Ethanol-free nanostructured lipid carrier hydrogels as alternatives to hydroalcoholic gels and compounded creams for dermal testosterone delivery: physicochemical stability, ex vivo human skin penetration and cellular compatibility.

Topical testosterone therapy is widely used for testosterone replacement therapy and gender-affirming hormone therapy, but available hydroalcoholic gels contain high ethanol concentrations that may compromise skin barrier integrity during repeated use. In parallel, testosterone creams are prepared through pharmaceutical compounding. However, they lack data on physicochemical stability, skin penetration potential, and cellular compatibility. This study aimed to develop ethanol-free nanostructured lipid carrier (NLC)-based hydrogels as alternatives for dermal testosterone delivery. Testosterone-loaded NLCs were prepared, characterized for physicochemical stability, and incorporated into hydrogel matrices based on Sepinov™ EMT 10, Sepilife™ G305 and Carbopol® 980. Their performance was compared with Ultrasicc®- and Pentravan®-based testosterone creams and the hydroalcoholic reference Testogel® in terms of physicochemical stability, ex vivo human skin penetration, ex vivo skin hydration, and cellular compatibility. The phospholipid-based Lipoid® S75/polysorbate 80 NLCs showed nanoscale particle sizes, high encapsulation efficiency, and sufficient storage stability over 12 weeks. Among the NLC-based hydrogels, the Carbopol-based formulation provided the most robust pH and rheological stability. Confocal Raman spectroscopy showed that NLC gels achieved testosterone accumulation in the stratum corneum comparable to ethanolic Testogel® and compounded Ultrasicc® cream. NLC gels maintained stratum corneum hydration and preserved keratinocyte viability. Remarkably, NLC gels and Ultrasicc® exhibited around 80% cell viability in contrast to Testogel® (71%) and Pentravan® (61%). In summary, Carbopol-based NLC gel exhibited the highest storage stability at both 8 and 23 °C and delivered testosterone to the human stratum corneum in a finite dose ex vivo setup in a similar manner to a marketed reference product.