Use of recombinant eg95 antigen b8 / 2 in acute myocardial infarction

Abstract

The application discloses application of recombinant Echinococcus granulosus secreted antigen B8 / 2 in acute myocardial infarction and belongs to the technical field of medicinal chemistry.The application provides a drug capable of preventing, relieving and / or treating acute myocardial infarction, wherein an effective component of the drug is recombinant Echinococcus granulosus secreted antigen B8 / 2, abbreviated as rEgAgB8 / 2.The rEgAgB8 / 2 can effectively delay acute myocardial infarction and inflammation reaction of mice, reduce myocardial infarction area, improve heart function deterioration and reverse pathological damage of organs, thereby providing a new idea for clinical treatment of acute myocardial infarction.

Description

Technical Field

[0001] This invention relates to the application of recombinant Echinococcus granulosus secretory antigen B8 / 2 in acute myocardial infarction, and belongs to the field of medicinal chemistry technology. Background Technology

[0002] Myocardial infarction (MI) is a leading cause of death worldwide, characterized by myocardial ischemia and hypoxia due to arterial blockage. In China, cardiovascular diseases, including MI, are the leading cause of death among residents, accounting for over 40% of all deaths. Recent studies have shown that the development of MI is accompanied by an inflammatory response, with dead cardiomyocytes releasing damage-associated molecular patterns (DAMPs), activating the innate immune system. Neutrophils, as the most sensitive sentinels, are first recruited to the infarct site, clearing damaged cellular debris and initiating the repair process. Subsequently, monocytes are recruited to the inflammatory area and differentiate into different macrophage subsets, with M1 macrophages promoting inflammation in the acute phase and M2 macrophages contributing to tissue repair and inflammation relief during the recovery phase. Persistent or excessive inflammation can lead to increased fibrosis, thereby impairing cardiac function and increasing the risk of heart failure. Therefore, reducing the inflammatory response in the acute phase and modulating the balance between M1 and M2 macrophages is crucial for reducing MI mortality and improving prognosis.

[0003] In recent years, numerous studies have found that parasitic infections can suppress the host's Th1-dominated inflammatory response and induce M2 macrophage polarization to regulate the host's immune response as a survival strategy to reduce host immune attack. This immunomodulatory function can be used to treat certain autoimmune or inflammatory diseases. Echinococcus granulosus larvae infect humans or livestock during their larval stage, leading to cystic echinococcosis (CE), a widespread global zoonotic disease. Echinococcus granulosus secretes antigen B (EgAgB), the main protein secreted in its cyst fluid. Due to its high antigenicity, EgAgB has been widely used in the immunodiagnosis of CE. EgAgB is a polylipoprotein with a molecular weight of approximately 160 kDa, composed of multiple 8 kDa subunits, including EgAgB8 / 1, EgAgB8 / 2, EgAgB8 / 3, EgAgB8 / 4, and EgAgB8 / 5 subunits. Recombinant EgAgB8 / 2 protein (GenBank: ACZ51457) has shown higher diagnostic value compared to other recombinant EgAgB subunits, and is used for serum diagnosis of cerebrovascular accidents (CE) in humans. It can also exert immunomodulatory effects by interacting with host immune cells to inhibit the production of pro-inflammatory cytokines, thereby alleviating the host's inflammatory response. Previous experiments have confirmed that rEgAgB8 / 2 can reduce intestinal inflammation by regulating M1 / 2 macrophage polarization. Our previous studies also showed that adult Trichinella spiralis secreted / excreted proteins improve myocardial infarction (MI) in mice by regulating macrophage differentiation into the M2 type. However, the therapeutic effects of rEgAgB8 / 2 on cardiovascular diseases, especially MI, have not yet been investigated. Summary of the Invention

[0004] The purpose of this invention is to provide the application of rEgAgB8 / 2 in acute myocardial infarction. Animal experiments have confirmed that rEgAgB8 / 2 can delay acute myocardial infarction and inflammatory response in mice, reduce the infarct area, improve cardiac function deterioration and reverse organ pathological damage, providing a new approach for the clinical treatment of acute myocardial infarction and subsequent ventricular remodeling.

[0005] This invention provides the use of recombinant Echinococcus granulosus secretory antigen B8 / 2 in the preparation of medicaments for the prevention, relief and / or treatment of acute myocardial infarction.

[0006] In one embodiment, the amino acid sequence of rEgAgB8 / 2 is shown in SEQ ID NO.1.

[0007] In one embodiment, the prevention, mitigation, and / or treatment of acute myocardial infarction includes at least one of the following:

[0008] (1) Reduce the mortality rate of acute myocardial infarction;

[0009] (2) Reduce the heart-to-weight ratio;

[0010] (3) Reduce the area of ​​myocardial infarction;

[0011] (4) Reduce the degree of myocardial fibrosis after myocardial infarction;

[0012] (5) Delays damage to cardiac function;

[0013] (6) Inhibit the level of pro-inflammatory cytokines and increase the expression of immune regulatory factors.

[0014] In one embodiment, rEgAgB8 / 2 is used alone as the active ingredient of the drug.

[0015] In one embodiment, the effective dose of rEgAgB8 / 2 is 0.25–0.5 mg / kg.

[0016] In one embodiment, the application includes preparing a drug for the prevention, relief, and / or treatment of acute myocardial infarction by mixing recombinant Echinococcus granulosus secretory antigen B8 / 2 with pharmaceutical excipients.

[0017] In one embodiment, the pharmaceutical excipient comprises fillers, binders, wetting agents, disintegrants, lubricants, and / or flavoring agents.

[0018] In one embodiment, the filler is starch, sucrose, lactose, calcium sulfate, and / or microcrystalline cellulose; the binder is a cellulose derivative, alginate, gelatin, and / or polyvinylpyrrolidone; the wetting agent is water, ethanol, starch, and / or syrup; the disintegrant is sodium carboxymethyl starch, carboxypropyl cellulose, croscarmellose, agar, calcium carbonate, and / or sodium bicarbonate; the lubricant is talc, calcium stearate, magnesium stearate, microcrystalline silica gel, and / or polyethylene glycol; and the flavoring agent is simple syrup, sucrose, lecithin, orange peel syrup, cherry syrup, lemon, fennel, peppermint oil, sodium alginate, gum arabic, gelatin, methylcellulose, sodium carboxymethyl cellulose, citric acid, tartaric acid, and / or sodium bicarbonate.

[0019] In one embodiment, the drug further comprises a pharmaceutically acceptable drug carrier.

[0020] In one embodiment, the drug carrier comprises microcapsules, microspheres, nanoparticles, and / or liposomes.

[0021] In one embodiment, the route of administration of the drug includes intradermal injection, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, intravenous infusion, arterial injection, intracavitary injection, and / or oral administration.

[0022] In one embodiment, the dosage form of the drug is powder, granules, capsules, tablets, pills, or oral liquid.

[0023] In one embodiment, the drug may also include other active ingredients with similar pharmacological activities.

[0024] Beneficial effects:

[0025] This invention demonstrates the preventive and therapeutic effects of rEgAgB8 / 2 on acute myocardial infarction in mice, providing a new strategy for the prevention and treatment of other common metabolic or immune-related diseases, specifically including:

[0026] (1) Reduce the mortality rate of acute myocardial infarction; reduce the weight of the heart;

[0027] (2) Reduce the area of ​​myocardial infarction;

[0028] (3) Reduce the degree of myocardial fibrosis after myocardial infarction;

[0029] (4) Delays damage to cardiac function;

[0030] (5) Inhibit the level of pro-inflammatory cytokines and increase the expression of immune regulatory factors.

[0031] This invention offers a novel immunotherapy approach for the treatment of myocardial infarction, overcoming the limitations of existing treatment strategies. In clinical application, it may serve as an adjunct or alternative to traditional drug therapy, reducing post-infarction heart failure and long-term complications. It provides a feasible and innovative method for the prevention and treatment of cardiovascular diseases, with significant social and economic benefits. This invention demonstrates the potential positive role of parasites in regulating the host's immune system, breaking the traditional notion that parasites are only harmful to the host. This contributes to a deeper understanding of the complex relationship between parasites and hosts, expands the therapeutic field of "helminth therapy" (cardiovascular diseases), further refines the molecular mechanisms of helminth immunomodulation, and provides new directions for immunotherapy research in human health. Attached Figure Description

[0032] Figure 1 Electrophoresis image of purified rEgAgB8 / 2.

[0033] Figure 2 Changes in survival rate of mice 28 days after modeling (n=18 / group, **P<0.01 vs MI+PBS group).

[0034] Figure 3 Changes in cardiac function in mice 7 days after modeling; A: Typical echocardiogram; B: Changes in heart rate and systolic function in each group of mice at the time of image acquisition; (n=5 / group, *P<0.05, **P<0.01, ***P<0.001 vs MI+PBS group).

[0035] Figure 4 The change in heart-to-body weight ratio in mice 7 days after modeling (n=6 / group, **P<0.01, ***P<0.001 vs MI+PBS group).

[0036] Figure 5 The infarct area of ​​the heart was measured 7 days after modeling in each group of mice.

[0037] Figure 6 Changes in cardiac structure and fibrosis in mice 7 days after modeling; A: Typical HE staining results of mice in each group; B: Representative Masson staining images of coronary sections of the heart (Scale bar: 1000 μm; enlarged views of infarct zone, Scale bar: 250 μm); (n = 5 / group, **P < 0.01, ***P < 0.001 vs MI+PBS group).

[0038] Figure 7 Changes in inflammatory factors and immunomodulatory factors in mice 7 days after modeling (n=5-6 / group, ***P<0.001 vs MI+PBS group). Detailed Implementation

[0039] Example 1: Preparation and purification of rEgAgB8 / 2

[0040] (Nanjing Zhongding Biotechnology Co., Ltd.): Using a PAS (PCR-based Accurate Synthesis) method, full-length splicing primers were designed, and protective base synthesis genes were designed at both ends of the primers. An 8×His tag was added to the C-terminus, and the fragment (shown in SEQ ID NO.2) was cloned into the *E. coli* expression vector pET-28a(+) via homologous recombination. The correct sequence and reading frame of the recombinant EgAgB8 / 2 / pPET-28a(+) were confirmed by double-stranded DNA sequencing. The recombinant plasmid was transformed into *E. coli* BL21(DE3) and cultured at 37°C until the logarithmic growth phase was reached. Then, expression was induced at 30°C with 1 mM IPTG for 4 hours. The expressed rEgAgB8 / 2 was a soluble protein and purified using nickel affinity chromatography. Endotoxins in the purified protein were removed using the ToxOut Endotoxin Removal Kit, and the residual endotoxin level was determined using the ToxinSensor Colorimetric LAL Endotoxin Detection Kit. The purified rEgAgB8 / 2 was stored in imidazole-free PBS buffer, and its concentration was determined using a BCA protein assay kit. SDS-PAGE was used to confirm the expression and purity of the target protein. Figure 1 The purified rEgAgB8 / 2 was then stored at -80°C for later use.

[0041] Example 2: Effect of rEgAgB8 / 2 on survival rate in mice with acute myocardial infarction

[0042] (1) Experimental materials:

[0043] Animals: Male C57BL / 6J mice, 6-8 weeks old, SPF grade, weighing approximately 18-22g, were purchased from the Experimental Animal Center of Bengbu Medical University. All mice were housed in a temperature- and humidity-controlled animal room with a 12-hour light / dark cycle and free access to standard rodent feed and water. The room temperature was maintained at 22-24℃, and the humidity at 40-60%. All experimental procedures were performed in accordance with the operating guidelines approved by the Ethics Committee of Bengbu Medical College, approval number

[2024] 617. Mice were randomly assigned to groups using a random number table. All analyses were performed under blinded conditions, and the researchers were unaware of the group assignments.

[0044] Instrument: Reward small animal inhalation anesthesia machine.

[0045] Reagent: Isoflurane.

[0046] (2) Experimental methods:

[0047] The "Gao et al. Circ Res, 2010" model was used: After anesthesia and disinfection with the gaseous anesthetic isoflurane, the mice were fixed in a supine position. An oblique incision was made in the 3rd-4th intercostal space on the left anterior chest wall. The anterior chest wall muscle tissue was bluntly dissected. The thorax was compressed with the left hand, and the heart was gently compressed outside the thoracic cavity with hemostatic forceps in the 4th intercostal space with the right hand. The left anterior descending coronary artery was ligated (location: the point where the upper margin of the left atrium and the main venous trunk are equidistant). After the apex of the heart turned grayish-white, the heart was quickly repositioned, the thoracic cavity was compressed to expel air, and the incision was sutured closed. Electrocardiogram showing signs of myocardial ischemia confirmed the successful modeling. The acute myocardial infarction period in mice after modeling was from day 0 to day 7.

[0048] Day 0 was defined as the day the model was established. The experiment was divided into 4 groups, with 18 mice in each group: ① Negative control group (Sham+PBS group): no model was established, but PBS was injected intraperitoneally on days 1, 3, and 5; ② rEgAgB8 / 2 control group (Sham+rEgAgB8 / 2): no model was established, but rEgAgB8 / 2 (5 μg / mouse) was injected intraperitoneally on days 1, 3, and 5; ③ MI model group (MI+PBS): PBS was injected intraperitoneally on days 1, 3, and 5 after model establishment; ④ MI treatment group (MI+rEgAgB8 / 2): rEgAgB8 / 2 (5 μg / mouse) was injected intraperitoneally on days 1, 3, and 5 after model establishment.

[0049] Observe and record the survival rate of mice in each group 28 days after modeling.

[0050] (3) Experimental results:

[0051] The survival status of mice in each group was observed for 28 days. The results showed that there was no significant difference in survival rate between the Sham+PBS group and the Sham+rEgAgB8 / 2 group. Within 28 days after MI surgery, the survival rate of mice in the MI+PBS group was 66.7%, which was significantly lower than that of the Sham+PBS group (100%); the survival rate of mice in the MI+rEgAgB8 / 2 group was 94.4%, which was significantly higher than that of the MI+PBS group. These results indicate that rEgAgB8 / 2 protein can significantly improve the survival rate of mice after MI surgery. Figure 2 Furthermore, rEgAgB8 / 2 is safe and non-toxic to mice.

[0052] Example 3: Effects of rEgAgB8 / 2 on cardiac function in mice with acute myocardial infarction

[0053] (1) Experimental materials:

[0054] Animals: Same as in Example 2.

[0055] Equipment: Reward small animal inhalation anesthesia machine, small animal ultrasound imaging system (VisualSonics, Canada).

[0056] Reagent: Isoflurane.

[0057] (2) Experimental methods: Ultrasound was performed 7 days after modeling. Five mice were used in each group. Mice were anesthetized with isoflurane and fixed on the ultrasound operating table. Hair was removed from the left anterior chest with depilatory cream and ultrasound coupling agent was applied. Under stable anesthesia, echocardiography was performed on the mice. Stroke volume (SV), left ventricular ejection fraction (LVEF), and left ventricular fractional shortening (LVFS) were analyzed using the LV trace method in long-axis B-mode to assess left ventricular systolic function.

[0058] (3) Experimental results:

[0059] Compared with the Sham+PBS group, the Sham+rEgAgB8 / 2 group showed no significant changes in heart morphology; the MI+PBS group showed significantly enlarged and rounded heart chambers, with a pear-shaped or spherical shape, and significantly decreased left ventricular anterior and posterior wall mobility; compared with the MI+PBS group, the MI+rEgAgB8 / 2 group showed smaller heart chambers, and significantly improved heart chamber morphology and ventricular wall motion. Figure 3 ).

[0060] Statistical results showed that compared with the Sham+PBS group, there was no significant difference in cardiac function in the Sham+rEgAgB8 / 2 group. In the MI+PBS group, SV, LVEF, and LVFS were significantly decreased 7 days after MI surgery, indicating a significant decrease in left ventricular systolic function. Compared with the MI+PBS group, SV, LVEF, and LVFS were significantly increased 7 days after MI surgery, indicating a significant improvement in left ventricular systolic function. These results indicate that rEgAgB8 / 2 can significantly improve cardiac dysfunction caused by acute myocardial infarction in MI mice.

[0061] Table 1. Cardiac function of mice in each group

[0062]

[0063] Example 4: Effect of rEgAgB8 / 2 on the heart-to-body weight ratio in mice with acute myocardial infarction

[0064] (1) Experimental materials:

[0065] Sample: Mouse hearts collected after the mice in Example 3 were euthanized.

[0066] Instrument: Micro electronic scale.

[0067] Reagent: PBS.

[0068] (2) Experimental methods:

[0069] After the ultrasound imaging measurement in Example 3, the weight of mice in each group was weighed and recorded. Blood was collected from the eyeballs, the thoracic cavity of the mice was opened, and the heart was perfused with PBS through the aorta to remove blood. The heart was removed (excess tissue was removed, and the left and right atrial appendages were preserved), washed again with PBS, dried with filter paper, and the weight of the heart was measured with a micro-scale electronic scale to calculate the heart-to-body weight ratio.

[0070] (3) Experimental results:

[0071] Compared with the Sham+PBS group, rEgAgB8 / 2 did not cause a significant change in the heart-to-body weight ratio in mice, while the heart-to-body weight ratio in the MI+PBS group increased significantly after surgery; after rEgAgB8 / 2 treatment, the heart-to-body weight ratio in mice decreased significantly, which was statistically significant. Figure 4 The calculation method for heart-to-body weight ratio is: Heart-to-body weight ratio = Heart weight (g) / Body weight (g).

[0072] The above results indicate that rEgAgB8 / 2 can reduce the heart-to-body weight ratio in mice with acute myocardial infarction.

[0073] Table 2. Heart-to-body weight ratio of mice in each group

[0074]

[0075] Example 5: Effect of rEgAgB8 / 2 on infarct area in mice with myocardial infarction

[0076] (1) Experimental materials:

[0077] Sample: Mouse heart tissue collected in Example 3.

[0078] Instrument: Stereo microscope.

[0079] Reagent: TTC solution.

[0080] (2) Experimental methods:

[0081] After collection, mouse hearts were rinsed with physiological saline and then rapidly frozen at -20°C for 10-15 minutes. Subsequently, each heart was sliced ​​into five sections from the ligation point to the apex, each section being 1-2 mm thick. The heart sections were incubated in 1% TTC staining solution at 37°C in the dark for 10-20 minutes. White areas represent infarcted tissue, while red areas represent non-infarcted tissue. Heart morphology was observed and recorded under a microscope, and the infarct area was analyzed using ImageJ software.

[0082] (3) Experimental results:

[0083] Compared with the Sham+PBS group, rEgAgB8 / 2 did not significantly alter the infarct area in mice, but after MI modeling, the infarct area significantly increased. Compared with the MI+PBS group, the hearts of mice in the MI+rEgAgB8 / 2 group were smaller, and the infarct area was reduced. This indicates that rEgAgB8 / 2 has a positive effect on cardiac morphology in mice with acute myocardial infarction. Figure 5 ).

[0084] Table 3. Infarct area in mice

[0085]

[0086] Example 6: Effects of rEgAgB8 / 2 on cardiac structure and myocardial fibrosis in mice after myocardial infarction

[0087] (1) Experimental materials:

[0088] Sample: Mouse heart tissue collected in Example 3.

[0089] Instrument: Microscope (Nikon, Japan).

[0090] Reagents: Xylene, anhydrous ethanol, 75% alcohol, glacial acetic acid, paraffin, Masson staining kit (China Servicebio), Oil Red O dye, hematoxylin & eosin (HE) dye (China Servicebio).

[0091] (2) Experimental methods:

[0092] The collected cardiac tissue was washed with pre-cooled PBS and then fixed by soaking in 4% paraformaldehyde. After being embedded in paraffin and sectioned, the tissue was dewaxed and hydrated, and then stained with hematoxylin and eosin and Masson staining kit. The slides were read and images were acquired under a microscope. The left ventricular wall thickness (LV Wall thickness) and fibrosis percentage were measured using ImageJ software.

[0093] (3) Experimental results:

[0094] As time progressed after MI surgery, the thickness of the left ventricular infarct wall in mice showed a decreasing trend, while the fibrotic area showed an increasing trend. Specifically, compared with the MI+PBS group, the MI+rEgAgB8 / 2 group showed significantly thicker left ventricular infarct wall and significantly improved left ventricular fibrosis area. There was no significant difference between the Sham+PBS group and the Sham+rEgAgB8 / 2 group. Figure 6 ).

[0095] The above results indicate that rEgAgB8 / 2 can delay the thinning of the ventricular wall in the infarct area of ​​the left ventricle in mice with myocardial infarction, reduce the degree of left ventricular fibrosis, and protect ventricular compliance after myocardial infarction.

[0096] Table 4. Mouse cardiac structure and degree of myocardial fibrosis

[0097]

[0098] Example 7: Effects of rEgAgB8 / 2 on the levels of pro-inflammatory and immunomodulatory cytokines in mice.

[0099] (1) Experimental materials:

[0100] Samples: Mouse serum and heart tissue collected in Example 3.

[0101] Materials: Tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) ELISA kit (Shanghai DaKeWei); reverse transcription kit (TransGen Biotech, China); quantitative real-time fluorescence kit (TransGen Biotech, China).

[0102] Instrument: Roche 96 real-time PCR system (USA).

[0103] (2) Experimental methods:

[0104] After collecting blood from mouse eyeballs, the serum was collected by centrifugation at 4500 rpm for 15 min at 4℃ and stored at -80℃ for subsequent ELISA detection. Mouse heart tissue was rinsed with pre-chilled PBS, and an appropriate amount was weighed, mixed with Trizol lysis buffer, and homogenized at 65 Hz for 60 s. Total RNA was extracted from the heart tissue according to the prescribed steps. cDNA was then synthesized from 2 μg of total RNA using a reverse transcription kit. A quantitative real-time assay kit was used, with 2 μl of cDNA as a template and a total sample volume of 20 μl, and GAPDH as an internal control. The above analysis. Through 2 -△△Cq The relative mRNA expression levels of the above-mentioned cytokines in cardiac tissue were detected.

[0105] (3) Experimental results:

[0106] The ELISA kit was used to detect the serum secretion levels of inflammatory factors (TNF-α, IL-10) in mice of each group, and the PT-PCR technique was used to detect the mRNA expression levels of corresponding inflammatory cytokines in the myocardial infarction area of ​​mice of each group at different time points (the apical area was detected in the Sham+PBS group and the Sham+rEgAgB8 / 2 group).

[0107] The results show ( Figure 7 Compared with the Sham+PBS group, the MI+PBS group showed increased serum levels of the pro-inflammatory cytokine TNF-α. Conversely, the MI+rEgAgB8 / 2 group showed significantly decreased serum levels of TNF-α and significantly upregulated levels of the immunomodulatory cytokine IL-10 compared to the MI+PBS group. The mRNA expression levels of TNF-α and IL-10 in cardiac tissue were consistent with those in serum. These results indicate that rEgAgB8 / 2 treatment can significantly inhibit the expression of pro-inflammatory factors and promote the expression of immunomodulatory cytokines, thereby protecting myocardial tissue from inflammatory attacks.

[0108] Table 5. Serum secretion levels of inflammatory factors (TNF-α, IL-10) in mice

[0109]

[0110] Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Anyone skilled in the art can make various modifications and alterations without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention should be determined by the claims.

Claims

1. The application of antigen B8 / 2 in the preparation of drugs for treating acute myocardial infarction, characterized in that, The amino acid sequence of antigen B8 / 2 is shown in SEQ ID NO.

1.

2. The application according to claim 1, characterized in that, The antigen B8 / 2 is used alone as the active ingredient of the drug.

3. The application according to claim 1 or 2, characterized in that, The application includes preparing the drug by mixing antigen B8 / 2 with pharmaceutical excipients.

4. The application according to claim 3, characterized in that, The pharmaceutical excipients include fillers, binders, wetting agents, disintegrants, lubricants, and / or flavoring agents.

5. The application according to claim 4, characterized in that, The filler is starch, sucrose, lactose, calcium sulfate, and / or microcrystalline cellulose; the binder is cellulose derivative, alginate, gelatin, and / or polyvinylpyrrolidone; the wetting agent is water, ethanol, starch, and / or syrup; the disintegrant is sodium carboxymethyl starch, carboxypropyl cellulose, croscarmellose, agar, calcium carbonate, and / or sodium bicarbonate; the lubricant is talc, calcium stearate, magnesium stearate, micronized silica gel, and / or polyethylene glycol; the flavoring agent is simple syrup, sucrose, lecithin, orange peel syrup, cherry syrup, lemon, fennel, peppermint oil, sodium alginate, gum arabic, gelatin, methylcellulose, sodium carboxymethyl cellulose, citric acid, tartaric acid, and / or sodium bicarbonate.

6. The application according to claim 1, characterized in that, The drug also contains a pharmaceutically acceptable drug carrier.

7. The application according to claim 6, characterized in that, The drug carrier comprises microcapsules, microspheres, nanoparticles, and / or liposomes.

8. The application according to any one of claims 1 to 7, characterized in that, The dosage form of the drug is powder, granules, capsules, tablets, pills, or oral liquid.

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