Methotrexate (MTX) is the first line of choice for the management of rheumatoid arthritis (RA) and has been reported for its low bioavailability and side effects. Combination therapy has been widely investigated to overcome bioavailability issues and to reduce adverse effects associated with monotherapy. Various phytoconstituents such as resveratrol (RSV) and curcumin have been found to possess potent anti-inflammatory activity via downregulating the signaling of cytokines (interleukin [IL]-1, IL-6, and tumor necrosis factor alpha) and nuclear factor kappa B signaling. The prime objective of this study was to develop transdermal gel containing MTX–RSV loaded nanoemulsions (NEs) to overcome bioavailability issues and adverse effects of RA monotherapy. The NEs optimized by using Box–Behnken Design were incorporated within gel, and an in vitro skin permeation study performed on rat skin by using vertical Franz diffusion cells exhibited controlled drug release up to 48 h. Subsequently, anti-inflammatory and potential anti-arthritic activities of the combination in nanocarrier were assessed in rats and showed 78.76 ± 4.16% inhibition in inflammation and better anti-arthritic effects. Consequently, integration of dual delivery with nanotechnology can hopefully produce successful therapeutic options for rheumatic diseases.

中文翻译：

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使用 Box-Behnken 设计优化和开发用于治疗类风湿性关节炎的甲氨蝶呤和白藜芦醇纳米乳剂

甲氨蝶呤 (MTX) 是治疗类风湿性关节炎 (RA) 的首选药物，并因其低生物利用度和副作用而被报道。联合疗法已被广泛研究以克服生物利用度问题并减少与单一疗法相关的不良反应。已发现白藜芦醇 (RSV) 和姜黄素等多种植物成分通过下调细胞因子（白介素 [IL]-1、IL-6 和肿瘤坏死因子 α）和核因子 kappa B 信号传导而具有强效抗炎活性. 本研究的主要目标是开发含有 MTX-RSV 纳米乳剂 (NEs) 的透皮凝胶，以克服 RA 单一疗法的生物利用度问题和不良反应。使用 Box-Behnken Design 优化的 NEs 被整合到凝胶中，以及使用垂直 Franz 扩散池对大鼠皮肤进行的体外皮肤渗透研究显示，药物释放可控制长达 48 小时。随后，在大鼠中评估了纳米载体中组合的抗炎和潜在的抗关节炎活性，并显示出 78.76 ± 4.16% 的炎症抑制和更好的抗关节炎作用。因此，将双重递送与纳米技术相结合有望为风湿病提供成功的治疗选择。