Exploiting response surface D-optimal design study for preparation and optimization of spanlastics loaded with miconazole nitrate as a model antifungal drug for topical application

Abstract

Abstract 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.