Advancements in Topical Antifungal Vehicles
February 2016 | Volume 15 | Issue 2 | Supplement | s44 | Copyright © 2016
Leon H. Kircik MD
Icahn School of Medicine at Mount Sinai, New York, NY;
Indiana University School of Medicine, Indianapolis, IN;
Physicians Skin Care, PLLC, Louisville, KY
The primary treatment for superficial fungal infections is antifungal topical formulations, and allylamines and azoles represent the two major classes of topical formulations that are used to treat these infections. The stratum corneum (SC) is composed of keratinocytes that are surrounded by a matrix of lipids. The efficacy of topically applied formulations depends on their ability to penetrate this lipid matrix, and the vehicle plays an integral role in the penetration of active molecule into skin. There are several challenges to formulating topical drugs, which include the biotransformation of the active molecules as they pass through the SC and the physical changes that occur to the vehicle itself when it is applied to the skin. This article will review current and emerging topical antifungal vehicles.
J Drugs Dermatol. 2016;15(Suppl 2):s44-48.
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Superficial cutaneous fungal infections (SCFIs) are commonly encountered in clinical practice in the United States, and comprise infections of the skin by dermatophytes and yeasts.1-3 Although SCFIs are seldom life threatening, they can severely affect patients’ quality of life.1-3 The most common of the SCFIs are dermatophyte infections, which result from fungi and affect the keratinized tissues of the skin, hair, and nails.
The primary treatment for SCFIs is antifungal topical formulations. 4-5 Allylamines and azoles represent the two major classes of topical formulations that are used to treat SCFIs.4,5 Although both classes of topical formulations are clinically effective, allylamines have fungicidal activity against dermatophytes.4,5 Conversely, the azoles are known to have greater activity against yeasts such as Candida spp and Malassezia spp, but topical allylamines have also shown to be efficacious for cutaneous candidiasis.4,5
Allylamines inhibit squalene epoxidase, which is a vital enzyme in the ergosterol biosynthesis pathway of fungal cell membrane formation.6 The subsequent alterations in the fungal cell membrane formation results in cellular permeability and growth inhibition.6 The allylamine antifungal agents in clinical use include naftifine, butenafine, and terbinafine.6
Azole antifungals also inhibit the synthesis of ergosterol by inhibiting the enzyme 14 alpha demethylase and thus disrupting the fungal cell membrane.6 The azole antifungal agents in clinical use contain either two or three nitrogens in the azole ring and are classified as imidazoles (eg, ketoconazole and miconazole, clotrimazole) or triazoles (eg, itraconazole and fluconazole).6
A meta-analysis conducted by Rotta et al evaluated the efficacy of topical antifungals used in dermatophytosis treatment.7 The investigators performed a comprehensive search for randomized, controlled trials comparing topical antifungals with one another or with placebo in dermatophytosis treatment through July 31, 2012 for all entries in MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, Literatura Latino Americana e do Caribe em Ciências da Saúde, and International Pharmaceutical Abstracts.7 The investigators concluded that there was not a statistically significant difference among the outcomes regarding mycologic cure rates at the end of treatment among the various antifungals, but the allylamines naftifine, butenafine, and terbinafine are possibly the best strategies for maintaining a cured status among patients.7
Although all of the Food and Drug Administration (FDA) approved antifungals prescribed today produce mycologic cure rates, a primary difficulty for antifungal topical drug delivery is the low diffusion rate of drugs across the stratum corneum (SC).8 The SC is composed of keratinocytes that are surrounded by a matrix of lipids. The efficacy of topically applied formulations depends on their ability to penetrate the lipid matrix of the SC.9,10 The primary lipids found in the stratum corneum are phospholipids, cholesterol-3-sulphate, cholesterol, ceramides, sterol esters, and free fatty acids. The sebaceous lipids in the SC include triglycerides, wax esters, and squalene. 9,10
In the topical administration of antifungals, the active drug should pass the SC, particularly into the viable epidermis. Consequently, the vehicle plays an integral role in the penetration of the active molecule into skin and ultimate clinical efficacy.11 Depending on the properties of the delivery vehicle, the penetration of the active drug can be quite variable.12 For example,