Displacement of Drugs From Cyclodextrin Complexes by Bile Salts: A Suggestion of an Intestinal Drug-Solubilizing Capacity From an In Vitro Model.
The dosing of drugs in an aqueous cyclodextrin formulation requires sufficient amount of cyclodextrins to fully solubilize the drug, as described by Stella's cyclodextrin utility number (UCD). However, this framework does not take biopharmaceutical elements into account, such as the displacement of drug from the cyclodextrin cavity by bile salts present in the small intestine. As bile salts in the intestine are present at concentrations above the critical micelle concentration, an understanding of the interaction between cyclodextrins and bile salts at such supramicellar concentrations (SMC) is required for a better biopharmaceutical understanding of the release mechanism from orally dosed cyclodextrin complexes. To address this, experiments were conducted by isothermal titration calorimetry to determine how various β-cyclodextrins and bile salt interacts at SMC. Combined analysis of the current results and earlier data demonstrated that direct interactions between bile salt micelles and cyclodextrin were negligible. From this knowledge, an extended form of the UCD was suggested to describe the concentration of cyclodextrins to achieve full drug solubilization in the intestine where bile salts are present. Dosing cyclodextrins above this limit will diminish the free drug concentration, potentially decreasing the amount of drug absorbed.
Biologics and Pharmaceutical Science, H. Lundbeck A/S, Valby DK-2500, Denmark; NSM, Research Unit for Functional Biomaterials, Roskilde University, Roskilde DK-4000, Denmark.
Niels Erik
NE
Olesen
NSM, Research Unit for Functional Biomaterials, Roskilde University, Roskilde DK-4000, Denmark.
Peter
P
Westh
Biologics and Pharmaceutical Science, H. Lundbeck A/S, Valby DK-2500, Denmark. Electronic address: rhol@lundbeck.com.
René
R
Holm
D001647:Bile Acids and Salts / Q000737:chemistry*; D004339:Drug Compounding; D004347:Drug Interactions; D065546:Drug Liberation; D006801:Humans; D007408:Intestinal Absorption; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012995:Solubility; D047392:beta-Cyclodextrins / Q000737:chemistry*
D001647:Bile Acids and Salts; D004364:Pharmaceutical Preparations; D047392:beta-Cyclodextrins; C031215:betadex
bile salts; calorimetry (ITC); complexation; cyclodextrin; intestinal absorption; mathematical model; micelle; solubilization