Liposome Formation from Bile Salt–Lipid Micelles in the Digestion and Drug Delivery Model FaSSIF_mod Estimated by Combined Time-Resolved Neutron and Dynamic Light Scattering

Abstract

The flow of bile secretion into the human digestive system was simulated by the dilution of a bile salt-lipid micellar solution. The structural development upon the dilution of the fed state bile model FeSSIF(mod6.5) to the fasted state bile model FaSSIF(mod) was investigated by small-angle neutron scattering (SANS) and dynamic light scattering (DLS) in crossed beam experiments to observe small and large structures in a size range of 1 nm to 50 μm in parallel. Because of the physiologically low lipid and surfactant concentrations of 2.625 mM egg-phosphatidylcholine and 10.5 mM taurocholate the sensitivity of the neutron-structural investigations was improved by partial solvent deuteration with 71% D(2)O, with control experiments in H(2)O. Static experiments of initial and end state systems after 6 days of development revealed the presence of mixed bile salt-lipid micelles of 5.1 nm size in the initial state model FeSSIF(mod6.5), and large liposomes in FaSSIF(mod), which represent the late status after dilution of bile secretion in the intestine in the fasted state. The liposomes depicted a size of 34.39 nm with a membrane thickness of 4.75 nm, which indicates medium to large size unilamellar vesicles. Crossed beam experiments with time-resolved neutron and light scattering experiments after fast mixing with a stopped-flow device revealed a stepwise structural dynamics upon dilution by a factor of 3.5. The liposome formation was almost complete five minutes after bile dilution. The liposomes 30 min after dilution resembled the liposomes found after 6 days and depicted a size of 44.56 nm. In the time regime between 3 and 100 s a kinetic intermediate was observed. In a further experiment the liposome formation was abolished when the dilution was conducted with a surfactant solution containing sodium dodecyl sulfate.

Structural and Functional Implications of the Interaction between Macrolide Antibiotics and Bile Acids

“…Bile acids are amphiphilic and form primary micelles of 2–10 bile acid molecules at lower (5–15 m m ) and vesicles (aggregation number 10–100 aggregates) at higher concentrations. [13] The main physiological functions of bile acids are the solubilization and transport of lipids and interaction with lipid soluble vitamins and drugs[13–15]. …”

“…It is suggested in the literature that lecithin and NaTC form mixed micelles with a cmc between 5–12 m m . [15] Therefore, in FaSSIF, no mixed micelles are formed, resulting in a high diffusion coefficients of monomeric bile acid (Figure 6). In contrast, the diffusion of lecithin is much slower, indicating the formation of large aggregates of this lipid.…”

Importance of Critical Micellar Concentration for the Prediction of Solubility Enhancement in Biorelevant Media

“…Considering that intestinal biorelevant media are prone to the formation of supramolecular arrangements such as liposomes and micelles [6], led us to hypothesize that surfactant properties of compounds could be linked to their ability to be solubilized in such milieu.…”

“…Nawroth et al investigated the structural development of bile salt-lipid solutions in the human digestive system from fed to fasted conditions [6]. The study showed that, while in FeSSIF small mixed bile salt-lipid micelles are formed, in FaSSIF predominantly large liposomes are created.…”

“…Fifty-one molecules were profiled -including marketed drugs and Roche proprietary compounds -with a broad range of solubility, lipophilicity, and ionization states. 6 …”