CN102225088A - 杜仲木脂素在制备防治高血压肾损害药物上的应用 - Google Patents
杜仲木脂素在制备防治高血压肾损害药物上的应用 Download PDFInfo
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Abstract
杜仲木脂素在制备防治高血压肾损害药物上的应用，杜仲木脂素是以杜仲为原料提取制备而成，用于制备防治高血压肾损害的药物。能较好地改善自发性高血压对肾小球、肾小管的损害，具有抑制III型胶原表达和系膜细胞增殖的药理作用，有效地防治高血压肾损害。
Description
技术领域
本发明涉及医药技术领域中将杜仲木脂素应用于制备防治高血压肾损害的药物。
背景技术
肾脏是是高血压损害最常累及靶器官。近年来，我国高血压肾脏疾病患者的数量呈上升趋势，高血压肾脏疾病已成为危害国人健康的重要疾病。因此，防治高血压肾损害是高血压病防治的重要目标。虽然高血压是肾脏靶器官损害的始动因素，但高血压发生后肾脏靶器官在损伤过程中的自身病理变化仍是有自身的特点的，它主要表现为肾小球硬化及间质纤维化，其机制不仅与肾小球基底膜结构损伤、舒血管物质/缩血管物质比例失衡导致的肾局部缺血缺氧性损伤有关，还与胶原生成增多、多种炎症递质表达引起的肾间质炎症、成纤维细胞和肾小球系膜细胞增殖有关。这些病理过程最终将导致高血压肾纤维化和肾功能衰竭。在这一过程中，肾小球系膜细胞增殖与III型胶原表达发挥了重要的作用，其虽受高血压因素诱导，但其病理改变趋势在疾病发展过程中持续存在：①肾小球系膜细胞增生是重要的病理形态学改变，肾小球系膜细胞增殖、激活，不断促进细胞外基质的沉积和肾小球硬化的发生；②III型胶原主要由系膜细胞合成，持续在肾小球内沉积，促进细胞外基质(ECM)蓄积，最终参与了肾小球硬化的发病机制。
目前，国内外广泛应用的第一线抗高血压药物包括利尿剂、钙通道阻滞剂、β受体阻滞剂、ACEI与ARB等五大类药物。在这些药物中，仅有ACEI与ARB类药物被研究证实具有可能的延缓肾脏疾病进展的作用，而其他几大类降压药物均无保护肾脏的功能，长期应用利尿剂类药物还可能加重电解质紊乱、对肾脏产生不利影响。因此，寻找和开发具有保护肾脏、兼具降压作用的新型药物，是防治高血压肾损害的有效途径。
杜仲(Eucommia ulmoides)，又名思仙、丝棉树，是我国特有的单种科植物、国家二类珍稀保护植物，主要分布于甘、陕、豫、鄂、晋、湘、川、滇、黔、桂、闽等省。其皮、茎、叶均可入药，其传统药理作用为“补肝肾、强筋骨、降血压等”。现代研究表明，杜仲含有多种活性成分，具有促进机体功能、抗衰老、抗癌等效果，尤其是具有对高血压的“双向调节”作用。在我国，杜仲亦常被单独或与其他药物联合，用以作为降血压的药物。而杜仲木脂素是从杜仲中分离出来的，木脂素化合物已知有28种，分别属于双环氧木脂素类、单环氧木脂素类、环木脂素类、新木脂素类和倍半木脂素类等。PDG标准品常用于杜仲木脂素成分及含量的鉴定。目前，国内外针对杜仲木脂素的药理作用研究较少。已有研究表明，杜仲木脂素具有较强的降压作用，可以抗高血压心血管重塑，并有效防治糖尿病并发症。
发明内容
本发明的目的旨在提供一种杜仲木脂素的在制备防治高血压肾损害上的药物的应用。
本发明将杜仲木脂素用于制备防治高血压肾损害的药物，所述的杜仲木脂素是由杜仲提取制备而成。
所述的杜仲木脂素特别适用于制备抑制肾皮质中III型胶原表达和/或肾小球系膜细胞增殖引起的抗高血压肾损害的药物。
所述的杜仲木脂素可以以含有杜仲木脂素的杜仲提取物的形式使用，用于制备以上的药物。
发明人通过研究表明，杜仲木脂素可以较好地改善自发性高血压对肾小球、肾小管的损害，抑制肾皮质III型胶原表达和肾小球系膜细胞增殖，发挥抗高血压肾损害的作用，因而为将杜仲木脂素开发成一种具有防治高血压肾损害的新型药物提供了实验依据。
本发明的杜仲木脂素的药物制剂，是通过将杜仲原料经过提取或其他方式加工，制成药物活性物质单独作用，或是与其它可配合使用的用于防治高血压肾损害的活性成分共同作用，需要时加入药物可接受的载体，按照制剂学的常规技术制成药物制剂。
所述的杜仲木脂素可以以提取物形式作为活性物质制成药物制剂。所述提取物可以是浸膏形式的物质，可以是干浸膏也可以是流浸膏，可以是粉末状物质，根据制剂的不同需要制成不同的形态。
本发明的杜仲木脂素经过加工制备的可制成适合服用的任何单位剂量形式的药物制剂，这些药物制剂可以是以下剂型：片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、口服液、口含剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、滴剂或贴剂；需要时可以制成稀释制剂、肠溶制剂。
本发明的杜仲木脂素在制备成药物制剂时可加入药物可接受的载体，所述药物可接受的载体选自：抗氧剂、螯合剂表面活性剂填充剂崩解剂润湿剂分散剂润滑剂溶剂缓释材料肠溶材料pH调节剂、矫味剂、色素等，常用的载体如：甘露糖醇、右旋糖苷、乳糖、葡萄糖、山梨醇、甘露醇、木糖醇、氧化钠、硅衍生物、纤维素及纤维素衍生物、亚硫酸钠、焦亚硫酸钠、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、吐温80、琼脂、碳酸钙、碳酸氢钙、聚乙二醇、环糊精、β-环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁等。
所述的杜仲木脂素可以通过通过杜仲采用现有的多种提取方案如选自粉碎、压榨、煅烧、研磨、过筛、渗漉、萃取、水提、醇提、水沉、醇沉、酯提、酮提、层析、过滤等多种方法得到。
本发明杜仲木脂素可以以提取物的形式制备得到，其中优选制备方法包括以下步骤：
1.取中药杜仲皮，用含水乙醇回流提取，提取液过滤，药液浓缩；
2.将浓缩的药液通过大孔树脂柱，依次用水、醇溶液洗脱。
3.收集醇洗脱液，洗脱，干燥，得到提取物粉末。
本发明的杜仲木脂素的提取物的较为优选制备方法包括以上步骤：
1.中药杜仲皮去外皮后，切成小段，用含水乙醇溶液加热回流提取1-3次，每次1-2h，提取液减压浓缩至0.5-1.5倍药材量体积；
2.将浓缩的药液通过大孔吸附树脂柱进行有效成分富集，依次用水，15-25％甲醇或乙醇，45-55％甲醇或乙醇溶液洗脱。
3.收集45-55％甲醇或乙醇洗脱液，浓缩，干燥得提取物粉末。
另外，收集水洗脱液，浓缩，干燥，粉碎，粉末用甲醇溶解，弃去不溶物，回收甲醇并干燥得环烯醚萜类部位。
在步骤1中的提取溶剂为含水乙醇，优选为40-95％的乙醇。
在步骤2中大孔吸附树脂柱为HP系列、D101、AB-8等弱极性树脂。
在步骤3中的浓缩液采用的干燥技术可以是多种，如真空干燥、喷雾干燥、冻干，优选冻干技术。
附图说明
图1：PDG的代表性色谱图。注：PDG样品保留时间为11.8min。
图2：杜仲木脂素的代表色谱图。注：检测峰分离度较好，5.5mg/mL杜仲木脂素样品溶液中PDG的质量浓度为0.265mg/mL，经计算杜仲木脂素提取物中PDG的含量为4.8％。
图3：杜仲木脂素对SHR大鼠肾小管损伤的影响。注：*表示与正常对照组比较P＜0.05；#表示与阴性对照组比较P＜0.05。
图4：杜仲木脂素对SHR大鼠肾小球损伤的影响。注：*表示与正常对照组比较P＜0.05；#表示与阴性对照组比较P＜0.05。
图5：杜仲木脂素对SHR大鼠肾皮质III型胶原表达的影响。注：*表示与正常对照组比较P＜0.05；#表示与阴性对照组比较P＜0.05。
图6：杜仲木脂素对Ang II诱导大鼠系膜细胞增殖的影响。注：*表示与正常对照组比较P＜0.05；#表示与阴性对照组比较P＜0.05。
具体实施方式
以下实施例旨在说明本发明而不是对本发明的限定。
实施例1
杜仲木脂素抗高血压肾损害的实验研究
样品来源：对由杜仲提取制备的杜仲木脂素样品的木脂素成分含量鉴定采用的是紫外分光光度法；
条件：检测波长：277nm；1cm光径；对照品：松脂醇二糖苷(PDG)。对照品及样品用50％甲醇溶解，空白管用50％甲醇。
标准溶液的制备：精密称取5.68mg PDG，置于25mL容量瓶，用50％甲醇溶液溶解并稀释至刻度，摇匀，得到227μg/mL PDG储备液，置于4℃冰箱保存。将储备液用50％甲醇按梯度稀释成227、113.5、56.75、28.38、14.19μg/mL。
样品溶液的制备：精密称取134.4mg杜仲木脂素样品，置于10mL容量瓶，用50％甲醇溶液溶解并稀释至刻度，摇匀，得到13.4mg/mL杜仲木脂素储备液，然后用50％甲醇稀释至60μg/mL。
紫外测定结果：60.0μg/mL的杜仲木脂素样品，经紫外检测OD值为0.553，木脂素类成分浓度为54.7μg/mL，含量为91.2％。
2.对PDG的含量的鉴定采用的是高效液相色谱法。
色谱条件：固定相：BDS Hypersil C18柱(250mm×4.6mm，10μm)；流动相：甲醇∶水＝25∶75；检测波长：277nm；温度：25℃；流速1.0ml/min；进样量：5μl。
标准溶液的制备：精密称取5.00mg PDG，置于10mL容量瓶，加25mL甲醇∶水＝1∶1溶解并稀释至刻度，摇匀，得到200μg/mL PDG储备液，置于4℃冰箱保存。将储备液用50％甲醇按梯度稀释成100、50、25、12.5、6.25μg/mL。
样品溶液的制备：精密称取281.5mg杜仲木脂素样品，置于25mL容量瓶，用50％甲醇溶液溶解并稀释至刻度，颠倒及震荡摇匀，得到11.26mg/mL杜仲木脂素储备液。取2mL储备液于2000ppm离心10min，上清液用50％甲醇稀释至5.5mg/mL。
HPLC测定结果：图1为PDG的代表性色谱图，PDG样品保留时间为11.8min，图2为杜仲木脂素样品的色谱图，从中可以看出检测峰分离度较好，5.5mg/mL杜仲木脂素样品溶液中PDG的质量浓度为0.265mg/mL，经计算杜仲木脂素样品中PDG的含量为4.8％。
1.整体实验
1.1实验方法
高血压(SHR)大鼠，及WKY大鼠直接购买。
分组：8周龄WKY正常大鼠7只作为正常对照，SHR28只随机分为4组，每组7只：蒸馏水(阴性对照)、卡托普利(100mg·kg-1·d-1)、依帕司他(60mg·kg-1·d-1)、杜仲木脂素(300mg·kg-1·d-1)
给药方法：灌胃给药，1天1次，连续16周。
25周龄大鼠尿样(新鲜、24h)肾功能生化指标的测定：NAG、ALB、UCR(按照试剂盒说明操作)。NAG酶是反映肾小管功能的指标，评价杜仲木脂素对SHR大鼠肾小管功能改变的影响；12h尿液中比值K＝ALB/UCR是反映肾小球功能的指标，评价杜仲木脂素对SHR大鼠肾小球功能改变的影响。
26周龄大鼠肾脏损害指标的测定：III型胶原。III型胶原是反映肾脏损害严重程度的指标；采用天狼星红染色，检测皮质部细胞外基质主要成分III型胶原的表达量，以胶原容积分数(％)表示。
1.2实验结果
1.2.1杜仲木脂素对肾功能生化指标的影响
①SHR组大鼠的NAG酶活性较WKY大鼠(正常组)明显增加(＊P＜0.05)；卡托普利、依帕司他可显著降低NAG酶活性(#P＜0.05)；给予杜仲木脂素可使NAG酶活性较正常对照组降低(#P＜0.05)。(见图1)
②SHR组大鼠K值较WKY大鼠(正常组)明显增高(＊P＜0.05)，卡托普利、依帕司他可显著降低K值(#P＜0.05)；给予杜仲木脂素可使K值较正常对照组降低(#P＜0.05)。(见图2)
1.2.2杜仲木脂素对肾皮质III型胶原表达的影响
SHR组大鼠肾皮质微血管外III型胶原表达较WKY大鼠(正常组)明显增加(＊P＜0.05)；卡托普利、依帕司他可显著降低III型胶原表达(#P＜0.05)；给予杜仲木脂素可使III型胶原表达较正常对照组降低(#P＜0.05)。(见图3)
2.细胞实验
2.1实验方法
用Ang II诱导大鼠肾小球系膜细胞后，给予低、中、高浓度的杜仲木脂素。应用MTT法测定Ang II诱导大鼠肾小球细胞的增殖情况，在24h、48h、72h进行细胞计数，并以OD值表示。实验分为7组：(1)正常对照组；(2)AngII模型组(阴性对照组)(10-7mol/L)；(3)AngII(10-7mol/L)+洛沙坦(1μmol/L)；(4)AngII(10-7mol/L)+依帕司他(1μmol/L)；(5)AngII(10-7mol/L)+杜仲木脂素(30mg/L)；(6)AngII(10-7mol/L)+杜仲木脂素(60mg/L)；(7)AngII(10-7mol/L)+杜仲木脂素(120mg/L)。
2.2实验结果
与正常对照组比较，Ang II模型组的系膜细胞增殖呈现显著增高趋势(＊P＜0.05)；洛沙坦、依帕司他在48h、72h可显著降低Ang II诱导的系膜细胞增殖(#P＜0.05)；给予杜仲木脂素可使Ang II诱导的系膜细胞增殖在48h、72h呈现显著下降(#P＜0.05)。(见图4)
3.结论
由以上实验可得出结论：杜仲木脂素具有抑制肾皮质中III型胶原表达和肾小球系膜细胞增殖的药理作用，并且可以通过这些作用抗高血压肾损害。
实施例2
取杜仲树皮(去外皮)2Kg，用8L 65％乙醇回流提取两次，每次1h，过滤，合并两次提取液浓缩至800ml。用D101大孔树脂拌样上样(大孔树脂柱体积3L)，水洗3倍柱体积，1％氨水继续洗3倍柱体积，再水洗至中性。用20％乙醇洗脱2倍柱体积，用45％乙醇洗2.5倍柱体积。45％乙醇洗脱液浓缩至600ml。洗脱液浓缩后干燥成粉末。用松脂醇二葡萄糖苷作为对照，提取物经紫外检测木脂素成分含量为85％，经HPLC检测松脂醇二葡萄糖苷含量为12.5％；将该提取物作为活性成分制备抗高血压肾损害的药物。
实施例3
杜仲树皮(去外皮)切碎后，用65％的乙醇回流提取1h，过滤，提取液浓缩。经过HPD100大孔树脂吸附后，水洗3倍柱体积，20％乙醇洗2倍柱体积，45％乙醇洗2倍柱体积，45％乙醇洗脱液收集并浓缩，冻干，得到提取物粉末。取粉末60g，加入微晶纤维素230g，PVP10g，混匀，加入乙醇适量制软材，制粒，烘干，整粒，加少量硬脂酸镁，压片，制成1000片；作为制备抗高血压肾损害的药物。
Claims (4)
1.杜仲木脂素在制备防治高血压肾损害药物上的应用，其特征在于：所述的杜仲木脂素是以杜仲为原料提取制备得到，用于制备抗高血压肾损害的药物。
2.根据权利要求1所述的应用，其特征在于，所述的杜仲木脂素以含有杜仲木指素的杜仲提取物的形式使用，用于制备抗高血压肾损害的药物。
3.杜仲木脂素在制备防治高血压肾损害药物上的应用，其特征在于：所述的杜仲木脂素是以杜仲为原料提取制备而成，用于制备抑制肾皮质中III型胶原表达和/或肾小球系膜细胞增殖引起的抗高血压肾损害的药物。
4.根据权利要求3所述的应用，其特征在于，所述的杜仲木脂素以含有杜仲木指素的杜仲提取物的形式使用，用于制备抗高血压肾损害的药物。
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