Transdermal flibanserin cubosomal hydrogel for hypoactive sexual desire disorder: box–behnken optimization and pharmacokinetic profiling in a rat model

Abstract Background Flibanserin is the first non-hormonal pharmacotherapy approved for hypoactive sexual desire disorder but shows limited oral bioavailability of about 33% due to extensive first-pass hepatic metabolism. This limitation reduces systemic exposure and may compromise clinical effectiveness. This study aimed to develop a nanostructured cubosomal hydrogel as a noninvasive transdermal delivery system for flibanserin to bypass first-pass metabolism, sustain drug release, and improve systemic bioavailability. Results: Flibanserin-loaded cubosomes were optimized using a Box–Behnken experimental design by varying the concentrations of monoolein, poloxamer 407, and polyvinyl alcohol to control particle size, entrapment efficiency, and nanostructural properties. The optimized dispersion, containing 9.93% monoolein, 1.36% poloxamer 407, and 0.03% polyvinyl alcohol, exhibited a mean particle size of 234.3 ± 8.6 nm and entrapment efficiency of 83.2 ± 5.7%, with a confirmed bicontinuous cubic structure. Incorporation into a 2% hydroxypropyl methylcellulose K4M hydrogel produced a cubosomal hydrogel with suitable topical characteristics, including a viscosity of 2.15 ± 0.19 Pa.s and spreadability of 4.7 cm. In rats, transdermal administration of the flibanserin cubosomal hydrogel achieved superior systemic exposure compared with an oral suspension, with 1.97-fold increase in relative bioavailability based on AUC 0−∞ from 66.4 to 130.7 ng.h/mL, prolonged T max from 0.5 to 2 h, and extended mean residence time indicating prolonged absorption and improved systemic availability. Conclusions: The optimized flibanserin-loaded cubosomal hydrogel successfully addresses key limitations of oral flibanserin therapy by enhancing transdermal permeation, sustaining plasma exposure, and avoiding first-pass hepatic metabolism. This nanostructured hydrogel represents a promising noninvasive platform for systemic flibanserin delivery and may provide a clinically relevant strategy to improve pharmacotherapy of hypoactive sexual desire disorder.