Formulation and optimization of leflunomide-loaded NLC-gel for improved skin permeation and anti-inflammatory efficacy

Arthritis is a chronic-inflammatory disorder that impairs joint function and necessitates efficient localised treatment. This research aimed to formulate and optimise leflunomide-loaded nanostructured lipid carriers (NLCs) for topical delivery. Dynasan 114 and corn oil were used as the solid and liquid lipids, respectively, and NLCs were formulated using high-speed homogenisation and probe sonication. Dual experimental design (1) Plackett–Burman for screening, and (2) Box–Behnken for formulation optimisation were employed. The optimised NLCs showed particle size (125.5 nm), PDI (0.188), zeta potential (−15.5 mV), and entrapment efficiency (92.20 ± 1.28%). FT-IR, DSC, P-XRD, and TEM validated the amorphous dispersion of leflunomide within the lipid matrix and the spherical morphology of the NLCs. The optimised NLCs were integrated into a Carbopol 980 NF (0.75%) gel base, demonstrating appropriate rheological properties such as extrudability (176 g), adhesiveness (−112 g), and pH (6.92). The gel formulation demonstrated prolonged drug release (96% over 24 h) and increased ex-vivo permeation with flux of 0.3632 mg/cm2/hour, hence validating enhanced diffusion through the skin barrier. The in-vivo pharmacodynamic study using a carrageenan-induced paw edoema model exhibited an 89.40% reduction in inflammation, exceeding the efficacy of the marketed leflunomide formulation. These findings suggest that the leflunomide-loaded NLC-based gel offers a promising platform for dermal drug distribution and enhanced anti-inflammatory activity.