Combination therapy for inhaled administration

Abstract

The present invention relates to a pharmaceutical composition for administration by nebulization, comprising an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and, optionally, a long-acting muscarinic antagonist (LAMA), for use in the treatment of respiratory diseases, particularly asthma and chronic obstructive pulmonary disease (COPD), and to a method for preparing the same. More specifically, the pharmaceutical composition herein comprises beclomethasone dipropionate (BPD), formoterol fumarate (FF), and, optionally, glycopyrronium bromide (GB). The present invention also relates to the use of the pharmaceutical formulation in a soft mist inhaler.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition for administration by nebulization, comprising an inhaled corticosteroid (ICS) in combination with a long-acting beta-2 agonist (LABA) and a long-acting muscarinic antagonist (LAMA), for use in the treatment of respiratory diseases, in particular asthma and chronic obstructive pulmonary disease (COPD), and to a method for preparing the same. The invention also relates to the use of said pharmaceutical formulation in a soft mist inhaler.

[0002] More specifically, the pharmaceutical compositions herein include dual therapy of beclomethasone dipropionate (BPD) and formoterol fumarate (FF), and triple therapy of beclomethasone dipropionate (BPD), formoterol fumarate (FF), and glycopyrronium bromide (GB). The composition is a propellant-free, multi-dose inhalation solution intended for administration by nebulization. [Background technology]

[0003] Delivery of drugs by inhalation allows deposition of the drug in different parts of the respiratory tract (e.g., throat, trachea, bronchi, and alveoli). Generally, the smaller the particle size, the longer the particle will remain suspended in the air and the further downstream the drug can be delivered in the respiratory tract.

[0004] The use of medicated aerosols is well known to be a promising treatment for respiratory diseases, particularly asthma and chronic obstructive pulmonary disease (COPD). Typically, metered-dose inhalers are used with propellant gases. After the recognition of the ozone-depleting potential of these propellant gases, attempts to develop alternative methods have increased. One alternative method is the development of nebulizers, in which solutions and suspensions of pharmacologically active substances are administered to the lungs in the form of a mist with the aid of a drug delivery device such as a nebulizer.

[0005] A nebulizer is a delivery device designed to overcome limitations in a patient's lungs. Sometimes referred to as a "respiratory therapy," nebulizers create a medication-containing mist that makes inhaling the medication into the lungs easy and comfortable. Nebulizers require a liquid formulation to function properly. Nebulizers work by forcing air through a cup containing the medication. This creates tiny mist-like particles of the liquid that can then be inhaled deeply into the airways. Other nebulizers use an ultrasonic mechanism to generate the mist.

[0006] The main advantages of nebulizers over other methods of pulmonary delivery are complete dispersion without the use of propellant gas; no patient coordination of inhalation and spraying / nebulization is required; and the easier delivery of higher doses of medication. Soft mist inhalers are portable inhalers that generate the mist without the use of an external energy source. While this is one advantage of soft mist inhalers, they also have other advantages over regular nebulizers. Soft mist inhalers deliver most of the mist to the lungs, with only a very small amount of medication delivered to the mouth. Soft mist inhalers also deliver the entire dose to the patient, and none is wasted in the environment, making this a safer approach.

[0007] A wide variety of nebulizers are available with different modes of operation, such as, for example, the one described in PCT patent application WO 97 / 12687 (a soft mist inhaler known under the trade name Respimat®). For administration by nebulizer, the active ingredient is usually suspended in finely divided form in saline or dissolved in a water-alcohol mixture in the presence of excipients such as buffers, stabilizers, surfactants and preservatives. Thus, medicinal products intended for inhalation by nebulization are dissolved or suspended in aqueous or ethanolic solutions, although solvent mixtures of water and ethanol may also be suitable, depending on the solution properties of the active substance.

[0008] The maximum concentration of the drug in the solution will depend on its solubility in the solvent and the dosage required to achieve the desired therapeutic effect. This type of propellant-free solution formulation is known in the art. Ethanol formulations are disclosed, for example, in WO97 / 01329 and WO2014 / 096115. Aqueous systems are described, for example, in WO98 / 27959. However, if the pharmaceutical ingredient is not sufficiently soluble in water, the aqueous formulation for inhalation cannot be used. In some cases, starting from an aqueous formulation, the solubility of the formulation ingredient can be increased by adding ethanol to the aqueous system. However, it has been found that the ethanol concentration in the aqueous aerosol formulation has a decisive effect on the particle size distribution of the aerosol generated by a nebulizer.

[0009] WO02 / 083113 discloses a pharmaceutical composition comprising (i) formoterol or a derivative thereof and (ii) a steroidal anti-inflammatory drug or a derivative thereof in a pharmacologically suitable fluid, wherein the composition is stable during long-term storage, and the fluid comprises water and a surfactant to dissolve the steroidal anti-inflammatory drug. The pharmaceutical composition is suitable for use in a propellant-free nebulizer.

[0010] US 2007 / 293460 A1 and US 2007 / 098644 refer to a method for delivering a combination therapy to the pulmonary system, comprising providing a nebulizer; providing an aqueous solution containing a long-acting corticosteroid, a long-acting beta-agonist, and a long-acting anticholinergic; and administering the aqueous solution and a surfactant to dissolve the long-acting corticosteroid to a patient using the nebulizer.

[0011] Propellant-free inhalable solutions are disclosed in WO 2012 / 110462 for any combination by using aqueous and / or alcoholic solvents, preferably ethanolic solutions, wherein the muscarinic receptor antagonist is dissolved in a solvent comprising at least 75% v / v water and, optionally, a water-miscible co-solvent; the aqueous solution may comprise 95% v / v water and 5% v / v ethanol or 97.5% v / v water and 2.5% v / v ethanol.

[0012] WO 02 / 36106 discloses a pharmaceutical composition comprising an anticholinergic drug and a steroid, and WO 2006 / 114379 discloses a pharmaceutical composition comprising one or more anticholinergic drugs, a betamimetics, and a steroid, optionally in combination with a pharmaceutically acceptable excipient. The solvent may be water alone or a mixture of water and ethanol. The relative proportion of ethanol to water is limited to a maximum of 70% by volume.

[0013] WO 07 / 134968 discloses a propellant-free aqueous formulation for inhalation containing one or more active substances, optional excipients, and ethanol in an amount of 10-50% (v / v). US 2003 / 0181478 discloses a spray formulation containing tiotropium and budesonide in a mixed solution of water (10% by volume) and ethanol (90% by volume), and further containing only benzalkonium chloride, an acid for adjusting the pH, and sodium edetate.

[0014] WO 2015 / 193213 discloses a combination of a muscarinic antagonist, particularly tiotropium, and a glucocorticoid such as ciclesonide, formulated as an inhalation solution containing water alone or a mixture of 95% v / v or less ethanol and 5% v / v or more water, such as a mixture of 90% v / v ethanol and 10% v / v water, benzalkonium chloride, or a stabilizer such as EDTA, butylhydroxyanisole, or butylhydroxytoluene. It also discloses that the formulation may further contain a beta-2 adrenergic receptor agonist, such as salbutamol (albuterol).

[0015] To minimize the possibility of microbial contamination, preservatives may be incorporated into nebulized inhalation formulations. The use of antimicrobial preservatives is less desirable because some of them have been associated with clinical side effects, such as pulmonary irritation, inflammation, and bronchospasm. Alternative methods may be considered.

[0016] Combinations of inhaled corticosteroids (ICS) with long-acting beta2-agonists (LABAs) and / or long-acting muscarinic antagonists (LAMAs) are available for the treatment of asthma and chronic obstructive pulmonary disease (COPD). In particular, a combination of the inhaled corticosteroid beclomethasone dipropionate (BPD), the long-acting beta-agonist formoterol fumarate (FF), and the long-acting muscarinic antagonist glycopyrronium bromide (GB) is available under the trade name Trimbow® (87mcg / 5mcg / 9mcg pressurized inhalation solution), and a combination of the inhaled corticosteroid beclomethasone dipropionate (BPD) and the long-acting beta-agonist formoterol fumarate (FF) is available under the trade name Foster® (100mcg / 6mcg pressurized inhalation solution), both sold by Chiesi Farmaceutici SpA, are available in a metered-dose inhaler device.

[0017] Trimbow® is a pressurized inhalation solution, also known as a pressurized metered-dose inhaler (pMDI), containing three active substances (beclomethasone dipropionate anhydrous, formoterol fumarate dihydrate, and glycopyrronium bromide) dissolved in a vehicle consisting of norflurane (propellant), ethanol (cosolvent), and hydrochloric acid (formulation stabilizer). Each delivered dose (the dose exiting the mouthpiece) contains 87 micrograms of beclomethasone dipropionate, 5 micrograms of formoterol fumarate dihydrate, and 9 micrograms of glycopyrronium (as 11 micrograms of glycopyrronium bromide). Each nominal metered dose / puff (the dose exiting the valve) contains 100 μg of BDP, 6 μg of FF, and 10 μg of glycopyrronium (as 12.5 micrograms of glycopyrronium bromide).

[0018] MDI formulations of beclomethasone dipropionate (BDP) + formoterol fumarate (FF) + glycopyrronium Br (GB) are described in EP 2515853; EP 2515854; EP 2515855; EP 3089735; EP 3096737; EP 315181; EP 3500241. Fostair® 100 / 6 inhalation solution, marketed by Chiesi Ltd., contains 100 micrograms of beclomethasone dipropionate, 6 micrograms of formoterol fumarate dihydrate, norflurane (HFA-134a), anhydrous ethanol, and hydrochloric acid for use in a pressurized metered dose inhaler (pMDI). The product Fostair® is described in EP 1787639.

[0019] Disadvantages of nebulizing MDI formulations containing ICS alone or in combination with LABAs and / or LAMAs include the presence of propellants, lack of coordination between inhaler actuation and patient inhalation (which is difficult for elderly and children), and low lung deposition and high oropharyngeal deposition. Methods for improving the administration of drugs, such as inhaled corticosteroids alone or in combination with LABAs and / or LAMAs, by nebulization, particularly by soft mist inhalers, are desirable. In view of the potential challenges and drawbacks associated with currently marketed formulations containing inhaled corticosteroids alone or in combination with LABAs and / or LAMAs, it would be highly advantageous to provide a solution-state formulation that does not contain propellants, stabilizers, and / or preservatives, has an adequate shelf life, and therefore allows for an effective aerosol that is well tolerated by patients.

[0020] Therefore, there is a need to provide a stabilized composition comprising an inhaled corticosteroid (ICS) together with a long-acting beta-agonist (LABA) and / or a long-acting muscarinic antagonist (LAMA) without the use of propellants, stabilizers, and / or preservatives. Furthermore, there is a need to improve drug delivery to the lungs and reduce the amount delivered to the mouth, ensuring that the entire dose is delivered to the patient and not wasted in the environment (a safer approach). Additionally, the use of soft mist inhalers is a propellant-free, portable system (no need for patient inhalation and ejection coordination) that provides better therapeutic efficiency. Summary of the Invention [Means for solving the problem]

[0021] The present inventors have discovered a stable pharmaceutical composition for nebulization containing a combination of an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and, optionally, a long-acting muscarinic antagonist (LAMA) for use in the treatment of respiratory diseases, particularly asthma and chronic obstructive pulmonary disease (COPD). Administration of all active ingredients in nebulized form, in which all active ingredients are dissolved in an alcoholic solvent, results in higher lung deposition of the active ingredients compared to other pharmaceutical forms. A solution of all ingredients, including solubilized ICS, is a more reliable method of delivering drugs to the lungs than a suspension, because suspensions tend to settle and require vigorously shaking the particles before administering the drug.

[0022] Thus, in a first aspect, the present invention provides a pharmaceutical composition comprising: (a) inhaled corticosteroids (ICS); (b) long-acting beta agonists (LABAs); (c) A pharmaceutical solution composition for delivery to the pulmonary system by a nebulizer, comprising, as an optional ingredient, a long-acting muscarinic antagonist (LAMA), wherein the solvent comprises ethanol in an amount of 75 to 100% v / v.

[0023] More specifically, pharmaceutical solution compositions are preferred in which the inhaled corticosteroid is selected from the group consisting of beclomethasone dipropionate, budesonide, ciclesonide, fluticasone propionate, fluticasone furoate, and mometasone; the long-acting β-agonist is selected from the group consisting of formoterol fumarate, salmeterol, indacaterol, vilanterol, and olodaterol; and the long-acting muscarinic antagonist is selected from the group consisting of glycopyrronium bromide, umeclidinium, aclidinium, ipratropium, tiotropium, and oxitropium.

[0024] The present invention also relates to the use of said pharmaceutical formulation in a nebulizer, preferably a soft mist inhaler. In a further aspect, the present invention relates to the use of the formulation in the manufacture of a medicament for the prevention and / or treatment of inflammatory and / or obstructive airways diseases such as asthma or chronic obstructive pulmonary disease (COPD).

[0025] The main advantage of the pharmaceutical formulations of the present invention is that they disperse completely without the use of propellant gases. Furthermore, they do not contain stabilizers and / or preservatives, such as benzalkonium chloride (BAC) and edetate disodium. Advantageously, the pharmaceutical compositions of the present invention are stable over time.

[0026] Additionally, the pharmaceutical compositions of the present invention improve the solubility of the active ingredient, provide a stable solution of the active ingredient compared to a suspension with a simple manufacturing process, and have a more efficient nebulizer, resulting in a lower concentration of the active ingredient in the formulation relative to an equivalent amount in the lung, thus providing better aerodynamic performance (lower oropharyngeal deposition and higher lung deposition) than pMDIs, and requiring a lower amount of active ingredient to produce a similar therapeutic effect.

[0027] Furthermore, due to the efficiency of the formulation and nebulization (e.g., via a soft mist inhaler), inhaled corticosteroid and beta-agonist and optional long-acting muscarinic antagonist therapeutics have been shown in vitro to deliver equivalent amounts of drug to the lungs from the inhaler, resulting in equivalent respirable fractions with one puff (one puff) compared to two puffs (two puffs / sprays) of p-MDI formulations. The formulations of the present invention delivered the same amount of drug to the lungs with one puff compared to two puffs of p-MDI formulations, with only a small amount of drug delivered to the oropharyngeal region. [Brief explanation of the drawings]

[0028] [Figure 1] Aerodynamic size distribution of formoterol, NGI, Formulation 1 (70% ethanol) vs. Formulation 2 (96% ethanol). [Figure 2] Aerodynamic particle size distribution of A) beclomethasone dipropionate, B) glycopyrronium bromide, and C) formoterol fumarate with NGI, Trimbow® pMDI (two puffs) vs. soft mist inhaler (single puff). [Figure 3] Aerodynamic particle size distribution of A) beclomethasone dipropionate and B) formoterol fumarate, NGI, Foster® pMDI (two puffs) versus soft mist inhaler (single puff). [Figure 4] Aerodynamic size distribution of budesonide. NGI, Formulation 1 (70% ethanol) vs. Formulation 2 (96% ethanol). [Figure 5]Aerodynamic size distribution of formoterol, NGI, Formulation 1 (70% ethanol) vs. Formulation 2 (96% ethanol). [Figure 6] Aerodynamic size distribution of budesonide, NGI, Symbicort® pMDI (single puff) vs. soft mist inhaler (single puff). [Figure 7] Aerodynamic size distribution of formoterol, NGI, Symbicort® pMDI (single puff) versus soft mist inhaler (single puff). DETAILED DESCRIPTION OF THE INVENTION

[0029] definition All terms used herein in this application, unless otherwise specified, are to be understood in their ordinary sense as known in the art. Other more specific terms used in this application are as set forth below and are intended to be applied uniformly throughout the specification and claims, unless a definition expressly set forth elsewhere provides a broader definition. Throughout the specification and claims, the word "comprise" and variations of this word are not intended to exclude other technical features, additives, ingredients, or steps. Furthermore, the word "comprise" encompasses the case of "consisting of." The following examples and figures are provided by way of illustration and are not intended to limit the present invention. Furthermore, the present invention includes all possible combinations of specific and preferred embodiments described herein.

[0030] The term "weight percentage" or "% w / w" refers to the weight percentage of each active ingredient compared to the total weight of all active ingredients present in a pharmaceutical composition. In the context of the present invention, the term "% v / v" refers to the volume percentage of the solvent used in the formulation. In the context of the present invention, when the term "antiseptic" is mentioned, it refers to a substance that is effective in inhibiting microbial growth, such as bacterial and fungal growth, in a solution, e.g., an aqueous solution. Examples include benzalkonium chloride (BAC) and various forms of edetate (ethylenediaminetetraacetate), e.g., edetate disodium. In the context of the present invention, the term "propellant" refers to the substance used to propel the active ingredient in a metered dose inhaler, such as a pMDI. Typical propellants are hydrofluorocarbons, such as norflurane. The expression "therapeutically effective amount," as used herein, refers to an amount of a compound that, when administered, is sufficient to prevent or alleviate some of the symptoms of one or more of the disorders or conditions being treated. The specific dose of a compound administered in accordance with the present invention will, of course, be determined by the particular circumstances surrounding the case, including the particular condition being treated, the duration of treatment, the nature of any concurrent treatment, and any other factors known to those skilled in the art. As used herein, the term "nominal dose" refers to the load, which is the amount of active pharmaceutical ingredient ("API") in the inhalation device before administration to a patient. The volume of solution containing the nominal dose is referred to as the "fill volume."

[0031] The "fine particle fraction" (FPF) is defined as the percentage (%) of particles smaller than 5 μm in the delivered dose. It is also known as the "respirable fraction." It is defined in the European Pharmacopoeia Chapter 2.9.18 (Preparations for inhalation: Aerodynamic Assessment of Fine particles) and its corresponding United States Pharmacopoeia Chapter is USP <601> Inhalation and Nasal Drug Products: Aerosols, Sprays and Powders - Performance Quality Tests. In these chapters, the fine particle dose (FPD) is defined as the mass of active substance less than 5 μm collected when an inhalation formulation is aerosolized according to the Pharmacopoeia chapters through any multistage impactor capable of aerodynamic particle size fractionation of powders. The "aerodynamic particle size distribution" (APSD) is the product deposition in the multistage impactor resulting from product injection. USP <601> The multi-stage instrument design, as defined in [2], consists of a connector between the impactor and the product (induction port), seven stages, and a micro-orifice collector (MOC) or internal filter holder (IFH) for very fine formulations. The stages consist of a removable cup and a jet with multiple nozzles (in order of decreasing particle size as the powder moves through the impactor) for all stages except stage 1. The size (μm) of these nozzles determines the aerodynamic deposition of the product powder in each of the stages, thus enabling the FPD calculations described above. "Delivered dose" (DD) is the dose delivered from the inhaler. This term is defined in the European Pharmacopoeia chapter "Inhalanda: Preparations for inhalation" and in the USP, see the USP <601> The delivered dose is obtained from the dose collection in the delivery device when sprayed / nebulized under the standard conditions defined in these chapters.

[0032] Solution preparation In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier, the compound being dissolved in a pharmaceutically acceptable solvent. (a) inhaled corticosteroids (ICS); (b) long-acting beta agonists (LABAs); (c) optionally, a long-acting muscarinic antagonist (LAMA); The present invention relates to a pharmaceutical solution composition for delivery to the pulmonary system by a nebulizer, comprising: a solvent comprising ethanol in an amount of 75-100% v / v. In one embodiment, the solvent comprises ethanol in an amount of 80-99% v / v. In another embodiment, the solvent comprises ethanol in an amount of 85-98% v / v. In a further embodiment, the solvent comprises ethanol in an amount of 90-97% v / v. In yet another embodiment, the solvent comprises ethanol in an amount of 92-96% v / v. In yet another embodiment, the solvent comprises ethanol in an amount of 94-96% v / v. In yet a further embodiment, the solvent comprises ethanol in an amount of about 96% v / v.

[0033] In one embodiment, the pharmaceutical solution composition comprises two active ingredients, hi a further embodiment, the two active ingredients are an inhaled corticosteroid, such as beclomethasone dipropionate, and a long-acting beta-agonist, such as formoterol fumarate. In one embodiment, the formulation according to the invention contains one or more pharmacologically acceptable acids and / or one or more buffers for adjusting the pH. In another embodiment, the acid is hydrochloric acid. In another embodiment, the buffer is a citrate buffer. In one embodiment, a formulation according to the present invention does not contain a propellant. In a further embodiment, the propellant is a hydrofluorocarbon. In another embodiment, the propellant is norflurane. The formulations of the present invention are prepared according to procedures well known in the art, which involve mixing the active ingredient with a solvent, eg, ethanol, for a specified period of time, adjusting the pH, and mixing for another specified period of time.

[0034] active ingredient In one embodiment, the inhaled corticosteroid is selected from the group consisting of beclomethasone dipropionate, budesonide, ciclesonide, fluticasone propionate, fluticasone furoate, and mometasone; the long-acting β-agonist is selected from the group consisting of formoterol fumarate, salmeterol, indacaterol, vilanterol, and olodaterol; and the long-acting muscarinic antagonist is selected from the group consisting of glycopyrronium bromide, umeclidinium, aclidinium, ipratropium, tiotropium, and oxitropium. In a further embodiment, the active substances that may be used in the formulations according to the invention are preferably selected from beclomethasone dipropionate (BDP), formoterol fumarate (FF), and optionally glycopyrronium bromide (GB).

[0035] As used herein, beclomethasone dipropionate (BDP) is the diester of beclomethasone (also called beclometasone), a synthetic corticosteroid developed for the preventive management of mild, moderate, or severe asthma in adults or children and for the preventive treatment of chronic reversible obstructive airway disease. Its chemical name is 9-chloro-11β,17,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione 17,21-dipropionate.

[0036] Formoterol is a selective β2-adrenergic receptor agonist. It is commercially available as formoterol fumarate (FF) and is administered by oral inhalation. Formoterol acts locally in the lungs as a bronchodilator. The chemical name of formoterol fumarate dihydrate is N-[2-hydroxy-5-[(1RS)-1-hydroxy-2-[[(1RS-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamido(E)-butenedioate dihydrate. Formoterol exhibits two asymmetric carbons, so there are four possible isomers, forming two racemates. Commercially available formoterol is a racemic mixture of the R,R(-) and S,S(+) enantiomers, which is routinely confirmed by testing for specific optical rotation. The diastereomeric R in the active substance is * S * The content of is controlled.

[0037] Glycopyrrolate is a long-acting muscarinic antagonist. It is a synthetic quaternary amine, also known as glycopyrronium. It is available in oral, intravenous, and inhaled forms. Glycopyrrolate is a quaternary ammonium salt with the following chemical name: 3-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium. The molecular formula is C 19 H 28 NO3. There are two asymmetric carbon atoms in the molecule. The product is a 50 / 50% mixture of enantiomers; therefore, the product is not optically active. The counterion is typically bromide; in this case, the long-acting muscarinic antagonist is glycopyrronium bromide (GB).

[0038] In one embodiment, the weight percentage (% w / w) ratio of beclomethasone dipropionate (BDP) to formoterol fumarate (FF) is generally 30-100% to 0.5-50%. In a further embodiment, the weight percentage ratio is 50-100% to 0.5-25%, respectively. In another embodiment, the weight percentage ratio is 70-100% to 0.5-10%, respectively. In yet another embodiment, the weight percentage ratio is 80-100% to 1-10%, respectively. In yet another embodiment, the weight percentage ratio is 90-100% to 2-8%, respectively. In a further embodiment, the weight percentage ratio is 94% to 6%.

[0039] In one embodiment, the weight percentage (% w / w / w) ratios of the three active ingredients, beclomethasone dipropionate (BDP), formoterol fumarate (FF), and glycopyrronium bromide (GB), are generally 30-100%, 0.5-50%, and 0.5-50%, respectively. In a further embodiment, the weight percentage ratios are 50-100%, 0.5-25%, and 1-25%, respectively. In another embodiment, the weight percentage ratios are 70-100%, 0.5-10%, and 2-20%, respectively. In yet another embodiment, the weight percentage ratios are 80-100%, 1-10%, and 5-17%, respectively. In yet another embodiment, the weight percentage ratios are 90-100%, 2-8%, and 7-15%, respectively. In a further embodiment, the weight percentage ratios are 84%, 11% and 5%, respectively.

[0040] Nebulizers and soft mist inhalers The spray formulations according to the present invention must meet high quality standards. The formulations according to the present invention may be inhaled orally or nasally. Particularly suitable are inhalers that can nebulize small amounts of liquid formulations in the dosage required for therapeutic purposes within a few seconds to form an aerosol suitable for therapeutic inhalation. In one embodiment, the nebulizer is capable of nebulizing an amount of active substance solution of less than 25 microliters, preferably less than 20 microliters, and most preferably less than 15 microliters, preferably in one puff to form an aerosol with an average particle size (or particle size) of less than 10 microns, preferably less than 5 microns, so that the inhalable portion of the aerosol already corresponds to a therapeutically effective amount.

[0041] As used herein, "atomized formulation" refers to a solution that is dispersed in the air to form an aerosol. Thus, an atomized solution is a specific form of aerosol. A nebulizer is a device that can generate very fine droplets for inhalation into the lungs. In this device, the liquid or solution to be nebulized is converted into a mist of droplets with a wide size distribution by methods known to those skilled in the art, including, but not limited to, compressed air, ultrasound, or a vibrating orifice. A nebulizer may further include a baffle, for example, in cooperation with the housing of the device, that selectively removes large droplets from the mist by impact. A soft mist inhaler is a specific type of nebulizer in which the mist is generated by high pressure generated during operation of the device, for example, by releasing a coil spring. These nebulizers do not require the assistance of an external power source. Thus, the mist inhaled into the lungs contains fine aerosol droplets. Nebulizers as used herein include, but are not limited to, soft mist inhalers.

[0042] In this type of inhaler, the formulation in solution state is stored in a reservoir. It is important that the active substance formulations used are sufficiently stable during storage and at the same time can be administered directly according to their medical purpose, preferably without further handling. Furthermore, they must not contain components that interact with the inhaler and impair the pharmaceutical quality of the inhaler or the solution or aerosol produced. In one embodiment, the nebulizer is a soft mist inhaler. When a formulation according to the invention is nebulized using soft mist inhaler technology, the mass emitted in at least 97%, preferably at least 98%, of the sprays (puffs) should correspond to the specified amount (with an acceptable range of no more than 25%, preferably no more than 20% of this amount). Preferably, 5 to 25 mg, more preferably 10 to 15 mg, of the formulation is delivered as the specified mass per puff.

[0043] Preferably, the pharmaceutical combination according to the present invention is used for producing a pharmaceutical composition for the treatment of obstructive pulmonary diseases selected from among bronchial asthma, severe asthma, acute asthma attack, chronic bronchitis and chronic obstructive pulmonary disease (COPD), as described above, but according to the present invention it is particularly preferred to use it for producing a medicament for the treatment of bronchial asthma and COPD.

[0044] In view of the above description and the following examples, one of ordinary skill in the art will be able to practice the claimed invention without undue experimentation. The foregoing will be better understood with reference to the following examples which detail specific procedures for the preparation of formulations in accordance with the present invention. The following examples should not be considered exhaustive, but merely illustrative of only some of the many embodiments contemplated by the present invention. [Example]

[0045] Example 1 - Effect of ethanol on solubilization and aerodynamic particle size distribution A study was conducted to evaluate the effect of ethanol on component solubilization and aerodynamic performance of aerosol solution formulations of beclomethasone dipropionate (BDP), glycopyrronium bromide (GB), and formoterol fumarate (FF).

[0046] formulation Beclomethasone dipropionate (BDP), glycopyrronium bromide (GLB), formoterol fumarate (FF), and HCl 1N were mixed in 70% ethanol (Formulation 1) and 96% ethanol (Formulation 2) for 2 hours at 25° C. to prevent evaporation. Both formulations were filtered and tested by reverse-phase HPLC for individual assays of all active ingredients.

[0047] [Table 1]

[0048] HPLC analysis method In all analyses, three independent reversed-phase HPLC analytical methods were used to determine each active ingredient. Beclomethasone dipropionate: A C18 column (Kromasil 100Å C18; 250 × 4.6 mm; 5 μm) was eluted with a 60 / 40 v / v organic (THF:AcN:MeOH 94:434:472 v / v / v) / aqueous (phosphate buffer pH 2.35) mobile phase using isocratic (1.4 mL / min) HPLC with UV (254 nm) detection. A beclomethasone dipropionate external standard prepared in the method diluent (56 / 44 v / v THF:AcN:MeOH 94:434:472 v / v / v / phosphate buffer pH 2.35) was used to quantify the active ingredient present in samples prepared in the same diluent using the response factors of the standard and sample solutions. Typical system suitability criteria were as follows: USP <621> Applied according to requirements.

[0049] Isocratic (1.0 mL / min) HPLC-UV (225 nm) detection was used with a glycopyrronium bromide:C18 column (Zorbax Extend RR C18, 50 x 4.6 mm, 3.5 μm) and a mobile phase consisting of 0.05M sulfate (heptanesulfonic acid) buffer pH 5.9 / MeOH:AcN:sulfuric acid in a ratio of 61.5:15:23.5:0.3 v / v. A glycopyrronium bromide external standard prepared in the method's diluent (35 / 65 v / v MeOH / water) was used to quantify the active ingredient present in samples prepared in the same diluent using the response factors of the standard and sample solutions. Typical system suitability criteria were as follows: USP <621> Applied according to requirements.

[0050] Formoterol fumarate: Isocratic (1.5 mL / min) HPLC-electrochemical detection was used with a C18 column (Supelcosil LC-ABZ, 250 x 4.6 mm, 5 μm) and a mobile phase consisting of 76 / 24 v / v phosphate buffer pH 5.6:AcN v / v. A formoterol fumarate external standard prepared in the method diluent (100% MeOH) was used to quantify the active ingredient present in samples prepared in the same diluent using the response factors of the standard and sample solutions. Typical system suitability criteria were as follows: USP <621> Applied according to requirements.

[0051] Data Analysis: Aerodynamic size distributions were plotted as a function of stage cutoff diameter as a percentage of the mass trapped on the filter from the induction port filter.

[0052] Aerodynamic particle size distribution (APSD) For APSD evaluation, Formulations 1 and 2 were filled into cartridges that fit into a soft mist inhaler (Respimat®). The in vitro aerodynamic particle size distribution of both formulations was evaluated using a Next Generation Impactor NGI (Copley Scientific Ltd), an impactor equipped with a mouthpiece adapter for insertion of the inhaler, an induction port, and an internal filter holder (IFH) for capturing smaller particles. The products were tested in accordance with the European Pharmacopoeia chapter 2.9.18 (apparatus E) and the United States Pharmacopoeia for soft mist inhalers. <601> The test was carried out according to the procedure detailed in Chapter (apparatus 6).

[0053] The NGI was cooled to 5°C for at least 75 minutes. The cooling chamber was then opened and after 30 minutes the NGI was connected to an HCP5 vacuum pump (Copley Scientific Ltd). For each experiment, 10 doses per NGI were delivered at 30 L / min, actuated for 5 seconds each. After the required actuation, the particles deposited on the different surfaces of the impactor were extracted with a suitable diluent (methanol) using a Gentle Rocker (Copley Scientific Ltd). The active ingredient was then quantified by HPLC using the same method as in the assay test described above, which establishes the distribution of particles according to their aerodynamic size.

[0054] Data Analysis: Aerodynamic size distributions were plotted as a function of stage cutoff diameter as a percentage of the mass trapped on the filter from the induction port filter.

[0055] result Assays of each active ingredient, summarized in Table 2 below, showed that the formulation providing the best results for higher active ingredient content (particularly beclomethasone dipropionate and formoterol fumarate) was Formulation 2, the formulation containing 96% ethanol. Without being bound by theory, this result may be due to the low solubility of these compounds in water.

[0056] [Table 2]

[0057] Also, when formoterol in formulations 1 and 2 are compared in the same assay, Figure 1 shows that ethanol affects the aerodynamic particle size distribution. Indeed, ethanol allows for a modification of the particle size within the respirable range (ultrafine particles or coarser particles). The data show that higher ethanol content results in smaller particle sizes. Ultrafine formulations are highly desirable as they provide deeper and more uniform lung distribution of inhaled therapeutic agents.

[0058] conclusion This study demonstrated that the solubilization of beclomethasone and formoterol was highly dependent on the ethanol content: beclomethasone and formoterol were not completely soluble in 70% ethanol (Formulation 1), whereas all the active ingredients were soluble in 96% ethanol (Formulation 2). Formulation 2 exhibited better aerodynamic properties than Formulation 1 in the NGI test. Therefore, these results suggest that higher ethanol content may result in a more efficient formulation for inhalation therapy.

[0059] Example 2 - Comparison of Trimbow® formulation pMDI vs. soft mist inhaler A study was conducted to compare the aerodynamic particle size distribution and emitted dose of a triple combination solution delivered using a soft mist inhaler device (Respimat®) with the commercially available Trimbow® pMDI (a commercially available triple combination product). The triple combination consisted of the following active ingredients: beclomethasone dipropionate (BDP), glycopyrronium bromide (GB), and formoterol fumarate (FF) at the concentrations shown in Table 3. A commercially available product, Trimbow® pMDI, was evaluated in this study as a representative triple combination product.

[0060] Formulations and inhaler systems Beclomethasone dipropionate (BDP), glycopyrronium bromide (GB), formoterol fumarate (FF) and HCl 1N were mixed in 96% ethanol for 2 hours at 25° C. The solution was then filtered and filled into cartridges that fit into a soft mist inhaler (Respimat®). Table 3 summarizes the products investigated in this study.

[0061] [Table 3]

[0062] Aerodynamic particle size distribution (APSD) In vitro aerodynamic evaluation was performed using a Next Generation Impactor NGI (Copley Scientific Ltd) equipped with a mouthpiece adapter for insertion of the inhaler, an induction port, and an internal filter holder (IFH) for capturing smaller particles. The product complies with the European Pharmacopoeia chapter 2.9.18 (apparatus E) and the United States Pharmacopoeia for soft mist inhalers. <601> The test was carried out according to the procedure detailed in Chapter (apparatus 6).

[0063] The NGI was cooled to 5°C for at least 75 minutes. The cooling chamber was then opened and after 30 minutes the NGI was connected to an HCP5 vacuum pump (Copley Scientific Ltd). For each experiment, 10 doses were released into the NGI for 5 seconds each at 30 L / min. After the required actuation, the particles deposited on the different surfaces of the impactor were extracted with an appropriate diluent (methanol) using a Gentle Rocker (Copley Scientific Ltd). The active ingredient was then quantified by HPLC using the same method as in Example 1.

[0064] Data Analysis: In vitro aerodynamic evaluation was performed using a Next Generation Impactor NGI (Copley Scientific Ltd) equipped with a mouthpiece adapter for insertion of the inhaler, an induction port, and an internal filter holder (IFH) for capturing smaller particles. The product complies with the European Pharmacopoeia chapter 2.9.18 (apparatus E) and the United States Pharmacopoeia for soft mist inhalers. <601> The test was carried out according to the procedure detailed in Chapter (apparatus 6).

[0065] The NGI was cooled to 5°C for at least 75 minutes. The cooling chamber was then opened and after 30 minutes the NGI was connected to an HCP5 vacuum pump (Copley Scientific Ltd). For each experiment, 10 doses were released into the NGI for 5 seconds each at 30 L / min. After the required actuation, the particles deposited on the different surfaces of the impactor were extracted with an appropriate diluent (methanol) using a Gentle Rocker (Copley Scientific Ltd). The active ingredient was then quantified by HPLC using the same method as in Example 1.

[0066] Data Analysis. NGI results were plotted as the mass collected on the filter from the induction port versus the stage cutoff diameter. The fine particle fraction (FPF%), mass median aerodynamic diameter (MMAD), and fine particle dose (FPD) were determined from analysis of the NGI data. Results are expressed as the mean of two NGI analyses.

[0067] Delivery amount The delivered volume was measured using a Dose Unit Sampler (DUSA) operated for 4 seconds at 28.3 L / min, USP <601> - the inhalation volume did not exceed 2.0 L. Five administrations were administered per device. The active pharmaceutical ingredient (API) deposited in the collection device was quantitatively collected using a DUSA shaker (Copley Scientific Ltd) and methanol. The API was then quantified by HPLC using the same method as described in Example 1. Results are expressed as the average of five determinations.

[0068] result Generally, drug particles from inhalers are deposited in different parts of the lung according to their size; larger particles are deposited in the mouth and throat, medium-sized particles are deposited in the central airways of the primary bronchi, while smaller particles are deposited in the terminal bronchioles and alveoli. In this study, a dose unit collector and a Next Generation Impactor (NGI) were used to determine the delivered dose and detailed deposition rates of the Trimbow® pMDI and soft mist inhalers, respectively. Table 4 shows that a single actuation of both devices released the same dose.

[0069] [Table 4]

[0070] However, results from the NGI assay indicate that one single dose of the soft mist inhaler can simulate the same aerodynamic particle size distribution as two doses of the Trimbow® pMDI for respirable particles (particles from stage 1 to the internal filter holder (IFH)). The soft mist inhaler also showed less deposition at the induction port (IP) than the Trimbow® pMDI, meaning that less of the coarser particles were retained in the mouth and throat (Figure 2). The MMAD value was approximately 1.2 μm, regardless of the device used.

[0071] In summary, these APSD results show that the soft mist inhaler provides the same lung deposition and less oropharyngeal deposition as the Trimbow® pMDI with two sprays, with one spray containing the same amount of drug per spray, which is equivalent to one dose required per treatment.Therefore, fewer sprays are required to achieve the same therapeutic effect, and less drug is delivered to the oropharyngeal area.Deposition in the oropharyngeal area is undesirable due to possible side effects.

[0072] [Table 5]

[0073] conclusion Soft mist inhalers represent a novel approach to the delivery of inhaled drugs and overcome some of the limitations of DPIs, particularly pMDIs. In this study, the soft mist inhaler and Trimbow® pMDI delivered similar doses, but similar lung deposition was observed with a single puff from the soft mist inhaler compared to two actuations of the Trimbow® pMDI—one single puff from the soft mist inhaler simulates the lung deposition profile (and potentially the same therapeutic effect) of two pMDI puffs. Furthermore, it has been shown that similar particle size distributions are achieved for each of the three active ingredients, despite their different physicochemical properties. Therefore, the concepts underlying this invention are applicable to different inhalable drug molecules.

[0074] Example 3 - Comparison of Foster® pMDI with comparable formulations using a soft mist inhaler (Respimat®) A study was conducted to compare the aerodynamic particle size distribution of a dual combination solution delivered using a soft mist inhaler device with the commercially available product, Foster® pMDI. The dual combination consisted of the following active ingredients: beclomethasone dipropionate (BDP) and formoterol fumarate (FF) at the concentrations shown in Table 6. A commercially available product, Foster® 100 / 6 μg pMDI, was evaluated in this study as a representative dual combination product.

[0075] Formulations and inhaler systems Beclomethasone dipropionate (BDP), formoterol fumarate (FF) and HCl 1N were mixed in 96% ethanol for 2 hours at 25° C. The solution was then filtered and filled into cartridges that fit into soft mist inhalers. Table 6 summarizes the products investigated in this study.

[0076] [Table 6]

[0077] Aerodynamic particle size distribution (APSD) In vitro aerodynamic evaluation was performed using a Next Generation Impactor NGI (Copley Scientific Ltd) equipped with a mouthpiece adapter for insertion of the inhaler, an induction port, and an internal filter holder (IFH) to capture smaller particles. Products were tested according to procedures detailed in the European Pharmacopoeia and the United States Pharmacopoeia for soft mist inhalers and pMDIs. The NGI was cooled to 5°C for at least 75 minutes. The cooling chamber was then opened and after 30 minutes the NGI was connected to an HCP5 vacuum pump (Copley Scientific Ltd). For each experiment, 10 doses were released into the NGI for 5 seconds each at 30 L / min. After the required actuation, the particles deposited on the different surfaces of the impactor were extracted with an appropriate diluent (methanol) using a Gentle Rocker (Copley Scientific Ltd). The active ingredient was then quantified by HPLC using the same method as in Example 1.

[0078] Data Analysis: In vitro aerodynamic evaluation was performed using a Next Generation Impactor NGI (Copley Scientific Ltd) equipped with a mouthpiece adapter for insertion of the inhaler, an induction port, and an internal filter holder (IFH) for capturing smaller particles. The product complies with the European Pharmacopoeia chapter 2.9.18 (apparatus E) and the United States Pharmacopoeia for soft mist inhalers. <601> The test was carried out according to the procedure detailed in Chapter (apparatus 6). The NGI was cooled to 5°C for at least 75 minutes. The cooling chamber was then opened and after 30 minutes the NGI was connected to an HCP5 vacuum pump (Copley Scientific Ltd). For each experiment, 10 doses were released into the NGI for 5 seconds each at 30 L / min.

[0079] After the required actuation, the particles deposited on the different surfaces of the impactor were extracted with an appropriate diluent (methanol) using a Gentle Rocker (Copley Scientific Ltd.) and the active ingredient was then quantified by HPLC using the same method as in Example 1. Data Analysis. NGI was plotted as the mass collected on the filter from the induction port versus the stage cutoff diameter. Fine particle fraction (FPF%) and mass median aerodynamic diameter (MMAD) were determined from analysis of the NGI data. Results are expressed as the mean of two NGI analyses.

[0080] result The deposition velocities of the Foster® pMDI and soft mist inhaler were determined using a Next Generation Impactor. The results showed that one single dose of the soft mist inhaler doubled the FPF value of a single puff of the Foster® pMDI. The MMAD value was approximately 1.2 μm, regardless of the device used (Table 7 and Figure 3).

[0081] [Table 7]

[0082] conclusion Results from this study indicate that one single puff with a soft mist inhaler can simulate the lung deposition rate (and potentially the same therapeutic effect) of two pMDI actuations. Taken together, these APSD results are consistent with those obtained in Example 2 and demonstrate the potential of the soft mist inhaler for dual treatment as well as triple therapy.

[0083] Example 4 - Effect of Ethanol on Aerodynamic Particle Size Distribution of Dual Combination Therapies A study was conducted to evaluate the effect of ethanol on the aerodynamic particle size distribution of a dual combination solution delivered using a soft mist inhaler device (Respimat®). The dual combination consisted of the following active ingredients: budesonide (BU) and formoterol fumarate (FF) at the concentrations shown in Table 8.

[0084] Formulations and inhaler systems Budesonide (BU) and formoterol fumarate (FF) were mixed, protected from evaporation, in 70% ethanol (Formulation 1) and 96% ethanol (Formulation 2) for 2 hours at 25° C. Both formulations were then filtered and filled into cartridges that fit into a soft mist inhaler (Respimat®). Table 8 summarizes the products investigated in this study.

[0085] [Table 8]

[0086] HPLC analysis method A single reversed-phase HPLC-UV analytical method was used for the determination of both active ingredients. Isocratic (1.0 mL / min) HPLC-UV detection (budesonide wavelength: 240 nm, formoterol fumarate wavelength: 214 nm) was employed using a C18 column (Hypersil BDS, 250 × 4.6 mm, 5 μm) with a mobile phase consisting of 50 / 50 v / v ACN / 0.1% formic acid. Formoterol fumarate and budesonide external standards prepared in the method diluent (75 / 25 v / v MeOH / water) were used to quantify the active ingredients present in samples prepared in the same diluent using the response factors of the standard and sample solutions. Typical system suitability criteria were as follows: USP <621> Applied according to requirements.

[0087] Aerodynamic particle size distribution (APSD) For APSD evaluation, Formulations 1 and 2 were filled into cartridges that fit into a soft mist inhaler (Respimat®). The in vitro aerodynamic particle size distribution of both formulations was evaluated using a Next Generation Impactor NGI (Copley Scientific Ltd), an impactor equipped with a mouthpiece adapter for insertion of the inhaler, an induction port, and an internal filter holder (IFH) for capturing smaller particles. The products were tested in accordance with the European Pharmacopoeia chapter 2.9.18 (apparatus E) and the United States Pharmacopoeia for soft mist inhalers. <601> The test was carried out according to the procedure detailed in Chapter (apparatus 6).

[0088] The NGI was cooled to 5° C. for at least 75 minutes. The cooling chamber was then opened and after 30 minutes the NGI was connected to an HCP5 vacuum pump (Copley Scientific Ltd). For each experiment, 10 doses were delivered per NGI, each nebulized for 5 seconds at 28.3 L / min. After the required actuation, the particles deposited on the different surfaces of the impactor were extracted with the appropriate diluent (75 / 25 v / v MeOH / water) using a Gentle Rocker (Copley Scientific Ltd.) and the active ingredient was then quantified by HPLC as described above.

[0089] Data Analysis. NGI results were plotted as the mass collected on the filter from the induction port versus the stage cutoff diameter. The fine particle fraction (FPF%), mass median aerodynamic diameter (MMAD), and fine particle dose (FPD) were determined from analysis of the NGI data. Results are expressed as the mean of two NGI analyses.

[0090] result The deposition velocities of Formulations 1 and 2 were determined by a Next Generation Impactor. The results showed that ethanol affected the aerodynamic particle size distribution (Table 9 and Figures 4 and 5). Indeed, higher ethanol content resulted in increased FPF values ​​and lower particle size distributions. Ultrafine particle size distributions are highly desirable in inhalation therapy as they result in more efficient treatment.

[0091] [Table 9]

[0092] conclusion In inhalation therapy, ultrafine formulations result in deeper and more uniform lung distribution. This study demonstrated that a higher ethanol content results in a lower particle size distribution, thus providing the formulation with better aerodynamic properties. The results are consistent with Example 1, supporting the possibility that ethanol may be necessary to produce a more efficient formulation for inhalation therapy.

[0093] Example 5 - Comparison of Symbicort® pMDI with an equivalent ethanol formulation delivered using a soft mist inhaler (Respimat®) A study was conducted to compare the aerodynamic particle distribution of a dual combination ethanol solution delivered using a soft mist inhaler device (Respimat®) with the commercial product Symbicort® pMDI (a commercial dual combination product). The dual combination consisted of the following active ingredients: budesonide (BU) and formoterol fumarate (FF) at the concentrations shown in Table 10. The commercially available product, Symbicort® 160 / 4.5 μg pMDI, was evaluated in this study as a representative dual combination product that does not contain ethanol in its formulation.

[0094] Formulations and inhaler systems Budesonide (BU) and formoterol fumarate (FF) were mixed, protected from evaporation, in 96% ethanol for 2 hours at 25° C. The solution was then filtered and filled into cartridges that fit into a soft mist inhaler (Respimat®). Table 10 summarizes the products investigated in this study.

[0095] [Table 10]

[0096] Aerodynamic particle size distribution (APSD) The in vitro aerodynamic particle size distribution of both formulations was assessed using a Next Generation Impactor NGI (Copley Scientific Ltd), an impactor equipped with a mouthpiece adapter for insertion of the inhaler, an induction port, and an internal filter holder (IFH) to capture smaller particles. The products were tested according to the procedures detailed in the European Pharmacopoeia and the United States Pharmacopoeia for soft mist inhalers and pMDIs. The NGI was cooled to 5° C. for at least 75 minutes. The cooling chamber was then opened and after 30 minutes the NGI was connected to an HCP5 vacuum pump (Copley Scientific Ltd). For each experiment, 10 doses were delivered per NGI, each nebulized for 5 seconds at 28.3 L / min.

[0097] After the required actuation, the particles deposited on the different surfaces of the impactor were extracted with the appropriate diluent (75 / 25 v / v MeOH / water) using a Gentle Rocker (Copley Scientific Ltd.) and the active ingredient was then quantified by HPLC using the same method as described in Example 4. Data Analysis. NGI was plotted as the mass collected on the filter from the induction port versus the stage cutoff diameter. Fine particle fraction (FPF%) and mass median aerodynamic diameter (MMAD) were determined from analysis of the NGI data. Results are expressed as the mean of two NGI analyses.

[0098] result The deposition rates of the Symbicort® pMDI and soft mist inhalers were determined by a Next Generation Impactor. The results showed that the soft mist inhaler composition affected the aerodynamic particle size distribution (Table 11 and Figures 6 and 7). The soft mist inhaler composition resulted in a smaller particle size distribution achieving an MMAD value of approximately 1.1 μm. This is highly positive, as a smaller particle size distribution leads to a more uniform deep lung distribution. Furthermore, the ethanol solution delivered by the soft mist inhaler resulted in an FPF value approximately 1.5 times higher than the pMDI product.

[0099] [Table 11]

[0100] conclusion This study demonstrated that soft mist inhaler compositions result in smaller particle size distribution, which translates to deeper and more efficient lung distribution. Furthermore, solutions delivered using soft mist inhalers exhibited higher FPF values, requiring lower doses to achieve a similar therapeutic effect than pMDIs, potentially resulting in fewer side effects due to less drug being delivered to the oropharyngeal region.

Claims

1. Dissolved in a pharmaceutically acceptable solvent (a) inhaled corticosteroids (ICS); (b) long-acting beta agonists (LABAs); (c) optionally, a long-acting muscarinic antagonist (LAMA); wherein the solvent comprises ethanol in an amount of 75-100% v / v; the ICS is selected from the group consisting of beclomethasone dipropionate, budesonide, ciclesonide, fluticasone propionate, fluticasone furoate and mometasone; the LABA is selected from the group consisting of formoterol fumarate, salmeterol, indacaterol, vilanterol, and olodaterol; the LAMA is selected from the group consisting of glycopyrronium bromide, umeclidinium, aclidinium, ipratropium, tiotropium, and oxitropium; A pharmaceutical solution composition for delivery to the pulmonary system by a soft mist inhaler.

2. 2. The pharmaceutical solution composition of claim 1, wherein the solvent comprises ethanol in an amount of 80-99% v / v.

3. 3. The pharmaceutical solution composition according to claim 1, wherein the solvent comprises ethanol in an amount of 90-97% v / v.

4. 4. The pharmaceutical solution composition of any one of claims 1 to 3, wherein the inhaled corticosteroid is beclomethasone dipropionate, the long-acting beta-agonist is formoterol fumarate, and the long-acting muscarinic antagonist is glycopyrronium bromide.

5. 5. The pharmaceutical solution composition according to any one of claims 1 to 4, wherein the weight percentage (% w / w) ratio of ICS to LABA is 50-99.5% to 0.5-50%.

6. 5. The pharmaceutical solution composition according to claim 1, wherein the weight percentage (% w / w / w) ratios of the ICS, LABA and LAMA are 30-99%, 0.5-50% and 0.5-50%, respectively, and the sum of said ratios of the ICS, LABA and LAMA is 100%.

7. 7. The pharmaceutical solution composition according to any one of claims 1 to 6, wherein the solution further comprises one or more pharmacologically acceptable acids and / or buffers for adjusting the pH.

8. A pharmaceutical solution composition according to any one of claims 1 to 7, which does not contain a propellant.

9. A pharmaceutical solution composition according to any one of claims 1 to 8, which does not contain a preservative.

10. A container containing the pharmaceutical solution composition of any one of claims 1 to 9, in a form suitable for use with a soft mist inhaler.

11. 11. A kit comprising the container of claim 10 and a soft mist inhaler.

12. The pharmaceutical solution composition according to any one of claims 1 to 9, for use in the prevention and / or treatment of inflammatory and / or obstructive airway diseases.

13. 13. The pharmaceutical solution composition for use in the prevention and / or treatment of inflammatory and / or obstructive airways diseases according to claim 12, wherein the disease is asthma or COPD.

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