Pharmaceutical preparation for a pressurized metered-dose inhaler

Abstract

The present invention generally relates to a pharmaceutical composition comprising a LABA 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 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, an acid, 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 Pressurized metered-dose inhalers (pMDIs) are well-known devices 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 and further ingredients such as excipients, acids, etc., the final pMDI formulation can be in the form of a solution or a suspension. As is known in the art, solutions are generally intended to be substantially free of precipitates or particles, while suspensions typically refer to formulations having a certain amount of insoluble material or precipitate. A pMDI device may use a propellant to eject droplets containing the pharmaceutical as an aerosol into the respiratory tract.

[0003] Aerosol inhalation compositions suitable for pMDI devices containing formoterol have been described in the literature.

[0004] WO01 / 89480 discloses a pharmaceutical composition comprising formoterol fumarate in a solution of an HFA propellant and a co-solvent, wherein the solution contains an amount of HCl such that the apparent pH is from 3 to 3.5.

[0005] WO20197236559 discloses a pharmaceutical composition comprising formoterol fumarate, beclomethasone dipropionate, an HFA propellant, a co-solvent, and the formulation is stabilized by the addition of an organic acid such as maleic acid.

[0006] WO2011 / 076843 describes a stabilized pharmaceutical composition comprising formoterol, glycopyrronium bromide dissolved in an HFA propellant and a co-solvent, and the formulation comprises 1M HCl in an amount that constitutes a range of 0.1 - 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. The formulation contained in the FEP-coated can has improved stability and a reduced amount of decomposition 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 desirable in order to obtain a commercially suitable formulation and especially to ensure the delivery of a constant amount of the active ingredient per actuation.

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, especially LABA agents in combination with corticosteroids.

[0010] The inventors have surprisingly found that by including a mixture of an acid and a chelating agent in a formulation containing a LABA agent optionally combined with a corticosteroid, the decomposition of the active ingredient is substantially avoided even when the formulation is contained in an aluminum canister, and thus the formulation is maintained stably over a long period, and the stability profile of the formulation is also improved when appropriate conditions are achieved.

[0011] Advantageously, the aerosol formulation comprising a 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, particularly 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 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 second aspect, the present invention relates to a canister for a pMDI device comprising the above pharmaceutical composition, wherein the can is made of aluminum or an FEP-coated can.

[0015] In a further aspect, the present invention relates to a pMDI device comprising the above can.

[0016] In an additional aspect, the present invention relates to the use of the pharmaceutical composition comprising a LABA agent, a co-solvent, a propellant, and a mixture of an acid and a chelating agent for use as a medicament.

[0017] In a further aspect, the present invention relates to the use of a pharmaceutical composition comprising a LABA 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, particularly asthma and COPD. **Modes for Carrying Out the Invention**

[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 "EDTA" refers to ethylenediaminetetraacetic acid.

[0023] Unless otherwise specified, the term "EDTANa 4 " or "tetrasodium EDTA" or "ethylenediaminetetraacetic acid tetrasodium salt" refers to a salt of ethylenediaminetetraacetic acid having four sodium atoms.

[0024] Unless otherwise specified, the term "EDTANa 2 " or "disodium EDTA" or "ethylenediaminetetraacetic acid disodium salt" refers to a salt of ethylenediaminetetraacetic acid having two sodium atoms.

[0025] Unless otherwise specified, the term "EDTANa 2 Ca" or "sodium calcium edetate" or "calcium disodium edetate" refers to a salt of ethylenediaminetetraacetic acid having two sodium atoms and one calcium atom.

[0026] Unless otherwise specified, the term "EDTACa" or "calcium edetate" refers to a salt of ethylenediaminetetraacetic acid having one calcium atom.

[0027] The term “% w / w” means the weight percentage of a component relative to the total weight of the formulation.

[0028] The term “% w / v” means the weight percentage of a component relative to the total volume of the formulation.

[0029] Regarding the term “apparent pH” as intended herein, it should be noted that the calculation of pH is generally characteristic of an aqueous liquid where water is the dominant component, for example. In a relatively aprotic solvent (such as 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. Even if the Nernst equation (describing the potential of an electrochemical cell as a function of the ionic concentrations participating in the reaction) for an electromagnetic field (EMF) is applied and the pH meter glass electrode system provides a valuable millivolt output with respect to 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”.

[0030] 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.

[0031] 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 corticosteroid, stabilizes the thus obtained formulation even when it is contained in an aluminum can.

[0032] According to certain embodiments, the formulations of the present invention are 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 formulations of the present invention are those described in WO2019 / 236559.

[0033] In certain embodiments, the formulations of the present invention are characterized by comprising a mixture of an inorganic acid and a chelating agent.

[0034] In a preferred embodiment, the formulations of the present invention are 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).

[0035] In other embodiments, the formulations of the present invention are characterized by comprising a chelating agent selected from the group consisting of EDTA, EDTANa 2 , EDTANa 2 Ca, EDTACa. More preferably the formulation comprises EDTANa 4 .

[0036] In a preferred embodiment, the formulations of the present invention are characterized by comprising a mixture of an inorganic acid, preferably hydrochloric acid (HCl) and a chelating agent, preferably EDTANa 4 .

[0037] In particular, in a more preferred embodiment, the formulations of the present invention are solutions comprising a mixture of HCl and EDTANa 4 . In this regard, formulations suitable for pMDI administration and comprising at least a LABA agent and optionally a corticosteroid are those of HCl and EDTANa 4It has surprisingly been found that it is particularly stable when using the mixture. From the data collected in the following experimental section, the use of the mixture of HCl and EDTANa 4 has been shown to improve the stability of the formulation with respect to the percentage of active ingredient remaining, for example when the formulation is contained in an aluminum can.

[0038] As shown in Tables 2, 3, 5 and 6, the addition of the mixture of HCl and EDTANa 4 to formulations containing formoterol fumarate and BDP contained in aluminum cans increases the stability of the formulation in terms of the percentage of active ingredient remaining, particularly formoterol fumarate, with respect to the corresponding formulations containing only HCl. As recognized with 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 beclomethasone dipropionate can be stabilized.

[0039] Advantageously, the total amount of water in the formulation of the present invention containing the mixture of HCl and EDTANa 4 is higher than 1500 ppm, more preferably higher than 2000 ppm, based on the total weight of the formulation. Preferably the total amount of water is less than 2500 ppm.

[0040] 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, and maintenance of optimal chemical conditions in commercially available cans, especially when formulated as a solution for pMDI devices.

[0041] According to the present invention, the formulation is a solution suitable for pMDI administration and contains a LABA agent and optionally a corticosteroid and a mixture of HCl and EDTANa 4

[0042] In one embodiment, the HCl is 1M, i.e., an aqueous solution containing 1M HCl in a specified amount is added to the pharmaceutical formulation.

[0043] In other embodiments, EDTANa 4 ​It 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 4 mg / ml. More preferably, it is contained at a concentration of 2 to 3 mg / ml.

[0044] In certain embodiments, the amount of 1M HCl contained in the pharmaceutical formulation ranges from 0.01 to 0.07% w / w (based on the total weight of the formulation). Preferably, the amount of 1M HCl ranges from 0.010 to 0.035% w / w; more preferably, the amount of 1M HCl ranges from 0.020 to 0.030% w / w; even more preferably, the amount of 1M HCl is 0.024% w / w.

[0045] In other embodiments, the amount of EDTANa 4 contained in the pharmaceutical formulation ranges from 0.00002 to 0.002% w / w. Preferably, the amount of EDTANa 4 ranges from 0.0001 to 0.0009% w / w; more preferably, the amount of EDTANa 4 ranges from 0.0001 to 0.0005% w / w; still more preferably, the amount of EDTANa 4 ranges from 0.0002 to 0.0003% w / w; even more preferably, the amount of EDTANa 4 is 0.00025% w / w.

[0046] In certain preferred embodiments, the amount of HCl ranges from 0.01 to 0.07% w / w, and the amount of EDTANa 4 ranges from 0.00002 to 0.00002% w / w. Preferably, the amount of HCl ranges from 0.010 to 0.035% w / w, and the amount of EDTANa 4 ranges from 0.0001 to 0.0009% w / w. More preferably, the amount of HCl ranges from 0.010 to 0.035% w / w, and the amount of EDTANa 4 ranges from 0.0001 to 0.0005% w / w. Even more preferably, the amount of HCl ranges from 0.020 to 0.030% w / w, and the amount of EDTANa 4The amount is in the range of 0.0002 to 0.0003% w / w. More preferably, the amount of HCl is 0.024% w / w, and the amount of EDTANa 4 is 0.00025% w / w.

[0047] In certain embodiments, the formulation of the present invention is a mixture of a LABA agent, an inorganic acid, preferably HCl, and a chelating agent, preferably EDTANa 4 and a corticosteroid.

[0048] In certain preferred embodiments, 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.

[0049] In a more preferred embodiment, the LABA is formoterol fumarate, preferably formoterol fumarate dihydrate.

[0050] In other embodiments, the formulation of the present invention contains salbutamol, or (R)-salbutamol (levalbuterol) or a pharmaceutically acceptable salt or hydrate thereof.

[0051] 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, and even more preferably 0.005 to 0.02% w / w.

[0052] In one embodiment, the corticosteroid component of the formulation of the present invention is selected from the group consisting of budesonide, beclomethasone, for example as the mono- or dipropionate ester, flunisolide, fluticasone, for example as the propionate or furoate ester, ciclesonide, mometasone, for example as the furoate ester, mometasone desonide, roflumilast, hydrocortisone, prednisone, prednisolone, methylprednisolone, naphrocort, deflazacort, halopredone acetate, fluocinonide acetonide, fluocinonide, clocortolone, tipredane, prednicarbate, alclometasone dipropionate, halometasone, rimexolone, deprodone propionate, triamcinolone, betamethasone, fludrocortisone, desoxycorticosterone, roflumilast, etiprednol dicloacetate.

[0053] Beclomethasone dipropionate (BDP) and budesonide are particularly preferred.

[0054] In a further preferred embodiment, the corticosteroid component is beclomethasone dipropionate (BDP).

[0055] In another embodiment of the present invention, the corticosteroid component, preferably BDP, is included in an amount of 0.01 - 0.7% w / w, more preferably 0.05 - 0.5% w / w, even more preferably 0.08 - 0.35% w / w.

[0056] In one embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising a LABA agent, a corticosteroid and a mixture of an acid and a chelating agent.

[0057] In a preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising a LABA agent, a corticosteroid and a mixture of an inorganic acid and a chelating agent.

[0058] In a further preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising a LABA 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, BDP and a mixture of an acid and a chelating agent.

[0059] In a particularly preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising formoterol fumarate, BDP and a mixture of an acid and a chelating agent.

[0060] In a further preferred embodiment, the present invention relates to a formulation, preferably a solution, comprising formoterol, BDP and a mixture of an inorganic acid and a chelating agent.

[0061] In a further preferred embodiment, the present invention relates to a formulation, preferably a solution, comprising formoterol, BDP and a mixture of 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 formulations also contain a propellant and preferably also a co-solvent as follows.

[0062] The propellant of the formulation of the present invention is selected from hydrofluoroalkanes (HFA) and hydrofluoroolefins (HFO) and mixtures thereof.

[0063] 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.

[0064] In one embodiment, 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).

[0065] In one embodiment, 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).

[0066] Preferably, the propellant is an HFA propellant, more preferably HFA134a.

[0067] In equally preferred embodiments, the propellant is HFA152a.

[0068] The HFA or HFO may be present in the formulation in an amount in the range of 75 to 95% (w / w), preferably 85 to 90% (w / w), based on the total weight of the formulation.

[0069] As described above, in certain embodiments, the formulation comprising the mixture of the inorganic acid and the chelating agent of the present invention may further comprise additional components such as excipients, additives or low volatility components, if desired. The addition of such components can be appropriately adjusted, for example, for modifying the physicochemical properties of the formulation. In this regard and also according to the above preferred embodiments, the present invention relates to the formulations detailed above which also comprise an HFA or HFO propellant, a co-solvent and, if desired, a low volatility component.

[0070] Preferably, the co-solvent is a polar compound capable of enhancing the solubility of the components within the formulation. Preferred co-solvents are aliphatic alcohols having 1 to 4 carbon atoms such as methanol, ethanol, propanol, isopropanol, preferably ethanol, more preferably anhydrous ethanol.

[0071] When present, the co-solvent is used in an amount constituting 5% w / w to 20% w / w, more preferably 10% to 15% w / w, based on the total weight of the formulation.

[0072] 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 glycols, propylene glycol, polyethylene glycol, glycerol or its esters, ascorbyl palmitate and isopropyl myristate, where isopropyl myristate and glycerol are particularly preferred.

[0073] In one embodiment, the formulation does not contain additional excipients other than those clearly defined above. For example, the formulation may not contain excipients other than co-solvents, propellants, inorganic acids and chelating agents (e.g., HCl and EDTANa 4 ).

[0074] In a preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising, consisting of or essentially consisting of a LABA agent and a corticosteroid, a mixture of an acid and a chelating agent, a propellant and an aliphatic alcohol having 1 to 4 carbon atoms.

[0075] In a more preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising, consisting of or essentially consisting of 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.

[0076] In a particularly preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising, consisting of or essentially consisting of formoterol fumarate, BDP, a mixture of HCl and EDTANa 4 , an HFA propellant, preferably HFA134a or HFA152a and ethanol, more preferably absolute ethanol.

[0077] In an even more particularly preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising, consisting of or essentially consisting of formoterol fumarate, BDP, a mixture of HCl and EDTANa 4 , HFA134a and ethanol, preferably absolute ethanol.

[0078] In equally preferred embodiments, the present invention relates to formoterol fumarate, BDP, a mixture of HCl and EDTANa 4Relates to a formulation suitable for pMDI administration, preferably a solution, comprising a mixture, HFA152a and ethanol, preferably anhydrous ethanol, consisting of or consisting essentially of the same.

[0079] In certain embodiments, the present invention relates to formoterol fumarate, BDP, 1M HCl in an amount in the range of 0.01 to 0.07% w / w, EDTANa in an amount in the range of 0.00002 to 0.002% w / w 4 Relates to a formulation suitable for pMDI administration, preferably a solution, comprising an HFA propellant selected from HFA134a and HFA152a and ethanol, preferably anhydrous ethanol, consisting of or consisting essentially of the same.

[0080] In certain preferred embodiments, the present invention relates to formoterol fumarate, BDP, 1M HCl in an amount in the range of 0.01 to 0.035% w / w, EDTANa in an amount in the range of 0.0001 to 0.0009% w / w 4 Relates to a formulation suitable for pMDI administration, preferably a solution, comprising an HFA propellant selected from HFA134a and HFA152a and ethanol, preferably anhydrous ethanol, consisting of or consisting essentially of the same.

[0081] In a more preferred embodiment, the present invention relates to formoterol fumarate, BDP, 1M HCl in an amount in the range of 0.020 to 0.030% w / w, EDTANa in an amount in the range of 0.0001 to 0.0005% w / w 4 Preferably 0.0002 to 0.0003% w / w, relates to a formulation suitable for pMDI administration, preferably a solution, comprising an HFA propellant selected from HFA134a and HFA152a and ethanol, preferably anhydrous ethanol, consisting of or consisting essentially of the same.

[0082] In a particularly preferred embodiment, the present invention relates to formoterol fumarate, BDP, 1M HCl in an amount of 0.024% w / w, EDTANa in an amount of 0.000025% w / w 4、relates to a formulation suitable for pMDI administration, preferably a solution, comprising HFA134a and ethanol, preferably anhydrous ethanol, consisting of or essentially consisting of the same.

[0083] In equally preferred embodiments, the present invention relates to formoterol fumarate, BDP, 1M HCl in an amount of 0.024% w / w, EDTANa in an amount of 0.000025% w / w 4 、relates to a formulation suitable for pMDI administration, preferably a solution, comprising HFA152a and ethanol, preferably anhydrous ethanol, consisting of or essentially consisting of the same.

[0084] According to the present invention, the formulation can be a solution, a suspension or a system comprising a solution and a suspension.

[0085] 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 and / or corticosteroid, are dissolved in the propellant and co-solvent system.

[0086] As far as the can or canister is 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 or anodized aluminum, fluorine passivated aluminum, etc. Alternatively, the canister can be a plastic can or a plastic-coated glass bottle.

[0087] Part or all of the inner surface of the metal canister may be lined with an inert organic coating.

[0088] 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.

[0089] 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.

[0090] 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 described in detail above. Aluminum cans are preferred.

[0091] In one embodiment, the present invention relates to a pMDI device comprising an aluminum or stainless steel canister filled with the formulation of the present invention described in detail above.

[0092] The canister of the pMDI device is typically crimped with a metering valve for delivering a therapeutically effective dose of the active ingredient. The metering valve assembly includes at least one rubber gas seal gasket 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.

[0093] The metering 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.

[0094] 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 manufacture can be used for the manufacture of large scale batches for the commercial production of filled canisters.

[0095] As a general example, the method may comprise: a) Preparation of a solution containing formoterol fumarate, BDP and ethanol; b) Addition of a quantity of 1M HCl in ethanol solution and mixing with the bulk solution; c) Addition of a quantity of EDTANa 4 in ethanol solution as an aqueous solution and mixing with the bulk solution; d) Filling of the canister with the solution; e) Crimping of the valve and gas supply with HFA propellant may be included.

[0096] The packaged formulations of the present invention are stable over a long period of time when stored under normal temperature and humidity conditions. Stability is evaluated by measurement of the content of the residual active ingredient.

[0097] In a further aspect, the present invention relates to the above formulations for use as a medicament. Accordingly, the present invention relates to the use of the formulations described herein for the manufacture of a medicament.

[0098] 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).

[0099] 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.

[0100] Other respiratory disorders for which the use of the pharmaceutical compositions of the present invention may be beneficial include chronic obstructive bronchitis, chronic bronchitis, emphysema, acute lung injury (ALI), cystic fibrosis, rhinitis, and those characterized by obstruction of the peripheral airways as a result of the presence of inflammation and mucus such as adult or acute respiratory distress syndrome (ARDS).

[0101] 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.

[0102] The present invention will now be described by way of the following examples, without limitation.

Example

[0103] Experimental Section Example 1 Tests were conducted to examine the chemical stability of a formulation intended for pMDI administration containing formoterol fumarate dihydrate (FF) and beclomethasone dipropionate (BDP). The formulation was a solution contained in an aluminum or FEP canister with a metering valve of 50 μl metered volume crimped on.

[0104] A certain amount 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

[0105] Formulations 1 - 2 were placed in a stability chamber at 40°C and 75% R.H. in an upside - down position, and the API assay and related degradation products were measured at T1 (1 month).

[0106] The formulation was 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).

[0107] The % API remaining is described in Tables 2 and 3.

Table 2

[0108]

Table 3

[0109] As can be seen from Tables 2 and 3, when a mixture of HCl and EDTANa 4 is added to Formulation 1, the chemical stability of formoterol fumarate (FF) and beclomethasone dipropionate (BDP) is improved even in aluminum cans. Notably, the % FF remaining can reach even higher values than 95%. Formulation 1 in aluminum cans shows a marked improvement in stability in terms of the % FF remaining.

[0110] Example 2 A second test was carried out to test the chemical stability of a formulation intended for pMDI administration, containing formoterol fumarate dihydrate (FF) and beclomethasone dipropionate (BDP) in an HFA152a propellant. The formulation is a solution contained in an aluminum or FEP can with a metering valve of 63 μl crimped on.

[0111] A certain amount of HCl was added to the formulation alone or as a mixture with EDTANa 4 to obtain Formulation 3 as described in Table 4.

Table 4

[0112] Formulation 3 was placed in a stability chamber at 40 °C and 75% R.H. with the position reversed top to bottom, and the API assay and related degradation products were measured at T1 (1 month).

[0113] 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).

[0114] The % API remaining is shown in Tables 5 and 6.

Table 5

[0115]

Table 6

[0116] As can be seen from Tables 5 and 6, when a mixture of HCl and EDTANa 4 is added to Formulation 3, the optimal chemical stability of formoterol (FF) and beclomethasone dipropionate (BDP) is achieved even in an aluminum can. Notably, the % FF remaining can reach even higher values than 95%.

Claims

1. A pharmaceutical composition comprising a LABA 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 1, 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, wherein the acid is selected from inorganic acids, organic acids, or mixtures thereof.

6. The pharmaceutical composition according to claim 1, wherein the acid is an inorganic acid, preferably HCl.

7. 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.

8. 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.

9. The pharmaceutical composition according to claim 1, wherein the amount of 1 M HCl is in the range of 0.01 to 0.07% w / w.

10. The pharmaceutical composition according to claim 9, wherein the amount of HCl is in the range of 0.010 to 0.035% w / w.

11. The pharmaceutical composition according to claim 10, wherein the amount of HCl is in the range of 0.020 to 0.030% w / w.

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

13. EDTANA ４ The pharmaceutical composition according to claim 12, wherein the amount is in the range of 0.0001 to 0.0009% w / w.

14. EDTANA ４ The pharmaceutical composition according to claim 13, wherein the amount is in the range of 0.0001 to 0.0005% w / w.

15. EDTANA ４ The pharmaceutical composition according to claim 14, wherein the amount is in the range of 0.0002 to 0.0003% w / w.

16. The amount of HCl is in the range of 0.01 to 0.07% 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 1.

17. 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 16, wherein the amount is in the range of 0.0001 to 0.0009% w / w.

18. 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 17, wherein the amount is in the range of 0.0001 to 0.0005% w / w.

19. The amount of HCl is in the range of 0.020 to 0.030% w / w, and EDTANa ４ The pharmaceutical composition according to claim 18, wherein the amount is in the range of 0.0002 to 0.003% w / w.

20. The amount of HCl is 0.024% w / w, and EDTANa ４ The pharmaceutical composition according to claim 19, wherein the amount of is 0.00025% w / w.

21. 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.

22. The pharmaceutical composition according to claim 21, wherein the corticosteroid is budesonide or beclomethasone dipropionate (BDP).

23. The pharmaceutical composition according to claim 22, wherein the corticosteroid is beclomethasone dipropionate (BDP).

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

25. The pharmaceutical composition according to claim 24, wherein the cosolvent is ethanol.

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

27. The pharmaceutical composition according to claim 26, wherein the propellant is selected from HFA134a, HFA152a, and mixtures thereof.

28. The pharmaceutical composition according to claim 27, wherein the propellant is HFA134a.

29. The pharmaceutical composition according to claim 27, wherein the propellant is HFA152a.

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

31. The LABA agent is formoterol fumarate dihydrate, the corticosteroid is beclomethasone dipropionate (BDP), 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.

32. The LABA agent is formoterol fumarate dihydrate, the corticosteroid is budesonide or beclomethasone dipropionate (BDP), 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.

33. The pharmaceutical composition according to claim 1, wherein the total amount of water is less than 2500 ppm.

34. The pharmaceutical composition according to claim 1, wherein the composition is contained in a canister made of aluminum, stainless steel, anodized aluminum, and fluorinated aluminum passivation.

35. A canister comprising a pharmaceutical composition according to any one of claims 1 to 33, wherein the canister is internally coated with a coating comprising at least one compound selected from epoxy-phenol resin, perfluoropolymer, perfluoroalkoxyalkane polymer, perfluoroalkoxyalkylene polymer, perfluoroalkylene polymer, polytetrafluoroethylene polymer (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.

36. A canister for a pMDI device comprising the pharmaceutical composition according to any one of claims 1 to 33.

37. A canister for the pMDI device of claim 36, made from an aluminum, stainless steel, or FEP-coated can.

38. A pMDI device comprising a canister made of aluminum, stainless steel, or an FEP-coated can, containing the pharmaceutical composition according to any one of claims 1 to 33.

39. A pharmaceutical composition according to claim 1 for the treatment and / or prevention of respiratory disorders.

40. The pharmaceutical composition according to claim 39 for the treatment and / or prevention of asthma or COPD.