TW202241401A - Fudosteine solution preparation for inhalation, preparation method and use thereof - Google Patents

Abstract

The invention belongs to the field of pharmaceutical preparations and provides a fudosteine solution preparation for inhalation, preparation method and use thereof. A concentration of the fudosteine in the solution preparation for inhalation is 25-300 mg/ml. The fudosteine solution preparation for inhalation of the present invention is an atomized inhalation solution, which contains the fudosteine with a specific concentration, has excellent aerosol generation properties, can be effectively deposited on a site of drug effect of a respiratory tract, achieves an excellent drug concentration, overcomes the problem that the aerosol of the fudosteine atomized inhalation preparation in the prior art does not achieve the best inhalation therapeutic effect, and has more excellent drug efficacy. Moreover, compared with oral administration, at the same dose, the present invention has higher drug distribution in a respiratory system, better expectorant efficacy, lower system exposure, and better safety. The fudosteine solution preparation for inhalation of the present invention has good application prospect.

Description

A solution preparation for inhalation of fudosteine and its preparation method and application

The invention relates to the field of pharmaceutical preparations, in particular to a fudosteine inhalation solution preparation and its preparation method and application.

Respiratory system disease is one of the diseases that people are familiar with. Respiratory system disease accounts for about 1/4 of internal medicine patients and brings mental and physical pain to patients. In my country's population statistics, respiratory system disease is the second cause of death , but there are not many drugs to choose from clinically, and the onset is slow.

Coughing up sputum is a common symptom of respiratory diseases. Increased sputum can stimulate the respiratory mucosa and cause coughing. When sputum blocks the bronchioles, it can not only cause asthma, but also cause secondary infection, further damage the respiratory tract, aggravate cough, expectoration and asthma, and in severe cases, it can inhibit breathing or suffocate to death. Excessive secretion of mucus will cause mucociliary clearance dysfunction and local defense function damage, leading to difficult control of infection and aggravation of airway obstruction, which directly affects the progress of the disease and the patient's subjective feelings. Important adjunct to airway inflammation.

Expectorants can make sputum thinner and less viscous, making it easier to cough up, or can accelerate the movement of mucous membranes and cilia in the respiratory tract and improve sputum transport function. Expectorants can promote the discharge of phlegm in the respiratory lumen, reduce irritation to the respiratory mucosa, indirectly play an antitussive and antiasthmatic role, and are also beneficial to control secondary infections.

Fudosteine, whose chemical name is (-)-(R)-2-amino-3-(3-hydroxypropylthio)propionic acid, is a new type of expectorant, manufactured by Mitsubishi Pharmaceutical Co., Ltd. and S.S. Pharmaceutical Co., Ltd. has developed a class of cysteine derivatives with an expectorant effect that has a basic skeleton of steine. It has multiple pharmacological effects on chronic respiratory diseases: inhibit the proliferation of respiratory epithelial cells, normalize the ratio of trehalose/sialic acid in sputum, restore the state of cilia transporting airway secretions, and have anti-inflammatory effects; Small side effects, wide indications, large market potential, etc.; suitable for chronic respiratory diseases such as bronchial asthma, chronic bronchitis, bronchiectasis, tuberculosis, pneumoconiosis, emphysema, atypical mycobacterial infection, and diffuse bronchiolitis expectorant in systemic diseases.

The oral preparations of fudosteine currently on the market include tablets, capsules, and granules. Although the oral solid preparations are convenient to take, they have a large dosage, slow onset of action, exert effects on the whole body, and have large side effects. Inhalation is a new drug dosage form, it can directly act on the affected part, increase the drug concentration in the respiratory tract or lungs, and has a quick effect, and the preparation avoids the first-pass effect of the liver, reduces the dosage of the drug, and improves the The bioavailability of the drug can reduce the distribution of the drug in other tissues and reduce side effects. It has the advantages of less stimulation by inhalation administration, convenient use, good patient compliance, less toxic and side effects, and suitable for long-term treatment.

Patent CN108078964A discloses a fudosteine dry powder inhaler. The dose of the inhaler is significantly lower than that of the oral solid preparation, and the therapeutic effect is high and the onset of effect is fast; Skills, inconvenient administration for patients, and uneven inhalation dose of multiple administrations, high production cost of special equipment and other issues. Patent CN109925300A discloses a solution preparation of fudosteine for atomized inhalation and its preparation method. Compared with oral preparations, the solution preparation of fudosteine for atomized inhalation has the advantages of high efficiency, low toxicity, good stability and high safety. characteristics; however, the aerosol generation characteristics of this inhaler are not clear, and the concentration and particle size distribution of the aerosol drug have not been studied, and the single dose of its preparation cannot achieve the best inhalation therapeutic effect. Preparations, etc. make the prescription too complicated, the drug loading of the preparation is low, and the safety hazard is relatively high.

It can be seen that the solid particles inhaled by the dry powder of fudosteine inhalation preparations in the prior art are irritating to the respiratory tract, the use has certain skills, it is inconvenient for patients to administer, and the inhalation dose of multiple administrations is uneven, and the production cost of special equipment is expensive. , the treatment effect of nebulized inhalation preparations still needs to be improved, and there is a great need for a new fudosteine inhalation preparation.

The object of the present invention is to provide a fudosteine inhalation solution preparation and its preparation method and application. The solution preparation for inhalation contains fudosteine at a specific concentration, has excellent aerosol generation properties, can effectively deposit on the drug effect site of the respiratory tract, and achieves an effective drug concentration.

The first aspect of the present invention provides a fudosteine inhalation solution preparation. According to an embodiment of the present invention, the concentration of fudosteine in the solution preparation for inhalation is 25-300 mg/ml.

The fudosteine inhalation solution preparation provided by the present invention contains fudosteine at a specific concentration, has excellent aerosol generation properties, can effectively deposit on the drug effect site of the respiratory tract, and achieves a superior drug concentration, which overcomes the prior art fudosteine The problem that the aerosol of the tank atomized inhalation preparation has not achieved the best inhalation treatment effect makes its drug effect more excellent. At the same time, compared with oral administration, it has higher drug distribution in the respiratory system at the same dose, better expectorant effect, and lower system exposure and better safety. The solution preparation for inhalation of fudosteine of the present invention It has a good application prospect.

According to an embodiment of the present invention, the concentration of fudosteine in the solution preparation for inhalation is 25-250 mg/ml.

According to an embodiment of the present invention, the concentration of fudosteine in the solution preparation for inhalation is 30-250 mg/ml. When the concentration of fudosteine in the solution preparation for inhalation is 30-250 mg/ml, the aerosol generation characteristics can be further improved, and a more effective drug concentration can be achieved.

According to an embodiment of the present invention, the concentration of fudosteine in the solution preparation for inhalation is 40-200 mg/ml.

According to an embodiment of the present invention, the concentration of fudosteine in the solution preparation for inhalation is 50-150 mg/ml.

According to an embodiment of the present invention, the inventors have found that in the low temperature cycle, as the concentration of fudosteine increases, the color of the solution formulation of fudosteine for inhalation deepens, so it is preferred that fudosteine in the solution formulation for inhalation The concentration is 50-150mg/ml. The preparation of fudosteine inhalation solution within this range is colorless or slightly pale yellow.

According to an embodiment of the present invention, the concentration of fudosteine in the solution preparation for inhalation is 50-100 mg/ml.

According to an embodiment of the present invention, the raw material of the fudosteine inhalation solution preparation includes fudosteine or a pharmaceutically acceptable salt or a hydrate thereof.

According to an embodiment of the present invention, the raw materials of the fodosteine inhalation solution preparation further include water for injection.

According to an embodiment of the present invention, the fudosteine inhalation solvent formulation further includes one or more pharmaceutical excipients suitable for pulmonary administration or inhalation administration.

According to an embodiment of the present invention, the pharmaceutical excipients used include osmotic pressure regulators and/or surfactants.

According to an embodiment of the present invention, the formulation of the fudosteine solution for inhalation does not contain a pH adjuster. For example, the fudosteine solution formulation for inhalation of the present invention does not contain at least one of the following pH regulators: Sodium hydroxide, sodium bicarbonate, sodium carbonate, sodium citrate, citric acid, sodium citrate, benzoic acid, ascorbic acid, hydrochloric acid, succinic acid, acetic acid, sulfuric acid, phosphoric acid, tartaric acid, maleic acid, malic acid, ethyl Diamine, ethanolamine phosphate buffers, borate buffers, boric acid buffers and combinations. In addition, the type of pH regulator not contained in the fudosteine inhalation solution preparation of the present invention is not limited thereto, and may be other types.

According to an embodiment of the present invention, no complexing agent or chelating agent is included in the formulation of fudosteine solution for inhalation.

Some existing fudosteine inhalation solution preparations contain complexing agents or chelating agents, which have brought potential safety hazards to the drug. The inventors have found that when the inhalation solution preparation contains a specific concentration of fudosteine, it can maintain The stability of the solution formulation for inhalation of fudosteine, without adding a complexing agent or chelating agent, eliminates the potential safety hazard of the drug, and at the same time, the concentration of the solution formulation for inhalation is 25-300mg/ml, preferably 30-250mg/ml The fudosteine has a relatively high nebulization speed, overcomes the problem that the fudosteine nebulized inhalation preparation aerosol in the prior art does not achieve the best inhalation therapeutic effect, and makes its drug effect more excellent.

For example, the fudosteine solution formulation for inhalation in the present invention does not contain at least one of the following complexing agents or chelating agents: One of edetate salts such as edetic acid, edetate disodium, edetate calcium sodium, etc., or a mixture in any proportion. And the type of complexing agent or chelating agent not contained in the fudosteine inhalation solution preparation of the present invention is not limited thereto, and may be other types.

The administration route of the fudosteine inhalation solution preparation provided by the present invention is atomized inhalation administration, which is to disperse the medicine or water into mist particles or particles suspended in the gas through the device, and deposit it in the respiratory tract and ( or) the lungs, so as to achieve the effect of local treatment of the respiratory tract. Generally, in the prescription of nebulized inhalation preparations, there are often pH regulators or complexing agents to regulate the stability or solubility of the product, but the inventor found in the screening of fudosteine inhalation solution preparations that the fudosteine inhalation solution of the present invention The formulation contains fudosteine at a specific concentration. At this concentration, there is no need to add pH value regulators and/or complexing agents and chelating agents, and still maintain very good stability and solubility.

According to an embodiment of the present invention, the fudosteine inhalation solution preparation consists of fudosteine or a pharmaceutically acceptable salt or a hydrate thereof and water for injection.

The fudosteine inhalation solution preparation composed of fudosteine or its pharmaceutically acceptable salt or its hydrate and water for injection has simple composition and good safety. At the same time, it can maintain good stability (especially long-term stability) and appropriate atomization speed. The aerosol generation property is excellent, and it can be effectively deposited on the drug effect site of the respiratory tract to achieve an effective drug concentration, which overcomes the existing technology Fodor The problem that the aerosol of Stein nebulized inhalation preparation does not achieve the best inhalation therapeutic effect.

According to an embodiment of the present invention, the single dose of the fudosteine inhalation solution preparation is 1-10 ml.

According to an embodiment of the present invention, the single dose of the fodosteine inhalation solution preparation is 2.5-8 ml.

According to an embodiment of the present invention, after the fudosteine inhalation solution preparation is atomized, the fudosteine fine particle dose range in the obtained fudosteine inhalation solution aerosol is ≥ 15%, preferably ≥ 30%. .

According to an embodiment of the present invention, the fodosteine solution formulation for inhalation delivers a total amount of 100-400 mg.

According to an embodiment of the present invention, the fudosteine solution formulation for inhalation has a continuous release time of ≤30 minutes during the nebulization process and directly reaches the lungs. For example, the sustained release time of the fudosteine inhalation solution formulation is 10-30 minutes during the nebulization process.

According to an embodiment of the present invention, the sustained release time of the fodosteine inhalation solution formulation is ≤20 minutes during the nebulization process.

According to an embodiment of the present invention, the delivery rate of the fodosteine solution formulation for inhalation is 0.07-0.51 mg/s.

4mg/s。 According to an embodiment of the present invention, the delivery rate of the fodosteine solution formulation for inhalation is 0.1-0. 4mg/s.

According to an embodiment of the present invention, the fodosteine solution formulation for inhalation is contained in a container.

According to an embodiment of the present invention, the container is an ampoule or a vial.

According to an embodiment of the present invention, the container is filled with nitrogen for protection.

The ampoule is protected by nitrogen filling. The stability of the fudosteine inhalation solution preparation at high temperature and high light can be improved by nitrogen filling protection.

According to an embodiment of the present invention, the material of the ampoule or vial is selected from any one of glass, polyethylene plastic, polypropylene plastic, and rubber. For example, the ampoule can be a borosilicate glass ampoule.

The second aspect of the present invention provides a method for preparing the fudosteine inhalation solution formulation described in the first aspect. According to an embodiment of the present invention, the method comprises: adding fudosteine into water for injection, and stirring until it is completely dissolved.

The third aspect of the present invention provides the use of the fudosteine inhalation solution formulation described in the first aspect in the preparation of medicines for treating lung diseases or respiratory diseases.

According to an embodiment of the present invention, the drugs for treating lung diseases or respiratory diseases include expectorant and/or antitussive drugs.

Beneficial effect: The fudosteine inhalation solution preparation of the present invention is an atomized inhalation solution, which contains fudosteine at a specific concentration, and the fudosteine inhalation solvent aerosol is obtained in combination with the delivery rate, the total amount of delivery and the aerodynamics of fine particles The generation properties are excellent, and it can effectively deposit on the drug effect site of the respiratory tract to achieve an effective drug concentration, which overcomes the problem that the fudosteine nebulized inhalation preparation aerosol in the prior art does not achieve the best inhalation therapeutic effect, and makes its drug effect more effective. excellent. At the same time, compared with oral administration, it has higher drug distribution in the respiratory system at the same dose, better expectorant effect, and lower system exposure and better safety. The solution preparation for inhalation of fudosteine of the present invention Has good application.

The fudosteine solution preparation for inhalation of the present invention does not contain complexing agent and/or pH regulator and still has good long-term stability, especially for more than one year.

The solution preparation for atomized inhalation provided by the present invention is a single dose, and the use process is convenient and easy to prepare; it can greatly reduce the microbial pollution and waste in the use process, and the single-dose dose avoids the repetition caused by multiple doses of large packaging solutions. Disadvantages of measuring and repeatedly diluting to prepare microorganisms that are easy to breed. The invention provides a new preparation and a preparation method thereof, which are lacking in the prior art, with accurate medicinal dosage, high-quality and stable drug quality, safe and simple clinical application.

The above-mentioned content of the present invention will be further described in detail below through specific implementation in the form of examples. However, this should not be construed as limiting the scope of the above-mentioned subject matter of the present invention to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention.

The present invention will be described below with reference to specific embodiments. It should be noted that these embodiments are only illustrative and do not limit the present invention in any way.

The raw materials and equipment used in the specific embodiment of the present invention are all known products, obtained by purchasing commercially available products.

In addition, the terms "first" and "second" are used for descriptive purposes only, and cannot be understood as indicating or implying relative importance or implicitly specifying the quantity of indicated technical features. Thus, the features defined as "first" and "second" may explicitly or implicitly include at least one of these features. In the description of the present disclosure, "plurality" means at least two, such as two, three, etc., unless specifically defined otherwise. the term

According to one embodiment of the present invention, the preferred administration route of the "fudosteine inhalation solution preparation" is atomized inhalation administration, which is to disperse fudosteine and other raw materials into a mist suspended in gas through a device Particles or particles are deposited in the respiratory tract and (or) lungs through inhalation, so as to achieve the effect of local treatment of the respiratory tract.

According to one embodiment of the present invention, the "pharmaceutically acceptable salt" refers to the salt formed by fudosteine and inorganic acid or organic acid, wherein the inorganic acid or organic acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, Phosphoric acid, methanesulfonic acid, phenylmethanesulfonic acid, oxalic acid, tartaric acid, maleic acid, citric acid or ascorbic acid.

According to one embodiment of the present invention, the "hydrate of fudosteine" refers to hemihydrate, monohydrate or polyhydrate of fudosteine.

According to a preferred embodiment of the present invention, the raw materials of the fudosteine inhalation solution preparation include fudosteine and water for injection, and do not include a complexing agent or a chelating agent or a pH regulator.

According to one embodiment of the present invention, wherein, "complexing agent or chelating agent" is selected from at least one of the following: One of edetate salts such as edetic acid, edetate disodium, edetate calcium sodium, etc., or a mixture in any proportion. And the type of complexing agent or chelating agent not contained in the fudosteine inhalation solution preparation of the present invention is not limited thereto, and may be other types.

According to an embodiment of the present invention, wherein the "pH value regulator" is selected from at least one of the following: Sodium hydroxide, sodium bicarbonate, sodium carbonate, sodium citrate, citric acid, sodium citrate, benzoic acid, ascorbic acid, hydrochloric acid, succinic acid, acetic acid, sulfuric acid, phosphoric acid, tartaric acid, maleic acid, malic acid, ethyl Diamine, ethanolamine phosphate buffers, borate buffers, boric acid buffers and combinations. In addition, the type of pH regulator not contained in the fudosteine inhalation solution preparation of the present invention is not limited thereto, and may be other types.

According to one embodiment of the present invention, the "pharmaceutical excipients suitable for pulmonary administration or inhalation administration" in the present invention can be, for example, osmotic pressure regulators, surfactants, etc., and can also be other known in the art Pharmaceutical excipients of any kind for pulmonary or inhaled administration. Among them, the osmotic pressure regulator can be, for example, sodium chloride, phosphate, citrate, etc., and the surfactant can be, for example, Tween, polyoxyethylene castor oil derivatives, poloxamer, lecithin, cyclodextrin Wait.

According to one embodiment of the present invention, the "single dose" refers to the pharmaceutical preparation obtained after the fudosteine inhalation solution preparation required by the patient is sealed in one dose by means of a packaging container. The packaging container can be an ampoule or other airtight container, preferably a nitrogen-filled ampoule made of glass, polyethylene plastic, polypropylene plastic or the like. According to one embodiment of the present invention, the single dose of the fudosteine inhalation solution formulation of the present invention is 1-10 ml, and the formulation can also be diluted for actual use. According to one embodiment of the present invention, the total delivery amount of fudosteine inhalation solution formulation in the present invention is 100-400mg, and the fudosteine inhalation solution formulation is continuously released in the body for ≤30min, and directly reaches the lungs, thereby being used for For bronchial asthma, chronic bronchitis, bronchiectasis, tuberculosis, pneumoconiosis, emphysema, atypical mycobacterial infection, diffuse bronchiolitis and other chronic respiratory diseases.

According to one embodiment of the invention, "fine particle dose" refers to the total mass of active substance present with an aerodynamic particle size smaller than a defined limit, emitted from the device with drive.

According to one embodiment of the present invention, "delivered total amount" refers to the sum of the amount of active substances collected by all filter papers and filter paper devices when a breathing simulator is used to simulate moist breathing of a human body. Embodiment 1, preparation of fudosteine inhalation solution preparation of the present invention

Add fudosteine to a certain amount of water for injection, stir until it is completely dissolved, and then dilute with water for injection to obtain the product. The dosage of each component is shown in Table 1 below. The concentration of fudosteine in the obtained solution preparation of fudosteine for inhalation was 30 mg/ml. Table 1 Element effect Dosage Fordosteine active substance 30g Water for Injection solvent up to 1000ml Embodiment 2, the preparation of fudosteine inhalation solution preparation of the present invention

Add fudosteine to a certain amount of water for injection, stir until it is completely dissolved, and then dilute with water for injection to obtain the product. The dosage of each component is shown in Table 2 below. The concentration of fudosteine in the obtained solution preparation of fudosteine for inhalation was 250 mg/ml. Table 2 Element effect Dosage Fordosteine active substance 250g Water for Injection solvent up to 1000ml Embodiment 3, preparation of fudosteine inhalation solution preparation of the present invention

Add fudosteine to a certain amount of water for injection, stir until it is completely dissolved, and then dilute with water for injection to obtain the product. The dosage of each component is shown in Table 3 below. The concentration of fudosteine in the obtained fudosteine solution preparation for inhalation was 40 mg/ml. table 3 Element effect Dosage Fordosteine active substance 40g Water for Injection solvent up to 1000ml Embodiment 4, the preparation of fudosteine inhalation solution preparation of the present invention

Add fudosteine to a certain amount of water for injection, stir until it is completely dissolved, and then dilute with water for injection to obtain the product. The dosage of each component is shown in Table 4 below. The concentration of fudosteine in the obtained solution preparation of fudosteine for inhalation was 200 mg/ml. Table 4 Element effect Dosage Fordosteine active substance 200g Water for Injection solvent up to 1000ml Embodiment 5, the preparation of fudosteine inhalation solution preparation of the present invention

Add fudosteine to a certain amount of water for injection, stir until it is completely dissolved, and then dilute with water for injection to obtain the product. The dosage of each component is shown in Table 5 below. The concentration of fudosteine in the obtained fudosteine solution preparation for inhalation was 50 mg/ml. table 5 Element effect Dosage Fordosteine active substance 50g Water for Injection solvent up to 1000ml Embodiment 6, the preparation of fudosteine inhalation solution preparation of the present invention

Add fudosteine to a certain amount of water for injection, stir until it is completely dissolved, and then dilute with water for injection to obtain the product. The dosage of each component is shown in Table 6 below. The concentration of fudosteine in the obtained fudosteine inhalation solution preparation was 100 mg/ml. Table 6 Element effect Dosage Fordosteine active substance 100g Water for Injection solvent up to 1000ml Embodiment 7, the preparation of fudosteine inhalation solution preparation of the present invention

Add fudosteine to a certain amount of water for injection, stir until it is completely dissolved, and then dilute with water for injection to obtain the product. The dosage of each component is shown in Table 7 below. The concentration of fudosteine in the obtained solution preparation of fudosteine for inhalation was 150 mg/ml. Table 7 Element effect Dosage Fordosteine active substance 150g Water for Injection solvent up to 1000ml Embodiment 8-9, preparation of fudosteine inhalation solution preparation of the present invention

Add 100g of fudosteine to a certain amount of water for injection, stir until it is completely dissolved, then dilute to 1000ml with water for injection, and set aside; Example 8 Fill the prepared solution into a medium borosilicate glass ampoule, Example 9 Fill the prepared solution into medium borosilicate glass ampoules after the air has been replaced with pure nitrogen. The dosage of each component is shown in Table 8 below. The concentration of fudosteine in the obtained fudosteine inhalation solution preparation was 100 mg/ml. Table 8 Element Example 8 Example 9 Fordosteine 100g 100g Water for Injection up to 1000ml up to 1000ml Nitrogen / Nitrogen filling Package Medium borosilicate glass ampoule Medium borosilicate glass ampoule Example 10. Pharmacokinetic and tissue distribution experiments of fudosteine by inhalation or oral administration in rats

Twenty-four male SD rats, weighing 180-200 g, were used in the experiment. Randomly grouped according to body weight, divided into fudosteine oral administration group, fudosteine aerosol inhalation administration group, 12 in every group, adopt the fudosteine solution administration (can be diluted) of embodiment 4, two The dosage of both groups was 30 mg/kg. Time points of blood collection in each group: before administration, 15min, 30min, 50min, 2h, 4h, 8h, 24h after administration, 3 animals at each time point, blood samples were anticoagulated with heparin sodium and centrifuged to separate plasma; Tissue collection time points: 15min, 50min, 4h, 24h after administration, 3 animals at each time point. The samples were processed and detected by LC-MS analysis method, and the target analyte was fudosteine. The experimental results are shown in Table 9: Table 9 group C _max ng/mL AUC _{(0-t )} hr*ng/mL lung tissue Oral group 1581.58 3085.64 inhalation group 2842.55 5919.47 trachea Oral group 1197.95 2160.38 inhalation group 7639.04 14966.33 plasma Oral group 16887.00 21321.93 inhalation group 11229.33 19102.34

The results showed that, compared with oral administration, the drug concentration and exposure in lung tissue and trachea were increased by aerosol inhalation at the same dose. The drug concentration and exposure in the lung tissue increased to 1.80 and 1.92 times, respectively, and to 6.38 and 6.93 times in the trachea. The plasma exposure decreased, and the drug concentration and exposure decreased to 0.66 and 0.90 times, respectively. Embodiment 11, the experiment of promoting the excretion of mouse phenol red

± s） 組別 n 酚紅排泄量（µg/mL） 對照組 10 1.38±0.46 福多司坦 60 mg/kg，P.O 10 1.96±0.49 福多司坦 60 mg/kg，吸入給藥 9 3.33±1.74 ^##** 福多司坦 40 mg/kg，吸入給藥 10 2.86±0.57** 福多司坦 20 mg/kg，吸入給藥 10 2.25±0.72 福多司坦 10 mg/kg，吸入給藥 9 1.38±0.45 ** P＜ 0.01 vs. 對照 ## P＜ 0.01 vs. 60mg/kg P.O n為小鼠個數 60 experimental mice were randomly divided into 6 groups according to body weight, 10 in each group, respectively: control group, fudosteine 60 mg/kg oral group, fudosteine 60 mg/kg, 40 mg/kg, 20 mg/kg, 10 mg/kg aerosol inhalation administration group. The control group inhaled physiological saline, and the treatment group was orally or inhaled the corresponding dose of fudosteine (fudosteine solution obtained in Example 6). After 30 minutes of administration, 1% phenol red saline solution was injected intraperitoneally, and euthanized mice were euthanized by excessive inhalation of CO ₂ after ₃₀ minutes. The syringe was inserted into the trachea and slowly injected, and then slowly sucked out. This was repeated 3 times. The combined lavage fluid was placed for a certain period of time to allow impurities to precipitate, and a transparent red supernatant was obtained. The color was measured at a wavelength of 545 nm, according to phenol red The amount of phenol red was calculated from the standard curve. The experimental results are shown in Table 10: Table 10. Effects of administration of fudosteine by different routes on the excretion of phenol red in mice (

± s ) group no Phenol red excretion (µg/mL) control group 10 1.38±0.46 Fudosteine 60 mg/kg, PO 10 1.96±0.49 Fudosteine 60 mg/kg by inhalation 9 3.33±1.74 ^## ** Fudosteine 40 mg/kg by inhalation 10 2.86±0.57** Fudosteine 20 mg/kg by inhalation 10 2.25±0.72 Fudosteine 10 mg/kg by inhalation 9 1.38±0.45 ** P＜0.01 vs. Control ## P＜0.01 vs. 60mg/kg PO n is the number of mice

In the phenol red excretion test in mice, inhalation administration of fudosteine 20-60 mg/kg can increase the excretion of phenol red in mice, and the level of increase increases with the increase of inhalation dose. Among them, inhalation administration of 60 mg/kg and 40 mg/kg fudosteine can significantly increase the excretion of phenol red in mice. It shows that aerosol inhalation of fudosteine can dilute sputum by promoting the secretion of airway serous fluid and play an expectorant effect, and this effect is dose-dependent. Compared with oral administration (P.O) 60 mg/kg, inhalation administration of fudosteine 20-60 mg/kg has better efficacy, and at the same dose, inhalation administration of fudosteine has significantly better expectorant effect than oral administration. Experimental example 12, fudosteine nebulization inhalation repeated administration toxicity test

SD rats were inhaled once a day with normal saline or fudosteine (using the fudosteine solution in Example 2, fully exposed to the maximum feasible dose, respectively: 39.34 mg/kg, 236.03 mg/kg ). During the experiment, all dose groups survived normally until the end of the experiment, and no abnormalities were found in animal weight, food consumption, and detailed clinical conditions, and no clinical and pathological indicators (including hematology, serum biochemistry, coagulation, and urinalysis) were found to be consistent with those for the test. Toxicological changes related to the test product, animal gross anatomy, organ weight and pathological examination showed no abnormalities related to the test product. In the toxicokinetic experiment, the exposure of fudosteine solution for inhalation increased with the increase of the administered dose. Under the conditions of this test, the no-observed-effect dose level (NOAEL) of fudosteine solution for inhalation in SD rats was 236.03 mg/kg. It shows that fudosteine solution is safe for inhalation administration.

Conclusion: The fudosteine solution prepared by the present invention is used for aerosol inhalation administration, which can increase the exposure of the respiratory system compared with oral administration. The exposure of the same dose in the trachea is increased by nearly 6 times, and the exposure in the lung tissue is increased by nearly 1 times. The pharmacodynamic mechanism of fudosteine is comprehensive. In the pharmacodynamic experiment of increasing the excretion of phenol red, compared with oral administration, inhalation of a quarter to an equal dose can achieve equivalent or better effects. When the inhalation dose is oral administration The drug effect is not good at one-sixth of the dose. Toxicity tests showed that aerosol inhalation of fudosteine was safe. The clinical dosage of fudosteine oral preparations is 400 mg each time for adults, 3 times a day. Based on the fudosteine solution prepared in Examples 1-6, combined with the research results of Experimental Examples 10-12, it is speculated that fudosteine can be inhaled at 100-400mg by nebulization each time, which can achieve equivalent or better efficacy compared with oral administration. The efficacy and safety are good. On this basis, further pharmaceutical research will be carried out, combined with the requirements of clinical nebulization inhalation medication specifications, to explore the optimal fudosteine nebulization inhalation formulation, in order to achieve the best comprehensive benefit in clinical use. Experimental Example 13, Risk Assessment of Prescription Variables

The active ingredient of this product (fudosteine is weakly acidic with a concentration of 50mg/ml and the pH value is 5.5), the solvent (purified water), and the preparation development investigates the influence of pH regulators (citric acid and sodium citrate) on the stability.

Method: The key quality attributes (CQAs) such as properties, pH value, color, related substances and content were mainly investigated, and the formulation was screened and optimized. Tables 11 and 12 show the risk assessment results of the formulation. Table 11 Prescription Risk Assessment Drug product critical quality attributes CQAs prescription variable Fordosteine Citric Acid Dosage Sodium citrate dosage character high Low Low pH value high high high Related substances (impurities) Low Low Low content high Low Low Remark "Low" indicates low risk, meaning a risk that is broadly acceptable and no further study is needed. "Medium" means medium risk, which means acceptable risk and further research is needed to reduce the risk. "High" indicates high risk, which means unacceptable risk and further research is needed to eliminate and reduce the risk. Risk refers to the stability risk of the formulation. Table 12 Prescription Risk Assessment Basis prescription variable Critical Quality Attributes CQAs in accordance with Fordosteine character The active ingredient of this product, fudosteine, has a preliminarily proposed concentration of 50mg/ml~150mg/ml. The raw material of fudosteine is white to slightly yellow crystalline powder, which has an impact on the shape and color, and this attribute is a high-risk attribute; fudosteine Dosteine is weakly acidic (50mg/ml concentration pH value is 5.5), and the amount (concentration) of raw materials will affect the pH, which is a high-risk attribute; the amount of fudosteine raw materials will not affect related substances in the product, and this attribute is low Risk attribute; the amount of fudosteine raw materials will affect the content of the product, and this attribute is a high-risk attribute. pH value relative substance content Sodium citrate and anhydrous citric acid dosage character Sodium citrate and citric acid are pH regulators, which have no effect on the traits, and this attribute is a low-risk attribute. pH value The pH value is mainly adjusted according to the pH regulator, so the dosage of sodium citrate and citric acid determines the pH value of the finished product, which is a high-risk attribute. relative substance Sodium citrate and anhydrous citric acid are pH regulators, which have no effect on color, related substances, and content. This attribute is a low-risk attribute.

Example 14, pH value screening This product preliminarily selects sodium citrate and citric acid as pH regulators, and the pH value of the solution may affect product stability. Use citric acid and 0.1mol/L citric acid solution, 0.1mol/L L sodium citrate solution was used to adjust the pH of the solution to 3.0-6.0, and the API concentration was 150 mg/ml. By testing the character, pH value, color, related substances and content of the sample, investigating its influence on the prescription, stability, etc., screening the pH value control range of the product solution, the results are shown in Tables 13 and 14. Table 13 Sodium citrate and anhydrous citric acid dosage screening prescription Prescription 1 Prescription 2 Prescription 3 Prescription 4 Prescription 5 composition w/v w/v w/v w/v w/v pH value 5.0 3.0 4.0 5.0 6.0 Fordosteine 15% sodium citrate / / / / Appropriate amount citric acid / Appropriate amount Appropriate amount Appropriate amount / Water for Injection Add to 100%

The 15% concentration of fudosteine in Table 13 refers to the mass-volume ratio of fudosteine in the entire pharmaceutical preparation. For example, the fudosteine solution for inhalation contains 150 mg of fudosteine, and the volume of the preparation is 1000 ml. Table 14 Investigation of the stability of the pH value of different solutions prescription investigation 0 days Store at 2-8°C for 2 days, then at 40°C for 2 days, cycle 3 times High temperature -10 days (80°C) Light - 10 days (4500lx±500lx) Prescription 1 content 90.0%~110.0% 98.55% 99.51% 95.65% 98.63% character Colorless to light yellow clear or almost clear liquid colorless clear liquid light yellow clear liquid yellow clear liquid yellow clear liquid pH value / 4.97 5.43 6.70 5.82 relative substance L-cystine 0.048% 0.048% 0.062% 0.046% L-cysteine not detected not detected not detected not detected Impurity A 0.033% 0.050% 0.025% 0.384% Impurity B not detected not detected not detected not detected largest unknown complex 0.085% 0.082 0.159% 0.103% total miscellaneous 0.25% 0.26 0.55% 0.61% Number of impurities 4 4 8 4 Prescription 2 content 90.0%~110.0% 95.67% 95.91% 89.54% 95.06% character Colorless to light yellow clear or almost clear liquid colorless clear liquid light yellow clear liquid yellow clear liquid yellow clear liquid pH value / 2.99 3.03 3.13 3.02 relative substance L-cystine 0.028% 0.025% 0.043% 0.029% L-cysteine not detected not detected not detected not detected Impurity A not detected 0.206% not detected 0.381% Impurity B not detected not detected not detected not detected largest unknown complex 0.097% 0.102% 0.163% 0.078% total miscellaneous 0.18% 0.39% 0.56% 0.56% Number of impurities 3 4 7 4 Prescription 3 content 90.0%~110.0% 98.54% 99.03% 95.95% 97.62% character Colorless to light yellow clear or almost clear liquid colorless clear liquid light yellow clear liquid yellow clear liquid yellow clear liquid pH value / 4.04 4.30 5.92 4.82 relative substance L-cystine 0.020% 0.028% 0.055% 0.027% L-cysteine not detected 0.026% not detected not detected Impurity A 0.070% 0.034% not detected 0.295% Impurity B not detected not detected not detected not detected largest unknown complex 0.086% 0.098% 0.111% 0.108% total miscellaneous 0.25% 0.27% 0.42% 0.51% Number of impurities 4 5 6 4 Prescription 4 content 90.0%~110.0% 99.76% 99.43% 96.07% 98.19% character Colorless to light yellow clear or almost clear liquid colorless clear liquid light yellow clear liquid yellow clear liquid yellow clear liquid pH value / 5.11 5.58 6.44 5.95 relative substance L-cystine 0.031% 0.034% 0.042% 0.037% L-cysteine not detected not detected not detected not detected Impurity A 0.038% 0.060% not detected 0.330% Impurity B not detected not detected not detected not detected largest unknown complex 0.097% 0.095% 0.109% 0.127% total miscellaneous 0.24% 0.27% 0.58% 0.57% Number of impurities 4 4 8 4 Prescription 5 content 90.0%~110.0% 98.60% 99.39% 96.09% 98.30% character Colorless to light yellow clear or almost clear liquid colorless clear liquid light yellow clear liquid yellow clear liquid yellow clear liquid pH value / 6.00 6.11 6.53 6.20 relative substance L-cystine 0.038% 0.034% 0.039% 0.023% L-cysteine not detected not detected not detected not detected Impurity A 0.074% 0.060% not detected 0.317% Impurity B not detected not detected not detected not detected largest unknown complex 0.089% 0.096% 0.170% 0.105% total miscellaneous 0.28% 0.27% 0.69% 0.51% Number of impurities 4 4 8 4

From the results of pH value screening, it can be seen that there is no difference in stability under low temperature cycle, high temperature, and light conditions when adding a pH regulator to adjust the pH value to 3.0-6.0 and directly preparing samples with pure water. Experimental example 15, stability test of fudosteine inhalation solution preparation of the present invention

Detect the stability of the solution preparation for inhalation with a concentration of fudosteine of 100 mg/ml in Example 8 of the present invention at 1 month, 2 months, 3 months, and 6 months respectively, and the results are shown in Tables 15 and 16 , where Tables 15 and 16 are the results at different temperatures and humidity, and Table 15 only shows the results of 3 months and 6 months. Table 15 Long-term test data of fudosteine solution for inhalation (30℃±2℃, 65%RH±5%RH) Example 8 investigation 0 days March June character It is light yellow clear liquid It is light yellow clear liquid It is light yellow clear liquid pH value 5.5 5.5 5.8 solution clarity clarify clarify clarify relative substance(%) L-cystine 0.03 0.02 0.02 L-cysteine ND ND ND Impurity A 0.04 0.11 0.15 Impurity B ND ND 0.006 largest unknown complex 0.09 0.13 0.11 total miscellaneous 0.20 0.37 0.35 quantity Compliance N/A N/A insoluble particles 26.0 capsules 20.3 capsules 134.7 grains 0.3 capsules 1.0 capsules 3.0 capsules sterile Compliance N/A N/A Visible foreign matter Compliance Compliance Compliance Osmolality (mOsmol/kg) 602 613 612 fine particle dose 58.13 57.22 53.11 Delivery Rate and Total Delivery 0.17 0.19 0.20 38.77 31.58 48.29 Content determination (%) 101.2 100.0 100.4 Remark "ND" means not detected; "N/A" means not detected Table 16 Accelerated test (40°C±2°C, 75%RH±5%RH) data of fudosteine solution for inhalation (5ml: 500mg) investigation Example 8 0 days January _ february _ March _ June _ character It is light yellow clear liquid It is light yellow clear liquid It is light yellow clear liquid It is light yellow clear liquid It is light yellow clear liquid pH value 5.5 5.6 5.7 5.6 6.0 solution clarity clarify clarify clarify clarify clarify relative substance(%) L-cystine 0.03 0.02 0.02 0.02 0.02 L-cysteine ND ND ND ND ND Impurity A 0.04 0.10 0.15 0.19 0.25 Impurity B ND ND ND ND 0.006 largest unknown complex 0.09 0.11 0.13 0.14 0.12 total miscellaneous 0.20 0.30 0.41 0.46 0.48 quantity Compliance N/A N/A N/A Compliance insoluble particles 26.0 capsules 5.3 capsules 27.0 capsules 28.7 grains 148.0 grains 0.3 capsules 0.3 capsules 1.3 capsules 3.7 capsules 6.0 capsules sterile Compliance N/A N/A N/A Compliance Visible foreign matter Compliance Compliance Compliance Compliance Compliance Osmolality (mOsmol/kg) 602 605 608 612 617 fine particle dose 58.13 N/A N/A 60.19 54.27 Delivery Rate and Total Delivery 0.17 N/A N/A 0.20 0.21 38.77 N/A N/A 40.86 47.82 Content determination (%) 101.2 99.2 100.3 100.0 99.7 Remark "ND" means not detected; "N/A" means not detected

Conclusion: The stability of the fudosteine inhalation solution preparation provided in Example 8 was tested in an accelerated test in a high-temperature and high-humidity environment. There was no significant change in all indicators except related substances, and the related substances increased slightly, which can be passed Nitrogen for improvement. According to the ICH Q1 stability guideline, this product is expected to achieve long-term stability for at least 12 months.

Table 17 below shows the stability of the fodosteine solution formulations for inhalation in Example 8 and Example 9 under nitrogen-free and nitrogen-filled conditions. Table 17 Nitrogen Protection Sample Stability Investigation investigation 0 days High temperature ( 60 °C ) -30 days Not filled with nitrogen After Nitrogen Not filled with nitrogen After Nitrogen Example 8 Example 9 Example 8 Example 9 content 90.0%~110.0% 101.2% 102.0% 100.6% 101.3% character Colorless to light yellow clear or almost clear liquid colorless clear liquid colorless clear liquid light yellow clear liquid light yellow clear liquid relative substance(%) L-cystine 0.03% 0.04% 0.02% 0.02% L-cysteine not detected not detected not detected not detected Impurity A 0.05% not detected 0.29% not detected Impurity B not detected not detected not detected not detected largest unknown complex 0.10% 0.06% 0.12% 0.06% total miscellaneous 0.22% 0.15% 0.49% 0.14%

Conclusion: From the results in Table 17, it can be seen that there is no significant change in the related substances after 30 days of high temperature after nitrogen filling, so nitrogen filling can improve the stability of this product. Experimental example 16. Aerosol generation experiment of fudosteine solution preparation for inhalation of the present invention

The different concentrations and volumes of fudosteine inhalation solutions prepared in the prescription were investigated to investigate the delivery rate, total delivery amount and fine particle dose. Determination of delivery rate and total delivery amount : determined according to the delivery rate and total delivery amount inspection method of liquid preparations for nebulizers (Chinese Pharmacopoeia 2020 Edition Four General Rules 0111).

Using a compressed air-driven nebulizer (Berry), take 1 stick of this product and transfer the entire contents to the nebulizer. Set up the device according to the requirements of the determination method of the Chinese Pharmacopoeia, and select the "adult mode" for the breathing mode. Turn on the nebulizer at the beginning of the breathing cycle and turn off the nebulizer at the end of the breathing cycle. The amount of drug collected on the filter paper was determined according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Sibu General Rules 0512). The amount of drug collected per unit time is the average delivery rate, and the total amount of drug collected is the total amount of delivery.

Dose measurement of fine particles: refer to (Chinese Pharmacopoeia 2020 Edition Four General Rules 0951) Determination of Aerodynamic Characteristics of Fine Particles of Inhalation Preparations, select device 3 (Next Generation Impactor, NGI), and measure method 3 under the item of inhalation liquid preparations for detection.

Using a compressed air-driven nebulizer (Berry), take 1 stick of this product and transfer the entire contents to the nebulizer. Connect the suction nozzle to the L-shaped connecting tube through the adapter. Turn on the compressor and set the atomization time to 2min. Turn off the compressor, remove the atomizer from the L-shaped connecting pipe, and turn off the vacuum pump. Remove the impactor, wash layers S4, S5, S6, S7 and additional filter paper (MOC) with eluent, and measure the amount of drug collected from S4~MOC according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Four General Rules 0512), namely Get the dose of fine particles (mg).

Results: as shown in Tables 18 and 19. Table 18 Summary of Delivery Rate and Total Delivery Test Results volume concentration Average delivery rate (mg/s) total delivery Atomization time Remark 10ml 10mg/ml 0.03 51mg 28.3min N/A 10ml 25mg/ml 0.07 128mg 31.7min N/A 10ml 37.5mg/ml 0.11 186mg 28.7min N/A 10ml 50mg/ml 0.13 242 mg 22.4min N/A 8ml 50mg/ml 0.11 187 20.0min N/A 5ml 75mg/ml 0.26 154mg 19.7min N/A 5ml 100mg/ml 0.18 194mg 18.2min N/A 5ml 125mg/ml 0.34 257mg 12.7min N/A 5ml 150mg/ml 0.28 285mg 17.0min N/A 5ml 200mg/ml 0.41 369mg 15.0min There is slight crystal precipitation in the atomization cup, which can be ignored 2.5ml 0.30 120mg 6.7min 5ml 250mg/ml 0.51 417mg 13.7min There are crystals in the atomization cup 5ml 300mg/ml 0.61 482mg 13.2min There are crystals in the atomization cup Note: In this experiment, the PIRI boy compressed spray atomizer was used for detection, and the maximum volume of the atomization cup was 10ml. Table 19 Summary of Fine Particle Dose Detection concentration Fine particle dose (%) 10mg/ml 56.0 25mg/ml 53.5 37.5mg/ml 53.2 50mg/ml 59.7 100mg/ml 58.0 125mg/ml 51.8 150mg/ml 52.1 200mg/ml 53.0 Note: dose of fine particles (%) = dose of fine particles (mg) / total amount delivered

Conclusions: The delivery rate, the total amount delivered, and the dose of fine particles may affect the amount of drug inhaled by patients, which will affect product safety and efficacy.

From the above results, it can be seen that the concentration of this product is 25mg/ml~250mg/ml, which can meet the delivery of a total amount of 100~400mg, and can achieve the corresponding drug effect. However, the higher the concentration, the crystals will be precipitated in the atomization cup, and too much crystals will lead to a lower effective utilization rate of this product. Therefore, the concentration of fudosteine solution for inhalation is preferably less than 250 mg/ml.

According to fudosteine inhalation solution clinical nebulization inhalation drug treatment, the nebulization time should not exceed 30min. From the above results, it can be known that the concentration of fudosteine solution for inhalation should be ≥30mg/ml.

From Table 19 the dosage of fine particles, it can be seen that the concentration of the active ingredient in the prescription of fudosteine inhalation solution formulation of the present invention is in the range of 25 mg to 200 mg/ml, and there is no significant difference in the dosage of different concentrations of fine particles, all of which can meet the clinical efficacy requirements or needs. It is more convenient for clinical use and patient compliance, preferably within 25 minutes to achieve better clinical application effect, preferably 50-200mg/ml. Embodiment 17, the use method of fudosteine inhalation solution preparation of the present invention

The method of using the fudosteine inhalation solution preparation of the present invention: directly use the fudosteine inhalation solution preparation prepared in any one of Examples 1-9 (can be appropriately diluted), and the use volume is 1-10ml.

In the description of this specification, descriptions referring to the terms "one embodiment", "some embodiments", "example", "specific examples", "some embodiments" or "some examples" mean that a combination of the embodiments or An example describes a particular feature, structure, material, or characteristic that is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the described specific features, structures, materials or characteristics may be combined in any suitable manner in any one or more embodiments or examples. In addition, those skilled in the art can combine and combine different embodiments or examples and features of different embodiments or examples described in this specification without conflicting with each other.

Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention, those skilled in the art can make the above-mentioned The embodiments are subject to changes, modifications, substitutions and variations.

none

Claims (17)

A solution preparation of fudosteine for inhalation, wherein the concentration of fudosteine in the solution preparation for inhalation is 25-300 mg/ml, preferably 25-250 mg/ml. A solution preparation of fudosteine for inhalation, wherein the concentration of fudosteine in the solution preparation for inhalation is 30-250 mg/ml. The fudosteine inhalation solution preparation as claimed in claim 2, wherein the concentration of fudosteine in the inhalation solution preparation is 40-200mg/ml, preferably 50-150mg/ml, more preferably 50-100mg /ml. The fudosteine inhalation solution preparation as described in any one of claims 1 to 3, wherein the raw materials of the fudosteine inhalation solution preparation include fudosteine or its pharmaceutically acceptable salt or its Hydrate. The fudosteine inhalation solution preparation according to claim 4, wherein the raw materials of the fudosteine inhalation solution preparation also include water for injection. The fudosteine inhalation solution formulation as described in claim 4, wherein the fudosteine inhalation solvent formulation also includes one or more pharmaceutical excipients suitable for pulmonary administration or inhalation administration; Optionally, the pharmaceutical excipients include osmotic pressure regulators and/or surfactants. The fudosteine inhalation solution preparation as claimed in claim 4, wherein the fudosteine inhalation solution preparation does not include a pH regulator. The fudosteine inhalation solution preparation as claimed in claim 4, wherein the fudosteine inhalation solution preparation does not include a complexing agent or a chelating agent. The fudosteine inhalation solution preparation as described in any one of claims 1 to 3, wherein the fudosteine inhalation solution preparation is made of fudosteine or its pharmaceutically acceptable salt or its hydrate Composed with Water for Injection. The fudosteine inhalation solution preparation according to any one of claims 1 to 3, wherein the single dose of the fudosteine inhalation solution preparation is 1-10ml, preferably 2.5-8ml. The fudosteine inhalation solution preparation as described in any one of claim items 1 to 3, wherein after the fudosteine inhalation solution preparation is nebulized, the obtained fudosteine inhalation solution aerosol The dose range of fudosteine fine particles is ≥ 15%, preferably ≥ 30%. The fudosteine inhalation solution formulation according to any one of claims 1 to 3, wherein the total delivery amount of the fudosteine inhalation solution formulation is 100-400 mg. The solution formulation for inhalation of fudosteine as described in any one of claims 1 to 3, wherein the solution formulation for inhalation of fudosteine has a continuous release time of ≤30min during the nebulization process and directly reaches the lungs; preferably ≤20min. The fudosteine inhalation solution preparation as described in any one of claims 1 to 3, wherein the delivery rate of the fudosteine inhalation solution preparation is 0.07~0.51mg/s, preferably 0.1-0.4mg /s. The fudosteine inhalation solution formulation as described in any one of claim items 1 to 3, wherein the fudosteine inhalation solution formulation is contained in a container; Optionally, the container is an ampoule or a vial; Optionally, there is nitrogen protection in the container; Optionally, the material of the ampoule or vial is selected from any one of glass, polyethylene plastic, polypropylene plastic, and rubber. A method for preparing fudosteine inhalation solution preparation according to any one of claims 1-15, which comprises: adding fudosteine into water for injection, mixing until completely dissolved. A use of the fudosteine inhalation solution preparation as described in any one of claims 1 to 15 in the preparation of medicines for treating lung diseases or respiratory diseases; Optionally, the drugs for treating lung diseases or respiratory diseases include expectorant and/or cough suppressant drugs.