Effective topical treatment for nail fungal infection, or onychomycosis (ONC), faces significant hurdles primarily due to the poor permeation of active ingredients across the nail plate. The nail plate is a thick, hard keratin structure. ONC is responsible for 15% to 50% of nail diseases, exhibiting an increasing global prevalence. Current topical treatments often suffer from relatively high cost and low efficacy, leading to recurrence rates that can reach 50%. If the infection remains untreated, the clinical condition can worsen, and the fungal infection may spread.
While Terbinafine hydrochloride (TB-HCl) is a lipophilic and keratinophilic active ingredient that successfully treats skin fungal infections topically, no topical terbinafine treatment for ONC currently exists. Consequently, the oral route is typically used, despite associated concerns regarding adverse effects. Though multiple studies have explored new methods for efficient TB-HCl delivery across the nail plate, no topical ONC treatment utilizing terbinafine has yet reached the market.
To address this challenge, significant research has focused on enhancing antifungal delivery using both chemical and physical enhancement methods. This study investigated combining new TB-HCl formulations with physical enhancement approaches, specifically nail microporation and microchanneling. Physical poration creates pores and channels that serve as sequestration sites for formulations, facilitating drug release and diffusion across the nail plate. This combined strategy offers a potential advantage of reducing drug use and hypothetically lowering the incidence of fungi resistance. Furthermore, the new formulations aimed to carry higher active loads (at least 2%) than current commercial 1% topical products.
Methods
New microemulsion (ME), liquid crystal (LC), and thermogel (TG) vehicles were developed based on TB-HCl solubility studies, enabling drug loads between 2% and 7%. In vitro release studies were performed using synthetic silicone and hydrophobic PTFE membranes. In vitro permeation tests (IVPTs) were conducted over 14 days using healthy human nail clippings in Franz diffusion cells under three regimens: multiple doses on non-porated nails (MD-NP), or a single large dose on either microporated (SD-MP) or micro-channeled (SD-MC) nails. Terbinafine was quantified using High Performance Liquid Chromatography (HPLC), and the resulting antifungal activity was evaluated via microbiological assays against T. rubrum and C. parapsilosis.
Key Findings
• The formulated vehicles successfully achieved TB-HCl loads of 2–7%, enabling higher active loads than typical commercial 1% topical products.
• In vitro permeation studies demonstrated that combining microporation or microchanneling resulted in significantly greater drug uptake into the nail and delivery to the receptor compared to applying multiple doses to non-porated nails (MD-NP).
• The enhanced delivery via poration/channeling occurred despite the application of a smaller total dose of the drug in the single-dose physical enhancement experiments (SD-MP/SD-MC) compared to the multiple-dose non-porated tests (MD-NP).
• Microemulsion vehicles provided the largest TB-HCl permeation fluxes across porated nails.
• The formulation ME5 7% yielded the best results overall, providing the highest drug flux into the receptor.
• Creating microchannels with the commercial blade resulted in increased nail retention and drug permeation compared to microporation.
• Microbiological tests confirmed that the ME5 7% and ME5 7%E (thickened version) formulations provided the largest inhibition of fungal growth against C. parapsilosis, aligning with the IVPT results.
• Only the receptor solution obtained from the ME5 7% experiment demonstrated inhibition activity against T. rubrum.
The novelty of this research lies in successfully combining high drug-load microemulsions with physical nail enhancement methods to achieve therapeutically relevant delivery of a drug currently limited to oral administration for ONC. Future implications of this work include the need for further research to clarify key factors impacting the efficiency of this approach. Specifically, future studies should investigate formulation properties (e.g., viscosity and surface tension), formulation metamorphosis after application, and the physical status of the active ingredient within the pores and channels created. Additionally, while the ME5-based formulations are promising against C. parapsilosis, the results should be confirmed with tests involving T. rubrum to align with the intended indication for onychomycosis.
Link to the study: https://tinyurl.com/2848vxap
