CN1319981C - 车前草总苷的制备工艺及其在医药中的应用 - Google Patents
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Abstract
车前草总苷及以车前草总苷为药品原料生产的药物制剂提供了用以含酸的低级醇为溶剂加热回流提取，再经大孔树脂纯化制备车前草总苷及以车前草总苷为药品原料生产的制备成车前草总苷胶囊、片剂、颗粒剂药物制剂的工艺，以及车前草总苷或其药物制剂作为治疗慢性肾小球肾炎或/和作为免疫抑制或/和作为利尿剂在医药领域中的应用。
Description
技术领域 本发明属于中药技术应用领域，特征上涉及治疗慢性肾小球肾炎，和/或具有免疫抑制作用，和/或具有利尿作用。车前草总苷来源于常用中药平车前(Plantago depressaWilld)及其同属植物(如P.asiatica L.、P.camtschatica Link、P.maritima L等)的全草。
背景技术 慢性肾小球肾炎(chronic glomeralonephritis)是由多种疾病引起，通过不同的发病机理，具有不同病理改变，原发于肾小球的一组疾病。其临床特点为病程长，多为缓慢进行型。本病预后较差。慢性肾小球肾炎的治疗除利尿及降压等对症治疗外，目前临床治疗慢性肾小球肾炎的药物主要是糖皮质激素(如强的松)及细胞毒类(如盐酸氮芥、环磷酰胺)药物单独或联合使用，由于这些药物有明显的毒副作用，因此，临床迫切需要一种高效低毒的慢性肾小球肾炎治疗药物。
发明内容 本发明的目的是从车前草及其同属植物中提取的车前草总苷对慢性肾炎动物模型有明显降低尿蛋白作用，并有利尿作用，而未发现有明显的毒副作用。可以将它单独或与其他中西药合并研制成为一种慢性肾炎治疗剂。
车前草为车前科植物平车前Plantago depressa Willd的干燥全草，又称当道，始载于《四声本草》，性味甘、寒。归肝、肾、肺、小肠经。具有清热利尿、凉血解毒等功效。治小便不通、淋浊、尿血、水肿、痈肿疮毒、带下。车前草总苷含量为药材的0.5～6％，为苯乙醇苷类化合物，主要有acteoside(类叶升麻苷)、cisacteoside、isoacteoside、hydroxyacteoside、Methoxyacteoside等成分，其中主要成分类叶升麻苷，占总苷的40～70％。
本发明提供了一类如结构式I的化合物
结构式(I)
结构式(II)
本发明提供的车前草总苷的化学组成是一类以结构式(I)为骨架R1或为氢(H)或为羟基(OH)或为甲氧基(OCH3)取代，R2或为氢(H)或为结构式(II)取代，R3或为氢(H)或为结构式(II)取代，R4为鼠李糖基或为氢(H)取代的混合物。其中主要成分类叶升麻苷的结构式是结构式(I)的R1、R2为氢取代，R3为结构式(II)取代，R4为鼠李糖基取代。
上述化合物的定量分析方法可以用常规方法进行，通常用色谱法。例如HPLC法；或用紫外分光光度法。
如上所述，本发明的总苷具有降低尿蛋白、利尿和改善血清肌肝和尿素氮水平等实际的治疗用途。
具体实施方式
实例1.车前草总苷的制备工艺
车前草粗粉，加入一定量的酸性醇，回流提取两次，滤过，合并两次滤液，减压回收醇至尽，水溶液离心除去沉淀后，通过大孔树脂柱，水洗，用20～80％的酸性醇洗脱，收集洗脱液减压回收醇至尽，水溶液再通过大孔树脂柱，水洗后，用60～100％的醇洗脱，收集洗脱液，加活性炭脱色，过滤，减压回收醇，得黄棕色车前草总苷。
实例2 车前草总苷的利尿作用试验
给大鼠1次灌胃给药，剂量为60mg/Kg和30mg/Kg，另设空白对照组(蒸馏水)，各组均按25ml/Kg的容量给予，同时腹腔注射生理盐水25ml/Kg(观察期间不再饮水)，然后置大鼠代谢笼，每笼放2只。记录1，2，3，4，6小时的尿量。3天后动物各组轮换再重复1次试验。可见，一次经口给予车前草总苷后尿量有增加，60mg/Kg组从给药后第一小时末开始至第六小时末的整个试验期间均显示有利尿作用，且有统计学差异。
车前草总苷的利尿作用(n＝24)
| 组别 | 剂量mg/Kg | 给药后不同时间累计尿量(ml)(X±SD) | ||||
| 1h | 2h | 3h | 4h | 6h | ||
| 对照总苷低总苷高 | 3060 | 2.68±1.093.18±0.743.64±0.41** | 4.13±0.574.47±1.185.05±0.71** | 4.97±0.515.27±1.245.44±0.66* | 5.56±0.915.98±1.356.46±0.66** | 6.77±1.247.17±1.437.48±0.76* |
注：T检验，与对照组比较：*p＜0.05，**p＜0.01
实例3 车前草总苷的免疫调节作用
方法：SRBC定量溶血测定法观察车前草总苷对小鼠抗体生成的影响。
用BALB/C小鼠，雌性，按体重均匀分为5组；受试药物按剂量设40、20、10mg/Kg体重三个剂量组，经口给予车前草总苷溶液；空白对照组经口给予同体积的蒸馏水。每天给药一次，连续给药9天。以腹腔注射15mg/Kg环磷酰胺为阳性对照组，在试验的第6～8天给药，每天一次。在给药的第六天全部小鼠腹腔注射5％SRBC以致敏，每只0.2ml(相当于3×108SRBC)致敏后96小时，放血处死小鼠，取脾。用RPMI1640培养液按15mg脾重/ml制成脾细胞悬液，依次在试管中加入等容量三脾细胞悬液、0.2％SRBC和1∶10豚鼠血清，混匀，37℃水浴温育1小时，离心，取上清液，于分光光度计测定吸光度，以OD值表示抗体生成水平。车前草总苷10～20mg/Kg经口给药可明显抑制致敏小鼠IgM抗体生成，对体液免疫呈较强的抑制作用。
车前草总苷对小鼠抗体生成的影响(X±SD)
| 剂量mg/Kg | 动物数只 | 抗体溶血值(OD) | 抑制率(％) | |
| 空白对照CY车前草总苷高车前草总苷中车前草总苷低 | 1520105 | 1210101010 | 1.006±0.1690.545±0.168**0.662±0.189**0.730±0.170**0.892±0.178 | 45.834.227.411.3 |
T检验 *p＜0.05 **p＜0.01
实例4 车前草总苷对大鼠C-BSA肾炎的作用观察
方法1：将阳离子化牛血清白蛋白(C-BSA)1mg，加入0.5mlD到PBS中，再加0.5ml不完全佐剂充分混匀，研磨成乳剂。在大鼠双侧腋下、腹股沟作多点皮下注射进行预免疫。预免疫一周后正式免疫，每只大鼠尾静脉注射C-BSA2.5mg，每周三次，四周后加量到4mg/只，直到试验结束。
在正式免疫四周后，开始给药，每日一次，连续给药四周。设车前草总苷高、中、低(分别为40、20、10mg/Kg)三个剂量组，经口给药；环磷酰胺(CY)10mg/Kg，腹腔注射给药，为阳性对照组。模型组经口给蒸馏水，另设空白对照组，经口给蒸馏水。观测药前、给药后1、2.5、4周24小时尿旦白总量，车前草总苷20～40mg/Kg，经口给药四周，对大鼠C-BSA肾炎有明显的治疗作用，其作用强度与腹腔注射10mg/Kg环磷酰胺的作用相似。
24小时尿蛋白量的变化(X±SD)
| 组别 | 剂量mg/Kg | 尿蛋白(mg/24h) | |||
| 给药前 | 给药10天 | 给药20天 | 给药30天 | ||
| 空白模型CY四味肾炎片车前草总苷高车前草总苷中车前草总苷低 | 81000502512.5 | 10.7±2.8(7)216.2±172.5(14)219.0±174.7(14)219.2±190.8(14)217.5±185.5(14)218.9±181.2(14)216.6±182.2(14) | 13.5±3.0(7)460.6±195.4(13)293.2±131.9(12)*501.5±177.5(13)427.3±213.0(14)442.7±242.0(12)431.0±220.8(12) | 13.1±3.4(7)454.5±220.1(13)283.0±156.5(11)*443.5±166.4(13)374.7±191.5(14)396.0±160.6(12)405.0±200.8(12) | 12.4±3.4(7)427.2±178.8(12)210.9±139.1(11)**380.4±159.2(12)246.9±114.8(14)**272.4±124.7(12)*333.9±227.8(12) |
注：T检验与模型组比较，*p＜0.05 **p＜0.01；()内数字为动物数。
实例5 车前草总苷对兔IgG加速型小鼠肾毒血清肾炎的作用
在无菌条件下，取小鼠肾皮质剪碎，研磨并过200目钢丝网，1500rpm离心10分钟，取沉淀物，加福氏完全佐剂，充分研磨使成均匀的含10％肾组织的乳剂，用此乳剂免疫兔，1ml/只，皮下多点注射，每周一次，共六次。第一次免疫要加入卡介苗原浆，浓度为4mg/ml乳剂。末次注射后5天，兔颈动脉放血，离心得血清，经灭活补体及BALB/C小鼠血球吸收后再离心得肾毒血清。
小鼠先腹腔注射兔IgG0.5mg(与0.25ml福氏完全佐剂充分混匀)，4天后尾静脉注射肾毒血清0.08ml/只，注射后5天，测小鼠尿蛋白及血浆白蛋白含量，按其测定值均匀6组，设模型对照组，阳性对照组，给环磷酰胺(CY)10mg/kg(i.p)，空白对照组，给蒸馏水(p.o)，给药组设四个剂量组，分别给车前草总苷80、40、20mg/kg(p.o)。连续给药21天。在给药后的第14天、21天测尿蛋白。车前草总苷40～80mg/kg口服3周，对兔IgG加速型小鼠肾毒血清肾炎有明显的治疗作用，其作用强度与CY10mg/kg(i.p)相似；20mg/kg剂量组的作用较弱。显示有一定的量效关系。22天放血处死，取小鼠肾作病理检查，常规固定，包埋，切片，P.A.S及Masson三色染色，光镜下观察，模型组动物大多有肾小球毛细管基底膜明显增厚，Mas-son染色标本可见部分肾小球毛细管呈纤维素样坏死，部分肾小球囊壁细胞增生，形成新月体，严重者肾小球与囊粘连，有纤维化和萎缩现象，部分肾小球管腔有蛋白管型存在。与模型组比，CY组及车前草总苷高、中、低剂量组肾脏病变较轻，肾小管腔内蛋白管型数量减少。
小鼠尿蛋白的变化(X±SD)
| 组别 | 剂量mg/kg | 尿蛋白(mg/dl) | ||
| 给药前 | 给药2周 | 给药3周 | ||
| 空白模型CY保肾康车前草总苷高车前草总苷中车前草总苷低 | 10100804020 | 24.0±9.7312±76(17)306±81(16)309±80(16)312±76(17)314±74(17)309±80(17) | 24.0±9.7277±44(13)202±76(12)*259±69(14)194±85(14)**191±91(15)**221±74(14)* | 26.0±8.4259±38(11)198±64(11)*244±76(14)183±75(14)**156±96(14)**188±85(13)* |
注：T检验，与模型组相比较 *p＜0.05 **p＜0.01；( )内数字代表动物数。
实例6.车前草总苷胶囊的制备
将100g车前草总苷加入适量乳糖，结晶纤维素，聚乙二醇3000，羧甲基淀粉钠，干压制粒后，加硬脂酸镁适量，分装成1000粒，即得。每粒含类叶升麻苷30mg。
实例7.车前草总苷片剂的制备
100g的车前草总苷，加入适量乳糖，淀粉，以60～80％乙醇为粘合剂制粒，干燥，整粒，加适量硬脂酸镁，压制成1000片，包薄膜衣，每片含类叶升麻苷30mg。
实例8.车前草总苷颗粒剂的制备
100g的车前草总苷，加入适量乳糖，糊精，糖粉，以60～80％乙醇为粘合剂制粒，干燥，整粒，分装成1000袋，每袋含类叶升麻苷30mg。
Claims (4)
1、车前草总苷在制备用于治疗慢性肾小球肾炎的药物中的应用，所述的车前草总苷是通过用学名为Plantago depressa Willd的中药平车前或其同属植物P.asiatica L.或P.camtschatica Link或P.maritima L.的全草粉碎后经酸性醇回流提取两次后，合并提取液，回收醇，离心除去沉淀，通过大孔树脂柱并用水洗后，树脂柱用20-80％酸性醇洗脱，收集醇洗脱液，减压回收醇，水溶液再通过大孔树脂柱并用水洗后，树脂柱用60-100％醇洗脱，收集醇洗脱液，加活性炭脱色，过滤后减压回收醇并浓缩的方法得到的以类叶升麻苷为主的苯乙醇苷类化合物的提取部位。
2、权利要求1所述的车前草总苷的应用，其特征在于：用于治疗慢性肾小球肾炎的药物是以车前草总苷为原料加不同辅料，经一定工艺加工成的胶囊剂或片剂或颗粒剂。
3、权利要求1所述的车前草总苷在制备具有免疫抑制作用的药物中的应用。
4、权利要求1所述的车前草总苷在制备用于治疗大鼠C-BSA肾炎或兔IgG加速型小鼠肾毒血清肾炎的药物中的应用。
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| CN106034521A (zh) * | 2016-05-31 | 2016-10-26 | 山东胜伟园林科技有限公司 | 一种使用氨基酸营养液的膜下滴灌方法及其在盐碱地中种植甜高粱的应用 |
| CN106509696A (zh) * | 2016-09-30 | 2017-03-22 | 南陵县石斛产业协会 | 一种车前草风味鳡鱼罐头 |
| CN112586515A (zh) * | 2020-12-22 | 2021-04-02 | 长江绿银(无锡)科技有限公司 | 一种北美车前中提取化感物质和苯乙醇苷类化合物的方法 |
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