Ionic Liquids Composed of Lactic Acid and Trometamol Enhance the Oral Absorption of 10 kDa Dextran, as a Model Compound of Mid-Sized Molecules

Abstract

Oral administration is the preferred route for drug administration owing to a high level of patient compliance and suitability for long-term treatment. However, drugs with a molecular weight of >1000 Da such as peptide-based therapeutics generally exhibit poor absorption from the gastrointestinal tract. In this study, we evaluated the potential of ionic liquids to enhance the oral absorption of mid-sized molecules such as dextran, which has a size of 10 kDa. In this study, the ionic liquids we tested enhanced the oral absorption of 10 kDa mid-sized dextran. Among the ionic liquids we tested, d/l-Lactic acid-trometamol ([Lac][Tris])-based ionic liquids consistently yielded higher values for maximum concentration (C_max; 153.9 ± 11.0 nmol/L) of dextran as well as for the area under the curve representing 0–2 h (AUC_{0–2 h}; 228.9 ± 54.1 nmol × h/L) compared with that of the other ionic liquids tested. The [Lac][Tris] = 5 : 1 ionic liquid achieved relatively higher values for both C_max and AUC_{0–2 h}. Interestingly, the observed oral absorption enhancement effect by the [Lac][Tris] = 5 : 1 ionic liquid for mid-sized molecules depended on the concentration of dextran (10 kDa). These results show that ionic liquid formulations can overcome the intestinal barrier and lead to systemic absorption of mid-sized molecules with molecular weights. Although further optimizations aimed at translating ionic liquid technology to the oral delivery of peptide drugs must be required, our results could expand the utility and possibility of ionic liquids as an oral absorption enhancer for mid-sized molecules such as peptides.