This work aimed to design a transdermal delivery of rhein loaded nanoemulgel to improve the bioavailability and efficacy of rhein in the treatment of osteoarthritis and reduce its systemic side effects. Rhein loaded nanoemulsion (Rh-NE) prepared by application of ternary phase diagram and spontaneous emulsification method. Box-Behnken design (BBD) was employed to optimize formulation and preparation process of Rh-NE. The optimal formulation was 11.09% mixed oil (rhein and caproyl 90), 22.96% mixed emulsifier (kolliphor RH 40: transcutol HP, 1:1, w/w), and the preparation process was 23.08 min ultrasonic time and 179.5 W ultrasonic power. The particle size of the optimized Rh-NE was 24.5 ± 3.2 nm, PDI was 0.15 ± 0.02, and zeta potential was −18.6 ± 1.8 mV. The Rh-NE was incorporated into hydrogel consisted of 0.85% carbomer, 0.2% poloxamer 188 and 8.0% glycerol to form rhein loaded nanoemulgel (Rh-NE/Gel). In vitro transdermal flux of Rh-NE/Gel was 91.4 ± 0.9 μg/cm²·h. It was found that the inhibition rate of swelling degree of auricle caused by xylene was (54%), inhibition rate of writhing reaction was (60%), percentage increase in pain threshold was (P < 0.01), and the inhibition rate of capillary permeability was (69%). The therapeutic effect of Rh-NE/Gel on osteoarthritis in model rats was significantly improved compared with control group; the swelling degree of joint and toe were significantly reduced by 91% and 71%, respectively, and the contents of inflammatory factors IL-1β and NO were decreased 35.7% and 52.4%, respectively. The developed Rh-NE/Gel could provide anti-osteoarthritis effect and reduce the release of proinflammatory mediators in OA model rats.

本工作旨在设计一种经皮给药的大黄酸纳米乳胶，以提高大黄酸治疗骨关节炎的生物利用度和功效，并减少其全身副作用。应用三元相图和自发乳化法制备大黄酸纳米乳液（Rh-NE）。采用Box-Behnken设计（BBD）优化Rh-NE的处方和制备工艺。最佳配方为11.09%混合油(大黄酸和己酰90)、22.96%混合乳化剂(kolliphor RH 40: transcutol HP, 1:1, w/w),制备工艺为超声时间23.08 min、超声功率179.5 W 。优化后的Rh-NE粒径为24.5±3.2 nm，PDI为0.15±0.02， zeta电位为-18.6±1.8 mV。将Rh-NE掺入由0.85％卡波姆、0.2％泊洛沙姆188和8.0％甘油组成的水凝胶中，形成负载大黄酸的纳米乳凝胶(Rh-NE/Gel)。Rh-NE/Gel的体外透皮通量为91.4 ± 0.9 μg/cm ² ·h。结果发现，二甲苯引起的耳廓肿胀程度的抑制率为（54%），扭体反应的抑制率为（60%），痛阈增加百分率（ P  <0.01），毛细血管的抑制率为（P<0.01）。渗透率为（69%）。Rh-NE/Gel对模型大鼠骨关节炎的治疗效果较对照组明显提高；关节和脚趾肿胀程度分别显着减轻91%和71%，炎症因子IL-1β和NO含量分别降低35.7%和52.4%。开发的Rh-NE/Gel可以在OA模型大鼠中提供抗骨关节炎作用并减少促炎介质的释放。