Mucin Mimics and Impacts the Function of Polymeric Inhibitors in Stabilizing Drug Supersaturation.

Abstract

Many drugs entering clinical trials today are poorly water-soluble and rely on supersaturating formulations, such as amorphous solid dispersions (ASD) to enhance their bioavailability. The in vivo performance of these formulations is often investigated through biorelevant dissolution testing using simulated intestinal fluid. Often overlooked in biorelevant dissolution is the presence of mucus within the intestinal environment and its possible role in affecting the formulation performance. In this study, the impact of mucins, the main structural glycoproteins of mucus, on the precipitation of two model compounds, carvedilol and nifedipine, from supersaturated solutions was investigated. The presence of mucin within the supersaturated environment was demonstrated to significantly alter the rate of drug precipitation in vitro. The impact of mucin on precipitation was then compared to commercially available polymer precipitation inhibitors hydroxypropyl methylcellulose (HPMC) and Kollidon VA 64, which are commonly used in ASD formulations. Surprisingly, when present at the same concentration (0.2% (w/v)), mucin reduces drug precipitation to an extent comparable to that of polymer precipitation inhibitors. Additionally, we observed that the presence of mucin in the supersaturated environment altered the precipitation inhibitory effects of HPMC and Kollidon VA64, suggesting that mucin could play an important and complicated role in formulation performance in the intestine.