Suspended triple inhalation aerosol composition and preparation method therefor

Abstract

Provided in the present invention are a suspended triple inhalation aerosol composition and a preparation method therefor. The aerosol composition comprises fluticasone furoate, vilanterol trifenatate, glycopyrrolate, a diluent, a surfactant and a propellant; has higher drug-delivery efficiency and drug-delivery dose, and higher lung deposition; and has the effects of better ameliorating Mch-induced elevated pulmonary resistance and decreased pulmonary compliance, thereby facilitating improvement to medication safety and patient compliance.

Description

Suspension type triple inhalation aerosol composition and preparation method thereof

[0001] The present application claims priority to the prior application filed on June 14, 2024 with the China National Intellectual Property Office and entitled "Suspension type triple inhalation aerosol composition and preparation method thereof", with the patent application number 202410775585.8. The prior application is incorporated herein by reference in its entirety. TECHNICAL FIELD

[0002] The present application belongs to the field of pharmaceutical preparations, and in particular relates to a suspension type triple inhalation aerosol composition and a preparation method thereof. BACKGROUND

[0003] Chronic obstructive pulmonary disease (COPD) has high heterogeneity, lacks clear biomarkers, is difficult to detect early, and the progress of targeted drugs and biological drugs is slow. The combination of existing compounds is the biggest progress in the field of COPD treatment in recent years, and binary and ternary compounds have achieved great success in clinical and market. However, the current drug composition is mostly dry powder inhalation drugs, which cannot meet the clinical needs of severe and extremely severe asthma and COPD patients, so it is still necessary to develop more efficient inhalation suspensions for treating asthma and COPD containing a combination of long-acting inhaled corticosteroids, long-acting anticholinergic drugs (LAMA) and long-acting beta2 receptor agonists (LABA). SUMMARY

[0004] To improve the above technical problems, the present application provides a composition comprising fluticasone furoate, vilanterol trifenatate, glycopyrronium bromide, a diluent, a surfactant and a propellant.

[0005] According to an embodiment of the present application, the diluent is selected from one or more of biodegradable polymers, sugar alcohols, monosaccharides, disaccharides, polysaccharides.

[0006] According to an embodiment of the present application, the biodegradable polymer is selected from one or more of polylactic acid, polyglycolic acid, hydroxypropyl cellulose, chitin, hyaluronic acid.

[0007] According to an embodiment of the present application, the sugar alcohol is selected from one or more of mannitol, xylitol, sorbitol, maltitol.

[0008] According to an embodiment of the present application, the monosaccharide is selected from one or more of glucose, fructose, galactose, ribose.

[0009] According to an embodiment of the present application, the disaccharide is selected from one or more of lactose, maltose, sucrose.

[0010] According to an embodiment of the present application, the polysaccharide is selected from one or more of starch, cellulose, glycogen.

[0011] According to an embodiment of the present application, the surfactant is selected from sorbitan esters or polyoxyethylene derivatives thereof, such as polyethylene glycol.

[0012] According to an embodiment of the present application, the polyethylene glycol is selected from PEG 400, PEG 600, PEG 800, PEG 1000, PEG 1500.

[0013] According to an embodiment of the present application, the propellant is selected from one or more of hydrocarbons, hydrofluorochloroalkanes, hydrofluorocarbons; for example, one or more of propane, n-butane, isobutane, trifluoro-monochloroethane, 1,1,1,2,3,3,3-heptafluoropropane (HFC-227ea), 1,1,1,2-tetrafluoroethane (HFC-134a), 1,1-difluoroethane (HFC-152a), 2,3,3,3-tetrafluoropropene (HFO-1234yf), monochlorodifluoroethane.

[0014] According to an embodiment of the present application, the composition can further comprise a stabilizer selected from one or more of stearate, amino acid, high molecular compound.

[0015] According to an embodiment of the present application, the stearate is selected from one or more of magnesium stearate, sodium stearate, calcium stearate.

[0016] According to an embodiment of the present application, the amino acid is selected from one or more of arginine, glycine, histidine, aspartic acid.

[0017] According to an embodiment of the present application, the high molecular compound is selected from one or more of polyvinyl alcohol, sodium alginate, sodium hyaluronate, chitosan, hydroxyethyl starch.

[0018] According to an embodiment of the present application, the fluticasone furoate, vilanterol trifenatate, glycopyrronium bromide are in micronized form; the particle size of the micronized ingredients is about 0.1-10 μm, for example, about 1-5 μm, such as about 1.0, 2.0, 3.0 μm.

[0019] According to an embodiment of the present application, the fluticasone furoate accounts for 0.01%-0.20% by mass of the composition, for example, 0.05%-0.10%, such as 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%. For example, 0.06%-0.09% or 0.065%-0.080%.

[0020] According to embodiments of the present application, vilanterol trifenatate comprises 0.005% to 0.100% by mass of the composition, for example 0.010% to 0.050%, such as 0.010%, 0.015%, 0.020%, 0.025%, 0.030%, 0.035%, 0.040%. For example, 0.020% to 0.040% or 0.025% to 0.030%.

[0021] According to embodiments of the present application, glycopyrronium bromide comprises 0.005% to 0.100% by mass of the composition, for example 0.010% to 0.050%, such as 0.010%, 0.011%, 0.012%, 0.013%, 0.014%, 0.015%, 0.016%, 0.017%, 0.018%, 0.019%, 0.020%, 0.021%, 0.022%, 0.023%, 0.024%, 0.025%, 0.026%, 0.027%, 0.028%, 0.029%, 0.030%, 0.031%, 0.032%, 0.033%, 0.034%, 0.035%, 0.036%, 0.037%, 0.038%, 0.039%, 0.040%, 0.041%, 0.042%, 0.043%, 0.044%, 0.045%, 0.046%, 0.047%, 0.048%. For example, 0.020% to 0.050%, 0.025% to 0.045%, 0.028% to 0.045%, 0.025% to 0.030%, 0.038% to 0.048%, or 0.043% to 0.046%.

[0022] According to embodiments of the present application, when a stabilizer is included in the composition, the stabilizer comprises 0.0001% to 0.0100% by mass of the composition, for example 0.0005% to 0.0050%, 0.0010% to 0.0030%, or 0.0015% to 0.0025%, such as 0.0002%, 0.0003%, 0.0004%, 0.0005%, 0.0006%, 0.0007%, 0.0008%, 0.0009%, 0.0010%, 0.0011%, 0.0012%, 0.0013%, 0.0014%, 0.0015%, 0.0016%, 0.0017%, 0.0018%, 0.0019%, 0.0020%, 0.0030%, 0.0040%.

[0023] According to embodiments of the application, the diluent comprises 0.01-1% by mass of the composition, for example 0.05-0.5%, 0.06-0.4%, 0.07-0.3%, 0.08-0.2%, 0.09-0.19%, 0.10-0.18%, 0.11-0.17%, or 0.12-0.16%, such as 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%.

[0024] According to embodiments of the application, the surfactant comprises 0.01-1% by mass of the composition, for example 0.05-0.5%, 0.1-0.4%, or 0.2-0.3%, such as 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%.

[0025] According to embodiments of the present application, the propellant comprises 97.59-99.96%, for example 98.00-99.90%, 99.00-99.85%, 99.10-99.80%, 99.20-99.75%, 99.30-99.70%, 99.40-99.65%, 99.40-99.60%, or 99.40-99.55%, by mass percent of the composition, such as 98.00%, 98.10%, 98.20%, 98.30%, 98.40%, 98.50%, 98.60%, 98.70%, 98.80%, 98.90%, 99.00%, 99.10%, 99.20%, 99.30%, 99.40%, 99.50%, 99.51%, 99.52%, 99.53%, 99.54%, 99.55%, 99.56%, 99.57%, 99.58%, 99.59%, 99.60%, 99.70%, 99.80%.

[0026] In some embodiments, the composition comprises the following components: fluticasone furoate, vilanterol trifenatate, glycopyrronium bromide, lactose, polyethylene glycol, and 1,1,1,2,3,3,3-heptafluoropropane (HFC-227ea);

[0027] In some embodiments, the composition comprises the following components: fluticasone furoate, vilanterol trifenatate, glycopyrronium bromide, lactose, polyethylene glycol 1000 (PEG 1000), and 1,1,1,2,3,3,3-heptafluoropropane (HFC-227ea);

[0028] In some embodiments, the composition comprises the following components, by mass percent:

[0029] In some embodiments, the composition comprises the following components, by mass percent:

[0030] In some embodiments, the composition comprises the following components: fluticasone furoate, vilanterol trifenatate, glycopyrronium bromide, magnesium stearate, lactose, polyethylene glycol, and 1,1,1,2,3,3,3-heptafluoropropane (HFC-227ea);

[0031] In some embodiments, the composition comprises the following components: fluticasone furoate, vilanterol trifenatate, glycopyrronium bromide, magnesium stearate, lactose, polyethylene glycol 1000 (PEG 1000), and 1,1,1,2,3,3,3-heptafluoropropane (HFC-227ea);

[0032] In some embodiments, the composition comprises, in mass percentage, the following components:

[0033] In some embodiments, the composition comprises, in mass percentage, the following components:

[0034] In some embodiments, the composition comprises, in mass percentage, the following components:

[0035] According to embodiments of the present application, the composition is an aerosol;

[0036] According to embodiments of the present application, the composition is a suspension aerosol.

[0037] The present application also provides a method for preparing the composition, comprising the following steps:

[0038] (1) adding the surfactant into the propellant after being heated and melted to disperse, to obtain a preparation solution;

[0039] (2) adding the remaining components in the composition except the surfactant into the preparation solution in (1) to disperse.

[0040] According to embodiments of the present application, the remaining components in the composition except the surfactant are fluticasone furoate, vilanterol trifenatate, glycopyrronium bromide and a diluent, or are fluticasone furoate, vilanterol trifenatate, glycopyrronium bromide, a diluent and a stabilizer.

[0041] According to embodiments of the present application, in the preparation method, the fluticasone furoate, vilanterol trifenatate and glycopyrronium bromide are in micronized form.

[0042] According to embodiments of the present application, the particle size of the micronized particles is about 0.1-10 μm, for example, about 1-5 μm, such as about 1.0, 2.0, 3.0 μm.

[0043] According to embodiments of the present application, the preparation method comprises a step of micronizing one or more components in the composition, for example, the components in the composition can be subjected to jet milling to obtain a target particle size of the micronized particles; for example, the glycopyrronium bromide and the diluent in the composition can be mixed and dissolved in a solvent, and then spray-dried to facilitate micronization.

[0044] According to an embodiment of the present application, the solvent is a mixed solution of an alcohol solvent and water, such as methanol, ethanol; the volume percentage of the alcohol solvent in the solvent is 20-80%, such as 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%;

[0045] The dispersion method can be high-speed shearing, with a shearing speed of 8000-20000 rpm, such as 9000-15000 rpm, for example, 10000 rpm.

[0046] According to an embodiment of the present application, the preparation method of the composition comprises the following scheme I and / or scheme II:

[0047] Scheme I: the preparation method of the composition comprises the following steps:

[0048] (A1) mixing glycopyrronium bromide and the diluent, and dissolving in a solvent to obtain a glycopyrronium bromide / diluent mixed solution;

[0049] (A2) spray drying the mixed solution to obtain a glycopyrronium bromide / diluent mixed spray-dried product;

[0050] (A3) weighing the surfactant, melting after heating, and dispersing in the propellant to obtain a preparation solution;

[0051] (A4) weighing the glycopyrronium bromide / diluent mixed spray-dried product, fluticasone furoate, and vilanterol trifenatate, and adding them into the preparation solution of step (A3) in sequence to obtain the composition;

[0052] According to an embodiment of the present application, the solvent in step (A1) is a mixed solution of an alcohol solvent and water, such as methanol, ethanol;

[0053] According to an embodiment of the present application, the volume percentage of the alcohol solvent in the solvent in step (A1) is 20-80%, such as 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%;

[0054] According to an embodiment of the present application, the dispersion method in steps (A3) and (A4) can be high-speed shearing, with a shearing speed of 8000-20000 rpm, such as 9000-15000 rpm, for example, 10000 rpm.

[0055] According to the embodiments of the present application, the glycopyrronium bromide / diluent mixed spray dry, fluticasone furoate, vilanterol trifenatate are all micronized; the particle size of each of the micronized is about 0.1-10 μm, for example, about 1-5 μm, such as about 1.0, 2.0, 3.0 μm.

[0056] Scheme II: the preparation method of the composition, comprising the following steps:

[0057] (B1) mixing glycopyrronium bromide with the stabilizer to obtain a glycopyrronium bromide / stabilizer mixture;

[0058] (B2) separately pulverizing the glycopyrronium bromide / stabilizer mixture and the diluent to a particle size of about 0.1-10 μm to obtain a micronized glycopyrronium bromide / stabilizer mixture and a micronized diluent powder;

[0059] (B3) weighing the surfactant, adding into the propellant after melting to disperse, to obtain a preparation solution;

[0060] (B4) weighing the micronized fluticasone furoate, glycopyrronium bromide / stabilizer mixture, vilanterol trifenatate, diluent, and adding into the preparation solution of step (B3) in sequence to disperse to obtain the composition.

[0061] According to the embodiments of the present application, the particle size in step (B2) is about 1-5 μm, such as about 1.0, 2.0, 3.0 μm.

[0062] According to the embodiments of the present application, the dispersion mode in step (B3) and step (B4) can be high-speed shearing, and the shearing rotation speed is 8000-20000 rpm, for example, 9000-15000 rpm, such as 10000 rpm.

[0063] In some embodiments, the preparation method of the composition, comprising the following steps:

[0064] (A1) mixing glycopyrronium bromide and lactose, and dissolving in an ethanol aqueous solution to obtain a glycopyrronium bromide / lactose mixed solution;

[0065] (A2) spray drying the mixed solution to obtain a glycopyrronium bromide / lactose mixed spray dry;

[0066] (A3) weighing polyethylene glycol, adding into the propellant after melting to disperse, to obtain a preparation solution;

[0067] (A4) weighing the glycopyrronium bromide / lactose mixed spray dry, fluticasone furoate, vilanterol trifenatate, and adding into the preparation solution of step (A3) in sequence to disperse to obtain the composition.

[0068] In some embodiments, the method for preparing the composition comprises the following steps:

[0069] (A1) mixing glycopyrronium bromide and lactose, and dissolving them in 47% ethanol aqueous solution to obtain a glycopyrronium bromide / lactose mixed solution;

[0070] (A2) spray drying the mixed solution to obtain a glycopyrronium bromide / lactose mixed spray-dried product;

[0071] (A3) weighing PEG1000, melting it after heating, adding propellant HFC-227ea, and dispersing it by high-speed shearing to obtain a preparation solution;

[0072] (A4) weighing the glycopyrronium bromide / lactose mixed spray-dried product, fluticasone furanoate, and vilanterol trifenatate, and adding them into the preparation solution of step (A3) in sequence, and dispersing them by high-speed shearing to obtain the composition.

[0073] In some embodiments, the method for preparing the composition comprises the following steps:

[0074] (B1) mixing glycopyrronium bromide and magnesium stearate to obtain a glycopyrronium bromide / magnesium stearate mixture, and obtaining a mixture of glycopyrronium bromide and magnesium stearate;

[0075] (B2) separately pulverizing the glycopyrronium bromide / magnesium stearate mixture and lactose to a particle size of about 0.1-10 μm to obtain a micronized glycopyrronium bromide / stabilizer mixture and micronized lactose;

[0076] (B3) weighing PEG1000, melting it after heating, adding propellant, and dispersing it to obtain a preparation solution;

[0077] (B4) weighing the micronized fluticasone furanoate, the glycopyrronium bromide / magnesium stearate mixture, vilanterol trifenatate, and lactose, and adding them into the preparation solution of step (B3) in sequence, and dispersing them to obtain the composition.

[0078] In some embodiments, the method for preparing the composition comprises the following steps:

[0079] (B1) mixing glycopyrronium bromide and magnesium stearate in a three-dimensional mixer to mix them uniformly, and obtaining a mixture of glycopyrronium bromide and magnesium stearate;

[0080] (B2) separately airflow-pulverizing the mixture of glycopyrronium bromide and magnesium stearate and lactose to a particle size of about 0.1-10 μm to obtain a micronized glycopyrronium bromide / stabilizer mixture and micronized lactose;

[0081] (B3) weighing PEG1000, melting it after heating, adding propellant HFC-227ea, and dispersing it by high-speed shearing to obtain a preparation solution;

[0082] (B4) Weighing micronized fluticasone furoate, glycopyrronium bromide / magnesium stearate mixture, vilanterol trifenatate, lactose, and adding them into the formulation solution of step (B3) in turn, and dispersing them by high-speed shearing to obtain the composition.

[0083] According to an embodiment of the present application, the preparation method can further comprise one or more of the following steps: valve sealing, filling, inverted storage, and outer packaging.

[0084] The present application also provides the composition prepared by the preparation method.

[0085] The present application also provides use of the composition in the preparation of a medicament for treating respiratory diseases.

[0086] The present application also provides a method for treating respiratory diseases, comprising administering to a patient a therapeutically effective amount of the composition.

[0087] According to an embodiment of the present application, the respiratory diseases are selected from chronic obstructive pulmonary disease, chronic bronchitis, asthma, chronic respiratory obstruction, pulmonary fibrosis, emphysema, allergic rhinitis, small airway disease, bronchiectasis, and cystic fibrosis.

[0088] According to an embodiment of the present application, the asthma is severe asthma or asthma that is not well controlled.

[0089] According to an embodiment of the present application, in the method for treating respiratory diseases, the delivery amount of vilanterol trifenatate is 5-20 μg per puff / inhalation, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 μg per puff / inhalation; the delivery amount of glycopyrronium bromide is 6-20 μg per puff / inhalation, for example, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 μg per puff / inhalation; and the delivery amount of fluticasone furoate is 20-50 μg per puff / inhalation, for example, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 μg per puff / inhalation.

[0090] According to an embodiment of the present application, in the method for treating respiratory diseases, the average delivery amount of vilanterol trifenatate is about 9.61 μg per puff / inhalation, the average delivery amount of glycopyrronium bromide is about 12.22 μg per puff / inhalation, and the average delivery amount of fluticasone furoate is about 39.86 μg per puff / inhalation. Advantages

[0091] The aerosol composition of the present application has the following advantages compared with existing drugs (such as fluticasone propionate): ① The inhalation aerosol requires a lower inspiratory flow rate for the patient, the breathing drive device has a higher development threshold, the patient benefits significantly, the requirement for coordination of inhalation and drug administration is reduced, and the lung deposition rate is higher; ② The aerosol composition of the present application can be placed in an aerosol device that is more familiar and more acceptable to asthma and COPD patients, such as Ventolin and Atrovent. ③ In terms of compound combinations, by improving the formulation adjuvant and matching the optimized preparation process, the FPF value and FPD value of each effective component in the aerosol composition of the present application are effectively improved, the drug delivery efficiency and drug delivery dose are higher, and the lung deposition amount is higher, which has a better effect of improving the Mch-induced increase in lung resistance and decrease in lung compliance, thereby facilitating the improvement of drug safety and patient compliance. BRIEF DESCRIPTION OF DRAWINGS

[0092] Figure 1 shows the fluticasone propionate three-way aerosol APSD level distribution diagram.

[0093] Figure 2 shows a comparison diagram of fluticasone propionate three-way aerosol and fluticasone propionate delivery dose uniformity; (A: P-23041102 fluticasone propionate three-way aerosol; B: fluticasone propionate inhalation powder).

[0094] Figure 3 shows a comparison diagram of fluticasone propionate three-way aerosol and fluticasone propionate FPF (%).

[0095] Figure 4 shows the improvement effect of fluticasone propionate on the increase in guinea pig lung resistance induced by acetylcholine (n = 8-11).

[0096] Figure 5 shows the improvement effect of fluticasone propionate on the decrease in guinea pig lung compliance induced by acetylcholine (n = 8-11).

[0097] Figure 6 shows the results of inflammatory cell counting in the BALF of rats. (Compared with the normal control group: ##P<0.01; compared with the model group: *P<0.05, **P<0.01).

[0098] Figure 7 shows the H&E staining diagram of the pathological section of the rat.

[0099] Figure 8 shows the results of pathological section scoring of the rat (##P<0.01 vs. control group, **P<0.01 vs. model group).

[0100] Figure 9 shows the detection of lung tissue inflammatory factors (##P<0.01 vs. control group, **P<0.01 vs. model group).

[0101] Figure 10 shows the effect of fluticasone propionate on the percentage increase in airway resistance (R aw ) of guinea pigs induced by Mch / His. (Compared with the blank control group:### P<0.001; compared with the model group: * P<0.05, ** P<0.01, *** P<0.001; compared with the low-dose fluticasone propionate group: & P<0.05, && P<0.01, &&& P<0.001.

[0102] Figure 11 shows the effect of fluticasone propionate on the percentage of decrease in dynamic lung compliance (Cdyn) of guinea pigs induced by Mch / His. dyn ) (compared with the blank control group: ##P<0.01, ###P<0.001; compared with the model group: *P<0.05, **P<0.01, ***P<0.001; compared with the low-dose fluticasone propionate group: &P<0.05, &&P<0.01, &&&P<0.001).

[0103] Figure 12 shows the effect of fluticasone propionate on airway hyperresponsiveness of asthmatic mice induced by Mch.

[0104] Figure 13 shows the effect of fluticasone propionate on inflammatory cells in BALF of asthmatic mice.

[0105] Figure 14 shows the effect of fluticasone propionate on inflammatory factors in lung tissue of asthmatic mice.

[0106] Figure 15 shows the effect of fluticasone propionate on pulmonary inflammatory infiltration of asthmatic mice (H&E staining, 100X, A: blank control group; B: model group; C: low-dose fluticasone propionate group; D: high-dose fluticasone propionate group; E: fluticasone propionate + vilanterol group; F: glycopyrronium group. DETAILED DESCRIPTION

[0107] The technical solutions of the present application will be further described in detail below in combination with specific examples. It should be understood that the following examples are only illustratively and explain the present application, and should not be interpreted as limiting the scope of protection of the present application. Any technology realized based on the above description of the present application is covered within the scope of protection intended by the present application.

[0108] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0109] In the present application, the term "fluticasone furoate" generally refers to the generic term for a medicament comprising three active ingredients: fluticasone furoate (FF), vilanterol trifenatate (VI), and glycopyrronium bromide (GLY). For metering purposes, "glycopyrronium bromide" is "glycopyrronium" on an active ingredient basis, "umeclidinium bromide (UMEC)" is "umeclidinium" on an active ingredient basis, and "vilanterol trifenatate" is "vilanterol" on an active ingredient basis.

[0110] In the present application, the term "fine particledose (FPD)" or microfine particle dose generally refers to the total mass of active agent present with an aerodynamic particle size less than a specified limit emitted with the drive device. The limit is generally set to 5 μιη unless explicitly stated otherwise to be set to another limit.

[0111] In the present application, the term "fine particle fraction (FPF)" or microfine particle fraction is generally defined as the FPD divided by the emitted dose and expressed as a percentage.

[0112] In the present application, the term "diluent" includes any and all solvents, solubilizing agents, complexing agents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, which are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated.

[0113] In the present application, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0114] In this application, the terms“comprising” (and any form of comprising, such as“comprise” and“comprises”),“having” (and any form of having, such as“have” and“has”),“including” (and any form of including, such as“include” and“includes”) or“containing” (and any form of containing, such as“contain” and“contains”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method or composition of the disclosure, and vice versa. Furthermore, compositions of the disclosure can be used to achieve methods of this disclosure.

[0115] The ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination, or sub-range between and including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, as well as all intervening values of each of these listed numbers, such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With regard to sub-ranges, “nested sub-ranges” extending from either end of a range are specifically contemplated. For example, nested sub-ranges of the exemplary range of 1 to 50 can include 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.

[0116] In this application, the term“about” generally means the normal error range of a corresponding value, for example, within 20%, more preferably within 10%, and most preferably within 5% of the corresponding value

[0117] Example 1

[0118] 1 Process Description:

[0119] ①Glycopyrronium bromide and magnesium stearate are placed in a three-dimensional mixer and mixed evenly;

[0120] ②The glycopyrronium bromide and magnesium stearate mixture and lactose are respectively subjected to jet milling to a target particle size of about 3.0 μm;

[0121] ③PEG1000 is weighed, heated and melted, and then added to the propellant HFC-227ea, and high-speed shearing is performed to disperse it at 10000 rpm;

[0122] ④The micronized fluticasone furoate, glycopyrronium bromide / magnesium stearate mixture, vilanterol trifenatate, and lactose are weighed and added to the solution prepared in ③ in sequence, and high-speed shearing is performed to disperse them at 10000 rpm for 20 min;

[0123] ⑤The weight is determined, and the mixture is mixed evenly, and a small amount of sample is taken to determine the content;

[0124] ⑥The valve is sealed, filled, and leak detection is performed;

[0125] ⑦The pre-pressing is 2 presses, and the storage is inverted, and the outer packaging is performed.

[0126] The amounts of the components in the following table are used to prepare the "Fluticasone furoate / glycopyrronium bromide / vilanterol trifenatate" three-way aerosol of Example 1 according to the above method:

[0127] Note: One puff is one press, and two puffs at a time means 2 presses.

[0128] 2. Preparation property test results:

[0129] Refer to the 2020 edition of "Chinese Pharmacopoeia" four-part general rules <0111> inhalation aerosol

delivery dose uniformity

[0130] One can of fluticasone furoate / glycopyrronium bromide / vilanterol trifenatate three-way aerosol prepared according to the above process is taken, and before testing, the sample is pre-pressed 2 times and inverted and placed at room temperature for 24 hours. Shake the balanced sample for 5 seconds, discard several puffs, and use them to saturate the valve rod; connect the device according to the law, start the vacuum pump, connect the flowmeter, adjust the vacuum pump valve to control the flow rate to be 28.3 L / min (range 26.9 L / min-29.7 L / min), and stabilize for 15 seconds. Shake the inhaler (aluminum can inserted into the driver) for 5 seconds, insert it into the suction nozzle adapter, press 1 time, suck for 5 seconds, turn off the vacuum pump, and remove the inhalation device. Repeat the above process to collect the specified dose. Add 20 ml of diluent to wash the filter paper and the inside of the collection tube, and shake well to dissolve the sample. Measure a total of 10 delivery doses before (initial 3 doses), in the middle (n / 2 puffs for 4 doses, n is the total number of puffs indicated), and after (last 3 doses). Use the analysis method specified under each variety to determine the drug content in each solution. The test results are shown in Table 1.

[0131] Table 1 Delivery dose uniformity results of the preparation of Example 1

[0132] Note: The above data are based on active ingredients.

[0133] As shown in Table 1, the average delivery amount of vilanterol trifenatate is 9.61 μg, the average delivery amount of glycopyrronium bromide is 12.22 μg, and the average delivery amount of fluticasone furoate is 39.86 μg; and in the above 10 test results, all are within 75% to 125% of the average value. The average values are all within 80% to 120% of the delivery dose label. It is shown that the fluticasone furoate vilanterol trifenatate glycopyrronium bromide aerosol of the present application has good delivery dose uniformity, which meets the requirements of the pharmacopoeia.

[0134] Refer to the 2020 edition of Chinese Pharmacopoeia, General Test <0951> Determination of Fine Particle Aerodynamic Characteristics of Inhalation Preparations

Device 3 Inhalation Aerosol

[0135] Determination by connecting device. Place the collection cup in the tray, install the tray on the bottom support, and ensure that each collection cup corresponds to the corresponding position of the bottom support. Close the lid, and turn the handle under the plate. Insert the L-shaped connecting tube into the inlet end of the impactor, and install a suitable mouthpiece adapter at the other end of the L-shaped connecting tube. After inserting the driver, the mouthpiece end should be flush with the mouth of the L-shaped connecting tube, and the other end of the driver should be perpendicular upward. Connect the outlet of the impactor to the vacuum pump, turn on the vacuum pump, adjust the flow control valve to make the gas flow rate at the inlet of the L-shaped connecting tube be 30 L / min (±5%), and stabilize for 15 seconds. Remove the flow meter and keep the vacuum pump running continuously. Shake the inhalation device for 5 seconds and then press (spray) it once; remove the inhalation device, shake it for 5 seconds, reinsert the mouthpiece adapter, and press (spray) it for the second time; repeat this process until 10 pressings (sprayings) are completed. After the last pressing (spraying), remove the inhalation device, start the timer, and wait for 5 seconds. Turn off the vacuum pump. Remove the impactor, take off the L-shaped connecting tube and the mouthpiece adapter, clean them with the solvents specified in the respective variety item, and dilute them quantitatively to an appropriate volume. Loosen the handle, open the impactor, remove the tray together with the collection cups, and quantitatively collect the drugs in each collection cup and dilute them to an appropriate volume. Use the analysis method specified in the respective variety item to determine the amount of drugs in each solution. Calculate the fine particle dose FPD≤5 μm and the FPF% value to evaluate the fine particle dose of the fluticasone furoate vilanterol trifenatate glycopyrronium bromide aerosol, and the test results are shown in Table 2.

[0136] Table 2 Fine particle dose results of the preparation of Example 1

[0137] Note: The above data are based on active ingredients.

[0138] As shown in Table 2 and Figure 1, the FPD≤5μm values ​​of vilanterol triphenylacetic acid, glycopyrronium bromide, and fluticasone furoate are 7.00μg, 8.51μg, and 24.43μg, respectively, and the FPF% values ​​of all three reach over 60%, indicating that the fluticasone tri-aerosol of the present invention has a high dosage of fine particles. Furthermore, the in vitro deposition of the three active ingredients (APIs) is similar.

[0139] 3. Comparison of delivery dose uniformity and fine particle dosage between the formulation of this invention and flutemet.

[0140] As shown in Figure 2, the delivery rate / average delivery rate of the fluticadimidine tri-aerosol formulation of the present invention was between 85% and 125% in all 10 test results, and the delivery rate / average delivery rate of fluticadimidine was also between 85% and 125%. The delivery dose uniformity of the fluticadimidine tri-aerosol formulation was similar to that of fluticadimidine. As shown in Figure 3, the FPF% values ​​of vilanterol triphenylacetate, fluticasone furoate, and glycopyrronium bromide in the fluticadimidine tri-aerosol formulation were all higher than those of fluticadimidine, with the FPF% value of fluticasone furoate being approximately twice that of fluticadimidine. This indicates that the formulation and manufacturing process of the present invention are superior, resulting in higher fine particle doses for all three APIs.

[0141] 4. Results of non-clinical pharmacodynamic experiments

[0142] 4.1 Pharmacodynamic evaluation of fluticasone propionate's effect on methacholine-induced bronchospasm in guinea pigs.

[0143] 4.1.1 Animal drug administration process

[0144] After acclimatization, guinea pigs were randomly assigned to groups. They were induced to undergo anesthesia using an isoflurane inhalation anesthesia machines. Once anesthetized, continuous oral and nasal inhalation anesthesia was administered. A small incision of approximately 1 cm was quickly made in the guinea pig's neck, and the airway was bluntly dissected. An intra-airway nebulizer needle was inserted to nebulize the medication (the model group received the appropriate solvent). The wound was sutured, and the guinea pigs were weaned off inhalation anesthesia and allowed to regain consciousness.

[0145] Table 3. Trial groupings for the bronchiectasis model (experimental groups include those receiving single or combined medications).

[0146] 4.1.2 Guinea Pig Lung Function Test

[0147] After 1 hour of administration, the guinea pigs were anesthetized by intraperitoneal injection of 1.5 g / kg of urethane in water, the hair on the neck was removed, the trachea was isolated for tracheal intubation, and the jugular vein was isolated and exposed. The guinea pigs were placed in a plethysmograph box, the tracheal intubation was connected to a respirator, and then the jugular vein intubation was performed. After the guinea pigs were stabilized for 2-3 min, 0, 0.025, 0.05, 0.1, 0.2, and 0.4 mg / kg of acetylcholine in saline were injected through the jugular vein intubation at a gradient concentration, and the respiratory function was detected for 2-3 min at each concentration to observe the increase in pulmonary resistance and the decrease in lung compliance induced by acetylcholine.

[0148] As shown in Tables 4-7 and Figures 4-5, after the model group guinea pigs were intravenously injected with 0.025, 0.05, 0.1, 0.2, and 0.4 mg / kg Mch, the airway resistance increased and the lung compliance decreased, which was dose-dependent. GLY / VI / FF in combination at 0.10 / 0.04 / 0.16 μg / kg and 0.20 / 0.08 / 0.32 μg / kg dose-dependently inhibited the increase in airway resistance and the decrease in lung compliance induced by 0.05, 0.1, 0.2, and 0.4 mg / kg Mch in guinea pigs (P<0.05-0.01). GLY / VI / FF in combination at 0.20 / 0.08 / 0.32 μg / kg had a stronger inhibitory effect on the decrease in lung function induced by Mch in guinea pigs than VI / FF at 0.08 / 0.32 μg / kg. GLY / VI / FF in combination at 0.10 / 0.04 / 0.16 μg / kg had a basically equivalent inhibitory effect on the decrease in lung function induced by Mch in guinea pigs as VI / FF at 0.08 / 0.32 μg / kg. GLY / VI / FF in combination at 0.20 / 0.08 / 0.32 μg / kg had a better effect on improving the increase in pulmonary resistance and the decrease in lung compliance induced by Mch than UMEC / VI / FF at 0.20 / 0.08 / 0.32 μg / kg.

[0149] 4.2 Pharmacodynamic evaluation of flutigavimab on smoking-induced acute lung injury in rats

[0150] 4.2.1 Establishment of a rat smoke exposure model

[0151] The rats were placed in a self-made exposure cabinet, connected to a smoking machine, and the cigarette smoke was sucked into the exposure cabinet, 10 cigarettes per round, 10 min per round, continuous smoking for 10 rounds, 100 min per day per rat, and continuous smoking for 14 days. The blank control group was exposed to air.

[0152] 4.2.2 Intratracheal administration method

[0153] The rats were placed in an inhalation anesthesia machine for isoflurane induction anesthesia. After the rats were anesthetized, the rats were quickly taken out and placed on the airway administration rack. Under laryngoscope observation, the airway nebulization needle was inserted into the airway through the oral cavity to nebulize the corresponding drug. Then, the rats were taken off the anesthesia machine and waited for them to wake up. The model group and the control group were given the corresponding solvent.

[0154] 4.2.3 Analysis of inflammatory cells in alveolar lavage fluid (BALF)

[0155] Table 8 Total white blood cell count and differential count in alveolar lavage fluid (Mean ± SEM, ×10 6 cells)

[0156] ##P<0.01 vs control group, *P<0.05, **P<0.01 vs model group

[0157] 4.2.4 Lung tissue pathological changes

[0158] Table 9 Pathological score results (Mean ± SEM)

[0159] ##P<0.01 vs control group, **P<0.01 vs model group

[0160] 4.2.5 Inflammatory factor determination results

[0161] Table 10 Inflammatory activity (Mean ± SEM)

[0162] ##P<0.01 vs control group, *P<0.05, **P<0.01 vs model group

[0163] The results shown in Tables 8-10 and Figures 6-9 show that the improvement of lung inflammation in smoke-exposed rats by single or combined use of drugs or triple combination is only related to whether fluticasone furoate (FF) is contained in the prescription, and there is no significant difference in anti-inflammatory effect between single use of fluticasone furoate (FF) and the prescription (P>0.05), and the anti-inflammatory effect of fluticasone furoate (FF) + glycopyrronium bromide (GLY) + vilanterol trifenatate (VI) is equivalent to that of the commercially available full-again prescription fluticasone furoate (FF) + umeclidinium bromide (UMEC) + vilanterol trifenatate (VI) of the same dose.

[0164] Example 2

[0165] Process Description

[0166] ①Glycopyrronium bromide and lactose were weighed separately and added to a 47% ethanol aqueous solution. Stirring was performed to dissolve them, obtaining a mixed solution of lactose and glycopyrronium bromide;

[0167] 2. Spray-drying the mixed solution of glycopyrronium bromide and lactose to obtain a spray-dried mixture of glycopyrronium bromide and lactose.

[0168] 3. Weighing PEG-1000, melting and adding into propellant HFC-227ea, and dispersing at a high speed of 10000 rpm;

[0169] 4. Weighing the spray-dried mixture of glycopyrronium bromide and lactose, fluticasone furoate and vilanterol trifenatate, and adding into the solution prepared in step 3 one by one, and dispersing at a high speed of 10000 rpm for 20 min;

[0170] 5. Determining the weight, mixing, and filling.

[0171] Results of the formulation property detection:

[0172] Table 11. Results of the formulation delivery dose uniformity of Example 2

[0173] Note: The above data are based on the active ingredients.

[0174] Table 12. Results of the formulation fine particle dose of Example 2

[0175] Note: The above data are based on the active ingredients.

[0176] Table 13. Results of the formulation influencing factor test of Example 2

[0177] As shown in Table 11, all the above determination results are within 75% to 125% of the average value. The average values are within 80% to 120% of the delivery dose label, which meets the requirements of the pharmacopoeia. As shown in Table 12, the FPF value of fluticasone furoate is 56.82%, the FPF value of vilanterol trifenatate is 62.63%, and the FPF value of glycopyrronium bromide is 35.81%, which is higher than the FPD value of glycopyrronium bromide in Comparative Example 5, indicating that the process of co-spray-drying glycopyrronium bromide and lactose can improve the FPD value of glycopyrronium bromide. As shown in Table 13, the related substances of the formulation of Example 2 were detected after being placed at 60°C and 10% RH for 0, 5, 10 and 30 days, respectively. The results show that there is no degradation impurity of glycopyrronium bromide and fluticasone furoate, and the degradation impurity of vilanterol trifenatate is 2.11% after 60°C for 30 days, and there is no obvious degradation. The prescription and raw materials have good compatibility.

[0178] Example 3

[0179] 1. Process description:

[0180] The same as Example 1.

[0181] The amount of each component in the following table was used to prepare the "fluticasone" trihedral aerosol of Example 3 according to the above method:

[0182] Note: One puff is one press, and two puffs at a time means 2 presses.

[0183] 2. Results of formulation property testing:

[0184] The method was the same as in Example 1.

[0185] Table 14 Delivery dose uniformity results of fluticasone trihedral aerosol

[0186] Note: The above data are based on active ingredients.

[0187] As shown in Table 14, the average delivery amount of vilanterol was 9.33 μg, the average delivery amount of glycopyrronium was 18.09 μg, and the average delivery amount of fluticasone furoate was 39.03 μg; and in the above 10 determination results, the delivery amounts were all within 75% to 125% of the average delivery amount. The average delivery amounts were all within 80% to 120% of the delivery dose label. This shows that the fluticasone trihedral aerosol of Example 3 has good delivery dose uniformity, and meets the requirements of the pharmacopoeia.

[0188] Table 15 Fine particle dose results of fluticasone trihedral aerosol

[0189] Note: The above data are based on active ingredients.

[0190] 3. Results of non-clinical pharmacodynamics experiments

[0191] 3.1 Bronchodilatory pharmacodynamics test of fluticasone on acetylcholine and histamine-induced bronchospasm in guinea pigs

[0192] 3.1.1 Animal dosing method

[0193] After the guinea pigs were adaptively fed, they were randomly grouped. After the guinea pigs were anesthetized by inhaling isoflurane, the mouth was opened by a mouth prop, the tongue was gently pulled, a high-pressure atomizing needle was inserted through the epiglottis into the trachea, and the drug was sprayed into the airway of the animal. 50 μL was sprayed into the airway of each guinea pig.

[0194] 3.1.2 Lung function determination

[0195] At 30 min after airway administration, the guinea pigs were anesthetized with 1.5 g / kg of urethane (15% urethane, 10 mL / kg body weight) by intraperitoneal injection. The trachea and the external jugular vein were cannulated. The guinea pigs were placed in a plethysmograph box, and the chest was cannulated. The airway resistance (Raw) and dynamic lung compliance (Cdyn) were measured by recording the airway flow rate, transpulmonary pressure, and tidal volume through a pneumotachograph. The airway constriction was induced by injecting different concentrations of a mixture of acetylcholine and histamine through the external jugular vein. The concentrations of the mixture of acetylcholine (Mch) and histamine (His) were as follows: 0 / 0 μg / kg, 2 / 1.25 μg / kg, 4 / 2.5 μg / kg, 6 / 3.75 μg / kg, and 8 / 5 μg / kg.

[0196] The results shown in Tables 16-19 and Figs. 10-11 indicate that the intravenous injection of Mch / His (2 / 1.25, 4 / 2.5, 6 / 3.75, and 8 / 5 μg / kg) induced a dose-dependent airway constriction in guinea pigs, increased the airway resistance, and decreased the dynamic lung compliance. The low-dose flutergavi (143 / 71 / 36 ng / kg) and the high-dose flutergavi (571 / 286 / 143 ng / kg) significantly inhibited the airway constriction induced by Mch / His, decreased the airway resistance, and increased the dynamic lung compliance. The fluticasone furoate + vilanterol (143 / 36 ng / kg) and the glycopyrronium (71 ng / kg) also significantly inhibited the increase in the percentage of the airway resistance induced by Mch / His. At the same dose, the flutergavi three-drug combination showed a stronger inhibitory effect on the airway constriction in guinea pigs than the fluticasone furoate + vilanterol two-drug combination and the glycopyrronium single drug.

[0197] 3.2 Pharmacodynamic effects of flutergavi on asthmatic mice

[0198] 3.2.1 Establishment of an asthmatic mouse model

[0199] After the adaptation period, the mice were randomly divided into groups. The mice were subcutaneously and intraperitoneally injected with 4% aluminum hydroxide gel containing 2 mg / mL ovalbumin (OVA), and the blank control group was injected with 4% aluminum hydroxide gel without OVA. The injection sites of each mouse were as follows: 25 μL (s.c.) in each of the two hind paws; 25 μL (s.c.) in each of the two inguinal grooves; 50 μL (s.c.) in each of the two back parts; 100 μL (s.c.) in the neck; and 200 μL (i.p.) in the abdomen. The first sensitization was recorded as D1, and 200 μL of 10 mg / mL ovalbumin solution was intraperitoneally injected on D14 to enhance the sensitization. From D21 to D28, the mice were exposed to the ovalbumin solution for 30 min once a day for 8 consecutive days.

[0200] 3.2.2 Method of animal administration

[0201] D21~D28, each group of animals was anesthetized by inhaling isoflurane, the tongue was pulled out in supine position, the mouth was opened by mouth prop, the high-pressure atomizing needle was inserted into the mouse epiglottis and trachea. Each animal was given 20 μL of drug solution by atomization. The animals in the blank control group and the model group were given 0.9% DMSO physiological saline solution (consistent with the high-dose solvent of fluticasone propionate) by airway atomization. After administration, each day was given 10 mg / mL ovalbumin solution by atomization for 30 min for excitation.

[0202] Table 20 Grouping of mouse asthma model test (single drug or combination in experimental group)

[0203] 3.2.3 Effect of fluticasone propionate on airway hyperresponsiveness of asthmatic mice

[0204] Table 21 Effect of fluticasone propionate on Mch-induced airway hyperresponsiveness of asthmatic mice (Penh, measured value)

[0205] Note: compared with the blank control group, ## P<0.01, ### P<0.001; compared with the model group, *P<0.05, **P<0.01, ***P<0.001.

[0206] Table 22 Effect of fluticasone propionate on Mch-induced airway hyperresponsiveness of asthmatic mice (Penh, percentage of increase)

[0207] Note: compared with the blank control group, # P<0.05, ## P<0.01, ### P<0.001; compared with the model group, *P<0.05, **P<0.01, ***P<0.001.

[0208] Table 23 Effect of fluticasone propionate on Mch-induced airway hyperresponsiveness of asthmatic mice (Penh PC 500 )

[0209] 3.2.4 Effect of fluticasone propionate on inflammatory cells in the bronchoalveolar lavage fluid of asthmatic mice

[0210] Table 24 Effect of fluticasone propionate on inflammatory cells in the bronchoalveolar lavage fluid of asthmatic mice (Mean ± SD)

[0211] Note: 5M03 animal died after airway hyperresponsiveness test, no lung lavage was performed. Compared with the blank control group, ### P<0.001; compared with the model group, **P<0.01, ***P<0.001; compared with the fluticasone propionate low-dose group, && P<0.01.

[0212] 3.2.5 Effect of fluticasone propionate on cytokines in lung tissues of asthmatic mice

[0213] Table 25 Effect of fluticasone propionate on inflammatory factors in lung tissues of asthmatic mice

[0214] Note: Compared with the blank control group, ### P<0.001; compared with the model group, **P<0.01, ***P<0.001; compared with the fluticasone propionate low-dose group, && P<0.01, &&& P<0.001.

[0215] 3.2.6 Effect of fluticasone propionate on pathological changes in lung tissues of asthmatic mice

[0216] Table 26 Effect of fluticasone propionate on lung inflammatory infiltration in asthmatic mice (pathological score)

[0217] Note: Compared with the blank control group, ### P<0.001; compared with the model group, *P<0.05, **P<0.01.

[0218] The results are shown in Tables 21-26 and Figures 12-15. The fluticasone propionate (100 / 50 / 25 ng / kg-400 / 200 / 100 ng / kg, fluticasone propionate / vilanterol / glycopyrronium) three-drug combination can effectively inhibit the airway hyperresponsiveness of OVA-induced asthmatic mice. Under the same dose conditions, the three-drug combination has a stronger inhibitory effect on airway hyperresponsiveness than the fluticasone propionate + vilanterol two-drug combination and the glycopyrronium single drug.

[0219] The fluticasone propionate three-drug combination can effectively inhibit the lung inflammatory cell infiltration and IL-4 content and up-regulate INF-γ in OVA-induced asthmatic mice. Under the same dose conditions, the three-drug combination has a basically consistent inhibitory effect on lung inflammation as the fluticasone propionate + vilanterol two-drug combination, while the glycopyrronium has no obvious effect on lung inflammation. It is speculated that the inhibition of lung inflammation in asthmatic mice is determined by the dose of fluticasone propionate, and adding glycopyrronium on the basis of fluticasone propionate + vilanterol has no effect on the inhibition of lung inflammation in asthmatic mice.

[0220] Comparative Example 1

[0221] Process description

[0222] ①Take the right amount of purified water, add hydroxypropyl-β-cyclodextrin powder, stirring to dissolve, get hydroxypropyl-β-cyclodextrin aqueous solution;

[0223] ②The hydroxypropyl-β-cyclodextrin aqueous solution is spray dried, and finally the hydroxypropyl-β-cyclodextrin micronized powder is obtained.

[0224] ③The glycopyrronium bromide powder is subjected to air flow crushing to obtain glycopyrronium bromide micronized powder;

[0225] ④Take PEG-1000, melt and add propellant HFC-134a, high-speed shear to disperse 10000 rpm;

[0226] ⑤Take hydroxypropyl-β-cyclodextrin micronized powder, fluticasone fruroate, glycopyrronium bromide, and vilanterol trifenatate in turn and add them to the solution prepared in ④, high-speed shear to disperse 10000 rpm, 20 min;

[0227] ⑥Determine the weight, mix well, and fill the sample.

[0228] Preparation property test results:

[0229] Table 27 Comparative Example 1 preparation delivery dose uniformity results

[0230] Note: The above data are based on active ingredients.

[0231] Table 28 Comparative Example 1 preparation fine particle dose results

[0232] Note: The above data are based on active ingredients.

[0233] Table 29 Comparative Example 1 preparation related substance test results

[0234] As shown in Table 27, in the above determination results, the delivery amount of Comparative Example 1 preparation is all within 75% to 125% of the average value. And the average value is within 80% to 120% of the delivery dose label, which meets the requirements of the pharmacopoeia. As shown in Table 28, the FPF value of glycopyrronium bromide is 13.13%, which is lower than the fine particle dose of fluticasone fruroate (29.48%) and vilanterol trifenatate (38.49%). As shown in Table 29, in the related substance test results, when the sample is placed at 60℃, 10% RH for 5 days, the degradation impurity of vilanterol trifenatate is 15.01%, and when it is placed for 30 days, the triphenylacetic acid degrades, and the result cannot be counted, indicating that the compatibility of the raw materials and accessories of this prescription is poor, which cannot meet the requirements of preparation development.

[0235] Comparative Example 2

[0236] Process Description:

[0237] ① Take an appropriate amount of purified water, add hydroxypropyl methyl cellulose coarse powder, stir to dissolve, get hydroxypropyl methyl cellulose aqueous solution;

[0238] ② Spray drying of hydroxypropyl methyl cellulose aqueous solution, finally get hydroxypropyl methyl cellulose micronized powder.

[0239] ③ The crude glycopyrronium bromide was subjected to jet milling to obtain glycopyrronium bromide micronized powder;

[0240] ④ Take PEG-1000, melt after adding propellant HFC-227ea, high speed shearing to disperse 10000 rpm;

[0241] ⑤ Take hydroxypropyl methyl cellulose micronized powder, fluticasone propionate, glycopyrronium bromide, vilanterol trifenatate, add them one by one into the solution prepared in ④, high speed shearing to disperse 10000 rpm, 20 min;

[0242] ⑥ Constant weight, mix well, fill.

[0243] Formulation property test results:

[0244] Table 30 Formulation delivery dose uniformity results of Comparative Example 2

[0245] Note: The above data are calculated based on the active ingredients.

[0246] Table 31 Formulation fine particle dose results of Comparative Example 2

[0247] Note: The above data are calculated based on the active ingredients.

[0248] Table 32 Formulation related substance test results of Comparative Example 2

[0249] From Table 30, in the above determination results, all are between 75% and 125% of the average value. And the average value is between 80% and 120% of the delivery dose label, which meets the requirements of the pharmacopoeia. From Table 31, the FPF value of glycopyrronium bromide is 17.29%, and the fine particle dose is low. From Table 32, the related substances of the preparation of Comparative Example 2 were detected when it was placed at 60°C, 10% RH for 0, 5, 10, 30 days. The results showed that there was basically no degradation impurity of fluticasone furoate and glycopyrronium bromide. The degradation impurity of vilanterol trifenatate was 5.00% when it was placed at 60°C for 30 days, indicating that vilanterol trifenatate had a certain degree of degradation; combined with the results of the preparation property test, this prescription cannot meet the requirements of the development of the preparation.

[0250] Comparative Example 3

[0251] Process Description

[0252] ①The crude glycopyrronium bromide powder was subjected to jet milling to obtain glycopyrronium bromide micronized powder;

[0253] ②PEG-1000 was weighed and added to the propellant HFC-227ea after being heated and melted, and high-speed shearing was used to disperse it at 10000 rpm;

[0254] ③Tilomisib, fluticasone furoate, glycopyrronium bromide, and vilanterol trifenatate were weighed and added to the solution prepared in ② one by one, and high-speed shearing was used to disperse them at 10000 rpm for 20 min;

[0255] ④Determine the weight, mix well, and fill.

[0256] Preparation property test results:

[0257] Table 33 Delivery dose uniformity results of the preparation of Comparative Example 3

[0258] Note: The above data are calculated based on the active ingredients.

[0259] Table 34 Fine particle dose results of the preparation of Comparative Example 3

[0260] Note: The above data are calculated based on the active ingredients.

[0261] Table 35 Influence factor test results of the preparation of Comparative Example 3

[0262] From Table 33, it can be seen that the delivery amount of the comparative example 3 preparation is all within 75% to 125% of the average value in the above determination results. And the average value is all within 80% to 120% of the delivery dose marked amount, which meets the requirements of the pharmacopoeia. From Table 34, it can be seen that the FPF value of glycopyrronium bromide is 27.44%, the FPF value of fluticasone furanoate is 30.50%, and the FPF value of vilanterol trifenatate is 36.51%, and the fine particle doses of the three APIs are close. From Table 35, it can be seen that the related substances of the comparative example 3 preparation are detected under the condition of 60°C and 10% RH for 0, 5 and 10 days respectively. The results show that glycopyrronium bromide and fluticasone furanoate have no degradation impurities at 60°C for 10 days, and vilanterol trifenatate in the trifenatate salt is severely degraded, which indicates that the compatibility of the raw materials and accessories of the prescription is poor, and cannot meet the requirements of the preparation development.

[0263] Comparative example 4

[0264] Process description

[0265] ①Take a suitable amount of purified water, add methyl cellulose coarse powder, stir to dissolve, and get methyl cellulose aqueous solution;

[0266] ②Spray drying of methyl cellulose aqueous solution, finally get methyl cellulose micronized powder.

[0267] ③Glycopyrronium bromide coarse powder is subjected to jet milling to obtain glycopyrronium bromide micronized powder;

[0268] ④Weigh PEG-1000, melt after heating, add propellant HFC-227ea, high-speed shearing to disperse 10000 rpm;

[0269] ⑤Weigh methyl cellulose, fluticasone furanoate, glycopyrronium bromide, vilanterol trifenatate, and add them one by one into the solution prepared in ④, high-speed shearing to disperse 10000 rpm, 20 min;

[0270] ⑥Determine the weight, mix well, and fill.

[0271] Preparation property test results:

[0272] Table 36 Delivery dose uniformity results of comparative example 4 preparation

[0273] Note: The above data are calculated based on the effective ingredients.

[0274] Table 37 Fine particle dose results of comparative example 4 preparation

[0275] Note: The above data are calculated based on the effective ingredients.

[0276] Table 38 Formulation influencing factor test results of Comparative Example 4

[0277] As shown in Table 36, the delivery amount of the formulation of Comparative Example 4 was all within 75% to 125% of the average value in the above determination results. The average value was all within 80% to 120% of the delivery dose label, which met the requirements of the pharmacopoeia. As shown in Table 37, the FPF value of fluticasone furfurate was 59.97%, the FPF value of vilanterol trifenate was 66.85%, and the FPF value of glycopyrronium bromide was 42.95%, indicating that the excipient can improve the FPD and FPF values of glycopyrronium bromide in the prescription. As shown in Table 38, the related substances of Comparative Example 4 were detected after the formulation was placed at 60°C and 10% RH for 0, 5, 10 and 30 days, respectively. The results showed that there was no degradation impurity of glycopyrronium bromide and fluticasone furfurate at 60°C for 30 days, and the degradation impurity of vilanterol trifenate was 8.49%, and obvious degradation impurities were produced, indicating that the compatibility of the raw materials and excipients of the prescription was poor. In order to ensure the quality of the product during the shelf life, the prescription was excluded.

[0278] Comparative Example 5

[0279] Process description:

[0280] ①The crude glycopyrronium bromide powder was subjected to jet milling to obtain glycopyrronium bromide micronized powder;

[0281] ②The prescription amount of PEG-1000 was weighed in the prescription amount of HFC-227ea, and dispersed at 10000 rpm for 1 min;

[0282] ③The prescription amount of micronized lactose (D90≤10 μm) was weighed in the solution prepared in ②, and dispersed at 10000 rpm for 1 min;

[0283] ④The prescription amount of fluticasone furfurate was weighed in the solution prepared in ③, and dispersed at 10000 rpm for 1 min;

[0284] ⑤The prescription amount of glycopyrronium bromide was weighed in the solution prepared in ④, and dispersed at 10000 rpm for 1 min;

[0285] ⑥The prescription amount of vilanterol trifenate was weighed in the solution prepared in ⑤, and dispersed at 10000 rpm for 20 min;

[0286] ⑦Determined the weight, mixed uniformly, and filled.

[0287] Formulation property detection results:

[0288] Table 39 Delivery dose uniformity results of the formulation of Comparative Example 5

[0289] Note: The above data are calculated based on the active ingredients.

[0290] Table 40 Comparative Example 5 formulation fine particle dose results

[0291] Note: The above data are based on active ingredients.

[0292] Table 41 Comparative Example 5 formulation related substance test results

[0293] From Table 39, the above test results show that the delivery amount of the Comparative Example 5 formulation is between 75% and 125% of the average value, and the average value is between 80% and 120% of the delivery dose label, which meets the requirements of the pharmacopoeia. From Table 40, the FPF value of fluticasone furfurate is 44.53%, the FPF value of vilanterol trifenatate is 49.67%, and the FPF value of glycopyrronium bromide is relatively low, only 10.63%. From Table 41, the related substances of the Comparative Example 5 formulation were tested after being placed at 60°C, 10% RH for 0, 5, 10, and 30 days, respectively. The results show that each API has no obvious degradation impurities, and the compatibility of the raw and auxiliary materials is good. However, due to the test results of the formulation characteristics, the FPF value of glycopyrronium bromide is relatively low, which cannot meet the requirements of the development of the formulation, so this prescription is excluded.

[0294] Comparative Example 6

[0295] Only HFC-227ea in Example 3 is replaced by HFC-134a, and the rest is the same as Example 3.

[0296] Process description:

[0297] ① Weigh the prescribed amount of PEG-1000 in the prescribed amount of HFC-134a, and disperse at 10000 rpm for 1 min;

[0298] ② Weigh the prescribed amount of micronized lactose (D90≤10μm) in the solution prepared in ②, and disperse at 10000 rpm for 1 min;

[0299] ③ Weigh the prescribed amount of fluticasone furfurate in the solution prepared in ③, and disperse at 10000 rpm for 1 min;

[0300] ④ Weigh the prescribed amount of glycopyrronium bromide in the solution prepared in ④, and disperse at 10000 rpm for 1 min;

[0301] ⑤ Weigh the prescribed amount of vilanterol trifenatate in the solution prepared in ⑤, and disperse at 10000 rpm for 20 min;

[0302] ⑥ Weigh, mix, and fill.

[0303] Formulation characteristic test results:

[0304] Table 42 Comparative Example 6 formulation delivery dose uniformity results

[0305] Note: The above data are based on active ingredients.

[0306] Table 43 Comparative Example 6 Preparation Fine Particle Dose Results

[0307] Note: The above data are based on active ingredients.

[0308] From Table 42, the same formulation ratio as Example 3, the propellant is replaced by HFC-134a to investigate the formulation characteristics of the formulation, the delivery dose uniformity test results, the delivery amount / average delivery amount are between 75%~125%, which meets the requirements of the pharmacopoeia. The average delivery amount / labeling amount exceeds the range of 80%~120% required by the pharmacopoeia, which does not meet the requirements of the pharmacopoeia. From Table 43, the FPF value of fluticasone furoate is 40.55%, the FPF value of vilanterol is 42.35%, and the FPF value of glycopyrronium is 34.17%, and the FPD of each API can meet the requirements of formulation development. Considering the above results, the propellant HFC-227ea is more suitable.

[0309] Comparative Example 7

[0310] Process Description:

[0311] The fixed amount of glycerol, poloxamer 188, DSPC, oleic acid, Tween 80, HS15, and lactose in the prescription were weighed, respectively, and the propellant was filled into the aluminum can by cold filling method, and the valve cover was covered, and the aerosol clamp machine was sealed. The 0-day sample was taken for related substance detection, and then placed in a constant temperature and humidity box at 60°C and 10% RH, and taken out at the 10th day for related substance detection. The results are shown in the table below.

[0312] Related substance detection results:

[0313] Table 44 Auxiliary Material Screening Related Substance Detection Results

[0314] From Table 44, different types of surfactants are added to the prescription, and the stability of the raw material is investigated by taking the related substances of each API as the evaluation index through the compatibility test of raw and auxiliary materials. From the test results, glycerol, poloxamer 188, distearoyl phosphatidylcholine, oleic acid, Tween 80, and 15-hydroxystearic acid polyethylene glycol ester are added to the prescription, respectively, and then placed at 60℃, 10% RH for 10 days. The detection of related substances shows that the above-mentioned auxiliary materials cause significant degradation of terbutaline trifenatate, indicating that the stability of the raw material decreases after the above-mentioned auxiliary materials are added to the prescription. However, after lactose is added to the prescription, each API does not show significant degradation, and it is preliminarily judged that lactose has good compatibility with the raw material. The compatibility of the raw and auxiliary materials of the prescription is further investigated, and the results are as follows:

[0315] Table 45: Detection results of lactose related substances

[0316] From Table 45, lactose is added to the prescription as an auxiliary material and placed at 60℃, 10% RH for 30 days. No impurity C is detected for glycopyrronium, the total impurities of fluticasone furoate are 0.21%, and the total impurities of vilanterol are 2.58%. After being placed at an accelerated condition (40℃, 75% RH) for 1 month, no impurity C is detected for glycopyrronium, the total impurities of fluticasone furoate are 0.09%, and the total impurities of vilanterol are 0.76%, all of which are within the acceptable range of the prescription screening. Therefore, lactose is selected as the auxiliary material in the embodiment.

[0317] The above has exemplarily described the embodiments of the technical scheme of the present application. It should be understood that the protection scope of the present application is not limited to the above-mentioned embodiments. Any modification, equivalent replacement, improvement, etc. made by those skilled in the art within the spirit and principle of the present application shall be included in the protection scope of the claims of the present application.

Claims

1. A composition comprising fluticasone furoate, vilanterol trifenatate, glycopyrronium bromide, a diluent, a surfactant and a propellant; Preferably, the diluent is selected from one or more of biodegradable polymers, sugar alcohols, monosaccharides, disaccharides, polysaccharides.

2. The composition of claim 1, wherein, The biodegradable polymers are selected from one or more of polylactic acid, polyglycolic acid, hydroxypropyl cellulose, chitin, hyaluronic acid; Preferably, the sugar alcohols are selected from one or more of mannitol, xylitol, sorbitol, maltitol; Preferably, the monosaccharides are selected from one or more of glucose, fructose, galactose, ribose; Preferably, the disaccharides are selected from one or more of lactose, maltose, sucrose; Preferably, the polysaccharides are selected from one or more of starch, cellulose, glycogen.

3. The composition according to claim 1 or 2, characterized in that, The surfactants are selected from sorbitan esters or polyoxyethylene derivatives thereof, such as polyethylene glycol; Preferably, the polyethylene glycol is selected from PEG400, PEG600, PEG800, PEG1000, PEG1500; Preferably, the propellant is selected from one or more of hydrocarbons, hydrofluorochloroalkanes, hydrofluorocarbons; for example, one or more of propane, n-butane, isobutane, trifluoro-monochloroethane, 1,1,1,2,3,3,3-heptafluoropropane (HFC-227ea), 1,1,1,2-tetrafluoroethane, 1,1-difluoroethane (HFC-152a), 2,3,3,3-tetrafluoropropene (HFO-1234yf), monochlorodifluoroethane; Preferably, the composition can further comprise a stabilizer selected from one or more of stearate salts, amino acids, high molecular compounds; Preferably, the stearate salts are selected from one or more of magnesium stearate, sodium stearate, calcium stearate; Preferably, the amino acids are selected from one or more of arginine, glycine, histidine, aspartic acid; Preferably, the high molecular compounds are selected from one or more of polyvinyl alcohol, sodium alginate, sodium hyaluronate, chitosan, hydroxyethyl starch; Preferably, the fluticasone furoate, vilanterol trifenatate, glycopyrronium bromide are in micronized form; the particle size of the micronized ingredients is about 0.1-10 μm, for example about 1-5 μm.

4. The composition according to any one of claims 1 to 3, characterized in that, The fluticasone furoate accounts for 0.01%-0.20% of the mass percentage of the composition, for example 0.05%-0.10%, for example 0.06%-0.09% or 0.065%-0.080%; Preferably, the vilanterol trifenatate accounts for 0.005%-0.100% of the mass percentage of the composition, for example 0.010%-0.050%, for example 0.020%-0.040% or 0.025%-0.030%; Preferably, the glycopyrronium bromide accounts for 0.005%-0.100% of the mass percentage of the composition, for example 0.010%-0.050%, for example 0.020%-0.050%, 0.025%-0.045% or 0.028%-0.045%; Preferably, when a stabilizer is included in the composition, the stabilizer is present in an amount of 0.0001% to 0.0100%, for example 0.0005% to 0.0050%, 0.0010% to 0.0030%, or 0.0015% to 0.0025%, by mass of the composition; Preferably, the diluent is present in an amount of 0.01% to 1%, for example 0.05% to 0.5%, 0.06% to 0.4%, 0.07% to 0.3%, 0.08% to 0.2%, 0.09% to 0.19%, 0.10% to 0.18%, 0.11% to 0.17%, or 0.12% to 0.16%, by mass of the composition; Preferably, the surfactant is present in an amount of 0.01% to 1%, for example 0.05% to 0.5%, 0.1% to 0.4%, or 0.2% to 0.3%, by mass of the composition; Preferably, the propellant is present in an amount of 97.59% to 99.96%, for example 98.00% to 99.90%, 99.00% to 99.85%, 99.10% to 99.80%, 99.20% to 99.75%, 99.30% to 99.70%, 99.40% to 99.65%, 99.40% to 99.60%, or 99.40% to 99.55%, by mass of the composition.

5. The composition according to any one of claims 1 to 4, characterized in that, The composition, comprising: fluticasone furoate, vilanterol trifenatate, glycopyrronium bromide, lactose, polyethylene glycol, and 1,1,1,2,3,3,3-heptafluoropropane (HFC-227ea); Preferably, the composition comprises, in mass percentages: Preferably, the composition comprises, in mass percentages: Preferably, the composition, comprising: fluticasone furoate, vilanterol trifenatate, glycopyrronium bromide, magnesium stearate, lactose, polyethylene glycol, and 1,1,1,2,3,3,3-heptafluoropropane (HFC-227ea); Preferably, the composition comprises, in mass percentages: Preferably, the composition comprises, in mass percentages: Preferably, the composition comprises, in mass percentages: Preferably, the composition is an aerosol; Preferably, the composition is a suspension aerosol.

6. A method for preparing the composition of any one of claims 1 to 5, comprising the steps of: (1) dispersing the surfactant in the propellant after being heated and molten to obtain a formulation solution; (2) dispersing the remaining components of the composition except for the surfactant in the formulation solution of (1); The remaining components of the composition except for the surfactant are fluticasone furoate, vilanterol trifenatate, glycopyrronium bromide, and the diluent, or are fluticasone furoate, vilanterol trifenatate, glycopyrronium bromide, the diluent, and the stabilizer; Preferably, in the method for preparing, the fluticasone furoate, vilanterol trifenatate, and glycopyrronium bromide are in micronized form; Preferably, the particle size of the micronized particles is about 0.1 to 10 μm, for example about 1 to 5 μm; Preferably, the method for preparing comprises a step of micronizing one or more components of the composition, for example, the components of the composition can be subjected to jet milling to obtain a target particle size of the micronized particles; for example, the glycopyrronium bromide and the diluent of the composition can be mixed and dissolved in a solvent, and then spray dried to facilitate micronization. Preferably, the solvent is a mixed solution of an alcohol solvent and water, and the alcohol solvent is, for example, methanol or ethanol; the volume percentage of the alcohol solvent in the solvent is 20-80%.

7. The preparation method according to claim 6, comprising the following Scheme I and / or Scheme II: Scheme I: the preparation method of the composition, comprising the following steps: (A1) mixing glycopyrronium bromide and the diluent, and then dissolving them in a solvent to obtain a glycopyrronium bromide / diluent mixed solution; (A2) spray drying the mixed solution to obtain a glycopyrronium bromide / diluent mixed spray-dried product; (A3) weighing the surfactant, melting it after heating, and then dispersing it in the propellant to obtain a preparation solution; (A4) weighing the glycopyrronium bromide / diluent mixed spray-dried product, fluticasone furanoate, and vilanterol trifenatate, and then adding them into the preparation solution of step (A3) in sequence to obtain the composition; Preferably, the solvent in step (A1) is a mixed solution of an alcohol solvent and water, and the alcohol solvent is, for example, methanol or ethanol; Preferably, the volume percentage of the alcohol solvent in the solvent in step (A1) is 20-80%. Preferably, the glycopyrronium bromide / diluent mixed spray-dried product, fluticasone furanoate, and vilanterol trifenatate are all micronized; the particle size of each micronized product is about 0.1-10 μm, for example, about 1-5 μm; Scheme II: the preparation method of the composition, comprising the following steps: (B1) mixing glycopyrronium bromide and the stabilizer to obtain a glycopyrronium bromide / stabilizer mixture; (B2) crushing the glycopyrronium bromide / stabilizer mixture and the diluent to a particle size of about 0.1-10 μm to obtain a micronized glycopyrronium bromide / stabilizer mixture and a micronized diluent powder; (B3) weighing the surfactant, melting it after heating, and then dispersing it in the propellant to obtain a preparation solution; (B4) weighing the micronized fluticasone furanoate, glycopyrronium bromide / stabilizer mixture, and vilanterol trifenatate, and then adding them into the preparation solution of step (B3) in sequence to obtain the composition; Preferably, the particle size in step (B2) is 1-5 μm.

8. The production method according to claim 6 or 7, characterized by, The preparation method of the composition, comprising the following steps: (A1) mixing glycopyrronium bromide and lactose, and then dissolving them in an ethanol aqueous solution to obtain a glycopyrronium bromide / lactose mixed solution; (A2) spray drying the mixed solution to obtain a glycopyrronium bromide / lactose mixed spray-dried product; (A3) weighing polyethylene glycol, melting it after heating, and then dispersing it in the propellant to obtain a preparation solution; (A4) weighing the glycopyrronium bromide / lactose mixed spray-dried product, fluticasone furanoate, and vilanterol trifenatate, and then adding them into the preparation solution of step (A3) in sequence to obtain the composition; Preferably, the preparation method of the composition, comprising the following steps: (A1) mixing glycopyrronium bromide and lactose, and then dissolving them in a 47% ethanol aqueous solution to obtain a glycopyrronium bromide / lactose mixed solution; (A2) spray drying the mixed solution to obtain a glycopyrronium bromide / lactose mixed spray-dried product; (A3) Weigh PEG1000, melt and add into propellant HFC-227ea, high speed shearing to disperse to obtain the preparation solution; (A4) Weigh glycopyrronium bromide / lactose mixed spray-dried substance, fluticasone fruroate, vilanterol trifenatate, add into the preparation solution of step (A3) in turn, high speed shearing to disperse to obtain the composition; Preferably, the preparation method of the composition comprises the following steps: (B1) Mix glycopyrronium bromide with magnesium stearate to obtain a glycopyrronium bromide / magnesium stearate mixture, to obtain a mixture of glycopyrronium bromide and magnesium stearate; (B2) Pulverize the glycopyrronium bromide / magnesium stearate mixture and lactose respectively to a particle size of about 0.1-10 μm to obtain micronized glycopyrronium bromide / stabilizer mixture and micronized lactose; (B3) Weigh polyethylene glycol, melt and add into propellant to disperse to obtain the preparation solution; (B4) Weigh micronized fluticasone fruroate, glycopyrronium bromide / magnesium stearate mixture, vilanterol trifenatate, lactose, add into the preparation solution of step (B3) in turn, disperse to obtain the composition; Preferably, the preparation method of the composition comprises the following steps: (B1) Mix glycopyrronium bromide with magnesium stearate in a three-dimensional mixer to mix uniformly to obtain a mixture of glycopyrronium bromide and magnesium stearate; (B2) Pulverize the mixture of glycopyrronium bromide and magnesium stearate, lactose respectively by airflow to a particle size of about 0.1-10 μm to obtain micronized glycopyrronium bromide / stabilizer mixture and micronized lactose; (B3) Weigh PEG1000, melt and add into propellant HFC-227ea, high speed shearing to disperse to obtain the preparation solution; (B4) Weigh micronized fluticasone fruroate, glycopyrronium bromide / magnesium stearate mixture, vilanterol trifenatate, lactose, add into the preparation solution of step (B3) in turn, high speed shearing to disperse to obtain the composition.

9. The composition prepared by the preparation method of any one of claims 6-8.

10. Use of the composition of any one of claims 1-5 or the composition of claim 9 in the preparation of a medicament for treating respiratory diseases; Preferably, the respiratory diseases are selected from chronic obstructive pulmonary disease, chronic bronchitis, asthma, chronic respiratory obstruction, pulmonary fibrosis, emphysema, allergic rhinitis, small airway disease, bronchiectasis and cystic fibrosis; Preferably, the asthma is severe asthma or asthma not well controlled.

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