长效镇痛氢溴酸高乌甲素溶致液晶注射剂的研究  

Study on long-acting analgesic lappaconitine hydrobromide lyotropic liquid crystal injection

作　　者：袁文秀 肖志超[3] 孙银银 陈蓉蓉 郭仕艳 甘勇 YUAN Wen-xiu;XIAO Zhi-Chao;SUN Yin-yin;CHEN Rong-rong;GUO Shi-yan;GAN Yong(Jiangxi University of Traditional Chinese Medicine,Nanchang 330004,China;Yangtze Delta Drug Advanced Research Institute,Nantong 226133,China;Yangtze River Pharmaceutical(Group)Co.,Ltd.,Taizhou 225300,China;State Key Laboratory of New Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 200125,China)

机构地区：[1]江西中医药大学,江西南昌330004 [2]南通市海门长三角药物高等研究院,江苏南通226133 [3]扬子江药业集团有限公司,江苏泰州225300 [4]中国科学院上海药物研究所,新药研究国家重点实验室,上海200125

出　　处：《药学学报》2023年第6期1685-1692,共8页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(82104078);药物制剂新技术国家重点实验室开放课题(2021年);中国科学院关键人才项目(人字2019-62号);中华人民共和国科学技术部国家重点研发计划(2020YFE0201700)。

摘　　要：长效镇痛是手术后常用临床治疗手段,长效镇痛作用的缓释注射剂具有用药频次少,作用平稳等优势。本研究制备了镇痛药物氢溴酸高乌甲素的溶致液晶注射剂,评价了其缓释机制、释药及药效学特征。偏光显微镜和冷冻透射电镜表征结果显示,用不同比例的单油酸甘油酯(glycerol monoleate, GMO)与大豆卵磷脂(soybean lecithin, SPC)组合可获得层状、立方相、六角相氢溴酸高乌甲素溶致液晶注射剂;体外溶出研究结果显示,不同形态液晶制剂的释药速率为层状液晶>立方相液晶>六角相液晶;释放数据数学模型拟合结果显示层状液晶、立方相液晶、六角相液晶体外释放均符合Ritger-Peppas模型,释放机制为Fick扩散;体内药效研究结果显示,氢溴酸高乌甲素溶致液晶注射剂镇痛效果可持续3天,切口及局部组织均未见异常,呈现良好的安全性和耐受性;体内凝胶储库的药物释放及消除过程研究显示,氢溴酸高乌甲素给药后3天可从溶致液晶中基本释放完全,缓释材料可在局部逐渐消除。所有动物实验获得中国科学院上海药物研究所实验动物伦理委员会批准(批准号:2021-08-GY-61)且实验均按照相关指导原则和规定进行。本研究制备的氢溴酸高乌甲素溶致液晶注射剂常温下呈现溶液状态,在给药部位与体液接触发生相变,形成药物储库,发挥缓慢释药作用。该制剂可降低系统毒性,延长镇痛持续时间,减少给药次数,提高术后患者顺应性,为后续长效缓释镇痛制剂的设计提供参考。Long-acting analgesia is a common clinical treatment method after surgery.The slow-release injection with long-acting analgesia has the advantages of less medication frequency and stable effect.In this study,the analgesic drug lappaconitine hydrobromide lyotropic liquid crystal injection was prepared,and its sustained release mechanism,drug release and pharmacodynamic characteristics were evaluated.The results of polarizing microscope and freeze-transmission electron microscope showed that the lyotropic liquid crystal injection of the liquid crystal precursor preparation of lappaconitine hydrobromide could be obtained by the combination of glycerol monooleate(GMO)and soybean lecithin(SPC)in different proportions.The results of dissolution study in vitro showed that the drug release rate of different forms of liquid crystal preparations was layered liquid crystal>cubic liquid crystal>hexagonal liquid crystal.The mathematical model fitting results of the release data showed that the external release of layered liquid crystal,cubic liquid crystal and hexagonal liquid crystal conforms to the Ritger-Peppas model,and the release mechanism was Fick diffusion.The results of pharmacodynamics study in vivo showed that the analgesic effect of lappaconitine hydrobromide lyotropic liquid crystal injection lasted for 3 days,and there was no abnormality in the incision and local tissue,showing good safety and tolerance.The study on drug release and elimination process of the in vivo gel repository showed that lappaconitine hydrobromide could be completely released from the lyotropic liquid crystal 3 days after administration,and the sustained-release materials could be gradually eliminated locally.All animal experiments were approved by the Experimental Animal Ethics Committee of the Shanghai Institute of Materia Medica,Chinese Academy of Sciences(No.2021-08-GY-61)and the experiments were conducted in accordance with the relevant guiding principles and regulations.The lyotropic liquid crystal injection of lappaconitine hydrobro

关 键 词：氢溴酸高乌甲素 溶致液晶 体外表征 体内药效 制剂消除 

分 类 号：R944[医药卫生—药剂学]