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Fabrication of an ionic-sensitive in situ gel loaded with resveratrol nanosuspensions intended for direct nose-to-brain delivery.

ABSTRACT

The objective of this study was to fabricate a composite in situ gelling formulation combining nanoparticulates and an ionic-triggered deacetylated gellan gum (DGG) matrix for challenging intranasal drug delivery. The prepared resveratrol nanosuspensions (Res-NSs) were distributed in DGG solutions. Parameters such as the in situ gelation capability, particle size, rheological properties, and texture profiles were used to describe the properties of the in situ gel. Pharmacokinetic and brain-targeting efficiency studies were performed after intranasal and intravenous administration, respectively. Biodistribution and localization using in vivo imaging systems and fluorescence microscopy are also described. The formulation containing 0.6% w/v DGG displayed a favorable gelling ability and the desired viscosity. The rheology results established that the DGG in situ gel possesses the characteristics of shear thinning, thixotropy and yield stress. The results of the textural profile revealed an increase in adhesiveness and viscosity for the in situ gel compared to the DGG solution. In vitro penetration studies followed a Higuchi mathematic model. Pharmacokinetics revealed a 2.88-times increase of bioavailability in the brain by intranasal Res-NSs in situ gel formulation. The drug targeting efficiency (458.2%) and direct transport percentages (78.18%) demonstrated direct delivery via the nose-brain pathway. The distribution and localization further illustrated the existence of direct nose-to-brain transport, bypassing the BBB. In sum, this hybrid in situ gel system is a promising approach for intranasal application in terms of the enhancement of nasal mucosal permeability and increased nasal cavity residence time by a nanotechnology delivery system and in situ gelling technology.