Purpose

Skin fungal infections are widely spreading worldwide and are considered a main cause of skin, mucous membranes, and systemic diseases. In an approach to enhance the topical delivery of miconazole nitrate (MZN) as a poorly permeable antifungal agent, spanlastics nanocarriers as a type of elastic vesicles were adopted in the current work.

Methods

MZN spanlastics were prepared and optimized according to a D-optimal response surface design to investigate the influence of formulation variables, edge activator (EA) percentage, EA type on particle size (PS), and drug entrapment efficiency percentage (% EE) as dependent variables. The spanlastics optimized formula (F7) was further assessed for its elasticity and physico-pharmaceutical properties before being incorporated into a gel. The F7 gel formula was also examined for its physical properties, in vitro release, in vitro antifungal activity against Candida albicans (ATCC® 10231), and ex vivo skin deposition studies. The results of the F7 gel formula were compared to the F7 aqueous dispersion.

Results

The D-optimal design revealed that F7, developed using Tween 60 as EA and Span 60 at a weight ratio 2:8, is the optimized formula. F7 was an elastic, spherical, non-aggregated vesicle with an average PS of 210 nm and a drug entrapment efficiency of 90%. The drug was present in an amorphous form within the vesicles. The gel form of F7 showed a prolonged drug release behavior relative to the solution form, where 75% of the drug was released over 10 h for the former and 5 h for the latter. The antifungal study revealed a significant (p < 0.05) increase in the zone of inhibition of Candida albicans (ATCC® 10231) demonstrated by spanlastics compared to MZN suspension at the same concentration level. MZN suspension showed cytotoxic activity at a concentration of 20 μg/mL and above; the incorporation of the drug in spanlastics dispersion or gel form increased the cell viability percentage. The skin deposition studies showed that F7 deposition in the dermal layer, where deep skin infections occur, is 164-folds that of the plain drug.

Conclusions

The results confirm the potential application of MZN-spanlastics to treat deeply seated skin fungal infections.

中文翻译：

---

利用响应面 D 最优设计研究负载硝酸咪康唑作为局部应用抗真菌药物模型的制备和优化

目的

皮肤真菌感染在世界范围内广泛传播，被认为是皮肤、粘膜和全身性疾病的主要原因。在增强硝酸咪康唑（MZN）作为一种渗透性差的抗真菌剂的局部递送的方法中，当前的工作采用了spanlastics纳米载体作为一种弹性囊泡。

方法

根据 D 最佳响应面设计制备和优化 MZN Spaplastics，以研究配方变量、边缘活化剂 (EA) 百分比、EA 类型对粒径 (PS) 的影响以及药物包封率 (% EE) 的影响变量。在将 Spanlastics 优化配方 (F7) 纳入凝胶之前，对其弹性和物理药物特性进行了进一步评估。还检查了 F7 凝胶配方的物理特性、体外释放、针对白色念珠菌(ATCC® 10231)的体外抗真菌活性以及离体皮肤沉积研究。将 F7 凝胶配方的结果与 F7 水分散体进行比较。

结果

D优化设计表明，以Tween 60作为EA和Span 60以2:8的重量比开发的F7是优化的配方。F7是一种有弹性、球形、非聚集的囊泡，平均PS为210 nm，药物包封率为90%。该药物以无定形形式存在于囊泡内。相对于溶液形式，F7 的凝胶形式显示出延长的药物释放行为，其中前者在 10 小时内释放了 75% 的药物，后者在 5 小时内释放了 75% 的药物。抗真菌研究表明，与相同浓度水平的 MZN 悬浮液相比，spanlastics 的白色念珠菌(ATCC® 10231)抑制区显着增加( p < 0.05)。MZN悬浮液在浓度为20μg/mL及以上时表现出细胞毒活性；以spanlastics分散体或凝胶形式加入药物可增加细胞活力百分比。皮肤沉积研究表明，F7 在发生深层皮肤感染的真皮层中的沉积量是普通药物的 164 倍。

结论

结果证实了 MZN-spanlastics 在治疗深层皮肤真菌感染方面的潜在应用。