妥曲珠利微晶体的制备及其在家兔体内的药动学

Preparation of toltrazuril micro-crystals and its pharmacokinetics in rabbit

采用反溶剂法制备妥曲珠利微晶体,利用显微镜观察妥曲珠利微晶体与妥曲珠利原药显微特征差异,并在25℃条件下测定两者体外溶出速率差异。将12只家兔随机分为2组,每组6只,分别按药物剂量10mg/kg灌胃,单剂量给药,采用HPLC检测血药浓度;用DAS2.0药代动力学程序计算药代动力学参数。结果显示,成功制备了妥曲珠利微晶体,微晶体与原药的显微特征差异明显,体外溶出速率明显加快;家兔单剂量灌胃妥曲珠利和微晶体后,主要药动学参数Cmax分别为(8.925±0.360)mg/L和(12.510±0.525)mg/L,tmax均为24h,AUC(0-∞)分别为(411.605±20.918)mg/(L·h)和(578.650±11.664)mg/(L·h),相对生物利用度为140.6%,药时数据符合一级吸收二室模型。结果表明,HPLC法适用于妥曲珠利血浆浓度的测定;妥曲珠利微晶体与妥曲珠利原药相比,体内吸收速率和吸收程度有较大的提高。

To improve the solubility and bioavailability of toltrazuril,the micro-crystals of toltrazuril were prepared by anti-solvent method,and its microscopic characteristics and in vitro-release were evaluated.Toltrazuril and its micro-crystals suspension were orally administrated on health rabbits to study their pharmacokinetic.Twelve rabbits were divided into two groups randomly and received single doses of toltrazuril or toltrazuril micro-crystals suspension at 10mg/kg,respectively.The phasma concentration of toltrazuri was determined by HPLC.The pharmacokinetic parameters were analyzed by DAS2.0software.The toltrazuril micro-crystals was successfully prepared,crystal size was 10times smaller than toltrazuril,the in vitro dissolution rate significantly accelerated.The main pharmacokinetic parameters of toltrazuril and micro-crystals were shown as Cmaxof（8.925±0.360）mg/L vs（12.50±0.525）mg/L,the tmaxboth 24h,AUC（0-∞）of（411.605±20.918）mg/（L·h）vs（578.650±11.664）mg/（L·h）.The relative bioavailability of micro-crystals was 140.6%.HPLC was suitable for the determination of toltrazuril plasma concentration in rabbit.Compared with toltrazuril,the solubility and bioavailability of toltrazuril micro-crystals in rabbit was greatly improved.