Application of naringenin chalcone in preparation of drugs for preventing and treating cholestatic liver disease

Abstract

The application belongs to the technical field of biological medicine, and particularly relates to application of naringin chalcone in preparation of a drug for preventing and treating cholestatic liver disease. The application is verified based on two classical animal models of causing cholestatic liver disease (CLD) in clinic, and combined with pathological detection and other industry gold standards, and it is confirmed that the naringin chalcone can be used as an active ingredient for preparing the drug for preventing and treating CLD. The mechanism is that: on the one hand, the naringin chalcone directly improves liver function by reducing the levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and other liver function indexes in serum; on the other hand, the naringin chalcone regulates metabolism of the organism, slows down the inflammatory response induced by CLD and corrects metabolic abnormalities, thereby playing a liver protection role and effectively preventing and treating the pathological progression of cholestatic liver disease. The application provides a new reference path for developing an effective drug for CLD.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology. More specifically, it relates to the application of naringenin chalcone in the preparation of drugs for the prevention and treatment of cholestatic liver disease. Background Technology

[0002] Cholestatic liver disease (CLD) is a group of hepatobiliary diseases caused by the interaction of various intrahepatic and extrahepatic factors, including immune, genetic, and environmental factors. Its core pathological mechanism is the obstruction of bile secretion and excretion. The most representative clinical CLDs include primary biliary cholangitis and primary sclerosing cholangitis, which can progress to cirrhosis, liver failure, and even death in severe cases. The main cause of CLD is obstruction of bile flow, leading to a large accumulation of bile acids in the liver. Under physiological conditions, bile acids play an important role in maintaining cholesterol and metabolic homeostasis; however, when their concentration is abnormally elevated, they are transformed into cytotoxic molecules, inducing neutrophil activation, inflammasomes, and macrophage-mediated inflammatory responses, causing oxidative stress and apoptosis. Furthermore, bile acids can inhibit the oxidative phosphorylation activity of hepatocyte mitochondria, directly interfering with mitochondrial energy metabolism, promoting excessive production of reactive oxygen species, thereby stimulating the production of inflammatory cytokines, activating hepatic stellate cells, and exacerbating liver damage through signaling pathways such as transforming growth factor and NF-κB. Early-stage chronic liver disease (CLD) often presents with no obvious symptoms. However, as it progresses, symptoms such as jaundice, dark urine, and pruritus may appear, gradually evolving into inflammation, fibrosis, cirrhosis, and even liver failure. CLD can also induce biliary reactions, manifested as dilation of the bile ducts lining the bile duct epithelial cells, and inflammation and fibrosis in the periportal region, further exacerbating liver dysfunction. Studies show a positive correlation between age and the incidence of cholestasis in patients with chronic liver disease; the risk of developing CLD increases significantly with age.

[0003] Among the limited clinical treatments currently available, Elafibranor is a representative oral dual peroxisome proliferator-activated receptor (PPAR) α / δ agonist. By simultaneously activating PPARα and PPARδ, it plays a crucial role in regulating hepatic lipid metabolism, inhibiting inflammatory responses, and combating fibrosis. It effectively reduces bile acid synthesis and improves bile flow, thereby alleviating liver inflammation and fibrosis. Based on its clear mechanistic advantages and clinical efficacy, erafibranor has become an ideal positive control drug for evaluating the efficacy of novel anti-cholestatic liver disease (CLD) drugs. However, even with the progress made by existing drugs, represented by erafibranor, the selection of drugs that can safely and effectively treat CLD in clinical practice remains severely limited, and the efficacy of most candidate drugs is far from comparable to existing clinical drugs.

[0004] Therefore, researchers have attempted to find alternatives from natural products. Flavonoids mainly fall into two categories: one is non-flavonoids, including flavonols (such as baicalin), flavonols (such as quercetin), dihydroflavonoids (such as glycyrrhizin), isoflavones (such as iris flavonoids), and flavanols (such as epigallocatechin gallate). The other is flavonoids. Existing technologies have fully disclosed that the aforementioned non-flavonoid components possess anti-inflammatory and antioxidant pharmacological activities, effectively alleviating liver damage caused by various etiologies with fewer adverse reactions. However, the chemical structure of flavonoids (such as naringenin chalcone) differs significantly from that of non-flavonoids, and existing technologies rarely disclose their application in liver injury, especially in cholestatic liver disease. Although a research paper (Rodriguez, RJ, Miranda, CL, Stevens, JF, Deinzer, ML, & Buhler, DR (2001). Influence of prenylated and non-prenylated flavonoids on liver microsomal lipid peroxidation and oxidative injury in rathepatocytes. Food and Chemical Toxicology, 39(5), 437-445.) showed that the flavonoid naringenin chalcone exhibited significant antioxidant activity in a tert-butyl hydroperoxide (TBH)-induced lipid peroxidation system, this study did not disclose its protective effect in a hepatocyte injury model.

[0005] Therefore, there is an urgent need to develop more effective CLD treatments to enrich patients' clinical options. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to overcome the deficiencies and shortcomings of the scarcity of drugs for the clinical treatment of cholestatic liver disease, and the particular lack of drugs with efficacy comparable to representative clinical drugs (such as erafibrino), and to provide the application of naringenin chalcone in the preparation of drugs for the prevention and treatment of cholestatic liver disease.

[0007] The above-mentioned objective of this invention is achieved through the following technical solution: The use of naringin chalcone or a pharmaceutically acceptable salt thereof as the sole active ingredient in the preparation of a drug for the prevention and treatment of cholestatic liver disease, wherein the naringin chalcone has the following structure: .

[0008] Furthermore, the cholestatic liver disease is cholestatic liver disease induced by 3,5-diethoxy-1,4-dihydro-2,4,6-trimethylpyridine or bile duct ligation.

[0009] Furthermore, the prevention and treatment of cholestatic liver disease includes one or more of the following: (1) The prevention and treatment of cholestatic liver disease is to reduce the extent of liver tissue necrosis; (2) The prevention and treatment of cholestatic liver disease is to reduce liver tissue edema; (3) The prevention and treatment of cholestatic liver disease is to reduce the infiltration of inflammatory cells; (4) The prevention and treatment of cholestatic liver disease is to reduce the content of extracellular collagen fiber deposition; (5) The prevention and treatment of cholestatic liver disease aims to slow down the weight loss of the patients. (6) The prevention and treatment of cholestatic liver disease is to reduce the content of serum liver function biochemical indicators; (7) The prevention and treatment of cholestatic liver disease is to reduce the expression level of genes related to bile acid metabolism; (8) The prevention and treatment of cholestatic liver disease is to reduce the content of inflammatory factors.

[0010] Furthermore, the serum liver function biochemical indicators are selected from at least one of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bile acids (TBA), total bilirubin (TBIL), and alkaline phosphatase (ALP).

[0011] Furthermore, the bile acid metabolism-related genes are selected from at least one of Cyp7a1 and Cyp8b1.

[0012] Furthermore, the inflammatory factors include at least one of TNF-α, IL-6, and IL-β.

[0013] Furthermore, the drug comprises an effective amount of naringenin chalcone and a pharmaceutically acceptable carrier or excipient.

[0014] Furthermore, the pharmaceutically acceptable excipient is selected from at least one of solvents, diluents, suspending agents, stabilizers, and thickeners.

[0015] As an optional implementation, the pharmaceutically acceptable excipient is selected from at least one of dimethyl sulfoxide, polyethylene glycol, and physiological saline. These excipients primarily function as solvents.

[0016] Furthermore, the dosage form of the drug includes any one of the following: solution, suspension, powder, tablet, granule, capsule, and emulsion.

[0017] Preferably, the concentration of the cellular administration dose of the naringenin chalcone is ≤208 μM, more preferably ≤104 μM.

[0018] Preferably, the animal dosage of the naringenin chalcone is 30-50 mg / kg, more preferably 35-45 mg / kg.

[0019] Compared with the prior art, the present invention has the following beneficial effects: This invention utilizes two classic clinical methods for inducing cholestatic liver disease (CLD): bile duct ligation surgery and feed induction with diethyl-1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate. Corresponding animal models were established, and their efficacy was validated using industry gold standards such as pathological testing. This confirmed that naringenin chalcone can serve as an active ingredient in drugs for the prevention and treatment of CLD. Its mechanism of action is twofold: firstly, it directly improves liver function by reducing serum levels of liver function indicators such as ALT, AST, and ALP, which are associated with liver damage-related pathological features; secondly, it improves the CLD-induced inflammatory response by regulating bile acid synthesis and metabolism pathways, thereby exerting a hepatoprotective effect and effectively preventing the progression of cholestatic liver disease. This invention provides a new reference pathway for the development of effective drugs for CLD. Attached Figure Description

[0020] Figure 1 A statistical graph showing the toxicity of different concentrations of naringenin chalcone to AML12 cells.

[0021] Figure 2 The image shows the cholestasis symptoms in mice in the blank control group, model group, positive drug control group, and NGC administration group in Example 1.

[0022] Figure 3 The image shows the HE (hematoxylin-eosin) staining results of mouse tissues from the blank control group, model group, positive drug control group, and NGC administration group in Example 1.

[0023] Figure 4 The image shows the Sirius red staining results of mouse tissues in the blank control group, model group, positive drug control group, and NGC-treated group in Example 1.

[0024] Figure 5 The image shows the MASSON staining results of mouse tissues from the blank control group, model group, positive drug control group, and NGC administration group in Example 1.

[0025] Figure 6 This is a graph showing the trend of body weight changes in mice in the blank control group, model group, positive drug control group, and NGC administration group in Example 1.

[0026] Figure 7 This is a statistical graph showing the data of biochemical indicators aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, and total bile acids in the serum of mice in the blank control group, model group, positive drug control group, and NGC-treated group in Example 1; where, **: P<0.01 compared with the model group; ***: P<0.001 compared with the model group; ****: P<0.0001 compared with the model group.

[0027] Figure 8 This is a statistical graph showing the data of inflammatory factors TNF-α and IL-6 in mouse tissues in the blank control group, model group, positive drug control group, and NGC administration group in Example 1; where ns: no significant difference compared with the model group; *: P<0.05 compared with the model group; **: P<0.01 compared with the model group; ***: P<0.001 compared with the model group; ****: P<0.0001 compared with the model group.

[0028] Figure 9 This is a statistical graph showing the data on bile acid metabolism-related genes Cyp7a1 and Cyp8b1 in the blank control group, model group, positive drug control group, and NGC-treated group in Example 1; where ***: P<0.001 compared with the model group; ****: P<0.0001 compared with the model group.

[0029] Figure 10 The image shows the HE, MASSON, and Sirius red staining results of mouse tissues in the blank control group, model group, positive drug control group, and NGC administration group in Example 2.

[0030] Figure 11 The image shows the cholestasis symptoms in mice in the blank control group, model group, positive drug control group, and NGC administration group in Example 2.

[0031] Figure 12 This is a statistical graph showing the biochemical indicators of alanine aminotransferase, total bilirubin, alkaline phosphatase, aspartate aminotransferase, and total bile acids in mice in the blank control group, model group, positive drug control group, and NGC-treated group in Example 2; where, **: P<0.01 compared with the model group; ***: P<0.001 compared with the model group; ****: P<0.0001 compared with the model group.

[0032] Figure 13This is a statistical graph showing the data of inflammatory factors TNF-α and IL-β and bile acid metabolism-related genes Cyp7a1 and Cyp8b1 in the blank control group, model group, positive drug control group and NGC administration group in Example 2; where ***: P<0.001 compared with the model group; ****: P<0.0001 compared with the model group. Detailed Implementation

[0033] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, but the embodiments do not limit the present invention in any way. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in this technical field.

[0034] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.

[0035] Naringin chalcone was purchased from Beijing Bettercare Biopharmaceutical Technology Co., Ltd., and its structure is shown below: .

[0036] Erafibrano was purchased from Beijing Bettercare Biomedical Technology Co., Ltd.

[0037] The cholestatic model in mice induced by bile duct ligation and diethyl-1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate, with bile duct hyperplasia, intrahepatic cholestasis, and fibrosis as its core histological features, typically reflects bile excretion disorders and accurately simulates the pathological process of clinical cholestatic liver disease. Furthermore, the modeling method is stable and controllable, thus it has gradually become a classic animal model for studying cholestasis-related liver injury and screening therapeutic drugs in recent years. This invention uses two classic animal models to elucidate the application of naringenin chalcone in cholestatic liver disease.

[0038] Example 1: Application of naringenin chalcone in DDC-induced cholestatic liver disease in mice Preparation of naringin chalcone (NGC) solution: Dimethyl sulfoxide, PEG300 (polyethylene glycol with a molecular weight of 300), and physiological saline were mixed at a volume ratio of 5:45:50 to prepare a mixed solvent with a total volume of 50 mL. 200 mg of NGC was then mixed thoroughly in the 50 mL mixed solvent to prepare the NGC solution.

[0039] 1. Drug cytotoxicity testing To evaluate the cytotoxic effect of NGC on AML12 cells, the CCK-8 assay was used to detect changes in cell viability after intervention with different concentrations of NGC solution. The results are as follows: Figure 1As shown, the viability of AML12 cells gradually decreased with increasing NGC concentration, suggesting that NGC has a concentration-dependent inhibitory effect on AML12 cells. Further dose-response analysis revealed that the half-maximal inhibitory concentration (IC50) of NGC on AML12 cells... 50 The concentration was 208 μmol / L (μM), and the IC50 concentration was... 50 It has a high content and good cell safety.

[0040] 2. Establishment of the DDC feed model and drug administration Mice were randomly divided into four groups of eight each: a control group, a model group, a positive drug control group, and an NGC-treated group. Diethyl-1,4-dihydro-2,4,6-trimethyl-3,5-pyridine dicarboxylate (DDC) compound was added to the diet to obtain DDC diet. During the first week, mice in the model group, positive drug control group, and NGC-treated group were fed the DDC diet to establish the mouse model. Subsequently, mice in the NGC group were intraperitoneally injected with 40 mg / kg of naringenin chalcone solution once daily for 21 days. Simultaneously, mice in the positive drug control group were intraperitoneally injected with 10 mg / mL of erafibrinolate solution (prepared using the same solvent as the NGC solution). Mice in the control and model groups were intraperitoneally injected with an equal dose of a mixed solvent (a mixture of dimethyl sulfoxide, PEG300, and physiological saline in a volume ratio of 5:45:50) once daily for 21 days.

[0041] 3. Get materials Mice were anesthetized with isoflurane at a concentration of 1 vol%–1.5 vol%. After observing that the mice were immobile, their whiskers were shaved, and approximately 600 μL of blood was collected from their eyeballs using forceps. The mice were then euthanized by cervical dislocation. The abdominal cavity was opened along the midline using dissecting scissors, and the heart, liver, spleen, lungs, kidneys, and brain were separated. The organs were carefully rinsed with physiological saline and blotted with filter paper. Tissue samples from various organs were fixed in paraformaldehyde according to their respective groups. Subsequent sections were stained with hematoxylin and eosin (HE), Masson's Law, and Sirius Red.

[0042] The results are as follows Figure 2 As shown, the cholestasis in the model mice became more severe with the prolonged duration of common bile duct ligation, and the bile gradually changed from pale yellow to dark green. However, the bile of mice treated with NGC solution was lighter in color and the change was not obvious, indicating that it can improve the cholestasis state to a certain extent.

[0043] HE staining results are as follows Figure 3As shown, compared with the blank control group, the model group showed obvious liver tissue necrosis, edema and a large number of inflammatory cell infiltrations, while the positive drug control group and the NGC administration group showed significant relief, with a smaller range of liver tissue necrosis and reduced inflammatory cell infiltration.

[0044] Sirius Red ( Figure 4 ) and Masson ( Figure 5 The staining results showed that the extracellular collagen fiber deposition content in the model group was significantly higher than that in the blank control group, and the symptoms were significantly relieved after NGC administration.

[0045] Weight results as follows Figure 6 As shown, the body weight of mice in the model group decreased gradually with the extension of ligation time, while the trend of body weight reduction in the NGC-treated group was slightly alleviated.

[0046] Depend on Figure 7 It was found that the biochemical indicators of aspartate aminotransferase, alanine aminotransferase, total bile acids, total bilirubin and alkaline phosphatase increased significantly after modeling, but decreased significantly after NGC administration. The reduction in some biochemical indicators was even better than that of the positive control drug, erafibrino.

[0047] At the molecular mechanism level, the gene expression levels of inflammatory factors TNF-α and IL-6 in liver tissue were detected using Q-PCR (real-time quantitative polymerase chain reaction) technology. The results are as follows: Figure 8 As shown, the model group mice experienced a strong liver inflammatory response due to cholestasis, leading to a sharp increase in the expression levels of TNF-α and IL-6; however, after NGC administration, the expression of these two core pro-inflammatory factors was significantly inhibited.

[0048] In addition, the results of testing on bile acid metabolism-related genes Cyp7a1 and Cyp8b1 are as follows: Figure 9 The results showed that NGC intervention corrected the abnormal expression state to some extent, suggesting that NGC may also participate in the improvement of cholestatic liver injury by regulating bile acid synthesis and metabolism. These results indicate that NGC alleviates cholestasis symptoms in mice during the pathogenesis of cholestatic liver disease.

[0049] Example 2: Application of naringenin chalcone in cholestatic liver disease induced by bile duct ligation Preparation of NGC suspension: Dimethyl sulfoxide, PEG300 (polyethylene glycol with a molecular weight of 300), and physiological saline were mixed at a volume ratio of 5:45:50 to prepare a mixed solvent with a total volume of 50 mL. 200 mg of NGC was then mixed thoroughly in 50 mL of the mixed solvent to prepare the NGC solution.

[0050] 1. Establishment of a surgical model for bile duct ligation (BDL) Mice were randomly divided into three groups of eight each: sham-operated group, model group, and NGC group. Mice were pre-treated with medication for 7 days before surgery. The BDL mouse model was established using a double ligation of the common bile duct, with animals fasted for 12 hours but allowed free access to water. After anesthesia with tribromoethanol, the mice were placed supine on the operating table, their limbs fixed with medical tape, and the area disinfected with 75% vol% ethanol. A midline incision, approximately 1.5 cm long, was made below the xiphoid process. The common bile duct was located after opening the abdominal cavity, taking care to avoid damaging the liver and pancreas. After separating the common bile duct, it was double-ligated with surgical sutures at the proximal end to the duodenum and the end near the liver. The duct was then repositioned layer by layer, the incision sutured, disinfected with iodine tincture, and the mice were fed as usual. The sham-operated group did not undergo ligation; the remaining procedures were the same as the double-ligated common bile duct model group. After surgery, the mice were placed on a temperature-controlled blanket until they awoke. Subsequently, mice in the NGC group were intraperitoneally injected with 40 mg / kg of naringenin chalcone solution once a day for 7 days; mice in the positive control group were intraperitoneally injected with 10 mg / mL of erafibrino solution (prepared using the same solvent as the NGC solution); mice in the control and model groups were intraperitoneally injected with an equal dose of a mixed solvent (i.e., a mixed solvent prepared by mixing dimethyl sulfoxide, PEG300 and physiological saline in a volume ratio of 5:45:50) once a day for 7 days.

[0051] 2. Get materials Mice were anesthetized with isoflurane at a concentration of 1 vol%–1.5 vol%. After observing that the mice were immobile, their whiskers were shaved, and approximately 600 μL of blood was collected from their eyeballs using forceps. The mice were then euthanized by cervical dislocation. The abdominal cavity was opened along the midline using dissecting scissors, and the heart, liver, spleen, lungs, kidneys, and brain were separated. The organs were carefully rinsed with physiological saline and blotted with filter paper. Tissue samples from various organs were fixed in paraformaldehyde according to their respective groups. Subsequent sections were stained with hematoxylin and eosin (HE), Masson's Law, and Sirius Red.

[0052] Figure 10 HE staining results showed that, compared with the sham-operated group, the model group had obvious liver tissue necrosis, edema and a large number of inflammatory cell infiltrations, while the NGC-treated group showed significant relief, with a smaller range of liver tissue necrosis and reduced inflammatory cell infiltration.

[0053] Figure 10 The results of the semi-quantitative determination of collagen density by Masson and Sirius Red staining showed that the extracellular collagen fiber deposition content in the model group was significantly higher than that in the control group, and the effect was significantly relieved after NGC administration.

[0054] The effects of naringenin chalcone on cholestasis symptoms in mice were then observed, and the results were as follows: Figure 11As shown, in terms of overall phenotypic observation, as the duration of common bile duct ligation increased, the cholestasis symptoms in the model group mice gradually worsened, and the bile color gradually changed from normal pale yellow to dark green, indicating that the bile composition and excretion status were significantly abnormal; while the color change of bile in mice after NGC administration was relatively insignificant, indicating that it can improve the cholestasis status to a certain extent.

[0055] The results are as follows Figure 12 As shown, the biochemical indicators of aspartate aminotransferase, alanine aminotransferase, total bile acids, total bilirubin, and alkaline phosphatase increased significantly after modeling, but decreased significantly after NGC administration.

[0056] At the molecular level, the gene expression levels of the inflammatory factors TNF-α and IL-β in liver tissue were detected using Q-PCR technology. The results are as follows: Figure 13 As shown, the model group mice experienced a strong liver inflammatory response due to cholestasis, which led to a sharp increase in the expression levels of TNF-α and IL-β. However, after NGC administration, the expression of these two core pro-inflammatory factors was significantly inhibited, and the inhibitory effect showed a dose-dependent characteristic.

[0057] In addition, the results of testing on bile acid metabolism-related genes Cyp7a1 and Cyp8b1 are as follows: Figure 13 As shown, the abnormal expression state of NGC was corrected to some extent after intervention. This suggests that NGC may also participate in the improvement of cholestatic liver injury by regulating bile acid synthesis and metabolism. These results indicate that NGC alleviates cholestasis symptoms in mice during the pathogenesis of cholestatic liver disease.

[0058] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. The use of naringenin chalcone or a pharmaceutically acceptable salt thereof as the sole active ingredient in the preparation of drugs for the prevention and treatment of cholestatic liver disease, characterized in that, The naringin chalcone has the following structure: 。 2. The application according to claim 1, characterized in that, The cholestatic liver disease mentioned is cholestatic liver disease induced by diethyl-1,4-dihydro-2,4,6-trimethyl-3,5-pyridine dicarboxylate or bile duct ligation.

3. The application according to claim 1, characterized in that, The prevention and treatment of cholestatic liver disease includes one or more of the following: (1) The prevention and treatment of cholestatic liver disease is to reduce the extent of liver tissue necrosis; (2) The prevention and treatment of cholestatic liver disease is to reduce liver tissue edema; (3) The prevention and treatment of cholestatic liver disease is to reduce the infiltration of inflammatory cells; (4) The prevention and treatment of cholestatic liver disease is to reduce the content of extracellular collagen fiber deposition; (5) The prevention and treatment of cholestatic liver disease aims to slow down the weight loss of the patients. (6) The prevention and treatment of cholestatic liver disease is to reduce the content of serum liver function biochemical indicators; (7) The prevention and treatment of cholestatic liver disease is to reduce the expression level of genes related to bile acid metabolism; (8) The prevention and treatment of cholestatic liver disease is to reduce the content of inflammatory factors.

4. The application according to claim 3, characterized in that, The serum liver function biochemical indicators are selected from at least one of aspartate aminotransferase, alanine aminotransferase, total bile acids, total bilirubin, and alkaline phosphatase.

5. The application according to claim 3, characterized in that, The bile acid metabolism-related genes are selected from at least one of Cyp7a1 and Cyp8b1.

6. The application according to claim 3, characterized in that, The inflammatory factors include at least one of TNF-α, IL-6, and IL-β.

7. The application according to claim 1, characterized in that, The drug comprises an effective amount of naringenin chalcone and pharmaceutically acceptable excipients.

8. The application according to claim 1, characterized in that, The pharmaceutically acceptable excipients are selected from at least one of solvents, diluents, suspending agents, stabilizers, and thickeners.

9. The application according to claim 1, characterized in that, The pharmaceutically acceptable excipients are selected from at least one of dimethyl sulfoxide, polyethylene glycol, and physiological saline.

10. The application according to claim 1, characterized in that, The dosage form of the drug includes any one of the following: solution, suspension, powder, tablet, granule, capsule, and emulsion.

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