Use of the compound rociletinib for the preparation of a medicament for acute liver injury by inhibiting ferroptosis

Abstract

The application discloses an effect of a compound, rociletinib, on acute liver injury by inhibiting ferroptosis, and belongs to the technical field of cell programmed death (ferroptosis) inhibitors. When treating acute liver injury, the intracavity injection dose of the compound is 20 mg / kg, and the compound is injected into the abdominal cavity twice during treatment with an interval of 1 h. The application provides an application of the compound, rociletinib, in treating acute liver injury, specifically, the ferroptosis inhibitor, rociletinib, described herein can be applied to treating / relieving acute liver injury. The application improves liver histology, liver inflammatory tissue, ALT / AST levels and the like by applying the ferroptosis inhibitor, rociletinib, to a mouse acute liver injury model caused by ConA, thereby achieving a therapeutic effect. The main advantage of the application lies in that the application provides evidence of the ferroptosis inhibitor, rociletinib, in inhibiting the ferroptosis process, thereby providing a new theoretical basis for treating acute liver injury and having a far-reaching application value.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of inhibitors of programmed cell death (ferroptosis), and particularly relates to application of rociletinib as a ferroptosis inhibitor and application of the drug in the field of treatment of acute liver injury. BACKGROUND

[0002] Current existing programmed cell death includes pyroptosis, apoptosis, necroptosis, autophagy, etc., and ferroptosis is a new type of programmed cell death mode, which is an iron and reactive oxygen species (ROS) dependent regulatory cell death form, different from the morphological characteristics of other cell deaths, and the mitochondria of ferroptosis cells are smaller than normal mitochondria, and the mitochondrial membrane density is concentrated, the mitochondrial cristae are reduced or disappeared, and the outer mitochondrial membrane is ruptured.

[0003] A large number of studies have shown that ferroptosis is involved in the occurrence and development of various diseases, and the mechanism is relatively complex; and liver disease is currently a common public safety problem worldwide, which threatens the health of many people, and more seriously, the incidence of many liver diseases is gradually increasing. The liver is an important metabolic organ of the human body, which has a variety of important physiological functions, and it is not only the center of material metabolism, but also an important secretory, excretory, biotransformation and barrier organ. The liver is the main site of iron storage, and when iron is excessive, the liver will become the main target organ of its damage and can cause liver fibrosis and liver cancer, etc.; and iron metabolism is related to ferroptosis, and regulation of ferroptosis can affect the progression of liver disease.

[0004] Concanavalin A (ConA) is often used to make an acute liver injury model. TNF-α can directly damage hepatocytes, leading to hepatocyte apoptosis. The pathological characteristics of the ConA-induced mouse liver injury experimental animal model are mainly immune liver injury caused by activated T lymphocytes. After intravenous injection of ConA into mice, most of it accumulates in the liver, indicating that the liver is the target organ of ConA-induced toxicity in vivo.

[0005] Acute liver injury refers to abnormal liver function caused by various reasons, and liver injury is the premise of the occurrence of acute liver injury, and severe liver injury can lead to liver function failure in patients, thereby threatening their lives. There are many causes of liver injury, and the main causes include viral infection, improper medication, excessive alcohol intake, etc. Therefore, it is currently urgently needed to develop new therapeutic drugs targeting the pathogenesis.

[0006] Rociletinib is an orally administered EGFR inhibitor that inhibits the activity of EGFR L858R / T790M and EGFR WT, with IC50 values ​​of 21.5 nM and 303.3 nM, respectively. Rociletinib is an irreversible, mutation-selective EGFR inhibitor primarily used to treat non-small cell lung cancer (NSCLC) patients with igneous activating EGFR mutations and dominant-resistant T790M mutations. However, there are no reports on the use of rociletinib as an inhibitor of ferroptosis or for the treatment of acute liver injury. Summary of the Invention

[0007] The technical problem to be solved by this invention is how to propose a new pharmaceutical use for the compound rociletinib.

[0008] The present invention solves the above-mentioned technical problems through the following technical means:

[0009] The first aspect of this invention proposes the use of the compound rociletinib as an inhibitor of ferroptosis.

[0010] The structural formula of the compound rociletinib is shown below, CAS: 1374640-70-6.

[0011]

[0012] The second aspect of the invention proposes the use of the compound rociletinib in any of the following:

[0013] (1) Use in the preparation of drugs for the prevention or treatment of diseases related to ferroptosis;

[0014] (2) Application in the preparation of drugs that inhibit lipid peroxidation during ferroptosis;

[0015] (3) Application in the preparation of drugs that reduce serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels;

[0016] (4) Application in the preparation of drugs that reduce liver GSH levels;

[0017] (4) Application in the preparation of drugs that inhibit the expression of ferroptosis-related proteins ACSL4 and NRF2;

[0018] (5) Application in the preparation of drugs that reduce the levels of inflammatory factors IL-1β and TNF-α in serum.

[0019] Preferably, the diseases associated with ferroptosis include, but are not limited to, cerebral hemorrhage, acute liver injury, acute kidney injury, hepatic and renal ischemia-reperfusion injury, diabetes, Parkinson's disease, and other related diseases.

[0020] Preferably, when treating acute liver injury, the intraperitoneal injection dose of rociletinib is 20 mg / kg, administered twice intraperitoneally with a 1-hour interval.

[0021] Preferably, in (1)-(5), the drug further includes a chemically acceptable salt of the compound rociletinib.

[0022] Preferably, in (1)-(5), the drug further includes a pharmaceutically acceptable carrier and / or excipients.

[0023] Preferably, the pharmaceutically acceptable excipient is selected from one or more of diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorbents, and lubricants.

[0024] Preferably, in (1)-(5), the drug is formulated into a pharmaceutically acceptable dosage form.

[0025] Preferably, the dosage form includes: injections, solutions, gels, suspensions, implants, creams, embolic agents, capsules, tablets, pills, and oral liquids.

[0026] The third aspect of this invention proposes a disease model of acute liver injury induced by concanavalin A (ConA). The model of acute drug-induced liver injury induced by ConA is treated with rociletinib. Rociletinib can repair liver tissue damage and necrosis caused by ConA, reduce the levels of ALT / AST, inflammatory factors and GSH in mouse serum, and has a significant therapeutic effect on acute drug-induced liver injury induced by concanavalin A (ConA).

[0027] The beneficial effects of this invention are as follows:

[0028] 1. This invention proposes a novel use for the compound rociletinib, which can reduce lipid peroxidation and the increase of reactive oxygen species during ferroptosis, inhibit the process of ferroptosis induced by different ferroptosis inducers, reduce cell death rate, and thus achieve a therapeutic effect on diseases related to ferroptosis mechanisms. The ferroptosis inhibitor achieves its therapeutic purpose by reducing the levels of ALT, AST, and various inflammatory factors in acute liver injury and restoring GSH levels in liver tissue.

[0029] 2. This invention provides the application of the compound rociletinib in the treatment of acute liver injury. Specifically, the described ferroptosis inhibitor rociletinib can be used to treat / alleviate acute liver injury. This invention utilizes the ferroptosis inhibitor rociletinib in a ConA-induced mouse model of acute liver injury to improve liver histology, liver inflammation, ALT / AST levels, etc., thereby achieving a therapeutic effect. Furthermore, this invention provides evidence of rociletinib's inhibition of ferroptosis, offering a new theoretical basis for the treatment of acute liver injury and possessing profound application value.

[0030] 3. Based on the study of the mechanism of cell death, this invention, through screening and cell activity experiments, discovered that the compound rociletinib can be used as an inhibitor of cell ferroptosis, and provides a treatment measure for rociletinib in the treatment of acute liver injury. Attached Figure Description

[0031] Figure 1 In Example 1 of this invention, rociletinib showed a significant inhibitory effect on the incidence of ferroptosis induced by different concentrations of RSL3.

[0032] Figure 2 In Example 1 of this invention, rociletinib showed a significant inhibitory effect on the incidence of ferroptosis induced by different ferroptosis inducers RSL3, Erastin, and FIN56.

[0033] Figure 3 In Example 1 of this invention, rociletinib showed a significant inhibitory effect on RSL3-induced ferroptosis in different cell types. Figure 3 Figure a shows the changes in the survival rate of RSL3-induced ferroptosis cells in MDA-MB-231 cells. Figure 3 b shows the changes in the survival rate of RSL3-induced ferroptosis cells in 4T1 cells. Figure 3 c shows the changes in the survival rate of RSL3-induced ferroptosis cells in MCA-205 cells;

[0034] Figure 4 In Example 1 of this invention, rociletinib reduced the increase in cellular lipid peroxidation induced by RSL3;

[0035] Figure 5 This is a HE-stained section showing the treatment of concanavalin A (ConA)-induced liver injury with rociletinib in Example 1 of the present invention.

[0036] Figure 6In Example 1 of this invention, rociletinib treatment reduced the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the serum of mice induced by concanavalin A (ConA). Figure 6 Image a shows the AST level detection results. Figure 6 b is the ALT level detection result image;

[0037] Figure 7 In Example 1 of this invention, rociletinib treatment increased the level of glutathione (GSH) in mouse liver tissue induced by concanavalin A (ConA).

[0038] Figure 8 This refers to the effect of rociletinib on the changes in ferroptosis-related proteins in mouse liver tissue induced by concanavalin A (ConA) in Example 1 of the present invention.

[0039] Figure 9 In Example 1 of this invention, rociletinib was used to treat the decrease of concanavalin A (ConA)-induced inflammatory factors in mouse liver tissue. Figure 9 Figure a shows the ELISA results of IL-1β level detection. Figure 9 b is the result of ELISA detection of TNF-α level. Detailed Implementation

[0040] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0041] Unless otherwise specified, all test materials and reagents used in the following examples are commercially available.

[0042] Unless otherwise specified in the embodiments, the techniques or conditions described in the literature in this field or in accordance with the product manual may be followed.

[0043] Example 1:

[0044] 1. Materials and Methods:

[0045] 1.1 Preparation of experimental materials:

[0046] Compounds rociletinib, Erastin, and RSL3 were all purchased from Shanghai Taoshu Biotechnology Co., Ltd., and were dissolved in sterile DMSO (dimethyl sulfoxide) to prepare the required concentrations. (CCK-8 (Cell Counting)) Kit-8 reagents: purchased from Shanghai Taoshu Biotechnology Co., Ltd., catalog number C0005; RSL3: purchased from Shanghai Taoshu Biotechnology Co., Ltd., catalog number T3646; Erastin: purchased from Shanghai Taoshu Biotechnology Co., Ltd., catalog number T1765; FIN56: purchased from MedChemExpress, catalog number HY-103087; Tissue / cell glutathione (GSH) assay kit: purchased from Nanjing Jiancheng Bioengineering Research Institute Co., Ltd.; BCA protein concentration assay kit: purchased from Beyotime, catalog number P0011; Lactate dehydrogenase cytotoxicity assay kit: purchased from Beyotime, catalog number C0016; Mouse aspartate aminotransferase (ALT) kit: purchased from Nanjing Jiancheng Bioengineering Research Institute Co., Ltd.; Mouse alanine aminotransferase (AST) kit: purchased from Nanjing Jiancheng Bioengineering Research Institute Co., Ltd.; Creatinine (CRE) kit: purchased from Nanjing Jiancheng Bioengineering Research Institute Co., Ltd.; Blood urea nitrogen (BUN) kit: purchased from Nanjing Jiancheng Bioengineering Research Institute Co., Ltd.; BODIPY 581 / 591C11: Invitrogen, D3861; Mouse IL-1β ELISA kit: R&D, DY401; Mouse IL-6DuoSet ELISA: R&D, DY406.

[0047] 1.2 Culture of HT-1080 human fibrosarcoma cells:

[0048] Culture conditions for the HT-1080 human fibrosarcoma cell line: DMEM high-glucose medium (GIBCO) containing 10% FBS (GIBCO), 37°C, 5% CO2, saturated humidity incubator.

[0049] 1.3 Rociletinib inhibits RSL3-induced ferroptosis

[0050] Mature HT1080 cells were digested with trypsin for 1 min, resuspended, and centrifuged at 1000 rpm for 3 min, discarding the supernatant. 6000 cells were seeded per well in a 96-well plate. After cell attachment, the cells were divided into three groups: a normal control group (Control) with the corresponding volume of DMSO; an RSL3 treatment group (1 μM RSL3 per well for 8 h); and an RSL3 + different concentrations of rociletinib group (5 μM, 2.5 μM, and 1 μM rociletinib were added to the culture medium 1 h before the 8 h treatment with different final concentrations of RSL3). After 8 h, cell viability was assessed using a CCK-8 assay. The experiment was repeated three times.

[0051] See results Figure 1 Analysis of cell viability in the ferroptosis-induced group showed that 1 μM RSL3 successfully induced ferroptosis. Cell viability analysis in the rociletinib-treated group indicated that rociletinib pretreatment inhibited ferroptosis. This demonstrates that rociletinib can inhibit RSL3-induced ferroptosis.

[0052] 1.4 Rociletinib inhibits Erastin and FIN56-induced ferroptosis

[0053] Mature HT1080 cells were digested with trypsin for 1 min, resuspended, centrifuged at 1000 rpm for 3 min, and the supernatant was discarded. 6000 cells were seeded per well in a 96-well plate. After cell attachment, the cells were divided into the following groups: Control group (with the corresponding volume of DMSO); FIN56 and Erastin treatment group (40 μM FIN56 or 20 μM Erastin per well for 8 h); and FIN56 / Erastin + rociletinib group (5 μM rociletinib added to the culture medium 1 h before the 8 h treatment with different final concentrations of FIN56 / Erastin). After 8 h, cell viability was assessed using a CCK-8 assay. The experiment was repeated three times.

[0054] See results Figure 2 Cell viability analysis showed that 40 μM FIN56 or 20 μM erastin successfully induced ferroptosis, and rociletinib pretreatment inhibited ferroptosis, indicating that rociletinib can inhibit ferroptosis induced by 40 μM FIN56 or 20 μM erastin.

[0055] 1.5 Rociletinib inhibited RSL3-induced ferroptosis in various cell types.

[0056] Mature MDA-MB-231, 4T1, and MCA205 cells were used, respectively. After trypsin digestion for 1 min, the cells were resuspended, centrifuged at 1000 rpm for 3 min, and the supernatant was discarded. Approximately 1*10n cells of each cell type were used. 4 Cells were seeded in 96-well plates and divided into three groups: a normal control group (Control) with the corresponding volume of DMSO; an RSL3 treatment group (each well treated with 1 μM RSL3 for 8 h); and an RSL3 + different concentrations of rociletinib group (5 μM, 2.5 μM, and 1 μM rociletinib added to the culture medium 1 h before the addition of different final concentrations of RSL3 for 8 h of treatment). After 8 h, cell viability was measured by CCK-8 assay, and the experiment was repeated 3 times.

[0057] See results Figure 3 Analysis of RSL3-induced cell viability showed that 1 μM RSL3 successfully induced ferroptosis. Cell viability assays in the drug-treated groups indicated that rociletinib pretreatment could inhibit ferroptosis, demonstrating that rociletinib can inhibit RSL3-induced ferroptosis in different cell types.

[0058] 1.6 Rociletinib inhibits lipid peroxidation during ferroptosis in vitro:

[0059] Using mature HT1080 cells, digest with trypsin for 1 min, resuspend, centrifuge at 1000 rpm for 3 min, and discard the supernatant. Divide each well into 7*10⁻⁶ cells. 4 Cells were seeded into 6-well plates. The groups were: normal control group; RSL3 treatment group (1 μM RSL3 added to culture medium for 6-8 h); and RSL3+rociletinib treatment group (5 μM rociletinib added to culture medium 1 h before adding 1 μM RSL3). After treatment, the cell culture supernatant was removed, and 500 μL of serum-free DMEM and 5 μM MBODIPY 581 / 591C11 were added to each well. The 6-well plates were incubated at 37°C for 30 min. Trypsin was added to digest the cells, and digestion was stopped after 1 min. The cells were transferred to EP tubes and centrifuged at 4°C for 5 min at 3000 rpm. After collection, the cells were resuspended in ice-cold PBS and centrifuged again. This washing process was repeated 3 times.

[0060] See results Figure 4 In cells treated with RSL3 alone, lipid peroxidation induced by ferroptosis was significantly increased. The addition of rociletinib could inhibit the level of lipid peroxidation. Therefore, rociletinib can inhibit the increase of lipid peroxidation during ferroptosis.

[0061] 1.7 The alleviating effect of rociletinib on concanavalin A (ConA)-induced acute liver injury in mice

[0062] Animal grouping: Fifteen 8-10 week old C57BL / 6 mice were selected and randomly divided into the following three groups: control group; ConA group (500mg / kg); rociletinib (40mg / kg) + ConA group (500mg / kg).

[0063] Animal treatment: The mouse acute liver injury model was induced by intraperitoneal injection of concanavalin A (ConA) (500 mg / kg). A certain amount of ConA was weighed, dissolved in sterile PBS, and administered via tail vein injection. Rociletinib was dissolved in sterile PBS and administered intravenously 1 hour before ConA injection. Blood samples were collected from the retro-orbital venous plexus for liver function testing during ConA injection. The mice were then dissected 24 hours later, and liver tissue was immediately removed, fixed with 4% paraformaldehyde, and prepared for H&E staining. Pathological examination of the sections was used to determine the success of the induction.

[0064] See results Figure 5 Analysis of pathological sections showed that the ConA treatment group had a significantly increased liver damage, while the liver damage was significantly relieved after treatment with rociletinib, suggesting that rociletinib can treat liver damage in vivo.

[0065] Detection of AST and ALT in mouse serum: Collect whole blood from mice in each group, let stand for 1-2 hours, and centrifuge directly at low speed to separate the serum for later use. Dilute the separated serum sample 5 times, and operate the sample according to the instructions of the AST and ALT detection kits.

[0066] See results Figure 6 Analysis of ALT and AST test results showed that the serum ALT and AST levels in the rociletinib treatment group were significantly reduced, indicating that rociletinib has a positive effect on alleviating ConA-induced liver damage and restoring liver function.

[0067] Detection of GSH levels in mouse liver tissue: The right lobe of mouse liver was accurately weighed, and 9 times the amount of PBS was added to prepare a tissue homogenate at a ratio of weight (g) / volume (mL) = 1 / 9. The homogenate was centrifuged at 2500 rpm for 5 min, and the supernatant was collected. The procedure was performed according to the GSH kit instructions.

[0068] See results Figure 7 Analysis of GSH test results showed that the GSH level in the rociletinib treatment group was significantly increased, indicating that rociletinib has a beneficial effect on alleviating ConA-induced oxidative stress and maintaining stable GSH levels.

[0069] Western blot assay: Tissue was lysed on ice for 20 min using RIPA lysis buffer, proteins were extracted, BCA quantification was performed, and the proteins were separated by electrophoresis on a polypropylene gel. The proteins were then transferred to a PVDF membrane, blocked at room temperature for 1 h, and diluted primary antibody (all primary antibodies were diluted 1:1000) was added. The membrane was incubated overnight at 4°C. On the second day, the membrane was incubated with secondary antibody (1:10000) for 1 h. After washing the membrane, images were acquired using an ECL chemiluminescence imaging system.

[0070] See results Figure 8 Western blot analysis showed that rociletinib treatment inhibited the expression of ferroptosis-related proteins ACSL4 and NRF2.

[0071] ELISA detection: After collecting mouse blood samples and letting them stand at room temperature for 2 hours, centrifuge them at 1500 rpm for 10 minutes at 4°C, and take the supernatant for ELISA detection.

[0072] See results Figure 9 ELISA analysis showed that rociletinib treatment reduced the levels of concanavalin A (ConA)-induced inflammatory factors in mouse liver tissue, among which... Figure 9 Figure a shows the ELISA results of IL-1β level detection. Figure 9 b is the result of ELISA detection of TNF-α level.

[0073] 1.8 Statistical Methods

[0074] Statistical analysis was performed using R software, and experimental data are expressed as Mean ± SEM. Tukes-Varsé test (ANOVA) was used for comparisons between cell and animal experiments, and Student's-test was used for comparisons between two groups. A p-value < 0.05 was considered statistically significant; different letters indicate p < 0.05.

[0075] 2 Results

[0076] 2.1 Rociletinib inhibits RSL3-induced ferroptosis in HT-1080 cells

[0077] Experimental results showed that, compared with the control group, stimulation with the ferroptosis inducer RSL3 significantly killed cells; while rociletinib significantly inhibited RSL3-induced cell death (p<0.01). Figure 1 As shown, this demonstrates that rociletinib significantly inhibits RSL3-induced ferroptosis.

[0078] 2.2 Rociletinib inhibited ferroptosis induced by different ferroptosis inducers in Erastin and FIN56 cells in HT-1080 cells.

[0079] Experimental results showed that, compared with the control group, stimulation by the ferroptosis inducers Erastin and FIN56 significantly killed cells; while rociletinib significantly inhibited Erastin and FIN56-induced cell death (p<0.01). Figure 2 As shown.

[0080] 2.3 Rociletinib inhibited ferroptosis induced by RSL3 in different cell types;

[0081] Experimental results showed that rociletinib could inhibit RSL3-induced ferroptosis in both human cells (MDA-MB-231) and mouse cells (4T1, MCA205). Figure 3 As shown.

[0082] 2.4 Rociletinib reduced the increase in cellular lipid peroxidation induced by RSL3.

[0083] Experimental results showed that, compared with the control group, stimulation with the ferroptosis inducer RSL3 significantly increased cellular lipid peroxidation; while rociletinib significantly inhibited RSL3-induced cellular lipid peroxidation (p<0.01). Figure 4 As shown, this indicates that rociletinib significantly inhibits RSL3-induced increases in cellular lipid peroxidation.

[0084] 2.5 The alleviating effect of rociletinib on concanavalin A-induced acute liver injury in mice

[0085] The experimental results showed that, compared with the concanavalin A (ConA) treatment group, the rociletinib treatment group had a significant reduction in necrotic areas, such as... Figure 5 As shown; the levels of ALT and AST in the serum of the rociletinib treatment group were significantly reduced, such as Figure 6 As shown; rociletinib treatment increased the level of glutathione (GSH) in the liver tissue of mice induced by concanavalin A (ConA), such as Figure 7 As shown; rociletinib treatment inhibits the expression of ferroptosis-related proteins ACSL4 and NRF2, such as Figure 8 As shown; rociletinib is effective in treating concanavalin A (ConA)-induced decrease in IL-1β and TNF-α levels in mouse liver tissue, such as... Figure 9 As shown in the figure. Therefore, rociletinib has a significant alleviating effect on concanavalin A-induced acute drug-induced liver injury in mice.

[0086] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. The use of the compound rociletinib in the preparation of a medicament for the prevention or treatment of acute liver injury, wherein the structural formula of the compound rociletinib is as follows: .

2. The application according to claim 1, characterized in that, The acute liver injury mentioned was acute liver injury induced by concanavalin A.

3. The application according to claim 1, characterized in that, The compound rociletinib reduces liver GSH levels.

4. The application according to claim 1, characterized in that, The compound rociletinib reduces serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

5. The application according to claim 1, characterized in that, When treating acute liver injury, the compound rociletinib is administered intraperitoneally at a dose of 20 mg / kg, twice with an interval of 1 hour.

6. The application according to claim 1, characterized in that, The drug may also be a pharmaceutically acceptable salt of the compound rociletinib.

7. The application according to claim 1, characterized in that, The drug also includes pharmaceutically acceptable excipients.

8. The application according to claim 7, characterized in that, The pharmaceutically acceptable excipients are selected from one or more of the following: diluents, binders, wetting agents, disintegrants, absorption enhancers, surfactants, and lubricants.

9. The application according to claim 1, characterized in that, The drug is formulated into a pharmaceutically acceptable dosage form.

10. The application according to claim 1, characterized in that, The dosage forms of the drugs include: injections, gels, suspensions, implants, creams, embolic agents, capsules, tablets, pills, and oral liquids.

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