Traditional Chinese medicine composition for treating depression and preparation method and application thereof

Abstract

The invention discloses a traditional Chinese medicine composition for treating depression as well as a preparation method and application of the traditional Chinese medicine composition. The preparation method comprises the following steps: weighing vinegar-processed rhizoma cyperi, ligusticum wallichii, fried rhizoma atractylodis, fried medicated leaven and fried fructus gardeniae which are equal in mass; crushing and sieving the vinegar rhizoma cyperi, the ligusticum wallichii, the fried rhizoma atractylodis and the fried medicated leaven to obtain traditional Chinese medicine powder; placing the traditional Chinese medicine powder in a 60-80% ethanol solution for decoction extraction, filtering, collecting filtrate, repeatedly extracting for 2-4 times, merging the filtrate, concentrating and drying to obtain thick paste; the fried cape jasmine is smashed and sieved, cape jasmine powder is obtained, then the cape jasmine powder and the thick paste are mixed, and the traditional Chinese medicine composition for treating depression is obtained. The preparation method disclosed by the invention can be used for efficiently and fully extracting active ingredients, such as ligustilide, atractydin I and alpha-cyperone, in the traditional Chinese medicine raw materials to obtain a new extract which is excellent in medicine effect, clear in ingredients and free from obvious toxic and side effects, and is expected to be developed as a novel medicine for improving and / or treating depression and anxiety disorder.

Description

Technical Field

[0001] The present invention relates to the technical field of Chinese medicine compositions, and in particular to a Chinese medicine composition for treating depression, and a preparation method and application thereof. Background Art

[0002] Depression is an emotional disease of the central nervous system with abnormal mood regulation as the main clinical feature. In recent years, the cumulative number of depression patients worldwide has exceeded 350 million, with a lifetime prevalence of 3.4%. According to statistics from the World Health Organization, depression will become the second largest disease in the world by 2030. The onset of depression is not only affected by biological and physiological factors, but also involves factors such as social living environment. It can occur at the same time as other diseases, with a high risk of recurrence and suicide rate. In addition, the onset of depression is gradually getting younger, and the number of adolescents suffering from depression is increasing, which seriously endangers people's physical and mental health. At present, the treatment of depression still relies on traditional antidepressants such as reuptake inhibitors and monoamine oxidase inhibitors. Although these drugs can provide some relief for depressive symptoms, only 1 / 3 of patients can show significant improvement, and the onset of these drugs may last for several weeks or even months, and there is a serious withdrawal effect. Therefore, it is urgent to develop more effective drugs for the treatment of depression.

[0003] The etiology and pathogenesis of depression are complex. At present, the main mechanisms of depression include the monoamine neurotransmitter hypothesis, the inflammatory cytokine hypothesis, the hypothalamus-pituitary-adrenal (HPA) axis hypothesis, and the brain-derived neurotrophic factor (BDNF) hypothesis, but they are still not clear enough. The disease currently lacks effective treatment and has a long course. Most patients need long-term or even lifelong treatment after diagnosis, which imposes a serious mental and economic burden on patients and their families. In recent years, with the continuous deepening of research on depression, four types of target-specific antidepressants represented by monoamine oxidase inhibitors (MAOI), tricyclic and tetracyclic antidepressants (TCAs), selective 5-HT reuptake inhibitors (SSRIs), and 5-HT and NE reuptake inhibitors (SNaRIs) have been developed. They have a certain effect on controlling the progression of depression, but long-term use has great toxic side effects and is prone to drug dependence. Patients are prone to withdrawal reactions after stopping the drug, and the disease recurs.

[0004] In traditional Chinese medicine theory, depression is classified as a "depression disease", which is mainly manifested as liver qi stagnation, liver depression turning into fire, liver depression and spleen deficiency, heart and spleen deficiency, and heart-kidney disharmony. Traditional Chinese medicine has the advantages of small toxic side effects, multi-target synergy, and significant antidepressant effect, and is widely used to improve and treat depression. Modern clinical and pharmacological studies have shown that Yueju Pills have significant antidepressant effects. However, the traditional use of Yueju Pills is to make the pills with water, and the whole medicine is directly used as medicine. Its formula ingredients are complex and the core effective ingredients are unclear. Therefore, it is particularly important to extract the key quality attributes of Yueju Pills, screen out the formula with clear effective ingredients, optimize the preparation process, and obtain Chinese medicine extracts with clear effective ingredients and excellent antidepressant effects. Summary of the invention

[0005] The purpose of the present invention is to provide a traditional Chinese medicine composition for treating depression, and a preparation method and application thereof. The preparation method of the present invention can efficiently and fully extract the effective ingredients in the traditional Chinese medicine raw materials, such as ligustilide, atractylodesin I and α-cyperone, to obtain a new extract with excellent efficacy, clear ingredients and no obvious toxic and side effects.

[0006] In order to achieve the above-mentioned purpose of the present invention, the following technical solutions are particularly adopted: The first aspect of the present invention provides a method for preparing a Chinese medicine composition for treating depression, the preparation method comprising the following steps: (a) Weigh equal amounts of vinegar-cooked Cyperus rotundus, Chuanxiong, stir-fried Atractylodes lancea, stir-fried Liushenqu, and stir-fried Gardenia jasminoides; (b) grinding and sieving the vinegar-cured cyperus rotundus, chuanxiong, stir-fried atractylodes and stir-fried liushenqu to obtain a Chinese medicine powder; (c) placing the Chinese medicine powder in a 60% to 80% ethanol solution for decoction extraction, filtering, collecting the filtrate, repeating the extraction 2 to 4 times, combining the filtrate, concentrating, and drying to obtain a thick paste, wherein the mass ratio of the Chinese medicine powder to the ethanol solution is 1: (10 to 15); (d) crushing and sieving the stir-fried gardenia to obtain gardenia powder, and then mixing the gardenia powder with the thick paste to obtain the traditional Chinese medicine composition for treating depression.

[0007] Preferably, in step (b), the particle size of the Chinese medicine powder is not less than 10 mesh, and the content of particles larger than 65 mesh is not higher than 40%.

[0008] Preferably, in step (b), the decocting time is 1 to 2 hours.

[0009] Preferably, in step (b), the relative density of the thick paste is 1.0-1.8.

[0010] Preferably, in the step (c), the particle size of the gardenia powder is not less than 100 mesh.

[0011] The second aspect of the present invention provides a traditional Chinese medicine composition for treating depression prepared by the above preparation method.

[0012] The third aspect of the present invention provides a use of a Chinese medicine composition for treating depression prepared by the above preparation method in preparing a Chinese medicine preparation for treating and / or improving depression or anxiety.

[0013] Preferably, the dosage forms of the traditional Chinese medicine preparation include tablets, pills, capsules and injections.

[0014] The fourth aspect of the present invention provides a traditional Chinese medicine pill for treating and / or improving depression or anxiety, wherein the traditional Chinese medicine pill comprises the traditional Chinese medicine composition for treating depression prepared by the preparation method and a binder.

[0015] Preferably, the preparation method of the Chinese medicine pills is the panning method, and the drying temperature during the preparation of the Chinese medicine pills is 40±10°C, and the drying time is 2-6h; The adhesive is a 70±5% ethanol solution.

[0016] Compared with the prior art, the beneficial effects of the present invention include at least: The present invention adopts two immobilized protein affinity chromatography models of 5-hydroxytryptamine 1A receptor (5-HT1AR) and 5-hydroxytryptamine transporter (5-HTT) to screen the active ingredients of Yueju Pills, and obtains active ingredients targeting dual targets, namely, artemisinin, atractylodesin and α-cyperone. Then, taking the active ingredients as indicators, the extraction process of Yueju Pills is optimized and studied, and a new extraction and preparation method is obtained. The preparation method can efficiently and fully extract the effective ingredients in Chinese medicinal raw materials, such as ligustilide, atractylodesin I and α-cyperone, to obtain a new extract with excellent efficacy, clear ingredients and no obvious toxic side effects, which is expected to be developed as a new drug for improving and / or treating depression and anxiety. DETAILED DESCRIPTION

[0017] The following embodiments of the technical solution of the present invention are described in detail in conjunction with the embodiments. The following embodiments are only used to more clearly illustrate the technical solution of the present invention, and are therefore only used as examples, and cannot be used to limit the protection scope of the present invention. It should be noted that, unless otherwise specified, the technical terms or scientific terms used in this application should have the common meanings understood by those skilled in the art to which the present invention belongs.

[0018] Example 1 This embodiment is a method for preparing a Chinese medicine composition for treating depression, and the preparation method comprises the following steps: (a) Weigh equal amounts of vinegar-cooked Cyperus rotundus, Chuanxiong, stir-fried Atractylodes lancea, stir-fried Liushenqu, and stir-fried Gardenia jasminoides; (b) grinding and sieving the vinegar-cured cyperus rotundus, chuanxiong, stir-fried atractylodes and stir-fried liushenqu to obtain a Chinese medicine powder, wherein all of the Chinese medicine powder passes through a No. 2 sieve, and the content of the Chinese medicine powder passing through a No. 4 sieve does not exceed 40%; (c) placing the Chinese medicine powder in a 60% ethanol solution for decoction extraction, filtering, collecting the filtrate, repeating the extraction 4 times, combining the filtrate, concentrating, and drying to obtain a thick paste, wherein the mass ratio of the Chinese medicine powder to the ethanol solution is 1:10, the decoction time is 1 h, and the relative density of the thick paste is 1.0; (d) crushing the stir-fried gardenia and sieving it through a 100-mesh sieve to obtain gardenia powder, and then mixing the gardenia powder with the thick paste to obtain the traditional Chinese medicine composition for treating depression.

[0019] Example 2 This embodiment is a method for preparing a Chinese medicine composition for treating depression, and the preparation method comprises the following steps: (a) Weigh equal amounts of vinegar-cooked Cyperus rotundus, Chuanxiong, stir-fried Atractylodes lancea, stir-fried Liushenqu, and stir-fried Gardenia jasminoides; (b) grinding and sieving the vinegar-cured cyperus rotundus, chuanxiong, stir-fried atractylodes and stir-fried liushenqu to obtain a Chinese medicine powder, wherein all of the Chinese medicine powder passes through a No. 2 sieve, and the content of the Chinese medicine powder passing through a No. 4 sieve does not exceed 40%; (c) placing the Chinese medicine powder in an 80% ethanol solution for decoction extraction, filtering, collecting the filtrate, repeating the extraction twice, combining the filtrate, concentrating, and drying to obtain a thick paste, wherein the mass ratio of the Chinese medicine powder to the ethanol solution is 1:15, the decoction time is 2 hours, and the relative density of the thick paste is 1.8; (d) crushing the stir-fried gardenia and sieving it through a 100-mesh sieve to obtain gardenia powder, and then mixing the gardenia powder with the thick paste to obtain the traditional Chinese medicine composition for treating depression.

[0020] Example 3 This embodiment is a method for preparing a Chinese medicine composition for treating depression, and the preparation method comprises the following steps: (a) Weigh equal amounts of vinegar-cooked Cyperus rotundus, Chuanxiong, stir-fried Atractylodes lancea, stir-fried Liushenqu, and stir-fried Gardenia jasminoides; (b) grinding and sieving the vinegar-cured cyperus rotundus, chuanxiong, stir-fried atractylodes and stir-fried liushenqu to obtain a Chinese medicine powder, wherein all of the Chinese medicine powder passes through a No. 2 sieve, and the content of the Chinese medicine powder passing through a No. 4 sieve does not exceed 40%; (c) placing the Chinese medicine powder in a 70% ethanol solution for decoction extraction, filtering, collecting the filtrate, repeating the extraction three times, combining the filtrate, concentrating, and drying to obtain a thick paste, wherein the mass ratio of the Chinese medicine powder to the ethanol solution is 1:12, the decoction time is 1.5 h, and the relative density of the thick paste is 1.6; (d) crushing the stir-fried gardenia and sieving it through a 100-mesh sieve to obtain gardenia powder, and then mixing the gardenia powder with the thick paste to obtain the traditional Chinese medicine composition for treating depression.

[0021] Example 4 This embodiment is a Chinese medicine pill for treating and / or improving depression or anxiety, and the Chinese medicine pill comprises a Chinese medicine composition for treating depression prepared by the preparation method of Example 3 and a binder; The preparation method of the traditional Chinese medicine pills is the panning method, and the drying temperature in the preparation process is 45° C. and the drying time is 2 hours; the adhesive is 70% ethanol solution.

[0022] Experimental example This experimental example is a research experiment on process parameters: 1. Medicinal material powder yield Weigh 1.0 kg of vinegar-cooked Cyperus rotundus, Ligusticum chuanxiong, stir-fried Gardenia jasminoides, Atractylodes lancea (stir-fried), and Liushenqu (stir-fried), and weigh 0.99 kg after drying overnight. Repeat the grinding of the dried medicinal materials with a traditional Chinese medicinal material grinder, and all of them pass through the No. 2 sieve, but are mixed with powder that can pass through the No. 4 sieve (no more than 40%) to obtain a coarse powder, which is dried in a drying oven overnight. The dried coarse powder is weighed to be 0.93 kg, and the calculated medicinal material powder yield is 94.1%.

[0023] 2. Extraction process research The four ingredients of vinegar-cured cyperus, chuanxiong, atractylodes (fried), and liushenqu (fried) in Yueju Pills were extracted by 70% ethanol. The selection of evaluation indexes was based on the core efficacy ingredients, prescription formula principles, stability and content of the measured ingredients identified in the previous affinity chromatography screening experiment (using two immobilized protein affinity chromatography models of 5-hydroxytryptamine 1A receptor (5-HT1AR) and 5-hydroxytryptamine transporter (5-HTT) to screen the active ingredients of Yueju Recipe). Finally, α-cyperone in vinegar-cured cyperus, ligustilide in chuanxiong, and atractylodesin in bran-fried atractylodes were determined as the evaluation indexes of this preparation. In order to systematically, comprehensively, and effectively optimize the process parameters, the content was determined by high performance liquid chromatography through orthogonal experiments to determine the optimal process.

[0024] 3. Orthogonal test of alcohol extraction process 3.1 Orthogonal Experimental Design Through single factor investigation of different proportions of ethanol (0%, 20%, 40%, 60%, 80%), it was found that 60% and 80% ethanol content were conducive to the dissolution of index components, so the alcohol extraction process was used for orthogonal experiment.

[0025] Weigh 12.5 g of vinegar-cured cyperus, 12.5 g of chuanxiong, 12.5 g of atractylodes (fried), and 12.5 g of liushenqu (fried), totaling 50 g, and conduct 9 parallel samples, which are randomly sampled and numbered as 1 to 9. The four factors of material-liquid ratio (A), ethanol ratio (B), extraction time (C), and extraction times (D) are calculated according to the orthogonal table L9 (3 4 ) Each test number is required to conduct a test, and the alcohol extracts are combined, concentrated, and dried to obtain a thick paste. The content of α-cyperone, ligustilide, and atractylodesin is used as an indicator to select the best extraction process. The design of each factor level is shown in Table 1. L9 (3 4 ) The results of the orthogonal design experiment are shown in Table 2, and the results of variance analysis are shown in Tables 3~5.

[0026] Table 1 Experimental factor level table Table 2L9 (3 4 )Intuitive analysis of orthogonal test results Table 3 ANOVA of orthogonal experimental results (ligustilide content) Table 4 ANOVA of orthogonal test results (α-cyperone content) Table 5 ANOVA analysis of orthogonal experimental results (atractylodesin content) From the K′ value and R′ value in Table 2, it can be seen that, with the contents of ligustilide, α-cyperone and atractylodesin as indicators for analysis, factors A3>A1>A2, B2>B1>B3, C2>C3>C1, D3>D1>D2, the extraction time factor has the greatest influence on the extraction process, and the optimal process is A3B2C2D3 according to intuitive analysis; the variance analysis results in Table 3 show that factor C extraction time has the greatest influence on the content of ligustilide, followed by factors A solid-liquid ratio, D extraction times, and B ethanol ratio; the variance analysis results in Table 4 show that factor C extraction time has the greatest influence on the content of α-cyperone, followed by factors B ethanol ratio, A solid-liquid ratio, and D extraction times; the variance analysis results in Table 5 show that factor A solid-liquid ratio has the greatest influence on the content of atractylodesin, followed by factors B ethanol ratio, D extraction time, and B ethanol ratio.

[0027] 3.3 Extraction process validation test The same batch of medicinal materials were used, and 25 g of vinegar-cured cyperus, 25 g of chuanxiong, 25 g of atractylodes (fried), and 25 g of liushenqu (fried) were weighed according to the prescription ratio, totaling 100.0 g. Three replicates were tested according to the optimal process A3B2C2D3 to determine the content and dry paste yield. The results are shown in Table 6. Table 6 Extraction process validation test results In summary, the dry extract yield and the contents of artemisinin, atractylodesin and α-cyperone were used as evaluation indicators, and the data were stable. Therefore, A3B2C2D3 was determined to be the best process, that is, 70% ethanol was added to the medicinal materials, the amount of 70% ethanol was 12 times that of the medicinal materials, and each extraction lasted 1.5 hours, for a total of 3 times.

[0028] 4. Filtration, concentration and drying After the medicinal materials are decocted and extracted with 70% ethanol, the residue is discarded to obtain a medicinal solution. In order to effectively remove impurities and reduce the dosage, the medicinal solution is filtered, and the filtrate obtained is concentrated to an appropriate amount and dried to a thick paste. The relative density of the thick paste is 1.0-1.8.

[0029] 5. Molding process research Weigh Gardenia according to the prescription, pass through a 100-mesh sieve, and store in a dry container. Weigh Cyperus rotundus, Rhizoma Chuanxiong, Atractylodes macrocephala (fried), and Rhizoma Cibotii (fried) according to the prescription, crush them, and use the optimal solution of the previous extraction process (12 times the amount, 70% ethanol ratio, 1.5 h each time, 3 times in total, dry in a water bath at 80℃ for 12 h to obtain a dry extract), use 70% ethanol as a binder, and use the panning method to make pills.

[0030] With 70% ethanol as a fixed excipient, the same batch of Yueju pills dry paste as raw materials, constant other process parameters, appearance, pill water content, dissolution time and pill quality difference as evaluation indicators, and with other conditions unchanged, the best process was selected with the particle size of medicinal powder (A), drying time (B) and drying temperature (C) as the investigation factors (Table 7). The OD value was calculated using the comprehensive weighted evaluation method, OD = appearance quality evaluation × 20% ÷ the highest score of appearance quality evaluation + the lowest value of pill water content × 30% ÷ pill water content + the lowest value of dissolution time limit × 30% ÷ dissolution time limit + the lowest value of pill quality difference × 20% ÷ pill quality difference; the effects of different factors on the comprehensive score of pills are shown in Tables 8 to 10.

[0031] Table 7 Investigation of formulation molding process factors Table 8 Effect of medicinal powder particle size on the comprehensive score of pills Table 9 Effect of drying time on comprehensive score Table 10 Effect of drying temperature on comprehensive score of pills From Tables 8 to 10, we can see that: The comprehensive score was the highest when the particle size of the medicinal powder was 100 mesh, so 100 mesh was selected as the fine powder particle size of the fried Gardenia medicinal material; the comprehensive score was the highest when the drying time was 2h. A short drying time would make it difficult to store, and a long drying time would lead to a decrease in the effective content in the tablets. Therefore, after comprehensive consideration, 42±3℃ was selected as the drying temperature for the pills.

[0032] 5.2 Process quality control of pelleting The pills should be spherical in appearance, evenly rounded, without any irregularities, without cracks, of moderate hardness, without sticking together, and with uniform color.

[0033] 5.3 Process Quality Control of Wet Pill Drying The purpose of wet pill drying is to reduce the moisture in the pills to meet the standards and prevent deterioration and contamination. The wet pill drying process should ensure that the pills are round and uniform without cracking after drying, and maintain appropriate hardness. During the process research, four temperatures of 60℃, 55℃, 50℃ and 45℃ were tried to dry the wet pills respectively. It was found that at above 50℃, the pills would soften and agglomerate within a certain period of time. Therefore, 45℃ was selected for drying overnight to obtain dried pills.

[0034] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein by equivalents. These modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention, and they should all be included in the scope of the claims and specification of the present invention.

Claims

1. A method for preparing a Chinese medicine composition for treating depression, characterized in that: The preparation method comprises the following steps: (a) Weigh equal amounts of vinegar-cooked Cyperus rotundus, Chuanxiong, stir-fried Atractylodes lancea, stir-fried Liushenqu, and stir-fried Gardenia jasminoides; (b) grinding and sieving the vinegar-cured cyperus rotundus, chuanxiong, stir-fried atractylodes and stir-fried liushenqu to obtain a Chinese medicine powder; (c) placing the Chinese medicine powder in a 60% to 80% ethanol solution for decoction extraction, filtering, collecting the filtrate, repeating the extraction 2 to 4 times, combining the filtrate, concentrating, and drying to obtain a thick paste, wherein the mass ratio of the Chinese medicine powder to the ethanol solution is 1: (10 to 15); (d) crushing and sieving the stir-fried gardenia to obtain gardenia powder, and then mixing the gardenia powder with the thick paste to obtain the traditional Chinese medicine composition for treating depression.

2. The preparation method according to claim 1, characterized in that: In the step (b), the particle size of the Chinese medicine powder is not less than 10 mesh, and the content of particles larger than 65 mesh is not higher than 40%.

3. The preparation method according to claim 1, characterized in that: In the step (b), the decoction time is 1 to 2 hours.

4. The preparation method according to claim 1, characterized in that: In the step (b), the relative density of the thick paste is 1.0-1.

8.

5. The preparation method according to claim 1, characterized in that: In the step (c), the particle size of the gardenia powder is not less than 100 mesh.

6. A Chinese medicine composition for treating depression prepared by the preparation method according to any one of claims 1 to 5.

7. Use of a Chinese medicine composition for treating depression prepared by the preparation method according to any one of claims 1 to 5 in preparing a Chinese medicine preparation for treating and / or improving depression or anxiety.

8. The use according to claim 7, characterized in that: The dosage forms of the traditional Chinese medicine preparation include tablets, pills, capsules and injections.

9. A Chinese medicine pill for treating and / or improving depression or anxiety, characterized in that: The Chinese medicine pills include a Chinese medicine composition for treating depression prepared by the preparation method according to any one of claims 1 to 5 and a binder.

10. The Chinese medicine pill according to claim 9, characterized in that: The preparation method of the Chinese medicine pills is the panning method, the drying temperature in the preparation process of the Chinese medicine pills is 40±10°C, and the drying time is 2-6h; The adhesive is a 70±5% ethanol solution.

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