Application of Zhongwuning in preparation of anti-aging drugs

Abstract

The application belongs to the technical field of new use of medicines, and provides application of Zhongwuning in preparation of anti-aging medicines. It is proved through experimental research that Zhongwuning can play an anti-aging role in multiple ways. Zhongwuning can significantly increase the spleen and thymus coefficients of D-galactose-induced aging model mice, significantly reduce the MDA content activity of D-galactose-induced aging model mice, and improve the activities of SOD and GSH-Px of D-galactose-induced aging model mice. Zhongwuning can significantly reduce the body inflammation level, significantly reduce the LPO and LF contents and the MAO-B activity in the brain tissue of D-galactose-induced aging model mice, and slow down the loss of hydroxyproline and hyaluronic acid in the aging skin of D-galactose-induced aging model mice. The Morris water maze experiment test results show that Zhongwuning has the effect of improving the learning and memory abilities of the aging model mice. Therefore, Zhongwuning has a certain application prospect in preparation of anti-aging medicines.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of new use of drugs, in particular, relates to the application of mesaconine in the preparation of anti-aging drugs. BACKGROUND

[0002] Biologically, aging is a spontaneous and inevitable process of living things with time, which is a complex natural phenomenon, showing structural degeneration and functional decline, and reduced adaptability and resistance. Physiologically, aging is regarded as the history of individual development from the zygote to old age. Pathologically, aging is the result of stress and strain, injury and infection, immune response decline, nutritional disorders, metabolic disorders, and accumulation of negligence and misuse of drugs. In addition, from a sociological point of view, aging is a personal loss of interest in new things, detachment from reality, and preference for nostalgia.

[0003] Among the many factors of aging, oxidative stress damage caused by free radicals and insufficient blood supply to the brain are two very important factors.

[0004] Oxidative stress damage refers to the occurrence of abnormal oxygen metabolism in the body, resulting in a large number of free radicals in the body. These free radicals can damage cells, proteins and DNA, leading to aging, and can also cause diseases such as diabetes, arteriosclerosis and Alzheimer's disease, which are harmful to the body. In addition, arteriosclerosis and cerebral thrombosis can increase cerebral circulation resistance and slow down cerebral blood flow, resulting in a decrease in cerebral blood supply and oxygen supply, and a large accumulation of oxygen free radicals and excitatory amino acids in brain cells, which can cause delayed damage and brain cell degeneration, affecting learning, memory and behavior function.

[0005] In recent years, drug anti-aging has become a hot topic in the field of aging. Metformin, rapamycin and other drugs have been proven to significantly delay the aging process and prevent aging-related diseases, and drug anti-aging has become increasingly important for human health. However, chemical drugs have many adverse reactions, are specific to targets, and are resistant to many drugs, making their scientific nature of oxygen resistance and anti-aging controversial. Natural drugs have a long history and are an important source of drug lead compounds and synthetic drugs, with fewer side effects and a wide range of effects. With the development of science and technology, experimental research on natural drugs is increasing, and the pharmacological effects are gradually becoming clear.

[0006] Mesaconine (CAS NO.: 6792-09-2; molecular formula: C 24 H 39NO9) is a new alkaloid with medicinal value, and its chemical structure is clear. It can be obtained by raw material extraction or chemical synthesis. The middle Wu Ning has obvious effect of improving heart function, and can effectively prevent and treat or improve acute heart failure caused by myocardial ischemia reperfusion injury. However, the middle Wu Ning has not been reported for anti-aging treatment or improvement. SUMMARY

[0007] In view of the above deficiencies in the prior art, the purpose of the present application is to provide the application of the middle Wu Ning in the preparation of anti-aging drugs. Research has proved that the middle Wu Ning can play an anti-aging role in many ways. It can significantly increase the spleen and thymus coefficients of D-galactose-induced aging model mice, significantly reduce the activity of malondialdehyde (MDA) content in mice, improve the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in mice, reduce the inflammation level of the body, reduce the content of peroxidized lipid (LPO) and lipofuscin (LF) in the brain tissue of mice, and reduce the content and activity of B-type monoamine oxidase (MAO-B); and can slow down the loss of hydroxyproline and hyaluronic acid in the aging skin of D-galactose-induced aging model mice. The test results of Morris water maze experiment show that the middle Wu Ning has the effect of improving the learning and memory ability of the aging model mice. Therefore, the middle Wu Ning has a certain application prospect in the preparation of anti-aging drugs.

[0008] In order to achieve the above purpose, the solution adopted by the present application is:

[0009] The application of the middle Wu Ning or its pharmaceutically acceptable salt in the preparation of anti-aging drugs.

[0010] Further, in the preferred embodiment of the present application, the anti-aging drug is a preparation prepared by taking the middle Wu Ning or its pharmaceutically acceptable salt as the active ingredient, and adding pharmaceutically common excipients or auxiliary ingredients.

[0011] Further, in the preferred embodiment of the present application, the pharmaceutically acceptable salt is an inorganic salt or an organic salt.

[0012] Further, in the preferred embodiment of the present application, the dosage form of the preparation includes liquid preparation, solid preparation or semi-solid preparation.

[0013] The application of the middle Wu Ning in the preparation of anti-aging drugs provided by the present application has the following beneficial effects:

[0014] The present application first discovers the application of the middle Wu Ning in the preparation of anti-aging drugs. Research has proved that:

[0015] (1) The middle Wu Ning can significantly improve the spleen and thymus coefficients of D-galactose-induced aging model animals;

[0016] (2) Zhong-Wuning can significantly reduce the content of MDA in the brain tissue of the D-galactose-induced aging model animals, and improve the activities of SOD and GSH-Px;

[0017] (3) Zhong-Wuning can significantly reduce the content of interleukin 1β (IL-1β) and tumor necrosis factor-α (TNF-α) in the serum of the D-galactose-induced aging model animals, and has a strong inhibitory effect on the secretion of inflammatory cytokines;

[0018] (4) Zhong-Wuning can significantly reduce the content of LPO and LF in the tissues of the D-galactose-induced aging model animals, and the activity of MAO-B;

[0019] (5) Zhong-Wuning can slow down the loss of hydroxyproline and hyaluronic acid in the aging skin of the D-galactose-induced aging model mice;

[0020] (6) The results of the Morris water maze experiment show that Zhong-Wuning has the effect of improving the learning and memory ability of the aging model mice.

[0021] The above test results show that Zhong-Wuning has application prospects in the preparation of anti-aging drugs. BRIEF DESCRIPTION OF DRAWINGS

[0022] Figure 1 is a comparison chart of the content of IL-1β in the serum samples of the mice in each group provided in Experimental Example 1 of the present application;

[0023] Figure 2 is a comparison chart of the content of TNF-α in the serum samples of the mice in each group provided in Experimental Example 1 of the present application;

[0024] Figure 3 is a comparison chart of the content of hydroxyproline in the skin of the mice in each group provided in Experimental Example 1 of the present application;

[0025] Figure 4 is a comparison chart of the content of hyaluronic acid in the skin of the mice in each group provided in Experimental Example 1 of the present application. DETAILED DESCRIPTION

[0026] In order to make the purpose, technical scheme and advantages of the embodiments of the present application more clear, the technical scheme in the embodiments of the present application will be clearly and completely described below. If the specific conditions are not specified in the embodiments, the conventional conditions or the conditions suggested by the manufacturers are adopted. If the manufacturers of the reagents or instruments are not specified, they are all conventional products that can be purchased in the market.

[0027] The features and performances of the present application will be further described in detail below in combination with the embodiments.

[0028] Embodiment 1

[0029] 1. Experimental animals: ICR mice, half male and half female, body weight 18-22 g, provided by Chengdu Dasuo Biological Technology Co., Ltd., production license number: SCXK (Chuan) 2015-030.

[0030] 2. Experimental method

[0031] 2.1 Animal modeling and grouping

[0032] Take 40 ICR mice, half male and half female, of which 10 are taken as normal control group, and 30 mice are randomly divided into three groups: (1) model group: distilled water; (2) positive group: longevity tablets (provided by Dali Bai Autonomous Prefecture Chinese Medicine Pharmaceutical Co., Ltd.), 0.702 g / kg; (3) Zhongwuning group (Zhongwuning is provided by Good Doctor Pharmaceutical Group Co., Ltd.): Zhongwuning, 6.7 mg / kg. All mice are fed with ordinary feed. Except for the normal control group, the rest of the animals are injected subcutaneously with 5% D-galactose, 0.5 mL per mouse, for 6 consecutive weeks, to cause aging model. The required concentration of each drug is prepared, and at the same time of modeling, each group of animals is given oral administration, once a day, for 6 consecutive weeks.

[0033] 2.2 Measurement index and method

[0034] 2.2.1 Organ index: 1 hour after the last administration, the animal eyeball is taken blood, centrifuged at 5000xg for 15 min at 4°C to obtain serum, and the animal is euthanized. The spleen and thymus are weighed and the organ index is calculated.

[0035] 2.2.2 The content and activity of MDA, SOD and GSH-Px are determined according to the instructions of the biochemical kit (Kit, Nanjing Jiancheng Biological Engineering Institute, Batch No.: 20160607).

[0036] 2.2.3 IL-1β and TNF-α in mouse serum samples are determined according to the instructions of the ELISA kit (Suzhou Calvin Biological Technology Co., Ltd., Batch No.: E20170201A).

[0037] 2.2.4 The left brain tissue of the animal is taken to make homogenate, and the content and activity of LPO, LF and MAO-B are determined according to the instructions of the ELISA kit (ELISA) detection kit, Suzhou Calvin Biological Technology Co., Ltd., Batch No.: E20170201A).

[0038] 2.2.5 After the mouse dorsal skin is depilated, about 1 cm 2 of skin tissue (avoiding the introduction of white adipose tissue) is taken and quickly frozen in liquid nitrogen; a small piece of mouse skin tissue is used to remove fat with acetone-ether (1:1), cut into small pieces, air dry, then accurately weigh 20 mg, and determine the levels of hydroxyproline and hyaluronic acid in the sample according to the instructions of the mouse hyaluronic acid and hydroxyproline kit.

[0039] 2.3 Statistical method: The experimental data were analyzed by SPSS 18.0 statistical software, and the data results were expressed as mean ± standard deviation (x ± s). The single factor analysis of variance was used for comparison among multiple groups, and the SNK method was used for pairwise comparison among multiple groups. P <0.05 was considered statistically significant.

[0040] 3. Experimental results

[0041] (1) Table 1 is the organ index of each group of mice:

[0042] Table 1 Organ index of each group of mice

[0043] Group number Spleen (g / 100g BW) Thymus (g / 100g BW) Normal control group 0.452±0.062 0.139±0.022 Model group 0.275 ± 0.035 # ]] 0.084 ± 0.018 ## ]] Positive group 0.393 ± 0.071 * ]] 0.133 ± 0.031 ** ]] Zhongwuning group 0.382 ± 0.052 * ]] 0.125 ± 0.022 ** ]]

[0044] Note: Compared with the normal control group, # P <0.05, ## P <0.01; compared with the model group, * P <0.05, ** P <0.01.

[0045] The thymus is the central organ of immune regulation, and plays an important role in the cellular immune function of the body and the occurrence of immune response. The spleen is the largest peripheral immune organ, which provides a settlement site for various mature lymphocytes and immune response. Aging of the body can lead to lighter thymus and spleen weight, and thymus and spleen coefficient can indirectly reflect the degree of aging of the body.

[0046] Table 1 data show that compared with the normal control group, the spleen and thymus coefficients of the model group animals were significantly reduced (P <0.01); compared with the model group, the positive group used the longevity tablets to significantly increase the spleen coefficient (P <0.05) and thymus coefficient (P <0.01), and the effect of the middle Wu Ning group on improving the spleen coefficient and thymus coefficient was close to the positive group, which was significantly improved compared with the model group.

[0047] (2) Table 2 is the MDA content, SOD and GSH-Px activity in the serum of each group of mice.

[0048] Group number MDA (nmol / mL) SOD (U / mL) GSH-Px (mg / L) Normal control group 3.50±0.79 210.25±31.45 120.67±18.18 Model group 9.21 ± 0.88 ## ]] 116.24 ± 30.07 ## ]] 61.76 ± 11.81 ## ]] Positive group 6.25 ± 0.67 * ]] 140.83 ± 27.66 * ]] 85.71 ± 11.12 * ]] Zhongwuning group 7.04 ± 0.55 * ]] 135.66 ± 28.16 * ]] 82.33 ± 13.62 * ]]

[0049] Note: Compared with the normal control group, ## P <0.01; compared with the model group, * P <0.05.

[0050] MDA is a product of lipid peroxidation in cells, and is an important indicator of oxidative stress. In cells, lipid peroxidation reaction generates MDA, and MDA is a highly reactive metabolic product that can covalently bind to intracellular proteins, nucleic acids and other biological molecules, resulting in cell function impairment and inflammatory response. Therefore, by determining the content of MDA, it can be determined whether the degree of oxidative stress in the individual cells is increased, thereby predicting the risk of related diseases, and for evaluating the antioxidant capacity and therapeutic effect of drugs. The content of MDA in the brain tissue of cerebral ischemia rats increases sharply.

[0051] SOD belongs to the antioxidant enzyme system, and is praised by the World Health Organization as the most promising drug enzyme in the 21st century. It is the first killer of oxygen free radicals in the body, and is the scavenger in the human body. It can convert superoxide anions into harmless oxygen and hydrogen peroxide, thereby eliminating harmful free radicals, improving abnormal blood lipids, preventing atherosclerosis, preventing the occurrence of cardiovascular diseases, and eliminating tissue cell lipid peroxidation, thereby delaying aging.

[0052] GSH-Px is an important peroxide decomposing enzyme widely existing in the body. Its physiological function is mainly to catalyze GSH to participate in peroxidation reaction, eliminate peroxide and hydroxyl radicals generated in the process of cell respiration metabolism, thereby reducing the peroxidation of cell membrane polyunsaturated fatty acids. The body can effectively eliminate lipid peroxide and other active oxygen through GSH-Px enzymatic reaction and terminate the free radical chain reaction, thereby preventing the damage of lipid peroxidation.

[0053] The D-galactose-induced aging model is very similar to the natural aging model of human beings. The data in Table 2 show that the MDA content of the brain tissue of animals treated with D-galactose increases (P<0.01), and the activities of SOD and GSH-Px decrease (P<0.01) in the model group.

[0054] The data in Table 2 show that compared with the model group, the positive group using the longevity tablet can significantly reduce the MDA content (P<0.05), and increase the activities of SOD and GSH-Px (P<0.05). The effect of reducing the MDA content and increasing the activities of SOD and GSH-Px of the middle Wu Ning group is close to that of the positive group, and compared with the model group, it has a significant increase (P<0.05).

[0055] (3) Chronic inflammation is one of the culprits that accelerate the aging of the body, the body with high levels of inflammatory cytokines. In the inflammatory state, the activity of matrix metalloproteinases increases, resulting in increased degradation of extracellular matrix. IL-1β is the abbreviation of interleukin 1β, is a cytokine, mainly in the immune response and inflammation play an important role. IL-1β is a typical pro-inflammatory cytokines, can induce IL-6, TNF-α and other inflammatory cytokines release and stimulate T cell activation, can stimulate local and systemic inflammatory response. TNF-α generally refers to tumor necrosis factor-α, tumor necrosis factor-α if the increase, usually indicate that the patient's body may be present inflammatory reaction or tumor lesions. Tumor necrosis factor-α is a phenotype of tumor necrosis factor, mainly from monocytes and phagocytes, can cause tumor tissue hemorrhage, necrosis, and will have the effect of killing, but also can cause anti-inflammatory effects of inflammatory response, and play an important role in the regulation of immune cells.

[0056] Figure 1 and Figure 2 The results showed that, compared with the normal control group of mice, the model group of mice inflammatory cytokines IL-1β, TNF-α levels were significantly increased (P<0.01), indicating that the model group of mice in the body with high levels of inflammation (compared with the normal control group, model group P<0.01).

[0057] After the intragastric administration of Zhongwuning group and positive group, the concentration of IL-1β, TNF-α in the serum of mice was significantly reduced (compared with the model group, P<0.01); further illustrate the Zhongwuning group on the secretion of inflammatory cytokines has a strong inhibitory effect. Zhongwuning has the effect of reducing the level of inflammation in the body.

[0058] (4) Table 3 is the content of LPO, LF and MAO-B activity in brain tissue of mice in each group:

[0059] Table 3 LPO, LF content and MAO-B activity in brain tissue of mice in each group

[0060] Group number LPO (nmol / mL) LF (ng / mL) MAO-B (U / mL) Normal control group 24.66±1.15 18.82±2.22 28.21±1.08 Model group 32.15 ± 1.33 # ]] 23.96 ± 2.03 # ]] 39.27 ± 1.56 # ]] Positive group 26.23 ± 1.53 * ]] 19.45 ± 2.88 * ]] 29.49 ± 1.82 * ]]> Zhongwuning group 27.05 ± 1.42 * ]] 20.02 ± 2.33 * ]] 30.52 ± 1.66 * ]]

[0061] Note: compared with the normal control group, # P<0.05; compared with the model group, * P<0.05.

[0062] LF is also known as senile, its accumulation increases with age, is one of the important indicators of aging. Deposition in the nerve, myocardium, liver and other tissues of senile cells in the yellow-brown irregular small body, the contents of electron density of the material, lipid droplets, vesicles, etc., is the residual body formed after the action of lysosomes can no longer be digested.

[0063] MAO-B is also called aging enzyme. The activity of monoamine oxidase in the brain increases with age, so its activity is closely related to aging. It widely exists in the liver, kidney, brain and other regions of the body, and is the main enzyme for inducing the metabolism of monamine substances in the body.

[0064] LPO is the product of the reaction of oxygen free radicals with polyunsaturated fatty acids. Under normal circumstances, the content of LPO is very low. When the body is damaged by free radicals and pathological changes occur or as the age increases, the lipid peroxidation reaction is enhanced, which can lead to the increase of LPO. Therefore, LPO can be one of the markers of aging of the body.

[0065] The data in Table 3 show that, compared with the normal control group, the contents of LPO and LF in the brain tissue of the model group and the activity of MAO-B were significantly increased (P<0.05); compared with the model group, the use of the longevity tablet in the positive group can significantly reduce the contents of LPO and LF in the brain tissue and the activity of MAO-B (P<0.05), and the effect of the middle-wuning group on reducing the contents of LPO and LF and the activity of MAO-B is close to that of the positive group, which has a significant decrease compared with the model group (P<0.05).

[0066] (5) In the process of aging of the body, the antioxidant system of the body decreases. Human aging is accompanied by a decrease in the content of collagen and hyaluronic acid in the skin.

[0067] Figure 3 and Figure 4 The results show that D-galactose treatment significantly reduces the contents of hydroxyproline and hyaluronic acid in the skin of the model group (P<0.01), and accelerates the aging of the skin. After the intragastrical administration of the middle-wuning group and the positive group, the loss of hydroxyproline and hyaluronic acid in the aging skin of the D-galactose-induced aging model mice can be slowed down.

[0068] Example 2

[0069] 1. Experimental animals: same as example 1.

[0070] 2. Experimental method:

[0071] 2.1 Animal modeling and grouping and administration

[0072] The same as example 1.

[0073] 2.2 Measurement index and method

[0074] After the administration, on the second day, all the mice were subjected to continuous Morris water maze test, and the positioning navigation experiment and spatial exploration experiment were performed in turn.

[0075] All mice were moved into the room for behavioral experiments 1 hour before the experiment every day to adapt to the environment of the room; 5Morris water maze experiment used a Morris water maze instrument, which included a movable platform and a water pool. The bottom and four walls of the pool were dyed white, and a certain amount of titanium dioxide was poured into the water in the pool in advance to hide the platform. A camera connected to a computer was installed directly above the pool to record the complete swimming trajectory of the mouse within a certain time and automatically calculate the total distance, time, swimming speed, and time required to find the platform.

[0076] Position navigation experiment: training 2 times a day, 1 time in the morning and 1 time in the afternoon, the mouse was put into the water from a fixed water entry point, and the time required for the mouse to find the hidden platform under the water was recorded. The result is the escape latency. If the mouse fails to find the platform within 60 seconds, the experimenter will guide the mouse to the hidden platform under the water and let it stand on the platform for 15 seconds to observe the surrounding environment, and the latency is recorded as 60 seconds.

[0077] Spatial exploration experiment: the position navigation experiment lasted for 5 days, and on the 6th day, the hidden platform in the water was removed, and any position in the pool was fixed as the water entry point for the experiment. Let the mouse swim and explore in the pool to find the platform for 60 seconds, and record its escape latency during the experiment, the total swimming time in the quadrant where the original platform was located, and the number of times it crossed the original platform location.

[0078] 2.3 Statistical method: The experimental data were analyzed by SPSS 25.0 statistical software. The comparison of means between multiple groups used one-way ANOVA, and the comparison between two groups used t-test. P<0.05 was considered statistically significant.

[0079] 3. Experimental results

[0080] (1) The results of the position navigation experiment are shown in Table 4:

[0081] Table 4 Latency of mice in the position navigation experiment

[0082] Group number First day Second day Third day Fourth day Fifth day Normal control group 55.2±1.6 49.3±1.3 35.6±1.8 28.4±1.0 20.6±2.0 Model group 63.0±1.0 57.2±1.6 54.6±1.2 55.1 ± 1.6 ## ]] 52.3 ± 2.1 ## ]] Positive group 62.1±1.2 54.4±1.3 48.3±1.5 39.1±1.2 35.5 ± 1.6 ** ]] Zhongwuning group 61.2±1.1 52.1±1.4 45.3±1.0 30.2±1.3 21.5 ± 1.6 ** ]]

[0083] Note: Compared with the normal control group, ## P<0.01; compared with the model group, ** P<0.01.

[0084] The results in Table 4 show that as the training time increases, the time for the mice in each group to find the platform gradually shortens, except for the model group. Compared with the normal control group, the latency of the mice in the model group to find the platform on the 4th and 5th days of training was significantly prolonged (P<0.01).

[0085] Compared with the model group, the latency of the mice in the medium Wu Ning group and the positive group to find the platform was significantly shortened on the 3rd day of training, and the latency of the mice in the medium Wu Ning group and the positive group to find the platform was significantly shortened on the 5th day of training, with a statistically significant difference (P<0.01).

[0086] (2) The results of the spatial exploration experiment are shown in Table 5:

[0087] Table 5 Latency and crossing times of mice in each group in the spatial exploration experiment

[0088]

[0089]

[0090] Note: Compared with the normal control group, # P<0.05, ## P<0.01; compared with the model group, * P<0.05, ** P<0.01.

[0091] The results in Table 5 show that, compared with the normal control group, the latency of the mice in the model group to find the platform was significantly shortened (P<0.01), the number of times of crossing the original platform was reduced (P<0.05), and the swimming distance was short.

[0092] Compared with the model group, the latency of the mice in the medium Wu Ning group and the positive group to find the platform was significantly shortened, the latency of the mice in the medium Wu Ning group and the positive group to find the platform was significantly shortened (P<0.01), the swimming distance was extended, and the number of times of crossing the escape platform was increased (P<0.05).

[0093] In summary, the study confirmed that medium Wu Ning can play an anti-aging role in multiple ways. It can significantly increase the spleen and thymus coefficients of D-galactose-induced aging model mice, significantly reduce the MDA content activity of D-galactose-induced aging model mice, and improve the activities of SOD and GSH-Px of D-galactose-induced aging model mice. It can significantly reduce the body inflammation level, significantly reduce the LPO, LF content and MAO-B activity in the brain tissue of D-galactose-induced aging model mice, and improve the learning and memory ability of the mice. The learning and memory ability of the mice in the medium Wu Ning group was better than that of the mice in the model group, the latency was shortened, and the number of times of crossing the platform and the effective area was increased. The experiment confirmed that medium Wu Ning can improve the learning and memory ability of the aging model mice. Therefore, medium Wu Ning has a certain application prospect in the preparation of anti-aging drugs.

[0094] The above merely provides the preferred embodiments of the present application, and is not used to limit the present application. For those skilled in the art, the present application can have various modifications and changes. Any modifications, equivalent replacements, improvements, etc. made within the principles and technical scope of the present application shall fall into the scope of the present application.

Claims

1. The use of quinine or its pharmaceutically acceptable salts in the preparation of medicaments for improving age-related decline in learning and / or memory.

2. The application according to claim 1, characterized in that: The drug for improving age-related decline in learning and / or memory is a preparation made with zhongwuning or its pharmaceutically acceptable salt as the active ingredient, plus commonly used pharmaceutical excipients or auxiliary ingredients.

3. The application according to claim 2, characterized in that: The pharmaceutically acceptable salt is either an inorganic salt or an organic salt.

4. The application according to claim 2, characterized in that: The dosage form of the preparation includes liquid preparations, solid preparations, or semi-solid preparations.

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