One-Step Emulsification Enables High Loading of Hydrophobic Drugs, But Not Transdermal Delivery: Phase-Inversion-Driven Double and Single Emulsions Stabilized by Silica Nanoparticles

Efficient transdermal delivery of hydrophobic small-molecule drugs remains a persistent challenge in dermatological therapeutics due to the limited solubility of active materials, stability of formulation, and the physical barrier posed by the stratum corneum. Here, we report a one-step emulsification strategy that enables the formation of water-in-oil-in-water (W/O/W) double emulsions and water-in-oil (W/O) single emulsions using silica nanoparticles as the sole stabilizer. A hydrophobic usnic acid derivative active material, usnic acid-cinnamic acid (UA-CA), was solubilized in aqueous solvents by the precise control of the polarity by addition of organic solvents. The aqueous phase was then incorporated into emulsions through a vortexing step with oil phase without the use of surfactants or multi-step emulsification processes. By tuning the polarity and volume fraction, phase behavior was correlated with emulsion morphology, demonstrating phase-inversion-driven enclosure of the inner dispersed phase to form double emulsions. While stable double emulsions and single emulsions with high UA-CA concentrations were successfully fabricated, ex vivo porcine skin permeation experiments revealed negligible transdermal transport efficacy (Cpermeate/Cfeed < 10–5) of the drug. These results highlights trade-off relationship between the emulsion stability and skin permeability, providing design principles for next-generation topical formulations.