Valsartan Sustained And Controlled Release Systems Based On Cyclodextrin Metal-Organic Framework Loaded Particles

Cubic?-cyclodextrin metal-organic framework?CD-MOF?has potential application in drug delivery due to its high specific surface area and porosity.In this study,CD-MOF was explored as an excellent valsartan?VAL?carrier with markedly higher payload than conventional CD complexation,achieving high solubility of VAL.The drug loading mechanism was studied by experimental characterization and molecular simulation.VAL was included by the chambers of??-CD?2 pairs and formed nano-clusters in the confined spherical cages of??-CD?6 which resulted in the high solubility confirmed by molecular simulation combined with powder X-ray diffraction?PXRD?,differential scanning calorimetry?DSC?,synchrotron radiation Fourier transform infrared spectroscopy?SR-FTIR?,¹³C solid-state nuclear magnetic resonance spectroscopy(¹³C SS-NMR),nitrogen adsorption and small angle X-ray scattering?SAXS?.It is interesting to find that the in vitro release rate for VAL loaded in CD-MOF?VAL/CD-MOF,VAL:CD=1.5:1?was slowed after ball milling,which was different from typical increase of solubilities of crystals by size reduction.Molecular simulation inferred that the reduced release rate of milled CD-MOF with ultrahigh drug payload was mainly due to the partial aggregation of the VAL nano-clusters.VAL/CD-MOF was prepared into gel skeleton sustained-release tablets and osmotic pump controlled-release tablets.Beagle was used as animal model to evaluate pharmacokinetics in vivo.VAL/CD-MOF gel matrix sustained-release tablets are critical in improving Tmax by 2-fold and achieving apparently sustained release in fasted pattern.Besides,the effect of food on drug absorption was effectively reduced under the fed pattern.VAL/CD-MOF was also prepared into 12-hour osmotic pump controlled-release tablets to realize the possibility of preparing osmotic pump controlled-release tablets from insoluble drugs.In order to conform to the metabolic model of Beagles,4/6-hour VAL/CD-MOF osmotic pump controlled-release tablets were prepared to investigate the effects of diet on bioavailability of drugs in vivo and provide support for the development of pharmaceutical preparations.