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The aim of this work was to develop a fast-dissolving film formulation containing EFdA for potential use as a topical vaginal microbicide for prevention of HIV sexual transmission. Solid state compatibility approaches were used to screen commonly used polymers for formulation development. Factorial design and desirability function were used to investigate the effect of two variables, the ratio of the polymers and the concentration of selected plasticizer on four mechanical responses including tensile strength, elongation at break, toughness and elastic modulus for optimization of the film formulation. Assessments of EFdA-loaded films included physicochemical characteristics, in vitro cytotoxicity, epithelia integrity, ex vivo permeability and bioactivity test. The optimal placebo film was composed of PVA, HPMC E5 and propylene glycol (7:3:3, w/w), and its mechanical characteristics were comparable to those of VCF® film (a commercial vaginal film product). Permeability studies using human ectocervical explants showed that there was no significant difference in cumulative permeated amount of EFdA between EFdA film and free EFdA. The results of in vitro cytotoxicity and bioactivity testing showed that 50% cytotoxic concentration (CC50) was several orders of magnitude higher than 50% effective concentration (EC50) of EFdA. Furthermore, epithelial integrity study showed that EFdA-loaded film had a much lower toxicity to HEC-1A cell monolayers as compared to VCF®.Therefore, EFdA-loaded vaginal film may be considered as a promising vaginal microbicide for HIV prevention.