Reduction of Ultraviolet- and Heat-Induced Aging Using Betulin-Loaded Arginine-Caprylate Self-Assembly: Randomized Double-Blind Clinical Trials.

Abstract

Background Betulin exhibits potent antibacterial, anti-inflammatory, and antioxidant properties, effectively preventing ultraviolet (UV)- and heat-induced skin aging. Its limited solubility in cosmetic solvents restricts its application.Methods To enhance betulin's applicability, a self-assembled nanocarrier, arginine-caprylate ion pair loaded with betulin (B-ACS), was developed. Structural properties, loading efficiency, skin permeability, and antioxidant activity were assessed. UVB-induced damage was examined in human keratinocytes (HaCaT; n = 3) by measuring inflammatory cytokines and matrix metalloproteinases (MMPs) via ELISA. Three-dimensional reconstructed human skin models were exposed to UVA (10 J/cm2) to evaluate collagen and aquaporin-3 protection. A pilot randomized, double-blind, placebo-controlled clinical trial (n = 12, 2 weeks) assessed 3 % (w/w) B-ACS cream on UV- and infrared-induced skin damage.Results B-ACS showed a particle size of 236.9 ± 10.3 nm, 98.3 ± 1.3 % encapsulation efficacy, and superior reactive oxygen species (ROS) scavenging (IC50 = 4.87 ppm) compared to free betulin (IC50 = 8.26 ppm). In HaCaT cells, B-ACS significantly reduced UVB-induced inflammatory cytokine and MMP expressions (p < 0.05). In reconstructed skin, it prevented UVA-induced collagen and aquaporin-3 degradation. Clinically, 3% B-ACS cream significantly improved elasticity (1.69-fold), brightness (2.59-fold), and pigmentation (1.91-fold); transepidermal water loss (TEWL) and heat-aging markers decreased 1.39-fold and 1.63-fold versus placebo, respectively (p < 0.05).Conclusion B-ACS enhances betulin's solubility and delivery, offering potent efficacy against UV- and heat-induced aging.