Anxiolytic traditional Chinese medicine composition, preparation method and application

Abstract

The application belongs to the technical field of medicine, and particularly relates to an anti-anxiety traditional Chinese medicine composition, a preparation method and application, which is prepared from the following traditional Chinese medicine raw materials in proportion by weight: 0.5-6 parts of vinegar northern bupleurum, 1-6 parts of scutellaria, 0.5-4 parts of lotus heart, and 1-5 parts of rose flower, water extraction, and preparation into a certain dosage form. The above-mentioned drugs are combined to soothe the liver and relieve depression, calm the heart and tranquilize the mind. The traditional Chinese medicine composition is used for treating extensive anxiety disorder caused by liver depression and fire. The pharmacodynamic and clinical efficacy research results show that the traditional Chinese medicine composition is an effective drug for treating anxiety disorder.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to an anti-anxiety traditional Chinese medicine composition, its preparation method, and its application. Background Technology

[0002] Anxiety disorder is a common mental disorder characterized by excessive worry and fear in everyday situations, interfering with daily activities and difficult to control. Common types include generalized anxiety disorder, panic disorder, social phobia, specific phobias, and separation anxiety disorder.

[0003] Besides psychotherapy, medication is also a common treatment method. Benzodiazepines, for example, have strong anti-anxiety effects, a rapid onset of action, can improve sleep, and have fewer side effects. Non-benzodiazepine anti-anxiety drugs (such as buspirone) do not have obvious sedative, drowsiness, or weight gain side effects, but their effects are weaker and their onset of action is slower. Selective serotonin reuptake inhibitors (SSRIs) have become the first-line drugs for treating anxiety disorders due to their safety and efficacy.

[0004] Currently, there are also research projects on traditional Chinese medicine solutions for anxiety disorders. For example, Chinese patent application CN 113908210 A discloses a traditional Chinese medicine anti-anxiety pack and its preparation method. The oral preparation includes the following components: clary sage, marjoram, cypress, peppermint, orange peel, ginseng, black goji berries, and mulberry. The oral preparation can regulate the body's internal environment, cross the blood-brain barrier, and thus enhance the body's anti-anxiety ability. Moreover, the traditional Chinese medicine components in the oral preparation are all of medicinal and edible origin, with mild and non-irritating effects, natural safety, and no toxic side effects. It can be taken for a long time with obvious effects.

[0005] CN115691659A discloses a method and composition for screening anti-anxiety and antidepressant food-derived formulas based on network pharmacology. It was found that the combination of licorice, jujube, wolfberry, mulberry leaf, astragalus, and honeysuckle, GDGSHJ, has good activity and good anti-anxiety and antidepressant effects in mouse behavior. Organ coefficients and liver and kidney sections indicate that GDGSHJ has no obvious toxic side effects.

[0006] CN112426454A discloses a traditional Chinese medicine compound composition with anti-anxiety effects, its preparation method, and its application. The composition comprises the following traditional Chinese medicine extracts, by mass percentage: 50-55% white peony root extract; 20-40% gardenia extract; 15-30% mimosa flower extract; and 1-5% peony bark extract. This traditional Chinese medicine compound composition has no toxic side effects and significant therapeutic effects. It can be used as a dietary supplement or health food ingredient for the prevention and treatment of anxiety disorders and the promotion of mental health.

[0007] The efficacy of traditional Chinese medicine in relieving anxiety needs further improvement. Summary of the Invention

[0008] The purpose of this invention is to address the shortcomings of existing technologies by providing an anti-anxiety traditional Chinese medicine composition, preparation method, and application, thereby improving the problem of poor anti-anxiety efficacy.

[0009] The anti-anxiety traditional Chinese medicine composition of the present invention is made from the following traditional Chinese medicine raw materials in the indicated weight ratios: 0.5-6 parts of vinegar-processed Bupleurum chinense, 1-6 parts of Scutellaria baicalensis, 0.5-4 parts of lotus seed heart, and 1-5 parts of rose.

[0010] As a preferred embodiment, the anti-anxiety traditional Chinese medicine composition is made from the following traditional Chinese medicine raw materials in the indicated weight ratios: 0.5-6 parts of vinegar-processed Bupleurum chinense, 1-6 parts of Scutellaria baicalensis, 0.5-4 parts of Nelumbo nucifera seed heart, 1-5 parts of Rosa rugosa, 1-7 parts of Lilium brownii, 1-6 parts of Rehmannia glutinosa, and 1-6 parts of Anemarrhena asphodeloides.

[0011] As a preferred embodiment, the anti-anxiety traditional Chinese medicine composition is made from the following traditional Chinese medicine raw materials in the indicated weight ratios: 0.5-6 parts of vinegar-processed Bupleurum chinense, 1-6 parts of Scutellaria baicalensis, 0.5-4 parts of Nelumbo nucifera seed heart, 1-5 parts of Rosa rugosa, 1-7 parts of Lilium brownii, 1-6 parts of Rehmannia glutinosa, 1-6 parts of Anemarrhena asphodeloides, 1-6 parts of Poria cocos, 0.8-5 parts of Valerian, 1-7 parts of Albizia julibrissin bark, 1-4 parts of Adenophora stricta, and 0.2-3 parts of processed Glycyrrhiza uralensis.

[0012] As a preferred embodiment, the anti-anxiety traditional Chinese medicine composition of the present invention is made from the following traditional Chinese medicine raw materials in the indicated weight ratios: 2-4 parts of vinegar-processed Bupleurum chinense, 2-5 parts of Scutellaria baicalensis, 1-3 parts of Nelumbo nucifera seed heart, 2-4 parts of Rosa rugosa, 3-7 parts of Lilium brownii, 4-6 parts of Rehmannia glutinosa, 2-5 parts of Anemarrhena asphodeloides, 2-5 parts of Poria cocos, 2-5 parts of Valerian, 4-6 parts of Albizia julibrissin bark, 2-4 parts of Adenophora stricta, and 0.5-2 parts of processed Glycyrrhiza uralensis.

[0013] The above-mentioned Chinese herbal medicine composition can be decocted and taken orally, or extracted with water or ethanol and taken orally.

[0014] As one example, a clinically acceptable dosage form was prepared.

[0015] As one embodiment, the traditional Chinese medicine composition is prepared as a decoction, tablet, capsule, granule, powder, syrup, pill, or oral liquid.

[0016] As one embodiment, it is prepared as soft capsules, dispersible tablets, orally disintegrating tablets, or pellets.

[0017] This invention provides a method for preparing an anti-anxiety traditional Chinese medicine composition. The preparation method is as follows: after mixing the traditional Chinese medicine raw materials, water is added for extraction 1 to 3 times, with 4 to 12 times the amount of water added each time; each extraction lasts 1 to 2 hours, the extracts are combined, filtered, and concentrated to obtain the final product.

[0018] As one embodiment, water is added for extraction twice, with 10-12 times the amount added each time; each extraction lasts 1-2 hours, the extract is filtered, concentrated, and the product is obtained.

[0019] As one embodiment, water is added for extraction twice. The first extraction is performed with 8-12 times the amount of water for 2 hours, and the second extraction is performed with 6-10 times the amount of water for 1.5 hours. The extract is then filtered and concentrated to obtain the final product.

[0020] As one example, the Chinese herbal medicine raw materials are soaked for 0.5 hours before the first extraction.

[0021] This invention provides the application of an anti-anxiety traditional Chinese medicine composition in the preparation of anti-anxiety drugs.

[0022] The beneficial effects of this invention are that the combined medicinal ingredients in the prescription have the effects of soothing the liver and relieving depression, calming the mind and soothing the nerves, and are used for mild to moderate generalized anxiety disorder caused by liver stagnation transforming into fire. Pharmacodynamic studies have shown that this compound traditional Chinese medicine has a significant effect on improving CRS-induced anxiety-like behavior in mice. Detailed Implementation

[0023] Specific embodiments are given to illustrate the invention in a more detailed description, but are only intended to explain the invention and not to limit its scope.

[0024] Example 1: Granule dosage form of the pharmaceutical composition of the present invention

[0025] Take 6 parts of vinegar-processed Bupleurum chinense, 6 parts of Scutellaria baicalensis, 4 parts of lotus seed heart, 5 parts of rose, 7 parts of lily, 6 parts of Rehmannia glutinosa, 6 parts of Anemarrhena asphodeloides, 6 parts of Poria cocos, 5 parts of valerian, 7 parts of Albizia julibrissin bark, 4 parts of Adenophora stricta, and 3 parts of prepared licorice root. Soak in water for 0.5 hours, then extract twice, adding 12 times and 10 times the amount of water respectively. The first extraction lasts for 2 hours, and the second extraction lasts for 1.5 hours. Filter, combine the filtrates, concentrate, dry, and pulverize to obtain the dry extract powder of the pharmaceutical composition of this invention, which is then used to prepare granules.

[0026] Example 2: Tablet Formation of the Pharmaceutical Composition of the Present Invention

[0027] Take 0.5 parts of vinegar-processed Bupleurum chinense, 1 part of Scutellaria baicalensis, 0.5 parts of lotus seed heart, 1 part of rose, 1 part of lily, 1 part of Rehmannia glutinosa, 1 part of Anemarrhena asphodeloides, 1 part of Poria cocos, 0.8 parts of valerian, 1 part of Albizia julibrissin bark, 1 part of Adenophora stricta, and 0.2 parts of prepared licorice root. Soak in water for 0.5 hours and extract twice, adding 6 times and 4 times the amount of water respectively. The first extraction lasts for 2 hours and the second extraction lasts for 1.5 hours. Filter, combine the filtrates, concentrate, dry, and pulverize to obtain the dry extract powder of the pharmaceutical composition of the present invention. Then, prepare the tablet dosage form of the pharmaceutical composition.

[0028] Example 3: Capsule dosage form of the pharmaceutical composition of the present invention

[0029] Take 5 parts of vinegar-processed Bupleurum chinense, 2 parts of Scutellaria baicalensis, 2 parts of lotus seed heart, 1.5 parts of rose, 2 parts of lily bulb, 2 parts of Rehmannia glutinosa, 5 parts of Anemarrhena asphodeloides, 4 parts of Poria cocos, 5 parts of valerian, 5 parts of Albizia julibrissin bark, 3 parts of Adenophora stricta, and 0.5 parts of prepared licorice root. Soak in water for 0.5 hours and extract twice, adding 7 times and 5 times the amount of water respectively. The first extraction lasts for 2 hours, and the second extraction lasts for 1.5 hours. Filter, combine the filtrates, concentrate, dry, and pulverize to obtain the dry extract powder of the pharmaceutical composition of the present invention. Then, prepare the pharmaceutical composition preparation in capsule form.

[0030] Example 4: Droplet Formulation of the Composition of the Present Invention

[0031] Take 4 parts of vinegar-processed Bupleurum chinense, 3 parts of Scutellaria baicalensis, 3 parts of lotus seed heart, and 2 parts of rose petals. Soak in water for 0.5 hours and extract twice. Add 6 times and 4 times the amount of 50% ethanol aqueous solution, respectively. The first extraction lasts for 2 hours and the second extraction lasts for 1.5 hours. Filter, combine the filtrates, concentrate, dry, and pulverize to obtain the dry extract powder of the pharmaceutical composition of the present invention. After pulverizing, add an appropriate amount of excipients to prepare the pills of the pharmaceutical composition.

[0032] Example 5: Soft capsule dosage form of the pharmaceutical composition of the present invention

[0033] Take 3 parts of vinegar-processed Bupleurum chinense, 4 parts of Scutellaria baicalensis, 2.5 parts of lotus seed heart, 2.5 parts of rose, 4 parts of lily, 3 parts of Rehmannia glutinosa, and 4 parts of Anemarrhena asphodeloides. Soak in water for 0.5 hours and extract twice, adding 7 times and 5 times the amount of water respectively. The first extraction lasts for 2 hours and the second extraction lasts for 1.5 hours. Filter, combine the filtrates, concentrate, dry, and pulverize to obtain the dry extract powder of the pharmaceutical composition of the present invention. After pulverizing, add an appropriate amount of excipients, mix well, use gelatin as the shell material, and press into soft capsules to obtain the soft capsules of the pharmaceutical composition.

[0034] Example 6: Microgranule dosage form of the pharmaceutical composition of the present invention

[0035] Take 2 parts of vinegar-processed Bupleurum chinense, 5 parts of Scutellaria baicalensis, 3.5 parts of lotus seed heart, 3 parts of rose, 5 parts of lily, 4 parts of Rehmannia glutinosa, 3 parts of Anemarrhena asphodeloides, 4 parts of Poria cocos, 4 parts of valerian, 5 parts of Albizia julibrissin bark, 4 parts of Adenophora stricta, and 1 part of prepared licorice root. Soak in water for 0.5 hours and extract twice, adding 6 times and 4 times the amount of water respectively. The first extraction lasts for 2 hours and the second extraction lasts for 1.5 hours. Filter, combine the filtrates, concentrate, dry, and pulverize to obtain the dry extract powder of the pharmaceutical composition of the present invention. After pulverizing, add an appropriate amount of excipients to prepare micro-pills of the pharmaceutical composition.

[0036] Example 7: Orally disintegrating tablet form of the pharmaceutical composition of the present invention

[0037] Take 1 part of vinegar-processed Bupleurum chinense, 5.5 parts of Scutellaria baicalensis, 2.5 parts of lotus seed heart, 3.5 parts of rose, 6 parts of lily, 5 parts of Rehmannia glutinosa, 2 parts of Anemarrhena asphodeloides, 3 parts of Poria cocos, 2 parts of valerian, 6 parts of Albizia julibrissin bark, 2 parts of Adenophora stricta, and 1 part of prepared Glycyrrhiza uralensis. Soak in water for 0.5 hours and extract twice, adding 6 times and 4 times the amount of water respectively. The first extraction lasts for 2 hours and the second extraction lasts for 1.5 hours. Filter, combine the filtrates, concentrate, dry, and pulverize to obtain the dry extract powder of the pharmaceutical composition of the present invention. After pulverizing, add an appropriate amount of excipients to prepare micro-pills of the pharmaceutical composition.

[0038] Example 8: Pharmacological and toxicological tests of the present invention

[0039] The purpose of this experiment was to observe the pharmacological and toxicological effects of the herbal compositions of this invention on anxiety model mice. The compositions A, B, C, and the control herbal composition of this invention were all prepared as dry extract powders, and were diluted with purified water to the required concentration. All dosages mentioned are crude drug dosages.

[0040] Preparation of each composition: The preparation methods of the above test compositions are the same, as follows:

[0041] Positive control drug: Diazepam (benzodiazepine). The human dosage for anxiety relief is 1 tablet (2.5 mg) three times daily. The clinically equivalent dose was administered at twice the recommended dose. The equivalent dose in mice was 7.5 mg * 0.0026 * 50 = 0.975 mg / kg. In this experiment, a dose of 1 mg / kg was used.

[0042] Formula A: 3 parts vinegar-processed Bupleurum chinense, 3 parts Scutellaria baicalensis, 1.5 parts lotus seed heart, and 3 parts rose. Soak in water for 0.5 hours and then extract twice, adding 10 times and 8 times the amount of water respectively. The first extraction lasts for 2 hours and the second extraction lasts for 1.5 hours. Filter separately, combine the filtrates, concentrate, dry, and pulverize to obtain dry extract powder of Formula A.

[0043] Formula B: 3 parts vinegar-processed Bupleurum chinense, 3 parts Scutellaria baicalensis, 1.5 parts lotus seed heart, 3 parts rose, 6 parts lily, 5 parts Rehmannia glutinosa, and 3 parts Anemarrhena asphodeloides. Soak in water for 0.5 hours and extract twice, adding 10 times and 8 times the amount of water respectively. The first extraction lasts for 2 hours and the second extraction lasts for 1.5 hours. Filter separately, combine the filtrates, concentrate, dry, and pulverize to obtain the dry extract powder of Formula B.

[0044] Formula C: 3 parts vinegar-processed Bupleurum chinense, 3 parts Scutellaria baicalensis, 1.5 parts lotus seed heart, 3 parts rose, 6 parts lily, 5 parts Rehmannia glutinosa, 3 parts Anemarrhena asphodeloides, 5 parts Poria cocos, 3 parts valerian, 5 parts Albizia julibrissin bark, 3 parts Adenophora stricta, and 1 part prepared licorice root. Soak in water for 0.5 hours and extract twice, adding 10 times and 8 times the amount of water respectively. The first extraction lasts for 2 hours and the second extraction lasts for 1 hour. Filter separately, combine the filtrates, concentrate, dry, and pulverize to obtain the dry extract powder of Formula C.

[0045] The control group of Chinese herbal medicines consisted of 3 parts of vinegar-processed Bupleurum chinense, 3 parts of Scutellaria baicalensis, 1.5 parts of Gardenia jasminoides, and 3 parts of Paeonia lactiflora. After soaking in water for 0.5 hours, the herbs were extracted twice, with the water volume being 12 times and 10 times that of the herbs, respectively. The first extraction lasted for 2 hours, and the second extraction lasted for 1 hour. The extracts were filtered separately, the filtrates were combined, concentrated, dried, and pulverized to obtain the dry extract powder of the control herbs.

[0046] Animal grouping and model preparation: After the adaptive feeding period, rats were weighed and randomly divided into 7 groups using a random number method: normal group, model group, diazepam group, formula A group, formula B group, formula C group, and control traditional Chinese medicine group, with 10 rats in each group. Except for the normal group, a mouse anxiety model was established using chronic restraint stress. Mice were subjected to restraint stress for 3 hours daily from 10:00 to 13:00, for a total of 21 days. Gavage administration began on day 8 of model establishment and continued for 14 days. Body weight was measured weekly, and behavioral tests were performed 1 hour after the last administration.

[0047] (1) Effects of each composition on the open field test of CRS-induced mice: The test was conducted 1 h after day 21 of the experiment (14 days after administration). The animals were placed in the center of a black open box of 80 cm × 80 cm × 40 cm and allowed to move freely for 30 s. The total distance traveled by the animals, the distance traveled in the central area, and the time spent in the central area were recorded in the next 5 minutes. The results are shown in Table 1.

[0048]

[0049] Note: Comparison between the model group and the blank group. ** P<0.01; Compared with the model group, each test group... # P<0.05, ## P<0.01; Comparison of each test group with composition A: ▲ P <0.05, ▲▲ P <0.01; Comparison of each test group with composition B: ■ P <0.05, ■■ P <0.01; Comparison of each test group with composition C: ☆ P <0.05, ☆☆ P <0.01; Comparison of each test group with the control traditional Chinese medicine group: ◆ P <0.05, ◆◆ P <0.01.

[0050] As shown in Table 1, there was no significant difference in the total distance among the groups (p>0.05), indicating that neither CRS nor drug administration had a significant effect on the spontaneous activity ability of mice. Compared with the blank group, the center distance and center time of the model group were significantly decreased (P<0.01); compared with the model group, the center distance and center time of the compositions A, B, and C of this invention, the control traditional Chinese medicine group, and the positive drug group were significantly increased (P<0.05 or P<0.01); compared with composition A, the center distance and center time of compositions B and C were significantly increased (P<0.05 or P<0.01); compared with composition B, the center distance and center time of composition A were significantly decreased (P<0.05), and the center distance and center time of composition C were significantly increased (P<0.01); compared with composition C, the center distance of compositions A, B, and the control traditional Chinese medicine group was significantly decreased (P<0.05 or P<0.01); compared with the control traditional Chinese medicine group, the center distance and center time of compositions B and C were significantly increased (P<0.05 or P<0.01).

[0051] The results showed that compositions A, B, C, the control herbal medicine, and the positive control drug all significantly improved the central region distance and central region time in CRS-induced mice during the open field experiment. Among them, compositions B and C were more effective than compositions A and the control herbal medicine; composition C was more effective than composition B.

[0052] (2) Effects of each composition on the CRS-induced elevated cross maze test in mice: The test was conducted 1 hour after day 22 (15 days after drug administration). The animals were placed in the center of the elevated cross maze with their heads facing the open arms. The number of times the animals entered the closed arms, the number of times they entered the open arms, and the time spent in the open arms were recorded within 5 minutes. The total number of times the animals entered the arms, the ratio of the number of times they entered the open arms, and the ratio of the time spent in the open arms were calculated. The results are shown in Table 2.

[0053]

[0054] Note: Comparison between the model group and the blank group. ** P<0.01; Compared with the model group, each test group... # P<0.05, ## P<0.01; Comparison of each test group with composition A: ▲ P <0.05, ▲▲ P <0.01; Comparison of each test group with composition B: ■ P <0.05, ■■ P <0.01; Comparison of each test group with composition C: ☆ P <0.05, ☆☆P <0.01; Comparison of each test group with the control traditional Chinese medicine group: ◆ P <0.05, ◆◆ P <0.01.

[0055] Table 2 shows that there was no significant difference in the total number of arm penetrations among the groups in the elevated cross maze (P > 0.05). Compared with the control group, the number of open arms and the time to open arms were significantly decreased in the model group (P < 0.01). Compared with the model group, the number of open arms and the time to open arms were significantly increased in groups A, B, and C, the control herbal medicine group, and the positive control group (P < 0.05 or P < 0.01). Compared with group A, the center distance and center time were significantly increased in groups B and C (P < 0.05 or P < 0.01). 1) Compared with group B, the number of open arms and the open arm time in group A and the positive control group of traditional Chinese medicine were significantly decreased (P<0.05), while the number of open arms and the open arm time in group C were significantly increased (P<0.01); compared with group C, the number of open arms and the open arm time in groups A, B and the control group of traditional Chinese medicine were significantly decreased (P<0.01); compared with the control group of traditional Chinese medicine, the number of open arms and the open arm time in groups B and C were significantly increased (P<0.05 or P<0.01).

[0056] The results showed that compositions A, B, C, the control herbal medicine, and the positive control drug all significantly improved the number of open arms and the open arm time in CRS-induced mice in the elevated cruciate maze experiment. Among them, compositions B and C were more effective than compositions A and the control herbal medicine; composition C was more effective than composition B.

[0057] (3) Effects of each composition on the CRS-induced light-dark box experiment in mice: The test was conducted 1 hour after day 21 of the experiment (14 days after drug administration). The animals were placed in the light box of the light-dark box with their backs to the opening. The total distance of the animals, the distance in the light area, the time in the light area, and the number of times they entered the light area were recorded within 5 minutes. The results are shown in Table 3.

[0058]

[0059] Note: Comparison between the model group and the blank group. ** P<0.01; Compared with the model group, each test group... # P<0.05, ## P<0.01; Comparison of each test group with composition A: ▲ P <0.05, ▲▲ P <0.01; Comparison of each test group with composition B: ■ P <0.05,■■ P <0.01; Comparison of each test group with composition C: ☆ P <0.05, ☆☆ P <0.01; Comparison of each test group with the control traditional Chinese medicine group: ◆ P <0.05, ◆◆ P <0.01.

[0060] Table 3 shows that there was no significant difference in the total distance traveled by each group in the light and dark chamber (P > 0.05). Compared with the blank group, the distance traveled in the light zone, the time spent in the light zone, and the number of times the light zone was observed in the model group were all significantly decreased (P < 0.01). Compared with the model group, the distance traveled in the light zone, the time spent in the light zone, and the number of times the light zone was observed in groups A, B, and C, the control herbal medicine group, and the positive control group were all significantly increased (P < 0.05 or P < 0.01). Compared with group A, the time spent in the light zone was significantly increased in group B (P < 0.05). In composition C, the distance traveled, time spent in the open area, and number of times the open area was significantly increased (P<0.01); compared with composition B, composition C showed significantly increased time spent in the open area and number of times the open area was increased (P<0.05); compared with composition C, composition A, composition B, and the control herbal group showed significantly decreased time spent in the open area and number of times the open area was decreased (P<0.05 or P<0.01); compared with the control herbal group, composition C showed significantly increased time spent in the open area and number of times the open area was increased (P<0.05 or P<0.01).

[0061] The results showed that compositions A, B, C, the control herbal medicine, and the positive control drug all significantly improved the central light zone distance, light zone time, and light zone number in CRS-induced mice during the light-dark chamber experiment. Among them, compositions B and C were more effective than composition A; and composition C was more effective than composition B and the control herbal medicine.

[0062] III. Research Conclusions

[0063] Pharmacological test results showed that compositions A, B, C, and the control traditional Chinese medicine could all improve anxiety-like behavior induced by CRS in mice. The efficacy of compositions B and C was better than that of compositions A and the control traditional Chinese medicine; and the effect of composition C was better than that of composition B.

[0064] Experimental Example 9: Clinical observation of the therapeutic efficacy of the composition of the present invention in treating anxiety disorders.

[0065] The purpose of this experiment is to observe the therapeutic effect of the composition of the present invention on patients with anxiety disorders.

[0066] Composition C: 3 parts vinegar-processed Bupleurum chinense, 3 parts Scutellaria baicalensis, 1.5 parts lotus seed heart, 3 parts rose, 6 parts lily, 5 parts Rehmannia glutinosa, 3 parts Anemarrhena asphodeloides, 5 parts Poria cocos, 3 parts valerian, 5 parts Albizia julibrissin bark, 3 parts Adenophora stricta, and 1 part prepared licorice root. After soaking in water for 0.5 hours, extract twice, adding 10 times and 8 times the amount of water respectively. The first extraction lasts for 2 hours, and the second extraction lasts for 1 hour. Filter separately, combine the filtrates, concentrate, dry, pulverize, add appropriate amount of excipients, mix well and granulate to obtain granules. Each packet contains dry extract powder of Composition C.

[0067] (1) The diagnostic criteria for generalized anxiety disorder in Western medicine refer to the diagnostic criteria of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-V). Core symptoms include: excessive worry and anxiety about activities and events for at least 6 months, with difficulty controlling one's worry. Accompanied by 3 or more of the following 6 symptoms: feeling tense or restless, easily fatigued, difficulty concentrating or sudden mental blanks, muscle tension, irritability, and sleep disturbances (frequent awakenings or difficulty falling asleep). At the same time, this anxiety, worry, or physical symptoms need to cause clinically significant distress or lead to impairment in social, occupational, or other important functions.

[0068] (2) TCM diagnostic criteria: formulated with reference to the relevant contents of "Internal Medicine of Traditional Chinese Medicine", "Guidelines for Diagnosis and Treatment of Common Diseases in Internal Medicine of Traditional Chinese Medicine - Western Medicine Diseases" (ZYYXH / T132—2008) issued by the China Association of Traditional Chinese Medicine, "Clinical Practice Guidelines for Generalized Anxiety Disorder Based on Individualization", "Guidelines for Diagnosis and Treatment of Generalized Anxiety Disorder by Integrated Traditional Chinese and Western Medicine", and "Clinical Terminology of Traditional Chinese Medicine Part 2: Syndromes" (revised version).

[0069] Diagnostic criteria: Characterized by persistent primary anxiety symptoms, and meeting two of the following criteria:

[0070] A. Frequent or persistent, undefined, and uncontrollable fear and anxiety.

[0071] B. Autonomic nervous system dysfunction or restlessness.

[0072] Syndrome differentiation criteria (liver qi stagnation transforming into fire syndrome):

[0073] Main symptoms: Irritability, sensitivity, suspicion, restlessness.

[0074] Secondary symptoms: insomnia, chest tightness, red eyes, bitter taste in mouth, dry throat, frequent sighing, palpitations, yellow urine, constipation, hot flashes, night sweats, and mouth and tongue sores. Tongue and pulse: red tongue, yellow coating, thready or thready-rapid or wiry pulse.

[0075] The primary symptoms in Traditional Chinese Medicine must meet two out of three criteria, and the secondary symptoms must meet three out of eight criteria, with insomnia being a must, consistent with the tongue and pulse.

[0076] Severity classification criteria:

[0077] Mild: 14 ≤ HAMA score < 21;

[0078] Moderate: 21 ≤ HAMA score < 29;

[0079] Severe: HAMA scale score ≥ 29 points.

[0080] Inclusion criteria: (1) meeting the Western medicine diagnostic criteria for anxiety disorder; (2) meeting the TCM diagnostic criteria and syndromes of liver qi stagnation and fire type; (3) aged 18 to 65 years (inclusive) and having signed an informed consent form; (4) not having taken any TCM or Western medicine related to this disease in the past month.

[0081] Exclusion criteria: (1) Individuals under 18 years of age or over 65 years of age; (2) Panic disorder, anxiety symptoms secondary to physical illness or other mental disorders (such as delusions, depression, obsessive-compulsive disorder, etc.) and anxiety caused by psychoactive substances, as well as diseases such as schizophrenia, menopausal syndrome and manic episodes; (3) Individuals with alcohol and drug dependence within 1 year, or patients with severe mental illness or epilepsy; (4) Individuals with anxiety episodes secondary to other mental or physical illnesses; (5) Individuals who do not meet the diagnostic criteria for mild to moderate generalized anxiety disorder and liver stagnation with fire in traditional Chinese medicine; (6) Individuals who are allergic to the test drug or its components; (7) Pregnant or women preparing for pregnancy, or women who are breastfeeding; (8) Individuals with severe and unstable physical illnesses such as cardiovascular disease, liver disease, kidney disease, blood disease, endocrine disease, or malignant tumors.

[0082] Exclusion criteria:

[0083] (1) Those who have entered the trial but are found to be ineligible for inclusion or ineligible for exclusion;

[0084] (2) Those who did not complete the trial according to the design plan and whose intervention factors significantly affected the determination of efficacy.

[0085] Experimental methods

[0086] The treatment method was as follows: First, patients were screened for anxiety using the General Anxiety Disorder Screening Scale (GAD-7), the Self-Rating Anxiety Scale (SAS), and the Hamilton Depression Rating Scale (HAMD-17). Only patients meeting the screening criteria and without concurrent depression were included in this study for subsequent clinical observation. A randomized, double-blind, placebo-controlled parallel clinical trial design was adopted. The selected patients were those with mild to moderate generalized anxiety disorder (liver stagnation transforming into fire syndrome). This experiment used a two-sample mean comparison for sample size calculation, setting ct = 0.05 and adding a dropout rate of 20%. Patients were randomly assigned in a 1:1 ratio to either the combination therapy group (Group C) or the placebo group, and observed for 8 weeks.

[0087] Observation indicators and detection methods

[0088] 1. Traditional Chinese Medicine Syndrome Assessment

[0089] The formula for calculating the reduction rate of TCM syndrome is: (Pre-treatment score minus post-treatment score) divided by the pre-treatment score, then multiplied by 100%. Based on the reduction rate, the therapeutic effect is divided into four levels: a reduction rate greater than or equal to 90% is considered cured; a reduction rate between 70% and 90% (inclusive but exclusive) is considered significantly effective; a reduction rate between 30% and 70% (inclusive but exclusive) is considered effective; and a reduction rate less than 30% is classified as ineffective. The overall effective rate is calculated by adding the number of clinically cured cases, significantly effective cases, and effective cases, then dividing by the total number of cases, and finally multiplying by 100%. The significantly cured rate is calculated by adding the number of clinically cured cases and the number of clinically significantly effective cases, then dividing by the total number of cases, and finally multiplying by 100%.

[0090] 2. Efficacy evaluation

[0091] Multiple scales were used to comprehensively assess the efficacy, including the Hamilton Anxiety Rating Scale (HAMA), the Generalized Anxiety Disorder Scale (GAD-7), the Self-Rating Anxiety Scale (SAS), the Pittsburgh Sleep Quality Index (PSQI), and the Traditional Chinese Medicine Syndrome Score Scale. The efficacy was primarily judged based on the reduction rate of the HAMA score. The formula for calculating the reduction rate is: (Pre-treatment score minus post-treatment score) divided by the pre-treatment score, then multiplied by 100%. Based on the reduction rate, the efficacy was divided into four levels: a HAMA score below 7 or a reduction rate of 75% or greater was considered cured; a reduction rate between 50% and 75% (inclusive but exclusive) was considered significant improvement; a reduction rate between 30% and 50% (inclusive but exclusive) was considered improvement; and a reduction rate less than 30% was classified as ineffective. The overall effective rate is calculated as follows: add the number of cured cases, the number of cases with significant improvement, and the number of cases with improvement, then divide by the total number of cases, and finally multiply by 100%. The significant cure rate is calculated in the same way: add the number of clinically cured cases and the number of clinically significant cases, divide by the total number of cases, and then multiply by 100%.

[0092] 3. Evaluation Criteria for Traditional Chinese Medicine Syndrome Therapy

[0093] The TCM syndrome efficacy evaluation standard was formulated with reference to the 2002 edition of the "Guiding Principles for Clinical Research of New Traditional Chinese Medicines (Trial)".

[0094] (1) Clinical recovery: When the subject’s clinical symptoms have completely or basically disappeared and the reduction rate is greater than or equal to 95%, the subject is judged to be clinically recovered.

[0095] (2) Significant effect: the main symptoms are controlled, the secondary symptoms are alleviated, and the reduction rate is less than 95% but greater than or equal to 70%.

[0096] (3) Effective: The main symptoms are relieved, but the secondary symptoms are not significantly improved. The reduction rate is less than 70% but greater than or equal to 30%.

[0097] (4) Ineffective: Clinical symptoms do not improve significantly or even worsen, with a deduction rate of less than 30%.

[0098] The overall effective rate is the sum of the clinical cure rate, the significant efficacy rate, and the effective rate. The formula for calculating the reduction rate is: (total score before treatment minus total score after treatment) divided by the total score before treatment, then multiplied by 100%.

[0099] 4. Serum immune marker assessment

[0100] Fasting venous blood (3 ml) was collected from both groups of patients at three time points: before treatment, 4 weeks after treatment, and 8 weeks after treatment. After centrifugation for 15 minutes, the blood samples were aliquoted into serum and stored at -80°C. The levels of interleukin-6 (IL-6), interleukin-17A (IL-17A), and tumor necrosis factor-α (TNF-α) were then measured using enzyme-linked immunosorbent assay (ELISA).

[0101] 5. Serum neurotransmitter detection

[0102] Similarly, fasting venous blood (3 ml) was collected from three groups of patients at three time points: before treatment, 4 weeks after treatment, and 8 weeks after treatment. After centrifugation for 15 minutes, the blood samples were aliquoted into serum and stored at -70°C. The levels of neurotransmitters GABA, Glu, and 5-HT in the patient serum were measured using ELISA.

[0103] 6. Detection of miRNAs in neuro-immune imbalance

[0104] At week 8 post-treatment, 3 ml of fasting venous blood was collected from both groups of patients. After centrifugation for 15 minutes, the blood samples were aliquoted into serum and stored at -80°C. The expression levels of target mRNAs miR-107-3p, miR-194-5p, microRNA-146a, and microRNA-155 in the patients' blood were quantitatively detected using qRT-PCR.

[0105] 7. Adverse reaction assessment

[0106] This study assessed adverse reactions during treatment through the following three aspects:

[0107] (1) General physical examination items: including the measurement of indicators such as blood pressure, heart rate, body temperature, and respiration.

[0108] (2) Auxiliary examinations: including electrocardiogram, blood routine, liver function and kidney function tests.

[0109] (3) Treatment Emergent Symptoms (TESS) scale: used to assess the incidence of adverse reactions during treatment.

[0110] These assessment items are routinely tested once before treatment and again within 8 weeks after treatment. If a result is found that was normal before treatment but abnormal after treatment, or if a result is abnormal before treatment and worsens after treatment, a follow-up examination should be conducted promptly. For patients whose results remain abnormal after follow-up examination, continued follow-up examinations are required until the results are normal, or until three consecutive follow-up examinations confirm that the results cannot be restored to normal.

[0111] 8. Data entry and management

[0112] Epidata 3.1 software was used to input the data for this clinical trial. Two data entry clerks independently entered the raw data from the CRF tables into the database. After all the data was entered, the Checks function in Epidata software was used to compare the data entered by the two clerks, and the original data was compared again to ensure the accuracy of the data and to control the error within 1%.

[0113] 9. Statistical processing

[0114] Per-protocol set (PPS) data analysis was performed, including all subjects who adhered to the trial protocol, had no missing baseline variables, had measurable primary variables, and did not commit material violations of the trial protocol. SPSS 25.0 software was used for data processing and statistical analysis. For normally distributed continuous data... The analysis indicates that ANOVA was used to compare the three groups at the same treatment time point, and paired t-tests were used to compare the data before and after treatment within the same group. For count data, descriptive statistical analysis was performed using absolute and relative numbers, with percentages or proportions being the primary indicators for relative numbers. The chi-square test was used for statistical analysis. Non-parametric tests were used for ordinal data. P< A value of 0.05 indicates that the tested data is statistically significant.

[0115] result

[0116] 1. General Information

[0117] Baseline data: In the treatment group, there were 10 males and 20 females, with an average age of (35.00 ± 12.64) years; in the placebo group, there were 3 males and 28 females, with an average age of (40.61 ± 14.34) years. There was no difference in gender between the two groups. P= 0.024), with no statistically significant difference in age ( P > 0.05).

[0118] Dropout rate. A total of 72 patients with liver stagnation and fire anxiety syndrome who met the criteria were included in this study, with 36 patients in the experimental group and 36 patients in the placebo group. Among them, 5 patients dropped out of the experimental group (1 patient dropped out due to adverse reaction of stomach pain, 2 patients dropped out because they could not adhere to the medication, 1 patient dropped out because it was ineffective, and 1 patient dropped out because they could not complete the follow-up). 4 patients dropped out of the placebo group (3 patients dropped out because it was ineffective, and 1 patient dropped out because they could not complete the follow-up).

[0119] Table 4. Comparison of primary baseline data (FAS) between the two groups of subjects.

[0120]

[0121] 2. Evaluation of anti-anxiety effect

[0122] There was no significant difference in the Hamilton Anxiety Rating Scale (HAMA) scores between the two groups before treatment. P> 0.05). Compared with the placebo group, there was no significant difference in the scores at week four in the treatment group ( P> 0.05); the score decreased significantly in week eight ( P< The score was 0.01, indicating that composition C was significantly more effective than placebo. Both groups showed a significant decrease in scores before and after treatment. P< The improvement in HAAMD score was more significant in the experimental group after treatment (0.001). This indicates that, over time, the treatment group showed a more significant improvement in HAMD score compared to the placebo group (see Table 5).

[0123] Table 5. Comparison of Hamilton Anxiety Rating Scale scores before and after treatment in the two groups (x±s, points)

[0124]

[0125] There was no significant difference in the Generalized Anxiety Disorder Scale (GAD-7) scores between the two groups before treatment. P> 0.05). Compared with the placebo group, there was no significant difference in the scores at week four in the treatment group ( P> 0.05); the score decreased significantly in week eight ( P< The score was 0.01, indicating that composition C was significantly more effective than placebo. Within both groups, the scores decreased significantly before and after treatment. P< The value was 0.01, indicating a time effect. There was no interaction effect between the time factor and the grouping factor. P> 0.05). Compared with the placebo group, the experimental group showed more significant improvement in GAD-7 score after treatment (see Table 6).

[0126] Table 6 Comparison of GAD-7 scale scores before and after treatment in the two groups of patients (x±s, points)

[0127]

[0128] There was no significant difference in the Self-Rating Anxiety Scale (SAS) scores between the two groups before treatment. P > The values ​​were 0.05, indicating comparability. At each evaluation time point after treatment, there were no significant differences between the groups at week four of treatment. P> 0.05), and at week eight after treatment, the difference between the two groups was significant ( P< The value 0.05 indicates that the treatment group had a significantly higher impact on the SAS score compared to the placebo group after week 8 of treatment. Differences before and after treatment were statistically significant within both groups. P< 0.01). The differences in SAS scores between the two groups at each time point before and after treatment were statistically significant ( P< The value was 0.01, indicating a time effect. There was no interaction effect between the time factor and the grouping factor. P> 0.05). Compared with the placebo group, the experimental group showed more significant improvement in SAS scores after treatment (see Table 7).

[0129] Table 7 Comparison of Self-Rating Anxiety Scale scores before and after treatment in the two groups (x±s, points)

[0130]

[0131] There was no statistically significant difference in the Pittsburgh Sleep Quality Index (PSQI) scores between the two groups before treatment. P> 0.05). At each evaluation time point after treatment, there were no statistically significant differences between groups at week four of treatment. P> 0.05), while at the eighth week after treatment, the difference between the two groups was more significant ( P= The value 0.05 indicates that the treatment group had a greater impact on PSQI scores than the placebo group after week 8 of treatment, and this effect was statistically significant. Within both groups, the differences before and after treatment were statistically significant. P< 0.01). The differences in PSQI scores between the two groups at each time point before and after treatment were statistically significant. P< The value was 0.01, indicating a time effect. There was no interaction effect between the time factor and the grouping factor. P> 0.05). Compared with the placebo group, the improvement in PSQI score was more significant in the experimental group after treatment (see Table 8).

[0132] Table 8 Comparison of PSQI scores before and after treatment in the two groups (x±s, points)

[0133]

[0134] 3. Evaluation of the efficacy of TCM syndrome differentiation before and after treatment in the two groups

[0135] There was no statistically significant difference in the TCM syndrome scores between the two groups before treatment. P> 0.05). At each evaluation time point after treatment, there were no statistically significant differences between groups at week four of treatment. P> 0.05), while at the eighth week after treatment, the difference between the two groups was more significant ( P< The difference was 0.01, indicating that the treatment group had a significantly higher TCM syndrome score than the placebo group after week 8 of treatment. The differences in TCM syndrome scores between the two groups at each time point before and after treatment were statistically significant. P< The value was 0.01, indicating a time effect. There was no interaction effect between the time factor and the grouping factor. P> 0.05). This indicates that the TCM syndrome scores of both groups showed a decreasing trend with the change of treatment time, and the decreasing trend of the treatment group was significantly higher than that of the placebo group. Baihe Jieyu Anshen Granules had a better effect on improving the TCM syndrome scores (see Table 9).

[0136] Table 9 Comparison of TCM syndrome scores before and after treatment in the two groups of patients (x±s, points)

[0137]

[0138] The efficacy of TCM syndrome differentiation was compared between the two groups. At week 8 after treatment, the overall effective rate of TCM syndrome differentiation in the placebo group was 50.00% (16 / 32), while the overall effective rate in the treatment group was 81.7% (27 / 21). There was no statistically significant difference between the two groups within each group. P> 0.05). The overall effective rate in the experimental group at week 8 after treatment was higher than that in the placebo group, and the difference was statistically significant. P= 0.008). This suggests that Baihe Jieyu Anshen Granules have a good therapeutic effect on improving TCM syndromes.

[0139] Table 10 Comparison of TCM syndrome efficacy before and after treatment in the two groups of patients (x±s, points)

[0140]

[0141] Note: # Compared with the placebo group, the experimental group after treatment P< 0.05, after treatment in the experimental group P< 0.05, # P< 0.05, ## P< 0.01, ### P< 0.001.

[0142] In terms of the efficacy of traditional Chinese medicine (TCM) in treating single symptoms such as irritability, sensitivity and suspicion, restlessness, insomnia, chest and rib distension, flushed face and red eyes, bitter taste in mouth and dry throat, the experimental group showed significantly better efficacy than the placebo group. P< 0.05). Both groups showed good therapeutic effects on palpitations, frequent sighing, yellow urine, constipation, mouth ulcers, hot flashes, and night sweats, with no statistically significant difference. P> 0.05), see Table 11.

[0143] Table 11. Therapeutic Effects of Traditional Chinese Medicine on Single Symptoms

[0144]

[0145] 4. Evaluation of treatment efficacy

[0146] In the placebo group, the overall effective rates at weeks 4 and 8 after treatment were 34.37% (11 / 32) and 46.87% (17 / 32), respectively, with no statistically significant difference within the group (P>0.05). In the experimental group, the overall effective rates at weeks 4 and 8 after treatment were 80.64% (25 / 32) and 87.09% (27 / 32), respectively. The difference within the group was statistically significant. P< 0.05); This suggests that both composition C and placebo can improve patients' anxiety behavior, with composition C having a stronger anti-anxiety effect (see Table 12).

[0147] Table 12 Comparison of treatment efficacy between the two groups (cases)

[0148]

[0149] Note: *Compared with the pre-treatment values ​​in this group. P< 0.05, * P< 0.05, ** P< 0.01, *** P< 0.001; # Compared with the placebo group, the experimental group after treatment P< 0.05.

[0150] 5. Assessment of adverse reactions before and after treatment in both groups

[0151] No serious adverse reactions were observed in either group.

[0152] in conclusion

[0153] Clinical studies have shown that this invention can effectively improve various TCM symptoms in patients with generalized anxiety disorder of the liver-heat type, with significant anti-anxiety effects and no obvious adverse drug reactions.

[0154] In summary, pharmacodynamic studies indicate that this invention significantly improves anxiety-like behaviors. Clinical efficacy studies demonstrate that this invention has significant anti-anxiety effects, improves sleep quality, and possesses the functions of soothing the liver and relieving depression, calming the mind and soothing the nerves. It can effectively improve various TCM symptoms in patients with generalized anxiety disorder caused by liver stagnation and fire, improve patients' quality of life, and has few adverse reactions and high safety.

[0155] Those skilled in the art should understand that the discussion of any of the above embodiments is merely exemplary and is not intended to imply that the scope of protection of this application is limited to these examples; under the concept of this application, the technical features of the above embodiments or different embodiments can also be combined, the steps can be implemented in any order, and there are many other variations of different aspects of one or more embodiments of this application as described above, which are not provided in detail for the sake of brevity.

[0156] One or more embodiments in this application are intended to cover all such substitutions, modifications, and variations that fall within the broad scope of this application. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of one or more embodiments in this application should be included within the protection scope of this application.

Claims

1. A traditional Chinese medicine composition for relieving anxiety, characterized in that, It is made from the following Chinese herbal raw materials in the following weight ratios: 0.5-6 parts vinegar-processed Bupleurum chinense, 1-6 parts Scutellaria baicalensis, 0.5-4 parts lotus seed heart, and 1-5 parts rose.

2. A traditional Chinese medicine composition for relieving anxiety, characterized in that, It is made from the following Chinese herbal raw materials in the indicated weight proportions: 0.5-6 parts vinegar-processed Bupleurum chinense, 1-6 parts Scutellaria baicalensis, 0.5-4 parts lotus seed heart, 1-5 parts rose, 1-7 parts lily bulb, 1-6 parts Rehmannia glutinosa, and 1-6 parts Anemarrhena asphodeloides.

3. A traditional Chinese medicine composition for relieving anxiety, characterized in that, It is made from the following Chinese medicinal materials in the indicated weight proportions: 0.5-6 parts of vinegar-processed Bupleurum chinense, 1-6 parts of Scutellaria baicalensis, 0.5-4 parts of Nelumbo nucifera seed heart, 1-5 parts of Rosa rugosa, 1-7 parts of Lilium brownii, 1-6 parts of Rehmannia glutinosa, 1-6 parts of Anemarrhena asphodeloides, 1-6 parts of Poria cocos, 0.8-5 parts of Valerian, 1-7 parts of Albizia julibrissin bark, 1-4 parts of Adenophora stricta, and 0.2-3 parts of prepared Glycyrrhiza uralensis.

4. The anti-anxiety traditional Chinese medicine composition according to any one of claims 1-3, characterized in that, The traditional Chinese medicine composition is formulated into a clinically acceptable dosage form.

5. The anti-anxiety traditional Chinese medicine composition according to claim 4, characterized in that: The traditional Chinese medicine composition can be prepared as decoction, tablet, capsule, granule, powder, syrup, pill or oral liquid.

6. The anti-anxiety traditional Chinese medicine composition according to claim 4, characterized in that, The traditional Chinese medicine composition is formulated into soft capsules, dispersible tablets, orally disintegrating tablets, or pills.

7. A method for preparing an anti-anxiety traditional Chinese medicine composition according to any one of claims 1-6, characterized in that, After mixing the Chinese herbal raw materials, add water to extract 1-3 times, adding 4-12 times the amount each time; each extraction lasts 1-2 hours. Combine the extracts, filter, collect the filtrate, concentrate, and you have the final product.

8. The preparation method according to claim 7, characterized in that, Extract twice with water, adding 6-12 times the amount each time; each extraction lasts 1-2 hours. Filter the extract, concentrate it, and you have the final product.

9. The preparation method according to claim 7, characterized in that, Extract twice with water. For the first extraction, add 8-12 times the amount of water and extract for 2 hours. For the second extraction, add 6-10 times the amount of water and extract for 1.5 hours. Filter the extract and concentrate it to obtain the final product.

10. The preparation method according to claim 9, characterized in that, Before the first extraction, the Chinese herbal raw materials are soaked for 0.5 hours.

11. The use of an anxiolytic traditional Chinese medicine composition according to any one of claims 1-6 or an anxiolytic traditional Chinese medicine composition prepared by the preparation method according to any one of claims 7-10 in the preparation of an anxiolytic medicament.

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