Interfacial molecular engineering-driven self-emulsification: a green strategy for surfactant-free, high-efficiency oral delivery of cyclosporine A†

We report a green chemistry strategy for oral peptide delivery using interfacial interactions to drive self-emulsification, avoiding the use of synthetic surfactants and organic solvents. By exploiting non-covalent interactions between food-grade trans-anethole (TA) and biodegradable cellulose polymers, we developed a solvent-free, hot-melt extruded system that spontaneously formed stable submicron emulsions upon contact with aqueous media. Unlike conventional self-emulsifying drug delivery systems requiring biosafety-concerning surfactants and energy-intensive processing, our design leverages renewable materials and continuous manufacturing while achieving superior performance – demonstrating 1.43-fold higher bioavailability than Neoral® in rats. Isothermal titration calorimetry tests and molecular dynamics simulations revealed how cellulose's substitution pattern precisely controlled emulsification through interfacial force modulation, enabling optimization without synthetic additives. This approach satisfies key green chemistry principles by: (1) completely avoiding organic reagents through melt processing, (2) replacing biosafety-concerning surfactants with biodegradable natural polymers, (3) reducing energy input via spontaneous emulsification, and (4) utilizing food-safe components that minimize environmental impact. The technology establishes a sustainable platform for low bioavailability drugs, combining enhanced therapeutic performance with inherently greener manufacturing.