Composition for treating or preventing acute attack of bronchial asthma as well as preparation method and application of composition

Abstract

The invention relates to a composition for treating or preventing acute attack of bronchial asthma as well as a preparation method and application of the composition. Specifically, the invention provides an aerosol inhalation composition, which contains budesonide and salbutamol or pharmaceutically acceptable salts thereof, and does not contain a metal chelating agent. The invention accidentally finds that the aerosol inhalation composition can unexpectedly reduce the generation of salbutamol R and D impurities, has high stability, increases the aerosol inhalation volume of a patient, has less aerosol residue, and is beneficial to absorption. The composition has an excellent effect of preventing and / or treating acute attack of asthma.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparation, in particular, to a composition for treating or preventing acute attack of bronchial asthma and a preparation method and use thereof. BACKGROUND

[0002] Asthma is a serious common disease characterized by airway inflammation, airway hyperresponsiveness and bronchial constriction, and is a heterogeneous disease with a spectrum of phenotypes and a range of severity. However, all asthma patients are prone to severe acute attack, and currently an estimated 235 million people worldwide are affected by asthma, with an 8% prevalence rate in children and adults, and acute asthma exacerbation accounts for a large part of health care utilization. Many asthma exacerbations can be controlled by short-acting beta2 receptor agonists (SABA) or simultaneous use of glucocorticosteroids (ICS), both of which can be associated with morbidity, but severe exacerbations can require hospitalization, higher or longer doses of ICS, and can lead to death.

[0003] Currently, budesonide inhalation suspension and salbutamol inhalation solution are both approved for marketing, salbutamol inhalation is effective for bronchospasm, but fails to treat inflammation, ICS drugs (such as budesonide) can treat inflammation but fail to dilate bronchi to treat airway spasm, but there is currently no research data on whether the two can be used in combination, if the two are administered in sequence and separately by nebulization, the administration time will be greatly prolonged, and the use purpose of preventing and reducing severe acute exacerbation cannot be quickly achieved. Although there are many control drugs for treating asthma on the market, currently only single SABA or ICS nebulization drugs are approved for the treatment of asthma attack (SABA). There is currently no combination drug that can reduce severe acute exacerbation of asthma by nebulization treatment.

[0004] Therefore, there is an urgent need in the art to develop a nebulization inhalation drug that can combine SABA and ICS for treating or preventing bronchial asthma, especially acute attack of bronchial asthma. SUMMARY

[0005] The present application aims to provide a nebulization inhalation drug that can combine SABA and ICS for treating or preventing bronchial asthma, especially acute attack of bronchial asthma.

[0006] The present application provides, in a first aspect, a nebulization inhalation composition comprising budesonide and salbutamol or a pharmaceutically acceptable salt thereof, without containing a metal chelating agent.

[0007] In another preferred embodiment, the nebulized inhalation composition comprises, by weight percent: budesonide 0.01-0.08%, salbutamol and pharmaceutically acceptable salts thereof 0.005-0.3%, a wetting agent 0.001-0.1%, an osmotic pressure adjusting agent 4.0-9.0%, a pH adjusting agent or buffer, and the balance being water for injection; the nebulized inhalation composition does not contain a metal chelating agent.

[0008] In another preferred embodiment, the nebulized inhalation composition comprises: 0.1-0.8 mg / ml budesonide and 0.1-3.0 mg / ml salbutamol.

[0009] In another preferred embodiment, the nebulized inhalation composition comprises:

[0010] 0.1-0.8 mg / ml budesonide,

[0011] 0.1-3.0 mg / ml salbutamol,

[0012] 0.02-1.0 mg / ml wetting agent,

[0013] pH 4.0-6.0;

[0014] EDTA is not contained.

[0015] In another preferred embodiment, the pH adjusting agent or buffer adjusts the pH to 4.0-6.5, preferably 5.0-6.0, more preferably 5.5-6.0.

[0016] In another preferred embodiment, the pH adjusting agent or buffer is selected from the group consisting of an organic acid, an inorganic acid, an organic base, an inorganic base, or a combination thereof.

[0017] In another preferred embodiment, the pH adjusting agent or buffer is selected from the group consisting of sodium hydroxide, hydrochloric acid, acetic acid, sulfuric acid, citric acid, sodium citrate, disodium hydrogen phosphate, or a combination thereof.

[0018] In another preferred embodiment, the pH adjusting agent or buffer is present in an amount of 0.05-5.0 mg / mL; preferably 0.1-2 mg / mL.

[0019] In another preferred embodiment, the salbutamol pharmaceutically acceptable salt is selected from the group consisting of salbutamol sulfate, salbutamol hydrochloride, levosalbutamol tartrate, levosalbutamol fumarate, salts of salbutamol isomers, or a combination thereof.

[0020] In another preferred embodiment, the wetting agent is selected from the group consisting of Tween 20, Tween 40, Tween 60, Tween 80, Span 20, Span 40, Span 60, Span 80, lecithin, poloxamer, or a combination thereof.

[0021] In another preferred embodiment, the osmotic pressure adjusting agent is selected from the group consisting of sodium chloride, lactose, glucose, glycerol, or a combination thereof.

[0022] In another preferred embodiment, the osmotic pressure adjusting agent is present in an amount of 1-10 mg / ml; preferably 5-9 mg / mL.

[0023] In a second aspect of the present application, a method for preparing the nebulization inhalation composition as described in the first aspect of the present application is provided, comprising the following steps:

[0024] The budesonide solution without EDTA is mixed with the salbutamol or pharmaceutically acceptable salt thereof solution under nitrogen to obtain the nebulization inhalation composition.

[0025] In another preferred embodiment, the method further comprises the following steps:

[0026] S1: mixing the wetting agent with 0.1-2% of the formulation volume of water for injection to obtain a wetting agent stock solution; mixing the budesonide with the wetting agent stock solution to obtain a budesonide suspension;

[0027] S2: mixing the budesonide suspension obtained in step S1 with the wetting agent stock solution under nitrogen to obtain a budesonide suspension, wherein the oxygen content is ≤5 ppm;

[0028] S3: mixing the salbutamol, pH adjusting agent or buffer, and osmotic pressure adjusting agent under nitrogen to obtain a salbutamol solution, wherein the oxygen content is ≤5 ppm;

[0029] S4: mixing the salbutamol solution obtained in step S3 with the budesonide suspension obtained in step S2 under nitrogen for no less than 5 min to obtain the nebulization inhalation composition.

[0030] In another preferred embodiment, step S1 comprises: mixing the wetting agent with 0.1-2% of the formulation volume of water for injection to obtain a wetting agent stock solution; mixing the budesonide with the wetting agent stock solution, and after stirring, obtaining a budesonide suspension.

[0031] In another preferred embodiment, step S2 comprises: injecting 3-10% of water for injection into a first liquid preparation tank, introducing nitrogen to obtain an oxygen content of ≤5 ppm, transferring the budesonide suspension obtained in step S1 into the first liquid preparation tank, and adding the budesonide suspension and the wetting agent stock solution to the first liquid preparation tank, and stirring and dispersing in two steps and sterilizing to obtain the budesonide suspension.

[0032] In another preferred embodiment, step S3 comprises: injecting 60-80% of water for injection into the second liquid preparation tank, introducing nitrogen gas until the oxygen content is ≤5ppm, adding salbutamol, pH adjuster or buffer, osmotic pressure adjuster, performing magnetic stirring, and filtering to obtain a salbutamol solution.

[0033] In another preferred embodiment, step S4 comprises: continuously introducing nitrogen gas into the third liquid preparation tank for not less than 5 min, adding the filtered salbutamol solution obtained in S3 and the homogenized budesonide suspension obtained in S2, adding the remaining amount of water for injection, performing magnetic stirring, and filling into 1-10 ml using a BFS device, and storing in the dark at 30°C or below.

[0034] In another preferred embodiment, in step S1, the magnetic stirring speed is 100-1000 rpm, and the stirring time is 5-30 min.

[0035] In another preferred embodiment, in step S2, the stirring speed in the first step is 1000-3000 rpm, the stirring time is 5-30 min, the stirring speed in the second step is 200-2000 rpm, and the stirring time is 5-30 min.

[0036] In another preferred embodiment, in step S2, the sterilization temperature is 100-125°C, and the sterilization time is 10-30 min.

[0037] In another preferred embodiment, in step S3, the magnetic stirring speed is 1000-3000 rpm (preferably 2000 rpm), and the stirring time is 10-40 min.

[0038] In another preferred embodiment, the filtering step is filtering through two 0.2 μm sterilizing filter cartridges.

[0039] In another preferred embodiment, in step S4, the homogenization conditions are a pressure of 500-2000 bar, a magnetic stirring speed of 500-1500 rpm, and a stirring time of 10-30 min.

[0040] In another preferred embodiment, in step S4, the BFS device filling size is 2-3 ml.

[0041] In a third aspect of the present application, there is provided the use of the nebulized inhalation composition according to the first aspect of the present application for the preparation of a medicament for preventing and / or treating a respiratory disease.

[0042] In another preferred embodiment, the respiratory disease is selected from the group consisting of bronchial asthma, bronchospasm, and / or alleviating asthma exacerbation, or a combination thereof.

[0043] In another preferred embodiment, the bronchial asthma comprises: acute bronchial asthma, chronic bronchial asthma, or a combination thereof; preferably acute bronchial asthma.

[0044] In another preferred embodiment, the drug is aerosolized by an aerosol inhaler, and is delivered to the lung by oral or nasal inhalation.

[0045] In another preferred embodiment, the prescription of the drug comprises:

[0046] 0.1-0.8 mg / ml budesonide,

[0047] 0.1-3.0 mg / ml salbutamol,

[0048] 0.02-1.0 mg / ml wetting agent,

[0049] pH 4.0-6.0;

[0050] EDTA is not contained.

[0051] In another preferred embodiment, the wetting agent is selected from the group consisting of Tween 80, Tween 40, Tween 60, Tween 20, Span 20, Span 40, Span 60, Span 80, lecithin, poloxamer, or a combination thereof.

[0052] In another preferred embodiment, the specification of the drug comprises 2.5-2.8 ml / branch.

[0053] In another preferred embodiment, the drug with a specification of 2.5 ml / branch comprises: 0.5 mg budesonide, 2.5 mg salbutamol.

[0054] In another preferred embodiment, the drug with a specification of 2.5 ml / branch comprises: 1 mg budesonide, 5 mg salbutamol.

[0055] It should be understood that, within the scope of the present application, each of the technical features of the present application described above and each of the technical features specifically described below (e.g., in the examples) can be combined with each other to form a new or preferred technical solution. Due to the limited space, they will not be listed one by one here. BRIEF DESCRIPTION OF DRAWINGS

[0056] Figure 1 Shown is a comparison result chart of the impurity content of the nitrogen-filled prescription and the sample prepared by the EDTA prescription in Comparative Example 1 after storage at 40°C for 6 months.

[0057] Figure 2 Shown is a comparison chart of the fine particle dose of budesonide in different specification samples in an embodiment of the present application.

[0058] Figure 3The figure shows the comparison of the amount of salbutamol fine particle dose deposited in each layer of different specifications of samples in an embodiment of the present application. DETAILED DESCRIPTION

[0059] The present inventors have developed an aerosolized inhalation composition. The aerosolized inhalation composition comprises budesonide and salbutamol or a pharmaceutically acceptable salt thereof, and does not contain a metal chelating agent. The present inventors have surprisingly found that the aerosolized inhalation composition prepared by the nitrogen method without EDTA can surprisingly reduce the generation of salbutamol R and D impurities, has high stability, increases the aerosolized inhalation amount of patients, has less aerosol residue, is helpful for absorption, and has excellent effects of preventing and / or treating acute asthma attacks. On this basis, the present application is completed.

[0060] TERMS

[0061] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the application belongs.

[0062] As used herein, the terms "comprises", "comprising", "includes", "including", "has", "having", "contains", "containing", or variations thereof, are intended to be inclusive, rather than exclusive, unless otherwise specified. "Comprises" or "comprising" is determined by the context based on the foregoing. "Comprises" or "comprising" does not exclude the presence of additional elements or steps. "Comprises" or "comprising" does not exclude additional steps or additional elements that are incorporated into the composition, composition of matter, or method, or that are otherwise used in the method, composition of matter, or composition.

[0063] Acute asthma attack

[0064] National and international guidelines revision (EPR-4 working group of the National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC) experts group 4 (EPR-4) 2020; GINA (Global Initiative for Asthma) Scientific Committee 2022) recommends the use of ICS and SABA as the preferred alternative to "SMART" (single maintenance and reliever therapy drug ICS (inhaled glucocorticoid) / formoterol (long-acting beta2 agonist, LABA)) for some patients. The GINA Scientific Committee published in 2023 that low-dose ICS-salbutamol combination preparations can be used on demand to quickly relieve asthma symptoms and for the prevention of asthma symptoms and bronchoconstriction. (Handbook 2023 GINA Handbook 56 pages, low-dose ICS-salbutamol - for the prevention of asthma symptoms and bronchoconstriction, GINA calls it AIR therapy; on demand to quickly relieve asthma symptoms, also known as rescue inhalation drug), GINA 2023 Handbook page 34: treatment with short-acting beta2 receptor agonists (SABA) alone is also an important risk factor for acute attacks. Compared with SAB alone, ICS-containing treatment can significantly reduce the risk of severe or fatal acute attacks.

[0065] ICS (Inhaled Corticosteroids, inhaled corticosteroids)

[0066] ICS (inhalation corticosteroids) reduces airway inflammation, edema and mucus secretion by local anti-inflammatory effect, and treats the root cause (controls chronic inflammation). It needs to be used regularly for a long time, and cannot quickly relieve symptoms.

[0067] Representative drugs include: Budesonide, Fluticasone Propionate and Beclomethasone. Used for the treatment of asthma (long-term control, especially moderate or severe or recurrent).

[0068] SABA (Short-Acting β2-Agonists, short-acting β2 receptor agonists)

[0069] SABA can quickly stimulate airway β2 receptors, relax bronchial smooth muscle, and treat the symptoms (rapidly relieve bronchospasm). The onset time is 5-15 minutes, and the maintenance time is 4-6 hours.

[0070] Representative drugs include: Albuterol, Levalbuterol and Terbutaline. Used for the treatment of acute asthma (emergency medication), acute symptom relief of COPD and prevention of exercise-induced bronchospasm (advance use).

[0071] Aerosol inhalation composition

[0072] The combination of ICS and SABA albuterol has become an internationally recognized clinical guideline for treatment and prevention. Developing a combined aerosol inhalation composition has become a clinically needed product for the treatment or prevention of bronchospasm, rapid relief of asthma symptoms or prevention of asthma attacks, and reduction of the risk of severe or fatal asthma attacks. In terms of clinical first aid, compared with the efficacy of dry powder inhalation and aerosol, aerosol inhalation undoubtedly has incomparable advantages, which is the original intention of the present application. Rapid relief of asthma symptoms is also called emergency inhalation drug in clinical practice, so the present application can also be called a clinical first aid drug, which can be used for preventing acute symptoms of asthma and preventing bronchospasm.

[0073] The compound ICS combined with albuterol aerosol inhalation composition provided by the present application does not contain EDTA, reduces the production of R and D impurities in albuterol, has high stability, increases the aerosol inhalation amount of patients, has less aerosol residue, and is helpful for absorption. The compound ICS combined with albuterol aerosol inhalation composition of the present application can significantly reduce the risk of severe or fatal acute attack, has good synergy, and has good treatment effect.

[0074] Nebulizer Residual Drug (NRD)

[0075] Nebulizer Residual Drug (NRD) refers to the amount of drug remaining in the nebulizer device (e.g. nebulizer cup, drug reservoir) after the nebulization process. It is usually expressed in mass (mg or μg) or percentage of the initial drug load.

[0076] Calculation formula:

[0077] Nebulizer Residual Drug (NRD) = Initial Drug Load - Nebulized Output (e.g. FPD + device adsorption or deposition loss)

[0078] or

[0079]

[0080] Fine Particle Dose (FPD)

[0081] Fine Particle Dose (FPD) refers to the mass of active pharmaceutical ingredient (API) in the inhaled formulation that reaches the effective deposition site in the lung (e.g. alveoli or small airways), usually referring to the total amount of particles with an aerodynamic diameter ≤5 μm. It reflects the lung delivery efficiency of the drug and directly affects the therapeutic effect. It is a key indicator for evaluating the performance of inhalers. Unit: microgram (μg) or milligram (mg).

[0082] Fine Particle Fraction (FPF)

[0083] Fine Particle Fraction (FPF) refers to the percentage of fine particles (usually ≤5 μm) in the total delivered dose (or total inhaled dose) of the drug.

[0084] Calculation formula: FPF (%) = FPD / Total Delivered Dose × 100%

[0085] FPF is used to measure the nebulization or dispersion efficiency of the inhalation device. The higher the FPF, the more drug can reach the deep lung.

[0086] Mass Median Aerodynamic Diameter (MMAD)

[0087] MMAD refers to the aerodynamic diameter of 50% of the mass of aerosol particles, with 50% being larger than this value and 50% being smaller than this value. It reflects the "typical" size of the particles.

[0088] MMAD 1-5 μm: suitable for deposition in alveoli (deep lung).

[0089] MMAD 5~10μm: mainly deposited in the upper respiratory tract (e.g. trachea, bronchi).

[0090] Geometric Standard Deviation (GSD)

[0091] Geometric Standard Deviation (GSD) is used to describe the width of the distribution of aerosol particle size (degree of dispersion). The smaller the GSD, the more concentrated the distribution; GSD≥1.2 is generally considered to be a wide distribution.

[0092] Calculation formula:

[0093]

[0094] (D 84％ and D 16％ are the particle sizes corresponding to the cumulative distribution of 84% and 16%).

[0095] GSD close to 1: uniform particle size (monodisperse).

[0096] GSD is large: large difference in particle size (polydisperse), which may affect the uniformity of lung deposition.

[0097] The present application optimizes particle size and distribution by evaluating delivery efficiency by FPD / FPF, combining MMAD and GSD, to ensure that the drug reaches the target site.

[0098] The technical scheme of the present application has the following main advantages:

[0099] (1) The compound ICS combined with salbutamol inhalation of the present application can significantly reduce the risk of severe or fatal acute asthma attacks, prevent bronchospasm, and be used to prevent asthma symptoms and bronchial constriction. Patients can also use these drugs on demand before exercise or allergen exposure.

[0100] (2) The compound ICS combined with salbutamol inhalation obtained by the present application does not contain EDTA, reduces the generation of R and D impurities in salbutamol, has high stability, increases the amount of inhalation of patients, has less residual amount of inhalation, and is helpful for absorption.

[0101] (3) The present application uses BFS equipment to fill, 1-10 ml per bottle, convenient to carry and store.

[0102] (4) The present application adopts the combination of heat sterilization and filtration sterilization to fully ensure the sterility of the product.

[0103] (5) The present application uses nitrogen protection during liquid preparation and packaging to prevent oxidation and fully ensure the stability of the product.

[0104] (6) The present application disperses the insoluble active budesonide by using pressure homogenization technology, which can ensure the product droplet size distribution range and further ensure the effectiveness of the product.

[0105] The application will be further described in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present application and not used to limit the scope of the present application. The experimental methods in the following examples, if not otherwise specified, are usually carried out according to the conventional conditions, such as the conditions described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or the conditions suggested by the manufacturers. Unless otherwise specified, the percentages and parts are calculated by weight. The experimental materials and reagents involved in the present application can be obtained from the market channels, unless otherwise specified.

[0106] Example 1

[0107] This example prepares a sample of 2.5 ml / branch containing budesonide 0.5 mg and salbutamol 2.5 mg. For 2.5 ml / branch: budesonide 0.5 mg and salbutamol 2.5 mg, the prescription composition is shown in Table 1 as follows:

[0108] Table 1

[0109] Formulation composition 1000 units (g) Formulation ratio (mg / ml) Budesonide 0.5 0.2 Salbutamol sulfate 3 1.2 Polysorbate 80 0.4 0.16 Citric acid 0.61 0.244 Sodium citrate 1 0.4 Sodium chloride (for injection) 17 6.8 Water for injection q.s. 2500 ml /

[0110] Note: The above amount of salbutamol sulfate is 3 mg / branch (i.e. 3 g / 1000 branches), which is equivalent to the amount of salbutamol 2.5 mg / branch.

[0111] The specific preparation process includes the following steps:

[0112] ① 0.4 g of polysorbate 80 is weighed into container 1, 200 ml of water for injection is added, and stirring is performed to dissolve.

[0113] ② The prescribed amount (0.5 g) of budesonide is added to the solution prepared in step ①, and a ZLE-B500 type laboratory homogenization emulsifier is used for homogenization, the homogenization speed is 3000 rpm, and the homogenization time is 30 min. After homogenization, the liquid medicine is sterilized at 121 ℃ for 15 min.

[0114] ③ 1250 ml of water for injection is added to container 2, nitrogen gas is introduced, the oxygen content is controlled to be ≤4 mg / L, 0.61 g of citric acid, 1 g of sodium citrate, 17 g of sodium chloride, 3 g of salbutamol sulfate are added, stirring is performed to dissolve, and a 0.22 μm filter membrane is used for filtration.

[0115] ④ Add the sterilized budesonide solution from step ② to the solution prepared in step ③, add water to a final volume of 2500 ml, and homogenize using a ZLE-B500 laboratory homogenizer at 3000 rpm for 10 minutes. Continue stirring the solution until filling is complete.

[0116] ⑤ Sample and test the pH and content of intermediate product solutions.

[0117] ⑥ The medicine is filled under continuous nitrogen purging, 2.5ml / vial.

[0118] ⑦ Use aluminum-plastic composite film bags filled with nitrogen for packaging, and control the oxygen content to ≤5% before warehousing.

[0119] Example 2

[0120] This embodiment prepares a sample in 2.5ml / vial containing 1mg budesonide and 5mg salbutamol. The formulation of 1mg budesonide and 5mg salbutamol in 2.5ml / vial is shown in Table 2 below:

[0121] Table 2

[0122] Formulation composition 1000 units (g) Formulation ratio (mg / ml) Budesonide 1 0.4 Salbutamol sulfate 6 2.4 Polysorbate 80 0.4 0.16 Citric acid 0.61 0.244 Sodium citrate 1 0.4 Sodium chloride (for injection) 17 6.8 Water for injection q.s. 2500 ml /

[0123] Note: The dosage of salbutamol sulfate mentioned above, 6 mg / vial (i.e., 6 g / 1000 vials), is equivalent to a dosage of salbutamol of 5 mg / vial.

[0124] The specific preparation process includes the following steps:

[0125] ① Weigh 0.4g of polysorbate 80 into container 1, add 200ml of water for injection, and stir to dissolve.

[0126] ② Add the prescribed amount (1g) of budesonide to the solution prepared in step ①, and homogenize it using a ZLE-B500 laboratory homogenizer at a speed of 3000rpm for 30min. After homogenization, sterilize the solution at 121℃ for 15min.

[0127] ③ Add 1250ml of water for injection to container 2, purge with nitrogen gas to control the oxygen content ≤4mg / L, add 0.61g of citric acid, 1g of sodium citrate, 17g of sodium chloride, and 6g of salbutamol sulfate, stir to dissolve, and filter using a 0.22μm filter membrane.

[0128] ④ Add the sterilized budesonide solution from step ② to the solution prepared in step ③, add water to a final volume of 2500 ml, and homogenize using a ZLE-B500 laboratory homogenizer at 3000 rpm for 10 minutes. Continue stirring the solution until filling is complete.

[0129] ⑤ Sample and test the pH and content of intermediate product solutions.

[0130] ⑥ The medicine is filled under continuous nitrogen purging, 2.5ml / vial.

[0131] Example 3

[0132] In this embodiment, samples with different pH values ​​(pH 4.0, pH 5.0, and pH 6.0) were prepared, and the formulation composition involved is shown in Table 3 below:

[0133] Table 3

[0134] Formulation composition 1000 units (g) Formulation ratio (mg / ml) Budesonide 1 0.4 Salbutamol sulfate 6 2.4 Polysorbate 80 0.4 0.16 Citric acid q.s. / Sodium citrate 1 0.4 Sodium chloride (for injection) 17 6.8 Water for injection q.s. 2500 ml /

[0135] The specific preparation process includes the following steps:

[0136] ① Weigh 0.4g of polysorbate 80 into container 1, add 200ml of water for injection, and stir to dissolve.

[0137] ② Add 1.0g of budesonide to the solution prepared in step ①, and homogenize it using a ZLE-B500 laboratory homogenizer at a speed of 3000rpm for 30min. After homogenization, sterilize the solution at 121℃ for 15min.

[0138] ③ Add 1250ml of water for injection to container 2, introduce nitrogen to control the oxygen content ≤4mg / L, add 1g of sodium citrate, 17g of sodium chloride, and 6g of salbutamol sulfate, stir for 10min to dissolve, and filter using a 0.22μm filter membrane.

[0139] ④ Add the sterilized budesonide solution from step ② to the solution prepared in step ③, add water to a final volume of 2250 ml, check the pH, and adjust the pH to 4.0±0.05, 5.0±0.05, and 6.0±0.05 respectively using 10% citric acid solution. Add water to a final volume of 2500 ml, and homogenize using a ZLE-B500 laboratory homogenizer at 3000 rpm for 10 minutes. Continue stirring the solution until filling is complete.

[0140] ⑤ Sample and test the pH and content of intermediate product solutions.

[0141] ⑥ Fill the container while the liquid is continuously purged with nitrogen, 2.5ml~2.8ml / vial.

[0142] ⑦ Use aluminum-plastic composite film bags filled with nitrogen for packaging, and control the oxygen content to ≤5% before warehousing.

[0143] Comparative Example 1

[0144] The main difference from Example 2 is that this comparative example contains EDTA (disodium edetate), and the specific formulation is shown in Table 4 below:

[0145] Table 4

[0146] Formulation composition 1000 units (g) Formulation ratio (mg / ml) Budesonide 1 0.4 Salbutamol sulfate 6 2.4 Polysorbate 80 0.4 0.16 Citric acid 0.61 0.244 Sodium citrate 1 0.4 Disodium edetate 0.2 0.008 Sodium chloride (for injection) 17 6.8 Water for injection q.s. 2500 ml /

[0147] The specific preparation process comprises the following steps:

[0148] ① 0.4 g of polysorbate 80 was weighed into a container 1, 200 ml of water for injection was added, and stirring was performed to dissolve.

[0149] ② 1 g of budesonide was added to the solution prepared in step ①, and a ZLE-B500 type laboratory homogenizing emulsifier was used for homogenization, the homogenization speed was 3000 rpm, and the homogenization time was 30 min. After homogenization, the drug solution was sterilized at 121 ℃ for 15 min.

[0150] ③ 1250 ml of water for injection was added to a container 2, 0.2 g of edetate disodium, 0.61 g of citric acid, 1 g of sodium citrate, 17 g of sodium chloride, and 6 g of salbutamol sulfate were added, stirring was performed for 10 min to dissolve, and a 0.22 μm filter membrane was used for filtration.

[0151] ④ The budesonide solution after sterilization in step ② was added to the solution prepared in step ③, water was added to 2500 ml, a ZLE-B500 type laboratory homogenizing emulsifier was used for homogenization, the homogenization speed was 3000 rpm, and the homogenization time was 10 min. The drug solution was continuously stirred before filling was completed.

[0152] ⑤ The intermediate product drug solution was sampled for detection of pH and content.

[0153] ⑥ Filling, 2.5 ml to 2.8 ml per branch.

[0154] ⑦ Aluminum-plastic composite film bag was used for packaging, and the product was put into the warehouse.

[0155] Example 4 Stability Comparison

[0156] Based on the samples prepared in Examples 1-3 and Comparative Example 1 described above, the stability data were compared and analyzed, and the specific steps were as follows:

[0157] ① Related substance detection

[0158] Detection method: high performance liquid chromatography (Chinese Pharmacopoeia 2020 edition four general rules 0512).

[0159] Chromatographic conditions:

[0160] Instrument: high performance liquid chromatograph, ultraviolet detector.

[0161] Chromatographic column: octadecylsilane bonded silica gel as filler (4.6 mm x 150 mm, 3 μm, YMC-Pack ODS-AQ-C18 column or chromatographic column with equivalent performance is recommended);

[0162] Mobile phase A: pH 3.2 phosphate buffer (take sodium dihydrogen phosphate 4 g, add water 1000 ml to dissolve, take phosphoric acid 0.25 g, add water 100 ml to dissolve. Take 900 ml of the above sodium dihydrogen phosphate solution and 100 ml of phosphoric acid solution and mix evenly);

[0163] Mobile phase B: acetonitrile

[0164] Flow rate: 1.5 ml / min;

[0165] Column temperature: 30°C;

[0166] Detection wavelength: 240 nm;

[0167] Injection volume: 100 μl;

[0168] Run time: 60 min.

[0169] Gradient program: as shown in Table 5 below:

[0170] Table 5

[0171] Time (min) Mobile phase A (%) Mobile phase B (%) 0 95 5 5 95 5 10 85 15 15 85 15 25 60 40 45 60 40 50 95 5 60 95 5

[0172] 2. Specific test operation:

[0173] Preparation of blank solution: accurately measure 1 ml of acetonitrile into a 10 ml volumetric flask, dilute to the mark with pH 3.2 phosphate buffer, shake well.

[0174] Preparation of test sample solution: accurately measure the sample prepared in the above examples 1-3 and comparative example 1 (2.5 ml, into a 10 ml volumetric flask, add 1 ml of acetonitrile to dissolve, dilute to the mark with pH 3.2 phosphate buffer, shake well.

[0175] Detection: accurately measure 100 μl of blank solution and test sample solution respectively, inject into the liquid chromatograph, record the chromatogram, and calculate by area normalization method.

[0176] Results:

[0177] Based on the above experimental process, the related substance data was statistically analyzed, and the impurity content (%) in the following Tables 6-8 = impurity peak area / total peak area x 100%), and the stability data results of the nitrogen-filled prescription of examples 1 or 2, different pH prescription of example 3 and EDTA-containing prescription of comparative example 1 are as follows:

[0178] 1) The stability data of the nitrogen-filled prescription (this prescription is the prescription of the sample prepared in the above example 2) is shown in Table 6:

[0179] Table 6

[0180]

[0181] Note: ND means Not Detected.

[0182] The results in Table 6 show that when the samples prepared using the nitrogen-filled formulation were stored at 40°C for 6 months, the content of each impurity increased only slightly. Specifically, compared with the storage day, the content of budesonide impurity L increased by only 0.01%, the content of salbutamol impurity R increased by only 0.01%, and the content of salbutamol impurity U increased by only 0.02%, indicating that the samples prepared using the nitrogen-filled formulation of the present invention have good stability.

[0183] 2) Stability data for Comparative Example 1 (EDTA formulation) are shown in Table 7:

[0184] Table 7

[0185]

[0186]

[0187] Note: ND means Not Detected.

[0188] Table 7 shows that after 6 months of storage at 40°C, the contents of various impurities in samples prepared using the EDTA-containing formulation increased significantly. Specifically, compared to the storage day, the content of salbutamol impurity D in the EDTA-containing formulation increased by 0.68%, significantly higher than the increase in salbutamol impurity D in the nitrogen-filled formulation of this invention (0.11, see Table 6). The content of salbutamol impurity U in the EDTA-containing formulation increased by 0.19%, significantly higher than the increase in salbutamol impurity U in the nitrogen-filled formulation of this invention (0.02, see Table 6). These results indicate that the samples prepared using the nitrogen-filled formulation of this invention have better stability compared to the EDTA-containing formulation. Figure 1 ).

[0189] 3) Stability data for Example 3 (different pH formulations) are shown in Table 8:

[0190] Table 8

[0191]

[0192]

[0193] The results in Table 8 show that after being stored at 40℃ for 6 months, the impurities in the samples at different pH values ​​increased. The change trends of the samples at different pH values ​​were not significantly different, and the samples showed good stability in the pH range of 4.0 to 6.0.

[0194] Example 5: Delivery Rate and Total Delivery Analyze

[0195] The delivery rate and total delivery amount of the compound sample prepared in Example 1-2, the budesonide single sample and the salbutamol sulfate single sample were compared and analyzed, and the specific steps were as follows:

[0196] ① Delivery rate and total delivery amount detection

[0197] Inspection method: inhalation preparation delivery rate and total delivery amount determination method (Chinese Pharmacopoeia 2020 edition four general rules 0111 "4. Inhalation liquid preparation") and high performance liquid chromatography (Chinese Pharmacopoeia 2020 edition four general rules 0512).

[0198] Instrument: high performance liquid chromatograph, ultraviolet detector; BRS100 type respiratory simulator (Copely company); filter paper (diameter: 67mm, material: glass fiber, source: Copely company); PARI LC PLUS atomizer and PARI TurboBOY compressor (Germany PARI)

[0199] Chromatographic conditions:

[0200] Chromatographic column: octadecylsilane bonded silica gel as filler (4.6mm x 150mm, 5μm, recommended to use Welch Ultimate XB-C18 column or chromatographic column with equivalent performance);

[0201] Mobile phase A: 0.08M sodium dihydrogen phosphate solution (adjust pH value to 3.10±0.05 with phosphoric acid): acetonitrile (9:1);

[0202] Mobile phase B: 0.08M sodium dihydrogen phosphate solution (adjust pH value to 3.10±0.05 with phosphoric acid): acetonitrile (6:4)

[0203] Flow rate: 1.5ml / min;

[0204] Column temperature: 30℃;

[0205] Detection wavelength: 240nm;

[0206] Injection volume: 100μl;

[0207] Run time: 20min;

[0208] Solvent: 0.08M sodium dihydrogen phosphate solution (adjust pH value to 3.10±0.05 with phosphoric acid): acetonitrile (1:1) gradient program: as shown in the following table 9:

[0209] Table 9

[0210] Time (min) Mobile phase A (%) Mobile phase B (%) 0 100 0 3 100 0 3.1 0 100 13 0 100 13.1 100 0 20 100 0

[0211] Specific test operation:

[0212] Preparation of control solution: Take budesonide and salbutamol sulfate control substance each in an appropriate amount, accurately weigh and determine, dissolve in solvent and quantitatively dilute to prepare a solution containing about 1 μg of budesonide per 1 ml and a solution containing about 5 μg of salbutamol sulfate per 1 ml, respectively.

[0213] Preparation of test solution: Place the filter paper in the filter paper device, then connect the filter paper device with the respiratory simulator, and then connect the nebulizer nozzle with the filter paper device through the nozzle adapter. Accurately take 2.5 ml of the test product (such as the sample prepared in Example 1 or Example 2, which is a compound sample) and place it in the nebulization cup. Set the respiratory simulator to the breathing mode shown in the table below. Turn on the respiratory simulator and set the working time of the respiratory simulator to 15 min. Start the nebulizer at the beginning of the breathing cycle, and turn off the nebulizer when the nebulization time is 1 min. At the same time, pause the respiratory simulator, take out the filter paper in the filter paper device and place it in a beaker, add 25 ml of acetonitrile, squeeze the filter membrane to dissolve, soak for 30 min, and ultrasonic for 5 min. Transfer the soaking liquid to a 50 ml volumetric flask through a funnel, place the filter paper in the funnel, wash the filter paper with 0.08M sodium dihydrogen phosphate solution for 3 times, dilute with 0.08M sodium dihydrogen phosphate solution to the mark, shake well, and use as the delivery rate test solution.

[0214] Replace the filter membrane in the filter paper device, install the device, start the nebulizer, and then restore the respiratory simulator to the end of the working time. Turn off the nebulizer. Take out the filter paper in the filter paper device and place it in a beaker. Rinse the filter paper device with acetonitrile and pour the washing liquid into the beaker containing the filter paper. Soak and dissolve, then rinse the filter paper device with acetonitrile for 3 times, pour the washing liquid into the beaker containing the filter paper, soak for 30 min, and ultrasonic for 5 min (the total amount of acetonitrile is 50 ml). Transfer the soaking liquid to a 100 ml volumetric flask through a funnel, place the filter paper in the funnel, wash the filter membrane with 0.08M sodium dihydrogen phosphate solution for 3 times, dilute with 0.08M sodium dihydrogen phosphate solution to the mark, shake well, and use as the total delivery amount test solution.

[0215] Take out the filter membrane of the aerosol loss, rinse the filter paper device with acetonitrile, pour the washing liquid into the beaker containing the filter paper, then rinse the filter membrane device with acetonitrile for 3 times, pour the washing liquid into the beaker containing the filter membrane, soak for 30 min, and ultrasonic for 5 min (the total amount of acetonitrile is 50 ml). Transfer the soaking liquid to a 100 ml volumetric flask through a funnel, place the filter membrane in the funnel, wash the filter membrane with 0.08M sodium dihydrogen phosphate solution for 3 times, dilute with 0.08M sodium dihydrogen phosphate solution to the mark, shake well, and use as the aerosol loss test solution.

[0216] First, add 50 ml of acetonitrile to dissolve, then add 0.08M sodium dihydrogen phosphate solution, collect the active substance on the nebulizer into a 100 ml volumetric flask, dilute with 0.08M sodium dihydrogen phosphate solution to the mark, and use as the nebulizer residue test solution.

[0217] Control, delivery rate test solution and delivery total test solution dilution solution: Pipet 2 ml of control solution, each delivery rate and delivery total test solution, into a 10 ml volumetric flask, dilute to 10 ml with 0.08 M sodium dihydrogen phosphate solution.

[0218] Detection: Inject 100 μl of delivery rate test solution dilution solution, delivery total test solution dilution solution and control solution into the liquid chromatograph, record the chromatogram, calculate the delivery rate and delivery total by peak area using the external standard method.

[0219] Calculation method: Correction factor:

[0220]

[0221] Material balance (%) = delivery total + exhaled + nebulizer residue

[0222] In the formula

[0223] f1: correction factor of the corresponding component of control solution 1;

[0224] W R1 : sample weight of the corresponding component of control solution 1, mg;

[0225] W R2 : sample weight of the corresponding component of control solution 2, mg;

[0226] A R1 : peak area of the corresponding component of control solution 1;

[0227] A R2 : peak area of the corresponding component of control solution 2;

[0228] V R1 : dilution volume of the corresponding component of control solution 1, ml;

[0229] V R2 : dilution volume of the corresponding component of control solution 2, ml;

[0230] A 递送速率 : peak area of the delivery rate test solution;

[0231] V 递送速率 : dilution volume of the delivery rate test solution, ml;

[0232] A 递送总量 : peak area of the delivery total test solution;

[0233] V 递送总量 : dilution volume of the delivery total test solution, ml;

[0234] G: sample added amount, μg;

[0235] A 气雾损失 : aerosol loss of test sample solution peak area;

[0236] V 气雾损失 : aerosol loss of test sample solution dilution volume, ml;

[0237] A 雾化器 : nebulizer residue of test sample solution peak area;

[0238] V 雾化器 : nebulizer residue of test sample solution dilution volume, ml;

[0239] S: control content;

[0240] 1000: mg→μg conversion factor;

[0241] F: conversion factor of control, salbutamol sulfate: 0.8299, molar mass of salbutamol (478.6) to molar mass of salbutamol sulfate (576.7); budesonide: 1;

[0242] Results:

[0243] Based on the above experimental process, the delivery rate and delivery total amount data of the compound sample prepared in Examples 1-2, the budesonide single sample and the salbutamol sulfate single sample were statistically analyzed, and the results are shown below:

[0244] 1) The delivery rate and delivery total amount data of the compound sample (2.5 ml: budesonide 0.5 mg and salbutamol 2.5 mg sample) prepared in Example 1 and the single sample (2 ml: budesonide 0.5 mg, 2.5 ml: salbutamol 2.5 mg) are shown in Table 10 below:

[0245] Table 10

[0246]

[0247]

[0248] The results of Table 10 show that the delivery rate and delivery total amount of the compound product are higher than those of the single product, the aerosol loss and the nebulizer residue are lower than those of the single product, and the therapeutic effect of the compound product is better than that of the two single products.

[0249] 2) The delivery rate and delivery total amount data of the compound sample (2.5 ml: budesonide 1 mg and salbutamol 5 mg sample) prepared in Example 2 and the single sample (2 ml: budesonide 1 mg, 2.5 ml: salbutamol 5 mg) are shown in Table 11 below:

[0250] Table 11

[0251]

[0252] The results of Table 11 show that the delivery speed and total amount of the compound product are higher than those of the single product, the aerosol loss and nebulizer residue are lower than those of the single product, and the curative effect of the compound product is better than that of using two single products.

[0253] Example 6 Fine particle dose comparison

[0254] Based on the compound samples, budesonide single product and salbutamol sulfate single product prepared in the above Examples 1-2, fine particle dose comparison analysis was carried out, and the specific steps were as follows:

[0255] ① Fine particle dose detection

[0256] Inspection method: inhalation preparation fine particle aerodynamic property determination method (Chinese Pharmacopoeia 2020 edition four general rules 0951) and high performance liquid chromatography (Chinese Pharmacopoeia 2020 edition four general rules 0512).

[0257] Instrument: high performance liquid chromatograph, ultraviolet detector; NGI impactor, equipped with NGI cooling cabinet (Copley company); MOC filter membrane (diameter: 76mm, material: glass fiber, source: Copley company); PARI LC PLUS nebulizer and PARI COMPACT N compressor (Germany PARI).

[0258] Chromatographic conditions:

[0259] Chromatographic column: octadecylsilane bonded silica gel as filler (4.6mm x 150mm, 5μm, recommended to use Welch Ultimate XB-C18 column or chromatographic column with equivalent performance);

[0260] Mobile phase A: 0.08M sodium dihydrogen phosphate solution (adjust pH value to 3.10±0.05 with phosphoric acid): acetonitrile (9:1);

[0261] Mobile phase B: 0.08M sodium dihydrogen phosphate solution (adjust pH value to 3.10±0.05 with phosphoric acid): acetonitrile (6:4)

[0262] Flow rate: 1.5ml / min;

[0263] Column temperature: 30℃;

[0264] Detection wavelength: 240nm;

[0265] Injection volume: 100μl;

[0266] Run time: 20min.

[0267] Solvent: 0.08M sodium dihydrogen phosphate solution (pH adjusted to 3.10 ± 0.05 with phosphoric acid): acetonitrile (1:1).

[0268] Gradient program: as shown in Table 9.

[0269] Specific test operation:

[0270] Preparation of control solution: accurately weigh budesonide and salbutamol sulfate control substance, dissolve and dilute quantitatively to prepare a solution containing about 1 μg of budesonide and 5 μg of salbutamol sulfate per 1 ml.

[0271] Preparation of test solution: according to the method for determination of fine particle aerodynamic properties of inhaled preparations (Chinese Pharmacopoeia 2020 edition four general rules 0951), use device 3 (i.e. NGI), pre-cool the assembled impactor and L-shaped connecting tube in the cooling device (5℃) for at least 90 minutes (at least 90 minutes for the first time, and at least 30 minutes thereafter, and measure the S1 temperature, which should be less than 10℃), connect the outlet of the impactor to the vacuum pump, turn on the vacuum pump, connect the flow meter to the L-shaped connecting tube, adjust the flow control valve to make the gas flow rate at the inlet of the L-shaped connecting tube 15 L / min (± 5%), and remove the flow meter. Accurately take 2.5 ml of the test sample (prepared in Example 1 or Example 2) and pour it into the atomizer, place the atomization device in the actual use direction, connect the mouthpiece to the L-shaped connecting tube through the mouthpiece adapter. Turn on the atomization pump, and time the atomization time for 5 minutes. Turn off the atomizer, turn off the vacuum pump, and remove the impactor. First, use 50 ml of acetonitrile, and then use 0.08M sodium dihydrogen phosphate solution to collect the active substances in the atomizer and mouthpiece into a 100 ml volumetric flask, dilute to the mark with 0.08M sodium dihydrogen phosphate solution, and use it as the atomizer residual test solution. In the same way, use 25 ml of acetonitrile and 0.08M sodium dihydrogen phosphate solution to collect the active substances in the MOC filter paper, L-shaped connecting tube and adapter, S1, S2, S3, S4, S5, S6 and S7 into 9 50 ml volumetric flasks, respectively, and dilute to the mark with 0.08M sodium dihydrogen phosphate solution, and use it as the test solution of each level.

[0272] Preparation of control solution and fine particle dose test solution: accurately take 2 ml of the control solution and each fine particle dose determination sample into a 10 ml volumetric flask, and dilute to 10 ml with 0.08M sodium dihydrogen phosphate solution.

[0273] Detection: 100 μl of the nebulizer residue sample dilution solution, the artificial throat sample dilution solution (L-type connecting tube and adapter), each level sample dilution solution, MOC sample dilution solution and control solution were injected into the liquid chromatograph, and the chromatogram was recorded. The nebulizer residue, artificial throat, and each level drug deposition were calculated by peak area according to the external standard method, and the fine particle dose (FPD), fine particle fraction (FPF), mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were calculated by using Copley data processing software CITDAS.

[0274] Results:

[0275] Based on the above experimental process, the compound sample prepared in Example 1-2, the budesonide single sample and the salbutamol sulfate single sample were subjected to fine particle dose data statistics, and the results are shown below:

[0276] 1) The fine particle dose data of the compound sample prepared in Example 1 (2.5 ml: budesonide 0.5 mg and salbutamol 2.5 mg sample) and the single sample (2 ml: budesonide 1 mg, 2.5 ml: salbutamol 2.5 mg) are shown in Table 12 below:

[0277] Table 12

[0278]

[0279] In combination Figure 2-3 The results of Table 12 show that the fine particle dose of the compound product is higher than that of the single product, and the therapeutic effect of the compound product is better than that of using two single products.

[0280] 1) The fine particle dose data of the compound sample prepared in Example 2 (2.5 ml: budesonide 1 mg and salbutamol 5 mg sample) and the single sample (2 ml: budesonide 1 mg, 2.5 ml: salbutamol 5 mg) are shown in Table 13 below:

[0281] Table 13

[0282]

[0283] In combination Figure 2-3 The results of Table 13 show that the fine particle dose of the compound product of the present application is higher than that of the single product and the compound product containing EDTA, indicating that the therapeutic effect of the compound product of the present application is better than that of using two single products or the compound product containing EDTA.

[0284] Example 7

[0285] The embodiment provides a composition for treating or preventing acute attack of bronchial asthma, which is prepared from the following raw materials: budesonide 25 g, salbutamol sulfate 100 g, Tween 80 12 g, citric acid 28 g, disodium hydrogen phosphate 50 g, sodium chloride 850 g and water for injection 98.9 kg.

[0286] The preparation method of the composition comprises the following steps:

[0287] S1: 12 g of Tween 80 is mixed with 200 g of water for injection, and is dissolved by magnetic stirring at 500 rpm for 10 min to obtain a wetting agent stock solution; and 25 g of budesonide is mixed with the wetting agent stock solution, and is stirred at 500 rpm for 10 min to obtain a budesonide suspension.

[0288] S2: 6 kg of water for injection is injected into a T1 solution preparation tank, nitrogen is introduced until the oxygen content is less than or equal to 5 ppm, the budesonide suspension is transferred into the T1 solution preparation tank, and the rinse water of the budesonide suspension and the wetting agent stock solution is added into the T1 solution preparation tank, and stirring is performed at 2000 rpm for 10 min; after dispersion is completed, the speed is reduced to 1000 rpm and stirring is continuously performed for 10 min; and sterilization is performed at 121 DEG C for 30 min to obtain a budesonide suspension;

[0289] S3: 70 kg of water for injection is injected into a T2 solution preparation tank, nitrogen is introduced until the oxygen content is less than or equal to 5 ppm, 100 g of salbutamol sulfate, 28 g of citric acid, 50 g of disodium hydrogen phosphate and 850 g of sodium chloride are added, and magnetic stirring is performed at 2000 rpm for 20 min to obtain a salbutamol sulfate solution.

[0290] S4: nitrogen is continuously introduced into a T3 solution preparation tank for 10 min, the salbutamol sulfate solution in the T2 solution preparation tank is filtered through two-stage 0.2 mu sterile filter elements and then added into the T3 solution preparation tank, the budesonide suspension in the T1 solution preparation tank is homogenized by adopting a pressure of 500-2000 bar and then added into the T3 solution preparation tank, the remaining amount of water for injection is added and the volume is fixed to 100 kg, and magnetic stirring is performed at 1000 rpm for 20 min; then, the composition is filled by adopting a BFS device, each injection is 2 ml, and the composition is stored in the dark at 25 DEG C.

[0291] Embodiment 8

[0292] The embodiment provides a composition for treating or preventing acute attack of bronchial asthma, which is prepared from the following raw materials: budesonide 50 g, levosalbutamol tartrate 200 g, Tween 80 12 g, citric acid 28 g, sodium citrate 50 g, sodium chloride 850 g and water for injection 98.9 kg.

[0293] The preparation method of the composition comprises the following steps:

[0294] S1: mix Tween 80 12g with 200g of water for injection, magnetically stir at 500 rpm for 10 min to dissolve, obtain wetting agent stock solution; mix the wetting agent stock solution with 50g of budesonide, magnetically stir at 500 rpm for 10 min, obtain budesonide suspension.

[0295] S2: inject 6kg of water for injection into T1 liquid preparation tank, pass nitrogen gas until the oxygen content is ≤5ppm, transfer the above budesonide suspension into T1 liquid preparation tank, and add the budesonide suspension and wetting water of the wetting agent stock solution into T1 liquid preparation tank, stir at 2000 rpm for 10 min, after dispersion is completed, the speed is reduced to 1000 rpm and continues to stir for 10 min, sterilize at 121℃ for 30 min, obtain budesonide suspension;

[0296] S3: inject 70kg of water for injection into T2 liquid preparation tank, pass nitrogen gas until the oxygen content is ≤5ppm, add levosalbutamol tartrate 200g, citric acid 28g, sodium citrate 50g, sodium chloride 850g, magnetically stir at 2000 rpm for 20 min, obtain levosalbutamol tartrate solution.

[0297] S4: continuously pass nitrogen into T3 liquid preparation tank for 10 min, filter the levosalbutamol tartrate solution in T2 liquid preparation tank through two-stage 0.2μm sterilizing filter and add it into T3 liquid preparation tank, homogenize the budesonide suspension in T1 liquid preparation tank at a pressure of 500-2000 bar and add it into T3 liquid preparation tank, add the remaining amount of water for injection and make up to 100kg, magnetically stir at 1000 rpm for 20 min, then use BFS equipment to fill, 4ml per bottle, store at 25℃ in the dark.

[0298] Example 9

[0299] The present embodiment provides a composition for treating or preventing acute attack of bronchial asthma, the raw materials of which are: budesonide 30g, levosalbutamol fumarate 150g, Tween 80 12g, citric acid 28g, disodium hydrogen phosphate 50g, sodium chloride 850g, water for injection 98.9kg.

[0300] The preparation method of the above composition comprises the following steps:

[0301] S1: mix Tween 80 12g with 200g of water for injection, magnetically stir at 500 rpm for 10 min to dissolve, obtain wetting agent stock solution; mix the wetting agent stock solution with 30g of budesonide, magnetically stir at 500 rpm for 10 min, obtain budesonide suspension.

[0302] S2: inject 6 kg of water for injection into the T1 liquid preparation tank, pass nitrogen gas until the oxygen content is ≤5 ppm, transfer the above budesonide suspension into the T1 liquid preparation tank, and add the budesonide suspension and the wetting agent stock solution into the T1 liquid preparation tank, stir at 2000 rpm for 10 min, after dispersion is completed, reduce the speed to 1000 rpm and continue stirring for 10 min, sterilize at 121°C for 30 min, and obtain a budesonide suspension;

[0303] S3: inject 70 kg of water for injection into the T2 liquid preparation tank, pass nitrogen gas until the oxygen content is ≤5 ppm, add levosalbutamol fumarate 150 g, citric acid 28 g, disodium hydrogen phosphate 50 g, and sodium chloride 850 g, and magnetically stir at 2000 rpm for 20 min to obtain a levosalbutamol fumarate solution.

[0304] S4: continuously pass nitrogen gas into the T3 liquid preparation tank for 10 min, filter the levosalbutamol fumarate solution in the T2 liquid preparation tank through two 0.2 μm sterilization filter cartridges, and then add it into the T3 liquid preparation tank, homogenize the budesonide suspension in the T1 liquid preparation tank at a pressure of 500-2000 bar, and then add it into the T3 liquid preparation tank, add the remaining amount of water for injection and make up to 100 kg, magnetically stir at 1000 rpm for 20 min, and then use a BFS device to fill each 2 ml, and store at 25°C in the dark.

[0305] Comparative Example 2

[0306] This comparative example provides a composition for treating or preventing acute onset of bronchial asthma, which is prepared from the following raw materials: budesonide 50 g, Tween 80 12 g, citric acid 28 g, sodium citrate 50 g, sodium chloride 850 g, and water for injection 98.9 kg.

[0307] The preparation method of the above composition comprises the following steps:

[0308] S1: mix Tween 80 12 g with 200 g of water for injection, magnetically stir at 500 rpm for 10 min to dissolve, and obtain a wetting agent stock solution; mix the wetting agent stock solution with 50 g of budesonide, and magnetically stir at 500 rpm for 10 min to obtain a budesonide suspension.

[0309] S2: inject 6 kg of water for injection into the T1 liquid preparation tank, pass nitrogen gas until the oxygen content is ≤5 ppm, transfer the above budesonide suspension into the T1 liquid preparation tank, and add the budesonide suspension and the wetting agent stock solution into the T1 liquid preparation tank, stir at 2000 rpm for 10 min, after dispersion is completed, reduce the speed to 1000 rpm and continue stirring for 10 min, sterilize at 121°C for 30 min, and obtain a budesonide suspension;

[0310] S3: inject 70 kg of water for injection into the T2 liquid preparation tank, pass nitrogen gas until the oxygen content is ≤5 ppm, add citric acid 28 g, sodium citrate 50 g, sodium chloride 850 g, and magnetically stir at 2000 rpm for 20 min to obtain solution A.

[0311] S4: continuously pass nitrogen gas into the T3 liquid preparation tank for 10 min, filter solution A in the T2 liquid preparation tank through two 0.2 μm sterilization filter cartridges, then add it into the T3 liquid preparation tank, homogenize the budesonide suspension in the T1 liquid preparation tank at a pressure of 500-2000 bar, then add it into the T3 liquid preparation tank, and dilute with water for injection to 100 kg, magnetically stir at 1000 rpm for 20 min, then use a BFS device to fill each with 2 ml, and store at 25°C in the dark.

[0312] Comparative Example 3

[0313] This comparative example provides a composition for treating or preventing acute onset of bronchial asthma, which is prepared from the following raw materials: salbutamol sulfate 200 g, Tween 80 12 g, citric acid 28 g, sodium citrate 50 g, sodium chloride 850 g, and water for injection 98.9 kg.

[0314] The preparation method of the above composition comprises the following steps:

[0315] S1: mix Tween 80 12 g with 200 g of water for injection, magnetically stir at 500 rpm for 10 min to dissolve it, and obtain a wetting agent stock solution;

[0316] S2: inject 6 kg of water for injection into the T1 liquid preparation tank, pass nitrogen gas until the oxygen content is ≤5 ppm, transfer all of the wetting agent stock solution into the T1 liquid preparation tank, and add the rinse water of the wetting agent stock solution into the T1 liquid preparation tank, stir at 2000 rpm for 10 min, after dispersion is completed, reduce the speed to 1000 rpm and continue stirring for 10 min, sterilize at 121°C for 30 min to obtain a suspension;

[0317] S3: inject 70 kg of water for injection into the T2 liquid preparation tank, pass nitrogen gas until the oxygen content is ≤5 ppm, add salbutamol sulfate 200 g, citric acid 28 g, sodium citrate 50 g, and sodium chloride 850 g, and magnetically stir at 2000 rpm for 20 min to obtain a salbutamol solution.

[0318] S4: continuously nitrogen for 10 min to T3 liquid preparation tank, the salbutamol sulfate solution in T2 liquid preparation tank was filtered through two 0.2 μm sterilization filter cores and then added to T3 liquid preparation tank, the wetting agent stock solution in T1 liquid preparation tank was homogenized at a pressure of 500-2000 bar and then added to T3 liquid preparation tank, the remaining amount of water for injection was added and the volume was made up to 100 kg, 1000 rpm magnetic stirring for 20 min, then BFS equipment was used for filling, 2 ml per bottle, 25℃, light shielding.

[0319] Test Example

[0320] 1. Experimental method: 50 patients with bronchial asthma aged 18-35 years were selected, and the patients did not have other diseases, and were divided into five groups, ten people in each group, and the compositions in Examples 7-9 and Comparative Examples 2-3 were used for three months, and no other therapeutic drugs were used, and the use method was: 2 times / day, 2 bottles / time, and the medication was stopped for three days after three months of medication.

[0321] 2. Experimental standard: the state of the patients was recorded on the third day of stopping medication, and the number of patients with symptoms cured, partially relieved, and not relieved was counted.

[0322] 3. Experimental data: see Table 14 below.

[0323] Table 14

[0324]

[0325]

[0326] Experimental conclusion: according to the experimental data, it can be seen that the combination of steroid glucocorticoids and short-acting β2 receptor agonists, using the nebulization administration method, has a faster effect, and is more convenient for patients with acute and severe asthma who cannot breathe independently, and compared with single administration, the treatment effect for asthma is better, especially for acute asthma.

[0327] All the documents mentioned in the present application are cited as references in the present application, just as each document is cited as a reference. In addition, it should be understood that those skilled in the art can make various modifications or modifications to the present application after reading the above teachings of the present application, and these equivalent forms also fall within the scope defined by the claims attached to the present application.

Claims

1. An aerosol inhalation composition, characterized in that, The nebulization inhalation composition comprises budesonide and salbutamol or pharmaceutically acceptable salts thereof, and does not contain a metal chelating agent.

2. The aerosol inhalation composition of claim 1, wherein, The nebulization inhalation composition comprises, by weight percentage: Budesonide 0.01-0.08%, Salbutamol and pharmaceutically acceptable salts thereof 0.005-0.3%, Wetting agent 0.001-0.1%, Osmotic pressure regulator 4.0-9.0%, pH regulator or buffer, The balance is water for injection; The nebulization inhalation composition does not contain a metal chelating agent.

3. The aerosol inhalation composition of claim 1, wherein The nebulization inhalation composition comprises: 0.1-0.8 mg / ml of budesonide and 0.1-3.0 mg / ml of salbutamol.

4. The aerosol inhalation composition of claim 1, wherein The salbutamol pharmaceutically acceptable salt is selected from the group consisting of salbutamol sulfate, salbutamol hydrochloride, levosalbutamol tartrate, levosalbutamol fumarate, a salt of a salbutamol isomer, or a combination thereof.

5. The aerosol inhalation composition of claim 2, wherein The wetting agent is selected from the group consisting of Tween 20, Tween 40, Tween 60, Tween 80, Span 20, Span 40, Span 60, Span 80, lecithin, poloxamer, or a combination thereof.

6. A method of preparing the nebulised inhalation composition of claim 1, characterised in that, The method comprises the following steps: Mixing the budesonide solution without EDTA with the salbutamol or pharmaceutically acceptable salt thereof solution under the condition of nitrogen, to obtain the nebulization inhalation composition.

7. The method of claim 6, wherein, The method further comprises the following steps: S1: mixing a wetting agent with 0.1-2% of the formulation volume of water for injection to obtain a wetting agent stock solution; mixing budesonide with the wetting agent stock solution to obtain a budesonide suspension; S2: mixing the budesonide suspension obtained in step S1 and the wetting agent stock solution under the condition of nitrogen to an oxygen content of ≤5 ppm to obtain a budesonide suspension; S3: mixing salbutamol, a pH regulator or buffer, and an osmotic pressure regulator under the condition of nitrogen to an oxygen content of ≤5 ppm to obtain a salbutamol solution; S4: mixing the salbutamol solution obtained in S3 and the budesonide suspension obtained in S2 under the condition of continuous nitrogen for not less than 5 min to obtain the nebulization inhalation composition.

8. Use of an atomised inhalation composition according to claim 1, characterised in that, The drug is used for preventing and / or treating respiratory diseases.

9. Use according to claim 8, characterized in that, The respiratory diseases are selected from the group consisting of bronchial asthma, bronchospasm, and / or alleviating asthma exacerbation, or a combination thereof; The drug is atomized by a nebulization inhaler and delivered to the lungs by oral or nasal inhalation.

10. The use according to claim 8, characterized in that, The drug has a specification of 2.5 ml / branch ~ 2.8 ml / branch; The drug with a specification of 2.5 ml / branch contains 0.5 mg of budesonide and 2.5 mg of salbutamol; The drug with a specification of 2.5 ml / branch contains 1 mg of budesonide and 5 mg of salbutamol.

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