(628g) Rational Selection of Intestinal Permeation Enhancers for Oral Macromolecular Drug Delivery
AIChE Annual Meeting
2019
2019 AIChE Annual Meeting
Nanoscale Science and Engineering Forum
Bionanotechnology for Gene and Drug Delivery I
Thursday, November 14, 2019 - 10:10am to 10:28am
Five proteins (insulin, 5.7 kDa; cytochrome C, 12 kDa; ovalbumin, 44 kDa; bovine serum albumin, 66 kDa; and mouse IgG, 150 kDa) and five dextrans with corresponding molecular weights were fluorescently labeled and characterized for hydrodynamic diameter, molecular weight, and surface charge. Permeability was measured in vitro using Caco-2 monolayers and in mice by intestinal injection. Solutions of one marker mixed with one of three enhancers (1-phenylpiperazine, silica nanoparticles, or sodium deoxycholate) were administered to cells or mice, and fluorescence measurements quantified permeation from media or blood samples.
The three permeation enhancers operated via different mechanisms in Caco-2 monolayers, and the effect of macromolecular size on permeation varied significantly with enhancer type. In Caco-2 monolayers, silica nanoparticles were efficacious for markers less than 40 kDa, while low concentrations of 1-phenylpiperazine increased permeability of all markers. Translation to mice was challenging in that effective in vitro enhancer concentrations were not reflective of required concentrations in vivo. However, with optimization of enhancer doses, significant permeability increases were observed in mice. For 4 kDa dextran, silica nanoparticles more than doubled the permeability and 1-phenylpiperazine achieved a remarkable 17-fold increase in permeability.
This study improves our understanding of how permeation enhancers aid intestinal absorption of macromolecular drugs by thoroughly examining the performance of three mechanistically distinct permeation enhancers. Ultimately, compatibility between enhancer mechanism and the properties of the macromolecules dictated permeation enhancer performance in mice.