A composition for improving sleep and use thereof

Abstract

The application provides a composition for improving sleep and application thereof, and belongs to the technical field of biological medicine. The composition for improving sleep provided by the application comprises ginsenoside RK1 and gamma-aminobutyric acid, the composition has a good sleep improving effect, can obviously increase the content of gamma-aminobutyric acid in brain tissue and the content of 5-hydroxytryptamine, and has a better sleep improving effect, can relieve insomnia, anxiety and nervousness, and can improve sleep quality. Meanwhile, the composition has no side effect on human bodies, has high product safety, has a simple preparation method, controllable quality, is convenient to operate, has low production cost, can realize industrialized continuous production, and the like.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and more specifically, to a composition comprising improving sleep and its application. Background Technology

[0002] Sleep problems have become a widespread issue in modern society, and good sleep has a significant impact on physical and mental health. Surveys indicate that approximately one-third of the global population suffers from sleep deprivation, with insomnia being particularly prevalent. The negative effects of insomnia and sleep disorders include daytime fatigue, poor concentration, mood swings, and a weakened immune system, severely impacting quality of life and work efficiency.

[0003] Currently, sleep medications are mainly classified into hypnotics, antidepressants, and sedatives. However, long-term use of these medications can cause side effects such as dizziness and nausea, as well as drug tolerance and addiction, negatively impacting health. Therefore, the development of naturally derived compositions with sleep-improving effects is receiving increasing attention. Consequently, developing products with sleep-improving efficacy has become a current research hotspot.

[0004] In view of this, the present invention is proposed. Summary of the Invention

[0005] The purpose of this invention is to provide a composition for improving sleep and its application, which combines ginsenoside RK1 and GABA (γ-aminobutyric acid) to obtain a composition that can synergistically improve sleep.

[0006] This invention is implemented as follows:

[0007] In a first aspect, the present invention provides a composition for improving sleep, the composition comprising ginsenoside RK1 and γ-aminobutyric acid.

[0008] In some embodiments, the mass ratio of ginsenoside RK1 to γ-aminobutyric acid in the above composition is 1:(6~20).

[0009] In some embodiments, the mass ratio of ginsenoside RK1 to γ-aminobutyric acid in the above composition is 1:(8~15).

[0010] In some embodiments, the mass ratio of ginsenoside RK1 to γ-aminobutyric acid in the above composition is 1:10.

[0011] In some embodiments, ginsenoside RK1 and γ-aminobutyric acid in the above composition are both monomeric components.

[0012] Secondly, the present invention provides the use of the above composition in the preparation of products that improve sleep.

[0013] Thirdly, the present invention provides the use of the above composition in the preparation of products that regulate the level of γ-aminobutyric acid in brain tissue.

[0014] Fourthly, the present invention provides the use of the above composition in the preparation of products that regulate 5-hydroxytryptamine levels in brain tissue.

[0015] Fifthly, the present invention provides a medicament comprising the above-described composition and pharmaceutically acceptable excipients.

[0016] The present invention has the following beneficial effects:

[0017] This invention relates to a composition formulated from ginsenoside RK1 and γ-aminobutyric acid (GABA). This composition exhibits excellent sleep-improving effects, significantly increasing the levels of GABA and serotonin in brain tissue, thereby enhancing sleep quality, alleviating insomnia, anxiety, and tension. Furthermore, this composition has no side effects on the human body, ensuring high product safety. The preparation method is simple, quality is controllable, easy to operate, and has low production costs, enabling continuous industrial production. Attached Figure Description

[0018] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0019] Figure 1 The structural formula of γ-aminobutyric acid;

[0020] Figure 2 The structural formula of ginsenoside RK1. Detailed Implementation

[0021] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0022] GABA (gamma-aminobutyric acid) is a neurotransmitter with the following structural formula: Figure 1As shown, it plays a role in inhibiting neuronal activity in the brain. Studies have shown that GABA can help reduce over-excitation in the brain by regulating the nervous system, thereby alleviating insomnia, improving sleep quality, and relieving sleep disorders. Ginsenoside RK1 (structural formula as shown) Figure 2 (As shown) is a rare active ingredient from ginseng. This ingredient can regulate the human nervous and endocrine systems, thereby promoting relaxation and sleep, improving sleep quality, and relieving insomnia. However, at present, ginsenoside RK1 is mainly used for anti-inflammatory, anti-cancer, and antibacterial purposes. There are no reports on the preparation of products that improve sleep by using ginsenoside RK1 or combining it with other ingredients.

[0023] Based on this, the present invention proposes to combine ginsenoside RK1 with GABA to prepare a new composition with sleep-improving effects.

[0024] Experimental results show that the sleep-improving effects of ginsenoside RK1 and GABA vary significantly depending on their ratio. The optimal ratio selected by this invention is a mass ratio of ginsenoside RK1 to GABA of 1:(6~20).

[0025] To achieve better results, the inventors optimized the mass ratio described above and found that when the mass ratio of the two components was 1:(8~15), the combination of ginsenoside RK1 and GABA exhibited a synergistic effect, while outside this range, the combination showed an antagonistic effect. Specifically, the combination index CI of ginsenoside RK1 and GABA was less than 1.

[0026] Furthermore, when the mass ratio of the two components is 1:10, the synergistic effect of the combination of ginsenoside RK1 and GABA is optimal, which can more effectively improve sleep.

[0027] Among them, ginsenoside RK1 and GABA are both known compounds that can be obtained by conventional preparation methods in the field or by purchasing. The present invention does not limit their preparation methods or sources.

[0028] The sleep improvement described in this invention is manifested in the ability of the above-mentioned composition to regulate the levels of γ-aminobutyric acid (GABA) and serotonin (5-HT) in brain tissue. Specifically, the above-mentioned composition can increase the levels of GABA and serotonin in brain tissue.

[0029] The compositions of the present invention can be used to prepare related sleep-improving products, including pharmaceuticals.

[0030] In some embodiments, the compositions of the present invention can be formulated into a pharmaceutical product using techniques known to those skilled in the art. The pharmaceutical product may or may not contain other ingredients; these other ingredients may be substances that improve sleep or pharmaceutically acceptable excipients.

[0031] In some embodiments, the pharmaceutical products prepared from the compositions of the present invention may further include pharmaceutically acceptable excipients, such as diluents, disintegrants, lubricants, excipients, binders, flow aids, fillers, surfactants, etc. Other excipients, such as flavoring agents and sweeteners, may also be added to the composition.

[0032] The diluent can be one or more components that increase the weight and volume of the tablets. Commonly used diluents include lactose, starch, pregelatinized starch, microcrystalline cellulose, sorbitol, mannitol, and inorganic calcium salts. The disintegrant can be one or a mixture of crospyvinylpyrrolidone, crospycarboxymethyl cellulose sodium, alginate, and microcrystalline cellulose. The lubricant includes one or a mixture of stearic acid, sodium stearate, magnesium stearate, calcium stearate, polyethylene glycol, talc, and hydrogenated vegetable oil. The binder can be one or more components that facilitate granulation, such as starch paste, hydroxypropyl methylcellulose, or polyvinylpyrrolidone. The glidant can be one or a mixture of micronized silica gel, talc, and magnesium trisilicate. The surfactant can be one or more components that improve wetting and increase drug dissolution, such as sodium lauryl sulfate.

[0033] In some embodiments, the medicament prepared from the compositions of the present invention can be a solid dosage form, a liquid dosage form, an oral dosage form, or an injectable dosage form. Oral dosage forms include, but are not limited to, the following dosage forms: hard capsules, soft capsules, sustained-release capsules, tablets, sugar-coated tablets, powders, granules, drop pills, water-honey pills, syrups, or oral liquids. Injectable dosage forms can be solutions, suspensions, emulsions, or lyophilized powders.

[0034] By taking or injecting the medicine prepared from the composition provided by this invention, sleep can be effectively improved. The medicine can be taken or injected into mammals, such as humans, rats, rabbits, sheep, pigs, cattle, cats, dogs, monkeys, etc., preferably humans.

[0035] When the composition provided by this invention is prepared into a medicine, the dosage depends on factors such as the specific severity of symptoms, the age, gender, weight, sensitivity differences, method of administration, timing of administration, interval of administration, nature of the preparation, and type of active ingredient. As a guideline, the dosage is as follows: the amount of the composition in the medicine for an adult (weight 60 kg) per day is usually 1µg to 400mg, preferably 1mg to 400mg, more preferably 100mg to 400mg, more preferably 200mg to 400mg, more preferably 200mg to 350mg, more preferably 300mg to 350mg (based on the total amount of ginsenoside RK1 and GABA (γ-aminobutyric acid)). The above dosage can usually be divided into 1 to 2 doses per day.

[0036] The present invention will be further described below with reference to specific embodiments.

[0037] The ginsenoside RK1 used in this invention embodiment was purified in our laboratory. The specific purification method is referred to in "Study on the Inhibitory Effect of Ginsenoside Rk1 on the Growth and Metastasis of Hepatocellular Carcinoma", Lu Haoping, 2022, Northwest University, DOI:10.27405 / d.cnki.gxbdu.2022.001760; GABA was purchased from Shanghai Licheng Nutrition Technology Co., Ltd.

[0038] Example 1

[0039] This embodiment is a composition for improving sleep, comprising the following components in parts by weight:

[0040] Ginsenoside RK1 1 part, GABA 4 parts.

[0041] Ginsenoside RK1 and GABA are mixed in a certain proportion and then thoroughly mixed to form composition 1.

[0042] Example 2

[0043] This embodiment is a composition for improving sleep, comprising the following components in parts by weight:

[0044] Ginsenoside RK1 1 part, GABA 6 parts.

[0045] Ginsenoside RK1 and GABA acid are mixed in a certain proportion and then mixed well to form composition 2.

[0046] Example 3

[0047] This embodiment is a composition for improving sleep, comprising the following components in parts by weight:

[0048] Ginsenoside RK1 1 part, GABA 8 parts.

[0049] Ginsenoside RK1 and GABA are mixed in a certain proportion and then mixed evenly to form composition 3.

[0050] Example 4

[0051] This embodiment is a composition for improving sleep, comprising the following components in parts by weight:

[0052] Ginsenoside RK1 1 part, GABA 10 parts.

[0053] Ginsenoside RK1 and GABA are mixed in a certain proportion and then mixed well to form composition 4.

[0054] Example 5

[0055] This embodiment is a composition for improving sleep, comprising the following components in parts by weight:

[0056] Ginsenoside RK1 1 part, GABA 12 parts.

[0057] Ginsenoside RK1 and GABA are mixed in a certain proportion and then mixed evenly to form composition 5.

[0058] Experimental Example 1

[0059] This experiment was conducted to verify the effect of the compositions of Examples 1-5 on the level of GABA in mouse brain tissue. The experimental groups were compositions 1, 2, 3, 4, and 5 of Examples 1-5. Ginsenoside RK1 and GABA were administered separately as controls.

[0060] Animal source: 120 male Kunming mice, weighing 18 kg each. 22g, provided by the Animal Center of Xi'an Jiaotong University, with a 3-day acclimatization observation period before the experiment.

[0061] Animal grouping: The experimental group consisted of 10 groups, namely ginsenoside RK1 group, GABA group 1, GABA group 2, GABA group 3, GABA group 4, GABA group 5, and combination 1. Five groups and a blank control group were included, with 10 mice in each group. The control group was given an equal volume of blank solution. Each mouse was given 0.2 ml / 10 g of solution by gavage once a day for 30 consecutive days.

[0062] Instruments, equipment, and reagents: GABA(γ) Gamma-aminobutyric acid (GABA) reagent kit (Nanjing Jiancheng Biotechnology Co., Ltd.); Microplate reader (BioTek Epoch).

[0063] Experimental Methods: After 30 days of continuous gavage, animals were fasted but allowed free access to water for 1 day. The following morning, after weighing, animals were euthanized by cervical dislocation, decapitated on ice, and the brain was extracted. The hypothalamus tissue was isolated, rinsed with pre-cooled physiological saline, dried with filter paper, and weighed. Nine times the volume of physiological saline was added at a body weight (g) to volume (mL) ratio of 1:9, and the tissue was homogenized using a glass homogenizer under ice-water bath conditions. Centrifugation was performed at 2500 r / min (13.5 cm radius) for 10 min, and the supernatant was collected for analysis. Detection and analysis were performed according to the GABA reagent kit's operating procedures.

[0064] The combination index CI of the ginsenoside RK1 / GABA combination is calculated as (A×B) / AB, where T is the GABA content in the control group and C is the GABA content in each experimental group. For example, A and B are the C / T values ​​of the ginsenoside RK1 group and the different doses of GABA administered alone, and AB is the C / T value of the ginsenoside RK1 group and GABA administered in combination. When CI < 1, the two combinations have a synergistic effect.

[0065] The statistical results are shown in Table 1:

[0066] Table 1. Effects of each composition on GABA content in mouse brain tissue (n=10, x±s)

[0067]

[0068] Note: Composition 1 The dosage of 5 was successively applied to the ginsenoside RK1 group and the GABA group. The combined dosage of the five phases.

[0069] As shown in Table 1, the drug combination index (CI) values ​​of compositions 2-5, compared with those of ginsenoside RK1 and the corresponding doses of GABA alone, were all less than 1. However, the CI value of composition 1 was greater than 1. This indicates that ginsenoside RK1 and GABA can synergistically upregulate GABA levels in mouse brain tissue within a certain ratio range, thereby improving sleep. However, outside the scope of this invention, there is no synergistic effect. GABA is an inhibitory neurotransmitter that mainly exerts its sedative-hypnotic effect through its specific binding to the GABA receptor (GABAA).

[0070] Experiment Example 2

[0071] This experiment aims to verify the effects of the compositions of Examples 1-5 on 5% of mouse brain tissue. Effects of HT levels

[0072] For the setup of the drug administration group, animal sources, and animal grouping, refer to Experimental Example 1.

[0073] Instruments, equipment and reagents: 5 serotonin (5) hydroxytryptamine, 5 HT reagent kit (Nanjing Jiancheng Biotechnology Co., Ltd.); ELISA reader (BioTek Epoch).

[0074] Methods: After 30 days of continuous gavage, animals were fasted but allowed free access to water for 1 day. The following morning, after weighing, animals were euthanized by cervical dislocation, decapitated on ice, and the brain was extracted. Hypothalamic tissue was isolated, rinsed with pre-cooled physiological saline, dried with filter paper, and weighed. Nine times the volume of physiological saline was added at a body weight (g):volume (mL) ratio of 1:9, and the tissue was homogenized using a glass homogenizer under ice-water bath conditions. Centrifugation was performed at 2500 r / min for 10 min with a radius of 13.5 cm, and the supernatant was collected for analysis. (Based on 5...) The HT reagent kit is used for detection and analysis.

[0075] Calculate the drug combination index CI = (AxB) / AB for the ginsenoside RK1 / GABA combination, where T is the control group (5). HT content, C is 5 for each experimental group HT content, for example, A and B are the C / T values ​​of ginsenoside RK1 and different doses of GABA administered alone, while AB is the C / T value of ginsenoside RK1 and different doses of GABA administered in combination. When CI < 1, the two saponin combinations have a synergistic effect.

[0076] The statistical results are shown in Table 2:

[0077] Table 2. Effects of each composition on mouse brain tissue 5 Effect of HT content (n=10, x±s)

[0078]

[0079] Note: Composition 1 The dosage of 5 was successively applied to the ginsenoside RK1 group and the GABA group. The combined dosage of the five phases.

[0080] As shown in Table 2, the drug combination index (CI) values ​​of compositions 2-5 are all less than 1, while the CI value of composition 1, compared with the individual effects of ginsenoside RK1 and the corresponding dose of GABA, is greater than 1. This indicates that ginsenoside RK1 and GABA can synergistically upregulate the levels of 5-hydroxyvitamin B5 in mouse brain tissue within a certain ratio range. HT levels, but outside the scope of this invention, do not have a synergistic effect. 5 HT is an important monoamine neurotransmitter involved in sleep regulation, and is found in the brain. A decrease in HT levels can lead to insomnia.

[0081] Experimental Example 3

[0082] This experiment aims to verify the effects of the compositions from Examples 1-5 on sodium pentobarbital sleep time and sleep latency in mice.

[0083] For the setup of the drug administration group, animal sources, and animal grouping, refer to Experimental Example 1.

[0084] Instruments, equipment, and reagents: Sodium pentobarbital (Sigma-Aldrich, USA)

[0085] Methods: After 30 consecutive days of gavage administration, 15 minutes after the last administration, mice in the control group and other dosage groups were intraperitoneally injected with 0.1 mL / 10 g·BW sodium pentobarbital solution at a concentration of 45 mg / kg·BW. Sleep patterns were observed after administration. Sleep duration and sleep latency were recorded for each group after pentobarbital administration. The absence of a righting reflex at the last administration was considered an indicator of sleep. If a mouse did not respond to touching, pulling, or turning actions for more than 60 seconds, it was considered to be asleep. The return of the righting reflex indicated awakening. The time from the disappearance of the righting reflex to its recurrence was recorded as the sleep duration. Simultaneously, the time from intraperitoneal injection to the mouse's lack of response was recorded as the sleep latency. The sleep prolongation rate and sleep latency shortening rate were calculated.

[0086] The statistical results are shown in Table 3:

[0087] Table 3. Effects of each composition on sodium pentobarbital sleep time in mice (n = 10, x ± s)

[0088]

[0089] Note: Composition 1 The dosage of 5 was successively applied to the ginsenoside RK1 group and the GABA group. The combined dosage of the five phases.

[0090] Table 3 shows that, after injection of sodium pentobarbital into mice, compared with the blank control group, the sleep duration prolongation rate and sleep latency shortening rate in the group treated with Composition 1 were lower than those in the group treated with ginsenoside RK1 alone, while the sleep duration prolongation rate and sleep latency shortening rate in the groups treated with Compositions 2-4 were higher than those in the groups treated with ginsenoside RK1 alone. This indicates that ginsenoside RK1 and GABA can synergistically prolong sleep duration and shorten sleep latency in mice within a certain ratio range, but outside the scope of this invention, there is no synergistic effect.

[0091] In summary, the combination of ginsenoside RK1 and GABA in this invention can upregulate the levels of GABA and 5-HT in mouse brain tissue, thereby prolonging sleep time and shortening sleep latency, achieving therapeutic effects on insomnia or improving sleep. In all animal experiments involved in this invention, all groups of animals moved freely, and no abnormal weight, food intake, or food consumption were observed. There were no statistically significant differences compared to the control group, indicating that the combination of ginsenoside RK1 and GABA is safe for in vivo treatment in mice.

[0092] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A composition for improving sleep, characterized by, The mass ratio of ginsenoside RK1 and gamma-aminobutyric acid in the composition is 1: (6-20).

2. The composition of claim 1, wherein, The mass ratio of ginsenoside RK1 and gamma-aminobutyric acid in the composition is 1: (8-15).

3. The composition of claim 1, wherein, The mass ratio of ginsenoside RK1 and gamma-aminobutyric acid in the composition is 1:

10.

4. The composition according to any one of claims 1 to 3, characterized in that, The ginsenoside RK1 and gamma-aminobutyric acid in the composition are monomer components.

5. Use of the composition of claim 4 in the preparation of a sleep-improving drug.

6. Use according to claim 5, characterized in that, The composition regulates the level of gamma-aminobutyric acid in brain tissue.

7. Use according to claim 5, characterized in that, The composition regulates the level of 5-hydroxytryptamine in brain tissue.

8. A medicament, characterized by comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof. The composition comprises the composition of any one of claims 1-3 and a pharmaceutically acceptable excipient.

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