Use of dimethyl mercaptopropionic acid

Abstract

The application discloses application of dimethyl mercaptopropionic acid and relates to the field of medicine. Specifically, the application provides application of dimethyl mercaptopropionic acid in preparation of a medicine for treating Alzheimer's disease. In the application, the dimethyl mercaptopropionic acid can reverse changes in protein expression levels of MAG, CD9 and P2ry12 in the brain of an Alzheimer's disease model mouse, plays a role in myelin regeneration protection and nerve immune regulation, can reduce expression levels of pathological proteins A beta and tau related to Alzheimer's disease, improves spatial learning ability and spatial memory ability of the Alzheimer's disease mouse, and can be used for treating Alzheimer's disease.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to the application of dimethylsulphoniopropionate. BACKGROUND

[0002] Neurodegeneration is a common feature of many brain diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), etc. AD is an age-related neurodegenerative disease characterized by memory loss and cognitive decline. With the global aging, AD has become an increasingly serious public health problem. The pathogenesis of AD has been the focus of scientists, but so far there is no exact conclusion. The main pathological features of AD are senile plaques formed by extracellular beta-amyloid (Aβ) deposition and neurofibrillary tangles formed by intracellular Tau protein hyperphosphorylation, and various hypotheses have been proposed accordingly. The drugs developed so far targeting these hallmark pathological features, even if they successfully reduce Aβ plaques, cannot stop the progression of the disease.

[0003] In the central nervous system, myelin is a multilayer lipid structure wrapped around the axon, which isolates the neuron axon from the surrounding environment and enables the effective propagation of action potentials along the axon. In addition to the classic amyloid hypothesis, myelin loss is also considered another key pathological feature of AD, and the related proteins that maintain the integrity of myelin are significantly reduced in the brain tissue of AD patients. Recently, it has been suggested that the combination of the only FDA-approved amyloid-targeting drug Aducanumab (aducanumab) and a drug targeting oligodendrocytes and promoting myelin regeneration may be more effective.

[0004] Dimethylsulphoniopropionate (DMSP) is a natural product widely distributed in the ocean, mainly produced by algal plants, corals and bacterial organisms, and serves as their osmotic agent, cryoprotectant and antioxidant. In addition, DMSP is an important part of the marine sulfur cycle. In addition to playing a role in natural biogeochemical processes, DMSP also has high biomedical research value. Studies have shown that DMSP can improve the antioxidant capacity of mammalian nerve cells, promote cell survival, and has an improvement effect on breast cancer, induced diabetes and Parkinson's disease, but there is no report on the application of DMSP in promoting myelin regeneration, nor in the treatment of AD.

[0005] Therefore, the prior art still needs to be improved and developed. SUMMARY

[0006] In view of the above deficiencies of the prior art, the purpose of the present application is to provide an application of dimethyl mercaptopropionic acid, aiming to develop a drug for treating Alzheimer's disease.

[0007] The technical solution of the present application is as follows:

[0008] In a first aspect of the present application, the application of dimethyl mercaptopropionic acid in the preparation of a drug for treating Alzheimer's disease is provided.

[0009] In a second aspect of the present application, the application of dimethyl mercaptopropionic acid in the preparation of a drug for treating myelin sheath damage is provided.

[0010] In a third aspect of the present application, the application of dimethyl mercaptopropionic acid in the preparation of a drug for neuroimmunomodulation is provided.

[0011] Optionally, the drug comprises dimethyl mercaptopropionic acid, and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, a pharmaceutically acceptable adjuvant, and a pharmaceutically acceptable prodrug.

[0012] Optionally, the pharmaceutically acceptable carrier comprises at least one of sugar, starch, and cellulose.

[0013] Optionally, the pharmaceutically acceptable excipient comprises at least one of a solvent, an excipient, a buffer, a lubricant, a coloring agent, a release agent, a coating agent, a flavoring agent, a preservative, and an antioxidant.

[0014] Optionally, the dosage form of the drug is selected from one of a solution, a pill, a tablet, a capsule, a powder, a lozenge, and a paste.

[0015] Optionally, the administration route of the drug comprises a combination of one or more of oral administration, intravenous injection, intraperitoneal injection, intramuscular injection, and subcutaneous injection.

[0016] Beneficial effects: In the present application, dimethyl mercaptopropionic acid can reverse the changes in the expression levels of MAG, CD9, and P2ry12 proteins in the brain of Alzheimer's disease model mice, and plays a role in myelin sheath regeneration protection and neuroimmunomodulation. At the same time, dimethyl mercaptopropionic acid can reduce the expression levels of Alzheimer's disease pathology-related proteins Aβ and tau, improve the spatial learning ability and spatial memory ability of Alzheimer's disease mice, and can be used for treating Alzheimer's disease. BRIEF DESCRIPTION OF DRAWINGS

[0017] Figure 1 A comparison chart of the escape latency of each group of mice in Example 1 of the present application over time.

[0018] Figure 2 A result chart of the residence time of each group of mice in the original platform quadrant in the 24h test in Example 1 of the present application.

[0019] Figure 3 The result graph of the number of times of crossing the platform of each group of mice in the 24h test in Example 1 of the present application.

[0020] Figure 4 The result graph of the time of staying in the original platform quadrant of each group of mice in the 72h test in Example 1 of the present application.

[0021] Figure 5 The result graph of the number of times of crossing the platform of each group of mice in the 72h test in Example 1 of the present application.

[0022] Figure 6 The result graph of the relative expression level of HT7 protein in the brain of each group of mice in Example 2 of the present application.

[0023] Figure 7 The result graph of the relative expression level of Tau-pS404 protein in the brain of each group of mice in Example 2 of the present application.

[0024] Figure 8 The result graph of the relative expression level of Aβ1-42 protein in the brain of each group of mice in Example 2 of the present application.

[0025] Figure 9 The result graph of GO enrichment analysis of differentially expressed proteins between DMSP(L) group and AD group of mice in Example 3 of the present application.

[0026] Figure 10 The result graph of GO enrichment analysis of differentially expressed proteins between DMSP(H) group and AD group of mice in Example 3 of the present application.

[0027] Figure 11 The result graph of PPI network analysis of common differentially expressed proteins of DMSP(L) / AD comparison group and AD / WT comparison group in Example 3 of the present application.

[0028] Figure 12 The result graph of PPI network analysis of common differentially expressed proteins of DMSP(H) / AD comparison group and AD / WT comparison group in Example 3 of the present application.

[0029] Figure 13 The result graph of PPI network analysis of common differentially expressed proteins of DMSP(L) / AD, DMSP(H) / AD and AD / WT comparison groups in Example 3 of the present application.

[0030] Figure 14 The result graph of the relative expression amount of MAG protein in the hippocampal tissue of mice in Example 4 of the present application.

[0031] Figure 15A relative expression result graph of CD9 protein in hippocampus tissue of mice in Example 4 of the present application.

[0032] Figure 16 A relative expression result graph of P2ry12 protein in hippocampus tissue of mice in Example 4 of the present application. DETAILED DESCRIPTION

[0033] The present application provides an application of dimethyl mercaptopropionic acid. To make the purpose, technical solution and effect of the present application more clear and explicit, the present application is further described in detail below. It should be understood that the specific embodiments described herein are only used to explain the present application and are not intended to limit the present application.

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs. The terminology used in the description herein is for describing the specific embodiments only and is not intended to be limiting of the present application.

[0035] The present application provides an application of dimethyl mercaptopropionic acid in preparing a medicament for treating Alzheimer's disease.

[0036] The present application provides an application of dimethyl mercaptopropionic acid in preparing a medicament for treating myelin sheath damage.

[0037] The present application provides an application of dimethyl mercaptopropionic acid in preparing a medicament for treating myelin sheath damage.

[0038] In the present application, dimethyl mercaptopropionic acid can reverse the changes in the expression levels of MAG, CD9 and P2ry12 proteins in the brain of Alzheimer's disease model mice, play a role in myelin sheath regeneration protection and neural immune regulation, and at the same time, dimethyl mercaptopropionic acid can reduce the expression levels of Alzheimer's disease pathological related proteins Aβ and tau, improve the spatial learning ability and spatial memory ability of Alzheimer's disease mice, and can be used for treating Alzheimer's disease. In addition, dimethyl mercaptopropionic acid has a regulatory function on biological processes such as the physiological state of glial cells, myelin sheath formation, axon guidance, the complement system, cholinergic synapses and metal ion response in the brain of Alzheimer's disease model mice.

[0039] In some embodiments, the medicament comprises dimethyl mercaptopropionic acid (active ingredient), and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, a pharmaceutically acceptable adjuvant, and a pharmaceutically acceptable prodrug.

[0040] In some embodiments, the medicament comprises a therapeutically effective amount of dimethylthiopropanoic acid, and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, a pharmaceutically acceptable adjuvant, a pharmaceutically acceptable prodrug.

[0041] In the present embodiments, a therapeutically effective amount means a dosage of dimethylthiopropanoic acid of the present embodiments sufficient to show an effect or clinical significance in an individual. Those skilled in the art will understand that the actual amount or dosage administered and the time course of administration will depend on the nature and severity of the disease being treated, the age and general condition of the subject being treated, and the mode of administration, etc.

[0042] In one embodiment, the pharmaceutically acceptable carrier includes one or more of a sugar, a starch, a cellulose and derivatives thereof, but is not limited thereto.

[0043] In some embodiments, the sugar can be selected from at least one of lactose, glucose, sucrose, but is not limited thereto; the starch can be selected from at least one of corn starch, potato starch, but is not limited thereto; the cellulose and derivatives thereof can be selected from at least one of sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, but is not limited thereto.

[0044] The pharmaceutically acceptable excipient means any excipient known to those skilled in the art that is suitable for a specific mode of administration, the excipient should be non-toxic, does not interfere with or impair the efficacy of the active ingredient of the present embodiments, and the excipient can be flexibly selected according to the specific dosage form of the medicament described in the above embodiments. In one embodiment, the pharmaceutically acceptable excipient includes at least one of a pharmaceutically acceptable solvent, an excipient, a buffer, a lubricant, a coloring agent, a release agent, a coating agent, a flavoring agent, a preservative, an antioxidant, but is not limited thereto.

[0045] In one embodiment, the excipient includes one or more of cocoa butter, suppository wax, vegetable oil, alcohol, ester, agar, but is not limited thereto.

[0046] In some embodiments, the vegetable oil can be selected from at least one of peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil, but is not limited thereto; the alcohol can be selected from propylene glycol, but is not limited thereto; the ester can be selected from at least one of ethyl oleate, ethyl dodecanoate, but is not limited thereto.

[0047] In one embodiment, the buffer includes one of magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol and phosphate buffer solution, but is not limited thereto.

[0048] In an embodiment, the lubricant includes one or both of sodium dodecyl sulfate and magnesium stearate, but is not limited thereto.

[0049] In an embodiment, the dosage form of the drug is selected from one of a solution, a pill, a tablet, a capsule, a powder, a lozenge, and a paste.

[0050] In an embodiment, the administration route of the drug includes one or more of a combination of oral administration, intravenous injection, intraperitoneal injection, intramuscular injection, and subcutaneous injection.

[0051] The following is described in detail through specific examples.

[0052] In the following examples, Alzheimer's disease is abbreviated as AD, and dimethyl mercaptopropionic acid is abbreviated as DMSP.

[0053] Embodiments of the present application use a three-transgenic AD model mouse (3xTg-AD) as the research object, set different dose DMSP administration groups, analyze the intervention effect and mechanism of DMSP on 3xTg-AD mice. First, the spatial learning and memory ability of the mice is evaluated through the Morris water maze experiment, then the relative expression amount of AD pathological related proteins (Aβ and phosphorylated tau protein) in the brain of the mice is detected using Western-Blot, and the proteomics of the hippocampal tissue of the AD mice treated and untreated with DMSP and the Wild-type (WT) mice is further studied to understand the mechanism of DMSP.

[0054] The DMSP used in the following examples is provided by the Changchun Research Institute.

[0055] The 3xTg-AD and WT mice used in the following examples are purchased from Jackson Laboratory. These mice express mutant human APPswe gene and tauP301L gene and mutant mouse PS1 M146V gene.

[0056] The 4-month-old 3xTg-AD mice are divided into a DMSP (L) group, a DMSP (H) group, and an AD control group (denoted as an AD group), each group having 20 mice, 10 female mice and 10 male mice. Among them, the DMSP (L) group is a DMSP low-dose administration group, and the DMSP (H) group is a DMSP high-dose administration group.

[0057] The DMSP(L) group was treated with 7 pg / mL DMSP in the drinking water for 12 weeks, and the DMSP(H) group was treated with 11 pg / mL DMSP in the drinking water for 12 weeks. The AD group of mice received normal drinking water. At the same time, the WT control group (denoted as the WT group) of mice also received normal drinking water. All mice were fed in a standard environment (the temperature in the animal room was maintained at 22 ± 2°C, and the day and night alternated every 12 hours), and the feed was purchased from the Guangdong Medical Laboratory Animal Center (Guangzhou, China). Specifically, the mouse group settings are shown in Table 1.

[0058] Table 1. Mouse group settings

[0059]

[0060] Example 1: Evaluation of the spatial learning and memory ability of mice by the Morris water maze experiment

[0061] The WT, AD, DMSP(L), and DMSP(H) groups of mice were trained in a circular pool (diameter 160 cm, height 50 cm) and mainly divided into two parts: the place navigation experiment and the spatial probe experiment.

[0062] Place navigation experiment: Each mouse was trained 4 times a day for 5 consecutive days. The maximum test time for each mouse in each training was 60 seconds, during which the time required for the mouse to find the hidden platform was measured, i.e., the escape latency, and a shorter escape latency was considered to have better spatial learning ability. If the mouse did not reach the platform within the specified time, the mouse was manually guided to the platform and stayed for 15 seconds. As shown in Figure 1 , the escape latency of the AD group of mice was significantly longer than that of the WT group of mice, indicating that the spatial learning ability of the AD group of mice was impaired. However, the escape latency of the DMSP(L) and DMSP(H) groups of mice showed that after DMSP treatment, the escape latency of the AD mice was shortened. One-way ANOVA showed that, as shown in Figure 1 , the DMSP-treated AD mice performed significantly better than the AD group of mice from the third day, and showed a significantly shortened total escape latency in the continuous 5-day training, which indicated that DMSP could improve the spatial learning impairment of AD mice and improve the spatial learning ability of AD mice.

[0063] Spatial probe test: Spatial probe test was performed 24h and 72h after the last day of the place navigation training to evaluate the short-term memory and long-term memory of the mice. The platform was removed and the mice were placed in the quadrant opposite to the original platform quadrant. Each mouse was allowed to swim for 60 seconds and the time spent in the original platform quadrant and the number of crossing the platform location were recorded. The longer time spent in the original platform quadrant and the more number of crossing the platform location were considered as better spatial memory ability. As shown in Figure 2 and 3 , the time spent in the original platform quadrant and the number of crossing the platform location of the AD group mice were significantly less than that of the WT group mice 24h after the training, while the DMSP treatment significantly reversed this phenomenon. The time spent in the original platform quadrant and the number of crossing the platform location of the DMSP-treated mice were significantly higher than that of the AD group mice. As shown in Figure 4 and 5 , the time spent in the original platform quadrant of the DMSP(L) group mice was still significantly higher than that of the AD group mice in the 72h probe test. The above results showed that DMSP could improve the spatial memory impairment of AD mice and improve the spatial memory ability of AD mice.

[0064] wherein, Figures 1-5 n = 10, # P < 0.05; ## P < 0.01; ### P < 0.001; *P < 0.05; **P < 0.01; ***P < 0.001.

[0065] Example 2: Detection of typical AD pathological features in the brain of mice

[0066] The main pathological features of AD are senile plaques formed by extracellular Aβ deposition and neurofibrillary tangles formed by intracellular Tau protein hyperphosphorylation. The relative expression levels of total tau, phosphorylated tau and Aβ proteins in the brain of mice were detected by Western-Blot, and the results are shown in Figures 6-8 wherein, n = 3; # P < 0.05; ### P < 0.001; #####P<0.0001; *P<0.05, **P<0.01, compared with AD group). The results of detecting the relative expression levels of total tau, phosphorylated tau and Aβ proteins in the brain of mice showed that DMSP treatment could reduce the expression levels of HT7 and Tau-pS404 in the brain of AD mice and reduce the aggregation of Aβ1-42 in the brain of AD mice.

[0067] Example 3 Proteomic analysis of hippocampal tissues of mice in DMSP(L) group, DMSP(H) group, AD group and WT group to understand the mechanism of DMSP

[0068] Data-independent acquisition (DIA) proteomic method was used to analyze the changes of protein expression levels in the hippocampal tissues of mice. The left hippocampus of 8 mice in each group (4 females + 4 males) was collected, and then 2 mice of the same sex were randomly selected and combined as one sample, i.e. 4 combined samples were obtained for each group. Total protein was extracted from the samples, and a part of it was used for protein concentration determination and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) detection. Another part was subjected to trypsin digestion, and the digested peptides were desalted before LC-MS / MS identification. LC-MS / MS identification consisted of two main steps: the first step was to establish a protein spectrum library using traditional data-dependent acquisition (DDA) method, and the second step was to collect mass spectrum data of each sample using data-independent acquisition (DIA) technology. The difference change fold≥1.2 or ≤0.83, and p value <0.05 were used as the screening criteria for differentially expressed proteins (DEPs). After obtaining DEPs, GO enrichment analysis was performed on DEPs, and reverse protein was subjected to protein-protein interaction (PPI) network analysis to describe the function of DMSP. GO overall contains three ontologies: biological process (Biological Process), cellular component (Cellular Component), and molecular function (Molecular Function). The corresponding -log10Pvalue (Pvalue is P value) of each entry under each ontology was sorted from large to small, and the top 10 entries were selected to obtain the top 30 entries of GO enrichment analysis.

[0069] Three comparison groups were established by the above method: (i) comparison between DMSP(L) group mice and AD group mice, i.e. DMSP(L) / AD comparison group; (ii) comparison between DMSP(H) group mice and AD group mice, i.e. DMSP(H) / AD comparison group; (iii) comparison between AD group mice and WT group mice, i.e. AD / WT comparison group. The results are as follows:Figures 9-13 As shown.

[0070] Compared to the AD group, 191 proteins were upregulated and 43 proteins were downregulated in the DMSP(L) group, while 100 proteins were upregulated and 46 proteins were downregulated in the DMSP(H) group. These DEPs were then subjected to GO enrichment analysis. Figure 9 and 10 As shown, DMSP induces significant changes in biological processes such as myelin formation, axonal development, metal ion response, and complement activation / alternative pathways. Changes in cellular components induced by DMSP primarily include myelin sheath, intersegmental axonal regions, protein complexes involved in cell adhesion, endoplasmic reticulum membrane components, and dense nuclear vesicles in neurons. Effects of DMSP on molecular function mainly include ubiquitin junctions, binding of the complement component C1q complex, structural components of the myelin sheath, binding of insulin-like growth factor, zinc ion binding, and the activity of post-translational modification-related enzymes (e.g., N-acetyltransferase activity, glycosyltransferase activity, and protein serine / threonine phosphatase inhibitor activity).

[0071] Compared to the WT group, a total of 479 DEPs were identified in the AD group. The results of the DMSP(L) / AD and AD / WT comparison groups contained 61 identical DEPs, of which 60 were reversal proteins. PPI network analysis of the reversal proteins yielded the following results: Figure 11 As shown, the results indicate that they are mainly involved in glial cell differentiation, myelination, axonal guidance, and complement pathways.

[0072] The detection results of the two comparison groups, DMSP(H) / AD and AD / WT, contained 44 identical DEPs, all of which were reversal proteins. The reversal protein PPI network analysis results are as follows: Figure 12 As shown, the results indicate that they are mainly involved in myelination, axonal guidance, cell junctions, and protein membrane localization; while the detection results of the three comparison groups, DMSP(L) / AD, DMSP(H) / AD, and AD / WT, contained 20 identical DEPs, all of which are reversal proteins. The reversal protein PPI network analysis is as follows: Figure 13 As shown, the results indicate that they are mainly involved in myelination, cell junctions, extracellular vesicles, and axonal guidance.

[0073] Example 4

[0074] Based on the results of proteomics analysis, both the DMSP low-dose treatment group and the DMSP high-dose treatment group showed effects on myelination, axon guidance and metal ion response, as shown in Table 2, according to the above PPI network analysis, the three reverse proteins CD9, MAG and P2ry12 were selected and verified by Western-Blot.

[0075] Table 2 DMSP treatment can reverse the expression level in AD and obtain WB verification of proteins selected according to PPI network analysis

[0076]

[0077]

[0078] The verification results are as follows Figures 14-16 (wherein the sample number n = 3; ## AD group, P <0.01; * indicates that the comparison between the drug group and the AD group, P <0.05; ** indicates that the comparison between the drug group and the AD group, P <0.01; *** indicates that the comparison between the drug group and the AD group, P <0.001). In addition to the classic amyloid beta hypothesis and tau protein hyperphosphorylation hypothesis, demyelination is also considered another key pathological feature of AD, which may occur before amyloid pathology develops. Myelin-associated glycoprotein (MAG) is located in the innermost layer of the myelin membrane that directly contacts the axon, and it participates in the formation of myelin and the maintenance of its integrity by mediating the interaction between glial cells and axons. CD9 antigen (CD9) appears in the last stage of myelination, CD9 participates in the communication between axons and glial cells, and plays an important role in the formation of the connection between the paranodal region of the Ranvier node. As shown in Figure 14 and 15 Compared with WT group mice, the expression levels of MAG and CD9 in the hippocampal tissue of AD group mice decreased, and the expression levels of MAG and CD9 improved after DMSP treatment, which maintained the integrity of myelin and helped the conduction of nerve impulse. Therefore, DMSP plays an important role in restoring myelin damage in AD mice brain, and can be used as a myelin regeneration protective agent for the treatment of myelin damage.

[0079] Microglia is the main immune cell of the central nervous system, which plays a key role in immune surveillance, synaptic pruning and clearance of abnormal proteins. P2Y purinoceptor 12 (P2ry12) is a purinergic receptor highly expressed in microglia in the brain, which can be used as a marker for steady-state microglia, and mice lacking this receptor show abnormal microglia migration and polarization. As shown in Figure 16As shown, the expression level of P2ry12 in the hippocampus tissue of the AD group mice is decreased compared with the WT group mice, and DMSP can increase the expression level of P2ry12 in the hippocampus tissue of the AD mice after treatment, and stabilize the physiological state of microglia cells. The above results show that DMSP can achieve the effect of nerve protection by coordinating the state of microglia cells, and can be used as a neuroimmunomodulator for neuroimmunomodulation. DMSP exerts the anti-AD therapeutic effect through the mechanism of playing a role in myelin regeneration protection and neuroimmunomodulation.

[0080] By Figures 14-16 The verification results of CD9, MAG and P2ry12 in the brain of the AD group mice are consistent with the proteomic results.

[0081] In summary, the application provides the application of dimethyl mercaptopropionic acid, and the dimethyl mercaptopropionic acid in the application can reverse the change of the expression level of MAG, CD9 and P2ry12 proteins in the brain of the AD model mice, plays a role in myelin regeneration protection and neuroimmunomodulation, and can reduce the expression level of the AD pathological related proteins Aβ and tau, improve the space learning ability and space memory ability of the AD mice, and can be used for treating AD.

[0082] It should be understood that the application is not limited to the above examples, and those skilled in the art can make improvements or changes according to the above description, and all these improvements and changes shall belong to the protection scope of the appended claims of the application.

Claims

1. The use of dimethylmercaptopropionic acid in the preparation of drugs for the treatment of Alzheimer's disease.

2. Application of dimethyl mercaptopropionic acid in the preparation of drugs for treating myelin sheath injury.

3. The application according to any one of claims 1-2, characterized in that, The drug includes dimethyl mercaptopropionic acid and pharmaceutically acceptable excipients.

4. The application according to claim 3, characterized in that, Pharmaceutically acceptable excipients include at least one of sugar, starch, and cellulose.

5. The application according to claim 3, characterized in that, The pharmaceutically acceptable excipients include at least one of solvents, excipients, buffers, lubricants, colorants, release agents, coating agents, flavoring agents, preservatives, and antioxidants.

6. The application according to claim 3, characterized in that, The dosage form of the drug is selected from one of the following: solution, pill, tablet, capsule, powder, lozenge, and paste.

7. The application according to claim 3, characterized in that, The drug can be administered via one or more of the following routes: oral, intravenous, intraperitoneal, intramuscular, and subcutaneous.

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