Co-Assembled Ion-pair Complex Nanoparticles from Tranexamic Acid and Metformin with Enhanced Transdermal Efficacy against UVB-Induced Pigmentation

Abstract

The aesthetic effect of skin pigmentation caused by ultraviolet radiation and its increased risk of melanoma have received more attention. Non-invasive transdermal delivery has been widely recognized, but the transdermal limitation of hydrophilic active ingredients through the skin barrier and the muti-target action pathways of inhibition of melanin synthesis still need to be further explored. We have developed a self-assembled nanosystem (S-PMT), which was co-assembled from an ion pair complex formed by tranexamic acid (TXA) and metformin (Met) with palmitoyl epigallocatechin gallate (p-EGCG).Transdermal delivery evaluation showed that S-PMT significantly enhanced the skin flux and intradermal retention of the active ingredient through its ion-pair properties, self-assembled nanostructure, and penetration enhancer salcaprozate sodium (SNAC), outperforming that of TXA or TXA/Met physical mixture. In vitro and in vivo studies have confirmed that S-PMT could synergistically inhibit p38/PKA-MITF pathways through scavenging reactive oxygen species (ROS) and tyrosinase signaling pathways, significantly suppressing UVB-induced intracellular tyrosinase activity and melanin synthesis, and inflammatory cytokine expression. Simultaneously, it exhibited excellent safety and skin tolerance. These results provided a basis for the clinical application of S-PMT in UVB induced skin pigmentation, making it a promising non-invasive therapeutic platform for skin pigmentation treatment.