Abstract
Abnormal skin pigmentation is one of the most common skin conditions worldwide. The search for safe, effective, and well-tolerated skin-whitening agents remains a major challenge for the pharmaceutical and cosmetics industries. Glabridin, often referred to as the “whitening gold”, is widely recognized as one of the most potent natural skin-whitening ingredients. However, its low bioavailability, poor skin permeability, and poor stability severely limit its efficacy in conventional topical formulations. In this study, we propose using glycyrrhizic acid to encapsulate glabridin, employing a “combined excipient and active ingredient” approach to improve the solubility, water dispersibility, and stability of glabridin, thereby enhancing its transdermal delivery efficiency. The micelles also inhibit melanin production and reduce tyrosinase activity. Compared with simple physically mixed solutions or glabridin used alone, these micelles significantly inhibited the expression of the TYR, TRP-1, and TRP-2 genes; downregulated the expression of α-MSH, cAMP, and MITF; and downregulated BMAL1 expression whilst upregulating PER1 expression. This study demonstrates that glycyrrhizic acid-glabridin micelles exert a synergistic effect by simultaneously targeting classical skin-whitening pathways and circadian regulatory networks, indicating great potential for skin whitening and providing a new strategy for developing novel, highly effective skin-whitening agents.