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Optimized Nanostructured Lipid Carriers Integrated into In Situ Nasal Gel for Enhancing Brain Delivery of Flibanserin.

ABSTRACT: Background and Aim:Flibanserin (FLB) is a multifunctional serotonergic agent used for treating hypoactive sexual desire disorder in premenopausal women via oral administration. FLB has a reported limited oral bioavailability of 33% that could be attributed to the drug's first-pass metabolism. In addition, FLB has a pH-dependent solubility that could be a challenging factor for drug dissolution in the body neutral fluid, and consequently, absorption via mucosal barriers. Thus, this work aims at investigating the potential of utilizing nanostructured lipid carriers (NLCs) to overcome the aforementioned drawbacks and to enhance nose-to-brain drug delivery. Methods:Box-Behnken design was applied to explore the impact of solid lipid % (SL%, X 1), liquid lipid % (LL%, X 2), and sonication time (ST, X 3) on particle size. The optimized NLC formulation was characterized and incorporated into gellan gum in situ gel. The prepared gel was subjected to in vitro drug release, in vivo pharmacokinetic performance, and histopathological assessment in rats. Results:Statistical analysis revealed a significant negative effect for both SL% and ST on NLCs size. In contrast, a significant positive effect was observed for the LL%. The optimized formulation showed spherical shape with vesicular size of 114.63 nm. The optimized FLB-NLC in situ gel exhibited adequate stability and enhanced in vitro release compared to raw FLB control gel. The plasma and brain concentrations of the drug after nasal administration in rats increased by more than 3-6-fold, respectively, compared to raw FLB in situ gel. In addition, the histopathological studies revealed the absence of any pathological signs. Conclusion:The aforementioned results highlight the safety of FLB-NLC in situ nasal gel and its potential to improve the drug bioavailability and brain delivery.

SUBMITTER: Fahmy UA

PROVIDER: S-EPMC7386805 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Optimized Nanostructured Lipid Carriers Integrated into In Situ Nasal Gel for Enhancing Brain Delivery of Flibanserin.

Fahmy Usama A UA Ahmed Osama A A OAA Badr-Eldin Shaimaa M SM Aldawsari Hibah M HM Okbazghi Solomon Z SZ Awan Zuhier A ZA Bakhrebah Muhammed A MA Alomary Mohammad N MN Abdulaal Wesam H WH Medina Carlos C Alhakamy Nabil A NA

International journal of nanomedicine 20200724

<h4>Background and aim</h4>Flibanserin (FLB) is a multifunctional serotonergic agent used for treating hypoactive sexual desire disorder in premenopausal women via oral administration. FLB has a reported limited oral bioavailability of 33% that could be attributed to the drug's first-pass metabolism. In addition, FLB has a pH-dependent solubility that could be a challenging factor for drug dissolution in the body neutral fluid, and consequently, absorption via mucosal barriers. Thus, this work a ...[more]

PMID: 32801690

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Project description:Neurodegenerative diseases are becoming prevalent as the population ages. Geniposide could inhibit oxidative stress, reduce apoptosis, protect neuron, and has been used for therapy of the neurodegenerative diseases. The bioavailability of geniposide by nasal route is greater than that by oral administration. However, mucociliary clearance is a rate-limiting factor for nasal route administration. The objective of this study was to develop and evaluate a mucoadhesive, thermoreversible in situ nasal gel of geniposide. The poloxamers (P407, P188) and the hydroxypropyl methylcellulose were used as thermoreversible and mucoadhesive polymers, respectively. Borneol was used as a permeation enhancer. The hydrogel was prepared with the cold method and optimized by the response surface methodology-central composite design. Gelation temperature, pH, clarity, gel strength, mucoadhesive strength, in vitro and ex vivo release kinetics of formulations were evaluated. The optimized amounts of poloxamer407 (P407), poloxamer188 (P188) and hydroxypropyl methylcellulose were determined to be 19.4-20.5%, 1.1-4.0% and 0.3-0.6% respectively. The second-order polynomial equation in terms of actual factors indicated a satisfactory correlation between the independent variables and the response (R2 = 0.9760). An ANOVA of the empirical second-order polynomial model indicated the model was significant (P<0.01). P407, P188, P407×P188, P4072 and P1882 were significant model terms. The effects of P407 on gelation temperature were greater than those of other independent variables. The pH values of all the formulations were found to be within 6.3-6.5 which was in the nasal physiological pH range 4.5-6.5. The drug content, gel strength, mucoadhesive strength of the optimized formulations were 97-101%, 25-50 sec and 4000-6000 dyn/cm2 respectively. The in vitro release kinetics of cumulative release of geniposide was fitted to the zero-order model. The ex vivo cumulative release kinetics of geniposide was fitted to the Weibull model. This study concludes that the release of geniposide is controlled by gel corrosion, and that the permeation of geniposide is time-dependent. The more residence time, mucoadhesive, thermoreversible in situ nasal gel of geniposide for neurodegenerative diseases is of compliance and potential application.

Dataset Information

Optimized Nanostructured Lipid Carriers Integrated into In Situ Nasal Gel for Enhancing Brain Delivery of Flibanserin.

Publications

Optimized Nanostructured Lipid Carriers Integrated into In Situ Nasal Gel for Enhancing Brain Delivery of Flibanserin.

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