Development of an Extended Release Nafamostat Formulation for Prescription Drug Overdose Protection

Prescription opioid abuse and overdose are major society burdens, resulting in significant costs, illnesses, and deaths.

PF614, an oxycodone-derived prodrug, was designed to reduce abuse as it requires exposure to trypsin in the small intestine to release oxycodone. Injection, insufflation, plugging, and dose dumping are not possible means of abuse of PF-614 due to its molecular design.

MPAR® (Figure 1) is a combination of Trypsin Activation Abuse Protection (TAAPTM) (Figure 2) prodrug platform (PF614) and a protease inhibitor (nafamostat) that provides overdose protection at a molecular level.

The short half-life of nafamostat required development of an extended release (ER) formulation to ensure trypsin inhibition is maintained for the duration that PF614 prodrug is transiting the small intestine.

Optimization of the PF614-MPAR formulation with evaluation of several variables including ER nafamostat release rate (modified by bead coating), ER and immediate release (IR) nafamostat dose ratio, and PF614:nafamostat dose ratio, is described.