Self-assembled micelles of Glycyrrhizic acid and Glabridin: A novel transdermal delivery system with enhanced whitening efficacy.

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 (Gla), 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. Various studies have shown that glycyrrhizic acid (GA), as a drug carrier, can significantly improve the solubility, stability, and bioavailability of poorly soluble drugs, and the nanoparticles made from it have great potential. In this study, we propose using GA to encapsulate Gla, employing a "combined excipient and active ingredient" approach to improve the solubility, water dispersibility, and stability of Gla, thereby enhancing its transdermal delivery efficiency. After encapsulation, the size of the micelles was only about 37 nm, the encapsulation efficiency reached up to 80%, and the cumulative penetration over 48 h reached 7.44 μg/cm3. The micelles also inhibit melanin production and reduce tyrosinase activity. Compared with a simple physical mixed solution or using Gla alone, high-concentration micelles reduced the expression of tyrosinase (TYR) to 0.2, tyrosinase-related protein-1 (TRP-1) to 0.6, and tyrosinase-related protein-2 (TRP-2) to 0.3. At the same time, they downregulated the expression of α-melanocyte-stimulating hormone (α-MSH), cyclic adenosine monophosphate (cAMP), and microphthalmia-associated transcription factor (MITF); and downregulated the Brain and Muscle ARNT-Like 1 (BMAL1) expression whilst upregulating the Period Circadian Regulator 1 (PER1) expression. This study demonstrates that GA-Gla 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.