Traditional Chinese medicine composition and application thereof in preparation of medicine for treating insomnia

Abstract

The invention relates to a traditional Chinese medicine composition and application thereof in preparation of medicines for treating insomnia, and particularly discloses a traditional Chinese medicine composition which comprises the following traditional Chinese medicine components in parts by weight: 1-10 parts of angelica sinensis, 1-10 parts of poria cocos, 1-10 parts of fried spina date seeds, 1-10 parts of perilla leaves, 2-10 parts of lilies and 1-10 parts of selfheal. The invention also discloses a traditional Chinese medicine extract prepared from the traditional Chinese medicine composition, and the traditional Chinese medicine extract is extracted by the following method: mixing the traditional Chinese medicine components in the traditional Chinese medicine composition according to the ratio, decocting with water for extraction, combining decoction, filtering, concentrating filtrate to obtain clear paste, and drying the clear paste to obtain dry paste. The traditional Chinese medicine composition and the traditional Chinese medicine extract have the purpose of treating insomnia.

Description

Technical Field

[0001] The invention specifically provides a traditional Chinese medicine composition and application thereof in preparing a medicine for treating insomnia, belonging to the field of traditional Chinese medicine pharmaceutical preparation. Background Art

[0002] Insomnia is one of the most common clinical diseases. It refers to insufficient sleep caused by various reasons, including insufficient sleep time, sleep depth and physical recovery. Chinese medicine calls it "insomnia" and "insomnia". According to the World Health Organization, the global incidence rate is 27%; the United States spends 30-107 billion US dollars on insomnia each year. In recent years, the incidence of neuropsychiatric diseases such as insomnia in my country has increased rapidly. Relevant literature shows that there are about 150 million insomnia patients in my country, and as many as 300 million people with poor sleep. 35% of the population have suffered from acute insomnia, and 9% to 12% of people suffer from chronic insomnia. Insomnia has become a social public health issue that has attracted widespread attention in the country.

[0003] There are three subtypes of insomnia:

[0004] 1. Difficulty falling asleep: It is difficult to fall asleep even after half an hour or even 1-2 hours of going to bed. This is more common in people with neurosis, major life events or anxiety.

[0005] 2. Difficulty in maintaining sleep: shallow sleep, easy awakening, dreamy type, awakening more than 3-4 times per night, difficult to fall asleep after waking up. Awakening 15%-20% of sleep time per night, normal people generally do not exceed 5%. More common in individuals with nervous personality.

[0006] 3. Early awakening type: often waking up at 3-4 am and unable to fall asleep after waking up. More common in patients with depression.

[0007] Western medicine treatment of insomnia emphasizes regular work and rest and the rational use of sedative hypnotic drugs. Sleeping pills are the first choice in clinical practice. Although sleeping pills have a faster hypnotic effect, they are often accompanied by more toxic side effects, such as aggravated respiratory depression, memory loss, dizziness, fatigue, drowsiness, etc. There are also drug resistance, the dosage needs to be continuously increased, relapse occurs when the drug is stopped, and it is easy to become addicted.

[0008] Traditional Chinese medicine has a long history of treating insomnia. It has unique advantages in using holistic concepts and syndrome differentiation to treat insomnia, and can better overcome the shortcomings of Western medicine treatment. There are now a large number of clinical reports. However, most of these clinical reports are individual case reports. Even clinical trial reports with fixed prescriptions often have shortcomings such as irregular trial design, weak pertinence, informal clinical trials, unclear standards, and poor quality. As a result, when industry insiders judge these reported prescriptions, they usually believe that individual case efficacy may exist, but the authenticity of universal efficacy cannot be confirmed. Summary of the invention

[0009] In order to solve the above problems, the present invention provides a Chinese medicine composition and its application in preparing a medicine for treating insomnia.

[0010] The specific technical solutions are as follows:

[0011] One aspect of the present invention provides a traditional Chinese medicine composition, which comprises the following traditional Chinese medicine components by weight: 1-10 parts of angelica sinensis, 1-10 parts of Poria cocos, 1-10 parts of stir-fried spiny jujube seeds, 1-10 parts of perilla leaves, 2-10 parts of lily bulbs, and 1-10 parts of selfheal;

[0012] Preferably, the Chinese medicine composition comprises the following Chinese medicinal materials in parts by weight: 3-8 parts of angelica, 5-9 parts of Poria, 5-9 parts of stir-fried spiny jujube seeds, 3-7 parts of perilla leaves, 8-10 parts of lily, and 5-9 parts of selfheal;

[0013] More preferably, the Chinese medicine composition comprises the following Chinese medicinal materials in parts by weight: 5 parts of Angelica sinensis, 7.5 parts of Poria cocos, 7.5 parts of stir-fried Ziziphus jujuba seeds, 4.5 parts of Perilla leaves, 10 parts of lily, and 7.5 parts of Prunella vulgaris.

[0014] Another aspect of the present invention provides a Chinese medicine extract, which is obtained from the above-mentioned Chinese medicine composition through a water decoction extraction method.

[0015] Another aspect of the present invention provides a method for preparing a Chinese medicine extract, comprising the following steps: mixing the Chinese medicinal material components in the Chinese medicine composition according to a ratio, decocting with water for extraction, combining the decoction, filtering, concentrating the filtrate, and obtaining a clear paste;

[0016] Preferably, the preparation method further comprises drying the obtained clear paste to obtain a dry paste.

[0017] Further, the water decoction is performed 1 to 3 times;

[0018] Preferably, the extraction is performed twice by decoction, with 8 to 12 times the amount of water added for the first time and extraction for 1 to 2 hours, and 6 to 10 times the amount of water added for the second time and extraction for 1 to 2 hours; preferably, 10 times the amount of water added for the first time and extraction for 1.5 hours, and 8 times the amount of water added for the second time and extraction for 1 hour.

[0019] Further, the filtration is centrifugal filtration or plate and frame filtration;

[0020] Preferably, the centrifugal filtration is centrifugal filtration through 300 mesh polyester cloth according to the enterprise equipment;

[0021] Preferably, the concentration is concentrated by reduced pressure concentration or concentrated by combining the enterprise drying method to a suitable relative density;

[0022] Preferably, the filtrate is concentrated to a clear paste with a relative density of 1.25-1.30 (60° C.);

[0023] Preferably, the dry paste has a paste yield of 13-18%.

[0024] Another aspect of the present invention provides a medicine comprising the above-mentioned Chinese herbal medicine extract.

[0025] Furthermore, the drug further comprises a pharmaceutically acceptable excipient;

[0026] Preferably, the dosage form of the drug is an oral dosage form;

[0027] Preferably, the oral dosage form is granules, oral liquid, tablets, syrups, pastes, capsules, and pills.

[0028] Furthermore, the dosage form of the drug is a granule, and the granule comprises the Chinese herbal extract, dextrin and xylitol;

[0029] Preferably, the mass ratio of dextrin to xylitol is 1:1 to 1:2;

[0030] Preferably, the granules are prepared by a wet granulation method;

[0031] Preferably, the wet granulation uses 70-95% ethanol as a wetting agent;

[0032] Preferably, the granules further comprise a flavoring agent;

[0033] Preferably, the flavoring agent is selected from sweeteners;

[0034] Preferably, the sweetener is steviol glycoside;

[0035] Preferably, the mass ratio of dextrin to xylitol is 1:1;

[0036] Preferably, 90%-95% ethanol is used as the wetting agent.

[0037] Another aspect of the present invention provides use of the above-mentioned Chinese medicine composition, the above-mentioned Chinese medicine extract or the above-mentioned medicine in preparing a medicine for treating insomnia.

[0038] The quality standard detection method of the traditional Chinese medicine extract or the medicine of the present invention uses jujuboside A in spinach seed and rosmarinic acid in selfheal as indicators for content determination.

[0039] The present invention has the following beneficial effects:

[0040] One third of a person's life must be spent sleeping, and a person will die if he does not sleep for five days. Sleep is a necessary process for life, an important part of the body's recovery, integration and consolidation of memory, and an indispensable part of health. In addition to the symptoms of insomnia, insomniacs usually experience lack of energy, fatigue, irritability, drowsiness and depression during the day.

[0041] Fatigue is currently a difficult-to-treat physical and mental state, and is also a common daytime functional disorder of insomnia. Western medicine has no obvious advantages in this regard, and fatigue is related to a variety of diseases. The composition of the present invention has more advantages in improving the fatigue state of insomniacs, especially in improving mental fatigue.

[0042] Hyperarousal is an abnormal state of increased response to stimuli, which can lead to increased heart rate, breathing and anxiety levels. Insomnia patients have a higher hyperarousal state, and high hyperarousal is associated with various mental system diseases and chronic diseases. The composition of the present invention also has better advantages in treating this aspect. The composition of the present invention has been proven to be truly effective in treating insomnia through formal and rigorous clinical trials.

[0043] The functions and indications of the Chinese medicine combination of the present invention and the formula explanation:

[0044] Functions and indications: It can reconcile yin and yang, nourish qi and blood, and calm the mind and nerves. It is mainly used for insomnia caused by the mismatch of yin and yang.

[0045] This prescription is derived from Suanzaoren Decoction in Synopsis of the Golden Chamber and Guipi Decoction in Jisheng Fang.

[0046] Main medicine: Chinese jujube seeds nourish the heart and liver, calm the mind, restrain sweat, and promote the production of body fluids. It is both astringent and tonic, and is an important medicine for nourishing the heart and calming the mind.

[0047] Minister drugs: Poria cocos benefits the heart and spleen and soothes the mind and nerves, and is combined with jujube kernel to take the meaning of sour jujube kernel soup; Angelica sinensis is sweet, warm and moist in nature, good at nourishing blood, and is a holy blood tonic. Combined with jujube kernel and Poria cocos, it is sweet, warm, sour and astringent, nourishes yin and blood, and is named Guipi Decoction. The two drugs are together the minister drugs.

[0048] Auxiliary drugs: Prunella vulgaris grows because of the extreme yang energy, lily is sweet and cold, clears the heart and relieves troubles, soothes the mind and calms the nerves, calms the gallbladder and strengthens the will; perilla leaves are pungent, warm and have a light energy, and can regulate qi and blood circulation, and lead yang into yin; perilla leaves and lily are a classic pair of drugs for treating insomnia. The lily flower opens during the day and closes at night, while the perilla leaves stand upright in the morning and droop at night, which has the wonderful effect of leading yang into yin, and when the yang energy interacts with the yin, one can sleep peacefully (Lüshantang Leibian). The above three drugs are collectively called adjuvant drugs.

[0049] The combination of these medicines can harmonize yin and yang, replenish qi and blood, calm the mind and nerves, and promote the reconstruction of the body's sleep circadian rhythm. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1Interaction plot of the decrease in insomnia PSQI scores at each time point compared with the baseline period (PPS).

[0051] Figure 2 Interaction diagram of the decrease in insomnia PSQI scores at each time point compared with the baseline period (FAS).

[0052] Figure 3 Clinical efficacy of Anshuiyin + Five Elements Music. AYP, before insomnia intervention; AYT, after insomnia intervention. * P<0.05.

[0053] Figure 4 Potential therapeutic targets for the intervention of Anshuiyin + Five Elements Music for insomnia. (A) Volcano plot of differential gene expression in leukocytes of insomnia patients after Anshuiyin + Five Elements Music intervention. (B) PPI network of differentially expressed genes. (C) KEGG pathway enrichment bubble plot of differentially expressed genes.

[0054] Figure 5 Safety evaluation of Anshuiyin + Five Elements Music intervention for insomnia. AYP, before insomnia intervention; AYT, after insomnia intervention. DETAILED DESCRIPTION

[0055] The following embodiments are only some embodiments of the present invention, rather than all embodiments. Therefore, the detailed description in the embodiments of the present invention provided below is not intended to limit the scope of the present invention claimed for protection, but merely represents selected embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without making creative work belong to the protection scope of the present invention.

[0056] In the present invention, unless otherwise specified, all equipment and raw materials can be purchased from the market or are commonly used in the industry. The methods in the following embodiments are all conventional methods in the art unless otherwise specified.

[0057] Example 1

[0058] This embodiment provides a preparation method of granules:

[0059] 1. Prescription

[0060] Angelica 5g, Poria 7.5g, stir-fried Ziziphus jujuba seeds 7.5g, Perilla leaves 4.5g, lily 10g, and Prunella vulgaris 7.5g.

[0061] 2. Preparation process

[0062] The above six ingredients were decocted twice with water. The first time, 10 times the amount of water was added and the extraction was performed for 1.5 hours. The second time, 8 times the amount of water was added and the extraction was performed for 1 hour. The decoctions were combined and centrifuged (4000r / min, 15 minutes) or filtered by centrifugation with 300 mesh polyester cloth or plate and frame filter press according to the enterprise equipment. The filtrate was concentrated under reduced pressure to a clear paste with a relative density of 1.25-1.30 (60°C), or concentrated to a suitable relative density in combination with the enterprise's drying method. The clear paste was dried under reduced pressure (70-80°C), crushed, and passed through a No. 5 sieve to obtain a dry paste powder. The pilot paste yield was 14.91%.

[0063] Take dry paste powder, mix dextrin and xylitol in equal proportions, add to the dry paste powder to 14g, mix well, dissolve stevioside (0.02% in total amount) in 90%-95% ethanol, use it as a wetting agent, granulate, dry (60-70℃), granulate, and package, 7g per bag.

[0064] It is also possible to use one-step granulation and other methods in combination with relevant equipment of the enterprise to carry out granulation.

[0065] Example 2

[0066] 1. Research Plan

[0067] (1) Ethical Review

[0068] This study has been approved by the Ethics Committee of Beijing University of Chinese Medicine, project number: 2020BZYLL0604.

[0069] (2) Research subjects

[0070] From January 1, 2021 to December 31, 2021, insomnia patients were recruited through recruitment advertisements in 8 affiliated hospitals, including Beijing University of Chinese Medicine Dongzhimen Hospital, Beijing University of Chinese Medicine Oriental Hospital, Beijing University of Chinese Medicine Third Affiliated Hospital, Beijing University of Chinese Medicine Zaozhuang Hospital, Xiamen Traditional Chinese Medicine Hospital, Beijing University of Chinese Medicine Sun Simiao Hospital, Beijing University of Chinese Medicine Shenzhen Hospital and China Academy of Chinese Medical Sciences Eye Hospital. Patients were from outpatients, inpatients or residents of surrounding communities.

[0071] (3) Diagnostic criteria

[0072] Refer to the diagnostic criteria for insomnia in the "Guidelines for the Diagnosis and Treatment of Insomnia in Chinese Adults (2017 Edition)": ① The presence of one or more abnormal sleep states; ② The presence of one or more daytime symptoms related to insomnia; ③ Abnormal sleep symptoms and related daytime symptoms cannot be simply explained by lack of appropriate sleep time or inappropriate sleeping environment; ④ Difficulties in sleeping and waking up cannot be better explained by other types of sleep disorders.

[0073] (4) Inclusion and exclusion criteria

[0074] 1) Inclusion criteria

[0075] ①Meet the diagnostic criteria for insomnia;

[0076] ② Aged between 18 and 80;

[0077] ③ Conscious, clear-minded, and able to communicate in language;

[0078] ④No symptoms of olfactory impairment;

[0079] ⑤Pittsburgh Sleep Quality Index>5;

[0080] ⑥ Understand and be able to cooperate with the corresponding trial plan and sign the informed consent form.

[0081] 2) Exclusion criteria

[0082] ① Those with systemic diseases (fever, pain, surgery, etc.) or other serious diseases of the circulatory system, hematopoietic system, digestive system, endocrine system, etc., as well as those with insomnia caused by external environmental interference factors;

[0083] ② Patients with moderate to severe anxiety and depression: Self-Rating Anxiety Scale (SAS) standard score ≥ 60 points, Self-Rating Depression Scale (SDS) standard score ≥ 63 points;

[0084] ③Severe mental illness, such as: schizophrenia, bipolar disorder, paranoid disorder, schizoaffective disorder, mental disorder caused by epilepsy, severe mental retardation.

[0085] ④ Those who are pregnant, breastfeeding or planning to become pregnant;

[0086] ⑤ Those who are allergic to aromatic drugs or have a history of severe adverse reactions, or those with severe allergic constitution;

[0087] ⑥ Those who are currently participating in clinical trials of other drugs.

[0088] (5) Shedding standard

[0089] ① Patients who were lost to follow-up during the experiment;

[0090] ② Subjects decide to withdraw due to their own physical or personal reasons: allergic reactions, unbearable adverse events / serious adverse events. Their case records should be kept, and the last test result should be taken as the final result for efficacy and adverse reaction data analysis.

[0091] (6) Elimination criteria

[0092] ① Patients who have not used one or more interventions required by the protocol;

[0093] ② Patients who have not fully completed the efficacy and safety indicators required by the regimen.

[0094] ③ After the start of the experiment, if the use of new insomnia-related drugs (traditional Chinese medicine, Chinese patent medicine and Western medicine) significantly affects the effectiveness and safety judgment, and the researcher judges that it is not suitable to continue, the patient should withdraw from this clinical trial.

[0095] ④ The subjects have poor compliance with the trial protocol, and the researchers and / or sponsors believe that this will affect the judgment of the drug's efficacy and / or safety.

[0096] ⑤ Subjects who should not be included in the group but have been included should be excluded, including those who were mistakenly included, misdiagnosed, or have no scale assessment records.

[0097] (7) Sample size calculation

[0098] In order to ensure the sample size, referring to the sample size requirements for Phase III clinical trials in the "Drug Registration Management Measures", it was finally decided to include 500 cases, with 375 cases in the experimental group and 125 cases in the control group according to the 3:1 ratio.

[0099] (8) Random setting method

[0100] A computer system is used for dynamic randomization. The subjects fill in relevant information in the medical evaluation management system. After the researchers determine that they meet the inclusion criteria or do not meet the exclusion criteria, they click on the system to agree to join the group, and the system automatically assigns the patients to groups.

[0101] (9) Active and Passive Intervention Schemes

[0102] Aiming at the principle of regulating the body of Qi stagnation "soothing the liver and promoting Qi circulation, relieving its stagnation", and the pathological characteristics of insomnia "disharmony of yin and yang, Qi and blood, dysfunction of viscera, causing the mind to be disturbed and the spirit to be restless", and taking into account the state of Qi deficiency and blood deficiency, a comprehensive TCM intervention concept based on the principles of calming the mind and regulating the spirit, relieving depression with aromatics, and calming the mind and regulating the body was created. A comprehensive TCM intervention program based on the Five Elements Music (Yu Diao) combined with the Medicine and Food Same Origin Sleeping Drink (granules in Example 1 of the present invention) was constructed.

[0103] The experimental group received basic treatment (Five Elements Music Therapy Yu Diao) combined with body-regulating food (sleeping drink) intervention, while the control group received basic treatment (Five Elements Music Therapy Yu Diao).

[0104] Basic treatment (five elements music therapy Yu Diao) is to listen to it for 30 minutes every night before going to bed. The Chinese medicine body-regulating food for sleeping is to drink 1 bag (each bag contains 7g of granules) at a time, twice a day.

[0105] (10) Efficacy evaluation criteria

[0106] 1) Main efficacy indicators

[0107] The difference in the total score of the Pittsburgh sleep quality index (PSQI) between the experimental group and the control group at week 12 compared with the baseline value.

[0108] The PSQI was constructed by Buysse et al. in 1988, and was introduced and translated into my country by Liu Xianchen et al. in 1996. The scale consists of 19 self-assessment items and 5 other-assessment items, of which the 19th self-assessment item and the 5 other-assessment items are not included in the scoring. The PSQI score ranges from 0 to 21 points, and the higher the score, the worse the sleep quality. The total PSQI score consists of 7 factors, namely, sleep quality factor, sleep time factor, sleep time factor, sleep efficiency factor, sleep disorder factor, hypnotic drug factor and daytime dysfunction factor. Each factor has a score of 0 to 3 points. The higher the score, the worse the state of sleep-related factors.

[0109] 2) Secondary efficacy indicators

[0110] ① The total score of the Pittsburgh Sleep Quality Index (PSQI) in the experimental group and the control group at the 4th and 8th week, and the difference between the scores of each factor measured three times in 12 weeks and the baseline (enrollment) score.

[0111] ② Insomnia Severity Index (ISI): The difference between the dynamic total scores of the experimental group and the control group compared with the baseline value at three measurement points in 12 weeks.

[0112] ISI was invented by Morin and is a brief patient self-assessment scale used to assess the severity of insomnia. ISI consists of 7 questions, each with a score of 0 to 4 points, and a total score of 0 to 28 points. The higher the score, the more severe the insomnia.

[0113] ③ Fatigue Scale-14 (FS-14): The dynamic total score and factor scores of the experimental group and the control group were measured three times during 12 weeks.

[0114] FS-14 is a scale for self-assessment of fatigue, compiled by Chalder and other experts in 1992. The FS-14 scale consists of 14 items, and each question only has to choose "yes" or "no". The full score is 14 points, and the higher the score, the more severe the fatigue. The 14 items can be divided into two factors, one is the "physical fatigue" factor, which consists of items 1 to 8, with a score range of 0 to 8 points, and the higher the score, the more severe the physical fatigue; the other is the "mental fatigue" factor, which consists of items 9 to 14, with a score range of 0 to 6 points, and the higher the score, the more severe the mental fatigue.

[0115] ④HyPerarousal Scale (HAS): The difference between the dynamic total score and each factor score of the experimental group and the control group compared with the baseline value at three measurement points in 12 weeks.

[0116] HAS is a self-assessment scale consisting of 26 items to assess the degree of self-overarousal. It consists of three factors, namely, introspection factor, reactivity factor and extreme reaction factor score. The lowest score of the scale is 0 points and the highest score is 78 points. The higher the score, the more serious the overarousal.

[0117] ⑤ Nine kinds of traditional Chinese medicine body mass scale (2009 version): changes in the conversion scores of each body constitution at baseline (entry) and exit (week 12).

[0118] According to the judgment and classification standards of the Chinese Medicine Association's "Classification and Determination Standards for Chinese Medicine Constitution" (ZZYXH / T157-2009) in 2009: original score = sum of the scores of each item, conversion score = (original score minus number of items / number of items) * 4) * 100%, sort by conversion score and take the highest score as the final judgment value of TCM constitution.

[0119] (11) Safety evaluation indicators

[0120] Safety indicators were tested and adverse reaction scales were recorded at the time of enrollment and at 3 months (12 weeks) of intervention to evaluate whether the active and passive combined intervention technology used was safe. Safety evaluation indicators were analyzed using the safety analysis set (SS). (12) Clinical research quality control plan

[0121] The trial was registered with the World Health Organization's International Clinical Trial Registry Platform. The research team identified three quality control personnel to regularly review the implementation of the sub-center projects to ensure that they were strictly carried out in accordance with the requirements of the Good Clinical Practice (GCP). A standardized operating procedure (SOP) was formulated during the research process, and researchers were uniformly trained to ensure homogeneity among different researchers.

[0122] The sleeping drink is managed by a dedicated person. The number, time and quality (packaging, labeling) of the delivery, distribution and receipt must be checked. If it is not up to standard, it will be returned. During the intervention, patients fill out paper / electronic check-in cards or check in daily in the WeChat group. The paper check-in records will be collected by the research team after the intervention. After enrollment, patients are allowed to take oral insomnia medications before enrollment, but are not allowed to add other treatments other than the intervention plan of this study after the intervention begins. Once discovered, the relevant intervention will be terminated.

[0123] (13) Data statistical methods

[0124] The independently developed medical evaluation management system can export the collected patient data, including basic information and scale data. SPSS20.0 statistical software is used for data statistical analysis.

[0125] ① Analysis of enrollment and completion status

[0126] The enrollment status of the subjects is presented in a graph, describing the number of cases entering each analysis set (FAS, PPS), the total number of cases, and the dropout situation.

[0127] ② Demographic data and baseline analysis

[0128] The full analysis set (FAS) was used to analyze the demographic data and baseline data, which were summarized according to the treatment groups. Descriptive statistics were performed on the basic information of the two groups of subjects during the screening period, such as age, gender, occupation, and BMI. For the measurement data, if it was normally distributed, the mean and standard deviation were described; if it was not normally distributed, the median and IQR were described. For the categorical data, the number of cases and percentages were described.

[0129] ③Efficacy analysis

[0130] This study was conducted as an intention-to-treat analysis, using the Per-Protocol Set (PPS) and Full Analysis Set (FAS) for efficacy statistics, with the FAS set used as the primary analysis result. The Per-Protocol Set did not fill in data, and the lost data in the Full Analysis Set were filled in with the last data before the lost data. The missing baseline value of the TCM constitution score was filled in with the EM filling method.

[0131] For each scale score, which is a repeated measurement data, generalized estimating equations are used to analyze and compare the trend of changes between the experimental group and the control group. The model takes each time point and group as independent variables, and the baseline value (data measured at enrollment) as a covariate. At the same time, the interaction between each time point and the group is considered. The least squares mean (LS mean) of the inter-group difference (control group-experimental group) at each time point and its corresponding 95% confidence interval are calculated, and the P value is provided. The generalized estimating equation model analysis will be analyzed using an unstructured covariance matrix (UN).

[0132] For other non-repeated measurement data, if the baseline is uniform and the data is normally distributed, t-test, paired t-test, variance analysis, etc. are used; if the data is not normally distributed, uncommon tests are used, such as rank sum test, paired rank sum test, Kruskal-Wallis test, etc. For data with uneven baselines, linear retrospective analysis can be used, with baseline values ​​as covariates and grouping as independent variables for statistical analysis.

[0133] 2. Research Results

[0134] A total of 520 subjects were recruited in this study, and 504 subjects were finally included in the analysis, including 408 subjects in the PPS set, including 311 subjects in the experimental group and 100 subjects in the control group; 473 subjects in the FAS set, including 360 subjects in the experimental group and 113 subjects in the control group. The baseline data of the FAS set were used for analysis.

[0135] (1) Baseline homogeneity comparison

[0136] The baseline data of the recruited population, such as gender, age, BMI, occupation, etc., were statistically tested in the experimental group and the control group. The results showed that there was no statistical difference in the above baseline data between the two groups, and the baseline data of the two groups were comparable (see Table 1).

[0137] Table 1 Baseline data of insomnia

[0138]

[0139]

[0140] (2) Comparison of shedding rate

[0141] Among the 504 included insomnia patients, 1 withdrew from the study due to adverse reactions, 2 withdrew due to work reasons, and 28 were lost to follow-up throughout the whole process, with a total of 473 people entering the FAS set. In the FAS set, 2 patients took banned drugs, 6 patients did not complete the intervention plan sufficiently, and among the remaining patients, 408 patients collected the main efficacy indicators completely, 88 dropped out / withdrawn, and the overall dropout (withdrawal) rate was 17.46%. There was no statistical difference in the dropout (withdrawal) rate between the two groups (P=0.400) (see Table 2).

[0142] Table 2 Dropout rate data of insomnia test group and control group

[0143]

[0144] (3) Evaluation of main efficacy indicators

[0145] From the analysis of PPS and FAS sets, there was a statistically significant difference in the difference of PSQI scores between the experimental group and the control group compared with the baseline value at week 12, and the difference of PSQI scores between the experimental group and the control group was higher than that of the control group.

[0146] 1) PPS Set

[0147] At week 12, the PSQI score of the control group decreased by an average of 3.52 points compared with the baseline value, and the PSQI score of the experimental group decreased by an average of 4.89 points compared with the baseline value. According to the generalized estimating equation analysis, there was a statistically significant difference between the two groups at week 12 (LS mean 1.00, 95% CI [0.32, 1.68], P = 0.004). The decrease in the score of the experimental group compared with the baseline value was higher than that of the control group (see Table 3).

[0148] 2)FAS set

[0149] At week 12, the PSQI score of the control group decreased by an average of 3.48 points compared with the baseline value, and the PSQI score of the experimental group decreased by an average of 4.64 points compared with the baseline value. According to the generalized estimating equation analysis, there was a statistically significant difference between the two groups at week 12 compared with the baseline value (LS mean 0.80, 95% CI [0.14-1.45], P = 0.017). The decrease in the score of the experimental group compared with the baseline value was higher than that of the control group (see Tables 3 and 4).

[0150] Table 3 Insomnia model effect test (PPS)

[0151]

[0152] Table 4 Generalized estimating equation results for the difference between PSQI scores and baseline for insomnia (PPS set)

[0153]

[0154] (4) Secondary efficacy indicators

[0155] 1) Dynamic changes in PSQI scores in weeks 4 and 8

[0156] Both groups could improve the PSQI score within the group, with statistical difference. In the PPS set, the LS mean gradually increased between the two groups, and there was no statistical difference in the LS mean between the two groups at week 4, and there was a difference in the LS mean between the two groups at week 8. In the FAS set, the LS mean gradually increased, and there was no statistical difference in the LS mean between the two groups at weeks 4 and 8.

[0157] Generalized estimating equation analysis showed that after correcting the baseline value, there was a statistically significant difference in the mean difference between the PSQI score after intervention and the baseline value in the experimental group and the control group (P=0.008), and there was a statistically significant difference in the difference between the PSQI score and the baseline value at different time points (4, 8, and 12 weeks) (P<0.001), and there was no statistically significant difference in the interaction effect (P=0.309).

[0158] In general, the decrease scores of PSQI scores in the experimental group at 4, 8, and 12 weeks compared with the baseline values ​​gradually increased, with statistical significance (P < 0.001); the absolute values ​​of the differences in PSQI scores in the control group at 4, 8, and 12 weeks compared with the baseline values ​​gradually increased, with statistical significance (P < 0.001).

[0159] There was no statistical difference in the difference of PSQI scores between the experimental group and the control group compared with the baseline value at week 4 (LS mean 0.51, 95% CI [-0.09, 1.10], P = 0.094); there was a statistical difference at week 8 (LS mean 0.70, 95% CI [0.06, 1.39], P = 0.048), and the decrease in the score of the experimental group compared with the baseline value was higher than that of the control group (see Figure 1 ).

[0160] Generalized estimating equation analysis showed that after correcting the baseline value, there was a statistically significant difference in the mean difference between the PSQI score after intervention and the baseline value in the experimental group and the control group (P=0.028). There was a statistically significant difference in the PSQI scores at different time points (4, 8, and 12 weeks) (P<0.001), and there was no statistically significant difference in the interaction effect (P=0.426).

[0161] In general, the differences between the PSQI scores at 4, 8, and 12 weeks in the experimental group and the baseline values ​​were statistically significant (P < 0.001); the differences between the PSQI scores at 4, 8, and 12 weeks in the control group and the baseline values ​​were statistically significant (P < 0.001).

[0162] There was no statistical difference in the PSQI score between the experimental group and the control group compared with the baseline value at week 4 (LS mean 0.42, 95% CI [-0.13, 0.97], P = 0.138); there was no statistical difference at week 8 (LS mean 0.57, 95% CI [-0.08, 1.21], P = 0.084) (see Table 5, Table 6, Figure 2 ).

[0163] Table 5 Insomnia model effect test (FAS)

[0164]

[0165] Table 6 Generalized Estimation Equation Results for PSQI Score Difference from Baseline (FAS Set)

[0166]

[0167] 2) TCM body mass scale score

[0168] The scores of Traditional Chinese Medicine Body Mass Scale were compared between the experimental group and the control group. In the PPS set, except for the special constitution, the scores of other constitutions could be improved. In the FAS set, after the intervention, the 9 TCM constitutions could be improved in both groups.

[0169] There was no difference in the constitution scores of the experimental group compared with the control group in PPS and FAS sets, but the score reduction coefficient of the Qi Yu constitution experimental group compared with the control group was the highest among the biased constitutions.

[0170] Paired rank-sum test analysis showed that the control group could improve the median score of the subjects' peaceful quality, with a statistically significant difference (P<0.001); for biased constitution, the control group could reduce the median score of biased constitution, and except for special constitution, the reduction scores of other biased constitutions were statistically significant.

[0171] The experimental group can improve the median score of the subjects' peacefulness, and there is a statistical difference (P<0.001). For those with biased constitution, the experimental group can reduce the median score of biased quality, and there are statistical differences.

[0172] Through linear regression analysis, there was no statistical difference in the scores of the nine TCM constitutions between the experimental group and the control group after correcting the baseline value. However, it can be seen from the results that, after correcting the baseline, Qi stagnation constitution has a better score reduction effect (see Table 7, Table 8, Table 9).

[0173] Table 7 Comparison within the insomnia control group

[0174]

[0175] Table 8 Intra-group comparison of insomnia test groups

[0176]

[0177] Table 9 Comparison between insomnia groups (experimental group score-control group score)

[0178]

[0179] The paired rank-sum test analysis showed that the control group could improve the median score of the subjects' peaceful quality, and there was a statistical difference (P<0.001); for the biased constitution, the control group could reduce the median score of the biased quality, and there were statistical differences.

[0180] The experimental group can improve the median score of the subjects' peacefulness, and there is a statistical difference (P<0.001). For those with biased constitution, the experimental group can reduce the median score of biased quality, and there are statistical differences.

[0181] Through linear regression analysis, there was no statistical difference in the scores of the nine TCM constitutions between the experimental group and the control group after correcting the baseline values. However, it can be found that for the biased constitution, the scores of Qi stagnation and Qi deficiency in the experimental group were lower than those in the control group (see Table 10, Table 11, Table 12).

[0182] Table 10 Comparison within the insomnia control group

[0183]

[0184] Table 11 Intra-group comparison of insomnia test groups

[0185]

[0186] Table 12 Comparison of insomnia groups (experimental group score-control group score)

[0187]

[0188] (5) Safety indicators

[0189] According to the analysis of safety indicators, 1 patient developed fatigue, drowsiness, and swollen eyes after taking the medicine, and the symptoms improved after stopping the medicine. The dosage was halved to one bag a day, and there was no above symptoms; 1 patient developed daytime sleepiness after taking the medicine, and the dosage was halved later, and there was no above symptoms; 1 patient developed high blood pressure after taking the medicine, and the blood pressure dropped after stopping the medicine. The subsequent dosage was halved without the above symptoms; 1 patient developed hot flashes after taking the medicine; 4 people had mild elevations in alanine aminotransferase and aspartate aminotransferase after taking the medicine, and 4 subjects in the test group had urine protein. No obvious abnormalities were found in the rest of the renal function, urine and stool routine, and electrocardiogram.

[0190] 3. Analysis and Discussion

[0191] In terms of the main efficacy indicators, both the experimental group and the control group can improve the sleep quality of insomnia patients. At week 12, the score reduction of the experimental group compared with the baseline was higher than that of the control group, indicating that the comprehensive Chinese medicine intervention program is better than the control group in improving sleep quality.

[0192] A stratified study of the severity of insomnia found that the TCM comprehensive intervention program had no statistically significant difference in efficacy at each time point compared with the five-element music program in the intervention of mild insomnia; in the intervention of moderate to severe insomnia, the TCM comprehensive intervention program showed a statistically significant efficacy advantage over the five-element music program in the fourth week, and the LS mean increased over time. Therefore, from the perspective of health economics, simple Yu-mode music intervention is recommended for patients with mild insomnia, and TCM comprehensive intervention is recommended for moderate to severe insomnia.

[0193] Fatigue is currently a difficult-to-treat physical and mental state, and is also a common daytime functional disorder of insomnia. Western medicine has no obvious advantages in this regard, and fatigue is correlated with a variety of diseases. In the present invention, it was found that the control group could not improve the FS-14 total score and the mental fatigue factor score, but could improve the physical fatigue factor score; the experimental group could improve the FS-14 total score and its factor scores. This shows that the comprehensive intervention program of traditional Chinese medicine is better than the intervention of five-element music alone in improving fatigue status, especially in improving mental fatigue.

[0194] Hyperarousal is an abnormal state of increased response to stimulation, which can lead to increased heart rate, breathing and anxiety levels. Insomnia patients have a higher hyperarousal state, and high hyperarousal state is associated with various mental illnesses and chronic diseases. Although both comprehensive Chinese medicine intervention and five-element music can improve the hyperarousal state, although there is no difference between the two groups at each time point, the treatment effects of both groups are on an upward trend, and the LS mean gradually increases. Perhaps after a longer period of treatment, the comprehensive Chinese medicine intervention program can show better advantages.

[0195] Although both the experimental group and the control group were able to improve the scores of the nine constitutions, and although there was no statistical difference between the two groups, the experimental group had a better effect on reducing the scores of Qi stagnation and Qi deficiency than the control group. These two constitutions were also the main constitutions related to insomnia found in the early stage of this study. This trend reflects the feasibility of the active and passive combination scheme constructed based on TCM constitution in this study. The lack of positive results may be related to the small number of people with Qi deficiency and Qi stagnation included and the insufficient statistical power.

[0196] According to the results, people who record sleep diaries can improve their sleep quality better than those who do not. Sleep diaries are widely used abroad, where patients record their sleep conditions the night before. The patient's sleep latency, total sleep time, and sleep efficiency can be calculated based on the content of the sleep diary. However, sleep diaries are still less used in my country, and patients have low acceptance, resulting in low quality of sleep data collected from sleep diaries in this study.

[0197] The results of this study found that in the experimental group, there were statistically significant differences in the LS mean values ​​of patients who kept sleep diaries compared with those who did not, and the PSQI score of patients who kept diaries decreased more from the baseline than the group who did not keep a diary; there was no statistical difference in the LS mean values ​​at week 12. In the control group, there were statistically significant differences in the LS mean values ​​of patients who kept sleep diaries compared with those who did not, and the PSQI score of patients who kept diaries decreased more from the baseline than the group who did not keep a diary. This proves that keeping a sleep diary can help improve sleep quality and can be effective in the early stages.

[0198] This study uses a sleep diary, which not only records sleep information, but also allows patients to record daily events that affect sleep, which helps patients to conduct self-examination and self-monitoring, and helps patients to exercise autonomy. According to the research results, it can be found that in the two groups, the people who recorded sleep diaries improved their sleep quality in the early stage better than those who did not record sleep diaries, reflecting the advantages of combining active and passive methods to prevent and treat diseases.

[0199] 4. Sleeping Drink + Five Elements Music

[0200] (1) Research subjects

[0201] A total of 30 healthy controls (HC), 8 patients before insomnia treatment (AYP) and 35 subjects after insomnia treatment (AYT) were included in this study. They were recruited from Beijing University of Chinese Medicine, Beijing University of Chinese Medicine Dongzhimen Hospital, Beijing University of Chinese Medicine Oriental Hospital, the Third Affiliated Hospital of Beijing University of Chinese Medicine, and the Eye Hospital of China Academy of Chinese Medical Sciences; the Ethics Committee of Beijing University of Chinese Medicine was entrusted to conduct ethical review and supervision (Ethics Number: 2021BZYLL0302).

[0202] (2) Observation indicators

[0203] 1) Basic Information

[0204] Including the subject's name, gender, age, ethnicity, height, weight, etc.

[0205] 2) Medical history

[0206] ① Past medical history (including major organs such as the heart, liver, spleen, lungs, and kidneys, as well as history of epilepsy and mental illness; major surgeries must indicate when, where, and what type of surgery was performed, and the current condition);

[0207] ②History of allergy;

[0208] ③ History of smoking and drinking;

[0209] ④Menstrual and reproductive history.

[0210] 3) Laboratory examination and index determination

[0211] ①Biochemistry, electrocardiogram, glycosylated hemoglobin, four blood lipids, BMI, blood, urine and stool routine tests;

[0212] ②Peripheral leukocyte mRNA sequencing.

[0213] 4) Scale evaluation

[0214] ① Pittsburgh Sleep Quality Index (PSQI), Hyperarousal Scale (HAS), Insomnia Severity Index (ISI), Fatigue Scale (FS-14);

[0215] ② Traditional Chinese Medicine body mass scale.

[0216] (3) Research results

[0217] 1) Macro-efficacy indicators

[0218] Sleeping drink + five-element music can significantly improve the sleep quality of insomnia patients (ISI) (see Figure 3 ).

[0219] 2) Micro-efficacy indicators

[0220] ① Peripheral leukocyte mRNA sequencing

[0221] After the intervention of Anshuiyin + Five Elements Music, the expression of 737 genes in the peripheral leukocytes of insomnia patients changed, including 292 down-regulated genes and 445 up-regulated genes, forming a complex PPI network with IL1, IL10, CCL2, CCL4, CXCL10, RSAD2, IFI35 as the core, and the functional enrichment was concentrated in Cytokine-cytokine receptor interaction, Viral Protein interaction with cytokine and cytokine receptor pathway (see Figure 4 ).

[0222] 3) Safety evaluation

[0223] Sleeping drink + five-element music had no significant effect on the blood routine, renal function and blood sugar status of insomnia patients, and the intervention measures were safe (see Figure 5 ).

[0224] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A Chinese medicine composition, characterized in that: The Chinese medicine composition comprises the following Chinese medicinal materials in parts by weight: 1-10 parts of angelica sinensis, 1-10 parts of Poria cocos, 1-10 parts of stir-fried spiny jujube seeds, 1-10 parts of perilla leaves, 2-10 parts of lily, and 1-10 parts of selfheal.

2. The Chinese medicine composition according to claim 1, characterized in that: The Chinese medicine composition comprises the following Chinese medicinal materials in parts by weight: 3-8 parts of angelica, 5-9 parts of Poria, 5-9 parts of stir-fried spiny jujube seeds, 3-7 parts of perilla leaves, 8-10 parts of lily, and 5-9 parts of selfheal; Preferably, the Chinese medicine composition comprises the following Chinese medicinal materials in parts by weight: 5 parts of angelica sinensis, 7.5 parts of Poria cocos, 7.5 parts of stir-fried spiny jujube seeds, 4.5 parts of perilla leaves, 10 parts of lily, and 7.5 parts of selfheal.

3. A Chinese medicine extract, characterized in that: The Chinese medicine composition according to claim 1 or 2 is obtained by water decoction extraction.

4. A method for preparing the Chinese herbal medicine extract according to claim 3, characterized in that: The method comprises the following steps: mixing the various Chinese medicinal materials in the Chinese medicinal composition according to a ratio, decocting with water for extraction, combining the decoctions, filtering, concentrating the filtrate, and obtaining a clear paste; Preferably, the preparation method further comprises drying the obtained clear paste to obtain a dry paste.

5. The preparation method according to claim 4, characterized in that: The water decoction is performed 1 to 3 times; Preferably, the extraction is performed by decoction in water twice, with 8 to 12 times the amount of water added for the first time and extraction for 1 to 2 hours, and 6 to 10 times the amount of water added for the second time and extraction for 1 to 2 hours.

6. The preparation method according to claim 4, characterized in that: The filtration is centrifugal filtration or plate and frame filter press; Preferably, the centrifugal filtration is filtering through a 300-mesh polyester cloth after centrifugation; Preferably, the concentration is reduced pressure concentration; Preferably, the filtrate is concentrated to a clear paste with a relative density of 1.25-1.30 (60° C.); Preferably, the dry paste has a paste yield of 13-18%.

7. A drug, characterized in that The medicine comprises the Chinese herbal extract according to claim 3.

8. The drug according to claim 7, characterized in that The drug further comprises a pharmaceutically acceptable excipient; Preferably, the dosage form of the drug is an oral dosage form; Preferably, the oral dosage form is granules, oral liquid, tablets, syrups, pastes, capsules, and pills.

9. The drug according to claim 7, characterized in that The dosage form of the drug is a granule, and the granule comprises the Chinese herbal extract according to claim 3, dextrin and xylitol; Preferably, the mass ratio of dextrin to xylitol is 1:1 to 1:2; Preferably, the granules are prepared by a wet granulation method; Preferably, the wet granulation uses 70-95% ethanol as a wetting agent; Preferably, the granules further comprise a flavoring agent; Preferably, the flavoring agent is selected from sweeteners; Preferably, the sweetener is steviol glycoside; Preferably, the mass ratio of dextrin to xylitol is 1:1; Preferably, 90%-95% ethanol is used as the wetting agent.

10. Use of the Chinese medicine composition according to claim 1, the Chinese medicine extract according to claim 3 or the medicine according to claim 7 in the preparation of a medicine for treating insomnia.

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