他克莫司软膏透皮一致性的体外Franz扩散池测定比较研究  

In vitro transdermal permeation consistency investigation of two tacrolimus ointments by Franz cell diffusion

作　　者：周刚 付晓婷 潘静茹 刘宗银 曹慧敏 朱召贞 宋敏[3] 杭太俊[3] ZHOU Gang;FU Xiao-ting;PAN Jing-ru;LIU Zong-yin;CAO Hui-min;ZHU Zhao-zhen;SONG Min;HANG Tai-jun(Inner Mongolia Institutes for Drug Control,Hohhot 010020,China;Jiangsu Institute for Food and Drug Control,Nanjing 210019,China;Shandong Rui an Pharmaceutical Co.,Ltd.,Jinan 251400,China;School of Pharmacy,China Pharmaceutical University,Nanjing 211198,China)

机构地区：[1]内蒙古自治区药品检验研究院,呼和浩特市010020 [2]江苏省食品药品监督检验研究院,南京210019 [3]中国药科大学药学院,济南251400 [4]山东瑞安药业有限公司,南京210009

出　　处：《药物分析杂志》2020年第12期2126-2133,共8页Chinese Journal of Pharmaceutical Analysis

摘　　要：目的:比较试验和参比0.1%他克莫司软膏透皮作用的一致性。方法:采用离体巴马香猪皮肤为体外透皮试验材料,分别以生理盐水-乙醇(1∶1)、pH 5.8磷酸盐缓冲溶液-乙醇(1∶1),pH 7.4磷酸盐缓冲溶液-乙醇(1∶1)为接收介质,改良Franz扩散池测定他克莫司软膏的渗透吸收规律,以LCMS/MS法分别测定接收液中药物的吸收总量和猪皮中药物的残留量随时间的变化行为,评价试验和参比软膏的透皮一致性。结果:0.1%他克莫司软膏试验制剂与参比制剂经离体巴马香猪皮在3种不同释放介质中12h的单位面积累积渗透量分别为(0.796±0.035)和(0.791±0.049)μg·cm^-2、(0.737±0.022)和(0.728±0.022)μg·cm^-2、(0.843±0.031)和(0.796±0.015)μg·cm^-2;12 h的单位面积药物残留量分别为4.64和4.94μg·cm^-2、4.79和4.75μg·cm^-2、5.04和5.05μg·cm^-2;在3种不同的释放介质中,试验制剂与参比制剂体外释放率比值的90%置信区间落在FDA一致性规定的75%~133.33%限度范围内,最大吸收速率(Jmax,μg·cm^-2·h-1)平均值比率的90%置信区间和12 h的单位面积渗透总量(Atotal,μg·cm^-2)平均值比率的90%置信区间均在欧盟一致性规定的80.00%~125.00%限度区间。结论:0.1%他克莫司软膏试验制剂与参比制剂在3种不同的释放介质中透皮渗透程度和速率均符合外用制剂的一致性要求,皮内药物残留特征相似。Objective:To investigate the quality consistency between a test and reference 0.1% tacrolimus ointments through the transdermal permeation determination. Methods:The modified Franz diffusion cell was employed for the in vitro transdermal permeation test through Bama miniature pig skin. Mixtures of Physiological saline-ethanol(1∶1),pH 5.8 phosphate buffer solution-ethanol(1∶1),pH 7.4 phosphate buffer solutionethanol(1∶1) were used as the receiving media,respectively. The cumulative permeation amounts in the receiving liquids and the drug residue amounts in the skin samples were measured by validated LC-MS/MS methods. The transdermal permeation characteristics of the test and reference 0.1% tacrolimus ointments were employed for the quality consistency evaluation. Results:The cumulative permeation amounts until12 h of the test and reference0.1% tacrolimus ointments in Bama miniature pig skin in the three different media were(0.796±0.035) and(0.791±0.049) μg·cm^-2,(0.737±0.022) and(0.728±0.022) μg·cm^-2,(0.843±0.031) and(0.796±0.015) μg·cm^-2,and the drug residues in the skins were 4.64 and 4.94 μg·cm^-2,4.79 and 4.75 μg·cm^-2,5.04 and 5.05 μg·cm^-2,respectively. The 90% confidence interval of the in vitro release rate ratio of the test and reference ointments was within the quality consistency range from75% to133.33%defined by the FDA guideline. The 90% confidence interval for the mean ratios of the maximum absorption rates(Jmax,μg·cm^-2·h-1) and the total amount of permeation per unit area of the skin(Atotal,μg·cm^-2) at the end of the experiment of the test and reference products were all within the quality consistency range from 80.00% to 125.00% according to European Union guidelines. Conclusion:The test and reference 0.1% tacrolimus ointments demonstrated to be quality consistent through the determination of the permeation characteristics through Bama miniature pig skin and the drug residues in the skin.

关 键 词：他克莫司软膏 体外透皮吸收 仿制药一致性 液相色谱-串联质谱法 

分 类 号：R917[医药卫生—药物分析学]