Abstract
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.
Highlights
Many pharmaceutical compounds being developed suffer from either poor aqueous solubility, high lipophilicity, or both.For these water-insoluble but cell-permeable compounds, lipidbased formulation can be an effective method for achieving a high absorption while at the same time minimizing absorptive variability between fasted and fed states when administered orally.[1,2] Self-emulsifying drug-delivery systems (SEDDS) are a class of lipid-based formulations in which mixtures of lipids, non-ionic surfactants, and sometimes co-solvents or cosurfactants form a pre-emulsion concentrate.[3]
It could be predicted that digestion of SEDDS F2−F3 would increase solubility because of the reported higher solubility in mixtures of di- and monoglycerides compared to triglycerides of the same chain length.[33]
The synchronicity of f and D indicate deposition and removal of mass, but no structural changes in the adsorbed film at this stage. Such changes were not observed for F3 within the 60 min lipolysis period (Figure 4b), but could be seen after 90 min lipolysis (Figure S2). These findings suggest that the adsorption or structural changes observed on the lipid membrane are dependent on lipolysis kinetics, which for F2 and F3 are controlled by changes in the lipid chain length, with shorter-chain lipids (F2) being digested more rapidly
Summary
Many pharmaceutical compounds being developed suffer from either poor aqueous solubility, high lipophilicity, or both. The adsorbed membrane was exposed to each emulsified SEDDS in FaSSIF medium for 5 min prior to the addition of porcine lipase to simulate digesting conditions for 60 min, allowing the influence of the emulsion structure and lipid digestion on membrane integrity to be monitored For this monitoring, a closed-loop lipolysis QCM-D experimental setup was used to enable continuous flow of the digestion medium over the supported lipid membrane (Figure 1). Lipolysis was initiated by adding a solution of porcine lipase extract (5 μL, 1000 TBU/mL) and FRAP analysis was performed at various time points throughout the 60 min digestion period to determine changes in membrane diffusivity.
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