Pharmaceutical preparation for a pressurized metered-dose inhaler

Abstract

The present invention generally relates to a pharmaceutical composition comprising a LABA agent, 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 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 and further ingredients such as excipients, acids, etc., 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] Aerosol inhalation compositions suitable for pMDI devices containing formoterol are described in the literature.

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

[0005] EP1480615B1 describes a pharmaceutical formulation suitable for pMDI administration, comprising formoterol in a solution of a liquefied HFA propellant and ethanol, wherein the remaining amount of water is less than 1500 ppm relative to the total weight of the formulation.

[0006] WO2019 / 7236559 describes 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.

[0007] WO2011 / 076843 describes a stabilized pharmaceutical composition comprising formoterol, glycopyrronium bromide dissolved in an HFA propellant and a co-solvent, and the formulation contains 1M HCl in an amount that constitutes a range of 0.1 - 0.3 μg / μl.

[0008] WO2015 / 101576 describes a pMDI device contained in an FEP-coated can, a solution of formoterol, beclomethasone dipropionate and glycopyrronium bromide, and is particularly suitable for use with HCl.

[0009] The chemical stability of the active pharmaceutical ingredient (API) contained in a pharmaceutical composition is particularly desirable in order to obtain a formulation suitable for commercialization and in particular 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

[0010] The above prior art provides effective formulations and technically configured devices, but there is a need to find an alternative aerosol formulation that is stable throughout the long product life, especially LABA agents in combination with corticosteroids.

[0011] The inventors have surprisingly found that by incorporating a chelating agent into a formulation containing an LABA agent optionally combined with a corticosteroid, when the formulation is contained in an FEP-coated canister, the decomposition of the active ingredient is substantially avoided, thus maintaining the formulation stable over a long period and improving the stability profile of the formulation when appropriate conditions are achieved.

[0012] Advantageously, the aerosol formulation containing the mixture of the acid and the chelating agent described herein can be used with excellent aerosolization ability 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**

[0013] **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 chelating agent.

[0014] In particular, the present invention relates to a formulation further comprising a corticosteroid agent and optionally also a LAMA agent.

[0015] In a second aspect, the present invention relates to a canister for a pMDI device comprising the above pharmaceutical composition, wherein the can is a can coated with FEP.

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

[0017] In an additional embodiment, the present invention relates to a pMDI device comprising the formulation of the present invention.

[0018] 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 chelating agent for the treatment and / or prevention of further respiratory disorders, especially asthma and COPD. **Mode for Carrying Out the Invention**

[0019] **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.

[0020] 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.

[0021] 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.

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

[0023] Unless otherwise specified, the term "EDTA" refers to ethylenediaminetetraacetic acid.

[0024] Unless otherwise specified, the term "EDTANa4" or "tetrasodium EDTA" or "ethylenediaminetetraacetic acid tetrasodium salt" refers to the salt of ethylenediaminetetraacetic acid having four sodium atoms.

[0025] Unless otherwise specified, the term "EDTANa2" or "disodium EDTA" or "ethylenediaminetetraacetic acid disodium salt" refers to the salt of ethylenediaminetetraacetic acid having two sodium atoms.

[0026] Unless otherwise specified, the term "EDTANa2Ca" or "sodium calcium edetate" or "calcium disodium edetate" refers to the salt of ethylenediaminetetraacetic acid having two sodium atoms and one calcium atom.

[0027] Unless otherwise specified, the term "EDTACa" or "calcium edetate" refers to the salt of ethylenediaminetetraacetic acid having one calcium atom.

[0028] The term "% w / w" means the weight percentage of the component with respect to the total weight of the formulation.

[0029] The term "% w / v" means the weight percentage of the component relative to the total volume of the formulation.

[0030] 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 predominant 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. Even if the Nernst equation (describing the potential of an electrochemical cell as a function of the ionic concentrations participating in the reaction) is applied with respect to the electromagnetic field (EMF) 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, such as those shown 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".

[0031] 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.

[0032] As described above, the present invention unexpectedly shows that the inclusion of a chelating agent in a formulation containing a LABA agent, optionally in combination with a corticosteroid, stabilizes the thus obtained formulation when contained in an FEP-coated can.

[0033] In certain embodiments, the formulations of the invention are characterized by including a chelating agent selected from the group consisting of EDTA, EDTANa2, EDTANa2Ca, EDTACa. More preferably the formulation includes EDTANa4.

[0034] In this regard, it has surprisingly been found that formulations suitable for pMDI administration and containing at least a LABA agent and optionally a corticosteroid are particularly stable when using EDTANa4. From the data collected in the experimental section below, it has been shown that the use of EDTANa4 stabilizes the formulation with respect to the percentage of active ingredient remaining when the formulation is contained in an FEP-coated can. As shown in Tables 2, 3, 5 and 6, the addition of EDTANa4 to formulations containing formoterol fumarate and BDP contained in FEP-coated cans stabilizes the formulation in terms of the percentage of active ingredient remaining, particularly formoterol fumarate. As recognized with the chelating agent, not only formoterol fumarate but also other active ingredients contained in the same formulation such as beclomethasone dipropionate can be stabilized.

[0035] As a further advantage, the formulations of the invention containing EDTANa4 are characterized by a total water content that may be higher than 1500 ppm.

[0036] Furthermore, when the total water content exceeds 5000 ppm, the present invention is particularly advantageous as shown in the experimental section.

[0037] In a preferred embodiment, the water content occupies 5000 - 13000 ppm, preferably 6000 - 12000 ppm, more preferably 10000 - 12000 ppm.

[0038] Generally, the amount of water is achieved by the presence of an aqueous solution of EDTANa4 and / or by appropriate addition of water.

[0039] The present invention, when formulated as a solution, especially for pMDI devices, provides several advantages over the prior art, such as increased long-term stability of the formulation, good shelf life, good reproducibility of the final formulation, maintenance of optimal chemical conditions in commercially available cans, and consistent effectiveness of the medicine.

[0040] In certain embodiments, EDTANa4 is added to the formulation as an aqueous solution containing it at a concentration of 1 - 5 mg / ml. Preferably, it is contained at a concentration of 2 - 4 mg / ml. More preferably, it is contained at a concentration of 2 - 3 mg / ml.

[0041] In certain embodiments, the amount of EDTANa4 contained in the pharmaceutical formulation ranges from 0.00002 to 0.002% w / w. Preferably, the amount of EDTANa4 ranges from 0.0001 to 0.0009% w / w; more preferably, the amount of EDTANa4 ranges from 0.0001 to 0.0005% w / w; still more preferably, the amount of EDTANa4 ranges from 0.0002 to 0.0003% w / w; even more preferably, the amount of EDTANa4 is 0.00025% w / w.

[0042] In certain preferred embodiments, the formulations of the present invention contain a LABA agent, a chelating agent, preferably EDTANa4, and a corticosteroid.

[0043] In certain embodiments, the LABA agent of the formulations 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.

[0044] In a further preferred embodiment, the LABA is formoterol fumarate, preferably formoterol fumarate dihydrate.

[0045] In other embodiments, the formulation of the present invention comprises salbutamol, or (R)-salbutamol (levalbuterol) or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0046] Preferably, the LABA according to the present invention is contained 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.

[0047] In certain embodiments, the corticosteroid component of the formulation of the present invention is budesonide, such as beclomethasone as one or two propionate esters, flunisolide, such as fluticasone as a propionate or furoate ester, ciclesonide, such as mometasone as a furoate ester, mometasone desonide, rofleponide, hydrocortisone, prednisone, prednisolone, methylprednisolone, naphrocort, deflazacort, halopredone acetate, fluocinonide acetonide, fluocinonide, clocortolone, tipredane, prednicarbate, alclometasone dipropionate, halometasone, rimexolone, deprodone propionate, triamcinolone, betamethasone, fludrocortisone, desoxycorticosterone, rofleponide, etiprednol dicloacetate, selected from the group consisting of.

[0048] Beclomethasone dipropionate (BDP) and budesonide are particularly preferred.

[0049] In a further preferred embodiment, the corticosteroid component is beclomethasone dipropionate (BDP).

[0050] 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, and even more preferably 0.08 to 0.35% w / w.

[0051] In certain embodiments, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising a LABA agent, a corticosteroid, and a chelating agent.

[0052] In certain preferred embodiments, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising a LABA agent, a corticosteroid, and a chelating agent.

[0053] In a more preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising a LABA agent, a corticosteroid, and EDTANa4.

[0054] 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 chelating agent.

[0055] In still a preferred embodiment, the present invention relates to a formulation, preferably a solution, comprising formoterol fumarate, BDP, and EDTANa4.

[0056] As described above, the formulation of the present invention is particularly suitable for administration as a pMDI solution. In this regard, the formulation also includes a propellant and preferably a co-solvent as follows.

[0057] The propellant of the formulation of the present invention is selected from hydrofluoroalkanes (HFAs), hydrofluoroolefins (HFOs), and mixtures thereof.

[0058] 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.

[0059] In certain embodiments, the HFO propellant of the formulations 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).

[0060] Preferably, the propellant is an HFA propellant, more preferably HFA134a.

[0061] In equally preferred embodiments, the propellant is HFA152a.

[0062] 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), based on the total weight of the formulation.

[0063] As noted above, in certain embodiments, the formulations containing 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 that also contain an HFA or HFO propellant, a co - solvent, and, if desired, a low - volatility component.

[0064] Preferably, the co - solvent is a polar compound that can enhance the solubility of the components within the formulation. Preferred co - solvents are aliphatic alcohols having 1 - 4 carbon atoms such as methanol, ethanol, propanol, isopropanol, etc., preferably ethanol, and more preferably absolute ethanol.

[0065] When present, the co-solvent is used in an amount that constitutes 5% w / w to 20% w / w, more preferably 10% to 15% w / w, based on the total weight of the formulation.

[0066] 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.

[0067] 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 chelating agent, a propellant, and an aliphatic alcohol having 1 to 4 carbon atoms, preferably ethanol, more preferably absolute ethanol.

[0068] 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 chelating agent, an HFA propellant, and an aliphatic alcohol having 1 to 4 carbon atoms, preferably ethanol.

[0069] 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, EDTANa4, an HFA propellant, preferably HFA134a or HFA152a, and ethanol, more preferably absolute ethanol.

[0070] In one embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising formoterol fumarate, BDP, EDTANa4 in an amount in the range of 0.00002 to 0.002% w / w, an HFA propellant selected from HFA134a and HFA152a, and ethanol, preferably anhydrous ethanol, consisting of or consisting essentially of the same.

[0071] In a preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising formoterol fumarate, BDP, EDTANa4 in an amount in the range of 0.0001 to 0.0009% w / w, an HFA propellant selected from HFA134a and HFA152a, and ethanol, preferably anhydrous ethanol, consisting of or consisting essentially of the same.

[0072] In a more preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising formoterol fumarate, BDP, EDTANa4 in an amount in the range of 0.0001 to 0.0005% w / w, preferably 0.0002 to 0.0003% w / w, an HFA propellant selected from HFA134a and HFA152a, and ethanol, preferably anhydrous ethanol, consisting of or consisting essentially of the same.

[0073] In a particularly preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising formoterol fumarate, BDP, EDTANa4 in an amount of 0.000025% w / w, HFA134a and ethanol, preferably anhydrous ethanol, consisting of or consisting essentially of the same.

[0074] In an equally preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising formoterol fumarate, BDP, EDTANa4 in an amount of 0.000025% w / w, HFA152a and ethanol, preferably anhydrous ethanol, consisting of or consisting essentially of the same.

[0075] According to the present invention, the formulation can be a system comprising a solution, a suspension or a solution and a suspension.

[0076] 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 a LABA and / or a corticosteroid, are completely and uniformly dissolved in a propellant and a co-solvent.

[0077] 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 a 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.

[0078] Part or all of the inner surface of the metal canister may be lined with an inert organic coating.

[0079] 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.

[0080] In this regard, suitable coated cans of the present invention may have their inner surface partially or completely coated with an inert organic or inorganic coating comprising, for example, an epoxy-phenol resin, a perfluoropolymer, a perfluoroalkoxyalkane polymer, a perfluoroalkoxyalkylene polymer (PFA), a perfluoroalkylene polymer, a polytetrafluoroethylene polymer (PTFE or Teflon), a fluorinated ethylene-propylene polymer (FEP), a polyethersulfone polymer (PES), a fluorinated ethylene-propylene polyethersulfone polymer (FEP-PES), a polyamide, a polyimide, a polyamideimide, a polyphenylene sulfide, a plasma, a mixture or a combination thereof.

[0081] In a preferred embodiment, the present invention relates to the above formulation contained in an FEP-coated can.

[0082] In other embodiments, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, consisting of or essentially consisting of formoterol fumarate, BDP, EDTANa4, an HFA propellant, preferably HFA134a or HFA152a, and ethanol, more preferably absolute ethanol, contained in an FEP-coated can.

[0083] In certain embodiments, the present invention relates to a pMDI device comprising an FEP-coated can filled with a formulation, preferably a solution, consisting of or essentially consisting of formoterol fumarate, BDP, EDTANa4, an HFA propellant, preferably HFA134a or HFA152a, and ethanol, more preferably absolute ethanol.

[0084] The canister of the pMDI device is typically crimped with a metering valve for delivering a therapeutically effective dose of the active ingredient.

[0085] 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.

[0086] The metering valve of the present invention can typically deliver a volume in the range of 25 to 150 μl, preferably in the range of 50 to 100 μl, more preferably in the range of 50 μl to 70 μl per actuation; 50 μl, 63 μl and 100 μl per actuation are most preferred. Suitable valves of the present invention are commercially available.

[0087] 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.

[0088] As a general example, the method may comprise: a) Preparation of a solution containing formoterol fumarate, BDP and ethanol; b) Addition of a certain amount of EDTANa4 (as an aqueous solution) to an ethanol solution and mixing of the bulk solution; c) Filling of the canister with the solution; d) Crimping of the valve and gas supply with an HFA propellant and may include the steps of.

[0089] The packaged formulation of the present invention is 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.

[0090] In a further aspect, the present invention relates to the above formulation for use as a medicament. Thus, the present invention relates to the use of the formulation described herein for the manufacture of a medicament.

[0091] Preferably, the formulation of the present invention is for the purpose of preventing or reducing symptoms of a wide range of respiratory disorders such as all types of asthma and chronic obstructive pulmonary disease (COPD).

[0092] In a preferred embodiment, the present invention relates to the formulation described herein for the treatment and / or prevention of respiratory disorders, preferably for the treatment and / or prevention of asthma or COPD.

[0093] Other respiratory disorders in which the use of the pharmaceutical composition of the present invention may be beneficial are those characterized by obstruction of the peripheral airways as a result of inflammation and mucus presence such as chronic obstructive bronchiolitis, chronic bronchitis, emphysema, acute lung injury (ALI), cystic fibrosis, rhinitis and adult or acute respiratory distress syndrome (ARDS).

[0094] As is recognized, 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 set forth above and below.

[0095] The present invention is illustrated, but not limited, by the following examples.

Example

[0096] 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 FEP-coated can with a metering valve of 50 μl metered volume crimped on.

[0097] A certain amount of EDTANa4 was added to the formulation, and thus Formulation 1 as described in Table 1 was obtained.

Table 1

[0098] Formulation 1 was placed in a stability chamber at 40 °C, 75% R.H. for 1 month in an upside-down position, and the API assay and related degradation products were measured at T1 (1 month).

[0099] The formulation was also tested for 6 months under another stability condition of 25 °C, 60% R.H., and the API assay and related degradation products were measured at T3 (3 months).

[0100] The API remaining % is described in Tables 2 and 3.

Table 2

[0101]

Table 3

[0102] As can be seen from Tables 2 and 3, when EDTANa4 was added according to Formulation 1, the chemical stability of formoterol (FF) and beclomethasone dipropionate (BDP) was achieved even in the presence of a residual water content exceeding 1500 ppm. It should be noted that the FF residual percentage can reach a value higher than 90%.

[0103] 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 FEP-coated can with a metering valve of 63 μl metering volume crimped on.

[0104] A certain amount of EDTANa4 was added to the formulation, and thus Formulation 2 described in Table 4 was obtained.

Table 4

[0105] Formulation 2 was placed in a stability chamber at 40 °C and 75% R.H. for 1 month 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 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). The API residual percentages are reported in Tables 5 and 6.

[0107] The API residual percentages are reported in Tables 5 and 6.

Table 5

[0108]

Table 6

[0109] As can be seen from Tables 5 and 6, when EDTANa4 is added according to Formulation 2, the chemical stability of formoterol (FF) and beclomethasone dipropionate (BDP) is achieved even in the presence of a residual water content exceeding 1500 ppm. It should be noted that the FF residual percentage can reach values higher than 90%.

Claims

1. A pharmaceutical composition comprising a LABA agent, a co-solvent, a propellant, 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 dihydrate.

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

5. The chelating agents are EDTA and EDTANa. ２ EDTANa ２ Selected from Ca and EDTACa, preferably EDTANA ４ The pharmaceutical composition according to claim 1.

6. EDTANA ４ The pharmaceutical composition according to claim 5, wherein the amount of is 0.00002 to 0.002% w / w.

7. EDTANA ４ The pharmaceutical composition according to claim 6, wherein the amount of is 0.0001 to 0.0009% w / w.

8. EDTANA ４ The pharmaceutical composition of claim 7, wherein the amount of is 0.0001 to 0.0005% w / w.

9. EDTANA ４ The pharmaceutical composition according to claim 8, wherein the amount of is 0.0002 to 0.0003% w / w.

10. EDTANA ４ The pharmaceutical composition of claim 9, wherein the amount of is 0.00025% w / w.

11. The pharmaceutical composition of claim 1 further comprises 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.

12. The pharmaceutical composition according to claim 11, wherein the corticosteroid is budesonide or beclomethasone dipropionate (BDP).

13. The pharmaceutical composition according to claim 12, wherein the corticosteroid is beclomethasone dipropionate (BDP).

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

15. The pharmaceutical composition according to claim 14, wherein the cosolvent is ethanol.

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

17. The pharmaceutical composition of claim 16, wherein the propellant is selected from HFA134a, HFA152a, and mixtures thereof.

18. The pharmaceutical composition according to claim 17, wherein the propellant is HFA134a.

19. The pharmaceutical composition according to claim 17, wherein the propellant is HFA152a.

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

21. The LAB A 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 pharmaceutical pharmaceutical pharmaceutical composition according to claim 1, wherein the co-solvent is ethanol and the composition is a solution.

22. 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.

23. The pharmaceutical composition according to claim 1, wherein the total amount of water is 5,000 to 13,000 ppm.

24. A canister comprising a pharmaceutical composition according to any one of claims 1 to 23, 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.

25. A canister according to claim 24, comprising a pharmaceutical composition, wherein the canister is a can with an FEP coating.

26. A canister for a pMDI device comprising any pharmaceutical composition of claims 1 to 23.

27. A canister for a pMDI device according to claim 26, wherein the canister is an FEP-coated can.

28. A pMDI device comprising an FEP-coated can containing a pharmaceutical composition according to any one of claims 1 to 23.

29. A pharmaceutical composition according to any one of claims 1 to 23, for use as a pharmaceutical.

30. A pharmaceutical composition according to claim 29 for the treatment and / or prevention of respiratory disorders.

31. A pharmaceutical composition according to claim 30 for the treatment and / or prevention of asthma or COPD.