Preparation and Biophysical Characterization of Quercetin Inclusion Complexes with β-Cyclodextrin Derivatives to be Formulated as Possible Nose-to-Brain Quercetin Delivery Systems

Abstract

Quercetin (Que) is a flavonoid associated with high oxygen radical scavenging activity and potential neuroprotective activity against Alzheimer's disease. Que's oral bioavailability is limited by its low water solubility and extended peripheral metabolism; thus, nasal administration may be a promising alternative to achieve effective Que concentrations in the brain. The formation of Que−2-hydroxypropylated−β-cyclodextrin (Que/HP-β-CD) complexes was previously found to increase the molecule's solubility and stability in aqueous media. Que−methyl−β-cyclodextrin (Que/Me-β-CD) inclusion complexes were prepared, characterized, and compared with the Que/HP-β-CD complex using biophysical and computational methods (phase solubility, fluorescence and NMR spectroscopy, differential scanning calorimetry (DSC), and molecular dynamics simulations (MDS)) as candidates for the preparation of nose-to-brain Que's delivery systems. DSC thermograms, NMR, fluorescence spectroscopy, and MDS confirmed the inclusion complex formation of Que with both CDs. Differences between the two preparations were observed regarding their thermodynamic stability and inclusion mode governing the details of molecular interactions. Que's solubility in aqueous media at pH 1.2 and 4.5 was similar and linearly increased with both CD concentrations. At pH 6.8, Que's solubility was higher and positively deviated from linearity in the presence of HP-β-CD more than with Me-β-CD, possibly revealing the presence of more than one HP-β-CD molecule involved in the complex. Overall, water solubility of lyophilized Que/Me-β-CD and Que/HP-β-CD products was approximately 7−40 times and 14−50 times as high as for pure Que at pH 1.2−6.8. In addition, the proof of concept experiment on ex vivo permeation across rabbit nasal mucosa revealed measurable and similar Que permeability profiles with both CDs and negligible permeation of pure Que. These results are quite encouraging for further ex vivo and in vivo evaluation toward nasal administration and nose-to-brain delivery of Que.

Versatile Nasal Application of Cyclodextrins: Excipients and/or Actives?

“…Inclusion complexes of quercetin with RM-β-CD and HP-β-CD were found to increase the solubility and stability in water of the drug. Moreover, ex vivo permeation studies across rabbit nasal mucosa evidenced the ability of both inclusion complexes to significantly increase the negligible permeability of quercetin across this physiological barrier [ 60 ].…”

Enhanced oral bioavailability of koumine by complexation with hydroxypropyl-β-cyclodextrin: preparation, optimization, ex vivo and in vivo characterization

“… 2020 ; Manta et al. 2020 ). In addition, HP-β-CD was the first β-CD derivative to be approved by the FDA for both oral and intravenous administration (Raza et al.…”

Comparative Interaction Studies of Quercetin with 2-Hydroxyl-propyl-β-cyclodextrin and 2,6-Methylated-β-cyclodextrin

“…Lyophilized inclusion complex of QUE-Me-β-CD and QUE-HP-β-CD were prepared by freeze-drying aqueous solution of QUE-Me-β-CD and QUE-HP-β-CD, in molar ratio of 1:2, using the neutralization method, as described previously by Manta et al [ 58 ]. Briefly, 2170 mg of 2,6Me-β-CD or 4800 mg of 2HP-β-CD were accurately weighed and transferred into a 600 mL glass vessel and suspended with 500 mL of purified water under magnetic stirring until complete dissolution of the cyclodextrin.…”