Use of shugan shunqi composition in the preparation of anxiolytic drugs

Abstract

The present application relates to the technical field of anxiety treatment drugs, in particular to the use of Shugan Shunqi composition in the preparation of anti-anxiety drugs. The function of Shugan Shunqi composition is to soothe liver, regulate qi and relieve pain. It is used for liver stagnation and qi stagnation syndrome, including distending fullness in both sides of the chest, stomachache, vomiting, belching, acid regurgitation and hiccup. Through clinical trials, it is found that in addition to the above uses, Shugan Shunqi composition can also be used for the treatment of anxiety, especially for dyspepsia with anxiety (liver stagnation and qi stagnation syndrome), and has an ideal therapeutic effect. In addition, the present technical solution improves the original Shugan Shunqi pill dosage form, improves the dissolution degree of the active ingredients through extraction, and overcomes the problems of limited drug user population and poor patient compliance by preparing multiple dosage forms and avoiding the addition of honey. Moreover, the improvement of the preparation method and the dosage form further improves the effect of the drug in treating anxiety.

Description

Technical Field

[0001] This invention relates to the field of drugs for treating anxiety disorders, specifically to the use of a liver-soothing and qi-regulating composition in the preparation of anti-anxiety drugs. Background Technology

[0002] Anxiety disorder is a common mental disorder characterized by persistent, excessive, and uncontrollable worry and fear that is disproportionate to or irrelevant to the actual situation. People with anxiety disorder often have excessive worry about minor things in daily life or things that might happen in the future. The diagnosis of anxiety disorder is usually based on the criteria listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), with different types of anxiety disorders having different diagnostic indicators. Treatment for anxiety disorder typically includes two main approaches: medication and psychotherapy, sometimes combined with lifestyle modifications and adjunctive therapies. Traditional Chinese medicine (TCM) is relatively slow-acting, mild in its effects, has fewer adverse reactions, and shows good long-term efficacy in the clinical prevention and treatment of anxiety disorder. TCM treatment plans for anxiety disorder are usually based on TCM theory and tailored to the individual's specific symptoms and constitution. TCM believes that anxiety disorder may be caused by various "syndromes," such as liver qi stagnation, deficiency of both heart and spleen, and disharmony between heart and kidney. Therefore, the treatment plan will select appropriate drug combinations according to the principle of syndrome differentiation and treatment. For example, Gui Pi Tang, composed of Angelica sinensis, Atractylodes macrocephala, longan pulp, and stir-fried jujube seed, is suitable for anxiety symptoms caused by deficiency of both heart and spleen.

[0003] Shugan Shunqi Pills are an optimized version of Chaihu Shugan Powder from the *Jingyue Quanshu* (Complete Works of Jingyue). It is a pure traditional Chinese medicine preparation composed of 13 herbs: Bupleurum, Cyperus (vinegar-processed), White Peony Root, Turmeric, Fried Immature Bitter Orange, Magnolia Bark, Costus Root, Buddha's Hand, Corydalis Rhizome (vinegar-processed), Ligusticum Rhizome, Malan Grass, Tangerine Peel, and Licorice Root. Shugan Shunqi Pills (National Medicine Approval Number Z20026802, Standard Number: WS-11169(ZD-1169)-2002-2011Z) are large, black, honey-coated pills, each weighing approximately 9g. Their functions and indications are: soothing the liver, regulating qi, and relieving pain; used for liver qi stagnation syndrome, characterized by: distension in the hypochondriac region, stabbing pain in the stomach, nausea, vomiting, and acid reflux. Experimental studies have shown that Shugan Shunqi Pills can effectively improve symptoms in functional dyspepsia models and gastrointestinal motility abnormality models, inhibit gastric acid secretion, promote gastrointestinal motility, improve serum gastrointestinal hormone levels, increase pepsin activity, and also have significant pharmacological effects of increasing intestinal absorption and relieving pain.

[0004] In addition to the above-mentioned therapeutic effects, some literature points out that Shugan Shunqi Pills also have the following therapeutic effects: Shugan Shunqi Pills have a dissolving effect on cholesterol stones and pigment stones, and can also inhibit the formation of new stones. They can also promote the appearance of high-amplitude interval peak-shaped potentials to varying degrees, suggesting that Shugan Shunqi Pills may have a good therapeutic effect on liver dysfunction and impaired flow of yang fluid (Chen Li, Lü Shanshan, Qiao Zhiwen, et al. Study on the choleretic efficacy of Shugan Shunqi Pills [J]. World Journal of Integrated Traditional and Western Medicine, 2014, 9(12): 1281-1284.). Shugan Shunqi Pills have a strong effect on improving the symptoms of functional dyspepsia and treating gastric ulcers (Lü Shanshan, Zhou Nianhua, Yang Hui, et al. Protective effect of Shugan Shunqi Pills on gastric ulcer and reflux esophagitis model mice [J]. China Pharmacy, 2014, 25(23): 2121-2124.). Shugan Shunqi Pills have a good anti-inflammatory effect and can significantly improve pathological changes such as swelling and hyperplasia caused by inflammation. They also have a certain effect on the treatment of gastrointestinal inflammations such as superficial gastritis (Qiao Zhiwen, Chen Li, Lü Shanshan, et al. Study on the anti-inflammatory effect of Shugan Shunqi Pills [J]. China Pharmacy, 2013, 24(47):4444-4446.). Therefore, the therapeutic uses of Shugan Shunqi Pills need to be further explored to enrich the selection of anti-anxiety drugs in clinical practice. Summary of the Invention

[0005] The present invention aims to provide the application of the liver-soothing and qi-regulating composition in the preparation of anti-anxiety drugs, in order to solve the technical problems that the uses and indications of the existing liver-soothing and qi-regulating pill need to be further developed, and that there is a lack of effective anti-anxiety traditional Chinese medicine in clinical practice.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] The application of the liver-soothing and qi-regulating composition in the preparation of anti-anxiety drugs, wherein the liver-soothing and qi-regulating composition is made from the following medicinal materials in parts by weight: 25-35 parts of Magnolia officinalis, 25-35 parts of Ligusticum chuanxiong, 25-35 parts of Cyperus rotundus, 25-35 parts of Paeonia lactiflora, 25-35 parts of Bupleurum chinense, 25-35 parts of Citrus aurantium, 25-35 parts of Curcuma longa, 25-35 parts of Citrus medica, 25-35 parts of Aucklandia lappa, 25-35 parts of Citrus reticulata peel, 20-30 parts of Glycyrrhiza uralensis, 25-35 parts of Corydalis yanhusuo, and 45-60 parts of Eupatorium fortunei.

[0008] Preferably, the liver-soothing and qi-regulating composition is made from the following medicinal materials in parts by weight: 31.4 parts Magnolia officinalis, 31.4 parts Ligusticum chuanxiong, 31.4 parts Cyperus rotundus, 31.4 parts Paeonia lactiflora, 31.4 parts Bupleurum chinense, 31.4 parts Citrus aurantium, 31.4 parts Curcuma longa, 31.4 parts Citrus medica, 31.4 parts Aucklandia lappa, 31.4 parts Citrus reticulata peel, 23.55 parts Glycyrrhiza uralensis, 31.4 parts Corydalis yanhusuo, and 58.85 parts Eupatorium fortunei.

[0009] This technical solution also provides the application of a liver-soothing and qi-regulating composition in the preparation of drugs for improving, adjuvant treatment, or treatment of functional dyspepsia accompanied by anti-anxiety, characterized in that the liver-soothing and qi-regulating composition is made from the following medicinal materials in parts by weight: Magnolia officinalis 25-35 parts, Ligusticum chuanxiong 25-35 parts, Cyperus rotundus 25-35 parts, Paeonia lactiflora 25-35 parts, Bupleurum chinense 25-35 parts, Citrus aurantium 25-35 parts, Curcuma longa 25-35 parts, Citrus medica 25-35 parts, Aucklandia lappa 25-35 parts, Citrus reticulata 25-35 parts, Glycyrrhiza uralensis 20-30 parts, Corydalis yanhusuo 25-35 parts, and Eupatorium fortunei 45-60 parts;

[0010] Preferably, the liver-soothing and qi-regulating composition is made from the following medicinal materials in parts by weight: 31.4 parts Magnolia officinalis, 31.4 parts Ligusticum chuanxiong, 31.4 parts Cyperus rotundus, 31.4 parts Paeonia lactiflora, 31.4 parts Bupleurum chinense, 31.4 parts Citrus aurantium, 31.4 parts Curcuma longa, 31.4 parts Citrus medica, 31.4 parts Aucklandia lappa, 31.4 parts Citrus reticulata peel, 23.55 parts Glycyrrhiza uralensis, 31.4 parts Corydalis yanhusuo, and 58.85 parts Eupatorium fortunei.

[0011] Furthermore, the dosage form of the liver-soothing and qi-regulating composition is any one of pills, granules, tablets, oral liquids, or capsules.

[0012] Furthermore, the liver-soothing and qi-regulating composition is prepared by the following method: the medicinal raw materials are pulverized and passed through an 80-120 mesh sieve, mixed evenly, and the active pharmaceutical ingredient is obtained; pharmaceutical excipients are added to the active pharmaceutical ingredient and it is prepared into a clinically acceptable oral formulation.

[0013] Furthermore, the liver-soothing and qi-regulating composition is prepared according to the following method: 1 / 2 to 2 / 3 of the weight of each medicinal material is pulverized and passed through an 80-120 mesh sieve; the coarse residue and fine powder are set aside separately; the remaining medicinal material is pulverized into coarse powder; the coarse powder and coarse residue are mixed evenly, and an ethanol solution of 6-8 times the total weight of the coarse powder and coarse residue is added. After soaking at 40-60℃ for 30-90 minutes, a first reflux extraction is performed for 1-2 hours, followed by a second reflux extraction of 6-8 times the total weight of the coarse powder and coarse residue for 1-2 hours. The extracts were combined, ethanol was recovered under reduced pressure, filtered, and the residue was recovered. The extract was concentrated into extract I, in which the concentration of the ethanol solution used in the extraction was 45-65%. The residue obtained after extraction was decocted with water 2-3 times, each time adding 6-10 times the amount of water as the residue, for 1-3 hours each time. The decoctions were combined, filtered, and the obtained filtrate was concentrated into extract II. Extracts I and II were combined, and then fine powder was added and mixed well to obtain the active pharmaceutical ingredient. Pharmaceutical excipients were added to the active pharmaceutical ingredient to prepare it into a clinically acceptable formulation.

[0014] Furthermore, the liver-soothing and qi-regulating composition is prepared by the following method: the medicinal raw materials are extracted by distillation to obtain a distilled aqueous phase, a distilled oil phase, and a residue; the residue is extracted by boiling in water to obtain a decoction, the decoction and the distilled aqueous phase are combined to obtain an extract, the extract is concentrated into an extract, and the extract, the distilled oil phase, and suitable excipients are prepared into a clinically acceptable oral dosage form.

[0015] Furthermore, the liver-soothing and qi-regulating composition is prepared according to the following method: the medicinal raw materials are extracted by distillation to obtain a distilled aqueous phase, a distilled oil phase, and a residue; the residue is extracted by boiling in water to obtain a decoction, and the decoction and the distilled aqueous phase are combined to obtain an extract; the distilled oil phase is treated with an inclusion agent to obtain an inclusion compound powder or an inclusion compound solution; the extract is concentrated and then combined with the inclusion compound powder or inclusion compound solution and suitable excipients to prepare a clinically acceptable oral dosage form.

[0016] Furthermore, the method for extracting the dregs by decoction is as follows: add 6 to 8 times the weight of the raw medicinal materials to water for a first decoction extraction for 2 to 3 hours; add 6 to 8 times the weight of the raw medicinal materials to water and adjust the pH value to 7.0 to 7.5, and perform a second decoction extraction for 2 to 3 hours.

[0017] Furthermore, the distillation extraction adopts an intermittent distillation extraction method, wherein the intermittent distillation extraction is performed alternately by high-heat distillation and gentle boiling distillation;

[0018] Preferably, the intermittent distillation extraction uses water or alcohol solution as the extraction solvent; the total extraction time is 1 to 8 hours; the intermittent distillation extraction process is carried out in a cycle of first 10 to 20 minutes of high-heat distillation extraction followed by 10 to 20 minutes of gentle boiling distillation extraction.

[0019] Furthermore, the inclusion agent is hydroxypropyl-β-cyclodextrin; the inclusion treatment method is as follows: take 3 to 5 times the mass of the distilled oil phase of the inclusion agent, dissolve it, and add the distilled oil phase dropwise at a rate of 1 to 2 ml / min under stirring conditions of 40 to 60 rpm. After the addition is completed, stir for 1.5 to 2.5 hours to obtain the inclusion solution; concentrate and dry it until the moisture content is less than 5.0%, and then pulverize it through an 80 to 100 mesh sieve to obtain the inclusion powder.

[0020] The present invention provides a liver-soothing and qi-regulating composition, the principle and beneficial effects of which are as follows:

[0021] Through animal and clinical trials, the inventors discovered that the liver-soothing and qi-regulating composition has therapeutic effects on anxiety disorders, particularly functional dyspepsia accompanied by anxiety symptoms. Furthermore, the preparation of the active pharmaceutical ingredients has a certain impact on the drug's anti-anxiety efficacy. The inventors further developed methods to enhance the therapeutic effect of the liver-soothing and qi-regulating composition on anxiety disorders, progressing from raw herb powder preparations to raw herb ethanol extract preparations, and then to raw herb distillation followed by decoction extraction preparations, progressively improving the drug's efficacy. Extracting the volatile oil components of the medicinal materials and adding them to the finished product through appropriate encapsulation, while controlling the pH value during the decoction extraction process, can further enhance the drug's therapeutic effect on anxiety disorders.

[0022] Anxiety and depression are two common but distinct mental health conditions. Although they often coexist in the same individual and their symptoms overlap to some extent, they differ significantly in clinical presentation, pathogenesis, and treatment. Clinically, anxiety disorders are primarily characterized by worry, fear, tension, and excessive focus on potential threats. Physical symptoms may accompany these symptoms, such as palpitations, rapid heartbeat, sweating, trembling, muscle tension, headache, and stomach upset. Patients may experience sleep disturbances, such as difficulty falling asleep or frequent awakenings. These may manifest as restlessness, pacing, or fidgeting. Depression, on the other hand, is characterized by persistent low mood, loss of interest and pleasure, and decreased self-esteem. Thinking may become slowed, lack of motivation, and loss of interest in daily activities. Symptoms may include excessive or insomnia, changes in appetite, weight fluctuations, fatigue, or lack of energy. Depressed patients may experience suicidal thoughts or behaviors. The diagnostic criteria and scales used for these two disorders are different; therefore, developing new treatment approaches and medications for these two distinct mental illnesses is crucial and necessary. This technical solution specifically targets anxiety disorders and has found that the liver-soothing and qi-regulating composition has a good therapeutic effect on anxiety disorders. Detailed Implementation

[0023] The specific embodiments listed in this invention are merely examples, and the invention is not limited to the specific embodiments described below. For those skilled in the art, any equivalent modifications and substitutions to the embodiments described below are also within the scope of this invention. Therefore, all equivalent transformations and modifications made without departing from the spirit and scope of this invention should be covered within its scope.

[0024] Unless otherwise specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. All reagents or instruments without a specified manufacturer are commercially available, conventional products. Numerous specific details are provided in the following detailed embodiments to better illustrate the invention. Those skilled in the art should understand that the invention can be practiced even without certain specific details. In other embodiments, methods, means, equipment, and steps well-known to those skilled in the art are not described in detail in order to highlight the spirit of the invention.

[0025] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Unless otherwise specified, all units used in this specification are International Standard Units (SI), and all numerical values ​​and ranges appearing in this invention should be understood to include systematic errors unavoidable in industrial production.

[0026] The specific formula for the liver-soothing and qi-regulating composition is as follows:

[0027] The formula consists of: Magnolia officinalis 25-35 parts, Ligusticum chuanxiong 25-35 parts, Cyperus rotundus (vinegar-processed) 25-35 parts, Paeonia lactiflora 25-35 parts, Bupleurum chinense 25-35 parts, Citrus aurantium (fried) 25-35 parts, Curcuma longa 25-35 parts, Citrus medica 25-35 parts, Aucklandia lappa 25-35 parts, Citrus reticulata 25-35 parts, Glycyrrhiza uralensis 20-30 parts, Corydalis yanhusuo (vinegar-processed) 25-35 parts, and Eriocaulon buergerianum (Wedelia trifoliata) 45-60 parts. This technical solution primarily focuses on the medicinal uses and does not adjust the formula composition. For ease of experimental research, a consistent formula will be used in subsequent experiments; please refer to the formula in the examples for details. Using the above formula and the specified value ranges, therapeutic effects on depression can be achieved.

[0028] Example 1

[0029] This embodiment provides a method for preparing a liver-soothing and qi-regulating preparation, which involves preparing medicinal materials into pills according to existing standards for liver-soothing and qi-regulating pills. Specifically, the medicinal materials are:

[0030] Magnolia officinalis 31.4 parts, Ligusticum chuanxiong 31.4 parts, Cyperus rotundus (vinegar-processed) 31.4 parts, Paeonia lactiflora 31.4 parts, Bupleurum chinense 31.4 parts, Citrus aurantium (fried) 31.4 parts, Curcuma longa 31.4 parts, Citrus medica 31.4 parts, Aucklandia lappa 31.4 parts, Citrus reticulata 31.4 parts, Glycyrrhiza uralensis 23.55 parts, Corydalis yanhusuo (vinegar-processed) 31.4 parts, and Eupatorium fortunei 58.85 parts;

[0031] The preparation method is as follows:

[0032] S1-1: Take each medicinal material according to the above weight proportions and set aside. Crush each medicinal material and pass it through a 100-mesh sieve (an 80-120-mesh sieve can be used in actual operation). Mix well to obtain the active pharmaceutical ingredient.

[0033] S1-2: Add an appropriate amount of binder (starch paste) to the active pharmaceutical ingredient to prepare it into water pills. Water pills are a conventional dosage form in the prior art and are prepared by conventional methods, which will not be described in detail here. The preparation method refers to the method for preparing a liver-soothing and qi-regulating preparation described in the applicant's prior patent CN101461925B, which can be found in process one of that patent. This process uses the method of directly pulverizing traditional Chinese medicine into fine powder to obtain the preparation.

[0034] Example 2

[0035] This embodiment provides a method for preparing a liver-soothing and qi-regulating preparation. The medicinal materials are the same as in Example 1. The preparation method is as follows: it is prepared according to process two in the specification of patent CN101461925B, as detailed below:

[0036] S2-1: Take the thirteen medicinal materials according to the above-mentioned weight proportions and set them aside;

[0037] S2-2: Take 2 / 3 of the weight of each medicinal material (in actual operation, 1 / 2 to 2 / 3 of the weight can be used) and crush it and pass it through a 100-mesh sieve (in actual operation, an 80 to 120-mesh sieve can be used). Set aside the coarse powder and fine powder after sieving separately.

[0038] S2-3: Take the remaining 1 / 3 of the weight of the medicinal material and crush it into coarse powder;

[0039] S2-4: Mix the coarse powder and coarse head thoroughly, add 7 times the total weight of the coarse powder and coarse head in ethanol solution (6 to 8 times can be used in actual operation), soak at 50℃ (40 to 60℃ can be used in actual operation) for 60 min (30 to 90 min can be used in actual operation), and then perform the first reflux extraction for 2 hours (1 to 2 hours can be used in actual operation). Then add 7 times the total weight of the coarse powder and coarse head in ethanol solution (6 to 8 times can be used in actual operation) and perform the second reflux extraction for 2 hours (1 to 2 hours can be used in actual operation). Combine the extracts, recover the ethanol under reduced pressure, filter, recover the residue, and concentrate the extract into extract I, wherein the volume fraction of the ethanol solution used in the extraction is 50% (45 to 65% can be used in actual operation).

[0040] S2-5: Add water to the extracted residue and decoct 2-3 times (2 times in actual operation). Each time, add water at a volume of 6-10 times that of the residue (8 times in actual operation) for 1-3 hours (1.5 hours in actual operation). Combine the decoctions, filter, and concentrate the filtrate to extract II, which is half the weight of the residue. Combine extract I and extract II, add the fine powder obtained in step S2-2, mix well, and obtain the active pharmaceutical ingredient.

[0041] S2-6: Add pharmaceutical excipients to the active pharmaceutical ingredient to prepare it into a clinically acceptable formulation. In this embodiment, the active pharmaceutical ingredient is specifically prepared into water pills, i.e., water is used as the binder. This type of formulation and the preparation method are conventional methods in the prior art and will not be described in detail here.

[0042] Example 3

[0043] This embodiment provides a method for preparing a liver-soothing and qi-regulating preparation. The raw materials are the same as in Example 1, and the general preparation process is as follows:

[0044] Referring to the drug composition of Example 1, thirteen medicinal herbs, including Magnolia officinalis, Ligusticum chuanxiong, Cyperus rotundus (processed with vinegar), Paeonia lactiflora, Bupleurum chinense, Citrus aurantium (fried), Curcuma longa, Citrus medica, Aucklandia lappa, Citrus reticulata peel, Glycyrrhiza uralensis, Corydalis yanhusuo (processed with vinegar), and Eupatorium fortunei, were added to a volatile oil extractor. Water (preferably 8 times the weight of the herbs) was added, and the mixture was intermittently distilled for 1-8 hours (preferably 3-6 hours, more preferably 6 hours). After extraction, three parts were obtained: a distilled aqueous phase, a distilled oil phase, and a residue. These three parts were then separated, and the distilled aqueous phase was passed through a 200-mesh sieve for later use. The specific operation of the intermittent distillation extraction was as follows: high heat distillation for 10-20 minutes (preferably 10 minutes), followed by adjusting the heat to control the distillation system at a gentle boil for 10-20 minutes (preferably 10 minutes). This process was repeated until the extraction was completed. Existing technologies generally use steam heating, and the heating intensity is controlled by controlling the steam pressure of the distillation equipment. High heat refers to controlling the heating steam pressure in the range of 0.04 to 0.06 MPa in actual operation, while micro-boiling heating (gentle heat heating) refers to controlling the steam pressure in the range of 0.01 to 0.02 MPa.

[0045] After the intermittent distillation extraction is completed, the residue is decocted twice more. The first time, 6 to 8 times the weight of the medicinal material (preferably 7 times) of water is added, and the decoction is decocted for 2 to 3 hours (preferably 3 hours). The second time, 6 to 8 times the weight of the medicinal material (preferably 7 times) of water is added, and the decoction is decocted for 2 to 3 hours (preferably 3 hours). Each time, the decoction is passed through a 160 to 200 mesh sieve (preferably 200 mesh sieve). The distilled aqueous phase and the two decoctions are combined for later use (hereinafter referred to as the extract).

[0046] Various formulations are prepared using extracts and distilled oil phases. The distilled oil phase requires inclusion treatment with an inclusion agent; the extract requires concentration and drying. These are all common steps in the formulation preparation process.

[0047] The method for incorporating the distilled oil phase using an inclusion agent is as follows: Take 3-5 times the mass of volatile oil (hydroxypropyl-β-cyclodextrin) and dissolve it in 3-5 times the mass of hydroxypropyl-β-cyclodextrin (water); under stirring conditions of 40-60 rpm, add the volatile oil dropwise at a rate of 1-2 ml / min, and stir for 1.5-2.5 hours after the addition is complete to obtain an inclusion complex solution; concentrate and dry until the moisture content is less than 5.0%, then pulverize and pass through an 80-100 mesh sieve to obtain the inclusion complex powder. Preferably, the inclusion agent is hydroxypropyl-β-cyclodextrin.

[0048] The specific process of extract concentration and drying is as follows: the extract is concentrated into a clear paste with a relative density of 1.20 to 1.25 and then dried to obtain a dry paste with a dry paste rate of 24% to 27%; the dry paste is pulverized and passed through an 80 to 100 mesh sieve to obtain ointment powder.

[0049] The specific preparation method is as follows:

[0050] S3-1: Take thirteen medicinal herbs, including Magnolia officinalis, Ligusticum chuanxiong, Cyperus rotundus (processed with vinegar), Paeonia lactiflora, Bupleurum chinense, Citrus aurantium (fried), Curcuma longa, Citrus medica, Aucklandia lappa, Citrus reticulata peel, Glycyrrhiza uralensis, Corydalis yanhusuo (processed with vinegar), and Eriocaulon buergerianum, and add them to a volatile oil extractor. Add water in an amount eight times the weight of the herbs and perform intermittent distillation extraction for 6 hours. After extraction, obtain three parts: distilled aqueous phase, distilled oil phase, and residue. Separate the distilled aqueous phase, distilled oil phase, and residue. Pass the distilled aqueous phase through a 200-mesh sieve for later use. The specific operation method of intermittent distillation extraction is as follows: distill over high heat for 10 minutes, then reduce the heat and simmer for 10 minutes. Repeat the above procedure until the extraction process is completed.

[0051] S3-2: After the intermittent distillation extraction is completed, the residue is decocted twice more. The first time, the amount of water added is 7 times the weight of the medicinal material, and the decoction is decocted for 3 hours. The second time, the amount of water added is 7 times the weight of the medicinal material, and the decoction is decocted for 3 hours. Each time the decoction is taken, the liquid is passed through a 200-mesh sieve. The distilled aqueous phase and the two decoction liquids are combined to obtain the extract for later use.

[0052] S3-3: Preparation of inclusion complex powder from distilled oil phase: Take 4 times the mass of distilled oil phase hydroxypropyl-β-cyclodextrin, dissolve it in 4 times the mass of water, and add the distilled oil phase dropwise at a rate of 1-2 ml / min under stirring at 50 rpm. After the addition is complete, stir for 2 hours to obtain inclusion complex solution. Dry the inclusion complex solution until the moisture content is less than 5.0%, and then pulverize it through an 80-mesh sieve to obtain inclusion complex powder.

[0053] S3-4: Perform conventional concentration and drying treatment on the extract. First, concentrate the extract to a relative density of 1.20-1.25 (30-70℃, measured by a Pomeranian hydrometer). Then, dry the concentrated material to obtain a dry paste, which is then pulverized by a water-cooled pulverizer and passed through an 80-mesh sieve for later use to obtain the ointment powder.

[0054] More specifically, the process of preparing the dry paste can be carried out using the following method:

[0055] Take the extract, start the single-effect concentrator, vacuum degree ≤ -0.09Mpa, temperature ≤ 75℃, steam pressure ≤ 0.30Mpa. Filter the extract through a 250-mesh bag filter and transfer it into the single-effect concentrator to concentrate it to a relative density of 1.20~1.25 (30~70℃, measured with a Pomeranian hydrometer). Flow it into a belt dryer at a rate of 200kg / h. Set the heating temperature of the first stage of the belt dryer to 90~100℃; the second stage to 70~80℃; and the third stage to 50~60℃. Collect the dried extract after the third stage drying, with a dry extract yield of 24%~27%.

[0056] S3-5: Granulation: Mix the inclusion complex powder, ointment powder, crospovidone, microcrystalline cellulose, and pregelatinized starch and granulate. After granulation, mix with magnesium stearate and compress to obtain liver-soothing and qi-regulating tablets. The excipients and dosage ranges used in tablet preparation are: crospovidone 4-8 parts (6 parts in the specific experiment), microcrystalline cellulose 10-20 parts (15 parts in the specific experiment), and magnesium stearate 0.75-1.5 parts (1.35 parts in the specific experiment). In the dry granulation step, pregelatinized starch is used only as a filler. The amount of pregelatinized starch added is based on the weight of other materials in the actual preparation process to ensure the predetermined total amount of materials.

[0057] Correspondingly, based on this embodiment, those skilled in the art can also select appropriate pharmaceutical excipients and combine them with inclusion complex powder (or inclusion complex solution), extract, etc., according to the needs of dosage form selection, to prepare them into tablets, granules, capsules, oral liquids, etc., which will not be elaborated here. The main components that achieve the drug efficacy are the active pharmaceutical ingredients, including inclusion complex powder and ointment powder. These active pharmaceutical ingredients can be prepared into various dosage forms according to specific needs and conventional methods of the prior art.

[0058] Example 4

[0059] This embodiment provides a method for preparing a liver-soothing and qi-regulating preparation. The raw materials are the same as in Example 3, but the preparation method differs from that in Example 3 in the following ways:

[0060] After the intermittent distillation extraction is completed, the residue is decocted twice more. The first time, 6 to 8 times the weight of the medicinal material (preferably 7 times) of water is added, and the decoction is carried out for 2 to 3 hours (preferably 3 hours). The second time, 6 to 8 times the weight of the medicinal material (preferably 7 times) of water is added. During the second decoction, sodium hydroxide is used to adjust the pH of the system consisting of the residue and water to 7.0 to 7.5 (preferably 7.2), and the decoction is carried out for 2 to 3 hours (preferably 3 hours). Each time, the decoction is passed through a 160 to 200 mesh sieve (preferably 200 mesh sieve). The distilled aqueous phase and the two decoctions are combined for later use (hereinafter referred to as the extract).

[0061] More specifically, step S3-2 also includes: adjusting the pH of the system consisting of the dregs and water to 7.2 with sodium hydroxide during the second decoction, and then decocting for 3 hours.

[0062] The remaining steps are the same as in Example 3.

[0063] Experimental Example 1

[0064] This experimental example is an animal experiment for treating anxiety / depression, as detailed below:

[0065] (1) Laboratory animals and grouping

[0066] This experiment used SD rats (SPF grade, weighing 160-200g) as experimental animals, both male and female. After one week of acclimatization feeding, the rats were randomly divided into 11 groups: blank control group, anxiety disorder model group, anxiety disorder treatment group 1, anxiety disorder treatment group 2, anxiety disorder treatment group 3, and anxiety disorder treatment group 4; and depression model group, depression treatment group 1, depression treatment group 2, depression treatment group 3, and depression treatment group 4. Among them, the blank control group consisted of 16 rats (including 8 rats for depression control and 8 rats for anxiety control), and each of the other groups had 8 rats. The blank control group received no treatment and had free access to water and food.

[0067] Depression Modeling: The modeling methods for the depression model group, depression drug treatment group 1, depression drug treatment group 2, depression drug treatment group 3, and depression drug treatment group 4 are as follows: The depression model was established by CUMS stimulation for 5 weeks. The stress stimulation methods included: 1) fasting and water restriction for 24 hours; 2) foot electrical stimulation; 3) moist bedding; 4) tilting the cage at 45°; 5) behavioral restraint; 6) continuous shaking of the cage; 7) olfactory stimulation. One of the above seven methods was randomly selected to stimulate the target rats every day, and the stimulation method was not repeated on consecutive days.

[0068] Anxiety modeling: The modeling methods for the anxiety model group, anxiety drug treatment group 1, anxiety drug treatment group 2, anxiety drug treatment group 3, and anxiety drug treatment group 4 are as follows: Anxiety rat model was established using the empty bottle drinking stimulation method. Uncertain empty bottle stimulation was performed during the modeling period, which lasted for 21 days. During the modeling period, the rats were allowed free access to food and drink.

[0069] (2) Dosing regimen

[0070] Blank control group: fed normally, without medication;

[0071] Anxiety disorder model group: Modeling was performed by gavage with an equal volume of physiological saline;

[0072] Anxiety disorder treatment group 1: The drug prepared in Example 1 was administered by gavage and dissolved in physiological saline;

[0073] Anxiety disorder treatment group 2: The drug prepared in Example 2 was dissolved in physiological saline by gavage;

[0074] Anxiety disorder treatment group 3: The drug prepared in Example 3 was dissolved in physiological saline by gavage;

[0075] Anxiety disorder treatment group 4: The drug prepared in Example 4 was dissolved in physiological saline by gavage.

[0076] Depression model group: Modeling was performed by gavage with an equal volume of physiological saline;

[0077] Depression treatment group 1: The drug prepared in Example 1 was administered by gavage and dissolved in physiological saline;

[0078] Depression treatment group 2: The drug prepared in Example 2 was dissolved in physiological saline by gavage;

[0079] Depression treatment group 3: The drug prepared in Example 3 was dissolved in physiological saline by gavage.

[0080] Depression treatment group 4: The drug prepared in Example 4 was dissolved in physiological saline by gavage;

[0081] Dosage design: Based on the usage and dosage recorded in the instructions for the marketed product - Shugan Shunqi Wan, the equivalent dose for rats was calculated to be 1.33g crude drug / kg, and the drug was administered according to this dose.

[0082] Dosage cycle: Administer once daily by gavage for 14 consecutive days.

[0083] (3) Experimental observation and results of depression

[0084] Effects of each group of drugs on the results of the forced swimming test

[0085] Forced swimming experiment was conducted after the last administration: Each experimental group of rats was placed in a cylindrical glass container with a water depth of approximately 20 cm, ensuring that the rats' limbs could not touch the bottom of the container. The water temperature was maintained uniformly across all groups. The rats were forced to swim for 6 minutes, and the total immobility time in the last 4 minutes was recorded. Immobility time was defined as the rats floating quietly in the water, exhibiting no struggling or climbing behavior except for keeping their heads above water. The experimental results are shown in Table 1.

[0086] Effects of each drug group on the results of sucrose preference in rats

[0087] After the last administration, a sucrose preference test was conducted on rats in each group. Before the experiment, sucrose training was performed by administering two bottles of 1% sucrose solution to each rat cage for 24 hours. The next day, a bottle of pure water was used instead of the 1% sucrose solution. After sucrose training, the rats were fasted for 12 hours before the sucrose preference test. Rats were housed individually and given one bottle each of 1% sucrose solution and pure water for 24 hours. To avoid positional preference, the locations of the two bottles were swapped every 12 hours. The consumption of each 1% sucrose solution and pure water was recorded at the end of the experiment. The experimental results were calculated as follows: Sucrose preference rate (%) = [Sucrose solution consumption / (Sucrose solution consumption + Pure water consumption)] × 100%. The experimental results are shown in Table 1.

[0088] Effects of each group of drugs on the results of the rat tail suspension test

[0089] The tail suspension test was performed after the last administration of medication. During the experiment, the tails of rats in each group were fixed in place by one-third, with their heads facing downwards. The time the rats remained motionless in this suspension was recorded. Motionlessness time was defined as the rats being completely still with their bodies vertically upside down, paws clenched. This tail suspension time was directly proportional to the rats' level of depression. The experimental results are shown in Table 1.

[0090] Table 1: Effects of each drug group on the forced swimming test, sucrose preference, and tail suspension test in rats (x-±SD)

[0091]

[0092] Compared with the blank control group, # p < 0.05 ## p < 0.01; compared with the model group, * P < 0.05 ** P < 0.01, compared with the antidepressant group 3, △ p < 0.05 △△ p < 0.01;

[0093] From the above experimental results, we can conclude that:

[0094] The liver-soothing and qi-regulating composition for treating depression provided by this invention can achieve effective antidepressant effects regardless of whether it is prepared by directly grinding raw herbs into powder (Example 1), by partially extracting raw materials through alcohol (Example 2), or by extracting volatile oils from all raw materials through steam distillation and combining the extracts (Examples 3 and 4). In Example 2, the alcohol extraction of the herbs yielded active pharmaceutical ingredients that showed a certain advantage in treating depression compared to raw herb powder. Examples 3 and 4 further fully utilized the volatile oil components in the herbs, further enhancing the efficacy based on Example 2.

[0095] Meanwhile, based on Example 3, Example 4 of the present invention further increases the magnolol content in the extract and finished drug by adjusting the pH value of the system composed of the dregs and water to 7.2 with sodium hydroxide during the second decoction of the dregs after volatile oil extraction. Tests showed that, under the same concentration, the magnolol content in the extract obtained after concentration in Example 4 reached 0.92 mg / g, a significant increase compared to the 0.71 mg / g in the example. Therefore, it is speculated that controlling the pH to a slightly alkaline state during the second decoction of the dregs facilitates the dissolution of some effective components in the dregs, thereby further improving the efficacy.

[0096] In general, the original efficacy of the liver-soothing and qi-regulating composition is mainly to treat indigestion and other diseases. This technical solution further develops the function of this composition and discovers that it also has ideal technical effects in treating depression. Furthermore, according to the specific implementation method of this experimental case, the rat modeling method is completely unrelated to functional dyspepsia, gastrointestinal motility abnormalities, etc. This indicates that the liver-soothing and qi-regulating composition can be used to treat symptoms unrelated to digestive system diseases, and the original uses of the liver-soothing and qi-regulating composition have no connection or technical inspiration for this new use. The liver-soothing and qi-regulating composition can play a role in treating depression, completely exceeding the expectations of those skilled in the art. Based on this, the inventors further developed methods to enhance the therapeutic effect of the liver-soothing and qi-regulating composition on depression, from raw herb powder preparations to raw herb ethanol extract preparations, and then to raw herb distillation followed by decoction extraction preparations, progressively improving the drug's efficacy.

[0097] Effects of each drug group on the results of the open field test in rats

[0098] After the last administration, an open field test was conducted. The open field test was performed in an open field test chamber with a height of 40 cm and a base area of ​​100 cm × 100 cm. In a quiet environment, rats were placed in the central square of the open field test chamber. After acclimatizing for 3 minutes, the experiment began. The total movement path length and the time spent at rest for each group of rats were recorded within 5 minutes. The experimental results are shown in Table 2.

[0099] Table 2: Effects of each drug group on the results of the open field test in rats (x-±SD)

[0100] Blank control group 174.25±24.55 254.21±32.84 Depression model group <![CDATA[105.78±23.42 ## ]]> <![CDATA[142.96±31.03 ## ]]> Depression treatment group 1 <![CDATA[133.91±31.57 * ]]> <![CDATA[183.31±25.84 * ]]> Depression treatment group 2 <![CDATA[146.23±19.85 * ]]> <![CDATA[205.46±24.19 * ]]> Depression treatment group 3 <![CDATA[165.01±18.72 ** ]]> <![CDATA[231.15±21.30 ** ]]> Depression treatment group 4 <![CDATA[171.29±24.07 **△ ]]> <![CDATA[242.35±28.61 **△ ]]>

[0101] Compared with the blank control group, # p < 0.05 ## p < 0.01; compared with the model group, * P < 0.05 ** P < 0.01, compared with the antidepressant group 3, △ p < 0.05 △△ p < 0.01;

[0102] The experimental results above show that the liver-soothing and qi-regulating composition for treating depression provided by the present invention can effectively treat depression in all groups. Furthermore, based on Example 3, the depression administration group 4 corresponding to Example 4 of the present invention has a further improvement in the total exercise pathway compared to the depression administration group 3.

[0103] (4) Experimental observation and results of anxiety disorder: The effects of each group of drugs on the behavior of rats in the elevated cross maze experiment (anxiety disorder).

[0104] After the last administration, an elevated cruciate maze test was performed to assess the effect of each drug group on the results of the elevated cruciate maze test in rats. The performance of each group of rats within 5 minutes was recorded, including:

[0105] 1) Number of times (OE) and time (OT) to enter the open arm;

[0106] 2) Number of times (CE) and time (CT) of entry into the closed arm;

[0107] Based on the above data, the percentage of open arm entry times (OE%) and the percentage of open arm dwell time (OT%) were calculated. The experimental results are shown in Table 3.

[0108] Table 3: Effects of each drug group on behavior in the elevated cross maze (x-±SD)

[0109]

[0110] Compared with the blank control group, # p < 0.05 ## p < 0.01; compared with the model group, * P < 0.05 ** P < 0.01, compared with the anxiety treatment group 3, △ p < 0.05 △△ p < 0.01;

[0111] The above experimental results show that all groups of drugs provided by this invention can effectively combat anxiety. Furthermore, based on Example 3, the anxiety group 4 showed further improvements in both OE% and OT% compared to the depression group 3. The original efficacy of the liver-soothing and qi-regulating composition is primarily for treating indigestion and other diseases, with no reported efficacy in treating anxiety. According to the specific implementation method of this experiment, the modeling method for experimental rats (anxiety symptoms) was completely unrelated to functional dyspepsia, gastrointestinal motility disorders, etc. This indicates that the mechanism and pathway of action of the liver-soothing and qi-regulating composition in treating anxiety are not significantly related to digestive system-related diseases, and the original use of the liver-soothing and qi-regulating composition has no connection or technical inspiration for this new use. It is highly likely that the liver-soothing and qi-regulating composition treats anxiety and other neurological diseases through a mechanism different from that used to treat functional dyspepsia, gastrointestinal motility disorders, etc. Based on this, the inventors further developed methods to enhance the therapeutic effect of the liver-soothing and qi-regulating composition on depression, progressing from raw herb powder preparations to raw herb ethanol extract preparations, and then to raw herb distillation followed by decoction extraction preparations, gradually improving the drug's efficacy.

[0112] Experimental Example 2

[0113] A clinical trial evaluating the efficacy and safety of Shugan Shunqi Pills in treating patients with functional dyspepsia accompanied by anxiety or depression symptoms and liver qi stagnation syndrome used the approved Shugan Shunqi large honey pill dosage form as the drug.

[0114] Case selection

[0115] 1) Diagnostic criteria:

[0116] (1) The diagnosis using both traditional Chinese medicine and Western medicine is based on the Technical Guidelines for Clinical Research of New Traditional Chinese Medicine Drugs for Functional Dyspepsia (FD) from the Center for Drug Evaluation of the National Medical Products Administration. The main symptoms of liver qi stagnation syndrome are abdominal distension or discomfort or pain; secondary symptoms include distension in the hypochondriac regions; irritability; acid reflux or heartburn; frequent belching; frequent sighing; and symptoms that are aggravated or worsened by emotional distress; pale red tongue with a thin white coating and wiry pulse. At least one main symptom must be present, plus any two secondary symptoms, and the diagnosis can be made by referring to the tongue and pulse.

[0117] (2) Diagnosis of accompanying mood disorder:

[0118] A score of ≥5 on the Generalized Anxiety Scale (GAD-7) is sufficient for a diagnosis of anxiety symptoms.

[0119] A score of ≥5 on the PHQ-9 Depression Screening Scale is sufficient for a diagnosis of comorbid depression.

[0120] 2) Inclusion criteria: Meeting the above diagnostic criteria;

[0121] Individuals with anxiety symptoms have a Generalized Anxiety Scale (GAD-7) score ≥5 and <19.

[0122] Individuals with depressive symptoms have a PHQ-9 Depression Screening Scale score ≥5 and <19.

[0123] Applicants must be between 18 and 70 years old, regardless of gender; voluntarily participate in the clinical trial, provide informed consent and sign an informed consent form; and be approved by the ethics committee of their hospital.

[0124] 3) Exclusion criteria include:

[0125] Those who do not meet the diagnostic criteria of Western medicine and traditional Chinese medicine; 13 C or 14 Individuals with a positive Hp test result in the C-breath test; those with indigestion caused by organic diseases of the digestive system, such as peptic ulcers, Barrett's esophagitis, erosive gastritis (grade 2 or above), moderate to severe atrophic gastritis (pathologically moderate to severe atrophy, moderate to severe intestinal metaplasia, and dysplasia), gastrointestinal tumors, gastrointestinal bleeding, hepatobiliary and pancreatic diseases, intestinal obstruction, inflammatory bowel disease, etc.; those with systemic diseases affecting gastrointestinal motility, such as diabetes, chronic renal insufficiency, connective tissue diseases, and nervous system disorders; those with severe primary heart, brain, liver, lung, kidney, blood, or serious diseases that affect their survival; those with a history of abdominal surgery (excluding appendectomy and cesarean section); pregnant or lactating women with recent plans to have children; and those who are blind, deaf, or mute. Individuals with intellectual disabilities, mental disorders, or other physical disabilities; those suspected of or with a history of alcohol or drug abuse; those who have participated in other drug clinical trials within the past 3 months, or those currently taking medications that may affect the effectiveness assessment of the investigational drug (such as nonsteroidal anti-inflammatory drugs, anticholinergic drugs, glucocorticoids, antidepressants, etc.); those with allergies, such as a history of allergies to two or more drugs or foods, or those known to be allergic to any component of this drug; those with a history of liver or kidney dysfunction; those with other conditions that, according to the researcher's judgment, reduce the likelihood of enrollment or complicate enrollment, such as frequent changes in work environment that could lead to loss to follow-up; patients diagnosed with major depressive disorder or major anxiety and depression; and other individuals deemed unsuitable for this study according to the researcher's judgment.

[0126] 4) Withdrawal criteria: Patients who fail to take medication as prescribed, with a dosage less than 80% or more than 120% of the prescribed dosage; patients who experience adverse reactions and are unsuitable to continue taking medication; patients whose condition worsens and affects their work or study; patients who develop certain comorbidities, complications, or special physiological changes and are unsuitable to continue undergoing the trial; patients who use drugs prohibited by the protocol; patients who withdraw from the trial midway, or patients who, although not explicitly requesting withdrawal, cease receiving medication and testing and are lost to follow-up.

[0127] 5) Exclusion criteria: Those who were mistakenly included but did not meet the inclusion criteria; those who met the inclusion criteria but never took the medication or had no follow-up records; those who used combination drugs outside the prescribed range, especially those who used drugs that had a significant impact on the investigational drug, affecting the assessment of efficacy and safety; and those who violated the medication regimen by using other Chinese or Western medicines.

[0128] 6) Termination Criteria: Serious safety issues occur during the trial; the drug treatment effect is found to be too poor or even ineffective and has no clinical value; the marketing authorization holder requests termination (e.g., due to funding reasons, management reasons, etc.).

[0129] Clinical data

[0130] Fifty patients with functional dyspepsia (FD) (33 with anxiety and 17 with depression) were selected as the study subjects, including 22 males and 28 females; age (46.90±12.08) years; height (162.02±7.25) cm; weight (56.40±10.43) kg; TCM syndrome score (9.38±3.43) points; anxiety symptom score (6.12±3.34) points; and depression symptom score (4.76±3.37) points.

[0131] Treatment

[0132] 1) Administer Shugan Shunqi Pills (National Drug Approval Number Z20026802, Manufacturer: Chongqing Xier'an Pharmaceutical Co., Ltd.) to the patient orally, 9 grams (1 bag) each time, 3 times a day, before breakfast, lunch and dinner.

[0133] The treatment course lasts for 4 weeks. During the trial, subjects should eat a light diet and avoid smoking, alcohol, spicy, cold, and greasy foods; they should also avoid emotional excitement and holding in anger.

[0134] 2) Combined medication and treatment

[0135] (1) During the trial, the use of other medications and treatments related to the treatment of this disease is prohibited, including antacids, H2 receptor antagonists, proton pump inhibitors, prokinetic agents, antidepressants, calcium channel blockers, beta-blockers, anticholinesterase drugs, anticonvulsants, opioids, 5-HT4 receptor agonists, dopamine D2 receptor antagonists, nonsteroidal anti-inflammatory drugs, and macrolide antibiotics, as well as other Chinese and Western medicines that are clearly indicated in their instructions to affect symptoms of functional dyspepsia, improve anxiety symptoms, or depressive symptoms. Treatments include, but are not limited to, acupuncture, massage, and physical therapy.

[0136] (2) The names of drugs (or other treatments) that must be continued for the co-existing diseases, dosage, frequency and time of use must be recorded in the study medical records. During the trial, the original types of drugs, usage and dosage should be kept unchanged as much as possible so that they can be analyzed and reported in the summary.

[0137] (3) If a subject experiences an adverse event during the trial, the corresponding drug may be used for treatment. However, the investigator shall assess whether the drug used will affect the efficacy or safety evaluation of the investigational drug and determine whether the subject needs to withdraw from the trial.

[0138] (4) After the clinical trial is completed, patients who have not recovered should be treated according to the current clinical routine methods.

[0139] Observation indicators

[0140] The patient's FD symptom score, TCM syndrome score, anxiety symptom score, depression symptom score, as well as safety indicators, vital signs, and adverse events were recorded after the first visit and after treatment.

[0141] 1) FD symptom score. The subject was scored based on various FD symptoms (0-2-4-6 points).

[0142] 2) Traditional Chinese Medicine syndrome scoring. Each primary and secondary symptom of the subject was scored separately.

[0143] 3) Anxiety symptom scoring. The Generalized Anxiety Scale (GAD-7) was used for self-reporting.

[0144] 4) Depression symptom rating. The Health Questionnaire Depression Symptom Scale (PHQ-9) was used for self-rating.

[0145] 5) Safety assessment: Occurrence and severity of adverse reactions and events. Changes in basic vital signs such as heart rate, respiration, blood pressure, and body temperature.

[0146] Efficacy evaluation criteria

[0147] 1) Criteria for evaluating the efficacy of single symptom treatment in FD:

[0148] Significant effect: Existing symptoms disappear. Effective: Existing symptoms decrease by 2 levels. Improved: Existing symptoms decrease by 1 level. Ineffective: Existing symptoms show no improvement or worsen.

[0149] 2) Evaluation criteria for FD efficacy:

[0150] Cure: Symptoms disappear. Significant effect: Symptom improvement percentage ≥ 80%. Improvement: Symptom improvement percentage ≥ 50%. Ineffective: Symptoms show no significant improvement, or even worsen; symptom improvement percentage < 50%.

[0151] Progress rate = [(progress) / total number of cases] × 100%; Significant effect rate = [(significant effect) / total number of cases] × 100%; Cure rate = [(cured) / total number of cases] × 100%; Overall effective rate = [(cured + significant effect + progress) / total number of cases] × 100%.

[0152] 3) Criteria for judging the efficacy of TCM syndrome differentiation:

[0153] Clinically cured: TCM symptoms and signs disappear or basically disappear, and the syndrome score decreases by ≥95%. Significantly effective: TCM symptoms and signs significantly improve, and the syndrome score decreases by ≥70%. Effective: TCM symptoms and signs improve, and the syndrome score decreases by ≥30%. Ineffective: TCM symptoms show no significant improvement, or even worsen, and the syndrome score decreases by <30%. Effective rate = [(effective) / total number of cases] × 100%; Significantly effective rate = [(significantly effective) / total number of cases] × 100%; Cured rate = [(cured) / total number of cases] × 100%; Total effective rate = [(cured + significantly effective + effective) / total number of cases] × 100%.

[0154] 4) Evaluation of treatment efficacy for anxiety and depression symptoms:

[0155] Cure: Return to normal levels. Significant effect: Symptom severity decreased by two levels. Effective: Symptom severity decreased by one level. Ineffective: Symptom severity did not improve, or even worsened. Effective rate = [(Cure + Significant effect + Effective) / Total number of cases] × 100%; Significant effect rate = [(Cure + Significant effect) / Total number of cases] × 100%; Cure rate = [(Cure) / Total number of cases] × 100%.

[0156] 5) Overall efficacy evaluation:

[0157] Cure: FD cured + effective improvement in anxiety or depressive symptoms. Significant Effect: FD significantly effective + effective improvement in anxiety or depressive symptoms. Improvement: FD improved + effective improvement in anxiety or depressive symptoms. Ineffective: FD ineffective + ineffective improvement in anxiety or depressive symptoms. Improvement Rate = [(Improvement) / Total Cases] × 100%; Significant Effect = [(Significant Effect) / Total Cases] × 100%; Cure Rate = [(Cure) / Total Cases] × 100%; Overall Effectiveness = [(Cure + Significant Effect + Improvement) / Total Cases] × 100%.

[0158] Statistical processing

[0159] SPSS 22.0 statistical software was used. Two-tailed tests were employed. For continuous data conforming to a normal distribution, expressed as (x±s), a t-test was used. For data not conforming to a normal distribution, a rank-sum test was used. Categorical data were expressed as frequency or percentage (%), and a chi-square test was used. 2 Test. P < 0.05 is considered statistically significant.

[0160] Clinical trial results

[0161] The clinical trial involved a total of 50 patients, with 46 ultimately completing the trial and 4 patients withdrawing midway.

[0162] The overall efficacy, functional dyspepsia (FD), TCM symptoms, anxiety symptoms, and depressive symptoms after treatment are shown in Tables 4 and 5.

[0163] Table 4: Overall treatment outcome, functional dyspepsia (FD), TCM symptoms, anxiety symptoms, and depressive symptoms at the end of treatment (n, %)

[0164]

[0165] Table 5: Individual efficacy of FD at the end of treatment (n, %)

[0166]

[0167] The experimental results showed that the overall efficacy rate, total effective rate of functional dysphagia (FD), and total effective rate of TCM syndrome efficacy were 60.87%, 63.04%, and 78.26%, respectively. Patients' anxiety and depression symptoms were significantly improved, with total effective rates reaching 93.48% and 100%, respectively. The total effective rates of FD for postprandial fullness and discomfort, early satiety discomfort, upper abdominal pain, and upper abdominal burning sensation were 58.70%, 86.96%, 73.91%, and 93.48%, respectively.

[0168] Tables 6 and 7 show the comparisons of FD symptoms, TCM syndromes, self-rating scores of anxiety and depression symptoms, and individual TCM scores before and after treatment. After treatment, the patients' FD symptoms, TCM syndromes, self-rating scores of anxiety and depression symptoms, and individual TCM scores all decreased compared with before treatment (all P < 0.05).

[0169] Table 6: Comparison of self-rating scores of FD symptoms, TCM syndromes, anxiety and depression symptoms before and after treatment ( * indicates P < 0.05 compared to before treatment.

[0170]

[0171] Table 7: Comparison of TCM individual scores before and after treatment ( * indicates P < 0.05 compared to before treatment.

[0172]

[0173] In conclusion, Shugan Shunqi Pills are safe and effective for functional dyspepsia accompanied by anxiety or depression symptoms (liver qi stagnation syndrome). They can improve patients' anxiety and depression symptoms and enhance their quality of life, making them worthy of clinical promotion and application.

[0174] Experimental Example 3: Exploration of Preparation and Processing Methods for Active Pharmaceutical Ingredients

[0175] (1) Exploration of batch distillation extraction

[0176] Research on oil phase extraction process (preparation of distilled oil phase by batch distillation):

[0177] The oil phase extraction method in this experiment was carried out in accordance with the method in Example 3, except that the intermittent distillation extraction process was slightly modified, and the extraction was performed on 20 kg of medicinal materials (each medicinal material was prepared according to the formula ratio in Example 3).

[0178] Test 1: The distillation process was carried out over high heat for 15 minutes, followed by a period of gentle boiling for another 15 minutes. This process was repeated until the extraction was complete, for a total of 6 hours. 23.0 mL of a clear, oily phase with a strong aroma was obtained.

[0179] Test 2: Extraction was carried out over high heat for 10 minutes, followed by adjusting the heat to maintain a gentle boil for another 10 minutes. This process was repeated until the extraction was complete, for a total of 4 hours. 22.1 mL of a clear, oily phase with a strong aroma was obtained.

[0180] Test 3: Distillation over high heat for 4 hours. 19.5 mL of distilled oil phase was obtained, which was an emulsified oil with a strong aroma of distilled oil phase.

[0181] Test 4: Distillation was carried out at a gentle boil for 4 hours. 15.2 mL of distilled oil phase was obtained, which was a clear oily substance with a strong aroma of distilled oil phase.

[0182] In the distillation extraction of medicinal materials, using high-heat distillation throughout the process results in inefficient extraction of the oil phase, and the obtained oil phase is turbid and of poor quality. While using gentle distillation throughout the process yields a clear oil phase, the amount is too small. Therefore, regardless of whether vigorous or gentle extraction conditions are used for continuous distillation of medicinal materials, the amount of oil obtained is unsatisfactory (not exceeding 20 mL). Alternating between high-heat and gentle distillation can effectively increase the extraction yield of the oil phase, and adding the oil phase to the finished drug product can further enhance its anti-anxiety and antidepressant effects.

[0183] Therefore, in preparing liver-soothing and qi-regulating preparations, the preferred method for oil phase extraction by distillation is to use a method with intermittent distillation fire cycling for 10-20 minutes and a total distillation time of 3-6 hours. The inventors have also preliminarily analyzed the reasons why the above method can increase the amount of oil phase obtained by distillation, which may be as follows: Simmering the herbs extracts the volatile oils, which float or partially dissolve in the hot water. After accumulating a certain amount, a high flame is used to boil the volatile oils, distilling them back into the collector for cooling and collection. If a high flame is used continuously, the amount of volatile oil is very small due to the large size of the extractor. Some volatile oil may remain on the walls of the extractor and not easily return to the collector, resulting in a relatively small amount. Prolonged high-flame distillation may cause incompatibility reactions between substances, leading to turbidity of the volatile oil. Continuous simmering distillation results in insufficient distillation intensity, making it difficult to distill and collect a large amount of volatile oil.

[0184] Experimental data from Example 1 show that fully utilizing the volatile oils in medicinal materials has a significant effect on improving the therapeutic effect of drugs. Further increasing the yield and quality of volatile oils is key to enhancing the overall therapeutic efficacy of the preparation. This experiment investigated the impact of distillation extraction methods on the yield and quality of volatile oils, creating conditions for improving the therapeutic effect of drugs.

[0185] (2) Exploration of pH value of decoction extraction

[0186] The study on the preparation process of the extract (adjustment of pH value during the second decoction extraction) was conducted as follows:

[0187] Test 1: The extract was prepared according to the optimal process of Example 4 of this invention. During the second water decoction extraction, the pH of the mixture of medicinal residue and water was adjusted to 7.2 to obtain the final extract. This extract was concentrated into a paste (60℃, density 1.30). The content of the principal herb, Magnolia officinalis (calculated as magnolol), in the paste was determined, as well as the identification spots of Aucklandia lappa, Citrus medica, Corydalis yanhusuo, Paeonia lactiflora, and Glycyrrhiza uralensis. The determination methods were based on the quality standard of Shugan Shunqi Pill (WS-11169(ZD-1169)-2002-2011Z), which included thin-layer chromatography identification of Aucklandia lappa, Citrus medica, Corydalis yanhusuo, Paeonia lactiflora, and Glycyrrhiza uralensis, and the content of magnolol.

[0188] Thin-layer chromatography identification results for costus root, bergamot, corydalis, peony root, and licorice showed that the spots of the control and test samples were clear; the magnolol content in the extract was 0.92 mg / g. Experimental studies found that adjusting the pH of the extraction system to 7.0-7.5 before the second decoction extraction yielded ideal extraction results, with the magnolol content in the extract reaching over 0.9 mg / g.

[0189] Test 2: The extract was prepared according to Example 3 of the present invention. The difference between Example 3 and Example 4 is that during the second water decoction extraction, the pH value of the mixture of medicinal residue and water was not adjusted, and the decoction extraction was carried out directly. The experimental results showed that the spots of the control and test samples of Costus root and Corydalis were clearer and lighter in color than the extract obtained in "Test 1". The content of magnolol in the extract was 0.71 mg / g.

[0190] The aforementioned experimental results indicate that during the second decoction extraction, the pH value of the system consisting of the dregs and water can be controlled between 7.0 and 7.5 (for example, controlling the pH of the second decoction extraction to 7.2). This method is highly effective in ensuring the transfer rate of Costus root, Citrus medica, Corydalis yanhusuo, Paeonia lactiflora, Glycyrrhiza uralensis, and Magnolia officinalis, and in increasing the content of Magnolia officinalis's active ingredients in the extract. In Test 2, because the pH value of the system consisting of the dregs and water in the second decoction extraction was not adjusted, the content of Magnolia officinalis decreased, and the spots for identifying Costus root and Corydalis yanhusuo were relatively weak, indicating that this extraction method directly affects the transfer rate of active ingredients in Magnolia officinalis, Costus root, and Corydalis yanhusuo.

[0191] The above experimental results indicate that, during the extraction process, the pH value of the extraction system needs to be adjusted during the second decoction extraction to ensure the extraction rate of the active ingredients. The content of the active ingredients is one of the key technical factors affecting the efficacy of the preparation. The inventors studied the effect of pH control during the water decoction extraction process on these active ingredients and further optimized the conditions to improve the therapeutic effect of the preparation.

[0192] (3) Screening of inclusion agents

[0193] The preparation process of the inclusion complex powder (solution) is described in the best embodiment of Example 4. The types of inclusion agents were studied, and the effects of hydroxypropyl-β-cyclodextrin and β-cyclodextrin on the preparation of inclusion complexes were investigated respectively.

[0194] Scheme 1: Dissolve 4 times the mass of distilled oil phase in 4 times the mass of water. Add the distilled oil phase dropwise at a rate of 1-2 ml / min while stirring at 50 rpm. After the addition is complete, stir for 2 hours to obtain an inclusion complex solution. The inclusion complex is a transparent, viscous liquid. After pulsating vacuum drying, it becomes a white, flaky solid that is easily broken.

[0195] Option 2: Replace the hydroxypropyl-β-cyclodextrin in Option 1 with an equal amount of β-cyclodextrin. β-cyclodextrin has poor solubility. After inclusion, the liquid is a white paste. After standing, an oily substance floats on the top layer. After pulsating vacuum drying, it becomes a white blocky solid.

[0196] The results showed that hydroxypropyl-β-cyclodextrin had a better encapsulation / solubilizing effect on the distilled oil phase of this product than β-cyclodextrin; therefore, hydroxypropyl-β-cyclodextrin was selected to prepare the inclusion complex. The preparation of the inclusion complex affects the compatibility between the distilled oil phase and the overall formulation, thus impacting the therapeutic effect of the drug.

[0197] In summary, the compositions of this scheme, prepared using various methods, have demonstrated therapeutic effects on depression and anxiety, achieving unexpected technological advancements compared to existing technologies. Furthermore, the preparation process and the method of obtaining the active pharmaceutical ingredients can influence the efficacy of the drug in treating depression and anxiety. This technical scheme investigated methods to enhance drug efficacy, from raw herb powder preparations to raw herb ethanol extract preparations, and then to raw herb distillation followed by decoction extraction preparations. It was found that the raw herb distillation followed by decoction extraction method fully utilizes volatile oils and other active ingredients, achieving the most ideal therapeutic effect. Moreover, by controlling the parameters of intermittent distillation extraction, the pH value of the second decoction extraction, and selecting a suitable inclusion agent for the distilled oil phase, the method plays a crucial role in improving the yield and quality of the key active ingredient volatile oil, increasing the extraction yield of the active ingredients, and enhancing the compatibility of the volatile oil and the preparation. This further ensures a more optimized treatment effect for depression and anxiety, resulting in more significant application effects.

[0198] The above descriptions are merely embodiments of the present invention, and common knowledge such as specific technical solutions and / or characteristics are not described in detail here. It should be noted that those skilled in the art can make various modifications and improvements without departing from the technical solutions of the present invention, and these should also be considered within the scope of protection of the present invention. These modifications and improvements will not affect the effectiveness of the implementation of the present invention or the practicality of the patent. The scope of protection claimed in this application should be determined by the content of its claims, and the specific embodiments described in the specification can be used to interpret the content of the claims.

Claims

1. The application of a liver-soothing and qi-regulating composition in the preparation of anti-anxiety drugs, characterized in that, The liver-soothing and qi-regulating composition is made from the following medicinal materials in parts by weight: 25-35 parts Magnolia officinalis, 25-35 parts Ligusticum chuanxiong, 25-35 parts Cyperus rotundus, 25-35 parts Paeonia lactiflora, 25-35 parts Bupleurum chinense, 25-35 parts Citrus aurantium, 25-35 parts Curcuma longa, 25-35 parts Citrus medica, 25-35 parts Aucklandia lappa, 25-35 parts Citrus reticulata peel, 20-30 parts Glycyrrhiza uralensis, 25-35 parts Corydalis yanhusuo, and 45-60 parts Eupatorium fortunei.

2. The application of the liver-soothing and qi-regulating composition according to claim 1 in the preparation of anxiolytic drugs, characterized in that, The liver-soothing and qi-regulating composition is made from the following medicinal materials in parts by weight: 31.4 parts Magnolia officinalis, 31.4 parts Ligusticum chuanxiong, 31.4 parts Cyperus rotundus, 31.4 parts Paeonia lactiflora, 31.4 parts Bupleurum chinense, 31.4 parts Citrus aurantium, 31.4 parts Curcuma longa, 31.4 parts Citrus medica, 31.4 parts Aucklandia lappa, 31.4 parts Citrus reticulata, 23.55 parts Glycyrrhiza uralensis, 31.4 parts Corydalis yanhusuo, and 58.85 parts Eupatorium fortunei.

3. The application of the liver-soothing and qi-regulating composition in the preparation of drugs for improving, adjuvantly treating, or treating functional dyspepsia accompanied by anxiety, characterized in that... The liver-soothing and qi-regulating composition is made from the following medicinal materials in parts by weight: 25-35 parts Magnolia officinalis, 25-35 parts Ligusticum chuanxiong, 25-35 parts Cyperus rotundus, 25-35 parts Paeonia lactiflora, 25-35 parts Bupleurum chinense, 25-35 parts Citrus aurantium, 25-35 parts Curcuma longa, 25-35 parts Citrus medica, 25-35 parts Aucklandia lappa, 25-35 parts Citrus reticulata peel, 20-30 parts Glycyrrhiza uralensis, 25-35 parts Corydalis yanhusuo, and 45-60 parts Eupatorium fortunei.

4. The use of the liver-soothing and qi-regulating composition according to claim 3 in the preparation of a drug for improving, adjuvantly treating, or treating functional dyspepsia with anxiety, characterized in that, The liver-soothing and qi-regulating composition is made from the following medicinal materials in parts by weight: 31.4 parts Magnolia officinalis, 31.4 parts Ligusticum chuanxiong, 31.4 parts Cyperus rotundus, 31.4 parts Paeonia lactiflora, 31.4 parts Bupleurum chinense, 31.4 parts Citrus aurantium, 31.4 parts Curcuma longa, 31.4 parts Citrus medica, 31.4 parts Aucklandia lappa, 31.4 parts Citrus reticulata, 23.55 parts Glycyrrhiza uralensis, 31.4 parts Corydalis yanhusuo, and 58.85 parts Eupatorium fortunei.

5. The application according to any one of claims 1-4, characterized in that: The dosage form of the liver-soothing and qi-regulating composition is any one of pills, granules, tablets, oral liquids, or capsules.

6. The application according to any one of claims 1-4, characterized in that: The liver-soothing and qi-regulating composition is prepared by the following method: the medicinal raw materials are pulverized and passed through an 80-120 mesh sieve, mixed evenly, and the active pharmaceutical ingredient is obtained; pharmaceutical excipients are added to the active pharmaceutical ingredient and it is prepared into a clinically acceptable oral preparation.

7. The use of the liver-soothing and qi-regulating composition according to claim 1 in the preparation of an anti-anxiety drug, characterized in that: The liver-soothing and qi-regulating composition is prepared according to the following method: 1 / 2 to 2 / 3 of the weight of each medicinal material is pulverized and passed through an 80-120 mesh sieve; the coarse residue and fine powder are set aside separately; the remaining medicinal material is pulverized into coarse powder; the coarse powder and coarse residue are mixed evenly, and an ethanol solution of 6-8 times the total weight of the coarse powder and coarse residue is added; the mixture is then soaked at a temperature of 40-60°C for 30-90 minutes. After a period of time, a first reflux extraction is performed for 1-2 hours. Then, a second reflux extraction is performed for 1-2 hours with 6-8 times the total weight of the coarse powder and coarse head in ethanol solution. The extracts are combined, the ethanol is recovered under reduced pressure, filtered, and the residue is recovered. The extract is concentrated to obtain extract I, in which the concentration of the ethanol solution used during extraction is 45-65%. The residue obtained after extraction is decocted with water 2-3 times, each time with 6-10 times the amount of water as the amount of residue, for 1-3 hours each time. The decoctions are combined, filtered, and the obtained filtrate is concentrated to obtain extract II. Extracts I and II are combined, and then fine powder is added and mixed well to obtain the active pharmaceutical ingredient. Pharmaceutical excipients are added to the active ingredient of a drug to prepare it into a clinically acceptable formulation.

8. The use of the liver-soothing and qi-regulating composition according to claim 1 in the preparation of an anti-anxiety drug, characterized in that, The liver-soothing and qi-regulating composition is prepared by the following method: the medicinal raw materials are extracted by distillation to obtain a distilled aqueous phase, a distilled oil phase, and a residue; the residue is extracted by boiling in water to obtain a decoction, the decoction and the distilled aqueous phase are combined to obtain an extract, the extract is concentrated into an extract, and the extract, the distilled oil phase, and suitable excipients are prepared into a clinically acceptable oral dosage form.

9. The use of the liver-soothing and qi-regulating composition according to claim 1 in the preparation of an anti-anxiety drug, characterized in that: The liver-soothing and qi-regulating composition is prepared by the following method: the medicinal raw materials are extracted by distillation to obtain a distilled aqueous phase, a distilled oil phase, and a residue; the residue is extracted by boiling in water to obtain a decoction, and the decoction and the distilled aqueous phase are combined to obtain an extract; the distilled oil phase is treated with an inclusion agent to obtain an inclusion compound powder or an inclusion compound solution; the extract is concentrated and then combined with the inclusion compound powder or inclusion compound solution and suitable excipients to prepare a clinically acceptable oral dosage form.

10. The use of the liver-soothing and qi-regulating composition according to claim 8 or 9 in the preparation of an anti-anxiety drug, characterized in that: The method for extracting the dregs by boiling water is as follows: add 6 to 8 times the weight of the raw medicinal materials to water for the first boiling extraction for 2 to 3 hours; add 6 to 8 times the weight of the raw medicinal materials to water and adjust the pH value to 7.0 to 7.5, and then boil for 2 to 3 hours for the second boiling extraction.

11. The use of the liver-soothing and qi-regulating composition according to claim 8 or 9 in the preparation of an anti-anxiety drug, characterized in that: The distillation extraction adopts an intermittent distillation extraction method, which alternates between high-heat distillation and gentle boiling distillation.

12. The use of the liver-soothing and qi-regulating composition according to claim 11 in the preparation of an anti-anxiety drug, characterized in that: The intermittent distillation extraction uses water or alcohol solution as the extraction solvent; the total extraction time is 1 to 8 hours; the intermittent distillation extraction process is carried out in a cycle of first 10 to 20 minutes of high-heat distillation extraction followed by 10 to 20 minutes of gentle boiling distillation extraction.

13. The use of the liver-soothing and qi-regulating composition according to claim 9 in the preparation of anxiolytic drugs, characterized in that: The inclusion agent is hydroxypropyl-β-cyclodextrin; the inclusion treatment method is as follows: take 3 to 5 times the mass of the distilled oil phase of the inclusion agent, dissolve it, and add the distilled oil phase dropwise at a rate of 1 to 2 ml / min under stirring conditions of 40 to 60 rpm. After the addition is completed, stir for 1.5 to 2.5 hours to obtain the inclusion solution; concentrate and dry it until the moisture content is less than 5.0%, and then pulverize it through an 80 to 100 mesh sieve to obtain the inclusion powder.

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