An antidepressant pharmaceutical composition, and a method of preparing and using the same

Abstract

The present application provides an antidepressant pharmaceutical composition, which is prepared from the following raw materials in the following proportions by weight: 8-12 parts of fried licorice, 8-12 parts of red dates, 16-24 parts of wheat, 8-12 parts of gardenia flowers, and 8-12 parts of dalbergia odorifera flowers. The present application also provides a preparation method and uses of the pharmaceutical composition. The present application is based on the Ganmai Dazao Decoction with the addition of dalbergia odorifera flowers and gardenia flowers, which not only calms the heart and nerves, and supplements heart qi, but also soothes the liver and stomach, regulates qi and relieves depression, clears heat and removes fire, cools the heart and calms the nerves, and is mainly used for treating liver qi stagnation type melancholia, and is applied to various types of depression, has a wider application range, and has a significant effect. The compatibility of various raw materials not only conforms to the compatibility theory of traditional Chinese medicine, but also can play a synergistic effect.

Description

Technical Field

[0001] This invention relates to an antidepressant drug composition, its preparation method, and its uses, belonging to the pharmaceutical field. Background Technology

[0002] Depression is a common mental disorder characterized by a significant and persistent low mood, accompanied by loss of interest and pleasure, often affecting an individual's work, study, and social functioning. Depression can be caused by a variety of factors, including genetic, biological, psychosocial, and environmental factors. The clinical criterion is a persistent episode lasting more than two weeks. Typical symptoms include low mood, insomnia or excessive sleep, changes in appetite, fatigue, feelings of inferiority or worthlessness, excessive self-blame, and difficulty concentrating. Severe cases may present with hallucinations and delusions. The etiology and pathogenesis of depression are not fully understood, but current research shows that family history, childhood trauma, abnormal brain structure and network connectivity, neurotic and introverted personality traits, and major traumatic events all have a significant impact. Experts recommend selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and paroxetine as ideal antidepressants.

[0003] Traditional Chinese medicine (TCM) classifies depression into the following types based on the principle of Qi stagnation: 1. Liver Qi stagnation type, usually treated with Chaihu Shugan San; 2. Liver Qi stagnation transforming into fire type, often treated with modified Danzhi Xiaoyao San; 3. Phlegm and Qi obstruction type, where Qi stagnation and phlegm stagnation obstruct each other, resulting in a feeling of something stuck in the throat, commonly known as plum pit Qi, treated with Banxia Houpu Tang; 4. Heart and spirit malnourishment type, where patients often exhibit unpredictable crying and laughing, treated with Ganmai Dazao Tang; 5. Qi and blood deficiency type, also known as heart and spleen deficiency, treated with Guipi Tang; 6. Heart and kidney Yin deficiency type, often seen in menopausal patients, treated with modified Tianwang Buxin Dan and Liuwei Dihuang Wan. For example, Wu Jianming's "A Controlled Study on the Antidepressant Efficacy of Modified Ganmai Dazao Decoction," published in *Chinese Clinical Doctors*, Vol. 30, No. 11, 2002, reveals that in cases of insufficient heart qi and stagnant liver qi, the Ganmai Dazao Decoction is modified by adding turmeric, cyperus, and nardostachys to soothe the liver and relieve depression. In cases of depression due to excessive grief and qi stagnation, which eventually leads to qi and yang deficiency, the modified Ganmai Dazao Decoction uses astragalus and cimicifuga to tonify qi and raise clear qi, acorus to open the orifices and awaken the mind, and aconite to warm kidney yang and strengthen liver yang, thus improving the lingering and stagnant negative symptoms of affective disorders. Ganmai Dazao Decoction is a classic formula for treating depression, primarily treating symptoms of qi stagnation and yin deficiency, and restlessness due to deficiency heat, especially when the heart is not properly nourished. Clinically, it is mainly used for positive type depression, i.e., manic depression. However, Ganmai Dazao Decoction is not very effective for negative type depression, thus its clinical application is quite limited. Summary of the Invention

[0004] To overcome the above problems, the present invention provides an antidepressant drug composition. Another technical solution of the present invention provides a method for preparing the drug composition and its uses.

[0005] This invention provides an antidepressant pharmaceutical composition, which is prepared from the following raw materials in the indicated weight ratios:

[0006] Prepared licorice root 8-12 parts, red dates 8-12 parts, wheat 16-24 parts, gardenia flower 8-12 parts, bitter orange flower 8-12 parts.

[0007] More preferably, it is prepared from raw materials in the following weight ratio:

[0008] 10 parts roasted licorice root, 10 parts red dates, 20 parts wheat, 10 parts gardenia flowers, and 10 parts bitter orange flowers.

[0009] The pharmaceutical composition of the present invention is prepared into a commonly used pharmaceutical formulation by adding pharmaceutically acceptable excipients or auxiliary ingredients, using the aforementioned raw material powder, water or organic solvent extract as the active ingredient.

[0010] The preparations mentioned above include tablets, capsules, pills, granules, and tea bags.

[0011] The present invention also provides a method for preparing the aforementioned antidepressant drug composition, characterized in that:

[0012] a. Weigh the raw materials according to their respective weight ratios;

[0013] b. Directly grind into powder, or decoct with water to extract, and add pharmaceutically acceptable excipients or auxiliary ingredients to the powder or extract to prepare commonly used pharmaceutical preparations;

[0014] or

[0015] The volatile oils of gardenia and bitter orange are extracted. The residue is then mixed with roasted licorice root, red dates, and wheat, and decocted with water. After the decoction is concentrated, the volatile oils and pharmaceutically acceptable excipients or auxiliary ingredients are added to prepare a commonly used pharmaceutical preparation.

[0016] The present invention also provides the use of the pharmaceutical composition in the preparation of an antidepressant medicament.

[0017] The present invention also provides the use of the pharmaceutical composition in the preparation of a medicament for the prevention of depression.

[0018] More preferably, the depression is liver qi stagnation type depression.

[0019] The present invention also provides the use of the pharmaceutical composition in the preparation of a medicine having the functions of relieving depression and calming the mind, clearing heat and soothing the liver, and nourishing qi and heart.

[0020] The pharmaceutical composition of this invention is made from the modified Ganmai Dazao Tang formula from the Han Dynasty, with the addition of gardenia and bitter orange flowers, characteristic aromatic herbs from Fujian. Ganmai Dazao Tang is a representative formula for treating menopausal syndrome (visceral irritability) for many years. Wheat is the principal ingredient, sweet and cool in nature, nourishing the heart and liver, relieving irritability, calming the mind, and soothing the nerves. Prepared licorice root is added, sweet and neutral in nature, entering the heart, lung, and spleen meridians, nourishing heart qi and moderating the effects of other herbs. Bitter orange flower is sweet and bitter in nature, with the special properties of soothing the liver and stomach, regulating qi, and relieving depression; bitter orange flower is the assistant ingredient. Jujube is sweet and warm in nature, entering the spleen, stomach, and heart meridians, tonifying the middle jiao and replenishing qi, nourishing blood and calming the mind, and moderating the effects of other herbs. Gardenia flower is bitter and cold in nature, clearing heat and reducing fire, cooling the heart and calming the mind; both are adjuvant ingredients. Prepared licorice root is the guiding ingredient, harmonizing the effects of all the herbs. When used together, this formula is primarily used to treat depression caused by stagnation of liver qi. It works synergistically to relieve depression, calm the mind, clear heat, soothe the liver, and nourish qi and heart.

[0021] This invention's medicine, based on the Ganmai Dazao Decoction, adds bitter orange blossom and gardenia flower. It not only calms the mind and soothes the nerves, and nourishes the heart qi, but also soothes the liver and stomach, regulates qi and relieves depression, clears heat and reduces fire, cools the heart and calms the mind. It is mainly used to treat depression of the liver qi stagnation type and can be applied to various types of depression. It has a wider range of applications and significant efficacy. The combination of each ingredient not only conforms to the theory of compatibility in traditional Chinese medicine, but also plays a synergistic role. Detailed Implementation

[0022] Example 1: Preparation process of the pharmaceutical composition of the present invention

[0023] Please provide the detailed preparation process of this invention.

[0024] Example 1: Preparation of the oral liquid of the present invention

[0025] Weigh out the raw materials: 10g of roasted licorice root, 10g of red dates, 20g of wheat, 10g of gardenia flower, and 10g of bitter orange flower.

[0026] The extract is boiled in water, concentrated, and prepared into an oral liquid.

[0027] Example 2: Preparation method of the drug granules of the present invention

[0028] Weigh the raw materials: 12g of prepared licorice root, 12g of red dates, 24g of wheat, 12g of gardenia flower, and 12g of bitter orange flower. Add water and decoct twice (extract at 100℃). Each time, add 10 times the amount of water and extract for 2 hours. Filter and concentrate the filtrate to a specific gravity of 1.12 (room temperature). Add (1:1 to 1:1.5) times the amount of dextrin to the filtrate to prepare a soft mass. Sieve, dry, and granulate the soft mass to obtain granules.

[0029] Example 3: Preparation method of the drug granules of the present invention

[0030] Weigh the raw materials: 8g of roasted licorice root, 8g of red dates, 16g of wheat, 8g of gardenia flower, and 8g of bitter orange flower. Add water and decoct twice (extract at 100℃). Each time, add 10 times the amount of water and extract for 2 hours. Filter and concentrate the filtrate to a specific gravity of 1.06 (room temperature). Spray dry (inlet air temperature 165℃, feed flow rate 400mL / min) to obtain powder. Add (1:1 to 1:1.5) times the amount of dextrin to make a soft mass. Sieve, dry, and granulate the soft mass to obtain granules.

[0031] Example 4: Preparation of the drug formulation granules of the present invention

[0032] The six raw materials are made into Chinese medicine granules, mixed, and then dextrin (1:1 to 1:1.2) times the amount is added to make soft material. The soft material is then sieved, dried, and granulated to obtain granules.

[0033] Example 5: Preparation of the drug granules of the present invention

[0034] Weigh out the raw materials: 10g of prepared licorice root, 10g of red dates, 20g of wheat, 10g of gardenia flower, and 10g of bitter orange flower. After extracting the volatile oil from gardenia flower and bitter orange flower, add the dregs to the prepared licorice root, red dates, and wheat, add 10 times the amount of water, decoct twice, 1.5 hours each time, filter, combine the filtrates, concentrate the filtrate to a clear extract with a relative density of 1.30 (30℃), add the extracted volatile oil and an appropriate amount of dextrin, mix well, make into granules, dry and granulate to obtain the final product.

[0035] Example 6: Preparation of the drug tablets of the present invention

[0036] Weigh out the raw materials: 10g of roasted licorice root, 10g of red dates, 20g of wheat, 10g of gardenia flower, and 10g of bitter orange flower. Add water and decoct twice (extract at 100℃). Each time, add 10 times the amount of water and extract for 2 hours. Filter and concentrate the filtrate to a clear extract with a relative density of 1.30 (30℃). Add an appropriate amount of dextrin, mix well, make into granules, compress into tablets, and dry to obtain the final product.

[0037] Example 7: Preparation of the drug capsule of the present invention

[0038] Weigh out the raw materials: 10g of roasted licorice root, 10g of red dates, 20g of wheat, 10g of gardenia flower, and 10g of bitter orange flower. Add water and decoct twice (extract at 100℃). Each time, add 10 times the amount of water and extract for 2 hours. Filter and concentrate the filtrate to a clear extract with a relative density of 1.30 (30℃). Add an appropriate amount of dextrin, mix well, make into granules, dry, and fill into capsules to obtain the final product.

[0039] Example 8: Preparation of the concentrated pill form of the present invention

[0040] Take 10 grams of roasted licorice root, 10 grams of red dates, 20 grams of wheat, 10 grams of gardenia flower, and 10 grams of bitter orange flower. Add water and decoct twice (extract at 100℃). Each time, add 10 times the amount of water and extract for 2 hours. Filter and concentrate the filtrate to a clear paste with a relative density of 1.30 (30℃). Add an appropriate amount of starch, mix well, roll into pills, and dry to obtain the final product.

[0041] Example 9: Preparation of the medicinal tea bag of the present invention

[0042] Weigh out the following raw materials: 10g roasted licorice root, 10g red dates, 20g wheat, 10g gardenia flower, and 10g bitter orange flower. Place them in a nylon tea bag to obtain the final product.

[0043] The following pharmacodynamic tests demonstrate the beneficial effects of this invention.

[0044] Experimental Example 1: Experimental Study on the Antidepressant Effect of the Invention Drug (Wheat and Jujube Tea)

[0045] 1. Materials

[0046] 1.1 Experimental Animals

[0047] 48 SPF-grade C57BL / 6 mice (extra were used to screen for successful models), male, 7 weeks old.

[0048] 2 methods

[0049] 2.1 Modeling, grouping, and drug administration

[0050] After being housed in a suitable environment for one week, six mice were randomly selected as controls, and the remaining mice were used to establish the model. A chronic, mild, unpredictable stress method (combined with isolation) was used to construct the model. Mice were exposed to unpredictable mild stress for five consecutive weeks, with two different stressors randomly assigned each day. The success of the model was assessed using a sucrose preference test after the model group showed a lower sucrose preference rate than the blank control group. The model mice were then randomly divided into five groups of six each: blank control group, liver qi stagnation type depression mouse model group, fluoxetine hydrochloride group, Ganmai Dazao Decoction group (TCM-1), low-dose wheat and jujube tea group (TCM-2), high-dose wheat and jujube tea group (TCM-3), gardenia group, and bitter orange flower group. (Among them, the Ganmai Dazao Decoction group was prepared according to the Ganmai Dazao Decoction prescription disclosed in the "Synopsis of Prescriptions of the Golden Chamber": 3 liang of licorice (9-12g), 1 sheng of wheat (15-30g), and 5-10 jujubes), and the wheat and jujube tea was prepared according to the method of Example 1; the gardenia group and the bitter orange group were extracted by decoction according to the method of Example 1.

[0051] In the 6th week after the start of modeling, the blank control group and the model group were administered 0.1 mL / 10 g of normal saline by gavage; the Ganmai Dazao Decoction group (TCM-1) (12 g / kg), the low-dose Maizao Tea group (TCM-2) (6 g / kg), and the high-dose Maizao Tea group (TCM-3) (12 g / kg) were administered by gavage; Gardenia and Bitter Orange flowers were administered by gavage at a dose of 12 g / kg; and the Fluoxetine group was administered by gavage at a dose of 10 mg / kg. All groups were administered by gavage once daily for 3 weeks.

[0052] 2.2 Daily observation before and after treatment

[0053] After modeling and drug treatment, observe the mice's daily activities, including eyes, daily grooming, changes in fur, response to external stimuli, stool (color, consistency, and size), behavior when struggling, and mental state.

[0054] 2.3 Mouse behavioral experiments

[0055] 2.3.1 Sugar Water Preference Experiment

[0056] Two days before the formal experiment, the positions of the 10% sucrose solution bottle and the regular drinking water bottle were switched every 2 hours for an acclimatization period of 8 hours. Mice were fasted and deprived of water for 24 hours before the experiment. At the start of the experiment, both bottles were weighed, and after 2 hours, the weights of both bottles were weighed again, and the weight consumed was calculated. The sucrose preference value = sucrose consumption / (sucrose consumption + regular water consumption).

[0057] 2.3.2 Forced Swimming Test

[0058] Mice were allowed to acclimatize in a quiet indoor environment for 0.5 hours, and then placed head up in a 100*100mm wide and 70mm deep water pool (water temperature 23±1℃). The immobility time within 6 minutes was observed and recorded.

[0059] 2.4 ELISA Experiment

[0060] Rinse the tissue with pre-cooled PBS (0.01M, pH 7.4) to remove residual blood, weigh, and mince. Add the tissue and the corresponding volume of PBS (1:9 weight-to-volume ratio) to a glass homogenizer and homogenize thoroughly on ice. Sonicate the homogenate or perform repeated freeze-thaw cycles. Centrifuge the homogenate at 5000×g for 5–10 min, collect the supernatant, and analyze it according to the manufacturer's instructions to calculate the sample concentration.

[0061] 3 Results

[0062] 3.1 Observation of daily behavior

[0063] Forty-eight SPF-grade C57BL / 6 mice were used in the experiment (extra were used to screen for successful models). Observations were made on the degree of squinting, daily grooming activity, changes in fur, responses to external stimuli, stool color, consistency, and size, behavior during struggle, and mental state. Before treatment after modeling, the model group mice exhibited a series of symptoms including squinting eyes; reduced daily grooming activity, dull or even sparse fur; sluggish responses to external stimuli (sound, manipulation, etc.); pale, soft, or even loose stools with smaller particles; weak and short-lived struggles; lethargy, drowsiness, and so on. As shown in Table 1, the behavioral scores of the model group mice were significantly higher than those of the blank control group. After treatment, the behavioral scores of the fluoxetine hydrochloride group, the Ganmai Dazao Decoction group (TCM-1), the low-dose Maizao Tea group (TCM-2), and the high-dose Maizao Tea group (TCM-3) all decreased (Table 1). These results indicate that Maizao Tea can significantly improve the daily behavioral symptoms of depressed mice.

[0064] Table 1. Observation table of daily behavior of the control group and the model group after modeling.

[0065]

[0066] Note: Compared with the control group, **P < 0.01; compared with the model group, ## P < 0.01.

[0067] 3.2 Mouse behavioral experiments

[0068] 3.2.1 Sugar Water Preference Rate Experiment

[0069] The experiment used the mice's preference for sugar water to conduct a sugar water preference test. The results are shown in Table 2. Before treatment after modeling, the sugar water preference rate of the model group mice (69.38% ± 2.99) was significantly lower than that of the blank control group (85.50% ± 3.94) (P < 0.05), showing a statistically significant difference. After treatment, compared with the model group, the sugar water preference rates of the fluoxetine hydrochloride group, the Ganmai Dazao Decoction group (TCM-1), the low-dose Maizao Tea group (TCM-2), and the high-dose Maizao Tea group (TCM-3) were all increased. The increase in the Ganmai Dazao Decoction group (TCM-1) (73.18% ± 8.55) compared with the model group (69.13% ± 1.20) was not significant (P > 0.05), indicating no statistical significance. The low-dose wheat and jujube tea group (TCM-2) (82.92% ± 4.13) and the high-dose wheat and jujube tea group (TCM-3) (86.88% ± 2.79) showed significant improvements compared to the model group (69.13% ± 1.20) (P > 0.05), indicating a statistically significant difference. The high-dose wheat and jujube tea group (TCM-3) showed the most significant increase in sugar water preference (P < 0.05). These results indicate a significant reduction in sugar water preference in the model group mice, which is one of the indicators of successful modeling of liver qi stagnation in mice. The improvement of sugar water preference caused by depression by wheat and jujube tea is dose-related. Wheat and jujube tea can significantly increase the sugar water preference in liver qi stagnation-type depressed mice, with effects comparable to fluoxetine hydrochloride treatment, and superior to Ganmai Dazao Decoction, single use of gardenia flower, and bitter orange flower.

[0070] Table 2 Results of the Sugar Water Preference Test

[0071]

[0072] Note: Compared with the control group, *P<0.05; compared with the model group, # P < 0.05, compared with the model group, ## P < 0.01, compared with TCM-1, ▲ P < 0.05.

[0073] 3.2.2 Forced Swimming Experiment

[0074] This experiment used a forced swimming test to detect the immobility time of mice within 6 minutes. The test results are shown in Table 3. Compared with the blank control group, the immobility time within 6 minutes in the model group was significantly increased (P < 0.05), which is statistically significant and is one of the indicators of successful modeling of liver qi stagnation in mice. Compared with the model group, the immobility time within 6 minutes of forced swimming was significantly decreased in the fluoxetine hydrochloride group, the Ganmai Dazao Decoction group (TCM-1), the low-dose Maizao Tea group (TCM-2), and the high-dose Maizao Tea group (TCM-3) (P < 0.05), all of which showed statistically significant differences. These results indicate that Maizao Tea can significantly reduce the immobility time of forced swimming in mice with liver qi stagnation, greatly improve depressive symptoms, and is superior to Ganmai Dazao Decoction, Gardenia jasminoides alone, and Citrus aurantium.

[0075] Table 3. Forced swimming immobility time

[0076]

[0077] Note: Compared with the control group, * P < 0.05, compared with the model group, # P < 0.05, compared with the model group, ## P < 0.01, compared with TCM-1, ▲ P < 0.05.

[0078] 3.6 ELISA Detection Experiment

[0079] The expression levels of DA, NE, and 5-HT in brain tissue were detected using ELISA. The results are shown in Table 4. Compared with the blank control group, the expression levels of DA, NE, and 5-HT in the model group brain tissue were significantly decreased (P < 0.05), showing statistical significance. Compared with the model group, the expression levels of DA, NE, and 5-HT were increased in the fluoxetine hydrochloride group, the Ganmai Dazao decoction group (TCM-1), the low-dose Maizao tea group (TCM-2), and the high-dose Maizao tea group (TCM-3). Compared with the model group, the dopamine levels (DA) in the low-dose fluoxetine hydrochloride group, the low-dose wheat and jujube tea group (TCM-2), and the high-dose wheat and jujube tea group (TCM-3) were significantly increased (P < 0.05), showing statistical differences. The DA level in the Ganmai Dazao Decoction group (TCM-1) was not significantly increased (P > 0.05), showing no statistical difference. Compared with the model group, the norepinephrine (NE) levels in the low-dose fluoxetine hydrochloride group, the low-dose wheat and jujube tea group (TCM-2), and the high-dose wheat and jujube tea group (TCM-3) were significantly increased (P < 0.05). The difference in NE levels was statistically significant in the Ganmai Dazao Decoction group (TCM-1) compared to the model group (P>0.05). However, the increase in 5-HT levels was not significant in the low-dose Maizao Tea group (TCM-2) and the high-dose Maizao Tea group (TCM-3) compared to the model group (P<0.05). Conversely, the increase in 5-HT levels was not significant in the fluoxetine hydrochloride group and the Ganmai Dazao Decoction group (TCM-1) compared to the model group (P>0.05). These results indicate that Maizao Tea significantly improves the expression levels of DA, NE, and 5-HT, and is superior to Ganmai Dazao Decoction, Gardenia jasminoides alone, and Citrus aurantium.

[0080] Table 4. Content of DA, NE, and 5-HT in brain tissue

[0081]

[0082] Note: Compared with the control group, ** P < 0.01, compared with the model group, # P < 0.05, compared with the model group, ## P < 0.01, compared with TCM-1, ▲ P < 0.05.

Claims

1. An antidepressant drug composition, characterized in that: It is prepared from the following raw materials in the following weight ratio: Prepared licorice root 8-12 parts, red dates 8-12 parts, wheat 16-24 parts, gardenia flower 8-12 parts, bitter orange flower 8-12 parts.

2. The antidepressant composition according to claim 1, characterized in that: It is prepared from the following raw materials in the following weight ratio: 10 parts roasted licorice root, 10 parts red dates, 20 parts wheat, 10 parts gardenia flowers, and 10 parts bitter orange flowers.

3. The antidepressant composition according to claim 1 or 2, characterized in that: It is a pharmaceutically commonly used preparation made by adding pharmaceutically acceptable excipients or auxiliary ingredients to the active ingredient, which is the powder, water or organic solvent extract of the raw material.

4. The antidepressant composition according to claim 3, characterized in that: The preparations mentioned are tablets, capsules, pills, granules, and tea bags.

5. A method for preparing the antidepressant drug composition according to any one of claims 1-4, characterized in that: a. Weigh the raw materials according to their respective weight ratios; b. Directly grind into powder, or decoct with water to extract, and add pharmaceutically acceptable excipients or auxiliary ingredients to the powder or extract to prepare commonly used pharmaceutical preparations; or The volatile oils of gardenia and bitter orange are extracted. The residue is then mixed with roasted licorice root, red dates, and wheat, and decocted with water. After the decoction is concentrated, the volatile oils and pharmaceutically acceptable excipients or auxiliary ingredients are added to prepare a commonly used pharmaceutical preparation.

6. Use of the pharmaceutical composition according to any one of claims 1-4 in the preparation of an antidepressant medicament.

7. The use according to claim 6, characterized in that: The depression mentioned is liver qi stagnation type depression.

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