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 spray administration, comprising a combination of two or three of an inhaled corticosteroid (ICS), a long-acting β2 agonist (LABA) and a long-acting muscarinic antagonist (LAMA) for use in the treatment of respiratory diseases, particularly asthma and chronic obstructive pulmonary disease (COPD), and a method for producing the same. The present invention also relates to the use of the pharmaceutical preparation in a soft mist inhaler.

[0002] More specifically, the pharmaceutical composition herein comprises a dual therapy of beclomethasone dipropionate (BPD) and formoterol fumarate (FF), and a 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 spraying.

Background Art

[0003] Drug delivery by inhalation enables the deposition of drugs in different parts of the airway (e.g., the larynx, trachea, bronchi and alveoli). Generally, the smaller the particle size, the longer the particles remain suspended in the air and the more downstream in the airway the drug can be delivered.

[0004] The use of dosing aerosols is well known to be effective in the treatment of respiratory diseases, particularly asthma and chronic obstructive pulmonary disease (COPD). Usually, metered-dose inhalers are used with a propellant gas. After the potential of these propellant gases to deplete the ozone layer was recognized, attempts to develop alternative methods have increased. One alternative is the development of nebulizers, where 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 the limitations of a patient's lungs. Sometimes called "respiratory therapy," nebulizers produce a mist containing medication, making it easier and more comfortable to inhale the medication into the lungs. Nebulizers require a liquid form of the formulation to function properly. Nebulizers work by forcing air through a cup containing the medication. This produces tiny mist-like particles of the liquid, which can then be deeply inhaled into the airways. Other nebulizers use an ultrasonic mechanism to generate the mist.

[0006] The main advantages of nebulizers over other methods of pulmonary ingestion are that they completely disperse without the use of propellant gases; patients do not need to coordinate inhalation with spraying / aerosolization; and higher doses of medication are easier to deliver. Soft mist inhalers, on the other hand, are portable inhalers that generate mist without using an external energy source. This is one of the advantages of soft mist inhalers, but there are other advantages compared to regular nebulizers as well. Soft mist inhalers deliver the majority of the mist to the lungs, with only a very small amount of medication delivered to the mouth. Soft mist inhalers are also a safer approach because the entire amount is delivered to the patient and none of it is discarded into the environment.

[0007] For example, a wide variety of nebulizers with different operating modes are available, such as the one described in PCT patent application WO97 / 12687 (a soft mist inhaler known by the trade name Respimat®). In nebulizer administration, the active ingredient is typically suspended in a fine powder form in physiological saline or dissolved in a water-alcohol mixture, in the presence of excipients such as buffers, stabilizers, surfactants, and preservatives. Therefore, pharmaceuticals intended for inhalation by spraying are dissolved or suspended in aqueous solution or ethanol solution, but depending on the solution properties of the active substance, a solvent mixture of water and ethanol may also be suitable.

[0008] In the case of a solution, the maximum concentration of a drug depends on its solubility in the solvent and the dose 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 component is not sufficiently soluble in water, an aqueous formulation for inhalation cannot be used. In some cases, the solubility of the formulation component can be increased by starting with an aqueous formulation and adding ethanol to the aqueous system. However, it has been found that the ethanol concentration in aqueous aerosol formulations has a decisive effect on the particle size distribution of the aerosol produced by the nebulizer.

[0009] WO02 / 083113 discloses a pharmaceutical composition comprising (i) formoterol or a derivative thereof and (ii) a steroidal anti-inflammatory agent 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 for dissolving the steroidal anti-inflammatory agent. 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 combination therapy agents 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 agent; and administering the aqueous solution and a surfactant to a patient using a nebulizer to dissolve the long-acting corticosteroid.

[0011] Propellant-free inhalable solutions are disclosed in WO 2012 / 110462 with respect to any combination using aqueous and / or alcoholic solvents, preferably ethanol solutions, wherein the muscarinic receptor antagonist is dissolved in a solvent comprising at least 75% v / v water and an optional component, a cosolvent miscible with water; 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 agent and a steroid, and WO 2006 / 114379 discloses a pharmaceutical composition comprising one or more anticholinergic agents, a beta-mimetics, and a steroid in combination with pharmaceutically acceptable excipients as optional components. 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 inhalation formulation containing one or more active substances, an excipient as an optional component, and 10-50% (v / v) of ethanol. 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), further containing only benzalkonium chloride, an acid for pH adjustment, and sodium edetate.

[0014] WO 2015 / 193213 discloses combinations of muscarinic antagonists, particularly tiotropium, with glucocorticoids such as ciclesonide, which are prepared as inhalation solutions containing water alone or a mixture of ethanol (less than 95% v / v) and water (more than 5% v / v), 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 is also stated that the formulations may further contain a β-2 adrenergic receptor agonist, such as salbutamol (albuterol).

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

[0016] The combination of inhaled corticosteroids (ICS) and long-acting β2-agonists (LABAs) and / or long-acting muscarinic antagonists (LAMAs) is available for the treatment of asthma and chronic obstructive pulmonary disease (COPD). In particular, the combination of the inhaled corticosteroid beclomethasone dipropionate (BPD), the long-acting β-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 the combination of the inhaled corticosteroid beclomethasone dipropionate (BPD) and the long-acting β-agonist formoterol fumarate (FF) is available under the trade name Foster® (100mcg / 6mcg pressurized inhalation solution). Both are sold by Chiesi Farmaceutici SpA and are available for use with metered-dose inhalation devices.

[0017] Trimbow® is a pressurized inhalation solution, also known as a pressurized metered-dose inhaler (pMDI), containing three active substances (beclomethasone dipropionate anhydride, formoterol fumarate dihydrate, and glycopyrronium bromide) dissolved in a medium consisting of norflurane (propellant), ethanol (cosolvent), and hydrochloric acid (formulation stabilizer). Each delivery dose (dose dispensed from 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 spray / puff (dose dispensed from the valve) contains 100 μg of BDP, 6 μg of FF, and 10 μg of glycopyrronium (as 12.5 micrograms of glycopyrronium bromide).

[0018] The MDI formulation of beclomethasone dipropionate (BDP) + formoterol fumarate (FF) + glycopyrronium Br (GB) is 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, and is used in pressurized metered-dose inhalers (pMDIs). The Fostair® product is described in EP 1787639.

[0019] The disadvantages of atomizing MDI formulations containing ICS alone or in combination with LABA and / or LAMA are the presence of a propellant, the lack of coordination between inhaler operation and patient inhalation (difficult for the elderly and children), and the low amount of deposition in the lungs and the high amount of deposition in the oropharyngeal region. A method is desired to improve the administration of drugs, such as inhaled corticosteroids alone or inhaled corticosteroids in combination with LABA and / or LAMA, by spraying, particularly by using a soft mist inhaler. Given the potential challenges and drawbacks associated with currently available formulations containing inhaled corticosteroids alone or in combination with LABA and / or LAMA, it is highly advantageous to provide a solution formulation that does not contain propellants, stabilizers, and / or preservatives, has a suitable shelf life, and thus enables an effective aerosol that is well tolerated by patients.

[0020] Therefore, there is a need to provide a stabilized composition that contains an inhaled corticosteroid (ICS) together with a long-acting β2-agonist (LABA) and / or a long-acting muscarinic antagonist (LAMA), without containing propellants, stabilizers, and / or preservatives. Furthermore, it is necessary to improve drug delivery to the lungs and reduce the amount delivered orally. Also, the entire amount should be delivered to the patient and not wasted into the environment (a safer approach). In addition, the use of soft mist inhalers is a propellant-free, portable system that provides better therapeutic efficiency (no coordination between patient inhalation and spraying is required). [Overview of the project] [Means for solving the problem]

[0021] The inventors have discovered a stable spray-administered pharmaceutical composition for use in the treatment of respiratory diseases, particularly asthma and chronic obstructive pulmonary disease (COPD), comprising a combination of an inhaled corticosteroid (ICS), a long-acting β2-agonist (LABA), and an optional long-acting muscarinic antagonist (LAMA). Because all active ingredients are dissolved in an alcohol solvent and administered in a spray form, a greater amount of the active ingredients are deposited in the lungs compared to other pharmaceutical forms. Since suspensions tend to precipitate and require vigorous shaking of the particles before drug administration, a solution of all components, including solubilized ICS, is a more reliable method for delivering the drug to the lungs compared to a suspension.

[0022] Thus, in a first aspect, the present invention relates to a pharmaceutical solution composition dissolved in a pharmaceutically acceptable solvent and comprising: (a) an inhaled corticosteroid (ICS); (b) a long-acting β-agonist (LABA); (c) optionally, a long-acting muscarinic antagonist (LAMA), wherein the solvent contains ethanol in an amount of 75 to 100% v / v, and the pharmaceutical solution composition is delivered to the pulmonary system by a nebulizer.

[0023] More specifically, a pharmaceutical solution composition is preferred, wherein 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 the 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 airway 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 using a propellant gas. Further, they do not contain stabilizers and / or preservatives such as benzalkonium chloride (BAC) and disodium edetate. Advantageously, the pharmaceutical compositions of the present invention are stable over time.

[0026] In addition, the pharmaceutical composition of the present invention improves the solubility of the active ingredient, provides a more stable solution of the active ingredient compared to a suspension by a simple manufacturing method, and makes the nebulizer more efficient, resulting in a lower concentration of the active ingredient in the formulation relative to the equivalent volume in the lung. Therefore, better aerodynamic performance is obtained compared to pMDI (less oropharyngeal deposition and more lung deposition), and less active ingredient is required to produce a similar therapeutic effect.

[0027] Furthermore, for formulation efficiency and atomization (e.g., via a soft mist inhaler), therapeutic agents of inhaled corticosteroids and beta-agonists and optional long-acting muscarinic antagonists have shown in vitro that an equivalent amount of drug is delivered from the inhaler to the lungs, yielding an equivalent inhalation fraction with one puff (single spray) compared to two puffs (two sprays / sprays) of p-MDI formulations. The formulations of the present invention deliver 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 drawing]

[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 using NGI, Trimbow® pMDI (double spray) versus soft mist inhaler (single spray). [Figure 3] A) Aerodynamic particle size distribution of beclomethasone dipropionate and B) formoterol fumarate. NGI, Foster® pMDI (double spray) vs. soft mist inhaler (single spray). [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 spray) vs. soft mist inhaler (single spray). [Figure 7] Aerodynamic size distribution of formoterol. NGI, Symbicort® pMDI (single spray) vs. soft mist inhaler (single spray). [Modes for carrying out the invention]

[0029] definition All terms used herein are to be understood in their ordinary meaning as is known in the art, unless otherwise stated. Other more specific terms used herein are set forth below and are intended to apply uniformly throughout this specification and the claims unless otherwise explicitly stated definitions provide a broader definition. Throughout this specification and the claims, the word “comprise” and variations thereof are not intended to exclude other technical features, additives, components, or processes. Furthermore, the word “comprise” includes the case of “consisting of.” The following examples and drawings are provided for illustrative purposes only and are not intended to limit the invention. Furthermore, the invention encompasses all possible combinations of the specific embodiments and preferred embodiments described herein.

[0030] The terms "weight percentage" or "% w / w" refer to the weight percentage of each active ingredient compared to the total weight of all active ingredients present in the pharmaceutical composition. In relation to the present invention, the term "% v / v" refers to the volume percentage of the solvent used in the formulation. In relation to the present invention, when the term "preservative" is used, it refers to a substance that is effective in inhibiting microbial growth, such as the growth of bacteria and fungi, in a solution, such as an aqueous solution. Examples include benzalkonium chloride (BAC) and various forms of EDTA (ethylenediaminetetraacetate), such as disodium EDTA. In relation to the present invention, the term "propellant" refers to a substance used to propel the active ingredient in a metered-dose inhalant, such as in a pMDI. Typical propellants are hydrofluorocarbons, such as norflurane. Where used herein, the term "therapeutic dose" refers to the amount of a compound that, when administered, is sufficient to prevent or partially alleviate the onset of one or more symptoms of the disorder or condition being treated. The specific dose of a compound administered in accordance with the present invention will, of course, be determined by the specific circumstances surrounding the case, including the specific condition being treated, the duration of treatment, the nature of any concurrent treatments, and any other factors known to the expert. As used herein, the term “nominal dose” refers to the loaded volume, which is the amount of active pharmaceutical ingredient ("API") in the inhalation device before administration to the patient. The volume of the solution containing the nominal dose is called the “filled volume.”

[0031] The "fine particle fraction" (FPF) is defined as the percentage (%) of particles smaller than 5 μm relative to the delivered volume. This is also known as the "inhalation fraction." This is defined in Chapter 2.9.18 of the European Pharmacopoeia (Preparations for inhalation: Aerodynamic Assessment of Fine particles), and the corresponding chapter in the United States Pharmacopoeia is USP. <601> Inhalation and Nasal Drug Products: Aerosols, Sprays and Powders - Performance Quality Tests. In these chapters, particulate dose (FPD) is defined as the mass of active material less than 5 μm in size collected when an inhalant is sprayed and passed through any multistage impactor capable of aerodynamic particle fractionation of powder according to the pharmacopoeia chapter. "Aerodynamic particle size distribution" (APSD) is the deposition of the product in the multistage impactor obtained from the product spray. USP <601> The design of the multi-stage apparatus, as defined, consists of a connector (induction port) between the impactor and the product, seven stages, and a micro-orifice collector (MOC) or internal filter holder (IFH) for very fine formulations. Each stage consists 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 stage, thus enabling the aforementioned FPD calculations. "Delivery volume" (DD) is the amount delivered from the inhaler. This term is defined in the chapter "Inhalanda: Preparations for inhalation" of the European Pharmacopoeia, and for USP, see the aforementioned USP. <601> It is defined in the chapters. The delivered amount is obtained from dose collection in the delivery device when sprayed / aerosolized under the standard conditions defined in these chapters.

[0032] Solution formulation In one embodiment, the present invention relates to a compound dissolved in a pharmaceutically acceptable solvent. (a) Inhaled corticosteroids (ICS) and (b) Long-acting β-agonists (LABAs) and (c)Optional ingredients include long-acting muscarinic antagonists (LAMAs) and The present invention relates to a pharmaceutical solution composition containing a solvent, wherein the solvent contains ethanol in an amount of 75-100% v / v, and is delivered to the lung system by a nebulizer. In one embodiment, the solvent contains ethanol in an amount of 80-99% v / v. In another embodiment, the solvent contains ethanol in an amount of 85-98% v / v. In yet another embodiment, the solvent contains ethanol in an amount of 90-97% v / v. In yet another embodiment, the solvent contains ethanol in an amount of 92-96% v / v. In yet another embodiment, the solvent contains ethanol in an amount of 94-96% v / v. In yet another embodiment, the solvent contains ethanol in an amount of about 96% v / v.

[0033] In one embodiment, the pharmaceutical solution composition comprises two active ingredients. In a further embodiment, the two active ingredients are an inhaled corticosteroid such as beclomethasone dipropionate and a long-acting β-agonist such as formoterol fumarate. In one embodiment, the formulation according to the present invention contains one or more pharmacologically acceptable acids and / or one or more buffering agents for adjusting pH. In another embodiment, the acid is hydrochloric acid. In another embodiment, the buffering agent is a citrate buffer. In one embodiment, the 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 formulation of the present invention is manufactured according to a procedure well known in the art, which includes mixing the active ingredient with a solvent, such as ethanol, for a specific time, adjusting the pH, and mixing for a further specific 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 orodaterol; and the long-acting muscarinic antagonist is selected from the group consisting of glycopyrronium bromide, umeclidinium, acridinium, ipratropium, tiotropium, and oxytropium. In further embodiments, the active substance that may be used in the formulation according to the present invention is preferably selected from beclomethasone dipropionate (BDP), formoterol fumarate (FF), and glycopyrronium bromide (GB) as an optional component.

[0035] As used herein, beclomethasone dipropionate (BDP) is a diester of beclomethasone (also known as beclometasone), a synthetic corticosteroid developed for the prophylactic management of mild, moderate, or severe asthma in adults or children, and for the prophylactic 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 marketed as formoterol fumarate (FF) and 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]formamide(E)-butenedioate dihydrate. Since formoterol exhibits two chiral carbons, there are four possible isomers, forming two racemates. Marketed formoterol is a racemic mixture of R,R(-) and S,S(+) enantiomers, which is conventionally confirmed by testing for specific optical rotations. Diastereoisomer R in the active substance * S * The content 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 inhalation forms. Glycopyrrolate is a quaternary ammonium salt with the following chemical name: 3-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium. Its molecular formula is C 19 H 28 It is NO3. The molecule contains two chiral carbons. The product is a 50 / 50% mixture of enantiomers. Therefore, the product is not optically active. The counterion is typically a 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 ratios are 50-100% to 0.5-25%, respectively. In another embodiment, the weight percentage ratios are 70-100% to 0.5-10%, respectively. In yet another embodiment, the weight percentage ratios are 80-100% to 1-10%, respectively. In yet another embodiment, the weight percentage ratios are 90-100% to 2-8%, respectively. In yet another 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 further embodiments, the weight percentage ratios are 84%, 11%, and 5%, respectively.

[0040] Nebulizers and soft mist inhalers The spray formulation according to the present invention must meet high quality standards. The formulation according to the present invention may be inhaled orally or via the nasal route. Particularly preferred is an inhaler that can spray a small amount of liquid formulation in the required dose for therapeutic purposes within a few seconds to produce an aerosol suitable for therapeutic inhalation. In one embodiment, the nebulizer can spray an amount of active substance solution of less than 25 microliters, preferably less than 20 microliters, most preferably less than 15 microliters, preferably in a single puff to form an aerosol having 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, “aerosolized formulation” refers to a solution that is dispersed in the air to form an aerosol. Therefore, an aerosolized solution is a specific form of aerosol. A nebulizer is a device capable of producing very fine droplets for lung inhalation. Within this device, a liquid or solution for atomization is transformed into a mist of droplets having a broad size distribution by methods known to those skilled in the art (including, but not limited to, compressed air, ultrasound, or a vibrating orifice). The nebulizer may further include, for example, a baffle in conjunction with the housing of the device to selectively remove larger droplets from the mist by impact. A soft mist inhaler is a specific type of nebulizer in which mist is produced by, for example, the release of a coil spring due to the high pressure generated during the operation of the device. These nebulizers do not require the assistance of an external power source. Therefore, the mist inhaled into the lungs contains fine aerosol droplets. Examples of nebulizers used herein include, but are not limited to, soft mist inhalers.

[0042] In this type of inhaler, the formulation in solution is stored in the reservoir. It is important that the active substance formulation used is sufficiently stable during storage and, at the same time, can be administered directly, if possible, without further handling, according to their medical purpose. Furthermore, they must not contain any 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 the formulation according to the present invention is sprayed using the technology of a soft mist inhaler, the mass discharged in at least 97%, preferably at least 98%, of a single spray (one puff) should correspond to a specified amount (with an acceptable range of 25% or less of this amount, preferably 20% or less). 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 combination of pharmaceuticals according to the present invention is used to produce pharmaceutical compositions for the treatment of obstructive pulmonary diseases selected from bronchial asthma, severe asthma, acute asthma attacks, chronic bronchitis, and chronic obstructive pulmonary disease (COPD), as described above, but according to the present invention, it is particularly preferred to use them to produce pharmaceuticals for the treatment of bronchial asthma and COPD.

[0044] In consideration of the above description and the following examples, those skilled in the art can implement the claimed invention without excessive experimentation. The foregoing will be better understood by referring to the following examples which detail specific procedures for the manufacture of the formulation according to the present invention. The following examples should not be considered exhaustive, but merely illustrate some of the many embodiments intended by the present invention. [Examples]

[0045] Example 1 - Effect of ethanol on solubilization and aerodynamic particle size distribution A study was conducted to evaluate the effects of ethanol on the solubilization and aerodynamic performance of aerosol 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) at 25°C for 2 hours, ensuring no evaporation occurred. Both formulations were filtered, and individual assays for all active ingredients were performed by reverse-phase HPLC.

[0047] [Table 1]

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

[0049] A glycopyrronium bromide C18 column (Zorbax Extend RR C18, 50 × 4.6 mm, 3.5 μm) and a mobile phase consisting of a 61.5:15:23.5:0.3 v / v sulfate (heptanesulfonic acid) buffer pH 5.9 / MeOH:AcN:sulfuric acid 0.05 M were used, along with isocratic (1.0 mL / min) HPLC-UV (225 nm) detection. A glycopyrronium bromide external standard prepared in the diluent (35 / 65 v / v MeOH / water) was used, and the active ingredient present in the sample prepared in the same diluent was quantified using the response coefficients of the standard and sample solutions. Typical system suitability criteria are based on USP standards. <621> Applicable according to requirements.

[0050] Formoterol fumarate: Isocratic (1.5 mL / min) HPLC-electrochemical detection was performed using a C18 column (Supelcosil LC-ABZ, 250 × 4.6 mm, 5 μm) and a mobile phase consisting of 76 / 24 v / v phosphate buffer pH 5.6:AcN v / v. An external standard of formoterol fumarate, prepared in the diluent (100% MeOH), was used, and the active ingredient present in samples prepared in the same diluent was quantified using the response coefficients of the standard and sample solutions. Typical system suitability criteria are based on USP standards. <621> Applicable according to requirements.

[0051] Data analysis. The aerodynamic size distribution was plotted as a function of the stage cutoff diameter, representing the percentage of mass collected by the filter from the induction port filter.

[0052] Aerodynamic particle size distribution (APSD) For APSD evaluation, formulations 1 and 2 were filled into cartridges compatible with 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), equipped with a mouthpiece adapter for inhaler insertion, an induction port, and an internal filter holder (IFH) for capturing smaller particles. The products were compared with the European Pharmacopoeia Chapter 2.9.18 (apparatus E) and the United States Pharmacopoeia for soft mist inhalers. <601> The test was conducted according to the procedure detailed in Chapter (apparatus6).

[0053] The NGI was cooled to 5°C for at least 75 minutes. Then, the cooling chamber was opened, and after 30 minutes, the NGI was connected to an HCP5 vacuum pump (Copley Scientific Ltd). For each experiment, the pump was operated at 30 L / min for 5 seconds each, releasing 10 doses per NGI. After the necessary operation, the particles deposited on different sides of the impactor were extracted using Gentle Rocker (Copley Scientific Ltd) with an appropriate diluent (methanol). The active ingredients were then quantified by HPLC using the same method as in the assay described above. This established the particle distribution according to the aerodynamic particle size.

[0054] Data analysis. The aerodynamic size distribution was plotted as a function of the stage cutoff diameter, representing the percentage of mass collected by the filter from the induction port filter.

[0055] result The assays for each active ingredient, summarized in Table 2 below, showed that formulation 2, containing 96% ethanol, provided the best results in terms of higher active ingredient content (particularly beclomethasone dipropionate and formoterol fumarate). While not bound by any particular theory, this result may be attributable to the low solubility of these compounds in water.

[0056] [Table 2]

[0057] Furthermore, when formoterol in formulations 1 and 2 is compared using the same assay, Figure 1 shows that ethanol affects the aerodynamic particle size distribution. In fact, ethanol allows for a change in particle size within the aspirable range (to ultrafine or coarser particles). The data shows that the higher the ethanol content, the smaller the resulting particle size. Ultrafine formulations are highly desirable because they allow inhaled medications to be distributed more deeply and evenly into the lungs.

[0058] conclusion This study demonstrated that the solubilization of beclomethasone and formoterol is highly dependent on the ethanol content. Beclomethasone and formoterol did not completely dissolve in 70% ethanol (Formulation 1), but all active ingredients dissolved in 96% ethanol (Formulation 2). In the NGI test, formulation 2 showed better aerodynamic properties than formulation 1. Therefore, these results suggest that a higher ethanol content may result in a more efficient inhalation therapy formulation.

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

[0060] Pharmaceuticals and inhaler systems Beclomethasone dipropionate (BDP), glycopyrronium bromide (GB), formoterol fumarate (FF), and HCl 1N were mixed in 96% ethanol at 25°C for 2 hours. The solution was then filtered and filled into a cartridge compatible with 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 the Next Generation Impactor NGI (Copley Scientific Ltd), which features a mouthpiece adapter for inhaler insertion, an induction port, and an internal filter holder (IFH) for capturing smaller particles. The product was evaluated against the European Pharmacopoeia Chapter 2.9.18 (apparatus E) and the United States Pharmacopoeia for soft mist inhalers. <601> The test was conducted according to the procedure detailed in Chapter (apparatus 6).

[0063] The NGI was cooled to 5°C for at least 75 minutes. Then, the cooling chamber was 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 at 30 L / min for 5 seconds each. After the necessary operation, the particles deposited on different sides of the impactor were extracted using Gentle Rocker (Copley Scientific Ltd) with an appropriate diluent (methanol). The active ingredients were then quantified by HPLC using the same method as in Example 1.

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

[0065] The NGI was cooled to 5°C for at least 75 minutes. Then, the cooling chamber was 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 at 30 L / min for 5 seconds each. After the necessary operation, the particles deposited on different sides of the impactor were extracted using Gentle Rocker (Copley Scientific Ltd) with an appropriate diluent (methanol). The active ingredients were then quantified by HPLC using the same method as in Example 1.

[0066] Data analysis. The NGI results were plotted against the stage cutoff diameter as the mass collected from the induction port to the filter. The particulate fraction (FPF%), aerodynamic median mass (MMAD), and particulate dose (FPD) were determined from the analysis of the NGI data. The results are expressed as the average of the two NGI analyses.

[0067] Delivery amount The delivery volume is measured using a dose unit collection device (DUSA) that operates at 28.3 L / min for 4 seconds, USP <601> The test was conducted according to the following procedure - the inhalation volume did not exceed 2.0 L. Five doses 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. The results are expressed as the average of five measurements.

[0068] result Generally, drug particles from inhalers deposit in different parts of the lungs according to their size; coarser particles deposit in the mouth and throat, medium-sized particles deposit in the central airways of the primary bronchi, while smaller particles deposit in the terminal bronchioles and alveoli. In this study, a dose unit sampling device and a next-generation impactor (NGI) were used to determine the delivery volume and detailed deposition rate of Trimbow® pMDI and soft mist inhalers, respectively. Table 4 shows that both devices released the same dose in a single activation.

[0069] [Table 4]

[0070] However, results from the NGI assay show that, with respect to breathable particles (particles from Stage 1 to the internal filter holder (IFH)), a single dose of the soft mist inhaler can simulate the same aerodynamic particle size distribution as two doses of Trimbow® pMDI. Furthermore, the soft mist inhaler showed less deposition at the induction port (IP) than Trimbow® pMDI, meaning that a smaller amount of coarser particles are 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 demonstrate that soft mist inhalers provide the same intrapulmonary deposition and less oropharyngeal deposition with a single spray containing the same amount of drug per spray as Trimbow® pMDI with two sprays, which is equivalent to one dose required per treatment. Therefore, fewer sprays are needed to achieve a similar therapeutic effect, and less drug is delivered to the oropharyngeal region. Oropharyngeal deposition is undesirable due to the potential side effects.

[0072] [Table 5]

[0073] conclusion Soft mist inhalers represent a novel approach to the delivery of inhaled drugs, overcoming some of the limitations of DPIs, particularly pMDIs. In this study, the soft mist inhaler and Trimbow® pMDI showed similar delivery rates, but similar intrapulmonary deposition was observed with a single spray from the soft mist inhaler compared to two sprays of Trimbow® pMDI—a single spray from the soft mist inhaler simulates the intrapulmonary deposition profile (and potentially the same therapeutic effect) of two pMDI sprays. 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 underlying concept of this invention is applicable to different inhalable drug molecules.

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

[0075] Pharmaceuticals and inhaler systems Beclomethasone dipropionate (BDP), formoterol fumarate (FF), and HCl 1N were mixed in 96% ethanol at 25°C for 2 hours. The solution was then filtered and filled into a cartridge suitable for a soft mist inhaler. 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 the Next Generation Impactor NGI (Copley Scientific Ltd), which features a mouthpiece adapter for inhaler insertion, an induction port, and an internal filter holder (IFH) for capturing smaller particles. The product was 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. Then, the cooling chamber was 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 at 30 L / min for 5 seconds each. After the necessary operation, the particles deposited on different sides of the impactor were extracted using Gentle Rocker (Copley Scientific Ltd) with an appropriate diluent (methanol). The active ingredients were then quantified by HPLC using the same method as in Example 1.

[0078] Data analysis. In vitro aerodynamic evaluation was performed using the Next Generation Impactor NGI (Copley Scientific Ltd), equipped with a mouthpiece adapter for inhaler insertion, an induction port, and an internal filter holder (IFH) for capturing smaller particles. The product was compared with the European Pharmacopoeia Chapter 2.9.18 (apparatus E) and the United States Pharmacopoeia for soft mist inhalers. <601> The test was conducted according to the procedure detailed in Chapter (apparatus 6). The NGI was cooled to 5°C for at least 75 minutes. Then, the cooling chamber was 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 at 30 L / min for 5 seconds each.

[0079] After the necessary operation, the particles deposited on different sides of the impactor were extracted with an appropriate diluent (methanol) using Gentle Rocker (Copley Scientific Ltd). The active ingredients were then quantified by HPLC using the same method as in Example 1. Data analysis. NGI was plotted against the stage cutoff diameter as the mass recovered from the induction port to the filter. The particulate fraction (FPF%) and aerodynamic median mass (MMAD) were determined from the analysis of the NGI data. The results are expressed as the average of the two NGI analyses.

[0080] result The deposition rates of Foster® pMDI and soft mist inhalers were determined using a next-generation impactor. The results showed that a single dose of the soft mist inhaler doubled the FPF value of a single spray of 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 The results of this study demonstrate that a single spray from a soft mist inhaler can simulate the lung deposition rate (and potentially the same therapeutic effect) of two pMDI (practical microinhaler) actions. In summary, these APSD results are consistent with those obtained in Example 2, suggesting the potential of soft mist inhalers not only for triple therapy but also for dual therapy.

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

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

[0085] [Table 8]

[0086] HPLC analysis method One reversed-phase HPLC-UV analysis method was used to determine both active ingredients. A C18 column (Hypersil BDS, 250 × 4.6 mm, 5 μm) was used, along with a mobile phase consisting of 50 / 50 v / v ACN / 0.1% formic acid, and isocratic (1.0 mL / min) HPLC-UV detection (budesonide wavelength: 240 nm, formoterol fumarate wavelength: 214 nm). Using external standards of formoterol fumarate and budesonide prepared in the diluent (75 / 25 v / v MeOH / water), the active components present in samples prepared in the same diluent were quantified using the response coefficients of the standard and sample solutions. Typical system suitability criteria are based on USP standards. <621> Applicable according to requirements.

[0087] Aerodynamic particle size distribution (APSD) For APSD evaluation, formulations 1 and 2 were filled into cartridges compatible with 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.), which features a mouthpiece adapter for inhaler insertion, an induction port, and an internal filter holder (IFH) for capturing smaller particles. The products were compared with the European Pharmacopoeia Chapter 2.9.18 (apparatus E) and the United States Pharmacopoeia for soft mist inhalers. <601> The test was conducted according to the procedure detailed in Chapter (apparatus 6).

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

[0089] Data analysis. The NGI results were plotted against the stage cutoff diameter as the mass recovered from the induction port to the filter. The particulate fraction (FPF%), aerodynamic median mass (MMAD), and particulate dose (FPD) were determined from the analysis of the NGI data. The results are expressed as the average of the two NGI analyses.

[0090] result The deposition rates of formulations 1 and 2 were determined using a next-generation impactor. The results showed that ethanol affected the aerodynamic particle size distribution (Table 9 and Figures 4 and 5). In fact, higher ethanol content resulted in increased FPF values ​​and a lower particle size distribution. An ultrafine particle size distribution is highly desirable because it leads to more efficient treatment in inhalation therapy.

[0091] [Table 9]

[0092] conclusion In inhalation therapy, ultrafine formulations result in deeper and more uniform lung distribution. This study demonstrated that higher ethanol content leads to a lower particle size distribution, and therefore to better aerodynamic properties of the formulation. The results are consistent with Example 1, supporting the possibility that ethanol should produce more efficient formulations 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 two-component ethanol solution delivered using a soft mist inhaler device (Respimat®) with that of the commercially available product Symbicort® pMDI (a commercially available two-component product). The two-component solution consists of the following active ingredients: budesonide (BU) and formoterol fumarate (FF) at the concentrations shown in Table 10. Symbicort® 160 / 4.5 μgp MDI, a commercially available product, was evaluated in this study as a representative product of two-drug combination therapy that does not contain ethanol in its formulation.

[0094] Pharmaceuticals and inhaler systems Budesonide (BU) and formoterol fumarate (FF) were mixed in 96% ethanol at 25°C for 2 hours, protected from evaporation. The solution was then filtered and filled into cartridges suitable for 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 evaluated using the Next Generation Impactor NGI (Copley Scientific Ltd), an impactor equipped with a mouthpiece adapter for inhaler insertion, an induction port, and an internal filter holder (IFH) for capturing 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. Then, the cooling chamber was opened, and after 30 minutes, the NGI was connected to an HCP5 vacuum pump (Copley Scientific Ltd). For each experiment, 10 doses were released per NGI, sprayed at 28.3 L / min for 5 seconds each.

[0097] After the necessary operation, the particles deposited on different sides of the impactor were extracted using a Gentle Rocker (Copley Scientific Ltd) with an appropriate diluent (75 / 25 v / v MeOH / water). The active ingredients were then quantified by HPLC using the same method as described in Example 4. Data analysis. NGI was plotted against the stage cutoff diameter as the mass recovered from the induction port to the filter. The particulate fraction (FPF%) and aerodynamic median mass (MMAD) were determined from the analysis of the NGI data. The results are presented as the average of the two NGI analyses.

[0098] result The deposition rates of Symbicort® pMDI and soft mist inhalers were determined using a next-generation impactor. The results showed that the soft mist inhaler composition influenced 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 deeper and more uniform lung distribution. Furthermore, the ethanol solution delivered via soft mist inhaler yielded an FPF value approximately 1.5 times higher than that of the pMDI product.

[0099] [Table 11]

[0100] conclusion This study demonstrated that soft mist inhaler compositions result in a smaller particle size distribution. Therefore, this is interpreted as deeper and more efficient lung distribution. Furthermore, solutions delivered using soft mist inhalers showed higher FPF values, requiring lower doses to achieve similar therapeutic effects compared to pMDIs, and potentially resulting in fewer side effects due to less drug 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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