Immuno-redox modulator loaded trehalosomal hydrogel for atopic dermatitis: formulation, optimization using D-optimal...

Gallic acid (GA) offers significant potential for managing atopic dermatitis (AD) owing to its potent antioxidant and anti-inflammatory properties; however, its hydrophilic nature (log P 0.7) severely limits skin permeation and localized bioavailability. To address this, the present study developed and optimized gallic acid-loaded trehalosomes using a D-optimal mixture design and a solvent-free fabrication method to enhance dermal retention and therapeutic outcomes. The optimized formulation (Opt-THL) was selected using a numerical desirability function (D = 0.835) that satisfied predefined constraints. Comprising phospholipid, trehalose, and Pluronic F127, it showed an entrapment efficiency of 72.4 ± 0.76%, particle size of 218.5 ± 0.70 nm, polydispersity index of 0.36 ± 0.001, and zeta potential of -32.2 ± 1.62 mV. It exhibited sustained release over 8 h, with release efficiency (RE%) of 56.81 ± 0.7% and mean dissolution time (MDT) of 1.87 ± 0.09 h. Integration of Opt-THL into a hydroxypropyl methylcellulose (HPMC) hydrogel (Opt-THL-Hgel) facilitated a biphasic release profile, effectively suppressing the initial burst and extending GA release for up to 24 h. Ex-vivo deposition studies revealed a significant 2.8-fold increase in skin retention compared to a conventional GA-hydrogel. In-vivo evaluation in a dinitrochlorobenzene-induced AD mouse model confirmed that Opt-THL-Hgel acts as a potent immuno-redox modulator, significantly reducing SCORAD indices and ear thickness, while restoring cutaneous antioxidant defenses (SOD, GPx, GSH) and downregulating pro-inflammatory cytokines (TNF-α, IL-6) compared with the AD model group (p < 0.05). These findings establish trehalosomes as a superior platform for the localized delivery of GA, offering a clinically relevant strategy for the long-term management of AD.