马钱子生物碱贴剂定位镇痛药动学机制研究.pdfVIP

马钱子生物碱贴剂的定位镇痛与药动学机制研究  *1,2 2 2 2 2 1 1 1 汤淮波 ，蔡骅林 ，李焕德 ，颜苗 ，邓阳 ，熊艳 ，张令君 ，李湘玲 ，  （1 湘潭大学化学学院药学教研室，湘潭，411105 ，hb876@163.com；  2  中南大学湘雅二医院临床药学教研室，长沙，410011 ）  摘要 目的：马钱子生物碱是马钱子的主要活性成分，它们对肌肉与关节的局部炎症有显著 的临床疗效。但它们也是剧毒物质，临床服用存在严重的毒性风险。本研究应用体外透皮扩 散的方法优化马钱子生物碱贴剂的制剂处方，并探索该贴剂临床疗效的药动学机制。方法： 采用改良 Franz 扩散池，选用离体猪耳朵皮为屏障，以士的宁和马钱子碱透皮速率为指标， 2 优化马钱子生物碱贴剂的制剂处方。1cm 马钱子生物碱贴剂贴于小鼠腹部，研究贴剂对醋 酸引起的扭体反应的影响。贴药后 1.0、2.0 、4.0 、6.0 与 8.0 小时分别取六只小鼠摘取眼球 取血，采血后处死，分离用药部位的皮肤与腹膜，测定样品士的宁与马钱子碱的含量。微透 析探针从腹部开口处埋入腹腔，给药后每隔 1.0 小时收集微透析液并测定样品士的宁和马钱 子碱的含量。结果：马钱子生物碱贴剂的优选制剂处方以 87-4098 为压敏胶，含 5%油酸、士 的宁 2.32%与马钱子碱 1.59%。小鼠腹部应用优选贴剂能显著降低醋酸引起的扭体反应次数。 马钱子活性成分主要蓄积于用药部位皮下深层组织而不会显著地升高血药浓度。用药期间腹 腔液中非蛋白结合的士的宁与马钱子碱浓度维持稳定。结论：上述研究结果暗示马钱子生物 碱贴剂通过用药部位的皮肤定位传递下深层组织并能持续地产生疗效。 关键词：马钱子；贴剂；定位传递；微透析  Abstract Objective: Strychnos alkaloids, main active constituents of Semen Strychni, are notable for its therapeutic effects on local inflammation of muscle and joint. However, they are also dangerous poisons, and its oral administration can be risk. The purpose of the current study was to develop the Strychnos alkaloids patches in vitro and investigate the pharmacokinetic mechanism of its curative effects in vivo. Methods：The percutaneous permeation experiment was carried out with modified Franz-type diffusion cell through porcine skin in vitro, and the concentration of each sample in the reception room was determined by HPLC. The fluxes of strychnine and brucine through the porcine skin were selected as the indexes to optimize the preparation of the Strychnos alkaloids patches. After the 1cm2 optimal patches were applied on the abdomen of the mice, the number of abdominal writhing response induced by acetic acid