In this work, we set out to better understand how the permeation enhancer sodium caprate (C10) influences the intestinal absorption of macromolecules. FITC-dextran 4000 (FD4) was selected as a model compound and formulated with 50–300 mM C10. Absorption was studied after bolus instillation of liquid formulation to the duodenum of anesthetized rats and intravenously as a reference, whereafter plasma samples were taken and analyzed for FD4 content. It was found that the AUC and C max of FD4 increased with increasing C10 concentration. Higher C10 concentrations were associated with an increased and extended absorption but also increased epithelial damage. Depending on the C10 concentration, the intestinal epithelium showed significant recovery already at 60–120 min after administration. At the highest studied C10 concentrations (100 and 300 mM), the absorption of FD4 was not affected by the colloidal structures of C10, with similar absorption obtained when C10 was administered as micelles (pH 8.5) and as vesicles (pH 6.5). In contrast, the FD4 absorption was lower when C10 was administered at 50 mM formulated as micelles as compared to vesicles. Intestinal dilution of C10 and FD4 revealed a trend of decreasing FD4 absorption with increasing intestinal dilution. However, the effect was smaller than that of altering the total administered C10 dose. Absorption was similar when the formulations were prepared in simulated intestinal fluids containing mixed micelles of bile salts and phospholipids and in simple buffer solution. The findings in this study suggest that in order to optimally enhance the absorption of macromolecules, high (≥100 mM) initial intestinal C10 concentrations are likely needed and that both the concentration and total dose of C10 are important parameters.

Over recent decades there has been an increase in the proportion of BCS class II and IV drug candidates in industrial drug development. To overcome the biopharmaceutical challenges associated with the less favorable properties of solubility and/or intestinal permeation of these substances, the development of formulations containing nanosuspensions of the drugs has been suggested. The intestinal absorption of aprepitant from two nanosuspensions (20 μM and 200 μM total concentrations) in phosphate buffer, one nanosuspension (200 μM) in fasted-state simulated intestinal fluid (FaSSIF), and one solution (20 μM) in FaSSIF was investigated in the rat single-pass intestinal perfusion model. The disappearance flux from the lumen (J) was faster for formulations containing a total concentration of aprepitant of 200 μM than for those containing 20 μM, but was unaffected by the presence of vesicles. The flux into the systemic circulation (J) and, subsequently, the effective diffusion constant (D) were calculated using the plasma concentrations. J was, like J, faster for the formulations containing higher total concentrations of aprepitant, but was also faster for those containing vesicles (ratios of 2 and 1.5). This suggests that aprepitant is retained in the lumen when presented as nanoparticles in the absence of vesicles. In conclusion, increased numbers of nanoparticles and the presence of vesicles increased the rate of transport and availability of aprepitant in plasma. This effect can be attributed to an increased rate of mass transport through the aqueous boundary layer (ABL) adjacent to the gut wall.

Medium chain fatty acids (MCFA) are digestion products of lipid-rich food and lipid-based formulations, and they are used as transient permeability enhancers in formulation of poorly permeable compounds. These molecules may promote drug absorption by several different processes, including solubilization, increased membrane fluidity, and increased paracellular transport through opening of the tight junctions. Therefore, understanding the aggregation behavior of MCFAs is important. A number of studies have measured the critical micelle concentration (CMC) of MCFAs experimentally. However, CMC is highly dependent on system conditions like pH, temperature, and the ionic strength of the buffer used in different experimental techniques. In this study, we investigated the aggregation behavior of four different MCFAs using the coarse-grained molecular dynamics (CG-MD) simulations with the purpose to explore if CG-MD can be used to study MCFA interactions occurring in water. The ratio of deprotonated and non-charged MCFA molecules were manipulated to assess aggregation behavior under different pH conditions and within the box sizes of 22 × 22 × 44 nm 3 and 44 nm 3 for 1 μs. CMCs were calculated by performing CG-MD simulations with an increasing number of MCFAs. The resulting aggregate size distribution and number of free MCFA molecules were used to determine the CMC. The CMCs from simulations for C 8 , C 10 , and C 12 were 1.8–3.5-fold lower than the respective CMCs determined experimentally by the Wilhelmy method. However, the variation of MCFA aggregate sizes and morphologies at different pH conditions is consistent with previous experimental observation. Overall, this study suggests that CG-MD is suitable for studying colloidal systems including various MCFAs. Electronic supplementary material The online version of this article (10.1208/s12249-018-1289-4) contains supplementary material, which is available to authorized users.

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