Liu Ying, Schwartz Joseph B, Schnaare Roger L, Sugita Edwin T
Pharmaceutical Development, West Pharmaceutical Services, Lionville, Pennsylvania, USA.
Pharm Dev Technol. 2003;8(4):419-30. doi: 10.1081/pdt-120024695.
Our previous study has successfully prepared a combination of immediate release, enteric coated, and controlled release (CR) beads and mathematically modeled in vitro drug release characteristics of the combination based on the release profiles of individual beads. The objectives of the present study are to evaluate the combination and individual beads in vivo and to mathematically model in vivo drug input characteristics of the combination based on the in vivo input of individual beads. Beagle dogs were used as an animal model, and theophylline as a model drug. In vivo percent drug absorbed at different times (input function) after administration of a capsule bead dosage form was calculated using the Wagner-Nelson deconvolution method using intravenous injection of theophylline in each dog as a reference. The in vivo input functions of individual beads were each fitted to appropriate mathematical equations. The in vivo input function of the bead combination dosage form was calculated based on the individual mathematical equations (expected), and verified experimentally in vivo (experimental). The results showed that all bead dosage forms behave in vivo as defined in vitro. Enteric coated beads significantly delay the time to reach the maximum concentration of drug (tmax=4.9 h) compared to uncoated immediate release beads (2 h). The lag time of enteric coated beads is 1.1 h. CR beads showed both longer tmax (6 h) and mean residence time (MRT=9.7 h) compared to the uncoated immediate release beads (tmax=2 h and MRT=7.1 h) as designed in vitro. The in vivo input functions for the three individual beads can be fitted to equations as a function of square root of time. The combined bead dosage form showed tmax of 2.4 h and MRT of 7.9 h. The experimental and expected in vivo input profiles agreed to within +/- 12% (residues at individual data points). Our results suggest that the drug input function of a combined multi-mechanism oral dosage form can be predicted from the in vivo performance of individual formulations using the dog as an in vivo model.
我们之前的研究已成功制备了速释、肠溶包衣和控释（CR）微丸的组合，并基于单个微丸的释放曲线对该组合的体外药物释放特性进行了数学建模。本研究的目的是在体内评估该组合及单个微丸，并基于单个微丸的体内输入情况对该组合的体内药物输入特性进行数学建模。使用比格犬作为动物模型，以茶碱作为模型药物。在每只犬静脉注射茶碱作为参考的情况下，采用Wagner-Nelson反卷积法计算给药胶囊微丸剂型后不同时间的体内药物吸收百分比（输入函数）。将单个微丸的体内输入函数分别拟合到合适的数学方程中。基于各个数学方程计算微丸组合剂型的体内输入函数（预期值），并在体内进行实验验证（实验值）。结果表明，所有微丸剂型在体内的行为与体外定义的一致。与未包衣的速释微丸（tmax = 2小时）相比，肠溶包衣微丸显著延迟了达到药物最大浓度的时间（tmax = 4.9小时）。肠溶包衣微丸的滞后时间为1.1小时。与体外设计一致，CR微丸与未包衣的速释微丸（tmax = 2小时，MRT = 7.1小时）相比，显示出更长的tmax（6小时）和平均驻留时间（MRT = 9.7小时）。三种单个微丸的体内输入函数可拟合为时间平方根的函数方程。组合微丸剂型的tmax为2.4小时，MRT为7.9小时。实验和预期的体内输入曲线在±12%范围内相符（各个数据点的残差）。我们的结果表明，以犬作为体内模型，可根据单个制剂的体内性能预测多机制组合口服剂型的药物输入函数。
