Department of Pharmacy, Uppsala University, 751 23 Uppsala, Sweden.
Division of Nano and Biophysics, Department of Physics, Chalmers Technical University, 412 96 Gothenburg, Sweden.
Langmuir. 2021 Aug 24;37(33):10200-10213. doi: 10.1021/acs.langmuir.1c01689. Epub 2021 Aug 11.
Self-emulsifying drug-delivery systems (SEDDS) have been extensively shown to increase oral absorption of solvation-limited compounds. However, there has been little clinical and commercial use of these formulations, in large part because the demonstrated advantages of SEDDS have been outweighed by our inability to precisely predict drug absorption from SEDDS using current in vitro assays. To overcome this limitation and increase the biological relevancy of in vitro assays, an absorption function can be incorporated using biomimetic membranes. However, the effects that SEDDS have on the integrity of a biomimetic membrane are not known. In this study, a quartz crystal microbalance with dissipation monitoring and total internal reflection fluorescence microscopy were employed as complementary methods to in vitro lipolysis-permeation assays to characterize the interaction of various actively digested SEDDS with a liquescent artificial membrane comprising lecithin in dodecane (LiDo). Observations from surface analysis showed that interactions between the digesting SEDDS and LiDo membrane coincided with inflection points in the digestion profiles. Importantly, no indications of membrane damage could be observed, which was supported by flux profiles of the lipophilic model drug felodipine (FEL) and impermeable marker Lucifer yellow on the basal side of the membrane. There was a correlation between the digestion kinetics of the SEDDS and the flux of FEL, but no clear correlation between solubilization and absorption profiles. Membrane interactions were dependent on the composition of lipids within each SEDDS, with the more digestible lipids leading to more pronounced interactions, but in all cases, the integrity of the membrane was maintained. These insights demonstrate that LiDo membranes are compatible with in vitro lipolysis assays for improving predictions of drug absorption from lipid-based formulations.
自乳化药物传递系统（SEDDS）已被广泛证明可以增加溶剂限制化合物的口服吸收。然而，这些制剂在临床和商业上的应用很少，很大程度上是因为我们无法使用当前的体外分析准确预测 SEDDS 对药物吸收的影响，SEDDS 的优势已被超过。为了克服这一限制并提高体外分析的生物学相关性，可以使用仿生膜来纳入吸收功能。然而，SEDDS 对仿生膜完整性的影响尚不清楚。在这项研究中，采用石英晶体微天平（QCM-D）和全内反射荧光显微镜（TIRFM）作为互补方法，与体外脂肪酶渗透测定法相结合，以表征各种主动消化的 SEDDS 与包含在十二烷中的卵磷脂（LiDo）的液态人工膜之间的相互作用。表面分析观察到，消化中的 SEDDS 与 LiDo 膜之间的相互作用与消化曲线中的拐点相吻合。重要的是，没有观察到膜损伤的迹象，这得到了亲脂性模型药物非洛地平（FEL）和不透性标记物 Lucifer yellow 在膜基底侧的通量曲线的支持。SEDDS 的消化动力学与 FEL 的通量之间存在相关性，但在溶解度和吸收曲线之间没有明显的相关性。膜相互作用取决于每个 SEDDS 中脂质的组成，更易消化的脂质导致更明显的相互作用，但在所有情况下，膜的完整性都得到了维持。这些研究结果表明，LiDo 膜与体外脂肪酶测定法兼容，可改善对基于脂质制剂药物吸收的预测。
