Use of Zheng Chaihu Yin medicinal composition or its preparation in preparing medicine for preventing or treating depression

Abstract

The present invention relates to the field of medical use, and specifically to the use of a Zheng Chaihu Yin pharmaceutical composition or a preparation thereof in the preparation of a drug for preventing or treating depression, wherein the Zheng Chaihu Yin pharmaceutical composition comprises bupleurum, dried orange peel, saposhnikovia, red peony root, liquorice and ginger. The present invention has found that the Zheng Chaihu Yin pharmaceutical composition or a preparation thereof (such as Zheng Chaihu Yin granules) is used for the treatment of depression, and the study has found that the Zheng Chaihu Yin granules can significantly improve the anxiety level of mice in an open field test, improve the despair behavior of mice in a tail suspension test, and reduce the behavioral despair level of mice in a forced swimming test.

Description

Technical Field

[0001] The present invention relates to the field of medical applications, and in particular to application of a Zheng Chaihu Yin medicinal composition or a preparation thereof in preparing a medicine for preventing or treating depression. Background Art

[0002] Depression is a common mental disorder characterized by significant and persistent low mood, accompanied by loss of interest and pleasure, which often affects an individual's work, study and social functions. Depression may be caused by multiple factors, including genetic, biological, psychosocial and environmental factors. "Persistent low mood, loss of interest and pleasure for at least two weeks" is its core criterion, accompanied by typical related symptoms, such as fatigue, difficulty concentrating, feelings of worthlessness or excessive self-blame, changes in diet, sleep, weight and other physical conditions (such as weight loss, poor sleep quality), etc. Clinical depression has greater intensity and longer duration, is more difficult to cope with than ordinary sadness, and causes far more damage than ordinary sadness. Clinical depression may affect people's ability to work, go to school, take care of children or maintain interpersonal relationships.

[0003] According to WHO statistics, about 3.8% of the world's population suffers from depression, including 5% of adults (4% of men and 6% of women) and 5.7% of people over 60 years old, a total of about 280 million people. Women are about 50% more likely to suffer from depression than men.

[0004] Depression is a group of clinical syndromes or states centered on the self-experience of depressed mood. The clinical manifestations are depressed mood, slow thinking, slow speech and movement, accompanied by symptoms such as poor appetite and sleep. There is no name for depression in ancient Chinese medical books. According to the symptoms, it is classified as a depression, and the disease is located in the liver. Chinese medicine believes that the liver is a rigid organ, which likes to be smooth and hates depression, and is responsible for dredging. Mental, emotional, psychological behavior are closely related to the liver's dredging function. When the liver's dredging function is stimulated by various stimuli, the liver loses its smoothness, and the qi is stagnant, then there will be depression, boredom, sensitivity and suspicion, and other emotional depression symptoms. The spleen is the foundation of the acquired constitution. Liver blood depends on the spleen's transportation and transformation of water and grain essence for survival, and the spleen's transportation and transformation depends on the liver's dredging, and the two affect each other. If the liver fails to dredge, the liver qi is stagnant, and the spleen fails to function properly, dizziness, poor appetite, and abdominal distension will occur. Qi stagnation will cause blood stasis, and qi disease and blood disease can cause symptoms such as lower abdominal pain, flank pain, and abdominal distension. Liver depression can easily turn into fire and generate phlegm over time, causing fire depression and phlegm coagulation, disturbing the clear mind, causing insomnia, dreaminess, etc. The symptoms of depression are complex and changeable, and its basic pathogenesis is liver qi stagnation.

[0005] Most of the drugs used to treat depression are chemical drugs, which have significant toxic side effects after long-term use, and have defects such as easy relapse, narrow antidepressant spectrum, and slow onset of action. Traditional Chinese medicine treatment has the advantages of mild prescription effects and few adverse reactions. In addition, Chinese medicine has complex action links, multiple compound ingredients, and multiple targets, and generally uses the effects of multiple links to produce synergistic reactions.

[0006] Chaihuyin granules are antipyretic agents with the effects of dispelling wind and cold, relieving fever and relieving pain. In the formula, Chaihu dispels heat and relieves fever, and is the main drug. Saposhnikovia dispels wind, overcomes dampness and relieves pain; ginger induces sweating and relieves the exterior, warms the lungs and relieves cough, and is the assistant drug. Red peony root clears heat and cools blood; tangerine peel regulates qi and strengthens the spleen, and is the adjuvant drug. Licorice harmonizes the drugs, and is the guiding drug. The whole formula has the effects of dispelling wind and cold, relieving fever and relieving pain. It is mainly used clinically for fever, chills, no sweating, headache, nasal congestion, sneezing, itchy throat and cough, and pain in the limbs caused by exogenous wind and cold; initial influenza and mild upper respiratory tract infection with the above symptoms. There are no reports on the treatment of depression. Summary of the invention

[0007] Therefore, the object of the present invention is to provide a new use of the Zheng Chaihu Yin pharmaceutical composition or its preparation, namely, the use of the Zheng Chaihu Yin pharmaceutical composition or its preparation in the preparation of a drug for preventing or treating depression.

[0008] To this end, the present application provides the use of the Zheng Chaihu Yin pharmaceutical composition or its preparation in the preparation of a drug for preventing or treating depression.

[0009] Furthermore, the Zheng Chaihu Yin medicinal composition includes bupleurum, tangerine peel, siler, red peony root, liquorice and ginger.

[0010] Furthermore, in terms of weight, the Zheng Chaihu Yin medicinal composition includes 80-150 parts of bupleurum, 80-150 parts of dried tangerine peel, 70-90 parts of siler, 30-50 parts of liquorice, 130-170 parts of red peony root and 60-80 parts of ginger.

[0011] Preferably, in parts by weight, the ingredients include 100 parts of bupleurum, 100 parts of dried tangerine peel, 80 parts of siler, 40 parts of liquorice, 150 parts of red peony root and 70 parts of ginger.

[0012] Furthermore, the preparation uses the Zheng Chaihu Yin pharmaceutical composition or an extract of the Zheng Chaihu Yin pharmaceutical composition as an active ingredient, with or without the addition of pharmaceutically acceptable excipients, and is prepared according to conventional processes in the art.

[0013] The Zheng Chai Hu Yin pharmaceutical composition or its preparation can be prepared in-house according to conventional methods in the art, or purchased from Jinghua Pharmaceutical Group Co., Ltd. For example, Zheng Chai Hu Yin granules.

[0014] Furthermore, the preparation method of the extract of the Zhengchaihu Yin pharmaceutical composition comprises: taking the Zhengchaihu Yin pharmaceutical composition, decocting with water, concentrating, adding ethanol and allowing to stand, filtering, recovering ethanol from the filtrate, and concentrating to obtain the extract.

[0015] Furthermore, the pharmaceutically acceptable excipients include one or several of fillers, disintegrants, lubricants, suspending agents, binders, sweeteners, flavoring agents, and preservatives.

[0016] Furthermore, the dosage form of the drug is a liquid preparation or a solid preparation; preferably, the solid preparation includes powder, tablets, capsules, granules or pills; the liquid preparation includes injections, mixtures, syrups or suspensions.

[0017] Furthermore, the depression is mild depression or moderate depression.

[0018] The technical solution of the present invention has the following advantages:

[0019] The present invention for the first time uses the Zhengchaihu Yin pharmaceutical composition or its preparation (such as Zhengchaihu Yin granules) for the treatment of depression, and it is found that Zhengchaihu Yin granules can significantly improve the anxiety level of mice in the open field test, improve the despair behavior of mice in the tail suspension test, and reduce the behavioral despair level of mice in the forced swimming test. Description of the Drawings

[0020] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following will briefly introduce the drawings required for the description of the specific embodiments or the prior art. Obviously, the following drawings are some embodiments of the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts.

[0021] Figure 1 is the activity time of each group of mice in the central area of the open field test;

[0022] Figure 2 is the percentage of the immobile time in the total time of each group of mice in the tail suspension test;

[0023] Figure 3 is the percentage of the immobile time in the total time of each group of mice in the forced swimming test;

[0024] Among them, Figure 1-3 in, ** indicates p < 0.01, * indicates 0.01 < p < 0.05, and ns indicates p > 0.05. Detailed Embodiments

[0025] The following examples are provided for a better understanding of the present invention, but are not intended to limit the best mode of implementation, nor to limit the content and protection scope of the present invention. Any product identical or similar to the present invention obtained by anyone under the inspiration of the present invention or by combining the features of the present invention with other prior arts shall fall within the protection scope of the present invention.

[0026] If no specific experimental steps or conditions are specified in the examples, the conventional experimental steps or conditions described in the literature in the field can be used. If no manufacturer is specified for the reagents or instruments used, they are all conventional reagent products that can be obtained commercially.

[0027] Example 1

[0028] The pharmaceutical composition of Zheng Chaihu Yin in this embodiment includes the following raw materials:

[0029] 100g of bupleurum, 100g of dried tangerine peel, 80g of saposhnikovia divaricata, 40g of licorice, 150g of red peony root and 70g of ginger.

[0030] The Zheng Chaihu Yin granules of this embodiment contain the above raw materials, and the preparation method is as follows: the above six ingredients are decocted twice with water, each time for 1.5 hours, and the decoctions are combined. Filter, concentrate the filtrate to a relative density of 1.10-1.20 (50°C), add ethanol to make the alcohol content reach 50%, stir, stand overnight, filter, recover ethanol from the filtrate, and concentrate to a clear paste with a relative density of 1.25-1.30 (50°C), take 1 part of the clear paste, 2 parts of sucrose, and 1.5 parts of dextrin, mix well, make granules, dry below 80°C and granulate, make granules, and obtain.

[0031] Example 2

[0032] The pharmaceutical composition of Zheng Chaihu Yin in this embodiment includes the following raw materials:

[0033] 80g of bupleurum, 150g of dried tangerine peel, 70g of saposhnikovia root, 50g of licorice, 130g of red peony root and 80g of ginger.

[0034] The Zheng Chai Hu Yin mixture of this embodiment contains the above raw materials, and the preparation method is as follows: the above six ingredients are decocted twice with water, each time for 1.5 hours, and the decoctions are combined, filtered, and the filtrate is concentrated to obtain the mixture.

[0035] Example 3

[0036] The pharmaceutical composition of Zheng Chaihu Yin in this embodiment includes the following raw materials:

[0037] 150g of Bupleurum, 80g of Tangerine Peel, 90g of Saposhnikovia, 30g of Licorice, 170g of Red Peony Root and 60g of Ginger.

[0038] The Zheng Chaihu Yin granules of this embodiment contain the above-mentioned raw materials, and the preparation method is as follows: the above six flavors are decocted twice with water, each time for 1.5 hours, and the decoctions are combined. Filter, concentrate the filtrate to a relative density of 1.10-1.20 (50°C), add ethanol to make the alcohol content reach 50%, stir, stand overnight, filter, recover ethanol from the filtrate, concentrate to a relative density of 1.25-1.30 (50°C), dry under reduced pressure to form a dry paste, crush, take 1 part of dry paste powder, 1.5 parts of dextrin, granulate with appropriate amount of ethanol, dry below 80°C and granulate, and make granules (without sucrose).

[0039] Experimental Example 1

[0040] 1. Experimental drugs

[0041] The Zheng Chaihuyin granules used in the study were provided by Jinghua Pharmaceutical Group Co., Ltd., packaged in 3g / bag.

[0042] 2. Experimental Design

[0043] (1) Preparation of Zheng Chaihu Yin Solution (ZCH)

[0044] Take 3 g of Zheng Chaihu Yin granules, add 3 ml of normal saline, shake and mix, and prepare a Zheng Chaihu Yin solution with a concentration of 1 g / ml (store in a refrigerator at 4°C).

[0045] (2) Preparation of lipopolysaccharide (LPS) solution

[0046] 10g LPS powder (Lipopolysaccharides from E.coli 0111:B4, Biyuntian, catalog number S1732-25mg, China), add 5ml normal saline, shake and mix, and prepare a storage solution with a concentration of 2mg / ml (stored in a -80℃ ultra-low temperature refrigerator); when using, take 1ml of the storage solution, add 1ml of normal saline, shake and mix thoroughly, and prepare a 1mg / ml LPS solution (stored in a -20℃ refrigerator);

[0047] (3) Animal grouping and drug administration

[0048] 8-week-old adult C57BL / 6 mice, SPF grade, male, a total of 100 mice. The experimental mice had a body weight of 18.2-23.8 g, with an average weight of (20.5±1.5) g. The 100 mice were randomly divided into five groups, namely, blank control (NC) group, model group (LPS), low-dose group (3g / kg), medium-dose group (6g / kg) and high-dose group (12g / kg), with 20 mice in each group.

[0049] Day 1: The low-dose group, medium-dose group and high-dose group were gavaged with different doses of Zheng Chai Hu Yin solution, wherein, according to the mass of Zheng Chai Hu Yin granules, the dosage of the low-dose group was 3 g / kg animal body weight, the medium-dose group was 6 g / kg animal body weight, and the high-dose group was 12 g / kg animal body weight (the NC group and the model group were not treated);

[0050] The next day: ① The low-dose group, medium-dose group and high-dose group were gavaged with different doses of Zheng Chaihu Yin solution, among which, according to the mass of Zheng Chaihu Yin granules, the dosage of the low-dose group was 3g / kg, the medium-dose group was 6g / kg, and the high-dose group was 12g / kg (the NC group and the model group were not treated); ② One hour after gavage, except for the NC group, the other four groups were intraperitoneally injected with 1mg / ml LPS solution once, and the injection dose was 1ml / g animal body weight to construct an acute depression model (see the literature: Run Yin 1, Kailing Zhang, et al. Lipopolysaccharide-induced depression-like model in mice: meta-analysis and systematic evaluation. Frontiers in Immunology. 2023);

[0051] Day 3: The low-dose group, medium-dose group and high-dose group were gavaged with different doses of Zheng Chai Hu Yin solution, wherein, according to the mass of Zheng Chai Hu Yin granules, the dosage of the low-dose group was 3 g / kg, the medium-dose group was 6 g / kg, and the high-dose group was 12 g / kg (the NC group and the model group were not treated);

[0052] Day 4: The low-dose group, medium-dose group and high-dose group were gavaged with different doses of Zheng Chaihu Yin solution, among which, based on the mass of Zheng Chaihu Yin granules, the dosage of the low-dose group was 3 g / kg, the medium-dose group was 6 g / kg, and the high-dose group was 12 g / kg (the NC group and the model group were not treated).

[0053] On the fourth day, 24 hours after administration, behavioral indices were tested and samples were collected.

[0054] (4) Behavioral testing

[0055] ①Open field test (OFT):

[0056] The OFT is used to evaluate the spontaneous behavior, exploratory activity, and tension of experimental animals in a novel environment. The shorter the time the mouse spends in the central area, the higher the anxiety level. During the test, the mouse is gently placed in the center of an open-field box with dimensions of 50 cm × 50 cm × 50 cm, which is divided into 25 squares. Nine squares are defined as the central area, and the 16 squares along the box walls are defined as the peripheral area. The mouse is allowed to move freely for 6 min, and a video recording device is used to record the time and distance the mouse moves in the central area during the last 5 min in the open field. The longer the mouse stays in the central area, the better its emotional state; the shorter the time, the more anxious it is. The time the mice in each group spend in the central area (Time in center) of the open field is shown in Figure 1 as follows.

[0057] References: HUANG H J, ZHU X C, HAN Q Q, et al. Ghrelin alleviates anxiety-and depression-like behaviors induced by chronic unpredictable mild stress in rodents[J]. Behav Brain Res, 2017, 326(3): 33 - 43.

[0058] The results are shown in Figure 1 as follows. Compared with the NC group, the time the LPS group mice spend in the central area of the open field is significantly reduced (p < 0.01). Compared with the LPS group mice, the time the low-dose group, medium-dose group, and high-dose group mice spend in the central area of the open field is significantly increased. Among them, the differences between the low-dose group and medium-dose group and the LPS group are extremely significant (p < 0.01), and the difference between the medium-dose group and the low-dose group is significant (0.01 < p < 0.05). The high-dose group may not have as good an effect as the medium-dose group due to the too high dose. This indicates that the anxiety level of the mice is significantly improved after taking Zhengchaihu Yin granules.

[0059] ② Tail suspension test (TST)

[0060] The TST is used to evaluate the despair behavior of mice. Compared with the forced swimming test, it is more sensitive to the antidepressant effect of low-dose drugs. The mouse is suspended 40 cm above the ground with tape 1 cm from the tip of its tail. The mouse is 15 cm away from the nearest object and is in an isolated state both auditorily and visually. The test period is 6 min, and a video recording device is used to record the immobile time of the mouse during the last 5 min. Only when the mouse is completely still is it considered behaviorally despairing. Record the percentage of the immobile time in the total time, that is, Immobility time (%).

[0061] References: STERU L, CHERMAT R, THIERRY B, et al. The tail suspension test: a new method for screening antidepressants in mice[J]. Psychopharmacology, 1985, 85(3): 367-70.

[0062] The results are shown as Figure 2 follows. Compared with the NC group, the immobility time of mice in the LPS group was significantly prolonged in the tail suspension test (p < 0.01). Compared with the LPS group, the immobility time of mice in the low-dose group, medium-dose group, and high-dose group was significantly shortened in the tail suspension test. Among them, the difference between the low-dose group and the LPS group was significant (0.01 < p < 0.05), the difference between the high-dose group and the low-dose group was significant (0.01 < p < 0.05), and the difference between the medium-dose group and the LPS group was extremely significant (p < 0.01). However, the high-dose group may not have a better effect than the medium-dose group due to the too high dose. This indicates that Zhengchaihu Yin Granules have good antidepressant effects.

[0063] ③ Forced swimming test (FST)

[0064] The forced swimming test can examine the level of behavioral despair in mice. We placed the mice after drug administration into a large round bucket with an inner diameter of 10 cm and a water depth of 25 cm, configured a backlight board system, and the water temperature was 23 - 25 °C, which was measured and monitored with a thermometer. First, adjust the room temperature to about 22 °C a few hours in advance, and place the animals in the test room the day before to let each mouse adapt to the experimental environment in advance. After 24 h, place the mice in water at 23 - 25 °C and let the mice swim in the water for 6 min. The first 2 min is used to adapt to the environment, and the immobility time of the mice during the last 4 min is recorded. The criterion for judging swimming immobility is as follows: only the head of the mouse floats on the water surface in the water, and the body no longer struggles and remains motionless. Note that gently pick up the animal and immerse it in the water, start timing after the animal maintains body balance, record the immobility time of the mouse during the last 4 min through VisuTrack software. When the time stops, pick up the animal with a net and wrap the animal in a dry towel prepared in advance to dry the moisture of the animal's fur to prevent excessive change in its body temperature. The longer the immobility time in the forced swimming test, the more depressed the mouse is. Record the percentage of the immobility time in the total time, that is, Immobility time (%).

[0065] References: PORSOLT R D, LE PICHON M, JALFRE M. Depression: a new animal model sensitive to antidepressant treatments[J]. Nature, 1977, 266(5604): 730 - 732.

[0066] The results are as Figure 3 shown. Compared with the NC group, the immobility time of mice in the LPS group was significantly prolonged in the forced swimming test (p < 0.01). Compared with the mice in the LPS group, the immobility time of mice in the low-dose group, medium-dose group, and high-dose group was significantly shortened in the forced swimming test (p < 0.05). Among them, the difference between the low-dose group and the LPS group was significant (0.01 < p < 0.05), the difference between the medium-dose group and the low-dose group was significant (0.01 < p < 0.05), the difference between the medium-dose group and the LPS group was extremely significant (p < 0.01), and the high-dose group may not have a better effect than the medium-dose group due to the too high dose. This indicates that Zhengchaihu Yin Granules have good antidepressant effects.

[0067] In summary, this study found that based on the mouse model of depression, the drug composition of Zhengchaihu Yin or its preparation (such as Zhengchaihu Yin Granules) is used for the treatment of depression. It was found that Zhengchaihu Yin Granules can significantly improve the anxiety level of mice in the open field test, improve the despair behavior of mice in the tail suspension test, and reduce the behavioral despair level of mice in the forced swimming test, showing good antidepressant effects.

[0068] Obviously, the above embodiments are merely examples given for clear illustration and are not limitations on the implementation manners. For those of ordinary skill in the art, other different forms of changes or variations can be made based on the above description. It is not necessary and impossible to list all the implementation manners here. And the obvious changes or variations derived therefrom are still within the protection scope of the present invention.

Claims

1. Use of the Zheng Chaihu Yin pharmaceutical composition or its preparation in the preparation of a drug for preventing or treating depression. The Zheng Chaihu Yin pharmaceutical composition is made of the following raw materials in parts by weight: 80-150 parts of bupleurum, 80-150 parts of dried tangerine peel, 70-90 parts of siler, 30-50 parts of liquorice, 130-170 parts of red peony root and 60-80 parts of ginger.

2. The use according to claim 1, characterized in that The preparation uses the Zheng Chaihu Yin medicinal composition or the extract of the Zheng Chaihu Yin medicinal composition as the active component, with or without the addition of pharmaceutically acceptable excipients, and is prepared according to conventional processes in the art.

3. The use according to claim 2, characterized in that: The preparation method of the extract of the Zheng Chai Hu Yin medicinal composition comprises: taking the Zheng Chai Hu Yin medicinal composition, adding water to boil, concentrating, adding ethanol to stand, filtering, recovering ethanol from the filtrate, and concentrating to obtain the extract.

4. The use according to claim 2, characterized in that: The pharmaceutically acceptable excipients are selected from one or more of fillers, disintegrants, lubricants, suspending agents, binders, flavoring agents, and preservatives.

5. The use according to claim 2, characterized in that: The pharmaceutically acceptable excipient is selected from sweeteners.

6. The use according to claim 1, characterized in that: The dosage form of the drug is a liquid preparation or a solid preparation.

7. The use according to claim 6, characterized in that The solid preparation is selected from powders, tablets, capsules, granules or pills; the liquid preparation is selected from mixtures, syrups or suspensions.

8. The use according to any one of claims 1 to 7, characterized in that: The depression is mild depression or moderate depression.

Images