Anxiolytic gamma-aminobutyric acid compositions and methods for their preparation

Abstract

The present application belongs to the technical field of health care products, and particularly relates to an anti-anxiety gamma-aminobutyric acid composition and a preparation method thereof. The anti-anxiety gamma-aminobutyric acid composition comprises the following components in parts by weight: 1-2 parts of a paeonol derivative, 0.1-0.5 parts of gamma-aminobutyric acid, 0.1-0.3 parts of astaxanthin, and 0.01-0.05 parts of a sea star saponin. The present application uses the gamma-aminobutyric acid, the paeonol derivative and the sea star saponin in combination. The paeonol derivative promotes passive diffusion of the gamma-aminobutyric acid into intestinal epithelial cells through a cell membrane, thereby greatly improving the ability of the gamma-aminobutyric acid to passively diffuse through the cell membrane of the intestinal epithelial cells. The sea star saponin has the effects of sedation, anti-anxiety and regulation of insomnia, and can effectively promote absorption of the gamma-aminobutyric acid. The present application can effectively promote absorption of active substances and has high bioavailability. The composition has the advantages of small dosage, good anti-anxiety effect, prolonged sleep duration and the like.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of health products, and particularly relates to an anti-anxiety gamma-aminobutyric acid composition and a preparation method thereof. BACKGROUND

[0002] Insomnia and anxiety, depression are often interrelated and influence each other. Anxiety, also known as anxiety neurosis, is manifested as excessive worry and fear in daily situations, which interferes with daily activities and is difficult to control. It is often manifested as tension, fear, cognitive impairment, and emotional depression. Insomnia is a sleep disorder that is difficult to fall asleep in a comfortable environment, and long-term insomnia leads to low prefrontal cortex function and enhanced fear response, promoting the occurrence of anxiety, forming a closed loop of "anxiety-insomnia-more anxiety", that is, anxiety is one of the important reasons for the difficulty in curing insomnia, therefore, it is particularly important to intervene anxiety with effective measures.

[0003] With the acceleration of the pace of life and the increase of social pressure, the number of people with anxiety is increasing. Clinically, psychological treatment and drug treatment are usually used for anxiety disorders. The current clinical anti-anxiety drugs mainly include benzodiazepine drugs and reuptake inhibitor drugs. However, these drugs also have certain limitations to varying degrees, such as some drugs have slow effect and need to be taken for a long time; some drugs are easily addictive after long-term use; and they can also cause gastrointestinal discomfort, fatigue, drug resistance, liver damage and other adverse reactions.

[0004] Gamma-aminobutyric acid (GABA) is the most important inhibitory neurotransmitter in the central nervous system of mammals, and plays a core role in regulating neuronal excitability and maintaining neural homeostasis. The existing technology shows that the drug has a certain effect on resisting anxiety, but it also has a low bioavailability, and the effect of single use is relatively poor. Danpi phenol also has a certain anti-anxiety effect, but its direct use in the treatment of anxiety disorder also has certain challenges, such as danpi phenol needs a high dose to achieve a significant effect, which increases the risk of adverse reactions.

[0005] Therefore, there is an urgent need for an anti-anxiety gamma-aminobutyric acid composition with little stimulation and effective regulation of the gastrointestinal tract. SUMMARY

[0006] In order to overcome the deficiencies of the prior art, the present application provides an anti-anxiety gamma-aminobutyric acid composition and a preparation method thereof, and the obtained composition has the characteristics of small dosage, significant effect of relieving anxiety and improving sleep.

[0007] One of the purposes of the present application is to provide an anti-anxiety gamma-aminobutyric acid composition.

[0008] The second purpose of the present application is to provide a preparation method of the anti-anxiety gamma-aminobutyric acid composition.

[0009] The present application adopts the following technical solutions:

[0010] An anti-anxiety gamma-aminobutyric acid composition comprises, by weight fraction, the following components: 1-2 parts of a paeonol derivative, 0.1-0.5 parts of gamma-aminobutyric acid, 0.1-0.3 parts of astaxanthin, and 0.01-0.05 parts of a starfish saponin.

[0011] Further, the preparation process of the paeonol derivative comprises the following steps:

[0012] (1) Paeonol is added to a solvent, and chloromethyl methyl ether is added dropwise for reaction, and after filtration, washing, and drying, an intermediate 1 is prepared;

[0013] (2) The intermediate 1, tert-butyl dimethyl chlorosilane, imidazole, and 1-butyl-3-methyl imidazole hexafluorophosphate are added to a solvent for reaction, and after washing, concentration, and purification, an intermediate 2 is prepared;

[0014] (3) 4-hydroxy-3,4-dihydronaphthalene-1(2H)-ketone, potassium carbonate, and the intermediate 2 are added to a solvent for heating reaction, and after washing, concentration, and purification, an intermediate 3 is prepared;

[0015] (4) The intermediate 3 and tetrabutylammonium fluoride are added to a solvent for reaction, and after filtration, concentration, purification, and drying, the paeonol derivative is obtained.

[0016] Further, in step (1), the molar ratio of the paeonol to chloromethyl methyl ether is 1:(2-2.2), the concentration of the paeonol in the solvent is 1-2 mol / L, the solvent is acetic acid, and the reaction time is 5-8 h.

[0017] Further, in step (2), the molar ratio of the intermediate 1, tert-butyl dimethyl chlorosilane, imidazole, and 1-butyl-3-methyl imidazole hexafluorophosphate is 5:(6-8):(12-15):(8-10), the concentration of the intermediate 1 in the solvent is 0.5-1 mol / L, the solvent is acetone, and the reaction time is 2-5 h.

[0018] Further, in step (3), the molar ratio of the intermediate 2, 4-hydroxy-3,4-dihydronaphthalene-1(2H)-ketone, and potassium carbonate is 1:(1.2-1.5):(2-2.5), the concentration of the intermediate 2 in the solvent is 0.2-0.5 mol / L, and the solvent is anhydrous N,N-dimethylformamide.

[0019] Further, in step (3), the heating reaction temperature is 95-110℃, and the time is 4-8 h.

[0020] Further, in step (4), the molar ratio of the intermediate 3 to tetrabutylammonium fluoride is 1:(1.2-1.5), and the concentration of the intermediate 3 in the solvent is 0.2-0.5 mol / L, and the solvent is tetrahydrofuran.

[0021] Further, the temperature of the reaction is 15-20°C, and the time is 3-6h.

[0022] The preparation method of the anti-anxiety GABA composition comprises the following steps: weighing the formula amount of paeonol derivative, GABA, astaxanthin and sea star saponin, mixing them uniformly, and adding excipients to obtain the composition.

[0023] Compared with the prior art, the anti-anxiety GABA composition has the following beneficial effects:

[0024] 1. The anti-anxiety GABA composition can effectively promote the absorption and bioavailability of active substances by compounding GABA, paeonol derivative and sea star saponin, and has the advantages of small dosage, good anti-anxiety effect, prolonged sleep duration, etc. In the present application, the paeonol derivative is prepared by introducing 4-hydroxy-3,4-dihydronaphthalene-1(2H)-ketone into paeonol. The naphthalene ring structure has higher hydrophobicity than the benzene ring, which improves the liposolubility of the derivative and promotes its passive diffusion into intestinal epithelial cells, thereby greatly improving its ability to passively diffuse through the intestinal epithelial cell membrane and increasing its bioavailability. Sea star saponin also has the effects of sedation, anti-anxiety and regulation of insomnia, and can effectively promote the absorption of GABA.

[0025] 2. The preparation method of the anti-anxiety GABA composition is simple and convenient to operate, which is conducive to industrial production and provides a new technical idea for anti-anxiety and sleep improvement. DETAILED DESCRIPTION

[0026] Hereinafter, the present application will be further described in conjunction with specific embodiments. It should be noted that the embodiments described below or technical features thereof can be combined with each other to form new embodiments without conflict. The specific conditions in the embodiments are carried out according to conventional conditions or manufacturer's recommended conditions. The reagents or instruments used, such as those without special instructions, are conventional products obtained through market channels.

[0027] Example 1

[0028] An anti-anxiety GABA composition comprises the following components in parts by weight: 1.5 parts of paeonol derivative, 0.3 parts of GABA, 0.2 parts of astaxanthin and 0.03 parts of sea star saponin.

[0029] The preparation process of the paeonol derivative comprises the following steps:

[0030]

[0031] (1) Dissolve paeonol in acetic acid, then drop chloromethyl methyl ether into the paeonol acetic acid solution, wherein the molar ratio of paeonol and chloromethyl methyl ether is 1:2, the concentration of paeonol in acetic acid is 1 mol / L; after the drop of chloromethyl methyl ether is completed, react for 7 h; filter the reaction solution, wash the filter cake with anhydrous ethanol, and dry to obtain intermediate 1;

[0032] The nuclear magnetic resonance result of intermediate 1 is as follows: 1 H NMR (400 MHz, CDCl3): δ 12.85 (s, 1H), 7.68 (s,1H), 6.41 (s, 1H), 4.58 (s, 2H), 3.90 (s, 3H), 2.60 (s, 3H); HRMS(ESI) calcd for C 10 H 11 ClO3, [M+H] + 215.04, found 215.04.

[0033] (2) Under nitrogen protection, add intermediate 1, tert-butyl dimethyl chlorosilane (TBDMSCl), imidazole and 1-butyl-3-methyl imidazole hexafluorophosphate into acetone in sequence, wherein the molar ratio of intermediate 1, tert-butyl dimethyl chlorosilane, imidazole and 1-butyl-3-methyl imidazole hexafluorophosphate is 5:7:14:9, the concentration of intermediate 1 in acetone is 0.5 mol / L; react for 4 h; quench the reaction by adding water to the mixture, concentrate to remove acetone in the reaction solution, extract the reaction solution with ethyl acetate, wash the combined ethyl acetate phase with pure water, filter and concentrate, and purify by chromatography (eluent, V 石油醚 :V 乙酸乙酯 =88:12) to obtain intermediate 2;

[0034] The nuclear magnetic resonance result of intermediate 2 is as follows: 1 H NMR (400 MHz, CDCl3): δ 7.68 (s, 1H), 6.41 (s,1H), 4.58 (s, 2H), 3.90 (s, 3H), 2.60 (s, 3H), 0.99 (s, 9H), 0.23 (s, 6H);HRMS(ESI) calcd for C 16 H 25 ClO3Si, [M]328.13, found 328.10.

[0035] (3) 4-hydroxy-3,4-dihydronaphthalen-l(2H)-one, potassium carbonate and intermediate 2 were added to anhydrous N,N-dimethylformamide, wherein the molar ratio of intermediate 2, 4-hydroxy-3,4-dihydronaphthalen-l(2H)-one, potassium carbonate and was 1:1.4:2.3, the concentration of intermediate 2 in anhydrous N,N-dimethylformamide was 0.4 mol / L, after stirring uniformly, the reaction was carried out at 100°C for 6h; the reaction solution was cooled to room temperature, poured into ice water, extracted with ethyl acetate, the organic layer was washed with water and saturated brine in turn, concentrated and purified by column chromatography (eluent, V 石油醚 :V 乙酸乙酯 =90:10) to obtain intermediate 3;

[0036] The nuclear magnetic resonance result of intermediate 3 is as follows: 1 H NMR (400 MHz, CDCl3): δ 7.86-7.84 (m, 1H), 7.68(s, 1H), 7.52-7.50 (m, 1H), 7.38-7.35 (m, 2H), 6.41 (s, 1H), 4.58 (s, 2H),4.45 (t, 1H), 3.90 (s, 3H), 2.60 (s, 3H), 2.54-2.45 (m, 2H), 2.04-1.80 (m,2H), 0.99 (s, 9H), 0.23 (s, 6H); HRMS(ESI) calcd for C 26 H 34 O5Si, [M]454.22,found 454.23.

[0037] (4) Under the protection of nitrogen, intermediate 3 was added to tetrahydrofuran, cooled to-5°C, and tetrabutylammonium fluoride was added, wherein the molar ratio of intermediate 3, tetrabutylammonium fluoride was 1:1.3, the concentration of intermediate 3 in tetrahydrofuran was 0.2 mol / L, and the reaction was carried out at 15°C for 5h; the reaction was quenched with saturated ammonium chloride solution, the reaction solution was extracted with ethyl acetate, the organic phase was filtered, concentrated and purified by chromatography (eluent, V 正己烷 :V 乙酸乙酯 =85:15), and then dried to obtain the paeonol derivative.

[0038] The nuclear magnetic resonance result of the paeonol derivative is as follows: 1H NMR (400 MHz, CDCl3): δ 12.85 (s, 1H),7.86-7.84 (m, 1H), 7.68 (s, 1H), 7.52-7.50 (m, 1H), 7.38-7.35 (m, 2H), 6.41(s, 1H), 4.58 (s, 2H), 4.45 (t, 1H), 3.90 (s, 3H), 2.60 (s, 3H), 2.54-2.45(m, 2H), 2.04-1.80 (m, 2H); HRMS(ESI) calcd for C 20 H 20 O5, [M+H] + 341.13, found341.13.

[0039] The preparation method of the above-mentioned anti-anxiety γ-aminobutyric acid composition comprises the following steps: weighing the formula amount of paeonol derivative, γ-aminobutyric acid, astaxanthin and sea star saponin, mixing them uniformly, and adding excipients.

[0040] Example 2

[0041] An anti-anxiety γ-aminobutyric acid composition comprises the following components in parts by weight: 1 part of paeonol derivative, 0.1 part of γ-aminobutyric acid, 0.1 part of astaxanthin and 0.01 part of sea star saponin.

[0042] The preparation process of the paeonol derivative comprises the following steps:

[0043] (1) Dissolve paeonol in glacial acetic acid, and then drop chloromethyl methyl ether into the glacial acetic acid solution of paeonol, wherein the molar ratio of paeonol to chloromethyl methyl ether is 1:2.1, and the concentration of paeonol in acetic acid is 1.5 mol / L; after the drop of chloromethyl methyl ether is completed, react for 5 h; filter the reaction solution, wash the filter cake with anhydrous ethanol, and dry to obtain intermediate 1; the H NMR result of intermediate 1 is the same as that of example 1. 1 The H NMR result of intermediate 1 is the same as that of example 1.

[0044] (2) Under nitrogen protection, sequentially add intermediate 1, tert-butyl dimethylchlorosilane (TBDMSCl), imidazole and 1-butyl-3-methylimidazolium hexafluorophosphate into acetone, wherein the molar ratio of intermediate 1, tert-butyl dimethylchlorosilane, imidazole and 1-butyl-3-methylimidazolium hexafluorophosphate is 5:6:12:8, and the concentration of intermediate 1 in acetone is 0.5 mol / L; react for 2 h; quench the reaction by adding water, concentrate to remove acetone in the reaction solution, extract the reaction solution with ethyl acetate, wash the combined ethyl acetate phase with pure water, filter, concentrate, and purify by chromatography (eluent, V 石油醚 :V乙酸乙酯 =88:12)to obtain intermediate 2; intermediate 2 has 1 The H NMR result is the same as that of Example 1.

[0045] (3) 4-hydroxy-3,4-dihydronaphthalen-l(2H)-one, potassium carbonate and intermediate 2 are added to anhydrous N,N-dimethylformamide, wherein the molar ratio of intermediate 2, 4-hydroxy-3,4-dihydronaphthalen-l(2H)-one, potassium carbonate and is 1:1.2:2, the concentration of intermediate 2 in anhydrous N,N-dimethylformamide is 0.3 mol / L, after stirring uniformly, the reaction is carried out at 95°C for 8 h; the reaction solution is cooled to room temperature, poured into ice water, extracted with ethyl acetate, the organic layer is washed with water and saturated brine in turn, concentrated and purified by column chromatography (eluent, V 石油醚 :V 乙酸乙酯 =90:10) to obtain intermediate 3; intermediate 3 has 1 The H NMR result is the same as that of Example 1.

[0046] (4) Under the protection of nitrogen, intermediate 3 is added to tetrahydrofuran, cooled to -5°C, and tetrabutylammonium fluoride is added, wherein the molar ratio of intermediate 3, tetrabutylammonium fluoride is 1:1.4, the concentration of intermediate 3 in tetrahydrofuran is 0.2 mol / L, the reaction is carried out at 18°C for 6 h; the reaction is quenched with saturated ammonium chloride solution, the reaction solution is extracted with ethyl acetate, the organic phase is filtered, concentrated and purified by chromatography (eluent, V 正己烷 :V 乙酸乙酯 =85:15) to obtain a paeonol derivative. The paeonol derivative has 1 The H NMR result is the same as that of Example 1.

[0047] The preparation method of the above-mentioned anti-anxiety γ-aminobutyric acid composition is the same as that of Example 1.

[0048] Example 3

[0049] An anti-anxiety γ-aminobutyric acid composition comprises, by weight fraction, the following components: 2 parts of a paeonol derivative, 0.5 parts of γ-aminobutyric acid, 0.3 parts of astaxanthin and 0.05 parts of asterosaponin.

[0050] The preparation process of the paeonol derivative comprises the following steps:

[0051] (1) Paeonol is dissolved in glacial acetic acid, and chloromethyl methyl ether is added dropwise to the paeonol glacial acetic acid solution, wherein the molar ratio of paeonol and chloromethyl methyl ether is 1:2.2, and the concentration of paeonol in acetic acid is 2 mol / L; after the addition of chloromethyl methyl ether is completed, the reaction is carried out for 8 h; the reaction solution is filtered, the filter cake is washed with anhydrous ethanol, and dried to obtain intermediate 1; intermediate 1 has 1 The H NMR result is the same as that of Example 1.

[0052] (2) Under nitrogen protection, intermediate 1, TBDMSCl, imidazole and 1-butyl-3-methylimidazolium hexafluorophosphate were added into acetone in turn, wherein the molar ratio of intermediate 1, tert-butyl dimethylsilyl chloride, imidazole and 1-butyl-3-methylimidazolium hexafluorophosphate was 5:8:15:10, and the concentration of intermediate 1 in acetone was 0.5 mol / L; the mixture was reacted for 5 h; the reaction was quenched by adding water, and the acetone in the reaction solution was removed by concentration; the reaction solution was extracted with ethyl acetate, and the combined ethyl acetate phase was washed with pure water; the filtrate was concentrated and purified by chromatography (eluent, V 石油醚 :V 乙酸乙酯 = 88:12) to obtain intermediate 2; the 1 H NMR result of intermediate 2 was the same as that of Example 1.

[0053] (3) 4-Hydroxy-3,4-dihydronaphthalen-l(2H)-one, potassium carbonate and intermediate 2 were added into anhydrous N,N-dimethylformamide, wherein the molar ratio of intermediate 2, 4-hydroxy-3,4-dihydronaphthalen-l(2H)-one, potassium carbonate and anhydrous N,N-dimethylformamide was 1:1.5:2.5, and the concentration of intermediate 2 in anhydrous N,N-dimethylformamide was 0.5 mol / L; after being stirred uniformly, the mixture was reacted at 110°C for 4 h; the reaction solution was cooled to room temperature, poured into ice water, and extracted with ethyl acetate; the organic layer was washed with water and saturated brine in turn; after being concentrated, the product was purified by column chromatography (eluent, V 石油醚 :V 乙酸乙酯 = 90:10) to obtain intermediate 3; the 1 H NMR result of intermediate 3 was the same as that of Example 1.

[0054] (4) Under nitrogen protection, intermediate 3 was added into tetrahydrofuran, and cooled to -5°C; tetra-n-butylammonium fluoride was added, wherein the molar ratio of intermediate 3 and tetra-n-butylammonium fluoride was 1:1.5, and the concentration of intermediate 3 in tetrahydrofuran was 0.5 mol / L; the mixture was reacted at 20°C for 4 h; the reaction was quenched with saturated ammonium chloride solution, and the reaction solution was extracted with ethyl acetate; the organic phase was filtered, concentrated and purified by chromatography (eluent, V 正己烷 :V 乙酸乙酯 = 85:15), and then dried to obtain the paeonol derivative. The 1 H NMR result of the paeonol derivative was the same as that of Example 1. The preparation method of the above anti-anxiety γ-aminobutyric acid composition was the same as that of Example 1.

[0055] Comparative Example 1

[0056] This comparative example was basically the same as Example 1, except that the paeonol derivative was replaced by paeonol; the other conditions were the same as those of Example 1.

[0057] Comparative Example 2

[0058] The present comparative example and Example 1 are basically the same, except that the addition of Asterosaponin is omitted; the others are the same as Example 1.

[0059] Test Example 1

[0060] 1.1 Experimental animals

[0061] C57BL / 6 mice were selected as experimental animals, weighing 20-24 g, SPF level, a total of 70, randomly divided into 7 groups, namely: model group, blank control group, Example 1 group, Example 2 group, Example 3 group, Comparative Example 1 group, Comparative Example 2 group, 10 in each group, adaptive feeding for one week, during which free water and food were provided.

[0062] 1.2 Construction of animal insomnia model

[0063] Except for the blank control group, the C57BL / 6 mice in the other groups were injected intraperitoneally with DL-4-chlorophenylalanine (PCPA) at a dose of 350 mg / kg / d, and the injection was continued for 7 days. The mice showed anxiety and depression-like behavior (such as weight loss, irritability, and increased aggression). The model was successfully constructed. The blank control group was given the same amount of normal saline by gavage every day.

[0064] 1.3 Drug intervention treatment

[0065] Examples 1-3 and Comparative Examples 1-2 were given 100 mg / kg / d of the composition by gavage (such as Example 1 was given the composition of Example 1 by gavage), and the blank control group and the model group were given the same volume of normal saline, for 7 consecutive days.

[0066] 1.4 Animal behavior experiment

[0067] 1.4.1 Open field experiment

[0068] After the last administration for 1 h, the mice in each group were placed in the open field box, and first allowed to adapt to the environment for 1 min. Then the mice were removed and placed in the center of the open field box. The activity of the mice in the box within 10 min was recorded. The whole experiment was kept quiet, and the total movement distance and movement rate of the mice were detected.

[0069] Table 1

[0070] Group Total distance of movement (cm) Average speed (cm / s) blank control group 2567.63 5.65 model group 3651.54 11.23 Example 1 2678.12 6.01 Example 2 2735.78 6.58 Example 3 2706.15 6.36 Comparative Example 1 2856.54 7.82 Comparative Example 2 3010.27 8.25

[0071] The distance and time spent moving in mice can serve as indicators of mouse behavior, reflecting the impact of drug intervention on anxiety or depression. Total distance and average speed are positively correlated with the activity level of the mice. Observing the experimental results in Table 1, it can be seen that compared with the blank control group, the model group showed a significant increase in distance and a significant increase in average speed; these results indicate that the mice in the model group exhibited higher levels of exploratory behavior, anxiety, and tension in the new environment. Compared with the model group, the distance and average speed of mice in Examples 1-3 decreased. This indicates that the composition obtained in this invention alleviates anxiety symptoms to some extent. Compared with Example 1, the mice in Comparative Examples 1 and 2 showed an increase in total distance and an increase in average speed, indicating more severe anxiety levels, suggesting that at the same dosage, the paeonol derivative is more effective than paeonol.

[0072] 1.4.2 Elevated Cross Maze Experiment

[0073] The elevated cruciate maze for mice consisted of two opposing open arms, two opposing closed arms, and a central platform connecting all four arms. The central platform connected the two open arms and the two closed arms. One hour after the last drug administration, the mice were placed in the box at the central platform and allowed to explore for approximately 10 minutes while white noise was played to eliminate distracting sounds. The time the mice spent in the closed arms was recorded within each 5-minute interval. The percentage of time the mice spent in the open arms was calculated as a percentage of the total time, and this was used as an indicator of the mice's anxiety level. The shorter the time the mice spent in the open arms, the more severe their anxiety symptoms. The experimental results are shown in Table 2.

[0074] Table 2

[0075] Group Percentage of time spent in open arms to total time (%) blank control group 29.54 model group 12.31 Example 1 28.52 Example 2 26.95 Example 3 28.13 Comparative Example 1 23.28 Comparative Example 2 20.35

[0076] As shown in Table 2, the mice in Examples 1-3 spent a longer time in the open arm than those in Comparative Examples 1 and 2, indicating that in the maze experiment, both paeonol derivatives and starfruit saponins could increase the time mice spent in the open arm. Comparing Example 1 and Comparative Example 1, it can be seen that within a smaller dosage range, the introduction of paeonol derivatives is much more effective than paeonol itself. That is, compared to paeonol, paeonol derivatives can reduce the dosage, and when used in combination with γ-aminobutyric acid and starfruit saponins, they can still maintain good efficacy and alleviate anxiety symptoms.

[0077] 1.4.3 Sodium pentobarbital sleep experiment

[0078] After the last administration, 1h, each group of mice was intraperitoneally injected with a sodium pentobarbital suspension at a dose of 50mg / kg, and the mice were placed on a cushion with their abdomens facing upwards, and the sleep latency and sleep duration of the mice were recorded. The sleep latency was recorded from the end of intraperitoneal injection to 1min after the mouse righting reflex disappeared (defined as falling asleep), and the sleep duration was recorded from the mouse falling asleep to the mouse righting reflex recovering (defined as waking up). The experimental results are recorded in Table 3.

[0079] Table 3

[0080] Group Sleep latency (s) Sleep duration (min) blank control group 215.52 65.13 model group 365.19 41.12 Example 1 218.51 85.89 Example 2 219.34 81.76 Example 3 219.63 83.45 Comparative Example 1 232.13 75.23 Comparative Example 2 246.45 64.12

[0081] As can be seen from Table 3, compared with the blank control group, the sleep latency of the mice in the model group was significantly prolonged, and the sleep duration was also shortened. Compared with the model group, the sleep latency of the mice in Examples 1-3 was shortened, and the sleep duration was prolonged.

[0082] In Comparative Examples 1-2, the paeonol derivative was replaced by paeonol, and the sea star saponin was omitted. The sleep latency of both was prolonged compared with Example 1, and the sleep duration also had a shortening trend, indicating that the paeonol derivative of the present application can synergistically act with components such as sea star saponin, shorten the sleep latency, prolong the sleep time, and thus increase the treatment effect on insomnia and anxiety.

[0083] The above embodiments are only preferred embodiments of the present application, and cannot be used to limit the scope of protection of the present application. Any non-substantial changes and substitutions made by those skilled in the art on the basis of the present application are within the scope of protection of the present application.

Claims

1. An anti-anxiety γ-aminobutyric acid composition, characterized in that, The product comprises, by weight, the following components: 1-2 parts of paeonol derivative, 0.1-0.5 parts of γ-aminobutyric acid, 0.1-0.3 parts of astaxanthin, and 0.01-0.05 parts of starfish saponins; the chemical structural formula of the paeonol derivative is as follows: ； The preparation process of the paeonol derivative includes the following steps: (1) Paeonol was added to a solvent, and chloromethyl methyl ether was added dropwise to react. After filtration, washing and drying, intermediate 1 was obtained. (2) Intermediate 1, tert-butyldimethylchlorosilane, imidazole and 1-butyl-3-methylimidazolium hexafluorophosphate were added to a solvent and reacted. After washing, concentration and purification, intermediate 2 was obtained. (3) Add 4-hydroxy-3,4-dihydronaphthyl-1(2H)-one, potassium carbonate and intermediate 2 to a solvent, heat and react, and then wash, concentrate and purify to obtain intermediate 3; (4) Add intermediate 3 and tetrabutylammonium fluoride to the solvent for reaction, and then filter, concentrate, purify and dry to obtain the paeonol derivative.

2. The anti-anxiety γ-aminobutyric acid composition according to claim 1, characterized in that, In step (1), the molar ratio of paeonol to chloromethyl methyl ether is 1:(2-2.2), the concentration of paeonol in the solvent is 1-2 mol / L, the solvent is acetic acid, and the reaction time is 5-8 h.

3. The anti-anxiety γ-aminobutyric acid composition according to claim 1, characterized in that, In step (2), the molar ratio of intermediate 1, tert-butyldimethylchlorosilane, imidazole and 1-butyl-3-methylimidazolium hexafluorophosphate is 5:(6-8):(12-15):(8-10); the concentration of intermediate 1 in the solvent is 0.5-1 mol / L, and the solvent is acetone; the reaction time is 2-5 h.

4. The anti-anxiety γ-aminobutyric acid composition according to claim 1, characterized in that, In step (3), the molar ratio of intermediate 2, 4-hydroxy-3,4-dihydronaphthyl-1(2H)-one, and potassium carbonate is 1:(1.2-1.5):(2-2.5), the concentration of intermediate 2 in the solvent is 0.2-0.5 mol / L, and the solvent is anhydrous N,N-dimethylformamide.

5. The anti-anxiety γ-aminobutyric acid composition according to claim 1, characterized in that, In step (3), the heating reaction is carried out at a temperature of 95~110℃ for 4~8h.

6. The anti-anxiety γ-aminobutyric acid composition according to claim 1, characterized in that, In step (4), the molar ratio of intermediate 3 to tetrabutylammonium fluoride is 1:(1.2-1.5), the concentration of intermediate 3 in the solvent is 0.2-0.5 mol / L, and the solvent is tetrahydrofuran.

7. The anti-anxiety γ-aminobutyric acid composition according to claim 1, characterized in that, In step (4), the reaction temperature is 15-20°C and the time is 3-6h.

8. A method for preparing the anti-anxiety γ-aminobutyric acid composition according to any one of claims 1-7, characterized in that, The process includes the following steps: weigh out the prescribed amounts of paeonol derivative, γ-aminobutyric acid, astaxanthin, and starfish saponins, mix them evenly, and add excipients to obtain the final product.

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