ethylenediaminetetraacetate" refers to the salt of ethylenediaminetetraacetic acid having two sodium atoms.

[0028] Unless otherwise specified, the term "EDTANa 2 Ca", or "calcium disodium ethylenediaminetetraacetate", or "calcium sodium edetate" refers to the salt of ethylenediaminetetraacetic acid having two sodium atoms and one calcium atom.

[0029] Unless otherwise specified, the term "EDTACa", or "calcium ethylenediaminetetraacetate" refers to the salt of ethylenediaminetetraacetic acid having one calcium atom.

[0030] The term "% w / w" means the weight percentage of the component with respect to the total weight of the formulation.

[0031] The term "% w / v" means the weight percentage of the component with respect to the total volume of the formulation.

[0032] Regarding the term "apparent pH" as intended herein, it should be noted that the calculation of pH is generally characteristic when the aqueous liquid, i.e., water is the dominant component. In a relatively aprotic solvent (e.g., the propellants used in the present invention, such as HFA or HFO-based), protons are non-hydrated and their activity coefficients can be different from those in an aqueous solution. Applying the Nernst equation (describing the potential of an electrochemical cell as a function of the ionic concentrations participating in the reaction) with respect to the electromagnetic field (EMF), even if the pH meter glass electrode system provides a valuable millivolt output with respect to the proton concentration and medium polarity, the pH meter reading represents the "apparent pH" of the present invention. In this regard, the apparent pH of the present invention can be measured by techniques known in the art, as shown, for example, 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".

[0033] The term "chelating agent" refers to an organic compound that can link with metal ions to form a complex ring-like structure called a chelate, as shown, for example, in Handbook of Toxicology of Chemical Warfare Agents, 2009.

[0034] As described above, the present invention unexpectedly shows that the inclusion of a mixture of an acid and a chelating agent in a formulation containing a LABA agent, optionally in combination with a LAMA agent and / or a corticosteroid, stabilizes the thus obtained formulation when contained in an aluminum can, especially when the formulation is in solution form.

[0035] According to one embodiment, the formulation of the present invention is characterized by comprising 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, the organic acids suitable for the formulation of the present invention are those described, for example, in WO2019 / 236559.

[0036] In a preferred embodiment, the formulation of the present invention is characterized by comprising a mixture of an inorganic acid and a chelating agent.

[0037] In a more preferred embodiment, the formulation of the present invention is characterized by comprising an inorganic acid selected from the group consisting of hydrochloric acid, nitric acid and phosphoric acid. Preferably the inorganic acid is hydrochloric acid (HCl). A mixture of hydrochloric acid and phosphoric acid is still more preferred.

[0038] In one embodiment, the formulation of the present invention is characterized by comprising a chelating agent selected from the group consisting of EDTA, EDTANa 2 、EDTANa 2 Ca, EDTACa. Preferably the formulation comprises EDTANa 4 .

[0039] In particular, in a preferred embodiment, the formulation of the present invention is characterized by comprising an inorganic acid, preferably hydrochloric acid (HCl) and a chelating agent, preferably EDTANa 4 .

[0040] In a particularly preferred embodiment, the formulation of the present invention comprises a mixture of HCl and EDTANa 4 . In this regard, it has surprisingly been found that a formulation suitable for pMDI administration and comprising at least a LAMA agent and optionally a LABA agent and / or a corticosteroid is particularly stable when using a mixture of HCl and EDTANa 4 . From the data collected in the experimental section below, it has been shown that the use of a mixture of HCl and EDTANa 4 enhances the stability even when the formulation is contained in an aluminum can. HCl and EDTANa 4The mixture thus imparts to the formulation thus obtained a stability in aluminum cans comparable to that obtained by FEP technology.

[0041] In a preferred embodiment, the formulation of the present invention is in the form of a solution.

[0042] As shown in the experimental part, Tables 2, 3, 5 and 6, the addition of the mixture of HCl and EDTANa to solution formulations containing formoterol fumarate, glycopyrronium bromide and BDP contained in aluminum cans enhances the stability of the formulation in terms of the remaining percentage of the active ingredient, especially formoterol fumarate, compared to the corresponding formulations containing HCl not mixed with EDTA. As recognized in the combination of the inorganic acid and the chelating agent, in fact, not only formoterol fumarate, but also other active ingredients contained in the formulation, such as glycopyrronium bromide and beclomethasone dipropionate, can be stabilized to the same extent as the stability obtained by the use of FEP technology. 4 The present invention provides several advantages over the prior art, such as an increase in the long-term stability of the formulation, a good shelf life, good reproducibility of the final formulation, maintenance of optimal chemical conditions in commercially available cans, and consistent delivery and effectiveness of the medicament, especially when formulated as a solution for pMDI devices.

[0043] Furthermore, the use of cans coated with FEP can be avoided by means of the mixture of inorganic acid and chelating agent, thus providing a simple manufacturing process and a final device system. As known from the prior art and as described above, formulations containing formoterol and glycopyrronium bromide contained in FEP-coated cans actually provide an improvement in stability that cannot be achieved when the same formulation is contained, for example, in aluminum cans.

[0044] The inventors have found that a combination of an inorganic acid and a chelating agent, especially HCl and EDTANa

[0045] The inventors have found that a combination of an inorganic acid and a chelating agent, especially HCl and EDTANa 4It was unexpectedly discovered that the mixture of the present invention can provide the same level of stability as that obtained using the prior art FEP technology.

[0046] According to the present invention, the formulation is suitable for pMDI administration and contains at least a LAMA agent and optionally a LABA agent and / or a corticosteroid and a mixture of HCl and EDTANa 4 thereof.

[0047] In one embodiment, the HCl is 1M, that is, an aqueous solution containing a specified amount of 1M HCl is added to the pharmaceutical formulation.

[0048] In other embodiments, EDTANa 4 is added to the formulation as an aqueous solution containing it at a concentration of 1 to 5 mg / ml. Preferably, it is contained at a concentration of 2 to 3 mg / ml.

[0049] In one embodiment, the amount of 1M HCl contained 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.

[0050] In other embodiments, the amount of EDTANa 4 contained in the pharmaceutical formulation is in the range of 0.00002 to 0.002% w / w. Preferably, the amount of EDTANa 4 is in the range of 0.0001 to 0.0009% w / w; more preferably, the amount of EDTANa 4 is in the range of 0.0001 to 0.0005% w / w; more preferably, the amount of EDTANa 4 is in the range of 0.0001 to 0.0003% w / w; even more preferably, the amount of EDTANa 4 is 0.0002% w / w.

[0051] In a preferred embodiment, the amount of 1M HCl contained in the pharmaceutical preparation is in the range of 0.01 to 0.08% w / w, and the amount of EDTANa 4 is in the range of 0.00002 to 0.002% w / w.

[0052] More preferably, the amount of HCl is in the range of 0.015 to 0.035% w / w, and the amount of EDTANa 4 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 EDTANa 4 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 EDTANa 4 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 EDTANa 4 is 0.0002% w / w.

[0053] In one embodiment, the formulation of the present invention is a solution containing a LABA agent, a LAMA agent, an inorganic acid, preferably HCl, and a chelating agent, preferably EDTANa 4 and a corticosteroid, in amounts according to the embodiments shown above.

[0054] In a preferred embodiment, the LABA agent of the formulation of the present invention is selected from the group consisting of fenoterol, formoterol fumarate, formoterol fumarate dihydrate, arformoterol, carmoterol (TA-2005), indacaterol, milbeterol, bambuterol, clenbuterol, vilanterol, olodaterol, abediterol, terbutaline, salmeterol, diastereoisomeric mixtures and pharmaceutically acceptable salts or hydrates thereof.

[0055] In a more preferred embodiment, the LABA is formoterol fumarate, preferably formoterol fumarate dihydrate.

[0056] In other embodiments, the formulation of the present invention comprises salbutamol, or (R)-salbutamol (levalbuterol) or a pharmaceutically acceptable salt or hydrate thereof.

[0057] Preferably, the LABA according to the present invention is included in an amount of 0.0005 to 0.04% w / w, more preferably 0.001 to 0.03% w / w, even more preferably 0.005 to 0.02% w / w.

[0058] In certain embodiments, the LAMA agent of the formulation of the present invention is selected from the group consisting of glycopyrronium, ipratropium, oxitropium, tiotropium, aclidinium, and umeclidinium with any pharmaceutically acceptable counterion.

[0059] A preferred LAMA agent is glycopyrronium bromide.

[0060] In certain embodiments, the LAMA agent, preferably glycopyrronium bromide, is present in the formulation of the present invention in the range of 0.005 to 0.14% (w / w), preferably 0.010 to 0.13% (w / w), more preferably 0.010 to 0.045% (w / w), where %(w / w) means the amount by weight of the component expressed as a percentage relative to the total weight of the composition.

[0061] In one embodiment, the corticosteroid component of the formulation of the present invention is budesonide, for example beclomethasone as the mono- or dipropionate ester, flunisolide, for example fluticasone as the propionate or furoate ester, ciclesonide, for example mometasone as the furoate ester, mometasone desonide, roflumilast, hydrocortisone, prednisone, prednisolone, methylprednisolone, naphrocort, deflazacort, halopredone acetate, fluocinolone acetonide, fluocinonide, clocortolone, tipredane, prednicarbate, alclometasone dipropionate, halometasone, rimexolone, deprodone propionate, triamcinolone, betamethasone, fludrocortisone, desoxycorticosterone, roflumilast, etiprednol dicloacetate, and is selected from the group consisting of.

[0062] Beclomethasone dipropionate (BDP) and budesonide are particularly preferred.

[0063] In a further preferred embodiment, the corticosteroid component is beclomethasone dipropionate (BDP).

[0064] According to another embodiment of the present invention, the corticosteroid component, preferably BDP, is included in an amount of 0.01 to 0.7% w / w, more preferably 0.05 to 0.5% w / w, even more preferably 0.08 to 0.35% w / w.

[0065] In one 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 an acid and a chelating agent.

[0066] In a 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 an inorganic acid and a chelating agent.

[0067] 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 EDTANa 4 In a further preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising formoterol fumarate, glycopyrronium bromide, BDP 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 glycopyrronium, formoterol, BDP, and a mixture of HCl and EDTANa

[0069] In a further preferred embodiment, the present invention relates to a formulation, preferably a solution, comprising a mixture of glycopyrronium, formoterol, BDP, HCl and EDTANa 4 As described above, the formulations of the present invention are particularly suitable for administration as a pMDI solution. In this regard, the formulation also includes a propellant and preferably a co-solvent as follows.

[0070] The propellant of the formulation of the present invention is selected from hydrofluoroalkanes (HFA) and hydrofluoroolefins (HFO) and mixtures thereof.

[0071] In certain embodiments, 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.

[0072] In certain embodiments, the HFO propellant of the formulation of the present invention is selected from the group consisting of 1,3,3,3 - tetrafluoropropene (HFO - 1234ze) and 2,3,3,3 - tetrafluoropropene (HFO - 1234yf).

[0073] Preferably, the propellant is an HFA propellant, more preferably HFA134a.

[0074] Preferably, the propellant is an HFA propellant, more preferably HFA134a.

[0075] In an equally preferred embodiment, the propellant is HFA152a.

[0076] The HFA or HFO may be present in the formulation in an amount in the range of 75 - 95% (w / w), preferably 85 - 90% (w / w).

[0077] According to the above preferred embodiment, the present invention relates to the formulations detailed above, which also contain a co - solvent and optionally a low - volatility component.

[0078] Preferably, the co - solvent is a polar compound capable of enhancing the solubility of the components in the formulation. Preferred co - solvents are aliphatic alcohols having 1 - 4 carbon atoms such as methanol, ethanol, propanol, isopropanol, etc., preferably ethanol, more preferably absolute ethanol.

[0079] When present, the co - solvent is used in an amount constituting 5% w / w - 20% w / w, more preferably 10% - 15% w / w.

[0080] In one embodiment, even if the formulation of the present invention consists of the above components, in a further embodiment, the formulation of the present invention may further contain additional components such as excipients, additives or low - volatility components, as desired. The addition of such components can be appropriately adjusted, for example, for modifying the physicochemical properties of the formulation.

[0081] The low - volatility component, when present, is a compound characterized by having a vapor pressure of less than 0.1 kPa, preferably less than 0.05 kPa at 25°C. Preferred low - volatility components are selected from the group consisting of glycol, propylene glycol, polyethylene glycol, glycerol or its esters, ascorbyl palmitate and isopropyl myristate, where isopropyl myristate and glycerol are particularly preferred.

[0082] In a further preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising 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.

[0083] In a particularly preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising or consisting essentially of glycopyrronium bromide, formoterol fumarate, BDP, a mixture of HCl and EDTANa 4 an HFA propellant, preferably HFA134a or HFA152a and ethanol, more preferably absolute ethanol.

[0084] In an even more particularly preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising or consisting essentially of glycopyrronium bromide, formoterol fumarate, BDP, a mixture of HCl and EDTANa 4 HFA134a and ethanol, preferably absolute ethanol.

[0085] In equally preferred embodiments, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising or consisting essentially of glycopyrronium bromide, formoterol fumarate, BDP, a mixture of HCl and EDTANa 4 HFA152a and ethanol, preferably absolute ethanol.

[0086] In one embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising or consisting essentially of glycopyrronium bromide, formoterol fumarate, BDP, 1M HCl in an amount in the range of 0.01 to 0.08% w / w, EDTANa in an amount in the range of 0.00002 to 0.002% w / w 4 an HFA propellant selected from HFA134a and HFA152a, ethanol, preferably absolute ethanol.

[0087] In one preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising glycopyrronium bromide, formoterol fumarate, BDP, 1M HCl in an amount in the range of 0.010 to 0.035% w / w, EDTANa in an amount in the range of 0.0001 to 0.0009% w / w 4 and an HFA propellant selected from HFA134a and HFA152a and ethanol, preferably anhydrous ethanol, consisting of or essentially consisting of the same.

[0088] In a more preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising glycopyrronium bromide, formoterol fumarate, BDP, 1M HCl in an amount in the range of 0.015 to 0.020% w / w, EDTANa in an amount in the range of 0.0001 to 0.0005% w / w, preferably 0.0001 to 0.0003% w / w 4 and an HFA propellant selected from HFA134a and HFA152a and ethanol, preferably anhydrous ethanol, consisting of or essentially consisting of the same.

[0089] In a particularly preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising formoterol fumarate, BDP, 1M HCl in an amount of 0.024% w / w, EDTANa in an amount of 0.000025% w / w 4 and HFA134a and ethanol, preferably anhydrous ethanol, consisting of or essentially consisting of the same.

[0090] In equally preferred embodiments, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising glycopyrronium bromide, formoterol fumarate, BDP, 1M HCl in an amount of 0.018% w / w, EDTANa in an amount of 0.00002% w / w 4 and HFA152a and ethanol, preferably anhydrous ethanol, consisting of or essentially consisting of the same.

[0091] In certain embodiments, the formulation does not contain additional excipients other than those clearly defined above. For example, the formulation may not contain co-solvents, propellants, inorganic acids, and chelating agents (e.g., HCl and EDTANa 4 ) other than excipients.

[0092] According to the present invention, the formulation can be a solution, a suspension, or a system comprising a solution and a suspension.

[0093] 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 co-solvent.

[0094] As far as cans or canisters are concerned, part or all of the canister of a pMDI device suitable for containing the formulation of the present invention can be made of metal, such as aluminum, or an alloy, stainless steel, anodized aluminum, fluorine-passivated aluminum, etc. Alternatively, the canister can be a plastic can or a plastic-coated glass bottle.

[0095] Part or all of the inner surface of the metal canister may be lined with an inert organic coating.

[0096] The coating is typically applied to the inner surface of the can, thus providing an inner layer that acts as an interface between the inner surface of the can and the formulation contained therein.

[0097] In this regard, a suitable coated can of the present invention is preferably internally surface partially or fully coated with an inert organic or inorganic coating comprising epoxy-phenolic resin, perfluoropolymer, 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, mixtures or combinations thereof.

[0098] In a preferred embodiment, the present invention relates to the above formulation contained in an aluminum or stainless steel pMDI canister. Thus, in one aspect, the present invention relates to an aluminum or stainless steel pMDI canister filled with the formulation of the present invention as described in detail above. Aluminum cans are preferred.

[0099] The canister of the pMDI device is typically crimped with a metering valve for delivering a therapeutically effective dose of the active ingredient.

[0100] The metering valve assembly includes at least one rubber gas seal made of a suitable elastomeric material selected from butyl or halobutyl rubber such as low density polyethylene, chlorobutyl or bromobutyl rubber (optionally a halogenated copolymer of isobutylene and isoprene), butadiene-acrylonitrile, neoprene, EPDM (a polymer of ethylene propylene diene monomer), TPE (thermoplastic elastomer), cycloolefin copolymer (COC) or combinations thereof.

[0101] The metered valve of the present invention can typically deliver a volume in the range of 25 to 150 μl per actuation, preferably in the range of 50 to 100 μl, more preferably in the range of 50 μl to 70 μl; 50 μl, 63 μl and 100 μl per actuation are most preferred. Suitable valves of the present invention are commercially available.

[0102] According to a further aspect of the present invention, there is provided a method of filling an aerosol inhaler with the pharmaceutical composition of the present invention. Conventional bulk manufacturing methods and mechanisms well known to those skilled in the art of pharmaceutical aerosol production can be used for the production of large batches for the commercial production of filled canisters.

[0103] As a general example, the method may comprise: a) Preparation of a solution containing formoterol fumarate, BDP, glycopyrronium bromide and ethanol; b) Addition of a certain amount of 1M HCl ethanol solution and mixing with the bulk solution; c) Addition of a certain amount of EDTANa 4 (as an aqueous solution) to the ethanol solution and d) Filling the canister with the solution; e) Crimping of the valve and gas supply with HFA propellant may include the steps of.

[0104] The packaged formulation of the present invention is stable for a long period of time when stored under normal temperature and humidity conditions.

[0105] Stability is evaluated by measuring the content of the remaining active ingredient.

[0106] In a further aspect, the present invention relates to the above-mentioned formulation for use as a medicament. Accordingly, the present invention relates to the use of the formulation described herein for the manufacture of a medicament.

[0107] Preferably, the formulations of the present invention are for the purpose of preventing or alleviating symptoms of a wide range of respiratory disorders such as all types of asthma and chronic obstructive pulmonary disease (COPD).

[0108] In a preferred embodiment, the present invention relates to the formulations described herein for the treatment and / or prevention of respiratory disorders, preferably for the treatment and / or prevention of asthma or COPD.

[0109] Other respiratory disorders in which the use of the pharmaceutical compositions of the present invention may be beneficial are those characterized by obstruction of the peripheral airways as a result of inflammation and the presence of mucus, such as chronic obstructive bronchitis, chronic bronchitis, emphysema, acute lung injury (ALI), cystic fibrosis, rhinitis and adult or acute respiratory distress syndrome (ARDS).

[0110] As will be appreciated, the embodiments described herein are intended to be included within the scope of the present invention in any and all possible combinations with all other preferred embodiments, as described above and below.

[0111] The present invention will now be described by way of the following examples and is not limited thereby.

Example

[0112] Experimental Section Example 1 Tests were carried out to examine the chemical stability of a formulation intended for pMDI administration containing formoterol fumarate dihydrate (FF), glycopyrronium bromide (GB) and beclomethasone dipropionate (BDP). The formulation was a solution contained in an aluminum can (Al) or an FEP-coated can (FEP) to which a metering valve with a metering volume of 63 μl was crimped.

[0113] A quantity of HCl was added to the formulation either alone or as a mixture with EDTANa 4 to obtain Formulations 1-2 as described in Table 1.

Table 1

[0114] Formulations 1 to 2 were placed in a stability chamber at 40 °C and 75% R.H. in an upside-down position for 1 month, and the API assay and related degradation products were measured at T1 (1 month).

[0115] The formulations were also tested for 6 months under another stability condition of 25 °C and 60% R.H., and the API assay and related degradation products were measured at T3 (3 months) and T6 (6 months). The % API remaining is shown in Tables 2 and 3.

Table 2

[0116]

Table 3

[0117] As can be seen from Tables 2 and 3, when a mixture of HCl and EDTANa 4 is added to Formulation 1, a significant improvement in the chemical stability of formoterol (FF), glycopyrronium bromide (GB), and beclomethasone dipropionate (BDP) is achieved. Notably, the % FF remaining can reach a value higher than 90% in aluminum cans, unlike Formulation 2 where the % FF decreases significantly after 3 months in aluminum cans.

[0118] Formulation 1 in aluminum cans shows a significant improvement in stability, being equivalent to the stability of the formulation in FEP-coated cans in terms of the % FF remaining.

[0119] As is clear from Tables 2 and 3, the mixture of HCl and EDTANa 4 of the present invention provides stability that is as high as that obtained using FEP technology in terms of the % remaining of the API, particularly formoterol.

[0120] Example 2 The second test was conducted to examine the chemical stability of a formulation intended for pMDI administration, containing formoterol fumarate dihydrate (FF), glycopyrronium bromide (GB) and beclomethasone dipropionate (BDP) in HFA152a propellant. The formulation was a solution contained in an aluminum can (Al) or an FEP-coated can (FEP) with a metering valve of 63 μl metering volume crimped on.

[0121] EDTANa 4 An amount of HCl in a mixture with it was added to the formulation, and thus Formulation 3 described in Table 4 was obtained.

Table 4

[0122] Formulation 3 was placed in a stability chamber at 40 °C and 75% R.H. in an upside-down position for 1 month, and the API assay and related degradation products were measured at T1 (1 month).

[0123] The formulation was also tested for 3 months under another stability condition of 25 °C and 60% R.H., and the API assay and related degradation products were measured at T3 (3 months).

[0124] The API remaining percentages are described in Tables 5 and 6.

Table 5

[0125]

Table 6

[0126] As can be seen from Tables 5 and 6, when a mixture of HCl and EDTANa 4 was added to Formulation 3, the optimal chemical stability of formoterol (FF), glycopyrronium bromide (GB) and beclomethasone dipropionate (BDP) was achieved.

[0127] Formulation 3 in an aluminum can shows a remarkable improvement in stability, which is equivalent to the stability of the formulation in an FEP-coated can after 3 months, particularly from the perspective of the remaining percentage of FF.

[0128] As is clear from Tables 5 and 6, the mixture of HCl and EDTANa of the present invention provides stability that is as high as that obtained using FEP technology, from the perspective of the remaining percentage of API, particularly formoterol. 4 ​

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 according to claim 1, wherein the LABA agent is selected from the group consisting of fenoterol, formoterol fumarate, formoterol fumarate dihydrate, alformoterol, carmoterol (TA-2005), indacaterol, milbeterol, bambuterol, clenbuterol, vilanterol, orodaterol, avesiderol, terbutaline, salmeterol, diastereoisomers, and pharmaceutically acceptable salts thereof or hydrates.

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

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

5. The pharmaceutical composition according to claim 1, further comprising a LAMA agent selected from the group consisting of glycopyrronium, ipratropium, oxytropium, trospium, tiotropium, acridinium, and umeclidinium, accompanied by any pharmaceutically acceptable counterion.

6. The pharmaceutical composition according to claim 5, wherein the LAMA agent is glycopyrronium bromide.

7. The pharmaceutical composition according to claim 1, wherein the acid is selected from inorganic acids, organic acids, or mixtures thereof.

8. The pharmaceutical composition according to claim 1, wherein the acid is an inorganic acid.

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

10. The chelating agents are EDTA and EDTANa. ２ EDTANa ２ Ca, EDTACa, preferably EDTANA ４ A pharmaceutical composition according to claim 1, selected from the following.

11. The mixture of the acid and the chelating agent is composed of HCl and EDTANa. ４ The pharmaceutical composition according to claim 1, which is a mixture of the above.

12. The pharmaceutical composition according to claim 9, wherein the amount of 1 M HCl is in the range of 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. EDTANA ４ The pharmaceutical composition according to claim 10, wherein the amount is in the range of 0.00002 to 0.002% w / w.

16. EDTANA ４ The pharmaceutical composition according to claim 15, wherein the amount is in the range of 0.0001 to 0.0009% w / w.

17. EDTANA ４ The pharmaceutical composition according to claim 16, wherein the amount is in the range of 0.0001 to 0.0005% w / w.

18. EDTANA ４ The pharmaceutical composition according to claim 17, wherein the amount is in the range of 0.0001 to 0.0003% w / w.

19. The amount of HCl is in the range of 0.01 to 0.08% w / w, and the amount of EDTA Na ４ is in the range of 0.00002 to 0.002% w / w, the pharmaceutical composition according to claim 11.

20. The amount of HCl is in the range of 0.010 to 0.035% w / w, and EDTANa ４ The pharmaceutical composition according to claim 19, wherein the amount is in the range of 0.0001 to 0.0009% w / w.

21. The amount of HCl is in the range of 0.015 to 0.020% w / w, and EDTANa ４ The pharmaceutical composition according to claim 20, wherein the amount is in the range of 0.0001 to 0.0005% w / w.

22. The amount of HCl is in the range of 0.015 to 0.020% w / w, and EDTANa ４ The pharmaceutical composition according to claim 21, wherein the amount is in the range of 0.0001 to 0.0003% w / w.

23. The amount of HCl is 0.018% w / w, and EDTANa ４ The pharmaceutical composition according to claim 22, wherein the amount of is 0.0002% w / w.

24. The pharmaceutical composition according to claim 1, further comprising a corticosteroid selected from budesonide, for example, beclomethasone (BDP) as a mono- or dipropionate ester; flunisolide, for example, fluticasone as a propionic acid or furoate ester; ciclesonide, for example, mometasone as a furoate ester; mometasone desonide; lofreponide; hydrocortisone; prednisone; prednisolone; methylprednisolone; naflocort; deflazacort; halopredone acetate; fluocinolone acetonide; fluocinonide; crocortolone; ticpredan; prednicarbart; alclomethasone dipropionate; halomethasone; rimexolone; deprodone propionate; triamcinolone; betamethasone; fludrocortisone; deoxycorticosterone; lofreponide; and etipredonol dicloacetate.

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

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

27. The pharmaceutical composition according to claim 1, wherein the cosolvent is an aliphatic alcohol having 1 to 4 carbon atoms.

28. The pharmaceutical composition according to claim 27, wherein the cosolvent is ethanol.

29. The pharmaceutical composition according to claim 1, wherein the propellant is selected from hydrofluoroalkanes (HFAs), hydrofluoroolefins (HFOs), and mixtures thereof.

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

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

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

33. The pharmaceutical composition according to claim 1, wherein the composition is a solution.

34. The LABA agent is formoterol fumarate dihydrate, the corticosteroid is beclomethasone dipropionate (BDP), the LAMA agent is glycopyrronium bromide, the propellant is HFA134a, the inorganic acid is HCl, and the chelating agent is EDTANa. ２ The pharmaceutical composition according to claim 1, wherein the cosolvent is ethanol and the composition is a solution.

35. The LABA agent is formoterol fumarate dihydrate, the corticosteroid is budesonide or beclomethasone dipropionate (BDP), the LAMA agent is glycopyrronium bromide, the propellant is HFA152a, the inorganic acid is HCl, and the chelating agent is EDTANa. ２ The pharmaceutical composition according to claim 1, wherein the cosolvent is ethanol and the composition is a solution.

36. A canister comprising the pharmaceutical composition according to any one of claims 1 to 35, wherein the canister is made of aluminum, stainless steel, anodized aluminum, and fluorinated aluminum passivated.

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

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

39. A pMDI device comprising an aluminum or stainless steel canister 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 pharmaceutical.

41. A pharmaceutical composition according to claim 40 for the treatment and / or prevention of respiratory disorders.

42. A pharmaceutical composition according to claim 41 for the treatment and / or prevention of asthma or COPD.