Budesonide inhalation spray and preparation process therefor

Abstract

Provided are a budesonide pharmaceutical composition, particularly a budesonide inhalation spray, and a preparation process therefor. The budesonide pharmaceutical composition comprises budesonide, ethanol, a stabilizer, and / or an antioxidant. The budesonide pharmaceutical composition, particularly the budesonide inhalation spray, has the advantages of good stability, uniform spray microparticle distribution, a high lung deposition rate, and / or convenient administration, which is suitable for industrial production.

Description

A budesonide inhalation spray and its preparation process

[0001] Citation of Related Applications

[0002] This application claims priority and benefits to Chinese invention patent applications No. 202410156065.9 and No. 202410155078.4 filed with the Intellectual Property Office of the People's Republic of China on February 2, 2024, the entire contents of which are hereby incorporated by reference into this document in their entirety. Technical Field

[0003] The present invention relates to the field of pharmaceutical preparations, and in particular to a budesonide inhalation spray and a preparation process thereof. Background Art

[0004] Budesonide is a glucocorticoid with highly effective local anti-inflammatory effects. Its structural formula is shown below (i.e., compound I). It effectively controls airway inflammation by enhancing the stability of endothelial cells, smooth muscle cells, and lysosomal membranes, thereby reducing the release of allergic mediators such as histamine. It also alleviates the enzymatic processes triggered by antigen-antibody binding, inhibiting the synthesis and release of bronchoconstrictor substances. Budesonide is currently the drug of choice for the treatment of asthma and COPD.

[0005] Budesonide can be administered via inhalation or oral administration, with inhalation being the preferred route. Drugs inhaled into the lungs avoid first-pass effects and degradation in the gastrointestinal tract, reaching the target site quickly at higher concentrations and achieving rapid onset of action. Furthermore, the inhaled dose is significantly lower than that of systemic administration, avoiding potential side effects associated with systemic administration.

[0006] Currently, commercially available formulations for budesonide inhalation administration include budesonide inhalation aerosols, budesonide inhalation powders, and budesonide nebulized inhalation suspensions. However, these developed formulations suffer from low administration efficiency, environmental concerns, uneven dosing, and difficulty maintaining the long-term stability of suspension formulations, limiting the application of budesonide in pulmonary administration. Therefore, there is an urgent need for new budesonide inhalation sprays that address one or more of these technical issues. Summary of the Invention

[0007] In a first aspect, the present disclosure provides a pharmaceutical composition comprising budesonide and a stabilizer and / or an antioxidant.

[0008] In yet another aspect, the present disclosure provides a pharmaceutical composition comprising budesonide, and glycerol and / or an antioxidant.

[0009] In yet another aspect, the present disclosure provides a pharmaceutical composition comprising budesonide, and a stabilizer and / or vitamin C. In yet another aspect, the present disclosure provides a pharmaceutical composition comprising budesonide, and glycerol and / or vitamin C. In some embodiments, the pharmaceutical composition comprises budesonide, glycerol, and vitamin C.

[0010] In some embodiments of the present disclosure, the pharmaceutical composition is a liquid preparation.

[0011] In some embodiments of the present disclosure, the pharmaceutical composition is an inhalation formulation.

[0012] In some embodiments of the present disclosure, the pharmaceutical composition is a liquid formulation for inhalation.

[0013] In some embodiments of the present disclosure, the pharmaceutical composition is an inhalation spray. In some embodiments of the present disclosure, the pharmaceutical composition is an inhalation liquid spray. In another aspect, the present disclosure provides an inhalation spray of budesonide, comprising budesonide, ethanol, and a stabilizer.

[0014] In yet another aspect, the present disclosure provides an inhalation spray of budesonide, comprising budesonide, ethanol, and an antioxidant.

[0015] In some embodiments of the present disclosure, the pharmaceutical composition, in particular the inhalation spray, comprises budesonide, a stabilizer and an antioxidant. In some embodiments of the present disclosure, the pharmaceutical composition, in particular the inhalation spray, further comprises a solvent.

[0016] In some embodiments of the present disclosure, the solvent is selected from ethanol and / or water.

[0017] In some embodiments of the present disclosure, the pharmaceutical composition, in particular the inhalation spray, comprises ethanol, or water, or ethanol and water.

[0018] In some embodiments of the present disclosure, the pharmaceutical composition, particularly the inhalation spray, comprises budesonide, ethanol, and a stabilizer.

[0019] In some embodiments of the present disclosure, the pharmaceutical composition, particularly the inhalation spray, comprises budesonide, ethanol, and an antioxidant.

[0020] In some embodiments of the present disclosure, the pharmaceutical composition, in particular the inhalation spray, further comprises one or more of a solvent, a pH adjuster, a metal ion chelator, and a bacteriostat. In some embodiments of the present disclosure, the pharmaceutical composition, in particular the inhalation spray, comprises budesonide, a stabilizer, ethanol, and an antioxidant.

[0021] In some embodiments of the present disclosure, the pharmaceutical composition, particularly the inhalation spray, comprises budesonide, a stabilizer, ethanol, an antioxidant, and a pH adjuster.

[0022] In some embodiments of the present disclosure, the pharmaceutical composition, particularly the inhalation spray, comprises budesonide, a stabilizer, ethanol, an antioxidant, a pH adjuster, and water.

[0023] In some embodiments of the present disclosure, the pharmaceutical composition, particularly the inhalation spray, comprises budesonide, a stabilizer, ethanol, an antioxidant, a pH adjuster, water, an optional metal ion chelator, and an optional bacteriostatic agent.

[0024] In some embodiments of the present disclosure, the pharmaceutical composition, particularly the inhalation spray, comprises budesonide, a stabilizer, ethanol, an antioxidant, a pH adjuster, water, a metal ion chelator, and an antibacterial agent.

[0025] In some embodiments of the present disclosure, the amount of budesonide in the pharmaceutical composition, especially the inhalation spray, is 0.1-10 w / w%; preferably 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%, 0.4-2 w / w%, 0.5-2 w / w%, 0.5-1.8 w / w%, 0.6-1.8 w / 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%, more preferably 0.25-5w / w% or 0.125-2.5w / w%, further preferably 0.25-3w / w% or 0.125-1.5w / w%, further preferably 0.5-1.5w / w% or 0.25-0.75w / w%, most preferably 1w / w% or 0.5w / w%; or, in some embodiments of the present disclosure, the amount of budesonide in the pharmaceutical composition, especially in the inhalation spray, is 0.1w / w%, 0.15w / w%, 0.2w / w%, 0.25w / w%, 0.3w / w%, 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%, 1.05 w / 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. 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%, 6.1w / 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%, 8.7 w / w%, 8.8 w / w%, 8.9 w / w%, 9 w / w%, 9.1 w / w%, 9.2 w / w%, 9.3 w / w%, 9.4 w / w%, 9.5 w / w%, 9.6 w / w%, 9.7 w / w%, 9.8 w / w%, 9.9 w / w% or 10 w / w%, or a range consisting of any of the foregoing values ​​as endpoints or any value therein.

[0026] In some embodiments of the present disclosure, the amount of budesonide in the pharmaceutical composition, particularly the inhalation spray, is 0.1 w / w%, 0.125 w / w%, 0.15 w / w%, 0.175 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%, or a range consisting of any of the foregoing values ​​as endpoints or any value therein.

[0027] In other embodiments of the present disclosure, the amount of budesonide in the pharmaceutical composition, in particular in the inhalation spray, is 1 w / w%, 0.5 w / w%, 0.25 w / w% or 0.125 w / w%, or a range consisting of any of the foregoing values ​​as endpoints or any value therein.

[0028] In other embodiments of the present disclosure, the amount of budesonide in the pharmaceutical composition, particularly the inhalation spray, is 0.125-0.25 w / w%, 0.125-0.5 w / w%, 0.125-1 w / w%, 0.25-0.5 w / w%, 0.25-1 w / w% or 0.5-1 w / w%.

[0029] In some embodiments of the present disclosure, the amount of budesonide in the pharmaceutical composition, especially the inhalation spray, is 0.1-90 mg / mL; preferably 0.5-85 mg / mL, 1.0-85 mg / mL, 1.5-85 mg / mL, 2.0-80 mg / mL, 3-80 mg / mL, 4-75 mg / mL, 4.5-75 mg / mL, 4-70 mg / mL, 5-65 mg / mL, 5-60 mg / mL, 6-55 mg / mL, 6-50 mg / mL, 6-45 mg / mL, 7-40 mg / mL, 7-35 mg / mL, 7-30 mg / mL, 8-25 mg / mL, 8-20 mg / mL, 8-15 mg / mL, 8~12mg / mL, 9~10mg / mL, 9~9.5mg / mL, 2~45mg / mL, 2.5~40mg / mL, 2.5~35mg / mL, 3~30mg / mL, 3~25mg / mL, 3.5~20mg / mL, 3.5~18mg / mL, 3.6~17mg / mL, 3.7~16mg / mL, 3.8~15mg / mL, 3.9~14mg / mL, 4~13mg / mL, 4.1~12mg / mL, 4.2~11mg / mL, 4.3~10mg / mL, 4.4~9mg / mL, 4.5~8mg / mL, 4.5~7mg / mL, 4.5~6mg / mL or 4.5-5 mg / mL, more preferably 4.5-45 mg / mL or 0.1-20 mg / mL, further preferably 5.6-27 mg / mL or 0.5-15 mg / mL, further preferably 8-14 mg / mL, 4-7 mg / mL, 0.9-4 mg / mL, most preferably 9.048 mg / mL, 4.524 mg / mL, 2.3 mg / mL or 1.1 mg / mL; or, in some embodiments of the present disclosure, the amount of budesonide in the pharmaceutical composition, especially the inhalation spray, is 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0 .7mg / mL, 0.8mg / mL, 0.9mg / mL, 1.0mg / mL, 1.1mg / mL, 1.2mg / mL, 1.3mg / mL, 1.4mg / mL, 1.5mg / mL, 1.6mg / mL, 1.7mg / mL, 1.8mg / mL, 1.9mg / mL, 2mg / mL, 2 .1mg / ml, 2.2mg / ml, 2.3mg / ml, 2.4mg / ml, 2.5mg / mL, 2.6mg / ml, 2.7mg / ml, 2.8mg / ml, 2.9mg / ml, 3mg / mL, 3.1mg / mL, 3.2mg / mL, 3.3mg / mL, 3.4mg / mL, 3.5 mg / mL, 3.6 mg / mL, 3.7 mg / mL, 3.8 mg / mL, 3.9 mg / mL, 4.0 mg / mL, 4.1 mg / mL, 4.2 mg / mL, 4.3 mg / mL, 4.4 mg / mL, 4.5 mg / mL, 4.6 mg / mL, 4.7 mg / mL, 4.8 mg / mL, 4.9 mg / mL, 5.0 mg / mL, 5.1 mg / mL, 5.2 mg / mL, 5.3 mg / mL, 5.4 mg / mL, 5.5 mg / mL, 5.6 mg / mL, 5.7 mg / mL, 5.8 mg / mL, 5.9 mg / mL, 6.0 mg / mL, 6.1 mg / mL, 6.2 mg / mL, 6.3 mg / mL, 6.4 mg / mL, 6.5 mg / mL, 6.6 mg / mL, 6.7 mg / mL, 6.8 mg / mL, 6.9 mg / mL, 7.0 mg / mL, 7.1 mg / mL, 7.2 mg / mL, 7.3 mg / mL, 7.4 mg / mL, 7.5 mg / mL, 7.6 mg / mL, 7.7 mg / mL, 7.8 mg / mL, 7.9 mg / mL, 8.0 mg / mL, 8.1 mg / mL, 8.2 mg / mL, 8.3 mg / mL, 8.4 mg / mL, 8.5 mg / mL, 8.6 mg / mL, 8.7 mg / mL, 8.8 mg / mL, 8.9 mg / mL, 9.0 mg / mL, 9.1 mg / mL, 9.2 mg / mL, 9.3 mg / mL, 9.4 mg / mL, 9.5 mg / mL, 9.6 mg / mL, 9.7 mg / mL, 9.8 mg / mL, 9.9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, 85 mg / mL or 90 mg / mL, or a range formed by any of the foregoing values as endpoints or any value therein.

[0030] In some other embodiments of the present disclosure, the amount of budesonide in the pharmaceutical composition, especially the inhalation spray, is 2-90 mg / mL; preferably 2.3-90 mg / mL, 3-85 mg / mL, 3.5-85 mg / mL, 3-80 mg / mL, 4-75 mg / mL, 4.5-75 mg / mL, 4-70 mg / mL, 5-65 mg / mL, 5-60 mg / mL, 6-55 mg / mL, 6-50 mg / mL, 6-45 mg / mL, 7-40 mg / mL, 7-35 mg / mL, 7-30 mg / mL, 8-25 mg / mL, 8-20 mg / mL, 8-15 mg / mL, 8-12 mg / mL. L, 9~10mg / mL, 9~9.5mg / mL, 2~45mg / mL, 2.5~40mg / mL, 2.5~35mg / mL, 3~30mg / mL, 3~25mg / mL, 3.5~20mg / mL, 3.5~18mg / mL, 3.6~17mg / mL, 3.7~16mg / mL , 3.8~15mg / mL, 3.9~14mg / mL, 4~13mg / mL, 4.1~12mg / mL, 4.2~11mg / mL, 4.3~10mg / mL, 4.4~9mg / mL, 4.5~8mg / mL, 4.5~7mg / mL, 4.5~6mg / mL or 4.5~5mg / mL , more preferably 4.5-45 mg / mL or 2-20 mg / mL, further preferably 5.6-27 mg / mL or 2.5-15 mg / mL, further preferably 8-14 mg / mL or 4-7 mg / mL, most preferably 9.048 mg / mL or 4.524 mg / mL; or, in some embodiments of the present disclosure, the amount of budesonide in the pharmaceutical composition, especially the inhalation spray, is 2 mg / mL, 2.5 mg / mL, 3 mg / mL, 3.1 mg / mL, 3.2 mg / mL, 3.3 mg / mL, 3.4 mg / mL, 3.5 mg / mL, 3.6 mg / mL, 3.7 mg / mL, 3.8 mg / mL, 3.9 mg / mL, 4.0mg / mL, 4.1mg / mL, 4.2mg / mL, 4.3mg / mL, 4.4mg / mL, 4.5mg / mL, 4.6mg / mL, 4.7mg / mL, 4.8mg / mL, 4.9mg / mL, 5.0mg / mL, 5.1mg / mL, 5.2mg / mL, 5.3mg / mL, 5.4mg / mL, 5.5mg / mL, 5.6mg / mL, 5.7mg / mL, 5.8mg / mL, 5.9mg / mL, 6.0mg / mL, 6.1mg / mL, 6.2mg / mL, 6.3mg / mL, 6.4mg / mL, 6.5mg / mL, 6.6mg / mL, 6.7mg / mL, 6.8mg / mL, 6.9mg / mL, 7.0mg / mL, 7.1mg / mL, 7.2mg / mL, 7.3mg / mL, 7.4mg / mL, 7.5mg / mL, 7.6mg / mL, 7.7mg / mL, 7.8mg / mL, 7.9mg / mL, 8.0mg / mL, 8.1mg / mL, 8.2mg / mL, 8.3mg / mL, 8.4mg / mL, 8.5mg / mL, 8.6mg / mL, 8.7mg / mL, 8.8mg / mL, 8.9mg / mL, 9.0mg / mL, 9.1mg / mL, 9.2mg / mL, 9.3mg / mL, 9.4mg / mL, 9.5mg / mL, 9.6 mg / mL, 9.7 mg / mL, 9.8 mg / mL, 9.9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, 85 mg / mL or 90 mg / mL, or a range consisting of any of the foregoing values ​​as endpoints or any value therein.

[0031] In some other embodiments of the present disclosure, the amount of budesonide in the pharmaceutical composition, particularly in the inhalation spray, is 9.048 mg / mL, 4.524 mg / mL, 2.262 mg / mL or 1.131 mg / mL, or a range consisting of any of the aforementioned values ​​as endpoints or any value therein.

[0032] In other embodiments of the present disclosure, the amount of budesonide in the pharmaceutical composition, particularly the inhalation spray, is 1.131-2.262 mg / mL, 1.131-4.524 mg / mL, 1.131-9.048 mg / mL, 2.262-4.524 mg / mL, 2.262-9.048 mg / mL or 4.524-9.048 mg / mL.

[0033] In some embodiments of the present disclosure, the single-dose pharmaceutical composition of the pharmaceutical composition, in particular the single-dose pharmaceutical composition of the inhalation spray, comprises budesonide in an amount of 3 to 380 mg; preferably 5 to 360 mg, 6 to 340 mg, 7 to 320 mg, 8 to 300 mg, 9 to 280 mg, 10 to 260 mg, 11 to 240 mg, 12 to 220 mg, 13 to 200 mg, 14 to 180 mg, 15 to 160 mg, 16 to 150 mg, 17 to 140 mg. g, 18~130mg, 19~120mg, 20~110mg, 21~100mg, 22~90mg, 23~80mg, 24~70mg, 25~60mg, 26~65mg, 27~50mg, 28~5 5mg, 29~50mg, 30~49mg, 31~48mg, 32~47mg, 33~46mg, 34~45mg, 35~44mg, 36~43mg, 37~42mg, 37~41mg, 37~40m g, 38~40mg, 38~39mg, 5~190mg, 6~170mg, 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, 15-23mg, 15-22mg, 15-21mg, 15-20mg, 16-20mg, 16-19mg, 17-19mg or 18-19mg, more preferably 19-190mg or 10-100mg, further preferably 24-115mg or 12-50mg, further preferably 30-50mg or 15-25mg, most preferably 38mg or 19mg;Alternatively, in some embodiments of the present disclosure, the single-dose pharmaceutical composition of the pharmaceutical composition, particularly the single-dose pharmaceutical composition of the inhalation spray, comprises budesonide in an amount of 3 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 g, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42m g, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59m g, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100 mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170m g, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg or 380 mg, or a range consisting of any of the foregoing values ​​as endpoints or any value therein. ;

[0034] In some embodiments of the present disclosure, a single dose pharmaceutical composition of the pharmaceutical composition, particularly a single dose pharmaceutical composition of the inhalation spray, comprises budesonide in an amount of 3 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 mg, 4.25 mg, 4.5 mg, 4.75 mg, 5 mg, 5.25 mg, 5.5 mg, 5.75 mg, 6 mg, 6.25 mg, 6.5 mg, 6.75 mg, 7 mg, 7.25 mg, 7.5 mg, 7.75 mg, 8 mg, 8.25 mg, 8.5 mg, 8.75 mg, 9 mg, 9.25 mg, 9.5mg, 9.75mg, 10mg, 10.25mg, 10.5mg, 10.75mg, 11mg, 11.25mg, 11.5mg, 11.75mg, 12mg, 12.25mg, 12.5mg, 12.75mg, 13mg, 13.25mg, 13.5mg, 13.75mg, 14mg, 14.25mg, 14.5mg, 14.75mg, 15mg, 15.25mg, 15.5mg, 15.75mg, 16mg, 16.25mg, 16.5mg, 16.75mg, 17mg, 17.25mg, 17.5mg, 17.75mg, 18mg, 18.25mg, 18.5mg, 18.75mg, 19mg, 19.25mg, 19.5mg, 19.75mg, 20mg, 20.25mg, 20.5mg, 20.75mg, 21mg, 21.25mg, 21.5mg, 21.75mg, 22mg, 22.25mg, 22.5mg, 22.75 mg, 23mg, 23.25mg, 23.5mg, 23.75mg, 24mg, 24.25mg, 24.5mg, 24.75mg, 25mg, 25.25mg, 25.5mg, 25.75mg, 26mg, 26.25mg, 26.5mg, 26.75mg, 27mg, 27.25 mg, 27.5mg, 27.75mg, 28mg, 28.25mg, 28.5mg, 28.75mg, 29mg, 29.25mg, 29.5mg, 29.75mg, 30mg, 30.25mg, 30.5mg, 30.75mg, 31mg, 31.25mg, 31.5mg, 31. 75mg, 32mg, 32.25mg, 32.5mg, 32.75mg, 33mg, 33.25mg, 33.5mg, 33.75mg, 34mg, 34.25mg, 34.5mg, 34.75mg, 35mg, 35.25mg, 35.5mg, 35.75mg, 36mg, 36.25 mg, 36.5 mg, 36.75 mg, 37 mg, 37.25 mg, 37.5 mg, 37.75 mg, 38 mg, 38.25 mg, 38.5 mg, 38.75 mg, 39 mg, 39.25 mg, 39.5 mg, 39.75 mg or 40 mg, or a range consisting of any of the foregoing values ​​or any value therein.

[0035] In some other embodiments of the present disclosure, each spray of the pharmaceutical composition, in particular each spray of the inhalation spray, contains budesonide in an amount of 20 to 1000 μg;Preferably 20 to 1000 μg, 25 to 950 μg, 30 to 900 μg, 35 to 850 μg, 40 to 800 μg, 40 to 750 μg, 40 to 700μg, 40~650μg, 40~600μg, 40~550μg, 40~500μg, 40~450μg, 40~400μg, 45~750μg, 45~700μg, 45~650μg, 45~600μg, 45~550μg, 45~500μg, 45~450 μg, 45~400μg, 50~700μg, 50~650μg, 50~600μg, 50~550μg, 50~500μg, 50~4 50μg, 50~400μg, 55~600μg, 55~550μg, 55~500μg, 55~450μg, 60~400μg, 6 0~350μg, 60~300μg, 60~250μg, 60~200μg, 60~150μg, 65~400μg, 65~350μg , 65~300μg, 65~250μg, 65~200μg, 65~150μg, 70~350μg, 70~300μg, 70~25 0μg, 70~200μg, 70~150μg, 75~300μg, 75~250μg, 75~200μg, 75~150μg, 80~ 250μg, 80~200μg, 80~150μg, 85~200μg, 85~150μg, 90~150μg, 90~140μg, 90~130μg, 90~120μg, 90~110μg, 95~150μg, 95~140μg, 95~130μg, 95~120 μg, 95~110μg, 95~115μg, 10~500μg, 10~400μg, 15~350μg, 15~300μg, 15~ 250μg, 20~200μg, 20~150μg, 20~140μg, 20~130μg, 20~120μg, 20~110μg, 2 0-100 μg, 25-100 μg, 25-90 μg, 25-80 μg, 25-70 μg, 30-70 μg, 35-70 μg, 35-65 μg, 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, more preferably 50-500 μg or 25-250 μg, further preferably 60-300 μg or 30-120 μg, further preferably 80-120 μg or 40-60 μg, most preferably 100 μg or 50 μg;Alternatively, in some embodiments of the present disclosure, each spray of the pharmaceutical composition, in particular each spray of the inhalation spray, comprises budesonide in an amount of 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, 38 μg, 39 μg, 40 μg, 41 μg, 42 μg, 43 μg, 44 μg, 45 μg, 46 μg, 47 μg, 48 μg, 49 μg, 50 μg, 51 μg, 52 μg, 53 μg, 54 μg, 55 μg, 56 μg, 57 μg, 58 μg, 59 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, 75 μg, 76 μg, 77 μg, 78 μg, 79 μg, 80 μg, 81 μg, 82 μg, 83 μg, 84 μg 8μg, 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, 87μ g, 88μg, 89μg, 90μg, 91μg, 92μg, 93μg, 94μg, 95μg, 96μg, 97μg, 98μg, 99μg, 100μg, 101μg, 102μg, 103μg, 104μg, 105μg, 106μg, 107μg, 108μg, 109μg, 110μg, 115μg, 120μg, 125μg, 130μg, 135μg, 140μg, 145μg, 150μg, 155μg, 160μg, 165μg, 17 0 μg, 175 μg, 180 μg, 195 μg, 200 μg, 210 μg, 220 μg, 230 μg, 240 μg, 250 μg, 260 μg, 270 μg, 280 μg, 290 μg, 300 μg, 350 μg, 400 μg, 450 μg, 500 μg, 550 μg, 600 μg, 650 μg, 700 μg, 750 μg, 800 μg, 850 μg, 900 μg, 950 μg or 1000 μg, or a range consisting of any of the foregoing values ​​as endpoints or any value therein.

[0036] In some embodiments of the present disclosure, each spray of the pharmaceutical composition, in particular each spray of the inhalation spray, contains budesonide in an amount of 10 to 1000 μg;Preferably 10~950μg, 20~1000μg, 25~950μg, 30~900μg, 35~850μg, 40~800μg, 40~ 750μg, 40~700μg, 40~650μg, 40~600μg, 40~550μg, 40~500μg, 40~450μg, 4 0~400μg, 45~750μg, 45~700μg, 45~650μg, 45~600μg, 45~550μg, 45~500μg , 45~450μg, 45~400μg, 50~700μg, 50~650μg, 50~600μg, 50~550μg, 50~500 μg, 50~450μg, 50~400μg, 55~600μg, 55~550μg, 55~500μg, 55~450μg, 60~4 00μg, 60~350μg, 60~300μg, 60~250μg, 60~200μg, 60~150μg, 65~400μg, 65 ~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, 90~14 0μg, 90~130μg, 90~120μg, 90~110μg, 95~150μg, 95~140μg, 95~130μg, 95~ 120μg, 95~110μg, 95~115μg, 10~500μg, 10~400μg, 15~350μg, 15~300μg, 1 5~250μg, 20~200μg, 20~150μg, 20~140μg, 20~130μg, 20~120μg, 20~110μg , 20-100 μg, 25-100 μg, 25-90 μg, 25-80 μg, 25-70 μg, 30-70 μg, 35-70 μg, 35-65 μg, 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, more preferably 50-500 μg or 25-250 μg, further preferably 60-300 μg or 30-120 μg, still more preferably 80-120 μg or 40-60 μg, most preferably 100 μg or 50 μg;Alternatively, in some embodiments of the present disclosure, each spray of the pharmaceutical composition, in particular each spray of the inhalation spray, comprises budesonide in an amount of 10 μg, 11 μg, 12 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, 38 μg, 39 μg, 40 μg. , 41μg, 42μg, 43μg, 44μg, 45μg, 46μg, 47μg, 48μg, 49μg, 50μg, 51μg, 52μg, 53μg, 54μg, 55μg, 56μg, 57μg, 58μg, 59μg, 60μg, 61μ g, 62μg, 63μg, 64μg, 65μg, 66μg, 67μg, 68μg, 69μg, 70μg, 71μg, 72μg, 73μg, 74μg, 75μg, 76μg, 77μg, 78μg, 79μg, 80μg, 81μg, 82μ g, 83μg, 84μg, 85μg, 86μg, 87μg, 88μg, 89μg, 90μg, 91μg, 92μg, 93μg, 94μg, 95μg, 96μg, 97μg, 98μg, 99μg, 100μg, 101μg, 102μg , 103μg, 104μg, 105μg, 106μg, 107μg, 108μg, 109μg, 110μg, 115μg, 120μg, 125μg, 130μg, 135μg, 140μg, 145μg, 150μg, 155μg, 16 0 μg, 165 μg, 170 μg, 175 μg, 180 μg, 195 μg, 200 μg, 210 μg, 220 μg, 230 μg, 240 μg, 250 μg, 260 μg, 270 μg, 280 μg, 290 μg, 300 μg, 350 μg, 400 μg, 450 μg, 500 μg, 550 μg, 600 μg, 650 μg, 700 μg, 750 μg, 800 μg, 850 μg, 900 μg, 950 μg or 1000 μg, or a range consisting of any of the foregoing values ​​as endpoints or any value therein.

[0037] In some embodiments of the present disclosure, each spray of the pharmaceutical composition, in particular each spray of the inhalation spray, comprises budesonide in an amount of 100 μg, 50 μg, 25 μg or 12.5 μg, or a range consisting of any of the aforementioned values ​​as endpoints or any value therein.

[0038] In some embodiments of the present disclosure, each spray of the pharmaceutical composition, in particular each spray of the inhalation spray, comprises budesonide in an amount of 12.5-25 μg, 12.5-50 μg, 12.5-100 μg, 25-50 μg, 25-100 μg or 50-100 μg.

[0039] In some embodiments of the present disclosure, per puff of the pharmaceutical composition, particularly per puff of the inhalation spray, the single dose pharmaceutical composition of the pharmaceutical composition comprises an amount of budesonide that is 380 times the amount of budesonide contained per puff.

[0040] In some other embodiments of the present disclosure, in the pharmaceutical composition, in particular in the inhalation spray, the amount of ethanol is 30-96 w / w%, preferably 40-96 w / w%, 40-90 w / w%, 40-85 w / w%, 40-80 w / w%, 40-75 w / w%, 40-70 w / w%, 40-65 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 53-5 7w / w%, more preferably 40-70w / w%, further preferably 50-60w / w%, further preferably 53-56w / w%, and most preferably 54-55w / w%; or, in some embodiments of the present disclosure, the amount of ethanol in the pharmaceutical composition, especially the inhalation spray, is 30w / w%, 31w / w%, 32w / w%, 33w / w%, 34w / w%, 35w / w%, 36w / w%, 37w / w%, 38w / w%, 39w / w%, 40w / w%, 41w / w%, 42w / w%, 43 w / w%, 44w / w%, 45w / w%, 46w / w%, 47w / w%, 48w / w%, 49w / w%, 50w / w%, 51w / w%, 22w / 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%, 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 a range consisting of any of the foregoing values ​​as endpoints or any value therein.

[0041] In some embodiments of the present disclosure, in the pharmaceutical composition, in particular the inhalation spray, the amount of ethanol is 20-96 w / w%, preferably 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%, 40-65 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. %, more preferably 40-70w / w%, further preferably 50-60w / w%, further preferably 53-56w / w%, most preferably 54-55w / w%; or, in some embodiments of the present disclosure, the amount of ethanol in the pharmaceutical composition, especially the inhalation spray, is 20w / w%, 21w / w%, 22w / w%, 23w / w%, 24w / w%, 25w / w%, 26w / w%, 27w / w%, 28w / w%, 29w / w%, 30w / w%, 31w / w%, 32w / w%, 33w / w%, 34w / w%, 35w / w%, 36w / w%, 37w / w%, 38w / w%, 39w / w%, 40w / w%, 41w / w%, 42w / w%, 43w / w%, 44w / w%, 45w / w%, 46w / w%, 47w / w%, 48w / w%, 49w / w%, 50w / w%, 51w / w%, 22w / 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 %. The present invention relates to an aqueous solution of at least one embodiment of the present invention, wherein the aqueous solution contains at least one of the following: 1. Amount of the aqueous solution of at least one embodiment of the present invention is preferably: 1. Amount of the aqueous solution of at least one embodiment of the present invention is preferably: 2. Amount of the aqueous solution of at least one embodiment of the present invention is preferably: 3. Amount of the aqueous solution of at least one embodiment of the present invention is preferably: 4. Amount of the aqueous solution of at least one embodiment of the present invention is preferably: 5. Amount of the aqueous solution of at least one embodiment of the present invention is preferably: 6. Amount of the aqueous solution of at least one embodiment of the present invention is preferably: 7. Amount of the aqueous solution of at least one embodiment of the present invention is preferably: 8.

[0042] In some other embodiments of the present disclosure, in the pharmaceutical composition, especially the inhalation spray, the amount of ethanol is 240-900 mg / mL; preferably 240-880 mg / mL, 260-850 mg / mL, 280-830 mg / mL, 300-800 mg / mL, 320-780 mg / mL, 340-750 mg / mL, 240-720 mg / mL, 260-700 mg / mL, 280-680 mg / mL, 300-650 mg / mL, 320-630 mg / mL, 340-630 mg / mL, 360-610 mg / mL, 380-590 mg / mL, 390-580 mg / mL, 400-570 mg / mL, 410-565 mg / mL, 420-560 mg / mL, 430-555 mg / mL , 440~550mg / mL, 450~545mg / mL, 455~540mg / mL, 460~535mg / mL, 465~530mg / mL, 470~525mg / mL, 475~520mg / mL, 480~515mg / mL, 480~510mg / mL, 480~505mg / mL, 480~500mg / mL, 480~495m g / 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, more preferably 320-850 mg / mL, further preferably 390-620 mg / mL, further preferably 450-530 mg / mL, most preferably 485-495 mg / mL;Alternatively, in some embodiments of the present disclosure, the amount of ethanol in the pharmaceutical composition, particularly the inhalation spray, is 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, 400 mg / mL, 405 mg / mL, 410 mg / mL, 415 mg / mL, 420 mg / mL, 425 mg / mL, 430 mg / mL, 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, 484m g / 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, 498 mg / mL, 499mg / mL, 500mg / mL, 505mg / mL, 510mg / mL, 515mg / mL, 520mg / mL, 525mg / mL, 530mg / mL, 535mg / mL, 540mg / mL, 545mg / mL, 550mg / mL, 555mg / mL, 5 60mg / mL, 565mg / mL, 570mg / mL, 575mg / mL, 580mg / mL, 585mg / mL, 590mg / mL, 595mg / mL, 600mg / mL, 610mg / mL, 620mg / mL, 630mg / mL, 640mg / mL, 650mg / mL, 660 mg / mL, 670 mg / mL, 680 mg / mL, 690 mg / mL, 700 mg / mL, 710 mg / mL, 720 mg / mL, 730 mg / mL, 740 mg / mL, 750 mg / mL, 760 mg / mL, 770 mg / mL, 780 mg / mL, 790 mg / mL, 800 mg / mL, 810 mg / mL, 820 mg / mL, 830 mg / mL, 840 mg / mL, 850 mg / mL, 860 mg / mL, 870 mg / mL, 880 mg / mL, 890 mg / mL, or 900 mg / mL, or a range consisting of any of the foregoing values ​​as endpoints or any value therein.

[0043] In some other embodiments of the present disclosure, in the pharmaceutical composition, especially in the inhalation spray, the amount of ethanol is 200-900 mg / mL; preferably 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, 240-7 20mg / mL, 260~700mg / mL, 280~680mg / mL, 300~650mg / mL, 320~630mg / mL, 340~630mg / mL, 360~610mg / m L, 380~590mg / mL, 390~580mg / mL, 400~570mg / mL, 410~565mg / mL, 420~560mg / mL, 430~555mg / mL, 440~ 550mg / mL, 450~545mg / mL, 455~540mg / mL, 460~535mg / mL, 465~530mg / mL, 470~525mg / mL, 475~520mg / mL, 480~515mg / mL, 480~510mg / mL, 480~505mg / mL, 480~500mg / mL, 480~495mg / mL, 480~490mg / mL, 485 ~510mg / mL, 485~510mg / mL, 485~505mg / mL, 485~500mg / mL or 485~495mg / mL, more preferably 320~850mg / mL, further preferably 390~620mg / mL, further preferably 450~530mg / mL, most preferably 485~495mg / mL; or, in some embodiments of the present disclosure, in the pharmaceutical composition, especially in the inhalation spray,The amount of ethanol is 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, 400 mg / mL, 405 mg / mL, 410 mg / mL, 415 mg / mL, 420 mg / mL, 425 mg / mL, 430 mg / mL L, 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, 498m g / mL, 499mg / mL, 500mg / mL, 505mg / mL, 510mg / mL, 515mg / mL, 520mg / mL, 525mg / mL, 530mg / mL, 535mg / mL, 540mg / mL, 545mg / mL, 550mg / mL, 555mg / mL, 56 0mg / mL, 565mg / mL, 570mg / mL, 575mg / mL, 580mg / mL, 585mg / mL, 590mg / mL, 595mg / mL, 600mg / mL, 610mg / mL, 620mg / mL, 630mg / mL, 640mg / mL, 650mg / mL, 660 mg / mL, 670 mg / mL, 680 mg / mL, 690 mg / mL, 700 mg / mL, 710 mg / mL, 720 mg / mL, 730 mg / mL, 740 mg / mL, 750 mg / mL, 760 mg / mL, 770 mg / mL, 780 mg / mL, 790 mg / mL, 800 mg / mL, 810 mg / mL, 820 mg / mL, 830 mg / mL, 840 mg / mL, 850 mg / mL, 860 mg / mL, 870 mg / mL, 880 mg / mL, 890 mg / mL or 900 mg / mL, or a range consisting of any of the foregoing values ​​as endpoints or any value therein.

[0044] In some other embodiments of the present disclosure, the single-dose pharmaceutical composition of the pharmaceutical composition, in particular the single-dose pharmaceutical composition of the inhalation spray, comprises ethanol in an amount of 1000-3700 mg; preferably 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, 2 2000-2400 mg, 2000-2350 mg, 2000-2300 mg, 2000-2250 mg, 2000-2200 mg, 2000-2150 mg, 2000-2100 mg, 2050-2300 mg, 2050-2250 mg, 2050-2200 mg, 2050-2150 mg, 2050-2100 mg, 2050-2090 mg, 2050-2080 mg, 2050-2070 mg or 2050-2060 mg, more preferably 1300-3500 mg, further preferably 1600-2600 mg, still more preferably 1900-2200 mg, and most preferably 2000-2100 mg;Alternatively, in some embodiments of the present disclosure, a single dose of the pharmaceutical composition, particularly a single dose of the inhalation spray, comprises ethanol in an amount of 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, 2050 mg, 2060 mg, 2070 mg, 2080 mg, 2090 mg, 2100 mg, 2110 mg, 2120 mg, 2130 mg, 2140 mg, 2150 mg, 2160 mg, 2170 mg, 2180 mg, 2190 mg, 2200 mg, 2219 80mg, 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 a range consisting of any of the foregoing values ​​as endpoints or any value therein.

[0045] In some other embodiments of the present disclosure, the single-dose pharmaceutical composition of the pharmaceutical composition, especially the single-dose pharmaceutical composition of the inhalation spray, contains 500-3700 mg of ethanol; preferably 550-3600 mg, 600-3600 mg, 650-3600 mg, 700-3600 mg, 750-3600 mg, 800-3600 mg, 850-3600 mg, 90 0~3600mg, 950~3600mg, 1000~3600mg, 1100~3500mg, 1200~3400mg, 1300~3300mg, 1400~320 0mg, 1500~3100mg, 1550~3000mg, 1600~2900mg, 1650~2800mg, 1700~2700mg, 1750~2600mg, 1800~2550mg, 1850~2500mg, 1900~2450mg, 1950~2400mg, 2000~2400mg, 2000~2350mg, 2000 ~2300mg, 2000~2250mg, 2000~2200mg, 2000~2150mg, 2000~2100mg, 2050~2300mg, 2050~225 0 mg, 2050-2200 mg, 2050-2150 mg, 2050-2100 mg, 2050-2090 mg, 2050-2080 mg, 2050-2070 mg or 2050-2060 mg, more preferably 1300-3500 mg, further preferably 1600-2600 mg, further preferably 1900-2200 mg, most preferably 2000-2100 mg;Alternatively, in some embodiments of the present disclosure, a single dose of the pharmaceutical composition, particularly a single dose of the inhalation spray, comprises ethanol in an amount of 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, mg, 750mg, 760mg, 770mg, 780mg, 790mg, 800mg, 810mg, 820mg, 830mg, 840mg, 850mg, 860mg, 870mg, 880mg, 890mg, 900mg, 910mg , 920mg, 930mg, 940mg, 950mg, 960mg, 970mg, 980mg, 990mg, 1000mg, 1050mg, 1100mg, 1150mg, 1200mg, 1250mg, 1300mg, 1350mg , 1400mg, 1450mg, 1500mg, 1550mg, 1600mg, 1650mg, 1700mg, 1750mg, 1800mg, 1850mg, 1900mg, 1950mg, 2000mg, 2010mg, 2010m g, 2020mg, 2030mg, 2040mg, 2050mg, 2060mg, 2070mg, 2080mg, 2090mg, 2100mg, 2150mg, 2200mg, 2250mg, 2300mg, 2350mg, 2400 2400 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg, 3050 mg, 3100 mg, 3150 mg, 3200 mg, 3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg, 3500 mg, 3550 mg, 3600 mg, 3650 mg, 3700 mg, or a range consisting of any of the foregoing values ​​as endpoints or any value therein. ;

[0046] In some embodiments of the present disclosure, each spray of the pharmaceutical composition, in particular each spray of the inhalation spray, comprises 2.7 to 9.8 mg of ethanol; preferably 2.7 to 9.6 mg, 2.8 to 9.4 mg, 2.9 to 9.2 mg, 3.0 to 9.0 mg, 3.1 to 8.8 mg, 3.2 to 8.6 mg, 3.3 to 8.4 mg, 3.4 to 8.2 mg, 3.5 to 8.0 mg, 3.6 to 7.8 mg, 3.7 to 7.6 mg, 3.8 to 7.4 mg, 3.9 to 7.2 mg, 4.0 to 7.0 mg, 4.1 to 6.9 mg, 4.2 to 6.8 mg, 4.3 to 6. .7mg, 4.4-6.6mg, 4.5-6.5mg, 4.6-6.4mg, 4.7-6.3mg, 4.8-6.2mg, 4.9-6.1mg, 5.0-6.0mg, 5.1-5.9mg, 5.2-5.8mg, 5.3-5.7mg, 5.4-5.6mg, more preferably 3.6-9.4mg, further preferably 4.3-6.8mg, further preferably 5.0-5.8mg, most preferably 5.4-5.5mg; or, in some embodiments of the present disclosure, each spray of the pharmaceutical composition, in particular each spray of the inhalation spray, comprises 2. 7mg, 2.8mg, 2.9mg, 3.0mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8mg, 3.9mg, 4.0mg, 4.1mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4 .6mg, 4.7mg, 4.8mg, 4.9mg, 5.0mg, 5.1mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 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 a range consisting of any of the foregoing values ​​as endpoints or any value therein.

[0047] In some embodiments of the present disclosure, the stabilizer is selected from one or more of n-propanol, isopropanol, glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenylethyl alcohol, butanol, butylene glycol, mannitol, polyethylene glycol or ethylene glycol; preferably, the stabilizer is selected from one or more of glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenylethyl alcohol, butanol, butylene glycol, polyethylene glycol or ethylene glycol; more preferably, the stabilizer is selected from one or more of glycerol, propylene glycol, oleic acid, phenylethyl alcohol or butanol; further preferably, the stabilizer is selected from glycerol, propylene glycol or a mixture thereof; even further preferably, the stabilizer is glycerol.

[0048] In some embodiments of the present disclosure, in the pharmaceutical composition, in particular in the inhalation spray, the amount of the stabilizer is 0.01-20 w / w%; preferably 0.01-15 w / w%, 0.01-10 w / w%, 0.01-5 w / w%, 0.05-15 w / w%, 0.05-10 w / w%, 0.05-5 w / w%, 0.1-15 w / w%, 0.1-10 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%, more preferably 0.5-10 w / w%. w%, further preferably 0.5-5w / w%, further preferably 1-5w / w%, further preferably 1-2w / w%, and most preferably 1w / w%; or, in some embodiments of the present disclosure, the amount of the stabilizer in the pharmaceutical composition, especially the inhalation spray, is 0.01w / w%, 0.05w / 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%, / 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%、1.6 w / 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%, 2.3 5w / 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%, 3.2 w / w%, 3.3w / w%, 3.4w / w%, 3.5w / w%, 3.6w / w%, 3.7w / w%, 3.8w / w%, 3.9w / w%, 4 w / 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 a range consisting of any of the foregoing values ​​as endpoints or any value therein.

[0049] In some embodiments of the present disclosure, in the pharmaceutical composition, especially the inhalation spray, the amount of the stabilizer is 0.09-90 mg / mL; preferably 0.09-90 mg / mL, 0.1-85 mg / mL, 0.5-80 mg / mL, 1-75 mg / mL, 1.5-70 mg / mL, 2-65 mg / mL, 2.5-60 mg / mL, 3-55 mg / mL, 3.5-50 mg / mL, 4-45 mg / mL, 4.5-40 mg / mL, 5-35 mg / mL, 5.5-30 mg / mL, 6-25 mg / mL, 6.5-20 mg / mL, 7-18 mg / mL, 7.5-16 mg / mL, 8-14 mg / mL, 8.5-12 mg / mL or 9-10 mg / mL, more preferably 1.8-45 mg / mL, further preferably 4.5-23 mg / mL, further preferably 7.2-18 mg / mL, most preferably 9.048 mg / mL; or, in some embodiments of the present disclosure, the amount of the stabilizer in the pharmaceutical composition, especially the inhalation spray, is 0.09 mg / mL, 0.1 mg / mL, 0.5 mg / mL, 1 mg / mL, 1.5 mg / mL, 2 mg / mL, 2.5 mg / mL, 3 mg / mL, 3.5 mg / mL, 4.0 mg / mL, 4.5 mg / mL, 5.0 mg / mL, 5.1 mg / mL, 5.2mg / mL, 5.3mg / mL, 5.4mg / mL, 5.5mg / mL, 5.6mg / mL, 5.7mg / mL, 5.8mg / mL, 5.9mg / mL, 6.0mg / mL, 6.1mg / mL, 6.2mg / mL, 6.3mg / mL, 6.4mg / mL, 6.5mg / mL, 6.6mg / mL, 6.7mg / mL, 6.8mg / mL, 6.9mg / mL, 7.0mg / mL, 7.1mg / mL, 7.2mg / mL, 7.3mg / mL, 7.4mg / mL, 7.5mg / mL, 7.6mg / mL, 7.7mg / mL, 7.8mg / mL, 7 .9mg / mL, 8.0mg / mL, 8.1mg / mL, 8.2mg / mL, 8.3mg / mL, 8.4mg / mL, 8.5mg / mL, 8.6mg / mL, 8.7mg / mL, 8.8mg / mL, 8.9mg / mL, 9.0mg / mL, 9.1mg / mL, 9.2mg / mL , 9.3mg / mL, 9.4mg / mL, 9.5mg / mL, 9.6mg / mL, 9.7mg / mL, 9.8mg / mL, 9.9mg / mL, 10mg / mL, 10.1mg / mL, 10.2mg / mL, 10.3mg / mL, 10.4mg / mL, 10.5mg / mL, 10.6 mg / mL, 10.7 mg / mL, 10.8 mg / mL, 10.9 mg / mL, 11 mg / mL, 11.1 mg / mL, 11.2 mg / mL, 11.3 mg / mL, 11.4 mg / mL, 11.5 mg / mL, 11.6 mg / mL, 11.7 mg / mL, 11.8 mg / mL, 11.9 mg / mL, 12 mg / mL, 12.1 mg / mL, 12.2 mg / mL, 12.3 mg / mL, 12.4 mg / mL, 12.5 mg / mL, 12.6 mg / mL, 12.7 mg / mL, 12.8 mg / mL, 12.9 mg / mL, 13 mg / mL, 13.1 mg / mL, 13.2 mg / mL, 13.3 mg / mL, 13.4 mg / mL, 13.5 mg / mL, 13.6 mg / mL, 13.7 mg / mL, 13.8 mg / mL, 13.9 mg / mL, 14 mg / mL, 14.1 mg / mL, 14.2 mg / mL, 14.3 mg / mL, 14.4 mg / mL, 14.5 mg / mL, 14.6 mg / mL, 14.7 mg / mL, 14.8 mg / mL, 14.9 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, 18.5 mg / mL, 19 mg / mL, 19.5 mg / mL, 20 mg / mL, 20.5 mg / mL, 21 mg / mL, 22 mg / mL, 23 mg / mL, 24 mg / mL, 25 mg / mL, 26 mg / mL, 27 mg / mL, 28 mg / mL, 29 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, 85 mg / mL or 90 mg / mL, or a range formed by any of the foregoing values as endpoints or any value therein.

[0050] In some embodiments of the present disclosure, the single-dose pharmaceutical composition of the pharmaceutical composition, in particular the single-dose pharmaceutical composition of the inhalation spray, comprises a stabilizer in an amount of 0.38 to 380 mg; preferably 0.38 to 350 mg, 1 to 330 mg, 3.8 to 300 mg, 5 to 280 mg, 8 to 250 mg, 10 to 220 mg, 12 to 200 mg, 15 to 180 mg, 18 to 150 mg, 20 to 1 30mg, 21~120mg, 22~110mg, 23~100mg, 24~90mg, 25~85mg, 26~80mg, 27~75mg, 28~70mg, 29~65m g, 30~60mg, 30.5~59mg, 31~58mg, 31.5~57mg, 32~56mg, 32.5~55mg, 33~54mg, 33.5~53mg, 34~52 mg, 34.5~51mg, 35~50mg, 35.5~49mg, 36~48mg, 36.5~47mg, 37~46mg, 37~45mg, 37~44mg, 37~43 mg, 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, more preferably 7.6~190mg, further preferably 19~90mg, further preferably 30~60mg, most preferably 38mg; or, in some embodiments of the present disclosure, the single-dose pharmaceutical composition of the pharmaceutical composition, especially the single-dose pharmaceutical composition of the inhalation spray, contains the stabilizer in an amount of 0.38mg, 0.5mg, 1mg, 3mg, 3.8mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 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, 3 5mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50m g, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120 mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 18 5 mg, 190 mg, 195 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg or 380 mg, or a range consisting of any of the foregoing values ​​as endpoints or any value therein.

[0051] In some embodiments of the present disclosure, each spray of the pharmaceutical composition, in particular each spray of the inhalation spray, contains a stabilizer in an amount of 1 to 1000 μg; preferably 1 to 950 μg, 5 to 900 μg, 10 to 850 μg, 15 to 800 μg, 20 to 750 μg, 25 to 700 μg, 30 to 650 μg, 35 to 600 μg, 40 to 550 μg, 45 to 500 μg, 50 to 450 μg, 55 to 400 μg, 60 to 350 μg, 65 to 300 μg, 70 to 250 μg, 75-200 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, more preferably 20-500 μg, further preferably 50-250 μg, further preferably 80-150 μg, and most preferably 100 μg;Alternatively, in some embodiments of the present disclosure, each spray of the pharmaceutical composition, in particular each spray of the inhalation spray, comprises the stabilizer in an amount 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, 70μg, 71μg, 72μg, 73μg, 74μg, 75μg, 76μg, 77μg, 78μg, 79μg, 80μg, 81μg, 82μg, 83μg, 84μg, 85 μg, 86μg, 87μg, 88μg, 89μg, 90μg, 91μg, 92μg, 93μg, 94μg, 95μg, 96μg, 97μg, 98μg, 99μg, 100μg, 10 1μg, 102μg, 103μg, 104μg, 105μg, 106μg, 107μg, 108μg, 109μg, 110μg, 115μg, 120μg, 125μg, 130μ g, 135μg, 140μg, 145μg, 150μg, 155μg, 160μg, 165μg, 170μg, 175μg, 180μg, 195μg, 200μg, 210μg, 2 20 μg, 230 μg, 240 μg, 250 μg, 260 μg, 270 μg, 280 μg, 290 μg, 300 μg, 350 μg, 400 μg, 450 μg, 500 μg, 550 μg, 600 μg, 650 μg, 700 μg, 750 μg, 800 μg, 850 μg, 900 μg, 950 μg or 1000 μg, or a range consisting of any of the foregoing values ​​as endpoints or any value therein. ;

[0052] In some embodiments of the present disclosure, 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, 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 or its salts, malic acid or its salts, citric acid or its salts, maleic acid or its salts, or one or more thereof; preferably, the antioxidant The antioxidant is selected from the group consisting 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, sodium thiosulfate), butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, tert-butylhydroquinone, and one or more of tea polyphenols; more preferably, the antioxidant is selected from the group consisting of vitamin C, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, butylated hydroxyanisole, butylated hydroxytoluene, tert-butylhydroquinone, propyl gallate, ascorbyl palmitate, and one or more of tea polyphenols; further preferably, the antioxidant is selected from the group consisting of vitamin C, sodium metabisulfite, sodium bisulfite, and sodium thiosulfate; most preferably, the antioxidant is vitamin C.

[0053] In some embodiments of the present disclosure, the amount of the antioxidant in the pharmaceutical composition, especially the inhalation spray, is 0.0001-5w / w%, preferably 0.0005-5w / w%, 0.001-5w / w%, 0.0011-5w / w%, 0.0012-5w / w%, 0.0013-5w / w%, 0.0014-5w / w%, 0.0015-5w / 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%, 0.00 05~0.2w / w%, 0.0005~0.1w / w%, 0.0005~0.015w / w%, 0.0005~0.01w / w%, 0.0 005~0.005w / w%, 0.001~0.2w / w%, 0.001~0.15w / w%, 0.001~0.1w / w%, 0.001 ~0.05w / w%, 0.001~0.01w / w%, 0.001~0.005w / w%, 0.0011~0.19w / w%, 0.001 1~0.1w / w%, 0.0011~0.05w / w%, 0.0011~0.01w / w%, 0.0011~0.005w / w%, 0.00 12~0.18w / w%, 0.0012~0.1w / w%, 0.0012~0.05w / w%, 0.0012~0.01w / w%, 0.0 012~0.005w / w%, 0.0013~0.17w / w%, 0.0013~0.1w / w%, 0.0013~0.05w / w%, 0 .0013~0.01w / w%, 0.0013~0.005w / w%, 0.0014~0.16w / w%, 0.0014~0.1w / w% ,0.0014~0.05w / w%, 0.0014~0.01w / w%, 0.0014~0.005w / w%, 0.0014~0.003w / w%, 0.0014-0.002w / w%, 0.0015-0.15w / w%, 0.0015-0.14w / w%, 0.0015-0.13w / w%, 0.0015-0.12w / w%, 0.0015-0.11w / w%, 0.0015-0.1w / w%, 0.0015-0.05w / w%, 0.0015-0.01w / w%, 0.0015-0.005w / w%, 0.0015-0.003w / w% or 0.0015-0.002w / w%, more preferably 0.0015-5w / w%, further preferably 0.001-0.2w / w%, further preferably 0.0015-0.11w / w%, most preferably 0.0015w / w%; or, in some embodiments of the present disclosure, the amount of the antioxidant in the pharmaceutical composition, especially the inhalation spray, is 0.0001w / w%, 0.0002w / w%, 0.0003w / w%, 0.0004w / w%, 0.0005w / w%, 0.0006w / w%, 0.0007w / w%, 0.0008w / w%, 0.0009w / w%, 0.001w / w%, 0.0011w / w%, 0.0012w / w%, 0.0013w / w%, 0.0014w / w%, 0.0015w / w%, 0.0016w / w%, 0.0017w / w%、0.0018w / w%、0.0019w / 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%, 0.0035w / w%, 0.004w / w%, 0.0045w / w%, 0.005w / w% , 0.0055w / w%, 0.006w / w%, 0.0065w / w%, 0.007w / w%, 0.0075w / w%, 0.008w / w% , 0.0085w / w%, 0.009w / w%, 0.0095w / 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.% or any value therein, or a range consisting of any of the foregoing values ​​as an endpoint.

[0054] In some embodiments of the present disclosure, in the pharmaceutical composition, particularly in the inhalation spray, the amount of the antioxidant is 0.001-50 mg / mL; preferably 0.001-47 mg / mL, 0.002-45 mg / mL, 0.003-40 mg / mL, 0.004-35 mg / mL, 0.005-30 mg / mL, 0.006-25 mg / mL, 0.007-20 mg / mL, 0.008-18 mg / mL, 0.009-15 mg / mL, 0.01-12 mg / mL, 0.01-10 mg / mL, 0.01-8 mg / mL, 0.01-5 mg / mL, 0.01-4 mg / mL, 0.0 1~3mg / mL, 0.01~2mg / mL, 0.01~1mg / mL, 0.011~5mg / mL, 0.011~4mg / mL, 0.011~3mg / mL, 0.011~2mg / 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, 0.012~0.1mg / mL, 0.013~0.1mg / mL, 0.013~0.09mg / mL, 0.013 ~0.08mg / mL, 0.013~0.07mg / mL, 0.013~0.06mg / mL, 0.013~0.05mg / mL, 0.013~0.04mg / mL, 0.013~0.03mg / mL, 0.013~0.02mg / mL, 0.014~0.06mg / mL, 0. 013~0.05mg / mL, 0.014~0.04mg / mL, 0.014~0.03mg / mL, 0.014~0.02mg / mL, 0.014~0.019mg / mL, 0.014~0.018mg / mL, 0.014~0.017mg / mL, 0.014~0.016m g / mL or 0.014-0.015 mg / mL, more preferably 0.007-12 mg / mL, further preferably 0.007-4.6 mg / mL, even more preferably 0.011-2.3 mg / mL, most preferably 0.014 mg / mL; or, in some embodiments of the present disclosure, in the pharmaceutical composition, especially in the inhalation spray, the amount of the antioxidant is 0.001 mg / mL, 0.002 mg / mL, 0.003 mg / mL, 0.004 mg / mL, 0.005 mg / mL, 0.006 mg / mL, 0.007 mg / mL, 0.008 mg / mL, 0.009 mg / mL, 0.01 mg / mL, 0.0.011 mg / mL, 0.012 mg / mL, 0.013 mg / mL, 0.014 mg / mL, 0.015 mg / mL, 0.016 mg / mL, 0.017 mg / mL, 0.018 mg / mL, 0.019 mg / mL, 0.02 mg / mL, 0.021 mg / mL, 0.022 mg / mL, 0.023 mg / mL, 0.024 mg / mL, 0.025 mg / mL, 0.026 mg / mL, 0.027 mg / mL, 0.028 mg / mL, 0.029 mg / mL, 0.03 mg / mL, 0.031 mg / mL, 0.032 mg / mL, 0.033 mg / mL, 0.034 mg / mL, 0.035 mg / mL, 0.036 mg / mL, 0.037 mg / mL, 0.038 mg / mL, 0.039 mg / mL, 0.04 mg / mL, 0.041 mg / mL, 0.042 mg / mL, 0.043 mg / mL, 0.044 mg / mL, 0.045 mg / mL, 0.046 mg / mL, 0.047 mg / mL, 0.048 mg / mL, 0.049 mg / mL, 0.05 mg / mL, 0.1 mg / mL, 0.5 mg / mL, 1 mg / mL, 1.5 mg / mL, 2 mg / mL, 2.5 mg / mL, 3 mg / mL, 3.5 mg / mL, 4.0 mg / mL, 4.5 mg / mL, 5.0 mg / mL, 6.0 mg / mL, 7.0 mg / mL, 8.0 mg / mL, 9.0 mg / mL, 10.0 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 21 mg / mL, 22 mg / mL, 23 mg / mL, 24 mg / mL, 25 mg / mL, 26 mg / mL, 27 mg / mL, 28 mg / mL, 29 mg / mL, 30 mg / mL, 31 mg / mL, 32 mg / mL, 33 mg / mL, 34 mg / mL, 35 mg / mL, 36 mg / mL, 37 mg / mL, 38 mg / mL, 39 mg / mL, 40 mg / mL, 41 mg / mL, 42 mg / mL, 43 mg / mL, 44 mg / mL, 45 mg / mL, 46 mg / mL, 47 mg / mL, 48 mg / mL, 49 mg / mL, and 50 mg / mL, or a range formed by any of the foregoing values as endpoints or any value therein.

[0055] In some embodiments of the present disclosure, the single-dose pharmaceutical composition of the pharmaceutical composition, in particular the single-dose pharmaceutical composition of the inhalation spray, comprises the antioxidant in an amount of 0.006-190 mg; preferably 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, 0.034-5 mg, 0.036-4 or, in some embodiments of the present disclosure, a single dose of the pharmaceutical composition is preferably 0.02-45 mg, more preferably 0.03-10 mg, even more preferably 0.04-1 mg, and most preferably 0.057 mg; or, in some embodiments of the present disclosure, a single dose of the pharmaceutical composition is preferably 0.051-0.1 mg, 0.052-0.09 mg, 0.053-0.08 mg, 0.054-0.07 mg, 0.055-0.06 mg, 0.056-0.06 mg, or 0.057-0.06 mg, more preferably 0.02-45 mg, further preferably 0.03-10 mg, even more preferably 0.04-1 mg, and most preferably 0.057 mg; or, in some embodiments of the present disclosure, a single dose of the pharmaceutical composition is preferably 0.051-0.1 mg, 0.052-0.09 mg, 0.053-0.08 mg, 0.054-0.07 mg, 0.055-0.06 mg, 0.056-0.06 mg, or 0.057-0.06 mg. The amount of the pharmaceutical composition, in particular the single-dose pharmaceutical composition of the inhalation spray, comprising the antioxidant in an amount 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, 0.027 mg, 0.028 mg, 0.029 mg, 0.03 mg, 0.031 mg, 0.032 mg, 0.033 mg, 0.034 mg g, 0.035mg, 0.036mg, 0.037mg, 0.038mg, 0.039mg, 0.04mg, 0.041mg, 0.042mg, 0.043mg, 0.044mg, 0.045mg, 0.046mg, 0.047mg, 0.048mg, 0.049mg, 0.0 5mg, 0.051mg, 0.052mg, 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, 0.0.066 mg, 0.067 mg, 0.068 mg, 0.069 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg or 190 mg, or a range consisting of any of the foregoing values ​​as endpoints or any value therein.

[0056] In some embodiments of the present disclosure, each spray of the pharmaceutical composition, in particular each spray of the inhalation spray, contains the antioxidant in an amount of 0.015-500 μg; preferably 0.015-450 μg, 0.02-400 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, 0.08-20 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, more preferably 0.05-50 μg, further preferably 0.075-5 μg, and even more preferably 0.1-0.5 μg , most preferably 0.15 μg; or, in some embodiments of the present disclosure, each spray of the pharmaceutical composition, in particular each spray of the inhalation spray, comprises the antioxidant in an amount of 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, 0.095 μg, 0.1 μg, 0.105 μg ,0.11μg, 0.115μg, 0.12μg, 0.125μg, 0.13μg, 0.135μg, 0.14μg, 0.145μg, 0.15μg, 0.155μg, 0.16μg, 0.165μg, 0.17μg, 0.175μ g,0.18μg,0.185μg,0.19μg,0.195μg,0.2μg,0.4μg,0.6μg,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, 8μg, 9μg, 10μg, 15μg, 20μg, 25μg, 30μg, 35μg, 40μg, 45μg, 50μg, 60μg, 70μg, 80μg, 90μg, 100μg, 120μg, 140μg, 160μg, 180μg, 200μg, 220μg, 240μg, 260μg, 280μg, 300μg, 320μg, 340μg, 360μg, 380μg, 400μg, 420μg, 440μg, 460μg, 480μg or 500μg, or a range consisting of any of the foregoing values ​​as endpoints or any value therein.

[0057] In some embodiments of the present disclosure, the pharmaceutical composition, in particular the inhalation spray, further comprises a metal ion chelator, wherein the metal ion chelator is selected from the group consisting of: 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, pyrophosphoric acid or a salt thereof, metaphosphoric acid or a salt thereof, and any combination thereof; preferably, the metal ion chelator is selected from the group consisting of: The chelating agent is selected from one or more of ethylenediaminetetraacetic acid or its salts, ethylene glycol tetraacetic acid or its salts, cyclohexanediaminetetraacetic acid or its salts, hydroxyethylethylenediaminetriacetic 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 hydroxyethylethylenediaminetriacetic acid or its salts; further preferably, the metal ion chelating agent is selected from 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, dicalcium ethylenediaminetetraacetic acid, and sodium calcium ethylenediaminetetraacetic acid; most preferably, the metal ion chelating agent is disodium ethylenediaminetetraacetic acid.

[0058] In some embodiments of the present disclosure, the amount of the metal ion chelating agent contained in the pharmaceutical composition, especially the inhalation spray, is 0.001-1w / w%, preferably 0.001-0.9w / w%, 0.001-0.8w / w%, 0.001-0.7w / w%, 0.001-0.6w / w%, 0.001-0.5w / w%, 0.001-0.4w / 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%, 0.006-0.1w / 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%, 0.005~0.0 2w / 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. 01~0.2w / w%, 0.01~0.1w / w%, 0.01~0.08w / w%, 0.01~0.06w / w%, 0.01~0.05w / w% , 0.01-0.04w / w% or 0.01-0.02w / w%, more preferably 0.001-0.5w / w%, further preferably 0.005-0.1w / w%, further preferably 0.01-0.05w / w%, most preferably 0.01w / w%; or, in some embodiments of the present disclosure, the amount of the metal ion chelator contained in the pharmaceutical composition, especially the inhalation spray, is 0.001w / w%, 0.002w / w%, 0.003w / w%, 0.004w / w%, 0.005w / w%, 0.006w / w%, 0.007w / w%, 0.008w / w%, 0.009w / w%, 0.01w / w%, 0.011w / w%, 0.012w / 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%, 0.021w / 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%, 0.057w / 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%, 1w / w%, or any value in a range consisting of any of the foregoing values ​​as endpoints.

[0059] In some embodiments of the present disclosure, the amount of the metal ion chelator contained in the pharmaceutical composition, especially the inhalation spray, is 0.009-9 mg / mL; preferably 0.009-8.5 mg / mL, 0.01-8 mg / mL, 0.015-7.5 mg / mL, 0.02-7 mg / mL, 0.025-6.5 mg / mL, 0.03-6 mg / mL, 0.035-5.5 mg / mL, 0.04-5 mg / mL, 0.045-4.5 mg / mL, 0.05-4 mg / mL, 0.055-3.5 mg / mL, 0.06-3 mg / mL, 0.065-2.5 mg / mL, 0.07-2 mg / mL. g / mL, 0.075-1.5 mg / mL, 0.08-1 mg / mL, 0.085-0.8 mg / mL, 0.085-0.6 mg / mL, 0.085-0.4 mg / mL, 0.09-0.3 mg / mL, 0.09-0.2 mg / mL or 0.09-0.1 mg / mL, more preferably 0.009-4.5 mg / mL, further preferably 0.045-0.9 mg / mL, further preferably 0.068-0.45 mg / mL, most preferably 0.09 mg / mL; or, in some embodiments of the present disclosure, the amount of the metal ion chelator included in the pharmaceutical composition, especially the inhalation spray, is 0.00 9mg / mL, 0.01mg / mL, 0.015mg / mL, 0.02mg / mL, 0.025mg / mL, 0.03mg / mL, 0.035mg / mL, 0.04mg / mL, 0.045mg / mL, 0.05mg / mL, 0.051mg / mL, 0.052mg / mL, 0 .053mg / mL, 0.054mg / mL, 0.055mg / mL, 0.056mg / mL, 0.057mg / mL, 0.058mg / mL, 0.059mg / mL, 0.06mg / mL, 0.061mg / mL, 0.062mg / mL, 0.063mg / mL, 0.064 mg / mL, 0.065mg / mL, 0.066mg / mL, 0.067mg / mL, 0.068mg / mL, 0.069mg / mL, 0.07mg / mL, 0.071mg / mL, 0.072mg / mL, 0.073mg / mL, 0.074mg / mL, 0.075mg / m L, 0.076mg / mL, 0.077mg / mL, 0.078mg / mL, 0.079mg / mL, 0.08mg / mL, 0.081mg / mL, 0.082mg / mL, 0.083mg / mL, 0.084mg / mL, 0.085mg / mL, 0.086mg / mL, 0.087mg / mL, 0.088mg / mL, 0.089mg / mL, 0.09mg / mL, 0.091mg / mL, 0.092mg / mL, 0.093mg / mL, 0.094mg / mL, 0.095mg / mL, 0.096mg / mL, 0.097mg / mL, 0.098mg / mL, 0.09 9mg / mL, 0.1mg / mL, 0.11mg / mL, 0.12mg / mL, 0.13mg / mL, 0.14mg / mL, 0.15mg / mL, 0.16mg / mL, 0.17mg / mL, 0.18mg / mL, 0.19mg / mL, 0.2mg / mL, 0.3mg / mL, 0.4mg / mL, 0 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, or 9 mg / mL, or a range consisting of any of the foregoing values ​​as endpoints or any value therein.

[0060] In some embodiments of the present disclosure, the single-dose pharmaceutical composition of the pharmaceutical composition, in particular the single-dose pharmaceutical composition of the inhalation spray, comprises the metal ion chelator in an amount of 0.038-38 mg; preferably 0.038-38 mg, 0.05-35 mg, 0.1-30 mg, 0.12-25 mg, 0.14-20 mg, 0.16-15 mg, 0.18-10 mg, 0.2-8 mg, 0.22-6 mg, 0.24-4 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 ~0.6mg, 0.34~0.5mg, 0.35~0.45mg, 0.36~0.4mg, 0.37~0.45mg or 0.38~0.4mg, more preferably 0.038~19mg, further preferably 0.19~3.8mg, even more preferably 0.25~1mg, most preferably 0.38mg; or, in some embodiments of the present disclosure, the single-dose pharmaceutical composition of the pharmaceutical composition, especially the single-dose pharmaceutical composition of the inhalation spray, contains the metal ion chelator in an amount of 0.038mg, 0.04mg, 0.06mg, 0.08mg, 0.1mg, 0.11mg, 0.12mg, 0.13mg, 0.14mg, 0.15mg, 0.16mg, 0.17mg, 0.18mg, 0.19mg, 0.2mg, 0.21mg, 0.22mg, 0.23mg, 0.24mg, 0.25mg, 0.26mg, 0.27mg, 0.2 8mg, 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, 0.7mg, 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, 1.9mg, 2.0mg, 2.5mg, 3.0mg, 3.5mg, 4.0mg, 4.5mg, 5.0mg, 6.0mg, 7.0mg, 8.0mg, 9.0mg, 10.0 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, 35 mg, 36 mg, 37 mg or 38 mg, or a range consisting of any of the foregoing values ​​as endpoints or any value therein.

[0061] In some embodiments of the present disclosure, each spray of the pharmaceutical composition, in particular each spray of the inhalation spray, contains the metal ion chelator in an amount of 0.1 to 100 μg; preferably 0.1 to 90 μg, 0.15 to 80 μg, 0.2 to 70 μg, 0.25 to 60 μg, 0.3 to 50 μg, 0.35 to 40 μg, 0.4 to 30 μg, 0.45 to 25 μg, 0.5 to 20 μg, 0.55 to 15 μg, 0.6 to 10 μg, 0.6 to 9 μg, 0.6 to 8 μg, 0.6 to 7 μg, 0.6 to 8 μg, 0.65 to 6 μg, 0.7 to 10 μg. 7μg, 0.7-6μg, 0.7-5μg, 0.7-4μg, 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, 0.9-1μg, 0.95-2μg, 0.95-1μg, 1-2μg, 1-1.5μg, 1-1.4μg, 1-1.3μg, 1-1.2μg or 1-1.1μg, more preferably 0.1-50μg, further preferably 0.5-10μg, still more preferably 0.75-2μg, most preferably or, in some embodiments of the present disclosure, each spray of the pharmaceutical composition, in particular each spray of the inhalation spray, comprises the metal ion chelator in an amount of 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 .9μg, 2μg, 3μg, 4μg, 5μg, 6μg, 7μg, 8μg, 9μg, 10μg, 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 or 100μg, or a range consisting of any of the foregoing values ​​as endpoints or any value therein.

[0062] In some embodiments of the present disclosure, the pharmaceutical composition, in particular the inhalation spray, optionally further comprises an antibacterial agent, and the antibacterial agent is selected from one or more of benzalkonium chloride, benzalkonium bromide, parahydroxybenzoates (such as methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, etc.), chlorobutanol, phenol, resorcinol, benzyl alcohol, phenylethyl 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, benzyl bromide, benzyl alcohol, phenylethyl 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, benzyl bromide, benzoic acid or its salts, and benzyl alcohol; further preferably, the antibacterial agent is selected from benzalkonium chloride and / or benzalkonium bromide; most preferably, the antibacterial agent is benzalkonium chloride.

[0063] In some embodiments of the present disclosure, the amount of the antibacterial agent in the pharmaceutical composition, especially the inhalation spray, is 0-2w / w%, preferably 0-1.5w / w%, 0-1w / w%, 0-0.5w / w%, 0-0.4w / w%, 0-0.3w / w%, 0-0.2w / w%, 0-0.1w / w%, 0.001-0.1w / w%, 0.002-0.09w / w%, 0.002-0.08w / w%, 0.004-0.07w / w%, 0.005-0.06w / w%, 0.005-0.05w / w%, 0.006-0.05w / w%, 0.006-0.04w / w%, 0.006-0.06 ... 0.03w / w%, 0.007-0.002w / w%, 0.008-0.002w / w% or 0.008-0.01w / w%, more preferably 0-0.5w / w%, further preferably 0.005-0.05w / w%, further preferably 0.005-0.015w / w%; most preferably 0.01w / w%; or, in some embodiments of the present disclosure, the amount of the antibacterial agent contained in the pharmaceutical composition, especially the inhalation spray, is 0.001w / w%, 0.002w / w%, 0.003w / w%, 0.004w / w%, 0.005w / w%, 0.006w / w%, 0.007w / w%, 0.008 w / w%, 0.009w / w%, 0.01w / w%, 0.011w / w%, 0.012w / 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%, 0.0 55w / 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%, 0.2w / 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%, 1.1w / 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 a range consisting of any of the aforementioned values ​​as endpoints or any value therein.

[0064] In some embodiments of the present disclosure, in the pharmaceutical composition, in particular in the inhalation spray, the amount of the antibacterial agent is 0-18 mg / mL; preferably 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, more preferably 0-6 mg / mL, further preferably 0.045-0.45 mg / mL, even more preferably 0.045-0.18 mg / mL, most preferably 0.09 mg / mL; or, in some embodiments of the present disclosure, the drug In the pharmaceutical composition, in particular the inhalation spray, the amount of the antibacterial agent is 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, 0.0 62mg / mL, 0.063mg / mL, 0.064mg / mL, 0.065mg / mL, 0.066mg / mL, 0.067mg / mL, 0.068mg / mL, 0.069mg / mL, 0.07mg / mL, 0.071mg / mL, 0.072mg / mL, 0.073mg / mL, 0.074mg / mL, 0.075mg / mL, 0.076mg / mL, 0.077mg / mL, 0.078mg / mL, 0.079mg / mL, 0.08mg / mL, 0.081mg / mL, 0.082mg / mL, 0.083mg / mL, 0.084mg / mL, 0.085mg / mL, 0.086mg / mL, 0.087mg / mL, 0.088mg / mL, 0.089mg / mL, 0.09mg / mL, 0.091mg / mL, 0.092mg / mL, 0.09 3mg / mL, 0.094mg / mL, 0.095mg / mL, 0.096mg / mL, 0.097mg / mL, 0.098mg / mL, 0.099mg / mL, 0.1mg / mL, 0.11mg / m L, 0.12mg / mL, 0.13mg / mL, 0.14mg / mL, 0.15mg / mL, 0.16mg / mL, 0.17mg / mL, 0.18mg / mL, 0.19mg / mL, 0.2mg / m L, 0.3mg / mL, 0.4mg / mL, 0.5mg / mL, 0.6mg / mL, 0.7mg / mL, 0.8mg / mL, 0.9mg / mL, 1mg / mL, 1.2mg / mL, 1.3mg / mL, 1.4mg / mL, 1.5mg / mL, 1.6mg / mL, 1.7mg / mL, 1.8mg / mL, 1.9mg / mL, 2mg / mL, 2.5mg / mL, 3mg / mL, 3.5mg / mL, 4mg / mL, 4.5mg / mL, 5mg / mL, 5.5mg / mL, 6mg / mL, 6.5mg / mL, 7mg / mL, 7.5mg / mL, 8mg / mL, 8.5mg / mL, 9mg / mL, 9.5mg / 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 or 18 mg / mL, or a range consisting of any of the foregoing values ​​as endpoints or any value therein.

[0065] In some embodiments of the present disclosure, a single-dose pharmaceutical composition of the pharmaceutical composition, in particular a single-dose pharmaceutical composition of the inhalation spray, comprises the antibacterial agent in an amount of 0 to 76 mg; preferably 0.01 to 76 mg, 0.02 to 70 mg, 0.05 to 60 mg, 0.1 to 50 mg, 0.1 to 40 mg, 0.12 to 30 mg, 0.14 to 20 mg, 0.15 to 15 mg, 0.16 to 10 mg, 0.18 to 10 mg, 0.2 to 8 mg, 0.22 to 6 mg, 0.24 to 4 mg, 0.26 to 2 mg, 0.28 to 1 mg, 0.3 to 0.9 mg, 0.31 to 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, more preferably 0-25 mg, further preferably 0.19-1.9 mg, even more preferably 0.19-0.76 mg, most preferably 0.38 mg; or, in some embodiments of the present disclosure, a single-dose pharmaceutical composition of the pharmaceutical composition, in particular a single-dose pharmaceutical composition of the inhalation spray, comprises the antibacterial agent in an amount of 0.01 mg, 0.02 mg, 0.04 mg, 0.06 mg, 0.08 mg, 0. 1mg, 0.11mg, 0.12mg, 0.13mg, 0.14mg, 0.15mg, 0.16mg, 0.17mg, 0.18mg, 0.19mg, 0.2mg, 0.21mg, 0.22mg, 0.23mg, 0.24mg, 0.25mg, 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, 0.39mg, 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, 0.7mg, 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, 1.9mg, 2.0mg, 2.5mg, 3.0mg, 3.5mg, 4.0mg, 4.5mg, 5.0mg, 6.0mg, 7.0mg, 8.0mg, 9.0mg, 10.0 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, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg or 76 mg, or a range consisting of any of the foregoing values ​​as endpoints or any value therein.

[0066] In some embodiments of the present disclosure, each spray of the pharmaceutical composition, in particular each spray of the inhalation spray, contains the antibacterial agent in an amount of 0-200 μg; preferably 0-150 μg, 0.05-120 μg, 0.1-100 μg, 0.1-90 μg, 0.15-80 μg, 0.2-70 μg, 0.25-60 μg, 0.3-50 μg, 0.35-40 μg, 0.4-30 μg, 0.45-25 μg, 0.5-20 μg, 0.55-15 μg, 0.6-10 μg, 0.6-9 μg, 0.6-8 μg, 0.6-7 μg, 0.65-8 μg, 0.65-7 μg. , 0.65~6μg, 0.7~7μg, 0.7~6μg, 0.7~5μg, 0.7~4μg, 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, 0.9~1μg, 0.95~2μg, 0.95~1μg, 1 ~2μg, 1~1.5μg, 1~1.4μg, 1~1.3μg, 1~1.2μg or 1~1.1μg, more preferably 0~60μg, further preferably 0.5~5μg, further preferably 0.75~2μg, most preferably 1μg; or, in some embodiments of the present disclosure, each spray of the pharmaceutical composition, especially each spray of the inhalation spray, contains the antibacterial agent in an amount of 0, 0.05μg, 0.1μg, 0. 15μg, 0.2μg, 0.25μg, 0.3μg, 0.35μg, 0.4μg, 0.45μg, 0.5μg, 0.55μg, 0.6μg, 0.65μg, 0.7μg, 0.75μg g, 0.8μg, 0.85μg, 0.9μg, 0.95μg, 1μg, 1.1μg, 1.2μg, 1.3μg, 1.4μg, 1.5μg, 1.6μg, 1.7μg, 1.8μg, 1.9μg, 2μg, 3μg, 4μg, 5μg, 6μg, 7μg, 8μg, 9μg, 10μg, 11μg, 12μg, 13μg, 14μg, 15μg, 16μg, 17μ g, 18μg, 19μg, 20μg, 21μg, 22μg, 23μg, 24μg, 25μg, 26μg, 27μg, 28μg, 29μg, 30μg, 35μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 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 a range consisting of any of the foregoing values ​​as endpoints or any value therein.

[0067] In some embodiments of the present disclosure, the pharmaceutical composition, in particular the inhalation spray, comprises a pH adjuster, and 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; preferably, 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; more preferably, the pH adjuster is selected from: one or more of hydrochloric acid, phosphoric acid, citric acid, acetic acid, and tartaric acid; further preferably, the pH adjuster is selected from: one or more of hydrochloric acid, phosphoric acid, and citric acid; most preferably, the pH adjuster is hydrochloric acid.

[0068] In some embodiments of the present disclosure, the pharmaceutical composition, particularly the inhalation spray, has a pH value of 2.5 to 4.5, preferably 2.5 to 4.0, 2.5 to 3.5, 2.6 to 3.5, 2.7 to 3.5, 2.8 to 3.5, 2.9 to 3.5, 3.0 to 3.4, 3.0 to 3.3, 3.0 to 3.2, more preferably 2.5 to 3.5, even more preferably 2.8 to 3.2, and even more preferably 2.9 to 3. 1, most preferably 3.0; or, in some embodiments of the present disclosure, the pharmaceutical composition, in particular the inhalation spray, has a pH value of 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 a range consisting of any of the foregoing values ​​as endpoints or any value therein.

[0069] In some embodiments of the present disclosure, the pharmaceutical composition, in particular the inhalation spray, further comprises water, which can be purified water or water for injection, preferably water for injection.

[0070] In some embodiments of the present disclosure, the amount of water in the pharmaceutical composition, especially the inhalation spray, is 4-70w / w%; preferably 4-68w / w%, 10-66w / w%, 15-64w / w%, 20-62w / w%, 22-60w / w%, 24-60w / w%, 26-58w / w%, 28-56w / w%, 30-54w / w%, 32-52w / w%, 34-50w / w%, 36-50w / w%, 36-49w / w%, 38-49w / w%, 40-48w / w %, 41-48w / w%, 42-48w / w%, 42-47w / w%, 43-47w / w%, 44-46w / w%, 45-46w / w%, more preferably 4-60w / w%, further preferably 30-60w / w%, further preferably 40-50w / w%, and most preferably 44-45w / w%; or, in some embodiments of the present disclosure, the amount of water in the pharmaceutical composition, especially the inhalation spray, is 4w / w%, 6w / w%, 8w / w%, 10w / w%, 12w / w%, 14w / w%, %, 16w / w%, 18w / w%, 20w / w%, 21w / w%, 22w / w%, 23w / w%, 24w / w%, 25w / w%, 26w / w%, 27w / w%, 28w / w%, 29w / w%, 30w / w%, 31w / w% , 32w / w%, 33w / w%, 34w / w%, 35w / w%, 36w / w%, 37w / w%, 38w / w%, 39w / w%, 40w / w%, 41w / w%, 42w / w%, 43w / w%, 44w / w%, 45w / w%, % w / 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% or 70w / w%, or a range consisting of any of the foregoing values ​​as endpoints or any value therein.

[0071] In some embodiments of the present disclosure, in the pharmaceutical composition, especially in the inhalation spray, the amount of water is 40-600 mg / mL; preferably 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, 240-460 mg / mL. g / mL, 260-450 mg / mL, 280-440 mg / mL, 300-430 mg / mL, 320-420 mg / mL, 340-410 mg / mL, 360-410 mg / mL, 380-400 mg / mL, 390-400 mg / mL, more preferably 100-480 mg / mL, further preferably 300-450 mg / mL, further preferably 360-430 mg / mL, most preferably 395-405 mg / mL;Alternatively, in some embodiments of the present disclosure, the amount of water in the pharmaceutical composition, particularly the inhalation spray, is 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. / mL, 260mg / mL, 270mg / mL, 280mg / mL, 290mg / mL, 300mg / mL, 305mg / mL, 310mg / mL, 315mg / mL, 320mg / mL, 325mg / mL, 330mg / mL, 335mg / mL, 340 mg / mL, 345mg / mL, 350mg / mL, 355mg / mL, 360mg / mL, 365mg / mL, 370mg / mL, 375mg / mL, 380mg / mL, 381mg / mL, 382mg / mL, 383mg / mL, 384mg / mL, 38 5mg / mL, 386mg / mL, 387mg / mL, 388mg / mL, 389mg / mL, 390mg / mL, 391mg / mL, 392mg / mL, 393mg / mL, 394mg / mL, 395mg / mL, 396mg / mL, 397mg / mL, 398mg / mL, 399mg / mL, 400mg / mL, 401mg / mL, 402mg / mL, 403mg / mL, 404mg / mL, 405mg / mL, 406mg / mL, 407mg / mL, 408mg / mL, 409mg / mL, 410mg / 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 or 600 mg / mL, or a range consisting of any of the foregoing values ​​as endpoints or any value therein. ;

[0072] In some embodiments of the present disclosure, the single-dose pharmaceutical composition of the pharmaceutical composition, in particular the single-dose pharmaceutical composition of the inhalation spray, comprises the water in an amount of 160-2500 mg; preferably 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, 1550-1700 mg, 1600-1690 mg. mg, 1620-1690 mg, 1620-1680 mg, 1640-1680 mg, 1650-1680 mg, 1660-1675 mg or 1670-1675 mg, more preferably 330-2000 mg, further preferably 1250-1900 mg, further preferably 1500-1800 mg, most preferably 1665-1685 mg; or, in some embodiments of the present disclosure, a single-dose pharmaceutical composition of the pharmaceutical composition, in particular a single-dose pharmaceutical composition of the inhalation spray, comprises the water The dosage is 160mg, 200mg, 300mg, 400mg, 500mg, 600mg, 700mg, 800mg, 900mg, 1100mg, 1150mg, 1200mg, 1250mg, 1300mg, 1350mg, 1400mg, 1450mg, 1500mg, 1550mg, 1600mg, 1610mg, 1620mg, 1630mg, 1640mg, 1650mg, 1660mg, 1670mg, 1680mg, 1690mg, 1 1700 mg, 1710 mg, 1720 mg, 1730 mg, 1740 mg, 1750 mg, 1760 mg, 1770 mg, 1780 mg, 1790 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg or 2500 mg, or a range consisting of any of the foregoing values ​​as an endpoint or any value therein.

[0073] In some embodiments of the present disclosure, each spray of the pharmaceutical composition, in particular each spray of the inhalation spray, comprises 0.4 to 6.6 mg of water; preferably 0.4 to 6.5 mg, 0.6 to 6.4 mg, 0.8 to 6.2 mg, 1 to 6 mg, 1.2 to 5.9 mg, 1.4 to 5.8 mg, 1.6 to 5.7 mg, 1.8 to 5.6 mg, 2 to 5.5 mg, 2.2 to 5.4 mg, 2.4 to 5.3 mg, 2.6 to 5.2 mg, 2.8 to 5.1 mg, 3 to 5 mg, 3.2 ~4.9mg, 3.4~4.9mg, 3.6~4.8mg, 3.8~4.8mg, 4~4.7mg, 4.1~4.7mg, 4.2~4.6mg, 4.3~4.6mg or 4.4~4.5mg, more preferably 0.8~5.3mg, further preferably 3~5mg, further preferably 4~4.8mg, most preferably 4.4~4.5mg; or, in some embodiments of the present disclosure, each spray of the pharmaceutical composition, especially each spray of the inhalation spray, comprises the amount of water of 0.4mg, 0 .5mg, 0.6mg, 0.7mg, 0.8mg, 0.9mg, 1mg, 1.1mg, 1.2mg, 1.3mg, 1.4mg, 1.5mg, 1.6mg, 1.7mg, 1.8mg, 1.9mg, 2.0mg, 2.1mg , 2.2mg, 2.3mg, 2.4mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2.9mg, 3.0mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3 .8mg, 3.9mg, 4.0mg, 4.1mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5.0mg, 5.1mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8mg, 5.9mg, 6.0mg, 6.1mg, 6.2mg, 6.3mg, 6.4mg, 6.5mg, 6.6mg, or a range consisting of any of the foregoing values ​​as endpoints or any value therein.

[0074] In some other embodiments of the present disclosure, in the pharmaceutical composition, especially the inhalation spray, the weight ratio of ethanol to water is 2:8-96:4 or 3:7-96:4; preferably 35:65-9:1, 35:65-85:15, 4:6-8:2, 45:55-75:25, 1:1-7:3, 55:45-65:35 or 55:45-6:4, more preferably 4:6-96:4, further The weight ratio of ethanol to water is preferably 4:6 to 7:3, more preferably 1:1 to 6:4, and most preferably 55:45; or, in some embodiments of the present disclosure, in the pharmaceutical composition, especially the inhalation spray, the weight ratio of ethanol to water is 2:8, 3:7, 32:68, 34:66, 36:64, 38:62, 4:6, 41:59, 42:58, 43:57, 44:56, 45:55, 46:54, 47:53、48:52、49:51、1:1、51:49、52:48、53:47、54:46、55:45、56:44、57:43、58:42、59:41、6:4、61:39、62:38、63:37、64:36、65:35、66:34、67:33、68:32、69:31、7:3、71:29、72:28、73:2 :7, 74:26, 75:25, 76:24, 77:23, 78:22, 79:21, 8:2, 81:19, 82:18, 83:17, 84:16, 85:15, 86:14, 87:13, 88:12, 89:11, 9:1, 91:9, 92:8, 93:7, 94:6, 95:5 or 96:4, or a range consisting of any of the foregoing values ​​as endpoints or any value therein.

[0075] In some embodiments of the present disclosure, in the pharmaceutical composition, especially the inhalation spray, the weight ratio of ethanol to water is 1:1 to 96:4; preferably 35:65 to 9:1, 35:65 to 85:15, 4:6 to 8:2, 45:55 to 75:25, 1:1 to 7:3, 55:45 to 65:35 or 55:45 to 6:4, more preferably 4:6 to 96:4, further preferably 4:6 to 7:3, More preferably, the weight ratio of ethanol to water is 1:1 to 6:4, and most preferably 55:45; or, in some embodiments of the present disclosure, the weight ratio of ethanol to water in the pharmaceutical composition, especially the inhalation spray, is 3:7, 32:68, 34:66, 36:64, 38:62, 4:6, 41:59, 42:58, 43:57, 44:56, 45:55, 46:54, 47:53, 48:52, 49: :51, 1:1, 1:2, 1:3, 1:4, 51:49, 52:48, 53:47, 54:46, 55:45, 56:44, 57:43, 58:42, 59:41, 6:4, 61:39, 62:38, 63:37, 64:36, 65:35, 66:34, 67:33, 68:32, 69:31, 7:3, 71:29, 72:28, 73:27 , 74:26, 75:25, 76:24, 77:23, 78:22, 79:21, 8:2, 81:19, 82:18, 83:17, 84:16, 85:15, 86:14, 87:13, 88:12, 89:11, 9:1, 91:9, 92:8, 93:7, 94:6, 95:5 or 96:4, or a range consisting of any of the foregoing values ​​as endpoints or any value therein.

[0076] In some embodiments of the present disclosure, the pharmaceutical composition, in particular the inhalation spray, comprises 0.01-20 w / w% of n-propanol, isopropanol, glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenylethyl alcohol, butanol, butylene glycol, mannitol, polyethylene glycol, ethylene glycol or a mixture thereof; preferably comprises 0.5-10 w / w% of glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenylethyl alcohol, butanol, butylene glycol, polyethylene glycol, ethylene glycol or a mixture thereof; further preferably comprises 0.5-5 w / w% of glycerol, propylene glycol, oleic acid, phenylethyl alcohol, butanol or a mixture thereof; still further preferably comprises 1-5 w / w% of glycerol, propylene glycol or a mixture thereof; more preferably comprises 1-5 w / w%, 1-4 w / w%, 1-3 w / w% or 1-2 w / w% of glycerol; most preferably comprises 1 w / w% of glycerol.

[0077] In some embodiments of the present disclosure, the pharmaceutical composition, particularly the inhalation spray, comprises 0.09-90 mg / mL of n-propanol, isopropanol, glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenylethyl alcohol, butanol, butylene glycol, mannitol, polyethylene glycol, ethylene glycol, or a mixture thereof; preferably comprises 1.8-45 mg / mL of glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenylethyl alcohol, butanol, butylene glycol, polyethylene glycol, ethylene glycol, or a mixture thereof; further preferably comprises 4.5-23 mg / mL of glycerol, propylene glycol, oleic acid, phenylethyl alcohol, butanol, or a mixture thereof; still further preferably comprises 7.2-18 mg / mL of glycerol, propylene glycol, or a mixture thereof; more preferably comprises 7.5-16 mg / mL, 8-14 mg / mL, 8.5-12 mg / mL, or 9-10 mg / mL of glycerol; and most preferably comprises 9.048 mg / mL of glycerol.

[0078] In some embodiments of the present disclosure, a single-dose pharmaceutical composition of the pharmaceutical composition, in particular a single-dose pharmaceutical composition of the inhalation spray, comprises 0.38-380 mg of n-propanol, isopropanol, glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenylethyl alcohol, butanol, butylene glycol, mannitol, polyethylene glycol, ethylene glycol, or a mixture thereof; preferably comprises 7.6-190 mg of glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenylethyl alcohol, butanol, butylene glycol, polyethylene glycol, ethylene glycol, or a mixture thereof; further preferably comprises 19-90 mg of glycerol, propylene glycol, oleic acid, phenylethyl alcohol, butanol, or a mixture thereof; still further preferably comprises 30-60 mg of glycerol, propylene glycol, or a mixture thereof; more preferably comprises 33-50 mg, 35-45 mg, 35-42 mg, 36-41 mg, 37-40 mg or 38-39 mg of glycerol; and most preferably comprises 38 mg of glycerol.

[0079] In some embodiments of the present disclosure, each spray of the pharmaceutical composition, in particular each spray of the inhalation spray, contains 1 to 1000 μg of n-propanol, isopropanol, glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenylethyl alcohol, butanol, butylene glycol, mannitol, polyethylene glycol, ethylene glycol or a mixture thereof; preferably contains 20 to 500 μg of glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenylethyl alcohol, butanol, butylene glycol, polyethylene glycol, ethylene glycol or a mixture thereof. alcohol, ethylene glycol or a mixture thereof; further preferably comprises 50-250 μg of glycerol, propylene glycol, oleic acid, phenylethyl alcohol, butanol or a mixture thereof; still more preferably comprises 80-150 μg of glycerol, propylene glycol or a mixture thereof; more preferably comprises 85-130 μg, 90-120 μg, 95-115 μg, 96-110 μg, 98-105 μg or 99-101 μg of glycerol; most preferably comprises 100 μg of glycerol.

[0080] In some embodiments of the present disclosure, the pharmaceutical composition, in particular the inhalation spray, comprises 0.0001 to 5 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, 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. antioxidants (including but not limited to sodium sulfite, 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 0.0015-5w / 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, ... sulphate), butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, tert-butylhydroquinone, tea polyphenols or a mixture thereof; more preferably comprising 0.001-0.2w / w% of vitamin C, ascorbyl palmitate, sodium sulfite, sodium bisulfite, sodium thiosulfate, butylated hydroxyanisole, butylated hydroxytoluene, tert-butylhydroquinone, propyl gallate, tea polyphenols or a mixture thereof; further preferably comprising 0.0015-0.11w / w% of vitamin C, sodium sulfite, sodium bisulfite, sodium thiosulfate, tert-butylhydroquinone, propyl gallate, tea polyphenols or a mixture thereof ; Further preferably, it contains 0.001-0.2w / w%, 0.0011-0.15w / w%, 0.0012-0.11w / w%, 0.0013-0.05w / w%, 0.0014-0.01w / w%, 0.0015-0.008w / w%, 0.0015-0.005w / w%, 0.0015-0.004w / w%, 0.0015-0.003w / w% or 0.0015-0.002w / w% of vitamin C; most preferably, it contains 0.0015w / w% of vitamin C.

[0081] In some embodiments of the present disclosure, the pharmaceutical composition, in particular the inhalation spray, comprises 0.001 to 50 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, 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 sulfite), The invention also provides a kind of food additives for the production of the present invention, wherein the food additives are selected from the group consisting of 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 or a mixture thereof; preferably comprising 0.007-12 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, gallic acid, butylated hydroxyanisole ... More preferably, the mixture contains 0.007-4.6 mg / mL of vitamin C, ascorbyl palmitate, sodium sulfite, sodium bisulfite, sodium thiosulfate, butylated hydroxyanisole, butylated hydroxytoluene, tert-butylhydroquinone, propyl gallate, tea polyphenols or a mixture thereof; further preferably, the mixture contains 0.011-2.3 mg / mL of vitamin C, sodium sulfite, sodium bisulfite, sodium thiosulfate, tert-butylhydroquinone, propyl gallate, tea polyphenols or a mixture thereof; further preferably, the mixture contains 0.011-2.0 mg / mL, 0.011-1. 8mg / mL, 0.011-1.5mg / mL, 0.011-1mg / mL, 0.012-0.8mg / mL, 0.012-0.06mg / mL, 0.012-0.04mg / mL, 0.012-0.02mg / mL, 0.013-0.019mg / mL, 0.013-0.018mg / mL, 0.013-0.017mg / mL, 0.014-0.016mg / mL or 0.014-0.015mg / mL of vitamin C; most preferably contains 0.014mg / mL of vitamin C.

[0082] In some embodiments of the present disclosure, a single-dose pharmaceutical composition of the pharmaceutical composition, in particular a single-dose pharmaceutical composition of the inhalation spray, comprises 0.006 to 190 mg 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, 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 or its salt, malic acid or its salt, citric acid or its salt, maleic acid or its salt or a mixture thereof; preferably containing 0.02-45 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, metabisulfite), fumaric acid or its salt, malic acid or its salt, citric acid or its salt, maleic acid or its salt or a mixture thereof; preferably containing 0.02-45 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, metabisulfite More preferably, the mixture contains 0.03-10 mg of vitamin C, ascorbyl palmitate, sodium sulfite, sodium bisulfite, sodium thiosulfate, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, tert-butylhydroquinone, tea polyphenols or a mixture thereof; more preferably, the mixture contains 0.04-1 mg of vitamin C, sodium sulfite, sodium bisulfite, sodium thiosulfate, tert-butylhydroquinone, Propyl gallate, tea polyphenols or a mixture thereof; further preferably comprising 0.042-1 mg, 0.044-0.8 mg, 0.046-0.6 mg, 0.048-0.4 mg, 0.05-0.2 mg, 0.051-0.1 mg, 0.052-0.09 mg, 0.053-0.08 mg, 0.054-0.07 mg, 0.055-0.06 mg, 0.056-0.06 mg or 0.057-0.06 mg of vitamin C; most preferably comprising 0.057 mg of vitamin C.

[0083] In some embodiments of the present disclosure, each spray of the pharmaceutical composition, in particular each spray of the inhalation spray, comprises 0.015 to 500 μg 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, 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 or its salt, malic acid or its salt, citric acid or its salt, maleic acid or its salt or a mixture thereof; preferably containing 0.05-50 μg of ascorbic acid antioxidants (including but not limited to vitamin C, isoascorbic acid, sodium ascorbate, potassium ascorbate, ascorbyl palmitate), sulfite Salt 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 a mixture thereof; more preferably comprising 0.075-5 μg of vitamin C, ascorbyl palmitate, sodium sulfite, sodium metabisulfite, sodium thiosulfate, butylated hydroxyanisole, butylated hydroxytoluene, tert-butylhydroquinone, propyl gallate, tea polyphenols or a mixture thereof; further preferably The invention claims a novel invention which comprises 0.1-0.5 μg of vitamin C, sodium sulfite, sodium bisulfite, sodium thiosulfate, tert-butylhydroquinone, propyl gallate, tea polyphenols or a mixture thereof; further preferably comprises 0.02-0.5 μg, 0.05-0.5 μg, 0.1-0.4 μg, 0.11-0.3 μg, 0.12-0.3 μg, 0.13-0.3 μg, 0.14-0.2 μg or 0.14-0.18 μg of vitamin C; most preferably comprises 0.15 μg of vitamin C.

[0084] In some embodiments of the present disclosure, the pharmaceutical composition, in particular the inhalation spray, comprises 0.001 to 1 w / w% of ethylenediaminetetraacetic acid (EDTA) or its salt, ethylene glycol tetraacetic acid (EGTA) or its salt, cyclohexanediaminetetraacetic acid (CDTA) or its salt, hydroxyethylethylenediaminetriacetic acid (HEDTA) or its salt, diethylenetriaminepentaacetic acid (DTPA) or its salt, dimercaptopropanesulfonic acid (DMPS) or its salt, dimercaptosuccinic acid (DMSA) or its salt, aminotrimethylenephosphonic acid (ArPA) or its salt, citric acid or its salt, acetic acid or its salt, phosphoric acid or its salt, pyrophosphate or its salt, metaphosphate or its salt, or a mixture thereof; preferably comprises 0.001 to 0.5 w / w% of ethylenediaminetetraacetic acid or its salt, ethylene glycol tetraacetic acid or its salt, cyclohexanediaminetetraacetic acid or its salt, hydroxyethylethylenediaminetriacetic acid (HEDTA) or its salt, diethylenetriaminepentaacetic acid (DTPA) or its salt, dimercaptopropanesulfonic acid (DMPS) or its salt, dimercaptosuccinic acid (DMSA) or its salt, aminotrimethylenephosphonic acid (ArPA) or its salt, citric acid or its salt, acetic acid or its salt, phosphoric acid or its salt, pyrophosphate or its salt, metaphosphate or its salt, or a mixture thereof; Diaminetriacetic acid or its salt, diethylenetriaminepentaacetic acid or its salt, or a mixture thereof; more preferably comprising 0.005-0.1w / w% of ethylenediaminetetraacetic acid or its salt, hydroxyethylethylenediaminetriacetic acid or its salt, or a mixture thereof; further preferably comprising 0.01-0.05w / w% of ethylenediaminetetraacetic acid (EDTA) or its salt, including but not limited to ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetate, dipotassium ethylenediaminetetraacetate, trisodium ethylenediaminetetraacetate, tripotassium ethylenediaminetetraacetate, calcium disodium ethylenediaminetetraacetate, dicalcium ethylenediaminetetraacetate and sodium calcium ethylenediaminetetraacetate, or a mixture thereof; further preferably comprising 0.001-0.5w / w%, 0.005-0.1w / w%, or 0.01-0.05w / w% of disodium ethylenediaminetetraacetate; most preferably comprising 0.01w / w% of disodium ethylenediaminetetraacetate.

[0085] In some embodiments of the present disclosure, the pharmaceutical composition, in particular the inhalation spray, comprises 0.009-9 mg / mL of ethylenediaminetetraacetic acid (EDTA) or its salt, ethylene glycol tetraacetic acid (EGTA) or its salt, cyclohexanediaminetetraacetic acid (CDTA) or its salt, hydroxyethylethylenediaminetriacetic acid (HEDTA) or its salt, diethylenetriaminepentaacetic acid (DTPA) or its salt, dimercaptopropanesulfonic acid (DMPS) or its salt, dimercaptosuccinic acid (DMSA) or its salt, aminotrimethylenephosphonic acid (ArPA) or its salt, citric acid or its salt, acetic acid or its salt, phosphoric acid or its salt, pyrophosphate or its salt, metaphosphate or its salt, or a mixture thereof; preferably comprises 0.009-4.5 mg / mL of ethylenediaminetetraacetic acid or its salt, ethylene glycol tetraacetic acid or its salt, cyclohexanediaminetetraacetic acid or its salt, hydroxyethylethylenediaminetriacetic acid or its salt, diethylenetriaminepentaacetic acid (DTPA) or its salt, dimercaptopropanesulfonic acid (DMPS) or its salt, dimercaptosuccinic acid (DMSA) or its salt, aminotrimethylenephosphonic acid (ArPA) or its salt, citric acid or its salt, acetic acid or its salt, phosphoric acid or its salt, pyrophosphate or its salt, metaphosphate or its salt, or a mixture thereof; Acid or its salt, or a mixture thereof; more preferably comprising 0.045-0.9 mg / mL of ethylenediaminetetraacetic acid or its salt, hydroxyethylethylenediaminetriacetic acid or its salt, or a mixture thereof; further preferably comprising 0.068-0.45 mg / mL of ethylenediaminetetraacetic acid (EDTA) or its salt, including but not limited to ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetate, dipotassium ethylenediaminetetraacetate, trisodium ethylenediaminetetraacetate, tripotassium ethylenediaminetetraacetate, calcium disodium ethylenediaminetetraacetate, dicalcium ethylenediaminetetraacetate and sodium calcium ethylenediaminetetraacetate, or a mixture thereof; further preferably comprising 0.07-0.4 mg / mL, 0.075-0.35 mg / mL, 0.08-0.2 mg / mL, 0.085-0.25 mg / mL or 0.09-0.1 mg / mL of disodium ethylenediaminetetraacetate; most preferably comprising 0.09 mg / mL of disodium ethylenediaminetetraacetate.

[0086] In some embodiments of the present disclosure, a single-dose pharmaceutical composition of the pharmaceutical composition, in particular a single-dose pharmaceutical composition of the inhalation spray, comprises 0.038 to 38 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, 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, or a mixture thereof; preferably comprises 0.038 to 19 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; more preferably comprising 0.19 to 3.8 mg of ethylenediaminetetraacetic acid or a salt thereof, hydroxyethylethylenediaminetriacetic acid or a salt thereof, or a mixture thereof; further preferably comprising 0.25 to 1 mg of ethylenediaminetetraacetic acid (EDTA) or a salt thereof, including but not limited to ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetate, dipotassium ethylenediaminetetraacetate, trisodium ethylenediaminetetraacetate, tripotassium ethylenediaminetetraacetate, calcium disodium ethylenediaminetetraacetate, dicalcium ethylenediaminetetraacetate and ethylenediaminetetraacetate. calcium sodium edetate, or a mixture thereof; further preferably comprising 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 of disodium edetate; most preferably comprising 0.38 mg of disodium edetate.

[0087] In some embodiments of the present disclosure, each spray of the pharmaceutical composition, in particular each spray of the inhalation spray, contains 0.1 to 100 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, 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, or a mixture thereof; preferably contains 0.1 to 50 μg of ethylenediaminetetraacetic acid or a salt thereof, ethylene glycol tetraacetic acid 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, or a mixture thereof; Diaminetetraacetic acid or its salt, hydroxyethylethylenediaminetriacetic acid or its salt, diethylenetriaminepentaacetic acid or its salt, or a mixture thereof; more preferably, it contains 0.5-10 μg of ethylenediaminetetraacetic acid or its salt, hydroxyethylethylenediaminetriacetic acid or its salt, or a mixture thereof; further preferably, it contains 0.75-2 μg of ethylenediaminetetraacetic acid (EDTA) or its salt, 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 and sodium calcium ethylenediaminetetraacetic acid, or a mixture thereof; further preferably, it contains 0.8-2 μg, 0.9-1.5 μg, 1-1.2 μg or 1-1.1 μg of disodium ethylenediaminetetraacetic acid; most preferably, it contains 1 μg of disodium ethylenediaminetetraacetic acid.

[0088] In some embodiments of the present disclosure, the pharmaceutical composition, in particular the inhalation spray, comprises 0-2 w / w% of benzalkonium chloride, benzalkonium bromide, parahydroxybenzoates (including but not limited to methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate), chlorobutanol, phenol, resorcinol, benzyl alcohol, phenylethyl alcohol, benzoic acid or its salt, sodium propionate, sorbic acid or its salt or a mixture thereof; preferably comprises 0-0.5 w / w% of benzalkonium chloride, benzyl alcohol, phenylethyl alcohol, benzoic acid or its salt, sodium propionate, sorbic acid or its salt ; More preferably, it comprises 0.005-0.05w / w% of benzalkonium chloride, benzalkonium bromide, benzoic acid or its salt, benzyl alcohol or a mixture thereof; Further preferably, it comprises 0.005-0.015w / w% of benzalkonium chloride, benzalkonium bromide or a mixture thereof; Still further preferably, it comprises 0.005-0.014w / w%, 0.006-0.013w / w%, 0.007-0.012w / w%, 0.008-0.011w / w% or 0.009-0.011w / w% of benzalkonium chloride; Most preferably, it comprises 0.01w / w% of benzalkonium chloride.

[0089] In some embodiments of the present disclosure, the pharmaceutical composition, in particular the inhalation spray, comprises 0-18 mg / mL of benzalkonium chloride, benzalkonium bromide, parahydroxybenzoates (including but not limited to methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate), chlorobutanol, phenol, resorcinol, benzyl alcohol, phenylethyl alcohol, benzoic acid or its salt, sodium propionate, sorbic acid or its salt or a mixture thereof; preferably comprises 0-6 mg / mL of benzalkonium chloride, benzyl bromide, benzyl alcohol, phenylethyl alcohol, benzoic acid or its salt, Sodium propionate, sorbic acid or its salt; more preferably comprising 0.045-0.45 mg / mL benzalkonium chloride, benzalkonium bromide, benzoic acid or its salt, benzyl alcohol or a mixture thereof; further preferably comprising 0.045-0.18 mg / mL benzalkonium chloride, benzalkonium bromide or a mixture thereof; further preferably comprising 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 benzalkonium chloride; most preferably comprising 0.09 mg / mL benzalkonium chloride.

[0090] In some embodiments of the present disclosure, a single-dose pharmaceutical composition of the pharmaceutical composition, in particular a single-dose pharmaceutical composition of the inhalation spray, comprises 0 to 76 mg of benzalkonium chloride, benzalkonium bromide, parahydroxybenzoates (including but not limited to methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate), chlorobutanol, phenol, resorcinol, benzyl alcohol, phenylethyl alcohol, benzoic acid or its salt, sodium propionate, sorbic acid or its salt or a mixture thereof; preferably comprises 0 to 25 mg of benzalkonium chloride, benzyl bromide, benzyl alcohol, phenylethyl alcohol, benzoic acid or its salt, sodium propionate, sorbic acid or its salt or a mixture thereof. Methanol, phenylethanol, benzoic acid or its salt, sodium propionate, sorbic acid or its salt; more preferably comprising 0.19-1.9 mg of benzalkonium chloride, benzalkonium bromide, benzoic acid or its salt, benzyl alcohol or a mixture thereof; further preferably comprising 0.19-0.76 mg of benzalkonium chloride, benzalkonium bromide or a mixture thereof; further preferably comprising 0.2-0.70 mg, 0.25-0.60 mg, 0.25-0.55 mg, 0.3-0.5 mg or 0.35-0.4 mg of benzalkonium chloride; most preferably comprising 0.38 mg of benzalkonium chloride.

[0091] In some embodiments of the present disclosure, each spray of the pharmaceutical composition, in particular each spray of the inhalation spray, contains 0 to 200 μg of benzalkonium chloride, benzalkonium bromide, parahydroxybenzoates (including but not limited to methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate), chlorobutanol, phenol, resorcinol, benzyl alcohol, phenylethyl alcohol, benzoic acid or its salt, sodium propionate, sorbic acid or its salt or a mixture thereof; preferably contains 0 to 60 μg of benzalkonium chloride, benzyl bromide, parahydroxybenzoate (including but not limited to methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate), chlorobutanol, phenol, resorcinol, benzyl alcohol, phenylethyl alcohol, benzoic acid or its salt, sodium propionate, sorbic acid or its salt or a mixture thereof; The present invention relates to a pharmaceutical composition comprising at least one of: a pharmaceutical composition comprising at least one of benzalkonium chloride, benzalkonium bromide, benzyl alcohol, phenylethyl alcohol, benzoic acid or its salts, sodium propionate, sorbic acid or its salts; more preferably comprising 0.5-5 μg of benzalkonium chloride, benzyl bromide, benzoic acid or its salts, benzyl alcohol or a mixture thereof; further preferably comprising 0.75-2 μg of benzalkonium chloride, benzyl bromide or a mixture thereof; further preferably comprising 0.75-1.8 μg, 0.8-1.5 μg or 0.9-1.1 μg of benzalkonium chloride; and most preferably comprising 1 μg of benzalkonium chloride.

[0092] A0) In some embodiments of the present disclosure, the pharmaceutical composition of the present disclosure, in particular the inhalation spray, comprises:

[0093] 0.1-10w / w% budesonide;

[0094] 20-96 w / w% ethanol; and

[0095] 0.01-20 w / w% n-propanol, isopropanol, glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenylethyl alcohol, butanol, butylene glycol, mannitol, polyethylene glycol, ethylene glycol or a mixture thereof; and

[0096] Optionally comprising 0.0001-5 w / w% butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate (PG), tertiary butylhydroquinone (TBHQ), ascorbic acid antioxidants (including but not limited to vitamin C, erythorbic acid, sodium ascorbate, potassium ascorbate, ascorbyl palmitate), tocopherol antioxidants (including but not limited to vitamin E, α-tocopherol, mixed concentrated tocopherols, tocopheryl 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;

[0097] 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, 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, or a mixture thereof;

[0098] Optionally comprising 0-2 w / w% benzalkonium chloride, benzalkonium bromide, parahydroxybenzoates (including but not limited to methylparahydroxybenzoate, ethylparahydroxybenzoate, propylparahydroxybenzoate, butylparahydroxybenzoate), chlorobutanol, phenol, resorcinol, benzyl alcohol, phenylethyl alcohol, benzoic acid or its salts, sodium propionate, sorbic acid or its salts, or a mixture thereof;

[0099] optionally comprising 4 to 70 w / w % water;

[0100] 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 a mixture thereof is included as a pH adjuster to adjust the pH value of the inhalation spray to 2.5 to 4.5.

[0101] A1) In some embodiments of the present disclosure, the pharmaceutical composition of the present disclosure, in particular the inhalation spray, comprises:

[0102] 0.1-10w / w% budesonide;

[0103] 30-96 w / w% ethanol; and

[0104] 0.01-20 w / w% n-propanol, isopropanol, glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenylethyl alcohol, butanol, butylene glycol, mannitol, polyethylene glycol, ethylene glycol or a mixture thereof; and

[0105] Optionally comprising 0.0001-5 w / w% butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate (PG), tertiary butylhydroquinone (TBHQ), ascorbic acid antioxidants (including but not limited to vitamin C, erythorbic acid, sodium ascorbate, potassium ascorbate, ascorbyl palmitate), tocopherol antioxidants (including but not limited to vitamin E, α-tocopherol, mixed concentrated tocopherols, tocopheryl 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;

[0106] 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, 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, or a mixture thereof;

[0107] Optionally comprising 0-2 w / w% benzalkonium chloride, benzalkonium bromide, parahydroxybenzoates (including but not limited to methylparahydroxybenzoate, ethylparahydroxybenzoate, propylparahydroxybenzoate, butylparahydroxybenzoate), chlorobutanol, phenol, resorcinol, benzyl alcohol, phenylethyl alcohol, benzoic acid or its salts, sodium propionate, sorbic acid or its salts, or a mixture thereof;

[0108] optionally comprising 4 to 70 w / w % water;

[0109] 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 a mixture thereof is included as a pH adjuster to adjust the pH value of the inhalation spray to 2.5 to 4.5.

[0110] A2) In some embodiments of the present disclosure, the pharmaceutical composition of the present disclosure, in particular the inhalation spray, comprises:

[0111] 0.25-5w / w% or 0.125-2.5w / w% budesonide;

[0112] 40-96 w / w% ethanol;

[0113] 0.5-10 w / w% glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenylethyl alcohol, butanol, butylene glycol, polyethylene glycol, ethylene glycol or a mixture thereof; and

[0114] 0.0015-5 w / w% ascorbic acid antioxidants (including but not limited to vitamin C, erythorbic 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; and

[0115] Optionally containing 0.001 to 0.5 w / w% of ethylenediaminetetraacetic acid or its salt, ethylene glycol tetraacetic acid or its salt, cyclohexanediaminetetraacetic acid or its salt, hydroxyethylethylenediaminetriacetic acid or its salt, diethylenetriaminepentaacetic acid or its salt, or a mixture thereof;

[0116] Optionally comprising 0-0.5 w / w% benzalkonium chloride, benzalkonium bromide, benzyl alcohol, phenylethyl alcohol, benzoic acid or its salt, sodium propionate, sorbic acid or its salt;

[0117] optionally comprising 4 to 60 w / w % water;

[0118] Optionally, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, tartaric acid, succinic acid, fumaric acid or a mixture thereof is included as a pH adjuster to adjust the pH value of the inhalation spray to 2.5 to 4.0.

[0119] A3) In some embodiments of the present disclosure, the pharmaceutical composition of the present disclosure, in particular the inhalation spray, comprises:

[0120] 0.25-3w / w% or 0.125-1.5w / w% budesonide;

[0121] 40-70 w / w% ethanol;

[0122] 0.5-5w / w% glycerol, propylene glycol, oleic acid, phenylethyl alcohol, butanol or a mixture thereof;

[0123] 0.001-0.2w / w% vitamin C, ascorbyl palmitate, sodium sulfite, sodium bisulfite, sodium thiosulfate, butylated hydroxyanisole, butylated hydroxytoluene, tert-butylhydroquinone, propyl gallate, tea polyphenols or a mixture thereof;

[0124] 30-60 w / w% water; and

[0125] hydrochloric acid, phosphoric acid, citric acid, acetic acid, tartaric acid or a mixture thereof as a pH adjuster to adjust the pH value of the inhalation spray to 2.5 to 3.5; and

[0126] Optionally comprising 0.005-0.1 w / w% of ethylenediaminetetraacetic acid or a salt thereof, hydroxyethylethylenediaminetriacetic acid or a salt thereof, or a mixture thereof;

[0127] Optionally, 0.005-0.05 w / w% of benzalkonium chloride, benzalkonium bromide, benzoic acid or its salt, benzyl alcohol or a mixture thereof is contained.

[0128] A4) In some embodiments of the present disclosure, the pharmaceutical composition of the present disclosure, in particular the inhalation spray, comprises:

[0129] 0.5-1.5w / w% or 0.25-0.75w / w% budesonide;

[0130] 50-60w / w% ethanol;

[0131] 1-5w / w% glycerol, propylene glycol or a mixture thereof;

[0132] 0.0015-0.11w / w% vitamin C, sodium sulfite, sodium bisulfite, sodium thiosulfate, tert-butylhydroquinone, propyl gallate, tea polyphenols or a mixture thereof;

[0133] 0.01-0.05 w / w% of EDTA or its salts, including but not limited to EDTA, disodium EDTA, dipotassium EDTA, trisodium EDTA, tripotassium EDTA, calcium disodium EDTA, dicalcium EDTA and sodium calcium EDTA, or mixtures thereof;

[0134] 40-50 w / w% water; and

[0135] hydrochloric acid, phosphoric acid, citric acid or a mixture thereof as a pH adjuster to adjust the pH of the inhalation spray to 2.8 to 3.2; and

[0136] Optionally, 0.005-0.015 w / w% of benzalkonium chloride, benzalkonium bromide or a mixture thereof is contained.

[0137] A5) In some embodiments of the present disclosure, the pharmaceutical composition of the present disclosure, in particular the inhalation spray, comprises:

[0138] 1w / w% budesonide;

[0139] 54w / w% ethanol;

[0140] 1w / w% glycerol;

[0141] 0.0015w / w% Vitamin C;

[0142] 0.01w / w% disodium edetate;

[0143] 0.01w / w% benzalkonium chloride;

[0144] 44 w / w% water; and

[0145] Hydrochloric acid was used as a pH adjuster to adjust the pH of the inhalation spray to 3.0.

[0146] A6) In some embodiments of the present disclosure, the pharmaceutical composition of the present disclosure, in particular the inhalation spray, comprises:

[0147] 0.5w / w% budesonide;

[0148] 54.27w / w% ethanol;

[0149] 1w / w% glycerol;

[0150] 0.0015w / w% Vitamin C;

[0151] 0.01w / w% disodium edetate;

[0152] 0.01w / w% benzalkonium chloride;

[0153] 44.23 w / w % water; and

[0154] Hydrochloric acid was used as a pH adjuster to adjust the pH of the inhalation spray to 3.0.

[0155] A7) In some embodiments of the present disclosure, the pharmaceutical composition of the present disclosure, in particular the inhalation spray, comprises:

[0156] 0.25w / w% budesonide;

[0157] 54.41w / w% ethanol;

[0158] 1w / w% glycerol;

[0159] 0.0015w / w% Vitamin C;

[0160] 0.01w / w% disodium edetate;

[0161] 0.01w / w% benzalkonium chloride;

[0162] 44.34 w / w % water; and

[0163] Hydrochloric acid was used as a pH adjuster to adjust the pH of the inhalation spray to 3.0.

[0164] A8) In some embodiments of the present disclosure, the pharmaceutical composition of the present disclosure, in particular the inhalation spray, comprises:

[0165] 0.125w / w% budesonide;

[0166] 54.48w / w% ethanol;

[0167] 1w / w% glycerol;

[0168] 0.0015w / w% Vitamin C;

[0169] 0.01w / w% disodium edetate;

[0170] 0.01w / w% benzalkonium chloride;

[0171] 44.40 w / w % water; and

[0172] Hydrochloric acid was used as a pH adjuster to adjust the pH of the inhalation spray to 3.0.

[0173] B0) In some embodiments of the present disclosure, the pharmaceutical composition of the present disclosure, in particular the inhalation spray, comprises:

[0174] 0.1-90 mg / mL budesonide;

[0175] 200-900 mg / mL ethanol; and

[0176] 0.09-90 mg / mL n-propanol, isopropanol, glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenylethyl alcohol, butanol, butylene glycol, mannitol, polyethylene glycol, ethylene glycol, or mixtures thereof; and

[0177] Optionally comprising 0.001-50 mg / mL butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate (PG), tertiary butylhydroquinone (TBHQ), ascorbic acid antioxidants (including but not limited to vitamin C, erythorbic acid, sodium ascorbate, potassium ascorbate, ascorbyl palmitate), tocopherol antioxidants (including but not limited to vitamin E, α-tocopherol, mixed concentrated tocopherols, tocopheryl 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;

[0178] Optionally comprising 0.009-9 mg / mL 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, or a mixture thereof;

[0179] Optionally comprising 0-18 mg / mL benzalkonium chloride, benzalkonium bromide, parabens (including but not limited to methyl paraben, ethyl paraben, propyl paraben, butyl paraben), chlorobutanol, phenol, resorcinol, benzyl alcohol, phenylethyl alcohol, benzoic acid or its salt, sodium propionate, sorbic acid or its salt, or a mixture thereof;

[0180] Optionally comprising 40-600 mg / mL water;

[0181] 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 a mixture thereof is included as a pH adjuster to adjust the pH value of the inhalation spray to 2.5 to 4.5.

[0182] B1) In some embodiments of the present disclosure, the pharmaceutical composition of the present disclosure, in particular the inhalation spray, comprises:

[0183] 2-90 mg / mL budesonide;

[0184] 240-900 mg / mL ethanol; and

[0185] 0.09-90 mg / mL n-propanol, isopropanol, glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenylethyl alcohol, butanol, butylene glycol, mannitol, polyethylene glycol, ethylene glycol, or mixtures thereof; and

[0186] Optionally comprising 0.001-50 mg / mL butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate (PG), tertiary butylhydroquinone (TBHQ), ascorbic acid antioxidants (including but not limited to vitamin C, erythorbic acid, sodium ascorbate, potassium ascorbate, ascorbyl palmitate), tocopherol antioxidants (including but not limited to vitamin E, α-tocopherol, mixed concentrated tocopherols, tocopheryl 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;

[0187] Optionally comprising 0.009-9 mg / mL 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, or a mixture thereof;

[0188] Optionally comprising 0-18 mg / mL benzalkonium chloride, benzalkonium bromide, parabens (including but not limited to methyl paraben, ethyl paraben, propyl paraben, butyl paraben), chlorobutanol, phenol, resorcinol, benzyl alcohol, phenylethyl alcohol, benzoic acid or its salt, sodium propionate, sorbic acid or its salt, or a mixture thereof;

[0189] Optionally comprising 40-600 mg / mL water;

[0190] 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 a mixture thereof is contained as a pH adjuster for adjusting the pH value of the inhalation spray to 2.5 to 4.5.

[0191] B2) In some embodiments of the present disclosure, the pharmaceutical composition of the present disclosure, in particular the inhalation spray, comprises:

[0192] 4.5–45 mg / mL or 2–20 mg / mL budesonide;

[0193] 320-850 mg / mL ethanol;

[0194] 1.8-45 mg / mL glycerin, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenylethyl alcohol, butanol, butylene glycol, polyethylene glycol, ethylene glycol, or mixtures thereof; and

[0195] 0.007-12 mg / mL of ascorbic acid antioxidants (including but not limited to vitamin C, erythorbic 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; and

[0196] Optionally comprising 0.009 to 4.5 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;

[0197] Optionally comprising 0-6 mg / mL benzalkonium chloride, benzalkonium bromide, benzyl alcohol, phenylethyl alcohol, benzoic acid or its salt, sodium propionate, sorbic acid or its salt;

[0198] Optionally comprising 100-480 mg / mL water;

[0199] Optionally, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, tartaric acid, succinic acid, fumaric acid or a mixture thereof is contained as a pH adjuster for adjusting the pH value of the inhalation spray to 2.5 to 4.0.

[0200] B3) In some embodiments of the present disclosure, the pharmaceutical composition of the present disclosure, in particular the inhalation spray, comprises:

[0201] 5.6–27 mg / mL or 2.5–15 mg / mL budesonide;

[0202] 390-620 mg / mL ethanol;

[0203] 4.5-23 mg / mL glycerol, propylene glycol, oleic acid, phenylethyl alcohol, butanol, or a mixture thereof;

[0204] 0.007-4.6 mg / mL vitamin C, ascorbyl palmitate, sodium sulfite, sodium bisulfite, sodium thiosulfate, butylated hydroxyanisole, butylated hydroxytoluene, tert-butylhydroquinone, propyl gallate, tea polyphenols or a mixture thereof;

[0205] 300-450 mg / mL water; and

[0206] hydrochloric acid, phosphoric acid, citric acid, acetic acid, tartaric acid or a mixture thereof as a pH adjuster to adjust the pH value of the inhalation spray to 2.5 to 3.5; and

[0207] Optionally comprising 0.045 to 0.9 mg / mL of ethylenediaminetetraacetic acid or a salt thereof, hydroxyethylethylenediaminetriacetic acid or a salt thereof, or a mixture thereof;

[0208] Optionally, it contains 0.045-0.45 mg / mL of benzalkonium chloride, benzalkonium bromide, benzoic acid or its salt, benzyl alcohol or a mixture thereof.

[0209] B4) In some embodiments of the present disclosure, the pharmaceutical composition of the present disclosure, in particular the inhalation spray, comprises:

[0210] 8.0-14 mg / mL or 4-7 mg / mL budesonide;

[0211] 450-530 mg / mL ethanol;

[0212] 7.2-18 mg / mL glycerol, propylene glycol, or a mixture thereof;

[0213] 0.011-2.3 mg / mL vitamin C, sodium sulfite, sodium bisulfite, sodium thiosulfate, tert-butylhydroquinone, propyl gallate, tea polyphenols or a mixture thereof;

[0214] 0.068-0.45 mg / mL EDTA or its salts, including but not limited to EDTA, disodium EDTA, dipotassium EDTA, trisodium EDTA, tripotassium EDTA, calcium disodium EDTA, dicalcium EDTA, and sodium calcium EDTA, or mixtures thereof;

[0215] 360-430 mg / mL water; and

[0216] hydrochloric acid, phosphoric acid, citric acid or a mixture thereof as a pH adjuster to adjust the pH of the inhalation spray to 2.8 to 3.2; and

[0217] Optionally comprises 0.045-0.18 mg / mL benzalkonium chloride, benzalkonium bromide or a mixture thereof.

[0218] B5) In some embodiments of the present disclosure, the pharmaceutical composition of the present disclosure, in particular the inhalation spray, comprises:

[0219] 9.048 mg / mL or 4.524 mg / mL budesonide;

[0220] 485-495 mg / mL ethanol;

[0221] 9.048 mg / mL glycerol;

[0222] 0.014 mg / mL vitamin C;

[0223] 0.09 mg / mL EDTA disodium;

[0224] 0.09 mg / mL benzalkonium chloride;

[0225] 395-405 mg / mL water; and

[0226] Hydrochloric acid was used as a pH adjuster to adjust the pH of the inhalation spray to 3.0.

[0227] B6) In some embodiments of the present disclosure, the pharmaceutical composition of the present disclosure, in particular the inhalation spray, comprises:

[0228] 9.048 mg / mL budesonide;

[0229] 488.57 mg / mL ethanol;

[0230] 9.048 mg / mL glycerol;

[0231] 0.014 mg / mL vitamin C;

[0232] 0.09 mg / mL EDTA disodium;

[0233] 0.09 mg / mL benzalkonium chloride;

[0234] 398.095 mg / mL water; and

[0235] Hydrochloric acid was used as a pH adjuster to adjust the pH of the inhalation spray to 3.0.

[0236] B7) In some embodiments of the present disclosure, the pharmaceutical composition of the present disclosure, in particular the inhalation spray, comprises:

[0237] 9.091 mg / mL budesonide;

[0238] 490.91 mg / mL ethanol;

[0239] 9.091 mg / mL glycerol;

[0240] 0.014 mg / mL vitamin C;

[0241] 0.09 mg / mL EDTA disodium;

[0242] 0.09 mg / mL benzalkonium chloride;

[0243] 400.00 mg / mL water; and

[0244] Hydrochloric acid was used as a pH adjuster to adjust the pH of the inhalation spray to 3.0.

[0245] B8) In some embodiments of the present disclosure, the pharmaceutical composition of the present disclosure, in particular the inhalation spray, comprises:

[0246] 2.262 mg / mL budesonide;

[0247] 492.28 mg / mL ethanol;

[0248] 9.048 mg / mL glycerol;

[0249] 0.014 mg / mL vitamin C;

[0250] 0.09 mg / mL EDTA disodium;

[0251] 0.09 mg / mL benzalkonium chloride;

[0252] 401.17 mg / mL water; and

[0253] Hydrochloric acid was used as a pH adjuster to adjust the pH of the inhalation spray to 3.0.

[0254] B9) In some embodiments of the present disclosure, the pharmaceutical composition of the present disclosure, in particular the inhalation spray, comprises:

[0255] 1.131 mg / mL budesonide;

[0256] 492.91 mg / mL ethanol;

[0257] 9.048 mg / mL glycerol;

[0258] 0.014 mg / mL vitamin C;

[0259] 0.09 mg / mL EDTA disodium;

[0260] 0.09 mg / mL benzalkonium chloride;

[0261] 401.71 mg / mL water; and

[0262] Hydrochloric acid was used as a pH adjuster to adjust the pH of the inhalation spray to 3.0.

[0263] C1) In some embodiments of the present disclosure, the single-dose pharmaceutical composition of the pharmaceutical composition of the present disclosure, in particular the single-dose pharmaceutical composition of the inhalation spray, comprises:

[0264] 3–380 mg budesonide

[0265] 1000-3700 mg ethanol; and

[0266] 0.38-380 mg n-propanol, isopropanol, glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenylethyl alcohol, butanol, butylene glycol, mannitol, polyethylene glycol, ethylene glycol, or mixtures thereof; and

[0267] Optionally comprising 0.006-190 mg of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate (PG), tertiary butylhydroquinone (TBHQ), ascorbic acid antioxidants (including but not limited to vitamin C, erythorbic acid, sodium ascorbate, potassium ascorbate, ascorbyl palmitate), tocopherol antioxidants (including but not limited to vitamin E, α-tocopherol, mixed concentrated tocopherols, tocopheryl 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;

[0268] optionally comprising 0.038-38 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, 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, or a mixture thereof;

[0269] Optionally comprising 0-76 mg benzalkonium chloride, benzalkonium bromide, parabens (including but not limited to methyl paraben, ethyl paraben, propyl paraben, butyl paraben), chlorobutanol, phenol, resorcinol, benzyl alcohol, phenylethyl alcohol, benzoic acid or its salt, sodium propionate, sorbic acid or its salt, or a mixture thereof;

[0270] Optionally comprising 160-2500 mg of water;

[0271] 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 a mixture thereof is included as a pH adjuster to adjust the pH value of the inhalation spray to 2.5 to 4.5.

[0272] C2) In some embodiments of the present disclosure, the single-dose pharmaceutical composition of the pharmaceutical composition of the present disclosure, in particular the single-dose pharmaceutical composition of the inhalation spray, comprises:

[0273] 19–190 mg or 10–100 mg budesonide;

[0274] 1300-3500 mg ethanol;

[0275] 7.6-190 mg glycerin, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenylethyl alcohol, butyl alcohol, butylene glycol, polyethylene glycol, ethylene glycol, or mixtures thereof; and

[0276] 0.02-45 mg of ascorbic acid antioxidants (including but not limited to vitamin C, erythorbic 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; and

[0277] Optionally containing 0.038-19 mg of ethylenediaminetetraacetic acid or its salt, ethylene glycol tetraacetic acid or its salt, cyclohexanediaminetetraacetic acid or its salt, hydroxyethylethylenediaminetriacetic acid or its salt, diethylenetriaminepentaacetic acid or its salt, or a mixture thereof;

[0278] Optionally comprising 0-25 mg of benzalkonium chloride, benzalkonium bromide, benzyl alcohol, phenylethyl alcohol, benzoic acid or its salt, sodium propionate, sorbic acid or its salt;

[0279] Optionally comprising 330-2000 mg of water;

[0280] Optionally, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, tartaric acid, succinic acid, fumaric acid or a mixture thereof is included as a pH adjuster to adjust the pH value of the inhalation spray to 2.5 to 4.0.

[0281] C3) In some embodiments of the present disclosure, the single-dose pharmaceutical composition of the pharmaceutical composition of the present disclosure, in particular the single-dose pharmaceutical composition of the inhalation spray, comprises:

[0282] 24–115 mg or 12–50 mg budesonide;

[0283] 1600-2600 mg ethanol;

[0284] 19-90 mg glycerol, propylene glycol, oleic acid, phenylethyl alcohol, butanol or their mixtures;

[0285] 0.03-10mg vitamin C, ascorbyl palmitate, sodium sulfite, sodium bisulfite, sodium thiosulfate, butylated hydroxyanisole, butylated hydroxytoluene, tert-butylhydroquinone, propyl gallate, tea polyphenols or a mixture thereof;

[0286] 1250-1900 mg water; and

[0287] hydrochloric acid, phosphoric acid, citric acid, acetic acid, tartaric acid or a mixture thereof as a pH adjuster to adjust the pH value of the inhalation spray to 2.5 to 3.5; and

[0288] Optionally comprising 0.19 to 3.8 mg of ethylenediaminetetraacetic acid or a salt thereof, hydroxyethylethylenediaminetriacetic acid or a salt thereof, or a mixture thereof;

[0289] Optionally contains 0.19 to 1.9 mg of benzalkonium chloride, benzalkonium bromide, benzoic acid or its salt, benzyl alcohol or a mixture thereof.

[0290] C4) In some embodiments of the present disclosure, the single-dose pharmaceutical composition of the pharmaceutical composition of the present disclosure, in particular the single-dose pharmaceutical composition of the inhalation spray, comprises:

[0291] 30-50 mg or 15-25 mg budesonide;

[0292] 1900-2200 mg ethanol;

[0293] 30-60 mg glycerin, propylene glycol or their mixture;

[0294] 0.04-1mg vitamin C, sodium sulfite, sodium bisulfite, sodium thiosulfate, tert-butylhydroquinone, propyl gallate, tea polyphenols or their mixtures;

[0295] 0.25-1 mg EDTA or its salts, including but not limited to EDTA, disodium EDTA, dipotassium EDTA, trisodium EDTA, tripotassium EDTA, calcium disodium EDTA, dicalcium EDTA, and sodium calcium EDTA, or mixtures thereof;

[0296] 1500-1800 mg water; and

[0297] hydrochloric acid, phosphoric acid, citric acid or a mixture thereof as a pH adjuster to adjust the pH of the inhalation spray to 2.8 to 3.2; and

[0298] Optionally contains 0.19 to 0.76 mg of benzalkonium chloride, benzalkonium bromide or a mixture thereof.

[0299] C5) In some embodiments of the present disclosure, the single-dose pharmaceutical composition of the pharmaceutical composition of the present disclosure, in particular the single-dose pharmaceutical composition of the inhalation spray, comprises:

[0300] 38mg or 19mg budesonide;

[0301] 2000-2100 mg ethanol;

[0302] 38mg glycerol;

[0303] 0.057mg vitamin C;

[0304] 0.38mg disodium edetate;

[0305] 0.38mg benzalkonium chloride;

[0306] 1665-1685 mg water; and

[0307] Hydrochloric acid was used as a pH adjuster to adjust the pH of the inhalation spray to 3.0.

[0308] C6) In some embodiments of the present disclosure, the single-dose pharmaceutical composition of the pharmaceutical composition of the present disclosure, in particular the single-dose pharmaceutical composition of the inhalation spray, comprises:

[0309] 38mg budesonide;

[0310] 2052mg ethanol;

[0311] 38mg glycerol;

[0312] 0.057mg vitamin C;

[0313] 0.38mg disodium edetate;

[0314] 0.38mg benzalkonium chloride;

[0315] 1672mg water; and

[0316] Hydrochloric acid was used as a pH adjuster to adjust the pH of the inhalation spray to 3.0.

[0317] D0) In some embodiments of the present disclosure, each spray of the pharmaceutical composition of the present disclosure, in particular each spray of the inhalation spray, comprises:

[0318] 10-1000 μg budesonide;

[0319] 2.7-9.8 mg ethanol; and

[0320] 1-1000 μg n-propanol, isopropanol, glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenylethyl alcohol, butanol, butylene glycol, mannitol, polyethylene glycol, ethylene glycol, or a mixture thereof; and

[0321] Optionally comprising 0.015-500 μg of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate (PG), tertiary butylhydroquinone (TBHQ), ascorbic acid antioxidants (including but not limited to vitamin C, erythorbic acid, sodium ascorbate, potassium ascorbate, ascorbyl palmitate), tocopherol antioxidants (including but not limited to vitamin E, α-tocopherol, mixed concentrated tocopherols, tocopheryl 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;

[0322] optionally comprising 0.1 to 100 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, 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, or a mixture thereof;

[0323] Optionally comprising 0-200 μg of benzalkonium chloride, benzalkonium bromide, parahydroxybenzoates (including but not limited to methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate), chlorobutanol, phenol, resorcinol, benzyl alcohol, phenylethyl alcohol, benzoic acid or its salts, sodium propionate, sorbic acid or its salts, or a mixture thereof;

[0324] Optionally containing 0.4-6.6 mg of water;

[0325] 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 a mixture thereof is included as a pH adjuster to adjust the pH value of the inhalation spray to 2.5 to 4.5.

[0326] D1) In some embodiments of the present disclosure, each spray of the pharmaceutical composition of the present disclosure, in particular each spray of the inhalation spray, comprises:

[0327] 20-1000 μg budesonide;

[0328] 2.7-9.8 mg ethanol; and

[0329] 1-1000 μg n-propanol, isopropanol, glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenylethyl alcohol, butanol, butylene glycol, mannitol, polyethylene glycol, ethylene glycol, or a mixture thereof; and

[0330] Optionally comprising 0.015-500 μg of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate (PG), tertiary butylhydroquinone (TBHQ), ascorbic acid antioxidants (including but not limited to vitamin C, erythorbic acid, sodium ascorbate, potassium ascorbate, ascorbyl palmitate), tocopherol antioxidants (including but not limited to vitamin E, α-tocopherol, mixed concentrated tocopherols, tocopheryl 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;

[0331] optionally comprising 0.1 to 100 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, 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, or a mixture thereof;

[0332] Optionally comprising 0-200 μg of benzalkonium chloride, benzalkonium bromide, parahydroxybenzoates (including but not limited to methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate), chlorobutanol, phenol, resorcinol, benzyl alcohol, phenylethyl alcohol, benzoic acid or its salts, sodium propionate, sorbic acid or its salts, or a mixture thereof;

[0333] Optionally containing 0.4-6.6 mg of water;

[0334] 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 a mixture thereof is included as a pH adjuster to adjust the pH value of the inhalation spray to 2.5 to 4.5.

[0335] D2) In some embodiments of the present disclosure, each spray of the pharmaceutical composition of the present disclosure, in particular each spray of the inhalation spray, comprises:

[0336] 50-500 μg or 25-250 μg budesonide;

[0337] 3.6-9.4 mg ethanol;

[0338] 20-500 μg glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenylethyl alcohol, butanol, butylene glycol, polyethylene glycol, ethylene glycol, or a mixture thereof; and

[0339] 0.05-50 μg of ascorbic acid antioxidants (including but not limited to vitamin C, erythorbic 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; and

[0340] Optionally comprising 0.1 to 50 μg of ethylenediaminetetraacetic acid or its salt, ethylene glycol tetraacetic acid or its salt, cyclohexanediaminetetraacetic acid or its salt, hydroxyethylethylenediaminetriacetic acid or its salt, diethylenetriaminepentaacetic acid or its salt, or a mixture thereof;

[0341] Optionally comprising 0-60 μg of benzalkonium chloride, benzalkonium bromide, benzyl alcohol, phenylethyl alcohol, benzoic acid or its salt, sodium propionate, sorbic acid or its salt;

[0342] Optionally containing 0.8-5.3 mg of water;

[0343] Optionally, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, tartaric acid, succinic acid, fumaric acid or a mixture thereof is included as a pH adjuster to adjust the pH value of the inhalation spray to 2.5 to 4.0.

[0344] D3) In some embodiments of the present disclosure, each spray of the pharmaceutical composition of the present disclosure, in particular each spray of the inhalation spray, comprises:

[0345] 60-300 μg or 30-120 μg budesonide;

[0346] 4.3-6.8 mg ethanol;

[0347] 50-250 μg glycerol, propylene glycol, oleic acid, phenylethyl alcohol, butanol or their mixtures;

[0348] 0.075-5 μg vitamin C, ascorbyl palmitate, sodium sulfite, sodium bisulfite, sodium thiosulfate, butylated hydroxyanisole, butylated hydroxytoluene, tert-butylhydroquinone, propyl gallate, tea polyphenols or a mixture thereof;

[0349] 3–5 mg of water; and

[0350] hydrochloric acid, phosphoric acid, citric acid, acetic acid, tartaric acid or a mixture thereof as a pH adjuster to adjust the pH value of the inhalation spray to 2.5 to 3.5; and

[0351] Optionally comprising 0.5-10 μg of ethylenediaminetetraacetic acid or a salt thereof, hydroxyethylethylenediaminetriacetic acid or a salt thereof, or a mixture thereof;

[0352] Optionally, 0.5 to 5 μg of benzalkonium chloride, benzalkonium bromide, benzoic acid or its salt, benzyl alcohol or a mixture thereof is contained.

[0353] D4) In some embodiments of the present disclosure, each spray of the pharmaceutical composition of the present disclosure, in particular each spray of the inhalation spray, comprises:

[0354] 80-120 μg or 40-60 μg budesonide;

[0355] 5.0-5.8 mg ethanol;

[0356] 80-150 μg glycerol, propylene glycol or their mixtures;

[0357] 0.1-0.5 μg vitamin C, sodium sulfite, sodium bisulfite, sodium thiosulfate, tert-butylhydroquinone, propyl gallate, tea polyphenols or a mixture thereof;

[0358] 0.75-2 μg EDTA or its salts, including but not limited to EDTA, disodium EDTA, dipotassium EDTA, trisodium EDTA, tripotassium EDTA, calcium disodium EDTA, dicalcium EDTA, and sodium calcium EDTA, or mixtures thereof;

[0359] 4–4.8 mg of water; and

[0360] hydrochloric acid, phosphoric acid, citric acid or a mixture thereof as a pH adjuster to adjust the pH of the inhalation spray to 2.8 to 3.2; and

[0361] Optionally, 0.75 to 2 μg of benzalkonium chloride, benzalkonium bromide or a mixture thereof is included.

[0362] D5) In some embodiments of the present disclosure, each spray of the pharmaceutical composition of the present disclosure, in particular each spray of the inhalation spray, comprises:

[0363] 100 μg budesonide;

[0364] 5.4 mg ethanol;

[0365] 100 μg glycerol;

[0366] 0.15 μg vitamin C;

[0367] 1 μg EDTA disodium;

[0368] 1 μg benzalkonium chloride;

[0369] 4.4mg water; and

[0370] Hydrochloric acid was used as a pH adjuster to adjust the pH of the inhalation spray to 3.0.

[0371] D6) In some embodiments of the present disclosure, each spray of the pharmaceutical composition of the present disclosure, in particular each spray of the inhalation spray, comprises:

[0372] 50 μg budesonide;

[0373] 5.427 mg ethanol;

[0374] 100 μg glycerol;

[0375] 0.15 μg vitamin C;

[0376] 1 μg EDTA disodium;

[0377] 1 μg benzalkonium chloride;

[0378] 4.423 mg water; and

[0379] Hydrochloric acid was used as a pH adjuster to adjust the pH of the inhalation spray to 3.0.

[0380] D7) In some embodiments of the present disclosure, each spray of the pharmaceutical composition of the present disclosure, in particular each spray of the inhalation spray, comprises:

[0381] 25 μg budesonide;

[0382] 5.427 mg ethanol;

[0383] 100 μg glycerol;

[0384] 0.15 μg vitamin C;

[0385] 1 μg EDTA disodium;

[0386] 1 μg benzalkonium chloride;

[0387] 4.423 mg water; and

[0388] Hydrochloric acid was used as a pH adjuster to adjust the pH of the inhalation spray to 3.0.

[0389] D7) In some embodiments of the present disclosure, each spray of the pharmaceutical composition of the present disclosure, in particular each spray of the inhalation spray, comprises:

[0390] 12.5 μg budesonide;

[0391] 5.427 mg ethanol;

[0392] 100 μg glycerol;

[0393] 0.15 μg vitamin C;

[0394] 1 μg EDTA disodium;

[0395] 1 μg benzalkonium chloride;

[0396] 4.423 mg water; and

[0397] Hydrochloric acid was used as a pH adjuster to adjust the pH of the inhalation spray to 3.0.

[0398] The inhalation spray of the present disclosure is adapted for use with a spray device. In some embodiments of the present disclosure, the spray device is a handheld inhalation device, such as a soft mist inhalation device (SMI), including but not limited to Respimat inhaler, RESPIMAT re-usable inhaler, or publication numbers CN110582316A, CN113038982A, CN115484999A, CN111195382A, CN216025661U, CN216025662U, CN215515024U, CN109745603A, CN108057151A, CN110882453A, CN21883331 8U, CN115068754A, WO2023169196A1, WO2023138422A1, CN116036423A, CN216603701U, CN116829218A, CN110769882A, CN110022921A, CN112423895A, CN112533656A, etc.

[0399] In some embodiments of the present disclosure, the pharmaceutical composition, in particular the inhalation spray, has a lung deposition rate of fine particles formed after atomization by a spray device that is 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%, further preferably, greater than 60%; still further preferably, greater than 70%; and even further preferably, greater than 75%.

[0400] In some embodiments of the present disclosure, the pharmaceutical composition, in particular the inhalation spray, has a mass median aerodynamic diameter (MMAD) of fine particles formed after atomization by a spray device of 1.5 to 5 μm; preferably 1.6 to 4.8 μm, 1.8 to 4.5 μm, 2.0 to 4.4 μm, 2.2 to 4.3 μm, 2.4 to 4.2 μm, 2.6 to 4.1 μm, 2.8 to 4.0 μm, 2.9 to 4.0 μm, 3.0 to 5 μm, 3.0 to 4.5 μm, 3.0 to 4.0 μm, 3.0 to 3.8 μm, 3.0 to 3.6 μm, 3.0 to 3.4 μm or 3.0 to 3.3 μm; further preferably 2.0 to 4.0 μm, and even more preferably 2.5 to 3.5 μm; or, In some embodiments of the present disclosure, the MMAD is 1.5 μm, 1.6 μm, 1.7 μm, 1.8 μm, 1.9 μm, 2.0 μm, 2.1 μm, 2.2 μm, 2.3 μm, 2.4 μm, 2.5 μm, 2.6 μm, 2.7 μm, 2.8 μm, 2.9 μm, 3.0 μm, 3.1 μm, 3.2 μm, 3.3 μm, 3.4 μm, 3.5 μm, 3.6 μm, 3.7 μm, 3.8 μm, 3.9 μm, 4.0 μm, 4.1 μm, 4.2 μm, 4.3 μm, 4.4 μm, 4.5 μm, 4.6 μm, 4.7 μm, 4.8 μm, 4.9 μm or 5.0 μm, or a range consisting of any of the foregoing values ​​as endpoints or any value therein.

[0401] In some embodiments of the present disclosure, the pharmaceutical composition, especially the inhalation spray, has a spray ellipticity of 1 to 2 after being atomized by a spray device; 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, 1 to 1.1; more preferably 1 to 1.5; even more preferably 1 to 1.3; and most preferably 1 to 1.2.

[0402] In some embodiments of the present disclosure, the pharmaceutical composition, particularly the inhalation spray, contains compound L (e.g., when stored at 40±2°C for 0 days, 10 days, or 30 days), and the content of compound L (e.g., as determined by HPLC) 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%. The structure of compound L is shown below:

[0403] In some embodiments of the present disclosure, the pharmaceutical composition, in particular the inhalation spray, contains the compound L (for example, when placed at 40±2°C for 0 days, 10 days or 30 days), wherein the mass ratio of the 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%.

[0404] In some embodiments of the present disclosure, the pharmaceutical composition, in particular the inhalation spray, contains the compound L (for example, when placed at 40±2°C for 0 days, 10 days or 30 days), wherein the content of the compound L does not exceed 1% of the labeled amount of budesonide, or does not exceed 0.1%, or does not exceed 0.05%, or does not exceed 0.03%, or does not exceed 0.02%, or does not exceed 0.01%.

[0405] In some embodiments of the present disclosure, the pharmaceutical composition, particularly the inhalation spray, contains Compound D (e.g., when stored at 40±2°C for 0 days, 10 days, or 30 days), and the content of Compound D (e.g., as determined by HPLC) 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%. The structure of Compound D is shown below:

[0406] In some embodiments of the present disclosure, the pharmaceutical composition, in particular the inhalation spray, contains the compound D (for example, when placed at 40±2°C for 0 days, 10 days or 30 days), wherein the mass ratio of the compound D 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%.

[0407] In some embodiments of the present disclosure, the pharmaceutical composition, in particular the inhalation spray, contains the compound D (for example, when placed at 40±2°C for 0 days, 10 days or 30 days), wherein the content of the compound D does not exceed 1% of the labeled amount of budesonide, or does not exceed 0.1%, or does not exceed 0.05%, or does not exceed 0.03%, or does not exceed 0.02%, or does not exceed 0.01%.

[0408] In a second aspect, the present disclosure provides a method for preparing a pharmaceutical composition, particularly an inhalation spray of budesonide, comprising the following steps:

[0409] (a1) Weigh the prescribed amount of stabilizer and dissolve it in the prescribed amount of water;

[0410] (a2) optionally adjusting the solution obtained in step (a1) to a desired pH range using a pH adjuster; and

[0411] (a3) Add the prescribed amount of ethanol and budesonide and stir to dissolve.

[0412] In some embodiments of the present disclosure, the water in step (a1) can be purified water or water for injection, preferably water for injection.

[0413] In some embodiments of the present disclosure, the preparation method comprises the following steps:

[0414] (b1) weighing a prescribed amount of a stabilizer, an optional antioxidant, an optional antibacterial agent, and an optional metal ion chelating agent, and dissolving them in a prescribed amount of water;

[0415] (b2) optionally adjusting the pH of the solution obtained in step (b1) to 2.5 to 4.5 with a pH adjuster; and

[0416] (b3) Add the prescribed amount of ethanol and budesonide and stir to dissolve.

[0417] In some embodiments of the present disclosure, the preparation method comprises the following steps:

[0418] (c1) weighing a prescribed amount of a stabilizer and an antioxidant, an optional antibacterial agent, and an optional metal ion chelating agent, and dissolving them in a prescribed amount of water for injection;

[0419] (c2) optionally adjusting the pH of the solution obtained in step (c1) to 2.5 to 3.5 with a pH adjuster; and

[0420] (c3) Add the prescribed amount of ethanol and budesonide and stir to dissolve.

[0421] In some embodiments of the present disclosure, the preparation method comprises the following steps:

[0422] (d1) Weigh the prescribed amount of glycerol, benzalkonium chloride, disodium EDTA, and vitamin C and dissolve them in the prescribed amount of water for injection;

[0423] (d2) adjusting the pH of the solution obtained in step (d1) to pH = 3.0 ± 0.2 with hydrochloric acid; and

[0424] (d3) Add the prescribed amount of ethanol and budesonide and stir to dissolve.

[0425] In a third aspect, the present disclosure provides a drug composition, in particular, a drug delivery system for an inhalation spray of budesonide, comprising a spray device and a container that can be assembled with the spray device, wherein the container contains the drug composition of the present disclosure, in particular, the inhalation spray of budesonide of the present disclosure.

[0426] In some embodiments of the present disclosure, the spray device is a handheld inhalation device.

[0427] In some embodiments of the present disclosure, the spray device is a soft mist inhalation device (SMI), including but not limited to Respimat inhaler, RESPIMAT re-usable inhaler, or publication numbers CN110582316A, CN113038982A, CN115484999A, CN111195382A, CN216025661U, CN216025662U, CN215515024U, CN109745603A, CN108057151A, CN110882453A, CN2188333 18U, CN115068754A, WO2023169196A1, WO2023138422A1, CN116036423A, CN216603701U, CN116829218A, CN110769882A, CN110022921A, CN112423895A, CN112533656A and other patent documents.

[0428] In a fourth aspect, the present disclosure provides the pharmaceutical composition of the present disclosure, in particular, use of the budesonide inhalation spray of the present disclosure in the preparation of a medicament for treating or preventing lung diseases.

[0429] In yet another aspect, the present disclosure provides the pharmaceutical composition of the present disclosure, particularly the inhalation spray of budesonide of the present disclosure, for treating or preventing lung diseases.

[0430] In yet another aspect, the present disclosure provides a method for treating or preventing a lung disease, comprising administering to a subject an effective amount of the budesonide pharmaceutical composition of the present disclosure, particularly the inhalation spray of budesonide of the present disclosure.

[0431] In yet another aspect, the present disclosure provides use of the pharmaceutical composition of the present disclosure, in particular the inhalation spray of budesonide of the present disclosure, in treating or preventing lung diseases.

[0432] In some embodiments of the present disclosure, the pulmonary disease includes, but is not limited to, asthma, chronic obstructive pulmonary disease, pneumonia, bronchitis, lung cancer, or diffuse interstitial pulmonary fibrosis.

[0433] In a fifth aspect, the present disclosure provides a use of glycerol in preparing a pharmaceutical composition, in particular an inhalation spray of budesonide. In some embodiments of the present disclosure, the pharmaceutical composition, in particular the inhalation spray of budesonide, is as described in the present disclosure.

[0434] In a sixth aspect, the present disclosure provides a use of vitamin C in preparing a pharmaceutical composition, in particular an inhalation spray of budesonide. In some embodiments of the present disclosure, the pharmaceutical composition, in particular the inhalation spray of budesonide, is as described in the present disclosure.

[0435] Technical Effects

[0436] The present disclosure provides a budesonide pharmaceutical composition, particularly a budesonide inhalation spray, which has one or more of the following advantages: good stability, effective control of the generation and content of impurities D, L, or total impurities; improved spray ellipticity; increased spray uniformity; increased uniformity of spray particle distribution; high lung deposition rate; good drug inhalation effect; convenient administration; and suitability for industrial production. In particular, the excipient vitamin C not only significantly inhibits the generation of impurities in the formulation, but also further improves the spray ellipticity, increases spray uniformity, and enhances drug inhalation effect.

[0437] BRIEF DESCRIPTION OF THE DRAWINGS

[0438] In order to better understand the present disclosure, the present disclosure is described in detail below with reference to the accompanying drawings.

[0439] FIG1 is a diagram showing the spray pattern of the budesonide inhalation spray of prescription 4 in Example 1.

[0440] FIG2 is a diagram showing the spray pattern of the budesonide inhalation spray of prescription 8 in Example 1.

[0441] FIG3 is a diagram showing the spray pattern of the budesonide inhalation spray of prescription 9 in Example 1.

[0442] FIG4 is a diagram showing the spray pattern of the budesonide inhalation spray of prescription 10 in Example 1.

[0443] FIG5 is a diagram showing the spray pattern of the budesonide inhalation spray of prescription 23 in Example 1.

[0444] FIG6 is a diagram showing the spray pattern of the budesonide inhalation spray of prescription 24 in Example 1.

[0445] FIG. 7 is a diagram showing the spray pattern of the budesonide inhalation spray of prescription 25 in Example 1.

[0446] definition

[0447] The term "subject" refers to a mammal. In some embodiments, the subject is a human.

[0448] The term "pharmaceutical composition" refers to a mixture of one or more compounds of Formula I or salts thereof disclosed herein and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds disclosed herein to a subject.

[0449] The term "treatment" means administering a compound of Formula I or a pharmaceutical composition as described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0450] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0451] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0452] The term "prevention" means administering the budesonide pharmaceutical composition of the present disclosure, particularly the budesonide inhalation spray, to prevent a disease or one or more symptoms associated with the disease, and includes preventing the occurrence of a disease or disease state in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0453] The term "effective amount" means an amount of a compound of Formula I disclosed herein that (i) treats a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein.

[0454] In the present disclosure, "% w / w" or "w / w%" refers to the percentage concentration by mass, and may also be expressed as "wt.%" or "wt%." In the present disclosure, the percentage concentration by mass refers to the weight of the component as a percentage of the total weight of all components of the pharmaceutical composition, particularly the inhalation spray, excluding the pH adjuster.

[0455] In the present disclosure, "mg / mL" refers to mass concentration. In the present disclosure, the mass concentration refers to the percentage of the weight of the component to the total volume of the pharmaceutical composition, especially the inhalation spray.

[0456] In this disclosure, the term "mass median aerodynamic diameter" or "MMAD (mass median aerodynamic diameter)" means: when the total mass of particles of various sizes smaller than a certain aerodynamic diameter in particulate matter accounts for 50% of the mass of all particulate matter (i.e., the sum of the masses of all particles of different sizes), then this particle size is called the mass median aerodynamic diameter.

[0457] In the present disclosure, the term "lung deposition rate" or "effective site deposition rate" refers to the percentage of the dose of particles smaller than or equal to 5 μm in the total delivered dose.

[0458] In the present disclosure, the term "ovality" adopts the SprayVIEW spray mode and spray shape analyzer, with the triggered spray orifice 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. Among them, the ovality is defined as follows: ovality = Dmax / Dmin. The closer it is to 1, the closer the spray shape is to a circle.

[0459] The "impurity L" in this disclosure is one of the specified impurities of budesonide, and its structural formula is See "BUDESONIDE" in the European Pharmacopoeia, section "IMPURITIES".

[0460] The "impurity D" in this disclosure is one of the specified impurities of budesonide, and its structural formula is See "BUDESONIDE" in the European Pharmacopoeia, section "IMPURITIES".

[0461] The term "single-dose pharmaceutical composition" refers to the smallest packaging unit containing a certain amount of a drug. For example, if a box of medicine contains seven capsules, each capsule is a single-dose pharmaceutical composition; or each bottle of injection solution is a single-dose pharmaceutical composition; or each bottle 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.

[0462] The term "single dose" refers to the amount of active ingredient in a single dose of a pharmaceutical composition. In this disclosure, the terms "single dose" and "unit dose" have the same meaning and are used interchangeably. For example, a pharmaceutical composition containing 3 to 380 mg of budesonide, particularly a 3 to 380 mg inhalation spray of budesonide, refers to a single dose of a pharmaceutical composition containing 3 to 380 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof as the active ingredient.

[0463] The term "per spray" refers to the minimum dosing unit consisting of the aerosol ejected each time the pharmaceutical composition, in particular the inhalation spray, is applied after being adapted to the spray device. For example, each bottle of inhalation spray solution can provide multiple spray administrations after being assembled into the spray device, such as 30 times (presses), 60 times (presses), 90 times (presses), or 120 times (presses), wherein the aerosol released by each spray (i.e., one actuation of the spray device) is each spray or each spray.

[0464] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art in the art of the present disclosure. The terms used herein in the specification of the present disclosure are only for the purpose of describing specific embodiments and are not intended to limit the present disclosure. Example

[0465] The present disclosure is described in more detail below through specific examples. It should be understood that the examples of the present disclosure are merely illustrative of the present disclosure and should not be construed as limiting the present disclosure in any way. Technical solutions obtained by making simple modifications to the present disclosure or by equivalently replacing conventional means or active ingredients based on the technical solutions of the present disclosure fall within the scope of protection of the present disclosure.

[0466] Example 1

[0467] Budesonide inhalation sprays with different formulations were prepared. The specific formulations are shown in Table 1-3:

[0468] Table 1

[0469] Table 2

[0470] Table 3

[0471] Preparation method:

[0472] (1) Weigh the prescribed amount of stabilizer, antibacterial agent, metal ion chelator and / or antioxidant, and stir and dissolve them in the prescribed amount of water for injection;

[0473] (2) adjusting the solution in step (1) to the desired pH value using a corresponding pH adjusting agent;

[0474] (3) Add the prescribed amount of anhydrous ethanol and budesonide to the above solution and stir to dissolve.

[0475] Example 2 Stability Study

[0476] The budesonide inhalation spray prepared in Example 1 was placed at a temperature of 40±2° C. for 0 days, 10 days, and 30 days, and samples were taken for analysis. The results are shown in Table 4.

[0477] Table 4

[0478] Note: NA means the item was not tested;

[0479] The stability test results show that:

[0480] (1) Comparing the data of Formulation 1 (without glycerol) and Formulation 4 (1 w / w% glycerol), it was found that glycerol can significantly improve the stability of the pharmaceutical composition of the present disclosure and significantly inhibit the generation of impurity L and total impurities.

[0481] (2) By comparing the data of prescription 4 (0.0015w / w% vitamin C), prescription 8 (no vitamin C), prescription 9 (0.01w / w% vitamin C), prescription 10 (0.11w / w% vitamin C), and prescription 11 (0.2w / w% vitamin C), it was found that the addition of vitamin C can significantly improve the stability of the pharmaceutical composition of the present disclosure and significantly inhibit the production of impurity L.

[0482] (3) Comparing the data of prescription 1, prescription 4 and prescription 8, it was found that glycerol and vitamin C can synergistically inhibit the production of impurity L.

[0483] (4) Comparing the data of prescription 4 (0.01w / w% disodium edetate), prescription 16 (not containing disodium edetate), and prescription 17 (0.05w / w% disodium edetate), it was found that disodium edetate can improve the stability of the pharmaceutical composition of the present disclosure.

[0484] (5) Comparing the data of prescription 8 (containing hydrochloric acid), prescription 12 (containing phosphoric acid) and prescription 13 (containing citric acid), it was found that when the pH adjuster was hydrochloric acid, it was more beneficial to the stability of the pharmaceutical composition of the present disclosure.

[0485] (6) Comparing the data of prescription 8 (pH value is 3.0), prescription 14 (pH value is 3.5) and prescription 15 (pH value is 4.0), or prescription 4 (pH value is 3.0), prescription 18 (pH value is 2.5), prescription 19 (pH value is 3.5), prescription 20 (pH value is 4.0), prescription 21 (pH value is 4.5) and prescription 22 (pH value is 5.0), it is found that when the pH value of the pharmaceutical composition of the present disclosure is 2.5 to 4.0, the generation of impurity L can be significantly inhibited. When the pH value of the pharmaceutical composition of the present disclosure is further controlled to 2.5 to 3.5, especially 2.5 to 3.0, the generation of impurity D can be effectively inhibited.

[0486] Example 3 Aerodynamic Particle Size Distribution Test

[0487] The budesonide inhalation sprays of formulations 1 to 7 prepared in Example 1 were assembled with a spray device. The particle distribution of the budesonide inhalation sprays of different formulations was tested according to the test method under Device 3, "Inhalation Aerosols and Inhalation Sprays," in the 2020 edition of the Chinese Pharmacopoeia, Part IV, General Rules 0951, "Determination of Aerodynamic Properties of Fine Particles of Inhalation Preparations." Based on the particle distribution results, the mass median aerodynamic diameter (MMAD) and lung deposition rate were calculated using Copley Inhaler Testing Data Analysis Software (CITADS software). The results are shown in Table 5.

[0488] Table 5

[0489] The test results show that: (1) As the concentration of glycerol in the pharmaceutical composition of the present disclosure increases, the MMAD of the spray also increases continuously, and the lung deposition rate first increases and then decreases. (2) When the concentration of glycerol in the pharmaceutical composition of the present disclosure is between 0.50 and 5.00 w / w%, the MMAD of the spray is between 2.0 and 4.0 μm, and the lung deposition rate is greater than or equal to 60%. (3) When the concentration of glycerol in the pharmaceutical composition of the present disclosure is 1.00 w / w%, the lung deposition rates of prescriptions 4 and 23 are both high, reaching 78% and 77%, respectively. (4) The change in the concentration of the active ingredient in the pharmaceutical composition of the present disclosure does not affect the lung deposition rate, and prescriptions 23-25 ​​all have high lung deposition rates. The above results show that the prescription of the present disclosure is conducive to inhalation administration.

[0490] Example 4 Spray Pattern Study

[0491] The budesonide inhalation sprays of Formulations 4, 8, 9, and 10 prepared in Example 1 were assembled into a spray device and sprayed. Using the SprayVIEW spray pattern analyzer, the spray orifice after triggering was used as the spray starting point. The horizontal cross-section of the spray was measured at a fixed distance of 30 mm from the starting point. The main measurements were the longest axis (Dmax), the shortest axis (Dmin), and the ovality of the spray profile within the cross-sectional area of ​​the spray. The ovality is defined as follows: ovality = Dmax / Dmin; the closer the ovality is to 1, the more circular the spray shape. The results are shown in Table 6, and the spray pattern diagrams of each formulation are shown in Figures 1 to 7.

[0492] Table 6

[0493] The test results show that: (1) adding the antioxidant vitamin C to the pharmaceutical composition of the present disclosure can improve the ellipticity of the spray; (2) when the content of vitamin C in the pharmaceutical composition of the present disclosure is 0.0015w / w%, the ellipticity of the spray aerosol of prescription 4, prescription 23, prescription 24 and prescription 25 is closer to 1, indicating that the pharmaceutical composition of the present disclosure has better spray symmetry after spraying, improves the uniformity of the spray, and improves the drug inhalation effect.

[0494] The above description is only a specific embodiment of the present disclosure and is not intended to limit the scope of the present disclosure. Any equivalent changes, modifications and combinations made by any person skilled in the art without departing from the concept and principle of the present disclosure shall fall within the scope of protection of the present disclosure.

Claims

1. A pharmaceutical composition comprising budesonide and a stabilizer and / or an antioxidant.

2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is an inhalation spray.

3. The pharmaceutical composition according to claim 1 or 2, wherein the stabilizer is glycerol and the antioxidant is vitamin C.

4. The pharmaceutical composition according to any one of claims 1 to 3, comprising budesonide, a stabilizer and an antioxidant, wherein the stabilizer is glycerol and the antioxidant is vitamin C.

5. The pharmaceutical composition according to claim 1 or 2, comprising budesonide, ethanol, and a stabilizer and / or an antioxidant.

6. The pharmaceutical composition according to claim 1 or 2, comprising budesonide, ethanol, a stabilizer and an antioxidant.

7. The pharmaceutical composition of claim 5 or 6, wherein the stabilizer is selected from one or more of n-propanol, isopropanol, glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenylethyl alcohol, butanol, butylene glycol, mannitol, polyethylene glycol, or ethylene glycol; or, the stabilizer is selected from one or more of glycerol, propylene glycol, oleic acid, linoleic acid, benzyl alcohol, phenylethyl alcohol, butanol, butylene glycol, polyethylene glycol, or ethylene glycol; or, the stabilizer is selected from one or more of glycerol, propylene glycol, oleic acid, phenylethyl alcohol, or butanol; or, the stabilizer is selected from glycerol, propylene glycol, or a mixture thereof; or, the stabilizer is glycerol.

8. The pharmaceutical composition of any one of claims 1 to 7, wherein the amount of the stabilizer contained in the pharmaceutical composition is 0.01-20 w / w%, 0.01-15 w / w%, 0.5-10 w / w%, 0.5-5 w / w%, 1-5 w / w%, 1-2 w / w%, or 1 w / w%; or, the amount of the stabilizer contained in the pharmaceutical composition is 0.09-90 mg / mL, 0.09-90 mg / mL, 1.8-45 mg / mL, 4.5-23 mg / mL, 7.2-18 mg / mL, or 9.048 mg / mL.

9. The pharmaceutical composition according to claim 5 or 6, wherein the antioxidant is selected from one or more of butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, tert-butylhydroquinone, ascorbic acid antioxidants, tocopherol antioxidants, vitamin A, retinyl palmitate, dibutylphenol, tea polyphenols, sulfite antioxidants, fumaric acid or its salts, malic acid or its salts, citric acid or its salts, maleic acid or its salts; or, the antioxidant is selected from one or more of ascorbic acid antioxidants, sulfite antioxidants, One or more of butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, tert-butylhydroquinone, and tea polyphenols; or, the antioxidant is selected from one or more of vitamin C, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, butylated hydroxyanisole, butylated hydroxytoluene, tert-butylhydroquinone, propyl gallate, ascorbyl palmitate, and tea polyphenols; or, the antioxidant is selected from vitamin C, sodium metabisulfite, sodium bisulfite, and sodium thiosulfate; or, the antioxidant is vitamin C.

10. The pharmaceutical composition according to any one of claims 1 to 7, wherein the amount of the antioxidant contained in the pharmaceutical composition is 0.0001-5 w / w%, 0.0005-5 w / w%, 0.0015-5 w / w%, 0.001-0.2 w / w%, 0.0015-0.11 w / w% or 0.0015 w / w%; or, the amount of the antioxidant contained in the pharmaceutical composition is 0.001-50 mg / mL, 0.001-47 mg / mL, 0.007-12 mg / mL, 0.007-4.6 mg / mL, 0.011-2.3 mg / mL or 0.014 mg / mL.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the pharmaceutical composition further comprises a pH adjuster; or, the pharmaceutical composition further comprises a pH adjuster and water.

12. The pharmaceutical composition according to claim 11, wherein 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 selected from one or more of hydrochloric acid, phosphoric acid, and citric acid; or, the pH adjuster is hydrochloric acid; and / or, the pH value of the pharmaceutical composition is 2.5-4.5, 2.5-4.0, 2.5-3.5, 2.8-3.2, 2.9-3.1, or 3.

0.

13. The pharmaceutical composition according to claim 11 or 12, wherein the water is purified water or water for injection; and / or the amount of water contained in the pharmaceutical composition is 4-70 w / w%, 4-68 w / w%, 4-60 w / w%, 30-60 w / w%, 40-50 w / w% or 44-45 w / w%; or the amount of water contained in the pharmaceutical composition is 40-600 mg / mL, 60-600 mg / mL, 100-480 mg / mL, 300-450 mg / mL, 360-430 mg / mL or 395-405 mg / mL.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the pharmaceutical composition further comprises a metal ion chelator and / or a bacteriostatic agent.

15. The pharmaceutical composition according to claim 14, wherein the metal ion chelator is selected from the group consisting of ethylenediaminetetraacetic acid or its salts, ethylene glycol tetraacetic acid or its salts, cyclohexanediaminetetraacetic acid or its salts, hydroxyethylethylenediaminetriacetic acid or its salts, diethylenetriaminepentaacetic acid or its salts, dimercaptopropanesulfonic acid or its salts, dimercaptosuccinic acid or its salts, aminotrimethylenephosphonic acid or its salts, citric acid or its salts, acetic acid or its salts, phosphoric acid or its salts, pyrophosphoric acid or its salts, metaphosphoric acid or its salts, and any combination thereof; or, the metal ion chelator is selected from the group consisting of ethylenediaminetetraacetic acid or its salts, ethylene glycol tetraacetic acid or its salts, One or more of cyclohexanediaminetetraacetic acid or its salts, hydroxyethylethylenediaminetriacetic acid or its salts, diethylenetriaminepentaacetic acid or its salts; or, the metal ion chelating agent is selected from one or more of ethylenediaminetetraacetic acid or its salts, hydroxyethylethylenediaminetriacetic acid or its salts; or, the metal ion chelating agent is selected from ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetic acid, dipotassium ethylenediaminetetraacetic acid, trisodium ethylenediaminetetraacetic acid, tripotassium ethylenediaminetetraacetic acid, calcium disodium ethylenediaminetetraacetic acid, dicalcium ethylenediaminetetraacetic acid and sodium calcium ethylenediaminetetraacetic acid; or, the metal ion chelating agent is disodium ethylenediaminetetraacetic acid; and / or The amount of the metal ion chelator contained in the pharmaceutical composition is 0.001-1w / w%, 0.001-0.9w / w%, 0.001-0.5w / w%, 0.005-0.1w / w%, 0.01-0.05w / w% or 0.01w / w%; or, the amount of the metal ion chelator contained in the pharmaceutical composition is 0.009-9mg / mL, 0.009-8.5mg / mL, 0.009-4.5mg / mL, 0.045-0.9mg / mL, 0.068-0.45mg / mL or 0.09mg / mL.

16. The pharmaceutical composition according to claim 14 or 15, wherein the antibacterial agent is selected from the group consisting of: benzalkonium chloride, benzalkonium bromide, parahydroxybenzoate, chlorobutanol, phenol, resorcinol, benzyl alcohol, phenylethyl alcohol, benzoic acid or its salts, sodium propionate, sorbic acid or its salts; or, the antibacterial agent is selected from the group consisting of: benzalkonium chloride, benzyl bromide, benzyl alcohol, phenylethyl alcohol, benzoic acid or its salts, sodium propionate, sorbic acid or its salts; or, the antibacterial agent is selected from the group consisting of: benzalkonium chloride, benzyl bromide, benzoic acid or its salts, benzyl alcohol; or, the antibacterial agent is selected from the group consisting of: benzalkonium chloride and / or benzalkonium bromide; or, the antibacterial agent is benzalkonium chloride; and / or, The amount of the antibacterial agent contained in the pharmaceutical composition is 0-2w / w%, 0-1.5w / w%, 0-0.5w / w%, 0.005-0.05w / w%, 0.005-0.015w / w% or 0.01w / w%; or, the amount of the antibacterial agent contained in the pharmaceutical composition is 0-18mg / mL, 0.01-16mg / mL, 0-6mg / mL, 0.045-0.45mg / mL, 0.045-0.18mg / mL or 0.09mg / mL.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the amount of budesonide contained in the pharmaceutical composition is 0.1-10 w / w%, 0.1-9 w / w%, 0.25-5 w / w%, 0.125-2.5 w / w%, 0.25-3 w / w%, 0.125-1.5 w / w%, 0.5-1.5 w / w%, 0.25-0.75 w / w%, 1 w / w% or 0.5 w / w%; or The amount of budesonide contained in the pharmaceutical composition is 0.1-90 mg / mL, 0.5-85 mg / mL, 4.5-45 mg / mL, 0.1-20 mg / mL, 5.6-27 mg / mL, 0.5-15 mg / mL, 8-14 mg / mL, 4-7 mg / mL, 0.9-4 mg / mL, 9.048 mg / mL, 4.524 mg / mL, 2.3 mg / mL or 1.1 mg / mL.

18. The pharmaceutical composition of any one of claims 5 to 17, wherein the amount of ethanol contained in the pharmaceutical composition is 30-96 w / w%, 40-96 w / w%, 40-70 w / w%, 50-60 w / w%, 53-56 w / w%, or 54-55 w / w%; or, wherein the amount of ethanol contained in the pharmaceutical composition is 240-900 mg / mL, 240-880 mg / mL, 320-850 mg / mL, 390-620 mg / mL, 450-530 mg / mL, or 485-495 mg / mL.

19. The pharmaceutical composition of any one of claims 1 to 18, wherein the pulmonary deposition rate of fine particles formed by atomization of the pharmaceutical composition by a spray device is greater than 50%, greater than 51%, greater than 60%, greater than 70% or greater than 75%; and / or the mass median aerodynamic diameter (MMAD) of the fine particles formed by atomization of the pharmaceutical composition by a spray device is 1.5 to 5 μm, 1.6 to 4.8 μm, 2.0 to 4.0 μm or 2.5 to 3.5 μm; and / or the ellipticity of the spray formed by atomization of the pharmaceutical composition by a spray device is 1 to 2, 1 to 1.9, 1 to 1.5, 1 to 1.3 or 1 to 1.

2.

20. The pharmaceutical composition of any one of claims 1 to 19, wherein the pharmaceutical composition contains no more than 1%, no more than 0.1%, no more than 0.05%, no more than 0.03%, no more than 0.02%, or no more than 0.01% of Compound L, and / or no more than 1%, no more than 0.1%, no more than 0.05%, no more than 0.03%, no more than 0.02%, or no more than 0.01% of Compound D, 21. A pharmaceutical composition which is an inhalation spray comprising budesonide, and glycerol and / or vitamin C.

22. The pharmaceutical composition of claim 21, comprising budesonide, ethanol, glycerol and vitamin C.

23. A method for preparing the pharmaceutical composition according to any one of claims 1 to 22, comprising the following steps: (1) Weigh the prescribed amount of stabilizer and / or antioxidant, optional antibacterial agent or optional metal ion chelating agent and dissolve them in the prescribed amount of water. (2) optionally adjusting the pH of the solution obtained in step (1) to 2.5 to 4.5 using a pH adjuster; and (3) Add the prescribed amount of ethanol and budesonide and stir to dissolve.

24. A drug delivery system comprising a spray device and a container that can be assembled with the spray device, wherein the container contains the pharmaceutical composition according to any one of claims 1 to 22; optionally, the spray device is a handheld inhalation device.

25. Use of the pharmaceutical composition according to any one of claims 1 to 22 in the preparation of a medicament for treating or preventing a lung disease; optionally, the lung disease comprises asthma, chronic obstructive pulmonary disease, pneumonia, bronchitis, lung cancer or diffuse interstitial pulmonary fibrosis.

26. A method for treating or preventing a lung disease, comprising administering the pharmaceutical composition of any one of claims 1 to 22 to a subject in need thereof; optionally, the lung disease comprises asthma, chronic obstructive pulmonary disease, pneumonia, bronchitis, lung cancer, or diffuse interstitial pulmonary fibrosis.

27. The pharmaceutical composition of any one of claims 1 to 22 for treating or preventing a lung disease; optionally, the lung disease comprises asthma, chronic obstructive pulmonary disease, pneumonia, bronchitis, lung cancer, or diffuse interstitial pulmonary fibrosis.

28. Use of the pharmaceutical composition of any one of claims 1-22 in treating or preventing a lung disease; optionally, the lung disease comprises asthma, chronic obstructive pulmonary disease, pneumonia, bronchitis, lung cancer, or diffuse interstitial pulmonary fibrosis.

29. Use of vitamin C and / or glycerol in the preparation of a pharmaceutical composition containing budesonide.

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