Pharmaceutical formulations for pressurized metered-dose inhalers

Abstract

A pharmaceutical formulation for use in a pressurized metered-dose inhaler. Generally, the present invention relates to pharmaceutical compositions comprising a LABA agent, optionally in combination with other active ingredients, a mixture of at least two inorganic acids, a propellant, and a solubilizer. The invention also provides pharmaceutical compositions for treating respiratory diseases such as asthma and COPD.

Description

[0001] This application is a divisional application of patent application No. 202180068883.8, filed on October 8, 2021, entitled "Pharmaceutical Formulation for Pressurized Metered Inhaler". Technical Field

[0002] Generally, the present invention relates to pharmaceutical compositions comprising a LABA agent, a mixture of at least two inorganic acids, a propellant, and a solubilizer; the present invention also relates to the use of such pharmaceutical compositions in the treatment and prevention of respiratory diseases. Background Technology

[0003] A pressurized metered-dose inhaler (pMDI) is a well-known device for administering a pharmaceutical product to the respiratory tract via inhalation. A pMDI device typically has a canister (or, as used herein, a “canister”) containing the drug and an actuator housing with a nozzle. The canister is typically fitted with a metering valve assembly. Depending on the active ingredient and other components such as excipients, acids, etc., the final pMDI formulation can be in the form of a solution or suspension. As is known in the art, solutions are generally expected to be substantially free of precipitates or particles, while suspensions typically refer to formulations containing some undissolved substances or precipitates. A pMDI device may use a propellant to expel droplets containing the pharmaceutical product as an aerosol into the respiratory tract.

[0004] Glycolone (also known as ganrobromium) is classified as a long-acting muscarinic antagonist (LAMA). When combined with LABA agents and corticosteroids, it is a particularly effective bronchodilator in the treatment of respiratory diseases.

[0005] The literature describes an aerosol inhalation composition suitable for pMDI devices, which contains a combination of formoterol and glycopyrronium bromide.

[0006] WO 2011 / 076842 describes a pharmaceutical composition comprising glycopyrronium bromide dissolved in an HFA propellant and a cosolvent, and containing an amount of 1M hydrochloric acid (HCl), wherein the formulation exhibits good stability characteristics.

[0007] WO 2011 / 076843 describes a stable pharmaceutical composition comprising formoterol, glycopyrronium bromide, and a cosolvent dissolved in an HFA propellant, wherein the formulation contains 1M HCl in an amount ranging from 0.1 to 0.3 µg / µl.

[0008] WO 2015 / 101576 describes a pMDI device particularly suitable for use with a solution of formoterol, beclomethasone dipropionate, and glycopyrronium bromide contained in an FEP-coated can. As disclosed therein, the formulation contained in the FEP-coated can is endowed with improved stability and reduced amounts of degradation products, primarily relating to N-(3-bromo)-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxy-phenyl)propyl-2-ylamino]ethyl]phenyl]formamide.

[0009] The chemical stability of the active pharmaceutical ingredient (API) contained in the pharmaceutical composition is particularly desirable in order to obtain a formulation suitable for the market and to ensure a constant dose of the active ingredient delivered each time it is activated.

[0010] While the aforementioned prior art provides effective formulation and device arrangements, there remains a need to find alternative aerosol formulations containing LABA agents (especially in combination with LAMA agents and corticosteroids) that are stable over an extended product life and have the potential to use commercially available cans (e.g., made of aluminum or stainless steel).

[0011] We were surprised to find that the inclusion of a mixture of inorganic acids in formulations containing LABA agents (optionally in combination with LAMA agents and / or corticosteroids) substantially prevented the degradation of the active ingredient, thereby maintaining formulation stability over an extended period of time, and when suitable conditions were met, it also utilized the improved stability of the formulation even when the formulation was contained in an aluminum can.

[0012] Advantageously, when formulated in a propellant in the presence of a cosolvent, the aerosol formulation comprising the inorganic acid mixture described in this application can be used in pMDI devices, particularly for the treatment of respiratory diseases such as asthma and / or COPD, and has excellent nebulization performance. Summary of the Invention

[0013] In one aspect, the present invention relates to a pharmaceutical composition comprising a LABA agent, a solubilizer, a propellant, and a mixture of at least two inorganic acids, preferably HCl and H3PO4.

[0014] In particular, the present invention relates to formulations that also contain LAMA agents and corticosteroids.

[0015] In another aspect, the present invention relates to the use of the pharmaceutical composition comprising a mixture of LABA agent, a solubilizer, a propellant and at least two inorganic acids as a medicine.

[0016] In another aspect, the present invention also relates to the use of a pharmaceutical composition comprising a mixture of a LABA agent, a solubilizer, a propellant and at least two inorganic acids for the treatment and / or prevention of respiratory diseases, particularly asthma and COPD. Detailed Implementation

[0017] Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as commonly understood by those skilled in the art.

[0018] Calculate the "molar ratio" between formoterol or its salt or solvation of the salt in the formulation and the selected acid in the formulation.

[0019] Unless otherwise stated, the term "LABA" or "LABA agent" includes, in its meaning, long-acting β2 agonists known in the art, such as formoterol fumarate, afortrol, or fenoterol.

[0020] Unless otherwise provided, the terms "formoterol fumarate" or "FF" refer to (R,R)-(±)formoterol fumarate or its dihydrate.

[0021] Unless otherwise stated, the term "LAMA" or "LAMA agent" includes, in its meaning, long-acting muscarinic receptor antagonists known in the art, such as glycopyrronium ions, methylscopolamine, and ipratropium ions.

[0022] glycopyrronium bromide, chemically defined as 3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidineonium bromide, has two chiral centers corresponding to four potential different stereoisomers with configurations of (3R,2'R)-, (3S,2'R)-, (3R,2'S)-, and (3S,2'S)-. Any of these pure enantiomers or diastereomers, or any combination thereof, can be used to carry out the present invention.

[0023] Unless otherwise stated, the term "glycopyrronium bromide" refers to a racemic mixture of (3S,2'R),(3R,2'S)-3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidineonium bromide, also known as glycopyrronium bromide (USAN name).

[0024] The term "% w / w" refers to the weight percentage of an ingredient relative to the total weight of the formulation.

[0025] The term "% w / v" refers to the weight percentage of an ingredient relative to the total volume of the formulation.

[0026] Regarding the term "apparent pH" as intended in this application, it should be noted that pH calculations are generally characteristic of aqueous liquids, such as those in which water is the predominant component. In relatively aprotic solvents (e.g., propellants used in this invention, such as HFA or HFO systems), protons are non-hydrated, and their activity coefficients may differ from those in aqueous solutions. Although the Nerst equation (which describes the potential of an electrochemical cell as a function of the concentration of ions participating in the reaction) applies to electromagnetic fields (EMF), and the pH meter glass electrode system will produce a variable millivolt output depending on the proton concentration and the polarity of the medium, the pH meter reading represents the "apparent pH" according to the invention. In this direction, the apparent pH according to the invention can be measured using 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".

[0027] As described above, the present invention unexpectedly demonstrates that the inclusion of a mixture of inorganic acids in formulations containing LABA agents (optionally in combination with LAMA agents and / or corticosteroids) stabilizes the resulting formulations, as detailed in this application, and even when contained in an aluminum can, the potential to utilize the synergistic effects between the selected acids is present.

[0028] According to one embodiment, the formulation of the present invention is characterized by comprising a mixture of two or more monocarboxylic acids or polycarboxylic acids (preferably inorganic acids), said mixture comprising at least hydrochloric acid (HCl) and / or phosphoric acid (H3PO4).

[0029] In a particularly preferred embodiment, the formulation of the present invention comprises a mixture of HCl and H3PO4. In this respect, it has been surprisingly found that formulations suitable for pMDI administration and containing at least a LABA agent and optionally a LAMA agent and / or corticosteroids are particularly stable when using a combination of HCl and H3PO4 in a selected molar ratio. As evident from the data collected in the Experimental Section below, the application of both acids synergistically improves stability relative to H3PO4 alone. This effect not only provides an increase in stability but also imparts a degree of stability in aluminum cans to the resulting formulations comparable to that achievable by using HCl and FEP alone.

[0030] Therefore, in one aspect, the formulation of the present invention comprises a mixture of two inorganic acids, preferably HCl and H3PO4, wherein the molar ratio (presumably in terms of the number of moles of HCl / H3PO4) comprises about 0.0018-0.0030, preferably about 0.0020-0.0030. More preferably, the molar ratio of HCl / H3PO4 comprises about 0.0022-0.0028, and still more preferably, the molar ratio of HCl / H3PO4 comprises about 0.0023-0.0027.

[0031] Advantageously, when used at different concentrations (e.g., expressed as molar concentration or % w / w), the preferred molar ratio can be set by appropriately adding acid.

[0032] In one preferred embodiment, the HCl is 1M, meaning a defined amount of an aqueous solution containing 1M HCl is added to the pharmaceutical formulation. In another preferred embodiment, H3PO4 is added at a concentration of 85% w / w, meaning a defined amount of H3PO4 (85% by weight in water, based on the total weight of H3PO4 and water) is added to the pharmaceutical formulation.

[0033] According to the present invention, the amount of 1M HCl contained in the pharmaceutical formulation is in the range of about 0.019% w / w to 0.021% w / w (based on the total weight of the formulation), and the amount of H3PO4 85% w / w is in the range of about 0.001% w / w to 0.002% w / w (based on the total weight of the formulation).

[0034] Preferably, the amount of HCl is in the range of about 0.019% w / w to 0.021% w / w (based on the total weight of the formulation), and the amount of H3PO4 85% w / w is 0.001% w / w (based on the total weight of the formulation). More preferably, the amount of HCl is 0.019% w / w (based on the total weight of the formulation), and the amount of H3PO4 85% w / w is 0.001% w / w (based on the total weight of the formulation).

[0035] As shown in Table 2 of the Experimental Section, adding a mixture of HCl and H3PO4 to a formulation containing formoterol fumarate, glycopyrronium bromide, and BDP contained in an aluminum can increases the stability of the formulation, in terms of the residual percentage of the active ingredient, particularly formoterol fumarate, compared to the corresponding formulation containing a single acid used alone. As can be understood, the combination of these inorganic acids effectively stabilizes not only formoterol fumarate but also other active ingredients contained in the formulation, such as glycopyrronium bromide and beclomethasone dipropionate, to a degree comparable to the stability achieved using FEP technology.

[0036] This invention has several advantages over the prior art, such as increased stability of the formulation over time, good shelf life, good reproducibility of the final formulation, maintenance of optimal chemical conditions in the in-vessel system readily available in the market, and consistent delivery and efficacy of the drug, especially when it is formulated as a solution for pMDI devices.

[0037] Furthermore, the preferred combination of acids can also avoid the use of FEP-coated cans, thus providing a simpler manufacturing process and final apparatus system. As is known from the prior art and as stated above, formulations containing formoterol and glycopyrronium bromide contained in FEP-coated cans are effectively endowed with improved stability that would not be achieved when the same formulation is contained, for example, in an aluminum can.

[0038] We have now discovered that, when contained in aluminum cans, combinations of inorganic acids, particularly HCl and H3PO4, unexpectedly provide a level of stability for formulations according to the invention, as can be observed in Tables 2 and 3, comparable to that obtained using prior art FEP techniques.

[0039] According to the present invention, the formulation may be a solution, a suspension, or a system comprising a solution and a suspension.

[0040] In a preferred embodiment, the formulation of the present invention is a solution. Preferably, one or more (more preferably all) of the pharmaceutically active ingredients of the formulation, such as LABA, LAMA and / or corticosteroids, are completely and uniformly dissolved in the propellant and solubilizer.

[0041] More preferably, the formulation of the present invention comprises a LABA agent, a mixture of at least two inorganic acids (preferably HCl and H3PO4) and / or a corticosteroid.

[0042] In one embodiment, the LABA agent of the formulation according to the invention is selected from: fenoterol, formoterol fumarate, formoterol fumarate dihydrate, afortrol, caroterol (TA-2005), indacaterol, milveterol, bambuterol, clenbuterol, vilanterol, olodaterol, abediterol, terbutaline, salmeterol, mixtures of their diastereomers, and pharmaceutically acceptable salts or hydrates thereof.

[0043] In one embodiment, LABA is formoterol fumarate, preferably formoterol fumarate dihydrate.

[0044] In another embodiment, the formulation of the present invention comprises salbutamol or (R)-salbutamol (L-salbutamol) or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0045] Preferably, the amount of LABA according to the present invention is between 0.0005-0.04% w / w, more preferably between 0.001-0.03% w / w, and even more preferably between 0.005-0.02% w / w.

[0046] In one embodiment, the LAMA agent of the formulation according to the invention is selected from: glycopyrronium, ipratropium, oxitropium, trospium, tiotropium, aclidinium, and umeclidinium, and any of their pharmaceutical counterions.

[0047] The preferred LAMA agent is glycopyrronium bromide.

[0048] In one embodiment, the LAMA agent, preferably glycopyrronium bromide, is present in the formulation of the present invention in an amount ranging from 0.005-0.14% (w / w), preferably 0.010-0.13% (w / w), more preferably 0.010-0.045% (w / w), where % (w / w) means the amount of the component by weight, expressed as a percentage relative to the total weight of the composition.

[0049] In one embodiment, the corticosteroid component of the formulation according to the invention is selected from: budesonide, beclomethasone (e.g., as monopropionate or dipropionate), flunisolone, fluticasone (e.g., as propionate or furoate), cicosone, mometasone (e.g., as furoate), mometasone desonide, roflusonide, hydrocortisone, prednisone, prednisolone, methylprednisolone, nafifocide, defocide, haloprednisolone acetate, fluocinolone acetonide, fluocinolone acetonide, clotropone, teprednisolone, prednicarbamate, aclomethasone dipropionate, halomethasone, limexolone, diprednisolone propionate, triamcinolone, betamethasone, fludrocortisone, deoxycorticosterone, roflusonide, epoxetine ester.

[0050] Beclomethasone dipropionate (BDP) and budesonide are particularly preferred.

[0051] In a still preferred embodiment, the corticosteroid component is beclomethasone dipropionate (BDP).

[0052] According to another embodiment of the invention, the amount of the corticosteroid component (preferably BDP) is between 0.01-0.7% w / w, more preferably between 0.05-0.5% w / w, and even more preferably between 0.08-0.35% w / w.

[0053] In one embodiment, the present invention relates to a formulation, preferably a solution, suitable for pMDI administration, comprising: a LABA agent, a LAMA agent, a corticosteroid, and a mixture of at least two inorganic acids.

[0054] In a further preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising: a LABA agent, a LAMA agent, a corticosteroid, and a mixture of HCl and H3PO4.

[0055] In a still preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution comprising: a LABA agent, a LAMA agent, a corticosteroid, and a mixture of HCl and H3PO4 in a molar ratio of about 0.0018-0.0030, preferably about 0.0020-0.0030, more preferably about 0.0022-0.0028, and even more preferably about 0.0023-0.0027.

[0056] In a particularly preferred embodiment, the present invention relates to a formulation, preferably a solution, suitable for pMDI administration, comprising: formoterol fumarate, glycopyrronium bromide, BDP, and a mixture of at least two inorganic acids.

[0057] In a still preferred embodiment, the present invention relates to a formulation, preferably a solution, comprising: glycopyrronium, formoterol, BDP, and a mixture of HCl and H3PO4.

[0058] In a still preferred embodiment, the present invention relates to a formulation, preferably a solution, comprising: formoterol fumarate, glycopyrronium bromide, BDP, and a mixture of HCl and H3PO4 in a molar ratio of about 0.0018-0.0030, preferably about 0.0020-0.0030, more preferably about 0.0022-0.0028, and even more preferably about 0.0023-0.0027.

[0059] As described above, the formulations of the present invention are particularly suitable for application as pMDI solutions. In this respect, the formulations of the present invention also contain a propellant and preferably a cosolvent, as described below.

[0060] The propellant of the formulation according to the invention is selected from hydrofluoroalkane (HFA) and hydrofluoroolefin (HFO) and mixtures thereof.

[0061] In one embodiment, the hydrofluoroalkane propellant is selected from 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 of the formulation according to the invention is selected from 1,3,3,3-tetrafluoropropylene (HFO-1234ze) and 2,3,3,3-tetrafluoropropylene (HFO-1234yf).

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

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

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

[0066] As described above, in one embodiment, the formulation comprising an inorganic acid mixture according to the present invention may optionally further comprise additional components, such as excipients, additives, or low-volatility components. The addition of these components can be suitably calibrated to adjust, for example, the chemical-physical properties of the formulation. In this respect, and also according to the preferred embodiments described above, the present invention relates to the formulation described in detail above, which further comprises an HFA or HFO propellant, a cosolvent, and optionally a low-volatility component.

[0067] Preferably, the co-solvent is a polar compound capable of increasing the solubility of the component in the formulation. A preferred co-solvent is an aliphatic alcohol having 1 to 4 carbon atoms, such as methanol, ethanol, propanol, isopropanol, etc., with ethanol being preferred, and anhydrous ethanol being more preferred.

[0068] When present, the amount of the cosolvent used comprises 5% w / w to 20% w / w, more preferably 10%-15% w / w, based on the total weight of the formulation.

[0069] When present, the low-volatility component 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: glycols, propylene glycol, polyethylene glycol, glycerol or its esters, ascorbyl palmitate, and isopropyl myristate, wherein isopropyl myristate and glycerol are particularly preferred.

[0070] In a preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising, consisting of, or substantially consisting of: a LABA agent, a LAMA agent and / or a corticosteroid, a mixture of at least two inorganic acids, a propellant, and an aliphatic alcohol having 1 to 4 carbon atoms, preferably ethanol, more preferably anhydrous ethanol.

[0071] In a still preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising, consisting of, or substantially consisting of: a LABA agent, a LAMA agent and / or a corticosteroid, a mixture of HCl and H3PO4, an HFA propellant, and an aliphatic alcohol having 1 to 4 carbon atoms, preferably ethanol, more preferably anhydrous ethanol.

[0072] In another preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution comprising, consisting of, or substantially consisting of the following components: glycopyrronium bromide, formoterol fumarate, BDP, a mixture of at least two inorganic acids, HFA propellant, and ethanol, more preferably anhydrous ethanol.

[0073] In yet another preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution comprising, consisting of, or substantially consisting of: glycopyrronium bromide, formoterol fumarate, BDP, HCl and H3PO4, HFA propellant (preferably HFA 134a or HFA 152a) and ethanol (more preferably anhydrous ethanol).

[0074] In another preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution comprising, consisting of, or substantially consisting of: glycopyrronium bromide, formoterol fumarate, BDP, a mixture of HCl / H3PO4 in a molar ratio of about 0.0018-0.0030, more preferably about 0.0020-0.0030, more preferably about 0.0022-0.0028, and even more preferably about 0.0023-0.0027, an HFA propellant selected from HFA 134a and HFA 152a, and ethanol.

[0075] In another preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution comprising, consisting of, or substantially consisting of: glycopyrronium bromide, formoterol fumarate, BDP, a mixture of HCl and H3PO4 in a molar ratio of about 0.0022-0.0028, preferably about 0.023-0.027, an HFA propellant selected from HFA 134a and HFA 152a, and ethanol.

[0076] In another preferred embodiment, the present invention relates to a formulation suitable for pMDI administration, preferably a solution, comprising, consisting of, or substantially consisting of the following components: glycopyrronium bromide, formoterol fumarate, BDP, an amount of 1M HCl in the range of about 0.019-0.021% w / w (based on the total weight of the formulation), an amount of H3PO4 85% w / w in the range of about 0.001-0.002% w / w (based on the total weight of the formulation), preferably 0.001% w / w (based on the total weight of the formulation), an HFA propellant selected from HFA 134a and HFA 152a, and ethanol.

[0077] In some embodiments, the formulation is free of excipients other than those explicitly defined above. For example, the formulation may be free of excipients other than a solubilizer, a propellant, and two inorganic acids (e.g., HCl and H3PO4). Preferably, the formulation is substantially free of other acids, more preferably substantially free of other acids or bases other than those defined above (e.g., HCl and H3PO4).

[0078] Regarding the can or jar, the jar suitable for containing the pMDI formulation of the present invention may be partially or entirely made of metal, such as aluminum or a metal alloy, stainless steel or anodized aluminum, fluorinated aluminum, etc. Alternatively, the jar may be a plastic can or a plastic-coated glass bottle.

[0079] Metal cans may have part or all of their inner surfaces lined with an inert organic coating.

[0080] The coating is typically applied to the inner surface of the can, thereby providing an inner layer that acts as the interface between the inner surface of the can and the formulation contained therein.

[0081] In this regard, suitable coated cans of the present invention can have their inner surfaces partially or entirely coated with an inert organic or inorganic coating, such as fluorinated ethylene-propylene polymer (FEP), polyethersulfone polymer (PES), fluorinated ethylene-propylene polyethersulfone polymer (FEP-PES), etc., according to existing technology. However, an advantage of the present invention is that such a coating may not be necessary to achieve suitable stability; that is, very high stability can be achieved even in non-FEP coated cans (e.g., standard aluminum cans).

[0082] In a preferred embodiment, the present invention relates to the above-described formulation, which is contained in a pMDI can made of aluminum or stainless steel. Therefore, in one aspect, the present invention relates to a pMDI can made of aluminum or stainless steel, filled with the formulation of the present invention as described in detail above. Aluminum cans are preferred.

[0083] The pMDI device typically has a small canister rolled up with a metering valve for delivering a therapeutically effective dose of the active ingredient. The metering valve assembly includes at least one rubber gasket seal made of a suitable elastomeric material selected from: EPDM (polymer of ethylene-propylene-diene monomers), butyl or halogenated butyl rubber, such as chlorobutyl or bromobutyl rubber (optionally a halogenated copolymer of isobutylene and isoprene), TPE (thermoplastic elastomer), cyclic olefin copolymer (COC), or combinations thereof.

[0084] Suitable valves for use in this invention are available on the market, for example from manufacturers well known in the art, such as Bespak, Aptar-Valois, and VARI.

[0085] The metering valve according to the invention is typically capable of delivering a volume in the range of 25-150 µl, preferably 50-100 µl, and more preferably 50 µl-70 µl per actuation; most preferably 50, 63, and 100 µl per actuation.

[0086] The efficacy of a pMDI device is a function of the dose deposited at the appropriate site in the lungs. Deposition is influenced by the aerodynamic particle size distribution of the formulation, which can be characterized in vitro by several parameters.

[0087] The following parameters of the particles emitted by pressurized pMDI can be determined:

[0088] i) The mass median aerodynamic diameter (MMAD) is the diameter around which the mass aerodynamic diameter of the emitted particle is uniformly distributed;

[0089] ii) The delivery dose is calculated by dividing the cumulative deposition in the ACI by the number of activating events per experiment;

[0090] iii) The inhalable dose (fine particle dose = FPD) is obtained from the deposition of the ACI at stage 3 (S3) to the filter (AF), which is equivalent to particles with a diameter <4.7 micrometers divided by the number of actuations per experiment;

[0091] iv) Inhalable fraction (fine particle fraction = FPF), which is the percentage ratio between the inhalable dose and the delivered dose.

[0092] v) The “ultrafine” dose is obtained from the deposition of the filter at level 6 (S6), which is equivalent to particles with a diameter ≤ 1.1 micrometers divided by the number of times each experiment is actuated.

[0093] According to another aspect of the invention, a method for filling an aerosol inhaler with the pharmaceutical composition of the invention is provided. Large-scale batches of filled canisters for commercial production can be prepared using conventional batch manufacturing methods and machinery well known to those skilled in the art of pharmaceutical aerosol manufacturing.

[0094] As a general example, the method may include the following steps:

[0095] a) Prepare a solution containing formoterol fumarate, BDP, glycopyrronium bromide and ethanol;

[0096] b) Fill the small container with the solution;

[0097] c) The addition results in an HCl / H3PO4 molar ratio of approximately 0.0018–0.0030 for both HCl and H3PO4.

[0098] d) Use valve coils and inflate with HFA propellant.

[0099] When stored under normal temperature and humidity conditions, the packaging formulation of the present invention is stable over an extended period of time.

[0100] Stability is assessed by measuring the content of residual active ingredients.

[0101] On the other hand, the present invention relates to the above-described formulations used as pharmaceuticals. Therefore, the present invention relates to the use of the formulations described in this application for the preparation of pharmaceuticals.

[0102] Preferably, the formulations of the present invention are used for preventive purposes or for symptom relief of a wide range of respiratory diseases, such as all types of asthma and chronic obstructive pulmonary disease (COPD).

[0103] In a preferred embodiment, the present invention relates to an preparation as described in this application for the treatment and / or prevention of respiratory diseases, preferably for the treatment and / or prevention of asthma or COPD.

[0104] Other respiratory diseases that may benefit from the use of the pharmaceutical compositions of the present invention are respiratory diseases characterized by peripheral airway obstruction caused by the presence of inflammation and mucus, such as chronic obstructive bronchitis, chronic bronchitis, emphysema, acute lung injury (ALI), cystic fibrosis, rhinitis, and adult or acute respiratory distress syndrome (ARDS).

[0105] As can be appreciated, all embodiments described in this application are intended to be included within the scope of the invention, as well as any possible combinations thereof with all other preferred embodiments set forth above and below.

[0106] The invention will now be described by way of the following non-limiting embodiments.

[0107] Experimental Section

[0108] Example 1

[0109] Studies were conducted to investigate the chemical stability of a formulation intended for pMDI administration, comprising formoterol fumarate dihydrate (FF), glycopyrronium bromide (GB), and beclomethasone dipropionate (BDP). The formulation is a solution contained in an aluminum can packaged with a 63 μl metering volume Bespak valve.

[0110] Different types and amounts of acids, either alone or in mixtures thereof, are added to the formulations to obtain formulations 1-4 as reported in Tables 1 and 2.

[0111]

[0112] Formulations 1-4 were placed in an inverted position in a stability chamber at 40°C and 75% RH for 1 month (1M), and then the API content and related degradation products were examined. The percentage of API residues is reported in Table 2.

[0113]

[0114] As can be observed from Table 2, significant improvements in the chemical stability of formoterol (FF), glycopyrronium bromide (GB), and beclomethasone dipropionate (BDP) were achieved when a mixture of HCl and H3PO4 was added according to formulations 1-2. Notably, %FF can reach or even exceed 95%. In fact, formulations 1 and 2 show significantly improved stability, for example, when compared to the stability of formulations 3 and 4, where H3PO4 is present alone and where %FF is actually less than 90%, based on FF % %, GB % %, and BDP % residue.

[0115] Example 2

[0116] The same analysis as in Example 1 was performed using the appropriate formulation but in the presence of only HCl, and in an aluminum FEP-coated can containing a Bespak valve with a metering volume of 63 μl.

[0117] The resulting formulation (Form. FEP) was placed in an inverted position in a stable compartment at 40°C and 75% RH for 1 month (1M), and then the API content and related degradation products were examined. The API % residue and related total degradation products are reported in Table 3.

[0118]

[0119] A comparison of Tables 2 and 3 above clearly shows that, based on the percentage of API residue (particularly concerning formoterol), the inorganic acid mixture according to the invention provides a stabilizing effect comparable to the high level of stability achievable using the FEP technique. In fact, in both cases, %FF can even exceed 95%, thus representing a significant degree of stability.

Claims

1. A pharmaceutical composition comprising a mixture of a LABA agent, a solubilizer, a propellant, and at least two inorganic acids.

2. The pharmaceutical composition according to claim 1, wherein the LABA agent is selected from: fenoterol, formoterol fumarate, formoterol fumarate dihydrate, aforterol, caroterol (TA-2005), indacaterol, mivitrol, bambuterol, clenbuterol, vilanterol, odoraterol, abebidetrol, terbutaline, salmeterol, mixtures of their diastereomers, and pharmaceutically acceptable salts or hydrates thereof.

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

4. The pharmaceutical composition according to any one of claims 1-3, wherein the mixture of the at least two inorganic acids contains at least HCl.

5. The pharmaceutical composition according to any one of claims 1-3, wherein the mixture of the at least two inorganic acids contains at least H3PO4.

6. The pharmaceutical composition according to any one of claims 1-5, wherein the mixture of the at least two inorganic acids is a mixture of HCl and H3PO4.

7. The pharmaceutical composition according to claim 6, comprising 0.0018 to 0.0030, preferably 0.0020 to 0.0030 molar ratios of HCl / H3PO4.

8. The pharmaceutical composition according to claim 7, comprising a molar ratio of HCl / H3PO4 of 0.0022 to 0.0028.

9. The pharmaceutical composition according to claims 7-8, comprising a molar ratio of HCl / H3PO4 of 0.0023 to 0.0027.

10. The pharmaceutical composition according to any one of claims 1-9, wherein the amount of 1 M HCl is in the range of about 0.019 to 0.021% w / w (based on the total weight of the formulation), and the amount of H3PO4 is 85% w / w in the range of about 0.001 to 0.002% w / w (based on the total weight of the formulation).

11. The pharmaceutical composition of claim 10, wherein the amount of HCl is in the range of about 0.019% to 0.021% w / w (based on the total weight of the formulation), and the amount of H3PO4 85% w / w is 0.001% w / w (based on the total weight of the formulation).

12. The pharmaceutical composition according to any one of claims 1-11, further comprising a LAMA agent selected from the following: glycopyrronium ions, ipratropium ions, oxytropium ions, troxammonium ions, tiotropium ions, adecium ions, and urodimemonium ions, and any of their pharmaceutical counterions.

13. The pharmaceutical composition of claim 12, wherein the LAMA agent is glycopyrronium bromide.

14. The pharmaceutical composition according to any one of claims 1-13, further comprising a corticosteroid selected from: budesonide, beclomethasone (BDP) (e.g., monopropionate or dipropionate form), flunisolone, fluticasone (e.g., propionate or furoate form), ccyclosone, mometasone (e.g., furoate form), mometasone disonide, roflusonide, hydrocortisone, prednisone, prednisolone, methylprednisolone, nafifocide, defocide, haloprednisolone acetate, fluocinolone acetonide, fluocinolone acetonide, clotropone, teprednisolone, prednicarbamate, aclomethasone dipropionate, halomethasone, limexolone, diprednisolone propionate, triamcinolone, betamethasone, fludrocortisone, deoxycorticosterone, roflusonide, epoxetine.

15. The pharmaceutical composition according to claim 14, wherein the corticosteroid is budesonide or beclomethasone dipropionate (BDP).

16. The pharmaceutical composition of claim 15, wherein the corticosteroid is beclomethasone dipropionate (BDP).

17. The pharmaceutical composition according to any one of claims 1-16, wherein the composition is a solution.

18. The pharmaceutical composition according to any one of claims 1-17, wherein the cosolvent is an aliphatic alcohol having 1-4 carbon atoms.

19. The pharmaceutical composition according to claim 18, wherein the cosolvent is ethanol.

20. The pharmaceutical composition according to any one of claims 1-19, wherein the propellant is selected from hydrofluoroalkane (HFA) and hydrofluoroolefin (HFO) and mixtures thereof.

21. The pharmaceutical composition of claim 20, wherein the propellant is selected from HFA134a, HFA152a, and mixtures thereof.

22. The pharmaceutical composition according to any one of claims 1-21, wherein the composition is contained in a container made of aluminum, stainless steel, anodized aluminum, and fluorine-passivated aluminum.

23. A container for a pMDI device, comprising a pharmaceutical composition according to any one of claims 1-21.

24. The can according to claim 23, made of aluminum.

25. The pharmaceutical composition according to any one of claims 1-22, used as a medicine.

26. The pharmaceutical composition according to any one of claims 1-22, for the treatment and / or prevention of respiratory diseases.

27. The pharmaceutical composition according to any one of claims 25-26, for the treatment and / or prevention of asthma or COPD.

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