Improved oral bioavailability of propranolol in healthy human volunteers using a liver bypass drug delivery system containing oleic acid

Abstract

Propranolol, a clinically proven lipophilic β-adrenergic blocking agent, undergoes extensive and unpredictable first-pass hepatic metabolism when administered as a conventional oral formulation. A nine-subject three-way cross-over study was performed in healthy human volunteers to assess the relative bioavailability of two novel oral formulations of propranolol, designed to bypass hepatic first-pass metabolism. These formulations contained a mixture of unsaturated fatty acids, mainly oleic acid, and surfactants in enteric-coated liquid-filled hard gelatin capsules. Using these formulations selective increases of up to more than 6-fold in AUC and 4-fold in C max were achieved in subjects who responded poorly to Inderal ®. The increased propranolol bioavailability achieved using the liver by pass formulations was associated with a reduction in the coefficient of variance for both C max and AUC of up to 44%, when compared to Inderal ®. The results of the present study suggest the possibility of developing a predictable reduced dose delivery system for basic lipophilic drugs which undergo extensive hepatic first-pass metabolism.