Monoammonium glycyrrhizinate micellar systems loaded with curcuminoids: composition-dependent self-assembly, release, and ex vivo skin permeation.

Monoammonium glycyrrhizinate (MAG) forms non-classical self-assembled micelles and serves as a drug-delivery agent with intrinsic pharmacological and permeation-enhancing properties. However, how drug-surfactant interactions influence micellar architecture and drug skin transport remains poorly understood. In this study, the influence of curcuminoids (CURD) encapsulated at three molar ratios (MAG:CUReq 22:1, 6:1, and 2:1) on MAG self-assembly and skin delivery was investigated. MAG-CURD micellar systems were successfully reconstituted from solvent-free amorphous solid dispersions. Mean micellar size decreased with higher CURD loads, while maintaining a stable ζ-potential (∼ -30 mV). TEM images and molecular dynamics simulations confirmed a structural transition from threadlike fibers to smaller, anisotropic aggregates driven by hydrophobic accommodation. Density and surface tension measurements revealed composition- and temperature-dependent critical aggregation concentrations, indicating a shift from entropy- to enthalpy-driven assembly at higher CURD ratios and temperatures. The micellar systems demonstrated good physical stability at 4 °C for 30 days, while Weibull modeling revealed a non-linear CURD release kinetics among MAG:CUReq ratios. Ex vivo skin permeation studies showed a 5-fold increase in the CURD permeation coefficient for the 22:1 compared with the control. ATR-FTIR analysis of porcine stratum corneum confirmed that MAG-CURD micelles induced less lipid disruption than pure MAG. These findings demonstrate that drug-carrier coupling modulates supramolecular architecture, aggregate stability, and skin barrier interactions, providing useful criteria for optimizing GA-based topical formulations.