Transdermal Delivery of Salbutamol from Nanoemulsions: Influence of Ternary Composition and Surfactant Architecture

Background/Objectives: Transdermal delivery of hydrophilic drugs remains limited by poor partitioning into the lipid-rich stratum corneum (SC). This study systematically investigated how ternary nanoemulsion composition and surfactant architecture jointly influence the transdermal delivery of salbutamol and whether the resulting composition-performance relationships are preserved across different skin models. Methods: Salbutamol-loaded nanoemulsions were prepared by the phase inversion temperature (PIT) method across a predefined ternary design space using two non-ionic surfactant systems: polyoxyl castor oil and polyoxyl hydroxystearate. Physicochemical characterization, ternary compositional mapping, in vitro permeation testing, generalized additive modeling (GAM), and attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy were combined to evaluate formulation-dependent transport across pig and mouse skin models, complemented by exploratory human-skin experiments. Results: Among the nanoemulsion formulations, pig skin showed the highest salbutamol permeation, with flux values reaching approximately 390 µg/cm²·h. Within the PHS-based system, mouse skin showed lower permeation and a stronger dependence on formulation composition than pig skin, while the simple aqueous vehicle also produced comparatively low permeation in the murine model. The aqueous-vehicle control produced substantially higher permeation than the nanoemulsions in pig skin but lower permeation in mouse skin, while receptor-phase salbutamol concentrations remained below the limit of quantification in human skin. Across both surfactant systems, the most favorable nanoemulsion-mediated permeation was generally associated with water-rich formulations containing comparatively low surfactant levels, whereas highly surfactant-rich regions showed reduced flux despite marked lipid- or protein-associated spectral changes in the descriptive ATR-FTIR analysis. Regression analyses suggested that droplet size and viscosity alone could not consistently explain permeation behavior, whereas compositional modeling revealed pronounced non-linear effects of the water-surfactant-oil balance. Conclusions: Overall, this study demonstrates that nanoemulsion-mediated delivery of hydrophilic drugs is governed primarily by ternary composition, with formulation effects varying across skin models. These findings highlight the importance of composition-based formulation design and appropriate skin-model selection during the development of transdermal systems for hydrophilic drugs.