Keemink Janneke, Hedge Oliver J, Bianco Valentina, Hubert Madlen, Bergström Christel A S
Department of Pharmacy, Uppsala University, Uppsala, Sweden; F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Department of Pharmacy, Uppsala University, Uppsala, Sweden.
J Pharm Sci. 2022 Jan;111(1):175-184. doi: 10.1016/j.xphs.2021.09.009. Epub 2021 Sep 10.
Permeation across Caco-2 cells in lipolysis-permeation setups can predict the rank order of in vivo drug exposure obtained with lipid-based formulations (LBFs). However, Caco-2 cells require a long differentiation period and do not capture all characteristics of the human small intestine. We therefore evaluated two in vitro assays with artificial lecithin-in-dodecane (LiDo) membranes and MDCK cells as absorptive membranes in the lipolysis-permeation setup. Fenofibrate-loaded LBFs were used and the results from the two assays compared to literature plasma concentrations in landrace pigs administered orally with the same formulations. Aqueous drug concentrations, supersaturation, and precipitation were determined in the digestion chamber and drug permeation in the receiver chamber. Auxiliary in vitro parameters were assessed, such as permeation of the taurocholate, present in the simulated intestinal fluid used in the assay, and size of colloidal structures in the digestion medium over time. The LiDo membrane gave a similar drug distribution as the Caco-2 cells and accurately reproduced the equivalent rank-order of fenofibrate exposure in plasma. Permeation of fenofibrate across MDCK monolayers did not, however, reflect the in vivo exposure rankings. Taurocholate flux was negligible through either membrane. This process was therefore not considered to significantly affect the in vitro distribution of fenofibrate. We conclude that the artificial LiDo membrane is a promising tool for lipolysis-permeation assays to evaluate LBF performance.
在脂解-渗透实验装置中，药物透过Caco-2细胞的渗透情况可预测基于脂质的制剂（LBFs）在体内的药物暴露等级顺序。然而，Caco-2细胞需要较长的分化期，且无法体现人类小肠的所有特征。因此，我们在脂解-渗透实验装置中评估了两种体外分析方法，以人工卵磷脂-十二烷（LiDo）膜和MDCK细胞作为吸收膜。使用了载有非诺贝特的LBFs，并将这两种分析方法的结果与文献中口服相同制剂的长白猪的血浆浓度进行了比较。在消化室中测定了药物的水溶液浓度、过饱和度和沉淀情况，并在接收室中测定了药物的渗透情况。评估了辅助体外参数，如分析中所用模拟肠液中牛磺胆酸盐的渗透率，以及消化介质中胶体结构随时间的大小。LiDo膜给出的药物分布与Caco-2细胞相似，并准确再现了非诺贝特在血浆中暴露的等效等级顺序。然而，非诺贝特透过MDCK单层的渗透情况并未反映体内暴露等级顺序。通过这两种膜的牛磺胆酸盐通量均可忽略不计。因此，该过程被认为不会对非诺贝特的体外分布产生显著影响。我们得出结论，人工LiDo膜是用于评估LBF性能的脂解-渗透分析的一种有前景的工具。
