Formulation And In Vitro And In Vivo Behavior Of Astilbin Nanosuspensions

Astilbin?AT?is an active natural dihydroflavonol glycoside compound,and has been reported to possess multiple pharmacological activities,such as immunosuppression,anti-inflammatory,and anti-oxidation.However,AT is poorly water-soluble and has bad oral absorption,which limits its application.In this study,astilbin nanosuspensions?AT-NS?was prepared to solve this problem,and increased the oral bioavailability of AT.Furthermore,the effects of particle size and crystal form on the behavior of AT-NS in vitro and in vivo were investigated,which provided a reference for the study of NS.AT-NS was prepared using a simplified wet media milling method.The formulation and process of AT-NS were determined by single factor test and Box-Behnken design,and the particle size and PDI of AT-NS were 215.17±4.83 nm,0.2087±0.0094 respectively.SEM showed that AT-NSs revealed well-defined,spherical shape.XRD displayed that AT-NS still retained some characteristic peaks,but the intensity and quantity were significantly reduced compared with coarse AT.In vitro dissolution study exhibited that the dissolution rate of AT-NS within 24 h was dramatically increased compared with coarse AT and physical mixture.And compared with coarse AT,the rats treated with AT-NS showed higher AUC_0-?and c_max after oral administration.AT-NS with three different particle sizes?215.17±4.83 nm,496.51±12.94 nm,and803.34±9.06 nm?were prepared using by adjusting the milling time of simplified wet media milling method.SEM and XRPD results showed that the three AT-NS had similar appearance and crystalline state.The dissolution of AT-NS were particle size dependent and in an order of 215.17 nm>496.51 nm>803.34 nm,however the AUC_0–?of pharmacokinetics was in an order of 496.51 nm>803.34 nm>215.17 nm.AT-NS with a larger particle size showed a higher accumulation in lung and liver because of reticuloendothelial system?RES?.In conclusion,particle size of AT-NS had obvious impact on dissolution,pharmacokinetics and tissue distribution.AT-NS with two different crystal forms were prepared by simplified wet media milling and antisolvent precipitation respectively.Compared with crystalline AT-NS,amorphous AT-NS demonstrated significant improvement in the in vitro dissolution and in vivo bioavailability in rats.Amorphous AT-NS showed a higher accumulation in heart,liver,and kidney,and there was no significant difference of AUC_0-?between the two in spleen and lung.Therefore,crystal form also had a large effect on in vitro and in vivo behavior of AT-NS.