Pharmaceutical composition comprising budesonide, tiotropium bromide, and olodaterol and preparation process therefor

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By preparing a pharmaceutical composition containing budesonide, tiotropium bromide, and olodaterol, and adding stabilizers and other ingredients, the problem of the lack of uniform and stable inhaled formulations in the prior art has been solved, and therapeutic effects suitable for inhaled sprays have been achieved.

WO2026158575A1PCT designated stage Publication Date: 2026-07-30CHIA TAI TIANQING PHARMA GRP CO LTD

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Patent Information

Authority / Receiving Office: WO · WO
Patent Type: Applications
Current Assignee / Owner: CHIA TAI TIANQING PHARMA GRP CO LTD
Filing Date: 2026-01-23
Publication Date: 2026-07-30

AI Technical Summary

Technical Problem

Currently, there are no inhaled sprays containing budesonide, tiotropium bromide, and olodaterol on the market, resulting in a lack of inhaled formulations with uniform and stable drug properties.

Method used

A pharmaceutical composition comprising budesonide, tiotropium bromide, and olodaterol, as well as a stabilizer, antioxidant, solvent, pH adjuster, metal ion chelating agent, and antibacterial agent, is provided, and is prepared as an inhaled liquid formulation or an inhaled spray.

Benefits of technology

It achieves homogeneity of pharmaceutical composition and stability of drug properties, making it suitable as an inhaled formulation for the treatment of chronic obstructive pulmonary disease and asthma.

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Abstract

Provided are a pharmaceutical composition comprising budesonide, tiotropium bromide, and olodaterol, as well as a stabilizer and / or an antioxidant, and a preparation process therefor. The pharmaceutical composition of the present disclosure, especially in the form of an inhalation spray, has the advantages of good stability, uniform spray delivery doses, a consistent spray state, a high lung deposition rate, and / or a good drug inhalation effect, which make the pharmaceutical composition particularly suitable for industrial production and clinical application.

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Description

A pharmaceutical composition containing budesonide, tiotropium bromide and olodaterol and its preparation process.

[0001] Cross-references to related applications

[0002] This application claims priority and benefit to Chinese patent application No. 202510121783.7, filed with the China National Intellectual Property Administration on January 24, 2025, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] This disclosure pertains to the field of pharmaceutical formulations and relates to a pharmaceutical composition containing budesonide, tiotropium bromide, and olodaterol, and its preparation process. Background Technology

[0004] Budesonide is a highly effective local anti-inflammatory glucocorticoid with the following structural formula (i.e., compound I). It effectively controls airway inflammation by enhancing the stability of endothelial cell, smooth muscle cell, and lysosomal membranes, thereby reducing the release of histamine and other allergic mediators, mitigating the enzymatic processes triggered by antigen-antibody binding, and inhibiting the synthesis and release of bronchoconstrictive substances. It is currently the first-line drug for the treatment of asthma and chronic obstructive pulmonary disease (COPD).

[0005] Tiotropium bromide is a long-acting antimuscarinic bronchodilator with the structural formula shown below (i.e., compound II), used to treat chronic obstructive pulmonary disease (COPD) and asthma. Tiotropium bromide primarily acts on M3 muscarinic receptors located in the airways to produce smooth muscle relaxation and bronchodilation. Inhaled tiotropium bromide is suitable for maintaining bronchospasm in COPD and preventing COPD exacerbations.

[0006] Odanoterol is a novel, long-acting β2-adrenergic agonist (LABA) with the structure shown below (i.e., compound III). It exerts its pharmacological effects by binding to and activating β2-adrenergic receptors, primarily located in the lungs. β2-adrenergic receptors are membrane-bound receptors, normally activated by endogenous adrenaline. Their signaling mediates smooth muscle relaxation and bronchodilation via downstream L-type calcium channel interactions. Receptor activation stimulates associated G proteins, which then activate adenylate cyclase, catalyzing the formation of cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA). Elevations in these two molecules induce bronchodilation by relaxing airway smooth muscle. It is through this mechanism that olodaterol is used to treat chronic obstructive pulmonary disease (COPD) and its characteristic progressive airflow obstruction.

[0007] Currently, there are no inhaled sprays containing budesonide, tiotropium bromide, or olodaterol on the market. Therefore, it is necessary to develop an inhaled formulation with uniform delivery and stable drug properties.

[0008] Invention Details

[0009] On one hand, this disclosure provides a pharmaceutical composition comprising budesonide, tiotropium bromide and olodaterol, as well as a stabilizer and / or an antioxidant.

[0010] In some embodiments of this disclosure, the pharmaceutical composition comprises budesonide, tiotropium bromide, olodaterol, a stabilizer, and an antioxidant.

[0011] In some embodiments of this disclosure, the pharmaceutical composition further comprises a solvent.

[0012] In some embodiments of this disclosure, the solvent is selected from one or both of ethanol and water.

[0013] In some embodiments of this disclosure, the pharmaceutical composition comprises ethanol and water.

[0014] In some embodiments of this disclosure, the pharmaceutical composition further comprises one or more of a solvent, a pH adjuster, a metal ion chelating agent, and a bacteriostatic agent. In some embodiments of this disclosure, the pharmaceutical composition comprises budesonide, tiotropium bromide, and olodaterol, as well as a stabilizer, an antioxidant, and ethanol.

[0015] In some embodiments of this disclosure, the pharmaceutical composition comprises budesonide, tiotropium bromide, and olodaterol, as well as stabilizers, antioxidants, ethanol, and water.

[0016] In some embodiments of this disclosure, the pharmaceutical composition comprises budesonide, tiotropium bromide, and olodaterol, as well as stabilizers, antioxidants, ethanol, and pH adjusters.

[0017] In some embodiments of this disclosure, the pharmaceutical composition comprises budesonide, tiotropium bromide, and olodaterol, as well as stabilizers, antioxidants, ethanol, pH adjusters, and water.

[0018] In some embodiments of this disclosure, the pharmaceutical composition comprises budesonide, tiotropium bromide, and olodaterol, as well as stabilizers, antioxidants, ethanol, pH adjusters, water, and metal ion chelators.

[0019] In some embodiments of this disclosure, the pharmaceutical composition comprises budesonide, tiotropium bromide, and olodaterol, as well as stabilizers, antioxidants, ethanol, pH adjusters, water, and antibacterial agents.

[0020] In some embodiments of this disclosure, the pharmaceutical composition comprises budesonide, tiotropium bromide, and olodaterol, as well as stabilizers, antioxidants, ethanol, pH adjusters, water, metal ion chelators, and antibacterial agents.

[0021] In some embodiments of this disclosure, the pharmaceutical composition is a liquid formulation.

[0022] In some embodiments of this disclosure, the pharmaceutical composition is an inhaled formulation.

[0023] In some embodiments of this disclosure, the pharmaceutical composition is an inhaled liquid formulation.

[0024] In some specific embodiments of this disclosure, the pharmaceutical composition is an inhalation spray.

[0025] In some embodiments of this disclosure, the amount of budesonide in the pharmaceutical composition is selected from 0.1–10 w / w%; or 0.1–9 w / w%, 0.1–8 w / w%, 0.1–7 w / w%, 0.1–6 w / w%, 0.1–5 w / w%, 0.125–5 w / w%, 0.15–5 w / w%, 0.2–5 w / w%, 0.2–4.5 w / w%, 0.25–4.5 w / w%, 0.25–4 w / w%, 0.3–4 w / w%, 0.3–3 w / w%, 0.4–3 w / w% / w%, 0.4–2w / w%, 0.5–2w / w%, 0.5–1.8w / w%, 0.6–1.8w / w%, 0.6–1.6w / w%, 0.7–1.6w / w%, 0.7–1.4w / w%, 0.8–1.4w / w%, or 0.8–1.2w / w%; or 0.125–2.5w / w%; or 0.125–1.5w / w%, or 0.125–1w / w%; or 0.125w / w%, 0.25w / w%, 0.5w / w%, or 1w / w.

[0026] 0.1w / w%、 0.15w / w%、0.2w / w%、0.25w / w%、0.3w / w%、0.35w / w%、0.4w / w%、0.45w / w%、0.5w / w%、0.55w / w%、0.6w / w%、0.65w / w% 0.7w / w%, 0.75w / w%, 0.8w / w%, 0.85w / w%, 0.9w / w%, 0.95w / w%, 1w / w%, 1.05w / w%, 1.1w / w%, 1.15w / w%, 1.2w / w%, 1.25w / w%, 1.3w / w%, 1.35w / w%, 1.4w / w% 1.45w / w%, 1.5w / w%, 1.55w / w%, 1.6w / w%, 1.65w / w%, 1.7w / w%, 1.75w / w%, 1.8w / w%, 1.85w / w%, 1.9w / w%, 1.95w / w%, 2w / w%, 2.05w / w%, 2.1w / w%, 2.15w / w%, 2.2w / w%, 2.25w / w%, 2.3w / w%, 2.35w / w%, 2.4w / w%, 2.45w / w%, 2.5w / w%, 2.55w / w%, 2.6w / w%, 2.65w / w%, 2.7w / w%, 2.75w / w%, 2.8w / w%, 2.85w / w%, 2.9 w / w%、2.95w / w%、3w / w%、3.1w / w%、3.2w / w%、3.3w / w%、3.4w / w%、3.5w / w%、3.6w / w%、3.7w / w%、3.8w / w%、3.9w / w%、4w / w%、4.1w / w%、4.2w / w%、4.3w / w%、4. 4w / w%, 4.5w / w%, 4.6w / w%, 4.7w / w%, 4.8w / w%, 4.9w / w%, 5w / w%, 5.1w / w%, 5.2w / w%, 5.3w / w%, 5.4w / w%, 5.5w / w%, 5.6w / w%, 5.7w / w%, 5.8w / w%, 5.9w / w%, 6 w / w%、6.1w / w%、6.2w / w%、6.3w / w%、6.4w / w%、6.5w / w%、6.6w / w%、6.7w / w%、6.8w / w%、6.9w / w%、7w / w%、7.1w / w%、7.2w / w%、7.3w / w%、7.4w / w%、7.5w / w%、7 .6w / w%、7.7w / w%、7.8w / w%、7.9w / w%、8w / w%、8.1w / w%、8.2w / w%、8.3w / w%、8.4w / w%、8.5w / w%、8.6w / w%、8.7w / w%、8.8w / w%、8.9w / w%、9w / w%、9.1w / w%、9.2w / w%, 9.3w / w%, 9.4w / w%, 9.5w / w%, 9.6w / w%, 9.7w / w%, 9.8w / w%, 9.9w / w%, or 10w / w%, or any range formed by the aforementioned values as endpoints, or any value therein.

[0027] In some embodiments of this disclosure, the amount of budesonide in the pharmaceutical composition is selected from 0.1–0.25 w / w%, 0.1–0.5 w / w%, 0.1–1 w / w%, 0.1–10 w / w%, 0.25–0.5 w / w%, 0.25–1 w / w%, 0.25–10 w / w%, 0.5–1 w / w%, 0.5–10 w / w%, or 1–10 w / w.

[0028] In some embodiments of this disclosure, the amount of budesonide in the pharmaceutical composition is selected from 0.1–100 mg / mL; or 0.1–50 mg / mL, 0.2–40 mg / mL, 0.3–30 mg / mL, 0.4–20 mg / mL, 0.5–10 mg / mL, 0.6–10 mg / mL, 0.7–10 mg / mL, 0.8–10 mg / mL, 0.9–10 mg / mL, 1–10 mg / mL; or 1.1–9.5 mg / mL; or 1.14–9.09 mg / mL; or 1.14–2.27 mg / mL, 2.27–4.55 mg / mL, or 4.55–9.09 mg / mL; or 1.14 mg / mL, 2.27 mg / mL, 4.55 mg / mL, or 9.09 mg / mL.

[0029] In some embodiments of this disclosure, the amount of budesonide in the pharmaceutical composition is selected from 0.1 mg / mL, 0.5 mg / mL, 1 mg / mL, 1.10 mg / mL, 1.11 mg / mL, 1.12 mg / mL, 1.13 mg / mL, 1.14 mg / mL, 1.15 mg / mL, 1.16 mg / mL, 1.17 mg / mL, 1.18 mg / mL, 1.19 mg / mL, 1.20 mg / mL, 1.50 mg / mL, 2.00 mg / mL, 2.20 mg / mL, 2.21 mg / mL, 2.22 mg / mL, 2.23 mg / mL, 2.24 mg / mL, 2.25 mg / mL, ... 2.26mg / mL, 2.27mg / mL, 2.28mg / mL, 2.29mg / mL, 2.30mg / mL, 2.31mg / mL, 2.32mg / mL, 2.33mg / mL, 2.34mg / mL, 2.35mg / mL, 2.36mg / mL, 2.37mg / mL, 2. 38mg / mL, 2.39mg / mL, 2.40mg / mL, 2.50mg / mL, 3.00mg / mL, 3.50mg / mL, 4.00mg / mL, 4.50mg / mL, 4.51mg / mL, 4.52mg / mL, 4.53mg / mL, 4.54mg / mL, 4.55m g / mL, 4.56mg / mL, 4.57mg / mL, 4.58mg / mL, 4.59mg / mL, 4.60mg / mL, 4.61mg / mL, 4.62mg / mL, 4.63mg / mL, 4.64mg / mL, 4.65mg / mL, 4.66mg / mL, 4.67mg / mL, 4.68mg / mL, 4.69mg / mL, 4.70mg / mL, 5.00mg / mL, 5.50mg / mL, 6.00mg / mL, 6.50mg / mL, 7.00mg / mL, 7.50mg / mL, 8.00mg / mL, 8.50mg / mL, 9.00mg / mL, 9.01 mg / mL, 9.02 mg / mL, 9.03 mg / mL, 9.04 mg / mL, 9.05 mg / mL, 9.06 mg / mL, 9.07 mg / mL, 9.08 mg / mL, 9.09 mg / mL, 9.10 mg / mL, 9.11 mg / mL, 9.12 mg / mL, 9.13 mg / mL, 9.14 mg / mL, 9.15 mg / mL, 9.16 mg / mL, 9.17 mg / mL, 9.18 mg / mL, 9.19 mg / mL, 9.20 mg / mL, 9.50 mg / mL, or 10.00 mg / mL, or any range formed by the aforementioned values as endpoints, or any value therein.

[0030] In some embodiments of this disclosure, the amount of budesonide in the pharmaceutical composition is selected from 0.91–2.27 mg / mL, 0.91–4.55 mg / mL, 0.91–9.09 mg / mL, 0.91–90.9 mg / mL, 2.27–4.55 mg / mL, 2.27–9.09 mg / mL, 2.27–90.9 mg / mL, 4.55–9.09 mg / mL, 4.55–90.9 mg / mL, or 9.09–90.9 mg / mL.

[0031] In some embodiments of this disclosure, a single dose of the pharmaceutical composition comprises 3–380 mg of budesonide; or 5–360 mg, 6–340 mg, 7–320 mg, 8–300 mg, 9–280 mg, 10–260 mg, 11–240 mg, 12–220 mg, 13–200 mg, 14–180 mg, 15–160 mg, 16–150 mg, 17–140 mg, 18–130 mg, 19–120 mg, 20–110 mg, etc. mg, 21~100mg, 22~90mg, 23~80mg, 24~70mg, 25~60mg, 26~65mg, 27~50mg, 28~55mg, 29~50mg, 30~49mg, 31~48mg, 3 2~47mg, 33~46mg, 34~45mg, 35~44mg, 36~43mg, 37~42mg, 37~41mg, 37~40mg, 38~40mg, 38~39mg, 5~190mg, 6~170m g, 7~150mg, 8~130mg, 9~100mg, 10~80mg, 11~60mg, 12~40mg, 12~39mg, 12~38mg, 12~37mg, 12~36mg, 13~35mg, 13 ~34mg, 13~33mg, 13~32mg, 13~31mg, 13~30mg, 14~29mg, 14~28mg, 14~27mg, 14~26mg, 14~25mg, 15~25mg, 15~24mg The amounts of budesonide in a single dose of the pharmaceutical composition are 15–23 mg, 15–22 mg, 15–21 mg, 15–20 mg, 16–20 mg, 16–19 mg, 17–19 mg, or 18–19 mg, or 10–100 mg, or 12–50 mg, or 30–50 mg, or 38 mg, 19 mg, or 9.5 mg; or, in some embodiments of this disclosure, the amount of budesonide contained in a single dose of the pharmaceutical composition is 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 9 mg.5mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg , 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53m g, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68 mg, 69mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, or 380mg, or any of the aforementioned values as endpoints, forming a range or any value therein.

[0032] In some embodiments of this disclosure, the pharmaceutical composition is an inhalation spray, and each spray contains 10–1200 μg of budesonide; or 10–950 μg, 10–1000 μg, 20–1200 μg, 25–950 μg, 30–900 μg, 35–850 μg, 40–800 μg, 40–750 μg, 40–700 μg, 40–650 μg, 40–600 μg, 40–550 μg, 40–500 μg, 40–450 μg, 40–400 μg, 45–750 μg, 45–700 μg, 45–650 μg, 45–600 μg, 45–5 ... 00μg, 45~450μg, 45~400μg, 50~700μg, 50~650μg, 50~600μg, 50~550μg, 50~ 500μg, 50~450μg, 50~400μg, 55~600μg, 55~550μg, 55~500μg, 55~450μg, 60 ~400μg, 60~350μg, 60~300μg, 60~250μg, 60~200μg, 60~150μg, 65~400μg, 6 5~350μg, 65~300μg, 65~250μg, 65~200μg, 65~150μg, 70~350μg, 70~300μg, 70~250μg, 70~200μg, 70~150μg, 75~300μg, 75~250μg, 75~200μg, 75~150μ g, 80~250μg, 80~200μg, 80~150μg, 85~200μg, 85~150μg, 90~150μg, 90~140 μg, 90~130μg, 90~120μg, 90~110μg, 95~150μg, 95~140μg, 95~130μg, 95~12 0μg, 95~110μg, 95~115μg, 10~500μg, 10~400μg, 15~350μg, 15~300μg, 15~2 50μg, 20~200μg, 20~150μg, 20~140μg, 20~130μg, 20~120μg, 20~110μg, 20~ 100μg, 25~100μg, 25~90μg, 25~80μg, 25~70μg, 30~70μg, 35~70μg, 35~65μg 35–60 μg, 35–55 μg, 35–50 μg, 40–70 μg, 40–65 μg, 40–60 μg, 40–55 μg, 45–70 μg, 45–65 μg, 45–60 μg, 45–55 μg or 45–50 μg, or 10–250 μg, or 10–120 μg, or 12.5–100 μg, or 100 μg, 50 μg, 25 μg, or 12.5 μg; or, in some embodiments of this disclosure, each spray of the pharmaceutical composition contains 10 μg, 11 μg, 12 μg, 12.5 μg, 13 μg, 14 μg, 15 μg, 16 μg, 17 μg, 18 μg, 19 μg, 20 μg, 21 μg, 22 μg, 23 μg, 24 μg, 25 μg, 26 μg, 27 μg, 28 μg, 29 μg, 30 μg, 31 μg, 32 μg, 33 μg, 34 μg, 35 μg, 36 μg, 37 μg, or 38 μg of budesonide. g, 39μg, 40μg, 41μg, 42μg, 43μg, 44μg, 45μg, 46μg, 47μg, 48μg, 49μg, 50μg, 51μg, 52μg, 53μg, 54μg, 55μg, 56μg, 57μg, 58μg, 59μg, 60μg , 61μg, 62μg, 63μg, 64μg, 65μg, 66μg, 67μg, 68μg, 69μg, 70μg, 71μg, 72μg, 73μg, 74μg, 75μg, 76μg, 77μg, 78μg, 79μg, 80μg, 81μg, 82μg, 83μg,84μg,85μg,86μg,87μg,88μg,89μg,90μg,91μg,92μg,93μg,94μg,95μg,96μg,97μg,98μg,99μg,100μg,101μg,102μg,103μg,10 4μg, 105μg, 106μg, 107μg, 108μg, 109μg, 110μg, 115μg, 120μg, 125μg, 130μg, 135μg, 140μg, 145μg, 150μg, 155μg, 160μg, 165μg, 170μg 175μg, 180μg, 195μg, 200μg, 210μg, 220μg, 230μg, 240μg, 250μg, 260μg, 270μg, 280μg, 290μg, 300μg, 350μg, 400μg, 450μg, 500μg, 550μg, 600μg, 650μg, 700μg, 750μg, 800μg, 850μg, 900μg, 950μg, 1000μg, 1050μg, 1100μg, 1150μg, or 1200μg, or any of the aforementioned values as endpoints, forming a range or any value therein.

[0033] In some embodiments of this disclosure, each spray of the pharmaceutical composition contains 1–25 μg, 10–50 μg, 10–100 μg, 10–1000 μg, 25–50 μg, 25–100 μg, 25–1000 μg, 50–100 μg, 50–1000 μg, or 100–1000 μg.

[0034] In some embodiments of this disclosure, each spray of the pharmaceutical composition contains 100 μg, 50 μg, 25 μg, 25 μg, or 12.5 μg of budesonide, or any of the aforementioned values as endpoints within a range or any value therein.

[0035] In some embodiments of this disclosure, a single dose of the pharmaceutical composition contains at least 60 times, or at least 90 times, or at least 120 times, or at least 150 times, or at least 180 times, or at least 210 times, or at least 240 times, or at least 270 times, or at least 300 times, or at least 320 times, or at least 340 times, or at least 360 times, or at least 380 times, or at least 400 times, or at least 420 times, or at least 450 times, or at least 480 times, or at least 500 times, or at least 550 times, or at least 600 times.

[0036] In some embodiments of this disclosure, a single dose of the pharmaceutical composition contains 60 times the amount of budesonide contained in each spray.

[0037] In some embodiments of this disclosure, a single dose of the pharmaceutical composition contains 380 times the amount of budesonide contained in each spray.

[0038] In some embodiments of this disclosure, the amount of tiotropium bromide in the pharmaceutical composition is selected from 0.0001–1 w / w%; or 0.005–1 w / w%, or 0.01–1 w / w%, 0.01–0.5 w / w%, 0.01–0.4 w / w%, 0.01–0.3 w / w%, 0.01–0.2 w / w%, 0.01–0.1 w / w%, 0.01–0.05 w / w%, 0.01–0.04 w / w%, 0.01–0.03 w / w%, or 0.01–0.025 w / w%; or 0.01–0.1 w / w%; or 0.01–0.05 w / w%; or 0.0125–0.025 w / w%; or 0.0125 w / w%, 0.025 w / w.

[0039] In some embodiments of this disclosure, the amount of tiotropium bromide in the pharmaceutical composition is selected from 0.0001 w / w%, 0.0005 w / w%, 0.001 w / w%, 0.0015 w / w%, 0.002 w / w%, 0.0025 w / w%, 0.003 w / w%, 0.0035 w / w%, 0.004 w / w%, 0.0045 w / w%, 0.005 w / w%, 0.0055 w / w%, 0.006 w / w%, 0.0065 w / w%, 0.007 w / w%, 0.0075 w / w%, 0.0 08w / w%, 0.0085w / w%, 0.009w / w%, 0.0095w / w%, 0.01w / w%, 0.0105w / w%, 0.011w / w%, 0.0115w / w%, 0.012w / w%, 0.0125w / w%, 0.013w / w%, 0.0135w / w%, 0.014w / w%, 0.0145w / w%, 0.015w / w%, 0.0155w / w%, 0.016w / w%, 0.0165w / w%, 0.017w / w%, 0.0175w / w%, 0.018w / w%, 0.0185w / w%, 0.019w / w%, 0.0195w / w%, 0.02w / w%, 0.0205w / w%, 0.021w / w%, 0.0215w / w%, 0.022w / w%, 0.022 5w / w%, 0.023w / w%, 0.0235w / w%, 0.024w / w%, 0.0245w / w%, 0.025w / w%, 0.03w / w%, 0.04w / w%, 0.05w / w%, 0.06w / w%, 0.07w / w %, 0.08w / w%, 0.09w / w%, 0.1w / w%, 0.15w / w%, 0.2w / w%, 0.25w / w%, 0.3w / w%, 0.35w / w%, 0.4w / w%, 0.45w / w%, 0.5w / w%, 0.55w / w%, 0.6w / w%, 0.65w / w%, 0.7w / w%, 0.75w / w%, 0.8w / w%, 0.85w / w%, 0.9w / w%, 0.95w / w%, or 1w / w%, or any of the aforementioned values as endpoints, forming a range or any value therein.

[0040] In some embodiments of this disclosure, the amount of tiotropium bromide in the pharmaceutical composition is selected from 0.005–0.0125 w / w%, 0.005–0.025 w / w%, 0.005–0.25 w / w%, 0.0125–0.025 w / w%, 0.0125–0.25 w / w%, or 0.025–0.25 w / w.

[0041] In some embodiments of this disclosure, the amount of tiotropium bromide in the pharmaceutical composition is selected from 0.04–10 mg / mL; or 0.1–9 mg / mL, 0.1–8 mg / mL, 0.1–7 mg / mL, 0.1–6 mg / mL, 0.1–5 mg / mL, 0.1–4 mg / mL, 0.1–3 mg / mL, 0.1–2 mg / mL, 0.1–1 mg / mL; or 0.11–0.50 mg / mL; or 0.110–0.300 mg / mL; or 0.114–0.227 mg / mL; or 0.114 mg / mL or 0.227 mg / mL.

[0042] In some embodiments of this disclosure, the amount of tiotropium bromide in the pharmaceutical composition is selected from 0.0455 mg / mL, 0.05 mg / mL, 0.100 mg / mL, 0.101 mg / mL, 0.102 mg / mL, 0.103 mg / mL, 0.104 mg / mL, 0.105 mg / mL, 0.106 mg / mL, 0.107 mg / mL, 0.108 mg / mL, 0.109 mg / mL, 0.110 mg / mL, 0.111 mg / mL, 0.112 mg / mL, 0.113 mg / mL, 0.114 mg / mL, 0.115 mg / mL, 0.120 mg / mL, 0.125 mg / mL, etc. mL, 0.130mg / mL, 0.135mg / mL, 0.140mg / mL, 0.145mg / mL, 0.150mg / mL, 0.155mg / mL, 0.160mg / mL, 0.165mg / mL, 0.170mg / mL, 0.175mg / mL, 0.180mg / mL, 0.185mg / mL, 0.190mg / mL, 0.195mg / mL, 0.200mg / mL, 0.205mg / mL, 0.210mg / mL, 0.215mg / mL, 0.220mg / mL, 0.221mg / mL, 0.222mg / mL, 0.223mg / mL, 0.2 24mg / mL, 0.225mg / mL, 0.226mg / mL, 0.227mg / mL, 0.228mg / mL, 0.229mg / mL, 0.230mg / mL, 0.240mg / mL, 0.250mg / mL, 0.300mg / mL, 0.350mg / mL, 0.400 mg / mL, 0.450mg / mL, 0.455mg / mL, 0.500mg / mL, 0.550mg / mL, 0.600mg / mL, 0.650mg / mL, 0.700mg / mL, 0.750mg / mL, 0.800mg / mL, 0.850mg / mL, 0.900mg / The values are 0.950 mg / mL, 1.000 mg / mL, 1.500 mg / mL, 2.000 mg / mL, 2.500 mg / mL, 3.000 mg / mL, 3.500 mg / mL, 4.000 mg / mL, 4.500 mg / mL, 5.000 mg / mL, 5.500 mg / mL, 6.000 mg / mL, 6.500 mg / mL, 7.000 mg / mL, 7.500 mg / mL, 8.000 mg / mL, 8.500 mg / mL, 9.000 mg / mL, 9.500 mg / mL, or 10.000 mg / mL, or any of the aforementioned values as endpoints, forming a range or any value therein.

[0043] In some embodiments of this disclosure, the amount of tiotropium bromide in the pharmaceutical composition is selected from 0.0455–0.114 mg / mL, 0.0455–0.227 mg / mL, 0.0455–0.455 mg / mL, 0.114–0.227 mg / mL, 0.114–0.455 mg / mL, or 0.227–0.455 mg / mL.

[0044] In some embodiments of this disclosure, the amount of tiotropium bromide contained in a single-dose pharmaceutical composition is 0.1–10 mg; or 0.1–9 mg, 0.1–8 mg, 0.1–7 mg, 0.1–6 mg, 0.1–5 mg, 0.1–4 mg, 0.1–3 mg, 0.1–2 mg, 0.15–1.9 mg, 0.19–1.9 mg; or 0.19–1.9 mg; or 0.19–0.475 mg, 0.475–0.95 mg, 0.95–1.9 mg; or 0.19 mg, 0.475 mg, 0.95 mg, or 1.9 mg.

[0045] In some embodiments of this disclosure, the amount of tiotropium bromide contained in a single-dose pharmaceutical composition is 0.10 mg, 0.11 mg, 0.12 mg, 0.13 mg, 0.14 mg, 0.15 mg, 0.16 mg, 0.17 mg, 0.18 mg, 0.19 mg, 0.20 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.40 mg, 0.40 mg, 0.405 mg, 0.41 mg, 0.415 mg, 0.42 mg, 0.425 mg, 0.43 mg, 0.435 mg, 0.44 mg, 0.445 mg, 0.45 mg, 0.455 mg, 0.46 mg, 0.465 mg, etc. 0.47mg, 0.475mg, 0.48mg, 0.485mg, 0.49mg, 0.495mg, 0.50mg, 0.55mg, 0.60mg, 0.65mg, 0.70mg, 0.75mg, 0.80mg, 0.85mg, 0.90mg, 0.95mg, 1.00mg, 1. 00mg, 1.01mg, 1.02mg, 1.03mg, 1.04mg, 1.05mg, 1.06mg, 1.07mg, 1.08mg, 1.09mg, 1.10mg, 1.11mg, 1.12mg, 1.13mg, 1.14mg, 1.15mg, 1.16mg, 1.17mg, 1 .18mg, 1.19mg, 1.20mg, 1.21mg, 1.22mg, 1.23mg, 1.24mg, 1.25mg, 1.26mg, 1.27mg, 1.28mg, 1.29mg, 1.30mg, 1.31mg, 1.32mg, 1.33mg, 1.34mg, 1.35mg , 1.36mg, 1.37mg, 1.38mg, 1.39mg, 1.40mg, 1.41mg, 1.42mg, 1.43mg, 1.44mg, 1.45mg, 1.46mg, 1.47mg, 1.48mg, 1.49mg, 1.50mg, 1.51mg, 1.52mg, 1.53m g, 1.54mg, 1.55mg, 1.56mg, 1.57mg, 1.58mg, 1.59mg, 1.60mg, 1.61mg, 1.62mg, 1.63mg, 1.64mg, 1.65mg, 1.66mg, 1.67mg, 1.68mg, 1.69mg, 1.70mg, 1.7 1mg, 1.72mg, 1.73mg, 1.74mg, 1.75mg, 1.76mg, 1.77mg, 1.78mg, 1.79mg, 1.80mg, 1.81mg, 1.82mg, 1.83mg, 1.84mg, 1.85mg, 1.86mg, 1.87mg, 1.88mg, 1.89mg, 1.90mg, 1.91mg, 1.92mg, 1.93mg, 1.94mg, 1.95mg, 1.96mg, 1.97mg, 1.98mg, 1.99mg, 2.00mg, 2.50mg, 3.00mg, 3.50mg, 4.00mg, 4.50mg, 5.00mg, 5.50mg, 6.00mg, 6.50mg, 7.00mg, 7.50mg, 8.00mg, 8.50mg, 9.00mg, 9.50mg, or 10.00mg, or any range formed by the aforementioned values as endpoints, or any value therein.

[0046] In some embodiments of this disclosure, the pharmaceutical composition is an inhalation spray, and each spray of the pharmaceutical composition contains 0.1–10 μg of tiotropium bromide; or, 0.1–9 μg, 0.1–8 μg, 0.1–7 μg, 0.1–6 μg, 0.1–5 μg, 0.5–5 μg, 0.5–4 μg, 0.5–3 μg, 0.5–2.5 μg, 0.5–1.25 μg, 1.25–2.5 μg, 2.5–5 μg; or 0.5–5 μg; or 0.5–3 μg; or 0.5–1.25 μg, 1.25–2.5 μg; or 0.5 μg, 1.25 μg, 2.5 μg, or 5 μg.

[0047] In some embodiments of this disclosure, each spray of the pharmaceutical composition contains 0.10 μg, 0.20 μg, 0.30 μg, 0.40 μg, 0.50 μg, 0.60 μg, 0.70 μg, 0.80 μg, 0.90 μg, 1.00 μg, 1.00 μg, 1.01 μg, 1.02 μg, 1.03 μg, 1.04 μg, 1.05 μg, 1.06 μg, 1.07 μg, 1.08 μg, 1.09 μg, 1.10 μg, 1.11 μg, 1.12 μg, 1.13 μg, 1.14 μg, 1.15 μg, 1.16 μg, 1.17 μg, 1.18 μg, 1.19 μg, 1.20 μg, 0.30 μg, 0.40 μg, 0.50 μg, 0.60 μg, 0.70 μg, 0.80 μg, 0.90 μg, 1.00 μg, 1.01 μg, 1.02 μg, 1.03 μg, 1.04 μg, 1.05 μg, 1.06 μg, 1.07 μg, 1.08 μg, 1.09 μg, 1.10 μg, 1.11 μg, 1.12 μg, 1.13 μg, 1.14 μg, 1.15 μg, 1.16 μg, 1.17 μg, 1.18 μg, 1.19 μg, 1.20 μg, 0.20 μg, 0.30 μg, 0.40 μg, μg, 1.21μg, 1.22μg, 1.23μg, 1.24μg, 1.25μg, 1.26μg, 1.27μg, 1.28μg, 1.2 9μg, 1.30μg, 1.31μg, 1.32μg, 1.33μg, 1.34μg, 1.35μg, 1.36μg, 1.37μg, 1. 38μg, 1.39μg, 1.40μg, 1.41μg, 1.42μg, 1.43μg, 1.44μg, 1.45μg, 1.46μg, 1 .47μg, 1.48μg, 1.49μg, 1.50μg, 1.51μg, 1.52μg, 1.53μg, 1.54μg, 1.55μg, 1 .56μg, 1.57μg, 1.58μg, 1.59μg, 1.60μg, 1.61μg, 1.62μg, 1.63μg, 1.64μg, 1.65μg, 1.66μg, 1.67μg, 1.68μg, 1.69μg, 1.70μg, 1.71μg, 1.72μg, 1.73μg ,1.74μg, 1.75μg, 1.76μg, 1.77μg, 1.78μg, 1.79μg, 1.80μg, 1.81μg, 1.82μ g, 1.83μg, 1.84μg, 1.85μg, 1.86μg, 1.87μg, 1.88μg, 1.89μg, 1.90μg, 1.91μg g, 1.92μg, 1.93μg, 1.94μg, 1.95μg, 1.96μg, 1.97μg, 1.98μg, 1.99μg, 2.00 μg, 2.01μg, 2.02μg, 2.03μg, 2.04μg, 2.05μg, 2.06μg, 2.07μg, 2.08μg, 2.0 9μg, 2.10μg, 2.11μg, 2.12μg, 2.13μg, 2.14μg, 2.15μg, 2.16μg, 2.17μg, 2. 18μg, 2.19μg, 2.20μg, 2.21μg, 2.22μg, 2.23μg, 2.24μg, 2.25μg, 2.26μg, 2.27μg, 2.28μg, 2.29μg, 2.30μg, 2.31μg, 2.32μg, 2.33μg, 2.34μg, 2.35μg, 2.36μg, 2.37μg , 2.38μg, 2.39μg, 2.40μg, 2.41μg, 2.42μg, 2.43μg, 2.44μg, 2.45μg, 2.46μg, 2.47μg, 2.4 8 μg, 2.49 μg, 2.50 μg, 3.00 μg, 3.50 μg, 4.00 μg, 4.50 μg, 5.00 μg, 5.50 μg, 6.00 μg, 6.50 μg, 7.00 μg, 7.50 μg, 8.00 μg, 8.50 μg, 9.00 μg, 9.50 μg, or 10.00 μg, or any range formed by the aforementioned values as endpoints, or any value therein.

[0048] In some embodiments of this disclosure, each spray of the pharmaceutical composition contains 0.50–1.25 μg, 0.50–2.50 μg, 0.50–5.00 μg, 1.25–2.50 μg, 1.25–5.00 μg, or 2.50–5.00 μg.

[0049] In some embodiments of this disclosure, each spray of the pharmaceutical composition contains 2.5 μg or 1.25 μg of tiotropium bromide, or any of the foregoing values as endpoints within a range or any value thereof.

[0050] In some embodiments of this disclosure, a single-dose pharmaceutical composition contains tiotropium bromide in an amount that is at least 60 times, or at least 90 times, or at least 120 times, or at least 150 times, or at least 180 times, or at least 210 times, or at least 240 times, or at least 270 times, or at least 300 times, or at least 320 times, or at least 340 times, or at least 360 times, or at least 380 times, or at least 400 times, or at least 420 times, or at least 450 times, or at least 480 times, or at least 500 times, or at least 550 times, or at least 600 times.

[0051] In some embodiments of this disclosure, a single-dose pharmaceutical composition contains 60 times the amount of tiotropium bromide contained in each spray.

[0052] In some embodiments of this disclosure, a single-dose pharmaceutical composition contains 380 times the amount of tiotropium bromide contained in each spray.

[0053] In some embodiments of this disclosure, the amount of olodaterol in the pharmaceutical composition is selected from 0.0001–1 w / w%; or 0.005–1 w / w%, preferably 0.01–1 w / w%, 0.01–0.5 w / w%, 0.01–0.4 w / w%, 0.01–0.3 w / w%, 0.01–0.2 w / w%, 0.01–0.1 w / w%, 0.01–0.05 w / w%, 0.01–0.04 w / w%, 0.01–0.03 w / w%, or 0.01–0.025 w / w%; or 0.01–0.1 w / w%; or 0.01–0.05 w / w%; or 0.0125–0.025 w / w%; or 0.0125 w / w%, 0.025 w / w.

[0054] In some embodiments of this disclosure, the amount of olodaterol in the pharmaceutical composition is selected from 0.0001 w / w%, 0.0005 w / w%, 0.001 w / w%, 0.0015 w / w%, 0.002 w / w%, 0.0025 w / w%, 0.003 w / w%, 0.0035 w / w%, 0.004 w / w%, 0.0045 w / w%, 0.005 w / w%, 0.0055 w / w%, 0.006 w / w%, 0.0065 w / w%, 0.007 w / w%, 0.0075 w / w%, 0.0 08w / w%, 0.0085w / w%, 0.009w / w%, 0.0095w / w%, 0.01w / w%, 0.0105w / w%, 0.011w / w%, 0.0115w / w%, 0.012w / w%, 0.0125w / w%, 0.013w / w%, 0.0135w / w%, 0.014w / w%, 0.0145w / w%, 0.015w / w%, 0.0155w / w%, 0.016w / w%, 0.0165w / w%, 0.017w / w%, 0.0175w / w%, 0.018w / w%, 0.0185w / w%, 0.019w / w%, 0.0195w / w%, 0.02w / w%, 0.0205w / w%, 0.021w / w%, 0.0215w / w%, 0.022w / w%, 0.022 5w / w%, 0.023w / w%, 0.0235w / w%, 0.024w / w%, 0.0245w / w%, 0.025w / w%, 0.03w / w%, 0.04w / w%, 0.05w / w%, 0.06w / w%, 0.07w / w %, 0.08w / w%, 0.09w / w%, 0.1w / w%, 0.15w / w%, 0.2w / w%, 0.25w / w%, 0.3w / w%, 0.35w / w%, 0.4w / w%, 0.45w / w%, 0.5w / w%, 0.55w / w%, 0.6w / w%, 0.65w / w%, 0.7w / w%, 0.75w / w%, 0.8w / w%, 0.85w / w%, 0.9w / w%, 0.95w / w%, or 1w / w%, or any of the aforementioned values as endpoints, forming a range or any value therein.

[0055] In some embodiments of this disclosure, the amount of olodaterol in the pharmaceutical composition is selected from 0.005–0.0125 w / w%, 0.005–0.025 w / w%, 0.005–0.25 w / w%, 0.0125–0.025 w / w%, 0.0125–0.25 w / w%, or 0.025–0.25 w / w.

[0056] In some embodiments of this disclosure, the amount of olodaterol in the pharmaceutical composition is selected from 0.04–10 mg / mL; or 0.1–9 mg / mL, 0.1–8 mg / mL, 0.1–7 mg / mL, 0.1–6 mg / mL, 0.1–5 mg / mL, 0.1–4 mg / mL, 0.1–3 mg / mL, 0.1–2 mg / mL, 0.1–1 mg / mL; or 0.11–0.50 mg / mL; or 0.110–0.300 mg / mL; or 0.114–0.227 mg / mL; or 0.114 mg / mL or 0.227 mg / mL.

[0057] In some embodiments of this disclosure, the amount of olodaterol in the pharmaceutical composition is selected from 0.0455 mg / mL, 0.05 mg / mL, 0.100 mg / mL, 0.101 mg / mL, 0.102 mg / mL, 0.103 mg / mL, 0.104 mg / mL, 0.105 mg / mL, 0.106 mg / mL, 0.107 mg / mL, 0.108 mg / mL, 0.109 mg / mL, 0.110 mg / mL, 0.111 mg / mL, 0.112 mg / mL, 0.113 mg / mL, 0.114 mg / mL, 0.115 mg / mL, 0.120 mg / mL, 0.125 mg / mL, etc. mL, 0.130mg / mL, 0.135mg / mL, 0.140mg / mL, 0.145mg / mL, 0.150mg / mL, 0.155mg / mL, 0.160mg / mL, 0.165mg / mL, 0.170mg / mL, 0.175mg / mL, 0.180mg / mL, 0.185mg / mL, 0.190mg / mL, 0.195mg / mL, 0.200mg / mL, 0.205mg / mL, 0.210mg / mL, 0.215mg / mL, 0.220mg / mL, 0.221mg / mL, 0.222mg / mL, 0.223mg / mL, 0.2 24mg / mL, 0.225mg / mL, 0.226mg / mL, 0.227mg / mL, 0.228mg / mL, 0.229mg / mL, 0.230mg / mL, 0.240mg / mL, 0.250mg / mL, 0.300mg / mL, 0.350mg / mL, 0.400 mg / mL, 0.450mg / mL, 0.455mg / mL, 0.500mg / mL, 0.550mg / mL, 0.600mg / mL, 0.650mg / mL, 0.700mg / mL, 0.750mg / mL, 0.800mg / mL, 0.850mg / mL, 0.900mg / The values are 0.950 mg / mL, 1.000 mg / mL, 1.500 mg / mL, 2.000 mg / mL, 2.500 mg / mL, 3.000 mg / mL, 3.500 mg / mL, 4.000 mg / mL, 4.500 mg / mL, 5.000 mg / mL, 5.500 mg / mL, 6.000 mg / mL, 6.500 mg / mL, 7.000 mg / mL, 7.500 mg / mL, 8.000 mg / mL, 8.500 mg / mL, 9.000 mg / mL, 9.500 mg / mL, or 10.000 mg / mL, or any of the aforementioned values as endpoints, forming a range or any value therein.

[0058] In some embodiments of this disclosure, the amount of olodaterol in the pharmaceutical composition is selected from 0.0455–0.114 mg / mL, 0.0455–0.227 mg / mL, 0.0455–0.455 mg / mL, 0.114–0.227 mg / mL, 0.114–0.455 mg / mL, or 0.227–0.455 mg / mL.

[0059] In some embodiments of this disclosure, a single-dose pharmaceutical composition contains 0.1–10 mg of olodaterol; or 0.1–9 mg, 0.1–8 mg, 0.1–7 mg, 0.1–6 mg, 0.1–5 mg, 0.1–4 mg, 0.1–3 mg, 0.1–2 mg, 0.15–1.9 mg, 0.19–1.9 mg; or 0.19–1.9 mg; or 0.19–0.475 mg, 0.475–0.95 mg, 0.95–1.9 mg; or 0.19 mg, 0.475 mg, 0.95 mg, or 1.9 mg.

[0060] In some embodiments of this disclosure, a single-dose pharmaceutical composition comprises 0.10 mg, 0.11 mg, 0.12 mg, 0.13 mg, 0.14 mg, 0.15 mg, 0.16 mg, 0.17 mg, 0.18 mg, 0.19 mg, 0.20 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.40 mg, 0.40 mg, 0.405 mg, 0.41 mg, 0.415 mg, 0.42 mg, 0.425 mg, 0.43 mg, 0.435 mg, 0.44 mg, 0.445 mg, 0.45 mg, 0.455 mg, 0.46 mg, 0.465 mg, ... 0.47mg, 0.475mg, 0.48mg, 0.485mg, 0.49mg, 0.495mg, 0.50mg, 0.55mg, 0.60mg, 0.65mg, 0.70mg, 0.75mg, 0.80mg, 0.85mg, 0.90mg, 0.95mg, 1.00mg, 1. 00mg, 1.01mg, 1.02mg, 1.03mg, 1.04mg, 1.05mg, 1.06mg, 1.07mg, 1.08mg, 1.09mg, 1.10mg, 1.11mg, 1.12mg, 1.13mg, 1.14mg, 1.15mg, 1.16mg, 1.17mg, 1 .18mg, 1.19mg, 1.20mg, 1.21mg, 1.22mg, 1.23mg, 1.24mg, 1.25mg, 1.26mg, 1.27mg, 1.28mg, 1.29mg, 1.30mg, 1.31mg, 1.32mg, 1.33mg, 1.34mg, 1.35mg , 1.36mg, 1.37mg, 1.38mg, 1.39mg, 1.40mg, 1.41mg, 1.42mg, 1.43mg, 1.44mg, 1.45mg, 1.46mg, 1.47mg, 1.48mg, 1.49mg, 1.50mg, 1.51mg, 1.52mg, 1.53m g, 1.54mg, 1.55mg, 1.56mg, 1.57mg, 1.58mg, 1.59mg, 1.60mg, 1.61mg, 1.62mg, 1.63mg, 1.64mg, 1.65mg, 1.66mg, 1.67mg, 1.68mg, 1.69mg, 1.70mg, 1.7 1mg, 1.72mg, 1.73mg, 1.74mg, 1.75mg, 1.76mg, 1.77mg, 1.78mg, 1.79mg, 1.80mg, 1.81mg, 1.82mg, 1.83mg, 1.84mg, 1.85mg, 1.86mg, 1.87mg, 1.88mg, 1.89mg, 1.90mg, 1.91mg, 1.92mg, 1.93mg, 1.94mg, 1.95mg, 1.96mg, 1.97mg, 1.98mg, 1.99mg, 2.00mg, 2.50mg, 3.00mg, 3.50mg, 4.00mg, 4.50mg, 5.00mg, 5.50mg, 6.00mg, 6.50mg, 7.00mg, 7.50mg, 8.00mg, 8.50mg, 9.00mg, 9.50mg, or 10.00mg, or any range formed by the aforementioned values as endpoints, or any value therein.

[0061] In some embodiments of this disclosure, the pharmaceutical composition is an inhalation spray, and each spray contains 0.1–10 μg of olodaterol; or, 0.1–9 μg, 0.1–8 μg, 0.1–7 μg, 0.1–6 μg, 0.1–5 μg, 0.5–5 μg, 0.5–4 μg, 0.5–3 μg, 0.5–2.5 μg, 0.5–1.25 μg, 1.25–2.5 μg, 2.5–5 μg; or 0.5–5 μg; or 0.5–3 μg; or 0.5–1.25 μg, 1.25–2.5 μg; or 0.5 μg, 1.25 μg, 2.5 μg, or 5 μg.

[0062] In some embodiments of this disclosure, each spray of the pharmaceutical composition contains 0.10 μg, 0.20 μg, 0.30 μg, 0.40 μg, 0.50 μg, 0.60 μg, 0.70 μg, 0.80 μg, 0.90 μg, 1.00 μg, 1.00 μg, 1.01 μg, 1.02 μg, 1.03 μg, 1.04 μg, 1.05 μg, 1.06 μg, 1.07 μg, 1.08 μg, 1.09 μg, 1.10 μg, 1.11 μg, 1.12 μg, 1.13 μg, 1.14 μg, 1.15 μg, 1.16 μg, 1.17 μg, 1.18 μg, 1.19 μg, 1.20 μg, 0.30 μg, 0.40 μg, 0.50 μg, 0.60 μg, 0.70 μg, 0.80 μg, 0.90 μg, 1.00 μg, 1.01 μg, 1.02 μg, 1.03 μg, 1.04 μg, 1.05 μg, 1.06 μg, 1.07 μg, 1.08 μg, 1.09 μg, 1.10 μg, 1.11 μg, 1.12 μg, 1.13 μg, 1.14 μg, 1.15 μg, 1.16 μg, 1.17 μg, 1.18 μg, 1.19 μg, 1.20 μg, 0.20 μg, 0.20 μg, 0.30 μg, μg, 1.21μg, 1.22μg, 1.23μg, 1.24μg, 1.25μg, 1.26μg, 1.27μg, 1.28μg, 1.2 9μg, 1.30μg, 1.31μg, 1.32μg, 1.33μg, 1.34μg, 1.35μg, 1.36μg, 1.37μg, 1. 38μg, 1.39μg, 1.40μg, 1.41μg, 1.42μg, 1.43μg, 1.44μg, 1.45μg, 1.46μg, 1 .47μg, 1.48μg, 1.49μg, 1.50μg, 1.51μg, 1.52μg, 1.53μg, 1.54μg, 1.55μg, 1 .56μg, 1.57μg, 1.58μg, 1.59μg, 1.60μg, 1.61μg, 1.62μg, 1.63μg, 1.64μg, 1.65μg, 1.66μg, 1.67μg, 1.68μg, 1.69μg, 1.70μg, 1.71μg, 1.72μg, 1.73μg ,1.74μg, 1.75μg, 1.76μg, 1.77μg, 1.78μg, 1.79μg, 1.80μg, 1.81μg, 1.82μ g, 1.83μg, 1.84μg, 1.85μg, 1.86μg, 1.87μg, 1.88μg, 1.89μg, 1.90μg, 1.91μg g, 1.92μg, 1.93μg, 1.94μg, 1.95μg, 1.96μg, 1.97μg, 1.98μg, 1.99μg, 2.00 μg, 2.01μg, 2.02μg, 2.03μg, 2.04μg, 2.05μg, 2.06μg, 2.07μg, 2.08μg, 2.0 9μg, 2.10μg, 2.11μg, 2.12μg, 2.13μg, 2.14μg, 2.15μg, 2.16μg, 2.17μg, 2. 18μg, 2.19μg, 2.20μg, 2.21μg, 2.22μg, 2.23μg, 2.24μg, 2.25μg, 2.26μg, 2.27μg, 2.28μg, 2.29μg, 2.30μg, 2.31μg, 2.32μg, 2.33μg, 2.34μg, 2.35μg, 2.36μg, 2.37μg , 2.38μg, 2.39μg, 2.40μg, 2.41μg, 2.42μg, 2.43μg, 2.44μg, 2.45μg, 2.46μg, 2.47μg, 2.4 8 μg, 2.49 μg, 2.50 μg, 3.00 μg, 3.50 μg, 4.00 μg, 4.50 μg, 5.00 μg, 5.50 μg, 6.00 μg, 6.50 μg, 7.00 μg, 7.50 μg, 8.00 μg, 8.50 μg, 9.00 μg, 9.50 μg, or 10.00 μg, or any range formed by the aforementioned values as endpoints, or any value therein.

[0063] In some embodiments of this disclosure, each spray of the pharmaceutical composition contains 0.50–1.25 μg, 0.50–2.50 μg, 0.50–5.00 μg, 1.25–2.50 μg, 1.25–5.00 μg, or 2.50–5.00 μg of olodaterol.

[0064] In some embodiments of this disclosure, each spray of the pharmaceutical composition contains 2.5 μg or 1.25 μg of olodaterol, or any of the foregoing values as endpoints within a range or any value therein.

[0065] In some embodiments of this disclosure, a single dose of the pharmaceutical composition contains at least 60 times, or at least 90 times, or at least 120 times, or at least 150 times, or at least 180 times, or at least 210 times, or at least 240 times, or at least 270 times, or at least 300 times, or at least 320 times, or at least 340 times, or at least 360 times, or at least 380 times, or at least 400 times, or at least 420 times, or at least 450 times, or at least 480 times, or at least 500 times, or at least 550 times, or at least 600 times the amount of olodaterol contained in each spray.

[0066] In some embodiments of this disclosure, a single dose of the pharmaceutical composition contains 380 times the amount of olodaterol contained in each spray.

[0067] In some embodiments of this disclosure, the stabilizer is selected from one or more of n-propanol, isopropanol, glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenethyl alcohol, butanol, butanediol, mannitol, polyethylene glycol, and ethylene glycol; preferably, the stabilizer is selected from one or more of glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenethyl alcohol, butanol, butanediol, polyethylene glycol, and ethylene glycol; more preferably, the stabilizer is selected from one or more of glycerol, propylene glycol, oleic acid, phenethyl alcohol, and butanol; even more preferably, the stabilizer is selected from glycerol, propylene glycol, or a mixture thereof; and even more preferably, the stabilizer is glycerol.

[0068] In some embodiments of this disclosure, the stabilizer is not present.

[0069] In some embodiments of this disclosure, when the stabilizer is present, the amount of the stabilizer in the pharmaceutical composition is selected from 0.01–20 w / w%; or 0.01–15 w / w%, 0.01–15 w / w%, 0.01–5 w / w%, 0.05–15 w / w%, 0.05–5 w / w%, 0.1–15 w / w%, 0.1–15 w / w%, 0.1–8 w / w%. 0.1–6 w / w%, 0.1–5 w / w%, 0.2–8 w / w%, 0.2–7 w / w%, 0.2–6 w / w%, 0.2–5 w / w%, 0.2–4 w / w%, or 0.2–3 w / w%; or 0.1–15 w / w%; or 0.1–12 w / w%; or 0.1–0.5 w / w%, 0.5–1 w / w%, 1–10 w / w%, or 10–12 w / w%; or 1 w / w%.

[0070] In some embodiments of this disclosure, when the stabilizer is present, the amount of the stabilizer in the pharmaceutical composition is selected from 0.01 w / w%, 0.05 w / w%, 0.1 w / w%, 0.15 w / w%, 0.2 w / w%, 0.25 w / w%, 0.3 w / w%, 0.35 w / w%, 0.4 w / w%, 0.45 w / w%, 0.5 w / w%, 0.55 w / w%, 0.6 w / w%, 0.65 w / w%, 0.7 w / w%, 0.75 w / w%, 0.8 w / w%, 0.85 w / w%, 0.9 w / w%, 0.95 w / w%, 1 w / w%, 1.05 w / w%, 1.1 w / w%, etc. 1.15w / w%, 1.2w / w%, 1.25w / w%, 1.3w / w%, 1.35w / w%, 1.4w / w%, 1.45w / w %, 1.5w / w%, 1.55w / w%, 1.6w / w%, 1.65w / w%, 1.7w / w%, 1.75w / w%, 1.8w / w %, 1.85w / w%, 1.9w / w%, 1.95w / w%, 2w / w%, 2.05w / w%, 2.1w / w%, 2.15w / w% , 2.2w / w%, 2.25w / w%, 2.3w / w%, 2.35w / w%, 2.4w / w%, 2.45w / w%, 2.5w / w% , 2.55w / w%, 2.6w / w%, 2.65w / w%, 2.7w / w%, 2.75w / w%, 2.8w / w%, 2.85w / w%, 2.9w / w%, 2.95w / w%, 3w / w%, 3.1w / w%, 3.2w / w%, 3.3w / w%, 3.4w / w%, 3 .5w / w%, 3.6w / w%, 3.7w / w%, 3.8w / w%, 3.9w / w%, 4w / w%, 4.1w / w%, 4.2w / w%, 4.3w / w%, 4.4w / w%, 4.5w / w%, 4.6w / w%, 4.7w / w%, 4.8w / w%, 4.9w / w%, 5w / w%, 5.1w / w%, 5.2w / w%, 5.3w / w%, 5.4w / w%, 5.5w / w%, 5.6w / w%, 5.7w / w%, 5.8w / w%, 5.9w / w%, 6w / w%, 6.5w / w%, 7w / w%, 7.5w / w%, 8w / w%, 8.5w / w%, 9w / w%, 9.5w / w%, 10w / w%, 11w / w%, 12w / w%, 13w / w%, 14w / w%, 15w / w%, 16w / w%, 17w / w%, 18w / w%, 19w / w%, or 20w / w%, or any of the aforementioned values as endpoints, forming a range or any value therein.

[0071] In some embodiments of this disclosure, when the stabilizer is present, the amount of the stabilizer in the pharmaceutical composition is selected from 0.01–1 w / w%, 0.01–20 w / w%, or 1–20 w / w.

[0072] In some embodiments of this disclosure, when the stabilizer is present, the amount of the stabilizer in the pharmaceutical composition is selected from 0.1–190 mg / mL; or 0.9–110 mg / mL, 0.9–100 mg / mL, 0.9–90 mg / mL, 0.9–80 mg / mL, 0.9–70 mg / mL, 0.9–60 mg / mL, 0.9–50 mg / mL, 0.9–40 mg / mL, 0.9–30 mg / mL, 0.9–20 mg / mL, 0.9–10 mg / mL; or 0.9–109.1 mg / mL, 0.9–90.9 mg / mL, 0.9–4.6 mg / mL, 0.9–9.1 mg / mL, 9.1–90.9 mg / mL; or 0.91–109.09 mg / mL, 0.91–4.55 mg / mL, 4.55–9.09 mg / mL, 9.09–90.91 mg / mL, 90.91–109.09 mg / mL; or 9.09 mg / mL.

[0073] In some embodiments of this disclosure, when the stabilizer is present, the amount of the stabilizer in the pharmaceutical composition is selected from 0.10 mg / mL, 0.50 mg / mL, 0.90 mg / mL, 0.91 mg / mL, 0.92 mg / mL, 0.93 mg / mL, 0.94 mg / mL, 0.95 mg / mL, 0.96 mg / mL, 0.97 mg / mL, 0.98 mg / mL, 0.99 mg / mL, 1.00 mg / mL, 1.50 mg / mL, 2.00 mg / mL, 2.50 mg / mL, 3.00 mg / mL, 3.50 mg / mL, 4.00 mg / mL, 4.50 mg / mL, and 4.51 mg / mL. , 4.52mg / mL, 4.53mg / mL, 4.54mg / mL, 4.55mg / mL, 4.56mg / mL, 4.57mg / mL, 4.58mg / mL, 4.59mg / mL, 4.60mg / mL, 4.61mg / mL, 4.62mg / mL, 4.63mg / mL, 4.6 4mg / mL, 4.65mg / mL, 4.66mg / mL, 4.67mg / mL, 4.68mg / mL, 4.69mg / mL, 4.70mg / mL, 5.00mg / mL, 5.50mg / mL, 6.00mg / mL, 6.50mg / mL, 7.00mg / mL, 7.50mg / m L, 8.00mg / mL, 8.50mg / mL, 9.00mg / mL, 9.01mg / mL, 9.02mg / mL, 9.03mg / mL, 9.04mg / mL, 9.05mg / mL, 9.06mg / mL, 9.07mg / mL, 9.08mg / mL, 9.09mg / mL, 9. 10mg / mL, 9.11mg / mL, 9.12mg / mL, 9.13mg / mL, 9.14mg / mL, 9.15mg / mL, 9.16mg / mL, 9.17mg / mL, 9.18mg / mL, 9.19mg / mL, 9.20mg / mL, 9.50mg / mL, 10.00mg / mL, 15.00mg / mL, 20.00mg / mL, 25.00mg / mL, 30.00mg / mL, 35.00mg / mL, 40.00mg / mL, 45.00mg / mL, 50.00mg / mL, 55.00mg / mL, 60.00mg / mL, 65.00mg / mL, 70.00mg / mL, 75.00mg / mL, 80.00mg / mL, 85.00mg / mL, 90.00mg / mL, 90.50mg / mL, 90.90mg / mL, 90.91mg / mL, 90.92mg / mL, 90.93mg / mL, 90.94mg / mL, 90.95mg / mL, 90.96mg / mL, 90.97mg / mL, 90.98mg / mL, 90.99mg / mL, 91.00mg / mL, 95.00mg / mL, 100.00mg / mL, 105 .00mg / mL, 109.00mg / mL, 109.01mg / mL, 109.02mg / mL, 109.03mg / mL, 109.04mg / mL, 109.05mg / mL, 109.06mg / The concentrations are 109.07 mg / mL, 109.08 mg / mL, 109.09 mg / mL, 109.10 mg / mL, 109.50 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 181.82 mg / mL, or 190 mg / mL, or any range formed by using the aforementioned values as endpoints, or any value therein.

[0074] In some embodiments of this disclosure, when the stabilizer is present, the amount of the stabilizer in the pharmaceutical composition is selected from 0.091–9.09 mg / mL, 0.091–181.82 mg / mL, or 9.09–181.82 mg / mL.

[0075] In some embodiments of this disclosure, when the stabilizer is present, a single-dose pharmaceutical composition of the pharmaceutical composition contains an amount of stabilizer of 0.38–760 mg; or 0.38–700 mg, 1–500 mg, 3.8–300 mg, 5–280 mg, 8–250 mg, 10–220 mg, 12–200 mg, 15–180 mg, 18–150 mg, 20–130 mg, 21–120 mg, 22–110 mg, 23–100 mg, 24–90 mg, 25–85 mg, 26–80 mg, 27–75 mg, 28–70 mg, 29–65 mg, 30–60 mg, 30.5–59 mg, 31–58 mg, 31.5–57 mg. g, 32-56mg, 32.5-55mg, 33-54mg, 33.5-53mg, 34-52mg, 34.5-51mg, 35-50mg, 35.5-49mg, 36-48mg, 36.5-47mg, 37-46mg, 37-45mg, 37-44mg, 37-43mg, 37.5-45mg, 37.5-44mg, 37.5-44mg, 37.5-43mg, 37.5-42mg, 38-44mg, 38-43mg, 38-42mg, 38-41mg, 38-40mg or 38-39mg, or 7.6-190mg, or 19-90mg, or 30-60mg, or 38mg.

[0076] In some embodiments of this disclosure, when the stabilizer is present, the amount of stabilizer contained in a single-dose pharmaceutical composition is 0.38 mg, 0.5 mg, 1 mg, 3 mg, 3.8 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, or 35 mg. , 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58m g, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120m g, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 210mg, 220mg, 230m g, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, 490mg, 500mg, 510mg, 520mg, 530mg, 540mg, 550mg, 560mg, 570mg, 580mg, 590mg, 600mg, 610mg, 620mg, 630mg, 640mg, 650mg, 660mg, 670mg, 680mg, 690mg, 700mg, 710mg, 720mg, 730mg, 740mg, 750mg, or 760mg, or any of the aforementioned values as endpoints, forming a range or any value therein.

[0077] In some embodiments of this disclosure, when the stabilizer is present, each spray of the pharmaceutical composition contains 1–2000 μg of the stabilizer; or 1–950 μg, 5–900 μg, 10–850 μg, 15–800 μg, 20–750 μg, 25–700 μg, 30–650 μg, 35–600 μg, 40–550 μg, 45–500 μg, 50–450 μg, 55–400 μg, 60–350 μg, 65–300 μg, 70–250 μg, 75–20 ... 0 μg, 80–190 μg, 82–180 μg, 85–170 μg, 88–160 μg, 90–150 μg, 91–145 μg, 92–140 μg, 93–135 μg, 94–130 μg, 95–125 μg, 96–120 μg, 97–115 μg, 98–110 μg, 99–105 μg or 100–102 μg, or 10–500 μg or 1000–2000 μg, or 50–250 μg, or 80–150 μg, or 100 μg.

[0078] In some embodiments of this disclosure, when the stabilizer is present, each spray of the pharmaceutical composition contains the stabilizer in amounts of 1 μg, 5 μg, 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 61 μg, 62 μg, 63 μg, 64 μg, 65 μg, 66 μg, 67 μg, 68 μg, 69 μg, 70 μg, 71 μg, 72 μg, 73 μg, 74 μg, and 75 μg. μg, 76μg, 77μg, 78μg, 79μg, 80μg, 81μg, 82μg, 83μg, 84μg, 85μg, 86μg, 87μg, 88μg, 89μg, 90μg, 91μg, 92μg, 9 3μg, 94μg, 95μg, 96μg, 97μg, 98μg, 99μg, 100μg, 101μg, 102μg, 103μg, 104μg, 105μg, 106μg, 107μg, 108μg, 10 9μg, 110μg, 115μg, 120μg, 125μg, 130μg, 135μg, 140μg, 145μg, 150μg, 155μg, 160μg, 165μg, 170μg, 175μg, 1 80μg, 195μg, 200μg, 210μg, 220μg, 230μg, 240μg, 250μg, 260μg, 270μg, 280μg, 290μg, 300μg, 350μg, 400μg, 4 50 μg, 500 μg, 550 μg, 600 μg, 650 μg, 700 μg, 750 μg, 800 μg, 850 μg, 900 μg, 950 μg, 1000 μg, 1050 μg, 1100 μg, 1150 μg, 1200 μg, 1300 μg, 1400 μg, 1500 μg, 1600 μg, 1700 μg, 1800 μg, 1900 μg, or 2000 μg, or any of the aforementioned values as endpoints, or any value therein.

[0079] In some embodiments of this disclosure, when the stabilizer is present, each spray of the pharmaceutical composition contains 1–100 μg, 1–2000 μg, or 100–2000 μg of the stabilizer.

[0080] In some embodiments of this disclosure, the antioxidant is selected from one or more of the following: butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate (PG), tert-butylhydroquinone (TBHQ), ascorbic acid antioxidants (including but not limited to vitamin C, isoascorbic acid, sodium ascorbate, potassium ascorbate, and ascorbyl palmitate), tocopherol antioxidants (including but not limited to vitamin E, α-tocopherol, mixed concentrated tocopherols, and tocopherol acetate), vitamin A, retinyl palmitate, dibutylphenol, tea polyphenols (TP), sulfite antioxidants (including but not limited to sodium sulfite, potassium sulfite, sodium metabisulfite, potassium metabisulfite, sodium bisulfite, potassium bisulfite, and sodium thiosulfate), fumaric acid or its salts, malic acid or its salts, citric acid or its salts, and maleic acid or its salts; preferably, the antioxidant is selected from... Self-ascorbic acid antioxidants (including but not limited to vitamin C, isoascorbic acid, sodium ascorbate, potassium ascorbate, ascorbyl palmitate), sulfite antioxidants (including but not limited to sodium sulfite, potassium sulfite, sodium metabisulfite, potassium metabisulfite, sodium bisulfite, potassium bisulfite, sodium thiosulfate), butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, tert-butylhydroquinone, and tea polyphenols, or one or more thereof; more preferably, the antioxidant is selected from vitamin C, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, butylated hydroxyanisole, butylated hydroxytoluene, tert-butylhydroquinone, propyl gallate, ascorbyl palmitate, and tea polyphenols, or one or more thereof; even more preferably, the antioxidant is selected from vitamin C, sodium metabisulfite, sodium bisulfite, and sodium thiosulfate, or one or more thereof; most preferably, the antioxidant is vitamin C.

[0081] In some embodiments of this disclosure, the antioxidant is absent.

[0082] In some embodiments of this disclosure, when the antioxidant is present, the amount of the antioxidant in the pharmaceutical composition is selected from 0.0001–10 w / w%, or 0.0001–8 w / w%, 0.0001–5 w / w%, 0.00011–5 w / w%, 0.0012–5 w / w%, 0.0013–5 w / w%, 0.0014–5 w / w%, 0.0015–5 w / w%. / w%, 0.0015~4w / w%, 0.0015~3w / w%, 0.0015~2w / w%, 0.0015~1w / w%, 0.0015~0.8w / w%, 0.0015~0.6w / w%, 0.0015~0.4w / w%, 0.0001~0.2w / w%, 0.0001~0.1w / w%, 0.0001~0.015w / w%, 0.0001~0.01w / w%, 0.0001~0.005w / w%, 0.0015~0.15w / w%, 0.0015~0.14w / w%, 0.00 15~0.13w / w%, 0.0015~0.12w / w%, 0.0015~0.11w / w%, 0.0015~0.1w / w%, 0.0015~0.05w / w %, 0.0015–0.01 w / w%, 0.0015–0.005 w / w%, 0.0015–0.003 w / w%, 0.0015–0.002 w / w% or 5–8 w / w%, or 0.0001–8 w / w%, or 0.001–0.0015 w / w%, 0.0015–5 w / w% or 5–8 w / w%, or 0.0015 w / w.

[0083] In some embodiments of this disclosure, when the antioxidant is present, the amount of the antioxidant in the pharmaceutical composition is selected from 0.0001 w / w%, 0.0002 w / w%, 0.0003 w / w%, 0.0004 w / w%, 0.0005 w / w%, 0.0006 w / w%, 0.0007 w / w%, 0.0008 w / w%, 0.0009 w / w%, 0.001 w / w%, 0.0011 w / w%, 0.0012 w / w%, 0.0013 w / w%, 0.0014 w / w%, 0.0015 w / w%, 0.0016 w / w%, 0.0017 w / w%, 0.0018 w / w%, 0.0019 w / w%. 0.002w / w%, 0.0021w / w%, 0.0022w / w%, 0.0023w / w%, 0.0024w / w%, 0.0025w / w%, 0.0026w / w%, 0.0027w / w%, 0.0028w / w%, 0.0029w / w%, 0.003w / w%, 0.003 5w / w%, 0.004w / w%, 0.0045w / w%, 0.005w / w%, 0.0055w / w%, 0.006w / w%, 0.00 65w / w%, 0.007w / w%, 0.0075w / w%, 0.008w / w%, 0.0085w / w%, 0.009w / w%, 0.00 95w / w%, 0.01w / w%, 0.02w / w%, 0.03w / w%, 0.04w / w%, 0.05w / w%, 0.06w / w%, 0 .07w / w%, 0.08w / w%, 0.09w / w%, 0.1w / w%, 0.11w / w%, 0.12w / w%, 0.13w / w%, 0 .14w / w%, 0.15w / w%, 0.16w / w%, 0.17w / w%, 0.18w / w%, 0.19w / w%, 0.2w / w%, 0 .21w / w%, 0.22w / w%, 0.23w / w%, 0.24w / w%, 0.25w / w%, 0.26w / w%, 0.27w / w%, 0.28w / w%, 0.29w / w%, 0.3w / w%, 0.31w / w%, 0.32w / w%, 0.33w / w%, 0.34w / w%, 0.35w / w%, 0.36w / w%, 0.37w / w%, 0.38w / w%, 0.39w / w%, 0.4w / w%, 0.41w / w%, 0.42w / w%, 0.43w / w%, 0.44w / w%, 0.45w / w%, 0.46w / w%, 0.47w / w%, 0.48w / w% , 0.49w / w%, 0.5w / w%, 0.55w / w%, 0.6w / w%, 0.65w / w%, 0.7w / w%, 0.75w / w%, 0.8w / w%, 0.85w / w%, 0.9w / w%, 0.95w / w%, 1.0w / w%, 1.1w / w%, 1.2w / w%, 1.3w / w%, 1.4w / w%, 1.5w / w%, 1.6w / w%, 1.7w / w%, 1.8w / w%, 1.9w / w%, 2.0w / w%, 2.5w / w%, 3.0w / w%, 3.5 w / w%, 4.0 w / w%, 4.5 w / w%, 5.0 w / w%, 5.5 w / w%, 6.0 w / w%, 6.5 w / w%, 7.0 w / w%, 7.5 w / w%, 8.0 w / w%, 8.5 w / w%, 9.0 w / w%, 9.5 w / w%, or 10.0 w / w%, or any range formed by the aforementioned values as endpoints, or any value therein.

[0084] In some embodiments of this disclosure, when the antioxidant is present, the amount of the antioxidant in the pharmaceutical composition is selected from 0.0002–0.0015 w / w%, 0.0002–5.0 w / w%, or 0.0015–5.0 w / w.

[0085] In some embodiments of this disclosure, when the antioxidant is present, the amount of the antioxidant in the pharmaceutical composition is selected from 0.0001–80 mg / mL; or 0.0001–80 mg / mL, 0.0002–75 mg / mL, 0.0003–74 mg / mL, 0.0004–73 mg / mL, 0.0005–50 mg / mL, 0.0006–45 mg / mL, 0.0007–20 mg / mL, 0.0008–10 mg / mL, 0.0 009~5mg / mL, 0.0009~1mg / mL, 0.0009~0.01mg / mL, 0.0009~0.011mg / mL, 0.0009~0.012mg / mL, 0.0009~0.013 mg / mL, 0.0009~0.014mg / mL, 0.001~1mg / mL, 0.01~1mg / mL, 0.011~1mg / mL, 0.012~2mg / mL, 0.012~1.5mg / mL, 0 .012~1mg / mL, 0.012~0.5mg / mL, 0.012~0.4mg / mL, 0.012~0.3mg / mL, 0.012~0.2mg / mL, 0.013~0.1mg / mL, 0.0 14~0.1mg / mL, 0.014~0.09mg / mL, 0.014~0.08mg / mL, 0.014~0.07mg / mL, 0.014~0.06mg / mL, 0.014~0.05mg / mL 0.014–0.04 mg / mL, 0.014–0.03 mg / mL, 0.014–0.02 mg / mL, 45–73 mg / mL, 45.15–72.90 mg / mL, 45.45–72.73 mg / mL; or 0.0009–72.73 mg / mL; or 0.0009–0.014 mg / mL, 0.014–45.45 mg / mL or 45.45–72.73 mg / mL; or 0.014 mg / mL.

[0086] In some embodiments of this disclosure, when the antioxidant is present, the amount of the antioxidant in the pharmaceutical composition is selected from 0.0001 mg / mL, 0.0002 mg / mL, 0.0003 mg / mL, 0.0004 mg / mL, 0.0005 mg / mL, 0.0006 mg / mL, 0.0007 mg / mL, 0.0008 mg / mL, 0.0009 mg / mL, 0.001 mg / mL, 0.0014 mg / mL, 0.01 mg / mL, 0.011 mg / mL, 0.012 mg / mL, 0.013 mg / mL, 0.014 mg / mL, 0.015 mg / mL, 0.016 mg / mL, 0... .017mg / mL, 0.018mg / mL, 0.019mg / mL, 0.02mg / mL, 0.021mg / mL, 0.022mg / mL, 0.023mg / mL, 0.024mg / mL, 0.025mg / mL, 0.026mg / mL, 0.027mg / mL, 0.028 mg / mL, 0.029mg / mL, 0.03mg / mL, 0.031mg / mL, 0.032mg / mL, 0.033mg / mL, 0.034mg / mL, 0.035mg / mL, 0.036mg / mL, 0.037mg / mL, 0.038mg / mL, 0.039mg / m L, 0.04mg / mL, 0.041mg / mL, 0.042mg / mL, 0.043mg / mL, 0.044mg / mL, 0.045mg / mL, 0.046mg / mL, 0.047mg / mL, 0.048mg / mL, 0.049mg / mL, 0.05mg / mL, 0.1 mg / mL, 0.5mg / mL, 1mg / mL, 1.5mg / mL, 2mg / mL, 2.5mg / mL, 3mg / mL, 3.5mg / mL, 4.0mg / mL, 4.5mg / mL, 5.0mg / mL, 6.0mg / mL, 7.0mg / mL, 8.0mg / mL, 9.0mg / m L, 10.0mg / mL, 15mg / mL, 20mg / mL, 25mg / mL, 30mg / mL, 35mg / mL, 40mg / mL, 45mg / mL, 45.10mg / mL, 45.20mg / mL, 45.30mg / mL, 45.40mg / mL, 45.41mg / mL, 4 5.42mg / mL, 45.43mg / mL, 45.44mg / mL, 45.45mg / mL, 45.46mg / mL, 50mg / mL, 55mg / mL, 60mg / mL, 65mg / mL, 70mg / mL, 71mg / mL, 72mg / mL, 72.10mg / mL, 72.20 mg / mL, 72.30 mg / mL, 72.40 mg / mL, 72.50 mg / mL, 72.60 mg / mL, 72.70 mg / mL, 72.71 mg / mL, 72.73 mg / mL, 72.74 mg / mL, 72.75 mg / mL, 72.80 mg / mL, 72.90 mg / mL, 73 mg / mL, 75 mg / mL, or 80 mg / mL, or any range formed by using the aforementioned values as endpoints, or any value therein.

[0087] In some embodiments of this disclosure, when the antioxidant is present, the amount of the antioxidant in the pharmaceutical composition is selected from 0.0014–0.014 mg / mL, 0.0014–45.46 mg / mL, or 0.014–45.46 mg / mL.

[0088] In some embodiments of this disclosure, when the antioxidant is present, a single dose of the pharmaceutical composition contains an amount of antioxidant of 0.006–190 mg; or 0.006–180 mg, 0.008–160 mg, 0.01–140 mg, 0.012–120 mg, 0.014–100 mg, 0.016–90 mg, 0.018–80 mg, 0.02–70 mg, 0.022–60 mg, 0.024–50 mg, 0.026–40 mg, 0.028–30 mg, 0.03–20 mg, 0.032–10 mg, 0.034– 5mg, 0.036–4mg, 0.038–3mg, 0.04–2mg, 0.042–1mg, 0.044–0.8mg, 0.046–0.6mg, 0.048–0.4mg, 0.05–0.2mg, 0.051–0.1mg, 0.052–0.09mg, 0.053–0.08mg, 0.054–0.07mg, 0.055–0.06mg, 0.056–0.06mg or 0.057–0.06mg, or 0.02–45mg, or 0.03–10mg, or 0.04–1mg, or 0.057mg.

[0089] In some embodiments of this disclosure, when the antioxidant is present, a single dose of the pharmaceutical composition comprises an amount of antioxidant of 0.006 mg, 0.008 mg, 0.01 mg, 0.011 mg, 0.012 mg, 0.013 mg, 0.014 mg, 0.015 mg, 0.016 mg, 0.017 mg, 0.018 mg, 0.019 mg, 0.02 mg, 0.021 mg, 0.022 mg, 0.023 mg, 0.024 mg, 0.025 mg, 0.026 mg, 0... .027mg, 0.028mg, 0.029mg, 0.03mg, 0.031mg, 0.032mg, 0.033mg, 0.034mg, 0.035mg, 0.036mg, 0.037mg, 0.038mg, 0.039m g, 0.04mg, 0.041mg, 0.042mg, 0.043mg, 0.044mg, 0.045mg, 0.046mg, 0.047mg, 0.048mg, 0.049mg, 0.05mg, 0.051mg, 0.05 2mg, 0.053mg, 0.054mg, 0.055mg, 0.056mg, 0.057mg, 0.058mg, 0.059mg, 0.06mg, 0.061mg, 0.062mg, 0.063mg, 0.064mg, 0.065mg, 0.066mg, 0.067mg, 0.068mg, 0.069mg, 0.07mg, 0.08mg, 0.09mg, 0.1mg, 0.2mg, 0.3mg, 0.4mg, 0.5mg, 0.6mg, 0.7 mg, 0.8mg, 0.9mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, or 190mg, or any of the aforementioned values as endpoints, forming a range or any value therein.

[0090] In some embodiments of this disclosure, when the antioxidant is present, each spray of the pharmaceutical composition contains an amount of antioxidant of 0–800 μg; or 0.01–450 μg, 0.015–400 μg, 0.025–350 μg, 0.03–300 μg, 0.035–250 μg, 0.04–200 μg, 0.045–150 μg, 0.05–100 μg, 0.055–80 μg, 0.06–60 μg, 0.065–50 μg, 0.07–40 μg, 0.075–30 μg, 0.0 8–20 μg, 0.085–10 μg, 0.09–8 μg, 0.1–6 μg, 0.105–4 μg, 0.115–2 μg, 0.120–1 μg, 0.125–0.9 μg, 0.130–0.8 μg, 0.135–0.7 μg, 0.14–0.6 μg, 0.145–0.5 μg, 0.15–0.4 μg, 0.15–0.3 μg, and 0.15–0.2 μg, or 0.05–50 μg, or 0.075–5 μg, or 0.1–0.5 μg, or 0.15 μg.

[0091] In some embodiments of this disclosure, when the antioxidant is present, each spray of the pharmaceutical composition contains 0.01 μg, 0.015 μg, 0.02 μg, 0.025 μg, 0.03 μg, 0.035 μg, 0.04 μg, 0.045 μg, 0.05 μg, 0.055 μg, 0.06 μg, 0.065 μg, 0.07 μg, 0.075 μg, 0.08 μg, 0.085 μg, 0.09 μg, 0.095μg, 0.1μg, 0.105μg, 0.11μg, 0.115μg, 0.12μg, 0.125μg, 0.13μg, 0.135μg, 0.14μg, 0.145μg, 0.15 μg, 0.155μg, 0.16μg, 0.165μg, 0.17μg, 0.175μg, 0.18μg, 0.185μg, 0.19μg, 0.195μg, 0.2μg, 0.4μg, 0.6 μg, 0.8μg, 1μg, 1.2μg, 1.3μg, 1.4μg, 1.5μg, 1.6μg, 1.7μg, 1.8μg, 1.9μg, 2μg, 3μg, 4μg, 5μg, 6μg, 7μg, 8 μg, 9μg, 10μg, 15μg, 20μg, 25μg, 30μg, 35μg, 40μg, 45μg, 50μg, 60μg, 70μg, 80μg, 90μg, 100μg, 120μg, 14 0 μg, 160 μg, 180 μg, 200 μg, 220 μg, 240 μg, 260 μg, 280 μg, 300 μg, 320 μg, 340 μg, 360 μg, 380 μg, 400 μg, 420 μg, 440 μg, 460 μg, 480 μg, 500 μg, 550 μg, 600 μg, 650 μg, 700 μg, 750 μg, or 800 μg, or any of the aforementioned values as endpoints, or any value therein.

[0092] In some embodiments of this disclosure, when the antioxidant is present, each spray of the pharmaceutical composition contains an amount of antioxidant of 0.015–0.15 μg, 0.015–500 μg, or 0.15–500 μg.

[0093] In some embodiments of this disclosure, the pharmaceutical composition comprises an antibacterial agent.

[0094] In some embodiments of this disclosure, the antibacterial agent is selected from one or more of benzalkonium chloride, benzalkonium bromide, parabens (such as methylparaben, ethylparaben, propylparaben, butylparaben, etc.), chlorobutanol, phenol, resorcinol, benzyl alcohol, phenethyl alcohol, benzoic acid or its salts, sodium propionate, sorbic acid or its salts; preferably, the antibacterial agent is selected from one or more of benzalkonium chloride, benzalkonium bromide, benzyl alcohol, phenethyl alcohol, benzoic acid or its salts, sodium propionate, sorbic acid or its salts; more preferably, the antibacterial agent is selected from one or more of benzalkonium chloride, benzalkonium bromide, benzoic acid or its salts, benzyl alcohol; even more preferably, the antibacterial agent is selected from benzalkonium chloride and / or benzalkonium bromide; most preferably, the antibacterial agent is benzalkonium chloride.

[0095] In some embodiments of this disclosure, the amount of the antibacterial agent is selected from 0–2 w / w%; or 0–1.5 w / w%, 0–1 w / w%, 0–0.5 w / w%, 0–0.4 w / w%, 0–0.3 w / w%, 0–0.2 w / w%, 0–0.1 w / w%, 0.001–0.1 w / w%, 0.002–0.09 w / w%, 0.002–0.08 w / w%, 0.004–0.07 w / w%, 0.005–0.06 w / w%. w / w%, 0.005–0.05 w / w%, 0.006–0.05 w / w%, 0.006–0.04 w / w%, 0.006–0.03 w / w%, 0.007–0.002 w / w%, 0.008–0.002 w / w%, or 0.008–0.01 w / w%; or 0–0.5 w / w%; or 0.005–0.05 w / w%; or 0.005–0.015 w / w%; or 0.01 w / w%.

[0096] In some embodiments of this disclosure, when the antibacterial agent is present, the amount of the antibacterial agent in the pharmaceutical composition is selected from 0.001 w / w%, 0.002 w / w%, 0.003 w / w%, 0.004 w / w%, 0.005 w / w%, 0.006 w / w%, 0.007 w / w%, 0.008 w / w%, 0.009 w / w%, 0.01 w / w%, 0.011 w / w%, 0.012 w / w%, 0 .013w / w%, 0.014w / w%, 0.015w / w%, 0.016w / w%, 0.017w / w%, 0.018w / w%, 0.019w / w%, 0.02w / w%, 0. 025w / w%, 0.03w / w%, 0.035w / w%, 0.04w / w%, 0.045w / w%, 0.05w / w%, 0.055w / w%, 0.06w / w%, 0.065w / w%, 0.07w / w%, 0.075w / w%, 0.08w / w%, 0.085w / w%, 0.09w / w%, 0.095w / w%, 0.1w / w%, 0.15w / w%, 0.2 w / w%, 0.25w / w%, 0.3w / w%, 0.35w / w%, 0.4w / w%, 0.45w / w%, 0.5w / w%, 0.55w / w%, 0.6w / w%, 0.65w / w %, 0.7w / w%, 0.75w / w%, 0.8w / w%, 0.85w / w%, 0.9w / w%, 0.95w / w%, 1w / w%, 1.1w / w%, 1.2w / w%, 1.3w / w%, 1.4w / w%, 1.5w / w%, 1.6w / w%, 1.7w / w%, 1.8w / w%, 1.9w / w%, or 2w / w%, or any of the aforementioned values as endpoints, forming a range or any value therein.

[0097] In some embodiments of this disclosure, the amount of the antibacterial agent is selected from 0–0.01 w / w%, 0–2.0 w / w%, or 0.01–2.0 w / w%.

[0098] In some embodiments of this disclosure, the amount of the antibacterial agent is selected from 0–19 mg / mL; or 0.01–16 mg / mL, 0.01–14 mg / mL, 0.02–12 mg / mL, 0.02–10 mg / mL, 0.03–9 mg / mL, 0.03–8 mg / mL, 0.04–7 mg / mL, 0.04–6 mg / mL, 0.05–5 mg / mL, 0.05–4 mg / mL, 0.06–3 mg / mL, 0.06–2 mg / mL, 0.07–1 mg / mL, 0.07–0.9 mg / mL, 0.07–0.8 mg / mL, 0.07– 0.7 mg / mL, 0.08–0.7 mg / mL, 0.08–0.6 mg / mL, 0.08–0.5 mg / mL, 0.08–0.4 mg / mL, 0.085–0.5 mg / mL, 0.085–0.4 mg / mL, 0.085–0.3 mg / mL, 0.09–0.4 mg / mL, 0.09–0.3 mg / mL, 0.09–0.2 mg / mL or 0.09–0.1 mg / mL; or 0.04–6 mg / mL; or 0.045–0.45 mg / mL; or 0.045–0.18 mg / mL; or 0.09 mg / mL.

[0099] In some embodiments of the present disclosure, the amount of the bacteriostatic agent is selected from 0 mg / mL, 0.01 mg / mL, 0.015 mg / mL, 0.02 mg / mL, 0.025 mg / mL, 0.03 mg / mL, 0.035 mg / mL, 0.04 mg / mL, 0.045 mg / mL, 0.05 mg / mL, 0.051 mg / mL, 0.052 mg / mL, 0.053 mg / mL, 0.054 mg / mL, 0.055 mg / mL, 0.056 mg / mL, 0.057 mg / mL, 0.058 mg / mL, 0.059 mg / mL, 0.06 mg / mL, 0.061 mg / mL, 0.062 mg / mL, 0.063 mg / mL, 0.064 mg / mL, 0.065 mg / mL, 0.066 mg / mL, 0.067 mg / mL, 0.068 mg / mL, 0.069 mg / mL, 0.07 mg / mL, 0.071 mg / mL, 0.072 mg / mL, 0.073 mg / mL, 0.074 mg / mL, 0.075 mg / mL, 0.076 mg / mL, 0.077 mg / mL, 0.078 mg / mL, 0.079 mg / mL, 0.08 mg / mL, 0.081 mg / mL, 0.082 mg / mL, 0.083 mg / mL, 0.084 mg / mL, 0.085 mg / mL, 0.086 mg / mL, 0.087 mg / mL, 0.088 mg / mL, 0.089 mg / mL, 0.09 mg / mL, 0.091 mg / mL, 0.092 mg / mL, 0.093 mg / mL, 0.094 mg / mL, 0.095 mg / mL, 0.096 mg / mL, 0.097 mg / mL, 0.098 mg / mL, 0.099 mg / mL, 0.1 mg / mL, 0.11 mg / mL, 0.12 mg / mL, 0.13 mg / mL, 0.14 mg / mL, 0.15 mg / mL, 0.16 mg / mL, 0.17 mg / mL, 0.18 mg / mL, 0.19 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL, 1.6 mg / mL, 1.7 mg / mL, 1.8 mg / mL, 1.9 mg / mL, 2 mg / mL, 2.5 mg / mL, 3 mg / mL, 3.5 mg / mL, 4 mg / mL, 4.5 mg / mL, 5 mg / mL, 5.5 mg / mL, 6 mg / mL, 6.5 mg / mL, 7 mg / mL, 7.5 mg / mL, 8 mg / mL, 8.5 mg / mL, 9 mg / mL, 9.5 mg / mL, 10 mg / mL, 10.5 mg / mL, 11 mg / mL, 11.5 mg / mL, 12 mg / mL, 12.5 mg / mL, 13 mg / mL, 13.5 mg / mL, 14 mg / mL, 14.5 mg / mL, 15 mg / mL, 15.5 mg / mL, 16 mg / mL, 16.5 mg / mL, 17 mg / mL, 17.5 mg / mL, 18 mg / mL, 18.2 mg / mL, or 19 mg / mL, or any range formed by using the foregoing values as endpoints, or any value therein.

[0100] In some embodiments of this disclosure, the amount of the antibacterial agent is selected from 0 to 0.091 mg / mL, 0 to 18.2 mg / mL, or 0.091 to 18.2 mg / mL.

[0101] In some embodiments of this disclosure, the pharmaceutical composition does not contain an antibacterial agent.

[0102] In some embodiments of this disclosure, a single dose of the pharmaceutical composition contains an antibacterial agent in an amount of 0–76 mg; or 0.01–76 mg, 0.02–70 mg, 0.05–60 mg, 0.1–50 mg, 0.1–40 mg, 0.12–30 mg, 0.14–20 mg, 0.15–15 mg, 0.16–10 mg, 0.18–10 mg, 0.2–8 mg, 0.22–6 mg, 0.24– 4mg, 0.26–2mg, 0.28–1mg, 0.3–0.9mg, 0.31–0.8mg, 0.32–0.7mg, 0.33–0.6mg, 0.34–0.5mg, 0.35–0.45mg, 0.36–0.4mg, 0.37–0.45mg or 0.38–0.4mg, or 0–25mg, or 0.19–1.9mg, or 0.19–0.76mg, or 0.38mg.

[0103] In some embodiments of this disclosure, when the antibacterial agent is present, a single dose of the pharmaceutical composition contains an amount of antibacterial agent of 0.01 mg, 0.02 mg, 0.04 mg, 0.06 mg, 0.08 mg, 0.1 mg, 0.11 mg, 0.12 mg, 0.13 mg, 0.14 mg, 0.15 mg, 0.16 mg, 0.17 mg, 0.18 mg, 0.19 mg, 0.2 mg, 0.21 mg, 0.22 mg, 0.23 mg, 0.24 mg, or 0.25 mg. , 0.26mg, 0.27mg, 0.28mg, 0.29mg, 0.3mg, 0.31mg, 0.32mg, 0.33mg, 0.34mg, 0.35mg, 0.36mg, 0.37mg, 0.38mg, 0.39m g, 0.4mg, 0.41mg, 0.42mg, 0.43mg, 0.44mg, 0.45mg, 0.46mg, 0.47mg, 0.48mg, 0.49mg, 0.5mg, 0.55mg, 0.6mg, 0.65mg, 0.7mg, 0.75mg, 0.8mg, 0.85mg, 0.9mg, 0.95mg, 1.0mg, 1.1mg, 1.2mg, 1.3mg, 1.4mg, 1.5mg, 1.6mg, 1.7mg, 1.8mg, 1.9 mg, 2.0mg, 2.5mg, 3.0mg, 3.5mg, 4.0mg, 4.5mg, 5.0mg, 6.0mg, 7.0mg, 8.0mg, 9.0mg, 10.0mg, 11mg, 12mg, 13mg, 14mg, 1 5mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, or 76mg, or any of the aforementioned values as endpoints, forming a range or any value therein.

[0104] In some embodiments of this disclosure, each spray of the pharmaceutical composition contains 0–200 μg of antibacterial agent; or 0–150 μg, 0.05–120 μg. 0.1~100μg, 0.1~90μg, 0.15~80μg, 0.2~70μg, 0.25~60μg, 0.3~50μg, 0.35~40μg, 0.4~30μg, 0.45~25μg, 0.5~20μg, 0.55~1 5μg, 0.6~10μg, 0.6~9μg, 0.6~8μg, 0.6~7μg, 0.6~6μg, 0.65~8μg, 0.65~7μg, 0.65~6μg, 0.7~7μg, 0.7~6μg, 0.7~5μg, 0.7~4μ g, 0.75~5μg, 0.75~4μg, 0.75~3μg, 0.75~2μg, 0.8~4μg, 0.8~3μg, 0.8~2μg, 0.8~1μg, 0.85~2μg, 0.85~1μg, 0.9~2μg, 0.9~1μ g, 0.95~2μg, 0.95~1μg, 1~2μg, 1~1.5μg, 1~1.4μg, 1~1.3μg, 1~1.2μg or 1~1.1μg, or 0~60μg, or 0.5~5μg, or 0.75~2μg, or 1μg.

[0105] In some embodiments of this disclosure, each spray of the pharmaceutical composition contains an amount of antibacterial agent of 0, 0.05 μg, 0.1 μg, 0.15 μg, 0.2 μg, 0.25 μg, 0.3 μg, 0.35 μg, 0.4 μg, 0.45 μg, 0.5 μg, 0.55 μg, 0.6 μg, 0.65 μg, 0.7 μg, 0.75 μg, 0.8 μg, 0.85 μg, 0.9 μg, 0.95 μg, 1 μg, 1.1 μg, 1.2 μg, 1.3 μg, 1.4 μg, 1.5 μg, 1.6 μg, 1.7 μg, 1.8 μg, 1.9 μg, 2 μg, 3 μg, 4 μg, 5 μg, 6 μg, 7 μg, 8 μg, 9 μg, 10 μg, 11μg, 12μg, 13μg, 14μg, 15μg, 16μg, 17μg, 18μg, 19μg, 20μg, 21μg, 22μg, 23μg, 24μg, 25μg, 26μg, 27μg, 28μg, 29μg, 30μg, 35μg, 40μg, 45μg, 50μg, 55μg, 60μg, 65μg, 70μg, 75μg, 80μg, 85μg, 90μg, 95μg, 100μg, 110μg, 120μg, 130μg, 140μg, 150μg, 160μg, 170μg, 180μg, 190μg, or 200μg, or any of the aforementioned values as endpoints, forming a range or any value therein.

[0106] In some embodiments of this disclosure, each spray of the pharmaceutical composition contains 0–1 μg, 0–200 μg, or 1–200 μg of antibacterial agent.

[0107] In some embodiments of this disclosure, the pharmaceutical composition comprises a metal ion chelating agent.

[0108] In some embodiments of this disclosure, the metal ion chelating agent is selected from ethylenediaminetetraacetic acid (EDTA) or its salts, ethylene glycol tetraacetic acid (EGTA) or its salts, cyclohexanediaminetetraacetic acid (CDTA) or its salts, hydroxyethylethylenediaminetriacetic acid (HEDTA) or its salts, diethylenetriaminepentaacetic acid (DTPA) or its salts, dimercaptopropanesulfonic acid (DMPS) or its salts, dimercaptosuccinic acid (DMSA) or its salts, aminotrimethylenephosphonic acid (ArPA) or its salts, citric acid or its salts, acetic acid or its salts, phosphoric acid or its salts, pyrophosphate or its salts, metaphosphate or its salts, and any combination thereof; preferably, the metal ion chelating agent is selected from ethylenediaminetetraacetic acid or its salts. The metal ion chelating agent is selected from one or more of the following: ethylenediaminetetraacetic acid (EDTA) or its salts, cyclohexanediaminetetraacetic acid (CTA) or its salts, hydroxyethylethylenediaminetriacetic acid (HTA) or its salts, and diethylenetriaminepentaacetic acid (DTA) or its salts; more preferably, the metal ion chelating agent is selected from one or more of EDTA or its salts, including but not limited to EDTA, disodium EDTA, dipotassium EDTA, trisodium EDTA, tripotassium EDTA, calcium disodium EDTA, and calcium EDTA; most preferably, the metal ion chelating agent is disodium EDTA.

[0109] In some embodiments of this disclosure, when the metal ion chelating agent is present, the amount of the metal ion chelating agent in the pharmaceutical composition is selected from 0.001–1 w / w%; or 0.001–0.9 w / w%, 0.001–0.8 w / w%, 0.001–0.7 w / w%, 0.001–0.6 w / w%, 0.001–0.5 w / w%, 0.001–0.4 w / w%, 0 .001~0.3w / w%, 0.001~0.2w / w%, 0.001~0.1w / w%, 0.002~0.1w / w%, 0.004~0.1w / w%, 0.00 6~0.1w / w%, 0.008~0.1w / w%, 0.01~0.1w / w%, 0.005~0.08w / w%, 0.005~0.06w / w%, 0.005~0 .04w / w%, 0.005~0.02w / w%, 0.005~0.01w / w%, 0.01~1w / w%, 0.01~0.9w / w%, 0.01~0.8w / w %, 0.01~0.7w / w%, 0.01~0.6w / w%, 0.01~0.5w / w%, 0.01~0.4w / w%, 0.01~0.3w / w%, 0.01~0. 2 w / w%, 0.01–0.1 w / w%, 0.01–0.08 w / w%, 0.01–0.06 w / w%, 0.01–0.05 w / w%, 0.01–0.04 w / w%, or 0.01–0.02 w / w%; or 0.001–0.5 w / w%; or 0.005–0.1 w / w%; or 0.01–0.05 w / w%; or 0.01 w / w%.

[0110] In some embodiments of this disclosure, when the metal ion chelating agent is present, the amount of the metal ion chelating agent in the pharmaceutical composition is selected from 0.001 w / w%, 0.002 w / w%, 0.003 w / w%, 0.004 w / w%, 0.005 w / w%, 0.006 w / w%, 0.007 w / w%, 0.008 w / w%, 0.009 w / w%, 0.01 w / w%, 0.011 w / w%, 0.012 w / w%, 0.013 w / w%, 0.014 w / w%, 0.015 w / w%, 0.016 w / w%, etc. w / w%, 0.017w / w%, 0.018w / w%, 0.019w / w%, 0.02w / w%, 0.021w / w%, 0.022w / w%, 0.023w / w%, 0.024w / w%, 0.025w / w%, 0.026w / w%, 0.027w / w%, 0.028w / w%, 0.029w / w%, 0.03w / w%, 0.031w / w%, 0.032w / w%, 0.033w / w%, 0.034w / w%, 0.035w / w%, 0.036w / w%, 0.037w / w%, 0.038w / w%, 0.039w / w%, 0.04w / w%, 0.041w / w%, 0.042w / w%, 0.043w / w%, 0.044w / w%, 0.045w / w%, 0.046w / w%, 0. 047w / w%, 0.048w / w%, 0.049w / w%, 0.05w / w%, 0.051w / w%, 0.052w / w%, 0.053w / w%, 0.054w / w%, 0.055w / w%, 0.056w / w%, 0.057 w / w%, 0.058w / w%, 0.059w / w%, 0.06w / w%, 0.065w / w%, 0.07w / w%, 0.075w / w%, 0.08w / w%, 0.085w / w%, 0.09w / w%, 0.095w / w%, 0.1w / w%, 0.2w / w%, 0.3w / w%, 0.4w / w%, 0.5w / w%, 0.6w / w%, 0.7w / w%, 0.8w / w%, 0.9w / w%, or 1w / w%, or any of the aforementioned values as endpoints, forming a range or any value therein.

[0111] In some embodiments of this disclosure, the amount of the metal ion chelating agent is selected from 0 to 0.01 w / w%, 0 to 2.0 w / w%, or 0.01 to 2.0 w / w%.

[0112] In some embodiments of this disclosure, the amount of the metal ion chelating agent is selected from 0–19 mg / mL; or 0.01–16 mg / mL, 0.01–14 mg / mL, 0.02–12 mg / mL, 0.02–10 mg / mL, 0.03–9 mg / mL, 0.03–8 mg / mL, 0.04–7 mg / mL, 0.04–6 mg / mL, 0.05–5 mg / mL, 0.05–4 mg / mL, 0.06–3 mg / mL, 0.06–2 mg / mL, 0.07–1 mg / mL, 0.07–0.9 mg / mL, 0.07–0.8 mg / mL, 0. 0.7–0.7 mg / mL, 0.08–0.7 mg / mL, 0.08–0.6 mg / mL, 0.08–0.5 mg / mL, 0.08–0.4 mg / mL, 0.085–0.5 mg / mL, 0.085–0.4 mg / mL, 0.085–0.3 mg / mL, 0.09–0.4 mg / mL, 0.09–0.3 mg / mL, 0.09–0.2 mg / mL or 0.09–0.1 mg / mL; or 0–6 mg / mL; or 0.045–0.45 mg / mL; or 0.045–0.18 mg / mL; or 0.09 mg / mL.

[0113] In some embodiments of the present disclosure, the amount of the metal ion chelator is selected from 0 mg / mL, 0.01 mg / mL, 0.015 mg / mL, 0.02 mg / mL, 0.025 mg / mL, 0.03 mg / mL, 0.035 mg / mL, 0.04 mg / mL, 0.045 mg / mL, 0.05 mg / mL, 0.051 mg / mL, 0.052 mg / mL, 0.053 mg / mL, 0.054 mg / mL, 0.055 mg / mL, 0.056 mg / mL, 0.057 mg / mL, 0.058 mg / mL, 0.059 mg / mL, 0.06 mg / mL, 0.061 mg / mL, 0.062 mg / mL, 0.063 mg / mL, 0.064 mg / mL, 0.065 mg / mL, 0.066 mg / mL, 0.067 mg / mL, 0.068 mg / mL, 0.069 mg / mL, 0.07 mg / mL, 0.071 mg / mL, 0.072 mg / mL, 0.073 mg / mL, 0.074 mg / mL, 0.075 mg / mL, 0.076 mg / mL, 0.077 mg / mL, 0.078 mg / mL, 0.079 mg / mL, 0.08 mg / mL, 0.081 mg / mL, 0.082 mg / mL, 0.083 mg / mL, 0.084 mg / mL, 0.085 mg / mL, 0.086 mg / mL, 0.087 mg / mL, 0.088 mg / mL, 0.089 mg / mL, 0.09 mg / mL, 0.091 mg / mL, 0.092 mg / mL, 0.093 mg / mL, 0.094 mg / mL, 0.095 mg / mL, 0.096 mg / mL, 0.097 mg / mL, 0.098 mg / mL, 0.099 mg / mL, 0.1 mg / mL, 0.11 mg / mL, 0.12 mg / mL, 0.13 mg / mL, 0.14 mg / mL, 0.15 mg / mL, 0.16 mg / mL, 0.17 mg / mL, 0.18 mg / mL, 0.19 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL, 1.6 mg / mL, 1.7 mg / mL, 1.8 mg / mL, 1.9 mg / mL, 2 mg / mL, 2.5 mg / mL, 3 mg / mL, 3.5 mg / mL, 4 mg / mL, 4.5 mg / mL, 5 mg / mL, 5.5 mg / mL, 6 mg / mL, 6.5 mg / mL, 7 mg / mL, 7.5 mg / mL, 8 mg / mL, 8.5 mg / mL, 9 mg / mL, 9.5 mg / mL, 10 mg / mL, 10.5 mg / mL, 11 mg / mL, 11.5 mg / mL, 12 mg / mL, 12.5 mg / mL, 13 mg / mL, 13.5 mg / mL, 14 mg / mL, 14.5 mg / mL, 15 mg / mL, 15.5 mg / mL, 16 mg / mL, 16.5 mg / mL, 17 mg / mL, 17.5 mg / mL, 18 mg / mL, 18.2 mg / mL, or 19 mg / mL, or any range formed by using the foregoing values as endpoints, or any value therein.

[0114] In some embodiments of this disclosure, the amount of the metal ion chelating agent is selected from 0 to 0.091 mg / mL, 0 to 18.2 mg / mL, or 0.091 to 18.2 mg / mL.

[0115] In some embodiments of this disclosure, the pharmaceutical composition does not contain a metal ion chelating agent.

[0116] In some embodiments of this disclosure, a single-dose pharmaceutical composition comprises a metal ion chelating agent in an amount of 0–76 mg; or 0.01–76 mg, 0.02–70 mg, 0.05–60 mg, 0.1–50 mg, 0.1–40 mg, 0.12–30 mg, 0.14–20 mg, 0.15–15 mg, 0.16–10 mg, 0.18–10 mg, 0.2–8 mg, 0.22–6 mg, 0.2 4–4 mg, 0.26–2 mg, 0.28–1 mg, 0.3–0.9 mg, 0.31–0.8 mg, 0.32–0.7 mg, 0.33–0.6 mg, 0.34–0.5 mg, 0.35–0.45 mg, 0.36–0.4 mg, 0.37–0.45 mg or 0.38–0.4 mg, or 0–25 mg, or 0.19–1.9 mg, or 0.19–0.76 mg, or 0.38 mg.

[0117] In some embodiments of this disclosure, the amount of metal ion chelating agent contained in a single-dose pharmaceutical composition is 0.01 mg, 0.02 mg, 0.04 mg, 0.06 mg, 0.08 mg, 0.1 mg, 0.11 mg, 0.12 mg, 0.13 mg, 0.14 mg, 0.15 mg, 0.16 mg, 0.17 mg, 0.18 mg, 0.19 mg, 0.2 mg, 0.21 mg, 0.22 mg, 0.23 mg, 0.24 mg, 0.25 mg, 0.26 mg, or 0.26 mg. mg, 0.27mg, 0.28mg, 0.29mg, 0.3mg, 0.31mg, 0.32mg, 0.33mg, 0.34mg, 0.35mg, 0.36mg, 0.37mg, 0.38mg, 0.39mg, 0. 4mg, 0.41mg, 0.42mg, 0.43mg, 0.44mg, 0.45mg, 0.46mg, 0.47mg, 0.48mg, 0.49mg, 0.5mg, 0.55mg, 0.6mg, 0.65mg, 0.7 mg, 0.75mg, 0.8mg, 0.85mg, 0.9mg, 0.95mg, 1.0mg, 1.1mg, 1.2mg, 1.3mg, 1.4mg, 1.5mg, 1.6mg, 1.7mg, 1.8mg, 1.9mg , 2.0mg, 2.5mg, 3.0mg, 3.5mg, 4.0mg, 4.5mg, 5.0mg, 6.0mg, 7.0mg, 8.0mg, 9.0mg, 10.0mg, 11mg, 12mg, 13mg, 14mg, 15 mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, or 76mg, or any of the aforementioned values as endpoints, forming a range or any value therein.

[0118] In some embodiments of this disclosure, each spray of the pharmaceutical composition contains 0–200 μg of a metal ion chelating agent; or 0–150 μg, 0.05–120 μg. 0.1~100μg, 0.1~90μg, 0.15~80μg, 0.2~70μg, 0.25~60μg, 0.3~50μg, 0.35~40μg, 0.4~30μg, 0.45~25μg, 0.5~20μg, 0.55~1 5μg, 0.6~10μg, 0.6~9μg, 0.6~8μg, 0.6~7μg, 0.6~6μg, 0.65~8μg, 0.65~7μg, 0.65~6μg, 0.7~7μg, 0.7~6μg, 0.7~5μg, 0.7~4μ g, 0.75~5μg, 0.75~4μg, 0.75~3μg, 0.75~2μg, 0.8~4μg, 0.8~3μg, 0.8~2μg, 0.8~1μg, 0.85~2μg, 0.85~1μg, 0.9~2μg, 0.9~1μ g, 0.95~2μg, 0.95~1μg, 1~2μg, 1~1.5μg, 1~1.4μg, 1~1.3μg, 1~1.2μg or 1~1.1μg, or 0~60μg, or 0.5~5μg, or 0.75~2μg, or 1μg.

[0119] In some embodiments of this disclosure, each spray of the pharmaceutical composition contains the following amounts of metal ion chelating agent: 0, 0.05 μg, 0.1 μg, 0.15 μg, 0.2 μg, 0.25 μg, 0.3 μg, 0.35 μg, 0.4 μg, 0.45 μg, 0.5 μg, 0.55 μg, 0.6 μg, 0.65 μg, 0.7 μg, 0.75 μg, 0.8 μg, 0.85 μg, 0.9 μg, 0.95 μg, 1 μg, 1.1 μg, 1.2 μg, 1.3 μg, 1.4 μg, 1.5 μg, 1.6 μg, 1.7 μg, 1.8 μg, 1.9 μg, 2 μg, 3 μg, 4 μg, 5 μg, 6 μg, 7 μg, 8 μg, 9 μg, 10 μg. g, 11μg, 12μg, 13μg, 14μg, 15μg, 16μg, 17μg, 18μg, 19μg, 20μg, 21μg, 22μg, 23 μg, 24μg, 25μg, 26μg, 27μg, 28μg, 29μg, 30μg, 35μg, 40μg, 45μg, 50μg, 55μg, 6 0 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 110 μg, 120 μg, 130 μg, 140 μg, 150 μg, 160 μg, 170 μg, 180 μg, 190 μg or 200 μg, or any of the aforementioned values as endpoints, or any value therein.

[0120] In some embodiments of this disclosure, each spray of the pharmaceutical composition contains 0–1 μg, 0–200 μg, or 1–200 μg of a metal ion chelating agent.

[0121] In some embodiments of this disclosure, the pharmaceutical composition comprises water.

[0122] In some embodiments of this disclosure, the pharmaceutical composition further comprises water, which may be purified water or water for injection.

[0123] In some embodiments of this disclosure, when the pharmaceutical composition contains water, the amount of water in the pharmaceutical composition is selected from 4–80 w / w%; or 4–68 w / w%, 10–66 w / w%, 15–64 w / w%, 20–62 w / w%, 22–60 w / w%, 24–60 w / w%, 26–58 w / w%, 28–56 w / w%, 30–54 w / w%, 32–52 w / w%, 34– 50 w / w%, 36–50 w / w%, 36–49 w / w%, 38–49 w / w%, 40–48 w / w%, 41–48 w / w%, 42–48 w / w%, 42–47 w / w%, 43–47 w / w%, 44–46 w / w%, 45–46 w / w%; or 4–60 w / w%; or 30–60 w / w%, or 40–50 w / w%; or 44–45 w / w.

[0124] In some embodiments of this disclosure, when the pharmaceutical composition contains water, the amount of water in the pharmaceutical composition is selected from 4 w / w%, 6 w / w%, 8 w / w%, 10 w / w%, 12 w / w%, 14 w / w%, 16 w / w%, 18 w / w%, 20 w / w%, 21 w / w%, 22 w / w%, 23 w / w%, 24 w / w%, 25 w / w%, 26 w / w%, 27 w / w%, 28 w / w%, 29 w / w%, 30 w / w%, 31 w / w%, 32 w / w%, 33 w / w%, 34 w / w%, 35 w / w%, 36 w / w%, 37 w / w%, 38 w / w%, 39 w / w%, 40 w / w%, and 41 w / w%. / w% , 42w / w% , 43w / w% , 44w / w% , 45w / w% , 46w / w% , 47w / w% , 48w / w% , 49w / w% , 50w / w% , 51w / w% , 52w / w% , 53w / w% , 54w / w% , 55w / w% , 56w / w% , 57w / w% , 58w / w% , 59w / w% , 60w / w% , 61w / w% , 62w / w% , 63w / w% , 64w / w% , 65w / w% , 66w / w% , 67w / w% , 68w / w% , 69w / w% , 70w / w% , 75w / w% or 80w / w%, or any of the aforementioned values as endpoints, constituting a range or any value therein.

[0125] In some embodiments of this disclosure, when the pharmaceutical composition contains water, the amount of water in the pharmaceutical composition is selected from 4 to 44 w / w%, 4 to 80 w / w%, or 44 to 80 w / w.

[0126] In some embodiments of this disclosure, when the pharmaceutical composition contains water, the amount of water in the pharmaceutical composition is selected from 30–730 mg / mL; or 60–600 mg / mL, 80–580 mg / mL, 100–560 mg / mL, 120–540 mg / mL, 140–520 mg / mL, 160–500 mg / mL, 180–490 mg / mL, 200–480 mg / mL, 220–470 mg / mL, 240 mg / mL, etc. ~460mg / mL, 260~450mg / mL, 280~440mg / mL, 300~430mg / mL, 320~420mg / mL, 340~410mg / mL, 360~410mg / mL, 380~400mg / mL, 390~400mg / mL; or 100~480mg / mL, or 300~450mg / mL; or 360~430mg / mL; or 360~405mg / mL.

[0127] In some embodiments of this disclosure, when the pharmaceutical composition contains water,The amount of water in the pharmaceutical composition is selected from 30 mg / mL, 36 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL, 200 mg / mL, 210 mg / mL, 220 mg / mL, 230 mg / mL, 240 mg / mL, 250 mg / mL, 260 mg / mL, 270 mg / mL, 280 mg / mL, 290 mg / mL, 300 mg / mL, 305 mg / mL, 310 mg / mL, 315 mg / mL, 320 mg / mL, 325 mg / mL, 330 mg / mL, 335 mg / mL, 340 mg / mL, 345 mg / mL, 350 mg / mL, 355 mg / mL, 360 mg / mL, 365 mg / mL, 370 mg / mL, 375 mg / mL, 380 mg / mL, 381 mg / mL, 382 mg / mL, 383 mg / mL, 384 mg / mL, 385 mg / mL, 386 mg / mL, 387 mg / mL, 388 mg / mL, 389 mg / mL, 390 mg / mL, 391 mg / mL, 392 mg / mL, 393 mg / mL, 394 mg / mL, 395 mg / mL, 396 mg / mL, 397 mg / mL, 398 mg / mL, 399 mg / mL, 400 mg / mL, 401 mg / mL, 402 mg / mL, 403 mg / mL, 404 mg / mL, 405 mg / mL, 406 mg / mL, 407 mg / mL, 408 mg / mL, 409 mg / mL, 410 mg / mL, 415 mg / mL, 420 mg / mL, 425 mg / mL, 430 mg / mL, 435 mg / mL, 440 mg / mL, 445 mg / mL, 450 mg / mL, 460 mg / mL, 470 mg / mL, 480 mg / mL, 490 mg / mL, 500 mg / mL, 510 mg / mL, 520 mg / mL, 530 mg / mL, 540 mg / mL, 550 mg / mL, 560 mg / mL, 570 mg / mL, 580 mg / mL, 590 mg / mL, 600 mg / mL, 610 mg / mL, 620 mg / mL, 630 mg / mL, 640 mg / mL, 650 mg / mL, 660 mg / mL, 670 mg / mL, 680 mg / mL, 690 mg / mL, 700 mg / mL, 720 mg / mL or 730 mg / mL,Or any of the aforementioned values as endpoints, forming a range or any value within that range.

[0128] In some embodiments of this disclosure, when the pharmaceutical composition contains water, the amount of water in the pharmaceutical composition is selected from 36–400 mg / mL, 36–730 mg / mL, or 400–730 mg / mL.

[0129] In some embodiments of this disclosure, when the pharmaceutical composition contains water, the amount of water contained in a single dose of the pharmaceutical composition is 150–3100 mg; or 160–2400 mg, 300–2200 mg, 500–2200 mg, 800–2100 mg, 1000–2000 mg, 1200–1900 mg, 1300–1800 mg, 1400–1700 mg, 1500–1750 mg, 1 550–1700 mg, 1600–1690 mg, 1620–1690 mg, 1620–1680 mg, 1640–1680 mg, 1650–1680 mg, 1660–1675 mg or 1670–1675 mg, or 330–2000 mg, or 1250–1900 mg, or 1500–1800 mg, or 1665–1685 mg, or 1672 mg, or 1675 mg.

[0130] In some embodiments of this disclosure, when the pharmaceutical composition contains water, the amount of water contained in a single dose of the pharmaceutical composition is 150 mg, 151 mg, 152 mg, 153 mg, 154 mg, 155 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1610 mg, 1620 mg, 1630 mg, 1640 mg, 1650 mg, etc. 1660mg, 1670mg, 1680mg, 1690mg, 1700mg, 1710mg, 1720mg, 1730mg, 1740mg, 1750mg, 1760mg, 1770mg, 1780mg, 1790mg, 1800mg, 1850mg, 1900mg, 1950mg, 2000mg, 2050mg, 2100mg, 2150mg, 2200mg, 2250mg, 2300mg, 2350mg, 2400mg, 2450mg, 2500mg, 2600mg, 2700mg, 2800mg, 2900mg, 3000mg, or 3100mg, or any of the aforementioned values as endpoints, forming a range or any value therein.

[0131] In some embodiments of this disclosure, when the pharmaceutical composition contains water, the amount of water contained in each spray of the pharmaceutical composition is 0.4–8.0 mg; preferably 0.4–6.5 mg, 0.6–6.4 mg, 0.8–6.2 mg, 1–6 mg, 1.2–5.9 mg, 1.4–5.8 mg, 1.6–5.7 mg, 1.8–5.6 mg, 2–5.5 mg, 2.2–5.4 mg, 2.4–5.3 mg. mg, 2.6–5.2 mg, 2.8–5.1 mg, 3–5 mg, 3.2–4.9 mg, 3.4–4.9 mg, 3.6–4.8 mg, 3.8–4.8 mg, 4–4.7 mg, 4.1–4.7 mg, 4.2–4.6 mg, 4.3–4.6 mg or 4.4–4.5 mg, or 0.8–5.3 mg, or 3–5 mg, or 4–4.8 mg, or 4.4–4.5 mg.

[0132] In some embodiments of this disclosure, when the pharmaceutical composition contains water, the amount of water contained in each spray of the pharmaceutical composition is 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, or 4.0 mg. 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5.0 mg, 5.1 mg, 5.2 mg, 5.3 mg, 5.4 mg, 5.5 mg, 5.6 mg, 5.7 mg, 5.8 mg, 5.9 mg, 6.0 mg, 6.1 mg, 6.2 mg, 6.3 mg, 6.4 mg, 6.5 mg, 6.6 mg, 6.7 mg, 6.8 mg, 6.9 mg, 7.0 mg, 7.1 mg, 7.2 mg, 7.3 mg, 7.4 mg, 7.5 mg, 7.6 mg, 7.7 mg, 7.8 mg, 7.9 mg, or 8.0 mg, or any of the aforementioned values as endpoints forming a range or any value therein.

[0133] In some embodiments of this disclosure, when the pharmaceutical composition contains water, the amount of water contained in each spray of the pharmaceutical composition is 0.4–4.4 mg, 0.4–8.0 mg, or 4.4–8.0 mg.

[0134] In some embodiments of this disclosure, the pharmaceutical composition comprises ethanol.

[0135] In some embodiments of this disclosure, when the pharmaceutical composition contains ethanol, the amount of ethanol in the pharmaceutical composition is selected from 20–96 w / w%; or 20–90 w / w%, 30–96 w / w%, 40–96 w / w%, 40–90 w / w%, 40–85 w / w%, 40–80 w / w%, 40–75 w / w%, 40–70 w / w%, 40–70 w / w%, 40–70 w / w%, 40–9 ... 0–65 w / w%, 40–60 w / w%, 42–60 w / w%, 44–60 w / w%, 46–60 w / w%, 48–60 w / w%, 50–60 w / w%, 52–58 w / w%, or 53–57 w / w%; or 40–70 w / w%; or 50–60 w / w%; or 53–56 w / w%; or 53–55 w / w%.

[0136] In some embodiments of this disclosure, when the pharmaceutical composition contains ethanol, the amount of ethanol in the pharmaceutical composition is selected from 20 w / w%, 21 w / w%, 22 w / w%, 23 w / w%, 24 w / w%, 25 w / w%, 26 w / w%, 27 w / w%, 28 w / w%, 29 w / w%, 30 w / w%, 31 w / w%, 32 w / w%, 33 w / w%, 34 w / w%, and 35 w / w%. / w%, 36w / w%, 37w / w%, 38w / w%, 39w / w%, 40w / w%, 41w / w%, 42w / w%, 43w / w%, 44w / w%, 45w / w%, 46 w / w%, 47w / w%, 48w / w%, 49w / w%, 50w / w%, 51w / w%, 22w / w%, 53w / w%, 54w / w%, 55w / w%, 56w / w%, 5 7w / w%, 58w / w%, 59w / w%, 60w / w%, 61w / w%, 62w / w%, 63w / w%, 64w / w%, 65w / w%, 66w / w%, 67w / w% , 68w / w%, 69w / w%, 70w / w%, 71w / w%, 72w / w%, 73w / w%, 74w / w%, 75w / w%, 76w / w%, 77w / w%, 78w / w %, 79w / w%, 80w / w%, 81w / w%, 82w / w%, 83w / w%, 84w / w%, 85w / w%, 86w / w%, 87w / w%, 88w / w%, 89w / w%, 90w / w%, 91w / w%, 92w / w%, 93w / w%, 94w / w%, 95w / w%, or 96w / w%, or any of the aforementioned values as endpoints, or any value therein.

[0137] In some embodiments of this disclosure, when the pharmaceutical composition contains ethanol, the amount of ethanol in the pharmaceutical composition is selected from 20–54 w / w%, 20–96 w / w%, or 54–96 w / w.

[0138] In some embodiments of this disclosure, when the pharmaceutical composition contains ethanol, the amount of ethanol in the pharmaceutical composition is selected from 180–900 mg / mL; or 200–880 mg / mL, 220–880 mg / mL, 240–880 mg / mL, 260–850 mg / mL, 280–830 mg / mL, 300–800 mg / mL, 320–780 mg / mL, 340–750 mg / mL. mg / mL, 240~720mg / mL, 260~700mg / mL, 280~680mg / mL, 300~650mg / mL, 320~630mg / mL, 340~630 mg / mL, 360~610mg / mL, 380~590mg / mL, 390~580mg / mL, 400~570mg / mL, 410~565mg / mL, 420~560 mg / mL, 430~555mg / mL, 440~550mg / mL, 450~545mg / mL, 455~540mg / mL, 460~535mg / mL, 465~530 mg / mL, 470~525mg / mL, 475~520mg / mL, 480~515mg / mL, 480~510mg / mL, 480~505mg / mL, 480~500 mg / mL, 480–495 mg / mL, 480–490 mg / mL, 485–510 mg / mL, 485–510 mg / mL, 485–505 mg / mL, 485–500 mg / mL or 485–495 mg / mL; or 320–850 mg / mL; or 390–620 mg / mL; or 450–530 mg / mL; or 450–495 mg / mL.

[0139] In some embodiments of this disclosure, when the pharmaceutical composition contains ethanol, the amount of ethanol in the pharmaceutical composition is selected from 180 mg / mL, 182 mg / mL, 200 mg / mL, 210 mg / mL, 220 mg / mL, 230 mg / mL, 240 mg / mL, 250 mg / mL, 260 mg / mL, 270 mg / mL, 280 mg / mL, 290 mg / mL, 300 mg / mL, 310 mg / mL, 320 mg / mL, 330 mg / mL, 340 mg / mL, 350 mg / mL, 360 mg / mL, 370 mg / mL, 380 mg / mL, 390 mg / mL, and 400 mg / mL. , 405mg / mL, 410mg / mL, 415mg / mL, 420mg / mL, 425mg / mL, 430mg / mL, 435mg / mL, 440mg / mL, 445mg / mL, 450mg / mL, 455mg / mL, 460mg / mL, 465mg / mL, 470mg / mL, 475mg / mL, 480mg / mL, 481mg / mL, 482mg / mL, 483mg / mL, 484mg / mL, 485mg / mL, 486mg / mL, 487mg / mL, 488mg / mL, 489mg / mL, 490mg / mL, 491mg / mL, 492mg / mL, 493mg / mL, 494mg / mL, 495mg / mL, 496mg / mL, 497mg / mL, 498mg / mL, 499mg / mL, 500mg / mL, 505mg / mL, 510mg / mL, 515mg / mL, 520mg / mL, 525mg / mL, 530 mg / mL, 535mg / mL, 540mg / mL, 545mg / mL, 550mg / mL, 555mg / mL, 560mg / mL, 565mg / mL, 570mg / mL, 575mg / mL, 580mg / mL, 585mg / mL, 590mg / mL, 595mg / mL, 60 0mg / mL, 610mg / mL, 620mg / mL, 630mg / mL, 640mg / mL, 650mg / mL, 660mg / mL, 670mg / mL, 680mg / mL, 690mg / mL, 700mg / mL, 710mg / mL, 720mg / mL, 730mg / mL, 7 40mg / mL, 750mg / mL, 760mg / mL, 770mg / mL, 780mg / mL, 790mg / mL, 800mg / mL, 810mg / mL, 820mg / mL, 830mg / mL, 840mg / mL, 850mg / mL, 860mg / mL, 870mg / mL,873 mg / mL, 880 mg / mL, 890 mg / mL, or 900 mg / mL, or any range formed by using the aforementioned values as endpoints, or any value therein.

[0140] In some embodiments of this disclosure, when the pharmaceutical composition contains ethanol, the amount of ethanol in the pharmaceutical composition is selected from 182–491 mg / mL, 182–873 mg / mL, or 491–873 mg / mL.

[0141] In some embodiments of this disclosure, when the pharmaceutical composition contains ethanol, the amount of ethanol contained in a single dose of the pharmaceutical composition is 750–3700 mg; or 1000–3600 mg, 1100–3500 mg, 1200–3400 mg, 1300–3300 mg, 1400–3200 mg, 1500–3100 mg, 1550–3000 mg, 1600–2900 mg, 1650–2800 mg, 1700–2700 mg, 1750–2600 mg, 1800–2550 mg, 1850–2500 mg, 1900–2450 mg, 1950–2400 mg, or 2000–2400 mg. 2000-2350mg, 2000-2300mg, 2000-2250mg, 2000-2200mg, 2000-2150mg, 2000-2100mg, 2050-2300mg, 2050-2250mg, 2050-2200mg, 2050-2150mg, 2050-2100mg, 2050-2090mg, 2050-2080mg, 2050-2070mg or 2050-2060mg, or 1300-3500mg, or 1600-2600mg, or 1900-2200mg, or 2000-2100mg, or 2047mg, or 2052mg.

[0142] In some embodiments of this disclosure, when the pharmaceutical composition contains ethanol, the amount of ethanol contained in a single dose of the pharmaceutical composition is 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2010 mg, 2010 mg, 2020 mg, 2030 mg, 2040 mg, 2... 050mg, 2060mg, 2070mg, 2080mg, 2090mg, 2100mg, 2150mg, 2200mg, 2250mg, 2300mg, 2350mg, 2400mg, 2450mg, 2500mg, 2550mg, 2600mg, 2650mg, 2700mg, 2750mg, 2800mg, 2850mg, 2900mg, 2950mg, 3000mg, 3050mg, 3100mg, 3150mg, 3200mg, 3250mg, 3300mg, 3350mg, 3400mg, 3450mg, 3500mg, 3550mg, 3600mg, 3650mg, 3700mg, or any of the aforementioned values as endpoints, forming a range or any value therein.

[0143] In some embodiments of this disclosure, when the pharmaceutical composition contains ethanol, the amount of ethanol contained in each spray of the pharmaceutical composition is 2.0–9.8 mg; or 2.7–9.6 mg, 2.8–9.4 mg, 2.9–9.2 mg, 3.0–9.0 mg, 3.1–8.8 mg, 3.2–8.6 mg, 3.3–8.4 mg, 3.4–8.2 mg, 3.5–8.0 mg, 3.6–7.8 mg, 3.7–7.6 mg, 3.8–7.4 mg, 3.9–7.2 mg, 4.0–7.0 mg, 4.1–6.9 mg, 4.2–6.8 mg, 4.3–6.7 mg, 4.4–6.6 mg, 4.5–6.5 mg, 4.6–6.4 mg, 4.7–6.3 mg, 4.8–6.2 mg, 4.9–6.1 mg, 5.0–6.0 mg, 5.1–5.9 mg, 5.2–5.8 mg, 5.3–5.7 mg, 5.4–5.6 mg, or 3.6–9.4 mg, or 4.3–6.8 mg, or 5.0–5.8 mg, or 5.3–5.5 mg, or 5.4–5.5 mg.

[0144] In some embodiments of this disclosure, when the pharmaceutical composition contains ethanol, the amount of ethanol contained in each spray of the pharmaceutical composition is 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5.0 mg, 5.1 mg, 5.2 mg, 5.3 mg, 5.4 mg, 5.5 mg, 5.6 mg, 5.7 mg. mg, 5.8mg, 5.9mg, 6.0mg, 6.1mg, 6.2mg, 6.3mg, 6.4mg, 6.5mg, 6.6mg, 6.7mg, 6.8mg, 6.9mg, 7.0mg, 7.1mg, 7.2mg, 7.3mg, 7.4mg, 7.5mg, 7.6mg, 7.7mg, 7.8mg, 7.9mg, 8.0mg, 8.1mg, 8.2mg, 8.3mg, 8.4mg, 8.5mg, 8.6mg, 8.7mg, 8.8mg, 8.9mg, 9.0mg, 9.1mg, 9.2mg, 9.3mg, 9.4mg, 9.5mg, 9.6mg, 9.7mg, or 9.8mg, or any of the aforementioned values as endpoints, forming a range or any value therein.

[0145] In some embodiments of this disclosure, when the pharmaceutical composition contains ethanol, the amount of ethanol contained in each spray of the pharmaceutical composition is 2.0–5.4 mg, 2.0–9.6 mg, or 5.4–9.6 mg.

[0146] In some embodiments of this disclosure, the pharmaceutical composition comprises a pH adjuster.

[0147] In some embodiments of this disclosure, the pH adjuster is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, lactic acid, tartaric acid, boric acid, malic acid, succinic acid, fumaric acid, methionine, and glucuronic acid; or, the pH adjuster is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, tartaric acid, succinic acid, and fumaric acid; or, the pH adjuster is selected from one or more of hydrochloric acid, phosphoric acid, citric acid, acetic acid, and tartaric acid; or, the pH adjuster is hydrochloric acid.

[0148] In some embodiments of this disclosure, the pH value of the pharmaceutical composition is 2.0 to 4.5; or, the pH value is 2.0 to 4.0, 2.0 to 3.5, 2.5 to 3.5, 2.6 to 3.5, 2.8 to 3.5, 2.9 to 3.5, 2.5 to 3.0; or, the pH value is 2.5 to 4.0; or, the pH value is 2.5 to 3.5; or, the pH value is 2.5 to 3.0; or, in some embodiments of this disclosure, the pH value is selected from 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, or 4.5, or any range formed by any of the foregoing values as endpoints, or any value therein.

[0149] In some embodiments of this disclosure, the pharmaceutical composition does not contain a pH adjuster.

[0150] In some embodiments of this disclosure, the pharmaceutical composition comprises 0.01 to 20 w / w% of n-propanol, isopropanol, glycerin, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenethyl alcohol, butanol, butanediol, mannitol, polyethylene glycol, ethylene glycol, or mixtures thereof; preferably, it comprises 0.5 to 10 w / w% of glycerin, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenethyl alcohol, butanol, butanediol, polyethylene glycol, ethylene glycol, or mixtures thereof; more preferably, it comprises 0.5 to 5 w / w% of glycerin, propylene glycol, oleic acid, phenethyl alcohol, butanol, or mixtures thereof; even more preferably, it comprises 1 to 5 w / w% of glycerin, propylene glycol, or mixtures thereof; more preferably, it comprises 1 to 5 w / w%, 1 to 4 w / w%, 1 to 3 w / w%, or 1 to 2 w / w% of glycerin; most preferably, it comprises 1 w / w% of glycerin.

[0151] In some embodiments of this disclosure, the pharmaceutical composition comprises 0.1–190 mg / mL of n-propanol, isopropanol, glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenethyl alcohol, butanol, butylene glycol, mannitol, polyethylene glycol, ethylene glycol, or mixtures thereof; preferably, it comprises 1.8–45 mg / mL of glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenethyl alcohol, butanol, butylene glycol, polyethylene glycol, ethylene glycol, or mixtures thereof; more preferably, it comprises 4.5–23 mg / mL of glycerol, propylene glycol, oleic acid, phenethyl alcohol, butanol, or mixtures thereof; even more preferably, it comprises 7.2–18 mg / mL of glycerol, propylene glycol, or mixtures thereof; more preferably, it comprises 7.5–16 mg / mL, 8–14 mg / mL, 8.5–12 mg / mL, or 9–10 mg / mL of glycerol; most preferably, it comprises 9.09 mg / mL of glycerol.

[0152] In some embodiments of this disclosure, the pharmaceutical composition comprises 0.0001–10 w / w% of butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, tert-butylhydroquinone, ascorbic acid antioxidants (including but not limited to vitamin C, isoascorbic acid, sodium ascorbate, potassium ascorbate, and ascorbate palmitate), tocopherol antioxidants (including but not limited to vitamin E, α-tocopherol, mixed concentrated tocopherols, and tocopherol acetate), vitamin A, retinyl palmitate, dibutylphenol, tea polyphenols (TP), and sulfite antioxidants (including but not limited to... Sodium sulfate, potassium sulfite, sodium metabisulfite, potassium metabisulfite, sodium bisulfite, potassium bisulfite, sodium thiosulfate), fumaric acid or its salts, malic acid or its salts, citric acid or its salts, maleic acid or its salts, or mixtures thereof; preferably containing 0.0015 to 5 w / w% of ascorbic acid antioxidants (including but not limited to vitamin C, isoascorbic acid, sodium ascorbate, potassium ascorbate, ascorbyl palmitate), sulfite antioxidants (including but not limited to sodium sulfite, potassium sulfite, sodium metabisulfite, potassium metabisulfite, sodium bisulfite, potassium bisulfite, sodium thiosulfate), and butanediol. Hydroxytoluene, butylated hydroxyanisole, propyl gallate, tert-butylhydroquinone, tea polyphenols, or mixtures thereof; more preferably, containing 0.0001–0.2 w / w% of vitamin C, ascorbyl palmitate, sodium sulfite, sodium bisulfite, sodium thiosulfate, butylated hydroxyanisole, butylated hydroxytoluene, tert-butylhydroquinone, propyl gallate, tea polyphenols, or mixtures thereof; even more preferably, containing 0.0015–0.11 w / w% of vitamin C, sodium sulfite, sodium bisulfite, sodium thiosulfate, tert-butylhydroquinone, propyl gallate, tea polyphenols, or mixtures thereof; even more preferably, containing 0.0015–0.11 w / w% of vitamin C, sodium sulfite, sodium bisulfite, sodium thiosulfate, tert-butylhydroquinone, propyl gallate, tea polyphenols, or mixtures thereof; even more preferably... The preferred concentrations are 0.0001–0.2 w / w%, 0.0011–0.15 w / w%, 0.0012–0.11 w / w%, 0.0013–0.05 w / w%, 0.0014–0.01 w / w%, 0.0015–0.008 w / w%, 0.0015–0.005 w / w%, 0.0015–0.004 w / w%, 0.0015–0.003 w / w%, or 0.0015–0.002 w / w% of vitamin C; the most preferred concentration is 0.0015 w / w% of vitamin C.

[0153] In some embodiments of this disclosure, the pharmaceutical composition comprises 0.0001–80 mg / mL of butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, tert-butylhydroquinone, ascorbic acid antioxidants (including but not limited to vitamin C, isoascorbic acid, sodium ascorbate, potassium ascorbate, and ascorbyl palmitate), tocopherol antioxidants (including but not limited to vitamin E, α-tocopherol, mixed concentrated tocopherols, and tocopherol acetate), vitamin A, retinyl palmitate, dibutylphenol, tea polyphenols (TP), and sulfite antioxidants (including but not limited to sodium sulfite, potassium sulfite, and...). Sodium metabisulfite, potassium metabisulfite, sodium bisulfite, potassium bisulfite, sodium thiosulfate), fumaric acid or its salts, malic acid or its salts, citric acid or its salts, maleic acid or its salts, or mixtures thereof; preferably containing 0.01–10 mg / mL of ascorbic acid antioxidants (including but not limited to vitamin C, isoascorbic acid, sodium ascorbate, potassium ascorbate, ascorbyl palmitate), sulfite antioxidants (including but not limited to sodium sulfite, potassium sulfite, sodium metabisulfite, potassium metabisulfite, sodium bisulfite, potassium bisulfite, sodium thiosulfate), butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, and other special antioxidants. The product contains butyl hydroquinone, tea polyphenols, or mixtures thereof; more preferably, it contains 0.01–4.5 mg / mL of vitamin C, ascorbyl palmitate, sodium sulfite, sodium bisulfite, sodium thiosulfate, butylated hydroxyanisole, butylated hydroxytoluene, tert-butyl hydroquinone, propyl gallate, tea polyphenols, or mixtures thereof; even more preferably, it contains 0.011–2.3 mg / mL of vitamin C, sodium sulfite, sodium bisulfite, sodium thiosulfate, tert-butyl hydroquinone, propyl gallate, tea polyphenols, or mixtures thereof; and even more preferably, it contains 0.011–2.0 mg / mL and 0.011–1.8 mg / mL of... Vitamin C at concentrations of 0.011–1.5 mg / mL, 0.011–1 mg / mL, 0.012–0.8 mg / mL, 0.012–0.06 mg / mL, 0.012–0.04 mg / mL, 0.012–0.02 mg / mL, 0.013–0.019 mg / mL, 0.013–0.018 mg / mL, 0.013–0.017 mg / mL, 0.014–0.016 mg / mL, or 0.014–0.015 mg / mL; most preferably, it contains 0.014 mg / mL of vitamin C.

[0154] In some embodiments of this disclosure, the pharmaceutical composition comprises 0-2 w / w% of benzalkonium chloride, benzalkonium bromide, parabens (including but not limited to methylparaben, ethylparaben, propylparaben, and butylparaben), chlorobutanol, phenol, resorcinol, benzyl alcohol, phenethyl alcohol, benzoic acid or its salts, sodium propionate, sorbic acid or its salts, or mixtures thereof; preferably comprising 0-0.5 w / w% of benzalkonium chloride, benzalkonium bromide, benzyl alcohol, phenethyl alcohol, benzoic acid or its salts, sodium propionate, sorbic acid or its salts, or mixtures thereof; more preferably... The sample contains 0.005–0.05 w / w% of benzalkonium chloride, benzalkonium bromide, benzoic acid or its salts, benzyl alcohol or mixtures thereof; more preferably, it contains 0.005–0.015 w / w% of benzalkonium chloride, benzalkonium bromide or mixtures thereof; even more preferably, it contains 0.005–0.014 w / w%, 0.006–0.013 w / w%, 0.007–0.012 w / w%, 0.008–0.011 w / w%, or 0.009–0.011 w / w% of benzalkonium chloride; most preferably, it contains 0.01 w / w% of benzalkonium chloride.

[0155] In some embodiments of this disclosure, the pharmaceutical composition comprises 0–19 mg / mL of benzalkonium chloride, benzalkonium bromide, parabens (including but not limited to methylparaben, ethylparaben, propylparaben, and butylparaben), chlorobutanol, phenol, resorcinol, benzyl alcohol, phenethyl alcohol, benzoic acid or its salts, sodium propionate, sorbic acid or its salts, or mixtures thereof; preferably comprising 0–6 mg / mL of benzalkonium chloride, benzalkonium bromide, benzyl alcohol, phenethyl alcohol, benzoic acid or its salts, sodium propionate, sorbic acid or its salts. Salts or mixtures thereof; more preferably, containing 0.045–0.45 mg / mL of benzalkonium chloride, benzalkonium bromide, benzoic acid or its salts, benzyl alcohol or mixtures thereof; even more preferably, containing 0.045–0.18 mg / mL of benzalkonium chloride, benzalkonium bromide or mixtures thereof; even more preferably, containing 0.05–0.15 mg / mL, 0.07–0.13 mg / mL, 0.08–0.12 mg / mL or 0.08–0.11 mg / mL of benzalkonium chloride; most preferably, containing 0.09 mg / mL of benzalkonium chloride.

[0156] In some embodiments of this disclosure, the pharmaceutical composition comprises 0.001–1 w / w% of ethylenediaminetetraacetic acid (EDTA) or a salt thereof, ethylene glycol tetraacetic acid (EGTA) or a salt thereof, cyclohexanediaminetetraacetic acid (CDTA) or a salt thereof, hydroxyethyl ethylenediaminetriacetic acid (HEDTA) or a salt thereof, diethylenetriaminepentaacetic acid (DTPA) or a salt thereof, dimercaptopropanesulfonic acid (DMPS) or a salt thereof, dimercaptosuccinic acid (DMSA) or a salt thereof, aminotrimethylenephosphonic acid (ArPA) or a salt thereof, citric acid or a salt thereof, acetic acid or a salt thereof, phosphoric acid or a salt thereof, pyrophosphate or a salt thereof, metaphosphate or a salt thereof, or a mixture thereof; preferably comprising 0.001–0.5 w / w% of ethylenediaminetetraacetic acid or a salt thereof, ethylene glycol tetraacetic acid or a salt thereof, cyclohexanediaminetetraacetic acid or a salt thereof, and hydroxyethyl ethylenediaminetetraacetic acid. Triacetic acid or its salts, diethylenetriaminepentaacetic acid or its salts, or mixtures thereof; more preferably, it contains 0.005 to 0.1 w / w% of ethylenediaminetetraacetic acid or its salts, hydroxyethylethylenediaminetriacetic acid or its salts, or mixtures thereof; even more preferably, it contains 0.01 to 0.05 w / w% of ethylenediaminetetraacetic acid (EDTA) or its salts, including but not limited to ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetic acid, dipotassium ethylenediaminetetraacetic acid, trisodium ethylenediaminetetraacetic acid, tripotassium ethylenediaminetetraacetic acid, calcium disodium ethylenediaminetetraacetic acid, dicalcium ethylenediaminetetraacetic acid, or mixtures thereof; even more preferably, it contains 0.001 to 0.5 w / w%, 0.005 to 0.1 w / w%, or 0.01 to 0.05 w / w% of disodium ethylenediaminetetraacetic acid; most preferably, it contains 0.01 w / w% of disodium ethylenediaminetetraacetic acid.

[0157] In some embodiments of this disclosure, the pharmaceutical composition comprises 0-19 mg / mL of ethylenediaminetetraacetic acid (EDTA) or a salt thereof, ethylene glycol tetraacetic acid (EGTA) or a salt thereof, cyclohexanediaminetetraacetic acid (CDTA) or a salt thereof, hydroxyethyl ethylenediaminetriacetic acid (HEDTA) or a salt thereof, diethylenetriaminepentaacetic acid (DTPA) or a salt thereof, dimercaptopropanesulfonic acid (DMPS) or a salt thereof, dimercaptosuccinic acid (DMSA) or a salt thereof, aminotrimethylenephosphonic acid (ArPA) or a salt thereof, citric acid or a salt thereof, acetic acid or a salt thereof, phosphoric acid or a salt thereof, pyrophosphate or a salt thereof, metaphosphate or a salt thereof, or a mixture thereof; preferably comprising 0-6 mg / mL of ethylenediaminetetraacetic acid or a salt thereof, ethylene glycol... Ethylenediaminetetraacetic acid (EDTA) or its salts, cyclohexanediaminetetraacetic acid (CDITA) or its salts, hydroxyethyl ethylenediaminetriacetic acid (EDTA) or its salts, diethylenetriaminepentaacetic acid (DTA) or its salts, or mixtures thereof, are preferred to contain 0.045 to 0.45 mg / mL of EDTA or its salts, hydroxyethyl ethylenediaminetriacetic acid (EDTA) or its salts, or mixtures thereof; even more preferably, EDTA or its salts, including but not limited to EDTA, disodium EDTA, dipotassium EDTA, trisodium EDTA, tripotassium EDTA, calcium disodium EDTA, dicalcium EDTA, or mixtures thereof, are preferred to contain 0.09 mg / mL of disodium EDTA.

[0158] A1) In some embodiments of this disclosure, the pharmaceutical composition of this disclosure comprises:

[0159] 0.1–10 w / w% budesonide;

[0160] 0.0001–1 w / w% tiotropium bromide;

[0161] 0.0001–1 w / w% adabutrol; and

[0162] 0.01–20 w / w% of n-propanol, isopropanol, glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenethyl alcohol, butanol, butanediol, mannitol, polyethylene glycol, ethylene glycol, or mixtures thereof; and / or

[0163] 0.0001–10 w / w% of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate (PG), tert-butylhydroquinone (TBHQ), ascorbic acid antioxidants (including but not limited to vitamin C, isoascorbic acid, sodium ascorbate, potassium ascorbate, ascorbate palmitate), tocopherol antioxidants (including but not limited to vitamin E, α-tocopherol, mixed concentrated tocopherols, tocopherol acetate), vitamin A, retinyl palmitate, dibutylphenol, tea polyphenols (TP), sulfite antioxidants (including but not limited to sodium sulfite, potassium sulfite, sodium metabisulfite, potassium metabisulfite, sodium bisulfite, potassium bisulfite, sodium thiosulfate), fumaric acid and / or its salts, malic acid and / or its salts, citric acid and / or its salts, maleic acid and / or its salts, or mixtures thereof;

[0164] Optionally comprising 0 to 2 w / w% of benzalkonium chloride, benzalkonium bromide, parabens (including but not limited to methylparaben, ethylparaben, propylparaben, butylparaben), chlorobutanol, phenol, resorcinol, benzyl alcohol, phenethyl alcohol, benzoic acid or its salts, sodium propionate, sorbic acid or its salts, or mixtures thereof;

[0165] Optionally comprising 0.001 to 1 w / w% of ethylenediaminetetraacetic acid (EDTA) or a salt thereof, ethylene glycol tetraacetic acid (EGTA) or a salt thereof, cyclohexanediaminetetraacetic acid (CDTA) or a salt thereof, hydroxyethyl ethylenediaminetriacetic acid (HEDTA) or a salt thereof, diethylenetriaminepentaacetic acid (DTPA) or a salt thereof, dimercaptopropanesulfonic acid (DMPS) or a salt thereof, dimercaptosuccinic acid (DMSA) or a salt thereof, aminotrimethylenephosphonic acid (ArPA) or a salt thereof, citric acid or a salt thereof, acetic acid or a salt thereof, phosphoric acid or a salt thereof, pyrophosphate or a salt thereof, metaphosphate or a salt thereof, or a mixture thereof;

[0166] Optionally contains 4–80 w / w% water;

[0167] Optionally contains 20–96 w / w% ethanol;

[0168] Optionally, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, lactic acid, tartaric acid, boric acid, malic acid, succinic acid, fumaric acid, methionine, glucuronic acid, or mixtures thereof are included as pH adjusters to adjust the pH of the pharmaceutical composition to 2.5 to 4.5.

[0169] A2) In some embodiments of this disclosure, the pharmaceutical composition of this disclosure comprises:

[0170] 0.125–5 w / w% budesonide;

[0171] 0.0125–0.5 w / w% tiotropium bromide;

[0172] 0.0125–0.5 w / w% adabutrol; and

[0173] 0.1–12 w / w% of glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenethyl alcohol, butanol, butanediol, polyethylene glycol, ethylene glycol, or mixtures thereof; and / or

[0174] 0.0001–8 w / w% of ascorbic acid antioxidants (including but not limited to vitamin C, isoascorbic acid, sodium ascorbate, potassium ascorbate, ascorbate palmitate), sulfite antioxidants (including but not limited to sodium sulfite, potassium sulfite, sodium metabisulfite, potassium metabisulfite, sodium bisulfite, potassium bisulfite, sodium thiosulfate), butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, tert-butylhydroquinone, tea polyphenols or mixtures thereof;

[0175] Optionally comprising 0.001 to 0.5 w / w% of ethylenediaminetetraacetic acid or a salt thereof, ethylene glycol tetraacetic acid or a salt thereof, cyclohexanediaminetetraacetic acid or a salt thereof, hydroxyethyl ethylenediaminetriacetic acid or a salt thereof, diethylenetriaminepentaacetic acid or a salt thereof, or a mixture thereof;

[0176] Optionally comprising 0 to 0.5 w / w% of benzalkonium chloride, benzalkonium bromide, benzyl alcohol, phenethyl alcohol, benzoic acid or its salts, sodium propionate, sorbic acid or its salts, or mixtures thereof;

[0177] Optionally contains 4–60 w / w% water;

[0178] Optionally contains 40–96 w / w% ethanol;

[0179] Optionally, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, tartaric acid, succinic acid, fumaric acid, or mixtures thereof are included as pH adjusters to adjust the pH of the pharmaceutical composition to 2.5–4.0.

[0180] A3) In some embodiments of this disclosure, the pharmaceutical composition of this disclosure comprises:

[0181] 1w / w% budesonide;

[0182] 0.025 w / w% tiotropium bromide;

[0183] 0.025w / w% adabutrol;

[0184] 1w / w% glycerin;

[0185] 0.0015 w / w% Vitamin C;

[0186] 0.01 w / w% disodium ethylenediaminetetraacetate;

[0187] 0.01 w / w% benzalkonium chloride;

[0188] 44.07w / w% water;

[0189] 53.86 w / w% ethanol;

[0190] Hydrochloric acid is used as a pH adjuster to adjust the pH of the pharmaceutical composition to 2.9.

[0191] A4) In some embodiments of this disclosure, the pharmaceutical composition described herein comprises:

[0192] 1w / w% budesonide;

[0193] 0.0125 w / w% tiotropium bromide;

[0194] 0.0125w / w% adabutrol;

[0195] 1w / w% glycerin;

[0196] 0.0015 w / w% Vitamin C;

[0197] 0.01 w / w% disodium ethylenediaminetetraacetate;

[0198] 0.01 w / w% benzalkonium chloride;

[0199] 44.08w / w% water;

[0200] 53.87 w / w% ethanol;

[0201] Hydrochloric acid is used as a pH adjuster to adjust the pH of the pharmaceutical composition to 2.9.

[0202] A5) In some embodiments of this disclosure, the pharmaceutical composition of this disclosure comprises:

[0203] 0.25w / w% budesonide;

[0204] 0.025 w / w% tiotropium bromide;

[0205] 0.025w / w% adabutrol;

[0206] 1w / w% glycerin;

[0207] 0.0015 w / w% Vitamin C;

[0208] 0.01 w / w% disodium ethylenediaminetetraacetate;

[0209] 0.01 w / w% benzalkonium chloride;

[0210] 44.41 w / w% water;

[0211] 54.27 w / w% ethanol;

[0212] Hydrochloric acid is used as a pH adjuster to adjust the pH of the pharmaceutical composition to 2.9.

[0213] A6) In some embodiments of this disclosure, the pharmaceutical composition of this disclosure comprises:

[0214] 0.50w / w% budesonide;

[0215] 0.025 w / w% tiotropium bromide;

[0216] 0.025w / w% adabutrol;

[0217] 1w / w% glycerin;

[0218] 0.0015 w / w% Vitamin C;

[0219] 0.01 w / w% disodium ethylenediaminetetraacetate;

[0220] 0.01 w / w% benzalkonium chloride;

[0221] 44.29w / w% water;

[0222] 54.14 w / w% ethanol;

[0223] Hydrochloric acid is used as a pH adjuster to adjust the pH of the pharmaceutical composition to 2.9.

[0224] A7) In some embodiments of this disclosure, the pharmaceutical composition of this disclosure comprises:

[0225] 0.125w / w% budesonide;

[0226] 0.025 w / w% tiotropium bromide;

[0227] 0.025w / w% adabutrol;

[0228] 1w / w% glycerin;

[0229] 0.0015 w / w% Vitamin C;

[0230] 0.01 w / w% disodium ethylenediaminetetraacetate;

[0231] 0.01 w / w% benzalkonium chloride;

[0232] 44.46 w / w% water;

[0233] 54.34 w / w% ethanol;

[0234] Hydrochloric acid is used as a pH adjuster to adjust the pH of the pharmaceutical composition to 2.9.

[0235] B1) In some embodiments of this disclosure, the pharmaceutical composition of this disclosure comprises:

[0236] 0.1–100 mg / mL budesonide;

[0237] 0.04–10 mg / mL tiotropium bromide;

[0238] 0.04–10 mg / mL olodaterol; and

[0239] 0.1–190 mg / mL of n-propanol, isopropanol, glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenethyl alcohol, butanol, butanediol, mannitol, polyethylene glycol, ethylene glycol, or mixtures thereof; and / or

[0240] 0.0001–80 mg / mL of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate (PG), tert-butylhydroquinone (TBHQ), ascorbic acid antioxidants (including but not limited to vitamin C, isoascorbic acid, sodium ascorbate, potassium ascorbate, ascorbate palmitate), tocopherol antioxidants (including but not limited to vitamin E, α-tocopherol, mixed concentrated tocopherols, tocopherol acetate), vitamin A, retinyl palmitate, dibutylphenol, tea polyphenols (TP), sulfite antioxidants (including but not limited to sodium sulfite, potassium sulfite, sodium metabisulfite, potassium metabisulfite, sodium bisulfite, potassium bisulfite, sodium thiosulfate), fumaric acid and / or its salts, malic acid and / or its salts, citric acid and / or its salts, maleic acid and / or its salts, or mixtures thereof;

[0241] Optionally comprising 0–19 mg / mL of benzalkonium chloride, benzalkonium bromide, parabens (including but not limited to methylparaben, ethylparaben, propylparaben, butylparaben), chlorobutanol, phenol, resorcinol, benzyl alcohol, phenethyl alcohol, benzoic acid or its salts, sodium propionate, sorbic acid or its salts, or mixtures thereof;

[0242] Optionally comprising 0–19 mg / mL of ethylenediaminetetraacetic acid (EDTA) or a salt thereof, ethylene glycol tetraacetic acid (EGTA) or a salt thereof, cyclohexanediaminetetraacetic acid (CDTA) or a salt thereof, hydroxyethyl ethylenediaminetriacetic acid (HEDTA) or a salt thereof, diethylenetriaminepentaacetic acid (DTPA) or a salt thereof, dimercaptopropanesulfonic acid (DMPS) or a salt thereof, dimercaptosuccinic acid (DMSA) or a salt thereof, aminotrimethylenephosphonic acid (ArPA) or a salt thereof, citric acid or a salt thereof, acetic acid or a salt thereof, phosphoric acid or a salt thereof, pyrophosphate or a salt thereof, metaphosphate or a salt thereof, or a mixture thereof;

[0243] Optionally contains 30–730 mg / mL of water;

[0244] Optionally contains 180–900 mg / mL ethanol;

[0245] Optionally, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, lactic acid, tartaric acid, boric acid, malic acid, succinic acid, fumaric acid, methionine, glucuronic acid, or mixtures thereof are included as pH adjusters to adjust the pH of the pharmaceutical composition to 2.5 to 4.5.

[0246] B2) In some embodiments of this disclosure, the pharmaceutical composition of this disclosure comprises:

[0247] 1–10 mg / mL budesonide;

[0248] 0.1–1 mg / mL tiotropium bromide;

[0249] 0.1–1 mg / mL olodaterol; and

[0250] 0.9–110 mg / mL of glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenethyl alcohol, butanol, butanediol, polyethylene glycol, ethylene glycol, or mixtures thereof; and / or

[0251] Ascorbic acid antioxidants (including but not limited to vitamin C, isoascorbic acid, sodium ascorbate, potassium ascorbate, ascorbate palmitate), sulfite antioxidants (including but not limited to sodium sulfite, potassium sulfite, sodium metabisulfite, potassium metabisulfite, sodium bisulfite, potassium bisulfite, sodium thiosulfate), butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, tert-butylhydroquinone, tea polyphenols or mixtures thereof, at concentrations of 0.0009–75 mg / mL;

[0252] Optionally comprising 0.045–0.45 mg / mL of ethylenediaminetetraacetic acid or a salt thereof, ethylene glycol tetraacetic acid or a salt thereof, cyclohexanediaminetetraacetic acid or a salt thereof, hydroxyethylethylenediaminetriacetic acid or a salt thereof, diethylenetriaminepentaacetic acid or a salt thereof, or a mixture thereof;

[0253] Optionally comprising 0.045–0.45 mg / mL of benzalkonium chloride, benzalkonium bromide, benzyl alcohol, phenethyl alcohol, benzoic acid or its salts, sodium propionate, sorbic acid or its salts, or mixtures thereof;

[0254] Optionally contains 300–450 mg / mL of water;

[0255] Optionally contains 320–850 mg / mL ethanol;

[0256] Optionally, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, tartaric acid, succinic acid, fumaric acid, or mixtures thereof are included as pH adjusters to adjust the pH of the pharmaceutical composition to 2.5–4.0.

[0257] B3) In some embodiments of this disclosure, the pharmaceutical composition of this disclosure comprises:

[0258] 9.09 mg / mL budesonide;

[0259] 0.227 mg / mL tiotropium bromide;

[0260] 0.227 mg / mL olodaterol;

[0261] 9.09 mg / mL glycerol;

[0262] 0.0136 mg / mL Vitamin C;

[0263] 0.09 mg / mL disodium ethylenediaminetetraacetate;

[0264] 0.09 mg / mL benzalkonium chloride;

[0265] 400.64 mg / mL water;

[0266] 489.64 mg / mL ethanol;

[0267] Hydrochloric acid is used as a pH adjuster to adjust the pH of the pharmaceutical composition to 2.9.

[0268] B4) In some embodiments of this disclosure, the pharmaceutical composition of this disclosure comprises:

[0269] 9.09 mg / mL budesonide;

[0270] 0.114 mg / mL tiotropium bromide;

[0271] 0.114 mg / mL olodaterol;

[0272] 9.09 mg / mL glycerol;

[0273] 0.0136 mg / mL Vitamin C;

[0274] 0.09 mg / mL disodium ethylenediaminetetraacetate;

[0275] 0.09 mg / mL benzalkonium chloride;

[0276] 400.73 mg / mL water;

[0277] 489.73 mg / mL ethanol;

[0278] Hydrochloric acid is used as a pH adjuster to adjust the pH of the pharmaceutical composition to 2.9.

[0279] B5) In some embodiments of this disclosure, the pharmaceutical composition of this disclosure comprises:

[0280] 2.27 mg / mL budesonide;

[0281] 0.227 mg / mL tiotropium bromide;

[0282] 0.227 mg / mL olodaterol;

[0283] 9.09 mg / mL glycerol;

[0284] 0.0136 mg / mL Vitamin C;

[0285] 0.09 mg / mL disodium ethylenediaminetetraacetate;

[0286] 0.09 mg / mL benzalkonium chloride;

[0287] 403.73 mg / mL water;

[0288] 493.36 mg / mL ethanol;

[0289] Hydrochloric acid is used as a pH adjuster to adjust the pH of the pharmaceutical composition to 2.9.

[0290] B6) In some embodiments of this disclosure, the pharmaceutical composition of this disclosure comprises:

[0291] 4.55 mg / mL budesonide;

[0292] 0.227 mg / mL tiotropium bromide;

[0293] 0.227 mg / mL olodaterol;

[0294] 9.09 mg / mL glycerol;

[0295] 0.0136 mg / mL Vitamin C;

[0296] 0.09 mg / mL disodium ethylenediaminetetraacetate;

[0297] 0.09 mg / mL benzalkonium chloride;

[0298] 402.64 mg / mL water;

[0299] 492.18 mg / mL ethanol;

[0300] Hydrochloric acid is used as a pH adjuster to adjust the pH of the pharmaceutical composition to 2.9.

[0301] B7) In some embodiments of this disclosure, the pharmaceutical composition of this disclosure comprises:

[0302] 1.14 mg / mL budesonide;

[0303] 0.227 mg / mL tiotropium bromide;

[0304] 0.227 mg / mL olodaterol;

[0305] 9.09 mg / mL glycerol;

[0306] 0.0136 mg / mL Vitamin C;

[0307] 0.09 mg / mL disodium ethylenediaminetetraacetate;

[0308] 0.09 mg / mL benzalkonium chloride;

[0309] 404.18 mg / mL water;

[0310] 494.00 mg / mL ethanol;

[0311] Hydrochloric acid is used as a pH adjuster to adjust the pH of the pharmaceutical composition to 2.9.

[0312] C1) In some embodiments of this disclosure, a single-dose pharmaceutical composition of the pharmaceutical composition described herein comprises:

[0313] 3-380mg budesonide;

[0314] 0.1–10 mg tiotropium bromide;

[0315] 0.1–10 mg olodaterol; and

[0316] 0.38–760 mg of n-propanol, isopropanol, glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenethyl alcohol, butanol, butanediol, mannitol, polyethylene glycol, ethylene glycol, or mixtures thereof; and / or

[0317] 0.006–190 mg of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate (PG), tert-butylhydroquinone (TBHQ), ascorbic acid antioxidants (including but not limited to vitamin C, isoascorbic acid, sodium ascorbate, potassium ascorbate, ascorbyl palmitate), tocopherol antioxidants (including but not limited to vitamin E, α-tocopherol, mixed concentrated tocopherols, tocopherol acetate), vitamin A, retinyl palmitate, dibutylphenol, tea polyphenols (TP), sulfite antioxidants (including but not limited to sodium sulfite, potassium sulfite, sodium metabisulfite, potassium metabisulfite, sodium bisulfite, potassium bisulfite, sodium thiosulfate), fumaric acid and / or its salts, malic acid and / or its salts, citric acid and / or its salts, maleic acid and / or its salts, or mixtures thereof;

[0318] Optionally comprising 0 to 76 mg of benzalkonium chloride, benzalkonium bromide, parabens (including but not limited to methylparaben, ethylparaben, propylparaben, butylparaben), chlorobutanol, phenol, resorcinol, benzyl alcohol, phenethyl alcohol, benzoic acid or its salts, sodium propionate, sorbic acid or its salts, or mixtures thereof;

[0319] Optionally comprising 0 to 76 mg of ethylenediaminetetraacetic acid (EDTA) or a salt thereof, ethylene glycol tetraacetic acid (EGTA) or a salt thereof, cyclohexanediaminetetraacetic acid (CDTA) or a salt thereof, hydroxyethyl ethylenediaminetriacetic acid (HEDTA) or a salt thereof, diethylenetriaminepentaacetic acid (DTPA) or a salt thereof, dimercaptopropanesulfonic acid (DMPS) or a salt thereof, dimercaptosuccinic acid (DMSA) or a salt thereof, aminotrimethylenephosphonic acid (ArPA) or a salt thereof, citric acid or a salt thereof, acetic acid or a salt thereof, phosphoric acid or a salt thereof, pyrophosphate or a salt thereof, metaphosphate or a salt thereof, or a mixture thereof;

[0320] Optionally contains 150–3100 mg of water;

[0321] Optionally contains 750–3700 mg of ethanol;

[0322] Optionally, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, lactic acid, tartaric acid, boric acid, malic acid, succinic acid, fumaric acid, methionine, glucuronic acid, or mixtures thereof are included as pH adjusters to adjust the pH of the pharmaceutical composition to 2.5 to 4.5.

[0323] C2) In some embodiments of this disclosure, a single-dose pharmaceutical composition of the pharmaceutical composition described herein comprises:

[0324] 9.5–38 mg budesonide;

[0325] 0.19–1.9 mg tiotropium bromide;

[0326] 0.19–1.9 mg olodaterol; and

[0327] 30–60 mg of glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenethyl alcohol, butanol, butanediol, polyethylene glycol, ethylene glycol, or mixtures thereof; and / or

[0328] 0.04–1 mg of ascorbic acid antioxidants (including but not limited to vitamin C, isoascorbic acid, sodium ascorbate, potassium ascorbate, ascorbyl palmitate), sulfite antioxidants (including but not limited to sodium sulfite, potassium sulfite, sodium metabisulfite, potassium metabisulfite, sodium bisulfite, potassium bisulfite, sodium thiosulfate), butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, tert-butylhydroquinone, tea polyphenols or mixtures thereof;

[0329] Optionally comprising 0.19 to 0.76 mg of ethylenediaminetetraacetic acid or a salt thereof, ethylene glycol tetraacetic acid or a salt thereof, cyclohexanediaminetetraacetic acid or a salt thereof, hydroxyethylethylenediaminetriacetic acid or a salt thereof, diethylenetriaminepentaacetic acid or a salt thereof, or a mixture thereof;

[0330] Optionally comprising 0.19 to 0.76 mg of benzalkonium chloride, benzalkonium bromide, benzyl alcohol, phenethyl alcohol, benzoic acid or its salt, sodium propionate, sorbic acid or its salt, or mixtures thereof;

[0331] Optionally contains 1500–1800 mg of water;

[0332] Optionally contains 1900–2200 mg of ethanol;

[0333] Optionally, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, tartaric acid, succinic acid, fumaric acid, or mixtures thereof are included as pH adjusters to adjust the pH of the pharmaceutical composition to 2.5–4.0.

[0334] C3) In some embodiments of this disclosure, a single-dose pharmaceutical composition of the pharmaceutical composition described herein comprises:

[0335] 9.5mg, 19mg or 38mg budesonide;

[0336] 0.475 mg or 0.95 mg tiotropium bromide;

[0337] 0.475 mg or 0.95 mg olodaterol;

[0338] 38mg glycerin;

[0339] 0.057mg Vitamin C;

[0340] 0.38 mg disodium ethylenediaminetetraacetate;

[0341] 0.38 mg benzalkonium chloride;

[0342] 1672mg water;

[0343] 2052mg ethanol;

[0344] Hydrochloric acid is used as a pH adjuster to adjust the pH of the pharmaceutical composition to 2.9.

[0345] D1) In some embodiments of this disclosure, the pharmaceutical composition of this disclosure is an inhalation spray, and each spray of the pharmaceutical composition comprises:

[0346] 10–1200 μg budesonide;

[0347] 0.1–10 μg tiotropium bromide;

[0348] 0.1–10 μg adabutrol; and

[0349] 1–2000 μg of n-propanol, isopropanol, glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenethyl alcohol, butanol, butanediol, mannitol, polyethylene glycol, ethylene glycol, or mixtures thereof; and / or

[0350] 0–800 μg of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate (PG), tert-butylhydroquinone (TBHQ), ascorbic acid antioxidants (including but not limited to vitamin C, isoascorbic acid, sodium ascorbate, potassium ascorbate, ascorbate palmitate), tocopherol antioxidants (including but not limited to vitamin E, α-tocopherol, mixed concentrated tocopherols, tocopherol acetate), vitamin A, retinyl palmitate, dibutylphenol, tea polyphenols (TP), sulfite antioxidants (including but not limited to sodium sulfite, potassium sulfite, sodium metabisulfite, potassium metabisulfite, sodium bisulfite, potassium bisulfite, sodium thiosulfate), fumaric acid and / or its salts, malic acid and / or its salts, citric acid and / or its salts, maleic acid and / or its salts, or mixtures thereof;

[0351] Optionally comprising 0–200 μg of ethylenediaminetetraacetic acid (EDTA) or a salt thereof, ethylene glycol tetraacetic acid (EGTA) or a salt thereof, cyclohexanediaminetetraacetic acid (CDTA) or a salt thereof, hydroxyethyl ethylenediaminetriacetic acid (HEDTA) or a salt thereof, diethylenetriaminepentaacetic acid (DTPA) or a salt thereof, dimercaptopropanesulfonic acid (DMPS) or a salt thereof, dimercaptosuccinic acid (DMSA) or a salt thereof, aminotrimethylenephosphonic acid (ArPA) or a salt thereof, citric acid or a salt thereof, acetic acid or a salt thereof, phosphoric acid or a salt thereof, pyrophosphate or a salt thereof, metaphosphate or a salt thereof, or a mixture thereof;

[0352] Optionally comprising 0–200 μg of benzalkonium chloride, benzalkonium bromide, parabens (including but not limited to methylparaben, ethylparaben, propylparaben, butylparaben), chlorobutanol, phenol, resorcinol, benzyl alcohol, phenethyl alcohol, benzoic acid or its salts, sodium propionate, sorbic acid or its salts, or mixtures thereof;

[0353] Optionally contains 0.4–8.0 mg of water;

[0354] Optionally contains 2.0–9.8 mg of ethanol;

[0355] Optionally, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, lactic acid, tartaric acid, boric acid, malic acid, succinic acid, fumaric acid, methionine, glucuronic acid, or mixtures thereof are included as pH adjusters to adjust the pH of the inhaled spray to 2.5–4.5.

[0356] D2) In some embodiments of this disclosure, the pharmaceutical composition of this disclosure is an inhalation spray, and each spray of the pharmaceutical composition comprises:

[0357] 12.5–100 μg budesonide;

[0358] 0.5–5 μg tiotropium bromide;

[0359] 0.5–5 μg odoratol; and

[0360] 80–150 μg of glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenethyl alcohol, butanol, butanediol, polyethylene glycol, ethylene glycol, or mixtures thereof; and / or

[0361] 0.1–0.5 μg of ascorbic acid antioxidants (including but not limited to vitamin C, isoascorbic acid, sodium ascorbate, potassium ascorbate, ascorbate palmitate), sulfite antioxidants (including but not limited to sodium sulfite, potassium sulfite, sodium metabisulfite, potassium metabisulfite, sodium bisulfite, potassium bisulfite, sodium thiosulfate), butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, tert-butylhydroquinone, tea polyphenols or mixtures thereof;

[0362] Optionally comprising 0.75–2 μg of ethylenediaminetetraacetic acid or a salt thereof, ethylene glycol tetraacetic acid or a salt thereof, cyclohexanediaminetetraacetic acid or a salt thereof, hydroxyethylethylenediaminetriacetic acid or a salt thereof, diethylenetriaminepentaacetic acid or a salt thereof, or a mixture thereof;

[0363] Optionally comprising 0.75–2 μg of benzalkonium chloride, benzalkonium bromide, benzyl alcohol, phenethyl alcohol, benzoic acid or its salt, sodium propionate, sorbic acid or its salt, or mixtures thereof;

[0364] Optionally contains 4–4.8 mg of water;

[0365] Optionally contains 5.0–5.8 mg of ethanol;

[0366] Optionally, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, tartaric acid, succinic acid, fumaric acid, or mixtures thereof are included as pH adjusters to adjust the pH of the pharmaceutical composition to 2.5–4.0.

[0367] D3) In some embodiments of this disclosure, each spray of the pharmaceutical composition of this disclosure comprises:

[0368] 100 μg budesonide;

[0369] 2.5 μg tiotropium bromide;

[0370] 2.5 μg adabutrol;

[0371] 100μg glycerol;

[0372] 0.15μg Vitamin C;

[0373] 1 μg disodium ethylenediaminetetraacetate;

[0374] 1 μg benzalkonium chloride;

[0375] 5.386 mg of water;

[0376] 4.407 mg ethanol;

[0377] Hydrochloric acid is used as a pH adjuster to adjust the pH of the pharmaceutical composition to 2.9.

[0378] D4) In some embodiments of this disclosure, each spray of the pharmaceutical composition of this disclosure comprises:

[0379] 100 μg budesonide;

[0380] 1.25 μg tiotropium bromide;

[0381] 1.25 μg adabutrol;

[0382] 100μg glycerol;

[0383] 0.15μg Vitamin C;

[0384] 1 μg disodium ethylenediaminetetraacetate;

[0385] 1 μg benzalkonium chloride;

[0386] 5.387 mg water;

[0387] 4.408 mg ethanol;

[0388] Hydrochloric acid is used as a pH adjuster to adjust the pH of the pharmaceutical composition to 2.9.

[0389] D5) In some embodiments of this disclosure, each spray of the pharmaceutical composition of this disclosure comprises:

[0390] 25 μg budesonide;

[0391] 2.5 μg tiotropium bromide;

[0392] 2.5 μg adabutrol;

[0393] 100μg glycerol;

[0394] 0.15μg Vitamin C;

[0395] 1 μg disodium ethylenediaminetetraacetate;

[0396] 1 μg benzalkonium chloride;

[0397] 5.427mg water;

[0398] 4.441 mg ethanol;

[0399] Hydrochloric acid is used as a pH adjuster to adjust the pH of the pharmaceutical composition to 2.9.

[0400] D6) In some embodiments of this disclosure, each spray of the pharmaceutical composition of this disclosure comprises:

[0401] 50 μg budesonide;

[0402] 2.5 μg tiotropium bromide;

[0403] 2.5 μg adabutrol;

[0404] 100μg glycerol;

[0405] 0.15μg Vitamin C;

[0406] 1 μg disodium ethylenediaminetetraacetate;

[0407] 1 μg benzalkonium chloride;

[0408] 5.414 mg water;

[0409] 4.429 mg ethanol;

[0410] Hydrochloric acid is used as a pH adjuster to adjust the pH of the pharmaceutical composition to 2.9.

[0411] D7) In some embodiments of this disclosure, each spray of the pharmaceutical composition of this disclosure comprises:

[0412] 12.5 μg budesonide;

[0413] 2.5 μg tiotropium bromide;

[0414] 2.5 μg adabutrol;

[0415] 100μg glycerol;

[0416] 0.15μg Vitamin C;

[0417] 1 μg disodium ethylenediaminetetraacetate;

[0418] 1 μg benzalkonium chloride;

[0419] 5.434 mg water;

[0420] 4.446 mg ethanol;

[0421] Hydrochloric acid is used as a pH adjuster to adjust the pH of the pharmaceutical composition to 2.9.

[0422] In some embodiments of this disclosure, the pharmaceutical composition is an inhalation spray, wherein the fine particles formed after atomization by the inhalation spray device have a lung deposition rate greater than 50%, preferably greater than 51%, greater than 52%, greater than 53%, greater than 54%, greater than 55%, greater than 56%, greater than 57%, greater than 58%, greater than 59%, greater than 60%, greater than 61%, greater than 62%, greater than 63%, greater than 64%, greater than 65%, greater than 66%, greater than 67%, greater than 68%, greater than 69%, greater than 70%, greater than 71%, greater than 72%, greater than 73%, greater than 74%, greater than 75%, greater than 76%, greater than 77%, greater than 78%, greater than 79%, or greater than 80%, more preferably greater than 60%; and even more preferably greater than 65%.

[0423] In some embodiments of this disclosure, the pharmaceutical composition is an inhalation spray, and the ellipticity of the spray formed after the inhalation spray is atomized by a spraying device is 1 to 2; preferably 1 to 1.9, 1 to 1.8, 1 to 1.7, 1 to 1.6, 1 to 1.5, 1 to 1.4, 1 to 1.3, 1 to 1.2, or 1 to 1.1; further preferably 1 to 1.5; even more preferably 1 to 1.3; and most preferably 1 to 1.2.

[0424] In some embodiments of this disclosure, the pharmaceutical composition is an inhalation spray containing compound L (e.g., after being stored at 40±2°C for 0, 10, or 30 days), wherein the content of compound L (e.g., as determined by HPLC) is not more than 1%, or not more than 0.1%, or not more than 0.05%, or not more than 0.03%, or not more than 0.02%, or not more than 0.01%.

[0425] In some embodiments of this disclosure, the pharmaceutical composition is an inhalation spray containing compound L (e.g., after being stored at 40±2°C for 0, 10, or 30 days). The mass ratio of compound L to budesonide is no more than 1%, or no more than 0.1%, or no more than 0.05%, or no more than 0.03%, or no more than 0.02%, or no more than 0.01%.

[0426] In some embodiments of this disclosure, the pharmaceutical composition is an inhalation spray containing compound L (e.g., after being stored at 40±2°C for 0, 10, or 30 days). The content of compound L is not more than 1%, or 0.1%, or 0.05%, or 0.03%, or 0.02%, or 0.01% of the labeled amount of budesonide.

[0427] In some embodiments of this disclosure, the pharmaceutical composition is an inhalation spray containing, for example, compound E (stored at 40±2°C for 0, 10, or 30 days) as shown below, wherein the content of compound E (e.g., as determined by HPLC) is not more than 1%, or not more than 0.1%, or not more than 0.05%, or not more than 0.03%, or not more than 0.02%, or not more than 0.01%.

[0428] In some embodiments of this disclosure, the pharmaceutical composition is an inhalation spray containing compound E (e.g., after being stored at 40±2°C for 0, 10, or 30 days). The mass ratio of compound E to olodaterol is no more than 1%, or no more than 0.1%, or no more than 0.05%, or no more than 0.03%, or no more than 0.02%, or no more than 0.01%.

[0429] In some embodiments of this disclosure, the pharmaceutical composition is an inhalation spray containing compound E (e.g., after being stored at 40±2°C for 0, 10, or 30 days). The content of compound E is not more than 1%, or 0.1%, or 0.05%, or 0.03%, or 0.02%, or 0.01% of the labeled amount of olodaterol.

[0430] In some embodiments of this disclosure, the pharmaceutical composition is an inhalation spray containing compound A as shown below (e.g., after being stored at 40±2°C for 0, 10, or 30 days). The content of compound A (e.g., as detected by HPLC) is not more than 1%, or not more than 0.1%, or not more than 0.05%, or not more than 0.03%, or not more than 0.02%, or not more than 0.01%.

[0431] In some embodiments of this disclosure, the pharmaceutical composition is an inhalation spray containing compound A (e.g., after being stored at 40±2°C for 0, 10, or 30 days), wherein the mass ratio of compound A to tiotropium bromide is no more than 1%, or no more than 0.1%, or no more than 0.05%, or no more than 0.03%, or no more than 0.02%, or no more than 0.01%.

[0432] In some embodiments of this disclosure, the pharmaceutical composition is an inhalation spray containing compound A (e.g., after being stored at 40±2°C for 0, 10, or 30 days). The content of compound A is not more than 1%, or 0.1%, or 0.05%, or 0.03%, or 0.02%, or 0.01% of the labeled amount of tiotropium bromide.

[0433] In any embodiment of this disclosure, the olodaterol may be in the form of a hydrochloride salt, wherein the ratio of hydrochloric acid to olodaterol is 1:1, and in any embodiment of this disclosure, the amount of olodaterol used is calculated as a compound of formula III.

[0434] In some embodiments of this disclosure, the olodaterol is selected from olodaterol hydrochloride.

[0435] On the other hand, this disclosure provides a method for preparing an inhalation spray containing budesonide, tiotropium bromide, and olodaterol, comprising the following steps:

[0436] (a1) Weigh out the prescribed amount of stabilizer and / or antioxidant, as well as optional antibacterial agent and optional metal ion chelating agent, and dissolve them in the prescribed amount of water. Adjust the pH of the resulting solution to the desired pH range using a pH adjuster.

[0437] (a2) Add the prescribed amount of tiotropium bromide and olodaterol to the solution obtained in step (a1), stir to dissolve, and adjust the pH value of the obtained solution to the required pH range with a pH adjuster to obtain an aqueous solution.

[0438] (a3) Weigh out the prescribed amount of budesonide and add it to the prescribed amount of ethanol, stir or sonicate to dissolve, and obtain an alcohol phase solution;

[0439] (a4) Mix the aqueous solution and the alcoholic solution thoroughly.

[0440] In some embodiments of this disclosure, the preparation method includes the following steps:

[0441] (b1) Weigh out the prescribed amount of stabilizer and / or antioxidant, as well as optional antibacterial agent and optional metal ion chelating agent, and dissolve them in the prescribed amount of water. Adjust the pH of the resulting solution to 2.5 to 4.5 with a pH adjuster.

[0442] (b2) Add the prescribed amounts of tiotropium bromide and olodaterol to the solution obtained in step (b1), stir to dissolve, and adjust the pH of the resulting solution to 2.5 to 4.5 with a pH adjuster to obtain an aqueous solution;

[0443] (b3) Weigh out the prescribed amount of budesonide and add it to the prescribed amount of ethanol, stir or sonicate to dissolve, and obtain an alcohol phase solution;

[0444] (b4) Mix the aqueous solution and the alcohol solution thoroughly.

[0445] In some embodiments of this disclosure, the preparation method includes the following steps:

[0446] (c1) Weigh out the prescribed amounts of benzalkonium chloride, disodium EDTA, glycerol and vitamin C and dissolve them in the prescribed amount of water. Adjust the pH of the resulting solution to 2.9 ± 0.2 using a pH adjuster.

[0447] (c2) Add the prescribed amounts of tiotropium bromide and olodaterol to the solution obtained in step (c1), stir to dissolve, and adjust the pH of the resulting solution to 2.9±0.2 with a pH adjuster to obtain an aqueous solution;

[0448] (c3) Weigh out the prescribed amount of budesonide and add it to the prescribed amount of ethanol, stir or sonicate to dissolve, and obtain an alcohol phase solution;

[0449] (c4) Mix the aqueous solution and the alcohol solution thoroughly.

[0450] In another aspect, this disclosure provides a drug delivery system for a pharmaceutical composition, comprising a spray device and a container assembleable with said spray device, said container containing the pharmaceutical composition of this disclosure.

[0451] In some embodiments of this disclosure, the spray device is a handheld inhalation device.

[0452] In some embodiments of this disclosure, the spray device is a soft mist inhalation device (SMI), including but not limited to Respimat inhalers, RESPIMAT re-usable inhalers, or those disclosed in CN110582316A, CN113038982A, CN115484999A, CN111195382A, CN216025661U, CN216025662U, CN215515024U, CN109745603A, CN108057151A, CN110882453A, and CN2188333. The inhalation device, inhaler, or nebulizer mentioned in patent documents such as 18U, CN115068754A, WO2023169196A1, WO2023138422A1, CN116036423A, CN216603701U, CN116829218A, CN110769882A, CN110022921A, CN112423895A, and CN112533656A.

[0453] In another aspect, this disclosure provides the use of the pharmaceutical compositions described herein in the preparation of medicaments for treating or preventing lung diseases. In some embodiments of this disclosure, the lung diseases include, but are not limited to, asthma, chronic obstructive pulmonary disease, pneumonia, bronchitis, lung cancer, or diffuse interstitial pulmonary fibrosis.

[0454] On another front, this disclosure provides pharmaceutical compositions for the treatment or prevention of lung diseases. In some embodiments of this disclosure, the lung diseases include, but are not limited to, asthma, chronic obstructive pulmonary disease, pneumonia, bronchitis, lung cancer, or diffuse interstitial pulmonary fibrosis.

[0455] In another aspect, this disclosure provides methods for treating or preventing lung diseases, the methods comprising administering an effective amount of the pharmaceutical composition described in this disclosure to a subject. In some embodiments of this disclosure, the lung diseases include, but are not limited to, asthma, chronic obstructive pulmonary disease, pneumonia, bronchitis, lung cancer, or diffuse interstitial pulmonary fibrosis.

[0456] On another front, this disclosure provides the use of the pharmaceutical compositions described herein in the treatment or prevention of lung diseases. In some embodiments of this disclosure, the lung diseases include, but are not limited to, asthma, chronic obstructive pulmonary disease, pneumonia, bronchitis, lung cancer, or diffuse interstitial pulmonary fibrosis.

[0457] Furthermore, this disclosure provides the use of glycerol in the preparation of pharmaceutical compositions. In some embodiments of this disclosure, the pharmaceutical composition is the pharmaceutical composition described above.

[0458] Furthermore, this disclosure provides the use of vitamin C in the preparation of pharmaceutical compositions. In some embodiments of this disclosure, the pharmaceutical composition is the pharmaceutical composition described above.

[0459] Technical effect

[0460] The pharmaceutical composition containing budesonide, tiotropium bromide, and olodaterol disclosed herein, particularly an inhalation spray, exhibits good stability and effectively controls the generation and content of impurities A, E, L, and / or total impurities, especially addressing the difficulty in controlling impurity E in olodaterol within the compound formulation. The inhalation spray of this disclosure possesses one or more of the following advantages: good stability; improved spray ellipticity; uniform spray delivery; improved spray uniformity; improved uniformity of spray particle distribution; continuous spray pattern; high pulmonary deposition rate; good drug inhalation effect; and convenient administration, making it particularly suitable for industrial production and clinical application.

[0461] Brief description of the attached figures

[0462] To better understand this disclosure, it will be described in detail below with reference to the accompanying drawings.

[0463] Figure 1 is a spray pattern diagram of the inhalation spray of Formulation 1 in Example 1.

[0464] Figure 2 is a spray pattern diagram of the inhalation spray of formulation 6 in Example 1.

[0465] Figure 3 is a spray pattern diagram of the inhalation spray of formulation 7 in Example 1.

[0466] Figure 4 is a spray pattern diagram of the inhalation spray of formulation 13 in Example 1.

[0467] Figure 5 is a spray pattern diagram of the inhalation spray of formulation 18 in Example 1.

[0468] Figure 6 is a spray pattern diagram of the inhalation spray of formulation 19 in Example 1.

[0469] Figure 7 is a spray pattern diagram of the inhalation spray of formulation 20 in Example 1.

[0470] Figure 8 is a spray pattern diagram of the inhalation spray of formulation 21 in Example 1. Detailed Implementation

[0471] definition

[0472] The term "subject" refers to a mammal. In some embodiments, the subject is a human.

[0473] The term "pharmaceutical composition" refers to a mixture of compounds of formula I, II, and III of this disclosure with pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of compounds of formula I, II, and III of this disclosure to a subject.

[0474] The term "treatment" means administering a compound of formula I, formula II, and formula III, or a pharmaceutical composition thereof, to improve or eliminate a disease or one or more symptoms associated with said disease, and includes:

[0475] (i) Suppress the disease or disease state, that is, curb its development;

[0476] (ii) Relieve the disease or disease state, even if the disease or disease state subsides.

[0477] The term “prevention” means administering the compounds of Formula I, Formula II and Formula III or pharmaceutical compositions described in this disclosure to prevent a disease or one or more symptoms associated with said disease, and includes preventing the occurrence of a disease or disease state in mammals, particularly when such mammals are susceptible to the disease state but have not yet been diagnosed with the disease state.

[0478] The term “effective amount” means the amount of the compound of formula I, formula II and formula III of this disclosure used to treat a particular disease, condition or disorder, (ii) reduce, improve or eliminate one or more symptoms of a particular disease, condition or disorder, or (iii) prevent or delay the onset of one or more symptoms of a particular disease, condition or disorder described herein.

[0479] In this disclosure, "%w / w" or "w / w%" refers to a percentage concentration by mass, and may also be expressed as "wt.%" or "wt%". In this disclosure, the percentage concentration by mass refers to the percentage by weight of the component relative to the total weight of all components in the pharmaceutical composition (e.g., the inhalation spray) excluding the pH adjuster.

[0480] In this disclosure, "mg / mL" refers to mass concentration. In this disclosure, mass concentration refers to the percentage of the weight of the component to the total volume of the pharmaceutical composition (e.g., the inhalation spray).

[0481] In this disclosure, the terms "lung deposition rate" or "effective site deposition rate" refer to the percentage of the total delivered dose consisting of particles of 5 μm or less.

[0482] In this disclosure, the term "ovality" is measured using the SprayVIEW spray pattern and spray pattern analyzer. The spray nozzle after triggering is taken as the spray starting point, and the horizontal cross-section of the spray is measured at a fixed distance of 30 mm from the starting point. The main measurements are the longest axis (Dmax), the shortest axis (Dmin), and the ovality within the spray profile of the spray cross-section. The ovality is defined as follows: ovality = Dmax / Dmin. The closer it is to 1, the closer the spray shape is to a circle.

[0483] In this disclosure, the amount or content of tiotropium bromide in the pharmaceutical composition is expressed as tiotropium (C 19 H 22 For example, 2.5 μg of tiotropium is equivalent to 3.009 μg of tiotropium bromide.

[0484] In this disclosure, olodaterol in the pharmaceutical composition is provided in the form of olodaterol hydrochloride, and its amount or content is expressed as olodaterol (C 21 H 26For example, 2.5 μg of olodaterol is equivalent to 2.736 μg of olodaterol hydrochloride (N2O5).

[0485] In this disclosure, differences in numerical precision do not alter their technical meaning. For example, the numerical values “1”, “1.0”, and “1.00” represent the same content.

[0486] The term "single-dose pharmaceutical composition" refers to the smallest packaged unit containing a certain amount of pharmaceutical product. For example, if a box of medicine contains seven capsules, then each capsule is a single-dose pharmaceutical composition; or each vial of injection solution is a single-dose pharmaceutical composition; or each vial of inhalation spray solution is a single-dose pharmaceutical composition. In this disclosure, the terms "single-dose pharmaceutical composition" and "unit-dose pharmaceutical composition" have the same meaning and are used interchangeably.

[0487] In this disclosure, the term "single dose" refers to the amount of active ingredient in a single-dose pharmaceutical composition. In this disclosure, the terms "single dose" and "unit dose" have the same meaning and are used interchangeably.

[0488] In this disclosure, the term "per spray" refers to the smallest unit of drug delivery consisting of the aerosol sprayed each time the inhalation spray is applied after being adapted to a spray device. For example, each bottle of inhalation spray solution can provide multiple sprays of drug delivery after being assembled into a spray device, such as 30, 60, 90, or 120 sprays. The aerosol released in each spray (i.e., once the spray device is driven) is considered a per spray or per puff.

[0489] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used in this disclosure is for the purpose of describing particular embodiments only and is not intended to be limiting of this disclosure.

[0490] The present disclosure is described in more detail below through specific embodiments. The following embodiments are provided for illustrative purposes and should not be construed as limiting the present disclosure in any way. Any technical solutions obtained by making simple modifications to the present disclosure or by using conventional methods or equivalent substitutions of active ingredients are within the scope of protection of the present disclosure.

[0491] Example 1

[0492] Inhalation sprays with different formulations were prepared, and the specific formulations are shown in Tables 1 and 2:

[0493] Table 1

[0494] Preparation method of inhalation spray containing budesonide, tiotropium bromide and olodaterol:

[0495] (1) Weigh out the prescribed amount of antibacterial agent, metal ion chelating agent, stabilizer and antioxidant and dissolve them in the prescribed amount of water. Adjust the solution to the required pH range with pH adjuster.

[0496] (2) Add the prescribed amount of tiotropium bromide and olodaterol (in the form of olodaterol hydrochloride), stir to dissolve, and adjust the pH of the solution to the required pH range with a pH adjuster to obtain an aqueous solution;

[0497] (3) Weigh out the prescribed amount of budesonide and add it to the prescribed amount of ethanol, stir or sonicate to dissolve, and obtain an alcohol phase solution;

[0498] (4) Mix the aqueous solution and the alcohol solution evenly.

[0499] Preparation method of Odaterol inhalation spray:

[0500] (1) Weigh out the prescribed amount of antibacterial agent and metal ion chelating agent and dissolve them in the prescribed amount of water. Adjust the solution to the required pH range using a pH adjuster.

[0501] (2) Add the prescribed amount of olodaterol (in the form of olodaterol hydrochloride), stir to dissolve, and adjust the pH of the solution to the required pH range with a pH adjuster to obtain an aqueous solution;

[0502] (3) Add the prescribed amount of ethanol to the aqueous phase solution and mix well.

[0503] Example 2 Chemical Stability Study

[0504] In accordance with the requirements of the "Guiding Principles for Stability Testing of Drug Substances and Preparations" in General Chapter 9001 of the 2020 edition of the Chinese Pharmacopoeia, samples of the drug composition disclosed herein were placed in an accelerated sample retention chamber (at a temperature of 40℃±2℃ and a relative humidity of 25%±5%), and samples were taken at different times to determine the content and related substances. The test results are shown in Table 3.

[0505] Table 3 Note: NA indicates that this item was not detected;

[0506] Stability test results show that:

[0507] (1) Comparing the data of formulation 1 and formulation 15 (without glycerin), it was found that glycerin can significantly improve the stability of the pharmaceutical composition disclosed herein and significantly inhibit the generation of impurity L, impurity A, impurity E and total impurities of olodaterol.

[0508] (2) Comparing the data of prescription 1 and prescription 13 (without vitamin C), it was found that vitamin C can significantly improve the stability of the pharmaceutical composition disclosed herein and significantly inhibit the generation of impurity L, impurity A, impurity E and total impurities of olodaterol.

[0509] (3) Comparing the data of prescriptions 1, 13, 15 and 16, it was found that glycerol and vitamin C can synergistically improve the stability of the pharmaceutical composition disclosed herein and significantly inhibit the generation of impurities L, A, E and total impurities of olodaterol.

[0510] (4) Comparing the data of prescription 1 (glycerol at 1 w / w%), prescription 2 (glycerol at 0.5 w / w%), prescription 3 (glycerol at 10 w / w%), prescription 4 (glycerol at 0.1 w / w%), and prescription 5 (glycerol at 12 w / w%), it was found that the total impurities control of olodaterol was better when the glycerol content was between 0.5 and 1 w / w%.

[0511] (6) Comparing the data of formulation 1 (pH 2.9), formulation 6 (pH 2.5), formulation 7 (pH 4.0), formulation 8 (pH 1.5), formulation 9 (pH 4.5), and formulation 10 (pH 5.5), it was found that the total impurities control of olodaterol was better when the pH range was 2.5 to 4.

[0512] (7) Comparing the data of prescription 1 (vitamin C 0.0015 w / w%), prescription 20 (vitamin C 0.0001 w / w%), prescription 21 (vitamin C 5 w / w%), and prescription 22 (vitamin C 8 w / w%), it was found that the total impurities control of olodaterol was better when the vitamin C content was between 0.0001 and 5 w / w%.

[0513] (8) Comparing the data of prescription 1, prescription 16 (a compound without vitamin C and glycerin) and prescription 17 (a monoclonal formulation of olodaterol without vitamin C and glycerin), it was found that olodaterol is prone to producing impurities in compound preparations. However, surprisingly, the addition of glycerin and / or vitamin C significantly inhibited the production of impurity E and total impurities of olodaterol.

[0514] Example 3: Study on Spray Patterns

[0515] The inhalation sprays of formulations 1, 6, 7, 13, 18, 19, 20, and 21 in this embodiment were assembled with the spray device and sprayed. Using SprayVIEW spray pattern and a spray pattern analyzer, the spray inlet after triggering was taken as the spray starting point. The horizontal cross-section of the spray was measured at a fixed distance of 60 mm from the starting point. The main measurements were the longest axis (Dmax), shortest axis (Dmin), and ellipticity within the spray profile of the cross-section. Ellipticity is defined as: Ellipticity = Dmax / Dmin; the closer it is to 1, the closer the spray shape is to a circle. The test results are shown in Table 4, and the spray pattern diagrams for each formulation are shown in Figures 1 to 8.

[0516] Table 4

[0517] The test results show that: (1) Adding antioxidant vitamin C to the pharmaceutical composition disclosed herein can improve the ellipticity of the spray; (2) When the content of vitamin C in the pharmaceutical composition disclosed herein is 0.0015 to 5 w / w%, and the pH range is between 2.5 and 4, the ellipticity of the spray aerosol of each formulation is closer to 1, indicating that the pharmaceutical composition disclosed herein has better spray symmetry after spraying, improves the uniformity of the spray, and improves the drug inhalation effect.

[0518] Example 4: Lung Deposition Rate Test

[0519] The inhalation sprays prepared in Example 1 (Formulas 1 to 16, 18, and 19) were assembled with spray devices and tested according to the particle distribution of the different formulations in the "Determination of Aerodynamic Properties of Fine Particles in Inhaled Preparations" section 3 of the General Chapter 0951 of the 2020 edition of the Chinese Pharmacopoeia, Part IV, for "Inhalation Aerosols and Inhalation Sprays". Based on the particle distribution results, the lung deposition rate was calculated using Copley Inhaler Testing Data Analysis Software (CITADS). The results are shown in Table 5.

[0520] Table 5

[0521] Test results show that the prescription disclosed herein has a good lung deposition rate.

[0522] Example 5: Delivery Dosage Uniformity Test

[0523] The inhalation sprays of formulations 1 to 10, 18, and 19 prepared in Example 1 were assembled with spray devices, and the delivery dose of the inhalation sprays of different formulations was tested according to the test device and method of "uniformity of delivery dose of inhaled aerosols" in General Chapter 0111 of Part IV of the Chinese Pharmacopoeia 2020. The test results are shown in Table 6.

[0524] Table 6

[0525] Comparing the data from prescriptions 1-10, 18, and 19, it was found that prescriptions 1, 2, 3, 6, 7, 18, and 19 had more uniform delivery doses, indicating that when the glycerol content is 0.5–10 w / w% and / or the pH range is between 2.5 and 4, the delivery dose is more uniform and more suitable for inhalation spray administration.

[0526] The above description is merely a specific embodiment of this disclosure and is not intended to limit the scope of this disclosure. Any equivalent changes, modifications, and combinations made by those skilled in the art without departing from the concept and principles of this disclosure shall fall within the scope of protection of this disclosure.

Claims

1. A pharmaceutical composition comprising budesonide, tiotropium bromide, and olodaterol, and a stabilizer.

2. A pharmaceutical composition comprising budesonide, tiotropium bromide, and olodaterol, as well as an antioxidant.

3. A pharmaceutical composition comprising budesonide, tiotropium bromide, olodaterol, and stabilizers and antioxidants.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition further comprises one or more of a solvent, a pH adjuster, a metal ion chelating agent, or a bacteriostatic agent.

5. The pharmaceutical composition according to claim 3 or 4, wherein the pharmaceutical composition comprises budesonide, tiotropium bromide, and olodaterol, and a stabilizer, an antioxidant, ethanol, and a pH adjuster; or the pharmaceutical composition comprises budesonide, tiotropium bromide, and olodaterol, and a stabilizer, an antioxidant, ethanol, a pH adjuster, and water; or the pharmaceutical composition comprises budesonide, tiotropium bromide, and olodaterol, and a stabilizer, an antioxidant, ethanol, a pH adjuster, water, and a metal ion chelating agent; or the pharmaceutical composition comprises budesonide, tiotropium bromide, and olodaterol, and a stabilizer, an antioxidant, ethanol, a pH adjuster, water, and a bacteriostatic agent; or the pharmaceutical composition comprises budesonide, tiotropium bromide, and olodaterol, and a stabilizer, an antioxidant, ethanol, a pH adjuster, water, a metal ion chelating agent, and a bacteriostatic agent.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the pharmaceutical composition is a liquid formulation; or, the pharmaceutical composition is an inhalation formulation; or, the pharmaceutical composition is an inhaled liquid formulation; or, the pharmaceutical composition is an inhalation spray.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the amount of budesonide in the pharmaceutical composition is selected from 0.1 to 10 w / w%; or 0.125 to 2.5 w / w%; or 0.125 to 1.5 w / w%, or 0.125 to 1 w / w%; or 0.125 w / w%, 0.25 w / w%, 0.5 w / w%, or 1 w / w%. Alternatively, the amount of budesonide in the pharmaceutical composition may be selected from 0.1–100 mg / mL; or 1.1–9.5 mg / mL; or 1.14–9.09 mg / mL; or 1.14–2.27 mg / mL, 2.27–4.55 mg / mL, or 4.55–9.09 mg / mL; or 1.14 mg / mL, 2.27 mg / mL, 4.55 mg / mL, or 9.09 mg / mL. Alternatively, a single dose of the pharmaceutical composition may contain 3 to 380 mg of budesonide; or 10 to 100 mg; or 12 to 50 mg; or 30 to 50 mg; or 38 mg, 19 mg, or 9.5 mg. Alternatively, the pharmaceutical composition is an inhalation spray, wherein each spray contains 10–1200 μg of budesonide; or 45–50 μg; or 10–250 μg; or 10–120 μg; or 12.5–100 μg; or 100 μg, 50 μg, 25 μg, or 12.5 μg.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the amount of tiotropium bromide in the pharmaceutical composition is selected from 0.0001 to 1 w / w%; or 0.01 to 0.1 w / w%; or 0.01 to 0.05 w / w%; or 0.0125 to 0.025 w / w%; or 0.0125 w / w% and 0.025 w / w%. Alternatively, the amount of tiotropium bromide in the pharmaceutical composition may be selected from 0.04–10 mg / mL; or 0.1–9 mg / mL, 0.1–8 mg / mL, 0.1–7 mg / mL, 0.1–6 mg / mL, 0.1–5 mg / mL, 0.1–4 mg / mL, 0.1–3 mg / mL, 0.1–2 mg / mL, 0.1–1 mg / mL; or 0.11–0.50 mg / mL; or 0.110–0.300 mg / mL; or 0.114–0.227 mg / mL; or 0.114 mg / mL or 0.227 mg / mL; Alternatively, the amount of tiotropium bromide contained in a single-dose pharmaceutical composition is 0.1–10 mg; or 0.1–9 mg, 0.1–8 mg, 0.1–7 mg, 0.1–6 mg, 0.1–5 mg, 0.1–4 mg, 0.1–3 mg, 0.1–2 mg, 0.15–1.9 mg, 0.19–1.9 mg; or 0.19–1.9 mg; or 0.19–0.475 mg, 0.475–0.95 mg, 0.95–1.9 mg; or 0.19 mg, 0.475 mg, 0.95 mg, or 1.9 mg; Alternatively, the pharmaceutical composition is an inhalation spray, wherein each spray contains 0.1–10 μg of tiotropium bromide; or, 0.1–9 μg, 0.1–8 μg, 0.1–7 μg, 0.1–6 μg, 0.1–5 μg, 0.5–5 μg, 0.5–4 μg, 0.5–3 μg, 0.5–2.5 μg, 0.5–1.25 μg, 1.25–2.5 μg, 2.5–5 μg; or 0.5–5 μg; or 0.5–3 μg; or 0.5–1.25 μg, 1.25–2.5 μg; or 0.5 μg, 1.25 μg, 2.5 μg, or 5 μg.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the amount of olodaterol in the pharmaceutical composition is selected from 0.0001 to 1 w / w%; or 0.005 to 1 w / w%, preferably 0.01 to 1 w / w%, 0.01 to 0.5 w / w%, 0.01 to 0.4 w / w%, 0.01 to 0.3 w / w%, 0.01 to 0.2 w / w%, 0.01 ~0.1 w / w%, 0.01~0.05 w / w%, 0.01~0.04 w / w%, 0.01~0.03 w / w%, or 0.01~0.025 w / w%; or 0.01~0.1 w / w%; or 0.01~0.05 w / w%; or 0.0125~0.025 w / w%; or 0.0125 w / w%, 0.025 w / w%. Alternatively, the amount of olodaterol in the pharmaceutical composition may be selected from 0.1–10 mg / mL; or 0.1–9 mg / mL, 0.1–8 mg / mL, 0.1–7 mg / mL, 0.1–6 mg / mL, 0.1–5 mg / mL, 0.1–4 mg / mL, 0.1–3 mg / mL, 0.1–2 mg / mL, 0.1–1 mg / mL; or 0.11–0.50 mg / mL; or 0.110–0.300 mg / mL; or 0.114–0.227 mg / mL; or 0.114 mg / mL or 0.227 mg / mL. L; or, the amount of olodaterol contained in a single dose of the pharmaceutical composition is 0.04–10 mg; or 0.1–9 mg, 0.1–8 mg, 0.1–7 mg, 0.1–6 mg, 0.1–5 mg, 0.1–4 mg, 0.1–3 mg, 0.1–2 mg, 0.15–1.9 mg, 0.19–1.9 mg; or 0.19–1.9 mg; or 0.19–0.475 mg, 0.475–0.95 mg, 0.95–1.9 mg; or 0.19 mg, 0.475 mg, 0.95 mg, or 1.9 mg; Alternatively, the pharmaceutical composition is an inhalation spray, wherein each spray contains 0.1–10 μg of olodaterol; or, 0.1–9 μg, 0.1–8 μg, 0.1–7 μg, 0.1–6 μg, 0.1–5 μg, 0.5–5 μg, 0.5–4 μg, 0.5–3 μg, 0.5–2.5 μg, 0.5–1.25 μg, 1.25–2.5 μg, 2.5–5 μg; or 0.5–5 μg; or 0.5–3 μg; or 0.5–1.25 μg, 1.25–2.5 μg; or 0.5 μg, 1.25 μg, 2.5 μg, or 5 μg.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the stabilizer is selected from one or more of n-propanol, isopropanol, glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenethyl alcohol, butanol, butanediol, mannitol, polyethylene glycol, and ethylene glycol; preferably, the stabilizer is selected from one or more of glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenethyl alcohol, butanol, butanediol, polyethylene glycol, and ethylene glycol; more preferably, the stabilizer is selected from one or more of glycerol, propylene glycol, oleic acid, phenethyl alcohol, and butanol; further preferably, the stabilizer is selected from glycerol, propylene glycol, or a mixture thereof; even more preferably, the stabilizer is glycerol; and / or, The amount of the stabilizer is selected from 0.01–20 w / w%; or 0.01–15 w / w%, 0.01–15 w / w%, 0.01–5 w / w%, 0.05–15 w / w%, 0.05–15 w / w%, 0.05–5 w / w%, 0.1–15 w / w%, 0.1–15 w / w%, 0.1–8 w / w%, 0.1–6 w / w%, 0.1–5 w / w%, 0.2–8 w / w%, 0.2–7 w / w%, 0.2–6 w / w%, 0.2–5 w / w%, 0.2–4 w / w%, or 0.2–3 w / w%. Or 0.1–15 w / w%; or 0.1–12 w / w%; or 0.1–0.5 w / w%, 0.5–1 w / w%, 1–10 w / w%, or 10–12 w / w%; or 1 w / w%; Alternatively, the amount of the stabilizer is selected from 0.1–190 mg / mL; or 0.9–110 mg / mL, 0.9–100 mg / mL, 0.9–90 mg / mL, 0.9–80 mg / mL, 0.9–70 mg / mL, 0.9–60 mg / mL, 0.9–50 mg / mL, 0.9–40 mg / mL, 0.9–30 mg / mL, 0.9–20 mg / mL, 0.9–10 mg / mL; or 0.9–109.1 mg / mL, 0.9–90.9 mg / mL, 0.9–4.6 mg / mL, 0.9–9.1 mg / mL, 9.1–90.9 mg / mL; or 0.91–109.09 mg / mL, 0.91–4.55 mg / mL, 4.55–9.09 mg / mL, 9.09–90.91 mg / mL, 90.91–109.09 mg / mL; or 9.09 mg / mL; Alternatively, a single dose of the pharmaceutical composition may contain a stabilizer in an amount of 0.38–760 mg; or 7.6–190 mg; or 19–90 mg; or 30–60 mg; or 38 mg. Alternatively, the pharmaceutical composition may be an inhalation spray, wherein each spray contains 1–2000 μg, or 10–500 μg, or 1000–2000 μg, or 50–250 μg, or 80–150 μg, or 100 μg of stabilizer.

11. The pharmaceutical composition according to any one of claims 2 to 10, wherein the antioxidant is selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate (PG), tert-butylhydroquinone (TBHQ), ascorbic acid antioxidants (including but not limited to vitamin C, isoascorbic acid, sodium ascorbate, potassium ascorbate, ascorbate palmitate), tocopherol antioxidants (including but not limited to vitamin E, α-tocopherol, mixed concentrated tocopherols, tocopherol acetate), vitamin A, retinyl palmitate, dibutylphenol, tea polyphenols (TP), sulfite antioxidants (including but not limited to sodium sulfite, potassium sulfite, sodium metabisulfite, potassium metabisulfite, sodium bisulfite, potassium bisulfite, sodium thiosulfate), fumaric acid or its salt, malic acid or its salt, citric acid or its salt, maleic acid or its salt; preferably, the antioxidant... The antioxidant is selected from one or more of the following: ascorbic acid antioxidants (including but not limited to vitamin C, isoascorbic acid, sodium ascorbate, potassium ascorbate, and ascorbyl palmitate); sulfite antioxidants (including but not limited to sodium sulfite, potassium sulfite, sodium metabisulfite, potassium metabisulfite, sodium bisulfite, potassium bisulfite, and sodium thiosulfate); butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, tert-butylhydroquinone (TBHQ), and tea polyphenols; more preferably, the antioxidant is selected from one or more of vitamin C, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, butylated hydroxyanisole (BHT), butylated hydroxytoluene (BHT), tert-butylhydroquinone (TBHQ), propyl gallate, ascorbyl palmitate, and tea polyphenols; further preferably, the antioxidant is selected from one or more of vitamin C, sodium metabisulfite, sodium bisulfite, and sodium thiosulfate; most preferably, the antioxidant is vitamin C; and / or... The amount of the antioxidant is selected from 0.0001 to 10 w / w%, or 0.0001 to 8 w / w%, or 0.001 to 0.0015 w / w%, 0.0015 to 5 w / w%, or 5 to 8 w / w%, or 0.0015 w / w%. Alternatively, the amount of the antioxidant may be selected from 0.0001–80 mg / mL; or 0.0009–72.73 mg / mL; or 0.0009–0.014 mg / mL, 0.014–45.45 mg / mL, or 45.45–72.73 mg / mL; or 0.014 mg / mL; Alternatively, a single dose of the pharmaceutical composition may contain an antioxidant in an amount of 0.006–190 mg, or 0.02–45 mg, or 0.03–10 mg, or 0.04–1 mg, or 0.057 mg. Alternatively, the pharmaceutical composition may be an inhalation spray, wherein each spray contains an antioxidant amount of 0–800 μg; or 0.05–50 μg; or 0.075–5 μg; or 0.1–0.5 μg; or 0.15 μg.

12. The pharmaceutical composition according to any one of claims 4 to 11, wherein the antibacterial agent is selected from one or more of benzalkonium chloride, benzalkonium bromide, parabens (such as methylparaben, ethylparaben, propylparaben, butylparaben, etc.), chlorobutanol, phenol, resorcinol, benzyl alcohol, phenethyl alcohol, benzoic acid or its salts, sodium propionate, sorbic acid or its salts; preferably, the antibacterial agent is selected from one or more of benzalkonium chloride, benzalkonium bromide, benzyl alcohol, phenethyl alcohol, benzoic acid or its salts, sodium propionate, sorbic acid or its salts; more preferably, the antibacterial agent is selected from one or more of benzalkonium chloride, benzalkonium bromide, benzoic acid or its salts, benzyl alcohol; even more preferably, the antibacterial agent is selected from benzalkonium chloride and / or benzalkonium bromide; most preferably, the antibacterial agent is benzalkonium chloride; and / or, The amount of the antibacterial agent is selected from 0-2 w / w%; or 0-0.5 w / w%; or 0.005-0.05 w / w%; or 0.005-0.015 w / w%; or 0.01 w / w%. Alternatively, the amount of the antibacterial agent may be selected from 0 to 19 mg / mL; Or 0.04–6 mg / mL; or 0.045–0.45 mg / mL; or 0.045–0.18 mg / mL; or 0.09 mg / mL; Alternatively, a single dose of the pharmaceutical composition may contain an antibacterial agent in an amount of 0–76 mg, or 0–25 mg, or 0.19–1.9 mg, or 0.19–0.76 mg, or 0.38 mg. Alternatively, the pharmaceutical composition is an inhalation spray, wherein each spray contains 0 to 200 μg of antibacterial agent; Or 0–60 μg, or 0.5–5 μg, or 0.75–2 μg, or 1 μg.

13. The pharmaceutical composition according to any one of claims 4 to 12, wherein the metal ion chelating agent is selected from ethylenediaminetetraacetic acid (EDTA) or a salt thereof, ethylene glycol tetraacetic acid (EGTA) or a salt thereof, cyclohexanediaminetetraacetic acid (CDTA) or a salt thereof, hydroxyethylethylenediaminetriacetic acid (HEDTA) or a salt thereof, diethylenetriaminepentaacetic acid (DTPA) or a salt thereof, dimercaptopropanesulfonic acid (DMPS) or a salt thereof, dimercaptosuccinic acid (DMSA) or a salt thereof, aminotrimethylenephosphonic acid (ArPA) or a salt thereof, citric acid or a salt thereof, acetic acid or a salt thereof, phosphoric acid or a salt thereof, pyrophosphate or a salt thereof, metaphosphate or a salt thereof, and any combination thereof; preferably, the metal ion chelating agent is selected from: ethylenediaminetetraacetic acid (EDTA) or a salt thereof. The metal ion chelating agent is selected from one or more of acetic acid or its salts, ethylene glycol tetraacetic acid or its salts, cyclohexanediaminetetraacetic acid or its salts, hydroxyethyl ethylenediaminetriacetic acid or its salts, and diethylenetriaminepentaacetic acid or its salts; more preferably, the metal ion chelating agent is selected from one or more of ethylenediaminetetraacetic acid or its salts, and hydroxyethyl ethylenediaminetriacetic acid or its salts; even more preferably, the metal ion chelating agent is selected from one or more of ethylenediaminetetraacetic acid or its salts, including but not limited to ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetic acid, dipotassium ethylenediaminetetraacetic acid, trisodium ethylenediaminetetraacetic acid, tripotassium ethylenediaminetetraacetic acid, calcium disodium ethylenediaminetetraacetic acid, and dicalcium ethylenediaminetetraacetic acid; most preferably, the metal ion chelating agent is disodium ethylenediaminetetraacetic acid; and / or, The amount of the metal ion chelating agent is selected from 0.001 to 1 w / w%; or 0.001 to 0.5 w / w%; or 0.005 to 0.1 w / w%. Or 0.01–0.05 w / w%; or 0.01 w / w%; Alternatively, the amount of the metal ion chelating agent may be selected from 0–19 mg / mL; or 0–6 mg / mL; or 0.045–0.45 mg / mL; or 0.045–0.18 mg / mL; or 0.09 mg / mL; Alternatively, the amount of metal ion chelating agent contained in a single dose of the pharmaceutical composition is 0–76 mg, or 0–25 mg, or 0.19–1.9 mg, or 0.19–0.76 mg, or 0.38 mg; Alternatively, the pharmaceutical composition is an inhalation spray, wherein each spray of the pharmaceutical composition contains 0 to 200 μg of a metal ion chelating agent; Or 0–60 μg, or 0.5–5 μg, or 0.75–2 μg, or 1 μg.

14. The pharmaceutical composition according to any one of claims 5 to 13, wherein the pharmaceutical composition comprises water, and the amount of said water is selected from 4 to 80 w / w%; or 4 to 68 w / w%, 10 to 66 w / w%, 15 to 64 w / w%, 20 to 62 w / w%, 22 to 60 w / w%, 24 to 60 w / w%, 26 to 58 w / w%, 28 to 56 w / w%, 30 to 54 w / w%, 32 to 52 w / w%. 34–50 w / w%, 36–50 w / w%, 36–49 w / w%, 38–49 w / w%, 40–48 w / w%, 41–48 w / w%, 42–48 w / w%, 42–47 w / w%, 43–47 w / w%, 44–46 w / w%, 45–46 w / w%; or 4–60 w / w%; or 30–60 w / w%, or 40–50 w / w%; or 44–45 w / w%. Alternatively, the amount of water is selected from 30–730 mg / mL; or 100–480 mg / mL; or 300–450 mg / mL; or 360–430 mg / mL; or 360–405 mg / mL; Alternatively, a single dose of the pharmaceutical composition may contain 150–3100 mg of water, or 330–2000 mg, or 1250–1900 mg, or 1500–1800 mg, or 1665–1685 mg, or 1672 mg, or 1675 mg. Alternatively, the pharmaceutical composition is an inhalation spray, wherein each spray contains 0.4–8.0 mg of water; preferably 0.4–6.5 mg, 0.6–6.4 mg, 0.8–6.2 mg, 1–6 mg, 1.2–5.9 mg, 1.4–5.8 mg, 1.6–5.7 mg, 1.8–5.6 mg, 2–5.5 mg, 2.2–5.4 mg, 2.4–5.3 mg, 2. 6–5.2 mg, 2.8–5.1 mg, 3–5 mg, 3.2–4.9 mg, 3.4–4.9 mg, 3.6–4.8 mg, 3.8–4.8 mg, 4–4.7 mg, 4.1–4.7 mg, 4.2–4.6 mg, 4.3–4.6 mg or 4.4–4.5 mg, or 0.8–5.3 mg, or 3–5 mg, or 4–4.8 mg, or 4.4–4.5 mg.

15. The pharmaceutical composition according to any one of claims 5 to 14, wherein the pharmaceutical composition comprises ethanol, and the amount of said ethanol is selected from 20 to 96 w / w%; or 20 to 90 w / w%, 30 to 96 w / w%, 40 to 96 w / w%, 40 to 90 w / w%, 40 to 85 w / w%, 40 to 80 w / w%, 40 to 75 w / w%, 40 to 70 w / w%, 40 to 65 w / w%, 40 to 60 w / w%, 42 to 60 w / w%, 44 to 60 w / w%, 46 to 60 w / w%, 48 to 60 w / w%, 50 to 60 w / w%, 52 to 58 w / w%, or 53 to 57 w / w%. Or 40-70 w / w%; or 50-60 w / w%; Or 53-56 w / w%; or 53-55 w / w%; Alternatively, the amount of ethanol is selected from 180–900 mg / mL; or 320–850 mg / mL; or 390–620 mg / mL; or 450–530 mg / mL; or 450–495 mg / mL; Alternatively, the amount of ethanol contained in a single dose of the pharmaceutical composition is 750–3700 mg, or 1300–3500 mg, or 1600–2600 mg, or 1900–2200 mg, or 2000–2100 mg, or 2047 mg, or 2052 mg. Alternatively, the pharmaceutical composition is an inhalation spray, wherein each spray contains 2.0–9.8 mg of ethanol; or 4.3–6.8 mg; or 5.0–5.8 mg; or 5.3–5.5 mg; or 5.4–5.5 mg.

16. The pharmaceutical composition according to any one of claims 4 to 15, wherein the pharmaceutical composition comprises a pH adjuster selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, lactic acid, tartaric acid, boric acid, malic acid, succinic acid, fumaric acid, methionine, and glucuronic acid; or, the pH adjuster selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, tartaric acid, succinic acid, and fumaric acid; or, the pH adjuster selected from one or more of hydrochloric acid, phosphoric acid, citric acid, acetic acid, and tartaric acid; or, the pH adjuster is hydrochloric acid; and / or, The pH value of the pharmaceutical composition is 2.0 to 4.5; or, the pH value is 2.0 to 4.0, 2.0 to 3.5, 2.5 to 3.5, 2.6 to 3.5, 2.8 to 3.5, 2.9 to 3.5, or 2.5 to 3.0; or, the pH value is 2.5 to 4.0; or, the pH value is 2.5 to 3.5; or, the pH value is 2.5 to 3.0; or, the pH value is selected from 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, or 4.5, or any range formed by any of the aforementioned values as endpoints, or any value therein.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the fine particles formed by atomization of the pharmaceutical composition by a spray device have a lung deposition rate of greater than 50%; preferably, the lung deposition rate is greater than 60%.

18. A method for preparing the pharmaceutical composition according to any one of claims 1 to 17, comprising the following steps: (a1) Weigh out the prescribed amount of stabilizer and / or antioxidant, optional antibacterial agent and optional metal ion chelating agent, and dissolve them in the prescribed amount of water. Adjust the pH of the resulting solution to the required pH range using a pH adjuster. (a2) Add the prescribed amount of tiotropium bromide and olodaterol to the solution obtained in step (a1), stir to dissolve, and adjust the pH value of the obtained solution to the required pH range with a pH adjuster to obtain an aqueous solution. (a3) Weigh out the prescribed amount of budesonide and add it to the prescribed amount of ethanol, stir or sonicate to dissolve, and obtain an alcohol phase solution; (a4) Mix the aqueous solution and the alcoholic solution evenly.

19. A drug delivery system comprising a spray device and a container assembleable with said spray device, said container containing the drug composition of any one of claims 1 to 17; optionally, said spray device is a handheld inhaler.

20. Use of the pharmaceutical composition of any one of claims 1 to 17 in the preparation of a medicament for treating or preventing lung diseases; optionally, the lung diseases include asthma, chronic obstructive pulmonary disease, pneumonia, bronchitis, lung cancer, or diffuse interstitial pulmonary fibrosis.

21. A method for treating or preventing lung diseases, comprising administering to a subject in need the pharmaceutical composition of any one of claims 1 to 17; optionally, the lung disease includes asthma, chronic obstructive pulmonary disease, pneumonia, bronchitis, lung cancer, or diffuse interstitial pulmonary fibrosis.

22. A pharmaceutical composition according to any one of claims 1 to 17 for the treatment or prevention of lung diseases; optionally, the lung diseases include asthma, chronic obstructive pulmonary disease, pneumonia, bronchitis, lung cancer, or diffuse interstitial pulmonary fibrosis.

23. Use of the pharmaceutical composition of any one of claims 1 to 17 in the treatment or prevention of lung diseases; optionally, said lung diseases include asthma, chronic obstructive pulmonary disease, pneumonia, bronchitis, lung cancer, or diffuse interstitial pulmonary fibrosis.

24. Use of glycerol in the preparation of pharmaceutical compositions containing olodaterol or any of the pharmaceutical compositions according to any one of claims 1 to 17.

25. Use of vitamin C in the preparation of a pharmaceutical composition containing olodaterol or a pharmaceutical composition according to any one of claims 1 to 17.

26. Use of glycerol and / or vitamin C in enhancing the stability of pharmaceutical compositions containing olodaterol or pharmaceutical compositions according to any one of claims 1 to 17.