Drug-loaded micelles in bio-relevant dissolution media: Impact of surfactant-bile interactions on drug solubility

IntroductionMore than 50 % of new drug molecules have poor water solubility which limits their clinical application. Oral delivery presents an additional challenge due to the endogenous surface-active substances in the gut... [ view full abstract ]

Introduction

More than 50 % of new drug molecules have poor water solubility which limits their clinical application. Oral delivery presents an additional challenge due to the endogenous surface-active substances in the gut that can interact strongly with the surfactants used to increase drug solubility, which results in variable and difficult to predict oral bioavailability. We aim to reveal the impact of bile salt-surfactant interactions on drug solubility by studying the influence of surfactant molecular structure on drug solubilization in biorelevant media.

METHODS

We studied the solubilization of Fenofibrate (Log P = 5.3) by 13 surfactants with different chain length (C₁₂-C₁₈) and head group (cationic, anionic, nonionic and zwitterionic). Porcine bile extract containing bile salts and phospholipids was used for biorelevant media preparation and sodium taurodeoxycholate (97 %) was used as pure bile salt for model experiments. Drug solubility was determined by HPLC. Bile salt-surfactant interactions were studied by determining the critical micellar concentration (CMC) of the single and mixed systems by surface tension measurments.

RESULTS AND DISCUSSION

Drastic decrease of Fenofibrate solubility in presence of bile extract was observed for anionic and cationic surfactants, whereas drug solubilization in nonionic surfactants was not significantly affected. Experiments at different surfactant-to-bile extract ratios showed linear decrease in Fenofibrate solubility with increasing bile extract fraction for Tween 20. However, increasing bile extract fraction from 0 to 20 % resulted in pronounced drop in Fenofibrate solubility for both anionic and cationic surfactants, see Figure 1. Identical results were obtained when bile extract was replaced with a pure bile salt (sodium taurodeoxycholate), which confirmed that surfactant-bile salt interactions are key. Measurements of CMC showed that nonionic surfactants do not form mixed micelles with the bile salts, thus retaining their solubilization capacity, whereas charged surfactants form mixed micelles with bile, which have low drug solubilization capacity. These findings advance the understanding of drug solubility in complex, biorelevant media and could be used to improve the in-silico models for prediction of oral bioavailability that currently neglect such type of effects.

Acknowledgements

The financial support of Project BG05M2OP001-2.009-0028 of Sofia University is gratefully acknowledged