Abstract
Flibanserin (FLB) is a multifunctional serotonergic agent that was recently approved by the FDA for the oral treatment of premenopausal women with hypoactive sexual desire disorder. FLB is a centrally acting drug that has a low oral bioavailability of 33% owing to its exposure to the hepatic first-pass effect, as well as its pH-dependent solubility, which could be an obstacle hindering the drug dissolution and absorption via mucosal barriers. Thus, this work aimed at overcoming the aforementioned drawbacks and promoting the nose-to-brain delivery of FLB via the formulation of an intra-nasal in situ niosomal gel. The Box–Behnken design was employed to study the impact of Span® 85 concentration (X1), hydration time (X2), and pH of the hydrating buffer (X3) on the vesicle size and drug entrapment. The optimized formulation exhibited a spherical shape with a vesicular size of 46.35 nm and entrapment efficiency of 92.48%. The optimized FLB niosomes integrated into gellan gum-based in situ gel exhibited enhanced ex vivo permeation and improved plasma and brain concentrations after nasal administration in rats compared to raw FLB. These findings highlight the capability of the proposed intra-nasal FLB niosomal in situ gel to boost the drug bioavailability and to promote its direct delivery to the brain.
Highlights
Flibanserin (FLB; 2H-benzimidazol-2-one, 1,3-dihydro-1-[2-[4-[3(tri-fluoromethyl) phenyl]-1piperazinyl]ethyl] was approved by US FDA in August 2015 under the trade name of Addyi® for treating premenopausal woman with generalized hypoactive sexual desire disorder (HSDD), which is the most common form of female sexual dysfunction that is associated with emotional distress and relationship problems [1,2]
A three-factor, three-level Box–Behnken design was utilized for the formulation and optimization of FLB niosomes with minimized vesicle size and maximized entrapment efficiency
Surfactant concentration has significantly influenced the niosomes’ vesicle size and drug entrapment, while the hydration time and pH exhibited a significant effect on only the entrapment efficiency
Summary
Flibanserin (FLB; 2H-benzimidazol-2-one, 1,3-dihydro-1-[2-[4-[3(tri-fluoromethyl) phenyl]-1piperazinyl]ethyl] was approved by US FDA in August 2015 under the trade name of Addyi® for treating premenopausal woman with generalized hypoactive sexual desire disorder (HSDD), which is the most common form of female sexual dysfunction that is associated with emotional distress and relationship problems [1,2]. FLB is a non-hormonal drug that selectively binds to serotonin receptors in the central nervous system (CNS). FLB acts as both serotonin agonist (5-HT1A) and antagonist (5-HT2A). It acts by decreasing serotonin and increasing dopamine and norepinephrine; this effect on the mentioned neurotransmitters is important for a healthy sexual response [3]. FLB has a half-life of 11 h with a rapid rise of plasma concentration within the first hour after oral administration followed by a gradual decrease thereafter. Possible drug degradation after oral administration by the acidic environment of gastrointestinal (GI) tract, mucosal enzymes, as well as the intestinal barriers could be challenging factors that contribute to FLB low bioavailability [5]
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