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目的研究自制制剂瑞格列奈磷脂复合物-固体分散体大鼠体内药动学及其生物利用度。方法建立UPLC-MS/MS方法用于大鼠血浆中瑞格列奈质量浓度的测定,并采用正己烷-乙醚(体积比为1∶4)的液-液萃取法,以格列齐特为内标物质,提取大鼠血浆中目标成分。测定12只大鼠口服灌胃0.32 mg·kg~(-1)参比制剂与受试制剂后不同时间点血浆中瑞格列奈的质量浓度,采用DAS2.1.1药动学软件计算药动学参数。色谱条件:色谱柱Phenomenex C_(18)(50 mm×2.1 mm,2.6μm),以乙腈-体积分数为0.05%的甲酸溶液-体积分数为0.1%的乙酸溶液为流动相,流速:0.2 mL·min~(-1),柱温:35℃,梯度洗脱。结果血浆中瑞格列奈质量浓度在0.25~200μg·L~(-1)内线性关系良好,定量下限为0.25μg·L~(-1);低、中、高3个质量浓度质控样品的日内和日间精密度均小于15%,准确度分别为93.33%、95.39%和91.38%;提取回收率分别为81.6%、90.6%和72.2%;基质效应的变异系数分别为3.13%、2.16%和2.24%,均小于15%。受试制剂瑞格列奈磷脂复合物-固体分散体的主要药动学参数:t_(1/2)为(2.58±1.64)h、t~(max)为(0.71±0.10)h、ρ~(max)为(90.03±44.59)μg·L~(-1)、AUC_(0-t)为(264.92±105.04)μg·h·L~(-1)、AUC_(0-∞)为(270.82±106.84)μg·h·L~(-1),受试制剂的相对生物利用度是参比制剂(瑞格列奈市售片)的2.3倍。结论本法适用于自制制剂大鼠血浆中瑞格列奈的浓度测定。与市售片相比,口服自制瑞格列奈磷脂复合物-固体分散体的生物利用度显著提高。
Objective To study the pharmacokinetics and bioavailability of homemade repaglinide-phospholipid complex-solid dispersion in rats. Methods The UPLC-MS / MS method was used to determine the concentration of repaglinide in rat plasma. The liquid-liquid extraction method of n-hexane-diethyl ether (1: 4 by volume) Internal standard substance, extracted from rat plasma target composition. The plasma concentration of repaglinide at different time points after the administration of 0.32 mg · kg -1 reference preparation and the test preparation was measured in 12 rats. The pharmacokinetics was calculated using DAS 2.1.1 pharmacokinetic software parameter. Chromatographic conditions: Phenomenex C_ (18) column (50 mm × 2.1 mm, 2.6 μm) with acetonitrile-0.05% formic acid solution and 0.1% acetic acid solution as mobile phase at a flow rate of 0.2 mL · min ~ (-1), column temperature: 35 ℃, gradient elution. Results The plasma concentration of repaglinide was linear in the range of 0.25 ~ 200 μg · L -1 with a lower limit of quantitation of 0.25 μg · L -1. The quality control samples with low, medium and high concentrations The intra-day and inter-day precision were less than 15%, with the accuracy of 93.33%, 95.39% and 91.38%, respectively. The recovery rates were 81.6%, 90.6% and 72.2% respectively. The coefficients of variation of matrix effects were 3.13% and 2.16 % And 2.24%, both less than 15%. The main pharmacokinetic parameters of the recombinant nateglinide-solid dispersion were: t 1/2 (2.58 ± 1.64) h and t max (0.71 ± 0.10) h, ρ ~ (90.03 ± 44.59) μg · L -1, 264.92 ± 105.04 μg · h · L -1 for AUC_ (0-t) and 270.82% for AUC_ (0-∞) ± 106.84) μg · h · L -1, the relative bioavailability of the test preparation was 2.3 times that of the reference formulation (repaglinide). Conclusion This method is suitable for the determination of repaglinide in plasma of homemade preparations. The bioavailability of orally administered repaglinide phospholipid complex-solid dispersions was significantly increased compared to the commercial tablets.