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WO2021093087A1 - 一种具有改善认知作用的中药组合物及其制备方法和中药制剂 - Google Patents

一种具有改善认知作用的中药组合物及其制备方法和中药制剂 Download PDF

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WO2021093087A1
WO2021093087A1 PCT/CN2019/126530 CN2019126530W WO2021093087A1 WO 2021093087 A1 WO2021093087 A1 WO 2021093087A1 CN 2019126530 W CN2019126530 W CN 2019126530W WO 2021093087 A1 WO2021093087 A1 WO 2021093087A1
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chinese medicine
traditional chinese
preparation
shichangpu
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PCT/CN2019/126530
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English (en)
French (fr)
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邹圣灿
张曾亮
李鑫
王尚龙
宗磊
宗建成
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美国琛蓝营养制品股份有限公司
青岛琛蓝医药科技发展有限公司
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Publication of WO2021093087A1 publication Critical patent/WO2021093087A1/zh
Priority to US17/693,327 priority Critical patent/US20220226413A1/en

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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)
    • A61K36/69—Polygalaceae (Milkwort family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • 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)
    • A61K36/64—Orobanchaceae (Broom-rape family)
    • 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)
    • A61K36/80—Scrophulariaceae (Figwort family)
    • A61K36/804—Rehmannia
    • 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)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/882—Acoraceae (Calamus family), e.g. sweetflag or Acorus calamus
    • 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)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/888—Araceae (Arum family), e.g. caladium, calla lily or skunk cabbage
    • 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)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/898—Orchidaceae (Orchid family)
    • A61K36/8988—Gastrodia
    • 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)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • 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
    • 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
    • A61K2236/37—Extraction at elevated pressure or temperature, e.g. pressurized solvent extraction [PSE], supercritical carbon dioxide extraction or subcritical water extraction
    • 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
    • A61K2236/53—Liquid-solid separation, e.g. centrifugation, sedimentation or crystallization

Definitions

  • the present invention relates to the technical field of traditional Chinese medicine, in particular to a traditional Chinese medicine composition with cognition-improving effect, a preparation method thereof, and a traditional Chinese medicine preparation.
  • MCI mild cognitive impairment
  • VCI vascular cognitive impairment
  • kidney deficiency Traditional Chinese medicine compounds such as heart-regulating decoction and kidney-tonifying decoction can protect nerves and improve learning and memory.
  • the degeneration of brain cognition is closely related to "kidney deficiency".
  • the source of the essence is lacking, the marrow sea is depleted, and the mental function is deprived, and dementia will gradually develop.
  • the old viscera is weak and weak, physiological or pathological products cannot be eliminated in time, accumulate in the body, produce phlegm and produce blood stasis, phlegm will clear the orifice and/or block the brain collaterals, so that the brain qi is not connected with the organs, and the mental function is ineffective. Dementia occurred.
  • Clinical studies have shown that insufficiency of kidney qi, turbid phlegm and obstruction of phlegm, and cerebral collateral stasis syndromes accounted for 97%, 78%, and 76%, respectively.
  • the publication number is CN1973887A.
  • the invention patent discloses a pharmaceutical composition, which is made from a certain proportion of gastrodia elata, ground dragon, calamus, polygala, rehmannia glutinosa, cistanche, etc. as raw materials, which can be used to improve memory.
  • the prescription to extract the effective ingredients is not complete, and other public technologies rarely include the volatile oil and mix it with the Chinese medicine extract.
  • the present invention provides a Chinese medicinal composition with cognition improvement effect, a preparation method thereof, and a Chinese medicinal preparation.
  • the traditional Chinese medicine composition has the effect of obviously improving cognition.
  • the present invention provides a traditional Chinese medicine composition with cognition improvement.
  • the traditional Chinese medicine composition is made from the following raw materials in parts by weight: 1-20 parts of Gastrodia, 1-15 parts of Polygala, 1-30 parts of Shichangpu, 0.1-10 parts of Cistanche, 0.1-10 parts of Rehmannia glutinosa, 0.01-1 part of curcumin.
  • Gastrodia "Chinese Pharmacopoeia” records that Gastrodia is sweet, mild in nature, enters the liver meridian, has the effect of calming the liver, extinguishing wind and relieving convulsions, and mainly treats headache, dizziness, limb numbness, convulsions in children, epilepsy, hypertension and otogenic vertigo .
  • the main component of Gastrodia is gastrodin, with a content of 0.33% to 0.67%.
  • a large number of studies have been conducted on the pharmacological effects of Gastrodia and its components, and new progress has been made in the treatment of various diseases mainly based on the nervous system.
  • Gastrodia has the effects of brain protection, improvement of cerebral circulation, anti-convulsions, anti-vertigo, anti-anxiety, analgesia, nourishment, delaying aging and so on. Clinically, it is mostly used as an auxiliary drug for vertebrobasilar artery insufficiency, neuropsychiatric symptoms, vascular dementia and epilepsy.
  • Polygala has the activities of removing phlegm and relieving cough, improving the mind and soothe the nerves, anti-aging, relaxing smooth muscle, anti-mutagenic, anti-cancer, immunological activity, antibacterial, sedative and hypnotic, anti-convulsive, anti-depressive and other activities.
  • the treatment of Alzheimer's disease (AD) is mainly through: improving the function of the cholinergic system; anti-oxidation, scavenging free radicals; protecting neurons; anti-anxiety and inhibiting the central nervous system.
  • Polygala saponins have the effects of enhancing learning ability, antioxidant, antibacterial, anti-inflammatory, soothing, antitussive and expectorant, and lowering blood pressure.
  • Polygala oligosaccharide ester compounds have the activities of neuroprotection, promotion of neuron growth, anti-dementia, anti-depression, improvement of learning and memory, sedation and hypnosis, anti-oxidation, anti-inflammatory and other activities.
  • Acorus calamus different chemical components have good medicinal effects in the central nervous system, cardio-cerebrovascular system, and digestive system. It has anticonvulsant, antidepressant, sedative and hypnotic, antitussive and antiasthmatic effects. It is clinically used in the treatment of epilepsy, forgetfulness, aphasia caused by stroke, tinnitus, senile dementia and other diseases. Volatile oil has excitatory and inhibitory two-way regulating effects on the central nervous system, protects nerve cells, has nootropic and brain protective effects; has anti-arrhythmic, anti-thrombotic, and protective effects on cardiomyocytes and blood vessels in the cardiovascular system.
  • Cistanche cistanche contains total phenethyl alcohol glycosides, which have various functions such as aphrodisiac, anti-oxidation, anti-aging, memory enhancement, etc., protective effect against myocardial ischemia, and protective effect against cerebral ischemia reperfusion injury.
  • Cistanche carbohydrates have pharmacological effects in immunoregulation, anti-aging, improving spleen deficiency, anti-virus, anti-tumor, and promoting hematopoiesis.
  • Rehmannia glutinosa and its polysaccharides of Rehmannia glutinosa can enhance the body’s hematopoiesis, enhance the body’s immunity, anti-oxidation, anti-mutation, central inhibitory effect, anti-tumor activity, and strengthen the cardiovascular system, reduce blood pressure, protect myocardium, and inhibit Thrombosis and lowering blood lipids.
  • Curcumin treatment can reduce nerve damage, reduce brain water content, and reduce the expression level of MMP-9. It can restore the decreased AKT and p-AKT cells in the hippocampal CA1 region of the Alzheimer’s disease (AD) model APP/PS1 double transgenic mice, suggesting that curcumin may regulate AKT and its phosphorylation process, thereby further Regulate the insulin signal transduction pathway of the PI3K/AKT pathway, thereby exerting an anti-AD effect.
  • AD Alzheimer’s disease
  • Curcumin treatment can reduce the expression of COX-2 and 5-lipoxygenase (5-LOX) mRNA and protein in hippocampal neurons of rats with epilepsy induced by pilocarpine, possibly by affecting the arachidonic acid metabolic pathway COX-2 and 5 -LOX expression, to reduce the brain damage of epileptic seizures and play a neuroprotective effect.
  • 5-LOX 5-lipoxygenase
  • the gastrodia elata used in the compound prescription of the present invention has the effect of dredging collaterals
  • Polygala and Shichangpu have the effect of resuscitation
  • Cistanche and Shudihuang have the effect of invigorating the kidney, improving brain cognition from three aspects.
  • Curcumin in turmeric is recognized as one of the ingredients for improving brain cognition and improving Alzheimer's disease.
  • the compound traditional Chinese medicine formed by the combination of the above drugs has been proved by pharmacological experiments to improve brain cognition.
  • the prescription is extracted by a compound extraction method, and the effective substances of Gastrodia, Polygala, Acorus, Cistanche, and Rehmannia glutinosa are extracted as completely as possible and concentrated and dried; the volatile oil of Acorus calamus and curcumin are packaged and dried by the volatile oil inclusion technology, and the traditional Chinese medicine compound is extracted.
  • the dry powder and the volatile oil inclusion compound are evenly mixed to form the final traditional Chinese medicine composition.
  • the traditional Chinese medicine composition is made of the following raw materials: 16-20 parts of Gastrodia, 10-14 parts of Polygala, 16-20 parts of Shichangpu, 5-7 parts of Cistanche, 5-7 parts of Rehmannia glutinosa, Curcumin 0.05 ⁇ 0.15 parts.
  • the traditional Chinese medicine composition is made of the following raw materials: 18 parts of Gastrodia, 12 parts of Polygala, 18 parts of Shichangpu, 6 parts of Cistanche, 6 parts of Rehmannia glutinosa, and 0.1 part of curcumin.
  • the present invention also provides a preparation method of the traditional Chinese medicine composition, which includes the following steps:
  • Alcohol extraction Gastrodia, Polygala and ethanol aqueous solution are heated to reflux, and alcohol extraction liquid and alcohol extraction residue are collected;
  • Water extraction add water and heat reflux for Shichangpu, collect Shichangpu medicinal solution, Shichangpu medicinal residue and Shichangpu volatile oil; Cistanche, Rehmannia glutinosa, alcohol extract medicinal residue, Shichangpu medicinal residue, add water and heat to reflux, and collect water extract liquid;
  • Filtration and concentration Mix the alcohol extraction liquid, Shichangpu liquid and water extraction liquid, and filter and concentrate to obtain the extract;
  • Mixing Mix the extract and pellets.
  • the volume percentage concentration of the ethanol aqueous solution is 50% to 80%.
  • the volume percentage concentration of the ethanol aqueous solution is 70%.
  • the amount of the ethanol aqueous solution is 8-20 times the total weight of Gastrodia and Polygala; the number of heating and refluxing is 1 to 5 times, and each time is 0.5 to 3 hours.
  • the amount of the ethanol aqueous solution is 10 times the total weight of Gastrodia and Polygala; the number of heating and refluxing is 3 times, each time is 1 hour.
  • Shichangpu is heated and refluxed with 8-30 times the weight of water, the number of heating and refluxing is 1 to 3 times, each time is 3 to 5 hours, and Shichangpu medicinal solution, Shichangpu medicinal residue and stone are collected.
  • Volatile oil of Acorus calamus; Cistanche cistanche, Rehmannia glutinosa, the alcohol-extracted medicinal residue, the Acorus calamus medicinal residue plus water 8-30 times the total weight of the medicinal materials are heated to reflux, the number of heating reflux is 1 to 5 times, each time is 0.5 to 3 hours , Collect the water extract liquid.
  • the Shichangpu is heated to reflux with 14 times the weight of water, and the number of heating and refluxing is once, each time is 5 hours.
  • the cistanche, radix rehmanniae, the alcohol-extracted medicinal residue, the calamus medicinal residue plus the water 10 times the total weight of the medicinal materials are heated and refluxed, and the number of heating and refluxing is 2 Times, 1.5 hours each time.
  • the weight ratio of the mixture of calamus calamus volatile oil and curcumin to ⁇ -cyclodextrin is 1: (1-5); the grinding time during inclusion is 1 to 4 hours, and the drying temperature is 40 ⁇ 60°C.
  • the weight ratio of the mixture of Acorus calamus volatile oil and curcumin to ⁇ -cyclodextrin is 1:1.5; the grinding time during inclusion is 2 hours, and the drying temperature It is 45°C.
  • the invention also provides a traditional Chinese medicine preparation, which consists of the traditional Chinese medicine composition of the invention and pharmaceutically acceptable auxiliary materials.
  • the dosage form of the traditional Chinese medicine preparation is capsule, tablet or granule.
  • the invention provides a Chinese medicinal composition with cognition improvement effect, a preparation method thereof and a Chinese medicinal preparation.
  • the traditional Chinese medicine composition is made of the following raw materials: 1-20 parts of Gastrodia, 1-15 parts Polygala, 1-30 parts Shichangpu, 0.1-10 parts Cistanche, 0.1-10 parts Rehmannia glutinosa, and 0.01 parts curcumin. ⁇ 1 serving.
  • the technical effects of the present invention are:
  • the gastrodia elata used in the compound prescription of the present invention has the effect of dredging collaterals
  • Polygala and Shichangpu have the effect of resuscitation
  • Cistanche and Shudihuang have the effect of invigorating the kidney, improving brain cognition from three aspects.
  • Curcumin in turmeric is recognized as one of the ingredients for improving brain cognition and improving Alzheimer's disease.
  • the compound traditional Chinese medicine formed by the combination of the above drugs has been proved by pharmacological experiments to improve brain cognition.
  • the present invention uses a compound extraction method to extract the prescription.
  • the effective substances of Gastrodia, Polygala, Acorus, Cistanche and Rehmannia glutinosa are extracted as completely as possible and concentrated and dried; the volatile oil of Acorus calamus and curcumin are packaged and dried by using the volatile oil inclusion technology.
  • the dry powder of the compound extract and the volatile oil inclusion compound are uniformly mixed to form the final traditional Chinese medicine composition.
  • the traditional Chinese medicine extract composition of the present invention has been explored through two processes to obtain a preparation method of the composition, and verified by pharmacodynamic experiments, the composition has an obvious cognitive improvement effect.
  • the invention discloses a traditional Chinese medicine composition with cognition-improving effect, a preparation method thereof, and a traditional Chinese medicine preparation.
  • Those skilled in the art can learn from the content of this article and appropriately improve the process parameters to achieve.
  • all similar replacements and modifications are obvious to those skilled in the art, and they are all deemed to be included in the present invention.
  • the method and application of the present invention have been described through the preferred embodiments. It is obvious that relevant persons can make changes or appropriate changes and combinations to the methods and applications described herein without departing from the content, spirit and scope of the present invention to achieve and Apply the technology of the present invention.
  • the traditional Chinese medicine composition with the function of improving cognition provided by the present invention, the preparation method thereof, and the raw materials or auxiliary materials used in the traditional Chinese medicine preparation can all be purchased from the market.
  • Example 1 Chinese medicine composition and preparation method thereof
  • Gastrodia 180g Polygala 120g, Acorus calamus 180g, Cistanche cistanche 60g, Rehmannia glutinosa 60g, and curcumin 1g.
  • the preparation method is:
  • step (2) the volatile oil is mixed with curcumin, and then encapsulated by cyclodextrin to synthesize pellets.
  • the weight ratio of the mixture of volatile oil and curcumin to ⁇ -cyclodextrin is 1:1.5, the grinding time is 2 hours, and the drying temperature is 45°C.
  • step (6) Mix the extract of step (4) with the pellets of step (5) to obtain.
  • Gastrodia 180g Polygala 120g, Acorus calamus 180g, Cistanche cistanche 60g, Rehmannia glutinosa 60g, and curcumin 1g.
  • the preparation method is:
  • step (3) Filtering and concentrating all the liquid medicine obtained in step (2) to obtain an extract
  • step (2) Mix the extract in step (2) with step (1) and curcumin to obtain.
  • Gastrodia 180g Polygala 120g, Acorus calamus 180g, Cistanche cistanche 60g, Rehmannia glutinosa 60g, and curcumin 1g.
  • the preparation method is:
  • Gastrodia 300g Earthworm 200g, Shichangpu 300g, Polygala 200g, Rehmannia glutinosa 100g, Cistanche cistanche 100g.
  • the preparation method is:
  • the extract is obtained by filtering and concentrating all the liquid medicine obtained in step (1).
  • Example 1 group Example 1 group, comparative example 1 group, comparative example 2 group, and comparative example 3 group; positive drug: Huperzine A.
  • mice On the first day, the mice are first placed in the test room for 1 hour of environmental adaptation and familiarization, and then placed in the open field box for 20 minutes (no objects in the box) to eliminate the open field box to the subject The influence of mice. After each mouse experiment, the open field box was cleaned with 75% ethanol.
  • Familiarization period On the second day (after the adaptation period is 24h), the mice are first placed in the test room for 1h environmental adaptation and familiarization, and then two yellow colors of the same size and texture are placed on the left and right ends of the same side in the open field box Cylindrical bottle as a familiar object, then put the mouse back to the object into the box, and record the mouse's exploration of the object within 5 minutes (timing standard: the time when the mouse’s nose or mouth is within 2cm of the object Walking on the object or just around the object is not counted). After each mouse experiment, the open field box was cleaned with 75% ethanol.
  • Test period After 2 hours of the familiarization period, first randomly replace a yellow cylindrical bottle in the open field box with a green Erlenmeyer flask of the same size as an unfamiliar object, and then put the mouse back to the object into the box, and record the small amount within 5 minutes
  • the time of the mouse's exploration of strange objects The Total Exploration Time of Novel Object, Tn
  • the exploration time of familiar objects The Total Exploration Time of Familiar Object, Tf).
  • Calculate the recognition index (Recognition Index): RI Tn/(Tn+Tf).
  • the open field box was cleaned with 75% ethanol.
  • Group Dose (crude drug) Number of animals/only Recognition index Control group - 17 0.5715 ⁇ 0.06626 Model group - 17 0.4180 ⁇ 0.02726* Positive drug group 0.67 piece/kg 17 0.5341 ⁇ 0.04280#
  • Example 1 group 1.002g/kg 17 0.5322 ⁇ 0.04504# Comparative example 1 group 1.002g/kg 17 0.5081 ⁇ 0.05318 Comparative example 2 groups 1.002g/kg 17 0.5269 ⁇ 0.04310# Comparative example 3 groups 1.200g/kg 17 0.5050 ⁇ 0.03855#
  • the novel object recognition experiment is a fine and sensitive behavioral method that uses the animal's natural instinct to approach and explore novel objects to detect animal recognition and memory. It can be seen from the statistical data that the recognition index of the model group was significantly lower than that of the normal control group, while the recognition index of the positive drug group, Example 1 group, comparative example 2 group, and comparative example 3 group, after intragastric administration, was significantly increased. It shows that the declarative memory ability of the model group mice is decreased, and the model is successfully established.
  • the positive drugs, the positive drug group, the example 1 group, the comparative example 2 group, and the comparative example 3 group can improve the declarative memory of the stressed mice. ability.
  • the recognition index is the highest in Example 1, and is closest to the control group.
  • Test method The grouping, sample preparation, and model processing methods for mice jumping from the platform are the same as above.
  • the platform was trained for 3 minutes, and then it was energized for 300 seconds.
  • the test was carried out 24 hours later, the drug was administered 1 hour before the test, and scopolamine hydrobromide and physiological saline were injected intraperitoneally 15-20 minutes before the test.
  • the mice were then placed on the platform, and the latency of the first jump off the platform and the number of errors (falling off the platform) within 300s were recorded. If the mouse does not jump off the platform within 300s, the number of errors is recorded as 0, and the incubation period is recorded as 300s.
  • the incubation period of the model group was significantly shorter than that of the control group, and the number of errors increased significantly, and the model was successfully established.
  • the incubation period of the positive drug, the example 1, the comparative example 1, and the comparative example 2 The model group was significantly extended.
  • the number of errors in the positive drug and Example 1 group was significantly less than that in the model group. It indicates that the memory ability of the mice in the model group is impaired in the platform jumping experiment, and the positive drugs and the Example 1 group can improve the memory function defect in the platform jumping experiment after the administration of the positive drugs and the example 1 group.
  • the above studies show that the drug combination of the present invention can improve the spatial memory deficit of mice to a certain extent, and can significantly improve the memory ability of mice in the jumping-off experiment.
  • the test procedure includes two parts: directional navigation and space exploration. A total of 5 days of continuous testing. The first part is the positioning and navigation experiment to test mice for 4 days, and the second part is the space exploration experiment, which is tested for 1 day. Rinse the black vegetarian toner with warm water to hide the platform, and keep it in sharp contrast with the color of the mouse when filming, which is easy to track.
  • the platform is located 0.8cm below the water surface, the water depth is 21cm high, and is positioned in the NW quadrant.
  • the water temperature in the water maze is maintained at a constant temperature of 22-24°C with a heating rod.
  • each mouse trains 4 times/d, and the time interval between each training is 15-20min. Each time during the test, the water entry point was selected in a semi-random manner. The experimenter held the mouse with his hand to face the pool wall and gently put it into the water. In each training, the mice can find the platform within 60 seconds, and the time spent on the platform for more than 2 seconds is used as a sign of successful search, and the time taken by the mouse from entering the water to successfully searching is recorded as the incubation period. If the mouse cannot find the platform within 60s, the experimenter will guide it to the platform by hand, and the incubation period is recorded as 60s.
  • mice board the platform let them stay on the platform for 10s to allow them to learn and remember spatially according to the reference objects in the 4 quadrants, and to reduce the tension of the mice. Calculate the average daily incubation period to evaluate the ability of animals to acquire spatial memory.
  • Space exploration experiment Remove the platform and test each mouse once for 60 seconds. Select the SE quadrant and place the mouse into the water facing the edge of the pool wall. The number of times the animal passes through the original platform position within 60s, the travel ratio and time ratio of the original platform quadrant (that is, the travel and time of the animal’s original platform quadrant account for the total travel and total Time ratio) to evaluate the animal’s spatial memory ability.
  • Comparative example 1 group 1.002g/kg 17 2531 ⁇ 208.0
  • Comparative example 2 groups 1.002g/kg 17 2413 ⁇ 178.2
  • Comparative example 3 groups 1.200g/kg 17 2539 ⁇ 175.9
  • the number of crossing platforms in the model group was significantly reduced compared with the control group, and the number of times to be tested drug intervention increased; the target quadrant run-length ratio and time were significantly increased compared with the model group. It is suggested that the drug to be tested can improve the spatial memory deficit of mice to a certain extent.
  • the evasion latency period of the model group was significantly longer than that of the control group, suggesting that the mice in the model group have a memory deficit.
  • the escape latency period of the model group was significantly longer than that of the control group, and the target quadrant stay time and the number of times of crossing the platform were significantly reduced in the model group compared with the control group.
  • the escape latency of the Example 1 group and the comparative example 3 group was significantly shorter than that of the model group, and the number of crossing platforms was significantly increased compared with the model group, suggesting that the positive drugs, the example 1 group, and the comparative example 3 groups can improve the spatial memory retrieval ability of mice after administration.
  • the comparative example 1 group and the comparative example 2 group can improve the space extraction ability defect of mice to varying degrees.

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Abstract

一种具有改善认知作用的中药组合物及其制备方法和中药制剂。以重量份计，该中药组合物由如下原料制成：天麻1～20份，远志1～15份，石菖蒲1～30份，肉苁蓉0.1～10份，熟地黄0.1～10份，姜黄素0.01～1份。采用复合提取方法对处方进行提取，将天麻、远志、石菖蒲、肉苁蓉、熟地黄药效物质尽可能提取完全并浓缩干燥；采用挥发油包合技术对石菖蒲挥发油以及姜黄素进行包合并干燥，中药复方提取物干粉与挥发油包合物混合均匀即最终中药组合物。复方中药经药理实验证明具有改善大脑认知作用。

Description

一种具有改善认知作用的中药组合物及其制备方法和中药制剂
本申请要求于2019年11月14日提交中国专利局、申请号为201911113149.X、发明名称为“一种具有改善认知作用的中药组合物及其制备方法和中药制剂”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
本发明涉及中药技术领域，特别涉及一种具有改善认知作用的中药组合物及其制备方法和中药制剂。
背景技术
随着世界老龄化趋势逐年增加，作为正常老龄化向痴呆过渡状态的轻度认知功能障碍(mild cognitive impaiment,MCI)、血管性认知功能障碍(Vascular cognitive impairment,VCI)越来越受到人们的关注。在发达国家，老年痴呆的死亡率仅次于心脏病、肿瘤、中风位居第四。随着世界人口日趋老龄化，该病已经成为当前老年医学面临的最严峻的问题之一。而老年痴呆的前期轻度的认知障碍被公认为是一种高度流行和可以预防的综合征。目前，针对老年痴呆患者还没有特效治疗方法。美国FDA批准的药物可短期改善痴呆症状但不能减缓病情发展。积极开展对MCI、VCI的研究和防治工作，对提高患者的生存质量有着重要的意义。
对轻度认知功能障碍积极进行干预是延缓认知功能进一步衰退的有效措施，但目前关于轻度认知功能障碍干预措施的报道较少，药物也仅有个别的多中心研究报道。因此，就目前国内外对轻度认知功能障碍的治疗现状及进展进行系统性研究。由于最多见的轻度认知功能障碍亚型是遗忘型认知功能障碍即阿尔茨海默病的前期，故而关于轻度认知功能障碍的干预策略多沿袭了阿尔茨海默病的治疗方案。
中药复方如调心方、补肾方等具有保护神经，提高学习记忆作用。脑认知作用退化与“肾虚”密切相关，肾亏之年、精髓乏源，髓海失养，神机失用，则渐发痴呆。同时年老脏腑虚衰，生理或病理产物不能及时排除，蓄积体内，生痰生瘀，痰蒙清窍和/或淤阻脑络，使脑气与脏器不相连接，神机失用，便发痴呆。临床研究表明，脑认知功能降低中的肾气不足、痰 浊蒙窍和脑络淤阻症候分别占97％、78％、76％。
公开号为CN1973887A发明专利公开了一种药物组合物，其由一定比例的天麻、地龙、石菖蒲、远志、熟地黄、肉苁蓉等为原料药制成的，可用于改善记忆力。但该处方提取药效成分不够完全，其它公开技术也少有将挥发油包合后与中药提取物共同混合。针对上述问题，需要提供一种将药效成分充分提取并保留的中药制剂及其制备方法。
发明内容
有鉴于此，本发明提供了一种具有改善认知作用的中药组合物及其制备方法和中药制剂。该中药组合物具有明显改善认知的作用。
为了实现上述发明目的，本发明提供以下技术方案：
本发明提供了一种具有改善认知作用的中药组合物，以重量份计，该中药组合物由如下原料制成：天麻1～20份，远志1～15份，石菖蒲1～30份，肉苁蓉0.1～10份，熟地黄0.1～10份，姜黄素0.01～1份。
天麻，《中国药典》记载天麻味甘、性微温，入肝经，具有平肝熄风镇惊的功效，主治头痛晕眩、肢体麻木、小儿惊风、癫痫、高血压和耳源性眩晕等。天麻的主要成分为天麻素，含量为0.33％～0.67％。近年来对天麻及其成分的药理作用进行了大量研究，在治疗以神经系统为主的多种疾病方面取得了新的进展。天麻具有脑保护作用、改善脑循环、抗惊厥、抗眩晕、抗焦虑、镇痛、益智，延缓衰老等作用。临床多用于椎基底动脉供血不足，神经精神症状，血管性痴呆以及癫痫的辅助用药。
远志，具有去痰止咳、益智安神、抗衰老、舒张平滑肌、抗诱变、抗癌、免疫活性、抑菌、镇静催眠、抗惊厥、抗抑郁等活性。对阿尔兹海默病(AD)的治疗主要通过：改善胆碱能系统功能；抗氧化、清除自由基；保护神经元；抗焦虑及抑制中枢神经等。远志皂苷具有增强学习能力、抗氧化、抑菌、抗炎、安神、镇咳祛痰、降血压作用。远志寡糖酯类化合物具有神经保护、促进神经元增值、抗痴呆、抗抑郁、改善学习记忆、镇静催眠、抗氧化、抗炎等活性。
石菖蒲，不同化学成分在中枢神经系统及心脑血管系统、消化系统有良好药效，有抗惊厥、抗抑郁、镇静催眠、镇咳平喘、抗肿瘤的作用。临 床上应用于癫痫、健忘、中风导致失语、耳鸣、老年性痴呆等疾病的治疗。挥发油对中枢神经系统具有兴奋、抑制双向调节作用，对神经细胞有保护，具有益智、脑保护作用；对心血管系统具有抗心律失常、抗血栓、保护心肌细胞及血管作用。
肉苁蓉，含有苯乙醇总苷，其具有壮阳、抗氧化、抗衰老、增强记忆力等多种功能、心肌缺血的保护作用、对脑缺血再灌注损伤的保护作用。肉苁蓉糖类具有免疫调节、抗衰老、改善脾虚、抗病毒抗肿瘤、促进造血等方面的药理作用。
熟地黄，其地黄多糖具有增强机体造血、增强机体的免疫力、抗氧化作用、抗突变作用、中枢抑制作用、具有抗肿瘤活性，并对心血管系统有强心、降压、保护心肌、抑制血栓形成和降血脂等作用。
姜黄素，治疗能够减轻神经功能损伤，降低脑组织含水量，并降低MMP-9表达水平。可以使阿尔茨海默氏病(AD)模型APP/PS1双转基因小鼠海马CA1区中减少的AKT和p-AKT细胞有所恢复，提示姜黄素可能通过调节AKT及其磷酸化过程，从而进一步调节PI3K/AKT途径的胰岛素信号转导通路，从而发挥抗AD作用。姜黄素治疗可降低匹罗卡品致痫大鼠海马神经元COX-2和5-脂氧合酶(5-LOX)mRNA及蛋白表达，可能通过影响花生四烯酸代谢通路COX-2和5-LOX表达，来减轻癫痫发作脑损伤，发挥神经保护作用。
本发明复方所用天麻具有通络作用，远志、石菖蒲具有开窍作用，肉苁蓉、熟地黄具有补肾作用，从三方面改善脑认知。姜黄中姜黄素是公认的改善脑认知、改善阿尔兹海默病的成分之一。以上药物组合形成的复方中药经药理实验证明具有改善大脑认知作用。
采用复合提取方法对处方进行提取，将天麻、远志、石菖蒲、肉苁蓉、熟地黄药效物质尽可能提取完全并浓缩干燥；采用挥发油包合技术对石菖蒲挥发油及姜黄素进行包合并干燥，中药复方提取物干粉与挥发油包合物混合均匀即最终中药组合物。
作为优选，以重量份计，该中药组合物由如下原料制成：天麻16～20份，远志10～14份，石菖蒲16～20份，肉苁蓉5～7份，熟地黄5～7份， 姜黄素0.05～0.15份。
优选地，以重量份计，该中药组合物由如下原料制成：天麻18份，远志12份，石菖蒲18份，肉苁蓉6份，熟地黄6份，姜黄素0.1份。
本发明还提供了该中药组合物的制备方法，包括如下步骤：
醇提：天麻、远志加乙醇水溶液加热回流，收集醇提药液、醇提药渣；
水提：石菖蒲加水加热回流，收集石菖蒲药液、石菖蒲药渣以及石菖蒲挥发油；肉苁蓉、熟地黄、醇提药渣、石菖蒲药渣加水加热回流，收集水提药液；
过滤浓缩：将醇提药液、石菖蒲药液、水提药液混合，过滤浓缩得浸膏；
包合：将石菖蒲挥发油和姜黄素混合，经环糊精包合得微丸；
混合：将浸膏与微丸混合。
作为优选，醇提步骤中，乙醇水溶液的体积百分浓度为50％～80％。
在本发明提供的具体实施例中，醇提步骤中，乙醇水溶液的体积百分浓度为70％。
作为优选，醇提步骤中，乙醇水溶液的用量为天麻、远志总重量的8～20倍；加热回流的次数为1～5次，每次0.5～3小时。
在本发明提供的具体实施例中，醇提步骤中，乙醇水溶液的用量为天麻、远志总重量的10倍；加热回流的次数为3次，每次1小时。
作为优选，水提步骤中，石菖蒲加8～30倍重量的水加热回流，加热回流的次数为1～3次，每次3～5小时，收集石菖蒲药液、石菖蒲药渣以及石菖蒲挥发油；肉苁蓉、熟地黄、所述醇提药渣、所述石菖蒲药渣加药材总重8～30倍的水加热回流，加热回流的次数为1～5次，每次0.5～3小时，收集水提药液。
在本发明提供的具体实施例中，石菖蒲加14倍重量的水加热回流，加热回流的次数为1次，每次5小时。
在本发明提供的具体实施例中，水提步骤中，肉苁蓉、熟地黄、所述醇提药渣、所述石菖蒲药渣加药材总重10倍的水加热回流，加热回流的次数为2次，每次1.5小时。
作为优选，包合步骤中，石菖蒲挥发油和姜黄素的混合物与β-环糊精的重量比为1：(1～5)；包合时的研磨时间为1～4小时，烘干温度为40～60℃。
在本发明提供的具体实施例中，包合步骤中，石菖蒲挥发油和姜黄素的混合物与β-环糊精的重量比为1：1.5；包合时的研磨时间为2小时，烘干温度为45℃。
本发明还提供了一种中药制剂，中药制剂由本发明中药组合物和药学上可接受的辅料组成。
作为优选，中药制剂的剂型为胶囊剂、片剂或颗粒剂。
本发明提供了一种具有改善认知作用的中药组合物及其制备方法和中药制剂。以重量份计，该中药组合物由如下原料制成：天麻1～20份，远志1～15份，石菖蒲1～30份，肉苁蓉0.1～10份，熟地黄0.1～10份，姜黄素0.01～1份。本发明具有的技术效果为：
本发明复方所用天麻具有通络作用，远志、石菖蒲具有开窍作用，肉苁蓉、熟地黄具有补肾作用，从三方面改善脑认知。姜黄中姜黄素是公认的改善脑认知、改善阿尔兹海默病的成分之一。以上药物组合形成的复方中药经药理实验证明具有改善大脑认知作用。
本发明采用复合提取方法对处方进行提取，将天麻、远志、石菖蒲、肉苁蓉、熟地黄药效物质尽可能提取完全并浓缩干燥；采用挥发油包合技术对石菖蒲挥发油以及姜黄素进行包合并干燥，中药复方提取物干粉与挥发油包合物混合均匀即最终中药组合物。本发明中药提取组合物，经两种工艺进行探索得组合物制备方法，经药效学实验验证，该组合物具有明显改善认知作用。
具体实施方式
本发明公开了一种具有改善认知作用的中药组合物及其制备方法和中药制剂，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内 对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。
本发明提供的具有改善认知作用的中药组合物及其制备方法和中药制剂中所用原料或辅料均可由市场购得。
下面结合实施例，进一步阐述本发明：
实施例1 中药组合物及其制备方法
1、本实施例配方为：
天麻180g，远志120g，石菖蒲180g，肉苁蓉60g，熟地黄60g，姜黄素1g。
2、制备方法为：
(1)将天麻、远志加10倍量70％乙醇加热回流3次，每次1小时，分别收集药液、药渣；
(2)将石菖蒲加14倍量水加热回流1次，5小时，分别收集药液，药渣以及挥发油；
(3)将肉苁蓉、熟地黄以及步骤(1)、(2)收集的中药渣加10倍量水加热回流2次，每次1.5小时，分别收集药液；
(4)将步骤(1)、(2)、(3)中所得全部药液过滤浓缩得浸膏；
(5)步骤(2)中挥发油与姜黄素混合，经环糊精包合成微丸。挥发油和姜黄素的混合物与β-环糊精的重量比为1：1.5，研磨时间为2小时，烘干温度为45℃。
(6)将步骤(4)浸膏与步骤(5)微丸混合即得。
对比例1
1、本实施例配方为：
天麻180g，远志120g，石菖蒲180g，肉苁蓉60g，熟地黄60g，姜黄素1g。
2、制备方法为：
(1)将天麻打粉过6号药典筛；
(2)远志、石菖蒲、肉苁蓉、熟地黄加10倍量水煎煮，煎煮2次，每次2小时，收集药液；
(3)将步骤(2)中所得全部药液过滤浓缩得浸膏；
(4)将步骤(2)中浸膏与步骤(1)、姜黄素混合即得。
对比例2
1、本实施例配方为：
天麻180g，远志120g，石菖蒲180g，肉苁蓉60g，熟地黄60g，姜黄素1g。
2、制备方法为：
(1)将天麻粗粉加70％乙醇溶液加热回流3次，每次2小时，药液比分别为10倍、8倍、8倍量，收集药液过滤，旋干得干膏；
(2)将远志加80％乙醇溶液加热回流3次，每次2小时，药液比分别为10倍、8倍、8倍量收集药液过滤，旋干得干膏；
(3)将石菖蒲加入10倍量水，热回流3次，每次2小时，药液比分别为10倍、8倍、8倍量收集药液过滤，旋干得干膏；
(4)将肉苁蓉加入10倍量水，热回流3次，每次2小时，药液比分别为10倍、8倍、8倍量收集药液过滤，旋干得干膏；
(5)将肉苁蓉加入10倍量水，热回流3次，每次2小时，药液比分别为10倍、8倍、8倍量收集药液过滤，旋干得干膏；
(6)将熟地黄加入10倍量水，热回流3次，每次2小时，药液比分别为10倍、8倍、8倍量收集药液过滤，旋干得干膏；
(7)将(1)-(6)中所得干膏，加姜黄素后混合均匀即得。
对比例3
1、本实施例配方为：
天麻300g，地龙200g，石菖蒲300g，远志200g，熟地黄100g，肉苁蓉100g。
2、制备方法为：
(1)将天麻、地龙、石菖蒲、远志、熟地黄、肉苁蓉加10倍量水煎煮，煎煮2次，每次2小时，收集药液；
(2)将步骤(1)中所得全部药液过滤浓缩得浸膏即得。
试验例1 药效实验
待试药：实施例1组、对比例1组、对比例2组、对比例3组；阳性药：石杉碱甲。
1.物体识别实验
试验方法：
适应期：第1天，先将小鼠置于测试房间进行1h的环境适应和熟悉，再将小鼠放入旷场箱内适应20min(箱内无物体)，以消除旷场箱对受试小鼠的影响。每只小鼠实验结束后，用75％乙醇清洗旷场箱。
熟悉期：第2天(适应期24h后)，先将小鼠置于测试房间进行1h的环境适应和熟悉，再于旷场箱内同侧左右两端放置两个大小和质地完全相同的黄色柱形瓶作为熟悉物体，然后将小鼠背朝物体放入箱内，记录5min内小鼠对物体探究的情况(计时标准：小鼠鼻或口距离物体2cm范围内探究的时间，其趴到物体上或只是物体附近走动不计入)。每只小鼠实验结束后，用75％乙醇清洗旷场箱。
测试期：熟悉期2h后，先随机将旷场箱内的一个黄色柱形瓶换为大小相同的绿色锥形瓶作为陌生物体，再将小鼠背朝物体放入箱内，记录5min内小鼠对陌生物体的探索时间(The Total Exploration Time of Novel Object,Tn)和熟悉物体的探索时间(The TotalExploration Time of Familiar Object,Tf)。计算识别指数(Recognition Index)：RI＝Tn/(Tn+Tf)。每只小鼠实验结束后，用75％乙醇清洗旷场箱。
统计方法：数据采用GraphPad Prism 7.01软件(GraphPad Software,Inc.,San Diego,California,USA)进行分析。所有组别测试进行参数检验前数据进行了正态性检验(Kolmogorov-Smirnov检验)和方差齐性检验(Levene检验)。除水迷宫逃避潜伏期外所有检验参数应用非成对T检验 (单尾)进行组间两两比较，检验水准设定为p<0.05。水迷宫逃避潜伏期应用双因素方差分析进行组间两两比较，事后检验应用Sidak's multiple comparisons test，检验水准设定为p<0.05。结果见表1：
表1 待试药物对小鼠新奇物体识别实验中识别指数的影响
Figure PCTCN2019126530-appb-000001
组别 剂量(生药) 动物数/只 识别指数
对照组 - 17 0.5715±0.06626
模型组 - 17 0.4180±0.02726*
阳性药组 0.67片/kg 17 0.5341±0.04280#
实施例1组 1.002g/kg 17 0.5322±0.04504#
对比例1组 1.002g/kg 17 0.5081±0.05318
对比例2组 1.002g/kg 17 0.5269±0.04310#
对比例3组 1.200g/kg 17 0.5050±0.03855#
注：与对照组比较，*p<0.05；与模型组比较，#p<0.05。
新奇物体识别实验是利用动物天生喜欢接近和探索新奇物体的本能来检测动物识别记忆的精细、敏感的行为学方法。由统计学数据可以看出，模型组识别指数较正常对照组显著下降，阳性药组、实施例1组、对比例2组、对比例3组、灌胃给药后识别指数则显著上升。表明模型组小鼠陈述记忆(Declarative memory)能力下降，造模成功，阳性药、阳性药组、实施例1组、对比例2组、对比例3组用药后可改善应激小鼠的陈述记忆能力。实施例1中识别指数最高，最接近对照组。
2.跳台实验法测试小鼠的空间学习能力
试验方法：小鼠跳台实验分组、样品配制、造模处理方法同上。实验开始时先进行跳台训练，适应3min，然后通电训练300s。24h后进行测试，测试前1h给药，前15-20min腹腔注射氢溴酸东莨菪碱和生理盐水。随后将小鼠放到跳台上，记录第一次跳下平台潜伏期及300s内错误(从跳台上下来)次数。如果300s内小鼠仍未跳下平台，错误次数记为0次，潜伏期记为300s。
结果详见表2、3：
表2 待试药物对小鼠跳台实验中潜伏期的影响
Figure PCTCN2019126530-appb-000002
组别 剂量(生药) 动物数/只 潜伏期(秒)
对照组 - 17 100.3±31.82
模型组 - 17 42.01±13.95*
阳性药组 0.67片/kg 17 94.12±29.48#
实施例1组 1.002g/kg 17 137.7±25.71##
对比例1组 1.002g/kg 17 103.5±28.91#
对比例2组 1.002g/kg 17 108.2±25.66#
对比例3组 1.200g/kg 17 83.39±23.71
注：与对照组比较，*p<0.05，**p<0.01；与模型组比较，#p<0.05，##p<0.01。
表3 待试药物对小鼠跳台实验中错误次数的影响
Figure PCTCN2019126530-appb-000003
组别 剂量(生药) 动物数/只 错误次数
对照组 - 17 1.375±0.2869
模型组 - 17 2.714±0.3696**
阳性药组 0.67片/kg 17 1.833±0.3445#
实施例1组 1.002g/kg 17 1.667±0.3333#
对比例1组 1.002g/kg 17 2.471±0.5153
对比例2组 1.002g/kg 17 2.600±0.5589
对比例3组 1.200g/kg 17 2.824±0.5767
注：与对照组比较，*p<0.05，**p<0.01；与模型组比较，#p<0.05，##p<0.01。
灌胃给药后，模型组较对照组潜伏期显著缩短，错误次数则显著增多，造模成功；灌胃给药后，阳性药、实施例1组、对比例1组、对比例2组潜伏期较模型组明显延长。阳性药、实施例1组错误次数则较模型组明显减少。表明模型组小鼠跳台实验记忆能力出现缺损，阳性药和实施例1组用药后可改善跳台实验记忆功能缺损。以上研究表明，本发明的药物组合可一定程度改善小鼠空间记忆能力缺损，可显著改善小鼠跳台实验记忆能力。
3.Morris水迷宫实验法测试小鼠的空间学习能力
实施方法：测试程序包括定向航行和空间探索两部分。共连续测试5d。第一部分为定位航行实验对小鼠进行测试4d，第二部分为空间探索实验，进行测试1d。将黑色素食用色粉以温水冲开以隐藏平台，并令其摄像时与小鼠颜色保持鲜明对比，便于追踪。平台位于水面下0.8cm，水深高21cm，定位于NW象限，水迷宫内的水温用加热棒保持恒温22-24℃。
定向航行实验：每只小鼠训练4次/d，每次训练时间间隔15-20min。测试时每次以半随机方式选择入水点，实验者将小鼠以手托起令其面向池壁，轻轻放入水中。每次训练中，小鼠60s内能寻找到平台，平台上停留时间超过2s作为寻台成功标志，把小鼠从入水到寻台成功所用时间记为潜伏期。若小鼠60s内未能找到平台，则由实验者用手将其引导至平台，潜伏期记为60s。小鼠登上平台后，让其平台上停留10s，以让其根据4个象限的参照物进行空间学习和记忆，并减少小鼠紧张。计算每天潜伏期平均值，以评价动物空间记忆的获得能力。
空间探索实验：撤去平台，每只小鼠测试1次，时间为60s。选择SE象限将小鼠面向池壁边缘轻放入水中，通过动物60s内穿过原平台位置的次数，原平台象限游程比率及时间比率(即动物原平台象限的游程及时间占总游程及总时间的比率)来评价动物的空间记忆能力。
结果详见表4-8：
表4 待试药物对小鼠水迷宫实验中逃避潜伏期的影响
Figure PCTCN2019126530-appb-000004
Figure PCTCN2019126530-appb-000005
Figure PCTCN2019126530-appb-000006
表5 待试药物对小鼠水迷宫实验中探索期逃避潜伏期的影响
Figure PCTCN2019126530-appb-000007
组别 剂量(生药) 动物数/只 逃避潜伏期(秒)
对照组 - 17 20.05±3.983
模型组 - 17 39.27±4.814**
阳性药组 0.67片/kg 17 22.91±3.922#
实施例1组 1.002g/kg 17 24.45±4.652#
对比例1组 1.002g/kg 17 32.12±5.158
对比例2组 1.002g/kg 17 30.16±5.256
对比例3组 1.200g/kg 17 27.10±4.234#
表6 待试药物对小鼠水迷宫实验中探索期目标象限停留时间的影响
Figure PCTCN2019126530-appb-000008
Figure PCTCN2019126530-appb-000009
组别 剂量(生药) 动物数/只 目标象限停留时间(秒)
对照组 - 17 17.30±0.8384
模型组 - 17 14.15±1.354*
阳性药组 0.67片/kg 17 15.04±0.9555
实施例1组 1.002g/kg 17 16.04±0.7052
对比例1组 1.002g/kg 17 15.60±0.9211
对比例2组 1.002g/kg 17 15.11±0.8451
对比例3组 1.200g/kg 17 15.88±1.3682
表7 待试药物对小鼠水迷宫实验中探索期目标象限路程的影响
Figure PCTCN2019126530-appb-000010
组别 剂量(生药) 动物数/只 目标象限路程(mm)
对照组 - 17 2821±167.1
模型组 - 17 2373±175.4
阳性药组 0.67片/kg 17 2867±207.6
实施例1组 1.002g/kg 17 2804±143.7
对比例1组 1.002g/kg 17 2531±208.0
对比例2组 1.002g/kg 17 2413±178.2
对比例3组 1.200g/kg 17 2539±175.9
表8 待试药物对小鼠水迷宫实验中探索期穿越平台次数的影响
Figure PCTCN2019126530-appb-000011
组别 剂量(生药) 动物数/只 穿越平台次数
对照组 - 17 3.125±0.3966
模型组 - 17 1.308±0.3820**
阳性药组 0.67片/kg 17 2.786±0.4591#
实施例1组 1.002g/kg 17 2.647±0.4922#
对比例1组 1.002g/kg 17 2.006±0.4180
对比例2组 1.002g/kg 17 1.967±0.4008
对比例3组 1.200g/kg 17 2.433±0.4563
注(表4-8)：与对照组比较，*p<0.05，**p<0.01，****p<0.0001；与模型组比较，#p<0.05。
灌胃给药后，穿越平台次数模型组较对照组显著减少，待试药干预后则次数增多；目标象限游程比和时间较模型组显著增加。提示待试药可一定程度改善小鼠空间记忆能力缺损。水迷宫训练期第4天逃避潜伏期模型组较对照组显著延长，提示模型组小鼠记忆存储能力缺损。水迷宫探索期，逃避潜伏期模型组较对照组显著延长，目标象限停留时间和穿越平台次数模型组较对照组显著减少，提示模型组小鼠记忆提取能力缺损；灌胃给药后，阳性药、实施例1组、对比例3组逃避潜伏期较模型组显著缩短，穿越平台次数较模型组显著增加，提示阳性药、实施例1组、对比例3组用药后可改善小鼠空间记忆提取能力缺损，对比例1组、对比例2组可不同程度上改善小鼠空间提取能力缺损。
综合经典动物记忆三联行为学实验，即物体识别实验、跳台实验和水迷宫实验结果，结果表明本发明配方对小鼠具有改善认知，提高记忆力的趋势和作用，优选的制备工艺更能将药效更好的实现，优于传统的提取工艺。
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. 一种具有改善认知作用的中药组合物，其特征在于，以重量份计，由如下原料制成：天麻1～20份，远志1～15份，石菖蒲1～30份，肉苁蓉0.1～10份，熟地黄0.1～10份，姜黄素0.01～1份。
  2. 根据权利要求1所述的中药组合物，其特征在于，以重量份计，由如下原料制成：天麻16～20份，远志10～14份，石菖蒲16～20份，肉苁蓉5～7份，熟地黄5～7份，姜黄素0.05～0.15份。
  3. 根据权利要求1所述的中药组合物，其特征在于，以重量份计，由如下原料制成：天麻18份，远志12份，石菖蒲18份，肉苁蓉6份，熟地黄6份，姜黄素0.1份。
  4. 权利要求1至3中任一项所述中药组合物的制备方法，其特征在于，包括如下步骤：
    醇提：天麻、远志加乙醇水溶液加热回流，收集醇提药液、醇提药渣；
    水提：石菖蒲加水加热回流，收集石菖蒲药液、石菖蒲药渣以及石菖蒲挥发油；肉苁蓉、熟地黄、所述醇提药渣、所述石菖蒲药渣加水加热回流，收集水提药液；
    过滤浓缩：将所述醇提药液、所述石菖蒲药液、所述水提药液混合，过滤浓缩得浸膏；
    包合：将所述石菖蒲挥发油和姜黄素混合，经环糊精包合得微丸；
    混合：将所述浸膏与所述微丸混合。
  5. 根据权利要求4所述的制备方法，其特征在于，醇提步骤中，所述乙醇水溶液的体积百分浓度为50％～80％。
  6. 根据权利要求4所述的制备方法，其特征在于，醇提步骤中，所述乙醇水溶液的用量为天麻、远志总重量的8～20倍；加热回流的次数为1～5次，每次0.5～3小时。
  7. 根据权利要求4所述的制备方法，其特征在于，水提步骤中，石菖蒲加8～30倍重量的水加热回流，加热回流的次数为1～3次，每次3～5小时，收集石菖蒲药液、石菖蒲药渣以及石菖蒲挥发油；肉苁蓉、熟地黄、 所述醇提药渣、所述石菖蒲药渣加药材总重8～30倍的水加热回流，加热回流的次数为1～5次，每次0.5～3小时，收集水提药液。
  8. 根据权利要求4所述的制备方法，其特征在于，包合步骤中，所述石菖蒲挥发油和姜黄素的混合物与β-环糊精的重量比为1：(1～5)；所述包合时的研磨时间为1～4小时，烘干温度为40～60℃。
  9. 一种中药制剂，其特征在于，所述中药制剂由权利要求1至3中任一项所述中药组合物和药学上可接受的辅料组成。
  10. 根据权利要求9所述的中药制剂，其特征在于，所述中药制剂的剂型为胶囊剂、片剂或颗粒剂。
PCT/CN2019/126530 2019-11-14 2019-12-19 一种具有改善认知作用的中药组合物及其制备方法和中药制剂 WO2021093087A1 (zh)

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Families Citing this family (4)

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Publication number Priority date Publication date Assignee Title
CN111084775A (zh) * 2020-02-17 2020-05-01 牡丹江医学院 一种用于治疗癫痫的药物组合物
CN113713048A (zh) * 2021-09-10 2021-11-30 云南永孜堂制药有限公司 固体形式的天麻醒脑中药组合物及其制法和用途
CN115887573B (zh) * 2022-12-07 2024-06-11 湖南中医药大学 一种减缓衰老改善脑功能退化的中药组合物和制备方法
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002062366A1 (en) * 2001-02-08 2002-08-15 Neuromedix Co., Ltd. Herbal composition for_the prevention and treatment of dementia
CN1583031A (zh) * 2004-06-01 2005-02-23 云南省昭通制药有限公司 一种天麻复方药物及其制备方法和应用
CN1981852A (zh) * 2005-11-09 2007-06-20 北京奇源益德药物研究所 一种天麻醒脑制剂及其制法和质控方法
CN101168025A (zh) * 2007-10-25 2008-04-30 张占军 一种防治老年性痴呆的药物组合物
CN104306745A (zh) * 2014-10-31 2015-01-28 云南永孜堂制药有限公司 一种天麻醒脑胶囊的质量控制方法

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1254263C (zh) * 2003-05-21 2006-05-03 中国医学科学院基础医学研究所 一种治疗老年性痴呆的中药组合物
CN1256126C (zh) * 2004-03-31 2006-05-17 北京师范大学 一种治疗血管性痴呆的中药组合物及其制备方法
CN105943888B (zh) * 2016-06-22 2020-02-21 深圳市老年医学研究所 一种改善记忆和轻度认知障碍的中药组合物及其制备方法
CN106692551A (zh) * 2017-01-22 2017-05-24 田金洲 一种用于治疗阿尔茨海默病的药物组合物及其制备方法和用途
CN108310234A (zh) * 2018-04-11 2018-07-24 昆药集团股份有限公司 一种治疗认知功能障碍的药物组合物及其制备方法、制剂与应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002062366A1 (en) * 2001-02-08 2002-08-15 Neuromedix Co., Ltd. Herbal composition for_the prevention and treatment of dementia
CN1583031A (zh) * 2004-06-01 2005-02-23 云南省昭通制药有限公司 一种天麻复方药物及其制备方法和应用
CN1981852A (zh) * 2005-11-09 2007-06-20 北京奇源益德药物研究所 一种天麻醒脑制剂及其制法和质控方法
CN101168025A (zh) * 2007-10-25 2008-04-30 张占军 一种防治老年性痴呆的药物组合物
CN104306745A (zh) * 2014-10-31 2015-01-28 云南永孜堂制药有限公司 一种天麻醒脑胶囊的质量控制方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SUI YUN-SHENG, SONG ZHI-HENG , TENG WEI-YU , TIAN LI: "Effect of curcumin on cognitive impairment of rats after hippocampus injected with Aβ1-42", CHINA JOURNAL OF MODERN MEDICINE, vol. 23, no. 10, 30 April 2013 (2013-04-30), CN, pages 16 - 19, XP055812056, ISSN: 1005-8982 *

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