A Double-Blind Randomised Clinical Trial of Terbinafine-Nanostructured Lipid Carriers: Should We Anticipate This Strategy for Effective Topical Treatment of Onychomycosis?

Abstract

Background: Oral terbinafine (TBF) is the drug of choice for onychomycosis management. To treat and heal the rough and thick nail tissue affected by fungal agents, a high dose and plasma concentration of this drug is necessary. This, however, poses a life-threatening risk due to the cytotoxic side effects, drug-drug interactions, and adverse physical and chemical properties associated with oral medications.

Objectives: This study aimed to employ nanostructured lipid carriers (NLCs) in a gel formulation to avoid side effects and to increase the absorption of topical TBF.

Methods: Terbinafine-loaded nanostructured lipid carriers (TBF-NLCs) were developed and optimised using an ultrasonic probe technique, resulting in the formulation of TBF-NLCs as a 1% w/w carbopol gel after verifying the characteristics associated with NLCs. In vitro antifungal susceptibility test (AFST) was conducted on 85 prevalent fungal species associated with onychomycosis, as well as on strains isolated from trial participants, following the CLSI M38-A2 and M27-A3 guidelines. A total of 60 volunteers were enrolled in this clinical randomised, double-blind, placebo-controlled study, divided equally into three groups prescribed with TBF cream 1%, TBF-NLCs gel 1%, and a placebo.

Results: A monodisperse suspension of spherical nanoparticles was successfully produced, exhibiting a zeta potential of 18.4 ± 1.02 mV, a Z-average of 131.7 ± 5.32 nm, a PDI index of 0.280 ± 0.017, and an EE percentage of 83.51 ± 3.52, all without any cytotoxic effects. The severity index showed a reduction from 65% and 55% to 35% and 10% in the TBF cream 1% and TBF-NLCs groups, respectively. From a mycological perspective, no significant negative results were noted during the 6th and 8th weeks of TBF-NLC 1% gel application.

Conclusion: The application of TBF-NLCs gel 1% demonstrated a quicker clinical recovery without adverse side effects compared to TBF cream, thus highlighting the effective nature of NLCs.

Keywords: NLCs; TBF‐NLC 1% gel; antifungal susceptibility test; clinical trial; mycological perspective; onychomycosis; severity index; terbinafine.

FIGURE 1

The FESEM image of terbinafine‐loaded NLCs (TBF‐NLC) providing direct visualisation of the particle's physical dimensions.

FIGURE 2

The ATR‐FTIR spectra of the freeze‐dried TBF‐NLC and starting materials terbinafine, GMS, Span 80, Tween 80, and oleic acid.

FIGURE 3

The DSC thermograph of TBF, GMS, and freeze‐dried terbinafine‐NLC.

FIGURE 4

In vitro release profiles of TBF from the NLC vehicle and its aqueous dispersion in PBS (pH = 6.8). The data is presented as mean ± SD (n = 3). The difference was significant for the 24 h period (p < 0.05).

FIGURE 5

Cell viability rate (HFF cell line) of TBF solution, placebo, and TBF‐NLCs.

FIGURE 6

Results for “severity index” after using TBF‐NLCs 1% gel, TBF cream1% as well as placebo in the studied groups.