Development of micro-beads that contain functional excipients for effective oral delivery of macromolecular drugs

Abstract

Biotechnology advancements have made it possible to produce proteins and peptides for therapeutic applications on a large scale. These peptides are mostly administered parenterally, which hampers patient compliance due to the intrusive nature of the injections. The oral route of drug administration remains the most popular and convenient delivery route. Whilst effective after administration as injections, these protein and peptide drugs are not sufficiently absorbed after oral administration due to pre-systemic enzymatic degradation as well as poor intestinal membrane permeability. With the aid of safe and effective absorption enhancers, these problems can be overcome. Previous studies have proven that Aloe vera leaf materials as well as other absorption enhancing agents (chitosan, N-trimethyl chitosan chloride (TMC) and bile salts) can increase intestinal membrane permeability of drugs across in vitro and ex vivo models when applied as solutions. These absorption enhancers have also proven effective when formulated into macro-beads. The purpose of this study was to develop and evaluate micro-beads containing selected drug absorption enhancers as functional excipients in order to effectively deliver macromolecular drugs across the intestinal epithelium using an ex vivo transport model. Spherical micro-beads were prepared by means of extrusion spheronisation, with each formulation containing fluorescein isothiocyanate (FITC)-dextran (FD-4) as model compound and a different absorption enhancer (i.e. Aloe vera gel, Aloe vera whole leaf extract, chitosan, TMC and sodium glycocholate hydrate). One micro-bead formulation containing only FD-4 was used as the control group. The microbead formulations were characterised in terms of FD-4 content, morphology, size and drug release profiles. The delivery of FD-4 across excised porcine jejunum by the different micro-bead formulations was evaluated using a Sweetana-Grass diffusion apparatus. All of the micro-bead formulations prepared in this study showed relatively spherical shapes along with fairly narrow particle size distribution values. Ex vivo transport studies revealed that all five of the selected drug absorption enhancers formulated into micro-beads, could increase FD-4 transport across the intestinal epithelium compared to the control group, albeit to varying extents. The micro-beads containing A. vera gel showed the highest increase in FD-4 transport of all the micro-bead formulations followed by A. vera whole leaf extract > TMC > chitosan > sodium glycocholate hydrate. This study has shown that absorption enhancers formulated into microbeads can effectively deliver macromolecular compounds across the intestinal epithelium. Although very promising results have been obtained from these ex vivo studies, it is important to mention that in vivo studies are needed to confirm if these absorption enhancing effects are sufficient to deliver macromolecular drugs at therapeutic levels.