Zeta Potential Changing Self‐Emulsifying Drug Delivery Systems: A Promising Approach to Improve Oral Bioavailability of BCS Class IV Drugs by Overcoming Mucus Barriers via Enhanced Mucus Permeation and Cellular Uptake

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.