Asthma-relieving pharmaceutical composition and application thereof

Abstract

The invention relates to application of baicalein, in particular to an antiasthmatic pharmaceutical composition and application of the antiasthmatic pharmaceutical composition in preparation of inhalation type antiasthmatic drugs. The composition is prepared from baicalein and auxiliary materials according to the mass ratio of 1: (0.3-3), and the auxiliary materials are one or more of leucine, mannitol, glycine, alanine, proline, isoleucine, threonine, asparaginic acid, arginine, methionine, lactose anhydrous, glucose and D-sorbitol. The invention also discloses application of the composition in preparation of inhalation type asthma-relieving medicines. The baicalein nanocrystalline dry powder inhalant prepared by the invention has the characteristics of high fine particle fraction (FPF), stable storage, small irritation and the like. According to the invention, the baicalein is prepared into the dry powder inhaler by taking the nanocrystal as the intermediate for the first time, and characterization shows that the preparation process of the preparation is good in repeatability. The advantages of the target preparation are proved through a series of in-vivo and in-vitro means.

Description

Technical Field

[0001] The invention relates to the use of baicalein, in particular to an antiasthmatic drug composition and the use thereof in preparing an inhaled antiasthmatic drug. Background Art

[0002] Asthma is one of the most common chronic non-communicable diseases in the world. Its main characteristics are chronic airway inflammation, nonspecific airway hyperresponsiveness and reversible airway obstruction, which in turn cause dyspnea and wheezing. [1] Asthma patients have a variety of pathological changes in their lungs, the most important of which is airway inflammation. Airway inflammation in asthma patients is mainly related to environmental triggers, such as airborne allergens that cause a large number of lymphocytes and eosinophils to infiltrate. Once these cells are activated, they release chemokines, such as histamine, which causes asthma patients to have airway hyperresponsiveness and mucus hypersecretion, ultimately leading to airway remodeling changes.

[0003] In the past 15 years, the incidence and mortality of asthma have been significantly reduced. However, most patients still have uncontrolled asthma. Currently, the commonly used asthma treatment drugs in clinical practice can cause a series of adverse reactions, such as hoarseness, central obesity and even affect the growth of children. Traditional Chinese medicine has a history of thousands of years in treating asthma, which was recorded in Zhang Zhongjing's "Treatise on Febrile and Miscellaneous Diseases" in the Eastern Han Dynasty. Compared with chemical drugs, traditional Chinese medicine has the advantages of safety, less side effects and low cost.

[0004] Baicalin (BAI) is one of the natural flavonoid compounds extracted from Scutellaria baicalensis, which has significant anti-asthmatic activity. In recent years, more and more scholars have found that BAI has a good anti-asthmatic effect. Studies have shown [13-16] that BAI can significantly reduce the airway hyperresponsiveness and serum inflammatory factors (IL-4, IL-5, IL-6, IgE, TGF-β1, etc.) levels of OVA-induced asthmatic mice, inhibit the production of mucus and collagen deposition around the airways; at the same time, a large amount of H&E staining results data showed that BAI can significantly alleviate the infiltration of inflammatory cells into the connective tissue around the bronchioles and blood vessels, as well as the airway wall thickening and airway epithelial cell shedding caused by OVA. These conclusions indicate that BAI is expected to provide a new treatment strategy for asthma. However, most of the current studies on the use of BAI to treat asthma are oral administration and nebulized inhalation administration. As a BCS-II drug, BAI is almost insoluble in water, and it is difficult to find a suitable (low irritation, low toxicity) dispersion medium during nebulized inhalation. After oral administration, the drug cannot reach the lesion directly, and because flavonoids have the defect of low oral bioavailability, it is difficult to meet the needs of clinical treatment. Therefore, it is necessary to develop a new method to overcome these defects and provide new ideas for the future BAI treatment of asthma. Summary of the invention

[0005] The purpose of the present invention is to overcome the deficiencies in the prior art and provide an antiasthmatic drug composition and an application in preparing an inhaled antiasthmatic drug.

[0006] To achieve the above purpose, the technical solution of the present invention is summarized as follows:

[0007] A pharmaceutical composition for relieving asthma, comprising baicalein and an auxiliary material in a mass ratio of 1:0.3-3, wherein the auxiliary material is one or more of leucine, mannitol, glycine, alanine, proline, isoleucine, threonine, aspartic acid, arginine, methionine, anhydrous lactose, glucose and D-sorbitol.

[0008] Preferably, the auxiliary material is one or more of leucine, mannitol, anhydrous lactose and glucose.

[0009] More preferably, the auxiliary materials are leucine and mannitol, which are mixed in a mass ratio of 1:3 to 3:1, preferably 1:1.

[0010] The baicalein is baicalein nanocrystals, which are prepared by subjecting baicalein to anti-solvent precipitation to prepare a baicalein suspension, and then subjecting it to high-pressure homogenization and washing to obtain baicalein nanocrystals; wherein the baicalein suspension is a mixture of baicalein, a stabilizer and an anti-solvent in a mass ratio of 200:0.1-0.3:100.

[0011] The stabilizer is P188, the anti-solvent is anhydrous ethanol, the anti-solvent is anhydrous ethanol, and the anti-solvent is water.

[0012] The high-pressure homogenization is to set the high-pressure homogenization pressure of the baicalein suspension to 600-800 bar, and the number of high-pressure homogenization cycles to 10-20 times.

[0013] Furthermore, the baicalein suspension was pre-homogenized at pressures of 200, 400, and 600 bar, respectively, and then high-pressure homogenized at 600-800 bar.

[0014] The particle size of the baicalin nanocrystal (BAI-NC) is less than 1000 nm.

[0015] An application of the antiasthmatic drug composition, and application of the composition in preparing an inhaled antiasthmatic drug.

[0016] An inhaled antiasthmatic drug preparation contains the antiasthmatic drug composition.

[0017] The preparation is an inhalable powder spray.

[0018] A method for preparing the inhalable antiasthmatic drug preparation comprises spray drying the antiasthmatic drug composition to obtain baicalin nanocrystal dry powder inhalation agent.

[0019] The powder aerosol particle size is less than 5 μm.

[0020] The spray drying conditions are as follows: the spray drying inlet temperature is set at 100-120° C., the spray drying pump speed is set at 10-20%, the spray drying air flow rate is set at 70-100 L / min, and the spray drying fan efficiency is set at 80-100%.

[0021] The present invention also provides the use of the above-mentioned inhaled antiasthmatic drug, which is used for relieving acute asthma attacks in rats.

[0022] The asthma rat model is obtained by sensitizing with OVA combined with Al(OH)3 and stimulating with OVA nasal drops.

[0023] Compared with the prior art, the present invention has the following gain effects:

[0024] The antiasthmatic drug composition of the present invention improves the defects of poor fluidity and low solubility of baicalin raw materials, effectively improves the bioavailability of baicalin in animals, and then the composition is prepared into nanocrystals containing baicalin by anti-solvent precipitation combined with high-pressure homogenization technology, and then the nanocrystals are spray-dried to obtain baicalin nanocrystal dry powder inhaler, the dry powder form can maintain the stability of the nanocrystals, and at the same time, the nanocrystal technology can well improve the solubility and in vitro cumulative release of baicalin, and at the same time, the use of a specific inhalation administration method can effectively make up for the defect of poor oral bioavailability of baicalin. The obtained inhaled antiasthmatic drug has the same alleviating effect on asthma attacks in rats as budesonide through inhalation administration, improves the airway stenosis of the lungs of asthmatic rats by reducing the levels of IL-4, IL-6 and TGF-β1 in rat serum, and can effectively alleviate the acute attack of asthma in rats. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 Scanning electron microscope images of the products obtained in each step provided in the embodiment of the present invention, wherein A: blank excipient; B: baicalin API; C: baicalin nanocrystalline dry powder inhaler (BAI-NC-DPI);

[0026] Figure 2 Cumulative release curves of drugs in different preparations provided in the embodiments of the present invention;

[0027] Figure 3 A double-stage impactor provided in an embodiment of the present invention;

[0028] Figure 4 The powder X-ray diffractometer experimental results of various forms of baicalin nanocrystal dry powder inhalation provided by the embodiments of the present invention;

[0029] Figure 5The atomization performance of the BAI-NC-DPI provided by the embodiment of the present invention;

[0030] Figure 6 The drug-time curves of BAI-NC-DPI and BAI-DPI provided in the embodiments of the present invention;

[0031] Figure 7 The rat tracheal intubation drug administration method provided by the embodiment of the present invention;

[0032] Figure 8 The tissue distribution of BAI-NC-DPI in rats provided by the embodiment of the present invention;

[0033] Fig. 9 The tissue distribution of BAI-DPI in rats provided by the embodiment of the present invention;

[0034] Fig.10 The distribution of BAI-NC-DPI and BAI-DPI in rat lungs provided in the embodiments of the present invention;

[0035] Fig.11 The weight and behavioral changes of rats in each group provided in the embodiment of the present invention; wherein A is the weight change of rats in each group, B is the behavioral changes;

[0036] Fig.12 Pathological changes of lung tissues of rats in each group provided in the embodiments of the present invention;

[0037] Fig.13 The detection results of serum inflammatory factors in each group of rats provided in the embodiments of the present invention; DETAILED DESCRIPTION

[0038] The following content will explain the present invention in combination with the drawings and specific embodiments, but is not intended to limit the scope of the present invention.

[0039] Example 1

[0040] Preparation of baicalin nanocrystal dry powder inhalation:

[0041] 1) 300 mg of baicalin was accurately weighed and dissolved in 30 mL of anhydrous ethanol, and added to 570 mL of deionized water containing 0.2% poloxamer 188 (P188) under magnetic stirring, and mixed for 5 min to obtain a baicalin suspension. The obtained baicalin suspension was subjected to high-pressure homogenization, specifically 5 cycles of 200 bar, 400 bar and 600 bar, and then circulated 15 times under 800 bar pressure to obtain baicalin nanocrystals. The baicalin nanocrystals were centrifuged at 12000 rpm for 15 min, the supernatant was discarded, and water was added to disperse, and washed 3 times in this way to completely remove P188.

[0042] 2) The baicalein nanocrystals after removal of P188 were mixed with mannitol and leucine at a ratio of 1.0:2.5:2.5 (w / w / w) and a solid content of 1.0%.

[0043] 3) spray drying the baicalin nanosuspension obtained above to obtain a nanocrystalline dry powder inhaler (BAI-NC-DPI) (see Figure 1 ). The above spray drying process parameters are as follows:

[0044] Inlet temperature: 110℃

[0045] Pump speed: 10%

[0046] Air flow: 80L / min

[0047] Spray rate: 80%.

[0048] BAI-DPI is prepared by weighing a prescribed amount of BAI, dissolving it in anhydrous ethanol at room temperature, adding it to deionized water containing a stabilizer (P188, 0.3% of the stabilizer in the system) under continuous stirring (500 rpm), and mixing for a certain period of time to obtain a BAI suspension. The prescribed amount of excipients is dissolved in the suspension, and then the suspension is treated according to the spray drying conditions described in the above step 3) to obtain a baicalein ordinary dry powder inhaler that has not been treated with nanocrystals.

[0049] Depend on Figure 1 The scanning electron micrograph of the nanocrystalline dry powder inhaler shows that under the scanning electron microscope, the drug particles are highly wrinkled spherical particles with an aerodynamic diameter of about 3μm. From the picture, it can be seen that the particles obtained by spray drying after mixing leucine and mannitol are wrinkled (A), BAI raw material (B) is irregular strip-shaped, and BAI-NC-DPI (C) is a highly wrinkled spherical particle. Then the dynamic dialysis method was used to investigate the in vitro release of the drug ( Figure 2 ), the in vitro cumulative release of the drug was significantly increased compared with that of the drug without nano-processing.

[0050] The saturated solubility of the drug was further investigated using the mass method. The saturated solubility of the drug in artificial lung fluid was 4.35 times higher than that of the drug without nano-treatment (Table 1).

[0051] Table 1

[0052]

[0053] According to the relevant guidance of the Chinese Pharmacopoeia (2020), a dual-stage impactor ( Figure 3 ) The fine particle fraction of the drug is measured, and the measuring method is as follows:

[0054] Depend on Figure 3 It can be seen that the double-stage impactor is composed of a conventional experimental container according to Figure 3 The equipment was built according to the records and operated at room temperature. In the first-stage distribution bottle D, 7 mL of the solvent specified under each variety was added as the absorption liquid. In the second-stage distribution bottle H, 30 mL of the solvent specified under each variety was added as the receiving liquid. The components of the instrument were connected so that the protrusion of the nozzle G of the secondary distribution bottle was just in contact with the bottom of the bottle. The secondary distribution bottle was fixed with an iron clamp, and all parts were kept tightly connected. The entire device should be on a vertical plane, so that C and E were parallel to each other and the device was kept stable. The outlet F was connected to the vacuum pump, the pump power was turned on, and the suction device was tightly connected horizontally to the simulated throat B through a suitable rubber nozzle adapter. The gas flow at the inlet of the device was adjusted to 60 ± 5 L / min. After 10 seconds, the vacuum pump was turned off and suctioned 4 times. Repeat the above operation and measure a total of 10 capsules. Calculate the percentage of the drug content in the secondary distribution bottle to the drug content in the capsule. Among them, D and H are methanol respectively.

[0055] In this example, the fine particle fraction of baicalin nanocrystal dry powder inhaler was determined to be 66.86, and the fine particle dose was relatively high, which met the quality requirements of dry powder inhaler.

[0056] The crystal form of the drug sample obtained in the above example was characterized by powder X-ray diffractometer. The measurement conditions were copper target, graphite monochromator diffracted beam monochromatic ratio, high voltage 40KV, single current 30mA, diffraction angle 2θ, scanning range 5-60°, scanning speed 2° / min. The results are shown in Figure 4 .

[0057] Figure 4 As shown, baicalein (BAI-API) has sharp absorption peaks at 8.74°, 10.26°, 11.66°, 13.99°, 16.89°, and 26.30°, and the blank excipient (Blank Excipient) has sharp absorption peaks at 5.99° and 18.92°. After simple physical mixing (PM), the characteristic peaks of baicalein did not disappear, indicating that the presence of leucine and mannitol had almost no effect on the crystal form of baicalein. After anti-solvent precipitation treatment (BAI-Susoension), the characteristic peaks of baicalein disappeared, indicating that during the anti-solvent precipitation process, the crystal structure of baicalein changed and became an amorphous structure. After spray drying, baicalein nanocrystalline dry powder inhaler (BAI-NC-DPI) still showed the same absorption peaks as the excipients, and no characteristic peaks of baicalein were seen, indicating that the spray drying process had no significant effect on the absorption peaks of BAI and the excipients. Nebulization performance of baicalin nanocrystal dry powder inhalation

[0058] The preparation was tested for atomization performance using a dispenser, such as Figure 5As shown. 10 mL of air was drawn from the syringe, and the three-way valve was connected to a 200 μL gun tip containing 3 mg of the drug powder obtained in the above example, compressed to 4 mL, and the three-way valve was opened to spray the powder out, and a digital camera was used to record the powder spraying process at different times. The baicalein nanocrystal dry powder inhaler can form uniform smoke and has good atomization performance.

[0059] Example 2 Pharmacokinetic Study

[0060] Twelve experimental Wistar rats were randomly divided into two groups, namely, the BAI-NC-DPI inhalation group and the BAI-DPI group (the prescribed amount of BAI was weighed, dissolved in anhydrous ethanol at room temperature, added to deionized water containing a stabilizer (P188, the stabilizer in the system was 0.3%) under continuous stirring (500rpm), mixed for a certain period of time to prepare a BAI suspension, the prescribed amount of excipients was dissolved in the suspension, and then treated under the spray drying conditions described in step 3) of Example 1 to obtain a baicalein ordinary dry powder inhaler without nanocrystal treatment), and the dosage was a BAI equivalent concentration of 18 mg / kg. Fasting for 2 hours before administration, free drinking water. Blood was collected at 0, 0.167, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 18, and 24 hours after administration and placed in a heparin-treated EP tube.

[0061] Blood sample collection and processing methods:

[0062] After administration, 0.25 mL of blood was collected from the fundus venous plexus of the rats, placed in a heparin-treated EP tube, centrifuged at 4000 rpm for 10 min, and plasma was separated. Ascorbic acid solution (a mixed aqueous solution of 1% ascorbic acid and 0.1% formic acid) was added to the plasma and stored in a -20°C refrigerator. 200 μL of plasma was taken, methanol and 20 μL of internal standard solution (20 μg / mL) were added, vortexed for 1 min, 600 μL of methanol solution was added, oscillated and mixed, centrifuged at 12000 rpm for 5 min, the supernatant was taken, and dried with nitrogen at room temperature; 200 μL of methanol was added for re-dissolution, and the sample was analyzed after passing through a 0.22 μm microporous filter membrane (see Figure 6 ).

[0063] Pharmacokinetic study results

[0064] After administration to each group, the drug-time curves were Figure 6 The average pharmacokinetic parameters are shown in Table 2. Compared with BAI-DPI, the maximum plasma concentration of BAI-NC-DPI in rats was C max and AUC 0-24 Both were significantly improved, and the peak time T max The V d All greater than 0.6L / kg, and V d，BAI-NC-DPI >Vd，BAI-DPI This result indicates that after inhalation, the drug may bind to lung tissue in large quantities, but bind less to plasma proteins. The tissue distribution experiment also confirms this speculation, and the nanocrystal technology can improve the binding ability of BAI to lung tissue to a certain extent. At the same time, using BAI-DPI as the reference preparation, the relative bioavailability of BAI-NC-DPI was 193%. This is because the nanocrystal technology greatly increases the solubility of BAI in the lungs, making the degree and rate of BAI absorption in the lungs greater, and the relative amount of drug entering the systemic circulation is greater. This discovery also opens up new ideas for the development of drugs for lung delivery of BAI for systemic treatment.

[0065] Table 2

[0066]

[0067] Example 3 Tissue Distribution

[0068] 60 Wistar rats were randomly divided into BAI-DPI group and BAI-NC-DPI group, 30 rats in each group. The rats were fasted for 12 hours before the experiment and had free access to water. The rats were anesthetized with 20% urethane (6 mL / kg), placed supine on an animal fixing board, and their limbs were fixed. The infrared quartz radiation lamp suspended above the animals was lit to keep their body temperature constant during the experiment. The ventral side of the neck was incised to expose the trachea, and a transverse incision was made between the fifth and sixth trachea at the tail of the thyroid cartilage, such as Figure 7 As shown, the gun tip connected to the drug delivery device was inserted into the tracheal incision about 3 cm, and the syringe piston was immediately pushed to compress the air in the syringe to 4 mL. The three-way valve was quickly opened to blow the powder in the gun tip into the rat lungs and stay for 5 seconds to allow the drug to be fully deposited in the lungs to complete the drug delivery. At 0, 1.5, 6, 12, and 24 hours after drug delivery, the rats were killed by drawing blood from the abdominal aorta, and the heart, liver, spleen, lung, and kidney were dissected and collected.

[0069] Tissue sample processing

[0070] Accurately weigh 100 mg of each tissue into a 1.5 mL EP tube, add each tissue to physiological saline at a mass-volume ratio of 1:5, homogenize for 3 minutes, and prepare a tissue homogenate. Add ascorbic acid solution (a mixed aqueous solution of 1% ascorbic acid and 0.1% formic acid) to the tissue homogenate. Accurately measure 200 μL of each tissue homogenate into a centrifuge tube, add 20 μL of internal standard solution (200 μg / mL), add 800 μL of methanol, vortex mix for 3 minutes, centrifuge at 12000 rpm for 10 minutes, take the supernatant, blow dry with nitrogen at room temperature, re-dissolve with 300 μL of methanol, filter through a 0.22 μm microporous membrane, and inject for analysis.

[0071] Tissue distribution results

[0072] After administration to each group, the tissue distribution results were as follows Figure 8 and Fig. 9 As shown in the figure, after administration, BAI-NC-DPI is rapidly released in the lungs and has a long retention time. Within 6 hours, the drug content in the lungs of rats is always higher than that in other tissues, and the difference is statistically significant (p<0.01). This result shows that BAI-NC-DPI can not only stay in the lungs for a long time, but also has good lung targeting efficiency and does not increase its accumulation in non-targeted tissues, thereby extending the therapeutic window of the drug. This also once again proves the view that most drugs can be deposited in the lungs. Fig.10 As shown, compared with BAI-DPI, BAI-NC-DPI drug retention time in the lungs is slightly longer, indicating that BAI-NC-DPI may prevent the phagocytosis of the drug by the ciliated epithelial cells covering the mucus layer of the airways, thereby ensuring the dual drug release effects of immediate and prolonged release in vivo.

[0073] Example 4 Pharmacodynamic Evaluation

[0074] Experimental animals and groups

[0075] Thirty-six Wistar rats, half male and half female, weighing about 180-200 g, were selected and adaptively fed for 7 days and randomly divided into 6 groups.

[0076] Model group (MOD) (6 rats): Asthma model was established, compressed air was given after modeling, and the rats were raised in the same environment as the drug-treated group.

[0077] Blank group (CON) (6 mice): no modeling and no medication.

[0078] Positive control group (POS) (6 mice): Asthma model was established and 5 mg / kg budesonide powder inhaler was given for treatment.

[0079] Medium dose group (MED) (6 mice): Asthma model was established and 18 mg / kg BAI-NC-DPI was given for treatment.

[0080] Low-dose group (LOW) (6 mice): Asthma model was established and 9 mg / kg BAI-NC-DPI was given for treatment.

[0081] High-dose group (HIGH) (6 mice): Asthma model was established and 36 mg / kg BAI-NC-DPI was given for treatment.

[0082] Establishment of asthma rat model:

[0083] Preparation of antigen solution: Weigh 1 g of aluminum hydroxide and 100 mg of OVA respectively, place in a beaker, add a small amount of physiological saline, stir evenly, transfer to a 100 mL volumetric flask, make up to volume, and store at 4°C for later use.

[0084] Preparation of OVA nasal drops: Weigh an appropriate amount of OVA, add it into physiological saline, stir and dissolve it to make the concentration of 1%, and store it at 4°C for later use.

[0085] Model establishment and drug administration: The allergic asthma rat model was established by sensitizing with OVA combined with Al(OH)3 and then stimulating with OVA nasal drops.

[0086] Except for the normal group, the other groups were intraperitoneally injected with 1 mL of newly prepared OVA plus Al(OH)3 antigen solution every other day from 0 to 14 days, and the blank group was replaced with an equal volume of normal saline. After the 15th day, the newly prepared OVA nasal drops were used for daily stimulation, and 100 μL was dropped on each side of the rat's nose. During the nasal drop process, the OVA nasal drops were slowly dripped into the rat's nose using the rat's own breathing pattern, so that the OVA nasal drops could be better and more evenly absorbed in the rat's nose, while the blank group was replaced with an equal amount of normal saline. The drug was administered from the 22nd day, and the corresponding drug dose was given before the nasal drops every day, once a day, for one week, and the blank group and the model group were given an equal amount of compressed air.

[0087] Behavioral observation and body weight record of rats

[0088] like Fig.11 As shown in (A), the weight of rats was recorded during the experiment. The weight of rats in the CON group increased normally, the growth of rats in the MOD group was restricted after modeling, and the weight of rats in the other groups decreased during the stimulation phase, and after drug administration, the weight increased slowly. In addition, Fig.11 (B) The behavioral changes of rats in each group during the whole experiment were recorded. The rats in the CON group were in good mental state, with shiny fur, agile movements, stable breathing, and good water and food intake. As the atomization progressed, the rats in the MOD group developed obvious coughing and wheezing, frequently scratched their faces, and had shortness of breath, and some rats even died. After drug treatment, the allergic symptoms of rats in each preparation group and the POS group were alleviated, and some rats in the low-dose group showed irritability or slow movements and unresponsiveness. Through continuous observation of the behavior of rats, it was found that the mental state of rats in the model group deteriorated with the continuous change of asthma symptoms, and the amount of food and water consumed continued to decrease, which may be the reason for their continuous weight loss. As the asthma of rats in other drug-treated groups was relieved by drug treatment, the amount of food and water consumed continued to increase, so the weight of rats showed an upward trend, indicating that drug treatment played a role and the therapeutic effect produced was related to the dosage.

[0089] H&E staining lung tissue pathological scoring

[0090] The lungs of the rats were completely removed, fixed with 4% paraformaldehyde, dehydrated to make them transparent, embedded in wax, sliced ​​and mounted, dewaxed, stained with hematoxylin and eosin (H&E), dehydrated, sealed, and photographed and observed under an optical microscope. The pathological changes of the lung tissues of the rats in each group were observed, and it was found that the lung tissue structure of the rats in the CON group was relatively intact, the alveoli did not shrink and collapse, the airway walls did not thicken significantly, and occasionally a small amount of granulocyte infiltration was seen in the local alveolar walls. However, compared with the CON group, a large number of granulocyte infiltrations around the alveolar walls, blood vessels, and bronchioles were observed in the lung tissues of the MOD rats, the alveoli were significantly thickened, and the cytoplasm of the bronchiolar epithelial cells was mostly loose and lightly stained. Eosinophils and lymphocytes were seen in a small number of bronchioles. The pathological score ( Fig.12 ) was significantly increased, and the difference was statistically significant (p<0.01). It was confirmed that the asthma rat model was successfully established. Compared with the MOD group, the pathological damage of the lung tissue of the rats in the LOW group was relatively improved compared with the MOD group, and the difference was statistically significant (p<0.05). The MED group and the POS group showed obvious improvement, the infiltration of inflammatory cells decreased, the thickening of the alveolar wall was significantly reduced, and the alveolar structure was relatively complete, and the difference was statistically significant (p<0.01). It was confirmed that BAI-NC-DPI can improve lung inflammation. No obvious histopathological changes were found in the POS, MED and HIGH groups. It can be preliminarily judged that the dosage is safe and BAI-NC-DPI is almost equivalent to budesonide powder inhaler.

[0091] Serum inflammatory factor test results

[0092] like Fig.13 Compared with the CON group, the levels of IL-4, IL-6, and TGF-β1 in the serum of the MOD group were significantly increased, and the difference was statistically significant (p<0.01). The levels of IL-4, IL-6, and TGF-β1 in the serum of the POS group and the HIGH, MED group and the BAI-NC-DPI group were significantly lower than those in the MOD group, and the difference was statistically significant (p<0.01), while there was no significant difference among the three groups (p>0.05). The levels of IL-4, IL-6, and TGF-β1 in the LOW group were significantly lower than those in the MOD group, and the difference was statistically significant (p<0.05), but compared with the other drug-administered groups, the downward trend was not obvious enough, and the difference was statistically significant (p<0.05).

Claims

1. An antiasthmatic pharmaceutical composition, characterized in that: The composition comprises baicalein and auxiliary materials in a mass ratio of 1:0.3-3, wherein the auxiliary materials are one or more of leucine, mannitol, glycine, alanine, proline, isoleucine, threonine, aspartic acid, arginine, methionine, anhydrous lactose, glucose and D-sorbitol.

2. The antiasthmatic pharmaceutical composition according to claim 1, characterized in that: The auxiliary material is one or more of leucine, mannitol, anhydrous lactose and glucose.

3. The antiasthmatic pharmaceutical composition according to claim 1, characterized in that: The baicalein is baicalein nanocrystals, which are prepared by subjecting baicalein to anti-solvent precipitation to prepare a baicalein suspension, and then subjecting it to high-pressure homogenization and washing to obtain baicalein nanocrystals; wherein the baicalein suspension is a mixture of baicalein, a stabilizer and an anti-solvent in a mass ratio of 200:0.1-0.3:

100.

4. The antiasthmatic pharmaceutical composition according to claim 3, characterized in that: The stabilizer is P188, the solvent is anhydrous ethanol and methanol; and the anti-solvent is water.

5. The antiasthmatic pharmaceutical composition according to claim 3, characterized in that: The high-pressure homogenization is to set the high-pressure homogenization pressure of the baicalein suspension to 600-800 bar, and the number of high-pressure homogenization cycles to 10-20 times.

6. Use of the antiasthmatic pharmaceutical composition according to claim 1, characterized in that: The composition is used in preparing an inhaled antiasthmatic drug.

7. An inhaled antiasthmatic drug preparation, characterized in that: A composition for treating asthma comprising the antiasthmatic drug composition according to claim 1.

8. The inhaled antiasthmatic drug preparation according to claim 7, characterized in that: The preparation is an inhalable powder spray.

9. A method for preparing the inhaled antiasthmatic drug preparation according to claim 7, characterized in that: The antiasthmatic drug composition according to claim 1 is spray-dried to obtain baicalin nanocrystal dry powder inhalation.

10. The method for preparing the inhaled antiasthmatic drug preparation according to claim 9, characterized in that: The spray drying conditions are as follows: the spray drying inlet temperature is set at 100-120° C., the spray drying pump speed is set at 10-20%, the spray drying air flow rate is set at 70-100 L / min, and the spray drying fan efficiency is set at 80-100%.

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