Topical hydrosulphide ion gels: A Paradigm shift in onychomycosis treatment

Onychomycosis, a chronic fungal infection of the human nail, affects about 10 % of the global population. Treatment failure occurs in roughly 50 % of patients due to difficulties in concentrating antifungal agents within the nail tissue. To address this issue, we have developed a hydrosulphide ion gel to deliver hydrogen sulphide (H₂S) gas into the human nail plate. Using sodium hydrogen sulphide (NaHS), which produces H₂S more effectively than three alternative chemical donors, maintaining a pH of 8.5 to optimise the hydrosulphide micro-species, and enclosing the gel in a microchamber, allows delivery of 1 mg/cm² of H₂S through the nail in just 4 h. This level of delivery exceeds what is typically achieved after 4 weeks of repeated commercial topical antifungal applications. The hydrosulphide ion gel generates H₂S in the liquid state, which then converts into gas within the nail. Both the liquid and gaseous forms of H₂S contribute to the gel's antifungal effects. The liquid H₂S exhibits kill assay IC₅₀ values of 2.8 µg/mL for Trichophyton rubrum and 3.7 µg/mL for Candida albicans. The H₂S gas shows minimum inhibitory concentrations (MICs) of 0.02 µg/mL for T. rubrum and 0.1 µg/mL for C. albicans. In vivo pharmacokinetic assessments in rodents demonstrate that the hydrosulphide ion gel enables targeted penetration into nail tissue without systemic exposure. Finally, in a fungal-infected human nail, a single 24-hour treatment achieves complete eradication, suggesting that topical application of a hydrosulphide ion gel could significantly reduce the current 6-month treatment cycle for chronic fungal nail infections. STATEMENT OF SIGNIFICANCE: Onychomycosis is a fungal infection of the human nail that can last for decades, causing recurring skin infections, tissue distortion, and difficulty walking and exercising. Current treatments are ineffective because, whether an antifungal agent is applied directly to the nail plate or taken as a tablet, it must penetrate the hard keratin of the nail where the fungus resides. We have designed a hydrosulphide ion gel to deliver hydrogen sulphide (H₂S) gas into the human nail plate. H₂S is very small, so it rapidly penetrates the nail, reaching levels within 4 h that are higher than those achieved by daily application of commercial antifungals for 4 weeks, without causing nail tissue damage or blood absorption. This alternative topical treatment could be life-changing for patients with chronic onychomycosis.