WO2022161177A1 - 一种具有改善睡眠作用的中药组合物及其制备方法和应用 - Google Patents

一种具有改善睡眠作用的中药组合物及其制备方法和应用 Download PDF

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WO2022161177A1
WO2022161177A1 PCT/CN2022/071699 CN2022071699W WO2022161177A1 WO 2022161177 A1 WO2022161177 A1 WO 2022161177A1 CN 2022071699 W CN2022071699 W CN 2022071699W WO 2022161177 A1 WO2022161177 A1 WO 2022161177A1
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chinese medicine
traditional chinese
medicine composition
parts
preparation
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PCT/CN2022/071699
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English (en)
French (fr)
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宋相容
谢永美
辜勇军
赵宇
罗波
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四川福生源科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A61K36/537—Salvia (sage)
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23F—COFFEE; TEA; THEIR SUBSTITUTES; MANUFACTURE, PREPARATION, OR INFUSION THEREOF
    • A23F3/00—Tea; Tea substitutes; Preparations thereof
    • A23F3/34—Tea substitutes, e.g. matè; Extracts or infusions thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
    • A61K36/258—Panax (ginseng)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A61K36/284—Atractylodes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
    • A61K36/734—Crataegus (hawthorn)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/331—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using water, e.g. cold water, infusion, tea, steam distillation or decoction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/39—Complex extraction schemes, e.g. fractionation or repeated extraction steps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/50—Methods involving additional extraction steps
    • A61K2236/51—Concentration or drying of the extract, e.g. Lyophilisation, freeze-drying or spray-drying

Definitions

  • the invention belongs to the technical field of traditional Chinese medicines, and in particular relates to a traditional Chinese medicine composition with the effect of improving sleep and a preparation method and application thereof.
  • insomnia is a kind of disease syndrome characterized by frequent inability to get normal sleep due to internal injury of emotions, diet, post-illness and old age, lack of endowment, timidity and timidity. Insufficiency of depth and inability to eliminate fatigue, restore physical strength and energy, in the light of cases, it is difficult to fall asleep, or insomnia is not sound. As one of the common clinical symptoms, insomnia is not a critical disease, but it often hinders people's normal life, work, study and health, and can aggravate or induce palpitations, chest pain, dizziness, headache, stroke and other symptoms. Intractable insomnia will bring long-term pain to patients, and even form dependence on sleeping drugs, and long-term use of sleeping drugs can cause iatrogenic diseases.
  • the insomnia rate of adults in my country is as high as 38%. Due to long-term insomnia, many people suffer from many related diseases. Sleep disorder has become a major killer of human beings, bringing huge hidden dangers to people's life, work and study. At present, benzodiazepines, barbiturates and other non-barbiturates are commonly used sleeping pills in clinical practice. They have obvious effects in the treatment of insomnia, but they have a greater impact on the liver and kidneys, and they are prone to adverse reactions. Drug dependence usually requires continuously increasing the dosage to maintain the effect, and it also produces great toxic and side effects, so it is not a drug suitable for long-term use.
  • TCM believes that there are two types of insomnia syndrome, which are caused by the dysfunction of qi, blood and viscera in the body. Therefore, for the treatment of insomnia, traditional Chinese medicine regulates the internal organs, so that qi and blood are reconciled, yin and yang are balanced, and the functions of the internal organs are returned to normal, which can often significantly improve sleep symptoms without causing drug dependence and iatrogenic diseases, so it is very popular. Therefore, based on the theory of traditional Chinese medicine, it is of great significance to develop a safe and effective traditional Chinese medicine composition for improving sleep, so as to solve the troubles of insomniac people on sleep problems.
  • the purpose of the present invention is to provide a traditional Chinese medicine composition with the effect of improving sleep, which is made from natural plants, has no toxic and side effects on the human body, and can be taken for a long time.
  • the invention provides a traditional Chinese medicine composition with the effect of improving sleep.
  • the raw medicines include the following parts by weight: 6-25 parts of Salvia miltiorrhiza, 5-20 parts of Panax notoginseng, 6-25 parts of Atractylodes Rhizoma, and 3-20 parts of Hawthorn.
  • the following raw materials are contained in parts by weight: 10-20 parts of Salvia miltiorrhiza, 10-18 parts of Panax notoginseng, 10-20 parts of Atractylodes Rhizoma and 8-15 parts of Hawthorn.
  • the present invention provides a preparation method of the above-mentioned traditional Chinese medicine composition, which comprises the steps of mixing Salvia miltiorrhiza, Panax notoginseng, Atractylodes Rhizoma and Hawthorn before crushing or mixing after crushing.
  • the invention provides the preparation method of the above-mentioned traditional Chinese medicine composition, comprising the following steps:
  • step B get the medicinal dregs after described step A extraction and add water with Atractylodes Rhizoma and Hawthorn, heat extraction, obtain water extract;
  • the ethanol extract in step A when concentrating the ethanol extract in step A, the ethanol extract in step A is concentrated to a medicinal material equivalent of 0.6 to 2:1; when concentrating the water extract in step B, the water extract in step B is concentrated Concentrate to a medicinal material equivalent of 0.6 to 2:1.
  • the present invention also provides a pharmaceutical preparation with the effect of improving sleep, which is prepared from the above-mentioned traditional Chinese medicine composition and a pharmaceutically acceptable carrier.
  • the dosage form of the pharmaceutical preparation includes decoction, tea, oral liquid, syrup, ointment, powder, granule, capsule, tablet or pill.
  • the pharmaceutically acceptable carrier comprises one of water, ethanol, sucrose powder, starch, microcrystalline cellulose, chitosan, mannitol, sorbitol, xylitol, sucralose and dextrin or multiple combinations.
  • the present invention provides a preparation method of the above-mentioned pharmaceutical preparation, which is prepared from the crude drug of the traditional Chinese medicine composition or the traditional Chinese medicine composition prepared by the preparation method and a pharmaceutically acceptable carrier.
  • the present invention also provides the application of the above-mentioned traditional Chinese medicine composition or the above-mentioned pharmaceutical preparation in the preparation of sleep-improving food, health care products and medicines.
  • the invention provides a traditional Chinese medicine composition with the effect of improving sleep.
  • the traditional Chinese medicine composition of the invention comprises Salvia miltiorrhiza, Atractylodes Rhizoma, Panax notoginseng and Hawthorn, and the raw materials are scientifically formulated and synergistic with each other, and play a role in nourishing the heart and spleen, nourishing the heart and soothing the mind, soothing the liver and nourishing blood, promoting blood circulation and removing blood stasis, and gastric digestion.
  • the effect of stagnation can fundamentally solve the internal cause of insomnia and improve sleep.
  • the raw materials in the present invention are compatible and complement each other to achieve the effect of improving sleep.
  • the invention provides a traditional Chinese medicine composition with the effect of improving sleep.
  • the traditional Chinese medicine composition of the present invention includes 3-30 parts of Salvia miltiorrhiza, preferably 6-25 parts, and more preferably 10-20 parts.
  • the Salvia miltiorrhiza is preferably 3, 6, 12, 15, 18, 25 or 30 servings.
  • the Salvia miltiorrhiza of the present invention enters the heart and liver meridians, activates blood and removes blood stasis, clears the heart and removes vexation, and has the functions of promoting blood circulation and removing blood stasis, calming the nerves and calming the heart.
  • the traditional Chinese medicine composition of the present invention includes 2-25 parts of Panax notoginseng, preferably 5-20 parts, more preferably 10-18 parts.
  • the Salvia miltiorrhiza is preferably 3, 6, 12, 15, 18, 25 or 20 servings.
  • the Panax notoginseng of the invention belongs to the liver and stomach meridians, and has the effects of removing blood stasis and stopping bleeding, promoting blood circulation and relieving pain.
  • the above-mentioned Salvia miltiorrhiza and Panax notoginseng are the monarch medicines, which together exert the effects of nourishing the heart and calming the nerves, soothing the liver and nourishing blood.
  • the traditional Chinese medicine composition of the present invention includes 3-30 parts of Atractylodes Rhizoma, preferably 6-25 parts, more preferably 10-20 parts.
  • the Atractylodes Rhizoma is preferably 3 parts, 6 parts, 15 parts, 18 parts, 30 parts, 21 parts or 25 parts.
  • the Atractylodes macrocephala of the invention returns to the spleen and stomach meridians, and has the functions of invigorating the spleen and stomach, invigorating the spleen and invigorating qi, drying dampness and diverting water.
  • the traditional Chinese medicine composition of the present invention includes 1-25 parts of hawthorn, preferably 3-20 parts, more preferably 8-15 parts.
  • the hawthorn is preferably 2, 6, 10, 15, 18, 20 or 24 portions.
  • the hawthorn of the present invention returns to the spleen, stomach and liver meridians, and has the effects of digestion and stomach, promoting qi and dissipating blood stasis.
  • Rhizoma and Hawthorn are both the monarch medicine and the minister medicine, and have the functions of invigorating the spleen to nourish the heart, dispelling stagnation in the stomach, nourishing the liver and prospering the blood.
  • the traditional Chinese medicine composition preferably includes 12 parts of Salvia miltiorrhiza, 20 parts of Panax notoginseng, 18 parts of Atractylodes Rhizoma, and 24 parts of Hawthorn;
  • Insomnia refers to frequent poor sleep, such as difficulty falling asleep after going to bed, very shallow sleep, easy to wake up, and is caused by the imbalance of the excitation and inhibition process of the central nervous system.
  • This disease belongs to the category of "insomnia” and "insomnia” in traditional Chinese medicine.
  • Traditional Chinese medicine believes that the mind is the master of the gods, and if the gods do not enter the house, they cannot sleep.
  • Can’t sleep the spleen governs transport and transformation, its transport and transformation function is abnormal, the function of transporting nutrients and nourishing the heart becomes poor, and the heart lacks nutrient supply, and there will still be “no sleep, no sleep”; “liver stores blood, blood "Sacrificing the soul”, the liver stores blood, and the soul takes blood as its home, so it can be considered that the soul belongs to the liver.
  • the present invention is based on the theory of traditional Chinese medicine, uses four traditional Chinese medicines, namely Salvia miltiorrhiza, Atractylodes Radix, Panax notoginseng and Hawthorn as raw materials. The effect of removing blood stasis and stomach stagnation can fundamentally solve the internal cause of insomnia.
  • the present invention also provides a method for preparing the above-mentioned traditional Chinese medicine composition, which includes the following steps: mixing Salvia miltiorrhiza, Panax notoginseng and ethanol solution, heating and refluxing for extraction, to obtain the ethanol extract and the salvia-panax notoginseng residue;
  • step B get the medicinal residues after the ethanol extraction of step A, add water with Atractylodes Rhizoma and Hawthorn, heat and extract, and obtain water extract;
  • step A ethanol extract is concentrated to no ethanol smell
  • step B water extract is concentrated, and merges to obtain the extract concentrate
  • salvia miltiorrhiza and Panax notoginseng are added to ethanol, heated and refluxed for extraction, and an ethanol extract is obtained.
  • the mass concentration of ethanol in the ethanol solution of the present invention is preferably 10-90%, more preferably 50%.
  • the mass and volume ratio of Salvia miltiorrhiza and Panax notoginseng of the present invention to the ethanol solution is preferably 1g:1 ⁇ 10mL, more preferably 1g:5mL.
  • the number of times of extraction according to the present invention is preferably 1 to 3 times, more preferably 2 times.
  • the heating and refluxing extraction time of the present invention is preferably 1 to 3 hours, more preferably 2 hours.
  • the medicinal residues, Atractylodes Rhizoma and Hawthorn after ethanol extraction in step A are added to water, heated and extracted to obtain a water extract.
  • the mass and volume ratio of the medicinal residues, Atractylodes Rhizoma and Hawthorn after ethanol extraction in step A of the present invention is preferably 1g:1-15mL, more preferably 1g:10mL.
  • the number of times of the heating extraction according to the present invention is 1 to 3 times, more preferably 2 times.
  • the heating extraction time of the present invention is preferably 1 to 3 hours, more preferably 2 hours.
  • the present invention concentrates the ethanol extract in step A until there is no ethanol smell, and concentrates the water extract in step B, and combines them to obtain an extract concentrate.
  • the ethanol extract in step A when the ethanol extract in step A is concentrated, the ethanol extract is preferably concentrated to a medicinal material equivalent of 0.6 to 2:1, more preferably 0.8:1.
  • the water extract in step B when the water extract in step B is concentrated, the water extract is preferably concentrated to a medicinal material equivalent of 0.6 to 2:1, more preferably 1:1.
  • the ethanol concentrate and the water concentrate are mixed and then concentrated again, and the obtained concentrate is the traditional Chinese medicine composition of the present invention.
  • the mixture of the ethanol concentrate and the water concentrate is preferably concentrated to a medicinal material equivalent of 0.8 to 2:1, more preferably 1.2:1.
  • the present invention also provides a pharmaceutical preparation with the effect of improving sleep, which is composed of each original medicinal material of the above-mentioned traditional Chinese medicine composition or an extract of each original medicinal material of the traditional Chinese medicinal composition and a pharmaceutically acceptable carrier.
  • the dosage form of the pharmaceutical preparation of the present invention preferably includes decoction, tea, oral liquid, syrup, ointment, powder, granule, capsule, tablet or pill.
  • the pharmaceutically acceptable carrier of the present invention preferably comprises one of water, ethanol, sucrose powder, starch, microcrystalline cellulose, chitosan, mannitol, sorbitol, xylitol, sucralose and dextrin or more.
  • the present invention also provides a preparation method of the pharmaceutical preparation, including the steps of mixing the traditional Chinese medicine composition obtained by the above preparation method and a pharmaceutically acceptable carrier to obtain the pharmaceutical preparation.
  • composition of each original medicinal material of the traditional Chinese medicine composition or the composition of the extract of each original medicinal material of the traditional Chinese medicinal composition according to the present invention can also be prepared by adding any other medicinal or edible ingredients or medicinal materials, after processing and using a pharmaceutically acceptable carrier Tea, oral liquid, syrup, ointment, powder, granules, capsules, tablets or pills; the processing includes but not limited to cutting into tablets, pulverizing into powder, and extracting and obtaining extracts.
  • the composition of the extracts of the original medicinal materials of the traditional Chinese medicine composition of the present invention is preferably prepared according to the above-mentioned preparation method of the traditional Chinese medicine composition, which will not be repeated here.
  • the present invention is based on the theory of syndrome differentiation and treatment of traditional Chinese medicine, through a large number of experiments, the traditional Chinese medicine composition with the best formula ratio is optimized, the traditional Chinese medicine composition is rigorously used, and the ratio is scientific and reasonable.
  • the results of the formula composition and dosage screening test show that the incomplete compositions of each group are similar to the negative control group (sterile water), and have no effect of prolonging the sleep time of mice induced by sodium pentobarbital.
  • the ingredients are all necessary ingredients for the composition to play a role in improving sleep; within the scope of the claimed prescription of the present invention, the composition of the present invention has the effect of prolonging the sleep time of mice induced by sodium pentobarbital, and as the prescription dosage increases , the effect is gradually enhanced until the corresponding threshold (the dosage of group 8) is reached, and after reaching the threshold, the effect of increasing the prescribed dosage on improving the effect of promoting sleep is not obvious.
  • the present invention selects the best extraction and separation method through a large number of experiments, the extraction process is reasonable, the operability is strong, and the extracted effective components have high content and few impurities.
  • Test of improving sleep function the three dose groups of oral liquid of the traditional Chinese medicine composition of the present invention, 2.5mL/kg/d, 5mL/kg/d, and 10mL/kg/d, were administered to mice for one month, and a direct sleep test was performed to prolong the pentobarbi Sodium sodium sleep time test, pentobarbital sodium subthreshold dose sleep test, barbital sodium sleep latency test.
  • the results showed that the oral liquid of the traditional Chinese medicine composition of the present invention 2.5mL/kg/d, 5mL/kg/d and 10mL/kg/d groups had no direct sleep effect on mice.
  • mice in each group were significantly longer than that in 0mL/kg/d group, and the difference was statistically significant (P ⁇ 0.05); 2.5mL/kg/d, 5mL/kg/d, 10mL/kg/d groups Compared with the 0mL/kg/d group, the animal sleep incidence rate in each group was significantly higher, and the 10mL/kg/d group compared with the 0mL/kg/d group had a statistically significant increase in the animal sleep incidence rate.
  • the sleep latency of the mice in each administration group was significantly shorter than that in the 0mL/kg/d group, and the difference was statistically significant in the 5mL/kg/d group and 10mL/kg/d group compared with the 0mL/kg/d group (P ⁇ 0.05).
  • the traditional Chinese medicine composition of the present invention has the function of improving sleep.
  • Acute oral toxicity test and 30-day feeding test the acute oral MTD of Chinese medicinal composition female and male mice provided by the invention is greater than 22400mg/kg, and according to the acute toxicity dose grading standard, the traditional Chinese medicinal composition of the present invention belongs to non-toxic grade.
  • the traditional Chinese medicine composition of the present invention is administered to rats at doses of 6.0 mg/kg/d, 12 mg/kg/d and 20.0 mg/kg/d (equivalent to 15 times, 30 times and 50 times of the recommended human dose) for 30 days.
  • the test animals were generally in good condition, and the results of body weight, hematological indexes and biochemical indexes showed that all indexes were within the normal range.
  • the Chinese medicine composition of the present invention was given to animals at 50 times the recommended dose of human body, and no harmful effects were observed.
  • the present invention also conducts a test of the Chinese medicine composition to improve sleep in humans, and the results of the test to improve sleep show that the clinical symptom scores of the test group before and after the test and the comparison between the control groups are significantly reduced (P ⁇ 0.01).
  • the sleep conditions of the group were significantly improved, and no other side effects were reported, indicating that the traditional Chinese medicine composition of the present invention has the function of improving sleep.
  • the Chinese medicinal material equivalent in the present invention refers to the weight ratio of the unit weight of the medicinal material to the extracted concentrate or extract.
  • the medicinal material equivalent is 2:1, it means that 2 weight parts of the medicinal material are extracted to obtain 1 weight part of the concentrated liquid or extract. paste.
  • Salvia 3g Salvia 3g, Panax notoginseng 2g, Atractylodes 3g, Hawthorn 1g.
  • step (2) Take the medicinal material slices or pulverized granules cut in step (1), add 100 mL of boiling water, and steep for 20 minutes to obtain the tea preparation of the present invention (the tea preparation can be repeatedly brewed 3 to 5 times).
  • Salvia 6g Panax notoginseng 6g, Atractylodes 3g, Hawthorn 18g.
  • Salvia 12kg Salvia 12kg, Panax notoginseng 20kg, Atractylodes 18kg, Hawthorn 24kg.
  • step (1) ethanol extraction medicinal residues and add 740kg of water together with Atractylodes Rhizoma and Hawthorn, decoct and extract by heating for 2 times, each time for 2 hours, and combine to obtain water extract;
  • step (1) ethanol extraction medicinal residues and add 49.6kg of water with Atractylodes Rhizoma and Hawthorn, heat, boil, decoct and extract for 2 times, each time for 1 hour, and combine to obtain a water extract;
  • Salvia 1.5kg Salvia 1.5kg
  • Panax notoginseng 1.5kg Atractylodes 1.5kg
  • Hawthorn 1.5kg Hawthorn 1.5kg.
  • Salvia 2100g Panax notoginseng 1500g
  • Atractylodes 900g Hawthorn 1800g.
  • step (1) ethanol extraction medicinal residues, add 32kg of water with Atractylodes Rhizoma and Hawthorn, heat and extract for 2 times, each time for 2 hours, and combine to obtain a water extract;
  • step (1) ethanol extraction medicinal residue and add 38.4kg water with Atractylodes Rhizoma and Hawthorn, heat and extract 3 times, each time for 1 hour, and combine to obtain water extract;
  • step (3) adding the concentrated solution to the fine powder prepared in step (1), mixing uniformly to obtain a soft material, extruding through a pill making machine, rolling the pills, and drying to obtain a total of 4.5kg of Chinese medicine concentrated pills weighing 5g per 100 pills .
  • step (2) Take an appropriate amount of the fine powder in step (1) and add suitable purified water in the coating pot to form a mother-made pill, continue to add purified water and medicinal powder, and repeatedly spheronize and enlarge to obtain pellets with a diameter of about 4 mm, which are polished and dried. Then get the Chinese medicine water pill.
  • Salvia 3kg Salvia 3kg, Panax notoginseng 25kg, Atractylodes 21kg, Hawthorn 20kg.
  • step (1) ethanol extraction medicinal residues and add 828kg of water with Atractylodes Rhizoma and Hawthorn, heat and decoct for 2 times, each time for 1.5 hours, and combine to obtain a water extract;
  • step (1) ethanol extraction medicinal residues and Atractylodes Rhizoma, hawthorn and add 75kg of water, decoct and extract by heating for 2 times, each time for 1 hour, merge to obtain water extract;
  • step (3) After taking 0.5kg of honey and refining it into refining honey, add the extract in step (3), continue to boil until it is pulled into flags or dripped into beads, take out, cool to obtain about 2.5kg of paste, and pack into 100g/cans , that is.
  • mice were adapted to the environment (temperature of 20-25°C, relative humidity of 40-70%), and were randomly divided into 11 groups (9 test drug groups, 1 negative control group and 1 positive control group) according to their body weight after 4 days of quarantine. ), 12 in each group.
  • test drug group was given the diluted solution of the prepared sample solution by gavage (dilute it with sterile water at 1:9 and shake well) 0.15mL/10g body weight, the negative control group 0.15mL/10g body weight of sterile water was given by gavage; positive control group was given 4mg/kg diazepam aqueous solution by gavage (administration volume was 0.15mL/10g body weight).
  • Table 2 The effect of different prescription compositions on prolonging the sleep time of mice induced by sodium pentobarbital
  • the homogeneity of variance test was performed on the original data of each experiment, and the data that met the requirement of homogeneity of variance were analyzed by one-way analysis of variance between multiple experimental groups and the negative control group (P value 1) or the positive control group (P value 2). Pairwise comparisons and statistical processing of the means are performed (appropriate variable transformation is performed on data with non-normal distribution or unequal variance, and statistical processing is performed with the transformed data after the requirements for normality or homogeneous variance are met).
  • group 1, group 2, group 3 and group 4 with incomplete prescription were similar to the negative control group, and had no effect on prolonging the sleep time of mice induced by sodium pentobarbital; compared with the negative control group and the positive control group , group 5 has the effect of prolonging the sleep time of pentobarbital sodium-induced mice, and the difference is statistically significant (P ⁇ 0.05), but its prolongation time is not as good as that of the positive control group; compared with the negative control group and the positive control group , both groups 6 and 7 have the effect of significantly prolonging the sleep time of pentobarbital sodium-induced mice, and the prolongation effect is equivalent to that of the positive control; compared with the negative control group and the positive control group, both groups 8 and 9 have significant The effect of prolonging the sleep time of mice induced by sodium pentobarbital was better than that of the positive control group.
  • each component in the composition is an essential component for the composition to play a role in improving sleep; within the scope of the prescription claimed in the claims, the composition of the present invention has the ability to prolong the sleep time of mice induced by pentobarbital sodium. And as the prescription dosage increases, the effect is gradually enhanced until reaching the corresponding threshold (the dosage of group 8). After reaching the threshold, continuing to increase the prescription dosage has little effect on improving the effect of promoting sleep.
  • Example 3 of the present invention The oral liquid prepared in Example 3 of the present invention, batch number: 20200518
  • the sample is a brownish-yellow liquid, and is stored in a cool, dry and ventilated place.
  • mice were adapted to the environment (temperature of 20-25°C, relative humidity of 40-70%). After 4 days of quarantine, they were randomly divided into three large groups according to their body weight, of which 48 mice in one group were randomly divided into 4 dose groups. There were 12 mice in each group. The direct sleep experiment was performed first, and then the extended pentobarbital sodium sleep time experiment was performed the next day; 48 mice in the two groups were randomly divided into 4 dose groups, 12 mice in each group, and the pentobarbital sodium was administered to the mice. Sodium subthreshold dose hypnosis experiment; 48 mice in 3 groups were randomly divided into 4 dose groups with 12 mice in each group, and the barbiturate sodium sleep latency experiment was carried out.
  • Dose selection and test substance administration method three dose groups of 2.5mL/kg/d, 5mL/kg/d, and 10mL/kg/d (respectively equivalent to 5 times the recommended intake of the test sample in humans) were set up. , 10 times, 20 times), and another 0 mL/kg/d group was set up to replace the test substance with sterile water.
  • the test sample was prepared with sterile water, and the concentration of low, medium and high doses were 25%, 50%, and 100%, respectively, and the corresponding dose of the test substance was administered to the mice once a day. 0.1mL/10g.
  • mice in each dose group were given continuous gavage for one month. After the last administration, the mice entered sleep with the disappearance of the righting reflex for 1 min, and the recovery of the righting reflex was the criterion for the awakening of the mice. The number of sleeping animals and sleep time in each group were recorded.
  • the animals in each dose group were given continuous intragastric administration for one month. After 15 minutes of the last administration, the animals in each group were intraperitoneally injected with sodium pentobarbital at a dose of 50 mg/kg, and the injection volume was 0.1 mL/10 g. To observe whether the test sample can prolong the sleep time of sodium pentobarbital. Comparing the difference between the control group and the experimental group in the prolongation of sleep time, if the sleep time prolongation is significant, the experimental result is positive.
  • the animals in each dose group were given continuous intragastric administration for one month. After 15 minutes of the last administration, the animals in each group were intraperitoneally injected with sodium pentobarbital at a dose of 35 mg/kg, and the injection volume was 0.1 mL/10 g. The number of sleeping animals in each group within 30 min of pentobarbital sodium administration was recorded. Comparing the differences in the number of animals falling asleep between the control group and the experimental group, if there is a significant increase in the incidence of falling asleep animals, the experimental result is positive.
  • the animals in each dose group were given continuous intragastric administration for one month, and 15 minutes after the last administration, the animals in each group were intraperitoneally injected with sodium barbital at a dose of 250 mg/kg, and the injection volume was 0.1 mL/10 g. , to observe the effect of the test sample on the sleep latency of sodium barbiturate. Comparing the difference between the sleep latency of the control group and the experimental group, if the sleep latency is shortened significantly, the experimental result is positive.
  • Test data statistics The original data of each test are tested for homogeneity of variance, and the data that meet the requirements of homogeneity of variance are statistically processed by the pairwise comparison method of the means between multiple test groups and a control group in the one-way analysis of variance method ; Carry out appropriate variable transformation for the data with non-normal distribution or unequal variance, and use the transformed data for statistical processing after meeting the requirements of normality or homogeneous variance.
  • mice were weighed respectively before and one month after the oral administration of different doses of the traditional Chinese medicine composition oral liquid of the present invention to mice, the initial body weight and the weight gain value were calculated, and statistical analysis was performed. There was no significant difference in the initial body weight between the 2.5mL/kg/d, 5mL/kg/d, 10mL/kg/d groups and the 0mL/kg/d group (P>0.05); the weight gain of each dose group after administration After the homogeneity of variance test, the requirement of homogeneity of variance was met, and statistical processing was carried out by the method of pairwise comparison of means between multiple experimental groups and a control group in one-way ANOVA. There was no significant difference between the 2.5mL/kg/d, 5mL/kg/d, 10mL/kg/d groups and 0mL/kg/d groups in each test group (P>0.05), see Table 3 for details.
  • mice were orally administered with different doses of the oral liquid of the traditional Chinese medicine composition of the present invention for one month. After the last administration, no direct sleep phenomenon occurred in each group of mice.
  • the oral liquid of the traditional Chinese medicine composition of the present invention 2.5mL/kg/d, 5mL/kg/d, and 10mL/kg/d groups did not have the effect of making the mice sleep directly.
  • mice were orally administered with different doses of the oral liquid of the traditional Chinese medicine composition of the present invention for one month, and intraperitoneal injection of sodium barbital was performed to observe the sleep latency of the mice.
  • Table 7 the sleep latency of the mice in each administration group was significantly shorter than the 0mL/kg/d group, and the 5mL/kg/d group and the 10mL/kg/d group were compared with the 0mL/kg/d group, and the difference was statistically significant. Academic significance (P ⁇ 0.05).
  • the traditional Chinese medicine composition of the present invention has the function of improving sleep.
  • Example 11 of the present invention the paste obtained in Example 11 of the present invention, specification: 100g/bottle, batch number: 20200827.
  • the form of the sample is a thick brown paste, which should be stored in a cool, dry and ventilated place. When using, add an appropriate amount of distilled water to dilute it before use.
  • the traditional Chinese medicine composition of the present invention is 6.0mL/kg/d, 12mL/kg/d, 20.0mL/kg/d (equivalent to 15 times the recommended dose of the human body, 30 times and 50 times) doses were administered to rats for 30 days. Compared with the 0 mg/kg/d group, the body weight and weight gain after 30 days of each dose group showed no significant difference (P>0.05). The results are shown in Table 9.
  • the traditional Chinese medicine composition of the present invention improves sleep and human body trial test 1
  • the test food group took the traditional Chinese medicine composition capsules (0.3g/capsule, batch number: 20200720) prepared in Example 5 of the present invention, and the control group took a placebo.
  • the appearance, color, weight, and taking method of the placebo were the same as those in Example 5 of the present invention. samples are the same.
  • Each subject took 2 capsules (about 1.2g of the original medicinal material) twice a day (morning and evening), each time with warm boiled water. During the test period, they had a normal diet, did not change their original eating habits, and stopped other drugs and health food for insomnia. The patients were observed after 21 days.
  • Symptom scores Accumulated scores according to the severity of insomnia symptoms (3 points for severe, 2 points for moderate, 1 point for mild, and 0 points for symptom elimination). There was no significant difference in symptom scores between the two groups before treatment (P>0.05). The blood, urine, stool routine, liver and kidney function, chest X-ray, electrocardiogram, B-ultrasound and other examinations in the two groups before the test were all within the normal range.
  • the traditional Chinese medicine composition of the present invention improves sleep and human body trial test 2
  • the test food group took the traditional Chinese medicine composition capsules (0.1g/capsule, batch number: 20200716) prepared in Example 6 of the present invention, and the control group took a placebo.
  • the appearance, color, weight, and taking method of the placebo were the same as those in Example 6 of the present invention. samples are the same.
  • Each subject took 2 capsules (about 1.6 g of the original medicinal material) twice a day (morning and evening), with warm water. During the test period, they had a normal diet, did not change their original eating habits, and stopped other drugs and health food for insomnia. The patients were observed after 21 days.
  • Symptom scores Accumulated scores according to the severity of insomnia symptoms (3 points for severe, 2 points for moderate, 1 point for mild, and 0 points for symptom elimination). There was no significant difference in symptom scores between the two groups before treatment (P>0.05). The blood, urine, stool routine, liver and kidney function, chest X-ray, electrocardiogram, B-ultrasound and other examinations in the two groups before the test were all within the normal range.

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Abstract

本发明提供了一种具有改善睡眠作用的中药组合物及其制备方法和应用，所述中药组合物包含下列重量份数的原料药：丹参3～30份、三七2～25份、白术3～30份和山楂1～25份。本发明提供的中药组合物经药理实验结果表明，可明显改善睡眠，且长期服用，无毒副作用。

Description

一种具有改善睡眠作用的中药组合物及其制备方法和应用
本申请要求于2021年01月26日提交中国专利局、申请号为CN202110114474.9、发明名称为“一种具有改善睡眠作用的中药组合物及其制备方法和应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明属于中药技术领域，具体涉及一种具有改善睡眠作用的中药组合物及其制备方法和应用。
背景技术
失眠是由情志、饮食内伤，病后及年迈，禀赋不足，心虚胆怯等病因引起心神失养或心神不安，从而导致经常不能获得正常睡眠为特征的一类病证，主要表现为睡眠时间、深度的不足以及不能消除疲劳、恢复体力与精力，轻者入睡困难，或寐而不酣，时寐时醒，或醒后不能再寐，重则彻夜不寐。作为临床常见病证之一，失眠虽不属于危重疾病，但常妨碍人们正常生活、工作、学习和健康，并能加重或诱发心悸、胸痹、眩晕、头痛、中风病等病证。顽固性的失眠，会给病人带来长期的痛苦，甚至形成对安眠药物的依赖，而长期服用安眠药物又可引起医源性疾病。
根据《睡眠白皮书》统计显示，我国成年人失眠率高达38％，由于长期失眠，许多人患上了诸多的相关疾病。睡眠障碍已成为人类的一大杀手，给人们的生活、工作、学习带来了巨大隐患。目前，临床上常用的安眠药有苯二氮卓类、巴比妥类和其他非巴比妥类，其治疗失眠的效果比较明显，但其对肝、肾影响较大，并且服用者容易产生对药品的依赖性，通常需要不断加大药用剂量才能保持效果，而且还会产生很大的毒副作用，因此并不是适合长期服用的药物。市面流行的各类改善睡眠产品主要为镇静安眠药和褪黑素类中药组合物，但是褪黑素改善睡眠功效尚不明确，长期或高剂量服用褪黑素可能对人体产生危害，如明显抑制人体生殖系统功能。中老年(因褪黑素分泌减少)人群若褪黑素白天残留较大，会有头晕和走路不稳等副作用，可能会给年纪大、身体较弱者带来危险。
中医认为失眠证有虚实两种，是机体内在气血、脏腑功能失调所致。因此，对失眠的治疗，中医药通过内脏的调治，使气血调和，阴阳平衡，脏腑功能归 于正常，常能明显改善睡眠症状，且不引起药物依赖及医源性疾患，因而颇受欢迎。故以中医药理论为基础，开发安全、有效改善睡眠的中药组合物，以解决失眠人群在睡眠问题上的烦恼具有重要的意义。
发明内容
本发明的目的在于提供一种具有改善睡眠作用的中药组合物，其采用天然植物制成，对人体无毒副作用，可以长期服用。
本发明提供了一种具有改善睡眠作用的中药组合物，包含下列重量份数的原料药：丹参3～30份、三七2～25份、白术3～30份和山楂1～25份。
优选的，包含下列重量份数的原料药：丹参6～25份、三七5～20份、白术6～25份和山楂3～20份。
优选的，包含下列重量份数的原料药：丹参10～20份、三七10～18份、白术10～20份和山楂8～15份。
本发明提供了上述中药组合物的制备方法，包括将丹参、三七、白术和山楂混合后粉碎或粉碎后混合。
本发明提供了上述中药组合物的制备方法，包括以下步骤：
A、取丹参和三七加入乙醇溶液，加热回流提取，得乙醇提取液；
B、取所述步骤A提取后的药渣与白术和山楂加入水，加热提取，得水提取液；
C、将所述步骤A的乙醇提液浓缩至无乙醇味，加入所述步骤B水提液浓缩，合并得提取浓缩物。
优选的，对所述步骤A的乙醇提液浓缩时，将步骤A乙醇提液浓缩至药材当量为0.6～2:1；对所述步骤B的水提液浓缩，将步骤B的水提液浓缩至药材当量为0.6～2:1。
本发明还提供了一种具有改善睡眠作用的药物制剂，由上述中药组合物和药学上可接受的载体制成。
优选的，所述药物制剂的剂型包括煎煮剂、茶剂、口服液、糖浆剂、膏剂、散剂、颗粒剂、胶囊剂、片剂或丸剂。
优选的，所述药学上可接受的载体包括水、乙醇、蔗糖粉、淀粉、微晶纤维素、壳聚糖、甘露醇、山梨醇、木糖醇、三氯蔗糖和糊精中的一种或多种组合。
本发明提供了上述药物制剂的制备方法，由所述中药组合物的原料药或所述制备方法制得的中药组合物和药学上可接受的载体制成。
本发明还提供了上述中药组合物或上述药物制剂在制备改善睡眠作用的食品、保健品和药品中的应用。
本发明提供了一种具有改善睡眠作用的中药组合物，包含下列重量份数的原料药：丹参3～30份、三七2～25份、白术3～30份和山楂1～25份。本发明所述中药组合物包括丹参、白术、三七和山楂，各原料药经科学组方，相互协同，共奏补益心脾，养心安神，疏肝养血，活血化瘀，和胃化滞的功效，可从根本上解决导致失眠的内在病因，改善睡眠。本发明中各原料药配伍，相辅相成，共同达到改善睡眠的功效。
具体实施方式
本发明提供了一种具有改善睡眠作用的中药组合物，包含下列重量份数的原料药：丹参3～30份、三七2～25份、白术3～30份和山楂1～25份。
以质量份计，本发明所述中药组合物包括丹参3～30份，优选为6～25份，进一步优选为10～20份。在本发明具体实施例中，所述丹参优选为3份、6份、12份、15份、18份、25份或30份。本发明所述丹参入心、肝经，活血祛瘀，通经止痛，清心除烦，有活血化瘀、安神宁心的作用。
以所述丹参的质量份为基准，本发明所述中药组合物包括三七2～25份，优选为5～20份，进一步优选为10～18份。在本发明具体实施例中，所述丹参优选为3份、6份、12份、15份、18份、25份或20份。本发明所述三七归肝、胃经，具有化瘀止血，活血定痛的功效。
在本发明中，上述丹参和三七共为君药，共同发挥养心安神、舒肝养血的功效。
以所述丹参的质量份为基准，本发明所述中药组合物包括白术3～30份，优选为6～25份，进一步优选为10～20份。在本发明具体实施例中，所述白术优选为3份、6份、15份、18份、30份、21份或25份。本发明所述白术归脾、胃经，具有补脾益胃，健脾益气，燥湿利水等功能。
以所述丹参的质量份为基准，本发明所述中药组合物包括山楂1～25份，优选为3～20份，进一步优选为8～15份。在本发明具体实施例中，所述山楂优选为2份、6份、10份、15份、18份、20份或24份。本发明所述山楂归脾、 胃、肝经，具有消食健胃，行气散瘀的功效。
在本发明中，上述白术和山楂共为君药，共为臣药，起到补脾以滋养心脏，和胃化滞，养肝以荣血的功能。
在本发明中，以质量份计，所述中药组合物优选包括丹参12份、三七20份、白术18份、山楂24份；
或者优选为丹参15份、三七15份、白术15份、山楂15份；
或者优选为丹参18份、三七12份、白术30份、山楂2份；
或者优选为丹参30份、三七18份、白术6份、山楂10份；
或者优选为丹参3份、三七25份、白术21份、山楂20份；
或者优选为丹参25份、三七3份、白术25份、山楂6份；
或者优选为丹参6份、三七6份、白术3份、山楂18份。
失眠是指经常睡眠不好，如上床后难以入睡，睡眠很浅，容易惊醒，是由中枢神经系统兴奋与抑制过程平衡失调所致。本病属于中医学“不寐”、“不得眠”范畴，中医认为心主神明，神不入舍，则不得眠，即心如果得不到充足的供养，心血不足就会出现心慌、气短、睡不着觉；脾主运化，其运化功能失常，输送养分荣养心脏的功能变差，心脏缺乏养分供给，依旧会出现“神不入舍，则不得眠”；“肝藏血，血舍魂”，肝是藏血的，而魂以血为舍，因此可以认为魂归于肝，如果肝血不足，人就会出现魂不守舍、多梦纷纭。本发明以传统中医理论为基础，以丹参、白术、三七和山楂四味中药为原料，各药经科学组方，相互协同，共奏补益心脾，养心安神，疏肝养血，活血化瘀，和胃化滞的功效，可从根本上解决导致失眠的内在病因。
本发明还提供了上述中药组合物的制备方法，包括如下步骤：将丹参、三七和乙醇溶液混合，加热回流提取，得乙醇提取液和丹参-三七药渣；
A、取丹参和三七加入乙醇，加热回流提取，得乙醇提取液；
B、取步骤A乙醇提取后的药渣与白术和山楂加入水，加热提取，得水提取液；
C、将步骤A乙醇提液浓缩至无乙醇味，步骤B水提液浓缩，合并得提取浓缩物；
本发明取丹参和三七加入乙醇，加热回流提取，得乙醇提取液。本发明所述乙醇溶液中乙醇的质量浓度优选为10～90％，进一步优选为50％。本发明所 述丹参和三七的质量和与乙醇溶液的体积比优选为1g:1～10mL，进一步优选为1g:5mL。本发明所述提取的次数优选为1～3次，进一步优选2次。本发明所述加热回流提取的时间优选为1～3h，进一步优选为2h。本发明进行多次加热回流提取时，优选将每次加热回流提取所得提取液合并，得乙醇提取液。
本发明取步骤A乙醇提取后的药渣与白术和山楂加入水，加热提取，得水提取液。本发明所述步骤A乙醇提取后的药渣、白术和山楂的质量和与水的体积比优选为1g:1～15mL，进一步优选为1g:10mL。本发明所述加热提取的次数为1～3次，进一步优选2次。本发明所述加热提取的时间优选为1～3h，进一步优选为2h。本发明进行多次加热提取时，优选将每次加热提取所得提取液合并，得水提取液。
得乙醇提取液和水提取液后，本发明将步骤A乙醇提液浓缩至无乙醇味，步骤B水提液浓缩，合并得提取浓缩物。本发明对步骤A乙醇提液进行浓缩处理时，优选将乙醇提取液浓缩至药材当量为0.6～2:1，进一步优选为0.8:1。本发明对步骤B水提液进行浓缩处理时，优选将水提取液浓缩至药材当量为0.6～2:1，进一步优选为1:1。
得乙醇浓缩液和水浓缩液后，本发明优选将乙醇浓缩液和水浓缩液混合后再次进行浓缩处理，得到的浓缩液即为本发明所述中药组合物。本发明对所述乙醇浓缩液和水浓缩液的混合物进行浓缩处理时，优选将乙醇浓缩液和水浓缩液的混合物浓缩至药材当量为0.8～2:1，进一步优选为1.2:1。
本发明还提供了一种具有改善睡眠作用的药物制剂，由上述中药组合物各原药材或中药组合物各原药材的提取物和药学上可接受的载体组成。本发明所述药物制剂的剂型优选包括煎煮剂、茶剂、口服液、糖浆剂、膏剂、散剂、颗粒剂、胶囊剂、片剂或丸剂。本发明所述药学上可接受的载体优选包括水、乙醇、蔗糖粉、淀粉、微晶纤维素、壳聚糖、甘露醇、山梨醇、木糖醇、三氯蔗糖和糊精中的一种或多种。
本发明还提供了所述药物制剂的制备方法，包括将上述制备方法得到的中药组合物和药学上可接受的载体混合，得药物制剂的步骤。
本发明所述的中药组合物各原药材或中药组合物各原药材的提取物的组合物亦可加入任何其他药用或食用的成分或药材，进行加工处理后和药学上可接受的载体制备成茶剂、口服液、糖浆剂、膏剂、散剂、颗粒剂、胶囊剂、片剂 或丸剂；所述加工处理包括但不限于切制成片、粉碎成粉以及提取并获得提取物。本发明所述中药组合物各原药材的提取物的组合物优选按照上述中药组合物的制备方法制备得到，在此不作赘述。
有益效果：本发明提供的具有改善睡眠作用的中药组合物及其制备方法和现有技术相比具有以下优点：
本发明是根据中医药辨证论治的理论，通过大量实验优选得到最佳组方配比的中药组合物，中药组合物用药严谨，配比科学合理。
配方组成及用量筛选试验结果表明：各组方不完整的组合物与阴性对照组(无菌水)类似，无延长戊巴比妥钠诱导小鼠睡眠时间的效果，本发明的组合物中各成分均为组合物发挥改善睡眠的必须成分；在本发明请求保护的处方范围内，本发明的组合物均具有延长戊巴比妥钠诱导小鼠睡眠时间的效果，且随着处方用量增大，其效果逐渐增强，直至达到相应的阈值(分组8的用量)，达到阈值后继续增大处方用量对提高促进睡眠的效果的作用不明显。
本发明根据各药味的理化性质，通过大量实验筛选出最佳的提取分离方法，提取工艺合理，可操作性强，提取得到的有效成分含量高，杂质少。
本发明提供的中药组合物经药理实验结果表明，可明显改善睡眠，且长期服用，无毒副作用。
改善睡眠功能试验：以本发明中药组合物口服液2.5mL/kg/d、5mL/kg/d、10mL/kg/d三个剂量组给予小鼠一个月，进行直接睡眠实验、延长戊巴比妥钠睡眠时间实验、戊巴比妥钠阈下剂量睡眠实验、巴比妥钠睡眠潜伏期实验。结果表明本发明中药组合物口服液2.5mL/kg/d、5mL/kg/d、10mL/kg/d组对小鼠均无直接睡眠作用。给药各组小鼠的睡眠时间均显著长于0mL/kg/d组，且差异具有统计学意义(P＜0.05)；2.5mL/kg/d、5mL/kg/d、10mL/kg/d组动物睡眠发生率与0mL/kg/d组比较，各组动物睡眠发生率明显增高，其中10mL/kg/d组与0mL/kg/d组比较，动物睡眠发生率增高具有统计学意义。各给药组小鼠的睡眠潜伏期明显短于0mL/kg/d组，且5mL/kg/d组和10mL/kg/d组与0mL/kg/d组比较，差异具有统计学意义(P＜0.05)。根据《保健食品检验与评价技术规范》之改善睡眠功能试验的结果判定，本发明中药组合物具有改善睡眠功能。
急性经口毒性试验以及30天喂养试验：本发明提供的中药组合物雌、雄性小鼠急性经口MTD大于22400mg/kg，根据急性毒性剂量分级标准，本发明中 药组合物属无毒级。
本发明中药组合物以6.0mg/kg/d、12mg/kg/d、20.0mg/kg/d(相当于人体推荐剂量的15倍、30倍、50倍)的剂量给予大鼠30天，受试动物一般情况良好，体重、血液学指标及生化指标结果显示，各项指标均在正常范围。根据卫生部《保健食品检验与评价技术规范》(2003年版)之30天喂养试验，给予动物人体推荐剂量50倍的本发明中药组合物，未观察到有害作用。
本发明还进行了中药组合物改善睡眠人体试食试验，改善睡眠试验结果表明，试食组试食前后自身比较及对照组组间比较，临床症状积分明显减小(P＜0.01)，试食组人群睡眠情况明显改善，且未报告其它副作用，表明本发明中药组合物有改善睡眠的功能。
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。在阅读了本发明之后，本领域技术人员对本发明的各种非实质性的修改均落于本申请所附权利要求所限定的范围。
本发明中药材当量是指单位药材重量与其提取出的浓缩液或浸膏的重量比值，如药材当量为2:1时，表明2重量份的药材经提取后获得1重量份的浓缩液或浸膏。本发明中所述的“份”是指重量份数，其可以被理解为单位质量如克、千克的整数倍，如：1份＝1g；1份＝25g；1份＝300g；1份＝1kg；1份＝12kg；1份＝50kg等。
实施例1
本发明中药组合物茶剂
1、原料重量份数
丹参3g、三七2g、白术3g、山楂1g。
2、制备步骤
(1)取所述重量份的丹参、三七、白术和山楂，切制成2mm的薄片或粉碎成过10目筛的颗粒；
(2)取步骤(1)切制的药材薄片或粉碎的颗粒，加入100mL煮沸的开水，泡20分钟，即得本发明的茶剂(该茶剂可反复冲泡3～5次)。
实施例2
本发明中药组合物散剂
1、原料重量份数
丹参6g、三七6g、白术3g、山楂18g。
2、制备步骤
取所述重量份的丹参、三七、白术和山楂，粉碎成过100目筛的细粉；经分装即得本组合物的散剂。
实施例3
本发明中药组合物口服液
1、原料重量份数
丹参12kg、三七20kg、白术18kg、山楂24kg。
2、制备步骤
(1)取所述丹参和三七，加入160kg的50％乙醇(体积浓度)，加热回流提取2次，每次2小时，合并得醇提取液；
(2)取步骤(1)乙醇提取药渣与白术、山楂一起加入740kg水，加热煎煮提取2次，每次2小时，合并得水提取液；
(3)将醇提液浓缩至无乙醇味，继续浓缩至53kg(药材当量(相对醇提部分)约为0.6:1)，水提液浓缩至123kg(药材当量约为0.6:1)，与醇提浓缩液混合，继续浓缩至92.5kg(药材当量约为0.8:1)。
(4)将木糖醇0.5kg、三氯庶糖0.05kg用纯化水溶解，加入浓缩液中，纯化水定容至150L，调pH至6.0～7.0，4℃冷藏静置24小时，0.45μm微孔滤膜过滤，灌装，即得本发明口服液。
实施例4
本发明中药组合物颗粒剂
1、原料重量份数
丹参1.8kg、三七1.2kg、白术3kg、山楂0.2kg。
2、制备步骤
(1)取上述丹参、三七，加入24kg 60％乙醇，加热回流提取2次，每次1小时，合并得醇提取液；回收乙醇；
(2)取步骤(1)乙醇提取药渣与白术、山楂加入49.6kg水，加热煮沸煎煮提取2次，每次1小时，合并得水提取液；
(3)将醇提液浓缩至2.5kg(药材当量(相对醇提部分)约为1.2:1)，水提液浓缩至5.2kg(药材当量约为1.2:1)，与醇提浓缩液混合，继续浓缩至3.1kg(药 材当量约为2:1)。
(4)将浓缩液加糊精3kg、淀粉3.2kg及适量纯化水，混合制软材，湿法挤出制粒，干燥，整粒，制得颗粒剂约8kg。
实施例5
本发明中药组合物胶囊剂
1、原料重量份数
丹参1.5kg、三七1.5kg、白术1.5kg、山楂1.5kg。
2、制备步骤
(1)取所述重量份的丹参、白术、三七和山楂，粉碎成过100目筛的细粉；加入适量硬脂酸镁混合均匀后，充填成0.3g/粒的胶囊。
实施例6
本发明中药组合物胶囊剂
1、原料重量份数
丹参2100g、三七1500g、白术900g、山楂1800g。
2、制备步骤
(1)取上述丹参、三七，加入36kg的80％乙醇，加热回流提取2次，每次2小时，合并得醇提取液；
(2)取步骤(1)乙醇提取药渣与白术、山楂加入32kg水，加热提取2次，每次2小时，合并得水提取液；
(3)将醇提液浓缩至2400g(药材当量(相对醇提部分)约为1.5:1)，水提液浓缩至5200g(药材当量约为1.2:1)，与醇提浓缩液混合，继续浓缩至3500g(药材当量约为1.8:1)。
(4)取上述浓缩液经喷雾干燥得颗粒1600g，适量硬脂酸镁适量，混合均匀后充填成内容物为0.1g/粒的胶囊。
实施例7
本发明中药组合物片剂
1、原料重量份数
丹参3.0kg、三七1.8kg、白术0.6kg、山楂1.0kg。
2、制备步骤
(1)取上述丹参、三七，加入14.4kg 70％乙醇，加热回流提取3次，每次 1小时，合并得醇提取液；
(2)取步骤(1)乙醇提取药渣与白术、山楂加入38.4kg水，加热提取3次，每次1小时，合并得水提取液；
(3)将醇提液浓缩至2.4kg(药材当量(相对醇提部分)约为2:1)，水提液浓缩至5.3kg(药材当量约为1.2:1)，与醇提浓缩液混合，继续浓缩至3.5kg(药材当量约为1.8:1)。
(4)将浓缩液加微晶纤维素3.5kg、淀粉1.5kg，混合制软材，湿法挤出制粒，干燥，整粒后加入适量硬脂酸镁，混合均匀，压制成0.5g/片的片剂。
实施例8
本发明中药组合物丸剂
1、原料重量份数
丹参1.5kg、三七2.5kg、白术1.2kg、山楂2kg。
2、制备步骤
(1)取上述丹参、三七，粉碎成100目的细粉；
(2)取白术、山楂加入19kg水，加热煎煮提取3次，每次1小时，合并得水提取液，浓缩至1.6kg(药材当量约为2:1)；
(3)将浓缩液加入步骤(1)制备的细粉中，混合均匀制得软材，经制丸机挤出，搓丸，干燥，制得每100丸重5g的中药浓缩丸共计4.5kg。
实施例9
本发明中药组合物丸剂
1、原料重量份数
丹参1.5kg、三七1.5kg、白术1.2kg、山楂1.0kg。
2、制备步骤
(1)取上述丹参、白术、三七和山楂，粉碎成80目的细粉；
(2)取适量步骤(1)的细粉于包衣锅内加入适宜纯化水，起母泛丸，继续加入纯化水和药粉反复滚圆加大制得直径约为4mm的小丸，经抛光、干燥后即得中药水丸。
实施例10
本发明中药组合物糖浆剂
1、原料重量份数
丹参3kg、三七25kg、白术21kg、山楂20kg。
2、制备步骤
(1)取所述丹参、三七，加入156kg 50％乙醇(体积浓度)，加热回流提取2次，每次1.5小时，合并得醇提取液；
(2)取步骤(1)乙醇提取药渣与白术、山楂加入828kg水，加热煎煮提取2次，每次1.5小时，合并得水提取液；
(3)将醇提液浓缩至18.5kg(药材当量(相对醇提部分)约为1.5:1)，水提液浓缩至34.5kg(药材当量约为2:1)，与醇提浓缩液混合，继续浓缩至34.5kg(药材当量约为2:1)，加入单糖浆溶液45.5kg，搅拌混合均匀，即得糖浆剂。
实施例11
本发明中药组合物膏剂
1、原料重量份数
丹参2.5kg、白术2.5kg、三七0.3kg、山楂0.6kg。
2、制备步骤
(1)取上述丹参、三七，加入30kg 60％乙醇，加热回流提取2次，每次2小时，合并得醇提取液；
(2)取步骤(1)乙醇提取药渣与白术、山楂加入75kg水，加热煎煮提取2次，每次1小时，合并得水提取液；
(3)将醇提液浓缩至5kg(药材当量(相对醇提部分)约为1:1)，水提液浓缩至5.9kg(药材当量约为1:1)，与醇提浓缩液混合，继续浓缩至2.5kg(药材当量约为2.5:1)。
(4)取蜂蜜0.5kg炼制成炼蜜后加入步骤(3)中提取液，继续熬至扯拉成旗或滴水成珠时，取出，冷却得膏约2.5kg，分装成100g/罐，即得。
测试例1
本发明中药组合物配方组成及用量筛选试验
为考察不同处方组成及用量的本发明组合物的促进睡眠的效果，确定该组合物有效的处方组成及用量范围，故按表1的处方分别制备组合物进行试验，并以阳性药物地西泮为对照，开展动物试验。
1材料与方法
1.1样品：按下述处方和制备方法制备各组的试验用样品：
表1各组样品处方组成
组别 丹参(份) 三七(份) 白术(份) 山楂(份)
分组1 20 8 15 /
分组2 10 18 / 24
分组3 12 / 24 9
分组4 / 25 12 18
分组5 3 2 3 1
分组6 12 6 25 20
分组7 24 15 9 12
分组8 30 25 30 25
分组9 36 30 36 30
该表中的“1份”＝10g，如：分组1中丹参的用量为10份，故其实际药材用量为100g。
称取上述各分组处方量的丹参、三七，加入2000g 60％乙醇，加热回流提取2次，每次2小时，合并得醇提取液；取乙醇提取药渣与处方量的白术、山楂一起，加入5000g纯化水，加热煎煮提取2次，每次1小时，合并得水提取液；将醇提液减压浓缩除乙醇，并继续浓缩至约500mL，水提液浓缩至约1000mL，合并浓缩后的水提液和醇提液，继续浓缩至500mL，作为各组的给药样品。
1.2实验动物：选用成都达硕实验动物有限公司繁殖的SPF级健康雌性小鼠132只，体重18.0-22.0g，实验动物生产许可证号为SCXK(川)2020-030，合格证号：20200508-03。
小鼠适应环境(温度为20-25℃，相对湿度为40-70％)，检疫4天后按体重随机分为11个组(9个试验药物组，1个阴性对照组和1个阳性对照组)，每组12只。
1.3剂量选择与受试物给予方式：试验药物组均分别灌胃给予制备的样品溶液的稀释液(将其与无菌水按1:9稀释后摇匀)0.15mL/10g体重，阴性对照组灌胃给予0.15mL/10g体重的无菌水；阳性对照组灌胃给予4mg/kg的地西泮水溶液(给药体积为0.15mL/10g体重)。
1.4主要仪器与试剂
1.4.1主要仪器：T1000型电子天平、JA2003型电子天平、电子秒表。
1.4.2主要试剂：戊巴比妥钠、地西泮水溶液、无菌水。
1.5试验方法及结果
参考《保健食品检验与评价技术规范》(2003年版)之改善睡眠功能检验方法进行延长戊巴比妥钠睡眠时间实验，各试验药物组、阴性对照组和阳性对照组动物均分别连续灌胃给药一个月，在末次给药15min后，各组动物按50mg/kg剂量腹腔注射戊巴比妥钠，注射体积为0.1mL/10g，以小鼠翻正消失1min为睡眠指标，观察受试样品能否延长戊巴比妥钠睡眠时间。比较各组间睡眠时间延长的差异，结果见表2：
表2不同处方量组合物对延长戊巴比妥钠诱导小鼠睡眠时间的影响
组别 动物数(只) 睡眠时间(s) P值1 P值2
阴性对照组 12 448.11±43.31 / ＜0.01％
阳性对照组 12 571.96±41.65 ＜0.01％ /
分组1 12 476.11±51.02 0.61 ＜0.01％
分组2 12 483.25±36.28 0.75 ＜0.01％
分组3 12 464.92±25.93 0.44 ＜0.01％
分组4 12 456.34±47.24 0.52 ＜0.01％
分组5 12 529.16±33.29 ＜0.05％ ＜0.01％
分组6 12 566.71±41.48 ＜0.01％ 0.36
分组7 12 589.32±31.11 ＜0.01％ 0.17
分组8 12 629.13±51.01 ＜0.01％ ＜0.05％
分组9 12 633.70±32.84 ＜0.01％ ＜0.05％
对各试验原始数据进行方差齐性检验，满足方差齐要求的数据资料，用单因素方差分析方法中对多个试验组与阴性对照组(P值1)或阳性对照组(P值2)间均数进行两两比较和统计处理(对非正态分布或方差不齐的数据资料进行 适当的变量转换，待满足正态或方差齐要求后，用转换所得的数据进行统计处理)。结果表明：组方不完整的分组1、分组2、分组3和分组4与阴性对照组类似，无延长戊巴比妥钠诱导小鼠睡眠时间的效果；与阴性对照组和阳性对照组相比，分组5具有延长戊巴比妥钠诱导小鼠睡眠时间的效果，且该差异具有统计学意义(P＜0.05)，但其延长时间不及阳性对照组；与阴性对照组和阳性对照组相比，分组6和分组7均具有显著延长戊巴比妥钠诱导小鼠睡眠时间的效果，其延长效果与阳性对照相当；与阴性对照组和阳性对照组相比，分组8和分组9均具有显著延长戊巴比妥钠诱导小鼠睡眠时间的效果，其延长效果优于阳性对照组。上述结果表明该组合物中各成分均为组合物发挥改善睡眠的必须成分；在权利要求中要求保护的处方范围内，本发明的组合物均具有延长戊巴比妥钠诱导小鼠睡眠时间的效果，且随着处方用量增大，其效果逐渐增强，直至达到相应的阈值(分组8的用量)，达到阈值后继续增大处方用量对提高促进睡眠的效果的作用不明显。
测试例2
本发明中药组合物改善睡眠功能试验
1材料与方法
1.1样品：本发明实施例3制备得到的口服液，批号：20200518样品形态为棕黄色液体，置阴凉干燥通风处保存。
1.2实验动物：选用成都达硕实验动物有限公司繁殖的SPF级健康雌性小鼠144只，体重18.0-22.0g，实验动物生产许可证号为SCXK(川)2020-030，合格证号：20200812-01。
小鼠适应环境(温度为20-25℃，相对湿度为40-70％)，检疫4天后按体重随机分为三个大组，其中1组小鼠48只，随机分为4个剂量组，每组12只，先进行直接睡眠实验，次日再进行延长戊巴比妥钠睡眠时间实验；2组小鼠48只，随机分为4个剂量组，每组12只，进行戊巴比妥钠阈下剂量催眠实验；3组小鼠48只，随机分为4个剂量组，每组12只，进行巴比妥钠睡眠潜伏期实验。
1.3剂量选择与受试物给予方式：设2.5mL/kg/d、5mL/kg/d、10mL/kg/d三个剂量组(分别约相当于受试样品人体推荐摄入量的5倍、10倍、20倍)，另设0mL/kg/d组以无菌水代替受试物。受试样品用无菌水配制，低、中、高剂量配 制浓度分别为25％、50％、100％，经口每日一次给予小鼠相应剂量的受试物，小鼠灌胃剂量为0.1mL/10g。
1.4主要仪器与试剂
1.4.1主要仪器：T1000型电子天平、JA2003型电子天平、电子秒表。
1.4.2主要试剂：戊巴比妥钠、巴比妥钠。
1.5试验方法
按照《保健食品检验与评价技术规范》(2003年版)之改善睡眠功能检验方法进行。
1.5.1小鼠直接睡眠实验
各剂量组动物连续灌胃一个月，在末次给药后，以小鼠翻正反射消失1min为进入睡眠，翻正反射恢复即为小鼠觉醒判定标准，记录各组入睡动物数及睡眠时间。
1.5.2延长戊巴比妥钠睡眠时间实验
各剂量组动物连续灌胃一个月，在末次给药15min后，各组动物按50mg/kg剂量腹腔注射戊巴比妥钠，注射体积为0.1mL/10g，以小鼠翻正消失1min为睡眠指标，观察受试样品能否延长戊巴比妥钠睡眠时间。比较对照组与实验组睡眠时间延长之间的差异，睡眠时间延长有显著性，则实验结果阳性。
1.5.3戊巴比妥钠阈下剂量催眠实验
各剂量组动物连续灌胃一个月，在末次给药15min后，各组动物按35mg/kg剂量腹腔注射戊巴比妥钠，注射体积为0.1mL/10g，以小鼠翻正消失1min为睡眠指标，记录给戊巴比妥钠30min内各组入睡动物数。比较对照组与实验组入睡动物数之间的差异，入睡动物发生率增加有显著性，则实验结果阳性。
1.5.4巴比妥钠睡眠潜伏期实验
各剂量组动物连续灌胃一个月，在末次给药15min后，各组动物按250mg/kg剂量腹腔注射巴比妥钠，注射体积为0.1mL/10g，以小鼠翻正消失1min为睡眠指标，观察受试样品对巴比妥钠睡眠潜伏期的影响。比较对照组与实验组睡眠潜伏期之间的差异，睡眠潜伏期缩短有显著性，则实验结果阳性。
1.6试验数据统计：对各试验原始数据进行方差齐性检验，满足方差齐要求的数据资料，用单因素方差分析方法中多个试验组与一个对照组间均数的两两比较方法进行统计处理；对非正态分布或方差不齐的数据资料进行适当的变量 转换，待满足正态或方差齐要求后，用转换所得的数据进行统计处理。
2结果
实验过程中动物饮水摄食正常，外观无异常。
2.1本发明中药组合物口服液对小鼠体重的影响
经口给予小鼠不同剂量的本发明中药组合物口服液之前及给药一个月后对小鼠分别进行称重，计算初始体重和体重增重值，并进行统计分析，结果显示：小鼠的初始体重2.5mL/kg/d、5mL/kg/d、10mL/kg/d组与0mL/kg/d组比较，差异均无显著性(P＞0.05)；给药后各剂量组体重增重经方差齐性检验，满足方差齐性要求，用单因素方差分析方法中多个实验组与一个对照组间均数的两两比较方法进行统计处理。各试验组中2.5mL/kg/d、5mL/kg/d、10mL/kg/d组与0mL/kg/d比较，差异均无统计学意义(P＞0.05)，详见表3。
表3本发明中药组合物口服液对小鼠体重的影响
Figure PCTCN2022071699-appb-000001
Figure PCTCN2022071699-appb-000002
2.2本发明中药组合物口服液对小鼠直接睡眠的影响
经口给予小鼠不同剂量的本发明中药组合物口服液一个月，末次给药后，各组小鼠均未发生直接睡眠现象。由表4可见，本发明中药组合物口服液2.5mL/kg/d、5mL/kg/d、10mL/kg/d组均无使小鼠直接睡眠的作用。
表4本发明中药组合物口服液对小鼠直接睡眠的影响
剂量(mL/kg/d) 动物数(只) 睡眠发生数(只)
0 12 0
2.5 12 0
5 12 0
10 12 0
2.3本发明中药组合物口服液对延长戊巴比妥钠诱导小鼠睡眠时间的影响
经口给予小鼠不同剂量的本发明中药组合物口服液一个月，腹腔注射戊巴比妥钠，观察小鼠的睡眠时间。由表5结果可见，给药各组小鼠的睡眠时间均显著长于0mL/kg/d组，且差异具有统计学意义(P＜0.05)。
表5本发明中药组合物口服液对延长戊巴比妥钠诱导小鼠睡眠时间的影响
剂量(mL/kg/d) 动物数(只) 睡眠时间(s) P值
0 12 534.92±24.1  
2.5 12 629.67±17.24 ＜0.05％
5 12 720.08±38.97 ＜0.05％
10 12 867.75±42.48 ＜0.05％
2.4本发明中药组合物口服液对戊巴比妥钠阈下剂量催眠的影响
经口给予小鼠不同剂量的本发明中药组合物口服液一个月，腹腔注射戊巴比妥钠，观察30min内各组小鼠睡眠发生率。由表6结果可见，2.5mL/kg/d、5mL/kg/d、10mL/kg/d组动物睡眠发生率与0mL/kg/d组比较，各组动物睡眠发生率明显增高，其中10mL/kg/d组与0mL/kg/d组比较，动物睡眠发生率增高具有统计学意义。
表6本发明中药组合物口服液对戊巴比妥钠阈下剂量诱导小鼠睡眠发生率的影响
Figure PCTCN2022071699-appb-000003
2.5本发明中药组合物口服液对巴比妥钠睡眠潜伏期的影响
经口给予小鼠不同剂量的本发明中药组合物口服液一个月，腹腔注射巴比妥钠，观察小鼠的睡眠潜伏期。由表7可见，各给药组小鼠的睡眠潜伏期明显短于0mL/kg/d组，且5mL/kg/d组和10mL/kg/d组与0mL/kg/d组比较，差异具有统计学意义(P＜0.05)。
表7本发明中药组合物口服液对巴比妥钠睡眠潜伏期的影响
剂量(mL/kg/d) 动物数(只) 睡眠潜伏期(s) P值
0 12 1394.92±98.58  
2.5 12 1261.33±210.08 0.06
5 12 1143.5±156.19 ＜0.05
10 12 1030.5±140.6 ＜0.05
根据《保健食品检验与评价技术规范》之改善睡眠功能试验的结果判定，本发明中药组合物具有改善睡眠功能。
测试例3
本发明中药组合物安全性试验
1材料与方法
1.1样品：本发明实施例11所得膏剂，规格：100g/瓶，批号：20200827。样品形态为棕褐稠膏，置阴凉干燥通风处保存，使用时加入适量蒸馏水稀释后使用。
1.2实验动物：清洁级健康成年ICR小鼠，雌雄各半，动物体重为18.0-22.0g，均由成都达硕实验动物有限公司提供，生产许可证号SCXK(川)2020-030，合格证号：20200904-01。清洁级SD成年大鼠，雌雄各半，体重为160～200g，由成 都达硕实验动物有限公司提供，生产许可证号SCXK(川)2020-030，合格证号：20200908-02。实验动物饲养温度为20-25℃，相对湿度为40-70％
1.3主要仪器：T-1000型电子天平，JJ-100型电子天平、JA-2003电子天平、AL104型电子天平、离心机、OLYMPUS显微镜、日立7100型全自动生化分析仪、BAKERSG-603生物安全柜、电热恒温培养箱、SX-700高压灭菌器、KYC-100C型恒温摇床、SIEMENSADVIA2120i血液分析仪。
1.4实验方法
1.4.1小鼠急性毒性试验：用于本品所用药材均为临床验证的安全性良好的中药材，预计该制剂无法测出LD50，从而进行ICR小鼠灌胃最大给药量实验，单次最大给药剂量为0.6mL/20g，一日给药2次，连续观察14天。
1.4.2大鼠30天饲喂试验：取SD大鼠雌雄各48只，分别分成空白组，低剂量组、中剂量组和高剂量组，其中低、中、高剂量动物组分别灌胃给予实施例11中的膏剂6.0mL/kg/d、12mL/kg/d、20.0mL/kg/d(相当于人体推荐剂量的约15倍、30倍、50倍)，空白组给予相同体积的蒸馏水，持续给药30天后，隔夜禁食，逐只称重，眼眶取血检测其血液学指标和血液生化指标。观察①一般行为学表现及死亡情况；②体重；③血液学指标；④血液生化指标。
2结果
2.1小鼠急性毒性试验
试验观察期间，各组动物饮食和活动正常，生长良好，未见任何中毒表现，无死亡。本发明中药组合物膏剂对小鼠体重和死亡数的影响见表8，结果表明本发明中药组合物对雌、雄小鼠经口MTD大于22400mg/kg，根据急性毒性剂量分级标准，该样品属于无毒级。
表8本发明中药组合物膏剂对小鼠急性经口毒性的影响
Figure PCTCN2022071699-appb-000004
2.2大鼠30天长期毒性试验
2.2.1一般行为学表现及死亡情况：本发明中药组合物以6.0mL/kg/d、12mL/kg/d、20.0mL/kg/d(相当于人体推荐剂量的15倍、30倍、50倍)的剂量给予大鼠30天，各组动物一般表现和行为均未见明显异常、无中毒表现、无死亡。
2.2.2本发明中药组合物对大鼠体重的影响：本发明中药组合物以6.0mL/kg/d、12mL/kg/d、20.0mL/kg/d(相当于人体推荐剂量的15倍、30倍、50倍)的剂量给予大鼠30天，各剂量组大鼠体重及第30天后增重与0mg/kg/d组比较，无显著性差异(P＞0.05)，结果见表9。
表9本发明中药组合物对大鼠体重的影响
Figure PCTCN2022071699-appb-000005
2.2.3本发明中药组合物对大鼠血液学指标的影响：经口给予大鼠本发明中药组合物30天，测定各剂量组大鼠血液白细胞计数、红细胞计数、血红蛋白水平及其分类等指标。由表10至表11可见，各项指标各剂量组与0mg/kg/d组比 较，差异均无统计学意义(P＞0.05)。
表10本发明中药组合物口服液对大鼠血液学指标的影响
Figure PCTCN2022071699-appb-000006
表11本发明中药组合物口服液对大鼠血液学指标的影响
Figure PCTCN2022071699-appb-000007
2.2.4本发明中药组合物对大鼠血液生化指标的影响：经口给予大鼠不同剂量的本发明中药组合物30天，测定各剂量组大鼠血清谷丙转氨酶、谷草转氨酶、总蛋白、白蛋白、尿素氮、肌酐、血糖及总胆固醇的水平。由表12和13可见，各项指标各剂量组与0mg/kg/d组比较，差异均无统计学意义(P＞0.05)。
表12本发明中药组合物口服液对大鼠血生化的影响
Figure PCTCN2022071699-appb-000008
表13本发明中药组合物口服液对大鼠血生化的影响
Figure PCTCN2022071699-appb-000009
测试例4
本发明中药组合物改善睡眠人体试食试验1
1试验方法：采用自身和组间两种对照设计，选择160例单纯的长期患有失眠症的患者(临床表现为因入睡困难，或寐而不酣，时寐时醒，或醒后不能 再寐等导致睡眠时间、深度的不足以及不能消除疲劳、恢复体力与精力等。)，年龄22～70岁，依据症状轻重随机分为试食组和对照组，每组80例。试食组男性36例，女性44例，平均年龄为54.55±9.48岁；对照组男性38例，女性42例，平均年龄为53.75±10.22。试食组服用本发明实施例5制备得到的中药组合物胶囊剂(0.3g/粒，批号：20200720)，对照组食用安慰剂，安慰剂外观、色泽、重量、服用方法与本发明实施例5的样品相同。受试者每人每日服2次(早晚各1次)，每次2粒胶囊(约相当于原药材1.2g)，用温开水送服。试验期间正常饮食，不改变原来的饮食习惯，并停用其他治疗失眠的药品及保健食品等，21天后观察患者情况。
症状积分观察：按失眠症状的轻重情况累计积分(重症3分、中度2分、轻度1分、症状消除0分)。两组症状积分在治疗前无显著性差异(P＞0.05)。试食前两组血、尿、便常规及肝肾功能、胸透、心电图、B超等检查均在正常范围。
2结果
试食组试食后与自身及对照组组间比较，临床症状积分明显减小(P＜0.01)，试食组人群睡眠情况明显改善，且未报告其它副作用，表明本发明中药组合物有改善睡眠的功能，结果见表14。
表14试食前后临床症状积分
分组 人数(人) 服用前 服用21天后 P(自身)
试食组 80 1.99±0.54 0.90±0.47**## P＜0.01
对照组 80 1.94±0.49 1.89±0.43 0.64
P(组间)   0.66 P＜0.01  
**与试食前比较，P＜0.01；##组间比较，P＜0.01。
测试例5
本发明中药组合物改善睡眠人体试食试验2
1试验方法：采用自身和组间两种对照设计，选择120例单纯的长期患有失眠症的患者(临床表现为因入睡困难，或寐而不酣，时寐时醒，或醒后不能再寐等导致睡眠时间、深度的不足以及不能消除疲劳、恢复体力与精力等。)，年龄25～74岁，依据症状轻重随机分为试食组和对照组，每组60例。试食组1男性27例，女性33例，平均年龄为50.14±7.61岁；对照组男性26例，女性34例，平均年龄为49.42±6.64。试食组服用本发明实施例6制备得到的中药 组合物胶囊剂(0.1g/粒，批号：20200716)，对照组食用安慰剂，安慰剂外观、色泽、重量、服用方法与本发明实施例6的样品相同。受试者每人每日服2次(早晚各1次)，每次2粒胶囊(约相当于原药材1.6g)，用温开水送服。试验期间正常饮食，不改变原来的饮食习惯，并停用其他治疗失眠的药品及保健食品等，21天后观察患者情况。
症状积分观察：按失眠症状的轻重情况累计积分(重症3分、中度2分、轻度1分、症状消除0分)。两组症状积分在治疗前无显著性差异(P＞0.05)。试食前两组血、尿、便常规及肝肾功能、胸透、心电图、B超等检查均在正常范围。
2结果
试食组试食后与自身及对照组组间比较，临床症状积分明显减小(P＜0.01)，试食组人群睡眠情况明显改善，且未报告其它副作用，表明本发明中药组合物有改善睡眠的功能，结果见表15。
表15试食前后临床症状积分
分组 人数(人) 服用前 服用21天后 P(自身)
试食组 60 1.82±0.43 0.83±0.42**## P＜0.01
对照组 60 1.76±0.39 1.62±0.59 0.71
P(组间)   0.51 P＜0.01  
**与试食前比较，P＜0.01；##组间比较，P＜0.01。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (10)

  1. 一种具有改善睡眠作用的中药组合物，其特征在于，包含下列重量份数的原料药：丹参3～30份、三七2～25份、白术3～30份和山楂1～25份。
  2. 根据权利要求1所述的中药组合物，其特征在于，包含下列重量份数的原料药：丹参6～25份、三七5～20份、白术6～25份和山楂3～20份。
  3. 根据权利要求1所述的中药组合物，其特征在于，包含下列重量份数的原料药：丹参10～20份、三七10～18份、白术10～20份和山楂8～15份。
  4. 权利要求1～3任一项所述的中药组合物的制备方法，其特征在于，包括将丹参、三七、白术和山楂混合后粉碎或粉碎后混合。
  5. 权利要求1～3任一项所述的中药组合物的制备方法，其特征在于，包括以下步骤：
    A、取丹参和三七加入乙醇溶液，加热回流提取，得乙醇提取液；
    B、取所述步骤A提取后的药渣与白术和山楂加入水，加热提取，得水提取液；
    C、将所述步骤A的乙醇提液浓缩至无乙醇味，加入所述步骤B的水提液浓缩，合并得提取浓缩物，所述提取浓缩物为所述中药组合物。
  6. 权利要求5所述的中药组合物的制备方法，其特征在于，对所述步骤A的乙醇提液浓缩时，将步骤A乙醇提液浓缩至药材当量为0.6～2:1；对所述步骤B的水提液浓缩，将步骤B的水提液浓缩至药材当量为0.6～2:1。
  7. 一种具有改善睡眠作用的药物制剂，其特征在于，由权利要求1～3任一项所述的中药组合物和药学上可接受的载体制成。
  8. 根据权利要求7所述的药物制剂，其特征在于，所述药物制剂包括煎煮剂、茶剂、口服液、糖浆剂、膏剂、散剂、颗粒剂、胶囊剂、片剂或丸剂；
    所述药学上可接受的载体包括水、乙醇、蔗糖粉、淀粉、微晶纤维素、壳聚糖、甘露醇、山梨醇、木糖醇、三氯蔗糖和糊精中的一种或多种组合。
  9. 权利要求7或8所述的药物制剂的制备方法，其特征在于，将权利要求4或5所述制备方法制得的中药组合物和药学上可接受的载体制成制剂。
  10. 权利要求1～3任一项所述的中药组合物或权利要求4～6任一项所述的制备方法得到的中药组合物或权利要求7或8所述的药物制剂或权利要求9所述制备方法得到的药物制剂在制备改善睡眠作用的食品、保健品和药品中的应用。
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