Abstract

Rheumatoid arthritis (RA) management via conventional monotherapy is often limited by poor transdermal flux and suboptimal articular accumulation. This study seeks to bridge a critical gap in monotherapy by engineering chitosan-coated nanobilosomal gel co-encapsulated with thymol and silibinin (CH-TH+SB-BG) in a 3:1 stoichiometric ratio. Compared with monotherapeutics, the CH-TH+SB-BG showed the highest drug content and a sustained drug release profile, accompanied by higher skin permeation and deposition, indicating the fluidizing effect of thymol and the dermal reservoir of silibinin. Interestingly, CH-TH+SB-BG was cytocompatible, owing to its higher IC50 than that of the pure drugs. A marked reduction in the paw volume and arthritic score and significant normalization of hematological, biochemical, and inflammatory biomarkers, compared with the monotherapeutics, indicate the synergistic anti-inflammatory potential of the developed gel. Furthermore, the dual loading effectively reduced oxidative stress, confirmed by a significant decrease in malondialdehyde level along with the restoration of glutathione and superoxide dismutase levels. The Bliss independence model mathematically validated pharmacological synergy. Radiographic and histopathological analysis confirmed the near-complete articular restoration and marked reduction in pannus formation. In conclusion, the developed transdermal gel can be a more effective and safer alternative to long-term oral administration, opening the way for novel topical management of RA.

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