Bile Salt Micelles and Phospholipid Vesicles Present in Simulated and Human Intestinal Fluids: Structural Analysis by Flow Field–Flow Fractionation/Multiangle Laser Light Scattering

• Published in: Journal of pharmaceutical sciences 2016-09, Vol.105 (9), p.2832-2839
• Main Authors: Elvang, Philipp A., Hinna, Askell H., Brouwers, Joachim, Hens, Bart, Augustijns, Patrick, Brandl, Martin
• Format: Article
• Language: English
• Subjects: Bile Acids and Salts - chemistry; Body Fluids - chemistry; Colloids; drug transport; duodenum; food effects; Fractionation, Field Flow; Humans; intestinal absorption; intestinal secretion/transport; Intestines - chemistry; Lasers; lipids; Micelles; oral drug delivery; Particle Size; phospholipids; Phospholipids - chemistry; Scattering, Radiation; Spectrophotometry, Ultraviolet; Taurocholic Acid - chemistry
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1016/j.xphs.2016.03.005

Knowledge about colloidal assemblies present in human intestinal fluids (HIFs), such as bile salt micelles and phospholipid vesicles, is regarded of importance for a better understanding of the in vivo dissolution and absorption behavior of poorly soluble drugs (Biopharmaceutics Classification System class II/IV drugs) because of their drug-solubilizing ability. The characterization of these potential drug-solubilizing compartments is a prerequisite for further studies of the mechanistic interplays between drug molecules and colloidal structures within HIFs. The aim of the present study was to apply asymmetrical flow field–flow fractionation (AF4) in combination with multiangle laser light scattering in an attempt to reveal coexistence of colloidal particles in both artificial and aspirated HIFs and to determine their sizes. Asymmetrical flow field–flow fractionation/multiangle laser light scattering analysis of the colloidal phase of intestinal fluids allowed for a detailed insight into the whole spectrum of submicron- to micrometer-sized particles. With respect to the simulated intestinal fluids mimicking fasted and fed state (FaSSIF-V1 and FeSSIF-V1, respectively), FaSSIF contained one distinct size fraction of colloidal assemblies, whereas FeSSIF contained 2 fractions of colloidal species with significantly different sizes. These size fractions likely represent (1) mixed taurocholate-phospholipid-micelles, as indicated by a size range up to 70 nm (in diameter) and a strong UV absorption and (2) small phospholipid vesicles of 90-210 nm diameter. In contrast, within the colloidal phase of the fasted state aspirate of a human volunteer, 4 different size fractions were separated from each other in a consistent and reproducible manner. The 2 fractions containing large particles showed mean sizes of approximately 50 and 200 nm, respectively (intensity-weighted mean diameter, Dz), likely representing mixed cholate/phospholipid micelles and phospholipid vesicles, respectively. The sizes of the smaller 2 fractions being below the size range of multiangle laser light scattering analysis (