From Solubilization to Structural Perturbation: The Mechanism of Polyquaternium-51-Driven Enhanced Transdermal Delivery of Glabridin

Effective delivery of hydrophobic drugs across the skin's stratum corneum remains a major challenge in transdermal drug delivery. Traditional solubilizing carriers, such as cyclodextrins, often suffer from overly strong drug binding that creates an interfacial release barrier. Moreover, they have limited ability to modulate the barrier structure of the stratum corneum itself. This study demonstrates a novel "carrier-driven" enhancement mechanism, where a "weakly-binding" carrier actively and reversibly disrupts the stratum corneum lipid organization to reduce the permeation energy barrier. We selected hydroxypropyl-β-cyclodextrin (HP-β-CD) and polyquaternium-51 (PMB) as model carriers, with the hydrophobic drug glabridin (GLD) as the model compound. Using an integrated approach of molecular dynamics (MD) simulations and multiple experimental techniques, we systematically elucidated the fundamental differences between these two delivery systems. First, MD simulations revealed the assembly mechanisms of HP-β-CD and PMB with glabridin in aqueous solution. Subsequently, the dominant conformations of these complexes were placed atop a mixed lipid bilayer to simulate the permeation process of glabridin. The permeation energy barriers were quantified using umbrella sampling simulations. These computational findings were strongly supported by experimental data from laser confocal microscopy, scanning electron microscopy, histology (HE staining), differential scanning calorimetry, and infrared spectroscopy. The results indicate that PMB, due to its flexible polymeric chain structure, exhibits a stronger affinity for skin lipids than HP-β-CD. Upon interacting with the skin lipids, PMB not only promotes the release of glabridin from the aqueous complex but also disrupts the tightly packed organization of the lipid bilayers. This dual action significantly facilitates the penetration of glabridin into deeper layers of the skin barrier. The novel mechanism elucidated in this work provides an innovative design strategy for developing the next generation of efficient and safe transdermal delivery systems.