CN108096270A - 一种治疗糖尿病肾病的药物组合物 - Google Patents
一种治疗糖尿病肾病的药物组合物 Download PDFInfo
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- CN108096270A CN108096270A CN201711415664.4A CN201711415664A CN108096270A CN 108096270 A CN108096270 A CN 108096270A CN 201711415664 A CN201711415664 A CN 201711415664A CN 108096270 A CN108096270 A CN 108096270A
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- plantago asiatica
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- linne polyoses
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Abstract
本发明涉及一种治疗糖尿病肾病的药物组合物，其中活性成分包括雷公藤乙素和车前子多糖，其中雷公藤乙素和车前子多糖的重量比为（1:20）~（20:1）。本发明的药物组合物中两种活性成分能产生协同作用，显著治疗糖尿病肾病，实现减毒增效。
Description
技术领域
本发明涉及制药领域，具体涉及一种治疗糖尿病肾病的药物。
背景技术
糖尿病肾病（diabetic nephropathy，DN）是指糖尿病微血管病变导致的肾小球硬化，又称糖尿病肾小球硬化症。DN是糖尿病主要的慢性并发症之一，是一种较为常见的疾病，也是导致终末期肾病（end-stage renal disease，ESRD）的主要原因，将近1/3的糖尿病患者发展为糖尿病肾病。随着全球范围内的糖尿病患者的不断增加，DN的患病率也随之提高。根据流行病学统计研究，预计到2030年，世界范围内的糖尿病患者将达到3.66亿，而糖尿病肾病患者将超过1亿。
DN的发病机制复杂，迄今尚未完全清楚。近年来临床及实验研究显示：糖代谢紊乱（糖基化终末产物的形成，多元醇通路的激活，蛋白激酶C活性增高）及肾脏血流动力学改变，在DN的发病过程中起着重要作用，同时也认为多种细胞因子的异常表达、遗传基因易感性、氧化应激加速、及细胞因子（转化生长因子、血管内皮生长因子、肿瘤坏死因子α等）的激活、激肽释放酶-激肽系统作用等引起组织损伤等因素也有一定的作用，各因素间又相互影响。
目前，DN临床西医治疗主要通过控制病人血糖、血压、调节脂质代谢，常用的药物包括：RAAS阻断剂（ACEI/ARB，醛固酮抑制剂，直接肾素抑制剂），利尿剂，NSAIDs，二甲双胍，锂和地高辛。另外，研究表明多种中药有效成分可经由抑制蛋白质糖基化终产物(AGEs）的生成、抑制肾脏氧化应激作用、抑制肾脏醛糖还原酶活性、抑制肾小球系膜的扩张、改善血液流变学等方面协同起效作用于DN。近年来针对DN防治的中药有效成分的研究成为热点，包括黄芪多糖等多糖类、槲皮素等黄酮类、小檗碱等生物碱类、雷公藤多苷等多苷类物质均有报道。
雷公藤（Tripterygium wilfordii Hook.f. ）系卫矛科雷公藤属植物，雷公藤多苷（Tripterygium glycosides）是从中药雷公藤中提取的有效组分，具有抗炎、免疫抑制等多种药理活性，临床应用广泛，但其在肝肾、胃肠道、免疫系统等方面体现的毒副作用也引起广泛关注。雷公藤乙素（Tripdiolide），又名雷公藤内酯二醇，是从雷公藤中分离出来的含有3个环氧基的二萜内酯类化合物，分子式为C20H24O7，分子结构中有α,β-不饱和醛酮内酯环，易溶于氯仿、二氯甲烷、乙醇、甲醇等，不溶于石油醚、正己烷，微溶于水。雷公藤乙素是雷公藤多苷的主要活性成分之一。
车前子为大粒车前（Plantago asiatica L.）或平车前（Plantag depressaWilld.）的干燥成熟种子，车前子被我国卫生部列为可用于保健食品的物质，也是我国传统中医用药之一。车前子细胞壁中含有大量的粘液物质，为车前子胶，常常被称为车前子多糖，能与胆酸相结合，促进胆固醇代谢，具有降低胆固醇的作用。车前子多糖由于是半发酵性膳食纤维，在肠道内不容易被消化，且能吸水增加体积，因而具有整肠通便的作用。同时它还有降低血糖、调节免疫活性、杀菌消炎、抗氧化等功效。
目前，将雷公藤乙素与车前子多糖组合用于防治糖尿病肾病的应用尚未见报道。
发明内容
本发明的目的是提供一种能有效防治糖尿病肾病，且毒副作用低的药物组合物。
为实现上述目的，本发明采用以下技术方案：
本发明的第一方面是提供一种能有效防治糖尿病肾病的药物组合物，包括活性成分雷公藤乙素和车前子多糖。
优选的，所述药物组合物中，雷公藤乙素和车前子多糖的重量比为（1:20）~（20:1）。
更优选的，雷公藤乙素和车前子多糖的重量比为（1:9）~（9:1）。
更优选的，雷公藤乙素和车前子多糖的重量比为（1:4）~（4:1）。
更优选的，雷公藤乙素和车前子多糖的重量比为3:2。
优选的，所述车前子多糖的制备方法如下：去脂后车前子加入氢氧化钠溶液，提取后过滤，将滤液用盐酸调节至中性，去蛋白后将粗多糖溶液浓缩，过氧化氢溶液去色素，离心取上清液浓缩，加入乙醇沉淀过夜，离心后滤渣依次用乙醇、丙酮和乙醚洗涤，冷冻干燥，即得。
优选的，所述药物组合物中进一步包括药学上可接受的辅料。
更优选的，所述药学上可接受的辅料选自填充剂、崩解剂、粘合剂、润滑剂、矫味剂中的一种或多种。
最优选的，填充剂选自甘露糖醇、山梨糖醇、乳糖、预胶化淀粉中的一种或多种；崩解剂选自交联羧甲基纤维素钠、交联羧甲基淀粉钠、交联聚维酮、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮中的一种或多种；粘合剂选自聚维酮、羟丙基纤维素中的一种或多种；润滑剂选自微粉硅胶、硬脂酸镁、二氧化硅、聚乙二醇中的一种或多种；矫味剂选自阿斯巴甜、薄荷香精、香蕉香精中的一种或多种。
优选的，所述药物组合物的剂型为片剂、胶囊剂、滴丸、糖浆剂等。
更优选的，所述片剂为崩解片。
本发明的另一方面是提供一种上述药物组合物在制备治疗糖尿病肾病的药物中的应用。
本发明具有积极有益的效果：
本发明的发明人经过反复多次试验，意外发现将雷公藤乙素和车前子多糖组合使用对于糖尿病肾病的防治具有协同增效的效果。此外，由于与安全性较好的车前子多糖组合应用即可产生较好的疗效，因此，在一定程度上降低了具有一定毒副作用的雷公藤乙素的用量，起到减毒增效的作用。
具体实施方式
下面结合实施例对本发明作更进一步的说明，但本发明的实施方式不限于此。下述实施例中所使用的实验方法如无特殊说明，均为常规方法。
实施例1、车前子多糖的提取
称取50g去脂后的车前子，加入30倍量0.5M的NaOH，80℃提取2h，重复三次，过滤，盐酸将滤液调节至中性，采用Sevag法去蛋白，将粗多糖溶液浓缩，加入15%体积的过氧化氢，60℃去色素后，离心，取上清液浓缩，加入4倍体积95%的乙醇，醇沉过夜，离心。滤渣依次用乙醇、丙酮和乙醚分别洗涤一次，冷冻干燥，即得。
如无特别说明，实施例2-11中使用的车前子多糖均为实施例1制备的车前子多糖。
实施例2
取25g雷公藤乙素、25g车前子多糖、100g微晶纤维素和220g甘露糖醇混匀，过100目筛，用乙醇制软材，过40目筛制粒，然后于40℃干燥30分钟，用80目筛整粒；最后将20g的聚维酮过100目筛后与颗粒混匀，再加入5g二氧化硅和5g阿斯巴甜，压片制成1000片崩解片，每片重量为400mg。
实施例3
取45g雷公藤乙素、5g车前子多糖、120g微晶纤维素和200g甘露糖醇混匀，过100目筛，用乙醇制软材，过40目筛制粒，然后于40℃干燥30分钟，用80目筛整粒；最后将15g的聚维酮过100目筛后与颗粒混匀，再加入8g二氧化硅和7g阿斯巴甜，压片制成1000片崩解片，每片重量为400mg。
实施例4
取5g雷公藤乙素、45g车前子多糖、100g交联羧甲基纤维素钠和220g山梨糖醇混匀，过100目筛，用乙醇制软材，过40目筛制粒，然后于40℃干燥30分钟，用80目筛整粒；最后将20g的羟丙基纤维素过100目筛后与颗粒混匀，再加入5g微粉硅胶和5g香蕉香精，压片制成1000片崩解片，每片重量为400mg。
实施例5
取40g雷公藤乙素、10g车前子多糖、80g交联羧甲基纤维素钠和230g山梨糖醇混匀，过100目筛，用乙醇制软材，过40目筛制粒，然后于40℃干燥30分钟，用80目筛整粒；最后将25g的羟丙基纤维素过100目筛后与颗粒混匀，再加入8g微粉硅胶和7g香蕉香精，压片制成1000片崩解片，每片重量为400mg。
实施例6
取10g雷公藤乙素、40g车前子多糖、90g交联羧甲基淀粉钠和240g乳糖混匀，过100目筛，用乙醇制软材，过40目筛制粒，然后于40℃干燥30分钟，用80目筛整粒；最后将20g的羟丙基纤维素过100目筛后与颗粒混匀，再加入15g微粉硅胶和5g薄荷香精，压片制成1000片崩解片，每片重量为400mg。
实施例7
将实施例2中的25g雷公藤乙素、25g车前子多糖替换成50g雷公藤乙素，其余与实施例1相同。
实施例8
将实施例2中的25g雷公藤乙素、25g车前子多糖替换成50g车前子多糖，其余与实施例2相同。
实施例9
将实施例2中的25g雷公藤乙素、25g车前子多糖替换成45g雷公藤乙素、5g车前子多糖，其余与实施例2相同。
实施例10
将实施例2中的25g雷公藤乙素、25g车前子多糖替换成5g雷公藤乙素、45g车前子多糖，其余与实施例2相同。
实施例11
将实施例2中的25g雷公藤乙素、25g车前子多糖替换成30g雷公藤乙素、20g车前子多糖，其余与实施例2相同。
试验例1、药物组合物在防治糖尿病肾病中的应用
取大鼠若干，按55mg/kg一次性腹腔注射链脲佐菌素溶液造模，1周后尾静脉采血测定空腹血糖（BG）及尿量，将血糖≥16.7mmol/L，尿量大于空白对照组的50%作为DN大鼠成模标准。取造模成功的大鼠140只，随机分为7组，即模型对照组、药物对照组（实施例7和8）和本发明药物组（实施例2和9-11），另取未造模大鼠20只作为空白对照组，以上每组大鼠雌雄各半。除模型对照组外，各组大鼠给予药物灌胃给药，每日一次，共计12周；其中模型对照组给予20ml/kg生理盐水，药物对照组和本发明药物组分别将实施例2和9-11制备的崩解片加蒸馏水配制成药物活性成分总浓度均为10mg/L的混悬溶液，按20ml/kg灌胃。实验期间大鼠标准饮食、自由饮水。8周后，收集各组大鼠24h尿液，记录尿量，一次性处死大鼠，大鼠血糖（BG）、血甘油三酯（TG）、血总胆固醇（TC）、血清肌酐（Scr）、BUN采用7600型全自动生化分析仪进行检测，24h尿蛋白量的测定按照试剂盒说明书进行操作，具体测定结果见表1。用ELISA双抗夹心法检测大鼠肾组织和血清中转化生长因子β1（TGF-β1）的含量，具体测定结果见表2。
表1 各组大鼠BG、TG、TC、Scr、BUN、24h尿蛋白量
表2 各组大鼠肾组织和血清中TGF-β1含量
由上述实验可以看出，本发明的药物组合物能够有效治疗糖尿病肾病，特别是雷公藤乙素和车前子多糖的组合使用产生了协同效果，减少了具有毒副作用的雷公藤乙素的使用量。在活性成分总量保持不变的情况下，使用本发明含雷公藤乙素和车前子多糖的药物组合物（实施例2和9-11）较单独使用含雷公藤乙素或车前子多糖的药物组合物（实施例7和8），大鼠BG、TG、TC、Scr、BUN、24h尿蛋白量值显著下降，肾脏TGF-β1值显著下降，血清TGF-β1值显著上升，DN大鼠肾脏修复明显，证实本发明药物组合物在防治糖尿病肾病方面的效果显著，其中雷公藤乙素和车前子多糖重量比为3:2的药物组合物效果最为突出，产生了难以预期的优异效果。
Claims (10)
1.一种防治糖尿病肾病的药物组合物，其特征在于，其中活性成分包括雷公藤乙素和车前子多糖。
2.根据权利要求1所述的药物组合物，其特征在于，雷公藤乙素和车前子多糖的重量比为（1:20）~（20:1）。
3.根据权利要求2所述的药物组合物，其特征在于，雷公藤乙素和车前子多糖的重量比为（1:9）~（9:1）。
4.根据权利要求4所述的药物组合物，其特征在于，雷公藤乙素和车前子多糖的重量比为3:2。
5.根据权利要求1所述的药物组合物，其特征在于，所述药物组合物中进一步包括药学上可接受的辅料。
6.根据权利要求5所述的药物组合物，其特征在于，所述药学上可接受的辅料选自填充剂、崩解剂、粘合剂、润滑剂、矫味剂中的一种或多种。
7.根据权利要求6所述的药物组合物，其特征在于，填充剂选自甘露糖醇、山梨糖醇、乳糖、预胶化淀粉中的一种或多种；崩解剂选自交联羧甲基纤维素钠、交联羧甲基淀粉钠、交联聚维酮、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮中的一种或多种；粘合剂选自聚维酮、羟丙基纤维素中的一种或多种；润滑剂选自微粉硅胶、硬脂酸镁、二氧化硅、聚乙二醇中的一种或多种；矫味剂选自阿斯巴甜、薄荷香精、香蕉香精中的一种或多种。
8.根据权利要求1所述的药物组合物，其特征在于，所述药物组合物的剂型为片剂、胶囊剂、滴丸、糖浆剂。
9.根据权利要求8所述的药物组合物，其特征在于，所述片剂为崩解片。
10.权利要求1-9任一项所述的药物组合物在制备治疗糖尿病肾病的药物中的应用。
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| ZHAO-HONG CHEN等: "Triptolide reduces proteinuria in experimental membranous nephropathy and protects against C5b-9-induced podocyte injury in vitro", 《KIDNEY INTERNATIONAL》 * |
| 刘颖斐 等: "车前子多糖治疗大鼠膜性肾病的实验探讨", 《中国实验方剂学杂志》 * |
| 张然 等: "车前子多糖对糖尿病小鼠氧化应激的影响", 《天津医药》 * |
| 王亚娟: "雷公藤乙素对糖尿病肾病大鼠肾脏中转化生长因子β1的影响", 《浙江中医杂志》 * |
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