Preparation method and application of epimedin C solution for inhalation

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to an epimedin C solution for inhalation as well as a preparation method and application thereof. The preparation provided by the invention can improve the bioavailability of the epimedin C, enhance lung targeting, reduce systemic toxicity and improve the stability of the epimedin C, can effectively treat lung inflammation, and has a good application prospect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical preparations, and particularly relates to a preparation method of an Epimedium C solution for inhalation and application thereof. BACKGROUND

[0002] Acute pneumonia is a highly prevalent respiratory infectious disease worldwide. Current clinical treatment relies on antibiotics and glucocorticoids, but there are side effects such as bacterial drug resistance and metabolic disorders.

[0003] Epimedium C is a component of Herba Epimedii, which has the potential to treat cardiovascular diseases and bone loss. Literature 1 (Lee C J, et al. Pharmacokinetics and oral bioavailability of epimedin C after oral administration of epimedin C and Herba Epimedii extract in rats. Biomed Chromatogr, 2013, 28(5): 630-636.) developed a liquid chromatography-tandem mass spectrometry (LC-MS / MS) method for evaluating the pharmacokinetics of icariin C after rats were fed with Herba Epimedii. The pharmacokinetic data showed that Epimedium C was distributed rapidly and eliminated slowly after administration (1 mg / kg). The bioavailability of oral Epimedium C monomer and Epimedium C in Epimedium extract was about 0.58% and 0.13%, respectively. Epimedium C is a flavonoid compound extracted from the traditional Chinese medicine Herba Epimedii, which has anti-inflammatory, antioxidant and other pharmacological activities. However, its traditional oral administration is limited by the first-pass effect and insufficient lung targeting, and the bioavailability is less than 1%, which limits its clinical application value.

[0004] CN115463116A discloses an Epimedium flavone nebulization inhalation preparation and its application. Epimedium C monomer, icariin monomer, combination of Epimedium C and icariin, or Epimedium total flavone with Epimedium C and icariin as main components are used to prepare the nebulization inhalation preparation, which can deliver the drug to the lungs, improve the lung bioavailability of the drug, prolong the lung action time of the drug, and achieve good effects of nebulization inhalation treatment of inflammation-related respiratory diseases. However, it uses surfactant Tween 80, phosphate buffer, etc., and the content of Epimedium C is low, only 10-90%. Long-term high-temperature heating and oxidation treatment can cause decomposition and loss. Excessive heating and long-term exposure to air should be avoided during storage.

[0005] The inhalation solution of demecolcine C provided by the application is an isotonic liquid preparation obtained by dissolving demecolcine C raw material with water for injection, wherein the concentration of demecolcine C in the liquid preparation is 5 mg / mL, and the liquid preparation contains 0.9% sodium chloride, appropriate amount of hydrochloric acid or sodium hydroxide and appropriate amount of antioxidant guaiacol, and the pH value is 5.0-7.0. SUMMARY

[0006] In view of the deficiencies of the prior art, the present application provides an inhalation solution of demecolcine C and a preparation method thereof, which can improve the bioavailability of demecolcine C, enhance the lung targeting, reduce the systemic toxicity and increase the stability of demecolcine C, so as to effectively treat acute pneumonia and overcome the defects in the prior art.

[0007] The technical scheme of the present application is as follows: a demecolcine C nebulization inhalation preparation, comprising demecolcine C, guaiacol, an osmotic pressure regulator, a pH regulator and water for injection.

[0008] A demecolcine C nebulization inhalation preparation, comprising 0.5% demecolcine C, 0.01% guaiacol, 0.9% osmotic pressure regulator, pH regulator and water for injection.

[0009] In some embodiments, the osmotic pressure regulator is sodium chloride, and the pH regulator is hydrochloric acid or sodium hydroxide.

[0010] In some embodiments, the pH of the demecolcine C nebulization inhalation preparation is 5.0-7.0.

[0011] The present application provides a preparation method of the demecolcine C nebulization inhalation preparation, comprising the following steps:

[0012] 1) Take 80% of the prescription amount of water for injection, and add guaiacol and stir until dissolved, then add demecolcine C and stir until dissolved. Finally, add sodium chloride and stir until completely dissolved;

[0013] 2) pH adjustment: adjust the pH of the solution to 5.0-7.0 with hydrochloric acid or sodium hydroxide.

[0014] 3) Volume and filtration: add water for injection to the full amount, and filter through 0.45 μm and 0.22 μm filter membranes twice.

[0015] 4) Filling and storage: sterilely fill into glass ampoule bottles, seal after melting, and store in a cool place at 2-8℃.

[0016] In some embodiments, the temperature of the water for injection in step 1) is 60℃.

[0017] The present invention also proposes the application of the above-mentioned nebulized inhalation formulation of choledochin C in the preparation of medicaments for the treatment or prevention of lung and respiratory tract inflammation-related diseases, wherein the diseases include asthma, bronchitis, emphysema, bronchiectasis, chronic obstructive pulmonary disease, glucocorticoid-resistant lung disease, pulmonary fibrosis, interstitial lung disease, lung inflammation caused by infection or chemotherapy, and pulmonary hypertension.

[0018] The beneficial effects of this invention are:

[0019] 1. Improved bioavailability: Compared with intravenous injection, intratracheal administration significantly prolongs the elimination half-life of the drug, with an absolute bioavailability of over 80%, greatly improving the situation of poor bioavailability of oral administration.

[0020] 2. Enhanced lung targeting: The drug concentration in lung tissue after tracheal administration was much higher than that in the intravenous injection group. At 2 hours, the lung tissue-plasma partition coefficient (Kp) in the tracheal administration group was 144.91, while the Kp in the intravenous group was 1.32, indicating that the drug was highly exposed in the lungs and the drug exposure in non-target organs such as the heart, liver, and kidneys was low.

[0021] 3. Enhanced anti-inflammatory effect: After intratracheal administration, Chaohuoding C can significantly reduce inflammatory cell infiltration and exudate accumulation in mice with acute pneumonia, and reduce the levels of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α in BALF bronchoalveolar lavage fluid. The efficacy is even more significant after the addition of guaiacol.

[0022] 4. Improved safety: It reduces the dose of drugs entering the systemic circulation, lowers the risk of toxicity to non-target organs, and avoids the adverse reactions caused by long-term use of antibiotics and glucocorticoids.

[0023] 5. Enhanced stability: The formulation is basically stable after being placed at a high temperature of 40°C for 30 days. It should be stored away from light when exposed to strong light, providing scientific guidance for the storage and transportation of the product. Attached Figure Description

[0024] Figure 1 IL-1β, IL-6, and TNF-α inflammatory factors in mouse bronchoalveolar lavage fluid

[0025] Figure 2 Plasma drug concentration-time curves for different routes of administration

[0026] Figure 3 Drug content in various tissues after administration via different routes

[0027] Figure 4 Tissue distribution of phorbol C in rats administered via tracheal administration

[0028] Figure 5 Tissue distribution of phorbol C in rats injected intravenously Detailed Implementation

[0029] The following embodiments are intended to enable those skilled in the art to more fully understand the present invention, but are not intended to limit the invention to the scope of the embodiments described.

[0030] (I) Overall Technical Solution

[0031] This invention provides a preparation and evaluation scheme for an inhaled ascorbic acid C solution. Using ascorbic acid C as the active ingredient, the formulation (containing sodium chloride, pH adjuster, and antioxidant) and preparation process (dissolving, filtering, sterilization, etc.) are optimized to produce a solution suitable for pulmonary administration. This formulation, administered intratracheally, can directly act on lung lesions, avoiding the first-pass effect of oral administration, improving bioavailability and reducing systemic toxicity. Simultaneously, its efficacy, quality stability, and pharmacokinetic characteristics are verified through in vitro and in vivo evaluations.

[0032] (II) Product Composition and Structure

[0033] 1. Formula components

[0034]

[0035] 2. Dosage Form and Structure: Single-dose sterile solution, packaged in glass ampoules, each ampoule contains 2mL:10mg. The solution is a clear yellow liquid with an osmotic pressure is isotonic with human body fluids and a pH value suitable for respiratory mucosa tolerance.

[0036] (III) Preparation Method

[0037] 1. Dissolving: Take 1.6 ml of water for injection (60℃), add 10 mg of astragaloside C, 18 mg of sodium chloride and 0.2 mg of guaiacol in sequence, and stir until completely dissolved.

[0038] 2. pH adjustment: Adjust the pH of the solution to 5.0-7.0 using hydrochloric acid or sodium hydroxide.

[0039] 3. Volume adjustment and filtration: Add water for injection to 2 ml, and filter twice through 0.45 μm and 0.22 μm filter membranes for sterilization.

[0040] 4. Filling and storage: Aseptically fill into glass ampoules, seal and store in a cool place at 2-8℃.

[0041] Test Example 1

[0042] The results of investigating the effects of different pH values ​​on properties, content, and related substances are shown in Table 1. When the pH was adjusted to 3.0 and 4.0, the properties of the solution changed after terminal sterilization, with the appearance of white flocculent matter, indicating that the solution was extremely unstable under these pH conditions. When the pH was adjusted to 8.0 to 10.0, the total impurity content before sterilization increased significantly compared to the solution without pH adjustment. The content after sterilization was lower than before sterilization under different pH conditions, while the total impurity content increased, and the pH fluctuated, indicating that astragaloside C is easily degraded under high temperature conditions. Therefore, the pH of the solution was controlled between 5.0 and 7.0.

[0043] Table 1 Results of pH value selection investigation

[0044]

[0045] Test Example 2

[0046] Based on Test Example 1, the effect of the antioxidant guaiacol on the stability of ascorbic acid C was investigated: After adding the antioxidant guaiacol, the content after sterilization remained unchanged compared to before sterilization, and the total impurity content did not increase. However, without adding the antioxidant, the content after sterilization was lower than before sterilization, and the total impurity content increased, indicating that the antioxidant guaiacol can significantly increase the stability of ascorbic acid C under high temperature conditions.

[0047] Table 2 Results of the stability study of guaiacol

[0048]

[0049] Test Example 3

[0050] The initial addition of water for injection was examined, and the results of solutions prepared after adding different amounts of water for injection are shown in Figure 3. Different initial addition amounts of water for injection did not significantly affect the dissolution time of API, but did affect the dissolution of sodium chloride. The smaller the amount of water added, the longer the dissolution time of sodium chloride. Furthermore, 50% and 60% water for injection resulted in a slightly turbid solution, which became clear and transparent after sonication for 5 minutes. As the initial addition of water for injection increased, the pH fluctuation before and after adding the full amount decreased, while there was no significant difference in concentration. Therefore, adding 80% water for injection to dissolve API and sodium chloride was considered the optimal condition.

[0051] Table 3 Results of the initial addition of water for injection

[0052]

[0053] Test Example 4

[0054] The order of adding raw materials and auxiliary materials was examined. Adding sodium chloride first and then API would prolong the dissolution time of API, while the order of addition had almost no effect on the dissolution of sodium chloride, but the properties of the final solution were not significantly different. The specific results are shown in Table 4. Considering the efficiency of large-scale production, the process parameter of adding API first and stirring to dissolve before adding sodium chloride was adopted.

[0055] Table 4 Results of the investigation on the order of adding raw and auxiliary materials

[0056]

[0057] The order of addition of ascorbic acid C and guaiacol was investigated, and the results are shown in Table 5. When ascorbic acid C was added first, followed by guaiacol, the dissolution time of API slowed down and the solution became slightly turbid. When ascorbic acid C was added later, the dissolution time of API accelerated and the solution became clear, indicating that guaiacol has a certain solubilizing effect on ascorbic acid C.

[0058] Table 5 Results of the investigation on the order of adding raw and auxiliary materials

[0059]

[0060]

[0061] Test Example 5

[0062] The effect of water temperature on the key quality attributes of the formulation was investigated, and the results are shown in Table 6. As the water temperature increased, the API dissolved faster, with no significant impact on content or total impurities. Considering the efficiency of large-scale production, a water temperature of 60℃ was selected as the process parameter for solution preparation.

[0063] Table 6 Results of the investigation on the temperature of water for injection

[0064]

[0065] Test Example 6

[0066] 1. Properties and physicochemical characteristics

[0067] Results: All three batches of small-scale test samples were clear yellow solutions with pH values ​​of 5.90, 5.79, and 5.91, respectively, all within the range of 5.0-7.0; the osmolar concentration ratio was 1.00, which met the isotonic requirements.

[0068] 2. Content and Impurities

[0069] The content of C in the three batches of samples was 99.50%, 101.45%, and 101.49%, respectively, all within the range of 95%-105% of the labeled amount.

[0070] Related substances: The total impurity contents were 0.79%, 0.77%, and 0.72%, respectively, all of which did not exceed the limit requirement of 1.0%.

[0071] 2. Stability

[0072] High-temperature test: The ascorbic acid C inhalation formulation sample with added guaiacol was placed at a high temperature of 40℃±2℃ for 30 days. The results are shown in Table 7. After 5, 10, and 30 days of placement at high temperature, compared with day 0, there were no significant changes in pH value, content, and sodium chloride content. The content of related substances also increased with the increase of placement time, but did not exceed 1.0%, which was within the controllable range. This indicates that the formulation is stable at a high temperature of 40℃±2℃ and is significantly stronger than the ascorbic acid C inhalation formulation sample without added guaiacol.

[0073] Table 7 Results of High Temperature Test (40℃±2℃) Influencing Factors

[0074]

[0075]

[0076] Intense light test: The results of the strong light test on the inhaled formulation of guaiacol-added ascorbic acid C are shown in Table 8. Under a light intensity of 4500 lx ± 500 lx, the pH value, content, and sodium chloride content of the formulation did not change significantly after 30 days compared with day 0. However, the total impurity content after 30 days exceeded 1.0%, indicating that API is easily degraded under strong light conditions. Therefore, it is necessary to store the formulation in the dark to ensure its stability.

[0077] Table 8 Results of Influencing Factors in Intensive Light Test (4500lx±500lx)

[0078]

[0079] Test Example 7

[0080] Methods: Sixty 6-8 week old mice were randomly divided into a normal blank control group, a model control group, a positive drug control group (dexamethasone acetate 5 mg / mL), and two experimental groups (0.01 mg / kg ascorbic acid C group and 0.01 mg / kg ascorbic acid C + guaiacol group), with 12 mice in each group. Mice were anesthetized by intraperitoneal injection of 1.25% tribromoethanol at a volume of 0.2 ml / 10 g. The normal control group was given an equal volume of sterile saline via tracheal infusion. The model control group was given 5 mg / kg LPS via tracheal infusion. The positive drug control group was given LPS solution and then intraperitoneally injected with dexamethasone acetate 5 mg / kg 1 hour later. The experimental groups were given LPS solution and then tracheally infused with ascorbic acid C and ascorbic acid C + guaiacol group 1 hour later.

[0081] Twenty-four hours after drug administration, six mice from each group were randomly selected for blood collection, euthanized by cervical dislocation, and their thoracic cavities were opened and irrigated with 0.3 mL of PBS. Irrigation was repeated three times, and the irrigating fluid was collected in centrifuge tubes. The centrifuges were then incubated at 4℃ and 3000 rpm. -1 Centrifuge for 10 min and collect the supernatant and cell pellet. Take a certain amount of the supernatant and follow the instructions of the enzyme-linked immunosorbent assay kit to determine the levels of TNF-α, IL-6, and IL-1β in the bronchoalveolar lavage fluid.

[0082] Results: The levels of IL-1β, IL-6, and TNF-α inflammatory factors in mouse bronchoalveolar lavage fluid were detected using an ELISA kit. (See attached table for details.) Figure 1 The results showed that, compared with the blank group, the levels of IL-1β, IL-6, and TNF-α in the model group were significantly increased (P<0.0001); compared with the model group, the levels of IL-1β and IL-6 in the positive drug group were significantly decreased (P<0.001 and P<0.0001, respectively). The levels of IL-1β, IL-6, and TNF-α in the 0.01 mg / kg ascorbic acid C experimental group and the ascorbic acid C + guaiacol group were significantly reduced (P<0.0001). The anti-inflammatory effect of the ascorbic acid C + guaiacol group was slightly better than that of the ascorbic acid C group.

[0083] Test Example 8: Plasma Pharmacokinetics of Asparagine C in Rats

[0084] Methods: Experimental animals were divided into four dosage groups: (1) low-dose tracheal administration group: 0.5 mg / kg; (2) medium-dose tracheal administration group: 1.0 mg / kg; (3) high-dose tracheal administration group: 2.0 mg / kg; and (4) intravenous administration group: 1.0 mg / kg. Each dosage group consisted of 4 animals, half male and half female, with a weight of 180–200 g.

[0085] After a 7-day acclimatization period, animals were fasted for 12 hours prior to the experiment, but water was permitted. A blank blood sample (approximately 200 μL) was collected via the fundus venous plexus and placed in a 1.5 mL centrifuge tube containing 2% heparin sodium. Intratracheal administration required anesthesia of the experimental animals using isoflurane. The collected whole blood was centrifuged at 4°C for 10 min at 4500 rpm within one hour. The supernatant plasma was collected and stored at -80°C for analysis. The samples were then analyzed by LC-MS / MS.

[0086] Plasma samples from the intravenous injection group at 5, 10, and 15 minutes need to be diluted 5-fold. Accurately pipette 20 μL of drug-containing plasma and add 80 μL of mixed blank plasma, then mix thoroughly. Accurately pipette 50 μL each of the diluted drug-containing plasma and the drug-containing plasma from the other dosage groups, add 150 μL of internal standard precipitant, vortex mix for 5 minutes, then centrifuge at 15000 rpm for 10 minutes in a high-speed refrigerated centrifuge at 2–8°C, and inject the supernatant.

[0087] LC-MS / MS Method: Column: ACQUITY HSS T3 (2.1×100mm, 1.8μm), Waters Corporation, pre-column is BEH C18 (3.9×5mm, 2.5μm); Mobile phase: 0.1% formic acid water (A): 90% acetonitrile + 0.1% formic acid (B) = 8:92; Flow rate: 0.35mL / min; Column temperature: 40℃; Injection volume: 2μL; Ion detection mode selected was negative ion mode of Multiple Reaction Monitoring (MRM), and ion source used was electrospray ionization (ESI).

[0088] Results: Drug concentration-time curves in rats after single intratracheal administration of 0.5, 1.0, and 2.0 mg / kg, and intravenous administration of 1.0 mg / kg are shown in the figure. Figure 2 As shown in the figure, the lungs have a rich blood flow. After administration via the trachea, astragalus C is rapidly absorbed into the bloodstream, and the peak drug concentration increases accordingly with increasing dosage. Intravenous injection of astragalus C is rapidly eliminated within 2 hours, while elimination is significantly slower in the tracheal administration group, prolonging the duration of action of the drug in the body.

[0089] Plasma pharmacokinetic parameters

[0090] The plasma pharmacokinetic parameters of rats after intratracheal and intravenous administration, calculated using WinNonlin, are shown in Table 8. The half-life of intravenous administration at 1.0 mg / kg was 0.255 ± 0.043 h, while the half-lives of intratracheal administration at 0.5 mg / kg, 1.0 mg / kg, and 2.0 mg / kg were 1.896 ± 0.612 h, 2.035 ± 0.876 h, and 2.38 ± 0.928 h, respectively. It can be seen that the half-life gradually increases with increasing intratracheal administration dose. Compared with intravenous administration, intratracheal administration significantly increased the half-life of ascorbic acid C in rats, thus increasing the duration of drug action. The times to peak concentration (AUC) for the three intratracheal administration groups were 0.866 ± 0.553 h, 0.777 ± 0.458 h, and 0.737 ± 0.388 h, respectively, with intravenous administration showing the shortest time to peak concentration. (0-t) AUC compared with intravenous injection (0-t) The absolute bioavailability was calculated by comparing the ratios. The absolute bioavailability of 0.5 mg / kg, 1.0 mg / kg and 2.0 mg / kg administered intratracheally was calculated to be 85.406±20.781%, 87.641±14.040% and 110.779±12.435%, respectively. The difference in absolute bioavailability among the different dosage groups may be due to individual differences among rats.

[0091] Table 8. Plasma pharmacokinetic parameters of rats after intravenous and intratracheal administration (n=4)

[0092]

[0093] Test Example 9: Tissue Distribution Study of Asparagine C in Rats

[0094] Methods: The experimental animals were divided into two groups: (1) tracheal administration group: the dosage was 2.0 mg / kg; (2) intravenous injection group: the dosage was 1.0 mg / kg. Each group consisted of 12 rats, half male and half female, with a weight of 180-200g.

[0095] Rats were fasted for 12 hours before the experiment but allowed free access to water. They were randomly divided into two groups, with four rats collected at each of the three time points. Rats in the tracheal administration group were anesthetized with isoflurane. Following aerosol and intravenous administration, rats were sacrificed at 0.167h, 0.75h, and 2h, respectively. Heart, liver, kidney, lung, and whole blood samples were collected. The tissues were rinsed with physiological saline, dried with filter paper, placed in EP tubes, and stored at -80℃ for analysis. Whole blood samples were centrifuged at 4℃ for 10 min within one hour, and the supernatant plasma was collected and stored at -80℃ for analysis.

[0096] After thawing the tissue samples, weigh 300 mg of tissue and place it in a homogenization tube. Add 1.5 mL of physiological saline at a weight-to-volume ratio of 5:1 g:5 mL, then add a steel ball and place the tube in a rapid homogenizer. Homogenize at 60 Hz for 30 seconds, repeating this process three times to obtain a tissue homogenate. The lung tissue homogenate from the tracheal administration group needs to be diluted 400 times. Accurately pipette 50 μL each of the diluted lung tissue homogenate and the remaining tissue homogenates, add 150 μL of internal standard precipitant, vortex mix for 5 min, and then centrifuge at 15000 rpm for 10 min in a high-speed refrigerated centrifuge at 2–8 °C. Collect the supernatant and inject it for analysis. Plasma samples from the tracheal administration group (0.167h, 0.75h) and the intravenous administration group (0.167h) were diluted 3 times. 50 μL of each of the diluted drug-containing plasma and other drug-containing plasma samples were precisely pipetted, and 150 μL of internal standard precipitant was added. After vortexing for 5 min, the mixture was centrifuged at 15000 rpm for 10 min in a high-speed refrigerated centrifuge at 2–8℃. The supernatant was then collected and injected for analysis.

[0097] LC-MS / MS Method: Column: ACQUITY HSS T3 (2.1×100mm, 1.8μm), Waters Corporation, pre-column is BEH C18 (3.9×5mm, 2.5μm); Mobile phase: 0.1% formic acid water (A): 90% acetonitrile + 0.1% formic acid (B) = 8:92; Flow rate: 0.35mL / min; Column temperature: 40℃; Injection volume: 2μL; Ion detection mode selected was negative ion mode of Multiple Reaction Monitoring (MRM), and ion source used was electrospray ionization (ESI).

[0098] Results: The distribution of chomphorn C in the heart, liver, kidney, and lung tissues after intravenous and tracheal administration was compared (see figure). Figures 3 to 5 .Depend on Figure 3 As shown in D, the drug concentration in lung tissue after tracheal administration was significantly higher than that in the intravenous injection group. However, in the heart, liver, and kidney tissues, the drug distribution in both the intravenous and tracheal administration groups was much lower, less than 2 μg / g. Figure 4 It can be seen that after intratracheal administration of oxytocin C, the lung tissue maintained a high drug concentration for 2 hours, indicating that intratracheal administration prolongs the drug's duration of action in the lungs. Figure 5 In the study, as time progressed, the drug concentration in each tissue of the intravenous injection group gradually decreased, and the drug concentration level in the lung tissue was not significantly different from that in plasma and other tissues, indicating that the drug could not accumulate at the target site after intravenous administration.

[0099] The tissue-plasma partition coefficient was calculated by comparing the drug concentration in tissues with that in plasma. The results are shown in Table 9. From 10 to 120 minutes after tracheal administration, the Kp value in the lungs changed from 1523.25 to 144.91. Generally, a Kp value greater than 1 indicates high drug exposure, and a Kp value less than 1 indicates low drug exposure. This indicates that the drug exposure level in lung tissue is extremely high. Ten minutes after administration, the Kp values ​​in the liver and kidneys were greater than 1, theoretically indicating high exposure, but compared to the high Kp value in lung tissue, the drug exposure level was low. With increasing time, the exposure level in the heart gradually increased, possibly due to drug absorption into the bloodstream and subsequent distribution to organs with rich blood flow. After intravenous injection of oxytocin C, the drug exposure level in lung tissue was much lower than that after tracheal administration. The tissue-plasma partition coefficient in the kidneys increased from 1.02 to 6.85, suggesting that the drug may be metabolized by the kidneys.

[0100] Table 9. Tissue-plasma partition coefficients at various time points

[0101]

[0102]

Claims

1. An atomized inhalation preparation of azanolide C, comprising azanolide C, guaiacol, an osmotic pressure regulator, a pH regulator and water for injection.

2. The inhalation formulation according to claim 1, characterized in that, comprising 0.5% azanolide C, 0.01% guaiacol, 0.9% osmotic pressure regulator, a pH regulator and water for injection.

3. The inhalation formulation according to claim 1, wherein The osmotic pressure regulator is sodium chloride and the pH regulator is hydrochloric acid or sodium hydroxide.

4. The inhalation formulation according to claim 1, wherein The pH of the azanolide C atomized inhalation preparation is 5.0-7.

0.

5. A method for preparing the azanolide C atomized inhalation preparation of claim 1, comprising the following steps: 1) Take 80% of the prescription amount of water for injection, add guaiacol and stir until dissolved, then add azanolide C and stir until dissolved, and finally add sodium chloride and stir until completely dissolved; 2) pH adjustment: adjust the pH of the solution to 5.0-7.0 with hydrochloric acid or sodium hydroxide; 3) Volume setting and filtration: add water for injection to the full amount, and filter twice through 0.45 μm and 0.22 μm filter membranes to remove bacteria; 4) Filling and storage: sterilely fill into glass ampoule bottles, seal after melting, and store in a cool place at 2-8°C.

6. The production method according to claim 5, characterized by, The temperature of the water for injection in step 1) is 60°C.

7. Use of the aerosolized inhalation formulation of azamiidine C according to claim 1 for the manufacture of a medicament for the treatment or prevention of diseases associated with inflammation of the lungs and airways, wherein, The diseases include asthma, bronchitis, emphysema, bronchiectasis, chronic obstructive pulmonary disease, glucocorticoid-resistant pulmonary disease, pulmonary fibrosis, interstitial lung disease, pulmonary inflammation caused by infection or chemotherapy, and pulmonary hypertension.

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