Background: 20(S)-protopanaxadiol (PPD) exhibits potential for treating various eye diseases, but its extremely low aqueous solubility (50 ng/mL) limits its clinical application. This study aimed to develop and characterize a water-insoluble PPD-loaded nanoemulsion (NE) eye drop with enhanced solubility and suitable physicochemical properties.

Methods: Solubility studies were conducted to select the optimal oil (castor oil), surfactant (Kolliphor EL), and co-surfactant (Kollisolv PG) based on PPD solubility at 30–70 °C. A comprehensive pseudo-triangular diagram system was constructed to investigate the nanoemulsion preconcentrate compositions. The optimized preconcentrate was dispersed in an aqueous phase to create NE eye drops, followed by evaluations of particle size, pH, and osmolarity.

Results: PPD showed remarkable solubility in Kollisolv PG (>40%), enabling high drug loading (>20%) in the preconcentrate. The optimized formulation (F13-2%E), consisting of PPD/Castor oil/Kolliphor EL/Kollisolv PG (2.00/2.13/4.98/1.78, w/w), achieved a maximum PPD solubility of 2.0% within the oil phase. The resulting NE exhibited a small and stable particle size (<50 nm), a physiologically acceptable pH (6.54), and an osmolarity of 343.67 mOsm/kg.

Conclusions: The study successfully developed a PPD-loaded NE eye drop using a pseudo-triangular diagram system. This formulation, characterized by high solubility and stable nano-sized particles, represents a promising candidate for the effective treatment of ocular diseases