Composition for treating insomnia, preparation method and application thereof

Abstract

The present invention provides a composition for treating insomnia, a preparation method thereof and an application thereof, and belongs to the field of pharmaceutical technology. Ginseng is fermented, ionic liquid is separated to obtain total ginsenosides, the remaining ginseng residue is mixed with Ziziphus jujuba, Bupleurum and Panax ginseng, and extracted with boiling water to obtain a Chinese medicine water extract, the remaining residue is fermented to obtain a Chinese medicine fermentation product, the fermented bacteria are embedded to obtain embedded probiotics, berberine / zopiclone / agomelatine cocrystal is prepared, and the eutectic is ball-milled and mixed with total ginsenosides, Chinese medicine water extract, Chinese medicine fermentation extract and embedded probiotics, added to polyacrylic acid resin and sodium alginate solution, and dripped into cold water to obtain a composition for treating insomnia, which can improve the distribution of intestinal flora, improve oxidative stress, reduce inflammatory response, promote sleep, improve sleep quality, have the effects of calming the nerves, soothing the liver and relieving depression, can significantly improve the symptoms of patients with sleep disorders and depressive insomnia, has small side effects, is safe to use, and has broad application prospects.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and in particular to a composition for treating insomnia, a preparation method thereof and an application thereof. Background Art

[0002] Insomnia is a common sleep disorder. Impaired daytime function is the main reason for patients to seek medical treatment. Improving sleep quality and restoring daytime function is the expected treatment goal for patients. However, insomnia is not only a sleep problem. Chronic insomnia, in particular, has the risk of leading to major diseases (such as anxiety, depression, hypertension, diabetes, cancer, etc.), and is often comorbid with physical and mental illnesses. Drug therapy is the most widely used clinical treatment for insomnia. How to choose the right drug for the patient to achieve treatment expectations and reduce the risk of comorbidities is a common confusion faced by clinicians.

[0003] At present, the commonly used sleeping pills in clinical practice include benzodiazepines, barbiturates and other non-barbiturates. The effect of treating insomnia is relatively obvious, but it has a great impact on the liver and kidneys. The user is prone to dependence on the drug. Usually, the drug dosage must be continuously increased to maintain the effect. In addition, it will produce great toxic side effects, so it is not suitable for long-term use. Some people who take large amounts of drugs for a long time will also experience nausea or vomiting, coarse tremors of the hands, tongue and eyelids, behavioral disorders, hallucinations, and even epileptic seizures if the dosage is suddenly reduced or stopped. Traditional Chinese medicine believes that insomnia is mostly caused by improper diet that damages the spleen and stomach, weakens the spleen's transportation and transformation function, causes phlegm turbidity, long-term accumulation and fire, phlegm and fire intertwined, internal disturbance of the mind and emotions, liver depression and fire, internal disturbance of phlegm and heat, yin deficiency and fire, heart and spleen deficiency, heart and gallbladder qi deficiency, etc.

[0004] Chinese invention patent CN103463354B discloses a Chinese medicine composition for treating insomnia, which comprises, by weight: 15-25 parts of Platycodon grandiflorum, 9-17 parts of Polygala tenuifolia, 9-20 parts of Moutan bark, 10-20 parts of Bupleurum chinense, 5-12 parts of Citrus aurantium, 10-25 parts of Angelica sinensis, 10-20 parts of Ligusticum chuanxiong, 20-35 parts of Pueraria root, 25-40 parts of White Peony Root, 9-18 parts of Cyperus rotundus, 10-19 parts of Notopterygium wilfordii, 16-25 parts of Pheretima chinensis, 10-20 parts of Achyranthes bidentata and 20-36 parts of Polygonum multiflorum. According to the theory of traditional Chinese medicine, the Chinese medicine composition has a curative effect on insomnia. Chinese invention patent CN 103372071 B discloses a pharmaceutical composition for treating insomnia, which uses Radix Glehniae, Semen Ziziphi Spinosae, Polygala Tenuifolia, Mother of Pearl, Acanthopanax Senticosus, Fructus Schisandrae Chinensis, and Rhizoma Chuanxiong as raw materials, and is prepared into any commonly used oral preparation according to the conventional preparation method of modern preparation technology, which has the effects of clearing away heat and calming the liver, nourishing the heart and calming the mind, and can improve insomnia, dreaminess, forgetfulness, irritability, dry mouth, slight bitterness, headache, dizziness, palpitations, shortness of breath, spontaneous sweating and fatigue. It has a definite and significant effect on insomnia caused by liver and gallbladder heat and restlessness.

[0005] However, the pharmaceutical compositions of the above invention patents have the disadvantages of complex formulation, unclear effective ingredients, large dosage, slow onset of effect, short efficacy time, poor efficacy, etc., and still cannot meet the current market demand. Summary of the invention

[0006] The purpose of the present invention is to provide a composition for treating insomnia, a preparation method thereof and an application thereof, which can improve the distribution of intestinal flora, improve oxidative stress, reduce inflammatory response, promote sleep, improve sleep quality, have the effects of calming the mind, soothing the liver and relieving depression, can significantly improve the symptoms of patients with sleep disorders and depressive insomnia, has little side effects, is safe to use, and has broad application prospects.

[0007] The technical solution of the present invention is achieved in this way:

[0008] The invention provides a preparation method of a composition for treating insomnia. The method comprises the following steps: fermenting ginseng, separating ginsenosides by ionic liquid, mixing remaining ginseng residues with spiny jujube seeds, bupleurum and Panax ginseng, extracting by boiling water to obtain a Chinese medicine water extract, fermenting remaining residues to obtain a Chinese medicine fermentation product, embedding fermented bacteria to obtain embedded probiotics, preparing berberine / zopiclone / agomelatine cocrystals, mixing with ginsenosides, Chinese medicine water extracts, Chinese medicine fermentation extracts and embedded probiotics by ball milling, adding the mixture to polyacrylic acid resin and sodium alginate solution, dropping the mixture into cold water, centrifuging, collecting particles, washing and drying the particles to obtain the composition for treating insomnia.

[0009] As a further improvement of the present invention, the following steps are included:

[0010] S1. Fermentation of ginseng: Ginseng was crushed, added to water, inoculated with long bifidobacterium seed solution, fermented, filtered, washed with residue, the eluate was collected and concentrated to obtain a first bacterial solution, and the remaining solid was dried to obtain ginseng residue; the filtrate was ginseng fermentation liquid;

[0011] S2. Extraction of total ginsenosides: The ginseng fermentation liquid obtained in step S1 was added to the ionic liquid, carbon dioxide was introduced, the extraction was stirred, ventilation was stopped, stratification was allowed to stand, the ionic liquid layer was collected, the carbon dioxide was heated to escape, the organic layer was collected, the solvent was removed under reduced pressure, and dried to obtain total ginsenosides;

[0012] S3. Water extraction of Chinese medicine: The ginseng residue, jujube seed, bupleurum, and spiny ginseng in step S1 were mixed and crushed to obtain a Chinese medicine powder, added to water, heated to boiling for extraction, filtered, the residue was retained, and the filtrate was dried to obtain a Chinese medicine aqueous extract;

[0013] S4. Fermentation of Chinese medicine: adding the filter residue obtained in step S3 to water, sterilizing, inoculating Lactobacillus bulgaricus and Lactobacillus acidophilus seed solution, fermenting, filtering, washing the filter residue, collecting and concentrating the eluate to obtain a second bacterial solution, freeze-drying the filtrate to obtain a fermented Chinese medicine extract;

[0014] S5. Encapsulation of probiotics: The first bacterial solution in step S1 and the second bacterial solution in step S4 are mixed, added to milk, and the mixture is dropped into the acid solution with a syringe, allowed to stand, centrifuged, the particles are collected, and washed with acid to obtain encapsulated probiotics;

[0015] S6. Preparation of berberine / zopiclone / agomelatine cocrystal: dissolving berberine in hot water to obtain solution A; dissolving zopiclone in acetic acid solution to obtain solution B; dissolving agomelatine in ethanol to obtain solution C; mixing solution A, solution B and solution C evenly, leaving the mixture open to evaporate the solvent, filtering, washing and drying to obtain berberine / zopiclone / agomelatine cocrystal;

[0016] S7. Secondary embedding: mix the ginsenosides prepared in step S2, the Chinese herbal medicine water extract prepared in step S3, the Chinese herbal medicine fermentation extract prepared in step S4, the embedded probiotics prepared in step S5, and the berberine / zopiclone / agomelatine cocrystal prepared in step S6, ball-mill them evenly, add them to an ethanol aqueous solution, add polyacrylic acid resin and sodium alginate, heat and stir to mix evenly, drop them into cold water with a syringe, centrifuge, collect the particles, wash, and dry them to obtain a composition for treating insomnia.

[0017] As a further improvement of the present invention, the bacterial content of the long bifidobacterium seed solution in step S1 is 10 8 -10 9 cfu / mL, the inoculation amount is 1-3v / v%, the fermentation culture conditions are 36-38°C, 100-200r / min, under anaerobic conditions, the fermentation culture is 24-36h, the mass ratio of ginseng to water is 1-3:10, the bacterial content of the first bacterial liquid is 10 11 -10 12 cfu / mL; the mass ratio of the ginseng fermentation broth and the ionic liquid in step S2 is 1-3:2-4, the ionic liquid is selected from at least one of 1-butyl-3-methylimidazolium bistrifluoromethanesulfonyl imide salt, 1-butyl-3-methylimidazolium hexafluoroantimonate, 1-hexyl-3-methylimidazolium hexafluoroantimonate, 1-hexyl-3-methylimidazolium hexafluorophosphate, and 1-hexyl-3-methylimidazolium tetrafluoroborate, the amount of carbon dioxide introduced is 2-4mL / s, and the heating temperature is 50-60°C for 20-30min.

[0018] As a further improvement of the present invention, the mass ratio of ginseng residue, spiny jujube seed, bupleurum, and spiny ginseng in step S3 is 5-7:12-17:3-5:1-2, the solid-liquid ratio of the Chinese medicine powder and water is 1:3-5 g / mL, and the heating and boiling extraction time is 2-4 h; the mass ratio of the filter residue and water in step S4 is 15-20:100, and the bacterial content of the bacterial seed liquid is 10 8 -10 9 cfu / mL, the inoculation amounts of the Lactobacillus bulgaricus and Lactobacillus acidophilus seed solutions were 2-4 v / v% and 1-2 v / v%, respectively, the fermentation culture conditions were 36-38°C, 100-200 r / min, under anaerobic conditions, the fermentation culture was performed for 36-48 h, and the bacterial content of the second bacterial solution was 10 11 -10 12 cfu / mL.

[0019] As a further improvement of the present invention, in step S5, the mass ratio of the first bacterial liquid, the second bacterial liquid, the milk, and the acid solution is 10-15:12-17:60-70:200, and the acid solution is an aqueous solution with a pH value of 3.8-4.2.

[0020] As a further improvement of the present invention, in step S6, the mass ratio of berberine, zopiclone and agomelatine is 7-10:1-2:0.5-1, the temperature of the hot water is 70-80°C, the concentration of the acetic acid solution is 10-15wt%, and the time of standing open to volatilize the solvent is 5-7 days.

[0021] As a further improvement of the present invention, the mass ratio of the total ginsenosides of Panax ginseng, the Chinese herbal medicine water extract, the Chinese herbal medicine fermentation extract, the embedded probiotics, the berberine / zopiclone / agomelatine cocrystal, the ethanol aqueous solution, the polyacrylic acid resin, and the sodium alginate in step S7 is 1-2:3-5:4-7:2-4:0.2-0.4:100:17-20:7-10, the ball milling time is 30-50 min, the heating temperature is 40-50° C., the temperature of the cold water is 2-4° C., and the polyacrylic acid resin is polyacrylic acid resin II or polyacrylic acid resin III.

[0022] As a further improvement of the present invention, the present invention specifically comprises the following steps:

[0023] S1. Fermentation of ginseng: 10-30 parts by weight of ginseng were crushed, added to 100 parts by weight of water, inoculated with a long bifidobacterium seed solution, the inoculation amount was 1-3v / v%, 36-38°C, 100-200r / min, under anaerobic conditions, fermented and cultured for 24-36h, filtered, the residue was washed, the eluate was collected and concentrated, and a bacterial content of 10 11 -10 12cfu / mL of the first bacterial liquid, and the remaining solid is dried to obtain ginseng residue; the filtrate is ginseng fermentation liquid;

[0024] The bacterial content of the long bifidobacterium seed liquid is 10 8 -10 9 cfu / mL;

[0025] S2. Extraction of total ginsenosides: 10-30 parts by weight of the ginseng fermentation broth obtained in step S1 was added to 20-40 parts by weight of the ionic liquid, carbon dioxide was introduced at an amount of 2-4 mL / s, the extraction was stirred, aeration was stopped, stratification was allowed to stand, the ionic liquid layer was collected, heated to 50-60 ° C, stirred for 20-30 min to release carbon dioxide, stratified, the organic layer was collected, the solvent was removed under reduced pressure, and dried to obtain total ginsenosides;

[0026] S3. Water extraction of Chinese medicine: 5-7 parts by weight of the ginseng residue in step S1, 12-17 parts by weight of spiny jujube seeds, 3-5 parts by weight of bupleurum, 1-2 parts by weight of spiny ginseng are mixed and crushed to obtain a Chinese medicine powder, which is added to water, wherein the solid-liquid ratio of the Chinese medicine powder to water is 1:3-5g / mL, heated and boiled for extraction for 2-4h, filtered, the residue is retained, and the filtrate is dried to obtain a Chinese medicine aqueous extract;

[0027] S4. Fermentation of Chinese medicine: 15-20 parts by weight of the filter residue obtained in step S3 was added to 100 parts by weight of water, sterilized, inoculated with Lactobacillus bulgaricus and Lactobacillus acidophilus seed solution, inoculation amounts were 2-4v / v% and 1-2v / v%, 36-38 ° C, 100-200r / min, under anaerobic conditions, fermented and cultured for 36-48h, filtered, the filter residue was washed, the eluate was collected and concentrated to obtain a bacterial content of 10 11 -10 12 cfu / mL of the second bacterial solution, and freeze-drying the filtrate to obtain a Chinese medicine fermentation extract;

[0028] The bacterial content of the bacterial seed liquid is 10 8 -10 9 cfu / mL;

[0029] S5. Encapsulation of probiotics: 10-15 parts by weight of the first bacterial solution in step S1 and 12-17 parts by weight of the second bacterial solution in step S4 were mixed, added to 60-70 parts by weight of milk, and the mixture was dropped into 200 parts by weight of an aqueous solution having a pH value of 3.8-4.2 using a syringe, allowed to stand, centrifuged, the particles were collected, and washed with an aqueous solution having a pH value of 3.8-4.2 to obtain encapsulated probiotics;

[0030] S6. Preparation of berberine / zopiclone / agomelatine cocrystal: dissolving 7-10 parts by weight of berberine in 100 parts by weight of hot water at 70-80°C to obtain solution A; dissolving 1-2 parts by weight of zopiclone in 100 parts by weight of 10-15wt% acetic acid solution to obtain solution B; dissolving 0.5-1 parts by weight of agomelatine in 100 parts by weight of ethanol to obtain solution C; mixing solution A, solution B and solution C, leaving the mixture open for 5-7 days to volatilize the solvent, filtering, washing and drying to obtain berberine / zopiclone / agomelatine cocrystal;

[0031] S7. Secondary embedding: 1-2 parts by weight of ginsenosides prepared in step S2, 3-5 parts by weight of Chinese herbal medicine water extract prepared in step S3, 4-7 parts by weight of Chinese herbal medicine fermentation extract prepared in step S4, 2-4 parts by weight of embedded probiotics prepared in step S5, and 0.2-0.4 parts by weight of berberine / zopiclone / agomelatine cocrystal prepared in step S6 are mixed, ball-milled for 30-50 minutes, added to 100 parts by weight of ethanol aqueous solution, 17-20 parts by weight of polyacrylic acid resin and 7-10 parts by weight of sodium alginate are added, heated to 40-50°C, stirred and mixed evenly, dripped into water at 2-4°C with a syringe, centrifuged, collected particles, washed, and dried to obtain a composition for treating insomnia.

[0032] The present invention further protects a composition for treating insomnia prepared by the above preparation method.

[0033] The present invention further protects the use of the above composition for treating insomnia in the preparation of medicines for treating sleep disorders and depressive insomnia.

[0034] The present invention has the following beneficial effects:

[0035] Ginseng is rich in saponins. Under the fermentation action of the probiotic Bifidobacterium longum, most of the common saponins are converted into highly active rare saponins. At the same time, the proliferation of probiotics is promoted. The obtained fermentation product also contains many other impurities. By adding to the ionic liquid and introducing carbon dioxide to increase the polarity of the ionic liquid, the saponin component is separated from the original solution and enters the ionic liquid layer, thereby purifying the fermentation product. After heating to allow the carbon dioxide to escape, the highly polar ionic liquid is converted into an ordinary ionic liquid, and the saponin component is separated from the ionic liquid. After liquid separation, high-purity ginsenosides of ginseng are obtained, including ginsenoside Rc, ginsenoside Rg1, ginsenoside Rg2, ginsenoside Rh3, ginsenoside Rg3, ginsenoside Rb1, etc., which have the effect of improving the body's oxidative stress, directly improve sleep rhythm by controlling the current of neuronal cell ion channels, alleviate the imbalance of sleep rhythm homeostasis caused by oxidative damage, inhibit the acetylation of brain tissue proteins caused by it, and can promote the biosynthesis pathway of dopamine in brain tissue without withdrawal effect.

[0036] The water extract and fermented extract of Ziziphus jujuba seed can change the content of γ-aminobutyric acid and 5-hydroxytryptamine, activate glutamate decarboxylase, synthesize glutamate into γ-aminobutyric acid, increase the level of γ-aminobutyric acid, and ultimately affect the γ-aminobutyric acid energy system, which improves sleep. At the same time, the Ziziphus jujuba saponins it contains also have a calming and tranquilizing effect. Bupleurum has the effects of evacuating fever, relieving liver depression, and raising yang energy. The fermented extract of Bupleurum can treat insomnia due to asthenia by increasing the content of 5-hydroxytryptamine in the brain and reducing the content of γ-aminobutyric acid. The water extract of Radix Acanthopanacis can significantly shorten the sleep latency, prolong its sleep duration, reduce the content of norepinephrine and dopamine, increase the content of nitric oxide, affect the activity of nitric oxide synthase, regulate excitatory neurotransmitters, inhibit protein catabolism and branched-chain amino acid metabolism in the body, accelerate the elimination of lactic acid, reduce the accumulation of free radicals, accelerate the removal of lipid peroxides in the body, and protect the mitochondrial oxidative phosphorylation function, thereby relieving fatigue and improving sleep rhythm.

[0037] Berberine gavage can regulate the structure of intestinal flora, increase the number of Escherichia coli, Bifidobacterium, and Lactobacillus, reduce the number of Clostridium perfringens and Enterococcus, and reverse the effect of sleep deprivation on the expression of IL-17, RORC, and Foxp3, thereby improving sleep quality through intestinal regulation. However, berberine is almost insoluble in water at room temperature, which greatly reduces its bioavailability. Agomelatine can improve sleep maintenance disorders, increase deep sleep and total sleep time, reduce total awakening time after falling asleep, and improve sleep efficiency. Zopiclone has a short onset time, can shorten sleep latency, improve sleep continuity, and reduce total awakening time after falling asleep. It is suitable for patients with difficulty falling asleep and sleep maintenance disorders. It has no drug dependence, withdrawal reactions are rare, and the probability of rebound insomnia is very low, but it is easy to have dry mouth and bitter mouth. In addition, zopiclone and agomelatine are almost insoluble in water, which also reduces their bioavailability. The present invention prepares berberine / zopiclone / agomelatine cocrystal, greatly improves the solubility of the cocrystal in water, improves its bioavailability, thereby greatly reducing the usage of various drugs, and minimizes the occurrence of adverse reactions. At the same time, under the synergistic effect of other components, it can better promote sleep and improve sleep quality.

[0038] The imbalance of intestinal flora can affect the synthesis of neurotransmitters and the secretion of melatonin, and may also cause inflammatory reactions, thereby affecting sleep. The present invention can well regulate the intestinal probiotic flora by adding embedded probiotics, thereby reducing oxidative stress and inflammatory reactions and improving sleep quality. The present invention embeds probiotics in milk, polyacrylic acid resin II and sodium alginate synergistically form an elastic gel, and milk protein forms a thixotropic gel after contacting the outer colloid. Under acidic gastric acid conditions, coagulation and precipitation occur. Under alkaline intestinal fluid conditions, the outer polyacrylic acid resin and sodium alginate shells disintegrate, and the shells of the embedded probiotics also dissolve, thereby releasing a large number of probiotics, entering the intestines for colonization, and playing a role in improving sleep.

[0039] The composition for treating insomnia prepared by the present invention can improve the distribution of intestinal flora, improve oxidative stress, reduce inflammatory response, promote sleep, improve sleep quality, has the effects of calming the mind, soothing the liver and relieving depression, can significantly improve the symptoms of patients with sleep disorders and depressive insomnia, has little side effects, is safe to use, and has broad application prospects. DETAILED DESCRIPTION

[0040] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0041] Polyacrylic acid resin II, purity>99%, was obtained by copolymerization of methacrylic acid and methacrylate in a ratio of 50:50 and was purchased from Hubei Qifei Pharmaceutical Chemical Co., Ltd.

[0042] 1-Hexyl-3-methylimidazolium tetrafluoroborate, density 1.149 g / mL, was purchased from Hubei Jiahui Xingcheng Biotechnology Co., Ltd.

[0043] Bifidobacterium longum, 10 billion cfu / g, Lactobacillus bulgaricus, 10 billion cfu / g, and Lactobacillus acidophilus, 10 billion cfu / g were purchased from Shaanxi Saien Biotechnology Co., Ltd.

[0044] Preparation method of bacterial seed liquid: inoculate the bacterial strain into Gao's medium, activate and culture for 18-24 hours at 37℃, 100r / min, and anaerobic conditions to obtain a liquid containing 10 8 -10 9 cfu / mL of bacterial seed solution.

[0045] Example 1

[0046] This embodiment provides a method for preparing a composition for treating insomnia, which specifically comprises the following steps:

[0047] S1. Ginseng fermentation: 10 parts by weight of ginseng were crushed and added to 100 parts by weight of water, and the long bifidobacterium seed solution was inoculated at an inoculation rate of 1v / v%, 36°C, 100r / min, and fermented for 24h under anaerobic conditions, filtered, the residue was washed, and the eluate was collected and concentrated to obtain a bacterial content of 10 11 -10 12 cfu / mL of the first bacterial liquid, and the remaining solid is dried to obtain ginseng residue; the filtrate is ginseng fermentation liquid;

[0048] S2. Extraction of total ginsenosides: 10 parts by weight of the ginseng fermentation broth prepared in step S1 was added to 20 parts by weight of 1-hexyl-3-methylimidazolium tetrafluoroborate ionic liquid, carbon dioxide was introduced at a rate of 2 mL / s, and the mixture was stirred for 30 min. The aeration was stopped, the stratification was allowed to stand, the ionic liquid layer was collected, the mixture was heated to 50 ° C, stirred for 20 min, carbon dioxide was released, the stratification was allowed to stand, the organic layer was collected, the solvent was removed under reduced pressure, and the mixture was dried to obtain total ginsenosides;

[0049] S3. Water extraction of Chinese medicine: 5 parts by weight of the ginseng residue in step S1, 12 parts by weight of spiny jujube seeds, 3 parts by weight of bupleurum, and 1 part by weight of spiny ginseng were mixed and crushed to obtain Chinese medicine powder, which was added to water. The solid-liquid ratio of the Chinese medicine powder to water was 1:3 g / mL. The mixture was heated and boiled for 2 h, filtered, the residue was retained, and the filtrate was dried to obtain a Chinese medicine water extract;

[0050] S4. Fermentation of Chinese medicine: 15 parts by weight of the filter residue obtained in step S3 was added to 100 parts by weight of water, sterilized, inoculated with Lactobacillus bulgaricus and Lactobacillus acidophilus seed solution, the inoculation amount was 2v / v% and 1v / v%, respectively, at 36 ° C, 100r / min, under anaerobic conditions, fermented and cultured for 36h, filtered, the filter residue was washed, the eluate was collected and concentrated to obtain a bacterial content of 10 11 -10 12 cfu / mL of the second bacterial solution, and freeze-drying the filtrate to obtain a Chinese medicine fermentation extract;

[0051] S5. Encapsulation of probiotics: 10 parts by weight of the first bacterial solution in step S1 and 12 parts by weight of the second bacterial solution in step S4 were mixed, added to 60 parts by weight of milk, and the mixture was dropped into 200 parts by weight of an aqueous solution having a pH value of 3.8 using a syringe, allowed to stand, centrifuged, the particles were collected, and washed with an aqueous solution having a pH value of 3.8 to obtain encapsulated probiotics;

[0052] S6. Preparation of berberine / zopiclone / agomelatine cocrystal: dissolving 7 parts by weight of berberine in 100 parts by weight of hot water at 70° C. to obtain solution A; dissolving 1 part by weight of zopiclone in 100 parts by weight of 10 wt% acetic acid solution to obtain solution B; dissolving 0.5 parts by weight of agomelatine in 100 parts by weight of ethanol to obtain solution C; mixing solution A, solution B and solution C for 20 min, leaving the mixture open for 5 days to volatilize the solvent, filtering, washing and drying to obtain berberine / zopiclone / agomelatine cocrystal;

[0053] S7. Secondary embedding: 1 part by weight of the total ginsenosides prepared in step S2, 3 parts by weight of the Chinese herbal medicine water extract prepared in step S3, 4 parts by weight of the Chinese herbal medicine fermentation extract prepared in step S4, 2 parts by weight of the embedded probiotics prepared in step S5, and 0.2 parts by weight of the berberine / zopiclone / agomelatine cocrystal prepared in step S6 are mixed, ball-milled for 30 minutes, added to 100 parts by weight of a 95wt% ethanol aqueous solution, 17 parts by weight of polyacrylic acid resin II and 7 parts by weight of sodium alginate, heated to 40°C, stirred and mixed for 30 minutes, dripped into 2°C water with a syringe, centrifuged, collected particles, washed, and dried to obtain a composition for treating insomnia.

[0054] Example 2

[0055] This embodiment provides a method for preparing a composition for treating insomnia, which specifically comprises the following steps:

[0056] S1. Ginseng fermentation: 30 parts by weight of ginseng were crushed and added to 100 parts by weight of water, inoculated with long bifidobacterium seed solution, the inoculation amount was 3v / v%, 38°C, 200r / min, under anaerobic conditions, fermented and cultured for 36h, filtered, the residue was washed, the eluate was collected and concentrated, and the bacterial content was 10 11 -10 12 cfu / mL of the first bacterial liquid, and the remaining solid is dried to obtain ginseng residue; the filtrate is ginseng fermentation liquid;

[0057] S2. Extraction of total ginsenosides: 30 parts by weight of the ginseng fermentation broth prepared in step S1 was added to 40 parts by weight of 1-hexyl-3-methylimidazolium tetrafluoroborate ionic liquid, carbon dioxide was introduced at a rate of 4 mL / s, and the mixture was stirred for 30 min. The ventilation was stopped, the stratification was allowed to stand, the ionic liquid layer was collected, the mixture was heated to 60 ° C, stirred for 30 min, the carbon dioxide was released, the stratification was allowed to stand, the organic layer was collected, the solvent was removed under reduced pressure, and the mixture was dried to obtain total ginsenosides;

[0058] S3. Water extraction of Chinese medicine: 7 parts by weight of the ginseng residue in step S1, 17 parts by weight of spiny jujube seeds, 5 parts by weight of bupleurum, and 2 parts by weight of spiny ginseng were mixed and crushed to obtain a Chinese medicine powder, which was added to water. The solid-liquid ratio of the Chinese medicine powder to water was 1:5 g / mL. The mixture was heated and boiled for 4 h, filtered, the residue was retained, and the filtrate was dried to obtain a Chinese medicine water extract;

[0059] S4. Fermentation of Chinese medicine: 20 parts by weight of the filter residue obtained in step S3 was added to 100 parts by weight of water, sterilized, inoculated with Lactobacillus bulgaricus and Lactobacillus acidophilus seed solution, the inoculation amount was 4v / v% and 2v / v%, respectively, at 38°C, 200r / min, under anaerobic conditions, fermented and cultured for 48h, filtered, the filter residue was washed, the eluate was collected and concentrated to obtain a bacterial content of 10 11 -10 12 cfu / mL of the second bacterial solution, and freeze-drying the filtrate to obtain a Chinese medicine fermentation extract;

[0060] S5. Encapsulation of probiotics: 15 parts by weight of the first bacterial solution in step S1 and 17 parts by weight of the second bacterial solution in step S4 were mixed, added to 70 parts by weight of milk, and the mixture was dropped into 200 parts by weight of an aqueous solution having a pH value of 4.2 using a syringe, allowed to stand, centrifuged, the particles were collected, and washed with an aqueous solution having a pH value of 4.2 to obtain encapsulated probiotics;

[0061] S6. Preparation of berberine / zopiclone / agomelatine cocrystal: dissolving 10 parts by weight of berberine in 100 parts by weight of hot water at 80° C. to obtain solution A; dissolving 2 parts by weight of zopiclone in 100 parts by weight of 15 wt% acetic acid solution to obtain solution B; dissolving 1 part by weight of agomelatine in 100 parts by weight of ethanol to obtain solution C; mixing solution A, solution B and solution C for 20 min, leaving the mixture open for 7 days to volatilize the solvent, filtering, washing and drying to obtain berberine / zopiclone / agomelatine cocrystal;

[0062] S7. Secondary embedding: 2 parts by weight of ginsenosides prepared in step S2, 5 parts by weight of Chinese herbal medicine water extract prepared in step S3, 7 parts by weight of Chinese herbal medicine fermentation extract prepared in step S4, 4 parts by weight of embedded probiotics prepared in step S5, and 0.4 parts by weight of berberine / zopiclone / agomelatine cocrystal prepared in step S6 are mixed, ball-milled for 50 minutes, added to 100 parts by weight of 95wt% ethanol aqueous solution, 20 parts by weight of polyacrylic acid resin II and 10 parts by weight of sodium alginate are added, heated to 50°C, stirred and mixed for 30 minutes, dripped into 4°C water with a syringe, centrifuged, collected particles, washed, and dried to obtain a composition for treating insomnia.

[0063] Example 3

[0064] This embodiment provides a method for preparing a composition for treating insomnia, which specifically comprises the following steps:

[0065] S1. Ginseng fermentation: 20 parts by weight of ginseng were crushed and added to 100 parts by weight of water, inoculated with a long bifidobacterium seed solution at an inoculation rate of 2 v / v%, 37 ° C, 150 r / min, and fermented for 30 h under anaerobic conditions, filtered, washed with the residue, and the eluate was collected and concentrated to obtain a bacterial content of 10 11 -10 12 cfu / mL of the first bacterial liquid, and the remaining solid is dried to obtain ginseng residue; the filtrate is ginseng fermentation liquid;

[0066] S2. Extraction of total ginsenosides: 20 parts by weight of the ginseng fermentation broth prepared in step S1 was added to 30 parts by weight of 1-hexyl-3-methylimidazolium tetrafluoroborate ionic liquid, carbon dioxide was introduced at a rate of 3 mL / s, and the mixture was stirred for 30 min. The aeration was stopped, the stratification was allowed to stand, the ionic liquid layer was collected, the mixture was heated to 55 ° C, stirred for 25 min, carbon dioxide was released, the stratification was allowed to stand, the organic layer was collected, the solvent was removed under reduced pressure, and the mixture was dried to obtain total ginsenosides;

[0067] S3. Water extraction of Chinese medicine: 6 parts by weight of ginseng residue in step S1, 15 parts by weight of spiny jujube seeds, 4 parts by weight of bupleurum, 1.5 parts by weight of spiny ginseng were mixed and crushed to obtain Chinese medicine powder, added to water, the solid-liquid ratio of the Chinese medicine powder to water was 1:4g / mL, heated and boiled for extraction for 3h, filtered, the residue was retained, and the filtrate was dried to obtain a Chinese medicine water extract;

[0068] S4. Fermentation of Chinese medicine: 7 parts by weight of the filter residue obtained in step S3 was added to 100 parts by weight of water, sterilized, inoculated with Lactobacillus bulgaricus and Lactobacillus acidophilus seed solution, the inoculation amount was 3v / v% and 1.5v / v%, respectively, at 37 ° C, 150r / min, under anaerobic conditions, fermented and cultured for 42h, filtered, the filter residue was washed, the eluate was collected and concentrated to obtain a bacterial content of 10 11 -10 12 cfu / mL of the second bacterial solution, and freeze-drying the filtrate to obtain a Chinese medicine fermentation extract;

[0069] S5. Encapsulation of probiotics: 12 parts by weight of the first bacterial solution in step S1 and 15 parts by weight of the second bacterial solution in step S4 were mixed, added to 65 parts by weight of milk, and the mixture was dropped into 200 parts by weight of a pH = 4 aqueous solution with a syringe, allowed to stand, centrifuged, the particles were collected, and washed with a pH = 4 aqueous solution to obtain encapsulated probiotics;

[0070] S6. Preparation of berberine / zopiclone / agomelatine cocrystal: 8.5 parts by weight of berberine were dissolved in 100 parts by weight of hot water at 75° C. to obtain solution A; 1.5 parts by weight of zopiclone were dissolved in 100 parts by weight of 12 wt% acetic acid solution to obtain solution B; 0.7 parts by weight of agomelatine were dissolved in 100 parts by weight of ethanol to obtain solution C; solution A, solution B and solution C were mixed for 20 min, left to stand in an open state for 6 days to evaporate the solvent, filtered, washed and dried to obtain berberine / zopiclone / agomelatine cocrystal;

[0071] S7. Secondary embedding: 1.5 parts by weight of ginsenosides prepared in step S2, 4 parts by weight of Chinese herbal medicine water extract prepared in step S3, 5.5 parts by weight of Chinese herbal medicine fermentation extract prepared in step S4, 3 parts by weight of embedded probiotics prepared in step S5, and 0.3 parts by weight of berberine / zopiclone / agomelatine cocrystal prepared in step S6 are mixed, ball-milled for 40 minutes, added to 100 parts by weight of 95wt% ethanol aqueous solution, 18.5 parts by weight of polyacrylic acid resin II and 8 parts by weight of sodium alginate are added, heated to 45°C, stirred and mixed for 30 minutes, dripped into 4°C water with a syringe, centrifuged, collected particles, washed, and dried to obtain a composition for treating insomnia.

[0072] Comparative Example 1

[0073] Compared with Example 3, the difference is that steps S1 and S2 are not performed, and the ginseng residue in step S3 is replaced with ginseng of equal mass.

[0074] Comparative Example 2

[0075] Compared with Example 3, the difference is that step S2 is not performed, the ginseng fermented liquid prepared in step S1 is freeze-dried, and an equal mass of the ginseng total saponins in step S7 is replaced.

[0076] Comparative Example 3

[0077] Compared with Example 3, the difference is that in step S4, no Lactobacillus bulgaricus seed liquid is inoculated, and the inoculation amount is 4.5 v / v%.

[0078] Comparative Example 4

[0079] Compared with Example 3, the difference is that in step S4, no Lactobacillus acidophilus seed liquid is inoculated, and the inoculation amount is 4.5 v / v%.

[0080] Comparative Example 5

[0081] Compared with Example 3, the difference is that step S4 is not performed and the Chinese medicinal fermentation extract is not added in step S7.

[0082] Comparative Example 6

[0083] Compared with Example 3, the difference is that step S5 is not performed, 12 parts by weight of the first bacterial solution in step S1 and 15 parts by weight of the second bacterial solution in step S4 are mixed and freeze-dried to prepare probiotic powder, which replaces the embedded probiotics in step S7 with equal mass.

[0084] Comparative Example 7

[0085] Compared with Example 3, the difference is that step S6 is not performed, berberine, zopiclone and agomelatine are mixed in a mass ratio of 8.5:1.5:0.7, and the berberine / zopiclone / agomelatine cocrystal added in step S7 is replaced by an equal mass.

[0086] Comparative Example 8

[0087] Compared with Example 3, the difference is that no secondary embedding is performed, 1.5 parts by weight of ginsenosides prepared in step S2, 4 parts by weight of Chinese medicine water extract prepared in step S3, 5.5 parts by weight of Chinese medicine fermentation extract prepared in step S4, 3 parts by weight of embedded probiotics prepared in step S5, and 0.3 parts by weight of berberine / zopiclone / agomelatine cocrystal prepared in step S6 are mixed and ball-milled for 40 minutes to prepare a composition for treating insomnia.

[0088] Comparative Example 9

[0089] Compared with Example 3, the difference is that no polyacrylic acid resin II is added in step S7, and the added amount of sodium alginate is 26.5 parts by weight.

[0090] Comparative Example 10

[0091] Compared with Example 3, the difference is that sodium alginate is not added in step S7, and the added amount of polyacrylic acid resin II is 26.5 parts by weight.

[0092] Test Example 1

[0093] After 7 days of adaptive feeding, SPF grade KM male mice were modeled, and the mice with successful modeling were randomly divided into model group, positive drug group, Example 1-3 group, and Comparative Example 1-10 group, with 10 mice in each group. Ten normal mice were taken as the normal group. Modeling method: Mice were intraperitoneally injected with 10mL / kg of para-chlorophenylalanine at 10-11 am every day to establish an insomnia model, and the injection was continued for 3 days. The behavior of mice with disappearance of circadian rhythm, increased daytime activity, abnormal sensitivity to sound, easy to gather, and increased aggressiveness was considered to be successful modeling. The positive drug group was gavaged with estazolam at 0.81g / kg body weight, and the Example 1-3 and Comparative Example 1-10 groups were gavaged with the corresponding composition for treating insomnia at 1g / kg body weight. The model group and the normal group were gavaged with normal saline at 1g / kg body weight, once a day, for 14 consecutive days, and mice were free to eat and drink water during the whole experiment.

[0094] 1. Effects on sleep latency and sleep time induced by sodium pentobarbital

[0095] 30 minutes after intragastric administration on the third day of administration, each group of mice was intraperitoneally injected with 2 wt% sodium pentobarbital (0.1 mL / 10 g), and the sleep latency and sleep time of the mice were observed and recorded within 120 minutes.

[0096] Sleep latency: the time from injection of sodium pentobarbital to disappearance of the righting reflex of the mouse (the mouse maintains a back-down position for more than 30 seconds);

[0097] Sleep time: the time from when the mouse's righting reflex disappears to when it wakes up again (turning over three times within 30 seconds is considered the end of sleep).

[0098] The results are shown in Table 1.

[0099] Table 1

[0100]

[0101]

[0102] Note: * compared with the model group, P < 0.05; # compared with the normal group, P < 0.05; a compared with Example 3, P < 0.05.

[0103] It can be seen from the above table that the compositions for treating insomnia prepared in Examples 1-3 of the present invention can significantly prolong sleep time and shorten sleep latency.

[0104] 2. Determination of neurotransmitters and inflammatory indicators

[0105] After the last oral administration, all mice were fasted but not watered for 12 h, anesthetized by intraperitoneal injection of 2 wt% sodium pentobarbital (0.1 mL / 10 g), blood was collected from the eyeballs, allowed to stand, centrifuged, and the upper serum was collected and frozen for later use.

[0106] After blood collection, mice in each group were killed, the medulla oblongata was quickly cut off from the foramen magnum, the skull was removed, the brain tissue was completely exposed, the hippocampus tissue was separated, washed, added with lysis buffer, crushed and homogenized under ice bath to prepare 10wt% hippocampus homogenate, centrifuged, and the supernatant of the hippocampus homogenate was obtained and frozen for later use.

[0107] Elisa method was used to detect the levels of dopamine (DA), 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (GABA) in the hippocampal homogenate and interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) in the serum. The operation was strictly in accordance with the instructions of the kit.

[0108] The results are shown in Table 2.

[0109]

[0110]

[0111] Note: * compared with the model group, P < 0.05; # compared with the normal group, P < 0.05; a compared with Example 3, P < 0.05.

[0112] It can be seen from the above table that the compositions for treating insomnia prepared in Examples 1-3 of the present invention can significantly reduce DA, IL-6, and TNF-α, and increase the contents of 5-HT and GABA.

[0113] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing a composition for treating insomnia, characterized in that: Fermenting ginseng, separating ginsenosides by ionic liquid, mixing the remaining ginseng residues with Semen Ziziphi Spinosae, Radix Bupleuri, and Radix Panax Ginseng, extracting with boiling water to obtain a Chinese medicine water extract, fermenting the remaining residues to obtain a Chinese medicine fermentation product, embedding the fermented bacteria to obtain embedded probiotics, preparing berberine / zopiclone / agomelatine cocrystals, mixing with ginsenosides, Chinese medicine water extracts, Chinese medicine fermentation extracts, and embedded probiotics by ball milling, adding to polyacrylic acid resin and sodium alginate solution, dropping into cold water, centrifuging, collecting particles, washing, and drying to obtain a composition for treating insomnia; The following steps are involved: S1. Ginseng fermentation: Ginseng is crushed, added to water, inoculated with long bifidobacterium strain seed liquid, fermented, filtered, the residue is washed, the eluate is collected and concentrated to obtain the first bacterial liquid, the remaining solid is dried to obtain ginseng residue; the filtrate is ginseng fermentation liquid; the bacterial content of the long bifidobacterium strain seed liquid is 10 8 -10 9 cfu / mL, inoculum size 1-3v / v%; S2. Extraction of total ginsenosides: The ginseng fermentation liquid obtained in step S1 was added to the ionic liquid, carbon dioxide was introduced, the extraction was stirred, ventilation was stopped, stratification was allowed to stand, the ionic liquid layer was collected, the carbon dioxide was heated to escape, the organic layer was collected, the solvent was removed under reduced pressure, and dried to obtain total ginsenosides; S3. Water extraction of Chinese medicine: Mix the ginseng residue, spiny jujube seeds, bupleurum, and spiny ginseng in step S1, crush them to obtain Chinese medicine powder, add them to water, heat and boil them for extraction, filter, retain the residue, and dry the filtrate to obtain a Chinese medicine water extract; the mass ratio of the ginseng residue, spiny jujube seeds, bupleurum, and spiny ginseng is 5-7:12-17:3-5:1-2; S4. Fermentation of Chinese medicine: adding the filter residue obtained in step S3 to water, sterilizing, inoculating Lactobacillus bulgaricus and Lactobacillus acidophilus seed solution, fermenting, filtering, washing the filter residue, collecting and concentrating the eluate to obtain a second bacterial solution, freeze-drying the filtrate to obtain a fermented Chinese medicine extract; S5. Encapsulation of probiotics: The first bacterial solution in step S1 and the second bacterial solution in step S4 are mixed, added to milk, and the mixture is dropped into the acid solution with a syringe, allowed to stand, centrifuged, the particles are collected, and washed with acid to obtain encapsulated probiotics; S6. Preparation of berberine / zopiclone / agomelatine cocrystal: dissolving berberine in hot water to obtain solution A; dissolving zopiclone in acetic acid solution to obtain solution B; dissolving agomelatine in ethanol to obtain solution C; mixing solution A, solution B and solution C uniformly, leaving the mixture to evaporate the solvent, filtering, washing and drying to obtain berberine / zopiclone / agomelatine cocrystal; the mass ratio of berberine, zopiclone and agomelatine is 7-10:1-2:0.5-1; S7. Secondary embedding: mix the ginsenosides prepared in step S2, the Chinese herbal medicine water extract prepared in step S3, the Chinese herbal medicine fermentation extract prepared in step S4, the embedded probiotics prepared in step S5, and the berberine / zopiclone / agomelatine cocrystal prepared in step S6, ball-mill them evenly, add them to an ethanol aqueous solution, add polyacrylic acid resin and sodium alginate, heat and stir to mix evenly, drop them into cold water with a syringe, centrifuge, collect the particles, wash, and dry them to obtain a composition for treating insomnia.

2. The preparation method according to claim 1, characterized in that: The fermentation conditions in step S1 are 36-38°C, 100-200r / min, anaerobic conditions, fermentation culture for 24-36h, the mass ratio of ginseng to water is 1-3:10, the bacterial content of the first bacterial liquid is 10 11 -10 12 cfu / mL; the mass ratio of the ginseng fermentation broth and the ionic liquid in step S2 is 1-3:2-4, the ionic liquid is selected from at least one of 1-butyl-3-methylimidazolium bistrifluoromethanesulfonyl imide salt, 1-butyl-3-methylimidazolium hexafluoroantimonate, 1-hexyl-3-methylimidazolium hexafluoroantimonate, 1-hexyl-3-methylimidazolium hexafluorophosphate, and 1-hexyl-3-methylimidazolium tetrafluoroborate, the amount of carbon dioxide introduced is 2-4mL / s, and the heating temperature is 50-60°C for 20-30min.

3. The preparation method according to claim 1, characterized in that: The solid-liquid ratio of the Chinese medicine powder and water in step S3 is 1:3-5 g / mL, and the heating and boiling extraction time is 2-4 h; the mass ratio of the filter residue and water in step S4 is 15-20:100, and the bacterial content of the bacterial seed liquid is 10 8 -10 9 cfu / mL, the inoculation amounts of the Lactobacillus bulgaricus and Lactobacillus acidophilus seed solutions were 2-4 v / v% and 1-2 v / v%, respectively, the fermentation culture conditions were 36-38°C, 100-200 r / min, under anaerobic conditions, the fermentation culture was performed for 36-48 h, and the bacterial content of the second bacterial solution was 10 11 -10 12 cfu / mL.

4. The preparation method according to claim 1, characterized in that: In step S5, the mass ratio of the first bacterial liquid, the second bacterial liquid, the milk, and the acid solution is 10-15:12-17:60-70:200, and the acid solution is an aqueous solution with a pH of 3.8-4.

2.

5. The preparation method according to claim 1, characterized in that: In step S6, the temperature of the hot water is 70-80° C., the concentration of the acetic acid solution is 10-15 wt %, and the time of leaving the solution in an open state to volatilize the solvent is 5-7 days.

6. The preparation method according to claim 1, characterized in that: In step S7, the mass ratio of ginsenosides, Chinese herbal medicine water extract, Chinese herbal medicine fermentation extract, embedded probiotics, berberine / zopiclone / agomelatine cocrystal, ethanol aqueous solution, polyacrylic acid resin, and sodium alginate is 1-2:3-5:4-7:2-4:0.2-0.4:100:17-20:7-10, the ball milling time is 30-50 min, the heating temperature is 40-50° C., the cold water temperature is 2-4° C., and the polyacrylic acid resin is polyacrylic acid resin II or polyacrylic acid resin III.

7. The preparation method according to claim 1, characterized in that: The specific steps include: S1. Fermentation of ginseng: 10-30 parts by weight of ginseng were crushed, added to 100 parts by weight of water, inoculated with a long bifidobacterium seed solution, the inoculation amount was 1-3v / v%, 36-38°C, 100-200r / min, under anaerobic conditions, fermented and cultured for 24-36h, filtered, the residue was washed, the eluate was collected and concentrated, and a bacterial content of 10 11 -10 12 cfu / mL of the first bacterial liquid, and the remaining solid is dried to obtain ginseng residue; the filtrate is ginseng fermentation liquid; The bacterial content of the long bifidobacterium seed liquid is 10 8 -10 9 cfu / mL; S2. Extraction of total ginsenosides: 10-30 parts by weight of the ginseng fermentation broth obtained in step S1 was added to 20-40 parts by weight of the ionic liquid, carbon dioxide was introduced at an amount of 2-4 mL / s, the extraction was stirred, aeration was stopped, stratification was allowed to stand, the ionic liquid layer was collected, heated to 50-60 ° C, stirred for 20-30 min to release carbon dioxide, stratified, the organic layer was collected, the solvent was removed under reduced pressure, and dried to obtain total ginsenosides; S3. Water extraction of Chinese medicine: 5-7 parts by weight of the ginseng residue in step S1, 12-17 parts by weight of spiny jujube seeds, 3-5 parts by weight of bupleurum, 1-2 parts by weight of spiny ginseng are mixed and crushed to obtain a Chinese medicine powder, which is added to water, wherein the solid-liquid ratio of the Chinese medicine powder to water is 1:3-5g / mL, heated and boiled for extraction for 2-4h, filtered, the residue is retained, and the filtrate is dried to obtain a Chinese medicine aqueous extract; S4. Fermentation of Chinese medicine: 15-20 parts by weight of the filter residue obtained in step S3 was added to 100 parts by weight of water, sterilized, inoculated with Lactobacillus bulgaricus and Lactobacillus acidophilus seed solution, inoculation amounts were 2-4v / v% and 1-2v / v%, 36-38 ° C, 100-200r / min, under anaerobic conditions, fermented and cultured for 36-48h, filtered, the filter residue was washed, the eluate was collected and concentrated to obtain a bacterial content of 10 11 -10 12 cfu / mL of the second bacterial solution, and freeze-drying the filtrate to obtain a Chinese medicine fermentation extract; The bacterial content of the bacterial seed liquid is 10 8 -10 9 cfu / mL; S5. Encapsulation of probiotics: 10-15 parts by weight of the first bacterial solution in step S1 and 12-17 parts by weight of the second bacterial solution in step S4 were mixed, added to 60-70 parts by weight of milk, and the mixture was dropped into 200 parts by weight of an aqueous solution having a pH value of 3.8-4.2 using a syringe, allowed to stand, centrifuged, the particles were collected, and washed with an aqueous solution having a pH value of 3.8-4.2 to obtain encapsulated probiotics; S6. Preparation of berberine / zopiclone / agomelatine cocrystal: dissolving 7-10 parts by weight of berberine in 100 parts by weight of hot water at 70-80°C to obtain solution A; dissolving 1-2 parts by weight of zopiclone in 100 parts by weight of 10-15wt% acetic acid solution to obtain solution B; dissolving 0.5-1 parts by weight of agomelatine in 100 parts by weight of ethanol to obtain solution C; mixing solution A, solution B and solution C, leaving the mixture open for 5-7 days to volatilize the solvent, filtering, washing and drying to obtain berberine / zopiclone / agomelatine cocrystal; S7. Secondary embedding: 1-2 parts by weight of ginsenosides prepared in step S2, 3-5 parts by weight of Chinese herbal medicine water extract prepared in step S3, 4-7 parts by weight of Chinese herbal medicine fermentation extract prepared in step S4, 2-4 parts by weight of embedded probiotics prepared in step S5, and 0.2-0.4 parts by weight of berberine / zopiclone / agomelatine cocrystal prepared in step S6 are mixed, ball-milled for 30-50 minutes, added to 100 parts by weight of ethanol aqueous solution, 17-20 parts by weight of polyacrylic acid resin and 7-10 parts by weight of sodium alginate are added, heated to 40-50°C, stirred and mixed evenly, dripped into water at 2-4°C with a syringe, centrifuged, collected particles, washed, and dried to obtain a composition for treating insomnia.

8. A composition for treating insomnia obtained by the preparation method according to any one of claims 1 to 7.

9. Use of the composition for treating insomnia as claimed in claim 8 in the preparation of medicines for treating sleep disorders and depressive insomnia.

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