Development and Optimization of Luliconazole Spanlastics to Augment the Antifungal Activity against Candida albicans

Abstract

Luliconazole is a new topical imidazole antifungal drug for the treatment of skin infections. It has low solubility and poor skin penetration which limits its therapeutic applications. In order to improve its therapeutic efficacy, spanlastics nanoformulation was developed and optimized using a combined mixture-process variable design (CMPV). The optimized formulation was converted into a hydrogel formula to enhance skin penetration and increase the efficacy in experimental cutaneous Candida albicans infections in Swiss mice wounds. The optimized formulation was generated at percentages of Span and Tween of 48% and 52%, respectively, and a sonication time of 6.6 min. The software predicted that the proposed formulation would achieve a particle size of 50 nm with a desirability of 0.997. The entrapment of luliconazole within the spanlastics carrier showed significant (p < 0.0001) antifungal efficacy in the immunocompromised Candida-infected Swiss mice without causing any irritation, when compared to the luliconazole treated groups. The microscopic observation showed almost complete removal of the fungal colonies on the skin of the infected animals (0.2 ± 0.05 log CFU), whereas the control animals had 0.2 ± 0.05 log CFU. Therefore, luliconazole spanlastics could be an effective formulation with improved topical delivery for antifungal activity against C. albicans.

Keywords: Candida albicans infections; lesion score; luliconazole; particle size; spanlastics.

Figure 1

Externally studentized residuals vs. run number for the quadratic × cubic model for luliconazole spanlastics particle size.

Figure 2

Effect of the binary mixture components (I) and the sonication time (II) at the mid-values of the other variables; Three-dimensional mixture−process plot (III) for the particle size of luliconazole spanlastics.

Figure 3

Transmission electron microscope photograph of optimized luliconazole spanlastics.

Figure 4

Establishment of infection expressed as lesion score after starting treatment in cutaneous candidiasis mouse model. Mice (n = 5/group) were applied topically with luliconazole 25 mg/kg/day as Luli group and equivalent dose of luliconazole spanlastics (Luli-span group) for 5 days. (A) The score of erythema were measured on days 1, 3 and 5. (B) Average lesion score in C. albicans induced cutaneous candidiasis in mice treated with different formulations and compared with control and untreated group on the 5th day. Data were presented as mean ± SD. @ significant Luli span vs. untreated (p < 0.0001). * Significant Luli span vs. Luli group (p < 0.0001) determined by student t test.

Figure 5

Macroscopic evaluation of infection was measured by a score of erythema in mice of all three groups at 1, 3 and 5 days. On the 1st day after induction of C. albicans cutaneous candidiasis, obvious infection developed in all groups. On 3rd day small recovery was observed in luliconazole (Luli group) and luliconazole spanlastics (Luli-span group). On 5th day significant recovery was observed in Luli-span group.