Mixed micellar system stabilized with saponins for oral delivery of vitamin K

Abstract

Poorly soluble vitamin K cannot be absorbed by patients suffering from cholestasis due to extremely low level of bile salts in the intestine. A formulation of vitamin K including glycocholic acid (i.e. Konakion® MM), does not increase bioavailability because it is unstable due to protonation of glycocholic acid at gastric pH. To develop a stable formulation, saponins were introduced as neutral surfactants to (partly) replace glycocholic acid. Experimental design was made to investigate the effect of the composition on particle size at neutral pH and upon acidification at pH 1.5. Two formulations that were within the optimized composition window were loaded with vitamin K and those showed superior stability at low pH as compared to Konakion® MM: sizes were between 43 and 46 nm at pH 7.3 and between 46 and 58 nm after 1 h incubation at pH 1.5, respectively, but large aggregates were formed at pH 1.5 in presence of Konakion® MM. Micelles were cytocompatible with Caco-2 cells at concentration of surfactants (saponins and glycocholic acid) up to 0.15 mg/ml. Uptake of vitamin K by Caco-2 cells was 4.2–4.9 nmol/mg protein for saponins-containing formulations and 7.1 nmol/mg protein for Konakion® MM. This, together with the superior stability at low pH, makes saponins-containing mixed micelles promising oral formulations for vitamin K.