Pharmaceutical formulations for pressurized metered dose inhalers

Abstract

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

Description

Technical Field

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

[0003] A pressurized metered dose inhaler (pMDI) is a well-known device for administering a drug product to the respiratory tract by inhalation. The pMDI device typically has a canister (or "can" as described herein) containing the drug and an actuator housing with a mouthpiece. The canister is typically crimped with a metering valve assembly. Depending on the active ingredient and other components such as excipients, acids and the like, the final pMDI formulation may be in the form of a solution or suspension. As known in the art, solutions are typically intended to be substantially free of precipitates or particles, while suspensions typically refer to formulations with some undissolved material or precipitates. The pMDI device can use a propellant to discharge droplets containing the drug product as an aerosol into the respiratory tract.

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

[0005] WO 01 / 89480 describes a pharmaceutical composition comprising formoterol fumarate in a solution of an HFA propellant and a co-solvent, the solution containing HCl in an amount such that the solution has an apparent pH of 3 to 3.5.

[0006] EP 1 480 615 B1 describes a pharmaceutical formulation suitable for pMDI administration comprising formoterol in a solution of liquefied HFA propellant, ethanol, wherein the amount of residual water is less than 1500 ppm based on the total weight of the formulation.

[0007] WO2019 / 7236559 describes a pharmaceutical composition comprising formoterol fumarate, beclomethasone dipropionate, HFA propellant, and a co-solvent, wherein the formulation is stabilized by adding an organic acid such as maleic acid.

[0008] WO2011 / 076843 describes a stable pharmaceutical composition comprising formoterol, glycopyrrolate dissolved in an HFA propellant and a co-solvent, wherein the formulation contains 1 M HCl in an amount ranging from 0.1-0.3 μg / μL.

[0009] WO2015 / 101576 describes a pMDI device particularly suitable for use with formoterol, beclomethasone dipropionate and glycopyrrolate solution, HCl contained in a FEP coated canister.

[0010] Chemical stability of the active pharmaceutical ingredient (API) contained in a pharmaceutical composition is particularly desirable in order to obtain a formulation suitable for the market and to ensure that a constant dose of the active ingredient is delivered with each actuation.

[0011] While the above-described prior art provides effective formulation and device technology arrangements, there remains a need to find alternative aerosol formulations containing LABA agents, particularly in combination with corticosteroids, which are stable over an extended product life.

[0012] We have surprisingly found that the inclusion of a chelating agent in a formulation comprising a LABA agent, optionally in combination with a corticosteroid, substantially avoids degradation of the active ingredient when the formulation is contained in a FEP coated can, thereby maintaining the stability of the formulation over an extended period of time and also taking advantage of the improvement in the stability characteristics of the formulation when appropriate conditions are achieved.

[0013] Advantageously, when formulated in a propellant, in the presence of a co-solvent, the aerosol formulation comprising a chelating agent as described herein can be used in a pMDI device, in particular for the treatment of respiratory diseases such as asthma and / or COPD, with excellent nebulization performance. SUMMARY OF THE INVENTION

[0015] In one aspect, the present invention is directed to a pharmaceutical composition comprising a LABA agent, a cosolvent, a propellant, and a chelating agent.

[0016] In particular, the invention relates to such formulations further comprising a corticosteroid agent and optionally a LAMA agent.

[0017] In a second aspect, the present invention relates to a canister for a pMDI device containing a pharmaceutical composition as described above, wherein the canister is a FEP coated canister.

[0018] In a further aspect, the present invention relates to the use of said pharmaceutical composition comprising a LABA agent, a co-solvent, a propellant and a chelating agent as a medicament.

[0019] In a further embodiment, the invention relates to a pMDI device comprising a formulation of the invention.

[0020] In a further aspect, the present invention further relates to the use of a pharmaceutical composition comprising a LABA agent, a cosolvent, a propellant and a chelating agent for the treatment and / or prevention of respiratory disorders, in particular asthma and COPD. DETAILED DESCRIPTION OF THE INVENTION

[0022] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

[0023] The "molar ratio" between formoterol or its salt or solvate of said salt and the acid is calculated taking into account the number of moles of formoterol or its salt or solvate of said salt in the formulation and the number of moles of the selected acid in the formulation.

[0024] Unless otherwise indicated, the term "LABA" or "LABA agent" includes within its meaning long-acting β2 agonists as known in the art, such as formoterol fumarate, arformoterol, or fenoterol.

[0025] Unless otherwise indicated, the term "formoterol fumarate" or "FF" refers to (R,R)-(±) formoterol fumarate or its dihydrate.

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

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

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

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

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

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

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

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

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

[0035] As described above, the present invention unexpectedly shows that the inclusion of a chelating agent in a formulation comprising a LABA agent, optionally in combination with a corticosteroid, when contained in a FEP coated can, stabilizes the formulation thus obtained.

[0036] In one embodiment, the formulation of the invention is characterized in that it comprises a chelating agent selected from EDTA, EDTANa2, EDTANa2Ca, EDTACa. More preferably, the formulation comprises EDTANa4.

[0037] In this respect, surprisingly found that, when using EDTANa4, be suitable for pMDI use and at least comprise LABA agent and optionally comprise the preparation of corticosteroid particularly stable.From the data collected in the experimental section below, it can be seen that when preparation is included in the FEP coating tank, use EDTANa4 to make preparation stable in terms of the residual % of active ingredient.As shown in Table 2,3,5 and 6, EDTANa4 is added in the preparation comprising formoterol fumarate and BDP, and the preparation is included in the FEP coating tank, and with respect to the residual % of active ingredient (particularly formoterol fumarate), the preparation is stabilized.It is understandable that chelating agent can not only stabilize formoterol fumarate, but also can stabilize other active ingredients contained in the preparation, for example beclomethasone dipropionate.

[0038] As a further advantage, the formulations according to the invention comprising EDTANa4 are characterized by the possibility of having a total amount of water above 1500 ppm.

[0039] Furthermore, we have found that the present invention is particularly advantageous when the amount of water is greater than 5000 ppm, as shown in the experimental part.

[0040] In a preferred embodiment, the amount of water is from 5000 to 13000 ppm, preferably from 6000 to 12000 ppm, more preferably from 10000 to 12000 ppm.

[0041] Typically, the water content is achieved by the presence of an aqueous solution of NaEDTA and / or by appropriate addition of water.

[0042] The present invention brings several advantages to the prior art such as stability of the formulation over time, good shelf life, good reproducibility of the final formulation, maintenance of optimal chemical conditions inside commercially readily available cans, and consistent efficacy of the drug, especially when formulated as a solution for use in a pMDI device.

[0043] In one embodiment, EDTANa4 is added to the formulation as an aqueous solution at a concentration of 1 to 5 mg / ml. Preferably, the concentration is 2 to 4 mg / ml. More preferably, the concentration is 2 to 3 mg / ml.

[0044] In one embodiment, the amount of EDTANa4 contained in the pharmaceutical preparation is within the range of 0.00002 to 0.002% w / w. Preferably, the amount of EDTANa4 is within the range of 0.0001 to 0.0009% w / w; more preferably, the amount of EDTANa4 is within the range of 0.0001 to 0.0005% w / w; still more preferably, the amount of EDTANa4 is within the range of 0.0002 to 0.0003% w / w; even more preferably, the amount of EDTANa4 is 0.00025% w / w.

[0045] In a preferred embodiment, the formulation of the present invention comprises a LABA agent, a chelating agent (preferably EDTANa4) and a corticosteroid.

[0046] In one embodiment, the LABA agent in the formulation according to the present invention is selected from: fenoterol, formoterol fumarate, formoterol fumarate dihydrate, arformoterol, carmoterol (TA-2005), indacaterol, milvterol, bambuterol, clenbuterol, vilanterol, olodaterol, abetrol, terbutaline, salmeterol, its diastereoisomer mixture and pharmaceutically acceptable salt or its hydrate.

[0047] In one embodiment, the LABA is formoterol fumarate, preferably formoterol fumarate dihydrate.

[0048] In another embodiment, the formulation of the present invention comprises salbutamol or (R)-salbutamol (levosalbutamol) or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0049] Preferably, the amount of LABA according to the present invention is 0.0005-0.04% w / w, more preferably 0.001-0.03% w / w, even more preferably 0.005-0.02% w / w.

[0050] In one embodiment, the corticosteroid component of the formulation according to the invention is selected from the group consisting of budesonide, beclomethasone, e.g. as monopropionate or dipropionate, flunisolide, fluticasone, e.g. as propionate or furoate, ciclesonide, mometasone, e.g. as furoate, mometasone desonide, roflenide, hydrocortisone, prednisone, prednisolone, methylprednisolone, nafecort, deflazacort, halopednisolone acetate, fluocinolone acetonide, fluocinolone acetonide, clocortolone, tipredan, prednicarbate, alclometasone dipropionate, halometasone, rimexolone, deproton propionate, triamcinolone, betamethasone, fludrocortisone, deoxycorticosterone, roflenide, eprednolate.

[0051] Beclomethasone dipropionate (BDP) and budesonide are particularly preferred.

[0052] In a more preferred embodiment, the corticosteroid component is beclomethasone dipropionate (BDP).

[0053] According to another embodiment of the present invention, the amount of the corticosteroid component (preferably BDP) is 0.01-0.7% w / w, more preferably 0.05-0.5% w / w, even more preferably 0.08-0.35% w / w.

[0054] In one embodiment, the invention is directed to a formulation suitable for pMDI administration, preferably a solution, comprising: a LABA agent, a corticosteroid, and a chelating agent.

[0055] In a preferred embodiment, the present invention is directed to a formulation suitable for pMDI administration, preferably a solution, comprising: a LABA agent, a corticosteroid, and a chelating agent.

[0056] 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 EDTANa4.

[0057] 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.

[0058] In a more preferred embodiment, the present invention relates to a formulation, preferably a solution, comprising formoterol fumarate, BDP and EDTANa4.

[0059] As mentioned above, the formulations of the present invention are particularly suitable for administration as pMDI solutions. In this regard, the formulations of the present invention further comprise a propellant and preferably a cosolvent, as described below.

[0060] The propellant in the formulation according to the invention is selected from hydrofluoroalkanes (HFAs) and hydrofluoroolefins (HFOs) and mixtures thereof.

[0061] 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.

[0062] In one embodiment, the HFO propellant in the formulation according to the invention is selected from: 1,3,3,3-tetrafluoropropene (HFO-1234ze) and 2,3,3,3-tetrafluoropropene (HFO-1234yf).

[0063] Preferably, the propellant is a HFA propellant, more preferably HFA134a.

[0064] In an equally preferred embodiment, the propellant is HFA152a.

[0065] The HFA or HFO may be present in the formulation in an amount of 75% to 95% (w / w), preferably 85% to 90% (w / w), based on the total weight of the formulation.

[0066] As mentioned above, in one embodiment, the preparation comprising a chelating agent according to the present invention may optionally further comprise other components such as excipients, additives or low volatility components. The addition of the components may be appropriately calibrated to adjust, for example, the chemical-physical properties of the preparation. In this regard, and also according to the above preferred embodiments, the present invention relates to the preparation as described in detail above, which further comprises an HFA or HFO propellant, a cosolvent and optionally comprises a low volatility component.

[0067] Preferably, the cosolvent is a polar compound capable of increasing the solubility of the component in the formulation. Preferred cosolvents are aliphatic alcohols having 1 to 4 carbon atoms, such as methanol, ethanol, propanol, isopropanol, etc., preferably ethanol, more preferably anhydrous ethanol.

[0068] When present, the co-solvent is used in an amount of 5% w / w to 20% w / w, more preferably 10 to 15% w / w, based on the total weight of the formulation.

[0069] When present, the low volatility component is a compound characterized by a vapor pressure below 0.1 kPa, preferably below 0.05 kPa at 25° C. Preferred low volatility components are selected from glycols, propylene glycol, polyethylene glycol, glycerol or its esters, ascorbyl palmitate and isopropyl myristate, with isopropyl myristate and glycerol being particularly preferred.

[0070] In a preferred embodiment, the present invention is directed to a formulation suitable for pMDI administration, preferably a solution, comprising, consisting of or consisting essentially of a LABA agent, and a corticosteroid, a chelating agent, a propellant and an aliphatic alcohol having 1 to 4 carbon atoms, preferably ethanol, more preferably anhydrous ethanol.

[0071] In a further preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising: a LABA agent, and a corticosteroid, a chelating agent, an HFA propellant and an aliphatic alcohol having 1 to 4 carbon atoms, preferably 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, consisting of or consisting essentially of formoterol fumarate, BDP, EDTANa4, an HFA propellant, preferably HFA 134a or HFA 152a, and ethanol, more preferably anhydrous ethanol.

[0073] In one embodiment, the present invention is directed to a formulation suitable for pMDI administration, preferably a solution, comprising: formoterol fumarate, BDP, EDTANa4 in an amount ranging from 0.00002 to 0.002% w / w, an HFA propellant selected from HFA 134a and HFA 152a, and ethanol, preferably anhydrous ethanol, consisting of or consisting essentially of the same.

[0074] 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 ranging from 0.0001 to 0.0009% w / w, an HFA propellant selected from HFA 134a and HFA 152a, and ethanol, preferably anhydrous ethanol, consisting of or consisting essentially of the same.

[0075] In a further preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising: formoterol fumarate, BDP, EDTANa4 in an amount ranging from 0.0001 to 0.0005% w / w, preferably 0.0002 to 0.0003% w / w, an HFA propellant selected from HFA 134a and HFA 152a, and ethanol, preferably anhydrous ethanol, consisting of or consisting essentially of the same.

[0076] 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, HFA 134a, and ethanol, preferably anhydrous ethanol, consisting of or consisting essentially of the same.

[0077] In a likewise preferred embodiment, the invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising, consisting of or consisting essentially of formoterol fumarate, BDP, EDTANa4 in an amount of 0.000025% w / w, HFA 152a, and ethanol, preferably anhydrous ethanol.

[0078] According to the present invention, the preparation of the present invention may be a solution, a suspension or a system comprising a solution and a suspension.

[0079] 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 corticosteroids, are completely and uniformly dissolved in the propellant and cosolvent.

[0080] With respect to cans or canisters, part or all of the canister of a pMDI device suitable for containing a formulation of the present invention may be made of metal, such as aluminum or a metal alloy, stainless steel or anodized aluminum, fluorine-passivated aluminum, etc. Alternatively, the canister may be a plastic canister or a plastic-coated glass bottle.

[0081] The metal can may have part or all of its interior surface lined with an inert organic coating.

[0082] The coating is typically applied to the interior surface of the can, thereby providing an interior layer that acts as an interface between the interior surface of the can and the formulation contained therein.

[0083] In this regard, suitable coated tanks of the present invention may have part or all of their inner surfaces coated with an inert organic or inorganic coating, which preferably comprises: epoxy phenol resin, perfluorinated polymer, perfluoroalkoxy alkane polymer, perfluoroalkoxy alkylene polymer (PFA), perfluoroalkylene polymer, poly-tetrafluoroethylene polymer (PTFE or Teflon), fluorinated-ethylene-propylene polymer (FEP), polyethersulfone polymer (PES), fluorinated-ethylene-propylene polyethersulfone polymer (FEP-PES), polyamide, polyimide, polyamideimide, polyphenylene sulfide, plasma, mixture or combination thereof.

[0084] In a preferred embodiment, the present invention relates to the above-described formulation contained in a FEP coated can.

[0085] In another embodiment, the present invention is directed to a formulation suitable for pMDI administration contained in a FEP coated canister, preferably a solution, comprising, consisting of or consisting essentially of: formoterol fumarate, BDP, EDTANa4, an HFA propellant, preferably HFA 134a or HFA 152a, and ethanol, more preferably anhydrous ethanol.

[0086] In one embodiment, the present invention is directed to a pMDI device comprising a FEP coated canister filled with a formulation, preferably a solution, comprising, consisting of or consisting essentially of: formoterol fumarate, BDP, EDTANa4, an HFA propellant, preferably HFA 134a or HFA 152a, and ethanol, more preferably anhydrous ethanol.

[0087] The cannula of a pMDI device is typically crimped with a metered valve for delivering a therapeutically effective dose of the active ingredient.

[0088] The metering valve assembly comprises at least one rubber gasket seal made of a suitable elastomeric material selected from: low density polyethylene, butyl or halogenated butyl rubber, such as chlorobutyl or bromobutyl rubber (optionally halogenated copolymers of isobutylene and isoprene), butadiene-acrylonitrile, chloroprene rubber, EPDM (polymer of ethylene propylene diene monomer), TPE (thermoplastic elastomer), cyclic olefin copolymer (COC) or a combination thereof.

[0089] Metering valves according to the invention are typically capable of delivering volumes in the range of 25 μl to 150 μl, preferably in the range of 50 to 100 μl, and more preferably in the range of 50 to 70 μl per actuation; most preferred are 50, 63 and 100 μl per actuation. Suitable valves for use in the invention are commercially available.

[0090] According to another aspect of the invention, there is provided a method of filling an aerosol inhaler with a pharmaceutical composition of the invention. Conventional bulk production methods and machinery well known to those skilled in the art of pharmaceutical aerosol manufacture can be used to prepare large scale batches of canisters for commercial production filling.

[0091] As a general example, the method may include the following steps:

[0092] a) preparing a solution comprising formoterol fumarate, BDP and ethanol;

[0093] b) adding a certain amount of EDTANa4 (as an aqueous solution) to the ethanol solution and mixing the bulk solution;

[0094] c) filling a tank with the solution;

[0095] d) Crimp with valve and inflate with HFA propellant.

[0096] The packaged formulations of the present invention are stable over extended periods of time when stored under normal conditions of temperature and humidity.Stability is assessed by measuring the amount of residual active ingredient.

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

[0098] Preferably, the formulations of the invention are used for prophylactic purposes or for the symptomatic relief of a wide range of respiratory disorders, such as all types of asthma and chronic obstructive pulmonary disease (COPD).

[0099] In a preferred embodiment, the invention relates to a formulation as described herein for use in the treatment and / or prevention of a breathing disorder, preferably for use in the treatment and / or prevention of asthma or COPD.

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

[0101] As will be appreciated, all embodiments described herein are intended to be included within the scope of the present invention, also in any possible combination with all other preferred embodiments as set forth above and below.

[0102] The invention will now be described by way of the following non-limiting examples.

[0103] Experimental Section

[0104] Example 1

[0105] A study was conducted to investigate the chemical stability of a formulation intended for pMDI administration comprising formoterol fumarate dihydrate (FF) and beclomethasone dipropionate (BDP). The formulation was a solution contained in a FEP coated canister crimped with a metering valve having a metering volume of 50 μl.

[0106] An amount of EDTANa4 was added to the formulation to provide Formulation 1 as reported in Table 1.

[0107] Table 1

[0108] Components Formulation 1 (% w / w) FF 0.010 BDP 0.172 <![CDATA[EDTANa4]]> 0.00025 Anhydrous ethanol 12.00 <![CDATA[H2O]]> 1 HFA 134a 86.818

[0109] Formulation 1 was placed in an inverted position in a stability chamber at 40°C, 75% RH for 1 month and the API assay and related degradation products were measured at T1 (1 month).

[0110] The formulations were also tested under different stability conditions at 25°C, 60% RH for 6 months, and the API assay and related degradation products were measured at T3 (3 months).

[0111] The % API residues are reported in Tables 2 and 3.

[0112] Table 2

[0113]

[0114] Table 3

[0115]

[0116] As can be observed from Tables 2 and 3, when EDTANa4 is added according to Formulation 1, chemical stability of formoterol (FF) and beclomethasone dipropionate (BDP) is achieved even at residual water contents greater than 1500 ppm. It is noteworthy that the % FF residual can reach values ​​even higher than 90%.

[0117] Example 2

[0118] A second study was conducted to investigate the chemical stability of a formulation intended for pMDI administration comprising formoterol fumarate dihydrate (FF) and beclomethasone dipropionate (BDP) in HFA152a propellant. The formulation was a solution contained in a FEP coated can crimped with a metering valve having a metering volume of 63 μl.

[0119] An amount of EDTANa4 was added to the formulation to provide Formulation 2 as reported in Table 4.

[0120] Table 4

[0121]

[0122]

[0123] Formulation 2 was placed in a stability chamber in an inverted position at 40°C, 75% RH for 1 month and the API assay and related degradation products were measured at T1 (1 month).

[0124] The formulations were also tested under different stability conditions at 25°C, 60% RH for 3 months and the API assay and related degradation products were measured at T3 (3 months).

[0125] The % API residues are reported in Tables 5 and 6.

[0126] Table 5

[0127] Table 6

[0128]

[0129] As can be observed from Tables 5 and 6, when EDTANa4 is added according to Formulation 2, chemical stability of formoterol (FF) and beclomethasone dipropionate (BDP) is achieved even at residual water contents greater than 1500 ppm. It is noteworthy that the % FF residual can reach values ​​even higher than 90%.

Claims

1. A pharmaceutical composition comprising a LABA agent, a cosolvent, a propellant and a chelating agent.

2. The pharmaceutical composition of claim 1, wherein the LABA agent is selected from fenoterol, formoterol fumarate, formoterol fumarate dihydrate, arformoterol, carmoterol (TA-2005), indacaterol, milvterol, bambuterol, clenbuterol, vilanterol, olodaterol, abetrol, terbutaline, salmeterol, a diastereoisomer mixture thereof and a pharmaceutically acceptable salt or a hydrate thereof.

3. The pharmaceutical composition according to any one of claims 1 and 2, wherein the LABA agent is formoterol fumarate dihydrate.

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

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the chelating agent is selected from EDTA, EDTANa2, EDTANa2Ca, EDTACa, preferably EDTANa4.

6. A pharmaceutical composition according to any one of claims 1 to 5, wherein the amount of EDTANa4 is in the range of 0.00002 to 0.002% w / w.

7. The pharmaceutical composition according to claim 6, wherein the amount of EDTANa4 is in the range of 0.0001 to 0.0009% w / w.

8. The pharmaceutical composition according to claim 7, wherein the amount of EDTANa4 is in the range of 0.0001 to 0.0005% w / w.

9. The pharmaceutical composition according to claim 8, wherein the amount of EDTANa4 is in the range of 0.0002 to 0.0003% w / w.

10. The pharmaceutical composition according to claim 9, wherein the amount of EDTANa4 is 0.00025% w / w.

11. The pharmaceutical composition according to any one of claims 1 to 10, further comprising a corticosteroid selected from the group consisting of budesonide, beclomethasone (BDP), e.g. as monopropionate or dipropionate, flunisolide, fluticasone, e.g. as propionate or furoate, ciclesonide, mometasone, e.g. as furoate, mometasone desonide, roflenide, hydrocortisone, prednisone, prednisolone, methylprednisolone, nafecort, deflazacort, halopednisolone acetate, fluocinolone acetonide, fluocinolone acetonide, clocortolone, tipredan, prednicarbate, alclomethasone dipropionate, halometasone, rimexolone, deproton propionate, triamcinolone, betamethasone, fludrocortisone, deoxycorticosterone, roflenide, eprednolate.

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

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

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the co-solvent is an aliphatic alcohol having 1 to 4 carbon atoms.

15. The pharmaceutical composition of claim 14, wherein the co-solvent is ethanol.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the propellant is selected from the group consisting of hydrofluoroalkanes (HFAs) and hydrofluoroolefins (HFOs) and mixtures thereof.

17. The pharmaceutical composition according to claim 16, wherein the propellant is selected from the group consisting of: 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 any one of claims 1 to 19, wherein the composition is a solution.

21. A pharmaceutical composition according to any one of claims 1 to 20, wherein the LABA agent is formoterol fumarate dihydrate, the corticosteroid is beclomethasone dipropionate (BDP), the propellant is HFA134a, the inorganic acid is HCl, the chelating agent is EDTANa2, the cosolvent is ethanol, and the composition is a solution.

22. A pharmaceutical composition according to any one of claims 1 to 20, wherein the LABA agent is formoterol fumarate dihydrate, the corticosteroid is budesonide or beclomethasone dipropionate (BDP), the propellant is HFA152a, the inorganic acid is HCl, the chelating agent is EDTANa2, the cosolvent is ethanol, and the composition is a solution.

23. A pharmaceutical composition according to any one of claims 1 to 22, wherein the total amount of water is 5000 to 13000 ppm.

24. A canister comprising a pharmaceutical composition according to any one of claims 1 to 23, wherein the inside of the canister is coated with a coating comprising at least a compound selected from the group consisting of epoxyphenol resins, perfluorinated polymers, perfluoroalkoxyalkane polymers, perfluoroalkoxyalkylene polymers, perfluoroalkylene polymers, poly-tetrafluoroethylene polymers (Teflon), fluorinated-ethylene-propylene polymers (FEP), polyethersulfone polymers (PES), fluorinated-ethylene-propylene polyethersulfone polymers (FEP-PES), polyamides, polyimides, polyamideimides, polyphenylene sulfide, plasmas, mixtures or combinations thereof.

25. The canister containing a pharmaceutical composition according to claim 24, wherein the canister is a FEP coated canister.

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

27. The canister for a pMDI device according to claim 26, wherein the canister is a FEP coated canister.

28. A pMDI device comprising a FEP coated canister 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 medicament.

30. The pharmaceutical composition according to claim 29, for use in the treatment and / or prevention of respiratory disorders.

31. The pharmaceutical composition according to claim 30, for use in the treatment and / or prevention of asthma or COPD.

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