Molecular dynamics simulations of self-emulsifying drug-delivery systems (SEDDS): influence of excipients on droplet nanostructure and drug localization.

In this study, molecular dynamics (MD) simulations were applied to model the lipidic nanoscale droplets that form when self-emulsifying drug-delivery systems (SEDDS) disperse into microemulsions in the gastrointestinal (GI) tract. The influence of the excipient composition on the droplet nanostructure and on the localization of drug molecules was monitored by the drug immersion depth and the molecular association bias between hydrophilic and hydrophobic moieties. A SEDDS standard system consisting of capric (C10) fatty acid chain length triglycerides and drug molecule cyclosporin A (CyA) was compared to systematic excipient variations. Investigating the drug-loading capacity of droplets yielded a negligible influence of drug molecules on the droplet nanostructure; increasing the drug load merely resulted in increased drug exposure to the aqueous environment. The variation of triglyceride fatty acid chain lengths yielded clearly distinguishable droplet association patterns (random, lamellar-like, and vesicle-like), which could prove beneficial for predicting and engineering drug solubilization in SEDDS. The addition of surfactant poly(ethylene glycol) (PEG-6) revealed the formation of an encapsulating surfactant shell with a negligible impact on the droplet interior triglyceride nanostructure, which could potentially be utilized to protect drug molecules from digestion. Mono- and diglyceride molecules displayed an increased tendency to accumulate at the droplet surface as well, in accordance with their capacity to act as surfactants, while also significantly interfering with the interior droplet nanostructure. The addition of monoglyceride molecules in particular caused the CyA molecule to be solubilized in a hydrophilic droplet core region consisting of polar triglyceride moieties. This mode of drug localization was in stark contrast to that of other systems, where CyA was predominantly found in the interfacial region of the aqueous environment.