Purpose

Methotrexate (MTX) is an antineoplastic drug used in the treatment of rheumatoid arthritis (RA). Given that it is a class IV drug with low permeability and solubility, this study aims to improve MTX skin permeation by loading it in transethosomes (TEs) and casting a transethosomal patch that allows for dose quantification to mitigate toxicity.

Methods

To accomplish this goal, MTX transethosomes (TEs) were developed using the thin film hydration technique and optimized using the Box-Behnken design (BBD) with soya phosphatidylcholine 50, Tween 80, and ethanol as independent variables using the desirability function. Furthermore, zeta potential (ZP) analysis and high-resolution transmission electron microscopy (HR-TEM) were used to confirm the stability and surface morphology of TEs. A transdermal patch was also designed and evaluated from the optimized TE (OPTZ TEs) batch using a solvent casting method with hydroxypropyl methylcellulose (HPMC) as the polymer, dimethyl sulfoxide (DMSO) as a permeation enhancer, and polyethylene glycol (PEG 400) as the plasticizer. Furthermore, ex vivo skin permeation and deposition through rat skin proved that the TE patch had better drug permeation and retention within the skin layers.

Results

The highest desirability batch had 92.19 ± 3.826 nm vesicle size, 0.35 ± 0.062 PDI, 74.05 ± 5.157% EE and 62.75 ± 4.448% Q8h which were within the predicted results. Furthermore, ZP was found to be more than − 30 mV, and HR-TEM results proved that the TE vesicles were spherical. The results of the evaluation parameters such as weight variation, folding endurance, and thickness were 0.07 ± 0.01 g, 82.3 ± 1.52 folds, and 0.93 ± 0.01, respectively, and were well within the limits. The TE patch incorporated more than 90% of the drug confirmed by the drug content analysis which allowed ex vivo permeation for almost 24 h providing a sustained release action with a permeation flux of 19 ± 1.08 and an enhancement ratio of 3.68 when compared to the MTX solution.

Conclusion

This study suggests that MTX-loaded transethosomal patch not only enhanced the skin permeation but also provided a 24-h release profile and reduced its toxicity.

Graphical Abstract

中文翻译：

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用于增强甲氨蝶呤透皮递送的转酶体的配制、表征和优化

目的

甲氨蝶呤 (MTX) 是一种用于治疗类风湿性关节炎 (RA) 的抗肿瘤药物。鉴于它是一种具有低渗透性和溶解性的 IV 类药物，本研究旨在通过将 MTX 装载到转体 (TE) 中并铸造转体贴片来改善 MTX 的皮肤渗透性，从而可以进行剂量量化以减轻毒性。

方法

为了实现这一目标，使用薄膜水合技术开发了 MTX 转酶体 (TE)，并使用 Box-Behnken 设计 (BBD) 进行优化，其中大豆磷脂酰胆碱 50、吐温 80 和乙醇作为自变量，并使用期望函数。此外，使用zeta电位（ZP）分析和高分辨率透射电子显微镜（HR-TEM）来确认TE的稳定性和表面形貌。还使用溶剂浇铸法，以羟丙基甲基纤维素（HPMC）作为聚合物，二甲亚砜（DMSO）作为渗透促进剂，聚乙二醇（PEG 400）作为渗透增强剂，从优化的TE（OPTZ TEs）批次中设计并评估了透皮贴剂。增塑剂。此外，通过大鼠皮肤的离体皮肤渗透和沉积证明TE贴片在皮肤层内具有更好的药物渗透和保留。

结果

最高合意性批次的囊泡大小为 92.19 ± 3.826 nm，PDI 为 0.35 ± 0.062，EE 为 74.05 ± 5.157%，Q8h 为 62.75 ± 4.448%，均在预测结果范围内。此外，ZP被发现超过-30 mV，HR-TEM结果证明TE囊泡是球形的。重量变化、耐折性、厚度等评价参数的结果分别为0.07±0.01g、82.3±1.52倍、0.93±0.01，完全在限度内。经药物含量分析证实，TE贴剂掺入了超过90%的药物，可实现近24小时的离体渗透，与MTX相比，提供缓释作用，渗透通量为19±1.08，增强比为3.68解决方案。

结论

这项研究表明，装载 MTX 的转体贴剂不仅增强了皮肤渗透性，而且还提供了 24 小时释放曲线并降低了其毒性。

图形概要