Enhancing Thermal Longevity and Transdermal Delivery of High-Dose Vitamin C: The Role of Particle-Reinforced Thixotropic Networks in Anhydrous Matrices

Background: Topical delivery of high-dose L-ascorbic acid (AA) is limited by rapid oxidative degradation in water and physical particle aggregation in lipophilic vehicles. Here, we engineered an anhydrous delivery system combining a structured wax–oil matrix with high-shear roll-milling process to stabilize up to 40% AA. Methods: Dispersion morphology and 3D ultrastructure were evaluated via optical microscopy and Cryo-SEM. Rheological flow profiles and thixotropic recovery were measured using a rotational rheometer. Accelerated chemical stability was monitored at 0–50 °C for 4 weeks via RP-HPLC. Percutaneous delivery kinetics were investigated across synthetic biomimetic membranes (Strat-M®) using a sequential toner-application regimen. Biological efficacy was clinically assessed in 15 human volunteers over 4 weeks using 3D optical skin analysis (ANTERA 3D®). Results: The high-shear roll-milling process homogenized AA aggregates into micro-dispersions, establishing an apparent yield-stress network with an ultra-high zero-shear plateau (105 P) and shear-thinning thixotropy. The milled formulation retained highly stable chemical potency (93.99%) at 50 °C for 4 weeks. Sequential application with an aqueous toner facilitated in situ active dissolution at the barrier interface, increasing the absolute delivered payload from the 20% system by >10.5-fold relative to the 5% formulation. A 4-week clinical evaluation confirmed measurable improvements in skin brightness (∆L* = 1.66%), and reductions in hyper-pigmentation (25.65%), wrinkle area (31.17%), and pore area (26.00%). Conclusions: The milling-integrated anhydrous matrix provides a robust formulation framework that resolves physical sedimentation and oxidative instability while enabling the stable delivery of high-dose payloads via enhanced thermodynamic concentration gradients for enhanced dermatological rejuvenation.