pH-Responsive carriers for oral drug delivery: challenges and opportunities of current platforms

Abstract

Oral administration is a desirable alternative of parenteral administration due to the convenience and increased compliance to patients, especially for chronic diseases that require frequent administration. The oral drug delivery is a dynamic research field despite the numerous challenges limiting their effective delivery, such as enzyme degradation, hydrolysis and low permeability of intestinal epithelium in the gastrointestinal (GI) tract. pH-Responsive carriers offer excellent potential as oral therapeutic systems due to enhancing the stability of drug delivery in stomach and achieving controlled release in intestines. This review provides a wide perspective on current status of pH-responsive oral drug delivery systems prepared mainly with organic polymers or inorganic materials, including the strategies used to overcome GI barriers, the challenges in their development and future prospects, with focus on technology trends to improve the bioavailability of orally delivered drugs, the mechanisms of drug release from pH-responsive oral formulations, and their application for drug delivery, such as protein and peptide therapeutics, vaccination, inflammatory bowel disease (IBD) and bacterial infections.

Keywords: bioavailability; controlled release; drug delivery; oral delivery; pH-Responsive.

Figure 1.

Drug release mechanisms and absorption process of pH-responsive oral delivery hydrogels/nanoparticles/microspheres (Wang & Zhang, ; Fox et al., 2015). Drugs release from pH-responsive hydrogels/nanoparticles/microspheres after the materials swelling and/or dissolution at specific pH. Drug molecules can cross the mucosal layer followed by a submucosal and areolar cell barrier where they interact with a plethora of transport pathways including paracellular or transcellular pathway or transcytosis pathway to enter systemic circulation. The paracellular pathway allows diffusion of molecules in the space between epithelial cells and is regulated by tight junctions formed between the cells. The transcellular pathway passes through the apical and basolateral cell membranes as well as the cytoplasm. It is restricted to hydrophobic molecules or molecules that have membrane pumps on the cell surface. The transcytosis pathway is an active transport pathway via receptor-mediated endocytosis and carrier-mediated transport. Transcytosis pathways are found in both epithelial and M cells. Particles on the scale of 1–1000 μm are not taken up by M cells (Kreuter, 1996), while particles of 50–1000 nm are phagocytized by M cells in Peyer’s patches. Only the size of the particles under 500 nm are used for cellular internalization in intestinal delivery to the systemic circulation (Moghimi et al., ; Sharpe et al., 2014), while particles <10 nm are cleared by lymph drainage (Moghimi et al., 2001).