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

PurposeTo investigate the mechanism of enhancing solubility and bioavailability of water-insoluble drug, valsartan(VAL), with beingmega-loaded by cyclodextrin metal organic framework (CD-MOF).MethodsVAL 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) C-13 solid-state nuclear magnetic resonance spectroscopy ( C-13 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.ResultsAs a carrier with payload 150% higher than conventional CD complexation, CD-MOF included molecules of VAL as complexations in the chambers of (-CD)(2), and nanoclusters in the confined spherical cages of (-CD)(6) confirmed by SAXS and C-13 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 (-CD)(6) are critical in dramatically improving theapparent solubility (39.5-fold) and oral bioavailability (1.9-fold) of VAL in contrast to -CD inclusion.ConclusionsThe new understanding of drug nanoclusters in CD-MOF will help to design more efficient drug delivery systems using CD-MOF carrier with nanocavities.