Preparation, and ex vivo and in vivo Characterization of Favipiravir-Loaded Aspasomes and Niosomes for Nose-to-Brain Administration

Abstract

Purpose: The present study aimed to develop and compare the intranasal applicability of favipiravir-loaded aspasomes (FAV-ASPs) using film hydration method, and favipiravir-loaded niosomes (FAV-NIOs) using ethanol injection method.

Methods: The FAV-ASP and FAV-NIO formulations were characterized according to nanoparticulate characteristics (DLS, drug loading, drug encapsulation efficacy, droplet size distribution), drug release and permeability behavior.

Results: The optimized FAV-ASP formulation (FAV-ASP8) consisted of FAV, ascorbyl palmitate, Span® 60 and cholesterol (30:25:25:50 w/w) with nano-scale size range (292.06 ± 2.10 nm), narrow polydispersity index (PDI) value (0.36 ± 0.03), adequate zeta potential (-74.73 ± 3.28 mV) and acceptable encapsulation efficiency (55.33 ± 0.41%). The optimized FAV-NIO formulation (FAV-NIO9) contained FAV, Span® 60 and cholesterol (30:30:40 w/w) with nano-scale size range (167.13 ± 1.60 nm), narrow PDI value (0.07 ± 0.01), adequate zeta potential (-27.1 ± 1.24 mV) and acceptable encapsulation efficiency (51.30 ± 0.69%). FAV-ASP8 and FAV-NIO9 were suitable for spraying into the nasal cavity (droplet size distribution <200 µm). In vitro drug release and permeability studies demonstrated enhanced solubility and increased blood-brain barrier (BBB) permeability of FAV formulations, respectively. The ex vivo human nasal permeability study revealed that FAV diffusion from FAV-ASP8 was higher than from FAV-NIO9 or initial FAV. Furthermore, the in vivo animal study showed that FAV-ASP8 had a higher BBB penetration compared to FAV-NIO9 and pure FAV. The in vitro-in vivo correlation study showed good correlation between the in vitro and the in vivo pharmacokinetic data.

Conclusion: FAV-ASP8 for nose-to-brain delivery system could be a promising formulation to improve FAV bioavailability compared to FAV-NIO9.

Keywords: aspasomes; ex vivo nasal permeability; favipiravir; in vivo nasal permeability; niosomes; nose-to-brain delivery.

Graphical abstract

Figure 1

Chemical structure of FAV and its metabolic activation.

Figure 2

EE% and DL% results of FAV-ASP8, FAV-ASP10 and FAV-NIO9. Results are expressed as means ± SD (n = 3), ***p-value < 0.001, ****p-value < 0.0001.

Figure 3

BBB-PAMPA results for FAV-ASP8, FAV-ASP10 and FAV-NIO9 in comparison with pure FAV. (A): permeability results, (B): flux results. Results are expressed as means ± SD (n = 6), **p-value < 0.01, and ***p-value < 0.001, ****p-value <0.0001.

Figure 4

Rapid equilibrium dialysis (RED) of the optimal formulations in comparison with pure FAV. Results are expressed as means ± SD (n = 6).

Figure 5

Cumulative in vitro release profile of the optimal formulations compared to pure FAV. Results are expressed as means ± SD (n = 3).

Figure 6

Ex vivo permeability study of FAV-ASP8 and FAV-NIO9 in comparison with pure FAV. Results are expressed as means ± SD (n = 3).

Figure 7

Plasma concentration–time profile after nasal administration of FAV-ASP8, FAV-NIO9 and pure FAV in rats. Results are expressed as means ± SD (n = 4), (ns) means non-significant.

Figure 8

The concentration of FAV in cerebrospinal fluid (CSF) after 1 hour of nasal administration. Results are expressed as means ± SD (n = 4), (ns) means non-significant, *p-value < 0.05, ***p-value < 0.001.

Figure 9

IVIVC graphs for the comparison of AUC _0-t values between the in vitro release and the in vivo PK data. Where (A): IVIVC for pure FAV, (B): IVIVC for FAV-ASP8, and (C): IVIVC for FAV-NIO9.

Figure 10

IVIVC graphs for the comparison of AUC _0-t values between the in vitro permeation and the in vivo PK data. (A): IVIVC for pure FAV, (B): IVIVC for FAV-ASP8, and (C): IVIVC for FAV-NIO9.