Tailored transethosomal systems for tadalafil transdermal delivery: Impact of Phosal and edge activators on skin permeation and cellular uptake.

Tadalafil (TDLF), a Biopharmaceutics Classification System (BCS) Class II drug, exhibits poor aqueous solubility and extensive first-pass metabolism, which limits its therapeutic efficacy. We developed Phosal-based transethosomes (TrEthOs) to overcome these challenges, thereby enhancing transdermal delivery. A Box-Behnken design was employed to optimize the formulation by evaluating the effects of Phosal type, polyethylene glycol (PEG) 400 concentration, and cholesterol content. The optimized TrEthOs exhibited a mean vesicle size of 129.74 nm and an entrapment efficiency of 67.3%, ensuring efficient encapsulation of the drug. Ex vivo permeation studies demonstrated a cumulative TDLF permeation of 70.24% over 6 hours, with a steady-state flux of 19.49 × 10(-4) mg/cm(2)·min. Confocal laser scanning microscopy confirmed deep skin penetration, while in vitro studies revealed significantly enhanced cellular uptake (P < 0.0001) and reduced cytotoxicity (IC₠₀ = 67.61 μg/mL) compared to pure TDLF (IC₠₀ = 34.85 μg/mL). The novel Phosal-based TrEthOs system presents a promising transdermal drug delivery strategy, potentially reducing dosing frequency and improving patient compliance. These outcomes emphasize the potential of advanced nanocarrier systems to optimize systemic bioavailability while minimizing adverse effects.