Absorption-Enhancing Mechanisms of Capryol 90, a Novel Absorption Enhancer, for Improving the Intestinal Absorption of P
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RESEARCH PAPER
Absorption-Enhancing Mechanisms of Capryol 90, a Novel Absorption Enhancer, for Improving the Intestinal Absorption o f Po o r l y A b s o r b e d D r u g s : C o n t r i b u t i o n s t o Tr a n s or Para-Cellular Pathways Hiroki Ukai 1 & Ayako Imanishi 1 & Ayaka Kaneda 1 & Erika Kimura 1 & Miku Koyama 1 & Masaki Morishita 1 & Hidemasa Katsumi 1 & Akira Yamamoto 1 Received: 24 August 2020 / Accepted: 26 October 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
ABSTRACT Purpose We have previously reported that Capryol 90 improves the intestinal absorption of insulin, a peptide drug, without causing serious damage to the intestinal epithelium. However, the effects of Capryol 90 and its related formulations on the intestinal absorption of other drugs, and their absorption-enhancing mechanisms are still unclear. The aim of this study is to evaluate the effects of Capryol 90 and its related formulations on the intestinal absorption of drugs and elucidate their absorption-enhancing mechanisms. Methods The intestinal absorption of 5(6)-carboxyfluorescein, fluorescein isothiocyanate-dextrans, and alendronate was evaluated using an in situ closed loop method. Brush border membrane vesicles (BBMVs) were labeled with fluorescent probes, and the fluidity of membrane was evaluated by a fluorescence depolarization method. The expression levels of tight junction (TJ) proteins were measured using a Western blot method and immunofluorescence staining. Results Among the tested excipients, Capryol 90 significantly improved the small and large intestinal absorption of drugs. In mechanistic studies, Capryol 90 increased the membrane fluidity of lipid bilayers in BBMVs. Additionally, Capryol 90 decreased the expression levels of TJ-associated proteins, namely claudin-4, occludin, and ZO-1. Conclusions Capryol 90 is an effective absorption enhancer for improving the intestinal absorption of poorly absorbed drugs via both transcellular and paracellular pathways.
KEY WORDS absorption enhancer . Caco-2 cells . intestinal absorption . membrane fluidity . tight junction * Akira Yamamoto [email protected] 1
Department of Biopharmaceutics, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-Ku, Kyoto 607-8414, Japan
INTRODUCTION Oral medication administration has been widely applied clinically as it is the most convenient and compliable route for patients (1). However, upon oral administration, absorption of hydrophilic molecules, such as polysaccharides, nucleic acids, and peptides/proteins, is hindered by intestinal barriers and degradation (2,3). Therefore, various delivery systems, such as modification of molecular structure, drug formulation modification, or nanoparticulate systems, have been studied to improve the intestinal absorption of poorly absorbed substances (4,5). Among these approaches, the use of formulation additives, including absorption enhancers, is a promising method, as they are easy to include in the formulations and can be used for a wide range of dr
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