Antidepressant pharmaceutical composition and application thereof

Abstract

The invention relates to an antidepressant pharmaceutical composition and application thereof, and particularly discloses a pharmaceutical composition for treating depression as well as a preparation method and application thereof. The active pharmaceutical ingredients of the pharmaceutical composition are prepared from the following traditional Chinese medicines in parts by weight: 500 to 600 parts of radix bupleuri, 500 to 600 parts of fructus aurantii immaturus, 500 to 600 parts of radix aucklandiae, 500 to 600 parts of pericarpium citri reticulatae, 500 to 600 parts of rhizoma pinelliae preparata, 750 to 900 parts of herba taraxaci, 500 to 600 parts of scorched fructus crataegi, 300 to 360 parts of scorched semen arecae, 500 to 600 parts of paederia scandens, 300 to 400 parts of radix codonopsis, 300 to 400 parts of rhizoma corydalis and 500 to 600 parts of fried medicated leaven. The pharmaceutical composition has a remarkable curative effect on depression, animal experiments show that the pharmaceutical composition can remarkably enhance the social coefficient (showing that the pharmaceutical composition can improve social fear of depression patients) and improve sweet water preference (showing that the pharmaceutical composition is beneficial to transformation of negative emotions such as interest deficiency of the depression patients), and the pharmaceutical composition is safe to take, free of adverse reaction and toxic and side effects and free of toxic and side effects. And the composition can take effect quickly, and can take effect generally within 1-2 weeks after medication.

Description

Field of the Invention

[0001] The present invention belongs to the field of pharmaceuticals, and particularly relates to an antidepressant pharmaceutical composition and its applications. Background of the Invention

[0003] Depression is a common mental disorder, mainly characterized by continuous and long-term low mood. Due to insufficient understanding of the disease, few patients adhere to regular treatment, so it also has the characteristics of low treatment rate and high recurrence rate.

[0004] Most cases of depression are acute or subacute onset, and are prone to occur in autumn and winter. The average age of onset is 20 - 30 years old, and the prevalence rate in women is higher than that in men (about 2:1). Statistics on the global burden of disease show that the disability-adjusted life years (all healthy life years lost from onset to death) of depressive disorders have risen to the 11th place. Research also shows that depressive disorders have become the third leading cause of disability-adjusted life years (life years lost due to premature death). It is predicted that by 2030, depression will replace cardiovascular diseases as the main cause of human disability, and the treatment cost for depression will account for 13% of the total burden of all diseases, becoming a major disease seriously affecting human life and health.

[0005] Depression is mainly clinically characterized by persistent low mood and cognitive dysfunction, including irritable mood, anhedonia, sleep disorders, guilt, etc. In severe cases, suicidal thoughts and behaviors may occur; and most cases tend to recur. Therefore, strengthening the research on drugs for treating depression has important social and economic significance.

[0006] The treatment of depression is rather difficult. At present, Western medicine has not fully elucidated the pathogenesis of depression, and the treatment usually uses antidepressant drugs, but the curative effect is poor and the side effects are large, and patients often cannot adhere to taking the drugs.

[0007] At present, most of the drugs for treating depression are chemical drugs. Currently, clinically, several types of antidepressants such as 5 - hydroxytryptamine reuptake inhibitors, monoamine oxidase inhibitors, phenylpiperazine derivatives, 5 - hydroxytryptamine - norepinephrine reuptake inhibitors, aminoketones, tricyclics, tetracyclic piperazine azepines, fluoxetine, etc. are mostly used. However, since depression is a mental disorder with very complex etiologies; when using chemical drugs for treatment, improper use may not only fail to treat depression, but may instead exacerbate the condition or transform into other mental disorders. In addition, most synthetic antidepressants have defects such as narrow antidepressant spectrum, large toxic and side effects when taken for a long time, high drug prices, and easy recurrence. In comparison, traditional Chinese medicine treatment of depression is relatively safe and effective, with certain advantages. Therefore, it is of great significance to explore the role of traditional Chinese medicine in the treatment of depression.

[0008] Depression can be classified into the category of "depressive syndrome" in traditional Chinese medicine, which is similar to the symptoms of "hysterical neurosis", "plum pit qi", and "lily disease" recorded in ancient Chinese medical classics. Patients often show symptoms such as depression, restlessness, fullness and distending pain in the chest and hypochondrium, or being prone to anger and crying. So far, traditional Chinese medicine believes that qi stagnation, liver failure to disperse, and spleen and stomach dysfunction are the main pathogenesis of depression, and the treatment usually adopts the methods of soothing the liver and relieving depression, promoting qi and resolving stagnation, and regulating the spleen and stomach.

[0009] Common Chinese patent medicines for treating depression currently available on the market include: Kaiyu Shugan Pills, Chaihu Shugan Pills, Shugan Jieyu Capsules, Xiaoyao Powder, Jieyu Pills, Yueju Pills, etc. However, the clinical application effects of these drugs are not very satisfactory, and the main disadvantages are: insufficient efficacy, or single action that only treats the symptoms but not the root cause, or slow action and too long medication cycle, etc. In addition, the commonly used traditional Chinese antidepressant drugs on the market generally have the problem of slow onset, usually taking 3 - 4 weeks or even longer to take effect well.

[0010] Therefore, it is very necessary to develop new traditional Chinese medicine compositions with good efficacy and / or quick onset for treating depression. Summary of the Invention

[0011] Therefore, a new type of drug composition for treating depression with good efficacy and / or quick onset and safe and non-toxic side effects on the human body is what people expect.

[0012] In the first aspect, the present application provides a drug composition for treating depression, and its active pharmaceutical ingredients are composed of traditional Chinese medicines in the following parts by weight: 500 - 600 parts of Bupleuri Radix, 500 - 600 parts of Aurantii Fructus Immaturus, 500 - 600 parts of Aucklandiae Radix, 500 - 600 parts of Citri Reticulatae Pericarpium, 520 - 580 parts of Pinelliae Rhizoma Praeparatum, 800 - 850 parts of Taraxaci Herba, 500 - 600 parts of Crataegi Fructus Praeparatus, 300 - 360 parts of Arecae Semen Praeparatus, 500 - 600 parts of Paederiae Herba, 300 - 400 parts of Codonopsis Radix, 300 - 400 parts of Corydalis Rhizoma, 500 - 600 parts of Massae Fermentatae.

[0013] In the second aspect, the present application provides a preparation method of a drug composition for treating depression, and this method includes:

[0014] 1) Weigh Bupleuri Radix, Aurantii Fructus Immaturus, Aucklandiae Radix, and Citri Reticulatae Pericarpium, and then carry out decoction and distillation to extract volatile oil. The obtained volatile oil is included with beta-cyclodextrin, and the remaining aqueous solution after decoction is collected for later use; the parts by weight of Bupleuri Radix, Aurantii Fructus Immaturus, Aucklandiae Radix, and Citri Reticulatae Pericarpium used are 500 - 600 parts of Bupleuri Radix, 500 - 600 parts of Aurantii Fructus Immaturus, 500 - 600 parts of Aucklandiae Radix, and 500 - 600 parts of Citri Reticulatae Pericarpium;

[0015] 2) Weigh Pinellia ternata, Taraxacum mongolicum, Hawthorn Fruit (parched), Areca Seed (parched), Paederia scandens, Codonopsis pilosula, Corydalis yanhusuo, and Six-Flavored Medicinal Leaven (parched), and combine them with the medicinal residues remaining after decocting in step 1). Decoct with water 1 - 3 times, combine the decoction liquids and then filter. The weight parts of Pinellia ternata, Taraxacum mongolicum, Hawthorn Fruit (parched), Areca Seed (parched), Paederia scandens, Codonopsis pilosula, Corydalis yanhusuo, and Six-Flavored Medicinal Leaven (parched) used are: 520 - 580 parts of Pinellia ternata, 800 - 850 parts of Taraxacum mongolicum, 500 - 600 parts of Hawthorn Fruit (parched), 300 - 360 parts of Areca Seed (parched), 500 - 600 parts of Paederia scandens, 300 - 400 parts of Codonopsis pilosula, 300 - 400 parts of Corydalis yanhusuo, and 500 - 600 parts of Six-Flavored Medicinal Leaven (parched);

[0016] 3) Combine the aqueous solution in step 1) with the filtrate in step 2), and concentrate under reduced pressure to a relative density of (measured at 60 °C);

[0017] 4) Add ethanol to the concentrate obtained in step 3), let it stand for 16 - 48 hours, filter, and continue to concentrate under reduced pressure to a thick paste with a relative density of (measured at 60 °C). Add appropriate excipients, mix evenly, and then mix evenly with the β - cyclodextrin inclusion complex of the volatile oil in step 1). Perform optional post - treatments such as drying and granulation packaging.

[0018] In a third aspect, the present application provides the use or method of the pharmaceutical composition of the first aspect of the present application or the pharmaceutical composition prepared by the method described in the second aspect of the present application for treating depression, including administering to a patient an effective amount of the pharmaceutical composition of the first aspect of the present application or the pharmaceutical composition prepared by the method described in the second aspect of the present application, or the pharmaceutical composition according to any embodiment of the present application.

[0019] In a fourth aspect, the present application provides the use of the pharmaceutical composition of the first aspect of the present application or the pharmaceutical composition prepared by the method described in the second aspect of the present application (or the pharmaceutical composition according to any embodiment of the present application) in the preparation of a drug for treating depression.

[0020] In a fifth aspect, the present application provides a pharmaceutical preparation (preferably an oral pharmaceutical preparation), which comprises the pharmaceutical composition of the first aspect of the present application or the pharmaceutical composition prepared by the method described in the second aspect of the present application (or the pharmaceutical composition according to any embodiment of the present application) and a pharmaceutically acceptable carrier or adjuvant.

[0021] According to traditional Chinese medicine theory, making use of the unique medicinal properties of traditional Chinese medicines, Bupleuri Radix has the functions of soothing the liver, relieving depression, clearing heat, and regulating gastrointestinal qi stagnation; Fructus Aurantii Immaturus has the functions of breaking qi to eliminate accumulation and purging phlegm to relieve fullness; Aucklandiae Radix is used for syndromes such as qi stagnation in the spleen and stomach, and epigastric distending pain; Pinelliae Rhizoma Praeparatum has the functions of eliminating fullness and resolving masses, suppressing the adverse rising qi to stop vomiting, and drying dampness and resolving phlegm; Citri Reticulatae Pericarpium has the functions of regulating qi and strengthening the spleen, and drying dampness and resolving phlegm; Taraxaci Herba is good at clearing heat and detoxifying; Massa Medicata Fermentata (parched) is used for syndromes such as indigestion, epigastric stuffiness and distension, dyspepsia, and diarrhea; Arecae Semen (parched) is good at promoting qi and eliminating accumulation; Crataegi Fructus (parched) is good at promoting digestion and resolving accumulation, dispersing stasis and promoting qi movement, and helping the spleen and strengthening the stomach; Paederiae Herba can remove dampness, reduce swelling, and detoxify; Corydalis Rhizoma is good at promoting blood circulation, dispersing stasis, regulating qi, and relieving pain; Codonopsis Radix is used for syndromes such as weakness of the spleen and stomach, qi deficiency, poor appetite due to spleen deficiency, and lassitude and weakness.

[0022] The pharmaceutical composition for treating depression of the present application has at least one of the following advantages:

[0023] It has a significant effect in treating depression, with strong efficacy, and is equivalent to or superior to the commonly used western medicines for treating depression;

[0024] As a traditional Chinese medicine composition, it is safe to take, has no obvious adverse reactions and toxic and side effects, patients have good tolerance and strong compliance, and it is suitable for long-term use;

[0025] It has a rapid onset of action and is suitable for quickly relieving symptoms. Usually, it can take effect quickly about one week after taking the medicine (even faster than most western anti-depressant medicines);

[0026] It is applicable to the treatment, consolidation, and maintenance of depression;

[0027] This pharmaceutical composition contains multiple components, can act on multiple targets simultaneously, comprehensively regulate the body, not only relieve depressive symptoms, but also improve appetite, sleep quality, etc., and improve the overall quality of life of patients;

[0028] This pharmaceutical composition is formulated according to traditional Chinese medicine theory, and dialectically treats depression of the liver qi stagnation type, with strong pertinence;

[0029] The treatment with traditional Chinese patent medicines not only focuses on symptom relief, but also pays attention to the overall regulation of the body and mind, which helps patients recover and prevent recurrence. Detailed implementation manners

[0030] Chinese Patent Application No. 01119486.3 (Publication No. CN1389230A) discloses a traditional Chinese medicine composition for treating stomach diseases, especially a traditional Chinese medicine composition suitable for bile reflux gastritis and non-ulcer dyspepsia. The traditional Chinese medicine composition is basically composed of twelve traditional Chinese medicines: Bupleuri Radix, Aurantii Fructus Immaturus, Aucklandiae Radix, Citri Reticulatae Pericarpium, Pinelliae Rhizoma Praeparatum, Taraxaci Herba, Crataegi Fructus (Fried to Charcoal), Arecae Semen Praeparatum, Paederiae Herba, Codonopsis Radix, Corydalis Rhizoma, and Medicata Fermentata. During the further in-depth study of this formula, the inventor unexpectedly found that this pharmaceutical composition also has very good therapeutic effects on depression. Based on this, the present invention is proposed, thus providing more pharmaceutical options for the treatment of depression.

[0031] I. Pharmaceutical Composition

[0032] In the first aspect of the present application, there is provided a pharmaceutical composition for treating depression, and its effective traditional Chinese medicine raw material components are composed of the following raw materials: 500 - 600 parts of Bupleuri Radix, 500 - 600 parts of Aurantii Fructus Immaturus, 500 - 600 parts of Aucklandiae Radix, 500 - 600 parts of Citri Reticulatae Pericarpium, 520 - 580 parts of Pinelliae Rhizoma Praeparatum, 800 - 850 parts of Taraxaci Herba, 500 - 600 parts of Crataegi Fructus (Fried to Charcoal), 300 - 360 parts of Arecae Semen Praeparatum, 500 - 600 parts of Paederiae Herba, 300 - 400 parts of Codonopsis Radix, 300 - 400 parts of Corydalis Rhizoma, and 500 - 600 parts of Medicata Fermentata.

[0033] Analyzed pharmacologically, the active ingredients in Bupleuri Radix, such as saikosaponins, have anti-inflammatory and antidepressant effects and can regulate neurotransmitters to improve the depressive state. Aurantii Fructus Immaturus contains volatile oils, flavonoid compounds, etc., which have the effects of regulating gastrointestinal function and antidepressant. The volatile oil components in Aucklandiae Radix have anti-inflammatory, analgesic, and antidepressant effects. The volatile oils and flavonoid compounds in Citri Reticulatae Pericarpium have anti-inflammatory, antioxidant, and antidepressant effects. The alkaloid components in Pinelliae Rhizoma, Arecae Semen, and Corydalis Rhizoma have sedative and antidepressant effects. The polysaccharides and flavonoid compounds in Taraxaci Herba have anti-inflammatory, immunomodulatory, and antidepressant effects. The flavonoid compounds and organic acids in Crataegi Fructus have antioxidant, anti-inflammatory, and antidepressant effects. The polysaccharides and saponins in Codonopsis Radix have immunomodulatory and antidepressant effects. The enzyme and vitamin components in Medicata Fermentata have the effects of promoting digestion and antidepressant.

[0034] Through the compatibility of various traditional Chinese medicines, the above pharmaceutical composition can comprehensively regulate the physical and mental states of depressive patients, relieve depressive symptoms, improve digestive function, and improve the quality of life. At the same time, the active ingredients in these traditional Chinese medicines have multiple effects such as anti-inflammatory, antioxidant, immunomodulatory, and antidepressant, and jointly play the therapeutic effect on depression.

[0035] All kinds of traditional Chinese medicinal materials used as raw materials in the compositions of the present application are common traditional Chinese medicines, which are described in detail in "Chinese Pharmacopoeia" and "Compendium of Chinese Materia Medica", etc., and can be easily obtained through commercial channels. The present application has no special restrictions on the origin of these traditional Chinese medicinal materials, etc., as long as they meet relevant national standards or regulations.

[0036] In addition, in the specification, examples and claims of the present application, certain terms are used to describe relevant technical content. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present application pertains.

[0037] In the present application, the terms "comprising" and "including" are used in an inclusive and open sense, which means that additional elements (or steps) may be included in addition to those specified. The terms "such as" and "for example" used herein are non-restrictive and are for illustrative purposes only. "Comprising" and "including but not limited to" can be used interchangeably. In addition, the terms "comprising" and "including" also cover the case where no additional elements (or steps) are included, that is, the technical solutions defined by "comprising" or "including" also cover the technical solutions consisting only of the elements (or steps) included or contained.

[0038] In the present application, for a pharmaceutical composition, "the pharmaceutical active ingredient consists of..." means that the active ingredient that plays a therapeutic role consists of and only consists of the specified components, but it does not exclude the inclusion of additives or Chinese herbal medicines that play other auxiliary roles in addition to the active components.

[0039] Unless the context clearly indicates otherwise, the term "or", as used herein, should be understood to mean "and / or".

[0040] The term "pharmaceutical composition" refers to a combination of various substances having a specific medical or biological use, and is generally expected to have a therapeutic or preventive effect on a specific disease after being administered to a subject. A pharmaceutical composition may contain only the specified active ingredient (bioactive substance), or may be provided together with conventional pharmaceutically acceptable carriers (such as excipients, diluents, carriers, adjuvants, sweeteners, processing aids, etc.) for various purposes. The term "pharmaceutical composition" in the present application should be interpreted in a broad sense.

[0041] In this specification, medicinal materials, components, etc. modified by "optional" mean that the medicinal material or component may be present in some embodiments as needed, and may not be present in other certain embodiments. Similarly, an operation or step modified by "optional" or "optionally" means that the step or operation may be present in the methods of some embodiments as needed, and may not be present in the methods of other certain embodiments.

[0042] In the context of this application, "portions" used to indicate the amount of medicinal materials or components refer to weight portions, and any reference weight can be selected as "1 portion". For example, "1 portion" can be 0.5g, 1g, 10g, 100g, 1kg, 10kg, 50kg, etc.

[0043] In a preferred embodiment, in the pharmaceutical composition of the present application, the weight ratio of bupleurum, immature bitter orange, costus root, tangerine peel, pinellia tuber, dandelion, charred hawthorn, charred betel nut, millet stalk, Codonopsis pilosula, Corydalis yanhusuo, and stir-fried Liushenqu is about 1:1:1:1:1:(1.4-1.6):1:(0.5-0.7):1:(0.5-0.7):(0.5-0.7):1; further preferably, the weight ratio of bupleurum, immature bitter orange, costus root, tangerine peel, pinellia tuber, dandelion, charred hawthorn, charred betel nut, millet stalk, Codonopsis pilosula, Corydalis yanhusuo, and stir-fried Liushenqu is about 1:1:1:1:1:1.5:1:0.6:1:0.6:0.6:1.

[0044] Those skilled in the art will appreciate that the dosage or weight of each medicinal material described in this specification (including those described in the examples) is inevitably subject to a certain range of error. Unless otherwise specified, the weight values ​​or weight portions described in this specification may vary within a range of ±5%, ±3%, ±2% or ±1%.

[0045] Preferably, the pharmaceutical composition described herein is dried. Most preferably, the pharmaceutical composition described herein is in the form of dry powder or granules.

[0046] Those skilled in the art should understand that the pharmaceutical composition for treating depression of the present application may contain other Chinese medicinal materials in addition to the Chinese medicinal materials specified above as needed or for other purposes.

[0047] In some preferred embodiments, the pharmaceutical composition is the pharmaceutical composition disclosed in Chinese patent application CN1389230A, especially the pharmaceutical composition disclosed in each example therein.

[0048] In some preferred embodiments, the pharmaceutical composition is a drug listed under “Dalitong Granules” on pages 883 to 885 of the “Chinese Pharmacopoeia” (2020 edition).

[0049] II. Preparation Method of Pharmaceutical Composition

[0050] The pharmaceutical composition described in the first aspect of the present application can be prepared from the twelve Chinese medicinal raw materials by conventional methods in the art, and the present application does not limit its specific preparation process. However, in order to improve extraction efficiency and reduce costs, the pharmaceutical composition is preferably prepared by the method described in the second aspect of the present application, which comprises the following steps:

[0051] 1) Weigh Bupleuri Radix, Aurantii Fructus Immaturus, Aucklandiae Radix, and Citri Reticulatae Pericarpium, then decoct and distill to extract volatile oil. The obtained volatile oil is included with beta-cyclodextrin (β-cyclodextrin), and the remaining aqueous solution after decoction is collected for later use.

[0052] 2) Weigh Pinelliae Rhizoma Praeparatum, Taraxaci Herba, Crataegi Fructus Carbonisatus, Arecae Semen Carbonisatum, Paederiae Herba, Codonopsis Radix, Corydalis Rhizoma, and Medicata Fermentata, and combine them with the medicinal residues remaining after decoction in step 1). Decoct with water 1 - 3 times, combine the decoctions and then filter.

[0053] 3) Combine the aqueous solution in step 1) with the filtrate in step 2), and concentrate under reduced pressure to a relative density of (measured at 60 °C);

[0054] 4) Add ethanol to the concentrate obtained in step 3), let it stand for 16 - 48 hours, filter, and continue to concentrate under reduced pressure to a thick paste with a relative density of (measured at 60 °C). Add appropriate excipients, mix well, and then mix evenly with the beta-cyclodextrin inclusion complex of the volatile oil in step 1), and perform optional post-treatments such as drying, granulation, and packaging.

[0055] In step 1) of the above method, the amounts of Bupleuri Radix, Aurantii Fructus Immaturus, Aucklandiae Radix, and Citri Reticulatae Pericarpium used, and in step 2), the amounts of Pinelliae Rhizoma Praeparatum, Taraxaci Herba, Crataegi Fructus Carbonisatus, Arecae Semen Carbonisatum, Paederiae Herba, Codonopsis Radix, Corydalis Rhizoma, and Medicata Fermentata used are as described in the first aspect of this application.

[0056] The extraction of the volatile oil in step 1) is carried out by decoction and distillation method. For example, it can be decocted and distilled with water for 2 - 12 hours to collect the volatile oil.

[0057] The combined decoction in step 2) can be carried out 1 time, 2 times, or 3 times, each time for 1 - 5 hours, such as 2 hours, 3 hours, or 4 hours. The decoction time for each time can be the same or different.

[0058] The addition of ethanol and standing in step 4) is to precipitate and separate out impurities. The added ethanol can be pure ethanol or an ethanol aqueous solution of 40 - 95%, preferably pure ethanol or an ethanol aqueous solution with a concentration higher than 75%. Preferably, ethanol is added to make the ethanol content 60 - 70%, and most preferably, the ethanol content is about 65%. The relative density of the thick paste is preferably (measured at 60 °C).

[0059] The excipients added to the thick paste in step 4) can be, for example, steviol glycosides, dextrin, etc. The drying in step 4) can adopt processes such as spray drying, freeze drying, vacuum drying, etc. The granulation in step 4) can adopt wet granulation or dry granulation. In some embodiments, the post-treatment steps such as drying and granulation can also be omitted, and instead, a mixture of the thick paste and the beta-cyclodextrin inclusion complex of the volatile oil (usually in paste form) can be directly provided as the raw drug for further processing.

[0060] In some preferred embodiments, the preparation method employed is the preparation method disclosed in Chinese Patent Application CN1389230A, especially the preparation methods disclosed in the respective examples thereof.

[0061] In some preferred embodiments, the preparation method employed is the preparation method described on pages 883 to 885 of "Daritong Granules" in the Chinese Pharmacopoeia (2020 Edition).

[0062] Before, after, or during steps 1), 2), 3), and 4) described above, other additional operations may be included. For example, when necessary, sterilization operations can be carried out.

[0063] III. Treatment Method and Pharmaceutical Use

[0064] The third aspect of the present application provides the use or method of the pharmaceutical composition of the first aspect of the present application or the pharmaceutical composition prepared by the method described in the second aspect of the present application for treating depression, including administering to a patient an effective amount of the pharmaceutical composition of the first aspect of the present application or the pharmaceutical composition prepared by the method described in the second aspect of the present application, or the pharmaceutical composition according to any embodiment of the present application.

[0065] The fourth aspect of the present application provides the use of the pharmaceutical composition of the first aspect of the present application or the pharmaceutical composition prepared by the method described in the second aspect of the present application (or the pharmaceutical composition according to any embodiment of the present application) in the preparation of a medicament for treating depression.

[0066] In the present application, the term "treatment" means inhibiting a subject's disease, disorder, and / or symptom, such as hindering its progression; and alleviating a disease, disorder, and / or symptom, such as causing the regression of a disease, disorder, and / or symptom. Treating a disease or disorder includes improving at least one symptom of a specific disease or disorder, even if the underlying pathophysiology is not affected. In particular, in the present application, "treatment" also encompasses the meaning of reducing the risk of onset of a certain disease by administering a drug, that is, "treatment" includes both prevention before the onset of the disease and remission, inhibition, and cure of the disease after the onset.

[0067] Among them, the patient is preferably a mammal, and more preferably a human.

[0068] In this text, "depression" includes any condition or symptom clinically or pathologically classifiable as depression, including but not limited to mild depression, major depression, treatment-resistant depression, bipolar depression, unipolar depression, seasonal depression, chronic depression, psychotic depression, postpartum depression, situational depression, atypical depression, and so on. The depressive symptoms that can be alleviated or improved by the pharmaceutical composition of the present application may include various psychological changes and physical symptoms. The psychological changes such as mood changes (including low mood), intense feelings of sadness, despair, mental dullness, inattention, pessimistic worry, anxiety, irritability, guilt, anger, worthlessness, reckless behavior, suicidal thoughts or attempts, and / or self-deprecation, etc.; the physical symptoms may include insomnia, anorexia, loss of appetite, weight loss, weight gain, decreased energy and libido, fatigue, restlessness, pain, headache, cramps, digestive problems, and / or abnormal hormonal circadian rhythm, etc.

[0069] The specific mode and dose of administration during treatment can be selected by the attending physician considering the specific conditions of the patient, especially conditions such as age, weight, lifestyle, activity level, disease severity, etc. Preferably, the pharmaceutical composition is administered orally.

[0070] Generally, the single dose for a mammal is about in the range of 1 - 20,000 mg / kg. For example, for the preferred treatment of human patients, when administered in the form of a traditional Chinese medicine extract premix, the appropriate dose can be in the range of 1 - 2,000 mg / kg, 2 - 1,000 mg / kg, 5 - 500 mg / kg, or 10 - 100 mg / kg. If necessary, this dose can also be divided into optionally equal portions for administration. The doses mentioned above can be repeated at certain intervals, for example, three times a day, once a day, once a week, and so on.

[0071] In this specification, "mg / kg" or "mg·kg -1 " means the number of milligrams of the drug administered per kilogram of body weight of the mammal (including humans) to be treated, and "g / kg" or "g·kg -1 " means the number of grams of the drug administered per kilogram of body weight of the mammal (including humans) to be treated.

[0072] The therapeutic effect of the pharmaceutical composition of the present application has been demonstrated by various recognized animal depression models (such as CSDS, CUMS, CRS) through indicators such as forced swimming behavior, tail suspension immobility time, sucrose preference, and social interaction coefficient. Specifically, animal model experiments show that the pharmaceutical composition of the present application can improve the forced swimming time and tail suspension immobility time (indicating a tendency to improve despair behavior), significantly enhance the social interaction coefficient (indicating that it can improve social phobia in depressive patients), and improve sucrose preference (indicating that it is beneficial to transform negative emotions such as anhedonia in depressive patients). Animal model experiments also show that the pharmaceutical composition of the present application can be used to rapidly relieve the symptoms of depression, and it can start to take effect within 1 to 2 weeks after administration, usually within 1 week or 2 weeks after administration, and preferably starts to show obvious effects about one week after the start of administration.

[0073] The pharmaceutical composition of the present application has been proven to be safe and reliable through animal experiments, and its formulation and preparation process are recorded in the Chinese Pharmacopoeia. It has been clinically applied for more than 20 years, and its safety has been fully verified.

[0074] Since the pharmaceutical composition of the present application is known to be used for the treatment of stomach diseases, especially bile reflux gastritis, non-ulcer dyspepsia, etc., this pharmaceutical composition can be used to treat stomach diseases and depression simultaneously, and is therefore particularly suitable for the treatment of functional dyspepsia with depression.

[0075] IV. Pharmaceutical Preparation

[0076] The fifth aspect of the present application provides a pharmaceutical preparation (preferably an oral pharmaceutical preparation), which comprises the pharmaceutical composition of the first aspect of the present application or the pharmaceutical composition prepared by the method described in the second aspect of the present application (or the pharmaceutical composition according to any embodiment of the present application) and a pharmaceutically acceptable carrier or adjuvant.

[0077] The pharmaceutical composition of the present application, as a drug active substance, can be added with a pharmaceutically acceptable carrier or adjuvant when needed, and made into the required preparation according to conventional pharmaceutical technology. The drug active substance in the preparation can be 0.1 - 99.9% (such as 1 - 99% or 50 - 98% or 50 - 95%, etc.), and the rest is a pharmaceutically acceptable carrier or adjuvant.

[0078] The preparation of the present application can be any pharmaceutically acceptable dosage form, including: it can be a granule, tablet, capsule, oral liquid, syrup, dispersible tablet, buccal tablet, effervescent tablet, pill. Preferably, the preparation of the present application is a granule, tablet, capsule, or pill, etc.

[0079] Preferably, the pharmaceutical preparation of the present application exists in unit dosage form, and the unit dosage form refers to the unit of the preparation, such as each tablet of the tablet, each bag of the granule, each capsule of the capsule, etc.

[0080] The preparation in unit dosage form preferably contains about 1% to about 90% (such as 20%-80% or 30-60%) of the active ingredient. For example, a single-dose unit dosage form such as a capsule, tablet or dragee may contain about 1 mg to about 100 g (such as 10 mg to 80 g, 50 mg to 50 g, 1 g - 20 g, etc.) of the active ingredient.

[0081] To prepare a suitable dosage form, the pharmaceutical composition of the present application as a pharmaceutical active substance can optionally be mixed or combined with an inorganic or organic, solid or liquid pharmaceutically acceptable carrier or adjuvant suitable for administration. For example, suitable carriers particularly include fillers such as sugars (such as lactose), mannitol or sorbitol, cellulose products and / or calcium phosphate (tricalcium phosphate or calcium hydrogen phosphate); binders such as starch paste, gelatin, methylcellulose and / or polyvinylpyrrolidone; disintegrants such as starch, carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar or alginic acid or its salts (such as sodium alginate).

[0082] The preferred levels and preferred aspects of the various specific embodiments and various features of the present application mentioned above can be combined arbitrarily, and all the technical solutions obtained by such combinations are within the scope of the present application.

[0083] The beneficial effects of the present application are manifested in that: the pharmaceutical composition of the present application has an obvious effect in treating depression, and at the same time has good safety and no side effects after long-term administration, representing a major breakthrough in the clinical treatment of this disease field. At the same time, compared with the traditional Chinese medicine composition for treating depression, the pharmaceutical composition for treating depression of the present application has at least one or more of the following advantages:

[0084] It has a significant effect in treating depression, with strong efficacy, equivalent to or better than that of commonly used western medicines for treating depression;

[0085] It is safe to take, has no obvious adverse reactions and toxic side effects, patients have good tolerance and strong compliance, and is suitable for long-term administration;

[0086] It has a rapid onset of action and is suitable for quickly relieving symptoms. Usually, it can take effect quickly about one week after taking the medicine (even faster than most western antidepressant medicines);

[0087] It is applicable to the treatment, consolidation and maintenance of depression;

[0088] The pharmaceutical composition contains multiple components and can act on multiple targets simultaneously, comprehensively conditioning the body, not only relieving depressive symptoms, but also improving appetite, sleep quality, etc., and improving the overall quality of life of patients;

[0089] The pharmaceutical composition is formulated according to traditional Chinese medicine theory and dialectically treats depression of the liver qi stagnation type, with strong pertinence;

[0090] Traditional Chinese medicine treatment not only focuses on symptom relief but also emphasizes the overall conditioning of the body and mind, which helps patients recover and prevent recurrence. Description of the Drawings

[0091] Figure 1 Shows the modeling and drug administration protocols for CSDS depression model mice.

[0092] Figure 2 Shows the drug administration test results of CSDS depression model mice, where: (A) is the social interaction test result after 3 days of drug administration; (B) is the forced swimming test result after 3 days of drug administration; (C) is the social interaction test result after 6 days of drug administration. Where: SS is the model group, DLT is the experimental group; ANOVA is used for statistical analysis, *: p < 0.05; **: p < 0.01.

[0093] Figure 3 Shows the drug administration test results of CSDS depression model mice, where: (A) is the test result of the tail suspension immobility test (TST); (B) is the test result of the forced swimming experiment (FST). Where: Ctrl is the normal control group, SS is the model group, FXT is the fluoxetine group, DLT is the experimental group; ANOVA is used for statistical analysis, *: p < 0.05; **: p < 0.01; ***: p < 0.001.

[0094] Figure 4 Shows the drug administration test results of CRS depression model mice, where: (A) is the test result of the tail suspension immobility test (TST); (B) is the test result of the forced swimming experiment (FST). Where: Ctrl is the normal control group, SS is the model group, FXT is the fluoxetine group, DLT is the experimental group; ANOVA is used for statistical analysis, *: p < 0.05; **: p < 0.01; ***: p < 0.001.

[0095] Figure 5 Shows the test results of the sucrose preference test (SPT), tail suspension immobility test (TST), and forced swimming experiment (FST) of CUMS depression model mice, where: (A) is the test result after 3 days of drug administration; (B) is the test result after 6 days of drug administration; (C) is the test result after 10 days of drug administration. Where: Ctrl is the normal control group, SS is the model group, FXT is the fluoxetine group, DLT is the experimental group; One-way ANOVA is used for statistical analysis, *: p < 0.05; **: p < 0.01; ***: p < 0.001. Specific Embodiment

[0097] The above contents of the present application are further described in detail below by the specific implementation methods of the embodiments. It should be understood that the specific examples described herein are only used to explain the present application and are not intended to limit the present application. Any modifications made without departing from the spirit and principles of the present application, as well as equivalent replacements or improvements made according to common technical knowledge and customary means in the art, should all be included in the protection scope of the present application.

[0098] The numbers reported in the following examples are as accurate as possible, but those skilled in the art understand that due to inevitable measurement errors and experimental operation problems, each number should be understood as an approximate number rather than an absolutely accurate number. For example, due to the error of the weighing instrument, the weight value of each drug in each embodiment composition should be understood to have an error within ± 3%.

[0099] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods; the materials, reagents, instruments, etc. used are conventional reagents, materials, instruments available from commercial channels unless otherwise specified.

[0100] Example 1: Preparation of Pharmaceutical Composition 1

[0101] The pharmaceutical composition of Example 1 is formulated as follows:

[0102] Bupleurum 154g

[0103] Citrus aurantium 154g

[0104] Wood fragrance 154g

[0105] Tangerine peel 154g

[0106] Qing Banxia 154g

[0107] Dandelion 231g

[0108] Scorched Hawthorn 154g

[0109] Burnt Betel Nut 92g

[0110] Cistanche deserticola 154g

[0111] Codonopsis pilosula 92g

[0112] Corydalis yanhusuo 92g

[0113] 154g of Liushenqu (fried).

[0114] The preparation process of the pharmaceutical composition of Example 1 is as follows:

[0115] The volatile oil is extracted by distillation from Bupleuri Radix, Fructus Aurantii Immaturus, Aucklandiae Radix, and Pericarpium Citri Reticulatae. The volatile oil is included with β-cyclodextrin, and the aqueous solution after distillation is collected separately in another container. The medicinal residues are combined with the other eight herbs such as Rhizoma Pinelliae, and decocted twice with water for 2 hours each time. The decoctions are combined, filtered. The filtrate is combined with the above-mentioned aqueous solution after distillation, and concentrated under reduced pressure to a clear extract with a relative density of 1.10 - 1.20 (measured at 60 °C). Ethanol is added to make the ethanol content reach 65%, allowed to stand for 24 hours, filtered, the filtrate is recovered ethanol, and concentrated under reduced pressure to a thick extract with a relative density of 1.12 - 1.35 (measured at 60 °C). Then, appropriate amounts of steviol glycoside and dextrin are added, and mixed evenly with the above-mentioned β-cyclodextrin inclusion complex to make granules, and dried to make about 1000 g of pharmaceutical composition 1.

[0116] The obtained pharmaceutical composition is yellowish-brown to brownish granules; slightly sweet and slightly bitter in taste.

[0117] Example 2: Effect of the pharmaceutical composition on the behavior of CSDS-depressed mice

[0118] The purpose of this experiment is to test the therapeutic effect of the pharmaceutical composition of the present application on the depression model of CSDS (chronic social defeat stress depression model) mice.

[0119] Experimental animals

[0120] Male C57BL / 6J mice at 7 weeks of age and male CD-1 (ICR) mice (retired mice) at 6 - 8 months of age were all purchased from Vital River Laboratories Inc., Beijing, China.

[0121] Before the start of the experiment, all mice were adaptively housed for more than 7 days under standard laboratory conditions. The standard laboratory conditions were: a 12 h light / dark cycle and constant temperature and humidity (temperature: 24 °C ± 1 °C, humidity: 50% - 60%). During this period, C57BL / 6J mice were housed at 5 per cage, and CD-1 mice were housed individually due to their aggressiveness. Before and during the experiment, all food and water were freely available, and the feed met national standards (Hygienic Standard for Formula Feed for Laboratory Animals, GB / T14924.2 - 2001 and Nutritional Composition Standard for Formula Feed for Laboratory Animals, GB / T14924.3 - 2010), provided by Qinglongshan Experimental Animal Breeding Factory.

[0122] All animal experimental procedures were approved by the Animal Ethics Committee of China Pharmaceutical University and conducted in accordance with the guidelines of the National Institutes of Health.

[0123] Establishment of chronic social defeat stress depression model (CSDS)

[0124] Before starting the model establishment, CD-1 mice with aggressiveness were screened for 3 consecutive days. C57BL / 6J mice were placed in the cages of CD-1 mice. If a CD-1 mouse started to attack a C57BL / 6J mouse within 1 min and the continuous attack duration was not less than 30 sec, then the CD-1 was considered aggressive. If a CD-1 was determined to be aggressive in the tests for 3 consecutive days, it was used for subsequent model establishment.

[0125] During the 10-day model establishment process, the mice to be modeled were caged together with the CD-1 that attacked them, separated by a perforated transparent partition. They were made to feel the fear stress of the CD-1 for 24 h to maintain their psychological stress state. During the daily model establishment process, each C57BL / 6J mouse in the model group was separately exposed to the cage of a strange and aggressive CD-1. It was 10 min on the first day, 9 min 30 sec on the second day, and then decreased by 30 sec each day in turn. After the daily model establishment was completed, they were put back on the opposite side of the CD-1.

[0126] Social Interaction Test (SI)

[0127] Before the test started, the mice were acclimated to the light and temperature in the behavioral test room for at least 30 min. In the first stage of the test, first, a C57BL / 6J mouse to be tested was placed in an open field of 40×40×40 cm, and an empty social cage was placed in the central social area. Its activities within 150 sec were recorded with a camera. Then the mouse was removed. In the second stage of the test, a social cage containing a strange CD-1 mouse was placed in the central social area, and then the same C57BL / 6J mouse to be tested was placed in the open field, and the activities of the C57BL / 6J mouse within 150 sec were recorded with a camera. The calculation formula for the Social Interaction Index (SI) is the ratio of the time (S2) that the C57BL / 6J mouse entered the social area in the second stage to the time (S1) that they entered the social area in the first stage (Social Interaction Ratio, SI). If the SI value < 1, then it can be considered that the mouse showed social avoidance behavior and was depressed.

[0128] Forced Swimming Test (FST)

[0129] Before the experiment begins, pour water at 20-25°C into a glass container with a diameter of 12 cm and a height of 30 cm. The water level is about 20 cm (make sure the mouse's tail cannot touch the bottom of the container). During the experiment, ensure that the tested mice are isolated from each other and cannot see each other. Use a camera to record the activities of these mice within 6 minutes. The experimental results were analyzed by two colleagues who were unaware of the experiment, and the time (Time of immobility or Timeimmobile) of the mice in the last 4 minutes was recorded. Immobility is defined as complete immobility or when the mouse stands upright on the water surface with its front paws together and only makes movements required to stay afloat. The forced swimming test can simulate human depression symptoms by subjecting animals to inescapable stimuli that cause behavioral despair in the animals.

[0130] Grouping and dosing regimen

[0131] 30 mice, after the CSDS modeling was completed, the mice with SI values ​​less than 1 were screened out by social interaction test (SI) and divided into two groups (model group SS and drug administration group DLT). The drug administration group was gavaged twice a day with a high-dose drug administration group mouse 4.4g / kg aqueous suspension of drug composition 1 (DLT) for a total of 7 days. The social interaction test (SI) and forced swimming test (FST) were performed 3 and 6 days after the start of drug administration (i.e., day 4 D4 and day 7 D7), respectively. The dosing regimen is summarized in Figure 1 middle.

[0132] Results and discussion

[0133] The experimental results are summarized in Figure 2 After the model group mice were gavaged with the aqueous suspension of drug composition 1 (DLT, 4.4 g / kg) for 3 days, the social coefficient of the depressed mice ( Figure 2 A) significantly increased, while the immobility time in swimming showed a downward trend ( Figure 2 B); Six days after intragastric administration of the aqueous suspension of drug composition 1 (DLT, 4.4 g / kg), the social behavior of mice was tested again, and it was found that DLT further improved the social behavior of mice, and the social coefficient was significantly increased ( Figure 2 C, p<0.01). The results suggest that pharmaceutical composition 1 can improve the social behavior indexes of social frustration model mice.

[0134] The above research results show that the pharmaceutical composition of Example 1 can significantly improve the social avoidance depression-like behavior of mice in the CSDS depression model when administered at 4.4 g / kg on the 3rd and 6th days, and reduce the immobility time in the forced swimming test, indicating that it has the effect of treating depression in clinical practice and has a fast onset of action.

[0135] Example 3: Effect of the drug composition on the behavior of CSDS depression mice (II)

[0136] To further verify the therapeutic effect of the pharmaceutical composition of the present application on the depression model of mice with CSDS (chronic social defeat stress depression model), the administration time was extended on the basis of the experiment in Example 2, and the commonly used antidepressant western medicine fluoxetine (FXT) was further introduced as a positive control drug.

[0137] Experimental animals

[0138] Similar to Example 2, male C57BL / 6J mice at 7 weeks of age and male CD-1 (ICR) mice (retired mice) at 6 - 8 months were all purchased from Vital River Laboratories Inc., Beijing, China. Before the experiment started, all mice were adaptively housed under standard laboratory conditions for 5 days. All mice were housed in the barrier facilities of the Animal Experiment Center of China Pharmaceutical University, and all food and water were freely available. All animal experimental procedures were approved by the Animal Ethics Committee of China Pharmaceutical University and were conducted in accordance with the guidelines of the National Institutes of Health.

[0139] Establishment of chronic social defeat stress depression model (CSDS)

[0140] The model establishment process was the same as that in Example 2.

[0141] Social interaction test (SI)

[0142] The same as Example 2.

[0143] Forced swim test (FST)

[0144] The same as Example 2.

[0145] Tail suspension immobility time test (TST)

[0146] The tail suspension test was carried out in a tail suspension box. During the experiment, it was ensured that the tested mice were isolated from each other and could not see each other. The mice were individually suspended about 20 cm above the ground with medical tape. The test lasted for 6 min, and the immobility time (Time immobile or Immobility time) of the mice during the last 4 min was analyzed by Anymaze software.

[0147] Grouping and dosing regimen

[0148] Forty-five mice were selected by SI after the CSD model was established, and the successfully modeled mice were divided into three groups (model group SS, fluoxetine group FXT, and experimental group DLT). Mice in the fluoxetine group were given a fluoxetine suspension of 15 mg / kg once daily by gavage, and mice in the experimental group were given an aqueous suspension of pharmaceutical composition 1 of 4.4 g / kg twice daily by gavage. TST and FST were detected on the 3rd, 6th, and 10th days after administration (tested on the 4th, 7th, and 11th days, i.e., 4d, 7d, 11d). The experimental results are shown in Figure 3 。

[0149] Results and Discussion

[0150] It was observed that 3 days after administration, the state of the mice in the experimental group was significantly better than that of the non-administered model group: the hair was smooth and shiny, the activity increased, and the body was strong, indicating an obvious improvement effect.

[0151] As Figure 3 shown, it was also found that after 3 days (4d), 6 days (7d), and 10 days (11d) of administration of the aqueous suspension of pharmaceutical composition 1, there was a tendency to improve despair behavior. After 6 days of administration, the immobility time in the tail suspension test (TSF) and the immobility time in the forced swimming test (FST) were significantly improved compared with the model group, while the improvement effect of the positive drug fluoxetine on the above indicators was significantly weaker at the same time; it is indicated that the pharmaceutical composition of the present application is superior to the positive control drug fluoxetine in improving the behavior of depressive model mice. The specific experimental results are summarized in Figure 3 。

[0152] Example 4: Effect of the pharmaceutical composition on the behavior of CRS depressive mice

[0153] The purpose of this experiment was to test the effect of the pharmaceutical composition of the present application on the behavior of mice with a chronic restraint stress depression model (CRS).

[0154] Experimental Animals

[0155] Similar to Example 2, 7-week-old male C57BL / 6J mice and 6-8-month-old male CD-1 (ICR) mice (retired mice) were all purchased from Vital River Laboratories Inc., Beijing, China. Before the experiment began, all mice were acclimatized for 5 days under standard laboratory conditions. All mice were housed in the barrier facility of the Animal Experiment Center of China Pharmaceutical University, and all food and water were available ad libitum. All animal experimental procedures were approved by the Animal Ethics Committee of China Pharmaceutical University and were conducted in accordance with the guidelines of the National Institutes of Health.

[0156] Establishment of the chronic restraint stress depression model (CRS)

[0157] The restraint stress was carried out using a perforated 50 ml conical tube. C57BL / 6J mice were placed in the tube for 4 - 6 h per day for 21 consecutive days. The tube was thoroughly cleaned and disinfected with a tasteless cleaning solution and wiped dry every day.

[0158] Forced swimming test (FST)

[0159] Same as Example 2.

[0160] Tail suspension immobility time test (TST)

[0161] Same as Example 3.

[0162] Grouping and dosing regimen

[0163] After the CRS model was established in 45 mice, the successfully modeled mice were screened by TST and FST and divided into three groups (model group SS, fluoxetine group Fluoxetine, and experimental group DLT). The fluoxetine group was given a fluoxetine aqueous suspension of 15 mg / kg once daily by gavage, and the experimental group was given an aqueous suspension of Drug Composition 1 of 4.4 g / kg twice daily by gavage. TST and FST were detected 3 and 6 days after dosing (testing on the 4th and 7th days, i.e., D4 and D7), and the body weight was weighed.

[0164] Results and discussion

[0165] The experimental results are summarized in Figure 4 . Three days after dosing, there were no significant changes in the tail suspension immobility time TST and the swimming immobility time FST; while six days after dosing, the above - mentioned indicators were significantly improved compared with the model group, and the effect was significantly better than that of the control drug fluoxetine ( Figure 4 ), indicating that the drug composition of the present application has a tendency to improve the despair behavior of CRS model mice.

[0166] Therefore, the administration of the drug composition of the present application can significantly improve the despair behavior of CRS model mice in a relatively short time. In addition, compared with the results of Example 3, it can be seen that the improvement effect of the drug composition of the present application on the despair behavior of CRS model mice is significantly stronger than that of CSDS model mice.

[0167] Example 5: Effects of the drug composition on the behavior of CUMS - induced depressive mice

[0168] The purpose of this experiment was to test the therapeutic effect of the drug composition of the present application on the depressive model of chronic unpredictable stress - induced (CUMS) mice.

[0169] Experimental animals

[0170] Six-week-old SPF male C57BL / 6J mice were all purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd. The animals were housed in the Animal Experiment Center of Jiangning Campus of China Pharmaceutical University, with constant temperature and humidity. The breeding environment temperature was 24±2°C, and the humidity was maintained at 60%±5%. The breeding room was kept under a 12-hour light / dark cycle, and during this period, the animals had free access to food and water. All animal experiments were approved by the Animal Ethics Committee of China Pharmaceutical University and were conducted in accordance with the operating procedures of experimental animals at China Pharmaceutical University. Establishment of the chronic unpredictable stress model (CUMS)

[0171] The chronic unpredictable stress model was constructed with reference to the method of Willner, P. The mice were individually caged and adapted to 1% sucrose solution for 2 days. At a fixed time each week, the sucrose preference (sucrose water preference) of each mouse was measured, and the measured values of the first two tests were used as the baseline, while sucrose-insensitive mice were excluded. After the third test, the mice were randomly grouped according to their sucrose preference scores: control group (Ctrl), model group (SS), experimental group (DLT), and positive drug group (FXT). Then, the CUMS protocol was applied to the mice. Briefly, under this protocol, 2-3 various mild stress stimuli were randomly and continuously applied every day, and the same type of stimulus did not appear continuously, so that the animals could not predict the occurrence of stress stimuli, including restraint (4 hours), forced swimming in ice water mixture (5 minutes), hot water swimming at 40°C (5 minutes), food and water deprivation (24 hours), tilted cage ((45°, 24 hours), circadian rhythm inversion (once), wet bedding (24 hours), bedding deprivation (24 hours), tail clamping (5 min), and tail suspension (twice, 5 minutes each time). The model construction lasted for 4-5 weeks. At a fixed time each week, the sucrose water preference test and grooming behavior score were performed, and the depression-tolerant mice were excluded according to the test results. The remaining depressed mice were subjected to subsequent drug treatment. During the treatment period, one stress stimulus was randomly applied every day to maintain the depressive state of the mice.

[0172] Sucrose preference test (SPT)

[0173] The sucrose preference test was performed according to the literature method. The mice were individually caged and fed freely. After 2 days of adaptation, the sucrose preference experiment was carried out for 7 consecutive days. On days 1-2, two water bottles (w-w) filled with water were placed in each cage, and the positions of the water bottles were exchanged every 12 hours to avoid repeated drinking from the same water bottle; on days 3-4, two water bottles filled with 1% sucrose water (s-s) were placed in each cage, and the positions of the water bottles were also changed every 12 hours; on days 5-7, the sucrose test was conducted. One water bottle filled with water and one with sucrose water (s-w) were placed in each cage. The water was withheld for 12 hours before the test, and the positions of the two water bottles were exchanged every 12 hours. The drinking volumes of the two water bottles were measured for 24 hours.

[0174] Mouse sucrose preference index = sugar water intake / (water intake + sugar water intake) * 100%

[0175] Forced swimming test (FST)

[0176] Same as Example 2

[0177] Tail suspension immobility time test (TST)

[0178] Same as Example 3

[0179] Grouping and dosing regimen

[0180] After successful establishment of the CUMS model, the mice were randomly grouped according to their sucrose preference scores: control group (Ctrl), model group (SS), experimental group (DLT), and positive drug group (FXT). After completion of the CUMS modeling, after excluding the mice insensitive to depression, the number of mice allocated to each group was as follows: 10 mice in the control group (Ctrl), 12 mice in the model group (SS), 12 mice in the Dalitong administration group (DLT), and 12 mice in the positive drug group (FXT, fluoxetine group). The experimental group was intragastrically administered an aqueous suspension of Drug Composition 1 at a dose of 4.4 g / kg (twice a day), and the positive drug group was intragastrically administered fluoxetine at a dose of 10 mg / kg per day. After 3 days (4d), 6 days (7d), and 10 days (11d) of dosing, sucrose preference test (SPT), forced swimming test (FST), and tail suspension test (TST) were performed.

[0181] Results and discussion

[0182] The CUMS model showed obvious depressive-like behaviors, indicating successful modeling. After 6 days of dosing, Drug Composition 1 significantly improved the sucrose preference in SPT and the immobility time in FST ( Figure 5 A, 5B); after 10 days of dosing, Drug Composition 1 significantly improved the sucrose preference in SPT and the immobility time in TST ( Figure 5 C), and was slightly stronger than the positive drug fluoxetine.

[0183] The experimental results showed that administration of Drug Composition 1 could significantly improve the sucrose preference of CUMS model mice in a relatively short time, indicating a good improvement effect on the typical depressive behavior of anhedonia.

[0184] Based on the results of Examples 2 to 5, it can be seen that:

[0185] 1) The drug composition of the present application can significantly improve depressive-like behaviors such as social avoidance and sucrose preference in model mice such as CSDS and CUMS;

[0186] 2. The drug composition of the present application has an improvement effect on despair behaviors such as the immobility time of tail suspension and the immobility time of swimming in model mice such as CSDS, CRS, and CUMS;

[0187] 3. In multiple model tests, the pharmaceutical composition of the present application showed an effect equivalent to or better than that of the typical antidepressant fluoxetine in improving depressive symptoms;

[0188] 4. The pharmaceutical composition of the present application has a rapid onset of action and significantly shows effects about one week after administration in multiple models, so it can be used to quickly relieve depressive symptoms.

[0189] Therefore, the pharmaceutical composition of the present application represents a novel therapy for depression.

[0190] Although the specific embodiments have been specifically described above, those skilled in the art can understand that, according to the disclosure and guidance of the above specification, those skilled in the art of the present application can also make appropriate changes and modifications to the above embodiments. Therefore, the present application is not limited to the specific embodiments disclosed and described above, and some modifications and changes to the present application also fall within the protection scope of the claims of the present application.

Claims

1. A pharmaceutical composition for treating depression, wherein the active pharmaceutical ingredient is composed of the following Chinese medicines in parts by weight: 500-600 parts of bupleurum, 500-600 parts of immature bitter orange, 500-600 parts of costusroot, 500-600 parts of dried tangerine peel, 500-600 parts of pinellia, 750-900 parts of dandelion, 500-600 parts of charred hawthorn, 300-360 parts of charred betel nut, 500-600 parts of millet vine, 300-400 parts of codonopsis pilosula, 300-400 parts of yanhusuo, and 500-600 parts of stir-fried liushenqu.

2. The pharmaceutical composition according to claim 1, characterized in that: The weight ratio of bupleurum, immature bitter orange, costusroot, dried orange peel, pinellia, dandelion, scorched hawthorn, scorched areca, millet vine, codonopsis pilosula, yanhusuo, and stir-fried liushenqu is approximately 1:1:1:1:1:(1.4-1.6):1:(0.5-0.7):1:(0.5-0.7):(0.5-0.7):

1.

3. The pharmaceutical composition according to claim 1, characterized in that: The weight ratio of bupleurum, immature bitter orange, costusroot, dried orange peel, pinellia, dandelion, scorched hawthorn, scorched areca, millet sedge, codonopsis pilosula, yanhusuo, and stir-fried liushenqu is approximately 1:1:1:1:1:1:1.5:1:0.6:1:0.6:0.6:

1.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition is prepared by a preparation method comprising the following steps: 1) Weighing radix bupleuri, immature bitter orange, costusroot and dried orange peel, then decocting and distilling to extract volatile oil, encapsulating the obtained volatile oil with beta-cyclodextrin, and collecting the remaining aqueous solution after decocting for later use; 2) Weigh out Pinellia ternata, Taraxacum mongolicum, charred Hawthorn, charred Areca catechu, Cistanche deserticola, Codonopsis pilosula, Corydalis yanhusuo, and stir-fried Liushenqu, and combine with the remaining residues after decoction in step 1), add water and decoct twice, combine the decoctions and filter; 3) combining the aqueous solution in step 1) with the filtrate in step 2), and concentrating under reduced pressure to a relative density of 1.10 to 1.20 (measured at 60° C.); 4) Add ethanol to the concentrate obtained in step 3), let it stand for 16-48 hours, filter, and continue to concentrate under reduced pressure to a thick paste with a relative density of 1.12-1.35 (measured at 60° C.), add appropriate amounts of auxiliary materials, mix well, and then mix well with the volatile oil-beta-cyclodextrin inclusion complex in step 1), and perform optional post-treatment such as drying, granulation and packaging.

5. A pharmaceutical preparation for treating depression, comprising the pharmaceutical composition according to any one of claims 1 to 4 and conventional adjuvants or excipients.

6. Use of a pharmaceutical composition in the preparation of a drug for treating depression, wherein the active pharmaceutical ingredient of the pharmaceutical composition is composed of the following Chinese medicines in parts by weight: 500-600 parts of bupleurum, 500-600 parts of immature bitter orange, 500-600 parts of costusroot, 500-600 parts of dried tangerine peel, 520-580 parts of pinellia, 800-850 parts of dandelion, 500-600 parts of charred hawthorn, 300-360 parts of charred areca, 500-600 parts of millet vine, 300-400 parts of codonopsis pilosula, 300-400 parts of yanhusuo, and 500-600 parts of stir-fried liushenqu.

7. The use according to claim 6, characterized in that: The weight ratio of bupleurum, immature bitter orange, costusroot, dried orange peel, pinellia, dandelion, charred hawthorn, charred areca, millet stalk, codonopsis pilosula, corydalis, and stir-fried liushenqu in the pharmaceutical composition is approximately 1:1:1:1:1:(1.4-1.6):1:(0.5-0.7):1:(0.5-0.7):(0.5-0.7):

1.

8. The use according to claim 6, characterized in that: The weight ratio of bupleurum, immature bitter orange, costusroot, dried orange peel, pinellia, dandelion, charred hawthorn, charred areca, millet sedge, codonopsis pilosula, yanhusuo and stir-fried liushenqu in the pharmaceutical composition is approximately 1:1:1:1:1:1.5:1:0.6:1:0.6:0.6:

1.

9. The use according to any one of claims 6 to 8, characterized in that: The pharmaceutical composition is prepared by a preparation method comprising the following steps: 1) Weighing radix bupleuri, immature bitter orange, costusroot and dried orange peel, then decocting and distilling to extract volatile oil, encapsulating the obtained volatile oil with beta-cyclodextrin, and collecting the remaining aqueous solution after decocting for later use; 2) Weigh out Pinellia ternata, Taraxacum mongolicum, charred Hawthorn, charred Areca catechu, Cistanche deserticola, Codonopsis pilosula, Corydalis yanhusuo, and stir-fried Liushenqu, and combine with the remaining residues after decoction in step 1), add water and decoct for 1-3 times, combine the decoctions and filter; 3) combining the aqueous solution in step 1) with the filtrate in step 2), and concentrating under reduced pressure to a relative density of 1.10 to 1.20 (measured at 60° C.); 4) Add ethanol to the concentrate obtained in step 3), let it stand for 16-48 hours, filter, and continue to concentrate under reduced pressure to a thick paste with a relative density of 1.12-1.35 (measured at 60° C.), add appropriate amounts of auxiliary materials, mix well, and then mix well with the volatile oil-beta-cyclodextrin inclusion complex in step 1), and perform optional post-treatment such as drying, granulation and packaging.

10. The use according to any one of claims 6 to 8, characterized in that: The pharmaceutical composition is used to quickly relieve the symptoms of depression, and preferably begins to take effect within 1 to 2 weeks after administration.

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