Intestinal Permeation Enhancers Safely Enable the Oral Delivery of Macromolecules

The unique physicochemical properties that make protein drugs powerful biologic therapeutics also prevent them from being delivered orally. They are structurally and chemically prone to degradation in the stomach, and their large size and hydrophilicity limit their absorption across the intestinal epithelium. Because oral drug delivery is much preferred by patients over parenteral delivery, herculean efforts have been made over the last several decades to improve the oral bioavailability of protein drugs. Permeation enhancers are chemicals that enhance the transport of molecules across the intestinal epithelium, and while they are widely studied, very few have made it into clinical formulations. One of the biggest concerns preventing the advancement of novel permeation enhancers is our poor understanding of how they function and how their chronic use will impact intestinal health. To address these concerns, this work used a combination of in vitro and in vivo models of the intestinal epithelium to assess the efficacy and toxicity profiles of phenylpiperazine and its derivatives as well as the bile salt sodium deoxycholate. For both 1-phenylpiperazine and sodium deoxycholate, this work is the first that assesses their ability to improve macromolecular absorption in the intestine. Additionally, this work extended the typical size range of macromolecular cargo studied up to 70 kDa to more accurately predict how these permeation enhancers may work with larger protein drugs. Finally, a month-long safety study was carried out in mice, leading to our ultimate conclusion that novel permeation enhancers are able to deliver cargos larger than previously published and can do so without irreparably damaging the intestinal epithelium.