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. 2020 May 27;12(6):485.
doi: 10.3390/pharmaceutics12060485.

Intranasal Niosomal In Situ Gel as a Promising Approach for Enhancing Flibanserin Bioavailability and Brain Delivery: In Vitro Optimization and Ex Vivo/ In Vivo Evaluation

Usama A Fahmy  1   2 , Shaimaa M Badr-Eldin  1   3 , Osama A A Ahmed  1   2 , Hibah M Aldawsari  1   4 , Singkome Tima  5 , Hani Z Asfour  6 , Mohammed W Al-Rabia  6 , Aya A Negm  7 , Muhammad H Sultan  8 , Osama A A Madkhali  8 , Nabil A Alhakamy  1   2   4   9
Affiliations

Intranasal Niosomal In Situ Gel as a Promising Approach for Enhancing Flibanserin Bioavailability and Brain Delivery: In Vitro Optimization and Ex Vivo/ In Vivo Evaluation

Usama A Fahmy et al. Pharmaceutics. .

Retraction in

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.

Keywords: Box-Behnken; Span® 85; cholesterol; ex vivo permeation; flibanserin; gellan gum; niosomes; pharmacokinetics.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Diagnostic plots for vesicle size of FLB niosomes (A); normal probability plot (B); studentized residuals vs. predicted values plot; (C) externally studentized residuals vs. run number plot; and (D) predicted vs. actual values plot.
Figure 1
Figure 1
Diagnostic plots for vesicle size of FLB niosomes (A); normal probability plot (B); studentized residuals vs. predicted values plot; (C) externally studentized residuals vs. run number plot; and (D) predicted vs. actual values plot.
Figure 2
Figure 2
Diagnostic plots for entrapment efficiency of FLB niosomes (A); normal probability plot (B); studentized residuals vs. predicted values plot (C); externally studentized residuals vs. run number plot; and (D) predicted vs. actual values plot.
Figure 2
Figure 2
Diagnostic plots for entrapment efficiency of FLB niosomes (A); normal probability plot (B); studentized residuals vs. predicted values plot (C); externally studentized residuals vs. run number plot; and (D) predicted vs. actual values plot.
Figure 3
Figure 3
Response 3D plots (A–C) and cube plot (D) for the effect of Span® 85 concentration (X1), Hydration time (X2), and hydrating buffer pH (X3) on the vesicle size of FLB niosomes.
Figure 3
Figure 3
Response 3D plots (A–C) and cube plot (D) for the effect of Span® 85 concentration (X1), Hydration time (X2), and hydrating buffer pH (X3) on the vesicle size of FLB niosomes.
Figure 3
Figure 3
Response 3D plots (A–C) and cube plot (D) for the effect of Span® 85 concentration (X1), Hydration time (X2), and hydrating buffer pH (X3) on the vesicle size of FLB niosomes.
Figure 4
Figure 4
Response 3D plots (A–C) and cube plot (D) for the effect of Span® 85 concentration (X1), hydration time (X2), and hydrating buffer pH (X3) on the entrapment efficiency of FLB niosomes.
Figure 4
Figure 4
Response 3D plots (A–C) and cube plot (D) for the effect of Span® 85 concentration (X1), hydration time (X2), and hydrating buffer pH (X3) on the entrapment efficiency of FLB niosomes.
Figure 5
Figure 5
Transmission electron microscope (TEM) of optimized FLB niosomes, 25,000× magnification.
Figure 6
Figure 6
Ex vivo permeation profile of optimized FLB niosomal in situ nasal gel compared to raw FLB in situ gel in simulated nasal fluid, pH 6.5 at 35°C (Results presented as mean ± SD, n = 3).
Figure 7
Figure 7
Mean (A) plasma concentrations and (B) brain concentrations versus time of FLB in rats after nasal administration of FLB niosomal in situ gel compared to control raw FLB in situ gel at a dose of 10 mg/kg. (Results presented as mean ± SD, n = 6). * Significant at P < 0.05, Sidak’s multiple comparisons test compared to raw FLB gel.
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