Advancements in Topical Antifungal Vehicles

the potency of topical corticosteroids has been evaluated by vasoconstrictor assay, and the same concentration of a topical corticosteroid can have potency that varies significantly in different vehicles.¹³

Vehicles contain a myriad of different chemicals, and 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.^14,15 Vehicles generally include ingredients that disrupt the skin barrier as they fluidize the lipid channels between corneocytes and transport the active drug into the cutaneous structures.¹⁴ Detergents and emulsifiers are often used as vehicle excipients, because they disrupt and penetrate the SC. Propylene glycol is probably the most common excipient in topical vehicles, because it has multifunctional properties that act as a solvent, humectant, penetration enhancer, in addition to antimicrobial characteristics. At high concentrations, propylene glycol induces desquamation, which widens the cellular pathways and also disrupts the epidermal barrier.

Topical delivery systems often have a rheologic agent that improves its spreadability.¹⁶ Microorganisms can form and proliferate in the water phase of a topical product, so topical formulations regularly include preservatives.¹⁶ Fragrance or coloring agents may also be incorporated into a vehicle to modify the cosmetic features of the product. The relationship of these various ingredients will determine the efficacy of the final product.¹⁶

For decades, dermatologists have relied on creams and ointments for the topical treatment of SCFIs, but patient dissatisfaction with these delivery vehicles can result in reduced patient compliance and exacerbate SCFIs. Consequently, newer delivery vehicles in dermatology have been developed to improve clinical efficacy, reduce adverse events such as irritation, and enhance patient adherence. The newer vehicles include gels and foams, which often provide better application properties, adherence, and patient satisfaction in comparison to traditional vehicles. In addition to the ease of spreadability, particularly in hair bearing areas, gels and foams are particularly well suited for application over larger areas.

Naftifine hydrochloride gel and cream, a topical allylamine, is a fungicidal that has shown to be efficacious against a wide spectrum of dermatophyte.^{17,18,19, 20,21} The active ingredient of naftifine gel and cream is naftifine hydrochloride. The gel vehicle contains alcohol, benzyl alcohol, edentate disodium, hydroxyethyl cellulose, purified water, propylene glycol, polysorbate 20 and trolamine.²² Propylene glycol acts as its primary penetration enhancer. The cream vehicle contains benzyl alcohol, cetyl alcohol, cetyl esters wax, isopropyl myristate, polysorbate 60, purified

water, sosium hydroxide, sorbitan monostearate, stearyl alcohol, and hydrochloric acid.²³ In this case, isopropyl myristate is the major penetration enhancer.

Naftifine inhibits squalene epoxidase, thus inhibiting the conversion of squalene to squalene epoxide in ergosterol biosynthesis. Naftifine has potent in vitro fungicidal activity against dermatophytes, which correlates with its clinical and mycological activity in patients with dermatophytosis, as well as some anti inflammatory properties.¹⁹ Naftifine application has also demonstrated a significant improvement in clinical symptoms and therapeutic success after courses of therapy between 2 to 6 weeks in a high percentage of patients with interdigital tinea pedis, tinea cruris, or corporis.^17,18,9

Naftifine gel 2% is approved for the topical treatment of interdigital tinea pedis caused by Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum in patients 18 years of age or older.²² Naftifine cream 2 % is indicated for the topical treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by Trichophyton rubrum in patients 18 years of age or older.²³ Both treatment regimens are applied topically once daily for two weeks in clinical studies. However, post-treatment improvement has been seen for up to two weeks in the case of tinea cruris and up to four weeks in the case of interdigital tinea pedis.^17,18 Similar trends in post-treatment improvement for up to four weeks after treatment cessation have also been demonstrated using naftifine gel 2% in subjects with interdigital type tinea pedis with or without moccasin-type infection.^17,24

Plaum et al conducted an open-label, single-exposure study that tested the hypothesis that one of the reasons for the efficacy of naftifine 2% cream or gel is that drug-levels remained in the SC after the cessation of therapy.²⁰ The investigators utilized a tape stripping methodology to assess the amount of drug available in the SC over a 28-day period following the cream or gel’s last application.20 Six subjects were given naftifine cream 2% and six subjects were given naftifine gel 2%. The 12 subjects had twelve application sites on their upper backs, and 11 of the sites were dosed with one of the test formulations for 14 days. The final site remained untreated to serve as the control site.²⁰

On days 15, 29, and 43, a selected test site was tape stripped to glean cells from the SC. The tape strips enabled the investigators