Impact of Intestinal Concentration and Colloidal Structure on the Permeation-Enhancing Efficiency of Sodium Caprate in the Rat

Abstract

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.

Intestinal Absorption of FITC-Dextrans and Macromolecular Model Drugs in the Rat Intestinal Instillation Model

“…Values are given as mean ± SD (CV%), except T max , which is given as median (min–max). FD4 data from ref ( 9 ). * n = 2 due to most levels below LLOQ.…”

“…The absorption study was performed as previously described. 9 Briefly, anesthesia was induced with isoflurane after which the animal was moved to a preheated preparatory table. Fur was shaved from the throat to the lower abdomen and the shaved area was disinfected with a medicinal sponge containing chlorhexidine.…”

“…The FD4 formulation was prepared in blank FaSSIF, pH 6.5, containing 0–300 mM C10 and 12.5 mg/mL FD4, and was administered as a 0.8 mL bolus, giving a dose of 10 mg of FD4. 9 …”

“…The impact of including bile salts and phospholipids in the formulation was studied in our previous publication. 9 No difference in the absorption of FD4 was observed when FD4 and C10 were prepared in the fasted and fed state simulated intestinal fluids FaSSIF-V2 or FeSSIF-V2, as compared to blank FaSSIF. Therefore, the simple buffer system (blank FaSSIF) was chosen for studying the absorption of macromolecules in this work.…”

“… 6 − 8 We recently used the rat intestinal instillation model to better understand the absorption mechanism of C10. 9 Higher C10 concentrations were correlated not only with higher fluorescein isothiocyanate (FITC)-dextran 4000 (FD4) bioavailability and C max but also more erosion of the enterocyte layer. The epithelial erosion was transient; however, the enterocyte layer had recovered 120 min after administration.…”