盐酸二甲双胍缓释片人体相对生物利用度及其药代动力学研究

Study on the relative bioavailability and pharmacokinetics of Metformin extended-release tablets in human volunteers

目的建立人血浆中盐酸二甲双胍的高效液相色谱测定方法,考察国产盐酸二甲双胍缓释片相对于普通片的生物等效性,并估算其药代动力学参数。方法血浆样品经乙氰沉淀蛋白后进行高效液相色谱分析。色谱柱为Nucleo-sil100-5硅胶柱(4.6mm×250mm,5μm),流动相为0.03mol/L磷酸二氢铵(pH7.0)-乙氰(75∶25,V/V),流速为1.0ml/min,检测波长为240nm。结果缓释片和普通片的主要药动学参数为单剂量时AUC0-24分别为(12.13±1.85)和(13.72±2.04)μg.h-1.ml-1;Cmax分别为(1.6±0.3)和(2.31±0.36)μg/ml;tmax分别为(4.7±0.87)和(1.95±0.54)h;t1/2分别为(4.04±1.16)和(4.26±0.64)h;多剂量时AUCss分别为(14.52±1.98)和(7.22±1.49)μg.h-1.ml-1;Cmax分别为(1.61±0.26)和(1.54±0.27)μg/ml;Cmin分别为(0.17±0.11)和(0.17±0.05)μg/ml;Cav分别为(0.61±0.09)和(0.60±0.12)μg/ml;tmax分别为(4.8±0.7)和(1.9±0.64)h;AUC0-24和AUCss经对数转换后方差分析和双单侧t检验,均无显著性差异。结论盐酸二甲双胍缓释片的相对生物利用度单剂量时为(88.8±9.3)%,多剂量时为(100.54±10.6)%,试验片和参比片吸收程度生物等效,试验片具有缓释特征。

Objective To establish an HPLC method for the study of bioavailability and pharmacokinetics of Metformin in human plasma. Methods A simple HPLC method using ultraviolet detection was developed, which established the direct injection of the plasma sample after deproteinating with acetonitrile. The mobile phase consisted of 0.03 mol/L ammonium dihydrogen phosphate （pH 7.0） and acetonitrile （75 ： 25, V/V）. Analysis was run at a flow-rate of 1.0 ml/min with the detector operated at wavelength 240 nm. Results The single-dose pharmacokinetic parameters of Metformin extended-release tablet and Metformin tablet were： AUC0-24（12.13±1.85） μg·h^-1·m^-1 and （13.72 ±2.04） μg·h^-1·m^-1, Cmax（1.6±0-3） μg/ml and （2.31±0.36） μg/ml, tmax（4. 7±0. 87）h and （1.95 ±0.54）h t1/2（4.04±1.16）h and （4.26±0.64）h; The multiple-dose pharmacokinetic parameters of Metformin extended-release tablet and Metformin tablet were： AUCss（14. 52 ±1.98）μg·h^-1·m^-1 and （7.22±1.49） μg·h^-1·m^-1, Cmax（1.61±0.26）μg/ml and （ 1.54 ±0. 27） μg/ml, Cmax（0. 17±0. 11 ） μg/ml and （0. 17±0.05） μg/ml, Cav（0. 61±0.09） μg/ml and （0.6±0. 12） μg/ml, tmax（4- 8 ±0. 7）h and （ 1.9±0.64）h. The statistical analysis for AUC0-24showed that there was no significant difference between Metformin extended-release tablet and Metformin tablet. Conclusion The single-dose and multiple-dose relative bioavailability of Metformin extended-release tablet were （88. 8±9.3） % and （100.54 ±10. 6）% , respectively. The bioavailability of Metformin extended-release tablet was equal to Metformin tablet. The test tablet posseses controlled release characteristic.