Muenster Uwe, Mueck Wolfgang, van der Mey Dorina, Schlemmer Karl-Heinz, Greschat-Schade Susanne, Haerter Michael, Pelzetter Christian, Pruemper Christian, Verlage Joerg, Göller Andreas H, Ohm Andreas
Bayer Pharma AG, Wuppertal, Germany.
Bayer Pharma AG, Wuppertal, Germany.
Eur J Pharm Biopharm. 2016 May;102:191-201. doi: 10.1016/j.ejpb.2016.03.001. Epub 2016 Mar 5.
The purpose of the study was to experimentally deduce pH-dependent critical volumes to dissolve applied dose (VDAD) that determine whether a drug candidate can be developed as immediate release (IR) tablet containing crystalline API, or if solubilization technology is needed to allow for sufficient oral bioavailability. pH-dependent VDADs of 22 and 83 compounds were plotted vs. the relative oral bioavailability (AUC solid vs. AUC solution formulation, Frel) in humans and rats, respectively. Furthermore, in order to investigate to what extent Frel rat may predict issues with solubility limited absorption in human, Frel rat was plotted vs. Frel human. Additionally, the impact of bile salts and lecithin on in vitro dissolution of poorly soluble compounds was tested and data compared to Frel rat and human. Respective in vitro - in vivo and in vivo - in vivo correlations were generated and used to build developability criteria. As a result, based on pH-dependent VDAD, Frel rat and in vitro dissolution in simulated intestinal fluid the IR formulation strategy within Pharmaceutical Research and Development organizations can be already set at late stage of drug discovery.
该研究的目的是通过实验推导pH依赖性溶解给药剂量的临界体积（VDAD），以确定候选药物是否可以开发为含结晶原料药的速释（IR）片剂，或者是否需要增溶技术以实现足够的口服生物利用度。分别绘制了22种和83种化合物的pH依赖性VDAD与人体和大鼠相对口服生物利用度（固体剂型的AUC与溶液剂型的AUC之比，Frel）的关系图。此外，为了研究Frel大鼠在多大程度上可以预测人体中溶解度限制吸收的问题，绘制了Frel大鼠与Frel人体的关系图。此外，测试了胆盐和卵磷脂对难溶性化合物体外溶出的影响，并将数据与Frel大鼠和人体的数据进行比较。生成了各自的体外-体内和体内-体内相关性，并用于建立可开发性标准。结果，基于pH依赖性VDAD、Frel大鼠以及模拟肠液中的体外溶出情况，制药研发机构内的IR制剂策略在药物发现的后期阶段就可以确定。
