Development and Pharmacokinetic Evaluation of Newly Formulated Letrozole Non-Aqueous Nanoemulgel Transdermal Systems for Hormone-Dependent Breast Cancer Therapy

<b>Background/Objectives:</b> Breast cancer remains the most prevalent malignancy among women worldwide, with letrozole (LZ) serving as a critical aromatase inhibitor for hormone receptor-positive cases. However, long-term oral administration of LZ is often associated with systemic adverse effects and poor patient compliance. To overcome these limitations, new non-aqueous nanoemulgels (NEMGs) were developed for transdermal delivery of LZ. <b>Methods:</b> The NEMGs were formulated using glyceryl monooleate (GMO), Sepineo P600^®, Transcutol, propylene glycol, and penetration enhancers propylene glycol laurate (PGL), propylene glycol monocaprylate (PGMC), and Captex^®. Physicochemical characterization, solubility, stability, and in vitro permeation studies were conducted using Strat-M^® membranes, while in vivo pharmacokinetics were evaluated in rat models. <b>Results:</b> The optimized GMO/PGMC-based NEMG demonstrated significantly enhanced drug flux, higher permeability coefficients, and shorter lag times compared with other NEMGs and suspension emulgels. In vivo, transdermal application of the GMO/PGMC-based NEMG over an area of 2.55 cm² produced dual plasma absorption peaks, with 57% of the LZ dose absorbed relative to oral administration over 12 days. Shelf-life and accelerated stability assessments confirmed excellent physicochemical stability with negligible crystallization. <b>Conclusions:</b> The developed LZ NEMG formulations offer a stable, effective, and patient-friendly transdermal drug delivery platform for breast cancer therapy. This system demonstrates potential to improve patient compliance and reduce systemic toxicity compared to conventional oral administration.