Mechanistic insights into drug supersaturation during lipid digestion in self-emulsifying drug delivery systems: A cryo-TEM and NMR study

Abstract

A self-emulsifying drug delivery system (SEDDS), composed of oil, surfactant, and co-surfactant, has been widely used to enhance the oral absorption of poorly water-soluble drugs. Upon oral administration, SEDDS spontaneously forms an emulsion upon contact with gastrointestinal fluids, thereby solubilizing the drug within oil droplets. Lipid digestion by lipase further facilitates the release of encapsulated drugs into the aqueous phase, generating drug supersaturation that can enhance absorption. In this study, morphological characterization at the nanometer scale using cryogenic transmission electron microscopy (Cryo-TEM) was combined with molecular-level characterization using NMR to provide a more quantitative and detailed understanding of the mechanism of drug supersaturation formation during lipid degradation. SEDDS formulations were prepared using Labrafac PG (PG), HCO-40 (HCO40), and polyethylene glycol 400, with naringenin (NAR) as a model drug. Cryo-TEM analysis revealed the transition of oil droplets into vesicles during lipid digestion in phosphate-buffered saline (PBS), whereas in fed-state simulated intestinal fluid (FeSSIF), vesicles did not form due to the solubilization of digested products by taurocholic acid (TCA)/lecithin micelles. ¹H NMR measurements of the emulsion quantitatively confirmed lipid digestion; in both PBS and FeSSIF, approximately 74 % of PG underwent lipase-mediated hydrolysis. NAR solubility measurements and permeation studies using a dialysis membrane demonstrated a reduced solubilization capacity and an increase in NAR supersaturation level during lipid digestion, particularly in FeSSIF, where TCA/lecithin micelles facilitated efficient NAR release into the aqueous phase. Conversely, vesicle retention in PBS limited NAR supersaturation. These findings highlight the importance of emulsion morphology changes in promoting drug release and supersaturation, thereby providing valuable insights for designing SEDDS formulations to enhance drug bioavailability.