An inhalation formulation for treating pulmonary edema and a method of preparing the same

Abstract

An inhalation preparation for treating pulmonary edema, comprising a pyridine sulfonamide phosphate compound represented by formula 1 or a pharmaceutically acceptable salt thereof and a cationic guar gum. The cationic guar gum can greatly improve the permeability of the pyridine sulfonamide phosphate compound or the pharmaceutically acceptable salt thereof in a Calu-3 cell model (an in vitro simulation of lung tissue epithelial cell model). The application also provides a preparation method of the inhalation preparation: under normal temperature and pressure, the main drug, the absorption promoter and the freeze-drying excipient are dissolved in water in proportion and are constant volume to the total amount, and are filtered and freeze-dried. The inhalation preparation prepared by the application has strong lung permeability, simple production process and good application prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to an inhaled formulation for treating pulmonary edema with a pyridine sulfonamide phosphate compound or a pharmaceutically acceptable salt thereof as the main component. This invention also relates to a method for preparing the inhaled formulation. Background Technology

[0002] Pulmonary edema is caused by the accumulation of fluid in the pulmonary interstitium or alveoli, leading to an increase in extravascular fluid volume or elevated capillary pressure. Acute pulmonary edema clinically manifests primarily as dyspnea, cyanosis, cough (with colorless or pink frothy phlegm), and diffuse moist rales in the lungs. Severe cases can lead to respiratory failure and death. Pulmonary edema has a high incidence and poor prognosis, making it a common and critical illness in clinical practice.

[0003] In previous research, the inventors discovered that a pyridine sulfonamide phosphate compound has a good diuretic effect (Patent Publication No.: CN110606860B). Based on this research and the above background, the inventors conducted in-depth research on the treatment of pulmonary edema using this type of compound, and conducted preclinical systematic research on the preferred compound I-1 from the above patent as a Class 1 new drug. Experimental studies confirmed that the active metabolite M3 of compound I-1 in vivo can selectively act on one subtype of the Na+-K+-2Cl- cotransporter, namely NKCC1. NKCC1 is highly expressed in the lungs; drugs that inhibit this target can directly regulate alveolar fluid secretion and clearance, while inhibiting the expression of pro-inflammatory factors, thereby treating pulmonary edema and lung injury caused by various reasons.

[0004]

[0005] However, previous studies have shown that compound I-1 is mainly converted into the active metabolite M3 in vivo to produce therapeutic effects. Since M3 is poorly soluble in water, it results in poor biomembrane permeability, which in turn affects the bioavailability of the drug.

[0006] Therefore, there is an urgent need to develop a novel formulation of compound I-1 that is well absorbed in vivo and easy to produce. Summary of the Invention

[0007] The purpose of this invention is to provide an inhaled formulation with strong pulmonary permeability and a simple manufacturing process, enabling the product to be better applied in the treatment of pulmonary edema. Another purpose of this invention is to provide a method for preparing this inhaled formulation.

[0008] In view of this, the present invention provides an inhaled formulation for treating pulmonary edema, comprising a pyridine sulfonamide phosphate compound of Formula 1 or a pharmaceutically acceptable salt thereof and cationic guar gum;

[0009]

[0010] Where X is O or CH2, or X does not exist; Y is CH2, or Y does not exist; when neither X nor Y exists, O is directly connected to P; when X exists but Y does not exist, X is directly connected to O; when Y exists but X does not exist, Y is directly connected to P.

[0011] Optionally, the pyridine sulfonamide phosphate compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof:

[0012]

[0013]

[0014] Optionally, the pharmaceutically acceptable salt is selected from sodium salts, potassium salts, calcium salts, magnesium salts, barium salts, trimethylamine salts, triethylamine salts, tripropylamine salts, tributylamine salts, and diisopropylethylamine salts;

[0015] Optionally, in the inhaled formulation, the amount of cationic guar gum is 1 to 100 parts by weight, preferably 1 to 50 parts by weight, and more preferably 1 to 20 parts by weight, based on 100 parts by weight of the pyridine sulfonamide phosphate compound of Formula 1 or its pharmaceutically acceptable salt.

[0016] Optionally, the inhaled formulation further includes a lyophilized excipient, which is one or more of mannitol, sodium chloride, glucose, lactose, anhydrous lactose, sucrose, hydrolyzed gelatin, dextran, dextran, glycine, albumin, polyethylene glycol, polyvinylpyrrolidone, alanine, maltose, and lysine hydrochloride, preferably mannitol.

[0017] Optionally, in the inhaled formulation, the amount of the lyophilized excipient ranges from 1 to 100 parts by weight, preferably from 1 to 50 parts by weight, and more preferably from 5 to 50 parts by weight, based on 100 parts by weight of the pyridine sulfonamide phosphate compound of Formula 1 or its pharmaceutically acceptable salt.

[0018] Optionally, the inhaled formulation is a solution, powder, or suspension.

[0019] In some embodiments of the first aspect of this invention, the cationic guar gum is used as an absorption enhancer. Guar gum is derived from the natural plant guar bean and is a regenerable plant gum. Cationic guar gum (CGG, or guar hydroxypropyltrimethylammonium chloride) is a quaternary ammonium salt derivative of guar gum produced by reacting guar gum with 3-chloro-2-hydroxypropyltrimethylammonium chloride as an etherifying agent. Cationic guar gum has good water solubility, stable viscosity, strong stability, and is environmentally friendly, and is widely used in cosmetics, papermaking, plant dyeing, and food industries. However, in the pharmaceutical field, the application of cationic guar gum as an absorption enhancer has not been reported in the literature. In the screening experiment of absorption enhancers, the inventors' research team found that after adding cationic guar gum, the membrane permeability of the compound I-1 inhalation formulation was significantly improved in the Calu-3 cell model.

[0020] In another aspect, the present invention provides a method for preparing the above-mentioned inhaled formulation for treating pulmonary edema, comprising the following steps:

[0021] Solution preparation: Mix and dissolve the pyridine sulfonamide phosphate compound of Formula 1 or its pharmaceutically acceptable salt, cationic guar gum, optional lyophilized excipient and water for injection in a predetermined ratio;

[0022] a) Sterilization filtration: The above-mentioned drug solution is sterilized and filtered through a filter membrane (preferably through two stages of 0.22μm PVDF);

[0023] b) Filling: Fill the sterilized and filtered medicine solution into sterilized glass bottles;

[0024] c) Partial stoppering: using sterilized rubber stoppers to partially stopper the glass bottles containing the medicine liquid;

[0025] d) Freeze-drying: The semi-stoppered drug solution is freeze-dried in a sterilized freeze dryer under a preset freeze-drying program;

[0026] e) Stoppering and aluminum-plastic capping: Full stoppering and aluminum-plastic capping of freeze-dried glass bottles.

[0027] Optionally, the freeze-drying process includes:

[0028] 1) Pre-freezing: Pre-freeze at -25±10℃ and normal pressure for 120±60 min, then increase the pressure to 0.2±0.2 mbar;

[0029] 2) Sublimation drying: Heat to 5±5℃ under 0.2±0.2mbar pressure (preferably for 1h), maintain for 10±5h, and optionally continue heating to 25±5℃ (for 2h) to end freeze drying.

[0030] Preferably, step 3) analytical drying is also included: after sublimation drying, the sample is kept at 25±5℃ under ultimate vacuum conditions (preferably for 3 hours).

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] 1. This invention is the first to use cationic guar gum as an absorption enhancer in an inhaled formulation for treating pulmonary edema. Calu-3 cell models showed that the apparent permeability coefficient of compound I-1 was 1.7 times that of the unadded compound after the addition of cationic guar gum, suggesting that the absorption of the drug in the lungs is expected to be significantly improved.

[0033] 2. The inhalation formulation of the present invention is an inhalation powder (a sterile powder that needs to be dissolved before use). After being prepared as a solution before use, it has good nebulization characteristics.

[0034] 3. The preparation process of the inhaled formulation of the present invention is simple, which can effectively control costs and reduce the expenses incurred by patients during treatment.

[0035] 4. The inhaled formulation of compound I-1 of this invention can directly reach the lungs to exert a therapeutic effect, significantly reducing the distribution of the drug in the kidney tissues, thereby reducing serious adverse effects such as electrolyte disturbances caused by potent diuretics such as furosemide injection and torasemide. Compared with existing clinical treatment drugs, it has significant clinical advantages of better efficacy and fewer side effects. Attached Figure Description

[0036] Figure 1 This is a graph showing the effect of cationic guar gum on the permeability of M3 in Calu-3 cells in Example 9, where n = 3. Detailed Implementation

[0037] The technical solution of the present invention will be clearly and completely described below by way of embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0038] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0039] Example 1: Investigation of the freeze-drying process

[0040] Table 1. Formulation table of intermediate drug solution for inhalation preparation of compound I-1

[0041] Element effect Single specification dosage Compound I-1 Active ingredients 100mg Cationic guar gum Absorption enhancer 1mg Mannitol freeze-dried excipients 30mg Water for Injection solvent Add to 1ml

[0042] Preparation process:

[0043] Add 500 mL of room temperature pure water to a clean dispensing container, start stirring, then add the prescribed amounts of cationic guar gum, mannitol and compound I-1, stir until completely dissolved, add pure water to 1 L, stir evenly, freeze dry to obtain lyophilized powder of compound I-1.

[0044] The freeze-drying process parameters are shown in Table 2.

[0045] Table 2 Freeze-drying process parameters

[0046]

[0047]

[0048] The appearance, moisture content, and related substances of the lyophilized compound I-1 obtained from processes 1 and 2 were tested. The related substances were detected using high-performance liquid chromatography (HPLC) as described in Section IV, General Chapter 0512 of the 2020 edition of the Chinese Pharmacopoeia. The results are shown in Table 3.

[0049] Table 3. Sample test results for various freeze-drying parameters.

[0050]

[0051]

[0052] The results above show that the lyophilized powder of compound I-1 obtained by processes 1 and 2 is not significantly different from the active pharmaceutical ingredient.

[0053] Example 2

[0054] This embodiment provides a method for preparing an inhaled formulation, wherein the inhaled formulation is a powder for inhaling compound I-1, and the content of compound I-1 is 100 mg / vial.

[0055] The preparation method is as follows:

[0056] a) Add 500 mL of room temperature pure water to a clean preparation container, start stirring, then add 30.00 g of mannitol and stir until completely dissolved; then add 1.00 g of cationic guar gum and 100.00 g of compound I-1 and stir until dissolved; add pure water to 1 L and stir well.

[0057] b) Two-stage filtration sterilization using a 0.22μm PVDF filter membrane; filling, partial stoppering, freeze-drying according to process 1 in Example 1, full stoppering and capping to complete packaging.

[0058] Example 3

[0059] This embodiment provides a method for preparing an inhaled formulation, wherein the inhaled formulation is a powder for inhaling compound I-1, and the content of compound I-1 is 100 mg / vial.

[0060] The preparation method is as follows:

[0061] a) Add 500 mL of room temperature pure water to a clean preparation container, start stirring, then add 30.00 g of mannitol and stir until completely dissolved; then add 20.00 g of cationic guar gum and 100.00 g of compound I-1 and stir until dissolved; add pure water to 1 L and stir well.

[0062] b) Two-stage filtration sterilization using a 0.22μm PVDF filter membrane; filling, partial stoppering, freeze-drying according to process 1 in Example 1, full stoppering and capping to complete packaging.

[0063] Example 4

[0064] This embodiment provides a method for preparing an inhaled formulation, wherein the inhaled formulation is a powder for inhaling compound I-1, and the content of compound I-1 is 50 mg / vial.

[0065] The preparation method is as follows:

[0066] a) Add 500 mL of room temperature pure water to a clean preparation container, start stirring, then add 20.00 g of mannitol and stir until completely dissolved; then add 1.00 g of cationic guar gum and 50.00 g of compound I-1, and stir until dissolved; add pure water to 1 L and stir well.

[0067] b) Sterilize by filtration using a 0.22μm PVDF filter membrane; fill, partially stopper, freeze dry according to process 1 in Example 1, fully stopper and cap to complete packaging.

[0068] Example 5

[0069] This embodiment provides a method for preparing an inhaled formulation, wherein the inhaled formulation is a powder for inhaling compound I-1, and the content of compound I-1 is 10 mg / vial.

[0070] The preparation method is as follows:

[0071] a) Add 500 mL of room temperature pure water to a clean preparation container, start stirring, then add 10.00 g of mannitol and stir until completely dissolved; then add 10.00 g of cationic guar gum and 10.00 g of compound I-1 and stir until dissolved; add pure water to 1 L and stir well.

[0072] b) Sterilize by filtration using a 0.22μm PVDF filter membrane; fill, partially stopper, freeze dry according to process 2 in Example 1, fully stopper and cap to complete packaging.

[0073] Example 6

[0074] This embodiment provides a method for preparing an inhaled formulation, wherein the inhaled formulation is a powder for inhaling compound I-1, and the content of compound I-1 is 5 mg / vial.

[0075] The preparation method is as follows:

[0076] a) Add 500 mL of room temperature pure water to a clean preparation container, start stirring, then add 5.00 g of mannitol and stir until completely dissolved; then add 1.00 g of cationic guar gum and 5.00 g of compound I-1, and stir until dissolved; add pure water to 1 L and stir well.

[0077] b) Sterilize by filtration using a 0.22μm PVDF filter membrane; fill, partially stopper, freeze dry according to process 2 in Example 1, fully stopper and cap to complete packaging.

[0078] Example 7

[0079] This embodiment provides a method for preparing an inhaled formulation, wherein the inhaled formulation is a powder for inhaling compound I-1, and the content of compound I-1 is 100 mg / vial.

[0080] The preparation method is as follows:

[0081] a) Add 500 mL of room temperature pure water to a clean preparation container, start stirring, then add 5.00 g of mannitol and stir until completely dissolved; then add 50.00 g of cationic guar gum and 100.00 g of compound I-1, and stir until dissolved; add pure water to 1 L and stir well.

[0082] b) Sterilize by filtration using a 0.22μm PVDF filter membrane; fill, partially stopper, freeze dry according to process 1 in Example 1, fully stopper and cap to complete packaging.

[0083] Example 8

[0084] This embodiment provides a method for preparing an inhaled formulation, wherein the inhaled formulation is a powder for inhaling compound I-1, and the content of compound I-1 is 100 mg / vial.

[0085] The preparation method is as follows:

[0086] a) Add 500 mL of room temperature pure water to a clean preparation container, start stirring, then add 5.00 g of mannitol and stir until completely dissolved; then add 100.00 g of cationic guar gum and 100.00 g of compound I-1 and stir until dissolved; add pure water to 1 L and stir well.

[0087] b) Sterilize by filtration using a 0.22μm PVDF filter membrane; fill, partially stopper, freeze dry according to process 1 in Example 1, fully stopper and cap to complete packaging.

[0088] In the following examples, M3 is a compound

[0089] Example 9: Investigating the effect of cationic guar gum on the absorption promotion of M3 using the Calu-3 cell model.

[0090] Calu-3 cells are derived from human respiratory epithelial cells. After culture, these cells undergo junctional differentiation, forming a polar monolayer membrane. Structurally, they form tight junctions and microcilia. In addition to expressing P-glycoprotein and certain amounts of hydrolases, transferases, and cytochromes, the membrane surface also exhibits mucus secretion function, making them excellent models for simulating lung epithelial cells in vitro. The Calu-3 cell model has been widely used in research on respiratory drug delivery systems both domestically and internationally.

[0091] This embodiment uses high performance liquid chromatography to investigate the permeability of M3 drug solution on Calu-3 cells. In Experimental Group 1, M3 and cationic guar gum (weight ratio 74.59:1, equivalent to a weight ratio of 100:1 for compound I-1 and cationic guar gum, as in Example 2) were dissolved in 100 ml of HBSS (Hank's buffer) (drug concentration 1 mg / ml); Experimental Group 2, M3 and cationic guar gum (weight ratio 3.73:1, equivalent to a weight ratio of 5:1 for compound I-1 and cationic guar gum, as in Example 3) were dissolved in 100 ml of HBSS (Hank's buffer) (drug concentration 1 mg / ml); Control Group 1, M3 and guar gum (weight ratio 74.59:1) were dissolved in 100 ml of HBSS (Hank's buffer) (drug concentration 1 mg / ml); Control Group 2, M3 and chitosan (weight ratio 74.59:1) were dissolved in 100 ml of HBSS (Hank's buffer) (drug concentration 1 mg / ml). Prepared in HBSS (Hank's buffer) (drug concentration 1 mg / ml); blank control group without absorption enhancer, M3 drug concentration 1 mg / ml. Specific experimental methods are as follows:

[0092] Calu-3 cells were cultured on Transwell cell culture plates for 12–16 days using the air-interface method. After aspirating the culture medium from each well, the monolayer of cells was washed twice with HBSS at 37°C. 0.5 mL and 1.0 mL of HBSS at 37°C were injected into the AP and BL sides, respectively. Cells were incubated for 1 hour to equilibrate. Immediately after incubation, the liquid on the AP side was aspirated, and 0.3 mL of HBSS solution (1 mg / mL for both experimental and control groups) (n=3) was added to the AP side. Timing was started, and cells were placed in a CO2 incubator. Cells were removed at specified time points, and 0.3 mL of solution was quickly aspirated from the BL side, with an equal amount of fresh HBSS at 37°C added immediately. The samples were filtered through a 0.22 μm filter and analyzed by HPLC. The amount of drug permeating the BL side at different time points was calculated, and a permeation curve was plotted with the cumulative drug permeation as the ordinate and time as the abscissa. The apparent permeability coefficient (Papp) was calculated. The results are as follows: Figure 1 As shown in Table 4.

[0093] Table 4 Results of cationic guar gum promoting M3 penetration in Calu-3 monolayer cells (mean ± SD, n = 3)

[0094]

[0095]

[0096] Note: Compared with the blank control group, the experimental group showed a statistically significant difference (P < 0.0001).

[0097] The above results indicate that with the addition of cationic guar gum, the penetration rate of M3 on Calu-3 monolayer cells gradually increased with the extension of experimental time, and the apparent permeability coefficient reached 1.7 times that of the blank control group; while the apparent permeability coefficients of guar gum and chitosan solutions used as controls did not show a significant increase. Since Calu-3 cells can effectively mimic lung epithelial cells in vitro, this data suggests that cationic guar gum has the potential to significantly improve drug absorption in the lungs, achieving better therapeutic effects.

[0098] Example 10: Aerosol generation experiment after compound I-1 inhalation formulation is dissolved

[0099] Using a German PARI BOY compressor nebulizer, two samples prepared in process 2 of Example 1 of this invention were taken and dissolved in 2 ml of purified water to form a solution of 100 mg / ml. The above 2 ml of drug solution was added to the nebulizer cup, and nebulization was started. Parameters such as nebulization time, delivery rate and total delivery volume, fine particle percentage (FPF) (%), and diameter in aerodynamic mass (MMAD) (μm) were recorded.

[0100] Table 5. Nebulization data of inhaled formulation of compound I-1

[0101]

[0102] Note:

[0103] [1] Aerodynamic mass median diameter (MMAD): When the total mass of particles of various sizes smaller than a certain aerodynamic diameter accounts for 50% of the total mass of all particles (i.e., the sum of the masses of all particles of different sizes), this diameter is called the mass median diameter.

[0104] [2]FPF(%): Drug deposition rate in the lungs.

[0105] The above results indicate that the inhalation formulation of the present invention has good nebulization characteristics after being prepared into a solution. The nebulization inhalation administration time can be controlled within 10 minutes. Its aerodynamic mass has a diameter of 2-5 μm and a fine particle percentage of more than 50%, which can meet the requirements of nebulization inhalation.

[0106] Example 11: Tissue distribution study of compound I-1 inhalation formulation

[0107] SD rats were administered a single oral-nasal inhalation of a reconstituted solution of inhaled compound I-1 (administered via nebulization at a dose of 14 mg / kg; reconstitution method: 90 vials of the sample prepared in Process 2 of Example 1 were dissolved in 100 ml of purified water to a concentration of 90 mg / ml). Sampling points were 1 / 2 of the administration time, 5 min after administration, 1 h after administration, and 8 h after administration. Brain, heart, spleen, liver, kidneys, nasopharynx (including turbinates), larynx (including epiglottis), main trachea, bronchi, lungs, and bronchoalveolar lavage fluid (2 mL of physiological saline lavage) were collected. The tissue content of the active ingredient M3 at different time points was determined by LC-MS / MS.

[0108] The results showed that after administration of the compound, M3 was mainly distributed in respiratory tissues such as the lungs and larynx (including the epiglottis), while the drug content in the liver and kidneys was very low. This indicates that the drug mainly acts on the lungs, and its distribution in the kidney tissues is significantly reduced. This can reduce serious adverse effects such as electrolyte disturbances caused by potent diuretics such as furosemide and torasemide injections. See Table 6 for details.

[0109] Table 6. Tissue M3 content (ng / g, ng / mL) - time (h) in SD rats after inhalation of compound I-1 solution.

[0110]

[0111] Note: The unit for lung lavage fluid content is "ng / 2mL". "ND" indicates that it is below the lower limit of quantification and cannot be calculated.

[0112] The above are preferred embodiments of the present invention and do not impose any limitations on the present invention. Based on the above description, researchers can make other variations, which are not exhaustive here, but all fall within the protection scope of the present invention.

Claims

1. An inhaled formulation for treating pulmonary edema, characterized in that, The compounds comprising, but not limited to, pyridine sulfonamide phosphates of Formula 1 or their pharmaceutically acceptable salts and cationic guar gum; Where X is O or CH2, or X does not exist; Y is CH2, or Y does not exist; when neither X nor Y exists, O is directly connected to P; when X exists but Y does not exist, X is directly connected to O; when Y exists but X does not exist, Y is directly connected to P.

2. The inhaled formulation for treating pulmonary edema according to claim 1, characterized in that, The pyridine sulfonamide phosphate compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof:

3. The inhaled formulation for treating pulmonary edema according to claim 1, characterized in that, The pharmaceutically acceptable salt is selected from sodium salts, potassium salts, calcium salts, magnesium salts, barium salts, trimethylamine salts, triethylamine salts, tripropylamine salts, tributylamine salts, and diisopropylethylamine salts.

4. The inhaled formulation for treating pulmonary edema according to any one of claims 1-3, characterized in that, In the inhaled formulation, the amount of cationic guar gum is 1 to 100 parts by weight, preferably 1 to 50 parts by weight, and more preferably 1 to 20 parts by weight, based on 100 parts by weight of the pyridine sulfonamide phosphate compound of Formula 1 or its pharmaceutically acceptable salt.

5. The inhaled formulation for treating pulmonary edema according to any one of claims 1-4, characterized in that, The inhaled formulation further includes a lyophilized excipient, which is one or more of mannitol, sodium chloride, glucose, lactose, anhydrous lactose, sucrose, hydrolyzed gelatin, dextran, dextran, glycine, albumin, polyethylene glycol, polyvinylpyrrolidone, alanine, maltose, and lysine hydrochloride, preferably mannitol.

6. The inhaled formulation for treating pulmonary edema according to claim 5, characterized in that, In the inhaled formulation, the amount of the lyophilized excipient ranges from 1 to 100 parts by weight, preferably from 1 to 50 parts by weight, and more preferably from 5 to 50 parts by weight, based on 100 parts by weight of the pyridine sulfonamide phosphate compound of Formula 1 or its pharmaceutically acceptable salt.

7. The inhaled formulation for treating pulmonary edema according to any one of claims 1-6, characterized in that, The inhaled formulation is a solution, powder, or suspension.

8. The method for preparing the inhaled formulation for treating pulmonary edema according to any one of claims 1-7, characterized in that, Includes the following steps: a) Solution preparation: Mix and dissolve the pyridine sulfonamide phosphate compound shown in Formula 1 or its pharmaceutically acceptable salt, cationic guar gum, optional lyophilized excipient and water for injection in a predetermined ratio; b) Sterilization filtration: The above-mentioned drug solution is sterilized and filtered through a filter membrane (preferably through two stages of 0.22μm PVDF); c) Filling: Fill the sterilized and filtered medicine solution into sterilized glass bottles; d) Partial stoppering: using sterilized rubber stoppers to partially stopper glass bottles containing pharmaceutical liquids; e) Freeze-drying: The semi-stopped drug solution is freeze-dried in a sterilized freeze dryer under a preset freeze-drying program. f) Stoppering and aluminum-plastic capping: Full stoppering and aluminum-plastic capping of freeze-dried glass bottles.

9. The method for preparing an inhaled formulation according to claim 8, characterized in that, The freeze-drying process includes: 1) Pre-freezing: Pre-freeze at -25±10℃ and normal pressure for 120±60 min, then increase the pressure to 0.2±0.2 mbar; 2) Sublimation drying: Heat to 5±5℃ under 0.2±0.2mbar pressure (preferably for 1h), maintain for 10±5h, optionally continue heating to 25±5℃ (preferably for 2h) to end freeze drying; Preferably, step 3) analytical drying is also included: after sublimation drying, the sample is kept at 25±5℃ under ultimate vacuum conditions (preferably for 3 hours).

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