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Rheumatoid arthritis (RA), a disease that causes joint destruction and bone erosion, is related to osteoclast activity. RA is generally treated with methotrexate (MTX). In this study, a MTX-Alendronate (ALN) conjugate was synthesized and characterized. The conjugate dramatically inhibited osteoclast formation and bone resorption compared with MTX and ALN used alone or in combination. Due to the characteristics of ALN, the MTX-ALN conjugate can adhere to the exposed bone surface and enhance drug accumulation in the pathological region for targeted therapy against osteoclastogenesis. Additionally, MTX was rapidly released in the presence of lysozyme under mildly acidic conditions, similar to inflammatory tissue and osteoclast-surviving conditions, which contributes to inflammatory inhibition; this was confirmed by the presence of pro-inflammatory cytokines. Our study highlights the use of the MTX-ALN conjugate as a potential therapeutic approach for RA by targeting osteoclastogenesis. [ABSTRACT FROM AUTHOR]

The purpose of this study was to formulate a reservoir-type transdermal delivery system (TDS) for 2,3,5,6-tetramethylpyrazine (TMP) to enable the delivery of a sufficient dose through human skin to achieve an effective therapeutic plasma concentration. To improve the penetration of TMP in the reservoir-type TDS, several chemical penetration enhancers were investigated using in vitro rat dorsal skin permeation studies. Eucalyptus oil was found to enhance the permeation of TMP to the greatest extent, with the optimal concentration being 5% and the flux being 542.6 ± 49.7 μg/cm2/h, which was 4.5-fold greater than control with no enhancer ( p < 0.01). The flux of the optimized reservoir-type TDS permeated through the human epidermis was 346.0 ± 27.7 μg/cm2/h. Based on the in vitro human skin permeation flux and the pharmacokinetics parameters observed, the clinical surface area of the TDS patch was predicted to be 20 cm2. The in vivo study conducted in rabbits showed that the TMP TDS patch containing 5% eucalyptus oil had a more favorable pharmacokinetic profile, with a lower Cmax and prolonged Tmax and mean residence time than that observed with the oral administration of TMP. The TMP reservoir-type TDS was shown to be a promising alternative route to oral administration or intravenous infusion of TMP. [ABSTRACT FROM AUTHOR]