Medical use of sishen pills or extracts thereof

Abstract

The present application belongs to the field of traditional Chinese medicine, and relates to medical uses of Sishen pills or extracts thereof. Specifically, any one selected from items (1)-(3) below in the preparation of a drug for sedative-hypnotic, treatment or prevention of insomnia, anti-anxiety, or sleep regulation: (1) a pharmaceutical composition comprising Myristicae Semen, Fructus Psoraleae, Schisandra chinensis, Evodia rutaecarpa, Fructus Jujubae, and Zingiber officinale; (2) an extract which is a water extract and / or an ethanol extract of the pharmaceutical composition in item (1); and (3) a pharmaceutical preparation comprising the extract in item (2) and one or more pharmaceutically acceptable excipients. The pharmaceutical composition, extract or pharmaceutical preparation described in the present application has good sedative-hypnotic, prophylactic or therapeutic effects on insomnia, or sleep regulation.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine and relates to the medicinal uses of Sishen Pill or its extracts. Specifically, the uses are sedation and hypnosis, prevention or treatment of insomnia, or sleep regulation. Background Technology

[0002] Insomnia is a neuropsychiatric disorder characterized by difficulty falling asleep or maintaining sleep under conditions of sufficient sleep duration and suitable environment, leading to daytime dysfunction. Its main symptoms include difficulty falling asleep, frequent awakenings, early awakenings, and non-restorative sleep. Insomnia is the most common sleep disorder, with a short-term incidence rate of 30%–50%. In major industrialized countries worldwide, at least 5%–10% of the population suffers from chronic insomnia, and 5%–7% have previously treated or are currently using prescription medications for insomnia. Epidemiological surveys of the general population in my country indicate that 15% of the population suffers from chronic insomnia.

[0003] Commonly used sedative-hypnotic drugs in clinical practice include benzodiazepines, represented by diazepam and lorazepam. Class II and non-benzodiazepines, represented by zaleplon and zopiclone. Currently used sedative-hypnotic drugs have varying degrees of side effects and medication safety issues. Benzodiazepines, with long-term use, are addictive and can lead to dependence, along with side effects such as drowsiness, fine motor incoordination, and memory loss. While non-benzodiazepine drugs have fewer side effects such as memory impairment and rebound insomnia after discontinuation, they can still cause daytime functional disturbances such as headaches, dizziness, and drowsiness; long-term use can also lead to tolerance and dependence.

[0004] While existing sedative-hypnotic drugs can prolong sleep time to some extent, they cannot improve sleep quality. Normal physiological sleep, based on brain electrical activity characteristics and sleep depth, can be divided into rapid eye movement (REM) sleep and non-rapid eye movement (NREM) sleep. NREM sleep is further divided into four stages: I, II, III, and IV. NREM stages III and IV are deep sleep stages, the main periods for restoring energy and physical strength. In a full night's sleep, REM sleep accounts for approximately 20%-25%, and NREM sleep accounts for approximately 75%-80%, with NREM stages III and IV accounting for approximately 13%-23% of the time. The effectiveness of sleep recovery is not only related to the total sleep time but also closely related to the time distribution and proportion of each sleep stage. Traditional benzodiazepines increase the time of NREM stages I and II, and can significantly shorten or completely eliminate NREM stage IV sleep. Newer non-benzodiazepine representative drugs, zolpidem and zopiclone, also shorten the time of REM and NREM stages III and IV. The disruption of normal sleep structure prevents drug-induced sleep from achieving the same restorative effects as normal physiological sleep. Currently used sedative-hypnotic drugs increase sleep time at the expense of sleep quality, which is one of the reasons for fatigue and drowsiness the day after using such drugs to induce sleep.

[0005] Insomnia seriously affects patients' physical and mental health and quality of life, and also places a heavy burden on society. Currently used sedative-hypnotic drugs can change sleep time, but cannot increase sleep depth or improve sleep quality. Therefore, the development of new sedative-hypnotic drugs that have the function of regulating sleep structure and can increase sleep depth and improve sleep quality in insomnia patients is of great significance.

[0006] Shenshen Pills were first recorded in "Chen's Treatise on Infantile Smallpox and Measles" written by Chen Wenzhong. It is composed of Ershen Pills (nutmeg, psoralen) and Wuweizi Powder (schisandra chinensis, evodia rutaecarpa). The combination of the two prescriptions has an excellent effect of warming and tonifying the spleen and kidney, and strengthening the intestine to stop diarrhea, and has been highly regarded by medical experts of all dynasties. It is used to treat diseases such as colitis, irritable bowel syndrome, and allergic colitis, and has definite clinical curative effects. In the acute and chronic colitis models of mice induced by dextran sulfate sodium, intragastric administration of Shenshen Pills at 2.25 g / kg / day can significantly improve the inflammatory damage of colon tissues and the disease activity index of mice. Its mechanism is mainly related to inhibiting the Th17 response and promoting Th17 generation. In the ulcerative colitis model of rats constructed by the 2,4,6-trinitrobenzenesulfonic acid-ethanol method, Shenshen Pills can also improve the general condition of the model rats, reduce the pathological damage of the colon and the NO level in tissues, and down-regulate the concentration of TNF-α in serum. The above studies indicate that the therapeutic effect of Shenshen Pills may be related to immune regulation and inhibition of oxidative stress response. In the study of irritable bowel syndrome, Shenshen Pills can reduce the diarrhea index of rats with irritable bowel syndrome of spleen-kidney yang deficiency type, reduce intestinal sensitivity, and improve the abnormal intestinal flora structure of rats in the model group, suggesting that Shenshen Pills may play a role in treating irritable bowel syndrome by regulating intestinal flora. The sedative-hypnotic effect and sleep structure regulation effect of Shenshen Pills have not been reported yet. Summary of the Invention

[0007] Through in-depth research and creative work, the inventor has surprisingly found that Shenshen Pills can inhibit the spontaneous activity of mice, and can cooperate with sodium pentobarbital to prolong the disappearance time of the righting reflex of mice and shorten the latency of the disappearance of the righting reflex; it has excellent sedative-hypnotic activity. Further, electroencephalogram analysis shows that Shenshen Pills can increase the normal sleep time, regulate the sleep structure, increase the slow-wave sleep time and the number of segments, and has a unique sleep regulation effect. While increasing the sleep time, it can improve the sleep quality by strengthening slow-wave sleep. It has the potential to be applied to sedative-hypnosis, treating or preventing insomnia, or for sleep regulation. Thus, the following invention is provided:

[0008] One aspect of the present invention relates to the use of any one of the following items (1)-(3) in the preparation of a drug for sedative-hypnosis, treating or preventing insomnia, anti-anxiety, or for sleep regulation:

[0009] (1) A pharmaceutical composition, including nutmeg, psoralen, schisandra chinensis, evodia rutaecarpa, Chinese dates, and ginger;

[0010] (2) An extract, which is an aqueous extract and / or an ethanol extract of the pharmaceutical composition in item (1);

[0011] (3) A pharmaceutical preparation, which contains the extract in item (2), and one or more pharmaceutically acceptable excipients.

[0012] In one or more embodiments of the present invention, the described use, wherein...

[0013] The pharmaceutical composition comprises: 1-3 parts by weight of nutmeg, 3-5 parts by weight of psoralea corylifolia, 1-3 parts by weight of schisandra chinensis, 0.5-1.5 parts by weight of evodia rutaecarpa, 1-3 parts by weight of jujube, and 1-3 parts by weight of ginger.

[0014] Preferably, the pharmaceutical composition comprises: 1.5-2.5 parts by weight of nutmeg, 3.5-4.5 parts by weight of psoralea corylifolia, 1.5-2.5 parts by weight of schisandra chinensis, 0.6-1.4 parts by weight of evodia rutaecarpa, 1.5-2.5 parts by weight of jujube, and 1.5-2.5 parts by weight of ginger.

[0015] Preferably, the pharmaceutical composition comprises: 1.8-2.2 parts by weight of nutmeg, 3.8-4.2 parts by weight of psoralea corylifolia, 1.8-2.2 parts by weight of schisandra chinensis, 0.8-1.2 parts by weight of evodia rutaecarpa, 1.8-2.2 parts by weight of jujube, and 1.8-2.2 parts by weight of ginger;

[0016] Preferably, the pharmaceutical composition comprises: 2 parts by weight of nutmeg, 4 parts by weight of psoralea corylifolia, 2 parts by weight of schisandra chinensis, 1 part by weight of evodia rutaecarpa, 2 parts by weight of jujube, and 2 parts by weight of ginger.

[0017] Preferably, the pharmaceutical composition comprises nutmeg, psoralea corylifolia, schisandra chinensis, evodia rutaecarpa, jujube, and ginger.

[0018] In one or more embodiments of the present invention, the use is described, wherein the extract is prepared by a preparation method comprising the following steps:

[0019] 1) Extract the drug composition with 50%-90% ethanol (preferably 60%-80% or 65%-75% ethanol, more preferably 70% ethanol) to obtain the ethanol extract and the residue.

[0020] 2) Extract the residue with water to obtain an aqueous extract;

[0021] 3) Combine the alcohol extract and the water extract to obtain the extract.

[0022] In one or more embodiments of the present invention, the use is described, wherein step 1) is reflux extraction;

[0023] Preferably, the extraction time is 0.5-5 hours, 0.5-2 hours, or 0.5-1.5 hours;

[0024] Preferably, the amount of water used is 2-20 times, 2-15 times, 8-12 times, or 10 times the amount;

[0025] Preferably, the water extract is a concentrated paste obtained after concentration.

[0026] In one or more embodiments of the present invention, the use is described, wherein step 2) involves decocting;

[0027] Preferably, the extraction time is 1 hour;

[0028] Preferably, the amount of ethanol used is 2-20 times, 2-15 times, 8-12 times, or 10 times.

[0029] Preferably, the alcohol extract is a concentrated paste obtained after concentration.

[0030] In one or more embodiments of the present invention, the use is described, wherein the pharmaceutical preparation comprises the extract of item (2) as the sole active ingredient, and one or more pharmaceutically acceptable excipients.

[0031] In one or more embodiments of the present invention, the unit dose of the pharmaceutical preparation is calculated based on the weight of the pharmaceutical composition used to prepare the extract, and is 20g-400g, 50g-300g, 80g-250g, 100g-200g, 120g-180g, 130g-160g, 110g, 120g, 130g, 140g, 150g, 160g, 170g, 180g, 190g, or 200g. Without being limited by theory, based on the high dose of 22.18g / kg in Example 2, with a specific surface area of ​​9.1 for humans and mice, and an adult weight of 60kg, the daily dosage is approximately 146g.

[0032] In one or more embodiments of the present invention, the use is described, wherein the sleep regulation is to increase sleep time and sleep depth, increase the number of slow-wave sleep segments, and / or prolong the duration of slow-wave sleep segments.

[0033] In the experiments of this invention, the results of prolonging the righting reflex time shown in Figure 1 demonstrate the sedative-hypnotic effect of the drug composition (extract). This refers to the discovery of the effect of Sishen Pill on sleep structure based on electroencephalogram (EEG) analysis. Figures 5 and 6 demonstrate the sleep regulation effect of the drug composition (extract).

[0034] Another aspect of the present invention relates to a pharmaceutical preparation comprising the extract described in any one of the present invention, one or more pharmaceutically acceptable excipients, and at least one compound for sedation and hypnosis.

[0035] Preferably, the compound is selected from benzodiazepines. Class of compounds and non-benzodiazepines Class of compounds;

[0036] Preferably, the benzodiazepine The compounds in this class are diazepam or lorazepam;

[0037] Preferably, the non-benzodiazepine The compounds are zaleplon or zopiclone.

[0038] Another aspect of the present invention relates to a combination drug product comprising an individually packaged first drug product and a second drug product, wherein,

[0039] The first pharmaceutical product comprises the pharmaceutical formulation described in any one of the present invention;

[0040] The second pharmaceutical product contains at least one compound for sedation and hypnosis, and one or more pharmaceutically acceptable excipients;

[0041] Preferably, the compound is selected from benzodiazepines. Class of compounds and non-benzodiazepines Class of compounds;

[0042] Preferably, the benzodiazepine The compounds in this class are diazepam or lorazepam;

[0043] Preferably, the non-benzodiazepine The compounds are zaleplon or zopiclone.

[0044] In this invention, the term "sedative-hypnotic" is a pharmacological concept, referring to a drug that, in small doses, can stabilize a person's emotions, while in large doses, it can induce a physiological sleep-like state.

[0045] Beneficial effects of the invention

[0046] The pharmaceutical compositions, extracts, pharmaceutical preparations, or combination pharmaceutical products described in this invention have good sedative-hypnotic, preventive or therapeutic, or sleep-regulating effects. Attached Figure Description

[0047] Figure 1A Effect of Sishenwan extract on sleep latency in mice. Note: n=10, compared with the solvent control group, *p<0.05, **p<0.01, ***p<0.001.

[0048] Figure 1B Effect of Sishenwan extract on sleep duration in mice. Note: n=10, compared with the solvent control group, *p<0.05, **p<0.01, ***p<0.001.

[0049] Figure 2A Effect of Sishenwan extract on the number of squares crossed in mice. Note: n=10, compared with the blank patch control group, ***p<0.001.

[0050] Figure 2B Effect of Sishenwan extract on the number of times mice stand up. Note: n=10, compared with the blank patch control group, ***p<0.001.

[0051] Figure 3A Effect of Sishenwan extract on sleep latency in a mouse PCPA insomnia model. Note: n=10. Compared with the solvent control group, *p<0.05, **p<0.01, ***p<0.001; compared with the PCPA model group, #p<0.05, ##p<0.01, ###p<0.001.

[0052] Figure 3B Effect of Sishenwan extract on sleep duration in a mouse PCPA insomnia model. Note: n=10. Compared with the solvent control group, *p<0.05, **p<0.01, ***p<0.001; compared with the PCPA model group, #p<0.05, ##p<0.01, ###p<0.001; compared with the diazepam group, $p<0.05, $$p<0.01.

[0053] Figure 4 Effects of Sishenwan extract on sleep and wakefulness in rats. Note: n=3, PS: REM sleep, SWS: slow-wave sleep. Compared with the control group, *p<0.05, **p<0.01.

[0054] Figure 5A Effect of Sishenwan extract on mean duration of sleep segments in rats. Note: n=3, PS: REM sleep, SWS: slow-wave sleep. *p<0.05 compared with the control group.

[0055] Figure 5B Effect of Sishenwan extract on the number of sleep segments in rats. Note: n=3, DZ: diazepam, SSW: Sishenwan, PS: REM sleep, SWS: slow-wave sleep. Compared with the control group, *p<0.05, **p<0.01, ***p<0.001. Compared with the diazepam group, #p<0.05, ##p<0.01, ###p<0.001.

[0056] Figure 6A Effect of Sishen Pill on the total number of sleep-wake transitions in rats. Note: n=3, *p<0.05 compared with the control group.

[0057] Figure 6B Effects of Sishen Pill on the number of sleep-wake transitions in rats. Note: n=3, W: Wake; S: Slow wave sleep; A: Active wake. Compared with the control group, *p<0.05. Detailed Implementation

[0058] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified in the examples, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0059] Example 1: Preparation of the alcohol extract of this traditional Chinese medicine combination

[0060] (1) Add 10 times the amount of 70% (by weight) ethanol (1 ml per gram of medicinal material) to the nutmeg, psoralea, schisandra, evodia, jujube and ginger in the weight ratio (2 parts by weight of nutmeg, 4 parts by weight of psoralea, 2 parts by weight of schisandra, 1 part by weight of evodia, 2 parts by weight of jujube) and heat (until the ethanol boils) under reflux for 2 hours, filter, and concentrate the filtrate to a thick paste for later use.

[0061] (2) Add 10 times the amount of water to the dregs and decoct twice, each time for 1 hour. Filter and concentrate the filtrate into a thick paste.

[0062] (3) Combine the water extract from step (2) with the alcohol extract from step (1) and mix well to obtain an extract containing 1.26g of crude drug per milliliter; for use in the following examples.

[0063] Example 2: Sedative-hypnotic effects of Sishenwan extract

[0064] 1. Effect of Sishenwan extract in combination with sodium pentobarbital on righting reflex in mice.

[0065] Laboratory animals: ICR mice, male, SPF grade, 22-25g, purchased from Spaford (Beijing) Laboratory Animal Co., Ltd.

[0066] Test sample: The prepared Sishenwan extract was weighed according to the extraction rate and the dosage of medicinal materials, and added to physiological saline to make a suspension for gavage.

[0067] Experimental Methods: Mice were acclimatized for one week after purchase and then randomly divided into four groups of 10 mice each, based on their body weight: a solvent control group (vehicle, physiological saline), a low-dose Sishenwan (5.55 g / kg crude drug), a medium-dose Sishenwan (11.09 g / kg crude drug), and a high-dose Sishenwan (22.18 g / kg crude drug). The administration method is as follows:

[0068] (1) The different dose groups of Sishen Pill were given the corresponding drug (20ml / kg) by gavage once, while the solvent control group was given an equal volume of physiological saline by gavage.

[0069] (2) 40 minutes after oral administration, all four groups were intraperitoneally injected with sodium pentobarbital (42 mg / kg, 5 ml / kg). The mice were placed in an independent space at about 25°C and the administration time was recorded.

[0070] (3) Observe the mouse’s sleep state and record the disappearance time of the righting reflex, i.e., the mouse does not recover after 60 seconds of lying supine position. If the mouse is considered to have entered sleep, record the recovery time of the righting reflex, i.e. the mouse can recover on its own after being turned over within 60 seconds. If the mouse recovers on its own after being turned over three times in a row, it is considered to have ended sleep.

[0071] (4) Calculate the sleep latency and sleep duration separately. The sleep latency is the time when the righting reflex disappears minus the time of drug administration, and the sleep duration is the time when the righting reflex recovers minus the time when the righting reflex disappears.

[0072] Experimental results: see Figure 1A-Figure 1B .

[0073] Figure 1A The results showed that a single oral administration of medium-dose Sishenwan (11.09 g / kg) and high-dose Sishenwan (22.18 g / kg) shortened the sleep latency induced by sodium pentobarbital, with a significant difference compared with the solvent control group (p < 0.01).

[0074] Figure 1B The results showed that a single oral administration of high, medium and low doses of Sishenwan significantly prolonged the duration of sleep induced by sodium pentobarbital, with statistically significant differences (p < 0.001).

[0075] The sodium pentobarbital synergistic hypnosis experiment is a classic experiment to verify the sedative-hypnotic effect of drugs. The fact that "extract + sodium pentobarbital" is superior to sodium pentobarbital alone indicates that the extract has a sedative-hypnotic effect. When used in synergy with sodium pentobarbital, it can prolong the time when the righting reflex disappears in mice.

[0076] The results showed that the extract of Sishenwan had a significant sedative and hypnotic effect.

[0077] 2. Central inhibitory effect of Sishenwan extract

[0078] Laboratory animals: ICR mice, male, SPF grade, 22-25g, purchased from Spaford (Beijing) Laboratory Animal Co., Ltd.

[0079] Test samples: The prepared Sishenwan extract was weighed according to the extraction rate and the dosage of the medicinal materials, and added to physiological saline to prepare a suspension for gavage. Diazepam was converted to the clinical dosage for mouse administration, and the corresponding mass of solid was weighed to prepare a physiological saline solution for intraperitoneal injection.

[0080] Experimental apparatus: Open field test chamber.

[0081] Experimental Methods: Mice were acclimatized for one week after purchase and then randomly divided into three groups of 10 mice each, based on their body weight: a solvent control group (vehicle, physiological saline), a positive control group (diazepam, 3 mg / kg), and a high-dose Sishenwan (based on crude drug weight, 22.18 g / kg) group. Treatment methods are as follows:

[0082] (1) The positive control group and the high-dose Sishenwan group were given the corresponding drugs (20ml / kg) by gavage once, while the solvent control group was given an equal volume of physiological saline by gavage.

[0083] (2) 40 minutes after gavage administration, the mice were placed facing the wall into one of the four corner squares of the opening box. The opening box was a black wooden box with three white lines in each direction painted on the bottom, forming 16 squares of equal size. The mice were allowed to explore the environment freely for 5 minutes, and their activity was observed for 5 minutes.

[0084] Experimental results: see Figure 2A and Figure 2B .

[0085] The results showed that, compared with the solvent control group, the number of times mice stood up was significantly reduced in the drug-treated group (p < 0.001). The number of times mice crossed grids showed a decreasing trend, but the difference was not statistically significant.

[0086] The results showed that the extract of Sishenwan had a central nervous system depressant effect.

[0087] Example 3: The intervention effect of Sishenwan extract on insomnia in a PCPA model

[0088] Laboratory animals: ICR mice, male, SPF grade, 22-25g, purchased from Spaford (Beijing) Laboratory Animal Co., Ltd.

[0089] Test samples: The prepared Sishenwan extract was weighed according to the extraction rate and the dosage of the medicinal materials, and a corresponding mass of extract was added to physiological saline to prepare a suspension for gavage. Diazepam was converted to the clinical dosage for mouse administration, and a corresponding mass of solid was weighed to prepare a physiological saline solution for intraperitoneal injection.

[0090] Experimental Methods: Mice were acclimatized for one week after purchase and then randomly divided into 6 groups (n=10 per group) according to body weight: solvent control group (vehicle, physiological saline), positive control group (diazepam 3 mg / kg, ip), PCPA model group (400 mg / kg, ip), high-dose Sishenwan group (5.55 g / kg based on raw drug dosage), medium-dose Sishenwan group (2.775 g / kg based on raw drug dosage), and low-dose Sishenwan group (1.39 g / kg based on raw drug dosage). The administration methods are as follows:

[0091] (1) Except for the solvent control group, mice in each group were injected intraperitoneally with PCPA (400mg / kg, 10ml / kg) to induce the model. The drugs were administered for three consecutive days. Twelve hours after the last administration, all six groups underwent the following pentobarbital sodium synergistic hypnosis experiment.

[0092] (2) The mice were given a single dose of Sishenwan (20 ml / kg) by gavage in different dosage groups, while the solvent control group was given an equal volume of physiological saline by gavage. 40 min after gavage, each group was injected intraperitoneally with sodium pentobarbital (42 mg / kg, 5 ml / kg). The mice were placed in an isolated space at approximately 25°C, and the administration time was recorded.

[0093] (3) Observe the sleep state of the mice and record the disappearance time of the righting reflex, i.e., if the mouse does not recover after being in a supine position for 60 seconds, it is considered to have entered sleep; record the recovery time of the righting reflex, i.e. if the mouse can recover spontaneously after being turned over within 60 seconds, and this is repeated three times, it is considered to have ended sleep. Calculate the sleep latency and sleep time respectively. The sleep latency is the time of disappearance of the righting reflex minus the time of drug administration, and the sleep time is the time of recovery of the righting reflex minus the time of disappearance of the righting reflex.

[0094] Experimental results: see Figures 3A-3B .

[0095] The results of the PCPA-induced insomnia experiment showed that, compared with the solvent control group, the sleep latency (sleep onset time) of mice in the PCPA model group was significantly prolonged. Figure 3A ), sleep duration was significantly shortened ( Figure 3B A single administration of the positive control drug diazepam and various doses of Sishenwan significantly shortened the sleep latency of model mice, with comparable effects. Both the positive control drug diazepam and various doses of Sishenwan significantly prolonged the sleep duration of model mice, with the high-dose Sishenwan showing the strongest effect when administered via gavage, superior to the positive control drug diazepam.

[0096] The results showed that the extract of Sishenwan could improve PCPA-induced insomnia in mice and had a more significant advantage in prolonging sleep time.

[0097] Example 4: Sleep-regulating effect of Sishenwan extract

[0098] Laboratory animals: SD rats, male, SPF grade, 200-250g, purchased from Speifer (Beijing) Laboratory Animal Co., Ltd.

[0099] Experimental instruments: DSI wireless physiological signal acquisition system (Dataquest ART4.31), HD-S21 small animal wireless physiological signal telemetry implant, NeuroScore 3.1.1 EEG analysis software.

[0100] Test samples: The prepared Sishenwan extract was weighed according to the extraction rate and the dosage of the medicinal materials, and a suspension was prepared by adding physiological saline for gavage. Diazepam was converted to the rat dosage according to the clinical use dosage, and a corresponding mass of solid was prepared into a physiological saline solution for intraperitoneal injection.

[0101] Experimental methods:

[0102] (1) Implantation surgery

[0103] After one week of acclimatization, the animals were subjected to surgery. Rats were anesthetized with 3 ml / kg of 10% chloral hydrate via intraperitoneal injection. The head and neck surgical area was prepared, and the skin was disinfected with iodine and alcohol swabs after shaving. The rat was placed prone on the stereotaxic instrument operating table, and the adapter position was adjusted to stabilize the rat's head. A 2 cm longitudinal incision was made in the head skin to expose the skull, and the periosteum was scraped away. The Bregma point was located and marked 2 mm to the left and right with a scalpel. A hole was drilled in the skull, and the sheath at the tip of the implant lead wire was peeled off to expose the metal wire. The wire was bent and inserted under the skull without penetrating the dura mater for recording brain electrical activity. The main body of the implant was placed subcutaneously on the rat's back. After the surgery, the wound was sutured, and the rat was placed in a warm environment until it recovered. Antibiotics were administered intraperitoneally for one week post-surgery.

[0104] (2) Drug administration and signal acquisition

[0105] One week after surgery, rats were randomly divided into three groups of three rats each, based on their body weight: a solvent control group (vehicle, physiological saline), a positive control group (diazepam 3 mg / kg, ip), and a Sishenwan (raw drug dosage, 5.55 g / kg) group. After administration, all rats were returned to their original cages. 30 minutes later, the implant was opened for EEG signal acquisition, which lasted for 3 hours.

[0106] (3) Electroencephalogram (EEG) analysis

[0107] Using the default rodent sleep scoring model of NeuroScore 3.1.1 electroencephalogram analysis software, the electroencephalogram signals were sleep-scored in units of 10 s, and the original signals were classified according to electroencephalogram characteristics into wakefulness, active wakefulness, slow-wave sleep, and paradoxical sleep.

[0108] Experimental results: See Figure 4 、 Figures 5A-5B and Figures 6A-6B 。

[0109] Figure 4 showed that the Shenshen Pills extract could significantly increase the slow-wave sleep time of rats (p < 0.01) and reduce the wakefulness time (p < 0.05). The results indicated that the Shenshen Pills could increase the sleep time and sleep depth of rats.

[0110] Figure 5A showed that the Shenshen Pills extract could significantly prolong the average duration of slow-wave sleep episodes and shorten the average duration of wakefulness episodes. In the Figure 5B statistical results for the number of episodes, the Shenshen Pills simultaneously increased the number of episodes of active wakefulness, wakefulness, and slow-wave sleep, showing significant differences compared with the control group and the diazepam group. The results indicated that the two drugs had different characteristics in regulating the sleep structure and might act through different mechanisms.

[0111] Figure 6A showed that the Shenshen Pills extract had a tendency to increase the total number of conversions between each stage of sleep and wakefulness. Figure 6B showed that it was visible that the Shenshen Pills extract could significantly increase the conversion between wakefulness and slow-wave sleep, while diazepam had no such effect.

[0112] The results indicated that the Shenshen Pills extract could increase the sleep time and sleep depth of rats at the electroencephalogram level, increase the number of slow-wave sleep episodes, and prolong the duration of slow-wave sleep episodes, having a sleep regulation effect.

[0113] Although the specific embodiments of the present invention have been described in detail, those skilled in the art will understand that, based on all the teachings that have been disclosed, various modifications and substitutions can be made to those details, and these changes are all within the protection scope of the present invention. The full scope of the present invention is given by the appended claims and any equivalents thereof.

Claims

1. Use of any one of the following (1)-(2) as the sole active ingredient in the preparation of a medicine for sedation and hypnosis, treatment or prevention of insomnia, or for sleep regulation: (1) An extract, which is an extract of a pharmaceutical composition consisting of 1-3 parts by weight of nutmeg, 3-5 parts by weight of psoralea corylifolia, 1-3 parts by weight of schisandra chinensis, 0.5-1.5 parts by weight of evodia rutaecarpa, 1-3 parts by weight of jujube and 1-3 parts by weight of ginger; the extract is prepared by a method including the following steps: 1) extracting the pharmaceutical composition with 60%-80% ethanol to obtain an alcohol extract and a residue; 2) extracting the residue with water to obtain an aqueous extract; 3) combining the alcohol extract and the aqueous extract to obtain the extract; (2) A pharmaceutical preparation comprising the extract in (1) which is the sole active ingredient, and one or more pharmaceutically acceptable excipients.

2. The use of the medicament according to claim 1 for sedation and hypnosis, treatment or prevention of insomnia, or for sleep regulation, wherein, The pharmaceutical composition consists of: 1.5-2.5 parts by weight of nutmeg, 3.5-4.5 parts by weight of psoralea corylifolia, 1.5-2.5 parts by weight of schisandra chinensis, 0.6-1.4 parts by weight of evodia rutaecarpa, 1.5-2.5 parts by weight of jujube, and 1.5-2.5 parts by weight of ginger.

3. The use of the medicament according to claim 1 for sedation and hypnosis, treatment or prevention of insomnia, or for sleep regulation, wherein, The composition of the pharmaceutical composition is as follows: 1.8-2.2 parts by weight of nutmeg, 3.8-4.2 parts by weight of psoralea corylifolia, 1.8-2.2 parts by weight of schisandra chinensis, 0.8-1.2 parts by weight of evodia rutaecarpa, 1.8-2.2 parts by weight of jujube, and 1.8-2.2 parts by weight of ginger.

4. The use of the medicament according to claim 1 for sedation and hypnosis, treatment or prevention of insomnia, or for sleep regulation, wherein, The composition of the pharmaceutical composition is as follows: 2 parts by weight of nutmeg, 4 parts by weight of psoralea corylifolia, 2 parts by weight of schisandra chinensis, 1 part by weight of evodia rutaecarpa, 2 parts by weight of jujube, and 2 parts by weight of ginger.

5. The use of the medicament according to claim 1 for sedation and hypnosis, treatment or prevention of insomnia, or for sleep regulation, wherein, In step 1) of the extract preparation method, extraction is performed using 70% ethanol.

6. The use of the medicament according to claim 1 for sedation and hypnosis, treatment or prevention of insomnia, or for sleep regulation, wherein, Step 1) of the extract preparation method is reflux extraction.

7. The use of the medicament according to claim 1 for sedation and hypnosis, treatment or prevention of insomnia, or for sleep regulation, wherein, In step 1) of the extract preparation method, the extraction time is 0.5-5 hours.

8. The use of the medicament according to claim 1 for sedation and hypnosis, treatment or prevention of insomnia, or for sleep regulation, wherein, In step 1) of the extract preparation method, the extraction time is 0.5-2 hours.

9. The use of the medicament according to claim 1 for sedation and hypnosis, treatment or prevention of insomnia, or for sleep regulation, wherein, In step 1) of the extract preparation method, the extraction time is 0.2-1.5 hours.

10. The use of the medicament according to claim 1 for sedation and hypnosis, treatment or prevention of insomnia, or for sleep regulation, wherein, In step 1) of the extract preparation method, the amount of ethanol used is 2-20 times.

11. The use of the medicament according to claim 1 for sedation and hypnosis, treatment or prevention of insomnia, or for sleep regulation, wherein, In step 1) of the extract preparation method, the amount of ethanol used is 2-15 times the amount of ethanol.

12. The use of the medicament according to claim 1 for sedation and hypnosis, treatment or prevention of insomnia, or for sleep regulation, wherein, In step 1) of the extract preparation method, the amount of ethanol used is 8-12 times the amount of ethanol.

13. The use of the medicament according to claim 1 for sedation and hypnosis, treatment or prevention of insomnia, or for sleep regulation, wherein, In step 1) of the extract preparation method, the amount of ethanol used is 10 times the normal amount.

14. The use of the medicament according to claim 1 for sedation and hypnosis, treatment or prevention of insomnia, or for sleep regulation, wherein, In step 1) of the extract preparation method, the alcohol extract is a thick paste obtained after concentration.

15. The use of the medicament according to claim 1 for sedation and hypnosis, treatment or prevention of insomnia, or for sleep regulation, wherein, Step 2 of the extract preparation method involves decoction.

16. The use of the medicament according to claim 1 for sedation and hypnosis, treatment or prevention of insomnia, or for sleep regulation, wherein, In step 2) of the extract preparation method, the extraction time is 1 hour.

17. The use of the medicament according to claim 1 for sedation and hypnosis, treatment or prevention of insomnia, or for sleep regulation, wherein, In step 2) of the extract preparation method, the amount of water used is 2-20 times the volume.

18. Use in the medicament for sedation and hypnosis, treatment or prevention of insomnia, or for sleep regulation according to claim 1, wherein, In step 2) of the extract preparation method, the amount of water used is 2-15 times the volume.

19. The use of the medicament according to claim 1 for sedation and hypnosis, treatment or prevention of insomnia, or for sleep regulation, wherein, In step 2) of the extract preparation method, the amount of water used is 8-12 times the volume.

20. Use in the medicament for sedation and hypnosis, treatment or prevention of insomnia, or for sleep regulation according to claim 1, wherein, In step 2) of the extract preparation method, the amount of water used is 10 times the normal amount.

21. The use of the medicament according to claim 1 for sedation and hypnosis, treatment or prevention of insomnia, or for sleep regulation, wherein, In step 2) of the extract preparation method, the water extract is a thick paste obtained after concentration.

22. Use in a medicament for sedation and hypnosis, treatment or prevention of insomnia, or for sleep regulation according to any one of claims 1 to 4, wherein, The unit dose of a pharmaceutical preparation is calculated based on the weight of the pharmaceutical composition used to prepare the extract, and ranges from 80g to 250g.

23. Use in a medicament for sedation and hypnosis, treatment or prevention of insomnia, or for sleep regulation according to any one of claims 1 to 4, wherein, The unit dose of a pharmaceutical preparation is calculated based on the weight of the pharmaceutical composition used to prepare the extract, and is 100g-200g.

24. Use in a medicament for sedation and hypnosis, treatment or prevention of insomnia, or for sleep regulation according to any one of claims 1 to 4, wherein, The unit dose of a pharmaceutical preparation is calculated based on the weight of the pharmaceutical composition used to prepare the extract, and is 120g-180g.

25. Use in a medicament for sedation / hypnosis, treatment or prevention of insomnia, or for sleep regulation according to any one of claims 1 to 4, wherein, The unit dose of the pharmaceutical preparation is calculated based on the weight of the pharmaceutical composition used to prepare the extract, and is 130g-160g.

26. Use in a medicament for sedation and hypnosis, treatment or prevention of insomnia, or for sleep regulation according to any one of claims 1 to 4, wherein, Sleep regulation involves increasing sleep duration and depth, increasing the number of slow-wave sleep segments, and / or prolonging the duration of slow-wave sleep segments.

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