(10) At high pH (pH > 8.5), the critical micelle concentration is high (reported to be 50–100 mM (10)). The critical aggregation concentration of C10 is also pH-dependent. At pH values below 6, phase separation occurs with C10 precipitating out as an oily phase. As the pH is reduced, and more C10 exists in the unionized form, lamellar bilayers form, which in dilute solution take the form of vesicles. (10,11) Under alkaline conditions where C10 predominantly exists in the ionized form (>pH 8.1), micelles are formed. (9,10) The aggregation behavior of C10 in aqueous solution is complex and depends on the fraction of the ionized and unionized species. However, being amphiphilic, C10 self-associates in aqueous solution which in turn affects the apparent p K a, increasing it to around 7 when in the aggregated form, depending on the C10 concentration. The p K a of the C10 monomer is approximately 4.8.
Sodium caprate is the sodium salt of the medium-chain fatty acid capric acid, also known as decanoic acid. 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. 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. However, the effect was smaller than that of altering the total administered C10 dose. Intestinal dilution of C10 and FD4 revealed a trend of decreasing FD4 absorption with increasing intestinal dilution. In contrast, the FD4 absorption was lower when C10 was administered at 50 mM formulated as micelles as compared to vesicles. 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). Depending on the C10 concentration, the intestinal epithelium showed significant recovery already at 60–120 min after administration. Higher C10 concentrations were associated with an increased and extended absorption but also increased epithelial damage. It was found that the AUC and C max of FD4 increased with increasing C10 concentration. 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. FITC-dextran 4000 (FD4) was selected as a model compound and formulated with 50–300 mM C10. In this work, we set out to better understand how the permeation enhancer sodium caprate (C10) influences the intestinal absorption of macromolecules.
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