Sivelestat sodium inhalation composition, pharmaceutical component and application of sivelestat sodium inhalation composition

Abstract

The invention belongs to the technical field of aerosol inhalation, and particularly relates to a sivelestat sodium aerosol inhalation composition, a medicine component and application of the sivelestat sodium aerosol inhalation composition. The prepared sivelestat sodium aerosol inhalation composition is composed of sivelestat sodium or tetrahydrate of sivelestat sodium and a phosphate buffer, other auxiliary materials such as a surfactant, an excipient and an osmotic pressure regulator are not added any more, the requirement of the inhalation composition for osmotic pressure can be met, good stability is achieved, and the preparation method is simple and convenient to operate. And meanwhile, the irritation or toxicity to respiratory mucosa and cilia caused by auxiliary material factors can be reduced. According to the medicine assembly, the solution containing the sivelestat sodium composition and the net type atomizer with specific parameters are used in cooperation, the good lung injury treatment effect is achieved, and meanwhile the medicine assembly has the advantages of being small in residual liquid medicine amount and high in total delivery amount.

Description

Technical Field

[0001] The invention belongs to the technical field of atomization inhalation, and particularly relates to a sivelestat sodium atomization inhalation composition, a drug component and applications thereof. Background Art

[0002] The English name of Sivelestat sodium is Sivelestat sodium, and its chemical name is N-{2-[4-(2,2-dimethylpropionyloxy)benzenesulfonylamino]benzoyl}aminoacetic acid sodium salt tetrahydrate, with a molecular formula of C 20 0H 21 N2NaO7S·4H2O, with a molecular weight of 528.5. Sivelestat sodium is the world's first drug for the treatment of acute lung injury with systemic inflammatory response syndrome (SIRS) developed by Ono Pharmaceutical Co., LTD of Japan. It was approved for marketing in Japan in April 2002. The only dosage form of Sivelestat sodium currently on the market is a lyophilized powder for injection, which was developed by Ono Pharmaceutical Co., Ltd. of Japan. It was copied and launched in my country in 2022 with a dosage of 5 mg / kg / day. Due to the existing injection preparations of Sivelestat sodium, patients need to take the drug continuously for a long time, such as 24-hour continuous infusion, and acute lung injury is usually severe, which makes medication difficult. Therefore, it is necessary to provide a simple medication method.

[0003] In this regard, the document "Study on the protective effect of nebulized inhalation of sivelestat sodium on the lungs of rats with severe brain injury" (Quan Mingtao, Jiang Zhixia, Shi Jiujun, Luo Wei, Fan Xueliang, Cheng Huagang, Chinese Journal of Emergency Medicine, 2012, 32(1): 51-53) explored the effect of nebulized inhalation of sivelestat sodium on the lungs of rats with severe brain injury, providing a theoretical basis for the implementation of lung protection in patients with severe brain injury. The results showed that nebulized inhalation of sivelestat sodium had a certain protective effect on severe brain injury tissues, and its mechanism may be related to inhibiting the production and activity of NE, reducing the direct damage of NE to lung tissue and inhibiting the lung injury caused by the inflammatory circulation reaction in the lung. However, the nebulized preparation of sivelestat sodium used in this experiment was a powder injection directly converted to nebulization. Whether the mannitol in the preparation can be used for inhalation administration is still controversial, as mannitol is prone to cause side effects such as airway constriction and asthma.

[0004] Patent CN107913261A discloses a sivelestat sodium dry powder inhaler, which is composed of an active ingredient sivelestat sodium, a dispersant, a glidant and a diluent. The dry powder inhaler is administered orally or nasally. However, since the main drug sivelestat is insoluble in water, after the dry powder is inhaled into the designated target organ or tissue, it will be difficult for the main drug to achieve the purpose of rapid onset of action in the absence of a cosolvent.

[0005] It can be seen that the compositions for inhalation of silvestat sodium reported in existing literature have problems such as slow onset of effect, excipients used that are not suitable for inhalation, and uneven content after atomization, which are difficult to meet clinical needs. Therefore, there is an urgent need for a silvestat sodium atomized inhalation preparation that is non-toxic, non-irritating, has stable and reliable quality, and can maintain good uniformity of inhaled droplets after atomization by an atomization device, has a large total drug delivery amount and a small residual amount, and a drug component used in conjunction with it. Summary of the invention

[0006] In order to solve the technical problems that the excipients used in the aforementioned sivelestat sodium inhalation composition are not suitable for inhalation, are irritating or toxic to the respiratory mucosa and cilia, and have high drug residues in the medicine cup after atomization, the present invention provides a sivelestat sodium inhalation composition that does not contain a surfactant and an osmotic pressure regulator, which is composed of sivelestat sodium and a phosphate buffer.

[0007] Specifically, the technical solution of the sivelestat sodium inhalation composition is as follows:

[0008] A sivelestat sodium inhalation composition consists of sivelestat sodium or its tetrahydrate and a phosphate buffer.

[0009] In the sivelestat sodium inhalation composition, the concentration of sivelestat sodium or its tetrahydrate in the solution before freeze-drying is 10-15 mg / ml.

[0010] In one or more embodiments of the present invention, the concentration of phosphate buffer in the solution of the sivelestat sodium inhalation composition before lyophilization is 0.1-0.2 mol / L, preferably 0.1 mol / L; the phosphate buffer salt used is selected from a combination of disodium hydrogen phosphate and hydrochloric acid or a combination of sodium dihydrogen phosphate and sodium hydroxide or a combination of sodium phosphate and sodium hydroxide; the three phosphate buffer salts have no significant difference in the solubility of the main drug.

[0011] In one or more embodiments of the present invention, the pH of the solution of the sivelestat sodium inhalation composition before lyophilization is 7.7-7.9.

[0012] In one or more embodiments of the present invention, the preparation method of the sivelestat sodium inhalation composition is as follows: weigh a prescribed amount of sivelestat sodium or its tetrahydrate and add it to water for injection, add phosphate buffer to completely dissolve the sivelestat sodium or its tetrahydrate, and then adjust the pH to 7.7-7.9 with phosphate buffer to obtain a solution before freeze-drying, and the solution is freeze-dried to obtain the sivelestat sodium inhalation composition.

[0013] In one or more embodiments of the present invention, the dosage of the sivelestat sodium inhalation composition is 2-5 mL, preferably 5 mL.

[0014] Another object of the present invention is to provide a pharmaceutical component comprising a sivelestat sodium inhalation composition, the pharmaceutical component comprising:

[0015] (a) an aqueous solution of a sivelestat sodium inhalation composition; and

[0016] (b) A mesh nebulizer used in conjunction with an aqueous solution of the sivelestat sodium inhalation composition.

[0017] In one or more embodiments of the present invention, in the aqueous solution of the sivelestat sodium inhalation composition, the concentration of the active ingredient sivelestat sodium tetrahydrate is 6 to 10 mg / ml, preferably 10 mg / ml.

[0018] In one or more embodiments of the present invention, the droplet size of the sivelestat sodium inhalation solution is: D10 is 0.5 μm-2.1 μm, D50 is 1.7 μm-4.1 μm, and D90 is 7.3 μm-8.2 μm.

[0019] In one or more embodiments of the present invention, the mass percentage of particles having an aerodynamic particle size of less than 4.2 μm in the droplets of the sivelestat sodium inhalation solution is not less than 60% of the droplets of the sivelestat sodium inhalation solution.

[0020] In one or more embodiments of the present invention, the number of micropores of the metal mesh of the mesh nebulizer used in conjunction with the aqueous solution of the sivelestat sodium inhalation composition is 2,000.

[0021] In one or more embodiments of the present invention, the nebulization rate of the mesh nebulizer used in conjunction with the aqueous solution of the sivelestat sodium inhalation composition is 0.2-0.4 ml / min, preferably 0.2 ml / min.

[0022] In one or more embodiments of the present invention, the vibration frequency of the mesh nebulizer used in combination with the aqueous solution of the sivelestat sodium inhalation composition is 130 KHz; the micropore size of the metal mesh of the mesh nebulizer is 3.4 μm±0.4 μm.

[0023] Another aspect of the present invention provides the use of a pharmaceutical component containing a sivelestat sodium inhalation composition in the preparation of a pharmaceutical product for treating lung diseases, wherein the sivelestat sodium composition is dissolved in water and then atomized by a mesh nebulizer and then inhaled.

[0024] The technical solution adopted by the present invention has the following advantages:

[0025] (1) In addition to the raw materials, the formulation of the aerosol inhalation composition of the present invention uses only one auxiliary material, namely, a phosphate buffer salt system, and no other auxiliary materials such as surfactants, excipients and osmotic pressure regulators are added. This can not only meet the osmotic pressure requirements of the inhalation composition, but also have good stability. At the same time, it can reduce the irritation or toxicity to the respiratory mucosa and cilia caused by auxiliary factors, facilitate the production of the formulation process and save costs.

[0026] (2) The present invention uses a solution containing the sivelestat sodium composition in combination with a mesh nebulizer with specific parameters, and also controls the particle size of the sivelestat sodium inhalation composition solution droplets, which not only achieves a good effect in treating lung injury, but also has the advantages of a small amount of residual drug solution and a high total amount of delivery. DETAILED DESCRIPTION

[0027] The present invention is further illustrated by the following examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention. Therefore, simple improvements to the present invention based on the method of the present invention are all within the scope of protection claimed by the present invention.

[0028] I. Explanation of terms

[0029] The specific abbreviations used in the present invention are as follows: "FPD" is the abbreviation for fine particle dose; "FPF" is the abbreviation for fine particle fraction; "MMAD" is the abbreviation for mass median aerodynamic diameter; GSD is the abbreviation for geometric standard deviation; "NGI" is the abbreviation for Next Generation Impactor.

[0030] The term "particle size" can refer to measurements made on a single particle or a distribution of particles. These parameters can be measured by a variety of techniques, including dynamic light scattering, static light scattering, laser diffraction, deposition, time of flight, or other methods known to those skilled in the art. Particle size distribution can also be quantified by the size of the distribution (Dx) corresponding to a certain percentage point, wherein a certain percentage (x) of the population is less than the defined size. For example, a distribution with a D90 value of 500 nm means that 90% of the distribution (based on volume) has a size less than 500 nm.

[0031] Ⅱ. The detection method of sivelestat sodium and related substances is as follows:

[0032] Chromatographic conditions:

[0033] Welch XB-C18 was used as the chromatographic column (150 mm×4.6 mm, 5 μm); acetonitrile-phosphate buffer (volume ratio 5:4) was used as the mobile phase; the detection wavelength was 240 nm; the injection volume was 10 μL; and the flow rate was 1.0 mL / min.

[0034] Preparation of reference solution:

[0035] Sivelestat mother solution: Accurately weigh 25.55 mg of Sivelestat into a 25 mL volumetric flask, add acetonitrile to dissolve it to the mark, and shake well to obtain.

[0036] Sodium propyl p-hydroxybenzoate mother solution: Accurately weigh 42.39 mg of sodium propyl p-hydroxybenzoate into a 100 mL volumetric flask, add acetonitrile to dissolve it to the mark, and shake well to obtain the mother solution.

[0037] Accurately pipette 1 mL of sivelestat mother solution and 1 mL of sodium propyl paraben mother solution, place them in a 100 mL volumetric flask, add 50% acetonitrile to dilute to the scale, shake well, and obtain.

[0038] Preparation of test solution:

[0039] Take 1 bottle of freeze-dried powder of this product, add 7.5mL of water to it, shake well, and use it as the experimental drug solution. Accurately measure 1mL, place it in a 100mL volumetric flask, and add 1mL of sodium propyl paraben mother solution, dilute to the scale with 50% acetonitrile, shake well, filter through a 0.45μm microporous filter membrane, and take the filtrate to obtain.

[0040] Establishment of standard curve:

[0041] Accurately pipette different volumes of Sivilestad mother solution and sodium propyl paraben mother solution, add 50% acetonitrile to dilute to the mark, and prepare a series of reference solutions with Sivilestad mass concentrations of 0.9954, 4.977, 9.954, 19.91, and 99.54 μg / mL (the internal standard solution concentration in different linear solutions is 4.208 μg / mL). Determine according to the chromatographic conditions under "2.1.1", draw a standard curve with mass concentration as the abscissa and peak area as the ordinate, and obtain a standard curve Y=0.8378X-0.0458 (r=1.0000), with a linear range of 0.9954-99.54 μg.

[0042] III. Fine particle dose determination method

[0043] According to the 2020 edition of the Chinese Pharmacopoeia, Part Four General Rules 0951, place the NGI at 5°C ± 3°C for at least 90 minutes, then turn on the vacuum pump and adjust the flow rate to 15L / min (±5%), and remove the flowmeter. Accurately measure 2mL of the liquid medicine into the nebulizer cup, connect the nebulizer to the artificial throat through the interface in the direction of use, turn on the nebulizer and the flow control valve at the same time, after nebulization, turn off the nebulizer, and turn off the vacuum pump after 5s. Clean the containers at each stage of nebulization with a diluent solvent as the test solution. Use high performance liquid chromatography to determine the content of sildenafil sodium in the washing fluid of each component. The test was performed according to the above method, and the measurement was performed in parallel 3 times. The measurement results were imported into the CopleyCitdas V3.10 software for calculation to obtain FPD, FPF, MMAD and GSD.

[0044] IV. Methods for determining delivery rate and total amount of delivery

[0045] According to the general rule 0111 of Part IV of ChP2020, the specific operation is as follows: accurately measure 2 mL of sample and place it in the nebulizer cup, connect the respiratory simulator and filter membrane, nebulizer, and nebulizer cup device, set the respiratory simulator parameters to adult mode (tidal volume 500 mL, respiratory rate 15 cycles / min, respiratory waveform sinusoidal, respiratory ratio 1:1), turn on the respiratory simulator, set the working time of the respiratory simulator to 60s±1s, and turn on the respiratory simulator and nebulizer at the same time. After the timing is turned off after 1 minute, turn off the nebulizer and collect the inhaled filter membrane ①; replace the new filter membrane, continue nebulization for 9 minutes, and collect the inhaled filter membrane ② and the exhaled filter membrane ③. Wash each filter membrane and component with a diluent solvent, filter with a 0.22μm microporous filter membrane, and use it as the test solution. The content of sildenastat sodium in the above washing solution was determined by high performance liquid chromatography. The delivery rate was the ratio of the sildenastat sodium content in the inhalation filter ① to the nebulization time. The total delivery amount was the sum of the sildenastat sodium content in the inhalation filter ① and ②. The total exhaled amount was the sildenastat sodium content in the exhaled filter. The medicine cup residue was the sildenastat sodium content in the nebulization cup. The recovery rate was the percentage of the total measured amount (the sum of sildenastat sodium in each component) to the dosage. Different nebulizers were selected for determination according to the above method, and each nebulizer was measured in parallel 3 times.

[0046] Example 1: Effect of different concentrations of sivelestat sodium on the stability of the composition

[0047] Preparation method: Weigh 0.375g, 0.75g, 1.0g, 1.5g and 2.0g of sivelestat sodium tetrahydrate respectively into a 200mL beaker, control the ambient temperature at 20-25°C, add 80mL of 0.2mol / L phosphate buffer solution, stir while adding until the solution is clear, adjust the pH of the solution to 7.9 with 0.2mol / L phosphate buffer solution at pH12; make the volume to 100mL, filter, fill into a vial, and freeze-dry.

[0048] The sivelestat sodium inhalation compositions with different main drug concentrations were placed at high temperature (60°C ± 2°C) and light (4500lx ± 500lx) for 30 days with the vials wrapped in tin foil to investigate the contents of related substances, as shown in Table 1.

[0049] Table 1.

[0050]

[0051]

[0052] The freeze-dried samples with different main drug concentrations placed for 0, 5, and 30 days were compared. As the placement time increased, the content of related substances under light and high temperature conditions gradually increased, and the increase was more obvious at high temperature. From the freeze-dried samples of different concentrations, when the main drug concentration was 10-15 mg / ml, the content of related substances increased more slowly. In particular, when the main drug concentration was 15 mg / mL, after being placed under light conditions for 30 days, the content of related substances only increased by 0.246% compared to 0 days, and after being placed under high temperature conditions for 30 days, the content of related substances only increased by 0.26% compared to 0 days.

[0053] Example 2: Effects of different concentrations of phosphate buffer on the solubility of sivelestat sodium and solution osmotic pressure

[0054] (1) Effect of different concentrations of phosphate buffer on the solubility of sivelestat sodium:

[0055] According to the different solubility properties of sivelestat sodium, sodium dihydrogen phosphate and sodium hydroxide buffer systems were used as the advantage, and 0.05mol / L, 0.075mol / L, 0.1mol / L, and 0.2mol / L phosphate buffer systems were selected. The results showed that with the increase of the concentration of the phosphate buffer solution, the solubility of sivelestat sodium tetrahydrate gradually increased; when using two concentrations of 0.05mol / L and 0.075mol / L, without adding other solvents, only sivelestat sodium tetrahydrate solutions below 7mg / mL could be prepared; 0.1mol / L phosphate buffer solution can make the concentration of sivelestat sodium tetrahydrate reach 15mg / mL, and 0.2mol / L phosphate buffer solution can make the concentration of sivelestat sodium tetrahydrate reach 30mg / mL.

[0056] (2) Effects of different concentrations of phosphate buffer on osmotic pressure

[0057] After experimental investigation, the osmotic pressure of phosphate buffer of different concentrations is shown in Table 2 below.

[0058] Table 2.

[0059] Phosphate buffer concentration Osmotic pressure 0.05mol / L 180mOsmol / kg 0.075mol / L 220mOsmol / kg 0.1mol / L 300mOsmol / kg 0.2mol / L 350mOsmol / kg

[0060] The results showed that as the concentration of the phosphate buffer system increased, the osmotic pressure also gradually increased. Since the osmotic pressure requirement of the inhalation solution is 260-320mOsmol / kg, the concentration of the phosphate buffer used was determined to be 0.1mol / L.

[0061] Example 3: Effect of different pH values ​​on the stability of sivelestat sodium inhalation composition

[0062] A 0.1 mol / L phosphate buffer solution was selected to prepare a 15 mg / mL sivelestat sodium tetrahydrate solution, and the solution was adjusted to pH 7.5, 7.7, 7.9, 8.1, 8.3, and 8.5, respectively, and the solutions of different pH were filled into vials for freeze drying. The above composition was placed under high temperature and high humidity conditions (60°C, 70% RH) for 10 days to investigate the content of related substances in the above composition, as shown in Table 3.

[0063] Table 3 Effect of different pH on related substances of sivelestat sodium inhalation composition

[0064] pH pH 7.5 pH 7.7 pH 7.9 pH 8.1 pH 8.3 pH 8.5 Maximum single impurity / % 0.305 0.225 0.312 0.461 0.422 0.633 Total impurities / % 0.591 0.471 0.553 0.773 0.646 0.901

[0065] The results show that when the pH exceeds the range of 7.7-7.9, the related substances tend to gradually increase. Therefore, the optimal pH is controlled between 7.7-7.9.

[0066] Example 4: Preparation and stability study of sivelestat sodium inhalation composition

[0067] Preparation method: Weigh 1.5 g of sivelestat sodium tetrahydrate into a 200 mL beaker, control the ambient temperature at 20-25°C, add 80 mL of 0.1 mol / L phosphate buffer solution, stir while adding until the solution is clear, adjust the pH of the solution to 7.9 with 0.1 mol / L phosphate buffer solution; make the volume to 100 mL, filter, fill into a vial, and freeze-dry.

[0068] Stability test:

[0069] The above samples were placed at a temperature of 60℃±2℃ and a light intensity of 4500lx±500lx for 30 days. Samples were taken on the 0th day, the 10th day and the 30th day to examine their properties, pH value, visible foreign matter, osmotic pressure molar concentration, content, etc. The experimental results are shown in Table 4.

[0070] Table 4.

[0071]

[0072] Example 5: Comparison of the effects of atomizing a solution of a sivelestat sodium inhalation composition using a mesh nebulizer and a compressed air nebulizer

[0073] Take 1 bottle (5 ml) of freeze-dried powder prepared in Example 4, add 7.5 mL of water to it, shake well, and use it as a solution for nebulized inhalation. Compare the effects of mesh nebulizer and compressed air nebulizer in nebulizing the solution of the sivelestat sodium inhalation composition. The air compression nebulizers are A (Yuyue Air Compression) and B (Bairui Air Compression), and the mesh nebulizers are C (feellife mesh) and D (yuwell mesh). Air compression nebulizers A and B and mesh nebulizers C and D are two types of jet nebulizers commonly used on the market. The four nebulizers nebulized the liquid medicine for the same time, and compared the drug administration effects of different nebulizers. The test results were processed using SPSS 22.0 statistical software, and the data were analyzed using one-way analysis of variance. P < 0.05 was considered statistically significant. The results are shown in Tables 5 and 6.

[0074] Table 5. Aerodynamic analysis of different atomizers

[0075]

[0076] Table 6 Delivery data of different nebulizers

[0077]

[0078] The results in Table 5 show that the MMAD and GSD of the mesh nebulizer are smaller than those of the air compression nebulizer, indicating that the solution of the silvestat sodium inhalation composition has a smaller and more uniform droplet size under the atomization of the mesh nebulizer. At the same time, the FPF value of the mesh nebulizer is 10 percentage points higher than that of the air compression nebulizer, and the particle size of the atomized solution is more uniform, indicating that the mesh nebulizer is more suitable as a nebulization device for the silvestat sodium inhalation solution.

[0079] The results in Table 6 show that there are obvious differences in the delivery rates of nebulizers with different atomization modes. The delivery rates of air compression nebulizers A and B are fast, but the total delivery volume is low, while the total delivery volume and the residual volume in the medicine cup of the mesh nebulizer are lower than those of air compression nebulizers C and D. Therefore, the mesh nebulizer has a higher atomization efficiency for the preparation.

[0080] Example 6: Effect of mesh atomizers with different numbers of micropores on atomization effect

[0081] Mesh nebulizers with different numbers of micropores but the same other parameters were selected to test their effects on the atomization effect when applied to the solution of the nebulized inhalation composition of sivelestat sodium (inhalation composition of Example 4). The results are shown in Table 7.

[0082] Table 7. Effect of different micropore numbers on atomization effect

[0083] sample No. 1 No. 2 No. 3 No. 4 Vibration frequency(KHz) 130 130 130 130 Number of micropores 1400 1600 1800 2000 Micropore size (μm) 3.4±0.4 3.4±0.4 3.4±0.4 3.4±0.4 Atomization rate (ml / min) 0.2 0.2 0.2 0.2 MMAD(μm) 5.1 4.9 4.5 4.1 FPD(mg) 3.3 3.9 4.2 4.8 FPF % 43 51 55 63

[0084] The results show that at the same atomization rate, the more micropores there are, the smaller the MMAD, the larger the FPD, and the higher the FPF, indicating that the number of micropores significantly affects the atomization efficiency of the preparation. When the number of micropores in the metal mesh is 2000, the particle size of the atomized solution is smaller and more uniform.

[0085] Example 7: Effect of different atomization rates on atomization effect

[0086] The mesh nebulizers with different atomization rates but the same other parameters were selected to detect the influence of the mesh nebulizer on the atomization effect when applied to the solution of the sivelestat sodium atomization inhalation composition (lyophilized powder of Example 4). The results are shown in Table 8.

[0087] Table 8. Effect of different atomization rates on atomization effect

[0088] sample No. 1 No. 2 No. 3 No. 4 Vibration frequency(KHz) 130 130 130 130 Number of micropores 2000 2000 2000 2000 Micropore size (μm) 3.4±0.4 3.4±0.4 3.4±0.4 3.4±0.4 Atomization rate (ml / min) 0.1 0.2 0.4 0.6 MMAD(μm) 4.5 4.1 4.2 4.6 FPD(mg) 4.4 5.0 4.6 3.9 FPF% 58 66 61 51

[0089] The results show that under the condition of the same number of micropores, the atomization rate will also affect the atomization effect. At an atomization rate of 0.2ml / min to 0.4ml / min, the uniformity of the solution after atomization is better.

[0090] Example 8

[0091] By controlling the droplet size, measuring the delivery rate, total delivery amount and fine particle dose, the effects on the atomization effect of the nebulized inhalation solution of Sivelestat Sodium were detected. The results are shown in Table 9.

[0092] Table 9. Effect of droplet size on atomization effect

[0093]

[0094]

[0095] The results show that at droplet sizes of 1 and 2, the MMAD, FPD and FPF values ​​are good, while at droplet sizes of 3 and 4, the atomization effect is poor.

Claims

1. A pharmaceutical component comprising a sivelestat sodium inhalation composition, the pharmaceutical component comprising: (a) an aqueous solution of a sivelestat sodium inhalation composition; and (b) A mesh nebulizer used in conjunction with an aqueous solution of the sivelestat sodium inhalation composition.

2. The drug assembly according to claim 1, characterized in that The droplet particle size of the sivelestat sodium inhalation solution is: D10 is 0.5μm-2.1μm, D50 is 1.7μm-4.1μm, and D90 is 7.3μm-8.2μm; the mass percentage of particles with an aerodynamic particle size less than 4.2μm in the sivelestat sodium inhalation solution is not less than 60%.

3. The drug assembly according to claim 1, characterized in that The number of micropores of the metal mesh of the mesh atomizer is 2000.

4. The drug assembly according to claim 1, characterized in that The atomization rate of the mesh atomizer is 0.2-0.4 ml / min, preferably 0.2 ml / min.

5. The drug assembly according to claim 1, characterized in that The vibration frequency of the mesh atomizer is 130 KHz; the micropore particle size of the metal mesh of the mesh atomizer is 3.4 μm±0.4 μm.

6. The drug assembly according to claim 1, characterized in that The sivelestat sodium inhalation composition consists of sivelestat sodium or its tetrahydrate and a phosphate buffer.

7. The drug assembly according to claim 1, characterized in that In the aqueous solution of the sivelestat sodium inhalation composition, the concentration of the active ingredient sivelestat sodium or its tetrahydrate is 6 to 10 mg / ml, preferably 10 mg / ml.

8. The drug assembly according to claim 1, characterized in that In the solution of the sivelestat sodium inhalation composition before freeze-drying, the concentration of sivelestat sodium or its tetrahydrate is 10-15 mg / ml, the concentration of the phosphate buffer is 0.1-0.2 mol / L, and the pH of the solution is 7.7-7.

9.

9. The drug assembly according to claim 1 or 8, characterized in that: In the solution of the sivelestat sodium inhalation composition before freeze-drying, the concentration of sivelestat sodium or its tetrahydrate is 15 mg / ml, the concentration of the phosphate buffer is 0.1 mol / L, and the pH of the solution is 7.7-7.

9.

10. Use of a pharmaceutical component comprising the sivelestat sodium inhalation composition according to any one of claims 1 to 9 in the preparation of a pharmaceutical product for treating lung diseases, wherein the sivelestat sodium composition is dissolved in water and then atomized by a mesh nebulizer for inhalation.

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