Abstract
Peroral delivery of hydrophilic drugs is one of the greatest challenges in biopharmaceutical research. Hydrophilic drugs usually present low bioavailability after oral administration. One of the causes of this low bioavailability is their poor intestinal permeation through the paracellular pathway. This pathway is actually restricted by the presence of tight junctions at the apical side of the enterocytes. In the last few years, great interest has been focused on the structure and cellular regulation of tight junctions, materializing in more in-depth knowledge of this intestinal barrier. Simultaneously, and on the basis of this understanding, continuous efforts are being made to develop agents that can modulate tight junctions and magnify the paracellular permeability of hydrophilic compounds without causing significant intestinal damage. This review focuses on strategies to improve the paracellular permeation of poorly absorbed drugs as a way to enhance their bioavailability after oral administration. Most of the research on this subject has been carried out using in vitro models (mainly Caco-2 cell monolayers), which yield useful information on the potential effects and mechanisms of action of absorption-enhancing compounds. However, in vivo studies, which are much more scarce, are needed to confirm the effects of potential enhancers and to evaluate the suitability of including these compounds as excipients in drug formulation. We review the in vitro and in situ studies involving the most promising paracellular permeation enhancers (e.g., medium chain fatty acids and chitosan and its derivatives), analyzing the degree of drug absorption enhancement achieved, as well as the potential associated toxicity. The few studies performed in vivo are also presented. In addition, the findings of recent absorption enhancers, such as zonula occludens toxin or thiolated polymers, are reviewed.
Keywords: paracellular permeation enhancement, tight junctions, sodium caprate, chitosan, oral bioavailability, drug delivery
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