Department of Pharmaceutics, Faculty of Pharmacy, Universitas Hasanuddin, Makassar 90245, Indonesia.
School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, United Kingdom.
ACS Appl Mater Interfaces. 2021 Apr 21;13(15):18128-18141. doi: 10.1021/acsami.1c03422. Epub 2021 Apr 11.
The poor solubility of itraconazole (ITZ) has limited its efficacy in the treatment of vaginal candidiasis. Accordingly, the improvement of ITZ solubility using a solid dispersion technique was important to enhance its antifungal activity. Besides, as the purpose of this research was to develop local-targeting formulations, bioadhesive-thermosensitive vaginal gel combined with the gel-flake system was found to be the most suitable choice. To obtain optimum solubility, entrapment efficiency, and drug-loading capacity, optimization of solid dispersion (SD) and gel-flake formulations of ITZ was performed using a composite central design. The results showed that the optimized formulation of SD-ITZ was able to significantly enhance its solubility in both water and simulated vaginal fluid to reach the values of 4.211 ± 0.23 and 4.291 ± 0.21 mg/mL, respectively. Additionally, the optimized formulation of SD-ITZ gel flakes possessed desirable entrapment efficiency and drug-loading capacity. The vaginal gel containing SD-ITZ gel flakes was prepared using PF-127 and PF-68, as the gelling agents, with the addition of hydroxypropyl methylcellulose (HPMC) as the mucoadhesive polymer. It was found that the obtained vaginal gel provided desirable physicochemical properties and was able to retain an amount of more than 4 mg of ITZ in the vaginal tissue after 8 h. Importantly, according to the antifungal activity using infection animal models, the incorporation of the solid dispersion technique and gel-flake system in the formulation of the bioadhesive-thermosensitive vaginal gel led to the most significant decrease of the growth of reaching <1 log colony-forming units (CFU)/mL or equivalent to <10% of the total colony after 14 days, indicating the improvement of ITZ antifungal activity compared to other treated groups. Therefore, these studies confirmed a great potential to enhance the efficacy of ITZ in treating vaginal candidiasis. Following these findings, several further experiments need to be performed to ensure acceptability and usability before the research reaches the clinical stage.
伊曲康唑（ITZ）溶解度低，限制了其在治疗阴道念珠菌病方面的疗效。因此，采用固体分散技术提高 ITZ 的溶解度对于增强其抗真菌活性非常重要。此外，由于本研究旨在开发局部靶向制剂，因此发现具有生物黏附性和温敏性的阴道凝胶与凝胶薄片系统相结合是最合适的选择。为了获得最佳的溶解度、包封效率和载药量，采用复合中心设计对 ITZ 的固体分散体（SD）和凝胶薄片制剂进行了优化。结果表明，SD-ITZ 的最佳配方能够显著提高其在水和模拟阴道液中的溶解度，分别达到 4.211±0.23 和 4.291±0.21mg/mL。此外，SD-ITZ 凝胶薄片的最佳配方具有理想的包封效率和载药量。含有 SD-ITZ 凝胶薄片的阴道凝胶采用 PF-127 和 PF-68 作为凝胶剂，加入羟丙基甲基纤维素（HPMC）作为黏膜黏附聚合物制备而成。结果表明，所得到的阴道凝胶具有理想的物理化学性质，并且能够在 8 h 后在阴道组织中保留超过 4mg 的 ITZ。重要的是，根据感染动物模型的抗真菌活性研究，将固体分散技术和凝胶薄片系统纳入生物黏附性和温敏性阴道凝胶的配方中，可使 的生长量减少到<1 对数集落形成单位（CFU）/mL 或相当于 14 天后总集落的 10%以下，表明与其他治疗组相比，ITZ 的抗真菌活性得到了提高。因此，这些研究证实了通过采用固体分散技术和凝胶薄片系统来提高 ITZ 治疗阴道念珠菌病的疗效具有很大的潜力。在研究进入临床阶段之前，还需要进行进一步的实验以确保其可接受性和可用性。
