A pharmaceutical composition for treating depression and a preparation method and application thereof

Abstract

The application discloses a kind of pharmaceutical composition for treating depression, belong to Chinese medicine technical field.The pharmaceutical composition for treating depression adopts the compatibility of food and medicine of Poria cocos and ganoderma lucidum spore, and the performance of pharmaceutical composition is optimized by adding suspension stabilizer.The preparation method is that the effective component of Poria cocos is purified by water extraction and alcohol precipitation, and the oil of ganoderma lucidum spore is extracted by CO2 supercritical extraction, and the active ingredient is reserved by low-temperature treatment throughout the process;then the suspension liquid is prepared by mixing the two with suspension stabilizer, and the obtained pharmaceutical composition overcomes the shortcomings of western medicine, such as damaging human health, has good palatability, and is suitable for long-term use.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine technology, specifically relating to a pharmaceutical composition for treating depression, its preparation method, and its application. Background Technology

[0002] Depression, a common affective disorder, has seen its incidence increase 10-20 times in the past 30 years and continues to rise, becoming the fourth leading cause of disease worldwide and one of the top ten causes of disease burden. Related neuroimaging studies have revealed significant functional abnormalities in the prefrontal cortex-amygdala-hippocampal neural circuit in patients with depression. This damage to neuroplasticity leads to the core symptoms of mood regulation disorders; approximately 65% ​​of depressed patients also experience intractable gastrointestinal symptoms, suggesting that the gastrointestinal-brain axis is involved in the disease process. Current clinical practice considers interventions or treatments using medications with few or no side effects.

[0003] Existing technology CN120305350A discloses a traditional Chinese medicine composition with antidepressant effects, which is prepared into an oral preparation using green tangerine peel, dried tangerine peel, white peony root, fritillaria thunbergii, alisma plantago-aquatica, stir-fried gardenia fruit, and peony bark. This preparation regulates the hypothalamic-pituitary-adrenal axis function and alleviates symptoms such as anhedonia and hopelessness in patients with depression. Existing technology CN120305338A discloses a traditional Chinese medicine preparation including poria cocos, ginkgo biloba leaf, astragalus membranaceus, hypericum perforatum, jujube, red ginseng, jujube seed, and valerian. These drugs work synergistically to improve depressive symptoms. Summary of the Invention

[0004] While existing technologies have some value in drug compatibility and preliminary efficacy verification, they are lacking in areas such as process standardization, safety verification, and preparation for clinical translation.

[0005] Traditional Chinese medicine (TCM) has demonstrated advantages in the treatment of depression due to its synergistic effects of multiple components, multi-target regulatory mechanisms, and relatively low adverse reaction rates. Poria cocos, a medicinal and edible herb, is described in the *Compendium of Materia Medica* as having a "mild and permeable flavor, ascending nature, generating body fluids, opening the pores, nourishing the water source and descending, promoting urination," thus possessing the effects of generating body fluids, promoting urination, strengthening the spleen, and calming the mind. Its medicinal properties are nourishing without being drastic, and beneficial without being overpowering. The main chemical components of Poria cocos are polysaccharides, fatty acids, and sterols. Studies have shown that Poria cocos polysaccharides and carboxymethyl Poria cocos polysaccharides possess anti-diabetic, antioxidant, and anti-inflammatory activities. Researchers have found that Poria cocos polysaccharides can improve intestinal barrier function by altering the composition of intestinal flora, thereby improving the intestinal flora imbalance caused by depression and thus improving depressive behavior.

[0006] Reishi spores are extremely tiny, oval-shaped seeds of Reishi mushrooms, ejected from the gills of the mushroom during its growth and maturation. Reishi spore powder contains many of the genetic materials of Reishi mushrooms, has a sweet taste and neutral properties, and can be used to treat symptoms such as restlessness, insomnia, forgetfulness, fatigue, and poor appetite caused by depression.

[0007] This invention uses Poria cocos to regulate intestinal flora; combined with the drug composition prepared from Ganoderma lucidum spores, the antidepressant effect is stable and without toxic side effects, making it suitable for long-term medication needs of patients with depression.

[0008] This invention discloses a pharmaceutical composition for treating depression, comprising Poria cocos extract granules, Ganoderma lucidum spore oil, and a suspension stabilizer.

[0009] The present invention also discloses a method for preparing a pharmaceutical composition for treating depression.

[0010] A method for preparing a pharmaceutical composition for treating depression, comprising the following specific steps: (1) Pulverize 50-120g of Poria cocos, sieve it, and then process it through an air jet mill; add water for extraction; after filtration, cool the filtrate for 30 min, add 300-500mL of 95wt% ethanol aqueous solution, stir at 100-300r / min for 10 min, refrigerate at 4℃ and stand for 6-15 h; after filtration, dry the filter cake and pulverize it to obtain Poria cocos extract granules; (2) Take 80-150g of Ganoderma lucidum spore powder, break the cell wall and pulverize it, add 20-80g of water and mix, then dry it in a vacuum drying oven at 50-60℃ for 1-2h to obtain spore powder particles; then soak it in 300-800mL of 95wt% ethanol aqueous solution at 20℃ for 1-2h for pretreatment, then perform CO2 supercritical extraction to collect the extract, remove ethanol, filter and obtain Ganoderma lucidum spore oil; (3) Take 30-80g of Ganoderma lucidum spore oil and preheat it in a water bath at 30-35℃ for 3-10 minutes. Add 30-80g of Poria cocos extract granules and stir at 100-300r / min for 15-30 minutes. Set aside. Separately, add 0.1-0.5g of suspension stabilizer to 500-1000mL of water and stir at 200-500r / min for 10-30 minutes at 20-40℃. Add the mixture to the prepared system and continue stirring for 10-30 minutes to prepare a suspension.

[0011] The airflow pulverization process in step (1) is carried out under nitrogen conditions with a pressure of 0.8-1.0 MPa and a flow rate of 30-80 m / s. 3 / h.

[0012] The water extraction process in step (1) involves adding 10 times the amount of water and decocting twice, each time for 2 hours.

[0013] The cell wall breaking and pulverizing process in step (2) is as follows: vibrating and grinding at 0-5℃ for 10-20 minutes under nitrogen conditions.

[0014] The CO2 supercritical extraction treatment conditions in step (2) are as follows: 25-50 mL of 95wt% ethanol aqueous solution is placed in the extraction vessel, and the extraction vessel temperature is set to 38-42℃, the extraction vessel pressure is set to 30-35 MPa, and the extraction time is set to 3-4 h.

[0015] In step (3), the ratio of Poria cocos extract granules to Ganoderma lucidum spore oil is 1:1 by mass.

[0016] The suspension stabilizer is at least one of gum arabic, guar gum, xanthan gum, and modified xanthan gum.

[0017] The method for preparing modified xanthan gum includes: taking 0.5-2g of xanthan gum, spreading it evenly, drying it in an oven at 50-60℃ for 1-2 hours, adding 0.05-0.2g of catalyst, stirring at 100-200r / min for 3-5 minutes, mixing, and then heating in a water bath at 50-60℃ for 1-3 hours under nitrogen atmosphere; then adding 1-10mL of water and 0.1-0.8g of additives, stirring continuously for 5-8 minutes to mix evenly, maintaining the reaction at 50-60℃ for 1-3 hours, drying at 20-40℃ for 24-48 hours, and pulverizing to obtain the product.

[0018] The catalysts involved in the modified xanthan gum are at least one of ferrous gluconate and zinc lactate.

[0019] The modified xanthan gum mentioned above involves at least one of the following additives: pregelatinized starch, maltodextrin, arabinogalactan, and montmorillonite.

[0020] The beneficial effects of this invention are: 1. Compared with existing technologies, Poria cocos is a medicinal and edible herb, and Ganoderma lucidum spore powder is a traditional medicinal ingredient, neither of which has been shown to be toxic. Furthermore, Ganoderma lucidum spore oil is extracted using CO2 supercritical extraction technology, leaving no organic solvent residue throughout the process, thus avoiding harmful impurities that may be introduced by traditional extraction methods and cannot be effectively removed. Poria cocos polysaccharides are prepared through a water extraction-alcohol precipitation process, without the involvement of toxic reagents, causing no damage to the body, and are suitable for the long-term medication needs of patients with depression.

[0021] 2. This invention has the effect of improving depressive symptoms, but conventional Western medicines can cause side effects such as dry mouth, nausea, constipation, and headaches. The high-dose drug composition is a traditional Chinese medicine suspension, without any toxic side effects, and its effects are more significant. For patients with depression, traditional Chinese medicine preparations are more reassuring and safer, beneficial for long-term treatment, and have good clinical application prospects.

[0022] 3. The present invention prepares a suspension stabilizer, which is modified and compounded to synergistically act on the active ingredients of Poria cocos and Ganoderma lucidum spore oil, harmonizes the taste, eliminates the unpleasant flavor of colloids and raw materials themselves, and avoids the effect of uneven local concentration on efficacy, thus providing a reliable formulation basis for the adjunctive treatment of depression. Detailed Implementation

[0023] A method for preparing a pharmaceutical composition for treating depression, comprising the following steps: (1) Crush 50-120g of Poria cocos, sieve and then perform air jet milling; extract with water twice, 2h each time; after filtration, add 300-500mL of 95wt% ethanol aqueous solution to the filtrate, stir at 100-300r / min for 10min, refrigerate at 4℃ and stand for 6-15h; after filtration, dry the filter cake in a vacuum drying oven at 20-50℃ for 1-2h to obtain Poria cocos extract granules; (2) Take 80-150g of Ganoderma lucidum spore powder, break the cell wall and pulverize it, add 20-80g of water and mix, dry in a vacuum drying oven at 50-60℃ for 1-2h to obtain spore powder particles; then soak in 300-800mL of 95wt% ethanol aqueous solution at 20℃ for 1-2h for pretreatment, and perform CO2 supercritical extraction treatment. Place 25-50mL of 95wt% ethanol aqueous solution in the extraction vessel, set the temperature to 38-42℃, the pressure of the extraction vessel to 30-35MPa, the extraction time to 3-4h, collect the extract, remove the ethanol, filter and obtain Ganoderma lucidum spore oil; (3) Take 30-80g of Ganoderma lucidum spore oil and preheat it in a water bath at 30-35℃ for 3-10 minutes. Add 30-80g of Poria cocos extract granules and stir at 100-300r / min for 15-30 minutes. Set aside. Separately, add 0.1-0.5g of suspension stabilizer to 500-1000mL of water and stir at 200-500r / min for 10-30 minutes at 20-40℃. Add the mixture to the prepared system and continue stirring for 10-30 minutes to prepare a suspension.

[0024] The parameters and sources of some substances in the examples are as follows: SPF-grade male SD rats: Three groups of 50 rats each, totaling 150 rats, were provided by an animal laboratory of a pharmaceutical university; all rats weighed 250-300g.

[0025] Ferrous gluconate: CAS No.: 299-29-6.

[0026] Pregelatinized starch: Take 10g of corn starch, sieve it, add 15g of water, stir at 100r / min for 20min at 95℃; take it out and dry it in a forced-air dryer at 65℃ for 6h, then pulverize and sieve it to obtain powdered pregelatinized starch.

[0027] Maltodextrin: CAS No.: 9050-36-6; glucose equivalent 5.0-8.0.

[0028] Arabingalactan: CAS No.: 9036-66-2; L-arabinose to D-galactose ratio is 1:5-6; food grade.

[0029] Montmorillonite: Pharmaceutical grade.

[0030] Example 1 A method for preparing a pharmaceutical composition for treating depression, comprising the following steps: (1) Pulverize 100g of Poria cocos, pass it through an 80-mesh sieve, and then place it under nitrogen conditions with a pressure of 0.8MPa and a flow rate of 50m. 3 The mixture was subjected to air jet milling at 95°C for 2 hours each time. After filtration, 500 mL of 95 wt% ethanol aqueous solution that had been refrigerated at 4°C for 30 minutes was added to the filtrate. The mixture was stirred at 300 r / min for 10 minutes and then refrigerated at 4°C for 12 hours. After filtration, the filter cake was dried in a vacuum drying oven at 40°C for 2 hours to obtain Poria cocos extract granules. (2) Take 100g of Ganoderma lucidum spore powder, vibrate and grind it at 4℃ for 15min under nitrogen, add 30g of water and mix, stir at 100r / min for 3min, dry in a vacuum drying oven at 60℃ for 2h to obtain spore powder particles; then soak it in 500mL of 95wt% ethanol aqueous solution at 20℃ for 2h for pretreatment, and then perform CO2 supercritical extraction treatment. Place 30mL of 95wt% ethanol aqueous solution in the extraction vessel, set the temperature to 40℃, the pressure of the extraction vessel to 32MPa, the extraction time to 4h, collect the extract, remove the ethanol, filter and obtain Ganoderma lucidum spore oil; (3) Take 50g of Ganoderma lucidum spore oil and preheat it in a 35℃ water bath for 5 minutes. Add 50g of Poria cocos extract granules and stir at 300r / min for 20 minutes to obtain the product.

[0031] Example 2 A method for preparing a pharmaceutical composition for treating depression, comprising the following steps: (1) Pulverize 100g of Poria cocos, pass it through an 80-mesh sieve, and then place it under nitrogen conditions with a pressure of 0.8MPa and a flow rate of 50m. 3 The mixture was subjected to air jet milling at 95°C for 2 hours each time. After filtration, 500 mL of 95 wt% ethanol aqueous solution that had been chilled at 4°C for 30 minutes was added to the filtrate. The mixture was stirred at 300 r / min for 10 minutes and then chilled at 4°C for 12 hours. After vacuum filtration, the filter cake was dried in a vacuum drying oven at 40°C for 2 hours to obtain Poria cocos extract granules. (2) Take 100g of Ganoderma lucidum spore powder, vibrate and grind it at 4℃ for 15min under nitrogen, add 30g of water and mix, stir at 100r / min for 3min, dry in a vacuum drying oven at 60℃ for 2h to obtain spore powder particles; then soak it in 500mL of 95wt% ethanol aqueous solution at 20℃ for 2h for pretreatment, and then perform CO2 supercritical extraction treatment. Place 30mL of 95wt% ethanol aqueous solution in the extraction vessel, set the temperature to 40℃, the pressure of the extraction vessel to 32MPa, the extraction time to 4h, collect the extract, remove the ethanol, filter and obtain Ganoderma lucidum spore oil; (3) Take 50g of Ganoderma lucidum spore oil and preheat it in a 35℃ water bath for 5min. Add 50g of Poria cocos extract granules and stir at 300r / min for 20min. Set aside. Separately, add 0.5g of gum arabic to 1000mL of water and stir at 500r / min for 30min at 25℃. Add to the set aside system and stir continuously for 20min to obtain the final product.

[0032] Example 3 A method for preparing a pharmaceutical composition for treating depression, comprising the following steps: (1) Pulverize 100g of Poria cocos, pass it through an 80-mesh sieve, and then place it under nitrogen conditions with a pressure of 0.8MPa and a flow rate of 50m. 3 The mixture was subjected to air jet milling at 95°C for 2 hours each time. After filtration, 500 mL of 95 wt% ethanol aqueous solution that had been chilled at 4°C for 30 minutes was added to the filtrate. The mixture was stirred at 300 r / min for 10 minutes and then chilled at 4°C for 12 hours. After vacuum filtration, the filter cake was dried in a vacuum drying oven at 40°C for 2 hours to obtain Poria cocos extract granules. (2) Take 100g of Ganoderma lucidum spore powder, vibrate and grind it at 4℃ for 15min under nitrogen, add 30g of water and mix, stir at 100r / min for 3min, dry in a vacuum drying oven at 60℃ for 2h to obtain spore powder particles; then soak it in 500mL of 95wt% ethanol aqueous solution at 20℃ for 2h for pretreatment, and then perform CO2 supercritical extraction treatment. Place 30mL of 95wt% ethanol aqueous solution in the extraction vessel, set the temperature to 40℃, the pressure of the extraction vessel to 32MPa, the extraction time to 4h, collect the extract, remove the ethanol, filter and obtain Ganoderma lucidum spore oil; (3) Take 50g of Ganoderma lucidum spore oil and preheat it in a 35℃ water bath for 5min. Add 50g of Poria cocos extract granules and stir at 300r / min for 20min. Set aside. Separately, add 0.5g of guar gum to 1000mL of water and stir at 500r / min for 30min at 30℃. Add it to the set aside system and continue stirring for 20min to make a suspension.

[0033] Example 4 A method for preparing a pharmaceutical composition for treating depression, comprising the following steps: (1) Pulverize 100g of Poria cocos, pass it through an 80-mesh sieve, and then place it under nitrogen conditions with a pressure of 0.8MPa and a flow rate of 50m. 3 The mixture was subjected to air jet milling at 95°C for 2 hours each time. After filtration, 500 mL of 95 wt% ethanol aqueous solution that had been chilled at 4°C for 30 minutes was added to the filtrate. The mixture was stirred at 300 r / min for 10 minutes and then chilled at 4°C for 12 hours. After vacuum filtration, the filter cake was dried in a vacuum drying oven at 40°C for 2 hours to obtain Poria cocos extract granules. (2) Take 100g of Ganoderma lucidum spore powder, vibrate and grind it at 4℃ for 15min under nitrogen, add 30g of water and mix, stir at 100r / min for 3min, dry in a vacuum drying oven at 60℃ for 2h to obtain spore powder particles; then soak it in 500mL of 95wt% ethanol aqueous solution at 20℃ for 2h for pretreatment, and then perform CO2 supercritical extraction treatment. Place 30mL of 95wt% ethanol aqueous solution in the extraction vessel, set the temperature to 40℃, the pressure of the extraction vessel to 32MPa, the extraction time to 4h, collect the extract, remove the ethanol, filter and obtain Ganoderma lucidum spore oil; (3) Take 50g of Ganoderma lucidum spore oil and preheat it in a 35℃ water bath for 5min. Add 50g of Poria cocos extract granules and stir at 300r / min for 20min. Set aside. Separately, add 0.5g of xanthan gum to 1000mL of water and stir at 500r / min for 30min at 30℃. Add it to the set aside system and continue stirring for 20min to make a suspension.

[0034] Example 5 A method for preparing a pharmaceutical composition for treating depression, comprising the following steps: (1) Pulverize 100g of Poria cocos, pass it through an 80-mesh sieve, and then place it under nitrogen conditions with a pressure of 0.8MPa and a flow rate of 50m. 3 The mixture was subjected to air jet milling at 95°C for 2 hours each time. After filtration, 500 mL of 95 wt% ethanol aqueous solution that had been chilled at 4°C for 30 minutes was added to the filtrate. The mixture was stirred at 300 r / min for 10 minutes and then chilled at 4°C for 12 hours. After vacuum filtration, the filter cake was dried in a vacuum drying oven at 40°C for 2 hours to obtain Poria cocos extract granules. (2) Take 100g of Ganoderma lucidum spore powder, vibrate and grind it at 4℃ for 15min under nitrogen, add 30g of water and mix, stir at 100r / min for 3min, dry in a vacuum drying oven at 60℃ for 2h to obtain spore powder particles; then soak it in 500mL of 95wt% ethanol aqueous solution at 20℃ for 2h for pretreatment, and then perform CO2 supercritical extraction treatment. Place 30mL of 95wt% ethanol aqueous solution in the extraction vessel, set the temperature to 40℃, the pressure of the extraction vessel to 32MPa, the extraction time to 4h, collect the extract, remove the ethanol, filter and obtain Ganoderma lucidum spore oil; (3) Take 50g of Ganoderma lucidum spore oil and preheat it in a 35℃ water bath for 5min. Add 50g of Poria cocos extract granules and stir at 300r / min for 20min. Set aside. Separately, add 0.5g of modified xanthan gum to 1000mL of water and stir at 500r / min for 30min at 30℃. Add it to the set aside system and stir continuously for 15min to make a suspension.

[0035] The preparation method of the modified xanthan gum is as follows: Take 1g of xanthan gum, spread it evenly in an oven at 55℃ and dry it for 2 hours. Then add 0.1g of ferrous gluconate, stir at 200r / min for 5 minutes to mix, and heat in a water bath at 60℃ for 3 hours under nitrogen. Then add 10mL of water and 0.5g of pregelatinized starch, stir continuously for 5 minutes to mix well, keep the reaction at 60℃ for 3 hours, dry at 40℃ for 48 hours and pulverize to obtain the final product.

[0036] Example 6 A method for preparing a pharmaceutical composition for treating depression, comprising the following steps: (1) Pulverize 100g of Poria cocos, pass it through an 80-mesh sieve, and then place it under nitrogen conditions with a pressure of 0.8MPa and a flow rate of 50m. 3 The mixture was subjected to air jet milling at 95°C for 2 hours each time. After filtration, 500 mL of 95 wt% ethanol aqueous solution that had been chilled at 4°C for 30 minutes was added to the filtrate. The mixture was stirred at 300 r / min for 10 minutes and then chilled at 4°C for 12 hours. After vacuum filtration, the filter cake was dried in a vacuum drying oven at 40°C for 2 hours to obtain Poria cocos extract granules. (2) Take 100g of Ganoderma lucidum spore powder, vibrate and grind it at 4℃ for 15min under nitrogen, add 30g of water and mix, stir at 100r / min for 3min, dry in a vacuum drying oven at 60℃ for 2h to obtain spore powder particles; then soak it in 500mL of 95wt% ethanol aqueous solution at 20℃ for 2h for pretreatment, and then perform CO2 supercritical extraction treatment. Place 30mL of 95wt% ethanol aqueous solution in the extraction vessel, set the temperature to 40℃, the pressure of the extraction vessel to 32MPa, the extraction time to 4h, collect the extract, remove the ethanol, filter and obtain Ganoderma lucidum spore oil; (3) Take 50g of Ganoderma lucidum spore oil and preheat it in a 35℃ water bath for 5min. Add 50g of Poria cocos extract granules and stir at 300r / min for 20min. Set aside. Separately, add 0.5g of modified xanthan gum to 1000mL of water and stir at 500r / min for 30min at 30℃. Add it to the set aside system and stir continuously for 15min to make a suspension.

[0037] The preparation method of the modified xanthan gum is as follows: Take 1g of xanthan gum, spread it evenly in an oven at 55℃ and dry it for 2 hours. Then add 0.1g of ferrous gluconate, stir at 200r / min for 5 minutes to mix, and heat in a water bath at 60℃ for 3 hours under nitrogen. Then add 10mL of water and 0.5g of maltodextrin, stir continuously for 5 minutes to mix well, keep the reaction at 60℃ for 3 hours, dry at 40℃ for 48 hours and pulverize to obtain the final product.

[0038] Example 7 A method for preparing a pharmaceutical composition for treating depression, comprising the following steps: (1) Pulverize 100g of Poria cocos, pass it through an 80-mesh sieve, and then place it under nitrogen conditions with a pressure of 0.8MPa and a flow rate of 50m. 3 The mixture was subjected to air jet milling at 95°C for 2 hours each time. After filtration, 500 mL of 95 wt% ethanol aqueous solution that had been chilled at 4°C for 30 minutes was added to the filtrate. The mixture was stirred at 300 r / min for 10 minutes and then chilled at 4°C for 12 hours. After vacuum filtration, the filter cake was dried in a vacuum drying oven at 40°C for 2 hours to obtain Poria cocos extract granules. (2) Take 100g of Ganoderma lucidum spore powder, vibrate and grind it at 4℃ for 15min under nitrogen, add 30g of water and mix, stir at 100r / min for 3min, dry in a vacuum drying oven at 60℃ for 2h to obtain spore powder particles; then soak it in 500mL of 95wt% ethanol aqueous solution at 20℃ for 2h for pretreatment, and then perform CO2 supercritical extraction treatment. Place 30mL of 95wt% ethanol aqueous solution in the extraction vessel, set the temperature to 40℃, the pressure of the extraction vessel to 32MPa, the extraction time to 4h, collect the extract, remove the ethanol, filter and obtain Ganoderma lucidum spore oil; (3) Take 50g of Ganoderma lucidum spore oil and preheat it in a 35℃ water bath for 5min. Add 50g of Poria cocos extract granules and stir at 300r / min for 20min. Set aside. Separately, add 0.5g of modified xanthan gum to 1000mL of water and stir at 500r / min for 30min at 30℃. Add it to the set aside system and stir continuously for 15min to make a suspension.

[0039] The preparation method of the modified xanthan gum is as follows: Take 1g of xanthan gum, spread it evenly in an oven at 55℃ and dry it for 2 hours. Then add 0.1g of ferrous gluconate, stir at 200r / min for 5 minutes to mix, and heat in a water bath at 60℃ for 3 hours under nitrogen. Then add 10mL of water and 0.5g of arabinogalactan, stir continuously for 5 minutes to mix, keep the reaction at 60℃ for 3 hours, dry at 40℃ for 48 hours and pulverize to obtain the final product.

[0040] Example 8 A method for preparing a pharmaceutical composition for treating depression, comprising the following steps: (1) Pulverize 100g of Poria cocos, pass it through an 80-mesh sieve, and then place it under nitrogen conditions with a pressure of 0.8MPa and a flow rate of 50m. 3 The mixture was subjected to air jet milling at 95°C for 2 hours each time. 1000 mL of water was added, and the mixture was decocted twice at 95°C for 2 hours each time. After filtration, 500 mL of 95 wt% ethanol aqueous solution that had been chilled at 4°C for 30 minutes was added to the filtrate. The mixture was stirred at 300 r / min for 10 minutes and then chilled at 4°C for 12 hours. After filtration, the filter cake was dried in a vacuum drying oven at 40°C for 2 hours to obtain Poria cocos extract granules. (2) Take 100g of Ganoderma lucidum spore powder, vibrate and grind it at 4℃ for 15min under nitrogen, add 30g of water and mix, stir at 100r / min for 3min, dry in a vacuum drying oven at 60℃ for 2h to obtain spore powder particles; then soak it in 500mL of 95wt% ethanol aqueous solution at 20℃ for 2h for pretreatment, and then perform CO2 supercritical extraction treatment. Place 30mL of 95wt% ethanol aqueous solution in the extraction vessel, set the temperature to 40℃, the pressure of the extraction vessel to 32MPa, the extraction time to 4h, collect the extract, remove the ethanol, filter and obtain Ganoderma lucidum spore oil; (3) Take 50g of Ganoderma lucidum spore oil and preheat it in a 35℃ water bath for 5min. Add 50g of Poria cocos extract granules and stir at 300r / min for 20min. Set aside. Separately, add 0.5g of modified xanthan gum to 1000mL of water and stir at 500r / min for 30min at 30℃. Add it to the set aside system and stir continuously for 15min to make a suspension.

[0041] The preparation method of the modified xanthan gum is as follows: Take 1g of xanthan gum, spread it evenly, and dry it in an oven at 55℃ for 2 hours. Then add 0.1g of ferrous gluconate, mix at 200r / min for 5 minutes, and heat in a water bath at 60℃ for 3 hours under nitrogen. After grinding and sieving, add 10mL of water, 0.25g of pregelatinized starch, and 0.25g of maltodextrin. Stir at 200r / min for 5 minutes to mix well, and keep the reaction at 60℃ for 3 hours. Dry at 40℃ for 48 hours and then pulverize to obtain the final product.

[0042] Example 9 A method for preparing a pharmaceutical composition for treating depression, comprising the following steps: (1) Pulverize 100g of Poria cocos, pass it through an 80-mesh sieve, and then place it under nitrogen conditions with a pressure of 0.8MPa and a flow rate of 50m. 3 The mixture was subjected to air jet milling at 95°C for 2 hours each time. After filtration, 500 mL of 95 wt% ethanol aqueous solution that had been chilled at 4°C for 30 minutes was added to the filtrate. The mixture was stirred at 300 r / min for 10 minutes and then chilled at 4°C for 12 hours. After vacuum filtration, the filter cake was dried in a vacuum drying oven at 40°C for 2 hours to obtain Poria cocos extract granules. (2) Take 100g of Ganoderma lucidum spore powder, vibrate and grind it at 4℃ for 15min under nitrogen, add 30g of water and mix, stir at 100r / min for 3min, dry in a vacuum drying oven at 60℃ for 2h to obtain spore powder particles; then soak it in 500mL of 95wt% ethanol aqueous solution at 20℃ for 2h for pretreatment, and then perform CO2 supercritical extraction treatment. Place 30mL of 95wt% ethanol aqueous solution in the extraction vessel, set the temperature to 40℃, the pressure of the extraction vessel to 32MPa, the extraction time to 4h, collect the extract, remove the ethanol, filter and obtain Ganoderma lucidum spore oil; (3) Take 50g of Ganoderma lucidum spore oil and preheat it in a 35℃ water bath for 5min. Add 50g of Poria cocos extract granules and stir at 300r / min for 20min. Set aside. Separately, add 0.5g of modified xanthan gum to 1000mL of water and stir at 500r / min for 30min at 30℃. Add it to the set aside system and stir continuously for 15min to make a suspension.

[0043] The preparation method of the modified xanthan gum is as follows: Take 1g of xanthan gum, spread it evenly, and dry it in an oven at 55℃ for 2 hours. Then add 0.1g of ferrous gluconate, mix at 200r / min for 5 minutes, and heat in a water bath at 60℃ for 3 hours under nitrogen. After grinding and sieving, add 10mL of water, 0.25g of pregelatinized starch, and 0.25g of arabinogalactan. Stir at 200r / min for 5 minutes to mix evenly, and keep the reaction at 60℃ for 3 hours. Dry at 40℃ for 48 hours and then pulverize to obtain the final product.

[0044] Example 10 A method for preparing a pharmaceutical composition for treating depression, comprising the following steps: (1) Pulverize 100g of Poria cocos, pass it through an 80-mesh sieve, and then place it under nitrogen conditions with a pressure of 0.8MPa and a flow rate of 50m. 3The mixture was subjected to air jet milling at 95°C for 2 hours each time. After filtration, 500 mL of 95 wt% ethanol aqueous solution that had been chilled at 4°C for 30 minutes was added to the filtrate. The mixture was stirred at 300 r / min for 10 minutes and then chilled at 4°C for 12 hours. After vacuum filtration, the filter cake was dried in a vacuum drying oven at 40°C for 2 hours to obtain Poria cocos extract granules. (2) Take 100g of Ganoderma lucidum spore powder, vibrate and grind it at 4℃ for 15min under nitrogen, add 30g of water and mix, stir at 100r / min for 3min, dry in a vacuum drying oven at 60℃ for 2h to obtain spore powder particles; then soak it in 500mL of 95wt% ethanol aqueous solution at 20℃ for 2h for pretreatment, and then perform CO2 supercritical extraction treatment. Place 30mL of 95wt% ethanol aqueous solution in the extraction vessel, set the temperature to 40℃, the pressure of the extraction vessel to 32MPa, the extraction time to 4h, collect the extract, remove the ethanol, filter and obtain Ganoderma lucidum spore oil; (3) Take 50g of Ganoderma lucidum spore oil and preheat it in a 35℃ water bath for 5min. Add 50g of Poria cocos extract granules and stir at 300r / min for 20min. Set aside. Separately, add 0.5g of modified xanthan gum to 1000mL of water and stir at 500r / min for 30min at 30℃. Add it to the set aside system and stir continuously for 15min to make a suspension.

[0045] The preparation method of the modified xanthan gum is as follows: Add 0.6g of montmorillonite to 10mL of water and stir at 800r / min for 5min at 45℃ to obtain a montmorillonite slurry for later use. Take 1g of xanthan gum, spread it evenly, and dry it in an oven at 55℃ for 2 hours. Then add 0.1g of ferrous gluconate, mix at 200r / min for 5 minutes, and heat in a water bath at 60℃ for 3 hours under nitrogen. After grinding and sieving, add 5mL of reserved montmorillonite slurry, 5mL of water, 0.25g of pregelatinized starch, and 0.25g of arabinogalactan. Stir at 200r / min for 5 minutes to mix evenly, and keep the reaction at 60℃ for 3 hours. Dry at 40℃ for 48 hours and then pulverize to obtain the final product.

[0046] Comparative Example 1 A method for preparing a pharmaceutical composition for treating depression, comprising the following steps: (1) Pulverize 100g of Poria cocos, pass it through an 80-mesh sieve, and then place it under nitrogen conditions with a pressure of 0.8MPa and a flow rate of 50m. 3The mixture was subjected to air jet milling at 95°C for 2 hours each time. After filtration, 500 mL of 95 wt% ethanol aqueous solution that had been chilled at 4°C for 30 minutes was added to the filtrate. The mixture was stirred at 300 r / min for 10 minutes and then chilled at 4°C for 12 hours. After vacuum filtration, the filter cake was dried in a vacuum drying oven at 40°C for 2 hours to obtain Poria cocos extract granules. (2) Take 100g of Ganoderma lucidum spore powder, vibrate and grind it at 4℃ for 15min under nitrogen, add 30g of water and mix, stir at 100r / min for 3min, dry in a vacuum drying oven at 60℃ for 2h to obtain spore powder particles; then soak it in 500mL of 95wt% ethanol aqueous solution at 20℃ for 2h for pretreatment, and then perform CO2 supercritical extraction treatment. Place 30mL of 95wt% ethanol aqueous solution in the extraction vessel, set the temperature to 40℃, the pressure of the extraction vessel to 32MPa, the extraction time to 4h, collect the extract, remove the ethanol, filter and obtain Ganoderma lucidum spore oil; (3) Take 50g of Ganoderma lucidum spore oil and preheat it in a 35℃ water bath for 5min. Add 50g of Poria cocos extract granules and stir at 300r / min for 20min. Set aside. Separately, add 0.5g of modified xanthan gum to 1000mL of water and stir at 500r / min for 30min at 30℃. Add it to the set aside system and stir continuously for 15min to make a suspension.

[0047] The preparation method of the modified xanthan gum is as follows: Add 0.6g of montmorillonite to 10mL of water and stir at 800r / min for 5min at 45℃ to obtain a montmorillonite slurry for later use. Take 1g of xanthan gum, spread it evenly in an oven at 55℃ and dry it for 2h. Then add 0.1g of zinc lactate, mix at 200r / min for 5min, and heat in a water bath at 60℃ for 3h under nitrogen. After grinding and sieving, add 5mL of the reserved montmorillonite slurry, 5mL of water, 0.25g of pregelatinized starch, and 0.25g of arabinogalactan. Stir at 200r / min for 5min to mix evenly, and keep the reaction at 60℃ for 3h. Dry at 40℃ for 48h and then pulverize to obtain the final product.

[0048] Test Example 1 Viscosity and dissolution time The compositions prepared in Examples 1-10 and Comparative Example 1 were added to 100 mL of water, stirred at 30 r / min to dissolve, and then placed in an NDJ-5S rotational viscometer. The viscosity was measured at 25 °C, with a preset dissolution time of 5 min for each composition. The preset viscosity was 750 mPa·s, and the dissolution time was recorded. The results are shown in Table 1.

[0049] Table 1. Results of dissolution time and viscosity measurements In Example 1, no suspending stabilizer was added, and the tested dissolution time and viscosity were slightly lower than the preset values, indicating that the mixture of Poria cocos particles and Ganoderma lucidum spore oil had poor stability and was prone to particle aggregation and oil phase separation. Examples 2-4 showed some improvement in dissolution time and viscosity. This was achieved by polar groups such as hydroxyl and carboxyl groups in the molecules binding to the surface of Poria cocos particles and the interface of Ganoderma lucidum spore oil, reducing interfacial tension, preventing particle and oil phase dispersion, and simultaneously forming a three-dimensional network through intermolecular entanglement, thereby increasing system viscosity, shortening dissolution time, and enhancing stability. Xanthan gum, with its strong hydrophilicity and interfacial activity, exhibits stronger affinity for water and both phases, forming a denser colloidal network. At the same addition amount, the synergistic effect of xanthan gum and Poria cocos polysaccharide added in Example 4 optimized viscosity and dissolution time.

[0050] Compared to the modified xanthan gum in Examples 5-7, which underwent dry heat modification and catalytic treatment, the molecular structure of the modified xanthan gum is more easily integrated into the system, shortening the dissolution time. In Example 9, the hydrophilic-hydrophobic balanced structure of arabinogalactan, combined with the exposed hydroxyl groups of pregelatinized starch, fills the pores of the xanthan gum network, effectively coating the oil phase and solid particles, and improving the uniformity of the pharmaceutical composition.

[0051] Furthermore, in Example 10, pharmaceutical-grade montmorillonite is added. After hydration, it is peeled off into negatively charged layered crystals, which undergo high-energy particle adsorption at the oil and water phase interface to form a physical shell. The resulting composite system not only ensures the uniform dispersion of drug components through synergistic thickening, but also improves the viscosity and palatability of the drug composition by harmonizing the taste and eliminating the unpleasant flavors of the colloid and raw materials themselves, while meeting the basic requirements of stability after dissolution of the drug carrier. This makes it more acceptable to patients with depression, especially suitable for depression treatment scenarios that require long-term medication.

[0052] Test Example 2 Sugar water consumption test Pre-treatment: Room temperature was controlled at 20-26℃ and relative humidity at 40-70%. Rats were fed SPF (Special Treatment) rat growth and reproduction diet with free access to water and food. After one week of acclimatization, 10 rats were randomly selected and divided into two cages (5 rats per cage) as a blank control group; the remaining 40 rats were kept isolated. Except for the blank control group, the isolated rats underwent a chronic unpredictable mild stress model for 4 weeks. Stress factors included: 24-hour fasting and water restriction, 24-hour diurnal cycle reversal, 24-hour damp bedding, 5-minute tail clamping, 5-minute swimming in 4℃ ice water, and 5-minute heat stress at 45℃. One stimulus was given daily in a randomized order to prevent the animals from predicting the next stimulus and to avoid adaptation.

[0053] After 28 days, except for the selected blank control group, the rats were randomly divided into 4 groups. The drug composition prepared in Example 10 was divided into 3 groups: high-dose group, medium-dose group, and low-dose group, as well as a drug group supplemented with Western medicine.

[0054] The following regimen was administered continuously for 14 days. High, medium, and low dose groups: The composition prepared in Example 10 of this invention was used, and the dosage was 2.4 g / (kg·d), 1 g / (kg·d), and 0.7 g / (kg·d) respectively.

[0055] In addition, the blank control group was supplemented with 2.4 g / (kg·d) of normal saline.

[0056] Additionally, the drug group was supplemented with paroxetine 0.05g / (kg·d). Paroxetine can treat various types of depression, and is particularly effective for depression accompanied by anxiety and reactive depression.

[0057] Rats were deprived of water but not food for 24 hours before the experiment. During the experiment, all rats were given one bottle of pure water and one bottle of 1wt% sucrose solution to test sucrose consumption. After 24 hours, the amount of sucrose consumed was weighed, and the proportion of sucrose consumed was calculated. The results are shown in Table 2. The formula is as follows: Table 2. Results of rat body weight and sucrose consumption (x±s, n=10) Sugar consumption is an effective indicator of anhedonia in animals, and anhedonia is a core symptom of depression.

[0058] After 14 days of administration, compared with the blank control group, the body weight and sucrose consumption rate of rats in both the drug group and the high-dose group decreased, while there was no significant difference in body weight and sucrose consumption rate in the low-dose group. Compared with the drug group, the body weight of rats in the high-dose group increased, and the difference in body weight was significant. The above results indicate that the Poria cocos polysaccharide in the Poria cocos granules of the present invention can regulate intestinal flora homeostasis, repair intestinal barrier function, reduce the release of inflammatory factors, improve intestinal flora imbalance caused by depression, thereby alleviating anhedonia, improving pleasure and appetite in depressed rats, increasing sucrose intake, maintaining body weight gain, and improving depressive symptoms.

[0059] Test Example 3 Open field experiment This experiment quantitatively evaluated the animals' spontaneous activity, exploratory behavior, and states of anxiety and depression. The total distance traveled reflected the mice's activity level and motor ability; when mice were in a depressed state, their movement distance was significantly shortened.

[0060] Pre-treatment: The room temperature was controlled at 20-26℃ and the relative humidity at 40-70%. SPF rats were fed a growth and reproduction diet and given free access to water and food. After one week of acclimatization, 10 rats were randomly selected and divided into two cages (5 rats per cage) as a control group; the remaining 40 rats were kept in isolation. Except for the control group, the isolated rats underwent a chronic unpredictable mild stress model for 4 weeks. Stress factors included: 24-hour fasting and water restriction, 24-hour diurnal cycle reversal, 24-hour damp bedding, 5 minutes of tail clamping, 5 minutes of swimming in 4℃ ice water, and 5 minutes of heat stress at 45℃. One stimulus was given daily in a randomized order to prevent the animals from predicting the next stimulus and to avoid adaptation.

[0061] After 28 days, except for the selected blank control group, the rats were randomly divided into 4 groups. The drug composition prepared in Example 10 was divided into 3 groups: high-dose group, medium-dose group, and low-dose group, as well as a drug group supplemented with Western medicine.

[0062] The following regimen was administered continuously for 14 days. High, medium, and low dose groups: The composition prepared in Example 10 of this invention was used, and the dosage was 2.4 g / (kg·d), 1 g / (kg·d), and 0.7 g / (kg·d) respectively.

[0063] In addition, the blank control group was supplemented with 2.4 g / (kg·d) of normal saline.

[0064] Additionally, the drug group was supplemented with paroxetine 0.05g / (kg·d). Paroxetine can treat various types of depression, and is particularly effective for depression accompanied by anxiety and reactive depression.

[0065] One day before the end of drug administration, all rats were placed in an open-field test chamber to observe their spontaneous activity. The open-field test chamber was a 40×40×50cm test chamber with a black bottom. Before the experiment, it was divided into 4×4cm square grids. The camera on top of the chamber was adjusted to face the bottom of the chamber and connected to a computer to record the distance the rats traveled and the number of times they entered the center within 5 minutes. The experiment was conducted in a quiet environment to prevent noise or other human factors from affecting the results. After each rat was tested, its feces were collected, and the bottom and inside of the chamber were wiped with a 75wt% ethanol solution to remove the odor of the previous rat. The next rat was tested only after the odor had dissipated. The results are shown in Table 3.

[0066] Table 3 Results of open field experiments (x±s, n=10) The more frequently a mouse enters the central grid, the stronger its curiosity and desire to explore new environments. Conversely, if a mouse enters the central grid less often, it may indicate anxiety or depression, and a reluctance to explore new environments.

[0067] After 14 days of administration, compared with the blank control group, the movement distance and number of times rats in the drug group and high-dose group increased significantly compared with the control group. The medium- and low-dose groups showed slight differences compared with the control group, verifying the effectiveness of the composition within the safe range. The high-dose group did not show a significant difference compared with the drug group, excluding the risk of high-dose side effects. Comparison of the movement trajectories of each group of rats in the open field experiment showed that the spontaneous activity ability of rats was significantly reduced after chronic unpredictable stress. After administration of the high-dose group, through the synergistic effect of intestinal regulation and nerve repair, the anxiety state of depressed rats was improved more gently, and the spontaneous activity ability of rats was increased. Poria cocos and Ganoderma lucidum spores were able to improve depressive symptoms.

[0068] Test Example 4 Forced swimming experiment In the experiment, mice were forced to swim in a confined space. They first tried to escape, then remained floating motionless, giving up hope of escape, exhibiting behavioral despair, similar to the clinical manifestations of depression in humans.

[0069] Pre-treatment: The room temperature was controlled at 20-26℃ and the relative humidity at 40-70%. SPF rats were fed a growth and reproduction diet and given free access to water and food. After one week of acclimatization, 10 rats were randomly selected and divided into two cages (5 rats per cage) as a control group; the remaining 40 rats were kept in isolation. Except for the control group, the isolated rats underwent a chronic unpredictable mild stress model for 4 weeks. Stress factors included: 24-hour fasting and water restriction, 24-hour diurnal cycle reversal, 24-hour damp bedding, 5 minutes of tail clamping, 5 minutes of swimming in 4℃ ice water, and 5 minutes of heat stress at 45℃. One stimulus was given daily in a randomized order to prevent the animals from predicting the next stimulus and to avoid adaptation.

[0070] After 28 days, except for the selected blank control group, the rats were randomly divided into 4 groups. The drug composition prepared in Example 10 was divided into 3 groups: a high-dose group, a medium-dose group, and a low-dose group, as well as a drug group supplemented with Western medicine.

[0071] The following regimen was administered continuously for 14 days. High, medium, and low dose groups: The composition prepared in Example 10 of this invention was used, and the dosage was 2.4 g / (kg·d), 1 g / (kg·d), and 0.7 g / (kg·d) respectively.

[0072] In addition, the blank control group was supplemented with 2.4 g / (kg·d) of normal saline.

[0073] Additionally, the drug group was supplemented with paroxetine 0.05 g / (kg·d). Paroxetine can treat various types of depression, with better efficacy in depression accompanied by anxiety and reactive depression. After the initial drug administration, rats were placed in a transparent, uncovered glass cylinder in water approximately 30 cm deep at a temperature of 32 ± 2 °C. The rats were kept upright upon entering the water. The total immobility time of each group of rats within 3 minutes was recorded, defined as the head floating on the surface, breathing through the nostrils, and the limbs only occasionally making slight movements. The results are shown in Table 4.

[0074] Table 4 Results of the forced swimming experiment (x±s, n=10) After 14 days of administration, compared with the blank control group, the forced swimming immobility time of rats in the drug group and high-dose group was significantly reduced, with highly significant differences compared with the control group. The medium-dose group showed a slight difference compared with the control group, while the low-dose group showed little difference. The high-dose group showed no significant difference compared with the drug group, while the low-dose group showed a significant difference. Comparing the forced swimming immobility time of rats in each group, the results indicate that the high-dose group, compared with the control group, can reduce depressive behavior in rats to a certain extent, alleviate HPA axis overactivation caused by chronic stress, and enhance the feeling of pleasure in rats. This may be due to the presence of Poria cocos polysaccharides, which, through anti-inflammatory and antioxidant effects, reduce oxidative stress damage in a depressive state, protect nerve cells, and improve spontaneous activity. These results suggest that the drug of this invention can improve depressive symptoms.

Claims

1. A pharmaceutical composition for treating depression, characterized in that, Includes Poria cocos extract granules, Ganoderma lucidum spore oil, and suspension stabilizer; The mass ratio of the Poria cocos extract granules to Ganoderma lucidum spore oil is 1:0.5-1.5; The suspension stabilizer is modified xanthan gum; The preparation method of the modified xanthan gum is as follows: Add 0.6g of montmorillonite to 10mL of water and stir at 800r / min for 5min at 45℃ to obtain a montmorillonite slurry for later use. Take 1g of xanthan gum, spread it evenly, and dry it in an oven at 55℃ for 2 hours. Then add 0.1g of ferrous gluconate, mix at 200r / min for 5 minutes, and heat in a water bath at 60℃ for 3 hours under nitrogen. After grinding and sieving, add 5mL of reserved montmorillonite slurry, 5mL of water, 0.25g of pregelatinized starch, and 0.25g of arabinogalactan. Stir at 200r / min for 5 minutes to mix well, and then maintain the reaction at 60℃ for 3 hours. Dry at 40℃ for 48 hours and then pulverize to obtain the product.

2. The pharmaceutical composition for treating depression according to claim 1, characterized in that, The preparation method of the Poria cocos extract granules is as follows: After pulverizing and sieving Poria cocos, it was subjected to air jet milling, water extraction was added, and after filtration, an ethanol aqueous solution was added and allowed to stand overnight to obtain Poria cocos extract granules.

3. The pharmaceutical composition for treating depression according to claim 1, characterized in that, The preparation method of the Ganoderma lucidum spore oil is as follows: Ganoderma lucidum spore powder was pulverized and then treated with water; then it was soaked in an ethanol aqueous solution and subjected to supercritical CO2 extraction to obtain Ganoderma lucidum spore oil.

4. The pharmaceutical composition for treating depression according to claim 2, characterized in that, The airflow pulverization process is carried out under nitrogen conditions with a pressure of 0.8-1.0 MPa and a flow rate of 30-80 m³ / h.

5. The pharmaceutical composition for treating depression according to claim 3, characterized in that, The CO2 supercritical extraction conditions are as follows: 25-50 mL of 95 wt% ethanol aqueous solution is placed in the extraction vessel, and the extraction vessel temperature is set to 38-42℃, the pressure to 30-35 MPa, and the time to 3-4 h.

6. A method for preparing a pharmaceutical composition for treating depression as described in any one of claims 1-5, characterized in that, Includes the following steps: Ganoderma lucidum spore oil is treated with a water bath, then Poria cocos extract granules are added, followed by an aqueous solution of a suspending stabilizer.

7. The use of the pharmaceutical composition for treating depression as described in any one of claims 1-5, characterized in that, The use of the pharmaceutical composition described herein for treating depression in the preparation of a drug for treating depression.

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