The current study was designed to create drug-loaded zeta potential shifting self-emulsifying drug delivery systems (SEDDS) to improve oral bioavailability of poorly soluble drugs via enhancing their cellular absorption, mucus diffusion. For this purpose, phosphorylated oleylamine was added to SEDDS at 2% (v/v) concentration that contained Cremophor EL, Labrasol, Tween 80, miglyol, propylene glycol, and Captex 355. The cytotoxicity of drug-loaded phosphorylated oleylamine-containing SEDDS was examined on Caco-2 cells. Moreover, phosphate cleavage via alkaline phosphatase (AP) was used to measure phosphate release. Simultaneously, mucus diffusion, shift in zeta potential, and cellular uptake studies were executed. Furthermore, proof-of-concept in vivo studies were conducted to evaluate oral bioavailability. Phosphorylated oleylamine was created by amide bond formation between oleylamine and 6-phosphogluconic acid via carbodiimide chemistry. The droplet size and zeta potential of phosphorylated SEDDS were 67 nm and −12.71 mV, respectively. After 6 h of incubation with AP, a rapid phosphate release and charge reversal were observed from phosphorylated oleylamine-containing SEDDS. Moreover, phosphorylated SEDDS demonstrated 3.1-fold enhanced mucus penetration and 3.24-fold enhanced cellular uptake in comparison to the control. Furthermore, in vivo studies exhibited a 9.2-fold enhanced relative oral bioavailability. Based on enhanced drug mucus diffusion, cellular uptake, and oral bioavailability, it can be estimated that drug-loaded phosphorylated oleylamine-containing SEDDS can be a vital tool to improve oral bioavailability of BCS Class IV drugs.
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