In vitro - in vivo - in silico approach in the development of inhaled drug products: Nanocrystal-based formulations with budesonide as a model drug

This study aims to understand the absorption patterns of three different kinds of inhaled formulations via in silico modeling using budesonide(BUD)as a model drug.The formulations investigated in this study are:(i)commercially available micronized BUD mixed with lactose(BUD-PT),(ii)BUD nanocrystal suspension(BUD-NC),(iii)BUD nanocrystals embedded hyaluronic acid microparticles(BUD-NEM).The deposition patterns of the three inhaled formulations in the rats’lungs were determined in vivo and in silico predicted,which were used as inputs in GastroPlus TM software to predict drug absorption following aerosolization of the tested formulations.BUD pharmacokinetics,estimated based on intravenous data in rats,was used to establish a drug-specific in silico absorption model.The BUD-specific in silico model revealed that drug pulmonary solubility and absorption rate constant were the key factors affecting pulmonary absorption of BUD-NC and BUD-NEM,respectively.In the case of BUD-PT,the in silico model revealed significant gastrointestinal absorption of BUD,which could be overlooked by traditional in vivo experimental observation.This study demonstrated that in vitro-in vivo-in silico approach was able to identify the key factors that influence the absorption of different inhaled formulations,which may facilitate the development of orally inhaled formulations with different drug release/absorption rates.