School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Department of Clinical Laboratory, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
Int J Pharm. 2020 Jul 30;585:119497. doi: 10.1016/j.ijpharm.2020.119497. Epub 2020 Jun 3.
Onychomycosis is a chronic nail disorder consisting of a fungal infection that causes physical and psychosocial discomfort to patients. However, its treatment remains challenging owing to the barrier of the highly keratinized nail plate and the short time that conventional formulations reside on nails. In this work, we developed an in situ film-forming system(IFFS) based on Eudragit® RLPO to co-deliver terbinafine hydrochloride (TBH) and urea, i.e., TBH-urea-RLPO IFFS, with the aim of overcoming the nail barrier, prolonging the residence time, and efficiently treating onychomycosis. The IFFS formulation formed a thin film with good appearance and adhesion upon application in situ. The physical states of TBH and urea in the film were evaluated with polarization microscopy and powder X-ray diffraction. TBH and urea were both amorphousmiscible components within the RLPO film. TBH release from TBH-urea-RLPO IFFS fitted to the Korsmeyer-Pappas model, and the cumulative release at 72 h was significantly higher than that from commercial preparations (Lamisil Pedisan® once). In vitro permeation of TBH from TBH-urea-RLPO IFFS through bovine hoof membranes was evaluated in comparison with the film containing TBH alone (TBH-RLPO) and commercial preparations. The retention and cumulative permeated amount of TBH were significantly enhanced for the TBH-urea-RLPO IFFS (170.80 ± 44.63 μg/cmvs 75.49 ± 21.50 μg/cmvs 60.25 ± 27.38 μg/cm; 61.81 ± 16.09 μg/cmvs 21.80 ± 11.56 μg/cmvs 7.91 ± 1.03 μg/cm, respectively), and the membranes treated with different formulations were observed with SEM and FTIR to identify the denaturing effect of urea on bovine hoof keratin. In vitro antifungal tests against Trichophyton rubrum,Microsporum canis, Fusarium, and Aspergillus fumigatus were cultured on Muller-Hinton agar; the findings indicated that TBH-urea-RLPO IFFS enhanced TBH antifungal activity. Overall, the results support that TBH-urea-RLPO IFFS is an efficient and promising approach for onychomycosis targeting treatment.
甲真菌病是一种慢性指甲疾病，由真菌感染引起，会给患者带来身体和心理上的不适。然而，由于高度角蛋白化的指甲板的屏障以及常规制剂在指甲上停留的时间较短，其治疗仍然具有挑战性。在这项工作中，我们开发了一种基于 Eudragit® RLPO 的原位成膜系统（IFFS），以共同递送盐酸特比萘芬（TBH）和尿素，即 TBH-urea-RLPO IFFS，以克服指甲屏障，延长滞留时间，并有效治疗甲真菌病。IFFS 制剂在原位应用时形成具有良好外观和附着力的薄膜。通过偏光显微镜和粉末 X 射线衍射评估了薄膜中 TBH 和尿素的物理状态。TBH 和尿素在 RLPO 薄膜中均为无定形可混溶成分。TBH-urea-RLPO IFFS 的 TBH 释放符合 Korsmeyer-Pappas 模型，72 小时的累积释放量明显高于商业制剂（Lamisil Pedisan®一次）。与仅含 TBH 的薄膜（TBH-RLPO）和商业制剂相比，评估了 TBH-urea-RLPO IFFS 通过牛蹄膜的体外透皮情况。TBH-urea-RLPO IFFS 的保留和累积透皮量显著增加（170.80±44.63μg/cmvs75.49±21.50μg/cmvs60.25±27.38μg/cm；61.81±16.09μg/cmvs21.80±11.56μg/cmvs7.91±1.03μg/cm），并通过 SEM 和 FTIR 观察处理不同配方的膜，以鉴定尿素对牛蹄角蛋白的变性作用。在 Muller-Hinton 琼脂上培养 Trichophyton rubrum、Microsporum canis、Fusarium 和 Aspergillus fumigatus 进行体外抗真菌试验；结果表明 TBH-urea-RLPO IFFS 增强了 TBH 的抗真菌活性。总体而言，结果支持 TBH-urea-RLPO IFFS 是一种针对甲真菌病靶向治疗的有效且有前途的方法。
