QbD-guided development and in silico, in vitro, ex vivo, and in vivo dermatokinetic evaluation of a fluvastatin-loaded transferosomal hydrogel for the management of melanoma.

Fluvastatin (FLV) is an HMG-CoA reductase inhibitor, a well-established clinically approved molecule that acts on major cellular cascades that are responsible for melanomagenesis. The present study was encouraged by the prospect of developing and evaluating the FLV-loaded transferosomal hydrogel (FLV-loaded TFS gel) as a carrier for the site-specific dermal delivery of FLV to melanoma cells. The nanocarrier revealed particle size, PDI and zeta potential of 97.04 ± 0.635 nm, 0.168 ± 0.001, and - 27.37 ± 0.349 mV, respectively, indicating a stable and uniform formulation. In vitro release study of FLV-loaded TFS revealed drug release of around 95.52 ± 3.26% and 74.33 ± 5.26% at pH 5.5 and 7.4, respectively, indicating improved release at tumor and skin pH. The in vitro cell culture studies of the FLV-loaded TFS in B16-F10 cells depicted increased cytotoxicity, superior apoptotic features, elevated ROS generation and improved cellular uptake, confirming the marked therapeutic potential of the formulation. Further, the optimized formulation was incorporated into a hydrogel, which displayed desirable pH, mechanical properties, and pH-responsive rheological behaviour, establishing its suitability for the topical application. In vivo dermatokinetics profiling of the FLV-loaded TFS gel revealed 2.93 and 3.82-fold enhancement in the AUC0-24h compared to the free FLV-loaded gel, signifying its potential in improving penetration of FLV to the deeper skin layers. An in vitro skin irritation study portrayed the safety of the developed nanoformulation for further preclinical and clinical applications. Overall, these findings highlighted the potential of transdermal nanoformulation as a non-invasive, effective, and patient-friendly approach for melanoma management.