Programa de Maestría y Doctorado en Ciencias Químicas, Universidad Nacional Autónoma de México, 04510, México City, Mexico.
Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, 04510, México City, Mexico.
AAPS PharmSciTech. 2020 Sep 27;21(7):264. doi: 10.1208/s12249-020-01805-x.
Although mebendazole (MBZ) has demonstrated antitumor activity in glioblastoma models, the drug has low aqueous solubility and therefore is poorly absorbed. Considering that other strategies are needed to improve its bioavailability, the current study was aimed to develop and evaluate novel microemulsions of MBZ (MBZ-NaH ME) for intranasal administration. MBZ raw materials were characterized by FTIR, DSC, and XDP. Subsequently, the raw material that contained mainly polymorph C was selected to prepare microemulsions. Two different oleic acid (OA) systems were selected. Formulation A was composed of OA and docosahexaenoic acid (3:1% w/w), while formulation B was composed of OA and Labrafil M2125 (1:1% w/w). Sodium hyaluronate (NaH) at 0.1% was selected as a mucoadhesive agent. MBZ MEs showed a particle size of 209 nm and 145 nm, respectively, and the pH was suitable for nasal formulations (4.5-6.5). Formulation B, which showed the best solubility and rheological behavior, was selected for intranasal evaluation. The nasal toxicity study revealed no damage in the epithelium. Furthermore, formulation B improved significantly the median survival time in the orthotopic C6 rat model compared to the control group. Moreover, NIRF signal intensity revealed a decrease in tumor growth in the treated group with MBZ-MaH ME, which was confirmed by histologic examinations. Results suggest that the intranasal administration of mebendazole-loaded microemulsion might be appropriated for glioblastoma treatment. Graphical abstract.
虽然甲苯咪唑（MBZ）在胶质母细胞瘤模型中显示出抗肿瘤活性，但该药物的水溶性低，因此吸收不良。考虑到需要其他策略来提高其生物利用度，本研究旨在开发和评估用于鼻内给药的新型 MBZ 微乳（MBZ-NaH ME）。通过 FTIR、DSC 和 XDP 对 MBZ 原料药进行了表征。随后，选择主要含有多晶型 C 的原料药来制备微乳。选择了两种不同的油酸（OA）系统。配方 A 由 OA 和二十二碳六烯酸（3:1%w/w）组成，而配方 B 由 OA 和 Labrafil M2125（1:1%w/w）组成。选择 0.1%的透明质酸钠（NaH）作为黏膜黏附剂。MBZ ME 的粒径分别为 209nm 和 145nm，pH 值适合鼻用制剂（4.5-6.5）。显示出最佳溶解度和流变行为的配方 B 被选为鼻内评价。鼻毒性研究表明上皮无损伤。此外，与对照组相比，配方 B 显著延长了 C6 大鼠原位模型的中位生存时间。此外，NIRF 信号强度显示载 MBZ-MaH ME 的治疗组肿瘤生长减少，这通过组织学检查得到证实。结果表明，载 MBZ 的微乳鼻内给药可能适合胶质母细胞瘤的治疗。
