Wei Zhang1,2, Tao Guo2, Caifen Wang2, Yuanzhi He2, Xi Zhang3, Guangyu Li3, Yizhi Chen4, Jun Li4, Yangjing Lin4, Xu Xu1, Li Wu5, Suxia Zhang6, Jiwen Zhang7,8. 1. School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai, 201418, China. 2. Center for Drug Delivery Systems Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. 3. Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 230032, China. 4. Hainan Hualon Pharmaceutical Co., Ltd, Haikou, 570311, China. 5. Center for Drug Delivery Systems Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. track_wuly@163.com. 6. School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai, 201418, China. Zhangsx@sit.edu.cn. 7. School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai, 201418, China. jwzhang@simm.ac.cn. 8. Center for Drug Delivery Systems Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. jwzhang@simm.ac.cn.
Abstract
PURPOSE: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: The new understanding of drug nanoclusters in CD-MOF will help to design more efficient drug delivery systems using CD-MOF carrier with nanocavities.
PURPOSE: 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). METHODS: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. RESULTS: 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. CONCLUSIONS: The new understanding of drug nanoclusters in CD-MOF will help to design more efficient drug delivery systems using CD-MOF carrier with nanocavities.
Authors: Ross S Forgan; Ronald A Smaldone; Jeremiah J Gassensmith; Hiroyasu Furukawa; David B Cordes; Qiaowei Li; Christopher E Wilmer; Youssry Y Botros; Randall Q Snurr; Alexandra M Z Slawin; J Fraser Stoddart Journal: J Am Chem Soc Date: 2011-12-20 Impact factor: 15.419
Authors: Renu Chadha; Madhu Bala; Poonam Arora; D V S Jain; Raghuvir R S Pissurlenkar; Evans C Coutinho Journal: Carbohydr Polym Date: 2013-12-24 Impact factor: 9.381