Expanding Transdermal Delivery with Lipid Nanoparticles: A New Drug-in-NLC-in-Adhesive Design.

A monolithic drug-in-NLC-in-adhesive transdermal patch, with a novel design, was developed for codelivery of olanzapine (OL) and simvastatin (SV). Nanostructured lipid carriers (NLC) and enhancers were used as passive strategies, while the pretreatment of the skin with Dermaroller was tested as an active approach. The formulation was optimized for composition in a quality by design basis, in terms of enhancer and adhesive, with focus on permeation behavior, adhesion properties, and cytotoxicity. Propylene glycol promoted the best permeation rate for both drugs, with enhancement ratios of 8.1 and 12.9 for OL and SV, respectively, relative to the corresponding Combo-NLC patch without enhancer. Molecular dynamics results provided a rationale for these observations. The adhesive type displayed an important role in skin permeation, reinforced by the presence of the enhancer. Finally, Dermaroller pretreatment did not promote a significant improvement in permeation, which highlights the role of the combination of NLC with chemical enhancer in the transdermal patch as the main driving force in the process. It is also observed that NLC are able to reduce cytotoxicity, especially that associated with SV. This work provides a promising in vitro-in silico basis for a future in vivo development.