WO2023024332A1 - 一种组合物在制备预防和治疗脑卒中药物中的应用 - Google Patents

一种组合物在制备预防和治疗脑卒中药物中的应用 Download PDF

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WO2023024332A1
WO2023024332A1 PCT/CN2021/137396 CN2021137396W WO2023024332A1 WO 2023024332 A1 WO2023024332 A1 WO 2023024332A1 CN 2021137396 W CN2021137396 W CN 2021137396W WO 2023024332 A1 WO2023024332 A1 WO 2023024332A1
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composition
preparation
medicament
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prevention
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王玮
王健松
廖弈秋
黄海文
罗志波
张琳
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广州白云山医药集团股份有限公司白云山制药总厂
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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)
    • A61K36/25—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/37—Digestive system
    • A61K35/413—Gall bladder; Bile
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/55—Glands not provided for in groups A61K35/22 - A61K35/545, e.g. thyroids, parathyroids or pineal glands
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/618—Molluscs, e.g. fresh-water molluscs, oysters, clams, squids, octopus, cuttlefish, snails or slugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/65—Amphibians, e.g. toads, frogs, salamanders or newts
    • 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
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/07—Basidiomycota, e.g. Cryptococcus
    • A61K36/074—Ganoderma
    • 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
    • A61K36/286—Carthamus (distaff thistle)
    • 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)
    • A61K36/71—Ranunculaceae (Buttercup family), e.g. larkspur, hepatica, hydrastis, columbine or goldenseal
    • A61K36/714—Aconitum (monkshood)
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to the field of traditional Chinese medicine, in particular to a pharmaceutical composition for preventing and treating stroke.
  • Stroke is a common disease in neurology. It is often caused by the sudden rupture of blood vessels in the brain or the inability of blood to flow into the brain due to vascular obstruction, which causes brain tissue damage. It has the characteristics of high morbidity, high mortality and high disability rate. A factor of death. In recent years, due to the increasing pressure of life and work, the incidence of stroke has been increasing year by year and tends to be younger. Stroke includes ischemic stroke and hemorrhagic stroke, and the incidence of ischemic stroke is relatively high, accounting for about 75% to 90% of the total number of strokes.
  • Ischemic stroke usually occurs in a quiet state, manifested as dysphagia, slurred articulation, crooked corners of the mouth, dysphagia, hemiplegia, sensory disturbance, and in severe cases, fecal incontinence, etc.; hemorrhagic stroke mostly occurs in an active state, It manifests as headache, nausea, jet-like vomiting, limb hemiplegia, sensory disturbance, and in severe cases, disturbance of consciousness and coma may occur.
  • the mechanism of brain injury caused by stroke is relatively complex, which is the result of the interaction of complex pathophysiological processes such as excitotoxicity, oxidative stress, inflammation, and apoptosis, so the efficacy of a single drug is limited.
  • Cerebral stroke belongs to the category of "stroke” in traditional Chinese medicine. Due to the deficiency of righteousness, diet, emotion, fatigue and internal injuries, etc., the qi and blood are reversed, resulting in wind, fire, phlegm, and blood stasis, resulting in cerebral arteries blockage or blood spillage outside the cerebral arteries. It is the basic pathogenesis, and the main clinical manifestations are sudden fainting, hemiplegia, crooked tongue, slurred or silent speech, and numbness in one side of the body.
  • the use of traditional Chinese medicine compound can play a role in multiple links of stroke and play a good therapeutic role.
  • the chemical drugs currently used to treat stroke are mainly thrombolytic drugs, anticoagulant drugs and neuroprotective agents.
  • thrombolytic drugs are used to shrink thrombus and reduce the degree of vascular occlusion.
  • Anticoagulant drugs are mainly used to improve microcirculation and restore blood flow.
  • Neuroprotective agents are mainly used to maintain nerves and delay nerve damage.
  • Traditional Chinese medicine is also widely used in the treatment of stroke.
  • Single herbs and compound drugs are mainly used to promote blood circulation and remove blood stasis, such as Angelica, Sanqi, Chuanqiong, etc.; compound drugs mainly include Compound Danshen Tablets, Buyang Huanwu Decoction, Oral drugs such as Guanxin Shutong Capsules, Yiqi Qiangxin Capsules, Bushen Yiqi Capsules, and Naoxintong Capsules, as well as injections such as Danhong Injection and Compound Danshen Injection.
  • these pharmaceutical compositions often have single efficacy, complex composition, or poor safety, and lack strict and systematic pharmacodynamic experiments that meet the requirements of modern pharmacology, making it difficult to carry out strict quality control and standardized production.
  • the object of the present invention is to provide a composition for preparing a medicament for preventing and treating stroke.
  • CN108057066B discloses a Chinese medicine composition for preventing and treating unstable angina pectoris, which consists of ginseng, aconite, ganoderma lucidum, safflower, artificial musk, bear bile, pearl, toad venom, borneol and bezoar (due to less natural sources of bezoar, generally used in vitro cultivation of bezoar).
  • the inventor surprisingly found that the traditional Chinese medicine composition can not only relieve angina pectoris, but also has a good therapeutic effect on stroke, especially ischemic stroke.
  • composition in the preparation of a medicament for preventing and treating cerebral apoplexy, the composition mainly consists of the following components by weight:
  • the composition mainly consists of the following components by weight:
  • the composition mainly consists of the following components by weight:
  • the composition mainly consists of the following components by weight:
  • the medicament is prepared from the composition and pharmaceutically acceptable excipients.
  • the drug can be prepared according to conventional methods in the art.
  • the medicament of the present invention is a composition obtained by pulverizing and mixing raw materials, or an extract obtained by mixing raw materials, or an extract obtained by separately extracting raw materials and mixing them.
  • the extract is further refined and purified.
  • the extraction method includes decoction extraction, reflux extraction, immersion extraction, ultrasonic extraction, percolation extraction, microwave extraction, etc.
  • the purification method includes water extraction and alcohol precipitation, alkali-soluble acid precipitation and various column chromatography purification methods, Such as macroporous resin column, silica gel column, gel column, reversed phase column, etc.
  • the dosage form of the drug is tablet, capsule, granule, pill, oral liquid or drop pill.
  • the above composition is added with suitable pharmaceutically acceptable auxiliary materials, and can be made into corresponding tablets, capsules, granules, pills, oral liquids or drop pills according to the conventional preparation process of the required dosage form.
  • the pharmaceutically acceptable adjuvant refers to the conventional pharmaceutical adjuvant in the field of pharmacy, selected from fillers, binders, disintegrants, lubricants, suspending agents, wetting agents, pigments, essences, solvents, surfactants Or one or more flavoring agents.
  • the filler is selected from starch, sucrose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose or glucose, etc.;
  • the binder is selected from cellulose derivatives, alginate, starch, water, Dextrin, gelatin or polyvinylpyrrolidone, etc.;
  • the disintegrant is selected from microcrystalline cellulose, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose or cross-linked sodium carboxymethyl cellulose ;
  • Described lubricant is selected from stearic acid, macrogol, calcium carbonate, sodium bicarbonate, micropowder silica gel, talcum powder or magnesium stearate;
  • Described suspending agent is selected from micropowder silica gel, beeswax, cellulose, solid polyethylene glycol;
  • the wetting agent is selected from glycerin, Tween-
  • the composition and the medicine prepared therefrom are used for preventing and treating stroke, and the stroke is ischemic stroke.
  • the composition and the medicine prepared therefrom improve neurological deficits, and/or reduce the size of cerebral infarction, and/or reduce the degree of brain tissue edema, and/or resist oxidative stress damage.
  • the anti-oxidative stress damage is to reduce MDA content, increase GSH content and SOD activity (P ⁇ 0.05).
  • composition of the present invention can effectively improve neurological deficits, reduce the size of cerebral infarction, reduce the degree of brain tissue edema, resist oxidative stress damage, and relieve the symptoms of stroke from various angles through the reasonable compatibility of various traditional Chinese medicine components. Block the progress of the disease; controllable quality, easy to standardize production; and safe and reliable, non-toxic and side effects on the human body.
  • Get 160 male SD rats (body weight 240 ⁇ 20g), after adaptive feeding 1 ⁇ 2, be divided into 8 groups at random, be respectively sham operation group, model group and embodiment 1,2,3,4,5, 6 groups (wherein, the medicinal taste of each group of embodiment is pulverized according to the prescription quantity, sieved and mixed, suspended with sodium carboxymethylcellulose solution to make a suspension, shaken up before administration), totally 8 groups, each group of 20 Only, begin to give corresponding drug gavage every day (embodiment 1,2,3,4,5,6 groups are administered by 57,63,67,71,83,89mg crude drug amount/Kg body weight respectively, sham operation group, model group was given an equal amount of sodium carboxymethylcellulose solution). Are administered for 4 weeks. Modeling was established on the second day after the end of administration.
  • Rats in each group were anesthetized by intraperitoneal injection of chloral hydrate, fixed on the operating table in lateral position, and the anal temperature of rats was maintained at 37 ⁇ 1°C during the experiment.
  • the operation was performed in the following steps: skin preparation, skin disinfection; midline incision in the neck, exposure of the common carotid artery, blunt separation of the internal carotid artery, clamping of the common carotid artery and the internal carotid artery, and slow insertion of the nylon thread through the main incision of the external carotid artery.
  • Oxidative stress indicators 24 hours after administration, the animals in each group were sacrificed, and 10 rats were taken, and the brain was quickly weighed, and a 10% brain tissue homogenate was prepared with normal saline. Centrifuge at low temperature, take the supernatant, and detect the content of malondialdehyde (MDA), reduced glutathione (GSH) and superoxide dismutase (SOD) activity in the brain tissue strictly according to the kit instructions.
  • MDA malondialdehyde
  • GSH reduced glutathione
  • SOD superoxide dismutase
  • ROS reactive oxygen species
  • the rat focal cerebral ischemia-reperfusion model was prepared by suture method.
  • the behavioral score, cerebral infarction volume, brain water content and MDA content in the brain tissue of the drug group in the example were significantly reduced.
  • GSH content and SOD activity in the brain tissue were significantly increased (P ⁇ 0.05), indicating that the drug of the embodiment can improve neurological impairment, reduce the degree of cerebral edema, and reduce the size of cerebral infarction.
  • This effect may be related to the reduction of oxidative stress, It is related to the protection of brain tissue from oxygen free radical damage.
  • the pharmaceutical composition of the present invention relieves the symptoms of cerebral apoplexy from various angles and blocks the progression of the disease through the reasonable compatibility of various traditional Chinese medicine components; it is safe and reliable, and has no toxic and side effects on the human body.
  • the pharmaceutical composition of the present invention can significantly reduce oxidative stress damage in ischemic stroke model animals, improve neurological deficits, protect brain tissue, and is suitable for the prevention and treatment of ischemic stroke.

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Abstract

一种组合物在制备预防和治疗脑卒中的药物中的应用，该组合物由人参、附子、灵芝、红花、人工麝香、熊胆、珍珠、蟾酥、冰片、牛黄制成。该组合物可以明显改善神经功能缺损，减轻脑水肿程度，降低脑梗死面积。

Description

[根据细则37.2由ISA制定的发明名称]　一种组合物在制备预防和治疗脑卒中药物中的应用 技术领域
本发明涉及中医药领域，具体涉及一种预防和治疗脑卒中的药物组合物。
背景技术
脑卒中是神经内科常见疾病，多因脑部血管突然破裂或因血管阻塞导致血液不能流入大脑而引起脑组织损伤，具有发病率高、死亡率高和致残率高的特点，是中国居民第一位死亡因素。近年来由于生活工作压力的增大，脑卒中的发病率逐年上升且趋于年轻化。脑卒中包括缺血性卒中和出血性卒中，其中，缺血性卒中的发病率较高，约占脑卒中总数的75％～90％。缺血性卒中多在安静状态下发病，表现为言语不利、吐字不清、口角歪斜、吞咽障碍、偏瘫、感觉障碍，严重者可出现大小便失禁等；出血性卒中多在活动状态下发病，表现为头疼、恶心、喷射样呕吐、肢体偏瘫、感觉障碍，严重者可出现意识障碍、昏迷等。
卒中所致的脑损伤机制较为复杂，是由兴奋性毒性、氧化应激、炎症、凋亡等复杂病理生理过程相互作用的结果，因此单一药物疗效有限。
脑卒中属中医“中风”等范畴，由于正气亏虚，饮食、情志、劳倦内伤等引起气血逆乱，产生风、火、痰、瘀，导致脑脉痹阻或血溢脑脉之外为基本病机，以突然昏仆、半身不遂、口舌歪斜、言语謇涩或不语、偏身麻木为主要临床表现的病证。采用中药复方可以针对脑卒中的多个环节发挥作用，起到良好的治疗作用。
目前用于治疗脑卒中的化学药物主要是溶栓药物、抗凝药物和神经保护剂。其中溶栓药物用于缩小血栓，减轻血管闭塞程度。抗凝药物主要用于改善微循环，恢复血流。神经保护剂主要是用于养护神经，延缓神经损伤。中药也被广泛用于脑卒中的治疗，单味药材以及复方药物主要以活血化瘀为主要功效，如当归、三七、川穹等；复方药物主要有复方丹参片、补阳还五汤、冠心舒通胶 囊、益气强心胶囊、补肾益气胶囊、脑心通胶囊等口服药物，以及丹红注射液、复方丹参注射液等注射制剂。但是，这些药物组合物往往功效单一、或组成复杂、或安全性较差，而且缺少符合现代药物学要求的严格的、***的药效学实验，难以进行严格的质量控制和标准化生产。
发明内容
基于此，本发明的目的在于提供一种组合物用于制备预防和治疗脑卒中的药物。
CN108057066B公开了一种防治不稳定型心绞痛的中药组合物，其由人参、附子、灵芝、红花、人工麝香、熊胆、珍珠、蟾酥、冰片和牛黄组成(由于天然牛黄来源较少，一般采用体外培育牛黄)。本发明人惊奇的发现，该中药组合物不仅可以缓解心绞痛，其对脑卒中，特别是缺血性脑卒中，同样具有良好的治疗效果，本发明记载的大量试验数据证明：该组合物通过各中药组分的合理配伍，能有效地改善神经功能缺损，降低脑梗死面积，减轻脑组织水肿程度，对抗氧化应激损伤，从多种角度缓解脑卒中的症状，阻断病程进展；且安全可靠、对人体无毒副作用。
具体技术方案如下：
一种组合物在制备预防和治疗脑卒中的药物中的应用，所述组合物主要由以下重量份的组分组成：
Figure PCTCN2021137396-appb-000001
Figure PCTCN2021137396-appb-000002
在本发明一些实施方式中，所述组合物主要由以下重量份的组分组成：
Figure PCTCN2021137396-appb-000003
在本发明一些实施方式中，所述组合物主要由以下重量份的组分组成：
Figure PCTCN2021137396-appb-000004
在本发明一些实施方式中，所述组合物主要由以下重量份的组分组成：
Figure PCTCN2021137396-appb-000005
Figure PCTCN2021137396-appb-000006
在本发明一些实施方式中，所述药物由所述组合物和药学上可接受的辅料制备而成。
在本发明一些实施方式中，所述药物可按本领域常规方法制备。本发明所述药物是各原料药粉碎后混合而成的组合物，或者各原料药混合后提取得到的提取物，或者各原料药单独提取后混合得到的提取物。任选的，提取物进一步精制纯化。其中，所述提取方法包括煎煮提取、回流提取、浸渍提取、超声提取、渗漉提取、微波提取等；所述纯化方法包括水提醇沉、碱溶酸沉以及各种柱色谱纯化方法，如大孔树脂柱、硅胶柱、凝胶柱、反相柱等。
在本发明一些实施方式中，所述药物的剂型为片剂、胶囊剂、颗粒剂、丸剂、口服液或滴丸剂。上述组合物加入适宜的药学上可接受的辅料，按所需剂型的常规制备工艺即可制成相应的片剂、胶囊剂、颗粒剂、丸剂、口服液或滴丸剂。
所述药学上可接受的辅料是指药学领域常规的药物辅料，选自填充剂、粘合剂、崩解剂、润滑剂、助悬剂、润湿剂、色素、香精、溶剂、表面活性剂或矫味剂中的一种或几种。所述填充剂选自淀粉、蔗糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素或葡萄糖等；所述粘合剂选自纤维素衍生物、藻酸盐、淀粉、水、糊精、明胶或聚乙烯吡咯烷酮等；所述崩解剂选自微晶纤维素、羧甲基淀粉钠、交联聚乙烯吡咯烷酮、低取代羟丙基纤维素或交联羧甲基纤维素钠；所述润滑剂选自硬脂酸、聚乙二醇、碳酸钙、碳酸氢钠、微粉硅胶、滑石粉或硬脂酸镁；所述助悬剂选自微粉硅胶、蜂蜡、纤维素、固态聚乙二醇；所述润 湿剂选自甘油、吐温-80、乙氧基氢化蓖麻油或卵磷脂；所述溶剂选自乙醇、液态聚乙二醇、异丙醇、吐温-80、甘油、丙二醇或植物油，所述植物油选自大豆油、蓖麻油、花生油、调和油等；所述表面活性剂选自十二烷基苯磺酸钠、硬脂酸、聚氧乙烯-聚氧丙烯共聚物、脂肪酸山梨坦或聚山梨酯(吐温)等；所述矫味剂选自阿斯巴甜、蔗糖素、香精、甜菊素、安赛蜜、柠檬酸或糖精钠。
在本发明一些实施方式中，所述的组合物及其制备得到的药物用于预防和治疗脑卒中，所述脑卒中为缺血性脑卒中。
在本发明的一些实施方式中，所述所述组合物及其制备得到的药物改善神经功能缺损，和/或降低脑梗死面积，和/或减轻脑组织水肿程度，和/或对抗氧化应激损伤。在本发明的一些实施方式中，所述对抗氧化应激损伤是降低MDA含量，升高GSH含量及SOD活性(P<0.05)。
本发明的有益效果：
本发明所述组合物通过各中药组分的合理配伍，能有效地改善神经功能缺损，降低脑梗死面积，减轻脑组织水肿程度，对抗氧化应激损伤，从多种角度缓解脑卒中的症状，阻断病程进展；质量可控、便于标准化生产；且安全可靠、对人体无毒副作用。
具体实施方式
以下为本发明的具体实施方式，所述的实施例是为了进一步描述本发明，但并不限制本发明。
实施例1
本实施例实验组的试验药物由以下重量份的组分组成：
Figure PCTCN2021137396-appb-000007
Figure PCTCN2021137396-appb-000008
实施例2
本实施例实验组的试验药物由以下重量份的组分组成：
Figure PCTCN2021137396-appb-000009
实施例3
本实施例实验组的试验药物由以下重量份的组分组成：
Figure PCTCN2021137396-appb-000010
Figure PCTCN2021137396-appb-000011
实施例4
本实施例实验组的试验药物由以下重量份的组分组成：
Figure PCTCN2021137396-appb-000012
实施例5
本实施例实验组的试验药物由以下重量份的组分组成：
Figure PCTCN2021137396-appb-000013
Figure PCTCN2021137396-appb-000014
实施例6
本实施例实验组的试验药物由以下重量份的组分组成：
Figure PCTCN2021137396-appb-000015
药效研究：对脑缺血再灌注模型大鼠的影响
1.实验方法
1.1动物分组及药物干预
取160只雄性SD大鼠(体质量240±20g)，适应性喂养1～2后，随机分为8组，分别为假手术组，模型组和实施例1、2、3、4、5、6组(其中，实施例各组药味按处方量粉碎、过筛后混合，以羧甲基纤维素钠溶液助悬制成混悬剂，给药前摇匀)，共8组，每组20只，开始每天予相应药物灌胃(实施例1、2、3、4、5、6组分别按57、63、67、71、83、89mg生药量/Kg体重给药，假手术组、模型组给予等量的羧甲基纤维素钠溶液)。均给药4周。给药结束后第2天造模。
1.2脑缺血再灌注模型大鼠的制备
术前12h禁食，自由饮水。各组大鼠腹腔注射水合氯醛麻醉，侧卧位固定于手术台上，实验过程中维持大鼠肛温37±1℃。手术按以下步骤操作：备皮，消毒皮肤；颈部正中切口，暴露颈总动脉，钝性分离颈内动脉，夹闭颈总动脉和颈内动脉，将尼龙线经颈外动脉主干切口缓慢向颈内动脉入颅方向轻柔推进，以颈总动脉分叉处为标记，推进18mm左右遇到轻微阻力，即到达较细的大脑中动脉停止，结扎阻断大脑中动脉，使局部脑血流充分阻断，缝合伤口，留置长约3cm的尼龙线于体外，碘伏消毒手术区。缺血1h后拔出阻塞线约10min实现再灌注。假手术组：不插线结扎，其余处理同给药组。手术过程中采用经颅多普勒血流分析仪监测脑血流情况。
1.3测定指标
1.3.1行为缺陷：缺血再灌注24h内密切观察各组动物状况，参考Zea Longa评分标准评价行为缺陷，其中0分为正常，无神经损伤症状；1分为不能完全伸展对侧前肢；2分为爬行时向对侧转圈；3分为行走时身体向对侧倾倒；4分为不能自发行走，意识丧失。
1.3.2脑梗死体积及脑含水量：给药后再灌注24h后，处死各组动物，取其中10只大鼠的全脑，称取脑组织湿重，切片，2％氯化三苯基四氮唑(TTC)溶液中染色30min，固定，分离苍白区(梗死区，未被染色)和非苍白区(正常区)，脑梗死体积(％)＝梗死区范围湿重/脑组织湿重×100％。将染色后的脑组织置烘箱中干燥至恒重，称其干重，按下式计算脑含水量：脑含水(％)量＝(脑组织湿重-脑组织干重)/脑组织湿重×100％。
1.3.3氧化应激指标：给药后再灌注24h后，处死各组动物，取其中10只大鼠，迅速取脑称重，用生理盐水制成10％脑组织匀浆液。低温离心，取上清液，严格按试剂盒说明书方法检测大脑组织中丙二醛(MDA)、还原型谷胱甘肽(GSH)含量和超氧化物歧化酶(SOD)活性。
2.实验结果
2.1各组大鼠行为缺陷评分比较
与假手术组相比，模型组大鼠行为学评分明显较高。与模型组相比，给予实施例药物的大鼠的行为学评分显著下降(P<0.05)，表明实施例药物可以改善神经功能缺损。结果见表1。
表1 各组大鼠行为缺陷评分比较(n＝20)
组别 行为学评分(分)
假手术组 0
模型组 3.40±0.55
实施例1组 2.61±0.44*
实施例2组 2.33±0.29*
实施例3组 2.47±0.27*
实施例4组 2.63±0.38*
实施例5组 2.52±0.31*
实施例6组 2.35±0.45*
注：与模型组比较，*P<0.05
2.2各组大鼠脑梗死体积及脑含水量比较
假手术组大鼠脑组织无梗死；与假手术组相比，模型组大鼠脑含水量明显较高(P<0.05)。与模型组相比，给予实施例药物的大鼠的脑梗死体积及脑含水量显著下降(P<0.05)，表明实施例药物可以减少缺血所致的脑梗死体积和脑含水量。结果见表2。
表2 各组大鼠脑梗死体积及脑含水量比较(％，n＝10)
组别 脑梗死体积 脑含水量
假手术组 - 66.97±4.39*
模型组 24.08±1.32 78.47±6.28
实施例1组 22.19±1.77* 74.89±3.26*
实施例2组 22.08±1.65* 73.29±6.17*
实施例3组 21.63±1.28* 71.32±4.20*
实施例4组 21.49±2.09* 71.56±6.24*
实施例5组 21.86±2.60* 73.20±5.17*
实施例6组 21.60±1.83* 72.02±3.19*
注：与模型组比较，*P<0.05
2.3各组大鼠氧化应激指标比较
与假手术组相比，模型组大鼠脑组织中MDA含量明显较高，GSH含量及SOD活性明显较低(P<0.05)。与模型组相比，给予实施例药物的大鼠的MDA含量明显降低，GSH含量及SOD活性明显升高(P<0.05)，表明实施例药物可以减轻氧化应激损伤。结果见表3。
表3 各组大鼠氧化应激指标比较(n＝10)
组别 MDA(μmol/mg Prot) GSH(μg/mg Prot) SOD(μU/mg Prot)
假手术组 9.13±0.76* 46.84±6.92* 69.05±8.14*
模型组 56.30±7.18 27.80±3.21 30.43±4.85
实施例1组 45.51±3.92* 33.41±3.35* 41.74±6.32*
实施例2组 41.42±4.55* 35.50±5.24* 46.21±4.49*
实施例3组 39.21±3.26* 36.45±4.06* 45.35±6.12*
实施例4组 40.25±5.47* 36.37±2.81* 38.72±4.50*
实施例5组 43.07±4.84* 34.01±5.65* 36.19±5.33*
实施例6组 39.84±3.27* 33.79±3.34* 45.84±3.26*
注：与模型组比较，*P<0.05
3.实验结论
脑卒中的危险因素(高血压、高血糖等)和缺血会导致活性氧(ROS)相关 酶***活化，产生大量的ROS，远超过机体抗氧化防御***的内源清除能力，出现氧化应激，大量研究显示，与正常人相比，脑卒中患者发病后SOD、GSH、过氧化氢酶(CAT)、谷胱甘肽过氧化物酶(GSH-Px)、总抗氧化能力(TAC)明显降低，MDA明显升高，上述指标的改变通过促进血小板聚集、增加内皮通透性、内皮细胞局灶性病变等加重病情。
本研究通过线栓法制备大鼠局灶性脑缺血再灌注模型，与模型组相比，实施例药物组大鼠行为学评分、脑梗死体积、脑含水量及脑组织中MDA含量明显降低，脑组织中GSH含量及SOD活性明显升高(P<0.05)，表明实施例药物可以改善神经功能缺损，减轻脑水肿程度，降低脑梗死面积，该作用可能与所述药物减轻氧化应激、保护脑组织免受氧自由基损伤有关。本发明所述药物组合物通过各中药组分的合理配伍，从多种角度缓解脑卒中的症状，阻断其病程进展；且安全可靠、对人体无毒副作用。
综上所述，本发明所述的药物组合物可以明显降低缺血性卒中模型动物氧化应激损伤，改善神经功能缺损，保护脑组织，适用于缺血性脑卒中的预防和治疗。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (10)

  1. 一种组合物在制备预防和治疗脑卒中的药物中的应用，所述组合物主要由以下重量份的组分组成：
    Figure PCTCN2021137396-appb-100001
  2. 根据权利要求1所述的组合物在制备预防和治疗脑卒中的药物中的应用，其特征在于，所述组合物主要由以下重量份的组分组成：
    Figure PCTCN2021137396-appb-100002
  3. 根据权利要求2所述的组合物在制备预防和治疗脑卒中的药物中的应用，其特征在于，所述组合物主要由以下重量份的组分组成：
    Figure PCTCN2021137396-appb-100003
    Figure PCTCN2021137396-appb-100004
  4. 根据权利要求3所述的组合物在制备预防和治疗脑卒中的药物中的应用，其特征在于，所述组合物主要由以下重量份的组分组成：
    Figure PCTCN2021137396-appb-100005
  5. 根据权利要求1-4任一项所述的组合物在制备预防和治疗脑卒中的药物中的应用，其特征在于，所述组合物中使用的牛黄为体外培育牛黄。
  6. 根据权利要求1-4任一项所述的组合物在制备预防和治疗脑卒中的药物中的应用，其特征在于，所述药物由权利要求1-4任一项所述的组合物和药学上可接受的辅料制备而成。
  7. 根据权利要求6所述的组合物在制备预防和治疗脑卒中的药物中的应用，其特征在于，所述药物的剂型为片剂、胶囊剂、颗粒剂、丸剂、口服液或滴丸剂。
  8. 根据权利要求1-4所述的组合物在制备预防和治疗脑卒中的药物中的应用，其特征在于，所述药物是各原料药粉碎后混合而成的组合物；或者各原料药混合后提取得到的提取物，或者各原料药单独提取后混合得到的提取物；任选的，提取物进一步精制纯化。
  9. 根据权利要求1-4任一项所述的组合物在制备预防和治疗脑卒中的药物中的应用，其特征在于，所述脑卒中为缺血性脑卒中。
  10. 根据权利要求1-4任一项所述的组合物在制备预防和治疗脑卒中的药物中的应用， 其特征在于，所述药物改善神经功能缺损，和/或降低脑梗死面积，和/或减轻脑组织水肿程度，和/或对抗氧化应激损伤。
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CHENG FANG, SHAOMIN: "Analysis of Curative Effect of Xinling Pill in Treating Coronary Heart Disease", JOURNAL OF NEW CHINESE MEDICINE, 31 December 1991 (1991-12-31), pages 53 - 54, XP093039877, DOI: 10.13457/j.cnki.jncm.1991.05.033 *

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