| Summary: | To avoid the first-pass metabolism of avanafil (AVA) and its altered absorption in the presence of food after oral administration, this study aimed to investigate the potential of TPGS-based mixed micelle (MM)-loaded film for transdermal delivery and the enhancement of bioavailability. A Box–Behnken design was employed to optimize the permeation behavior of AVA from the transdermal film across the skin. The variables were the hydrophile-lipophile balance (HLB) of the surfactant (X<sub>1</sub>), the concentration of mixed micelles (MMs) in the film (X<sub>2</sub>), and the concentration of the permeation enhancer (X<sub>3</sub>). The initial permeation of AVA after 1 h (Y<sub>1</sub>), and the cumulative permeation of AVA after 24 h (Y<sub>2</sub>) were the dependent variables. Ex vivo studies were carried out on freshly isolated rat skin to investigate the drug’s permeation potential and results were visualized using a fluorescence laser microscope. Moreover, the pharmacokinetic behavior after a single application on male Wistar rats, in comparison with films loaded with raw AVA, was evaluated. The results showed that the optimum factor levels were 9.4% for the HLB of the surfactant used, and 5.12% MMs and 2.99% penetration enhancer in the film. Imaging with a fluorescence laser microscope indicated the ability of the optimized film to deliver the payload to deeper skin layers. Furthermore, optimized AVA-loaded TPGS-micelles film showed a significant increase (<i>p</i> < 0.05) in the C<sub>max</sub> of AVA and the area under the AVA plasma curve (approximately three-fold). The optimized AVA-loaded TPGS-MM film thus represents a successful delivery system for enhancing the bioavailability of AVA.
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