A traditional Chinese medicine composition for synergistically improving sleep and daytime fatigue, a preparation method and application thereof

Abstract

The application provides a traditional Chinese medicine composition for synergistically improving sleep and daytime fatigue, a preparation method and application, and relates to the field of traditional Chinese medicines. The traditional Chinese medicine composition comprises a daytime formula and a nighttime formula. In terms of weight parts, the monarch drug of the daytime formula is gardenia 2-5 parts, soybean sprout 2-5 parts, bergamot 1-5 parts and perilla stem 2-5 parts; the monarch drug of the nighttime formula is gardenia 2-5 parts, soybean sprout 2-5 parts, bergamot 1-5 parts and perilla stem 2-5 parts; the daytime formula further comprises American ginseng, astragalus and mint; and the nighttime formula further comprises jujube seed, lily, lotus seed, Chinese plum and jujube. The daytime formula has the functions of clearing heart and liver, benefiting qi and refreshing spirit, and aims at relieving the insomnia patients of 'daytime inattentiveness'; the nighttime formula has the functions of clearing heart and liver, nourishing yin and tranquilizing spirit, and focuses on improving 'nighttime insomnia', and significantly synergistically improves sleep and daytime fatigue.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine, and in particular to a traditional Chinese medicine composition that synergistically improves sleep and daytime fatigue, as well as its preparation method and application. Background Technology

[0002] Insomnia refers to a subjective experience where a patient is dissatisfied with the duration and / or quality of their sleep, which affects their daytime social functioning. With the accelerated pace of modern life, psychological factors have gradually become important influences on sleep. Long-term insomnia seriously affects patients' quality of life and mental and physical health, and is closely related to the occurrence of anxiety, depression, and cardiovascular and cerebrovascular diseases. Currently, commonly used clinical treatments for insomnia include cognitive behavioral therapy (CBT) and sedative-hypnotic drugs. However, CBT is relatively difficult to implement clinically, and patient compliance is poor, while hypnotic drugs have side effects such as drowsiness and daytime fatigue, and are prone to dependence and tolerance. Furthermore, current clinical treatments focus primarily on nighttime sleep, with insufficient attention paid to daytime functional impairments caused by insomnia. Therefore, from the perspective of the holistic view of Traditional Chinese Medicine (TCM), actively exploring new and effective prescriptions is of great significance for improving the overall health of insomnia patients. Providing a TCM composition that can effectively treat insomnia, especially synergistically improve daytime fatigue, is a technical problem that urgently needs to be solved by those skilled in the art.

[0003] Existing technology CN116983345A discloses a traditional Chinese medicine composition for treating anxiety, depression, and insomnia, and its application, comprising the following raw materials in parts by weight: Gardenia jasminoides 7-15 parts, fermented soybean 8-18 parts, Bupleurum chinense 7-15 parts, Paeonia lactiflora 6-18 parts, Hypericum perforatum 1-6 parts, Ziziphus jujuba var. spinosa 8-25 parts, and Acanthopanax senticosus 10-28 parts. However, this traditional Chinese medicine composition mainly targets the improvement of nighttime sleep and does not address daytime fatigue. Furthermore, given the chronic nature of insomnia, long-term use may damage the spleen and stomach. Summary of the Invention

[0004] This invention addresses the shortcomings of current traditional Chinese medicine compositions for improving insomnia, which only target nighttime sleep and have no effect on daytime fatigue. It provides a traditional Chinese medicine composition that synergistically improves both sleep and daytime fatigue. Through the synergistic interaction of daytime and nighttime formulas, it addresses daytime fatigue while improving nighttime sleep. Furthermore, this invention's composition is based on the concept of food and medicine sharing the same origin, making it more suitable for long-term use by insomnia patients.

[0005] Another objective of this invention is to provide a method for preparing a traditional Chinese medicine composition that synergistically improves sleep and daytime fatigue.

[0006] Another objective of this invention is to provide the application of a traditional Chinese medicine composition that synergistically improves sleep and daytime fatigue in the preparation of a medicament that synergistically improves daytime fatigue and nighttime sleep quality.

[0007] Another object of the present invention is to provide a pharmaceutical preparation.

[0008] In a first aspect, the present invention protects a traditional Chinese medicine composition for synergistically improving sleep and daytime fatigue, comprising a daytime formula and a nighttime formula: By weight, the principal herbs in the daytime prescription are 2-5 parts gardenia, 2-6 parts fermented soybean, 1-5 parts citron, and 2-5 parts perilla stem; By weight, the principal herbs in the nighttime formula are 2-5 parts gardenia, 2-6 parts fermented soybean, 1-5 parts citron, and 2-5 parts perilla stem; The daytime formula also includes American ginseng, astragalus, and peppermint; The nighttime formula also includes jujube seed, lily bulb, lotus seed, dried plum, and jujube.

[0009] According to the traditional Chinese medicine composition for synergistically improving sleep and daytime fatigue provided by the present invention, preferably, the mass ratio of gardenia, fermented soybean, citron, and perilla stem in the principal ingredient of the daytime formula is 1:1:1:1. According to the traditional Chinese medicine composition for synergistically improving sleep and daytime fatigue provided by the present invention, preferably, the mass ratio of gardenia, fermented soybean, citron, and perilla stem in the principal ingredient of the nighttime formula is 1:1:1:1.

[0010] The traditional Chinese medicine composition for synergistically improving sleep and daytime fatigue provided by the present invention preferably contains, by weight, 1-2 parts of American ginseng, 2-5 parts of astragalus, and 1-3 parts of peppermint in the daytime formula.

[0011] The traditional Chinese medicine composition for synergistically improving sleep and daytime fatigue provided by the present invention preferably includes, by weight, 1-3 parts of Alpinia oxyphylla and 2-4 parts of Rubus idaeus.

[0012] According to the traditional Chinese medicine composition for synergistically improving sleep and daytime fatigue provided by the present invention, preferably, by weight, the nighttime formula contains 3-5 parts of jujube seed, 2-4 parts of lily bulb, 2-5 parts of lotus seed, 2-4 parts of dried plum, and 2-5 parts of jujube.

[0013] The traditional Chinese medicine composition for synergistically improving sleep and daytime fatigue provided by the present invention preferably includes, by weight, the daytime formula as follows: 3 parts gardenia, 3 parts fermented soybean, 3 parts citron, 3 parts perilla stem, 1 part American ginseng, 3 parts astragalus, 1 part alpinia oxyphylla, 3 parts raspberry, and 2 parts peppermint. The nighttime formula includes: 3 parts gardenia, 3 parts fermented soybean, 3 parts Buddha's hand, 3 parts perilla stem, 3 parts jujube seed, 3 parts lily bulb, 3 parts lotus seed, 3 parts dried plum, and 3 parts jujube.

[0014] Secondly, the present invention also provides a method for preparing a traditional Chinese medicine composition that synergistically improves sleep and daytime fatigue, comprising the following steps: Take each raw material according to the formula, add water to extract, concentrate, dry, and make into a powder. The amount of water added is 30 to 60 times the total weight of the raw materials.

[0015] Thirdly, the present invention also provides the application of a traditional Chinese medicine composition that synergistically improves sleep and daytime fatigue in the preparation of a drug that synergistically improves daytime fatigue and nighttime sleep quality.

[0016] Fourthly, the present invention also provides a pharmaceutical preparation prepared from raw materials comprising the aforementioned traditional Chinese medicine composition for synergistically improving sleep and daytime fatigue.

[0017] Beneficial effects: This invention provides a traditional Chinese medicine composition for synergistically improving sleep and daytime fatigue, comprising a daytime formula and a nighttime formula. The principal herbs in both formulas are: 2-5 parts Gardenia jasminoides, 2-6 parts Fermented soybean, 1-5 parts Citrus medica, and 2-5 parts Perilla frutescens stem. The daytime formula aims to clear the heart and soothe the liver, invigorate qi and refresh the mind, relieving daytime lethargy in insomnia patients. The nighttime formula aims to clear the heart and soothe the liver, nourish yin and calm the mind, improving nighttime insomnia. The entire formula works by guiding the body's defenses and promoting yang energy to refresh the mind during the day and guiding yang energy into yin energy to calm the mind at night. The treatment focuses on clearing the heart and soothing the liver to regulate the body's functions. The formula uses the principle of food and medicine sharing the same origin to nourish the spleen and stomach, conforming to the natural waxing and waning of yin and yang and the diurnal rhythm. It fully embodies the advantages of traditional Chinese medicine in the unity of man and nature, the holistic concept, and syndrome differentiation and treatment, significantly and synergistically improving nighttime sleep and daytime fatigue. Attached Figure Description

[0018] To make the content of this invention easier to understand, the invention will be further described in detail below with reference to specific embodiments and accompanying drawings.

[0019] Figure 1 This study describes the effect of the traditional Chinese medicine composition in Example 1 of the present invention on the seven individual items and total score of the subjects' PSQI scale.

[0020] Figure 2 This invention relates to the effects of the traditional Chinese medicine composition in Example 1 on two individual items and the total score of the subjects on the FS-14 scale.

[0021] Figure 3 This invention relates to the effect of the traditional Chinese medicine composition in Example 1 on the total score of the subjects' ESS scale.

[0022] Figure 4 This study examines the effects of the traditional Chinese medicine composition in Example 1 of the present invention on three individual items and the total score of the subjects on the DASS-21 scale.

[0023] Figure 5 This study examines the effects of the traditional Chinese medicine composition in Example 1 of the present invention on the main symptoms, secondary symptoms, and total score of the TCM syndrome scale of the subjects.

[0024] Figure 6This invention relates to the effect of the herbal composition in Example 1 on the time spent in WAKE, NREM, and REM sleep cycles in mice during a 24-hour sleep-wake cycle. Figure 7 The effect of the herbal composition in Example 1 of this invention on the total number of WAKE, NREM, and REM cycles in mice during a 24-hour sleep-wake cycle. Figure 8 This invention relates to the effect of the traditional Chinese medicine composition in Example 1 on the sleep latency of mice.

[0025] Figure 9 This invention relates to the effect of the traditional Chinese medicine composition in Example 1 on the duration of sleep in mice.

[0026] Figure 10 This invention relates to the effect of the traditional Chinese medicine composition in Example 1 on the swimming time of mice under load. Detailed Implementation

[0027] The following examples are for illustrative purposes only and are not intended to limit the scope of the invention. Where specific techniques or conditions are not specified in the examples, they should be performed according to the techniques or conditions described in the literature in this field, or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased from legitimate channels.

[0028] The abbreviations of this invention are explained as follows: Table 1: English Abbreviations

[0029] In a specific embodiment, the present invention provides a traditional Chinese medicine composition for synergistically improving sleep and daytime fatigue, comprising a daytime formula and a nighttime formula: By weight, the principal herbs in the daytime prescription are 2-5 parts gardenia, 2-6 parts fermented soybean, 1-5 parts citron, and 2-5 parts perilla stem; By weight, the principal herbs in the nighttime formula are 2-5 parts gardenia, 2-6 parts fermented soybean, 1-5 parts citron, and 2-5 parts perilla stem; The daytime formula also includes American ginseng, astragalus, and peppermint; The nighttime formula also includes jujube seed, lily bulb, lotus seed, dried plum, and jujube.

[0030] It should be noted that: The invention is defined as follows: Human sleep follows a circadian rhythm under the influence of the body's vital energy (ying and wei). Normal sleep is not merely about "nighttime rest," but also about "daytime essence." Therefore, the herbal composition of this invention treats insomnia by regulating the day and night, conforming to the natural waxing and waning of yin and yang and the circadian rhythm, fully embodying the advantages of traditional Chinese medicine's "harmony between man and nature," holistic view, and syndrome differentiation. Insomnia is increasingly affecting younger people and becoming chronic, with emotional and mental factors becoming increasingly important. The liver governs emotions and regulates the five internal organs; emotional distress leads to stagnation of liver qi, which over time transforms into heat. This affects the liver, disturbing the mind and spirit, resulting in liver fire disturbing the heart, considered a major pathogenesis of modern insomnia. Therefore, the treatment principle focuses on clearing the heart and soothing the liver. Furthermore, the herbal composition of this invention uses only food-grade medicinal materials, employing gentle and effective methods, advocating for nourishing the spleen and stomach through diet. The selection of medicinal and food-grade materials makes it more suitable for long-term use by insomnia patients.

[0031] The formula uses gardenia, fermented soybean, bergamot, and perilla stem as the principal herbs. Gardenia is red and bitter, entering the heart to treat irritability; fermented soybean is black and salty, entering the kidney to treat restlessness. The combination of these two herbs clears heat and irritability from the heart and liver, with a balance of ascending and descending properties, one purging and the other astringing. This further stimulates the yin essence of the kidneys in the lower burner to nourish the yin of the heart, preventing the heat from recurring. The liver is the source of insomnia, and liver qi can also rebel and invade the stomach. Bergamot primarily enters the liver and stomach, focusing on "soothing," while perilla stem primarily enters the lungs and spleen, focusing on "descending." The combination of these two herbs, one ascending and the other descending, ensures that the liver's dispersing and descending functions are balanced, and the stomach's descending functions are orderly, thus harmonizing yin and yang and promoting restful sleep.

[0032] Insomnia patients often experience daytime discomfort such as drowsiness, fatigue, weakness, dizziness, and emotional distress. During the day, Yang energy rises, so the herbal composition of this invention is used during the day to follow this rising Yang energy. American ginseng and astragalus are added to tonify Qi and raise Yang, while peppermint clears the head and eyes, thus improving daytime mental state and reducing daytime fatigue. Prolonged insomnia can deplete Qi and damage Yin. American ginseng tonifies Qi and Yin without being overly warming, while astragalus warms and tonifies the spleen and lungs without being overly drying. The combination of these two herbs, one warming and one cooling, tonifies without causing stagnation, improving daytime drowsiness. Peppermint, pungent and cool, ascends to the head and eyes, synergizing with astragalus's "raising Yang" effect to relieve dizziness and difficulty concentrating; its cooling properties also counteract the warming effects of ginseng and astragalus, ensuring the entire formula is "refreshing without causing internal heat."

[0033] At night, add jujube seed, lily bulb, lotus seed, and dried plum, which enter the heart meridian, to jointly nourish the heart and calm the mind. Jujube seed and dried plum are both sour and astringent, while lily bulb and lotus seed are both sweet and moistening. The sourness is aided by the sweetness, which promotes the generation of yin more quickly. When liver blood is sufficient, the soul is stored in the liver; when heart yin is sufficient, the spirit is at peace, directly improving the root cause of insomnia. Dried plum's sourness and astringency, combined with the sourness and astringency of jujube seed, can restrain the floating deficiency fire; lily bulb clears the heart and calms the mind, preventing excessive astringency; lotus seed connects the heart and kidneys, allowing the floating yang to return to the gate of life. With the upper and lower parts calling to each other, water and fire are in balance, so that "when sleeping at night, blood returns to the liver and the soul is at peace." Jujube seed and dried plum focus on "astringency," while lily bulb and lotus seed focus on "tonification." The combination of these four herbs prevents both excessive nourishment and excessive astringency, ensuring that tonification is not cloying and astringency is not stagnation. Prolonged illness inevitably leads to deficiency; therefore, it is essential to first strengthen the areas unaffected by pathogenic factors. Thus, jujubes are added to the formula, which not only invigorate qi and strengthen the spleen, nourish blood and calm the mind, but also embody the principle of "treating liver disease by first strengthening the spleen." The entire formula works by guiding the defensive qi and yang energy during the day to promote alertness, and by guiding yang energy into yin energy at night to aid calmness. The treatment aims to clear the heart, soothe the liver, and regulate the body's functions. The formula utilizes the principle of food and medicine sharing the same origin to nourish the spleen and stomach. Clinically, it has been used for patients with insomnia due to liver fire disturbing the heart, achieving very satisfactory therapeutic results. Furthermore, the medication is safe and has no significant side effects.

[0034] In some specific embodiments, by weight, the principal ingredient of the daytime formula mentioned in this invention, gardenia can be 2 parts, 3 parts, 4 parts, 5 parts, or any other range of values; fermented soybean can be 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, or any other range of values; Buddha's hand can be 1 part, 2 parts, 3 parts, 4 parts, 5 parts, or any other range of values; and perilla stem can be 2 parts, 3 parts, 4 parts, 5 parts, or any other range of values.

[0035] In some specific embodiments, by weight, the principal ingredient of the nighttime formula mentioned in this invention, gardenia can be 2 parts, 3 parts, 4 parts, 5 parts, or any other range of values; fermented soybean can be 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, or any other range of values; Buddha's hand can be 1 part, 2 parts, 3 parts, 4 parts, 5 parts, or any other range of values; and perilla stem can be 2 parts, 3 parts, 4 parts, 5 parts, or any other range of values.

[0036] In some specific embodiments, the mass ratio of Gardenia, Fermented Soybean, Citrus medica, and Perilla stem in the principal ingredient of the daytime formula mentioned in this invention is 1:1:1:1.

[0037] In some specific embodiments, the mass ratio of Gardenia, Fermented Soybean, Citrus medica, and Perilla stem in the principal ingredient of the night formula mentioned in this invention is 1:1:1:1.

[0038] In some specific embodiments, the present invention further preferably contains, by weight, 1-2 parts of American ginseng, 2-5 parts of astragalus, and 1-3 parts of peppermint in the daytime formula.

[0039] For example, a preferred combination is 1 part American ginseng, 3 parts astragalus, and 2 parts peppermint.

[0040] In some specific embodiments, in order to better synergistically improve sleep and relieve daytime fatigue, the present invention further preferably includes, by weight, 1-3 parts of Alpinia oxyphylla and 2-4 parts of Rubus idaeus.

[0041] For example, a preferred combination is 1 part Alpinia oxyphylla and 3 parts Rubus idaeus.

[0042] Simultaneously, the addition of Alpinia oxyphylla and Rubus idaeus tonifies the kidneys and strengthens essence, preventing excessive upward movement of Qi. The formula balances tonification and astringency. Alpinia oxyphylla warms and tonifies kidney Yang, raising clear Yang, while Rubus idaeus nourishes kidney essence and astringes floating Yang. The combination of warming and astringing ensures that Yang Qi rises to the brain without becoming excessive, and Yin essence is retained in the kidneys without leakage. Alpinia oxyphylla strengthens kidney Qi and astringes the seminal gate, while Rubus idaeus strengthens the bladder and retains body fluids. Together, they reduce nighttime awakenings and latent awakenings, ensuring sleep continuity.

[0043] In some specific embodiments, the present invention further preferably contains, by weight, 3-5 parts of jujube seed, 2-4 parts of lily bulb, 2-5 parts of lotus seed, 2-4 parts of dried plum, and 2-5 parts of jujube.

[0044] For example, the preferred ingredients are 3 parts jujube seed, 3 parts lily bulb, 3 parts lotus seed, 3 parts dried plum, and 3 parts jujube.

[0045] In some specific embodiments, in order to achieve better effects in improving daytime fatigue and nighttime sleep, the traditional Chinese medicine composition for synergistically improving sleep and daytime fatigue mentioned in this invention can be specifically composed as follows: The daytime formula includes: 3 parts gardenia, 3 parts fermented soybean, 3 parts citron, 3 parts perilla stem, 1 part American ginseng, 3 parts astragalus, 1 part alpinia oxyphylla, 3 parts raspberry, and 2 parts peppermint. The nighttime formula includes: 3 parts gardenia, 3 parts fermented soybean, 3 parts Buddha's hand, 3 parts perilla stem, 3 parts jujube seed, 3 parts lily bulb, 3 parts lotus seed, 3 parts dried plum, and 3 parts jujube.

[0046] In some embodiments, the present invention also provides a method for preparing a traditional Chinese medicine composition that synergistically improves sleep and daytime fatigue, comprising the following steps: Take each raw material according to the formula, add water to extract, concentrate, dry, and make into a powder. The amount of water added is 30 to 60 times the total weight of the raw materials.

[0047] In the preparation method mentioned in this invention, water extraction is a conventional method for preparing traditional Chinese medicine. By adding a specific amount of water, different extraction conditions can be controlled to fully extract the key active components.

[0048] In daytime formulas, the active components extracted from gardenia can reduce oxidative stress, alleviate nerve tissue damage, and decrease nerve cell apoptosis. Simultaneously, it can regulate neurotransmitter expression. Gardenia oil in the extract can increase the expression of the protein kinase-cyclic adenosine monophosphate effector-binding protein-brain-derived neurotrophic factor (BDNF) signaling pathway, protecting the central nervous system. Gardenia extract can also reduce the level of rate-limiting enzymes in the tricarboxylic acid cycle, inhibiting the body's energy metabolism and achieving a sedative-hypnotic effect. Regarding anti-fatigue effects, American ginseng saponins can increase the activity of lactate dehydrogenase (LDH), muscle glycogen and liver glycogen content, and reduce blood lactate levels, exhibiting certain anti-fatigue capabilities. Astragalus polysaccharides, one of the main active components of astragalus, can improve the exercise endurance of chronically fatigued mice. The molecular mechanism is related to reducing oxidative stress levels in tissues and improving skeletal muscle mitochondrial autophagy, origin, and mitochondrial fusion-division. Peppermint oil can improve symptoms of mental fatigue and has a good anti-mental fatigue effect. Its mechanism of action is related to its regulation of amino acid neurotransmitter content in brain regions related to mental fatigue through the olfactory system.

[0049] Alpinia oxyphylla also exhibits significant anti-fatigue effects; mice treated with Alpinia oxyphylla showed better endurance in exercise tests. Multiple active ingredients in Alpinia oxyphylla have also been experimentally confirmed to have clear neuroprotective effects, with protocatechuic acid and juglansine showing synergistic neuroprotective effects. Raspberries contain various active ingredients such as terpenes, flavonoids, alkaloids, and coumarins, indicating that the active complexes in raspberries can improve sexual function and relieve physical fatigue.

[0050] In traditional Chinese medicine, jujube seed is widely used to treat insomnia and improve sleep. The main active ingredients in jujube seed are concentrated in saponins, flavonoids, alkaloids, and fatty acids, such as jujube seed saponin A, jujube seed saponin B, spinosin, and betulinic acid, all of which have anti-insomnia effects. Their mechanism of action may involve regulating gut microbiota, the hypothalamic-pituitary-adrenal axis, neurotransmitters, and inflammatory factors. Lily bulb is rich in various active ingredients, including polysaccharides, saponins, phenols, alkaloids, and flavonoids, and has sedative and hypnotic effects. Lotus seeds also contain sedative and hypnotic active ingredients. Ume plum also has sedative, hypnotic, and anticonvulsant effects; different concentrations of ume plum decoction significantly reduced spontaneous activity in mice, shortened sleep onset time, prolonged sleep duration, and significantly increased the number of mice falling asleep at subthreshold doses of sodium pentobarbital. Ume plum contains succinic acid, which has been found to have a central nervous system depressant effect, suggesting it may be one of the effective components for sedation, hypnosis, and anticonvulsant effects. Jujube can reduce anxiety and promote sleep by inhibiting central nervous system excitation; flavonoids and saponins are its important active substances. Jujube seed saponin A can regulate the physiological rhythm of mice and increase serotonin levels; cyclic peptide alkaloids can activate GABAA receptors, promote Cl- influx, and prolong the duration of action of pentobarbital. Compared with the benzodiazepine diazepam, jujube seed saponin A has a slower sedative effect but a longer duration, making it more beneficial for health. Meanwhile, jujube water extract can also promote the transcription of neurotrophic factors such as nerve growth factor (NGF), BDNF, glial cell-derived neurotrophic factor (GDNF), and antioxidant enzymes NQO1, GCL, and GST in astrocytes, thus playing a protective role in brain tissue.

[0051] The traditional Chinese medicine composition mentioned in this invention, which synergistically improves sleep and daytime fatigue, regulates mental fatigue and improves daytime fatigue through the synergistic effect of the multiple components of the above-mentioned daytime formula, while also achieving a sedative-hypnotic effect and improving nighttime sleep. Similarly, the nighttime formula improves sleep quality, not only prolonging sleep time but also reducing seizures and other issues, thus avoiding daytime fatigue caused by poor nighttime sleep quality. Both complement each other, synergistically improving sleep and daytime fatigue; the effects of each component are organically integrated and indispensable.

[0052] In some specific embodiments, the amount of water added as mentioned in this invention can be, for example, 30 times, 35 times, 40 times, 45 times, 50 times, 55 times, 60 times, or any range thereof, of the total mass of the raw materials.

[0053] In some embodiments, the present invention also provides the use of a traditional Chinese medicine composition that synergistically improves sleep and daytime fatigue in the preparation of a medicament that synergistically improves daytime fatigue and nighttime sleep quality.

[0054] In some embodiments, the present invention also provides a pharmaceutical preparation prepared from raw materials comprising the traditional Chinese medicine composition for synergistically improving sleep and daytime fatigue.

[0055] In some specific embodiments, the pharmaceutical preparations mentioned in this invention may be made alone from the traditional Chinese medicine composition mentioned in this invention that synergistically improves sleep and daytime fatigue, or, according to actual needs, from the traditional Chinese medicine composition mentioned in this invention that synergistically improves sleep and daytime fatigue.

[0056] In some specific embodiments, the dosage form of the pharmaceutical preparation mentioned in this invention is not limited in any way. For example, it may include any one of the dosage forms such as granules, tablets, pills, capsules, powders, mixtures, and oral liquids, which can be determined according to actual production and usage needs.

[0057] Example 1 This embodiment provides a traditional Chinese medicine composition for synergistically improving sleep and daytime fatigue, including a daytime formula and a nighttime formula: Daytime prescription: Gardenia 3g, Fermented soybean 3g, Buddha's hand 3g, Perilla stem 3g, American ginseng 1g, Astragalus 3g, Alpinia oxyphylla 1g, Raspberry 3g, Peppermint 2g Nighttime prescription: Gardenia 3g, fermented soybean 3g, Buddha's hand 3g, perilla stem 3g, jujube seed 3g, lily bulb 3g, lotus seed 3g, dried plum 3g, jujube 3g.

[0058] This embodiment also provides a method for preparing a traditional Chinese medicine composition that synergistically improves sleep and daytime fatigue, comprising the following steps: Take each raw material according to the formula, add water to extract, concentrate, dry, and make into a powder. The amount of water added is 40 times the total weight of the raw materials.

[0059] Example 2 This embodiment provides a traditional Chinese medicine composition for synergistically improving sleep and daytime fatigue, including a daytime formula and a nighttime formula. The difference from Example 1 is that the principal herbs in both the daytime and nighttime formulas are: Gardenia 3g, fermented soybean 6g, Buddha's hand 5g, perilla stem 5g.

[0060] Example 3 This embodiment provides a traditional Chinese medicine composition for synergistically improving sleep and daytime fatigue, including a daytime formula and a nighttime formula. The difference from Example 1 is that the principal herbs in both the daytime and nighttime formulas are: Gardenia 3g, fermented soybean 2g, Buddha's hand 1g, perilla stem 2g.

[0061] Comparative Example 1 This comparative example provides a traditional Chinese medicine composition that synergistically improves sleep and daytime fatigue, including a daytime formula and a nighttime formula: Daytime prescription: Gardenia 3g, fermented soybean 3g, bergamot 3g, perilla stem 3g; Nighttime prescription: Gardenia 3g, fermented soybean 3g, Buddha's hand 3g, perilla stem 3g.

[0062] Comparative Example 2 This embodiment provides a traditional Chinese medicine composition for synergistically improving sleep and daytime fatigue, including a daytime formula and a nighttime formula: Daytime prescription: American ginseng 1g, astragalus 3g, alpinia oxyphylla 1g, raspberry 3g, peppermint 2g; Nighttime prescription: American ginseng 1g, astragalus 3g, alpinia oxyphylla 1g, raspberry 3g, peppermint 2g.

[0063] Comparative Example 3 This embodiment provides a traditional Chinese medicine composition for synergistically improving sleep and daytime fatigue, including a daytime formula and a nighttime formula: Daytime prescription: 3g of jujube seed, 3g of lily bulb, 3g of lotus seed, 3g of dried plum, and 3g of jujube; Nighttime prescription: 3g of jujube seed, 3g of lily bulb, 3g of lotus seed, 3g of dried plum, and 3g of jujube.

[0064] Experimental Example 1: Clinical Trial of Traditional Chinese Medicine Composition for Treating Insomnia 1. Research Subjects 1.1 Sample Source Insomnia patients who visited Xiyuan Hospital of China Academy of Chinese Medical Sciences between December 2024 and January 2025.

[0065] Test drug: Traditional Chinese medicine prepared in Example 1.

[0066] 1.2 Diagnostic criteria This diagnosis was formulated with reference to the "Guidelines for the Diagnosis and Treatment of Insomnia in Chinese Adults (2017 Edition)" and the "International Classification of Sleep Disorders (Third Edition)" designated by the American Sleep Disorders Association in 2014. The diagnosis of chronic insomnia is defined as meeting the criteria for AF, while the diagnosis of short-term insomnia is defined as meeting the criteria for A, B, C, and F.

[0067] A. The patient reports, or the patient's parents or caregivers observe, that the patient exhibits one or more of the following: ① Difficulty falling asleep; ② Difficulty maintaining sleep; ③Wake ​​up earlier than your expected wake-up time; ④ Refusing to go to bed at the appropriate time; ⑤ Difficulty falling asleep without intervention from parents or caregivers.

[0068] B. The patient reports, or the patient's parents or caregivers observe, that the patient has one or more of the following symptoms related to nighttime sleep difficulties: ① Fatigue or lethargy; ② Decreased attention, focus, or memory; ③Impairment in social, family, occupational, or academic functions; ④ Emotionally unstable or easily irritable; ⑤ Daytime naps; ⑥ Behavioral problems (e.g., hyperactivity, impulsivity, or aggression); ⑦ Decreased motivation, energy, or work initiative; ⑧ Prone to making mistakes or accidents; ⑨ They are very concerned about or dissatisfied with their sleep quality.

[0069] C. These sleep / wake complaints cannot be fully explained by inappropriate sleep opportunities (such as sufficient sleep time) or environment (such as a dark, quiet, safe, and comfortable environment).

[0070] D. These sleep difficulties and related daytime symptoms occur at least 3 times a week.

[0071] E. These sleep difficulties and related daytime symptoms persist for at least 3 months.

[0072] F. These sleep difficulties and related daytime symptoms cannot be better explained by other sleep disorders.

[0073] 1.3 Inclusion Criteria (1) Subjects aged 18-65 years (inclusive), gender not limited; (2) Meets the Western medical diagnostic criteria for "insomnia"; (3) PSQI total score > 7 points; (4) Those who have not used long-acting sedative-hypnotic drugs within the past month; (5) Understand the purpose of the study, be able to truthfully assess your own psychological state and cooperate voluntarily, sign the informed consent form, and voluntarily accept the treatment of this study. The informed consent process complies with the relevant provisions of GCP.

[0074] 1.4 Exclusion Criteria (1) Secondary insomnia and environmental sleep disorders caused by physical illness or mental disorders; (2) Due to work reasons, the circadian rhythm is reversed; (3) The patient is taking medications that affect sleep (such as olanzapine, clozapine, etc.) and is also taking anti-anxiety, antidepressant and other psychotropic drugs; (4) Patients with mental illness and severe anxiety or depression (patients with a score of ≥21 on the depression subscale and ≥15 on the anxiety subscale of the Depression-Anxiety-Stress Self-Rating Scale). (5) Cognitive impairment prevents subjects from understanding the trial instructions, completing the questionnaire or providing informed consent, as well as from taking medication on time, having poor adherence or being unable to persist with follow-up; (6) Individuals addicted to alcohol or dependent on psychotropic drugs; (7) Those with severe cardiovascular, cerebrovascular, respiratory, or other systemic diseases, malignant tumors, or neurological diseases, or a history of severe traumatic brain injury. Those with abnormal liver and kidney function (AST, ALT > 1.5 times the upper limit of normal reference value, Scr exceeding the upper limit of normal range), and those with clinically significant ECG abnormalities; (8) Diabetic patients with poorly controlled blood glucose; (9) Pregnant or lactating women; (10) Patients who have participated in other clinical trials within the past month; (11) Individuals known to be allergic to certain drugs and items used in this study and interventions.

[0075] 1.5 Rejection Criteria (1) Cases in which patients were found to be ineligible for inclusion after selection, but were included due to error; (2) Prohibited drugs and methods specified in the plan were used; (3) Cases that have not received medication after inclusion should be excluded; (4) Cases for which there are no evaluable records after medication.

[0076] 1.6 Shedding Criteria (1) Poor subject compliance; subjects failed to follow the management protocol. (2) Individuals lost to follow-up or who dropped out naturally during the trial; (3) If serious adverse reactions, complications or concurrent events occur, the patient should not continue to participate in the clinical trial and the investigator should ask the patient to withdraw.

[0077] When a participant drops out, researchers should contact them as soon as possible through home visits, phone calls, or letters to inquire about the reasons, record the last treatment date, and complete any assessment items that can be performed. For cases where participants withdraw due to adverse reactions or ineffective treatment, researchers should take appropriate treatment measures based on their actual situation to protect the rights of the participants. The reasons for withdrawal should be recorded in detail in the observation form, and the observation form should be retained for future reference.

[0078] 1.7 Criteria for Suspension / Withdrawal 1.7.1 Termination Criteria A: Criteria for Subjects to Discontinue Trials (1) The subject terminates the procedure voluntarily, such as by withdrawing the informed consent form; (2) If the subject's condition continues to worsen during the trial, and a dangerous event may occur, the clinical trial should be stopped based on the doctor's judgment. To protect the subject, the subject should withdraw from the clinical trial and receive other treatment; (3) During the trial, the subject developed certain comorbidities, complications, or special physiological or pathological changes, making it unsuitable for the subject to continue the trial; (4) Subjects who have poor compliance during the trial, cannot adhere to daily medication, or withdraw from the clinical trial without giving any reason and are lost to follow-up due to no longer receiving treatment and testing; (5) Subjects who experienced adverse events or serious adverse events; (6) The subject becomes pregnant.

[0079] When the test is terminated, all CRF tables should be retained for future reference.

[0080] B: Criteria for the complete termination of clinical trials (1) Serious safety issues were discovered during the experiment; (2) The experiment found that the drug treatment was too ineffective or even ineffective and had no clinical value; (3) A major error was found in the clinical trial protocol, making it difficult to evaluate the efficacy of the drug; or a well-designed protocol was significantly deviated from during implementation.

[0081] 1.7.2 Exit Criteria Subjects may withdraw from the trial early if they experience unsatisfactory treatment results, intolerance of adverse reactions, a desire for alternative treatments, or without any other justification. Regardless of the reason for withdrawal, efforts should be made to contact the patient to obtain follow-up data, while also ensuring the safety of the subject after withdrawal.

[0082] 2. Research Methods 2.1 Content of Data Observation The Pittsburgh Sleep Quality Index (PSQI) was used to assess the subjective sleep quality of insomnia patients. The PSQI consists of seven items, each scored on a scale of 0 to 3. The total PSQI score is calculated by summing the scores of all items, ranging from 0 to 21. A total score greater than 7 indicates poor sleep quality, and the score is negatively correlated with sleep quality. During each medical visit, the subjects' subjective perception of sleep quality was assessed using the PSQI items, including subjective sleep latency, total sleep time, total time spent in bed, and number of sleep awakenings.

[0083] 2.2 Criteria for Evaluating Therapeutic Effect The efficacy evaluation indicators were recorded once each at patient enrollment, at week 2 (14±3 days) after treatment, and at week 4 (28±3 days) after treatment.

[0084] 2.2.1 Main clinical efficacy evaluation indicators The Pittsburgh Sleep Quality Index was used as the indicator for assessing sleep quality. The efficacy index was calculated based on the scores of each factor and the total score before and after treatment to evaluate the treatment effect. The specific method is as follows: Therapeutic effect index = (Total score before treatment - Total score after treatment) / Total score before treatment × 100%; Cure: Normal sleep, with symptoms basically or completely disappeared, and the efficacy index ≥75%; Significant effect: prolonged sleep time, accompanied by the disappearance of most symptoms, 75% > efficacy index ≥ 50%; Effective: Increased sleep duration, accompanied by improvement in symptoms or partial improvement in symptoms, with an efficacy index ≥25% (50% > efficacy rate). Ineffective: Symptoms show no significant change or worsen, with an efficacy index of <25%.

[0085] 2.2.2 Secondary clinical efficacy evaluation indicators (1) Fatigue Scale-14 (FS-14) This scale was jointly developed in 1992 by a number of experts, including Trndie Chalder of the Psychological Medicine Research Laboratory at Kings College Hospital and G. Berelowitz of Queen Mary University Hospital. The scale consists of 14 items, including physical fatigue and mental fatigue. The highest score for physical fatigue is 8, and the highest score for mental fatigue is 6. The maximum total score is 14; the higher the score, the more severe the fatigue.

[0086] (2) Epworth Sleepiness Scale (ESS) Also known as the Epworth Daytime Sleepiness Scale, it was developed by JohnsMW to assess excessive daytime sleepiness. The scale consists of 8 items, each scored from 0 to 3, for a total of 24 points. A score >6 indicates sleepiness, >11 indicates excessive sleepiness, and >16 indicates dangerous sleepiness.

[0087] (3) Depression-Anxiety-Stress Scale (DASS-21) The DASS scale was originally developed by Lovibond et al. in 1995. This study used the simplified Chinese version of DASS-21 revised by Xi Xu et al. (2010). The full scale contains 21 items, with three subscales—depression, anxiety, and stress—each containing 7 items. All subscales use a 4-point scoring system from "0" (disagree) to "3" (always agree). The score for each subscale is obtained by multiplying the score by 2; a higher score indicates a stronger emotional state. In the depression subscale, 10, 14, and 21 are the cutoff values ​​for mild, moderate, and severe depression, respectively. In the anxiety subscale, 8, 10, and 15 are the cutoff values ​​for mild, moderate, and severe anxiety, respectively. In the stress subscale, 15, 19, and 26 are the cutoff values ​​for mild, moderate, and severe stress, respectively.

[0088] 2.3 Safety Indicators Complete blood count, urinalysis, liver function tests, kidney function tests, and electrocardiogram (once before and once after the test).

[0089] 2.4 Data Analysis This prospective, self-controlled study evaluated the efficacy of treatment by statistically analyzing patients' PSQI scores, FS-14, ESS, and DASS-21 before and after treatment. Data were analyzed using SPSS 28.0 statistical software. Quantitative data were expressed as mean ± standard deviation. For data conforming to a normal distribution, t-tests were used; for those not conforming to a normal distribution, non-parametric tests were used. p < 0.05 was considered statistically significant.

[0090] 3. Results 3.1 Baseline Information The study included 10 participants, 8 females and 2 males. The mean age was 37.20 ± 14.73 years, with the oldest being 65 years and the youngest 23 years. The mean BMI was 21.50 ± 3.22 kg / m², with 2 participants underweight, 6 of normal weight, 1 overweight, and 1 obese. The mean disease duration was 5.07 ± 4.05 years, with the longest being 10 years and the shortest being 0.17 years (2 months). The mean PSQI score was 11.90 ± 2.96, the mean FS-14 score was 9.40 ± 2.63, the mean ESS score was 5.60 ± 3.44, the mean DASS-21 score was 27.20 ± 16.28, and the mean score of the Traditional Chinese Medicine Syndrome Scale was 24.30 ± 7.60.

[0091] 3.2 Clinical efficacy rate The clinical efficacy rate was calculated based on the PSQI reduction rate. After taking the traditional Chinese medicine composition of Example 1 of this invention, 1 case was clinically cured, 6 cases showed significant improvement, 2 cases were effective, and 1 case was ineffective, with a total efficacy rate of 90%.

[0092] 3.3 Changes in PSQI Items and Total Score The subjects' PSQI scores decreased from 11.90±2.96 to 6.40±2.32 (2 weeks of medication) (***p<0.001) and 5.60±2.37 (4 weeks of medication) (****p<0.0001). Further analysis of the seven PSQI items revealed that sleep quality scores decreased from 2.10±0.57 to 0.80±0.63 (2 weeks of medication) (***p<0.001) and 1.00±0.67 (4 weeks of medication) (**p<0.01); sleep onset time scores decreased from 2.50±0.71 to 1.40±0.70 (2 weeks of medication) (**p<0.01) and 1.10±0.5... 7 points (after 4 weeks of medication) (***p<0.001); Sleep duration score decreased from 1.70±0.82 to 0.70±0.82 (after 4 weeks of medication) (*p<0.05); Daytime dysfunction score decreased from 2.70±0.48 to 1.40±1.08 (after 2 weeks of medication) (**p<0.01) and 1.10±0.99 (after 4 weeks of medication) (**p<0.01), see details. Figure 1 .

[0093] 3.4 Changes in Items and Total Score of the FS-14 Quantitative Questionnaire No significant difference was observed in the subjects' FS-14 scores after 2 and 4 weeks of medication. Further analysis of physical and mental fatigue scores revealed that the physical fatigue score decreased from 6.30±1.64 to 3.60±2.63 after 2 weeks of medication (*p<0.05). See details below. Figure 2 .

[0094] 3.5 Changes in the total score of the ESS scale No significant difference was observed in the subjects' total ESS score after 2 and 4 weeks of medication. (See details below.) Figure 3 .

[0095] 3.6 Changes in DASS-21 Quantitative Questionnaire Items and Total Score The subjects' DASS-21 scores decreased from 27.20±16.28 to 9.80±9.64 (after 4 weeks of medication) (*p<0.05). Further analysis of the three DASS-21 items revealed that the stress score decreased from 12.60±7.31 to 5.00±4.14 (after 2 weeks of medication) (*p<0.05) and 4.60±4.99 (after 4 weeks of medication) (*p<0.05); no significant differences were found in depression and anxiety scores after 2 and 4 weeks of medication. (See details below.) Figure 4 .

[0096] 3.7 Changes in individual and total scores of TCM syndrome scoring The subjects' TCM syndrome scores decreased from 24.30±7.60 to 11.30±7.56 (2 weeks of medication) (**p<0.01) and 8.80±7.35 (2 weeks of medication) (***p<0.001). Further analysis of the two individual items of the TCM syndrome score revealed that the score for the primary TCM syndrome decreased from 13.00±3.80 to 5.00±4.35 (2 weeks of medication) (***p<0.001) and 4.20±4.05 (4 weeks of medication) (***p<0.001); the score for the secondary TCM syndrome decreased from 11.30±5.03 to 6.30±3.74 (2 weeks of medication) (*p<0.05) and 4.60±3.89 (4 weeks of medication) (**p<0.01). See details below. Figure 5 .

[0097] 3.3 Security No adverse reactions were reported.

[0098] 4. Conclusion The study employed a prospective, self-controlled trial design to analyze clinical data from 10 insomnia patients, exploring the therapeutic effect of the present invention on insomnia accompanied by daytime fatigue. The results showed varying degrees of improvement in patients' sleep quality, sleep onset time, sleep duration, and daytime functional impairment. Simultaneously, symptoms related to physical fatigue, stress, and liver fire disturbing the heart also significantly improved, with a clinical efficacy rate of 90%. This lays the foundation for conducting more systematic double-blind randomized controlled trials in the future.

[0099] Experiment Example 2: Animal Experiment 1 on the Treatment of Insomnia with Traditional Chinese Medicine Composition 1. Materials 1.1 Medicines and Reagents Test drug: Traditional Chinese medicine prepared in Example 1.

[0100] Positive control drug: Lemborexant (MCE).

[0101] 1.2 Animals Eighteen SPF-grade male C57BL / 6N mice (7-8 weeks old, weighing 20-25g, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.) were selected for the experiment. All mice were housed under identical conditions: caged, with 12 hours of light and 12 hours of darkness daily (7:00-19:00), an ambient temperature of 22±2℃, and a relative humidity of 50-60%. Mice were fed standard feed and clean drinking water, and had free access to food and water. A 7-day acclimatization period was provided before the experiment to allow the mice to fully adapt to the conditions. All animal experiments complied with and strictly adhered to the relevant guidelines of the China Animal Protection Association.

[0102] 2. Experimental Methods 2.1 Electrode implantation surgery After acclimatization, all mice underwent electrode implantation surgery. After isoflurane anesthesia, the mice's hind legs were clamped with forceps to check for the knee-jerk reflex. Once the reflex completely disappeared, the electrode implantation surgery was performed. First, the mice were fixed on the experimental table, and hair was trimmed 2 mm to the left and right of the sagittal suture to expose the skin, which was then disinfected with 75% alcohol. After disinfection, an incision was made along the sagittal suture 1.5 cm anterior and posterior to the Bregma origin with a scalpel to expose the skull. The scalp on both sides of the sagittal suture was grasped with a leather clip to expose the visual field. The periosteum in the exposed area was removed with hydrogen peroxide to prevent electrode dislodgement due to periosteal necrosis. Holes were drilled in the skull using a 0.8 mm diameter drill bit, 3 mm posterior to the Bregma origin and 3 mm to the left and right of the sagittal suture, as the implantation points for the positive and negative electrodes. Holes were drilled 3 mm anterior to the Bregma origin and 3 mm to the left or right of the Bregma origin as reference electrode implantation points. Electrodes were inserted into both sides of the neck and embedded, then secured with 502 glue. After 1 minute of fixation to allow the glue to harden, dental cement was evenly applied to completely cover the wound and electrodes. Following the surgery, the mice were moved to a heated blanket to regain consciousness, then transferred back to their cages and placed in a light:dark (12h:12h) environment for acclimatization for 7-14 days, ready for testing.

[0103] 2.2 Experimental Grouping C57BL / 6N mice were randomly divided into three groups using an Excel random number table: a blank control group (Control group) (n=6), a model group (Model group) (n=6), and the traditional Chinese medicine group (ZYFTF group) of Example 1 (n=6).

[0104] 2.3 Experimental Modeling Mice in the Model and ZYFTF groups were intraperitoneally injected with para-chlorophenylalanine (PCPA) at 350 mg / kg once daily for 3 days. The Control group received an equal dose of saline for 3 consecutive days. When the animals exhibited loss of circadian rhythm, excessive daytime activity, weight loss, irritability, and increased aggression, showing significant differences from the control group, the model was successfully established.

[0105] 2.4 Experimental drug administration The dosage of ZYFTF in the mouse group was calculated based on the equivalent dose for humans and mice, using the dosage for a 70kg adult. The equivalent dose coefficient for mice was 9.1 times that of humans, calculated using the equivalent body surface area methodology in "Methodology of Pharmacological Research of Traditional Chinese Medicine". The blank control group and the model group were given physiological saline. All mice in the above groups were administered the drug via gavage, starting after model establishment and continuing for 7 days. ZYFTF was administered twice daily, morning and evening, according to the mice's diurnal rhythm.

[0106] 2.5 Electroencephalogram (EEG) and Electromyogram (EMG) Detection Seven days after drug administration, all mice underwent electroencephalography (EEG) and electromyography (EMG) tests. The recording cables were acclimatized to the mice for 24 hours prior to each test. The male and female terminals of the electrodes implanted in the mice's heads were connected, with the female wire connected to the lower end of a 6-wire universal wheel. The upper end of the universal wheel was connected to a Labchart signal amplifier and a Labchart signal acquisition unit. Mice were allowed free movement, eating, and drinking, and the electrical signals of their cerebral cortex cell populations were recorded. The signals were processed using Labchart software and analyzed using Lunion software. The mice were consistently kept in a light:dark (12h:12h) environment.

[0107] 3. Results 3.1 Effects of ZYFTF on sleep in PCPA-induced insomnia mice 3.1.1 Effects of ZYFTF on cumulative sleep at different time points in PCPA-induced insomnia mice The effects on the duration (in minutes) of WAKE, NREM, and REM sleep in mice during a 24-hour sleep-wake cycle are shown in the figure. Figure 6 Where Light represents illumination and Dark represents darkness, with n=6 for each group.

[0108] Seven days after treatment, analysis of cumulative WAKE levels in mice showed that, compared with the Control group, the cumulative WAKE levels in the Model group were significantly higher at 24 hours (p<0.05), while no significant change was observed in the cumulative WAKE levels in the ZYFTF group (p>0.05). Compared with the Model group, the cumulative WAKE levels in the ZYFTF group were significantly lower at 24 hours and during the light exposure period (p<0.001, p<0.05). Figure 6 (A in the middle).

[0109] Seven days after treatment, analysis of NREM sleep accumulation in mice showed that, compared with the Control group, the 24-hour NREM accumulation in the Model group was significantly reduced (p<0.05), while no significant change was observed in the NREM accumulation in the ZYFTF group (p>0.05); compared with the Model group, the 24-hour NREM accumulation in the ZYFTF group was significantly increased (p<0.01). Figure 6 (B in the middle).

[0110] Seven days after treatment, analysis of cumulative REM sleep in mice showed no significant differences in cumulative REM sleep over 24 hours, during dark and light periods, among the three groups (p > 0.05). Figure 6 (C in the middle).

[0111] The results showed that after 7 days of administration, the diurnal regulation formula could effectively reduce the increase in 24-hour WAKE accumulation in PCPA-induced insomnia mice, as well as the increase in WAKE accumulation during the light period, and increase 24-hour NREM accumulation.

[0112] 3.1.2 Effect of ZYFTF on sleep-wake cycles in mice The results of a study on the number of wake occurrences in mice under dark and light cycles showed that, compared with the control group, the number of wake occurrences in the model group was significantly increased over 24 hours (p<0.05); the number of wake occurrences in the ZYFTF group at each time period showed a decreasing trend compared with the model group, but the difference was not statistically significant (p>0.05). Figure 7 (A in the middle).

[0113] The results of a study on the frequency of NREM sleep during dark and light cycles in mice showed that, compared with the control group, the ZYFTF group mice had a significantly higher frequency of NREM sleep within 24 hours (p<0.05), while no other significant differences were observed. Figure 7 (B in the middle).

[0114] The results of a study on the frequency of REM sleep during dark and light cycles in mice showed that, compared with the control group, the ZYFTF group mice had a significantly higher frequency of REM sleep within 24 hours (p<0.05); compared with the model group mice, the ZYFTF group mice also had a significantly higher frequency of REM sleep within 24 hours (p<0.05). Figure 7 (C in the middle).

[0115] By analyzing the number of awakenings, NREM sleep, and REM sleep in mice over 24 hours, during the dark and light periods, this study explored the effect of ZYFTF on sleep fragmentation in mice. The results showed that the diurnal variation formula had no significant effect on reducing the number of awakenings, but it could increase the number of REM sleep occurrences within 24 hours.

[0116] 4. Conclusion The herbal composition of this invention can effectively improve the sleep state of PCPA-induced insomnia mice, reduce the increase in 24-hour WAKE accumulation in PCPA-induced insomnia mice, reduce the increase in WAKE accumulation during light exposure, increase 24-hour NREM accumulation, and increase the number of REM sleep occurrences within 24 hours.

[0117] Experiment Example 3: Animal Experiment 2 on the Treatment of Insomnia with Traditional Chinese Medicine Composition 1. Materials 1.1 Medicines and Reagents Test drug: Traditional Chinese medicine prepared in Example 1.

[0118] Positive control drug: Lemborexant (MCE).

[0119] 1.2 Animals Thirty SPF-grade male C57BL / 6N mice, aged 7-8 weeks (weighing 20-25g, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.), were selected for the experiment. All mice were housed under identical conditions: caged, with 12 hours of light and 12 hours of darkness daily (7:00-19:00), an ambient temperature of 22±2℃, and a relative humidity of 50-60%. Mice were fed standard feed and clean drinking water, and had free access to food and water. A 7-day acclimatization period was provided before the experiment to allow the mice to fully adapt to the conditions. All animal experiments complied with and strictly adhered to the relevant guidelines of the China Animal Protection Association.

[0120] 2. Experimental Methods 2.1 Experimental Grouping Thirty C57BL / 6N mice were randomly divided into a blank control group (Control), a model group (Model), the daytime formula group of Example 1 (ZFZ), the traditional Chinese medicine group of Example 1 (ZYFTF), the nighttime formula group of Example 1 (YFZ), and a positive control group (Lemborexant) using the Excel random number table method.

[0121] 2.2 Experimental Modeling Mice in the Model group, ZFZ group, ZYFTF group, YFZ group, and Leemborexant group were intraperitoneally injected with PCPA at 350 mg / kg once daily for 3 days. The normal control group was treated with the same dose of the solvent for 3 consecutive days. When the animals exhibited loss of diurnal rhythm, excessive daytime activity, weight loss, irritability, and increased aggression, showing significant differences from the control group, it indicated that the model was successfully established.

[0122] 2.3 Experimental drug administration The dosages for the ZFZ, ZYFTF, YFZ, and Leemborexant groups were calculated based on the equivalent doses in humans and mice. Using the dosage for a 70kg adult, and based on the equivalent body surface area as defined in "Methodology of Pharmacological Research of Traditional Chinese Medicine," the equivalent dose coefficient of 9.1 times between mouse and human surface area was used as the dosage for both the traditional Chinese medicine and the positive control. The blank control group and the model group were given drinking water. All mice in the above groups were administered the medicine by gavage, starting after model establishment and continuing for 7 days.

[0123] 2.4 Behavioral testing of mice 2.4.1 Pentobarbital-induced suprathreshold sleep synergistic experiment Twelve hours after administration on day 7, mice in each group were intraperitoneally injected with 45 mg / kg sodium pentobarbital. The mice were then lifted by their tails and placed belly-up on a mat. Sleep latency and duration were recorded. The disappearance of the righting reflex was defined as sleep, and the return of the righting reflex was defined as wakefulness. If the recovery of the righting reflex was uncertain, the mice were immediately repositioned back to their supine position after the first righting. If the mice automatically turned over within 1 minute, the previous time was considered the recovery time; otherwise, the time of the second turn was used. Sleep patterns were observed, with the absence of the righting reflex for more than 1 minute considered sleep onset. Sleep latency and duration were recorded for each group.

[0124] 2.4.2 Weighted Swimming Experiment On day 8, the weight-bearing swimming experiment was started in mice. The mice were placed in a custom-made swimming tank with a water depth of 35 cm and a water temperature of (25±1) ℃, and subjected to weight-bearing swimming exercises. The weight standard was a lead strip with 5% of the mouse's body weight tied to the base of the mouse's tail. Swimming exhaustion was defined as the time from when the mouse entered the water until the mouse's nose entered the water and remained submerged for 10 seconds and could not float on its own.

[0125] 3. Results 3.1 Pentobarbital-induced suprathreshold sleep synergistic experiment Sleep latency results showed that compared with the control group, the sleep latency of mice in the model group was prolonged (p < 0.05), while ZYFTF and YFZ significantly shortened the sleep latency compared with the model group. The sleep latency of the control group, model group, ZFZ group, ZYFTF group, YFZ group, and Leemborexant group were 245.4 ± 41.3 s, 387.8 ± 25.3 s, 327.8 ± 20.1 s, 238.8 ± 20.8 s, 233.3 ± 32.8 s, and 294.8 ± 7.4 s, respectively (see [link to study]). Figure 8 ).

[0126] Sleep duration results showed that compared with the control group, the sleep duration of mice in the model group was shortened (p<0.05), while ZYFTF significantly prolonged sleep duration compared with the model group. The sleep latency of the control group, model group, ZFZ group, ZYFTF group, YFZ group, and Leemborexant group were 2466.0±123.9s, 921.0±172.4s, 1269.0±99.4s, 2451.8±545.4s, 2005.0±116.1s, and 1810.0±380.7s, respectively (see [link to study]). Figure 9 ).

[0127] 3.2 Weighted Swimming Experiment The results of the weight-bearing swimming experiment showed that compared with the control group, the weight-bearing swimming time of mice in the model group was shorter, but the difference was not statistically significant (p>0.05). Compared with the model group, the weight-bearing swimming time of mice in the ZFZ and ZYFTF groups was longer (p<0.05), with the ZFZ group showing a more significant difference. The weight-bearing swimming times of the control group, model group, ZFZ group, ZYFTF group, YFZ group, and Lemborexant group were 274.8±18.8s, 140.2±6.3s, 389.0±53.3s, 349.4±51.6s, 215.6±46.4s, and 255.8±43.4s, respectively (see...). Figure 10 ).

[0128] Experiment Example 4: Formulation Screening Experiment 1. Materials 1.1 Medicines and Reagents Test drugs: Traditional Chinese medicines prepared in Example 1, Comparative Example 1, Comparative Example 2 and Comparative Example 3.

[0129] Positive control drug Lemborexant (MCE).

[0130] 1.2 Animals Thirty-five SPF-grade male C57BL / 6N mice (7-8 weeks old, weighing 20-25g, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.) were selected for the experiment. All mice were housed under identical conditions: caged, with 12 hours of light and 12 hours of darkness daily (7:00-19:00), an ambient temperature of 22±2℃, and a relative humidity of 50-60%. Mice were fed standard feed and clean drinking water, and had free access to food and water. A 7-day acclimatization period was provided before the experiment to allow the mice to fully adapt to the conditions. All animal experiments complied with and strictly adhered to the relevant guidelines of the China Animal Protection Association.

[0131] 2. Experimental Methods 2.1 Experimental Grouping C57BL / 6N mice were randomly divided into four groups using the Excel random number table method: a blank control group (Control group), a model group (Model group), the traditional Chinese medicine group of Example 1, the traditional Chinese medicine group of Comparative Example 1, the traditional Chinese medicine group of Comparative Example 2, the traditional Chinese medicine group of Comparative Example 3, and the positive control group (Lemborexant group), with 5 mice in each group.

[0132] 2.2 Experimental Modeling Mice in the model group, the herbal medicine group of Example 1, the herbal medicine group of Comparative Example 1, the herbal medicine group of Comparative Example 2, the herbal medicine group of Comparative Example 3, and the Leemborexant group were intraperitoneally injected with PCPA (350 mg / kg) once daily for 3 days. The normal control group was treated with an equal dose of the solvent for 3 consecutive days. When the animals exhibited loss of diurnal rhythm, excessive daytime activity, weight loss, irritability, and increased aggression, showing significant differences from the control group, it indicated that the model was successfully established.

[0133] 2.3 Experimental drug administration In Example 1, the dosages of the traditional Chinese medicine (TCM) group, Comparative Example 1, Comparative Example 2, Comparative Example 3, and the Leemborexant group were calculated based on the equivalent doses for humans and mice. The dosage was based on the dosage for a 70kg adult, and the equivalent body surface area was used for conversion according to the "Methodology of Pharmacological Research of Traditional Chinese Medicine." The equivalent dose coefficient of 9.1 times between the mouse and human body surface areas was used as the TCM dosage and the positive control dosage. The blank control group and the model group were given drinking water. All mice in the above groups were administered the medication by gavage at a dose of 0.1 ml / 10g, starting after model establishment, once daily for 7 consecutive days.

[0134] 2.4 Behavioral testing of mice 2.4.1 Pentobarbital-induced suprathreshold sleep synergistic experiment Twelve hours after administration on day 7, mice in each group were intraperitoneally injected with 45 mg / kg sodium pentobarbital. The mice were then lifted by their tails and placed belly-up on a mat. Sleep latency and duration were recorded. The disappearance of the righting reflex was defined as sleep, and the return of the righting reflex was defined as wakefulness. If the recovery of the righting reflex was uncertain, the mice were immediately repositioned back to their supine position after the first righting. If the mice automatically turned over within 1 minute, the previous time was considered the recovery time; otherwise, the time of the second turn was used. Sleep patterns were observed, with the absence of the righting reflex for more than 1 minute considered sleep onset. Sleep latency and duration were recorded for each group.

[0135] 2.4.2 Weighted Swimming Experiment On day 8, the weight-bearing swimming experiment was started in mice. The mice were placed in a custom-made swimming tank with a water depth of 35 cm and a water temperature of (25±1) ℃, and subjected to weight-bearing swimming exercises. The weight standard was a lead strip with 5% of the mouse's body weight tied to the base of the mouse's tail. Swimming exhaustion was defined as the time from when the mouse entered the water until the mouse's nose entered the water and remained submerged for 10 seconds and could not float on its own.

[0136] result The experimental results are shown in Table 1. Compared with the Control group, the sleep latency of mice in the Model group was prolonged (p<0.05) and the sleep duration was shortened (p<0.05). Compared with the Model group, the sleep latency of the Example 1 group, Leemborexant group, Comparative Example 1 group, and Comparative Example 3 group was significantly shortened (p<0.05). Compared with the Model group, the sleep duration of the Example 1 group was significantly prolonged (p<0.05).

[0137] The results of the weight-bearing swimming time showed that the weight-bearing swimming time of mice in the Model group was significantly shorter than that in the Control group (p < 0.05). Compared with the Model group, Example 1 and Comparative Example 2 significantly prolonged the weight-bearing swimming time (p < 0.05), with Example 1 being more significant.

[0138] For Comparative Examples 1-3, their performance in sleep latency, sleep duration, and weight-bearing swimming time was significantly worse than that in Example 1. However, combining the above 14 herbs to form Example 1 significantly shortened the sleep latency of the experimental animals and prolonged the sleep duration and weight-bearing swimming time, achieving unexpected technical effects. The types of herbs in the herbal composition of this invention are closely related to their effects on treating insomnia and fatigue; therefore, removing some herbs may reduce the efficacy of the herbal composition of this invention.

[0139] Table 2: Effects of the herbal composition of the present invention on the hypnotic effect of sodium pentobarbital at a suprathreshold dose in mice

[0140] Note: Compared with the control group, #p < 0.05; compared with the model group, *p < 0.05.

[0141] In Table 2 above, data showing significant differences have been marked with *. The results for daytime fatigue (weight-bearing swimming time) in Examples 2 and 3, as well as Comparative Examples 1 and 3, showed no significant differences based on statistical results. Comparative Example 2 primarily used daytime medications such as ginseng and peppermint, which are key anti-fatigue drugs. Therefore, Comparative Example 2 should have a better anti-daytime fatigue effect than the other groups, but its overall improvement effect was poorer than that of the Examples 1 and 2.

[0142] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. A traditional Chinese medicine composition for synergistically improving sleep and daytime fatigue, characterized in that, It consists of a daytime square and a nighttime square: The daytime formula, by weight, consists of the following components: Gardenia 2-5 parts, fermented soybean 2-6 parts, Buddha's hand 1-5 parts, perilla stem 2-5 parts, American ginseng 1-2 parts, astragalus 2-5 parts, peppermint 1-3 parts, alpinia oxyphylla 1-3 parts, raspberry 2-4 parts; The nighttime formula, by weight, comprises the following components: Gardenia 2-5 parts, fermented soybean 2-6 parts, Buddha's hand 1-5 parts, perilla stem 2-5 parts, jujube seed 3-5 parts, lily bulb 2-4 parts, lotus seed 2-5 parts, dried plum 2-4 parts, jujube 2-5 parts.

2. The traditional Chinese medicine composition for synergistically improving sleep and daytime fatigue according to claim 1, characterized in that, The mass ratio of Gardenia jasminoides, fermented soybean, Citrus medica, and Perilla frutescens stem in the principal ingredient of the daytime formula is 1:1:1:

1.

3. The traditional Chinese medicine composition for synergistically improving sleep and daytime fatigue according to claim 1 or 2, characterized in that, The mass ratio of Gardenia jasminoides, fermented soybean, Citrus medica, and Perilla frutescens stem in the principal ingredient of the nighttime formula is 1:1:1:

1.

4. The traditional Chinese medicine composition for synergistically improving sleep and daytime fatigue according to claim 1, characterized in that, By weight: The daytime formula consists of the following ingredients: 3 parts gardenia, 3 parts fermented soybean, 3 parts citron, 3 parts perilla stem, 1 part American ginseng, 3 parts astragalus, 1 part alpinia oxyphylla, 3 parts raspberry, and 2 parts peppermint. The nighttime formula consists of the following components: 3 parts gardenia, 3 parts fermented soybean, 3 parts Buddha's hand, 3 parts perilla stem, 3 parts jujube seed, 3 parts lily bulb, 3 parts lotus seed, 3 parts dried plum, and 3 parts jujube.

5. A method for preparing a traditional Chinese medicine composition according to any one of claims 1 to 4 that synergistically improves sleep and daytime fatigue, characterized in that, Includes the following steps: Take each raw material according to the formula, add water to extract, concentrate, dry, and make into a powder. The amount of water added is 30 to 60 times the total weight of the raw materials.

6. The use of a traditional Chinese medicine composition according to any one of claims 1 to 4 in the preparation of a medicament for synergistically improving daytime fatigue and nighttime sleep quality.

7. A pharmaceutical preparation, characterized in that, It is prepared from raw materials including the traditional Chinese medicine composition according to any one of claims 1 to 4 that synergistically improves sleep and daytime fatigue.

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