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

被引：45

作者：

Manta, Konstantina ^{[1
]}

Papakyriakopoulou, Paraskevi ^{[1
]}

Chountoulesi, Maria ^{[1
]}

Diamantis, Dimitrios A. ^{[2
]}

Spaneas, Dimitrios ^{[1
]}

Vakali, Vasiliki ^{[3
]}

Naziris, Nikolaos ^{[1
]}

Chatziathanasiadou, Maria, V ^{[2
]}

Andreadelis, Ioannis ^{[3
]}

Moschovou, Kalliopi ^{[3
]}

Athanasiadou, Ioanna ^{[1
]}

Dallas, Paraskevas ^{[1
]}

Rekkas, Dimitrios M. ^{[1
]}

Demetzos, Costas ^{[1
]}

Colombo, Gaia ^{[4
]}

Banella, Sabrina ^{[4
]}

Javornik, Uros ^{[5
]}

Plavec, Janez ^{[5
]}

Mavromoustakos, Thomas ^{[3
]}

Tzakos, Andreas G. ^{[2
,6
]}

Valsami, Georgia ^{[1
]}

机构：

[1] Natl & Kapodistrian Univ Athens, Sch Hlth Sci, Dept Pharm, Zografos 15771, Greece

[2] Univ Ioannina, Dept Chem, Sect Organ Chem & Biochem, Ioannina 45110, Greece

[3] Natl & Kapodistrian Univ Athens, Sch Sci, Dept Chem, Zografos 15771, Greece

[4] Univ Ferrara, Dept Life Sci & Biotechnol, I-44121 Ferrara, Italy

[5] Natl Inst Chem, Slovenian NMR Ctr, Ljubljana 1001, Slovenia

[6] Univ Reascarch Ctr Ioannina URCI, Inst Mat Sci & Comp, Ioannina 45110, Greece

来源：

MOLECULAR PHARMACEUTICS | 2020年 / 17卷 / 11期

关键词：

quercetin; cyclodextrin inclusion complexes; nasal delivery; nasal permeation; phase solubility; NMR and fluorescence spectroscopy; DSC; molecular dynamics simulations; AMBER; CLASSIFICATION; SOLUBILITY; ABSORPTION; STATE; PH;

D O I：

10.1021/acs.molpharmaceut.0c00672

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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-beta-cyclodextrin (Que/HP-beta-CD) complexes was previously found to increase the molecule's solubility and stability in aqueous media. Que-methyl-beta-cyclodextrin (Que/Me-beta-CD) inclusion complexes were prepared, characterized, and compared with the Que/HP-beta-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-H CD more than with Me-beta-CD, possibly revealing the presence of more than one HP-beta-CD molecule involved in the complex. Overall, water solubility of lyophilized Que/Me-beta-CD and Que/HP-beta-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.

引用

页码：4241 / 4255

页数：15

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