Abstract：
Fungal infections are the fourth common cause of infection affecting around 50 million populations across the globe. Dermatophytes contribute to the majority of superficial fungal infections. Clotrimazole (CTZ), an imidazole derivative is widely preferred for the treatment of topical fungal infections. Conventional topical formulations enable effective penetration of CTZ into the stratum corneum, however, its low solubility results in poor dermal bioavailability, and variable drug levels limit the efficacy. The aim was to increase dermal bioavailability and sustain drug release, thereby potentially enhancing drug retention and reducing its side effects. This work evaluated the CTZ loaded solid lipid nanoparticles (SLN) consisting of precirol and polysorbate-80 developed using high pressure homogenization and optimized with QbD approach. Prior to release studies, CTZ-SLNs were characterized by different analytical techniques. The laser diffractometry and field emission scanning electron microscopy indicated that SLNs were spherical in shape with mean diameter of 450 ± 3.45 nm. DSC and XRD results revealed that the drug remained molecularly dispersed in the lipid matrix. The CTZ-SLNs showed no physicochemical instability during 6 months of storage at different temperatures. Further, the Carbopol with its pseudoplastic behavior showed a crucial role in forming homogenous and stable network for imbibing the CTZ-SLN dispersion for effective retention in skin. As examined, in-vitro drug release was sustained up to 24 h while ex-vivo skin retention and drug permeation studies showed the highest accumulation and lowest permeation with nanogel in comparison to pure drug and Candid® cream. Further, the in-vivo antifungal efficacy of nanogel suggested once-a-day application for 10 days, supported by histopathological analysis for complete eradication infection. In summary, the findings suggest, that nanogel-loaded with CTZ-SLNs has great potential for the management of fungal infections caused by Candida albicans.
摘要：
真菌感染是感染的第四个常见原因，影响全球约5000万人口。皮肤癣菌导致大多数浅表真菌感染。克霉唑（CTZ），咪唑衍生物广泛优选用于治疗局部真菌感染。常规的局部制剂能够使CTZ有效渗透到角质层中，然而,它的低溶解度导致皮肤生物利用度差，和可变的药物水平限制了疗效。目的是增加皮肤生物利用度和维持药物释放，从而潜在地增强药物保留并减少其副作用。这项工作评估了使用高压均质化开发并使用QbD方法优化的由precirol和聚山梨酯-80组成的负载CTZ的固体脂质纳米颗粒（SLN）。在发布研究之前，CTZ-SLN通过不同的分析技术表征。激光衍射和场发射扫描电子显微镜显示，SLN呈球形，平均直径为450±3.45nm。DSC和XRD结果表明药物保持分子分散在脂质基质中。CTZ-SLN在不同温度下储存6个月期间没有显示物理化学不稳定性。Further,具有假塑性行为的Carbopol在形成均匀和稳定的网络以吸收CTZ-SLN分散体以有效保留在皮肤中方面表现出关键作用。如检查，体外药物释放持续24小时，而体外皮肤滞留和药物渗透研究显示，与纯药物和Candid®乳膏相比，纳米凝胶的积累最高，渗透最低。Further,纳米凝胶的体内抗真菌功效建议每天一次，持续10天，完全根除感染的组织病理学分析支持。总之,研究结果表明,负载有CTZ-SLN的纳米凝胶在治疗白色念珠菌引起的真菌感染方面具有巨大潜力。
