Inhaled drug composition for preventing or treating respiratory diseases

Abstract

Disclosed is a pharmaceutical composition for inhalation comprising a long-acting beta-2 agonist and a long-acting muscarinic antagonist. The long-acting beta-2 agonist may comprise olodaterol, or the long-acting beta-2 agonist may comprise arformoterol, and the composition may have a pH value of 3.5 to 5.5. The long-acting beta-2 agonist may comprise indacaterol, and the composition may have a pH value of 2.5 to 4.5. The long-acting muscarinic antagonist may comprise rebefenacin, and the composition may have a pH value of 3.5 to 5.5. The long-acting muscarinic antagonist may comprise glycopyrronium bromide, and the composition may have a pH value of 2.5 to 4.5. The long-acting muscarinic antagonist may comprise tiotropium bromide, and the composition may have a pH value of 2.0 to 4.0. The use of the pharmaceutical composition in the manufacture of an inhalable pharmaceutical composition for preventing or treating respiratory diseases such as asthma and chronic obstructive pulmonary disease is disclosed.

Description

[Technical Field]

[0001] The present application relates to the field of drugs for preventing or treating diseases, and more particularly to inhaled drug compositions for preventing or treating respiratory diseases such as asthma and chronic obstructive pulmonary disease. [Background technology]

[0002] Chronic obstructive pulmonary disease (COPD) is a serious respiratory disease with a constantly increasing prevalence worldwide. It is estimated to affect over 100 million people in China, is currently the fourth leading cause of death in the UK and the US, and is ranked third in terms of disease impact globally in 2020.

[0003] COPD is a preventable and treatable disease characterized by airflow limitation that is not fully reversible. Airflow obstruction is usually gradual and is associated with an abnormal inflammatory response to toxic particles or gases in the lungs, primarily due to smoking. COPD affects the lungs but also has significant systemic effects. COPD is associated with mucus hypersecretion, emphysema, and bronchitis.

[0004] The main goals of COPD treatment include smoking cessation, symptom relief, improvement of physiology, and suppression of complications such as ventilatory abnormalities and disease attacks. However, a holistic approach to COPD treatment involves maintaining good hygiene and health care in combination with smoking cessation, avoidance of indoor and outdoor exposure to pollutants and allergens, avoidance of occupational allergen contact, and the use of medications and supportive therapies in a stepwise manner as the disease progresses.

[0005] Current treatment and prevention strategies for COPD and asthma include the use of long-acting bronchodilators or one or more inhaled corticosteroids (ICS).

[0006] Currently, therapies for treating or preventing COPD and asthma include the use of long-acting bronchodilators and inhaled corticosteroids, either alone or in combination.

[0007] Inhaled bronchodilators are the cornerstone of COPD therapy because they can relieve symptoms, reduce disease episodes, and improve quality of life. These drugs also improve airflow limitation and overfilling, thus reducing respiratory effort and improving exercise tolerance. Bronchodilators can also reduce respiratory muscle fatigue and improve mucociliary clearance.

[0008] More specifically, the choice of bronchodilator includes beta-2 agonists and anticholinergics. Furthermore, beta-2 agonists can be short-acting for immediate relief of asthma symptoms or long-acting for long-term prevention of asthma symptoms.

[0009] Long-acting β2 agonists (LABAs) or ultra-long-acting β2 agonists (ULABAs) are effective in improving lung function, reducing symptoms, and preventing exercise-induced dyspnea in patients with asthma and COPD. LABAs induce prolonged bronchodilation by sustained relaxation of airway smooth muscle. In addition to prolonged bronchodilation, LABAs also exert effects on non-smooth muscle, such as inhibiting airway smooth muscle cell proliferation and the release of inflammatory mediators, stimulating mucociliary transport, protecting airway mucosa cells, and attenuating neutrophil migration and activation.

[0010] Additionally, the use of LABAs can reduce the frequency of medication. Commercially available twice-daily LABAs include salmeterol, formoterol, and arformoterol, while commercially available once-daily ultra-long-acting beta-2 agonist ULABAs include indacaterol, vilanterol, carmoterol, and olodaterol.

[0011] Anticholinergics are also used as bronchodilators and are potential alternatives to beta-2 agonists, especially LABAs. However, anticholinergics can also be used together with LABAs to treat asthma. Anticholinergics work by competing with acetylcholine for receptor sites on the vagus nerve or neuromuscular junction, thereby preventing reflex transmission induced by asthma-provoking substances.

[0012] Because β2-agonist responsiveness decreases with age, the use of anticholinergics is beneficial in elderly patients, and it is also advantageous to use anticholinergics in patients who cannot tolerate β2-agonists.

[0013] Although beta-2 agonists and anticholinergics provide symptomatic relief of bronchoconstriction, COPD requires monotherapy with steroids due to the separate inflammatory component, and most inhaled corticosteroids require multiple doses.

[0014] Corticosteroids exert inhibitory effects on inflammatory cells and inflammatory mediators involved in the pathology of respiratory disorders such as COPD. Treatment with corticosteroids / glucocorticoids is considered one of the most potential and effective treatments currently available for COPD.

[0015] However, the use of corticosteroids has always been limited due to the potential side effects associated with their use, including suppression of the hypothalamic-pituitary-adrenal (HPA) axis, adverse effects on bone growth in children and bone mineral density in the elderly, ophthalmic complications (cataract formation and glaucoma), and skin atrophy.

[0016] Treatment options for acute COPD exacerbations, including bronchodilators, inhaled corticosteroids, and antibiotics, remain limited, and novel, effective anti-inflammatory agents are needed. Preliminary findings published in Respiratory Research indicate that inhaled high-molecular-weight hyaluronic acid can shorten the duration of respiratory failure and noninvasive ventilation in patients with acute COPD exacerbations. High-molecular-weight hyaluronic acid is a naturally occurring sugar that is abundant in cellular matrices, including those in the lung. Its multiple properties make it an attractive candidate for the treatment of acute COPD exacerbations.

[0017] Currently, there are several commercially available inhaled drug compositions that contain a combination of a LABA and an inhaled corticosteroid, examples of which are used to treat asthma and chronic obstructive pulmonary disease include salmeterol / fluticasone propionate (Advair® diskus and Advair® HFA) and formoterol fumarate dihydrate / budesonide.

[0018] Therefore, in patients affected by respiratory disorders such as COPD, combination therapy with a bronchodilator and an ICS can improve pulmonary efficiency, reduce inflammatory responses, and provide symptomatic relief compared to high doses of the ICS alone. The choice of specific bronchodilators and ICS plays a crucial role in the formulation of fixed-dose combination therapy.

[0019] Combination therapy also reduces costs and provides control of respiratory compromise. Minimizing dose frequency is a major step in simplifying COPD treatment to improve patient compliance with therapy.

[0020] US 2009 / 0088408 A1 discloses pharmaceutical compositions of anticholinergics, corticosteroids and P agonists and their application in the treatment of respiratory diseases, examples of which are inhalable powder or suspension aerosol compositions containing tiotropium bromide or ipratropium bromide.

[0021] US 2005 / 0042174 A1 discloses the combined administration of a β2 agonist, an anticholinergic drug and an anti-inflammatory steroid.

[0022] WO 2006 / 105401 A1 discloses a combination of an anticholinergic drug with a corticosteroid and a long-acting beta-2 agonist for simultaneous or sequential use to prevent or treat respiratory, inflammatory or obstructive airways diseases.

[0023] US 2008 / 0279948 A1 discloses a drug containing a beta-2 agonist, glycopyrronium bromide, and mometasone furoate, and examples of its application include the beta-2 agonist indacaterol maleate.

[0024] US 2008 / 0286363 A1 discloses a drug containing a β2 agonist (e.g., indacaterol maleate), glycopyrronium bromide, and a corticosteroid, an example of which is the corticosteroid 3-methylthiophene-2-carboxylic acid-(6S,9R,10S,11S,13S,16R,17R)-9-chloro-6-fluoro-11-hydroxy-17-methoxycarbonyl-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl ester.

[0025] US 2010 / 0166671 A1 discloses drugs containing antimuscarinic agents, beta-2 agonists, and corticosteroids, examples of which include glycopyrronium bromide, formoterol fumarate, and mometasone furoate.

[0026] US 7,439,393 B2 discloses some phenylethanolamine derivatives for treating respiratory diseases. The application of these compounds in combination therapy with other therapeutic agents is also disclosed.

[0027] US 2008 / 0041369 A1 discloses a propellant-free aerosol formulation, which contains, inter alia, olodaterol, a corticosteroid (such as budesonide, beclomethasone, or fluticasone), and an anticholinergic (such as tiotropium bromide, oxitropium bromide, or ipratropium bromide).

[0028] US 2005 / 0239778 A1 discloses drug combinations comprising, inter alia, olodaterol and at least one other active substance, such as a steroid.

[0029] US 2008 / 0317862 A1 discloses a drug containing an antimuscarinic agent and a corticosteroid for treating inflammatory or obstructive airway diseases. In particular, this application discloses an aerosol composition containing glycopyrronium bromide and mometasone furoate.

[0030] US 2006 / 0069073 A1 discloses the combination of glycopyrronium bromide with one or more steroids as second active substances.

[0031] CN 112804997 A discloses an inhalation solution of a combination of indacaterol maleate and glycopyrronium bromide.

[0032] TW 202012369 A1, CN 111936124 A disclose a propellant-free aerosol formulation, which contains, inter alia, a pharmaceutically acceptable salt of glycopyrronium, a pharmaceutically acceptable salt of indacaterol, and water, and also discloses that this combination is particularly suitable for aerosolizing the active agent using an atomizer for therapeutic applications in asthma and COPD.

[0033] CN 109715160 A discloses an aerosol containing indacaterol or a derivative thereof, the components of which further include at least one pharmaceutically acceptable salt of glycopyrronium bromide or at least one corticosteroid, such as budesonide, mometasone, beclomethasone, fluticasone, and pharmaceutically acceptable salts thereof.

[0034] US 2021 / 0322311 A1 discloses a propellant-free liquid formulation, which contains, inter alia, tiotropium bromide and olodaterol and physiologically acceptable salts thereof.

[0035] US 7,056,916 B2 discloses inhalation formulations containing olodaterol, including inhalable powder aerosols, propellant-containing aerosols, or propellant-free inhalation solutions.

[0036] US 2020 / 0368214 A1 discloses a propellant-free inhalation aerosol, which contains inter alia the drug combination of vilanterol or umeclidinium bromide or both vilanterol and umeclidinium bromide.

[0037] WO 2021 / 009573 A1 discloses a pressure vessel with an inner coating of a polymer or copolymer, which contains, inter alia, umeclidinium bromide or vilanterol or a combination of both drugs.

[0038] WO 2020 / 100040 A1 discloses an inhaler containing a propellant, which contains, inter alia, a drug combination and formulation of umeclidinium bromide and vilanterol.

[0039] CN 112752572 A discloses a liquid, propellant-free drug formulation and a method of using the drug by nebulizing the drug formulation in an inhaler. The liquid, propellant-free drug formulation contains an active substance selected from, among others, umeclidinium bromide, vilanterol triphenylacetate, and combinations thereof.

[0040] WO 2020 / 220855 A1 discloses a propellant-free atomized inhalation formulation and a method for producing the same, which contains, among other things, the active ingredients umeclidinium bromide and vilanterol. The drug combination containing umeclidinium bromide and vilanterol is stable, does not contain a propellant, and the particle size of the atomized droplets is advantageous for inhalation into the lungs.

[0041] CN 113274596 A discloses a pressurized metered-dose tank for treating respiratory diseases, containing at least a formulation of a corticosteroid, a LABA drug, a LAMA drug, and an HFA152a or HFO propellant. In particular, this application relates to an aerosol containing formoterol, beclomethasone, and glycopyrronium bromide.

[0042] CN 111150728 A discloses a stable pressurized aerosol solution composition combining glycopyrronium bromide and formoterol.

[0043] WO 2020 / 229966 A1 discloses a stable suspension-type aerosol containing glycopyrronium bromide. The aerosol formulation further contains one or more β2 agonists. An example of this application is a compound aerosol containing glycopyrronium bromide and formoterol.

[0044] CN 112804991 A discloses a propellant-free liquid formulation and its method of use by atomization in an inhaler. Specifically, the formulation is a combined aerosol of umeclidinium bromide and formoterol.

[0045] WO 2020 / 084549 A1 discloses a nebulizer composition containing glycopyrronium bromide and formoterol and a manufacturing method for treating pneumonia and obstructive airway diseases.

[0046] US 2018 / 0104184 A1 discloses a nebulizer composition containing tiotropium bromide and formoterol for treating pneumonia and obstructive airway diseases and a method for producing the same.

[0047] US 6,433,027 B1 discloses a novel pharmaceutical composition relating to anticholinergic compounds and its manufacturing process. An example of this application is an inhalation spray containing tiotropium bromide and formoterol.

[0048] CN 111481550 A discloses a drug combination containing tiotropium bromide and arformoterol, examples of which include aerosols and inhalation atomizers containing these two active ingredients.

[0049] WO 2010 / 048384 A1 discloses compositions and methods for preventing and / or treating airway and / or respiratory diseases. In particular, this application discloses an inhalable liquid formulation containing arformoterol ((R,R)-formoterol) and tiotropium bromide.

[0050] CN 107233311 A discloses an aerosolizing agent containing arformoterol and glycopyrronium bromide as active ingredients and a method for preparing the same.

[0051] US 2017 / 0027908 A1 or JP 2017-061456 A discloses an inhalation drug composition for the prevention and / or treatment of respiratory, inflammatory or obstructive airway diseases, which contains, inter alia, glycopyrronium bromide, a β2 agonist, and a corticosteroid. [Prior art documents] [Patent documents]

[0052] [Patent Document 1] US Patent Application Publication No. 2009 / 0088408 [Patent Document 2] US Patent Application Publication No. 2005 / 0042174 [Patent Document 3] International Publication No. 2006 / 105401 [Patent Document 4] US Patent Application Publication No. 2008 / 0279948 [Patent Document 5] US Patent Application Publication No. 2008 / 0286363 [Patent Document 6] US Patent Application Publication No. 2010 / 0166671 [Patent Document 7] U.S. Patent No. 7,439,393 [Patent Document 8] US Patent Application Publication No. 2008 / 0041369 [Patent Document 9] US Patent Application Publication No. 2005 / 0239778 [Patent Document 10] US Patent Application Publication No. 2008 / 0317862 [Patent Document 11] US Patent Application Publication No. 2006 / 0069073 [Patent Document 12] Chinese Patent Application Publication No. 112804997 [Patent Document 13] Taiwan Patent Application Publication No. 202012369 [Patent Document 14] Chinese Patent Application Publication No. 111936124 [Patent Document 15] Chinese Patent Application Publication No. 109715160 [Patent Document 16] US Patent Application Publication No. 2021 / 0322311 [Patent Document 17] U.S. Patent No. 7,056,916 [Patent Document 18] US Patent Application Publication No. 2020 / 0368214 [Patent Document 19] International Publication No. 2021 / 009573 [Patent Document 20] International Publication No. 2020 / 100040 [Patent Document 21] Chinese Patent Application Publication No. 112752572 [Patent Document 22] International Publication No. 2020 / 220855 [Patent Document 23] Chinese Patent Application Publication No. 113274596 [Patent Document 24] Chinese Patent Application Publication No. 111150728 [Patent Document 25] Chinese Patent Application Publication No. 111481550 [Patent Document 26] International Publication No. 2020 / 229966 [Patent Document 27] Chinese Patent Application Publication No. 112804991 [Patent Document 28] International Publication No. 2020 / 084549 [Patent Document 29] US Patent Application Publication No. 2018 / 0104184 [Patent Document 30] U.S. Patent No. 6,433,027 [Patent Document 31] International Publication No. 2010 / 048384 [Patent Document 32] Chinese Patent Application Publication No. 107233311 [Patent Document 33] US Patent Application Publication No. 2017 / 0027908 Summary of the Invention

[0053] Inhaled drug compositions comprising one or more bronchodilators are provided, particularly long-acting beta-2 agonists and long-acting muscarinic antagonists. In some embodiments, the use of one or more bronchodilators, particularly long-acting beta-2 agonists and long-acting muscarinic antagonists, in the manufacture of inhaled drug compositions for the prevention and / or treatment of respiratory diseases is provided. In some embodiments, methods for the manufacture of the drug compositions are further provided. In some embodiments, the use of the drug compositions for the prevention and / or treatment of respiratory diseases is further provided. In some embodiments, the drug compositions are for the prevention and / or treatment of respiratory diseases. In some embodiments, methods for the prevention and / or treatment of respiratory diseases are provided, comprising administering the drug compositions.

[0054] In some embodiments, the respiratory disease comprises a respiratory, inflammatory, or obstructive airways disease. In some embodiments, the respiratory disease comprises asthma. In some embodiments, the respiratory disease comprises chronic obstructive pulmonary disease.

[0055] In some embodiments, the long-acting β2 agonist comprises or consists of olodaterol. In some embodiments, the long-acting β2 agonist comprises or consists of arformoterol, and the composition has a pH of 3.0 to 5.5, such as 3.5 to 5.5, such as 4.0 to 5.5, or further such as 4.5 to 5.5. In some embodiments, the long-acting β2 agonist comprises or consists of indacaterol, and the composition has a pH of 2.5 to 4.5, such as 3.0 to 4.5, or such as 2.5 to 4.0, or further such as 3.0 to 4.0. In some embodiments, the long-acting muscarinic antagonist comprises or consists of revefenacin, and the composition has a pH of 3.5 to 5.5, such as 4.0 to 5.5, or further for example, 4.5 to 5.5. In some embodiments, the long-acting muscarinic antagonist comprises or consists of glycopyrronium bromide, and the composition has a pH of 2.5 to 4.5, such as 2.5 to 4.0, or further for example, 2.5 to 3.5. In some embodiments, the long-acting muscarinic antagonist comprises or consists of tiotropium bromide, and the composition has a pH of 2.0 to 4.0, such as 2.5 to 4.0, or further for example, 2.5 to 3.5.

[0056] In some embodiments, the long-acting beta-2 agonist comprises or consists of at least one selected from the group consisting of indacaterol, formoterol, arformoterol, vilanterol, carmoterol, and olodaterol. In some embodiments, the long-acting muscarinic antagonist comprises at least one selected from the group consisting of glycopyrronium bromide, umeclidinium bromide, tiotropium bromide, aclidinium bromide, and rebefenacin.

[0057] In some embodiments, the long-acting beta-2 agonist comprises indacaterol and the long-acting muscarinic antagonist comprises glycopyrronium bromide. In some embodiments, the long-acting beta-2 agonist comprises indacaterol and the long-acting muscarinic antagonist comprises umeclidinium bromide. In some embodiments, the long-acting beta-2 agonist comprises indacaterol and the long-acting muscarinic antagonist comprises tiotropium bromide. In some embodiments, the long-acting beta-2 agonist comprises indacaterol and the long-acting muscarinic antagonist comprises aclidinium bromide. In some embodiments, the long-acting beta-2 agonist comprises indacaterol and the long-acting muscarinic antagonist comprises rebefenacin. In some embodiments, the long-acting beta-2 agonist comprises formoterol and the long-acting muscarinic antagonist comprises glycopyrronium bromide. In some embodiments, the long-acting beta 2 agonist comprises formoterol and the long-acting muscarinic antagonist comprises umeclidinium bromide. In some embodiments, the long-acting beta 2 agonist comprises formoterol and the long-acting muscarinic antagonist comprises tiotropium bromide. In some embodiments, the long-acting beta 2 agonist comprises formoterol and the long-acting muscarinic antagonist comprises aclidinium bromide. In some embodiments, the long-acting beta 2 agonist comprises formoterol and the long-acting muscarinic antagonist comprises rebefenacin. In some embodiments, the long-acting beta 2 agonist comprises arformoterol and the long-acting muscarinic antagonist comprises glycopyrronium bromide. In some embodiments, the long-acting beta-2 agonist comprises arformoterol and the long-acting muscarinic antagonist comprises umeclidinium bromide, hi some embodiments, the long-acting beta-2 agonist comprises arformoterol and the long-acting muscarinic antagonist comprises tiotropium bromide.In some embodiments, the long-acting beta 2 agonist comprises arformoterol, and the long-acting muscarinic antagonist comprises aclidinium bromide. In some embodiments, the long-acting beta 2 agonist comprises arformoterol, and the long-acting muscarinic antagonist comprises rebefenacin. In some embodiments, the long-acting beta 2 agonist comprises vilanterol, and the long-acting muscarinic antagonist comprises glycopyrronium bromide. In some embodiments, the long-acting beta 2 agonist comprises vilanterol, and the long-acting muscarinic antagonist comprises umeclidinium bromide. In some embodiments, the long-acting beta 2 agonist comprises vilanterol, and the long-acting muscarinic antagonist comprises tiotropium bromide. In some embodiments, the long-acting beta 2 agonist comprises vilanterol, and the long-acting muscarinic antagonist comprises aclidinium bromide. In some embodiments, the long-acting beta 2 agonist comprises vilanterol, and the long-acting muscarinic antagonist comprises rebefenacin. In some embodiments, the long-acting beta 2 agonist comprises carmoterol, and the long-acting muscarinic antagonist comprises glycopyrronium bromide. In some embodiments, the long-acting beta 2 agonist comprises carmoterol, and the long-acting muscarinic antagonist comprises umeclidinium bromide. In some embodiments, the long-acting beta 2 agonist comprises carmoterol, and the long-acting muscarinic antagonist comprises tiotropium bromide. In some embodiments, the long-acting beta 2 agonist comprises carmoterol, and the long-acting muscarinic antagonist comprises aclidinium bromide. In some embodiments, the long-acting beta 2 agonist comprises carmoterol, and the long-acting muscarinic antagonist comprises rebefenacin. In some embodiments, the long-acting beta-2 agonist comprises olodaterol and the long-acting muscarinic antagonist comprises glycopyrronium bromide.In some embodiments, the long-acting beta 2 agonist comprises olodaterol and the long-acting muscarinic antagonist comprises umeclidinium bromide. In some embodiments, the long-acting beta 2 agonist comprises olodaterol and the long-acting muscarinic antagonist comprises tiotropium bromide. In some embodiments, the long-acting beta 2 agonist comprises olodaterol and the long-acting muscarinic antagonist comprises aclidinium bromide. In some embodiments, the long-acting beta 2 agonist comprises olodaterol and the long-acting muscarinic antagonist comprises rebefenacin.

[0058] In some embodiments, the long-acting β2 agonist is present in an amount of 1 to 100 μg / mL, for example, 5 to 100 μg / mL, for example, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 25, 26, 28, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 μg / mL, or a range between any two of these values. In some embodiments, the long-acting muscarinic antagonist is present in a concentration of 1-100 μg / mL, e.g., 5-100 μg / mL, e.g., 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 25, 26, 28, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 μg / mL, or a range between any two of these values. In some embodiments, the weight ratio of the long-acting beta-2 agonist to the long-acting muscarinic antagonist is 100:1 to 1:100, for example, 1:80 to 80:1, further for example, 1:60 to 60:1, further for example, 1:50 to 50:1, further for example, 1:40 to 40:1, further for example, 1:30 to 30:1, further for example, 1:20 to 20:1, further for example, 1:15 to 15:1. In some embodiments, the weight ratio of the long-acting beta-2 agonist to the long-acting muscarinic antagonist is 100:1 to 1:1, for example, 1:80 to 1:1, further for example, 1:60 to 1:1, further for example, 1:50 to 1:1, further for example, 1:40 to 1:1, further for example, 1:30 to 1:1, further for example, 1:20 to 1:1, further for example, 1:15 to 1:1.In some embodiments, the weight ratio of the long-acting beta-2 agonist to the long-acting muscarinic antagonist is 1:1 to 1:100, for example, 1:1 to 80:1, further for example, 1:1 to 60:1, further for example, 1:1 to 50:1, further for example, 1:1 to 40:1, further for example, 1:1 to 30:1, further for example, 1:1 to 20:1, further for example, 1:1 to 15:1.

[0059] In some embodiments, the composition further comprises hyaluronic acid. In some embodiments, the hyaluronic acid is high molecular weight hyaluronic acid (HMW-HA). In some embodiments, the weight percent of the hyaluronic acid is 0.500% or less. In some embodiments, the weight percent of the hyaluronic acid is 0.001%-0.500%, e.g., 0.010%-0.400%, e.g., 0.100%-0.300%, e.g., 0.300%. In some embodiments, the molecular weight of the high molecular weight hyaluronic acid is in the range of 1,000,000-10,000,000 Daltons.

[0060] In some embodiments, the drug composition further comprises sodium chloride, ethylenediaminetetraacetic acid (EDTA), and / or a cyclodextrin. In some embodiments, the drug composition further comprises sodium chloride. In some embodiments, the drug composition further comprises EDTA or a cyclodextrin. In some embodiments, the drug composition further comprises EDTA. In some embodiments, the drug composition further comprises a cyclodextrin. In some embodiments, the drug composition further comprises EDTA and a cyclodextrin. In some embodiments, the drug composition further comprises a polysorbate, such as polysorbate 80. In some embodiments, the drug composition further comprises ethyl oleate. In some embodiments, the composition further comprises a glucocorticoid. In some embodiments, the cyclodextrin comprises α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin. In some embodiments, the cyclodextrin is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin. In some embodiments, the cyclodextrin comprises or consists of α-cyclodextrin. In some embodiments, the cyclodextrin comprises or consists of β-cyclodextrin. In some embodiments, the cyclodextrin comprises or consists of γ-cyclodextrin. In some embodiments, the cyclodextrin comprises hydroxypropyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin. In some embodiments, the cyclodextrin is selected from the group consisting of hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin. In some embodiments, the cyclodextrin comprises or consists of hydroxypropyl-β-cyclodextrin. In some embodiments, the cyclodextrin comprises or consists of sulfobutyl-β-cyclodextrin.

[0061] In some embodiments, the weight percent of sodium chloride is 1.00% or less. In some embodiments, the weight percent of sodium chloride is 0.01%-1.00%, such as 0.10%-1.00%, further such as 0.50%-1.00%, further such as 0.85%. In some embodiments, the weight percent of EDTA is 0.100% or less. In some embodiments, the weight percent of EDTA is 0.001%-0.100%, such as 0.010%-0.050%, such as 0.020%-0.040%, such as 0.030%. In some embodiments, the weight percent of cyclodextrin is 10% or less, such as 5.0% or less, such as 2.5% or less, such as 1.50% or less. In some embodiments, the weight percentage of the cyclodextrin is 0.01% to 10%, such as 0.01% to 5.0%, for example, 0.01% to 2.5%, for example, 0.01% to 1.50%, for example, 0.01% to 1.00%, for example, 0.10% to 1.00%, further for example, 0.20% to 0.80%, further for example, 0.25% to 0.75%, further for example, 0.30% to 0.70%, further for example, 0.40% to 0.60%, or further for example, 0.50%. In some embodiments, the weight percentage of the polysorbate is 0.100% or less. In some embodiments, the weight percentage of the polysorbate is between 0.001% and 0.100%, such as between 0.010% and 0.050%, such as between 0.020% and 0.040%, such as 0.030%.

[0062] In some embodiments, the drug composition further comprises a buffer, such as, for example, a citric acid / citrate buffer, further, for example, a citric acid / sodium citrate buffer, hi some embodiments, the drug composition further comprises a pH adjuster, such as, for example, hydrochloric acid, further, for example, dilute hydrochloric acid.

[0063] In some embodiments, the long-acting beta-2 agonist comprises olodaterol and the long-acting muscarinic antagonist comprises rebefenacin. In some embodiments, the long-acting beta-2 agonist comprises olodaterol and the long-acting muscarinic antagonist comprises rebefenacin, and the composition has a pH of 4.0 to 5.5. In some embodiments, the long-acting beta-2 agonist comprises olodaterol and the long-acting muscarinic antagonist comprises rebefenacin, and the composition further comprises EDTA.

[0064] In some embodiments, the long-acting beta-2 agonist includes arformoterol, the long-acting muscarinic antagonist includes rebefenacin, and the pH of the composition is 4.0 to 5.5, e.g., 4.5 to 5.5, or e.g., 4.0 to 5.0. In some embodiments, the long-acting beta-2 agonist includes arformoterol, the long-acting muscarinic antagonist includes rebefenacin, and the composition further comprises EDTA. In some embodiments, the long-acting beta-2 agonist includes arformoterol, the long-acting muscarinic antagonist includes rebefenacin, and the composition further comprises a buffer, such as, for example, a citric acid / citrate buffer, or further, for example, a citric acid / sodium citrate buffer. In some embodiments, the long-acting beta-2 agonist comprises arformoterol, the long-acting muscarinic antagonist comprises rebefenacin, and the composition further comprises a buffer, such as a citric acid / citrate buffer, e.g., a citric acid / sodium citrate buffer, at a concentration of 0.1 mM or greater, e.g., 0.1 mM to 20 mM, e.g., 0.1 mM to 10 mM, e.g., 1 mM to 10 mM. In some embodiments, the long-acting beta-2 agonist comprises arformoterol, the long-acting muscarinic antagonist comprises rebefenacin, and the composition further comprises sodium chloride, e.g., 1.00% or less by weight of sodium chloride, e.g., 0.01% to 1.00% by weight of sodium chloride.

[0065] In some embodiments, the long-acting beta-2 agonist comprises indacaterol, the long-acting muscarinic antagonist comprises glycopyrronium bromide, and the pH of the composition is 2.5 to 4.0, e.g., 3.0 to 4.0, or e.g., 2.5 to 3.5, further e.g., 3.0 to 3.5, further e.g., 3.5. In some embodiments, the long-acting beta-2 agonist comprises indacaterol, the long-acting muscarinic antagonist comprises glycopyrronium bromide, and the composition further comprises EDTA and / or cyclodextrin, e.g., cyclodextrin, further e.g., EDTA and cyclodextrin. In some embodiments, the long-acting beta-2 agonist comprises indacaterol, the long-acting muscarinic antagonist comprises glycopyrronium bromide, and the composition further comprises sodium hyaluronate. In some embodiments, the long-acting beta-2 agonist comprises indacaterol, the long-acting muscarinic antagonist comprises glycopyrronium bromide, and the composition further comprises sodium hyaluronate, and at least one selected from the group consisting of EDTA and a cyclodextrin. In some embodiments, the long-acting beta-2 agonist comprises indacaterol, the long-acting muscarinic antagonist comprises glycopyrronium bromide, and the composition further comprises sodium hyaluronate and a cyclodextrin.

[0066] In some embodiments, the long-acting beta-2 agonist comprises indacaterol, the long-acting muscarinic antagonist comprises rebefenacin, and the pH of the composition is 3.0 to 4.5, such as 3.5 to 4.5, further such as 3.5 to 4.0, or such as 4.0 to 4.5, further such as 4.0. In some embodiments, the long-acting beta-2 agonist comprises indacaterol, the long-acting muscarinic antagonist comprises rebefenacin, and the composition further comprises EDTA and a cyclodextrin, such as a cyclodextrin, further such as EDTA and a cyclodextrin.

[0067] In some embodiments, the long-acting beta-2 agonist comprises indacaterol, the long-acting muscarinic antagonist comprises tiotropium bromide, and the pH of the composition is 2.0 to 4.0, such as 2.5 to 4.0, such as 2.5 to 3.5, such as 2.5 to 3.0, or even 2.5. In some embodiments, the long-acting beta-2 agonist comprises indacaterol, the long-acting muscarinic antagonist comprises tiotropium bromide, and the composition further comprises a cyclodextrin.

[0068] In some embodiments, the composition is an aerosolized inhalable drug composition. In some embodiments, the composition is an aerosolized inhalable drug composition administered by a vibrating screen, ultrasonic nebulization, or air compressor.

[0069] In some embodiments, the pharmaceutical composition is an inhalation spray (soft mist), an aerosol (MDI), or a nebulizer.

[0070] In some embodiments, the drug composition is administered by means of a metered dose inhaler (MDI).

[0071] In some embodiments, the drug composition further comprises one or more auxiliary ingredients: excipients, propellants, cosolvents, fillers, non-volatile components, buffers, pH adjusters, surfactants, preservatives, complexing agents, antioxidants, or combinations thereof.

[0072] In some embodiments, the drug composition is a spray, and the method for preparing the spray comprises mixing a bronchodilator and high molecular weight hyaluronic acid, particularly a long-acting beta-2 agonist, a long-acting muscarinic antagonist, and high molecular weight hyaluronic acid, in a solvent.

[0073] In some embodiments, the drug composition is an aerosol, and the method for producing the aerosol includes mixing a bronchodilator, high molecular weight hyaluronic acid, and a propellant, particularly a long-acting beta-2 agonist, a long-acting muscarinic antagonist, high molecular weight hyaluronic acid, and a propellant, in a solvent. In some embodiments, the propellant is a hydrofluoroalkane. In some embodiments, the hydrofluoroalkane is 1,1,1,2-tetrafluoroethane and / or 1,1,1,2,3,3,3-heptafluoropropane. In some embodiments, the hydrofluoroalkane is 1,1,1,2-tetrafluoroethane. In some embodiments, the hydrofluoroalkane is 1,1,1,2,3,3,3-heptafluoropropane. In some embodiments, the hydrofluoroalkane is 1,1,1,2-tetrafluoroethane and 1,1,1,2,3,3,3-heptafluoropropane. In some embodiments, the hydrofluoroalkane is 1,1,1,2-tetrafluoroethane and 1,1,1,2,3,3,3-heptafluoropropane.

[0074] In some embodiments, the active ingredients of the drug composition are present in a fixed or loose combination and are used for simultaneous, sequential or separate administration together with excipients in pharmaceutical forms suitable for inhalation applications.

[0075] In the embodiments of the present application, the long-acting β2 agonist, long-acting muscarinic antagonist or other components, such as indacaterol, formoterol, arformoterol, vilanterol, carmoterol, and olodaterol, glycopyrronium bromide, umeclidinium bromide, tiotropium bromide, aclidinium bromide, and rebefenacin, hyaluronic acid such as high molecular weight hyaluronic acid, EDTA, ethyl oleate, etc., are mentioned, and unless otherwise specified, these mentioned components or pharmaceutically acceptable salts thereof are included. For example, when an embodiment of the present application refers to a pharmaceutical composition of the present application comprising a long-acting β2 agonist and a long-acting muscarinic antagonist, these embodiments of the present application should be considered to refer to a pharmaceutical composition of the present application comprising a long-acting β2 agonist or a pharmaceutically acceptable salt thereof, and a long-acting muscarinic antagonist or a pharmaceutically acceptable salt thereof. When in the embodiments of the present application it is referred to that the pharmaceutical composition of the present application comprises EDTA, it should be considered and analogized that in those embodiments of the present application it is referred to that the pharmaceutical composition of the present application comprises EDTA and its pharmaceutically acceptable salts. [Brief explanation of the drawings]

[0076] [Figure 1] 1 shows the change in revefenacin content in a stability test of arformoterol tartrate-revefenacin compositions with different buffer concentrations. [Figure 2] 1 shows the change in arformoterol content in a stability test of arformoterol tartrate-levefenacin compositions with different buffer concentrations. [Figure 3] 1 shows the change in pH value during stability testing of arformoterol tartrate-levefenacin compositions with different buffer concentrations. [Figure 4] 1 shows the change in revefenacin content in a stability test of arformoterol tartrate-revefenacin compositions containing different types of auxiliary ingredients. [Figure 5]1 shows the change in arformoterol content in a stability test of arformoterol tartrate-levefenacin compositions containing different types of auxiliary ingredients. [Figure 6] 1 shows the change in indacaterol content in a stability study of indacaterol maleate-glycopyrronium bromide compositions at different pH values. [Figure 7] 1 shows the change in glycopyrronium bromide content in a stability test of indacaterol maleate-glycopyrronium bromide compositions containing different types of auxiliary ingredients. [Figure 8] 1 shows the change in total impurity content in stability studies of indacaterol maleate-glycopyrronium bromide compositions containing different types of auxiliary ingredients. [Figure 9] 1 shows the changes in indacaterol content and glycopyrronium bromide content during a stability test of indacaterol maleate-glycopyrronium bromide compositions at pH 4 containing different types of auxiliary ingredients. [Figure 10] 1 shows the change in total impurity content during stability testing of indacaterol maleate-glycopyrronium bromide compositions at pH 4 containing different types of auxiliary ingredients. [Figure 11] 1 shows the changes in indacaterol content and glycopyrronium bromide content during a stability test of indacaterol maleate-glycopyrronium bromide compositions at pH 3 containing different types of auxiliary ingredients. [Figure 12] 1 shows the change in total impurity content during stability testing of indacaterol maleate-glycopyrronium bromide compositions at pH 3 containing different types of auxiliary ingredients. [Figure 13] 1 shows the changes in indacaterol content and glycopyrronium bromide content during a stability test of an indacaterol maleate-glycopyrronium bromide-sodium hyaluronate composition with a pH value of 4 containing different types of auxiliary ingredients. [Figure 14]1 shows the change in total impurity content during stability testing of indacaterol maleate-glycopyrronium bromide-sodium hyaluronate compositions with a pH value of 4 containing different types of auxiliary ingredients. [Figure 15] 1 shows the changes in indacaterol content and glycopyrronium bromide content during a stability test of an indacaterol maleate-glycopyrronium bromide-sodium hyaluronate composition with a pH value of 3 containing different types of auxiliary ingredients. [Figure 16] 1 shows the change in total impurity content during stability testing of indacaterol maleate-glycopyrronium bromide-sodium hyaluronate compositions with a pH value of 3 containing different types of auxiliary ingredients. [Figure 17] 1 shows the change in indacaterol content in a stability test of indacaterol maleate-levefenacin compositions at different pH values. [Figure 18] 1 shows the change in indacaterol content in a stability test of indacaterol maleate-levefenacin compositions at different pH values. [Figure 19] 1 shows the change in total impurity content in stability testing of indacaterol maleate-levefenacin compositions at different pH values. [Figure 20] 1 shows the change in total impurity content during stability testing of indacaterol maleate-levefenacin compositions with pH value of 4 containing different types of auxiliary ingredients. [Figure 21] 1 shows the change in indacaterol total impurity content in a stability study of indacaterol maleate-tiotropium bromide compositions at different pH values. [Figure 22] 1 shows the change in tiotropium bromide total impurity content in a stability study of indacaterol maleate-tiotropium bromide compositions at different pH values. [Figure 23] 1 shows the change in total impurity content during stability testing of indacaterol maleate-tiotropium bromide compositions at pH 3 with different types of auxiliary ingredients. [Figure 24]1 shows the change in total impurity content in a stability study of indacaterol maleate-tiotropium bromide compositions at pH 3, 4, or 5 with or without added sodium hyaluronate. DETAILED DESCRIPTION OF THE INVENTION

[0077] In order to further explain the technical means and effects adopted by the present application to achieve the specified objectives, the following will describe in detail the specific embodiments, structures, features and effects of the present application with reference to the drawings and preferred examples.

[0078] The term "and / or" (or "and / or", "and / or"), as used in this application, refers to covering any and all possible combinations of one or more associated listed items. When used with a list of two or more items, the term "and / or" (or "and / or", "and / or") means that any one of the listed items can be used alone, or any combination of two or more of the listed items can be used. For example, if a composition (or combination, structure, proposition, etc.) is described as including ingredients (or conditions) A, B, C, and / or D, the composition (or combination, structure, proposition, etc.) can include A only, B only, C only, D only, the combination of A and B, the combination of A and C, the combination of A and D, the combination of B and C, the combination of B and D, the combination of C and D, the combination of A, B, and C, the combination of A, B, and D, the combination of A, C, and D, the combination of B, C, and D, or the combination of A, B, C, and D.

[0079] As used in this application, including in the examples, unless otherwise specified, all numerical values ​​can be considered as if preceded by the words "substantially," "approximately," or "about," even if such terms do not explicitly appear. The phrase "approximately" or "about" can be used when describing a range and / or location to indicate that the stated value and / or location is within a range of reasonably expected values ​​and / or locations. For example, a numerical value may be ±0.1% of the value (or numerical range), ±1% of the value (or numerical range), ±2% of the value (or numerical range), ±5% of the value (or numerical range), ±10% of the value (or numerical range), ±15% of the value (or numerical range), ±20% of the value (or numerical range), etc. Any numerical range described in this application is intended to include all subranges or intermediate values ​​contained therein.

[0080] The disclosure of specific parameter values ​​and ranges does not exclude other values ​​and ranges useful in this application. It is anticipated that two or more specific exemplary values ​​for a given parameter can determine the endpoints of a range of values ​​that the parameter can claim. For example, if parameter X is recited in this application as having a value A and a value Z, parameter X is expected to have a range of values ​​from about A to about Z. Similarly, two or more numerical ranges for a published parameter (whether these ranges are nested, overlapping, or entirely different) are expected to include all possible combinations of ranges that can be claimed using the endpoints of the published ranges. For example, if parameter X is exemplified in this application as having a value in the range of 1 to 10, subranges of parameter X are also recited, and include, by way of example only, such as 1 to 9, 1 to 8, 1 to 7, 2 to 9, 2 to 8, 2 to 7, 3 to 9, 3 to 8, 3 to 7, 2 to 8, 3 to 7, 4 to 6, or 7 to 10, 8 to 10, or 9 to 10. Ranges are inclusive of their endpoints and values ​​within the endpoints, e.g., a range of 0 to 5 includes 0, >0, 1, 2, 3, 4, <5, and 5. [Example]

[0081] Example 1 Stability Test of Olodaterol Hydrochloride-Levefenacin Composition at Different pH Values ​​and in the Presence of EDTA Buffer solutions with pH 4.0, 4.5, 5.0, and 5.5 were prepared using 5 mM (mmol / L) citric acid and sodium citrate solutions (two pH 5.0 solutions and one each for the remaining solutions). The prescribed amount of sodium chloride was weighed and dissolved in 200 mL of pH buffer solution. The prescribed amounts of olodaterol hydrochloride and levefenacin were precisely added and mixed uniformly, and each solution was made up to 250 mL with pH buffer solution. EDTA was then added to one of the pH 5.0 solutions and stirred until completely dissolved. The resulting solutions were filled into low-density polyethylene PET bottles at 2 mL per bottle. The experimental formulation is shown in Table 1.

[0082] [Table 1]

[0083] A stability test was conducted to measure the contents of olodaterol and rebefenacin in the samples at the initial state and after standing for 2 weeks at 60°C. The results are shown in Table 2.

[0084] [Table 2]

[0085] After all samples were left to stand at 60°C for two weeks, the change in olodaterol content was within 2%, and the rebefenacin content was almost unchanged, indicating good stability. [Example]

[0086] Example 2 Stability Study of Arformoterol Tartrate-Levefenacin Composition at Different pH Values Three buffer solutions with pH 4.0, 4.5, and 5.0 were prepared by mixing appropriate amounts of 5 mM citric acid solution and sodium citrate solution. 450 mL of each pH buffer solution was taken, and the prescribed amounts of sodium chloride, arformoterol tartrate, and lebefenacin were precisely added and mixed uniformly. The buffer solution was adjusted to 500 mL. The resulting solution was filled into low-density polyethylene PET bottles at 2 mL per bottle. The formulation for the experiment is shown in Table 3.

[0087] [Table 3]

[0088] A stability test was conducted to measure the arformoterol and rebefenacin contents in the samples at the initial state and after 4 weeks at 25±2°C. The results are shown in Table 4.

[0089] [Table 4]

[0090] After 4 weeks of storage at 25±2°C, all samples showed good stability, with the arformoterol content changing within a 3% range and the rebefenacin content remaining almost unchanged. The long-term storage condition for the commercially available arformoterol tartrate inhalation solution is 2-8°C, while the accelerated storage condition is 25±2°C, allowing for storage for 3 months under accelerated conditions. [Example]

[0091] Example 3 Stability Test of Arformoterol Tartrate-Levefenacin-Hyaluronic Acid Composition at Different pH and Different EDTA Concentrations The prescribed amount of sodium chloride was added to 450 mL of 5 mM citric acid / sodium citrate buffer solution (pH 4.5, 5.5, 5.0, 4.5, and 5.5, respectively) in order, and after stirring and dissolving, precisely weighed prescribed amounts of arformoterol tartrate, lebefenacin, and hyaluronic acid were added and mixed uniformly. The volume was adjusted to 500 mL with pH buffer, and the resulting solution was filled into low-density polyethylene PET bottles at 2 mL per bottle. The formulation for the experiment is shown in Table 5.

[0092] [Table 5]

[0093] A stability test was conducted to measure the arformoterol and rebefenacin contents in the samples at the initial state and after 4 weeks at 25±2°C. The results are shown in Table 6.

[0094] [Table 6]

[0095] After all samples were left to stand at 25±2°C for 4 weeks, the change in arformoterol content was within a 5% range, and the rebefenacin content was found to be almost unchanged. [Example]

[0096] Example 4 Stability Study of Arformoterol Tartrate-Levefenacin Composition at Different Buffer Concentrations 1 L of citric acid / sodium citrate buffer solutions of different concentrations and pH 5 were prepared (pH was adjusted with dilute hydrochloric acid for those without buffer). The prescribed amount of sodium chloride was added to the buffer solution and stirred to dissolve, after which lebefenacin and arformoterol tartrate were added and stirred until completely dissolved. The resulting drug solutions were filled into low-density polyethylene PET bottles at 2 mL per bottle and sealed in aluminum foil bags. The experimental formulations are shown in Table 7.

[0097] [Table 7]

[0098] Stability tests were conducted to measure the arformoterol and revefenacin contents and sample pH values ​​in the initial state and after 3 months of storage at 25°C and 60% RH (relative humidity). The results are shown in Table 8 and Figures 1 to 3. Figure 1 shows the change in revefenacin content during the stability test of arformoterol-revefenacin compositions with different buffer concentrations. Figure 2 shows the change in arformoterol content during the stability test of arformoterol-revefenacin compositions with different buffer concentrations. Figure 3 shows the change in pH during the stability test of arformoterol-revefenacin compositions with different buffer concentrations.

[0099] [Table 8]

[0100] The addition of a pH buffer is beneficial for product stability, and it was found that as the pH buffer concentration increased, the stability of both the active pharmaceutical ingredients, rebefenacin and arformoterol, significantly improved, and the pH became more stable during the storage period. [Example]

[0101] Example 5 Stability Study of Arformoterol Tartrate-Levefenacin Composition at Different pH Values 1 mM citric acid / sodium citrate buffer solutions with pH values ​​of 4.5, 4.75, 5.25, and 5.5 were prepared, and the prescribed amount of sodium chloride was added and stirred until completely dissolved. The prescribed amounts of rebefenacin and arformoterol tartrate were then added and stirred until completely dissolved. The resulting drug solutions were filled into low-density polyethylene PET bottles at 2 mL per bottle and sealed in aluminum foil bags. The experimental formulations are shown in Table 9.

[0102] [Table 9]

[0103] A stability test was conducted to measure the arformoterol and rebefenacin contents and sample pH values ​​in the initial state and after storage for 3 months at 40°C, 75% RH or 25°C, 60% RH. The results are shown in Table 10.

[0104] [Table 10]

[0105] As can be seen, after storage at 40°C and 75% RH for 3 months, the rebefenacin content in the arformoterol tartrate-rebefenacin composition having a pH value in the range of 4.5 to 5.5 decreased by within 5%, demonstrating that the pharmaceutical solution was relatively stable. After storage at 25°C and 60% RH for 2 months, the arformoterol content in the arformoterol tartrate-rebefenacin composition having a pH value in the range of 4.5 to 5.5 decreased by within 5%, demonstrating that the pharmaceutical solution was more temperature-sensitive than the arformoterol solution. The commercially available single-solution product could be stored at 25°C and 60% RH for 6 weeks, and in some embodiments, the composition was relatively stable within the pH range of 4.5 to 5.5. [Example]

[0106] Example 6 Stability test of arformoterol tartrate-levefenacin composition after addition of auxiliary ingredients Meanwhile, the effect of adding auxiliary ingredients such as sodium chloride, EDTA, and polysorbate to the arformoterol tartrate-lebefenacin composition (solvent: 10 mM citric acid-sodium citrate buffer solution at pH 5) on product stability was examined. The experimental formulation is shown in Table 11. The prepared drug solution was placed in a low-density polyethylene bottle and sealed in an aluminum foil bag.

[0107] [Table 11]

[0108] Stability tests were conducted to measure the arformoterol and rebefenacin contents and sample pH values ​​in the initial state and after 3 months of storage under accelerated conditions of 45°C and 75% RH. The results are shown in Table 12 and Figures 4 and 5. Figure 4 shows the change in rebefenacin content during the stability test of arformoterol tartrate-rebefenacin compositions containing different types of auxiliary ingredients. Figure 5 shows the change in arformoterol content during the stability test of arformoterol tartrate-rebefenacin compositions containing different types of auxiliary ingredients.

[0109] [Table 12]

[0110] The addition of the auxiliary ingredient sodium chloride was found to be significantly beneficial to the stability of lebefenacin compared with no auxiliary ingredients or the addition of EDTA and polysorbate, whereas the addition of sodium chloride, EDTA, and polysorbate did not significantly affect the stability of arformoterol solution. [Example]

[0111] Example 7 Stability Study of Indacaterol Maleate-Glycopyrronium Bromide Compositions at Different pH Values Soft mist solutions of indacaterol maleate and glycopyrronium bromide at different pH levels were prepared using the following formulation. Six 500 mL aliquots of 0.02 mM citric acid solution were prepared. The pH was adjusted to 2.5, 3.0, 3.5, 4.0, 4.5, and 5.0 using 1 M (mol / L) sodium hydroxide solution. Indacaterol maleate and glycopyrronium bromide were added to the solution. To enhance dissolution of indacaterol during dissolution, the entire solution was sonicated in a 30°C water bath for 20 minutes until no visible particulate matter remained. The experimental formulation is shown in Table 13.

[0112] [Table 13]

[0113] The drug solution was placed in a glass bottle and a stability test was conducted. The indacaterol and glycopyrronium bromide contents and total impurity contents in the samples were measured initially and after 4 weeks at 60°C. The results are shown in Table 14 and Figures 6 to 8. Figure 6 shows the change in indacaterol content during a stability test of an indacaterol maleate-glycopyrronium bromide composition at different pH values. Figure 7 shows the change in glycopyrronium bromide content during a stability test of an indacaterol maleate-glycopyrronium bromide composition containing different types of auxiliary ingredients. Figure 8 shows the change in total impurity content during a stability test of an indacaterol maleate-glycopyrronium bromide composition containing different types of auxiliary ingredients.

[0114] [Table 14]

[0115] Analysis of changes in the drug solutions at different pH levels over the stability period revealed that the stability of indacaterol and glycopyrronium bromide was poor at both pH 5 and pH 4.5. Indacaterol was relatively stable at pH 2.5-4, with the best stability at pH 3.5, while glycopyrronium bromide was relatively stable at pH 2.5-3.5. Taking into account the changes in the contents of indacaterol and glycopyrronium bromide and the total impurity content, it was determined that in some embodiments, the most preferred pH for the indacaterol-glycopyrronium bromide composition is 3.5. [Example]

[0116] Example 8 Stability test of indacaterol maleate-glycopyrronium bromide composition after addition of auxiliary ingredients The effect of adding auxiliary ingredients such as EDTA and cyclodextrin to the indacaterol maleate-glycopyrronium bromide composition on stability was also investigated. The experimental formulation is shown in Table 15. The pH was adjusted to the desired level using citric acid and sodium citrate solutions, and the resulting solution was placed in a glass bottle and sealed.

[0117] [Table 15]

[0118] The drug solution was placed in a glass bottle and a stability test was conducted. The indacaterol content, glycopyrronium bromide content, and total impurity content in the sample were measured initially and after 4 weeks at 60°C. The results are shown in Table 16 and Figures 9 to 12. Figure 9 shows the changes in indacaterol content and glycopyrronium bromide content during a stability test of an indacaterol maleate-glycopyrronium bromide composition with a pH of 4 and containing different auxiliary ingredients. Figure 10 shows the changes in total impurity content during a stability test of an indacaterol maleate-glycopyrronium bromide composition with a pH of 4 and containing different auxiliary ingredients. Figure 11 shows the changes in indacaterol content and glycopyrronium bromide content during a stability test of an indacaterol maleate-glycopyrronium bromide composition with a pH of 3 and containing different auxiliary ingredients. FIG. 12 shows the change in total impurity content during stability testing of indacaterol maleate-glycopyrronium bromide compositions at pH 3 containing different types of auxiliary ingredients.

[0119] [Table 16]

[0120] After adding cyclodextrin or simultaneously adding cyclodextrin and EDTA to a composition with a pH of 4, the decrease in the indacaterol content and glycopyrronium bromide content in the composition was smaller, and the increase in the total impurity content was smaller, indicating that the addition of cyclodextrin or cyclodextrin and EDTA can significantly improve the stability of the drug solution. On the other hand, when the effects of adding EDTA and simultaneously adding EDTA and cyclodextrin to a composition with a pH of 3 were examined, the stability trends indicated that while the addition of EDTA can improve the stability of the composition, the simultaneous addition of EDTA and cyclodextrin can significantly improve the stability of the composition compared to the addition of EDTA alone. [Example]

[0121] Example 9 Stability test of indacaterol maleate-glycopyrronium bromide-sodium hyaluronate composition after addition of auxiliary ingredients Solutions of indacaterol maleate, glycopyrronium bromide, and sodium hyaluronate were prepared at different pH levels using the following formulation. Eight 20 mM citric acid solutions were prepared, and the pH was adjusted to 2.5, 3.0, 3.5, 4.0, 4.5, and 5.0 with 1 M sodium hydroxide. Glycopyrronium bromide and indacaterol maleate were then added and dissolved. The effect of adding auxiliary ingredients such as EDTA and cyclodextrin on solution stability was examined. The specific formulations are shown in Table 17.

[0122] [Table 17]

[0123] The drug solution was placed in a glass bottle and a stability test was conducted. The indacaterol content, glycopyrronium bromide content, and total impurity content in the sample were measured initially and after 4 weeks at 60°C. The results are shown in Table 18 and Figures 13 to 16. Figure 13 shows the changes in indacaterol content and glycopyrronium bromide content during a stability test of an indacaterol maleate-glycopyrronium bromide-sodium hyaluronate composition with a pH of 4 and containing different auxiliary ingredients. Figure 14 shows the changes in total impurity content during a stability test of an indacaterol maleate-glycopyrronium bromide-sodium hyaluronate composition with a pH of 4 and containing different auxiliary ingredients. Figure 15 shows the changes in indacaterol content and glycopyrronium bromide content during a stability test of an indacaterol maleate-glycopyrronium bromide-sodium hyaluronate composition with a pH of 3 and containing different auxiliary ingredients. FIG. 16 shows the change in total impurity content in the stability test of indacaterol maleate-glycopyrronium bromide-sodium hyaluronate composition with pH 3 containing different types of auxiliary ingredients.

[0124] [Table 18]

[0125] It was found that the addition of the auxiliary ingredients EDTA and cyclodextrin to indacaterol-glycopyrronium bromide-sodium hyaluronate compositions with pH values ​​of 3.0 and 4.0 improved the stability of both solutions. Comparing the results of adding cyclodextrin with those of adding cyclodextrin and EDTA simultaneously, it was found that cyclodextrin had the greatest effect on improving solution stability. [Example]

[0126] Example 10 Stability study of indacaterol maleate-levefenacin composition at different pH values Citric acid / sodium citrate buffer solutions were prepared at 20 mM concentration and pH values ​​of 2.5, 3.0, 3.5, 4.0, and 5.5. Indacaterol maleate was added in the following formulation and sonicated until completely dissolved. Sodium chloride and lebefenacin were then added and stirred until completely dissolved. The resulting solutions were placed in glass bottles and sealed. The formulations for the experiments are shown in Table 19.

[0127] [Table 19]

[0128] The samples were placed at a high temperature of 60°C for 4 weeks to undergo a stability test, and the changes in indacaterol content, rebefenacin content, and total impurity content (total impurities were determined using the area normalization method) in the samples were measured, as shown in Table 20 and Figures 17 to 19. Figure 17 shows the changes in indacaterol content during the stability test of indacaterol maleate-rebefenacin compositions at different pH values. Figure 18 shows the changes in indacaterol content during the stability test of indacaterol maleate-rebefenacin compositions at different pH values. Figure 19 shows the changes in total impurity content during the stability test of indacaterol maleate-rebefenacin compositions at different pH values.

[0129] [Table 20]

[0130] The above results show that the indacaterol maleate-levefenacin compound solution is stable at pH values ​​between 3.5 and 4.5, more stable than pH values ​​between 2.5 and 5.0, after being left at high temperature for 4 weeks. [Example]

[0131] Example 11 Stability test of indacaterol maleate-levefenacin composition after addition of auxiliary ingredients In addition, the effect of adding auxiliary ingredients such as EDTA (0.03% w / w) and cyclodextrin (0.05% w / w) to the indacaterol maleate-lebefenacin composition at pH 4 in Example 10 on the stability of the drug solution was examined. The experimental formulation is shown in Table 21. The pH was adjusted to the desired value using citric acid and sodium citrate solutions, and the prepared drug solution was placed in a glass bottle and sealed.

[0132] [Table 21]

[0133] The samples were left in a high temperature environment at 60°C for 4 weeks to undergo stability testing, and the changes in the total impurities content in the samples were measured, as shown in Table 22 and Figure 20. Figure 20 shows the changes in the total impurities content in the stability test of indacaterol maleate-levefenacin compositions with pH 4 containing different types of auxiliary ingredients.

[0134] [Table 22]

[0135] As can be seen from the results, the improvement in the stability of the drug solution by adding cyclodextrin is more significant, and the simultaneous addition of cyclodextrin and EDTA to the drug solution can significantly increase the stability of the drug solution. [Example]

[0136] Example 12 Stability study of indacaterol maleate-tiotropium bromide compositions at different pH values 20 mM citric acid / sodium citrate buffer solutions with pH values ​​of 2.5, 3.0, 3.5, 4.0, and 5.5 were prepared, and indacaterol maleate was added according to the formulation ratios in Table 23 and sonicated until completely dissolved. Sodium chloride and tiotropium bromide were then added and stirred until completely dissolved. The resulting solutions were placed in glass bottles and sealed. The formulations for the experiments are shown in Table 23.

[0137] [Table 23]

[0138] The samples were placed at a high temperature of 60°C for 4 weeks to undergo a stability test, and the changes in the indacaterol and tiotropium bromide contents and total impurity contents in the samples were measured as shown in Table 24 and Figures 21 and 22. Figure 21 shows the change in the total impurity content of indacaterol in a stability test of indacaterol-tiotropium bromide maleate compositions at different pH values. Figure 22 shows the change in the total impurity content of tiotropium bromide in a stability test of indacaterol maleate-tiotropium bromide compositions at different pH values.

[0139] [Table 24]

[0140] The results show that when the sample pH was between 2.5 and 4.5, the indacaterol content decreased by less than 5%, and when the sample pH was between 2.5 and 3.5, the tiotropium bromide content changed by less than 5%. Furthermore, when analyzed together with the results for the total impurities of indacaterol and tiotropium bromide, it is best to select a suitable pH for the indacaterol maleate-tiotropium bromide composition between 2.5 and 3.5. [Example]

[0141] Example 13: Stability test of indacaterol-tiotropium bromide composition after addition of auxiliary ingredients On the other hand, the effect on stability of adding auxiliary ingredients such as EDTA (0.03% w / w) and cyclodextrin (0.05% w / w) to the indacaterol maleate-tiotropium bromide composition having a pH value of 3 in Example 12 was investigated. The experimental formulation is shown in Table 25. The pH was adjusted to the desired value using citric acid and sodium citrate solutions, and the prepared drug solution was placed in a glass bottle and sealed.

[0142] [Table 25]

[0143] The samples were left in a high temperature environment at 60°C for 4 weeks, and then a stability test was conducted to measure the change in the total impurity content in the samples, as shown in Table 26 and Figure 23. Figure 23 shows the change in the total impurity content in the stability test of indacaterol maleate-tiotropium bromide compositions at pH 3 with different types of auxiliary ingredients added.

[0144] [Table 26]

[0145] The results of the change in total impurity content in Table 26 and Figure 23 show that the addition of cyclodextrin can significantly improve the stability of the drug solution compared to the addition of no auxiliary ingredients or the addition of EDTA. [Example]

[0146] Example 14 Stability test of indacaterol maleate-tiotropium bromide composition after addition of auxiliary ingredients On the other hand, the effect of adding sodium hyaluronate to the indacaterol maleate-tiotropium bromide compositions of Example 12, each having a pH of 3, 4, or 5, was investigated. The experimental formulation is shown in Table 27. The pH was adjusted to the desired value using citric acid and sodium citrate solutions, and the prepared solutions were placed in glass bottles and sealed.

[0147] [Table 27]

[0148] After leaving the samples in a high-temperature environment at 60°C for 4 weeks, a stability test was conducted and the changes in total impurity content in the samples were measured as shown in Table 28 and Figure 24. Figure 24 shows the changes in total impurity content in the stability test of indacaterol maleate-tiotropium bromide compositions with or without added sodium hyaluronate and pH 3, 4, or 5. The terms "without HA" and "with HA" in Figure 24 mean "without added sodium hyaluronate" and "with added sodium hyaluronate," respectively.

[0149] [Table 28]

[0150] As can be seen from the results of the change in total impurities in Table 28 and Figure 24, there was no obvious change in the stability of the drug solution after adding sodium hyaluronate, and the trend of the change in stability was consistent with that before adding sodium hyaluronate. [Example]

[0151] Example 15 Preparation of a long-acting β2 agonist-long-acting muscarinic antagonist-hyaluronic acid drug composition Preparation of olodaterol hydrochloride-lebefenacin-hyaluronic acid spray The prescribed amounts of olodaterol hydrochloride, lebefenacin, high molecular weight hyaluronic acid, and edetate calcium disodium were precisely weighed, the prescribed amount of ethanol was added, and the mixture was stirred uniformly. The appropriate amount of water for injection and the appropriate amount of benzalkonium chloride were added, and the pH was adjusted to 4.5-5.5 with citric acid / sodium citrate buffer, and the mixture was filled to produce a spray. The specific ingredient composition of the prepared spray is shown in Table 29.

[0152] [Table 29]

[0153] Preparation of olodaterol hydrochloride-glycopyrronium bromide-hyaluronic acid aerosol The prescribed amounts of ethyl oleate and polysorbate 80 were weighed and mixed uniformly, and the prescribed amounts of olodaterol hydrochloride, glycopyrronium bromide, and high molecular weight hyaluronic acid were precisely added and mixed uniformly. The resulting solution was transferred to a mixing vessel containing hydrofluoroalkane (HFA) propellant. The specific component composition of the prepared aerosol is shown in Table 30.

[0154] [Table 30]

[0155] Preparation of olodaterol hydrochloride-glycopyrronium bromide-hyaluronic acid inhalation spray The prescribed amounts of glycerin and ethanol were weighed and mixed uniformly, and the prescribed amounts of olodaterol hydrochloride, glycopyrronium bromide, and high molecular weight hyaluronic acid were precisely added and mixed uniformly. The pH was adjusted to 4.5-5.5 with dilute hydrochloric acid, and the resulting solution was transferred to a mixing vessel containing HFA (hydrofluoroalkane). The specific component composition of the prepared inhalation spray is shown in Table 31.

[0156] [Table 31]

[0157] Preparation of olodaterol hydrochloride-lebefenacin-hyaluronic acid inhalation spray The prescribed amount of EDTA-2Na was weighed and mixed uniformly, and the prescribed amounts of olodaterol hydrochloride, lebefenacin, and high molecular weight hyaluronic acid were precisely added and mixed uniformly. The pH was adjusted to 4.5-5.5 with citric acid, and the mixture was filled to produce an inhalation spray. The specific component composition of the prepared inhalation spray is shown in Table 32.

[0158] [Table 32]

[0159] Preparation of olodaterol hydrochloride-lebefenacin-hyaluronic acid aerosol The prescribed amounts of propylene glycol and ethanol were weighed and mixed uniformly, and the prescribed amounts of olodaterol hydrochloride, lebefenacin, and high molecular weight hyaluronic acid were precisely added and mixed uniformly. The resulting solution was transferred to a mixing vessel containing HFA, mixed, recycled, and filled into a special container. The specific component composition of the prepared aerosol is shown in Table 33.

[0160] [Table 33]

[0161] Preparation of olodaterol hydrochloride-glycopyrronium bromide-hyaluronic acid aerosol The prescribed amounts of ethyl oleate and polysorbate 80 were weighed and mixed uniformly, and the prescribed amounts of vilanterol, glycopyrronium bromide, and high molecular weight hyaluronic acid were precisely added and mixed uniformly. The resulting solution was transferred to a mixing vessel containing HFA. The specific formulation is shown in Table 34.

[0162] [Table 34]

[0163] Preparation of olodaterol hydrochloride-glycopyrronium bromide-hyaluronic acid aerosol The prescribed amounts of sodium chloride and EDTA were weighed and dissolved in water for injection and mixed uniformly, and the prescribed amounts of vilanterol, glycopyrronium bromide, and high molecular weight hyaluronic acid were precisely added and mixed uniformly, and the pH was adjusted with citric acid and sodium citrate buffer. The resulting solution was transferred into a low-density polyethylene vial and sealed with aluminum foil. The specific formulation is shown in Table 35.

[0164] [Table 35]

[0165] Preparation of olodaterol hydrochloride-glycopyrronium bromide-hyaluronic acid aerosol The prescribed amounts of sodium chloride and EDTA were weighed and dissolved in water for injection and mixed uniformly, and the prescribed amounts of olodaterol, glycopyrronium bromide, and high molecular weight hyaluronic acid were precisely added and mixed uniformly, and the pH was adjusted with citric acid and sodium citrate buffer. The resulting solution was transferred into a low-density polyethylene vial and sealed with aluminum foil. The specific formulation is shown in Table 36.

[0166] [Table 36]

[0167] The above embodiments are merely preferred embodiments of the present application, which do not limit the scope of protection of the present application, and any insubstantial changes and substitutions made by those skilled in the art based on the present application also belong to the scope of protection claimed by the present application.

Claims

1. 1. A drug composition for inhalation comprising: long-acting beta ２ an agonist or a pharmaceutically acceptable salt thereof, and a long-acting muscarinic antagonist or a pharmaceutically acceptable salt thereof; where: The long-acting beta ２ The agonist comprises olodaterol, or The long-acting beta ２ the agonist comprises arformoterol and the pH value of the composition is between 3.5 and 5.5; or The long-acting beta ２ the agonist comprises indacaterol and the pH value of the composition is between 2.5 and 4.5; or the long-acting muscarinic antagonist comprises rebefenacin and the pH value of the composition is 3.5 to 5.5; or the long-acting muscarinic antagonist comprises glycopyrronium bromide and the pH value of the composition is 2.5 to 4.5; or The long-acting muscarinic antagonist comprises tiotropium bromide, and the pH value of the composition is 2.0-4.

0.

2. The long-acting beta ２ 2. The composition of claim 1, wherein the agonist is at least one selected from the group consisting of indacaterol, formoterol, arformoterol, vilanterol, carmoterol, and olodaterol.

3. 3. The composition of claim 1, wherein the long-acting muscarinic antagonist is at least one selected from the group consisting of glycopyrronium bromide, umeclidinium bromide, tiotropium bromide, aclidinium bromide, and rebefenacin.

4. The long-acting beta ２ The composition according to any one of claims 1 to 3, wherein the content of the agonist or a pharmaceutically acceptable salt thereof is 1 to 100 µg / mL, optionally 5 to 100 µg / mL.

5. 5. The composition according to any one of claims 1 to 4, wherein the content of the long-acting muscarinic antagonist or a pharmaceutically acceptable salt thereof is 1 to 100 μg / mL, optionally 5 to 100 μg / mL.

6. The long-acting beta ２ 6. The composition of any one of claims 1 to 5, wherein the weight ratio of the agonist or a pharmaceutically acceptable salt thereof to the long-acting muscarinic antagonist or a pharmaceutically acceptable salt thereof is from 100:1 to 1:100, alternatively from 1:80 to 80:1, alternatively from 1:60 to 60:1, alternatively from 1:50 to 50:1, alternatively from 1:40 to 40:1, alternatively from 1:30 to 30:1, alternatively from 1:20 to 20:1, alternatively from 1:15 to 15:

1.

7. The long-acting beta ２ the agonist comprises olodaterol and the long-acting muscarinic antagonist comprises rebefenacin; Optionally, the pH value of the composition is between 4.0 and 5.5; 7. The composition of any one of claims 1 to 6, optionally further comprising EDTA.

8. The long-acting beta ２ the agonist comprises arformoterol, the long-acting muscarinic antagonist comprises rebefenacin, and the pH value of the composition is 4.0 to 5.5; Optionally, the pH value of the composition is 4.5 to 5.5; Optionally, the pH value of the composition is 4.0 to 5.0; Optionally, the composition further comprises EDTA; Optionally, the composition further comprises a buffer; Optionally, the buffer is a citric acid / citrate buffer; Optionally, the buffer is a citric acid / sodium citrate buffer; Optionally, the concentration of the buffer is between 0.1 mM and 20 mM; Optionally, the composition further comprises sodium chloride; Optionally, in the composition, the weight percentage of the sodium chloride is 0.01% to 1.00%.

9. The long-acting beta ２ the agonist comprises indacaterol, the long-acting muscarinic antagonist comprises glycopyrronium bromide, and the pH value of the composition is 2.5 to 4.0; Optionally, the pH value of the composition is 3.0 to 4.0; Optionally, the pH value of the composition is between 2.5 and 3.5; Optionally, the pH value of the composition is 3.0 to 3.5; Optionally, the composition further comprises EDTA and / or cyclodextrin; Optionally, the composition further comprises a cyclodextrin; Optionally, the composition further comprises EDTA and a cyclodextrin; Optionally, the composition further comprises sodium hyaluronate; Optionally, the composition further comprises sodium hyaluronate and at least one selected from the group consisting of EDTA and cyclodextrin; 7. The composition of any one of claims 1 to 6, optionally further comprising sodium hyaluronate and cyclodextrin.

10. The long-acting beta ２ the agonist comprises indacaterol, the long-acting muscarinic antagonist comprises rebefenacin, and the pH value of the composition is 3.0 to 4.5; Optionally, the pH value of the composition is between 3.5 and 4.5; Optionally, the pH value of the composition is 3.5 to 4.0; Optionally, the pH value of the composition is 4.0 to 4.5; Optionally, the composition further comprises EDTA and / or cyclodextrin; Optionally, the composition further comprises a cyclodextrin; 7. The composition of any one of claims 1 to 6, optionally further comprising EDTA and a cyclodextrin.

11. The long-acting beta ２ the agonist comprises indacaterol, the long-acting muscarinic antagonist comprises tiotropium bromide, and the pH value of the composition is 2.0 to 4.0; Optionally, the pH value of the composition is from 2.5 to 4.0; Optionally, the pH value of the composition is between 2.5 and 3.5; Optionally, the pH value of the composition is 2.5 to 3.0; 7. The composition of any one of claims 1 to 6, optionally further comprising a cyclodextrin.

12. further comprising hyaluronic acid or a pharmaceutically acceptable salt thereof; Optionally, the hyaluronic acid is a high molecular weight hyaluronic acid; Optionally, the composition according to any one of claims 1 to 11, wherein the weight percentage of hyaluronic acid is between 0.01% and 0.50%.

13. further comprising sodium chloride, EDTA or a pharmaceutically acceptable salt thereof, and / or cyclodextrin or derivatives thereof or a pharmaceutically acceptable salt thereof; Optionally, the cyclodextrin comprises α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin; Optionally, the cyclodextrin comprises hydroxypropyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin; Optionally, the weight percent of said sodium chloride is 0.01% to 1.00%; Optionally, the weight percentage of the EDTA or its pharmaceutically acceptable salts is 0.001% to 0.100%; 13. The composition of any one of claims 1 to 12, optionally wherein the weight percentage of the cyclodextrin is from 0.01% to 10%, optionally from 0.01% to 1.00%.

14. The composition according to any one of claims 1 to 13, which is a pharmaceutical composition for inhalation for the prevention or treatment of respiratory diseases, in particular for the prevention or treatment of respiratory diseases.

15. 15. The composition of claim 14, wherein the respiratory disease comprises asthma or chronic obstructive pulmonary disease.

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