Polymeric mixed micellar nanogel enhances dermal delivery and therapeutic efficacy of tofacitinib citrate.

This study aimed to develop and evaluate a polymeric-surfactant stabilized mixed micellar (MM) gel of tofacitinib citrate (TFC) for localized management of rheumatoid arthritis (RA). TFC-MM gel was formulated via a simple and scalable cold dispersion self-assembly approach using Lipoid S75, Tween 80, and Poloxamer 407, incorporated into a Carbopol hydrogel matrix. The optimized formulation exhibited nanosized particles (i.e., 67.2 nm), narrow size distribution (PDI ∼ 0.11), and high drug entrapment (i.e., 80.7%). The developed micellar gel showed sustained kind of drug release (i.e., 98.6% in 12 h) compared to the marketed formulation (i.e., 58.2%). Ex vivo permeation and dermatokinetic evaluation using Wistar rat skin showed significantly higher drug deposition and skin retention than those observed with marketed formulations. Confocal imaging further supported improved penetration into deeper skin layers. In vivo pharmacological evaluation in BALB/c mice and Wistar rat models demonstrated superior antinociceptive, anti-inflammatory, and anti-arthritic efficacy vis-à-vis marketed tofacitinib and diclofenac gels. Importantly, mechanistic therapeutic validation was established through a significant reduction in key pro-inflammatory cytokines (IL-6, TNF-α, and IL-1β), along with improvements in biochemical and haematological markers, including CRP, ESR, and leukocyte counts. The formulation also depicted good dermal compatibility and cellular safety. Overall, this study establishes a simple and scalable mixed micellar nanocarrier approach for topical delivery of TFC, demonstrating improved dermal bioavailability, enhanced therapeutic efficacy, and mechanistic anti-inflammatory validation. The findings highlight the potential of MM nanogels as clinically translatable nanocarrier systems for topical RA therapy.