Transdermal\nDelivery of Tofacitinib Citrate via Mannose-Decorated\nTransferosomes Loaded with Tofacitinib Citrate in Arthritic Joints

Transdermal drug delivery systems are a promising option\nfor the\ntreatment of rheumatoid arthritis (RA) because they can lower systemic\nadverse effects of immunosuppressants. Janus kinase (JAK) inhibitors\nwere found to be effective for the treatment of RA by inhibiting the\nJAK-STAT pathway and preventing autoimmune joint destruction. The\naim of this study is to deliver tofacitinib (a JAK 1 and 3 inhibitor)\nthrough mannose-decorated transferosomes (MDTs) directly to inflamed\njoints. Transferosomes are composed of phospholipids, Cremophor A25,\nPEG400, Labrafac lipophile, and oleic acid to enhance the permeation\nof tofacitinib and control nanovesicle size (∼70–200\nnm). Permeation through rat skin was evaluated, where the skin permeation\nof MDTs (Q24: 38.8 ± 9.82 μg/cm<sup>2</sup>) and flux (0.5311\n± 0.072 μg/cm<sup>2</sup>/h) were significantly greater\nthan those of the uncoated transferosomes (Q24 of T1: 1.522 ±\n0.329 μg/cm<sup>2</sup>, Q24 of T2: 3.5002 ± 0.998 μg/cm<sup>2</sup>, and Q24 of T3: 18.226 ± 5.25 μg/cm<sup>2</sup>). In addition, MDTs seem to permeate the skin intact, as shown by\nthe transmission electron microscopy (TEM) images of the recipient\nbuffer removed from the Franz diffusion cell. A histopathology assay\nwas performed during the <i>in vivo</i> evaluation of MDTs\nin an arthritic rat model, in which, significantly less inflammation\nwas observed when MDTs were applied directly to the joint compared\nto when applied to the dorsal skin and untreated arthritic joints.\nFurthermore, significantly lower tumor necrosis factor-α (TNFα),\nIL-6, and IL-1β levels (<i>P</i> < 0.05) were detected\nby enzyme-linked immunosorbent assay (ELISA) in homogenates of the\njoints treated with MDTs than in untreated arthritic joints. In conclusion,\nthis study proposed effective MDTs that could deliver tofacitinib\ndirectly to inflamed joints possibly by targeting the macrophages\ncirculating in the proximity of the site of inflammation.