Abstract

Onychomycosis is a progressive fungal infection of the nails that involves the deeper nail layer and nail bed. It is important to maintain sufficient drug concentration in the diseased tissues after topical application. In this study, a stable topical delivery system for efinaconazole (EFN) was designed to enhance absorption potential through the skin and nail plate by incorporating ethanol, diethylene glycol monoethyl ether (Transcutol P) and isopropyl myristate, and cyclomethicone into the topical solution as a delivery vehicle, permeation enhancers, and a wetting agent, respectively. In addition, the stability of EFN in the formulation was significantly improved by adding butylated hydroxytoluene, diethylenetriamine pentaacetic acid, and citric acid as an antioxidant, chelating agent, and pH-adjusting agent, respectively, without discoloration. The optimum EFN formulation (EFN-K) showed 1.46-fold greater human skin permeation than that of the reference control (commercial 10% EFN topical solution). Furthermore, after a 24-hour incubation, the amount of infiltrated EFN from EFN-K in the human nail plate was 4.11-fold greater than that of the reference control, resulting in an 89.7% increase in nail flux at 7 days after treatment. EFN-K significantly accelerated structural recovery of the keratin layer in a Trichophyton mentagrophytes-infected guinea pig onychomycosis model, decreasing the mean viable fungal cell count by 54.3% compared to the vehicle-treated group after once-daily treatment for 4 weeks. Thus, the accelerated skin and nail penetration effect of EFN-K is expected to achieve good patient compliance, and improve the complete cure rate of onychomycosis.

Highlights

  • Onychomycosis is one of the most chronic and prevalent nail disorders, and is commonly caused by fungi, such as dermatophytes (Trichophyton rubrum and Trichophyton mentagrophytes), non-dermatophyte molds, and yeasts (Candida albicans), which more frequently affect toenails than fingernails (Shirwaikar et al, 2008; Lasenna & Tosti, 2015)

  • To improve the stability of the prepared formulations, ethylenediaminetetraacetic acid (EDTA) or Diethylenetriaminepentaacetic acid (DTPA), butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT), and sorbic acid or citric acid were used as a chelating agent, antioxidant, and pH-adjusting agent, respectively

  • Edetate salts, such as sodium EDTA and DTPA, as well as citric acid and sorbic acid possess antimicrobial activity and show synergistic effects when used in combination (Heydari et al, 2013)

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Summary

Introduction

Onychomycosis is one of the most chronic and prevalent nail disorders, and is commonly caused by fungi, such as dermatophytes (Trichophyton rubrum and Trichophyton mentagrophytes), non-dermatophyte molds, and yeasts (Candida albicans), which more frequently affect toenails than fingernails (Shirwaikar et al, 2008; Lasenna & Tosti, 2015). Due to the low penetration of drugs through the nail plate, high recurrence rate, low clinical efficacy, and patient preference for topical solutions, the need for an efficacious treatment for onychomycosis remains unmet (Singal & Khanna, 2011; Lasenna & Tosti, 2015). Oral antifungals currently used in the treatment of onychomycosis have several limitations, including in terms of safety due to hepatotoxicity and drug–drug interactions (Lasenna & Tosti, 2015; Matsuda et al, 2016). Safe and efficacious topical formulations with greater nail plate penetration and clinical efficacy, and fewer side effects, are required

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