Soft capsule for improving anxiety state as well as preparation method and application of soft capsule

Abstract

The invention discloses a soft capsule for improving an anxiety state as well as a preparation method and application of the soft capsule, and belongs to the technical field of pharmaceutical preparations. Comprising contents and a capsule shell wrapping the contents. The content consists of a compound extract, phospholipid and emotional fish oil. The compound extract is prepared from bupleurum chinense, salvia miltiorrhiza, cape jasmine, angelica sinensis, bighead atractylodes rhizome, poria cocos, dried ginger, mint and liquorice; the capsule shell comprises chitosan, sodium alginate, a rosemary extract microcapsule, vitamin C palmitate, titanium dioxide, pachymaran and the like, and the rosemary extract microcapsule is prepared from a rosemary extract through pachymaran microencapsulation. Through the synergistic effect of all the components, the compatibility of the compound extract and the emotional fish oil is effectively improved, the stability of an oil phase system is improved, the oxidative rancidity risk of the emotional fish oil is reduced, meanwhile, the emotional fish oil is matched with the gastrointestinal absorption characteristics of people with weakness of the spleen and the stomach, and a pharmaceutical preparation choice is provided for conditioning the anxiety state.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically a soft capsule for improving anxiety, its preparation method, and its application. Background Technology

[0002] With the accelerating pace of modern life and increasing pressures, the incidence of mood disorders is showing a significant upward trend, with anxiety and depression becoming important factors affecting people's physical and mental health. Currently, Western medicine's treatment of these problems largely relies on chemical drugs, which can alleviate symptoms to some extent, but their clinical application is limited.

[0003] Traditional Chinese medicine (TCM) has a long history and rich practical experience in the field of emotional regulation. Danzhi Xiaoyao San, a classic formula for improving liver stagnation and fire syndrome, is widely used in the treatment of emotional disorders due to its core effects of soothing the liver, relieving stagnation, clearing heat, and nourishing blood. However, traditional Danzhi Xiaoyao San still has many limitations in practical application: First, the original formula contains peony bark, which is bitter and cold in nature, and long-term use can easily damage the spleen and stomach, making it unsuitable for people with weak spleen and stomach function. While white peony root has the function of nourishing blood and softening the liver, its astringent properties can, to some extent, restrict the formula's core function of soothing the liver and dispersing stagnation, affecting the conditioning effect. Second, traditional Danzhi Xiaoyao San is mostly available in decoctions and pills, which not only have problems with poor taste and inconvenience in carrying and taking, but also, due to limitations in the preparation process, result in low dissolution rate and bioavailability of the active ingredients, making it difficult to fully exert the medicinal effect.

[0004] Modern nutritional and neuroscience research has confirmed that Omega-3 polyunsaturated fatty acids, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are important nutrients for maintaining normal brain nerve function and regulating the body's mood stability. Fish oil, as a core natural source of Omega-3 polyunsaturated fatty acids, has been shown in studies to have good anti-inflammatory activity, and can also target the regulation of neurotransmitter secretion in the brain, showing potential for anti-depression and anti-anxiety.

[0005] Based on the overall mood-regulating advantages of compound extracts and high-EPA mood-regulating fish oil, as well as the targeted neuromodulation characteristics of high-EPA fish oil, the inventors conceived of combining the two to enhance mood regulation through synergistic effects. However, during actual research and development, they discovered technical challenges in their combined application: the active ingredients of traditional Chinese medicine compound formulas like Danzhi Xiaoyao San are mostly water-soluble, resulting in poor compatibility with the lipid-soluble system of fish oil. Direct mixing of the two presents compatibility issues, failing to form a homogeneous and stable mixture, and easily leading to stratification. Simultaneously, high-EPA fish oil is chemically highly unstable, easily oxidized and rancid by external factors such as oxygen, light, and temperature, leading to the loss of its mood-regulating efficacy.

[0006] Based on this, it is of great significance to provide a mood-regulating drug formulation that combines a traditional Chinese medicine compound such as Danzhi Xiaoyao San with fish oil, and effectively improves the compatibility, system stability, and dissolution and absorption of the active ingredients in the combination. Summary of the Invention

[0007] The purpose of this invention is to provide a soft capsule for improving anxiety, its preparation method and application, which effectively improves the compatibility of compound extracts with mood-enhancing fish oil, improves the stability of the oil phase system, and reduces the risk of fish oil oxidative rancidity.

[0008] The objective of this invention is achieved through the following technical solution: A soft capsule for improving anxiety, characterized in that it comprises contents and a single-layer shell enclosing the contents; The contents include compound extracts, phospholipids, and mood-enhancing fish oil; The compound extract is composed of nine medicinal materials: Bupleurum chinense, Salvia miltiorrhiza, Gardenia jasminoides, Angelica sinensis, Atractylodes macrocephala, Poria cocos, dried ginger, Mentha haplocalyx, and Glycyrrhiza uralensis. The mood-enhancing fish oil is a fish oil rich in Omega-3 fatty acids, wherein the total content of Omega-3 fatty acids is ≥75%, the content of EPA is ≥45%, and the mass ratio of EPA to DHA is (2~3):1; The capsule shell comprises chitosan, sodium alginate, rosemary extract microcapsules, vitamin C palmitate, titanium dioxide, and poria cocos polysaccharide. The rosemary extract microcapsules are obtained by microencapsulating rosemary extract with Poria cocos polysaccharide.

[0009] This application can effectively improve the problems mentioned in the background art, such as the poor compatibility between the water solubility of the compound extract and the oil solubility of the fish, as well as the easy occurrence of oxidative rancidity due to high EPA. The specific functions of the relevant components are as follows: Phospholipids: By combining with compound extracts to form traditional Chinese medicine phospholipid complexes, the intermolecular forces at the interface between the two phases are balanced, reducing the stratification phenomenon in the system during preparation, improving the uniformity and stability of the oil phase suspension, and enhancing the self-emulsification ability of the oil phase contents in the gastrointestinal tract, laying the foundation for the absorption of effective ingredients.

[0010] Chitosan and sodium alginate: Although phospholipids can effectively improve the compatibility between compound extracts and fish oil during the preparation stage, two problems still exist in practical application and storage: First, the oil-phase system formed by the traditional Chinese medicine phospholipid complex and the emotional fish oil is prone to oil droplet aggregation during long-term storage, affecting the product's shelf life and quality stability. Second, the target population of this application is individuals with spleen and stomach deficiency and liver stagnation leading to internal heat, characterized by anxiety. These individuals have relatively weak intestinal mucosal adsorption capacity, and relying solely on the self-emulsifying properties of phospholipids is insufficient to improve the slow dispersion and poor absorption of oil droplets. Therefore, this application incorporates chitosan and sodium alginate, which synergistically achieve a dual effect of preventing aggregation during storage and pre-dispersion during the gastrointestinal tract.

[0011] Rosemary extract microcapsules and vitamin C palmitate: The two work together to form an antioxidant barrier in the capsule shell. After being modified by microencapsulation of Poria cocos polysaccharide, the compatibility between rosemary extract and the water-soluble components of the capsule shell can be improved, and the slow release of antioxidant components can be achieved, thus enhancing the long-lasting protective effect.

[0012] Titanium dioxide primarily plays a supporting role in light shielding, working in conjunction with rosemary extract microcapsules to strengthen the antioxidant barrier of the capsule shell and reduce light-induced oxidation of the mood-enhancing fish oil.

[0013] Poria polysaccharides: Poria polysaccharides can regulate the spleen and stomach, protect the intestinal mucosa, and are suitable for people with liver stagnation and fire-induced anxiety due to spleen and stomach deficiency.

[0014] Through the synergistic effect of the above components, the core problems of oxidation of high EPA fish oil and poor stability of the compound oil phase system can be improved, while optimizing the problems of oil phase aggregation and poor absorption by the spleen and stomach.

[0015] Preferably, the raw materials of the compound extract are as follows, by weight: Bupleurum chinense 2-18 parts, Salvia miltiorrhiza 2-18 parts, Gardenia jasminoides 2-10 parts, Angelica sinensis 2-18 parts, Atractylodes macrocephala 5-20 parts, Poria cocos 2-20 parts, Zingiber officinale 2-5 parts, Mentha haplocalyx 5-10 parts, Glycyrrhiza uralensis 2-5 parts.

[0016] Preferably, the raw materials of the compound extract are as follows, by weight: Bupleurum chinense 15 parts, Salvia miltiorrhiza 15 parts, Gardenia jasminoides 10 parts, Angelica sinensis 15 parts, Atractylodes macrocephala 20 parts, Poria cocos 15 parts, Zingiber officinale 5 parts, Mentha haplocalyx 10 parts, Glycyrrhiza uralensis 5 parts.

[0017] Preferably, the phospholipid is a high-purity phospholipid with a soybean phosphatidylcholine (PC) content of ≥90%; the mass ratio of the compound extract, phospholipid and fish oil is 1:(1~3):(0.5~3).

[0018] Preferably, the rosemary extract microcapsules have a particle size of 1~10μm and a microcapsule encapsulation rate of 80%~95%.

[0019] Preferably, by mass, the ratio of chitosan:sodium alginate:rosemary extract microcapsules:vitamin C palmitate:titanium dioxide:poria polysaccharide is (3~5):(1~2):(0.4~0.8):(0.3~0.5):(0.1~0.3):(1.0~2.0). The titanium dioxide content is controlled within a reasonable range of 0.1% to 0.3%, which avoids insufficient light-blocking effect due to low addition and the drawbacks of excessively high addition such as capsule embrittlement and rapid disintegration. This meets the requirement for rapid dissolution of the oil phase contents, ensuring that the active ingredients can be absorbed and utilized by the intestines in a timely manner.

[0020] Preferably, the chitosan in the capsule shell material is polyethylene glycol (PEG) modified chitosan. This application has found that the chitosan in the capsule shell contains a large number of free amino groups, which readily undergo strong ion adsorption with the phosphate groups of phospholipids in the contents, leading to a decrease in the self-emulsification efficiency of phospholipids. In the unique ionic environment of gastrointestinal fluid in individuals with weak spleen and stomach, this phenomenon is amplified, further affecting the oil droplet dispersion efficiency and absorption effect. To solve this problem, this application grafts PEG onto chitosan, introducing PEG chains onto the chitosan molecular chain. Utilizing its steric hindrance effect, PEG chains shield the positively charged adsorption sites of chitosan, eliminating ion adsorption and improving the self-emulsification efficiency of phospholipids.

[0021] In addition, this application also provides a method for preparing a soft capsule for improving anxiety, comprising the following steps: S1. Preparation of contents: S11. Take 9 medicinal materials, extract volatile oil by steam distillation, extract the residue by decoction, centrifuge and filter the decoction, combine it with the saturated aqueous solution of volatile oil, concentrate and dry to obtain fluid extract; S12. Preparation of traditional Chinese medicine-phospholipid complex: The fluid extract obtained in step S11 is mixed with high-purity phospholipids, an organic solvent is added, and the mixture is stirred at a constant temperature under nitrogen protection and light protection. After removing the solvent by rotary evaporation under reduced pressure, the mixture is cooled to obtain the traditional Chinese medicine-phospholipid complex. S13. Preparation of oil phase suspension: Add the traditional Chinese medicine-phospholipid complex to the fish oil, stir and mix at a constant temperature of 50°C to obtain a uniform and stable oil phase suspension. S2. Preparation of capsule shell solution: Chitosan, sodium alginate, rosemary extract microcapsules, vitamin C palmitate, titanium dioxide, poria cocos polysaccharide, gelatin, glycerin and purified water are mixed to prepare capsule shell solution; S3. Preparation of soft capsules: Using a soft capsule pelletizing machine, the capsule shell liquid is wrapped in an oil phase suspension, pelletized and dried to obtain soft capsules.

[0022] Furthermore, this application also provides its use in the preparation of oral medications for improving anxiety states caused by liver stagnation and internal heat.

[0023] Compared with the prior art, the beneficial effects of the present invention are: 1. The compound extract (9 medicinal herbs) provided in this application is a modified version of the classic formula Danzhi Xiaoyao San. Combining this modified formula with mood-enhancing fish oil can effectively improve anxiety. Specifically, the compound extract replaces peony bark in the original formula with danshen (Salvia miltiorrhiza). Danshen has the effects of promoting blood circulation, removing blood stasis, clearing the mind, and relieving irritability. Compared to the heat-clearing and blood-cooling effects of peony bark, it enhances the core effects of the entire formula in soothing the liver, relieving depression, promoting blood circulation, and calming the mind, thus meeting the emotional regulation needs of people with anxiety and helping to improve anxiety-related symptoms. Removing the astringent white peony root from the original formula avoids its astringent properties from hindering the overall effect of soothing the liver and dispersing stagnation, while making the entire formula more mild and reducing potential irritation to the spleen and stomach from long-term use, thus lowering the potential risks of long-term use and making it more suitable for long-term use by people with anxiety. The combination of these two ingredients achieves a synergistic effect of overall regulation by traditional Chinese medicine and targeted regulation of brain function by Omega-3 fatty acids, helping to better improve anxiety and further enhance the conditioning effect of anxiety.

[0024] 2. This application incorporates phospholipids during the preparation of the compound extract and the emotional fish oil, allowing them to combine with the compound extract to form a traditional Chinese medicine phospholipid complex. This reduces system stratification during preparation, improves the uniformity and stability of the oil phase suspension, and enhances the self-emulsification ability of the oil phase contents in the gastrointestinal tract, alleviating the problem of incompatibility between water-soluble and lipid-soluble components. By preparing each component into a soft capsule dosage form, the capsule shell protects the contents, reducing the impact of external factors on the high-EPA emotional fish oil and lowering its probability of oxidative rancidity. The addition of chitosan and sodium alginate to the soft capsule shell further optimizes the phospholipid effect, reducing oil droplet aggregation and stratification during long-term storage, while improving oil droplet dispersion and absorption in the gastrointestinal tract, thus meeting the needs of the target population. The addition of rosemary extract microcapsules and vitamin C to the capsule shell further enhances the phospholipid effect. Palmitate and titanium dioxide, along with rosemary extract modified by microencapsulation with Poria cocos polysaccharide, improve compatibility with the capsule shell and achieve slow release. These two components synergistically form an antioxidant barrier, while titanium dioxide assists in light shielding and enhances the antioxidant effect, further mitigating the problem of oxidative rancidity in high-EPA fish oil. By adding Poria cocos polysaccharide to the capsule shell, it synergistically improves absorption efficiency with chitosan and sodium alginate. Furthermore, this application uses a soft capsule dosage form, solving the problems of poor taste, inconvenience in carrying and taking traditional Danzhi Xiaoyao San decoctions and pills.

[0025] In summary, the synergistic effect of the components can effectively improve the problems existing in the background technology, such as the poor compatibility between the water solubility of the compound extract and the oil solubility of the fish oil, and the easy oxidation and rancidity of the fish oil. Detailed Implementation

[0026] Example 1 S1. Preparation of contents: S11. By weight, take 15 parts of Bupleurum chinense, 15 parts of Salvia miltiorrhiza, 10 parts of Gardenia jasminoides, 15 parts of Angelica sinensis, 20 parts of Atractylodes macrocephala, 15 parts of Poria cocos, 5 parts of dried ginger, 10 parts of Mentha haplocalyx, and 5 parts of Glycyrrhiza uralensis. Grind the above medicinal materials into 100 mesh and mix them evenly. Add them to a 1000 ml round-bottom distillation flask and add 8 times the amount of distilled water (based on the total mass of the ground medicinal materials, g:ml=1:8). Extract the volatile oil by steam distillation for 6 hours. Collect the volatile oil through a volatile oil extractor and retain the saturated aqueous solution with a small amount of dissolved volatile oil in the lower layer. After distillation, decoct the residue twice. For the first decoction, add 8 times the amount of distilled water (based on the total mass of the ground medicinal materials, g:ml=1:8) and decoct for 1.5 hours. For the second decoction, add 6 times the amount of distilled water. Add double the amount of water (based on the total mass of the pulverized medicinal materials, g:ml=1:6), decoct for 1 hour, combine the two decoctions, centrifuge at 3000 r / min for 15 min, filter through a 120 mesh filter, take the filtrate and combine it with the above saturated aqueous solution of volatile oil, concentrate under vacuum at 60℃ to a thick paste, and then dry in a vacuum drying oven at 60℃ and a vacuum degree of -0.08~-0.10 MPa to obtain the compound extract.

[0027] S12. Preparation of traditional Chinese medicine-phospholipid complex: Take the compound extract obtained above and mix it with high-purity soybean phosphatidylcholine (PC content ≥90%) (the weight ratio of compound extract to high-purity soybean phosphatidylcholine is 1:1). Add 60 ml of anhydrous ethanol, sonicate for 15 min (power 300W, room temperature), and then place it in a nitrogen-protected, light-protected reaction device. Stir at 40℃ for 3 h at a stirring speed of 300 r / min. After stirring, remove the anhydrous ethanol by rotary evaporation under reduced pressure at 40℃. After cooling, the traditional Chinese medicine-phospholipid complex is obtained.

[0028] S13. Preparation of oil phase suspension: Add emotional fish oil (the mass ratio of compound extract to emotional fish oil is 1:2, and the emotional fish oil contains 50% EPA, 3:1 EPA to DHA, and 80% Omega-3 fatty acids by total mass of emotional fish oil) to the above-mentioned traditional Chinese medicine-phospholipid complex, place it in a 50℃ constant temperature water bath stirring pot, and stir at 200r / min to obtain an oil phase suspension.

[0029] S2. Preparation of capsule shell solution: Weigh each component according to the mass ratio of chitosan:sodium alginate:rosemary extract microcapsules:vitamin C palmitate:titanium dioxide:poria polysaccharide:gelatin:glycerol:purified water = 5:2:0.8:0.5:0.3:2.0:40:20:40, add them to a mixing tank and stir at 70℃ until all components are completely dissolved. The stirring speed is 250r / min to prepare the capsule shell solution. The capsule shell solution is pasteurized and then cooled. S3. Preparation of soft capsules: Using a fully automatic soft capsule compression machine, the cooled capsule shell liquid is wrapped in an oil phase suspension and compressed into oval soft capsules. The thickness of the capsule shell is controlled at 0.3 mm, and the content of each soft capsule is 800 mg. After compression, the soft capsules are placed in a shaping tray for shaping. After washing and screening, they are first dried at 25℃ and RH60% for 12 h, and then dried at 35℃ and RH40% for 12 h. Afterwards, they are sterilized with ethylene oxide to obtain compound soft capsules.

[0030] The preparation method of the above-mentioned rosemary extract microcapsules is as follows: Rosemary extract and Poria cocos polysaccharide are mixed at a mass ratio of 3:8, and an appropriate amount of purified water is added (solid-liquid ratio 1:50~1:80, g:ml). The mixture is placed in a constant temperature water bath at 30~40℃ and stirred at 200r / min until completely dissolved to obtain a rosemary extract-Poria cocos polysaccharide mixture. The mixture is subjected to high-speed shearing or ultrasonic emulsification to form a stable emulsion system. The mixture is then transferred to a freeze dryer, first frozen at -40℃ for 10h, and then freeze-dried at ≤35℃ and vacuum degree -0.08~-0.10MPa for 24h. After removal, the mixture is pulverized to obtain rosemary extract microcapsules with a particle size of 1~10μm (encapsulation rate 95%).

[0031] Example 2 Compared to Example 1, the following parameters were adjusted, while the remaining parameters, preparation steps, and process conditions were completely consistent with Example 1: (1) By weight, take 18 parts of Bupleurum chinense, 15 parts of Salvia miltiorrhiza, 5 parts of Gardenia jasminoides, 5 parts of Angelica sinensis, 18 parts of Atractylodes macrocephala, 12 parts of Poria cocos, 5 parts of dried ginger, 8 parts of Mentha haplocalyx and 5 parts of Glycyrrhiza uralensis.

[0032] (2) When preparing the traditional Chinese medicine-phospholipid complex, the weight ratio of the compound extract to high-purity soybean phosphatidylcholine is 1:1.1, and 65 ml of anhydrous ethanol is added; (3) When preparing the oil phase suspension, the parameters of the emotional fish oil are: based on the total mass of the emotional fish oil, the EPA content is 45%, the mass ratio of EPA to DHA is 2:1, and the total content of Omega-3 fatty acids is 80%.

[0033] (4) Weigh the components of the capsule shell according to the following mass ratio: chitosan: sodium alginate: rosemary extract microcapsules: vitamin C palmitate: titanium dioxide: poria cocos polysaccharide: gelatin: glycerin: purified water = 4:1.5:0.6:0.4:0.2:1.5:40:20:40.

[0034] Example 3 Compared to Example 1, the following parameters were adjusted, while the remaining parameters, preparation steps, and process conditions were completely consistent with Example 1: (1) By weight, take 15 parts of Bupleurum chinense, 12 parts of Salvia miltiorrhiza, 10 parts of Gardenia jasminoides, 18 parts of Angelica sinensis, 20 parts of Atractylodes macrocephala, 10 parts of Poria cocos, 2 parts of dried ginger, 5 parts of Mentha haplocalyx and 5 parts of Glycyrrhiza uralensis.

[0035] (2) Preparation of traditional Chinese medicine-phospholipid complex: The weight ratio of compound extract to high-purity soybean phosphatidylcholine is 1:1.4, and 70 ml of anhydrous ethanol is added; (3) When preparing the oil phase suspension, the total content of Omega-3 fatty acids in the emotional fish oil is 75%.

[0036] (4) Weigh the components of the capsule shell according to the following mass ratio: chitosan: sodium alginate: rosemary extract microcapsules: vitamin C palmitate: titanium dioxide: poria cocos polysaccharide: gelatin: glycerin: purified water = 3:1:0.4:0.3:0.1:1.0:40:20:40.

[0037] Example 4 Compared to Example 1, the chitosan in the capsule shell material was replaced with an equal mass of PEG-2000 modified chitosan, while the remaining parameters, preparation steps, component ratios, and process parameters were the same as in Example 1.

[0038] The preparation method of the PEG-2000 modified chitosan is as follows: Prepare materials according to the mass ratio of chitosan: PEG2000: succinic anhydride: citric acid = 100:55:5:9.

[0039] Take PEG2000, succinic anhydride and citric acid accounting for 10% of the total mass of citric acid, place them in a 65℃ constant temperature water bath, and stir magnetically for 10 min until they melt into a transparent liquid to obtain carboxylated PEG2000 melt. Take chitosan and the remaining 90% citric acid, add purified water (solid-liquid mass-volume ratio 1:20, g:mL), and stir at 200 r / min for 30 min at room temperature until the chitosan is completely dissolved to obtain a chitosan-citric acid aqueous solution.

[0040] The molten carboxylated PEG2000 was rapidly poured into a chitosan-citric acid aqueous solution, and the mixture was stirred at 200 r / min at room temperature for 30 min to obtain a crude solution. Then, two volumes of food-grade 95% ethanol were added to the crude solution, and the mixture was stirred for 5 min before being filtered through an 80-mesh filter to collect the precipitated wet product. The wet product was then dried in a vacuum drying oven at 40℃ and a vacuum degree of -0.08 to -0.10 MPa for 4 h until constant weight was obtained, yielding PEG2000-grafted modified chitosan. The grafting rate of the obtained PEG2000-grafted modified chitosan was found to be 55%–60%.

[0041] Comparative Example 1 Compared to Example 1, the emotional fish oil was removed, but the remaining preparation steps, component ratios, and process parameters were the same as in Example 1.

[0042] Comparative Example 2 Compared to Example 1, chitosan and sodium alginate were removed, while the remaining preparation steps, component ratios, and process parameters were the same as in Example 1.

[0043] Comparative Example 3 Compared to Example 1, the rosemary extract microcapsules in the capsule shell solution were replaced with an equal mass of unmicroencapsulated rosemary extract, while the remaining preparation steps, component ratios, and process parameters were the same as in Example 1.

[0044] Comparative Example 4 Compared to Example 1, the phospholipid component was removed, but the remaining preparation steps, component ratios, and process parameters were the same as in Example 1.

[0045] Comparative Example 5 Compared to Example 1, the capsule shell adhesive solution was replaced with a conventional adhesive solution composed only of gelatin, glycerin, and purified water in a mass ratio of 40:20:40. At the same time, the capsule shell thickness was kept the same as in Example 1, and the remaining preparation steps, component ratios, and process parameters were consistent with those in Example 1.

[0046] Experimental Example 1. Verification of the effect of anxiety reduction.

[0047] Eighty healthy SPF-grade male ICR mice, weighing 18–22 g, were randomly divided into 8 groups of 10 mice each. There was no statistically significant difference in body weight between groups (P>0.05). After 7 days of acclimatization, the mice were used in the experiment. All 8 groups of mice were administered the drug orally once daily for 14 consecutive days (details of the medication are shown in Table 1). One hour after the last administration, an elevated cruciate maze test was performed: the percentage of mice entering the open arm (OE%) and the percentage of time spent in the open arm (OT%) were recorded during the 5-minute test period to evaluate anxiety-like behavior (results are shown in Table 2).

[0048] During the period, the animals' appearance, behavior, secretions, excrement, mortality, and weight changes were recorded. On the 14th day, all surviving animals were euthanized and gross dissections were performed to observe whether there were any visible lesions in the major organs (heart, liver, spleen, lungs, and kidneys) (the results are shown in Table 2).

[0049] Table 1: Experimental Groups and Drug Dosage Table Table 2: Results of Detection of Anxiety-like Behavior and Organ Lesions in Rats In this context, "*" indicates that compared with the control group, P<0.05, indicating a statistically significant difference.

[0050] Tables 1 and 2 show that the soft capsules prepared in Examples 1-4 of this invention significantly increased the proportion of mice entering the open arm (OE%) and the proportion of time spent in the open arm (OT%) (P<0.05), demonstrating a clear anti-anxiety effect. Comparative Example 1, without fish oil, showed a poor effect in improving anxiety-like behavior in mice. Comparative Example 4, due to the absence of phospholipids, could not resolve the compatibility issue between the compound extract and fish oil, making it difficult for the effective components to fully exert their effects, thus failing to show a significant anti-anxiety effect. Throughout the administration period, the mice in each dosage group were in good general condition, with normal activity levels and coat luster, no abnormalities in feeding or defecation, and no animal deaths. The weight gain curves of the mice were basically consistent with the control group, with no statistically significant difference between groups (P>0.05). After the last administration, the mice were sacrificed for gross necropsy. Macroscopic observation revealed that the appearance, size, and color of the heart, liver, spleen, lungs, kidneys, gastrointestinal tract, brain, and reproductive organs of all groups were normal, without any visible pathological changes such as swelling, atrophy, hemorrhage, adhesion, or necrosis.

[0051] 2. Comprehensive verification of core performance.

[0052] The following experiments were conducted to verify the effectiveness of the finished products prepared in Examples 1-4 and Comparative Examples 1-6 in addressing key issues such as water-lipid compatibility, long-term system stability, fish oil antioxidant properties, and gastrointestinal fluid oil droplet dispersion: (1) Oil phase dispersibility: After standing at room temperature for 6 hours, observe the layering / agglomeration of oil phase suspensions in Examples 1-4 and Comparative Examples 1-6, and rate them as Grade A (no / slight layering, no agglomeration), Grade B (obvious layering, small amount of agglomeration), and Grade C (severe layering, large amount of agglomeration); (2) Long-term stability: The finished soft capsules were stored at 25℃±2℃ and RH60%±5% for 6 months. The soft capsules were first artificially broken, and the internal oil phase suspension was taken out and the average particle size of the oil droplets was measured by a laser particle size analyzer. (3) Antioxidant properties of fish oil: The finished soft capsules were accelerated to oxidation at 40℃±2℃ and RH75%±5% for 30 days. The soft capsules were first artificially broken, and the internal oil phase suspension was taken out. The fish oil was then further extracted and the peroxide value was tested (POV≤0.25g / 100g indicates that no oxidative rancidity has occurred).

[0053] (4) Gastrointestinal fluid dispersion efficiency: The soft capsule was first artificially ruptured, and the internal oil phase suspension was added to artificial intestinal fluid (pH 6.8, suitable for people with weak spleen and stomach). The gastrointestinal peristalsis was simulated at 37℃ for 20 minutes, and the average particle size of oil droplets and the proportion of oil droplets ≤1μm were measured by laser particle size analyzer.

[0054] Table 3: Comprehensive Verification Results of Core Performance Table 3 shows that: Examples 1-3 effectively improved the problems of poor compatibility between the compound extract and the oil-soluble fish, easy stratification and aggregation of the oil phase system, easy oxidation and rancidity of fish oil, and low gastrointestinal absorption efficiency in people with weak spleen and stomach. The oil phase dispersibility of all three reached Grade A, with no obvious stratification and aggregation within 6 hours of standing at room temperature, maintaining a uniform system suitable for formulation production; after long-term storage for 6 months, the average particle size of oil droplets was ≤2.7μm, ensuring the stability of the system within the product's shelf life; after 30 days of accelerated oxidation of fish oil, the peroxide value was ≤0.14g / 100g, reducing the risk of oxidative deterioration of fish oil; after 20 minutes in the gastrointestinal fluid environment, the average particle size of oil droplets was ≤1.7μm, and the proportion of oil droplets ≤1μm was ≥78%, optimizing the dispersion state of the effective ingredients to meet the absorption needs of people with weak spleen and stomach; the various performance indicators synergistically complement each other, suitable for long-term conditioning scenarios for people with liver stagnation and fire-type anxiety.

[0055] Example 4: Based on Example 1, PEG-2000 modified chitosan was used. The PEG chains on its surface shielded the positively charged adsorption sites, reducing the ion adsorption with phospholipids. Therefore, the self-emulsification efficiency of phospholipids was effectively improved, enhancing the dispersion stability of the system and the dispersion efficiency of gastrointestinal fluid oil droplets. This is more suitable for conditioning scenarios for people with weak spleen and stomach and anxiety who have high requirements for absorption.

[0056] In Comparative Example 2, the removal of chitosan and sodium alginate prevented the stabilization of the oil phase system and the pre-dispersion of oil droplets in the gastrointestinal fluid, resulting in poor system stability and gastrointestinal absorption efficiency, making it difficult to solve the problems of long-term storage stratification and insufficient absorption. In Comparative Example 3, the lack of microencapsulation modification of the rosemary extract led to poor compatibility with the water-soluble components of the capsule shell, easily affecting the slow release of antioxidant components, weakening the antioxidant barrier effect of fish oil, and significantly impacting its oxidative protection performance. In Comparative Example 4, the absence of phospholipid components prevented the balance of water-lipid interfacial forces, resulting in decreased oil phase dispersibility, stability, and gastrointestinal dispersion efficiency, making it difficult to solve the compatibility problem between the compound extract and fish oil. In Comparative Example 5, the use of conventional capsule shell gel instead of functional composite capsule shells resulted in the lack of functional components such as antioxidants and stabilizing dispersants, leading to poor system stability and antioxidant effect of fish oil, making it difficult to solve the problem of synergistic protection and enhancement of multiple components.

Claims

1. A soft capsule for improving anxiety, characterized in that, Includes the contents and a single-layered capsule surrounding the contents; The contents include compound extracts, phospholipids, and mood-enhancing fish oil; The compound extract is composed of nine medicinal materials: Bupleurum chinense, Salvia miltiorrhiza, Gardenia jasminoides, Angelica sinensis, Atractylodes macrocephala, Poria cocos, dried ginger, Mentha haplocalyx, and Glycyrrhiza uralensis. The mood-enhancing fish oil is a fish oil rich in Omega-3 fatty acids, wherein the total content of Omega-3 fatty acids is ≥75%, the content of EPA is ≥45%, and the mass ratio of EPA to DHA is (2~3):1; The capsule shell comprises chitosan, sodium alginate, rosemary extract microcapsules, vitamin C palmitate, titanium dioxide, and poria cocos polysaccharide. The rosemary extract microcapsules are obtained by microencapsulating rosemary extract with Poria cocos polysaccharide.

2. The soft capsule for improving anxiety according to claim 1, characterized in that, The raw materials of the compound extract are as follows, by weight: Bupleurum chinense 2-18 parts, Salvia miltiorrhiza 2-18 parts, Gardenia jasminoides 2-10 parts, Angelica sinensis 2-18 parts, Atractylodes macrocephala 5-20 parts, Poria cocos 2-20 parts, Zingiber officinale 2-5 parts, Mentha haplocalyx 5-10 parts, Glycyrrhiza uralensis 2-5 parts.

3. The soft capsule for improving anxiety according to claim 1, characterized in that, The raw materials of the compound extract are as follows, by weight: Bupleurum chinense 15 parts, Salvia miltiorrhiza 15 parts, Gardenia jasminoides 10 parts, Angelica sinensis 15 parts, Atractylodes macrocephala 20 parts, Poria cocos 15 parts, Zingiber officinale 5 parts, Mentha haplocalyx 10 parts, Glycyrrhiza uralensis 5 parts.

4. The soft capsule for improving anxiety according to claim 1, characterized in that, The phospholipids are high-purity phospholipids with a soybean phosphatidylcholine content of ≥90%; the mass ratio of the compound extract, phospholipids and fish oil is 1:(1~3):(0.5~3).

5. The soft capsule for improving anxiety according to claim 1, characterized in that, The rosemary extract microcapsules have a particle size of 1~10μm and a microcapsule encapsulation rate of 80%~95%.

6. The soft capsule for improving anxiety according to claim 1, characterized in that, By weight, chitosan: sodium alginate: rosemary extract microcapsules: vitamin C palmitate: titanium dioxide: poria cocos polysaccharide = (3~5): (1~2): (0.4~0.8): (0.3~0.5): (0.1~0.3): (1.0~2.0).

7. The soft capsule for improving anxiety according to claim 1, characterized in that, The chitosan in the shell material is polyethylene glycol modified chitosan.

8. A method for preparing a soft capsule for improving anxiety as described in any one of claims 1-7, characterized in that, Includes the following steps: S1. Preparation of contents: S11. Take 9 medicinal materials, extract volatile oil by steam distillation, extract the residue by decoction, centrifuge and filter the decoction, combine it with the saturated aqueous solution of volatile oil, concentrate and dry to obtain fluid extract; S12. Preparation of traditional Chinese medicine-phospholipid complex: The fluid extract obtained in step S11 is mixed with phospholipids, an organic solvent is added, and the mixture is stirred at a constant temperature under nitrogen protection and light protection. After removing the solvent by rotary evaporation under reduced pressure, the mixture is cooled to obtain the traditional Chinese medicine-phospholipid complex. S13. Preparation of oil phase suspension: Add the traditional Chinese medicine-phospholipid complex to the fish oil, stir and mix at a constant temperature of 50°C to obtain an oil phase suspension; S2. Preparation of capsule shell solution: Chitosan, sodium alginate, rosemary extract microcapsules, vitamin C palmitate, titanium dioxide, poria cocos polysaccharide, gelatin, glycerin and purified water are mixed to prepare capsule shell solution; S3. Preparation of soft capsules: Using a soft capsule pelletizing machine, the capsule shell liquid is wrapped in an oil phase suspension, pelletized and dried to obtain soft capsules.

9. The use of a soft capsule for improving anxiety state as described in any one of claims 1 to 7 in the preparation of an oral pharmaceutical formulation for improving anxiety state caused by liver stagnation and internal heat.

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