MOF Capacitates Cyclodextrin to Mega-Load Mode for High-Efficient Delivery of Valsartan

• DOI: 10.1007/s11095-019-2650-3
• Publication Date: 2019-06-03T22:20:07Z
• Authors: Wei Zhang; Tao Guo; Caifen Wang; Yuanzhi He; Xi Zhang; Guangyu Li; Yizhi Chen; Jun Li; Yangjing Lin; Xu Xu; Li Wu; Suxia Zhang; Jiwen Zhang
• Keywords: Nanoclusters; Small-angle X-ray scattering; Nanocages; Powder Diffraction

To investigate the mechanism of enhancing solubility and bioavailability of water-insoluble drug, valsartan (VAL), with being mega-loaded by cyclodextrin metal organic framework (CD-MOF).VAL was successfully mega-loaded into CD-MOF by magnetic agitation of VAL in ethanolic solution. Characterizations including powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), synchrotron radiation-based Fourier transform-infrared spectroscopy (SR-FTIR) 13C solid-state nuclear magnetic resonance spectroscopy ( 13C SS-NMR), nitrogen gas adsorption, and small-angle X-ray scattering (SAXS) were carried out to confirm the mechanism and incorporation behavior of VAL in CD-MOF. Ball milling process combined with molecular modeling was also used to confirm the mechanism. Improvement of bioavailability in vivo was confirmed by pharmacokinetic experiment in beagles.As a carrier with payload 150% higher than conventional CD complexation, CD-MOF included molecules of VAL as complexations in the chambers of (γ-CD)2, and nanoclusters in the confined spherical cages of (γ-CD)6 confirmed by SAXS and 13C SS-NMR. Ball milling combined with molecular modeling inferred that the reduced release rate of the milled CD-MOF with ultrahigh drug payload was mainly due to the partial aggregation of the VAL nanoclusters. The molecules of VAL as nanoclusters in the cages of (γ-CD)6 are critical in dramatically improving the apparent solubility (39.5-fold) and oral bioavailability (1.9-fold) of VAL in contrast to γ-CD inclusion.The new understanding of drug nanoclusters in CD-MOF will help to design more efficient drug delivery systems using CD-MOF carrier with nanocavities.