硝苯地平骨架缓释微丸的制备及在家犬体内的药物动力学

目的制备硝苯地平骨架缓释微丸;考察其在家犬体内的药物动力学及相对生物利用度;建立准确、可靠的HPLC方法用以测定硝苯地平血浆样品质量浓度。方法以聚乙二醇4000为载体材料,利用固体分散技术,采用挤出-滚圆法制备硝苯地平24h骨架缓释微丸;采用HPLC法对家犬体内血药质量浓度进行分析;利用统计矩的非隔室动力学理论计算药物动力学参数;采用差示扫描量热法推断药物的可能存在形式。结果药物可能以无定型形式存在于固体分散体中;在实验所选定的色谱条件下,硝苯地平质量浓度在5.0~200.0μg.L-1内线性关系良好(r=0.999 7),准确度、精密度及回收率均符合要求;自制缓释微丸与参比制剂的主要药物动力学参数分别为:tmax(5.0±1.1)、(5.7±0.8)h;ρmax(29.9±7.3)、(33.8±6.4)μg.L-1;AUC0-t(311.3±71.1)、(308.6±70.1)μg.h.L-1;相对生物利用度为(102.1±18.4)%;体内外相关性良好(r=0.936 8)。结论自制硝苯地平骨架缓释微丸与参比制剂生物等效。

Preparation of nifedipine sustained-release matrix pellets and it's pharmacokinetics in dogs

Objective To prepare nifedipine sustained-release matrix pellets and evaluate it′s pharmacokinetics between in vivo and in vitro correlation in dogs.Methods Nifedipine sustained-release matrix pellets were prepared by method of extrusion-spheronization with solid dispersion technology;HPLC method was developed to quantify the drug plasma concentration of dogs,the pharmacokinetics parameters of nifedipine were analyzed by non-compartment model.The correlation between in vitro release and in vivo absorption was evaluated.Results Differential scanning calorimetry(DSC) thermograms indicated the presence of nifedipine in amorphous form.The concentration of nifedipine was determined by HPLC with UV detection in dog plasma.The assay was linear from 5.0 to 200.0 μg·L-1 with goodness of fit(r2) greater than 0.99 observed with three precision and accuracy batch during validation.The main pharmacokinetic parameters of the self-made pellets and reference formulation were as follows:tmax(5.0±1.1) h and(5.7±0.8) h;ρmax(29.9±7.3) μg·L-1 and(33.8±6.4) μg·L-1;AUC0-t(311.3±71.1) g·h·L-1 and(308.6±70.1) μg·h·L-1,Relative bioavailability was(102.1±18.4)%.Dissolution tests indicated the goodness in in vivo and in vitro correlation(r=0.936 8).Conclusions Self-made nifedipine sustained-release matrix pellets are bioequivalent to reference formulation.