(621b) A Permeation Enhancer for Oral Delivery of Therapeutic Macromolecules

Despite its convenience and superior patient compliance, oral route has always been an elusive paradigm for delivery of macromolecules, one of the most sought-after therapeutic interventions for a variety of diseases. Oral peptide delivery is hindered by physiological limitations of the gastrointestinal tract including poor intestinal permeability, and enzymatic/acidic degradation. Although several innovative approaches have been tested, none has reached clinical potential. One such approach includes use of Chemical Permeation Enhancers (CPEs) to modulate intestinal permeability by interacting with epithelial cellular structure. The utility of CPEs however is often hindered by a direct correlation between their potency and toxicity. Here, we report on a novel permeation enhancer, Dimethyl palmitoyl ammonio propanesulfonate (PPS), with excellent enhancement potential and minimal toxicity. PPS has been shown to enhance mannitol transport across Caco-2 epithelial monolayers while being minimally toxic. Continuing the work, PPS was tested for dose- and time-dependent cytotoxicity, delivery of two model fluorescent molecules, sulforhodamine-B and FITC-insulin in vitro, and absorption enhancement of salmon calcitonin (sCT) in vivo. The studies revealed that PPS enhanced Caco-2 monolayer transport of FITC-Insulin by 2.5-folds in a time- and dose-dependent manner via both paracellular and transcellular pathway. TEER measurements in Caco-2 monolayers confirmed reversible modulation of cellular structure by PPS. Further, PPS enhanced relative bioavailability of sCT by 45-fold following intestinal administration in rats, without inducing irreversible damage to the intestinal epithelium. These results highlight the efficacy and potential of PPS as an excellent permeation enhancer which provides new opportunities for developing efficacious oral delivery systems for therapeutic macromolecules.