Medicine for preventing, relieving or treating insomnia caused by disharmony between liver and spleen and preparation method thereof

Abstract

The invention relates to the technical field of traditional Chinese medicines, in particular to a medicine for preventing, relieving or treating insomnia caused by liver-spleen disharmony and a preparation method thereof. The medicine is prepared from the following components: bupleurum chinense, radix paeoniae alba, ligusticum wallichii, angelica sinensis, fried jujube kernel, vine of multiflower knotweed, cortex albiziae, schisandra chinensis, rhizoma polygonati, cinnamon, lily and honey-fried licorice root, clinical and pharmacological experiments show that the medicine has a better treatment effect on insomnia caused by liver-spleen disharmony, the preparation process is simple, the used auxiliary materials are conventional auxiliary materials, and the medicine is suitable for further expanded production.

Description

Technical Field

[0001] The invention relates to the technical field of traditional Chinese medicines, and in particular to a medicine for preventing, alleviating or treating insomnia caused by liver-spleen disharmony and a preparation method thereof. Background Art

[0002] Insomnia is a subjective experience and the most common type of sleep disorder. It is mainly manifested as "difficulty falling asleep, difficulty maintaining sleep, or waking up early, difficulty falling asleep after waking up, poor sleep quality, and daytime dysfunction. Studies have found that about 15% of the population in my country suffers from chronic insomnia, and the incidence of short-term insomnia is more than 30%. Insomnia not only troubles the elderly, but also radiates to people of all ages, including middle-aged and young people, affecting their work and study. For the "three highs", it increases the risk of cardiovascular and cerebrovascular diseases such as coronary heart disease and stroke. Insomnia is one of the problems that urgently need to be solved, which seriously endangers human physical and mental health. Therefore, it is urgent to find a simple, effective and safe treatment method.

[0003] Western medicine believes that insomnia may be caused by the patient himself and the external specific conditions related to him. The internal factors include the patient's age, gender, personality and genetics, while the external specific conditions include the patient's sleeping environment, living environment, quality, interpersonal relationships, etc. In this regard, some scholars have summarized the common causes of insomnia into: psychological factors, physiological factors, environmental factors, physical diseases, mental illnesses, drug use or withdrawal, etc., and sleep-wake rhythm disorders. In terms of treatment, the commonly used treatment methods in Western medicine currently include drug therapy, physical therapy, psychotherapy, and traditional Chinese medicine treatment. Among them, drug therapy is the most convenient and effective, but the commonly used sedative hypnotic drugs also have different degrees of side effects. For example, drug dependence and tolerance determine that they cannot be used for a long time; and sedatives and hypnotic drugs also have a "hangover" phenomenon, which affects the patient's work or study the next day, and may increase the daytime sleep the next day, thereby affecting the patient's sleep at night the next day, which complicates the treatment.

[0004] In recent years, scholars have gradually tended to combine traditional Chinese and Western medicine to treat insomnia, and reduce the dosage of sedatives and hypnotic drugs. Some studies have reported that the use of shallow acupuncture combined with estazolam can effectively improve the sleep quality and daytime dysfunction of patients with liver depression and fire type insomnia, which may be related to the reduction of plasma ACTH and CORT levels. Other studies have found that paroxetine combined with gardenia and fermented soya bean soup can significantly improve insomnia in patients with depression. For example:

[0005] Chinese patent 202210957451.9 discloses a Chinese medicine composition for treating insomnia and a preparation method thereof The present invention discloses a Chinese medicine composition for treating insomnia and a preparation method thereof, and relates to the technical field of Chinese medicine compositions. Its formula includes the following ingredients: Polygala, Semen Ziziphi Spinosae, Radix Pseudostellariae, Oyster, Cinnamon Twig, Rhizoma Chuanxiong, Citron, Rhizoma Alismatis, Atractylodes Macrocephalae, Angelica Sinensis, Curcuma, Radix Bupleuri and Ginseng. The present invention is based on the basic Chinese medicine formula for regulating the liver and qi, nourishing blood and calming the mind, and further adds compound ingredients such as Rhizoma Chuanxiong, Oyster, Cinnamon Twig, and finds that it can have a good therapeutic effect on insomnia. Compared with existing Chinese medicine formulas, it has definite efficacy, good therapeutic effect and high safety. It contains tonics such as ginseng and is not suitable for taking.

[0006] Chinese patent application CN201710570175.X discloses a Chinese medicine composition that can effectively treat insomnia and a preparation method thereof. The components of the Chinese medicine composition and their weight ratios are as follows: 3-12g of bupleurum, 8-16g of angelica, 10-32g of prepared rehmannia, 5-12g of white peony root, 5-10g of calamus, 15-25g of poria, 15-25g of codonopsis, 3-16g of atractylodes, 3-16g of curcuma, 9-3 5g, 8-16g of Cyperus rotundus, 10-26g of Ziziphus jujuba, 6-15g of Lilium, 3-12g of Polygala tenuifolia, 3-6g of Schisandra chinensis, 5-10g of Platycodon grandiflorum, 3-10g of Citrus aurantium, 3-12g of Citrus aurantium, 10-25g of August fried, 10-16g of Albizzia julibrissin, 10-25g of Polygonum multiflorum, 15-25g of Poria, 5-12g of Chuanxiong, 8-16g of Morinda officinalis, 5-16g of Epimedium (fried), 3-16g of Citrus reticulata, 3-12g of Licorice. The Chinese medicinal ingredients contained are too complex to be mass-produced.

[0007] Chinese patent application CN201910125786.2 discloses a formula for treating insomnia, the formula components are as follows: 25-35 parts of Bupleurum chinense, 15-25 parts of Curcuma aromatica, 20-30 parts of Poria, 25-35 parts of raw dragon bone, 25-35 parts of raw oyster, 30-40 parts of magnetite, 25-35 parts of Polygala tuberosa, 25-35 parts of Acorus calamus, 20-30 parts of Ziziphus jujuba seeds, 25-35 parts of Polygala tenuifolia, 15-25 parts of Chuanxiong, 15-25 parts of Anemarrhena asphodeloides, 20-30 parts of Schisandra chinensis, 15-25 parts of White Peony Root, 15-25 parts of Toosendan Fruit, 20-30 parts of Lilium, 15-25 parts of Albizzia julibrissin. The Chinese medicinal ingredients contained in it, such as Poria, are difficult to obtain, and the effectiveness of the ingredients is difficult to determine. Summary of the invention

[0008] In view of the defects of the prior art, the purpose of the present invention is to solve the above problems and provide a medicine for treating insomnia caused by liver-spleen disharmony and its preparation method and its preparation method. The medicine is effective for insomnia caused by liver-spleen disharmony; symptoms include poor sleep, difficulty falling asleep, early awakening, difficulty falling asleep after waking up; or poor appetite, fatigue, hot flashes, night sweats, and irritability; and has the effects of nourishing yin and calming the mind, soothing the liver and regulating qi, and harmonizing the spleen and stomach.

[0009] Specifically, the purpose of the present invention is achieved by:

[0010] The first object of the present invention is to provide a medicine for preventing, alleviating or treating insomnia caused by liver and spleen disharmony. The medicine is composed of the following components, measured by weight: 10-15 parts of bamboo leaf bupleurum, 12-18 parts of white peony root, 10-15 parts of chuanxiong, 10-15 parts of angelica, 26-34 parts of stir-fried jujube seeds, 12-18 parts of Polygonum multiflorum, 10-15 parts of julibrissin bark, 8-12 parts of Schisandra chinensis, 8-12 parts of polygonatum, 2-5 parts of cinnamon, 26-34 parts of lily and 8-12 parts of roasted liquorice.

[0011] In a preferred embodiment of the present invention, the medicine is composed of the following components, by weight: 11-13 parts of bamboo leaf bupleurum, 14-16 parts of white peony root, 11-13 parts of chuanxiong, 11-13 parts of angelica, 28-32 parts of stir-fried jujube seeds, 14-16 parts of Polygonum multiflorum, 11-13 parts of julibrissin bark, 9-11 parts of Schisandra chinensis, 9-11 parts of polygonatum, 2-4 parts of cinnamon, 28-32 parts of lily and 9-11 parts of roasted licorice.

[0012] In a preferred embodiment of the present invention, the medicine is composed of the following components, by weight: 12 parts of bamboo leaf bupleurum, 15 parts of white peony root, 12 parts of chuanxiong, 12 parts of angelica, 30 parts of stir-fried jujube seeds, 15 parts of Polygonum multiflorum, 12 parts of Albizzia julibrissin, 10 parts of Schisandra chinensis, 10 parts of Polygonatum sibiricum, 3 parts of cinnamon, 30 parts of lily and 10 parts of roasted licorice.

[0013] The second object of the present invention is a pharmaceutical preparation, which is selected from any one of a decoction, a hard capsule, an ointment, a tablet, a granule, a pill, an oral liquid, a syrup, a powder, a pill, a suspension, a solution, an injection, a lyophilized powder injection, an injection, a suppository, a plaster, a cream, a spray and a patch.

[0014] Furthermore, the pharmaceutical preparation contains the Chinese medicine composition of the present invention and pharmaceutically acceptable excipients.

[0015] In a preferred embodiment of the present invention, when the drug is prepared into a medicament, a unit dose of the medicament contains 0.1-1000 mg of the medicinal material, and more preferably, the unit dose is 120-250 mg. In an embodiment of the present invention, the unit dose is 171 mg / tablet.

[0016] Furthermore, the pharmaceutically acceptable excipients include but are not limited to fillers, disintegrants, lubricants, and adhesives. Furthermore, the disintegrant may be one or more of hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, and cross-linked polyvinyl pyrrolidone, and low-substituted hydroxypropyl cellulose is more preferred; the filler may be one or more of lactose, dextrin, calcium sulfate, sucrose, microcrystalline cellulose, and mannitol; the adhesive may be selected from a 50% ethanol solution of 3% hydroxypropyl methylcellulose; the lubricant may be selected from one or more of sodium lauryl sulfate, magnesium stearate, talc, and solid silicon dioxide.

[0017] The third object of the present invention is to provide a drug for preventing, alleviating or treating insomnia caused by liver-spleen disharmony. The insomnia is any one of liver depression and qi stagnation type, spleen and stomach weakness type, and liver yang hyperactivity type.

[0018] A fourth object of the present invention is to provide a preparation of a preparation, the preparation of the pharmaceutical preparation comprising the following steps:

[0019] S1: Weigh each medicinal material according to the prescribed amount and crush it into coarse powder;

[0020] S2: Mix all the crude powders of medicinal materials obtained in S1 and boil them three times, filter them, combine the decoctions, and concentrate them into extracts;

[0021] S3: The extract obtained in S2 is mixed with pharmaceutically acceptable excipients to prepare different pharmaceutical preparations.

[0022] Furthermore, the preparation of the oral liquid comprises the following steps:

[0023] S33a: Take an appropriate amount of sucrose and add it to boiling water to make it evenly dissolved, filter it, and make a simple syrup;

[0024] S33b: adding the monosaccharide syrup obtained in S33a to the extract obtained in S2, and then adding purified water;

[0025] S33c: Add potassium sorbate to the mixture obtained in S33b, mix well, and fill to obtain an oral solution.

[0026] Furthermore, the preparation of the hard capsule comprises the following steps:

[0027] S32a: drying the extract obtained in S2 under reduced pressure to obtain a dry extract;

[0028] S32b: crushing the dry extract obtained in S32a, adding starch and mixing evenly;

[0029] S32c: The mixture obtained in S32b is granulated with a 3% hydroxypropyl methylcellulose solution in 50% ethanol, and the granules are dried, sized, and filled into capsules to obtain hard capsules.

[0030] Furthermore, the preparation of the decoction comprises the following steps:

[0031] S1: Weigh each medicinal material according to the prescribed amount and crush it into coarse powder;

[0032] S2: Mix all the crude powders of medicinal materials obtained in S1 and boil them three times, filter them, combine the decoctions, and concentrate them into extracts;

[0033] S31: Heat the extract obtained in S2 and honey, mix well, and concentrate to obtain a decoction.

[0034] Furthermore, the preparation of the tablet comprises the following steps:

[0035] S32a: drying the extract obtained in S2 under reduced pressure to obtain a dry extract;

[0036] S32b: crushing the dry extract obtained in S32a, adding starch and mixing evenly;

[0037] S32c: The mixture obtained in S32b is granulated with a 3% hydroxypropyl methylcellulose solution in 50% ethanol, and the granulated mixture is dried. Sodium lauryl sulfate is added thereto, and the granulated mixture is tableted.

[0038] Specifically, the pharmacological effects of some raw materials in the formula of the present invention are as follows:

[0039] Bupleurum chinense has the effects of soothing the liver and relieving depression, and calming the nerves. It is used clinically to relieve fever, relieve liver depression, and raise yang. Bupleurum chinense is used by the Bai people to treat colds, upper respiratory tract infections, cholecystitis, irregular menstruation, and rectal prolapse. Modern pharmacological studies have shown that Bupleurum chinense has anti-fatty liver, anti-liver damage, antitussive, and anti-inflammatory effects. White peony root can nourish blood and soften the liver, and relieve anxiety: it belongs to the liver and spleen meridians. It is used to nourish blood and regulate menstruation, restrain yin and stop sweating, soften the liver and relieve pain, and suppress liver yang. It is used for blood deficiency and sallow complexion, irregular menstruation, spontaneous sweating, night sweats, flank pain, abdominal pain, limb cramps, headaches and dizziness. Chuanxiong has the effects of promoting blood circulation and qi, and improving circulation: it belongs to the liver, gallbladder, and pericardium meridians. It is used to promote blood circulation and qi, dispel wind and relieve pain. It is used for chest pain, chest and flank tingling, swelling and pain due to falls, irregular menstruation, amenorrhea and dysmenorrhea, abdominal pain due to lumps, headaches, and rheumatic pain. Angelica sinensis can nourish blood and regulate menstruation, improve sleep quality; it belongs to the liver, heart, and spleen meridians. It is used to nourish blood and promote blood circulation, regulate menstruation and relieve pain, and moisten the intestines and promote bowel movements. It is used for blood deficiency and sallow complexion, dizziness and palpitations, irregular menstruation, amenorrhea and dysmenorrhea, abdominal pain due to deficiency and cold, rheumatic arthralgia, injuries from falls, carbuncles, ulcers, and constipation due to dry intestines. Stir-fried jujube seeds can calm the mind and nourish the heart: it belongs to the heart meridian, spleen meridian, liver meridian, and gallbladder meridian. It is used to treat insomnia due to deficiency, palpitations, thirst, and sweating. It has the effects of nourishing the liver, calming the mind, calming the mind, and restraining sweat.

[0040] At the same time, in the prescription, Polygonum multiflorum is used to nourish blood and calm the mind, and strengthen the body constitution: it goes to the heart and liver meridians. It is used to nourish blood and calm the mind, dispel wind and dredge the meridians. It is used for insomnia and dreaminess, blood deficiency and body pain, rheumatic pain, and skin itching. Albizzia bark soothes the liver and relieves depression, calms the mind and helps sleep. It goes to the heart, liver, and lung meridians. It is used to relieve depression and calm the mind, promote blood circulation and reduce swelling. It is used for restlessness, depression and insomnia, lung abscess, sores, and pain from falls. Schisandra chinensis has the effect of astringing and consolidating, and improving sleep. It goes to the lung, heart, and kidney meridians. It is used to astringe and consolidate, replenish qi and produce body fluid, and nourish the kidney and calm the heart. It is used for long-term cough and asthma, nocturnal emission and spermatorrhea, enuresis and frequent urination, long-term diarrhea, spontaneous sweating and night sweats, thirst due to body fluid loss, internal heat and thirst, palpitations and insomnia. Polygonatum sibiricum can nourish the spleen and lungs and enhance the body's resistance. It goes to the spleen, lung, and kidney meridians. It is used to replenish qi and nourish yin, strengthen the spleen, moisten the lungs, and benefit the kidneys. It is used for spleen and stomach qi deficiency, fatigue, insufficient stomach yin, dry mouth and poor appetite, lung deficiency and dry cough, cough due to overwork and hemoptysis, insufficient essence and blood, sore waist and knees, premature graying of hair, internal heat and thirst. Cinnamon is mainly used to warm yang and dispel cold, and promote blood circulation. It belongs to the kidney, spleen, heart and liver meridians. It is used to replenish fire and yang, guide fire back to the origin, dispel cold and relieve pain, and warm and dredge the meridians. It is used for impotence, cold uterus, cold pain in the waist and knees, asthma caused by kidney deficiency, floating of virtual yang, dizziness and red eyes, cold pain in the heart and abdomen, vomiting and diarrhea caused by deficiency and cold, abdominal pain caused by cold hernia, dysmenorrhea and amenorrhea. Lily can clear the heart and calm the mind, and improve sleep quality. It belongs to the heart and lung meridians. It is used to nourish yin and moisten the lungs, clear the heart and calm the mind. It is used for yin deficiency and dry cough, cough due to overwork and hemoptysis, deficiency and restlessness, palpitations, insomnia and dreaminess, and mental confusion. Roasted licorice harmonizes various medicines, moistens the lungs and harmonizes the middle, and belongs to the heart, lung, spleen and stomach meridians. It is used to tonify the spleen and stomach, and replenish qi and restore the pulse. Used for spleen and stomach weakness, fatigue, palpitations, and irregular pulse.

[0041] The prescription of the present invention mainly treats insomnia caused by liver-spleen disharmony; symptoms include difficulty falling asleep, easy awakening and dreaming, dizziness, or accompanied by restlessness, emotional instability, fatigue and poor appetite, pale complexion, pain in the flanks, white or greasy tongue coating, and stringy pulse. The syndrome of this prescription is mostly caused by emotional frustration, anger and liver damage, or improper diet, fatigue and spleen damage, etc., which lead to liver qi stagnation and spleen deficiency, affecting the mind and causing the mind to be malnourished or uneasy. The liver is responsible for dredging and dispersing, which helps the spleen's transportation and transformation function. The spleen is responsible for healthy transportation, and the qi is unobstructed, which helps the dredging and dispersing of liver qi. Therefore, when pathological changes occur, they can affect each other and form liver-spleen disharmony syndrome. The liver function is impaired, the qi and blood flow is not smooth, and the brain is difficult to enter a sleeping state, so it is difficult to fall asleep. Liver qi stagnation or liver blood deficiency causes the mind to be malnourished, resulting in easy awakening and dreaminess during sleep. The liver stores blood, and the liver function is poor, and the blood cannot nourish the head normally, causing dizziness. Irritability, emotional instability, and pain in the flanks are all signs of liver qi stagnation. Spleen deficiency leads to fatigue, poor appetite, and a dull complexion. The cold and heat phenomena of this syndrome are not obvious, so white fur is still seen. If dampness is strong, greasy fur can be seen. Stringy pulse is a sign of liver loss of softness. The treatment is mainly to soothe the liver and strengthen the spleen, nourish the heart and calm the mind. In this prescription, bamboo leaf bupleurum, white peony root and Chuanxiong are combined as the main medicines, playing the core role of soothing the liver and promoting qi, nourishing blood and softening the liver, and relieving depression and calming the mind. Bamboo leaf bupleurum soothes the liver and relieves depression, making the liver qi smooth; white peony root nourishes blood and softens the liver, relieves urgency and stops pain; Chuanxiong activates blood circulation and promotes qi, dispels wind and stops pain. The combination of the three can not only nourish the liver, but also help the liver function, taking into account both qi and blood, and treating the liver and spleen, and playing the effects of soothing the liver and promoting qi, nourishing blood and softening the liver, and relieving depression and calming the mind.

[0042] Compared with the prior art, the present invention has achieved unexpected technical effects:

[0043] The combination of the drugs of the present invention can play a significant therapeutic effect in preventing, alleviating or treating insomnia caused by liver depression and qi stagnation type, spleen and stomach weakness type, and liver yang hyperactivity type. The Chinese medicine composition of the present invention is based on the Chinese medicine formula based on basic liver and kidney conditioning, and further adds compound ingredients such as polygonatum, cinnamon, and lily. It is found that it can play a good therapeutic effect on insomnia. Compared with existing hormones, it has good therapeutic effect and can be further expanded for production.

[0044] In the clinical experiment, after 4 weeks of treatment, the PSQI scores of insomnia patients were statistically analyzed and it was found that at the end of the third week, there was a significant difference between the treatment groups and the control group, and the difference was more obvious at the end of the fourth week, further indicating that the therapeutic effect of the present invention is better than that of the control group. The total efficacy of the two groups after treatment, the effective rate, cure rate and insomnia relief rate were evaluated by the treatment effect before and after treatment of the patients in the treatment groups and the control group. There was a statistically significant difference (P<0.05).

[0045] After successful modeling of rats, the therapeutic effect of the tablets prepared in Example 5 was better than that of the comparative examples 1-4. The duration of sleep in each administration group was significantly prolonged and the latency to fall asleep was significantly shortened, and the differences were statistically significant (P < 0.05). The improvement effect of the tablets in Example 5 was significantly better than that in the four control groups and the positive control group, and the difference was significant (P < 0.05). The results show that the Chinese medicine composition of the present invention can prolong the duration of sleep and significantly shorten the latency to fall asleep, and has a significant hypnotic and sleep-aiding effect on insomnia rats.

[0046] The preparation process is simple, and the auxiliary materials used are all conventional auxiliary materials, which can be obtained through commercial channels and are suitable for further expanded production. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 PSQI scores of the treatment groups and the control group were statistically analyzed at the 1st, 2nd, 3rd and 4th week.

[0048] Figure 2 : After 4 weeks of treatment, the total efficacy of the two groups was evaluated based on the treatment effects before and after treatment.

[0049] Figure 3 : The insomnia remission rate of the control group and treatment groups ①, ② and ③ after stopping medication for one week, one month and three months.

[0050] Figure 4 : Body weight of rats in each group after modeling.

[0051] Figure 5 : Comparison of body weights of rats in each group after drug treatment and modeling.

[0052] Figure 6 : Comparison of the sleep duration of rats in each group after drug administration. The results show that the Chinese medicine composition of the present invention can significantly prolong the sleep duration and has a significant sleep-aiding effect on model rats.

[0053] Figure 7 : Comparison of the sleep latency of rats in each group after drug administration. The results show that the Chinese medicine composition of the present invention can significantly shorten the sleep latency of insomnia rats and has a significant hypnotic effect on model rats. DETAILED DESCRIPTION

[0054] The present invention is further explained below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention. After reading the present invention, various equivalent modifications to the present invention by those skilled in the art all fall within the scope of protection of the claims of this application.

[0055] Firstly, Cuscuta australis is the main drug of the present invention, and its extraction method is explored.

[0056] Example 1: A drug for preventing, alleviating or treating insomnia caused by liver and spleen disharmony, specifically as follows:

[0057] Prescription for 1000 tablets

[0058]

[0059] Preparation process:

[0060] 1) Weigh each medicinal material according to the prescribed amount and crush it into coarse powder;

[0061] 2) Mix all the obtained crude powders of medicinal materials and boil them for 3 times; Mix all the medicinal materials and boil them for 3 times, boil them for 2.5 hours with 15 times the amount of water for the first time, boil them for 1.5 hours with 10 times the amount of water for the second time, and boil them for 1 hour with 6 times the amount of water for the third time, filter, combine the decoction, filter, combine the decoction, and concentrate to an extract with a relative density of 1.10-1.15 at 65°C;

[0062] 3) drying the obtained extract at 70° C. under reduced pressure to obtain a dry extract;

[0063] 4) crushing the obtained dry extract, evenly adding starch and mixing to obtain a mixture;

[0064] 5) The obtained mixture is granulated with 3% hydroxypropyl methylcellulose ethanol solution, dried, added with sodium lauryl sulfate, and compressed into tablets.

[0065] Example 2: A drug for preventing, alleviating or treating insomnia caused by liver-spleen disharmony, specifically as follows:

[0066] Prescription for 1000 tablets

[0067]

[0068] The preparation process is the same as that of Example 1.

[0069] Example 3: A drug for preventing, alleviating or treating insomnia caused by liver and spleen disharmony, specifically as follows:

[0070] Prescription for 1000 tablets

[0071]

[0072]

[0073] The preparation process is the same as that of Example 1.

[0074] Example 4: A drug for preventing, alleviating or treating insomnia caused by liver and spleen disharmony, as follows: Prescription for 1000 tablets

[0075]

[0076]

[0077] The preparation process is the same as that of Example 1.

[0078] Example 5: A drug for preventing, alleviating or treating insomnia caused by liver and spleen disharmony, as follows: Prescription for 1000 tablets

[0079]

[0080] The preparation process is the same as that of Example 1.

[0081] Example 6: A drug for preventing, alleviating or treating insomnia caused by liver and spleen disharmony, specifically as follows: Prescription for 1000 tablets

[0082]

[0083]

[0084] Preparation process: weigh each medicinal material according to the prescribed amount, and crush the medicinal materials into coarse powder; mix all the medicinal materials, decoct for 3 times, decoct for 2.5 hours with 15 times the amount of water for the first time, decoct for 1.5 hours with 10 times the amount of water for the second time, and decoct for 1 hour with 6 times the amount of water for the third time, filter, combine the decoctions, and concentrate into an extract with a relative density of 1.10-1.15 at 80°C, add 10% of the prepared amount of starch and mix evenly, concentrate and dry at 70°C under reduced pressure to form a dry extract, crush evenly, granulate with 70% ethanol, dry, granulate, and fill capsules to obtain.

[0085] Example 7: A drug for preventing, alleviating or treating insomnia caused by liver and spleen disharmony, specifically as follows:

[0086] Prescription for 1000 bottles of oral solution (10ml)

[0087]

[0088] Preparation process: weigh each medicinal material according to the prescription amount, and crush the medicinal materials into coarse powder; mix all the medicinal materials, decoct 3 times, the first time with 15 times the amount of water for 2.5 hours, the second time with 10 times the amount of water for 1.5 hours, the third time with 6 times the amount of water for 1 hour, filter, combine the decoctions, and concentrate them into an extract with a relative density of 1.10-1.15 at 80°C, take sucrose and add it to the boiling water to dissolve it evenly, filter it, and make a monosyrup, add the monosyrup to the above-mentioned drug filtrate to make the final sugar content 20-60%, add purified water to the full amount, and then add 0.2% of the prepared amount of potassium sorbate, mix evenly, and fill it to obtain the oral solution.

[0089] Example 8: A drug for preventing, alleviating or treating insomnia caused by liver-spleen disharmony, specifically as follows:

[0090] Prescription for 1000 bags (10g)

[0091]

[0092] Preparation process: weigh each medicinal material according to the prescribed amount and crush the medicinal materials into coarse powder; mix all the medicinal materials and boil them three times, boil them for 2.5 hours with 15 times the amount of water for the first time, boil them for 1.5 hours with 10 times the amount of water for the second time, and boil them for 1 hour with 6 times the amount of water for the third time, filter, combine the decoctions, and concentrate them into an extract with a relative density of 1.10-1.15 at 80°C, add 4 times the weight of sucrose powder according to the weight of the extract, mix them evenly, granulate, dry, and granulate to obtain granules.

[0093] Comparative Example 1: A drug for preventing, alleviating or treating insomnia caused by liver and spleen disharmony, specifically as follows:

[0094] Prescription for 1000 tablets

[0095]

[0096]

[0097] The preparation process is the same as that of Example 1.

[0098] Comparative Example 2: A drug for preventing, alleviating or treating insomnia caused by liver and spleen disharmony, specifically as follows: Prescription for 1000 tablets

[0099]

[0100] The preparation process is the same as that of Example 1.

[0101] Comparative Example 3: A drug for preventing, alleviating or treating insomnia caused by liver and spleen disharmony, as follows: Prescription for 1000 tablets

[0102]

[0103] The preparation process is the same as that of Example 1.

[0104] Comparative Example 4: A drug for preventing, alleviating or treating insomnia caused by liver and spleen disharmony, specifically as follows: Prescription for 1000 tablets

[0105]

[0106]

[0107] The preparation process is the same as that of Example 1.

[0108] 1. Clinical trials of the drug of the present invention

[0109] 1.1 Basic Information

[0110] From February 2020 to October 2023, 120 patients with insomnia who visited the outpatient clinic of Guizhou Guihang Hospital were screened and included in the experiment. They were divided into 4 groups by random number table method, with 30 cases in each group. In the treatment group, the patients were aged 35-60 years old, with an average age of 47.33±4.28 years old, and the course of chronic insomnia was 18.59±6.48 months; in the treatment group, the patients were aged 36-62 years old, with an average age of 46.76±6.19 years old, and the course of chronic insomnia was 20.51±9.26 months; in the treatment group, the patients were aged 36-61 years old, with an average age of 48.55±5.36 years old, and the course of chronic insomnia was 19.88±7.77 months; in the control group, the patients were aged 36-60 years old, with an average age of 46.38±5.79 years old, and the course of chronic insomnia was 19.22±4.19 months. There was no significant difference in general data such as gender, disease condition, age and other influencing factors between the treatment groups and the control group (P>0.05), and the patients were comparable.

[0111] 1.2 Drugs and treatments selected for this study

[0112] Control group: Oral estazolam tablets, Guizhou Tongjitang Pharmaceutical Co., Ltd., National Medicine Standard H52020664, 2 mg, taken 1 hour before bedtime, taken continuously for 4 weeks. Treatment group ①: Tablets prepared in Example 1, 4 tablets at a time, taken 1 hour before bedtime. Treatment group ②: Tablets prepared in Example 2, 4 tablets at a time, taken 1 hour before bedtime. Treatment group ③: Tablets prepared in Example 5, 4 tablets at a time, taken 1 hour before bedtime.

[0113] 1.3 Diagnostic criteria

[0114] Western medicine diagnostic criteria: Western medicine refers to the criteria of the "Guidelines for the Diagnosis and Treatment of Insomnia in Chinese Adults (2017 Edition)". Difficulty falling asleep, difficulty sleeping continuously, and daytime symptoms such as fatigue, general discomfort, lack of concentration, and decreased physical strength.

[0115] Traditional Chinese medicine refers to the diagnostic criteria for insomnia in the "Standards for Diagnosis and Treatment Effects of Traditional Chinese Medicine Diseases and Syndromes".

[0116] Main symptoms:

[0117] ①: Difficulty falling asleep; ②: Easy to wake up after sleeping; ③: Restlessness and dreaminess.

[0118] Secondary symptoms:

[0119] ① One of the following symptoms: emotional depression, irritability, chest and flank distension, bitter taste in the mouth, dry mouth, bad breath, and dull headache; ②: One of the following symptoms: memory loss, dizziness, and loss of appetite; ③: The main manifestation is irritability, dizziness, and insomnia.

[0120] If one of the main symptoms and one of the secondary symptoms are met, insomnia caused by liver-spleen disharmony can be diagnosed.

[0121] The patients selected for this clinical trial all met the above criteria, and their insomnia lasted for more than 6 months; the average number of insomnia episodes per week was ≥ 3 times; their mental and cognitive abilities were normal, and they did not have family genetic diseases; their Epworth Sleepiness Scale score was 9 points; their Pittsburgh Sleep Quality Index score was > 7 points; and the patients and their families signed the informed consent form.

[0122] 1.4 Observation indicators

[0123] Pittsburgh Sleep Quality Index (PSQI): According to the revised version of the PSQI in China, a total PSQI score of >7 is used as the cutoff for sleep quality problems. 8 to 12 points indicate mild sleep disorder, 13 to 17 points indicate moderate sleep disorder, and 18 to 21 points indicate severe sleep disorder. The higher the score, the worse the sleep quality.

[0124] 1.5 Criteria for determining efficacy

[0125] According to the Guiding Principles for Clinical Research of New Chinese Medicines, the reference literature uses the reduction rate of the total PSQI score as the criterion for judging the efficacy. The reduction rate is calculated using the nimodipine method: reduction rate (%) = (total score before treatment - total score after treatment) / total score before treatment × 100%.

[0126] Cure: Insomnia disappears, and the score reduction rate is ≥80%;

[0127] Significantly effective: Insomnia almost completely disappears, with a reduction rate of ≥50%;

[0128] Improvement: Insomnia is significantly alleviated, with a reduction rate of ≥30%;

[0129] Ineffective: There is no improvement in insomnia after treatment, and the score reduction rate is less than 30%.

[0130] 1.6 Statistical analysis standards

[0131] All data were plotted in GraphPad Prism 9.0. If the experimental results were normal and the variance was equal, one-way ANOVA was used, and the results were expressed as mean ± standard error (X ± S). The t test was used; the count data (%) was analyzed by X 2 The test P<0.05 indicated that the difference was statistically significant.

[0132] 2.1 Treatment outcomes

[0133] 2.1.1 Comparison of PSQI scores and efficacy of the four groups of patients before and after treatment. Figure 1 shown.

[0134] Figure 1After 4 weeks of treatment, PSQI scores were statistically analyzed in the 1st, 2nd, 3rd and 4th weeks. It can be seen that at the end of the 3rd week, there were significant differences between the treatment groups and the control group, and the difference was even more obvious at the end of the 4th week, further indicating that the treatment effect of the present invention is better than that of the control group.

[0135] Figure 2 :The total efficacy of the two groups after treatment was evaluated by the treatment effect before and after treatment. After 4 weeks of treatment, the total effective rates of treatment group ①, treatment group ②, treatment group ③, and control group were 93.33%, 90.00%, 96.67%, and 73.33%, respectively, with statistically significant differences (P<0.05).

[0136] 2.1.2 Statistics of insomnia relief rates of the four groups of patients after stopping medication for one week, one month, and three months

[0137] Treatment group ①, treatment group ②, treatment group ③ and control group each stopped taking the medicine for 1 month, and collected the insomnia remission rate after 1 week, 1 month and 3 months of stopping the medicine. The calculation method of insomnia remission rate is as follows:

[0138] Insomnia relief rate = cases counted at the second time / (cured, markedly effective and effective cases at the fourth weekend)

[0139] The results are as follows Figure 3 As shown, the insomnia remission rate of the control group, treatment group ①, treatment group ②, and treatment group ③ gradually decreased with the passage of time. One week after stopping the medication, 18, 25, 24, and 27 individuals in the control group, treatment group ①, treatment group ②, and treatment group ③ had insomnia remission; one month after stopping the medication, 15, 22, 22, and 25 individuals in the control group, treatment group ①, treatment group ②, and treatment group ③ had insomnia remission; three months after stopping the medication, 8, 20, 19, and 24 individuals in the control group, treatment group ①, treatment group ②, and treatment group ③ had insomnia remission.

[0140] 2. Animal Experiments of the Drug of the Invention

[0141] 2.1 Animals and Modeling:

[0142] SD rats were purchased from Guizhou University of Traditional Chinese Medicine (Experimental Animal Institute), experimental animal certificate number SCXK (Guizhou) 2021-0003, 6-week-old female, weighing 152.43±10.74g, ambient temperature: (24±2)℃, relative humidity 42%±5%, and light intensity alternating between 12h during the day and 12h during the night.

[0143] Modeling method: p-Chlorophenylalanine (PCPA) was used for modeling. p-Chlorophenylalanine, as a tryptophan hydroxylase inhibitor, can block and deplete the synthesis of 5-hydroxytryptamine in the brain. PCPA suspension (350 mg / kg) was injected intraperitoneally to induce insomnia, and the drug was administered intraperitoneally for 4 consecutive days.

[0144] 2.2 Grouping and administration method

[0145] Normal control group; model group; positive drug group (estazolam, 12.6 mg / kg), once a day; Chinese medicine tablets in Example 5 (human weight is calculated according to 70 kg, 4 tablets per day, equivalent to rat dosage, 4.3 g / kg / time / day in crude drug amount), Chinese medicine tablets in Comparative Example 1 (human weight is calculated according to 70 kg, 4 tablets per day, equivalent to rat dosage, 4.3 g / kg / time / day in crude drug amount), Chinese medicine tablets in Comparative Example 2 (human weight is calculated according to 70 kg, 4 tablets per day, equivalent to rat dosage, 4.3 g / kg / time / day in crude drug amount), Calculation, 4 tablets per day, equivalent to rat dosage, calculated as 4.3g / kg / time / day based on crude drug dosage), Comparative Example 3 group of Chinese medicine tablets (human weight is calculated according to 70kg, 4 tablets per day, equivalent to rat dosage, calculated as 4.3g / kg / time / day based on crude drug dosage), Comparative Example 4 group of Chinese medicine tablets (human weight is calculated according to 70kg, 4 tablets per day, equivalent to rat dosage, calculated as 4.3g / kg / time / day based on crude drug dosage), Comparative Example 5 group of Chinese medicine tablets (4.3g / kg). The normal control group and the model group were given an equal amount of 0.9% saline, 10mL / kg for intragastric administration; the above modeling group and normal control group, 10 rats in each group, were continuously administered by intragastric administration for 10 days.

[0146] 2.3 Symptoms of model rats

[0147] ① The rats' food and water intake increased significantly in the first 12-36 hours, and they showed certain excitement behaviors;

[0148] ② Obvious irritability, increased activity, and increased aggressiveness during the day;

[0149] ③ Increased sensitivity to external stimuli such as sound and light, and disappearance of one's own circadian rhythm;

[0150] ④The total amount of sleep is severely reduced, almost reaching complete insomnia;

[0151] If more than 3 of the above conditions are met, the rat model is successfully established.

[0152] 2.4 Treatment process

[0153] After continuous drug intervention, the eating, sleeping, body weight and response to external stimuli of rats in the positive control group and each drug-treated group were improved, while the condition of some rats in the model control group remained unchanged or worsened; the normal control group lived a normal life during the modeling and intervention period.

[0154] 2.5 Results Analysis

[0155] Figure 4 After modeling, compared with the normal control group, the weight gain of rats in the seven modeling groups was significantly reduced, showing a negative growth, and the differences were statistically significant compared with the normal group (P < 0.01), indicating that the modeling was successful.

[0156] Figure 5 After drug administration, compared with the normal control group, the weight gain of the rats in the model control group was significantly reduced, and the difference was statistically significant (P < 0.05). Compared with the model control group, the weight gain of the rats in each drug administration group was significantly increased, and the differences were all statistically significant (P < 0.05). Compared with the comparative examples 1-4 groups, there was a significant difference between the Example 5 group and the comparative examples 1-4 groups, indicating that the therapeutic effect of the tablets prepared in Example 5 is better than that of the comparative examples 1-4 groups.

[0157] Figure 6 : Compared with the normal control group, the sleep duration of the rats in the model control group was significantly shortened, and the differences were statistically significant (P < 0.01), indicating that the model was successfully established; compared with the model control group, the sleep duration of the rats in each drug-treated group was significantly prolonged, and the differences were statistically significant (P < 0.05). The sleep duration improvement effect of the tablets of Example 5 was significantly better than that of the four control groups and the positive control group, and the difference was significant (P < 0.05). The results show that the Chinese medicine composition of the present invention can prolong the sleep duration and has a significant hypnotic effect on insomnia rats.

[0158] Figure 7 : Compared with the normal control group, the sleep latency of the rats in the model control group was significantly prolonged, and the differences were statistically significant (P < 0.01), indicating that the model was successfully established; compared with the model control group, the sleep latency of the rats in each drug-treated group was significantly shortened, and the differences were statistically significant (P < 0.05). The tablets of Example 5 had a significantly better effect on improving the sleep latency than the four control groups and the positive control group, and the difference was significant (P < 0.05). The results show that the Chinese medicine composition of the present invention can significantly shorten the sleep latency of insomnia rats and has a significant hypnotic effect on insomnia rats.

Claims

1. A medicine for preventing, alleviating or treating insomnia caused by liver and spleen disharmony, Features: The medicine is composed of the following components, in parts by weight: 10-15 parts of bamboo leaf bupleurum, 12-18 parts of white peony root, 10-15 parts of chuanxiong, 10-15 parts of angelica, 26-34 parts of stir-fried jujube seeds, 12-18 parts of Polygonum multiflorum vine, 10-15 parts of julibrissin bark, 8-12 parts of Schisandra chinensis, 8-12 parts of polygonatum, 2-5 parts of cinnamon, 26-34 parts of lily and 8-12 parts of roasted liquorice.

2. The drug according to claim 1, Features: The medicine is composed of the following components, measured by weight: 11-13 parts of bamboo leaf bupleurum, 14-16 parts of white peony root, 11-13 parts of chuanxiong, 11-13 parts of angelica, 28-32 parts of stir-fried jujube seeds, 14-16 parts of Polygonum multiflorum, 11-13 parts of julibrissin bark, 9-11 parts of Schisandra chinensis, 9-11 parts of polygonatum, 2-4 parts of cinnamon, 28-32 parts of lily and 9-11 parts of roasted liquorice.

3. The drug according to claim 1, Features: The medicine is composed of the following components, by weight: 12 parts of bamboo leaf bupleurum, 15 parts of white peony root, 12 parts of chuanxiong, 12 parts of angelica, 30 parts of stir-fried jujube seeds, 15 parts of Polygonum multiflorum, 12 parts of Albizzia julibrissin, 10 parts of Schisandra chinensis, 10 parts of Polygonatum sibiricum, 3 parts of cinnamon bark, 30 parts of lily and 10 parts of roasted liquorice.

4. A pharmaceutical preparation, Features: The preparation is selected from any one of decoction cream, hard capsule, ointment, tablet, granule, pill, oral solution, syrup, powder, pill, suspension, solution, injection, lyophilized powder injection, injection, suppository, plaster, cream, spray and patch; the pharmaceutical preparation contains any one of claims 1-3 and pharmaceutically acceptable excipients.

5. The preparation according to claim 4, Features: When the drug is prepared into a medicament, a unit dose of the medicament contains 0.1 to 1000 mg of the medicinal material, and more preferably, the unit dose is 120 to 250 mg.

6. The preparation according to claim 4, Features: The pharmaceutically acceptable excipients include, but are not limited to, fillers, disintegrants, lubricants, and binders.

7. The preparation according to claim 4, Features: The preparation of the pharmaceutical preparation comprises the following steps: S1: Weigh each medicinal material according to the prescribed amount and crush it into coarse powder; S2: Mix all the crude powders of medicinal materials obtained in S1 and boil them three times, filter them, combine the decoctions, and concentrate them into extracts; S3: The extract obtained in S2 is mixed with pharmaceutically acceptable excipients to prepare different pharmaceutical preparations.

8. Use of the preparation according to claim 4 in preventing, alleviating or treating insomnia caused by liver and spleen disharmony.

9. The use according to claim 7, Features: The insomnia is any one of liver depression and qi stagnation type, spleen and stomach weakness type, and liver yang hyperactivity type.

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