Solubilization of drugs by physiological mixtures of bile salts.

Abstract

The solubilization of a number of steroids was determined in bile salt simple micelles and a bile salt/phospholipid micellar system to provide a better basis to predict the extent of drug solubilization in vivo. Excess solid drug was dispersed in taurodeoxycholate or mixed micelle solutions prepared with fixed mole ratios of taurocholate, taurodeoxycholate, taurochenodeoxycholate, glycodeoxycholate, glycocholate, and glycochenodeoxycholate with egg phosphatidylcholine. Drug concentrations were determined from the absorbance following centrifugation. Using NMR spectroscopy, the diffusivities of the simple and mixed micelles were 2 x 10(-6) and 8 x 10(-7) cm2/s, respectively. From the change in the concentration of drug in solution with a change in the lipid concentration, the solubilization ratio (SR) was calculated. The SR and aqueous solubility were used to calculate the micelle/aqueous partition coefficients (Km/w). Km/w was correlated with octanol/water partition (Po/w) for the TDC and mixed micelle data sets with correlation lines of logKm/w = 0.74logPo/w + 1.55 (r2 = 0.91) and logKm/w = 0.61 logPo/w + 2.44 (r2 = 0.95), respectively. With such data, a refined, predictive relationship between the in vitro and the in vivo solubilization with additional information concerning the bile salt/lipid concentration in the human intestine appears possible.