A Fisetin Delivery System for Neuroprotection: A Co-Amorphous Dispersion Prepared in Supercritical Carbon Dioxide

Abstract

Fisetin (FIS), a senolytic flavonoid, mitigates age-related neuroprotective changes. An amorphous FIS dispersion with a co-carrier was prepared using supercritical fluid extraction with carbon dioxide (scCO2). Characterisation, including powder X-ray diffraction and Fourier-transform infrared spectroscopy, confirmed amorphization and assessed intermolecular interactions. The amorphous FIS dispersion exhibited enhanced solubility, dissolution profiles, and bioavailability compared to the crystalline form. In vitro, the amorphous FIS dispersion demonstrated antioxidant activity (the ABTS, CUPRAC, DDPH, FRAP assays) and neuroprotective effects by inhibiting acetylcholinesterase and butyrylcholinesterase. FIS modulated gut microbiota, reducing potentially pathogenic gram-negative bacteria without affecting probiotic microflora. These improvements in solubility, antioxidant and neuroprotective activities, and gut microbiome modulation suggest the potential for optimising FIS delivery systems to leverage its health-promoting properties while addressing oral functionality limitations.

Enhanced Antioxidant and Neuroprotective Properties of Pterostilbene (Resveratrol Derivative) in Amorphous Solid Dispersions

“…The increase in apparent solubility had a positive impact on the passive diffusion of PTR in the GIT and BBB models. Similar results for the ASDs of polyphenol were reported by Wdowiak et al [ 50 ] (curcumin and piperine), Sip et al [ 54 ] (fisetin), and Deng et al [ 103 ] (piperine).…”

“…In recent years, CUPRAC and FRAP assays have been widely used to assess the antioxidant activity of various compounds, including those with potential importance for neurodegenerative diseases. These assays have been instrumental in evaluating the antioxidant potential of fisetin [ 54 ], greek sage [ 108 ], naringenin [ 104 ], and Cannabis sativa extracts [ 109 ].…”

“…They are prepared by dispersing the active substance in a carrier, usually a pharmacologically inert polymer. Techniques such as hot melt extrusion [ 50 ], solvent evaporation [ 51 ], ball milling [ 52 ], spray drying [ 53 ], supercritical carbon dioxide extraction [ 54 ], and freeze drying [ 55 ] are used to obtain the ASDs of polyphenols. Due to the thermodynamic instability of amorphous drugs, their recrystallization may occur during storage.…”

Myricetin Amorphous Solid Dispersions—Antineurodegenerative Potential

“…Amorphous materials lack long-range order in their atomic arrangement, while crystalline materials exhibit a regular and repeating pattern. Confirming the amorphous/crystalline nature of a substance is crucial as it affects its physical and chemical properties, including solubility, stability, and bioavailability [ 46 , 47 , 48 , 50 , 55 , 56 , 59 ].…”

“…It provides information about the presence of specific bonds and interactions between the polymer and other components in the dispersion. This analysis helps assess the drug–polymer compatibility and potential interactions that may influence the stability and performance of the ASD formulation [ 46 , 50 , 54 , 59 , 70 ]. In this study, infrared spectroscopy was used to demonstrate potential interactions between MYR and PVP30.…”