Antifungal drug-loaded ionic liquid-in-water emulsion for nail fungal infections.

Onychomycosis is a prevalent and therapeutically challenging fungal infection, largely due to the highly keratinised nail plate that severely restricts drug penetration. Voriconazole (VCZ) is a broad-spectrum antifungal agent; however, its poor aqueous solubility and limited permeability hinder its use in topical and localised delivery. Rather than relying on transungual drug transport, minimally invasive hollow microneedles (MNs) offer an alternative strategy by enabling direct administration of liquid formulations into the periungual and subungual soft tissues surrounding the nail unit. In this study, a choline-geranic acid (CAGE) ionic liquid (IL)-based submicron ionic liquid-in-water (IL/W) emulsion (1:9 v/v CAGE:2% w/v poloxamer 188 aqueous phase) was developed as an antifungal delivery platform with particular relevance to nail fungal infections. CAGE ILs with different choline-to-geranic acid molar ratios were synthesised and structurally confirmed. VCZ solubility increased markedly with increasing geranic acid content, reaching 13.27 ± 0.09 mg/g in CAGE 1:4 compared with negligible solubility in aqueous media. A CAGE-based emulsion exhibited a mean droplet size of 582.50 ± 9.97 nm, a low polydispersity index (0.263 ± 0.015), and a zeta potential of -8.80 ± 2.98 mV, and demonstrated good droplet size stability at 25 °C and 37 °C. Syringeability testing showed low break-loose forces (< 1.5 N) for all formulations, while the CAGE 1:4 emulsion required a significantly lower glide force (1.15 ± 0.07 N) compared with neat CAGE 1:4 (14.57 ± 0.24 N), supporting its suitability for hollow MNs assisted delivery. Ex vivo studies using neonatal porcine skin as a proof-of-concept soft tissue model demonstrated efficient formulation delivery following hollow MN-assisted administration. VCZ delivery was markedly enhanced by the combined use of the selected CAGE composition and hollow MNs. VCZ-loaded CAGE 1:4 delivered via hollow MNs achieved 80.66 ± 12.58 µg permeation at 24 h (87.23 ± 13.60% of the administered dose), while the CAGE-based emulsion maintained high permeation efficiency (74.47 ± 14.40% of dose) at a reduced VCZ loading. Cytocompatibility assessment using human skin-derived primary fibroblasts showed cell viability above 80% at concentrations ≤ 100 µg/mL. In vitro disk diffusion assessment against Candida albicans showed that CAGE-containing formulations produced clear zones of inhibition, whereas VCZ-alone discs did not produce an observable inhibition zone under these diffusion-limited assay conditions. This study demonstrates that the integration of CAGE IL, emulsion formulation, and hollow MNs-assisted delivery provides an effective strategy to enhance antifungal drug solubility, injectability, and delivery performance, offering a promising proof-of-concept periungual/subungual delivery platform for antifungal therapy of nail fungal infections.