Abstract

Triptolide (extract of herb Tripterygium wilfordii) is widely used in rheumatoid arthritis due to its potent immunosuppressant effect. The marketed oral (tablet dosage forms) and parenteral injections have short duration of action (half-life = 38 min) and not limited to multiorgan toxicity, which restrict the use of triptolide in clinical practice. In this study, a triptolide-loaded Pluronic® F68-reduced graphene oxide transdermal (non-invasive) hydrogel was developed to achieve sustained release of triptolide. Fourier transform infrared spectroscopy, X-ray diffraction, and Raman spectroscopy confirmed the synthesis of Pluronic^® F68-reduced graphene oxide. Transmission electron microscopy showed flat wrinkled-nanosheets. The developed hydrogel showed desirable viscosity (11,261–11,365 cps), adhesiveness (0.25 mJ), hardness (6.5 g), and cohesiveness (1.85) for transdermal application. The ex vivo release study demonstrated the ability of the Pluronic^® F68-reduced graphene oxide hydrogel to prolong release up to 14 h (63.64–96.78%), owing to the strong π–π interactions between the graphene oxide and the triptolide. The in vivo pharmacokinetic parameters in the rat model confirmed the improvement in the relative bioavailability (3.3-fold) with Pluronic^® F68-reduced graphene oxide hydrogel in comparison to the control hydrogel without reduced graphene oxide. The anti-rheumatoid efficacy model suggest the potential application of Pluronic^® F68-reduced graphene oxide hydrogel to treat knee rheumatoid arthritis (70–75% resolution) to substitute tablets and parenteral injections.

摘要

雷公藤甲素（草药的提取物雷公藤）被广泛由于其强效的免疫抑制剂的效果应用于类风湿性关节炎。市售的口服（片剂剂型）和肠胃外注射剂的作用持续时间短（半衰期 = 38 分钟）且不限于多器官毒性，这限制了雷公藤内酯在临床实践中的使用。在这项研究中，开发了一种装载雷公藤内酯的 Pluronic® F68 还原氧化石墨烯透皮（非侵入性）水凝胶，以实现雷公藤内酯的持续释放。傅里叶变换红外光谱、X 射线衍射和拉曼光谱证实了 Pluronic ^®的合成F68 还原氧化石墨烯。透射电子显微镜显示平坦的皱纹纳米片。开发的水凝胶显示出理想的粘度 (11,261–11,365 cps)、粘附性 (0.25 mJ)、硬度 (6.5 g) 和内聚性 (1.85)，适用于透皮应用。的体外释放研究证明的能力的Pluronic ^® F68-还原的石墨烯氧化物的水凝胶，以延长释放高达14小时（63.64-96.78％），由于氧化石墨烯和雷公藤之间的强π-π相互作用。在体内大鼠模型中的药代动力学参数证实了在相对生物利用度（3.3倍）与普朗尼克改善^®与没有还原氧化石墨烯的对照水凝胶相比，F68 还原氧化石墨烯水凝胶。抗类风湿功效模型表明 Pluronic ^® F68 还原氧化石墨烯水凝胶在治疗膝类风湿性关节炎（70-75% 分辨率）方面的潜在应用，以替代片剂和肠胃外注射。