Influence of Physiological Gastrointestinal SurfactantRatio on the Equilibrium Solubility of BCS Class II Drugs InvestigatedUsing a Four Component Mixture Design

摘要

The absorption of poorly water-soluble drugs is influenced by the luminal gastrointestinal fluid content and composition, which control solubility. Simulated intestinal fluids have been introduced into dissolution testing including endogenous amphiphiles and digested lipids at physiological levels; however, in vivo individual variation exists in the concentrations of these components, which will alter drug absorption through an effect on solubility. The use of a factorial design of experiment and varying media by introducing different levels of bile, lecithin, and digested lipids has been previously reported, but here we investigate the solubility variation of poorly soluble drugs through more complex biorelevant amphiphile interactions. A four-component mixture design was conducted to understand the solubilization capacity and interactions of bile salt, lecithin, oleate, and monoglyceride with a constant total concentration (11.7 mM) but varying molar ratios. The equilibrium solubility of seven low solubility acidic (zafirlukast), basic (aprepitant, carvedilol), and neutral (fenofibrate, felodipine,griseofulvin, and spironolactone) drugs was investigated. Solubilityresults are comparable with literature values and also our own previouslypublished design of experiment studies. Results indicate that solubilizationis not a sum accumulation of individual amphiphile concentrations,but a drug specific effect through interactions of mixed amphiphilecompositions with the drug. This is probably due to a combined interactionof drug characteristics; for example, lipophilicity, molecular shape,and ionization with amphiphile components, which can generate specificdrug–micelle affinities. The proportion of each component canhave a remarkable influence on solubility with, in some cases, thehighest and lowest points close to each other. A single-point solubilitymeasurement in a fixed composition simulated media or human intestinalfluid sample will therefore provide a value without knowledge of thesurrounding solubility topography meaning that variability may beoverlooked. This study has demonstrated how the amphiphile ratiosinfluence drug solubility and highlights the importance of the envelopeof physiological variation when simulating in vivo drug behavior.