Application of sofogliflozin in preparation of medicine for preventing and / or treating Alzheimer disease

Abstract

The present invention relates to the use of sofogliflozin or a pharmaceutically acceptable derivative thereof in the preparation of a medicament for preventing and / or treating Alzheimer's disease (AD). According to the invention, the sofogliflozin is found for the first time, and experiments prove that the sofogliflozin can obviously improve the cognitive disorder symptom of a mouse with AD disease and improve the cognitive function of the mouse; furthermore, the inventor studies the pathological mechanism of the sofogliflozin to find that the sofogliflozin can significantly reduce the deposition of beta-amyloid protein in the brain tissue of an AD mouse, so that the sofogliflozin can prevent, relieve, improve or treat the AD disease or delay the progress of the AD disease, is expected to become a candidate therapeutic drug for the Alzheimer's disease, and has great clinical application prospects and values.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to use of sogliflozin or a pharmaceutically acceptable derivative thereof in preparing a medicament for preventing and / or treating Alzheimer's disease. Background Art

[0002] Alzheimer's disease (AD) is the most common neurodegenerative disease. Its pathological characteristics are the deposition of β-amyloid protein (Aβ) in the brain to form senile plaques (SP) and neurofibrillary tangles (NFT) caused by the aggregation of hyperphosphorylated tau protein. The pathogenesis of AD is complex, involving the interaction of multiple factors such as genetics, metabolic disorders, neurotransmitter dysfunction, and blood-brain barrier damage. Despite continuous global research investment, existing therapies are still mainly symptomatic and cannot reverse the disease process.

[0003] Currently, AD treatment drugs are mainly divided into the following categories:

[0004] (I) Cholinesterase inhibitors (ChEIs) (such as donepezil): improve symptoms by enhancing cholinergic signaling but have no substantial effect on disease progression;

[0005] (II) Glutamate receptor inhibitors (such as memantine): modulate glutamate neurotoxicity, but have limited efficacy and side effects;

[0006] (III) Antioxidants and neuroprotectants: delay neuronal damage, but lack specific targets;

[0007] (IV) Monoclonal antibody drugs (such as lencanemab): Targeted clearance of Aβ plaques, but there is a risk of cerebral vascular edema / hemorrhage, and they are only effective in a limited window period between abnormal Aβ deposition and cognitive impairment, and cannot repair irreversible neuronal damage that has already occurred.

[0008] The main benefits of these drugs are to delay further deterioration of cognitive function and alleviate clinical symptoms, but they do not change the development trend of the disease; in addition, these therapies generally have problems such as single target, delayed treatment timing and safety risks.

[0009] Sotagliflozin, whose chemical name is (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol, is a dual inhibitor of sodium-glucose co-transporter 2 (SGLT2) and sodium-glucose co-transporter 1 (SGLT1). It can inhibit SGLT2 to increase the excretion of glucose, and inhibit SGLT1 to reduce the amount of glucose entering the blood through the gastrointestinal tract. It can be used to treat diabetes, heart failure, etc.; it is reported that sotagliflozin can be used to reduce the risk of cardiovascular death, heart failure hospitalization and heart failure emergency in adults with heart failure or diabetes, chronic kidney disease and other cardiovascular risk factors. Summary of the invention

[0010] Purpose of the Invention

[0011] The object of the present invention is to provide the use of sogliflozin or a pharmaceutically acceptable derivative thereof in the preparation of a medicament for preventing and / or treating Alzheimer's disease (AD).

[0012] The present invention discovers for the first time that sogliflozin or a pharmaceutically acceptable derivative thereof can significantly improve the cognitive function of AD (including reducing memory loss and cognitive dysfunction caused by AD), delay the course of the disease, and provide a new and effective treatment option for AD.

[0013] Solution

[0014] To achieve the above object, the present invention adopts the following technical solution:

[0015] In a first aspect, the present invention provides use of sogliflozin or a pharmaceutically acceptable derivative thereof in the preparation of a medicament for preventing and / or treating Alzheimer's disease.

[0016] The structural formula of sogliflozin is shown in the following formula I:

[0017]

[0018] In a specific embodiment, the pharmaceutically acceptable derivative of sogliflozin is a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0019] Preferably, the pharmaceutically acceptable derivative of solafloxacin is a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, wherein the prodrug is a drug that can be converted into solafloxacin in vivo.

[0020] Preferably, the pharmaceutically acceptable salt of sogliflozin is a salt selected from the following types: hydrochloride, nitrate, sulfate, phosphate, bromate, hydrobromide, citrate, formate, acetate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, benzoate, phthalate, malonate, maleate, perchlorate, fumarate, succinate, tartrate, lactate, gluconate, pamoate, aspartate or glutamate.

[0021] In the above use, the treatment of Alzheimer's disease includes one or more of the following:

[0022] (1) Delaying the progression of Alzheimer's disease;

[0023] (2) Improve symptoms caused by Alzheimer's disease;

[0024] Preferably, the treatment of Alzheimer's disease is to improve the cognitive function of Alzheimer's patients, including alleviating, relieving or reversing memory loss, cognitive dysfunction, etc. caused by Alzheimer's disease.

[0025] In the above use, the prevention and / or treatment of Alzheimer's disease is preferably achieved by the following mechanism: reducing the deposition of β-amyloid protein in brain tissue, preferably reducing the deposition of β-amyloid protein in the cerebral cortex and / or hippocampus.

[0026] In the above-mentioned use, preferably, the medicine comprises a preventive and / or therapeutically effective amount of sogliflozin or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier and / or excipient.

[0027] Further preferably, the preventive effective amount of sogliflozin or a pharmaceutically acceptable derivative thereof is 8-12 mg / kg body weight, 10 mg / kg body weight, and the therapeutic effective amount is 20-40 mg / kg body weight, preferably 30 mg / kg body weight.

[0028] Preferably, the drug is administered by one or more of the following methods: oral administration, injection, implantation, spraying and / or inhalation;

[0029] Preferably, the drug is administered orally;

[0030] Further preferably, the dosage form of the drug is an oral preparation, preferably selected from the following: tablets, granules, powders, capsules or liquids.

[0031] In a second aspect, the present invention provides a method for preventing and / or treating Alzheimer's disease, the method comprising: administering a preventively and / or therapeutically effective amount of sogliflozin or a pharmaceutically acceptable derivative thereof to a subject in need thereof.

[0032] The term "effective amount" refers to the amount or dosage of an active ingredient that provides the desired effect to the patient being diagnosed or treated by single or multiple administrations to the patient. The effective amount can be determined by the participating diagnostician as a person skilled in the art through known techniques and observations obtained under similar circumstances. In determining the effective amount or dosage of the active ingredient to be administered, the participating diagnostician should consider a variety of factors, including but not limited to: the species of the mammal; size, age and general health; the specific disease involved; the degree of involvement or severity of the disease; the response of the individual patient; the specific compound administered; the mode of administration; the bioavailability properties of the administered formulation; the selected dosage regimen; the use of concomitant drug therapy; and other relevant circumstances.

[0033] Beneficial Effects

[0034] The present invention provides the use of sogliacin or its pharmaceutically acceptable derivatives in the preparation of drugs for preventing and / or treating Alzheimer's disease. The inventors have confirmed through experiments on AD disease animal models that sogliacin can significantly improve the memory loss and cognitive impairment symptoms of AD disease mice, and even improve their cognitive level to a level close to that of normal mice; further, the inventors studied its mechanism of influence on AD disease pathology and found that sogliacin can significantly reduce the deposition of β-amyloid protein in the cerebral cortex and hippocampal tissue of AD disease mice, thereby reducing the toxic effect of β-amyloid protein on nerve cells, and thus can prevent, alleviate, improve or treat AD disease or its symptoms. Therefore, sogliacin or its pharmaceutically acceptable derivatives are very promising candidate therapeutic drugs for Alzheimer's disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] One or more embodiments are exemplarily described by the pictures in the accompanying drawings, and these exemplary descriptions do not constitute limitations on the embodiments. The special word "exemplary" here means "used as an example, embodiment or illustrative". Any embodiment described as "exemplary" here is not necessarily interpreted as being superior or better than other embodiments.

[0036] Figure 1 The figure shows the distance from each experimental group of mice to the target platform during the training phase in the Morris water maze positioning navigation experiment of Example 1; wherein the horizontal axis shows the training time, and the vertical axis shows the distance to the target platform (cm); ** indicates: on the 5th day of training, compared with the AD model control group (i.e., APP / PS1 group), P<0.01.

[0037] Figure 2The figure shows the escape latency of mice in each experimental group during the training phase in the Morris water maze positioning navigation experiment of Example 1; wherein the horizontal axis shows the training time, and the vertical axis shows the escape latency (s); *** indicates: on the 5th day of training, compared with the AD model control group (i.e., APP / PS1 group), P<0.001.

[0038] Figure 3 The Morris water maze spatial exploration experiment of Example 1 shows the number of crossings of the target quadrant by mice in each experimental group after the target platform is hidden; wherein the horizontal axis shows the group, and the vertical axis shows the number of crossings in the target quadrant; * indicates: compared with the AD model control group (i.e., APP / PS1 group), P<0.05; *** indicates: compared with the AD model control group (i.e., APP / PS1 group), P<0.001; ns indicates that there is no significant difference between the two groups.

[0039] Figure 4 The Morris water maze spatial exploration experiment of Example 1 shows the residence time of mice in each experimental group in the target quadrant after the target platform is hidden; wherein the horizontal axis shows the group, and the vertical axis shows the residence time in the target quadrant; * indicates: compared with the AD model control group (i.e., APP / PS1 group), P<0.05; ** indicates: compared with the AD model control group (i.e., APP / PS1 group), P<0.01; ns indicates that there is no significant difference between the two groups.

[0040] Figure 5 The representative trajectory diagrams of the mice in each experimental group searching for the target platform in each quadrant after hiding the target platform in the Morris water maze spatial exploration experiment of Example 1 are shown.

[0041] Figure 6 Representative histological sections showing Aβ plaque deposition in the hippocampus and cerebral cortex of mice in each experimental group in Example 1.

[0042] Figure 7 The figure shows the density of Aβ plaques per square millimeter in the hippocampus of mice in each experimental group in Example 1; wherein the horizontal axis shows the group, and the vertical axis shows the density of Aβ plaques in the hippocampus (%); ** indicates: compared with the AD model control group (ie, APP / PS1 group), P<0.01.

[0043] Figure 8 The density of Aβ plaques per square millimeter in the cerebral cortex of mice in each experimental group in Example 1 is shown; wherein the horizontal axis shows the group, and the vertical axis shows the density of Aβ plaques in the cerebral cortex (%); **** indicates: compared with the AD model control group (i.e., APP / PS1 group), P<0.001. DETAILED DESCRIPTION

[0044] In order to make the purpose, technical solution and advantages of the present invention clearer, the technical solution of the present invention will be clearly and completely described in conjunction with the embodiments below. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0045] In addition, in order to better illustrate the present invention, numerous specific details are provided in the specific embodiments below. It should be understood by those skilled in the art that the present invention can also be implemented without certain specific details. In some embodiments, raw materials, elements, methods, means, etc. well known to those skilled in the art are not described in detail, so as to highlight the main purpose of the present invention.

[0046] Unless explicitly stated otherwise, throughout the specification and claims, the term “comprise” or variations such as “include” or “comprising”, etc., will be understood to include the stated elements or components but not to exclude other elements or components.

[0047] The present invention is further described in detail below by way of examples.

[0048] Example 1: Effects of Sogliflozin on cognitive function of AD mice and its pathological mechanism

[0049] In this example, 6-month-old male APP / PS1 double transgenic mice (purchased from Beijing Weishanglide Co., Ltd.) were used as AD model mice, and male mice of the same age were used as wild mice controls to study the improvement effect of sotagliflozin (abbreviated as Sota in the accompanying drawings, purchased from MecChemExpress, stored in a dark, dry place at -20°C) on cognitive impairment (including spatial memory and learning ability) in AD mice.

[0050] APP / PS1 double transgenic mice are constructed by gene editing technology. They co-express human-mouse chimeric amyloid precursor protein (APP) carrying the Swedish mutation (APPswe) and presenilin 1 mutant (PS1-dE9) lacking exon 9 under the drive of the prion protein promoter. This model is a widely recognized and used Alzheimer's disease (AD) research model in the field because it can stably simulate the core pathology of AD (Aβ deposition) and progressive cognitive deficits. Its pathological process is presented in stages:

[0051] (1) Characteristics of Aβ deposition: Initial deposition of β-amyloid protein (Aβ) plaques appears in the brain at 6 months of age, a large number of dense plaques form in the cortex and hippocampus at 9 months of age, and the plaque load reaches a plateau at 12 months of age;

[0052] (2) Cognitive dysfunction: Morris water maze behavioral testing showed that the spatial learning ability of 9-month-old APP / PS1 mice was significantly impaired, as manifested by prolonged escape latency, shortened target quadrant residence time, and decreased memory consolidation ability, which is highly consistent with the characteristics of early cognitive decline in AD patients.

[0053] The experimental groups are as follows:

[0054] 1) Low-dose administration group (i.e., APP / PS1+10 mg / kg Sota group), which was treated by gavage of 10 mg / kg sotagliflozin in corn oil solution to 6-month-old male APP / PS1 double transgenic mice;

[0055] 2) high-dose administration group (i.e., APP / PS1+30 mg / kg Sota group), which was treated by gavage of 30 mg / kg sotagliflozin in corn oil solution to 6-month-old male APP / PS1 double transgenic mice;

[0056] 3) wild-type mouse control group (i.e., WT group), which was treated as follows: 30-week-old male wild-type C57BL-6 mice were intragastrically administered with the same volume of corn oil (purchased from MecChemExpress);

[0057] 4) AD disease model control group (ie, APP / PS1 group): the treatment method was as follows: 6-month-old male APP / PS1 double transgenic mice were gavaged with the same volume of corn oil (purchased from MecChemExpress).

[0058] Specifically, the treatment of mice in each experimental group is as follows:

[0059] Male APP / PS1 mice of similar body weight and age of 6 months were selected and randomly divided into disease model group, low-dose administration group and high-dose administration group, with 8 mice in each group; at the same time, 8 male wild-type C57BL-6 mice of similar body weight and age of 30 weeks were selected as wild-type mouse control group; the low-dose administration group and the high-dose administration group were gavaged daily with 10 mg / kg and 30 mg / kg of sogliflozin solution dissolved in corn oil, respectively, while the wild-type mouse control group and the AD disease model control group were gavaged daily with an equal amount of corn oil for 8 weeks.

[0060] Afterwards, Morris water maze was used to evaluate the spatial memory and learning ability of mice in each group, and brain tissue sampling and related histological tests were performed, as follows:

[0061] 1. Morris water maze test

[0062] A circular pool with a diameter of 100 cm and a height of 60 cm was used, in which a target platform with a diameter of 10 cm was placed in the northeast quadrant, 0.5 cm below the water surface; the water temperature in the pool was controlled at 21±1℃, and black reference objects were posted along the wall of the pool to provide visual reference for the mice.

[0063] The experiment was conducted in two stages: an orientation navigation test (days 1-5) and a spatial exploration test (day 6), which were used to test the learning and memory abilities of mice regarding their sense of spatial position and direction (i.e., spatial orientation).

[0064] During the localization navigation test, the mouse was slowly placed in the water facing the pool wall and allowed to find the hidden platform within 60 seconds. The time required to find the platform was recorded as the escape latency, and the distance from the mouse's entry point to the target exploration path was recorded as the distance to the target platform. If the mouse found the platform within 60 seconds, it was allowed to stay on the platform for 20 seconds; if the mouse failed to find the platform within 60 seconds, it was gently placed on the platform and stayed for 20 seconds. Each mouse was trained 4 times a day. The escape latency of the mouse on each training day was obtained by averaging the results of 4 training sessions.

[0065] During the spatial exploration test, the target platform was removed and each mouse was slowly placed into the water from the southwest quadrant. During the experiment, the mouse's stay time and number of crossings in the quadrant where the target platform was located within 60 seconds were recorded to observe the mouse's spatial learning ability.

[0066] During the entire water maze test, video tracking and analysis were performed using SMART 3 software (Panlab HARVARD, USA).

[0067] The results are as follows Figure 1-5 As shown, where:

[0068] Figure 1 and Figure 2 The data are shown separately for the distance to the target platform and the escape latency of mice in each experimental group during the training phase of the Morris water maze positioning navigation test; it shows that the distance to the target platform and the escape latency of mice in the AD disease model group (i.e., APP / PS1 group) were significantly higher than those in the wild-type mouse control group (i.e., WT group), indicating that the AD model mice were successfully constructed; after AD mice were treated with different doses of sogliflozin, compared with the AD disease model group, the distance to the target platform and the escape latency of mice were significantly shortened in both the low-dose and high-dose groups (P<0.01).

[0069] Figure 3 and Figure 4The figures show the number of crossings and the time the mice in each experimental group stayed in the target quadrant after hiding the target platform in the Morris water maze spatial exploration experiment, which showed that the number of crossings and the time the mice in the AD disease model group (i.e., APP / PS1 group) stayed in the target quadrant were significantly lower than those in the wild-type mouse control group (i.e., WT group), indicating that the AD model mice were successfully constructed; after the AD mice were treated with different doses of sogliflozin, compared with the AD disease model group, the time the mice stayed in the target quadrant and the number of crossings were significantly increased in both the low-dose and high-dose groups, and even reached a level comparable to that of the wild-type control.

[0070] Figure 5 The data show the trajectories of mice in each experimental group in each quadrant in the Morris water maze spatial exploration experiment, after the target platform was hidden, while searching for the target platform in each quadrant. It shows that the trajectories of wild-type mice (i.e., WT group) were mainly concentrated near the target area, and the activity paths were relatively concentrated. In contrast, the activities of AD model mice (i.e., APP / PS1 group) were more dispersed, and the time spent in the target area was reduced, showing a significant decrease in spatial memory ability. The trajectories of mice in the solafloxacin-treated group were more concentrated, and they stayed more near the target area, close to the performance of the WT group. This indicates that solafloxacin can significantly improve the spatial memory ability of APP / PS1 mice, bringing it to a level close to that of normal healthy mice.

[0071] The above results indicate that sogliflozin treatment can significantly improve the spatial memory and learning ability of AD mice, that is, improve the cognitive impairment of mice and enhance their cognitive ability.

[0072] 2. Brain tissue sampling and related histological examination

[0073] (1) Sample collection: After the water maze test, the mice in each experimental group were anesthetized and perfused transcardially with pre-cooled PBS solution. The brain tissue was immediately obtained and fixed in 4% paraformaldehyde at 4°C for 24 h.

[0074] (2) Paraffin sectioning: The fixed brain tissue was sliced ​​at different depths and placed in different concentrations of ethanol and xylene for dewaxing, followed by paraffin embedding. The thickness of the tissue sections after embedding was 5 μm for immunohistochemical staining analysis;

[0075] (3) Immunohistochemical staining: After the paraffin sections were dewaxed again, they were placed in ethanol solutions of different concentrations and treated in turn, and antigen repair was performed with citric acid buffer. After repair, the sections were washed with PBS solution for 3 times, 5 minutes each time. 3% hydrogen peroxide was added and incubated at room temperature for 10 minutes to eliminate endogenous peroxidase activity. The sections were washed with PBS solution again for 3 times, 5 minutes each time. Goat serum was used to block the sections for 1 hour. Anti-Aβ1-42 antibody (as primary antibody) was added and incubated at 4°C overnight. The next day, the sections were washed with phosphate buffer for 3 times, 5 minutes each time. Horseradish peroxidase-labeled secondary antibody was added and incubated at room temperature for 1 hour. Freshly prepared DAB colorimetric solution was added, and the sections were observed under a microscope, and the color development was terminated after rinsing with tap water. Hematoxylin counterstaining solution was added, and the sections were rinsed with tap water after staining for 3 minutes. The sections were then dehydrated to make them transparent and sealed with neutral gum. After sealing, the sections were placed in a ventilated environment to dry, and the images were observed and collected using an Olympus microscope.

[0076] (4) Result analysis: The images collected under the microscope were analyzed using ImageJ software, and the density of β-amyloid plaques per square millimeter was counted. The results were expressed as the average percentage of plaque area per square millimeter.

[0077] The results are as follows Figure 6-8 As shown, where:

[0078] Figure 6 The representative tissue immunostaining results of Aβ plaques in the hippocampus and cerebral cortex of mice in each experimental group are shown; brown particles represent Aβ plaques; Figure 6 It can be seen that there are almost no Aβ plaques in the hippocampus and cerebral cortex of wild-type mice (i.e., WT group). In contrast, a large amount of Aβ plaques were deposited in AD model mice (i.e., APP / PS1 group), which is consistent with the molecular phenotype of AD disease; and the Aβ plaque deposition in the mice in the solafloxacin-treated group was significantly reduced compared with that in the AD model mice. In particular, the Aβ plaque deposition in the high-dose treatment group was close to that in the WT group, which shows that solafloxacin can significantly reduce the Aβ plaques in the brain tissue of AD mice, bringing it to a level close to that of normal healthy mice.

[0079] Figure 7 and Figure 8 The Aβ plaque density per square millimeter in the hippocampus and cerebral cortex of mice in each experimental group is shown respectively; Figure 7 and Figure 8 It can be seen that compared with the AD model mice (i.e., APP / PS1 group), the density of Aβ plaques in the hippocampus and cerebral cortex of the mice in the solafloxacin-treated group was greatly reduced; these results indicate that solafloxacin can significantly inhibit the deposition of β-amyloid protein plaques in the mouse brain.

[0080] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. Use of sogliflozin or a pharmaceutically acceptable derivative thereof in the preparation of a medicament for preventing and / or treating Alzheimer's disease.

2. The use according to claim 1, characterized in that The pharmaceutically acceptable derivative of sogliflozin is a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

3. The use according to claim 2, characterized in that: The prodrug of solafloxacin is a drug that can be converted into solafloxacin in a living body.

4. The use according to claim 2, characterized in that: The salt of sogliflozin is a salt type selected from the following: hydrochloride, nitrate, sulfate, phosphate, bromate, hydrobromide, citrate, formate, acetate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, benzoate, phthalate, malonate, maleate, perchlorate, fumarate, succinate, tartrate, lactate, gluconate, pamoate, aspartate or glutamate.

5. The use according to any one of claims 1 to 4, characterized in that: The treatment of Alzheimer's disease includes one or more of the following: (1) Delaying the progression of Alzheimer's disease; (2) Improve symptoms caused by Alzheimer's disease; Preferably, the treatment of Alzheimer's disease is to improve the cognitive function of Alzheimer's patients, preferably including alleviating, relieving or reversing memory loss or cognitive dysfunction caused by Alzheimer's disease.

6. The use according to any one of claims 1 to 5, characterized in that: The prevention and / or treatment of Alzheimer's disease is achieved through the following mechanism: reducing the deposition of β-amyloid protein in brain tissue, preferably reducing the deposition of β-amyloid protein in the cerebral cortex and / or hippocampus.

7. The use according to any one of claims 1 to 6, characterized in that: The medicine comprises a preventive and / or therapeutically effective amount of sogliflozin or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier and / or excipient.

8. The use according to claim 7, characterized in that The effective preventive amount of sogliflozin or a pharmaceutically acceptable derivative thereof is 8-12 mg / kg body weight, preferably 10 mg / kg body weight, and the effective therapeutic amount is 20-40 mg / kg body weight, preferably 30 mg / kg body weight.

9. The use according to any one of claims 1 to 8, characterized in that The administration method of the drug is one or more selected from the following: oral administration, injection, implantation, spraying and / or inhalation; Preferably, the drug is administered orally.

10. The use according to any one of claims 1 to 8, characterized in that The dosage form of the drug is an oral preparation, preferably selected from the following: tablets, granules, powders, capsules or liquids.

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