Formulation and optimization of NEs for enhancing topical delivery of methotrexate in CFA induced arthritis rat model

Methotrexate (MTX) is widely used in treating cancers and inflammatory conditions like psoriasis and rheumatoid arthritis (RA), however is associated with side effects. NEs offer enhanced stability, protection, and improved permeation via various delivery routes. MTX-loaded oil-in-water NEs (O/W NEs) were formulated to improve entrapment efficiency, permeation ability, and efficacy in CFA-induced arthritis model. The area of NEs was identified by pseudoternary phase diagrams, optimization of MTX-NEs was performed using I-optimal mixture design, and characterized for %entrapment efficiency, droplet size, polydispersity index, zeta potential, morphology, and %transmittance. The MTX-NE gel was evaluated for rheology, in vitro drug release, ex vivo permeation, and efficacy in a CFA-induced arthritic rats. The MTX-NEs were prepared using Smix ratio of 3:1 with 0.2 N sodium hydroxide as aqueous phase. It showed >90% entrapment efficiency, size of 161.4 ± 13.5 nm, and 94 ± 1.8% of %transmittance. MTX-NE gel showed sustained release of 86 ± 1.8% MTX, and cumulative permeation of 77.6 ± 1.4% with a flux of 0.184 µg/cm2.h. Efficacy studies in a CFA-induced rat model resulted in significant reduction of paw edema, radiographic, histopathological, and inflammatory biomarkers. The optimized MTX-NE gel showed enhanced delivery, sustained release, and significant anti-arthritic effects, supporting its potential as an effective for RA therapy.