Quality by Design-Driven Development and Optimization of Anti-Rheumatic Solid Lipid Nanoparticles-Loaded Hydrogel: Formulation Characterization, Rheological Evaluation, and Preclinical Efficacy

Abstract

Purpose

Rheumatoid arthritis is a chronic autoimmune disease requiring long-term therapy, often limited by systemic adverse effects and inadequate drug delivery to inflamed joints. This study aimed to develop and optimize a ferulic acid-loaded solid lipid nanoparticle hydrogel using a Quality-by-Design approach to improve topical anti-arthritic therapy.

Methods

Nanoparticles were prepared by hot-homogenization and optimized using a Box-Behnken design. The optimized nanoparticles were characterized by dynamic light scattering, zeta potential, scanning and transmission electron microscopy, followed by in-vitro evaluation and incorporation into a xanthan gum-based gel. The hydrogel was further assessed for physicochemical properties, stability, in-vitro drug release, ex-vivo skin permeation, dermal safety, anti-inflammatory activity using the carrageenan-induced paw edema model, and anti-arthritic efficacy in the complete Freund’s adjuvant-induced arthritis model.

Results

The optimized nanoparticles exhibited a favourable in-vitro safety profile with 95.6 ± 0.4% cell viability, significantly inhibited protein denaturation (74.3 ± 0.2%), and effectively suppressed COX-2 activity (IC₅₀ = 40.86 µg/ml). The hydrogel demonstrated desirable physicochemical properties, excellent stability, and sustained drug release, achieving 83.2 ± 0.3% cumulative drug release and 72.9 ± 0.4% ex-vivo skin permeation after 8 h. In vivo studies showed superior anti-inflammatory and anti-arthritic efficacy compared with the conventional gel, as evidenced by significant reductions in paw edema, preservation of body weight, and marked protection against cartilage and bone damage.

Conclusion

The Quality-by-Design optimized ferulic acid loaded solid lipid nanoparticles-based hydrogel is a promising topical drug delivery system for rheumatoid arthritis, offering sustained release, enhanced dermal permeation, and improved local therapeutic efficacy.

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Pujari, P., Maste, M. & Salve, P. Quality by Design-Driven Development and Optimization of Anti-Rheumatic Solid Lipid Nanoparticles-Loaded Hydrogel: Formulation Characterization, Rheological Evaluation, and Preclinical Efficacy. J Pharm Innov 22, 197 (2027). https://doi.org/10.1007/s12247-026-11074-z