Flibanserin (FLB) is a drug used for female hypotensive sexual desire disorder approved by the FDA in August 2015. FLB exhibits extensive hepatic first-pass metabolism and low aqueous solubility, hence poor oral bioavailability. In this study, beta hydroxypropyl cyclodextrin-FLB inclusion complexes were incorporated into orally fast dissolving films. This dosage form was expected to improve FLB aqueous solubility, which would give fast onset of action and decrease presystemic metabolism, hence improving oral bioavailability. The inclusion complex at a ratio of 1:1 was prepared by the kneading method. Differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and powder X-ray diffractometry (XRD) were used to confirm complex formation. The Box-Behnken design (15 different formulae of FLB fast-dissolving oral films (FLBFDOFs) were utilized for the optimization of the prepared films. The Expert Design 11 program was utilized to examine the effects of three selected factors, polymer concentration (X1), plasticizer concentration (X2), and disintegrant concentration (X3) on four responses: disintegration time (DT), initial dissolution rate (IDR), dissolution efficiency (DE), and film quality (QF). Numerical optimization was performed by minimizing disintegration time (Y1), while maximizing the initial drug dissolution rate (Y2), dissolution efficiency (Y3), and the quality factor (Y4). The statistical analysis showed that X1 has a significant positive effect on the disintegration time and a significant negative effect on IDR. While X2 and X3 produced a nonsignificant negative effect on IDR. Dissolution efficiency was maximized at the middle concentration of both X2 and X3. The best film quality was observed at the middle concentration of both X1 and X2. In addition, increasing X3 leads to an improvement in film quality. The optimized film cast from an aqueous solution contains hydroxypropyl cellulose (2%) as a hydrophilic film-forming agent and propylene glycol (0.8%) as a plasticizer and cross povidone (0.2%) as a disintegrant. The prepared film released 98% of FLB after 10 min and showed good physical and mechanical properties. The optimized formula showed a disintegration time of 30 s, IDR of 16.6% per minute, DE15 of 77.7%, and QF of 90%. This dosage form is expected to partially avoid the pre-systemic metabolism with a fast onset of action, hence improving its bioavailability that favors an advantage over conventional dosage forms.
Keywords: 2-hydroxy-beta-cyclodextrin; fast-dissolving oral film; flibanserin; hydroxypropyl cellulose.