(128a) Improving the Oral Delivery of Macromolecules through the Study of Permeation Enhancers

Oral delivery is a convenient and patient-friendly route of drug administration compared to injections. However, the oral route cannot be utilized for proteins and peptides due to their enzymatic degradation in the gastrointestinal tract and slow transport across the intestinal epithelium. While the former issue has been tackled by development of encapsulation strategies, the latter is typically addressed by using chemicals to promote drug absorption across the epithelium.

Intestinal permeation enhancers (IPEs) aid transport by altering the structure of either the cellular membrane or the tight junctions between epithelial cells. Unfortunately, enhancer efficacy often appears to be inextricably linked to toxicity, and as a result, permeation enhancers are not widely used in oral formulations. We asked whether the experimentally observed correlation between potency and toxicity of IPEs is fundamental in nature or whether it is a consequence of limited understanding of the rules governing their behavior.

To understand the general principles behind potency and safety of IPEs, we selected fifty enhancers from 11 distinct chemical categories (anionic, cationic, zwitterionic, and nonionic surfactants, bile salts, fatty acids, fatty esters, fatty amines, sodium salts of fatty acids, azone-like molecules, and others) and studied their potency and toxicity in Caco-2 monolayers at concentrations that span three orders of magnitude. Potency was measured by reduction of transepithelial electrical resistsnce, which correlates with molecular flux of hydrophilic solutes. Toxicity was measured via cell viability assays in the same model.

Of the 150 enhancer formulations (50 IPEs, three concentrations each) tested in this study, 83% followed the ‘expected' behavior in that their potency correlated with their toxicity. However, interestingly, 8% formulations demonstrated the ‘desired' behavior, that is, substantial efficacy without marked toxicity. Structures of these chemicals and possible origins of their desired behavior will be discussed. Our results show that enhancer potency does not necessitate toxicity and that certain compounds or classes of compounds are much more likely than others to yield safe and effective enhancers. These compounds, though small in number, can be found through experimentation and in the future, through understanding gained from these studies. These results provide valuable direction as to what classes of enhancers are most beneficial for future study and most likely to serve as safe and effective additions to oral formulations.