Drug nanoclusters formed in confined nano-cages of CD-MOF: dramatic enhancement of solubility and bioavailability of azilsartan

• Main Authors: Yuanzhi He, Wei Zhang, Tao Guo, Guoqing Zhang, Wei Qin, Liu Zhang, Caifen Wang, Weifeng Zhu, Ming Yang, Xiaoxiao Hu, Vikramjeet Singh, Li Wu, Ruxandra Gref, Jiwen Zhang
• Format: Article
• Language: English
• Published: Elsevier 2019-01-01
• Series: Acta Pharmaceutica Sinica B
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211383518303745

Tremendous efforts have been devoted to the enhancement of drug solubility using nanotechnologies, but few of them are capable to produce drug particles with sizes less than a few nanometers. This challenge has been addressed here by using biocompatible versatile γ-cyclodextrin (γ-CD) metal-organic framework (CD-MOF) large molecular cages in which azilsartan (AZL) was successfully confined producing clusters in the nanometer range. This strategy allowed to improve the bioavailability of AZL in Sprague–Dawley rats by 9.7-fold after loading into CD-MOF. The apparent solubility of AZL/CD-MOF was enhanced by 340-fold when compared to the pure drug. Based on molecular modeling, a dual molecular mechanism of nanoclusterization and complexation of AZL inside the CD-MOF cages was proposed, which was confirmed by small angle X-ray scattering (SAXS) and synchrotron radiation-Fourier transform infrared spectroscopy (SR-FTIR) techniques. In a typical cage-like unit of CD-MOF, three molecules of AZL were included by the γ-CD pairs, whilst other three AZL molecules formed a nanocluster inside the 1.7 nm sized cavity surrounded by six γ-CDs. This research demonstrates a dual molecular mechanism of complexation and nanoclusterization in CD-MOF leading to significant improvement in the bioavailability of insoluble drugs. KEY WORDS: γ-Cyclodextrin metal-organic framework, Nanoclusterization, Azilsartan, Mechanism, Solubility, Bioavailability, Molecular modeling