Optimizing a Skin Depigmentation Formula Using a 2 ⁴ Factorial Design: Evaluating 4- <i>n</i> -Butylresorcinol, Undecylenoyl Phenylalanine, Diglucosyl Gallic Acid, and <i>trans</i> -Resveratrol

The aim of this study was to evaluate the skin depigmentation properties of mixtures containing 4-<i>n</i>-butylresorcinol (BR), undecylenoyl phenylalanine (UP), diglucosyl gallic acid (DG), and <i>trans</i>-resveratrol (TR) through the inhibition of melanocyte-stimulating hormone (MSH), inflammatory mediators, tyrosinase enzyme activity, and copper ion chelation. A 2⁴ full factorial design with 33 experimental runs was used to assess the effects of different concentrations of BR, UP, DG, and TR in the mixtures on skin depigmentation. There was no significant effect of BR, UP, DG, or TR concentrations on anti-MSH and copper chelating activities. However, BR and UP showed a positive interaction effect on anti-inflammatory and anti-tyrosinase activities, while DG concentration was negatively correlated with anti-inflammatory activity. The optimized mixture contained 0.1% BR, 0.5% UP, 1% DG, and 0.1% TR, yielding anti-MSH (35.20%), anti-inflammatory (24.66%), anti-tyrosinase (98.12%), and copper chelating (54.66%) activities. This study demonstrates that a combination of BR, UP, DG, and TR can effectively target multiple pathways in melanogenesis, providing a synergistic skin-whitening effect. The optimized mixture shows promise for dermatological and cosmetic applications and may warrant further <i>in vivo</i> and clinical investigations.