Transdermal Delivery of Methotrexate Loaded in Chitosan Nanoparticles to Treat Rheumatoid Arthritis

Introduction: Methotrexate shows high efficiency in the treatment of Rheumatoid arthritis, but its adverse effects cannot be tolerated by many patients. Additionally, Methotrexate suffers from rapid clearance from blood. Polymeric nanoparticles were used to solve these problems including chitosan. Methods: Herein, a new nanoparticulate system to deliver Methotrexate (MTX) using chitosan nanoparticles (CS NPs) was developed to be used transdermally. CS NPs were prepared and characterized. The drug release was studied in vitro and ex vivo using rat skin. The drug performance in vivo was investigated on rats. Formulations were applied topically once a day on the paws and knee joints of arthritis rats for 6 weeks. Paw thickness was measured and synovial fluid samples were collected. Results: The results showed that CS NPs were monodispersed, and spherical with a size of 279.9 nm and a charge above +/- 30mV. Further, 88.02% of MTX was entrapped in the NPs. CS NPs prolonged MTX release and enhanced its permeation (apparent permeability similar to 35.00cm/h) and retention (retention capacity similar to 12.01%) through rats' skin. The transdermal delivery of MTX-CS NPs improves the progress of the disease compared to free MTX, as reflected by the lower arthritic index values, lower proinflammatory cytokines (TNF-alpha and IL-6), and higher anti-inflammatory cytokine (IL-10) in the synovial fluid. Further, the oxidative stress activities were significantly higher in the group treated with the MTX-CS NPs, as indicated by GSH. Finally, MTX-CS NPs were more effective in reducing lipid peroxidation in synovial fluid. Conclusion: In conclusion, loading Methotrexate in chitosan nanoparticles controlled its release and enhance its effectiveness against rheumatoid when applied dermally.