Effective transdermal delivery of methotrexate through nanostructured lipid carriers in an experimentally induced...

Rheumatoid arthritis (RA), an autoimmune and inflammatory pathology, is resulted due to the disruption of immune-homeostasis and failure of host immune-surveillance mechanism leading to cartilage degradation and bone erosion. Orally and parenterally administered methotrexate (MTX) have had adverse systemic complications in RA therapeutics. Therefore, transdermal application of MTX is recommended for the treatment of RA [1]. Present study is designed to develop MTX loaded nanostructured lipid carriers and chemical enhancer co-incorporated hydrogel (gel-(MTX-NLCs+CE)) for an efficient transdermal delivery of MTX in a Freund's adjuvants induced experimental animal model of RA. A gel-(MTX-NLCs+CE) was formulated and evaluated for its biocompatibility in hyper keratinocytes (HaCaT) and human monocytic cells (U937). Further, systemic and local inflammation was assessed by the estimation of pro-inflammatory cytokines & joint-destructive enzymes (TNF-α, IL-6, MMP-1 & IL-1β,; iNOS & COX-2) in the serum and synovial fluid, respectively in an experimentally induced RA animal model. Prepared formulations were also evaluated with respect to arthritis index, arthritis score and histopathology of paw and ankle bones. The biocompatibility study of formulation on U937 and HaCaT is suggestive of safe and greater therapeutic efficacy of the developed formulations. Our results show that transcutaneous ability of MTX loaded nanostructured lipid carries (NLCs) and chemical enhancer (CE) co-incorporated hydrogel significantly (p<0.001) decreases the inflammation in RA animal model. In conclusion, developed NLCs-based gel formulation loaded with MTX opens new avenues for developing novel therapeutic modality for RA patients with the acceptably minimum adverse effects.