CN117137961A - 山茱萸总鞣质提取物在制备老年痴呆防治药物中的应用 - Google Patents
山茱萸总鞣质提取物在制备老年痴呆防治药物中的应用 Download PDFInfo
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- CN117137961A CN117137961A CN202311220167.4A CN202311220167A CN117137961A CN 117137961 A CN117137961 A CN 117137961A CN 202311220167 A CN202311220167 A CN 202311220167A CN 117137961 A CN117137961 A CN 117137961A
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- tannin extract
- dogwood
- total tannin
- senile dementia
- extract
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- 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)
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- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61K2236/50—Methods involving additional extraction steps
- A61K2236/55—Liquid-liquid separation; Phase separation
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- Chemical Kinetics & Catalysis (AREA)
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- Medicines Containing Plant Substances (AREA)
Abstract
本发明公开了山茱萸总鞣质提取物在制备老年痴呆防治药物中的应用,属于中药领域。所述的山茱萸总鞣质提取物通过包括如下步骤的方法制备得到:将山茱萸原料粉碎,用丙酮水溶液或丙酮‑乙醚溶液作溶剂进行回流提取,提取液通过苯乙烯型大孔吸附树脂柱,水洗柱后用乙醇水溶液洗脱,洗脱液减压浓缩后经干燥得到山茱萸总鞣质提取物。该山茱萸总鞣质提取物用于治疗老年性痴呆具有较好的疗效和较高的安全性,其可用于制备老年痴呆防治药物。
Description
技术领域
本发明属于中药领域,涉及植物提取物及其医疗用途,具体涉及山茱萸总鞣质提取物在制备老年痴呆防治药物中的应用。
背景技术
山茱萸(Cornus officinalis Sieb.et Zucc.)系山茱萸科山茱萸属,多年生小乔木或灌木,于秋末冬初成熟。山茱萸的干燥成熟果肉,始载于《神农本草经》,为我国传统珍贵的中药材。山茱萸在我国主要分布于陕西、河南、浙江、安徽、湖北等地。野生于海拔400-2000米杂木林中、溪旁或向阳山坡的灌丛中,各地有栽培,其开发具有广阔的发展前景。《中国药典》记载其酸、涩,微温;归肝、肾经,补益肝肾,收涩固脱,用于眩晕耳鸣,腰膝酸痛,阳痿遗精,遗尿尿频,崩漏带下,大汗虚脱,内热消渴。近年来研究表明,山茱萸的药理功效是多方面的,如氧化、抗炎杀菌、抗疲劳、抗衰老、抗肿瘤及心血管保护作用等。山茱萸科植物中含有许多类化学物质如苷类、黄酮类、挥发油类和鞣质、有机酸等,但通常认为莫诺苷和马钱苷是其主要有效成分,并以其含量作为评价山茱萸质量的主要依据。对山茱萸的开发,集中于提取环稀醚萜苷、黄酮、多糖等,如“山茱萸有效成分的提取及相关基础研究”(郑州大学[D],2007)以五环三萜酸、皂苷为有效成分,“一种酶解提取山茱萸多糖的方法”(专利申请号:200810120569.6)以多糖为有效成分。对于鞣质类化合物,通常认为药效低,且口味苦涩,而作为杂质去除,如“壳聚糖用于山茱萸水提液除鞣质工艺的探讨”(《中草药》,2008,(05))一文中用壳聚糖沉淀山茱萸中鞣质。
目前鞣质主要分为三类:缩合鞣质、可水解鞣质及复合鞣质,其中双子叶植物尤以可水解鞣质居多。而可水解鞣质根据水解后产生的酚酸种类不同又分为没食子酸鞣质(主要水解产生没食子酸)和逆没食子酸鞣质(又称鞣花鞣质,主要水解产生鞣花酸)两类。研究显示,山茱萸中鞣质类型主要为鞣花鞣质(“山茱萸化学成分及药理研究概况”《中国中医药信息杂志》,2002,(10)发现山茱萸果实中的11个鞣质类化合物里7个为鞣花鞣质)。研究表明没食子酸鞣质和鞣花鞣质两类鞣质的药理活性和应用侧重点不一样:如“没食子酸、并没食子酸的分离、性能及应用研究”(安徽大学[D],2012)一文指出并没食子酸(鞣花酸)及鞣花鞣质抑制酪氨酸酶活性较好,多用于化妆品美白;没食子酸及没食子酸鞣质对肾脏和肝脏亲和力较好,多用于抑制肿瘤形成;“用于性良好度的富含鞣花单宁的提取物组合物”(专利申请号:201280064146.1)中来自夏栎中的鞣质提取物(主要富含鞣花鞣质)用于治疗性功能障碍;“红景天总鞣质提取物及其在制备治疗老年性痴呆病药物中的应用”(专利申请号:03117651.8)中来自红景天中的鞣质提取物用于治疗老年性痴呆,而红景天中的鞣质类型主要为没食子酸鞣质(“红景天总鞣质提取工艺、质量标准和药理活性研究”(华南热带农业大学[D],2006)以没食子酸作为红景天中总鞣质含量的质量检测标准)。
应用方面,山茱萸主要用于养肝补肾、抗疲劳、改善心脑血管功能等保健食品或药物,如“山茱萸果核提取物及其保肝应用”(专利申请号:201811175854.8),“一种山茱萸补益肝肾含片及其生产方法”(专利申请号:201510820355.X),“一种养肝益肾的山茱萸保健口服液”(专利申请号:201510855993.5),一种缓解体力疲劳的三七黄精山茱萸石斛保健酒(专利申请号:201811175854.8),“基于倾向评分匹配回顾性评价人参-山茱萸治疗慢性心力衰竭的临床疗效”(《中医临床研究》,2023,15(05))等。
老年痴呆是一种以进行性记忆力衰退、记忆、理解、判断、推理、计算和抽象思维等多种认知功能减退并伴有幻觉、妄想、行为紊乱和人格改变为主要特点的脑部退行性疾病。其病临床多表现为进行性痴呆,发病起因尚不明确,该病治则为改善认知功能障碍,促进患者生活能力的恢复与提高。然而,由于种种原因,老年性痴呆的临床治疗仍然是一个亟待攻克的世界性难题。近年来,国内外众多学者围绕中药天然药物活性成分治疗老年性痴呆开展了大量基础性研究和临床应用研究,以期开发出防治该病的新药,其中研究较多的包括:黄芪、人参、灵芝、熟地黄、枸杞子、白芍等。目前尚未见用山茱萸鞣质提取物治疗老年性痴呆的基础或临床研究报道。
发明内容
本发明的目的在于提供一种新的山茱萸提取物即山茱萸总鞣质提取物。本发明的另一目的在于提供所述山茱萸总鞣质提取物在制备老年痴呆防治药物中的应用。
本发明的目的通过下述技术方案实现:
一种山茱萸总鞣质提取物,其通过包括如下步骤的方法制备得到:将山茱萸原料粉碎,用丙酮水溶液或丙酮-乙醚溶液作溶剂进行回流提取,提取液通过苯乙烯型大孔吸附树脂柱,水洗柱后用乙醇水溶液洗脱,洗脱液减压浓缩后经干燥得到山茱萸总鞣质提取物。其中,所述的丙酮水溶液的质量浓度优选为60-70%,丙酮-乙醚溶液中丙酮、乙醚的体积比为4-6:1;山茱萸原料与丙酮水溶液或丙酮-乙醚溶液的固液比优选为1:15-20(kg/L);所述的回流的温度优选为50-65℃,回流提取的次数优选为两次,每次0.5-2h;所述的乙醇水溶液的质量浓度优选为35-75%;所述的减压浓缩的温度优选为50-56℃;所述的干燥包括冷冻干燥、喷雾干燥。
所述的山茱萸原料优选选自山茱萸属山茱萸科山茱萸和川鄂山茱萸中的至少一种。
根据《中国药典》2020年版一部附录XB“鞣质含量测定法”测得山茱萸总鞣质提取物中总鞣质含量达42-89%。此外,通过苯酚-硫酸显色法检测提取物中是否含有多糖,显色结果显示山茱萸总鞣质提取物中不含山茱萸多糖类成分;利用萘酚试验显色法检测提取物中是否含有苷类物质,显色结果显示山茱萸总鞣质提取物中不含山茱萸苷类成分。
所述的山茱萸总鞣质提取物用于治疗老年性痴呆具有较好的疗效和较高的安全性,基于此,所述的山茱萸总鞣质提取物或含有所述的山茱萸总鞣质提取物的组合物具有制备老年痴呆防治药物的应用。
一种老年痴呆防治药物,其含有山茱萸总鞣质提取物,或含有山茱萸总鞣质提取物的组合物。进一步地,所述的老年痴呆防治药物还含有制药中可以被接受的辅料成分。
所述的老年痴呆防治药物为口服型药物制剂或注射型药物制剂。将山茱萸总鞣质提取物或含有山茱萸总鞣质提取物的组合物与辅料成分混合,按照常规制剂工艺,可制备成口服型药物制剂或注射型药物制剂。如与口服制剂中可以被接受的崩解剂、润滑剂、赋形剂、粘合剂、填充剂等常用辅料混合后,按照常规制剂工艺,即可制备成片剂、胶囊剂、软胶囊剂、颗粒剂和丸剂等口服固体药用制剂;与常用的增溶剂、乳化剂、润湿剂、稀释剂、防腐剂、稳定剂、较味剂等混合,按照常规制剂工艺,即可制备成水剂、糖浆剂等口服液体制剂;与注射剂中常用的适当溶剂和附加剂进行配比和混合,还可以制备成冻干粉针剂等注射药用制剂。
本发明的有益效果:本发明将现有技术中通常作为杂志除去的山茱萸总鞣质提取出来,并提出了与原山茱萸应用范围不同的新医疗用途,即在制备老年痴呆防治药物中的应用。
附图说明
图1是山茱萸总鞣质提取物的制备流程图。
具体实施方式
以下实施例用于进一步说明本发明,但不应理解为对本发明的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
若未特别指明,实施例中所用的技术手段为本领域技术人员所熟知的常规手段。
实施例1山茱萸总鞣质提取物的制备
将山茱萸原料1000g,适当粉碎,用20L 70%丙酮溶液进行提取,即20倍量,于65℃下回流提取两次,每次1.5h。合并提取液,趁热过滤,滤液合并后通过HPD-400大孔吸附树脂(天津允开树脂科技有限公司)柱,用水清洗柱子,再经70%乙醇洗柱,乙醇洗脱液置于50℃减压浓缩,回收溶剂,浓缩液冷冻干燥或喷雾干燥得到100g提取物。根据《中国药典》2020年版一部附录XB“鞣质含量测定法”测定,总鞣质含量82%。经检测,山茱萸总鞣质提取物不含多糖类成分和苷类成分。
实施例2山茱萸总鞣质提取物的制备
将川鄂山茱萸将山茱萸原料1000g,适当粉碎,用15L 60%丙酮溶液进行提取,即15倍量,于50℃下回流提取两次,每次0.5h。合并提取液,趁热过滤,滤液合并后通过HPD-400大孔吸附树脂(天津允开树脂科技有限公司)柱,用水清洗柱子,再经70%乙醇洗柱,乙醇洗脱液置于50℃减压浓缩,回收溶剂,浓缩液冷冻干燥或喷雾干燥得到100g提取物。根据《中国药典》2020年版一部附录XB“鞣质含量测定法”测定,总鞣质含量63%。经检测,山茱萸总鞣质提取物不含多糖类成分和苷类成分。
实施例3不同药物剂型的制备
取上述实施例1或实施例2中的山茱萸总鞣质提取物70g,粉碎过筛后按照相关规定量直接填充胶囊制备成胶囊剂1000粒。
取上述实施例1或实施例2中的山茱萸总鞣质提取物70g,另取淀粉20g、硬脂酸镁1.8g,混合制备成颗粒后压片成片剂1000片。
取上述实施例1或实施例2中的山茱萸总鞣质提取物70g,另取蔗糖40g、45%乙醇150mL、柠檬酸750mg、苯甲酸450mg,混合加水定容至10L,均匀分成1000支,得到口服糖浆剂。
取上述实施例1或实施例2中的山茱萸总鞣质提取物70g,另取乙二胺四乙酸钠盐(EDTA-2Na)0.12g、注射用水1L,无菌环境下充分搅拌溶解,经玻砂过滤器过滤后,收集滤液并定量(1mL)注入安剖瓶中,再置于冷冻干燥器内冷冻干燥28h,加盖封口,得到1000支注射用冻干粉针剂。
实施例4总鞣质含量为73%的山茱萸总鞣质提取物的制备
将山茱萸原料1000g,适当粉碎,用20L 65%丙酮溶液进行提取,即20倍量,于62℃下回流提取两次,每次1.3h。合并提取液,趁热过滤,滤液合并后通过HPD-400大孔吸附树脂(天津允开树脂科技有限公司)柱,用水清洗柱子,再经68%乙醇洗柱,乙醇洗脱液置于52℃减压浓缩,回收溶剂,浓缩液冷冻干燥或喷雾干燥得到100g提取物。根据《中国药典》2020年版一部附录XB“鞣质含量测定法”测定,总鞣质含量73%。经检测,山茱萸总鞣质提取物不含多糖类成分和苷类成分。
实施例5山茱萸总鞣质提取物对D-半乳糖所致小鼠记忆获得障碍模型的改善作用
试验动物:健康雄性C57小鼠180只,体重25~38g,雌雄各半,随机分为6组。
造模药物:D-半乳糖(D-gal)。
供试药物:实施例4制备的山茱萸总鞣质提取物(含总鞣质73%);阳性对照药:脑复康(吡拉西坦)。
仪器:Morris水迷宫,上海玉研仪器有限公司生产。
造模与给药:将180只小鼠随机分为以下六组:空白对照组、模型组、阳性对照组和山茱萸总鞣质提取物高、中、低剂量治疗组,每组30只。参照文献方法,除空白对照组组外,其他各组动物每天颈皮下注射150mg/kg剂量的D-gal以复制建立老年痴呆模型,持续给药造模8周。阳性对照组小鼠接受D-gal处理后给予500mg/kg/d剂量吡拉西坦(用50mL的0.9%的生理盐水将5片该药物溶解,配制成0.032g/mL溶液)进行灌胃干预。山茱萸总鞣质提取物高、中、低剂量组每日在颈皮下注射D-gal后按300、150、50mg/kg/d剂量灌胃给药,正常对照组和模型组给予等量蒸馏水。
模型评价方法:为了评估小鼠的空间、记忆及学习认知水平,本研究采用Morris水迷宫实验进行相应的行为学考察。水迷宫实验在药物干预实验结束的前一周进行,具体内容主要包括:(1)适应性训练:保留隐蔽平台,每天于同一时间点让小鼠在水池中自由游泳,此阶段连续进行3天;(2)巡航实验:撤掉隐蔽平台,每天于同一时间点将小鼠放入迷宫,记录小鼠完成寻找并停留在平台位置上的时间即逃避潜伏期,若动物在60秒内仍未成功探索到平台,则逃避潜伏期记为60秒,可人工引导至平台并停留10秒,此实验阶段连续进行3天;(3)空间探索实验:实验最后一天撤去隐蔽平台,小鼠依然从同一入水点进行投放,记录小鼠在60秒内在原平台象限的停留时间及穿越的平台次数。
试验结果:Morris水迷宫实验结果发现(如表1所示),与空白对照组相比,模型组小鼠的逃避潜伏期较正常显著延长(P<0.01),且平台穿越次数也明显减少(P<0.01)。而给药干预后,山茱萸总鞣质提取物高、中、低各剂量组及阳性对照组小鼠的逃避潜伏期明显缩短(P<0.05或P<0.01),同时平台穿越次数也得到了明显提高(P<0.05或P<0.01),且均呈现一定剂量效应。综合这些结果,不难看出,山茱萸总鞣质提取物可显著改善D-gal诱导的痴呆小鼠学习与认知功能。
表1.各组实验小鼠逃避潜伏期和穿越次数实验结果(n=30)
注:与对照组相比*P<0.05,**P<0.01;与模型组相比#P<0.05,##P<0.01;与阳性对照组相比&P<0.05,&&P<0.01;山茱萸总鞣质提取物的剂量(mg/kg)是指含总鞣质73%的提取物的总量。
实施例6不同中药植物鞣质提取物对D-半乳糖所致小鼠记忆获得障碍模型改善作用的比较
试验动物:健康雄性C57小鼠240只,体重25~38g,雌雄各半,随机分为8组。
造模药物:D-半乳糖。
供试药物:实施例4制备的山茱萸总鞣质提取物(含总鞣质73%);阳性对照药:脑复康(吡拉西坦);商用石榴皮鞣质提取物(西安博孚生物科技有限公司)、五倍子鞣质提取物(长沙上禾生物科技有限公司)、地榆鞣质提取物(陕西永源生物技术有限公司)、覆盆子鞣质提取物(三原天域生物制品有限公司)中鞣质含量均在70%左右。上述所有中药植物中的鞣质提取物给药剂量均用按300mg/kg/d高剂量灌胃给药。
仪器:Morris水迷宫,上海玉研仪器有限公司生产。
造模与给药:将240只小鼠随机分为以下八组:空白对照组、模型组、阳性对照组和山茱萸总鞣质提取物治疗组、石榴皮鞣质提取物治疗组、五倍子鞣质提取物治疗组、地榆鞣质提取物治疗组、覆盆子鞣质提取物治疗组,每组30只。参照文献方法,除空白对照组组外,其他各组动物每天颈皮下注射150mg/kg剂量的D-gal以复制建立老年痴呆模型,持续给药造模8周。阳性对照组小鼠接受D-gal处理后给予500mg/kg/d剂量吡拉西坦(用50mL的0.9%的生理盐水将5片该药物溶解,配制成0.032g/mL溶液)进行灌胃干预。山茱萸总鞣质提取物治疗组、石榴皮鞣质提取物治疗组、五倍子鞣质提取物治疗组、地榆鞣质提取物治疗组、覆盆子鞣质提取物治疗组在颈皮下注射D-gal后均以300mg/kg/d剂量灌胃给药,正常对照组和模型组给予等量蒸馏水。
模型评价方法:为了评估小鼠的空间、记忆及学习认知水平,本研究采用Morris水迷宫实验进行相应的行为学考察。水迷宫实验在药物干预实验结束的前一周进行,具体内容主要包括:(1)适应性训练:保留隐蔽平台,每天于同一时间点让小鼠在水池中自由游泳,此阶段连续进行3天;(2)巡航实验:撤掉隐蔽平台,每天于同一时间点将小鼠放入迷宫,记录小鼠完成寻找并停留在平台位置上的时间即逃避潜伏期,若动物在60秒内仍未成功探索到平台,则逃避潜伏期记为60秒,可人工引导至平台并停留10秒,此实验阶段连续进行3天;(3)空间探索实验:实验最后一天撤去隐蔽平台,小鼠依然从同一入水点进行投放,记录小鼠在60秒内在原平台象限的停留时间及穿越的平台次数。
试验结果:Morris水迷宫实验结果发现(如表2所示),与空白对照组相比,模型组小鼠的逃避潜伏期较正常显著延长(P<0.01),且平台穿越次数也明显减少(P<0.01)。而只有山茱萸鞣质治疗组和阳性对照组小鼠的逃避潜伏期显著缩短(P<0.05或P<0.01),同时平台穿越次数也得到了明显提高(P<0.05或P<0.01)。石榴皮鞣质提取物治疗组、五倍子鞣质提取物治疗组、地榆鞣质提取物治疗组及覆盆子鞣质提取物治疗组均对痴呆小鼠逃避潜伏期和穿越次数没有显著影响,说明这几种富含鞣质的提取物对痴呆没有治疗疗效。综合这些结果,不难看出,山茱萸总鞣质提取物对D-gal诱导的痴呆小鼠学习与认知功能的改善作用具有特异性,而其他中药植物的鞣质提取物对治疗痴呆没有效果。
表2.各组实验小鼠逃避潜伏期和穿越次数实验结果(n=30)
注:与对照组相比*P<0.05,**P<0.01;与模型组相比#P<0.05,##P<0.01;与阳性对照组相比&P<0.05,&&P<0.01;与山茱萸鞣质治疗组相比@P<0.05,@@P<0.01。
实施例7临床疗效
病例:7例,其中男性4例,女性3例,均为阿尔茨海默病患者,平均年龄为57-74岁,病程0.6-4年。
治疗方法:每天口服山茱萸胶囊6粒,分2次服用,每粒胶囊含鞣质含量为73%的山茱萸总鞣质提取物70mg,连续服药8周。
诊断和判断标准采用美国精神病学会《精神疾病论断和统计手册(第四版)》(DSM-IV)和中华全国医学会老年学会制定的《老年痴呆诊断、辩证分型及疗效评价标准》。简易精神状态检查表(MMSE)评分,》5分为显效,4-2分为有效,<2为无效;日常生活自理能力表(ADL)评分,》6分为显效,5-3分为有效,<3分为无效。
治疗结果:结果(表3)表明,山茱萸总鞣质提取物可以显著改善老年性痴呆患者临床症状,提高认知能力,改善认知缺陷和社会活动能力。
表3.山茱萸总鞣质提取物对老年痴呆患者治疗前后MMSE、ADL积分影响
实施例8初步急性毒性试验结果
实验方法:取C57小鼠60只,体重25~8g,雌雄各半,随机分为6组,禁食不禁水16小时,经预试验找出山茱萸总鞣质提取物(含总鞣质73%)最大致死剂量为11.54g/kg,最小致死剂量为5.25g/kg,按1:0.866比例用蒸馏水将山茱萸鞣质提取物致死剂量进行等比稀释,得到6组不同剂量,分别给6组小鼠一次性灌胃(0.3mL/10g B.W)。试验周期持续7天,每天记录小鼠毒性反应及死亡数,用改良寇氏法计算LD50。
实验结果:雌性小鼠的口服半数致死量(LD50值)为7.6g/kg,雄性小鼠的口服半数致死量(LD50值)为6.9g/kg;山茱萸总鞣质提取物(含总鞣质73%)大剂量(7.44-11.54g/kg)时雄性小鼠口服有腹泻症状。用改良寇氏法计算LD50为7.0326±1.1268g/kg。
表4.山茱萸鞣质总提取物对小鼠得急性毒性试验
Claims (10)
1.一种山茱萸总鞣质提取物,其特征在于,通过包括如下步骤的方法制备得到:将山茱萸原料粉碎,用丙酮水溶液或丙酮-乙醚溶液作溶剂进行回流提取,提取液通过苯乙烯型大孔吸附树脂柱,水洗柱后用乙醇水溶液洗脱,洗脱液减压浓缩后经干燥得到山茱萸总鞣质提取物。
2.根据权利要求1所述的山茱萸总鞣质提取物,其特征在于:所述的丙酮水溶液的质量浓度为60-70%,丙酮-乙醚溶液中丙酮、乙醚的体积比为4-6:1;山茱萸原料与丙酮水溶液或丙酮-乙醚溶液的固液比为1:15-20。
3.根据权利要求1所述的山茱萸总鞣质提取物,其特征在于:所述的回流的温度为50-65℃。
4.根据权利要求1所述的山茱萸总鞣质提取物,其特征在于:所述的乙醇水溶液的质量浓度为35-75%。
5.根据权利要求1所述的山茱萸总鞣质提取物,其特征在于:所述的减压浓缩的温度为50-56℃。
6.根据权利要求1所述的山茱萸总鞣质提取物,其特征在于:所述的山茱萸原料选自山茱萸属山茱萸科山茱萸和川鄂山茱萸中的至少一种。
7.权利要求1-6任一项所述的山茱萸总鞣质提取物或含权利要求1-6任一项所述的山茱萸总鞣质提取物的组合物在制备老年痴呆防治药物中的应用。
8.一种老年痴呆防治药物,其特征在于:包含权利要求1-6任一项所述的山茱萸总鞣质提取物。
9.根据权利要求8所述的老年痴呆防治药物,其特征在于:包含制药中可以被接受的辅料成分。
10.根据权利要求7所述的应用或权利要求8或9所述的老年痴呆防治药物,其特征在于:所述的老年痴呆防治药物为口服型药物制剂或注射型药物制剂。
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