In Silico Drug Screening Based Development of Novel Formulations for Onychomycosis Management

Abstract

Onychomycosis is a prominent fungal infection that causes discoloration, thickening, and mutilation leading to the separation of the nail from the nail bed. Treatment modalities for onychomycosis may include oral, topical, or combination therapy with antifungals and at times may require chemical or surgical intervention. The burden of side effects of antifungals is enormous, and therefore using molecular docking-based drug selection in context with the target keratin protein would ensure better disease management. Ciclopirox, Amorolfine HCl, Efinaconazole, Tioconazole, and Tavaborole were submitted for assessment, revealing that Amorolfine HCl is the best fit. Consequently, two formulations (Nail lacquer and nanoemulgel) were developed from Amorolfine HCl to validate the in silico screening outcomes. The formulations were further fortified with over-the-counter ingredients vis-a-vis with vitamin E in nail lacquer and undecylenic acid in nanoemulgel for their prominent roles in improving nail health. Both the formulations were systematically designed, optimized, and characterized. Amorolfine HCl containing nanoemulgel (NEG) was developed using undecylenic acid as an oil phase and thioglycolic acid as a penetration enhancer. The quality parameters evaluated were particle size, the zeta potential for nanoemulsion (NE) (78.04 ± 4.724 nm and -0.7mV, respectively), in vitro cumulative drug release (96.74% for NE and 88.54% for NEG), and transungual permeation (about 73.49% for NEG and 54.81% for NE). Nail lacquer was evaluated for the drying time, non-volatile content, and blush test. In vitro cumulative drug release of the developed nail lacquer and comparator marketed formulations were around 81.5% and 75%, respectively. Similarly, the transungual drug permeation was 6.32 μg/cm² and 5.89 μg/cm², respectively, in 24 h. The in silico guided preparation of both formulations containing Amorolfine HCl and over the counter ingredients is amenable for therapeutic use against onychomycosis and will be evaluated in the in vivo model.

Keywords: Box–Behnken design; amorolfine HCl; nail lacquer; nanoemulgel; transungual permeation; undecylenic acid; vitamin E.

Figure 1

Amorolfine HCl docked structure showing hydrogen bond donor–acceptor residues and hydrophobic surface.

Figure 2

Various qualities of films obtained during optimization of nail lacquer with different ratios of solvents (Ethanol: Water) and polymers (HPC: Eudragit RS).

Figure 3

Effect of independent factors on the drying time with contour plot (a) and 3-D response surface (b) of nail lacquer by the application BBD.

Figure 3

Effect of independent factors on the drying time with contour plot (a) and 3-D response surface (b) of nail lacquer by the application BBD.

Figure 4

Effect of independent factors on the non-volatile content with contour plot (a) and 3-D response surface (b) of nail lacquer by the application BBD.

Figure 5

(a) Comparison of in vitro release behaviour of optimized formulation with marketed formulation of nail lacquer. (b) Transungual permeation studies profile carried on human nail of optimized formulation with marketed formulation of nail lacquer.

Figure 5

(a) Comparison of in vitro release behaviour of optimized formulation with marketed formulation of nail lacquer. (b) Transungual permeation studies profile carried on human nail of optimized formulation with marketed formulation of nail lacquer.

Figure 6

(a) Solubility of Amorolfine HCl in different oilsIt was highest in undecylenic acid (0.78 ± 0.0152 mg/mL). (b) Solubility in different surfactants (Tween 80-1.7 ± 0.0218 mg/mL) and co- surfactants (Transcutol-1.4 ± 0.0253 mg/mL).

Figure 7

Pseudo-ternary phase diagram of nanoemulsion formulations composed of oil phase (undecylenic acid) and Smix (Tween 80 and transcutol) in ratio of (a) 1:1, (b) 2:1, (c) 3:1, and (d) 4:1.

Figure 8

(a) Zeta sizing of optimized formulation Amorolfine HCl nanoemulsion (78.04 ± 4.724 nm). (b) TEM image of Amorolfine HCl nanoemulsion slightly spherical structure with dimension between 100–120 nm.

Figure 9

Mechanical properties of Amorolfine HCl nanoemulgel.

Figure 10

(a) Comparison of in vitro release behaviour of Amorolfine HCl NEG and NE following the Higuchi model. (b) Transungual permeation studies profile carried on human nail of Amorolfine HCl NEG and NE.