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):409-17. doi: 10.1081/pdt-120024694.
An in vitro/in vivo relationship of a combined multi-mechanistic dosage form has now been established in the literature. In our previous study, we successfully prepared a combination of immediate release, enteric coated, and controlled-release (CR) beads and mathematically modeled in vitro and in vivo drug release characteristics of the combination based on the release profiles of individual beads. The objective of the present study is to develop in vitro/in vivo correlations (IVIVC) for three individual beads and the combination using theophylline as a model drug and the beagle dog as an animal model. In the study, an IVIVC correlation is estimated by two-stage procedures: deconvolution followed by comparison of the fraction of drug absorbed to the fraction of drug dissolved. The Wagner-Nelson mass balance method was used to deconvolute plasma drug concentration-time curves. In vitro, a two-stage medium (0.1 N HCl and pH 6.5 phosphate buffer) was used for the dissolution test; a 2h first stage (acidic) was selected based on the average gastric emptying time in a fasted dog. In vivo, t(lag) was used for the gastric emptying process for enteric coated beads and the combination, which contains enteric coated beads. A time-scaling technique was used to consider the rate difference between in vitro dissolution and in vivo absorption in the process of IVIVC. As shown in the results, a point-to-point correlation was established for each formulation. The linear regression analysis of the correlation was r2>0.99 for all three individual beads and 0.97 for the combined bead dosage form. The results suggest level A IVIVCs indicating an appropriateness for the in vitro and in vivo models used in this study.
目前，文献中已建立了一种联合多机制剂型的体外/体内关系。在我们之前的研究中，我们成功制备了速释、肠溶包衣和控释（CR）微丸的组合，并根据单个微丸的释放曲线对该组合的体外和体内药物释放特性进行了数学建模。本研究的目的是以茶碱为模型药物、比格犬为动物模型，建立三种单个微丸及其组合的体外/体内相关性（IVIVC）。在该研究中，通过两阶段程序估计IVIVC相关性：去卷积，然后比较吸收药物分数与溶解药物分数。采用Wagner-Nelson质量平衡法对血浆药物浓度-时间曲线进行去卷积。体外，采用两阶段介质（0.1 N HCl和pH 6.5磷酸盐缓冲液）进行溶出试验；根据禁食犬的平均胃排空时间选择2小时的第一阶段（酸性）。体内，对于肠溶包衣微丸和含有肠溶包衣微丸的组合，t(lag)用于胃排空过程。在IVIVC过程中，采用时间缩放技术来考虑体外溶出和体内吸收之间的速率差异。结果表明，每种制剂都建立了点对点相关性。所有三种单个微丸的相关性线性回归分析r2>0.99，联合微丸剂型为0.97。结果表明为A级IVIVC，表明本研究中使用的体外和体内模型是合适的。
