Nano-sized water-in-oil-in-water emulsion enhances intestinal absorption of calcein, a high solubility and low permeability compound

Our goal was to develop safe and stable multilayer emulsions capable of enhancing intestinal absorption of biopharmaceutics classification system (BCS) class III drugs. First, w/o emulsions were prepared using calcein as a model BCS class III compound and condensed ricinoleic acid tetraglycerin ester as a hydrophobic emulsifier. Then water-in-oil-in-water (w/o/w) emulsions were prepared with shirasu porous glass (SPG) membranes. Particle size analyses and calcein leakage from oil droplets in w/o/w emulsions led us to select stearic acid hexaglycerin esters (HS-11) and Gelucire 44/14 as hydrophilic emulsifiers. Analyses of the absorption-enhancing effects of w/o/w emulsions on intestinal calcein absorption in rats showed that calcein bioavailability after intraduodenal (i.d.) administration of HS-11 or Gelucire 44/14 + polyvinyl alcohol (PVA) w/o/w emulsions prepared with 0.1-μm pore-sized SPGs was significantly higher than that of the calcein control. However, serum calcein concentration vs. time profiles after i.d. administration of w/o/w emulsions prepared with 1.1-μm and 30-μm pore-sized SPGs and an emulsion prepared with a calcein-containing outer water phase were comparable to control profiles. These results suggested that HS-11 or Gelucire 44/14 + PVA are safe outer water phase additives and that 0.1-μm pore-sized SPGs are important for preparing w/o/w emulsions that enhanced intestinal calcein absorption.