Strategically-Designed Polymer Synthons As Pharmaceutical Excipients in Oral Drug Delivery

Synthetic polymer excipients, equipped with tunable structures and properties, can enable more bioavailable, inexpensive, and safe oral drug formulations when rationally designed to solubilize active pharmaceutical ingredients in amorphous solid dispersions. However, the underlying polymer-drug interactions in these materials to control drug supersaturation generation and maintenance currently remain poorly understood. We present a new approach to discover specialized excipients for a highly-crystalline drugs, driven by molecular evolution-inspired ideas to rapidly construct polymer synthons (macromolecules with structural subunits correlating to desired noncovalent interactions, analogous to the retrosynthetic analysis taught in organic chemistry) using high-throughput synthesis and screening protocols. In this manner, the molar mass and chemical composition state spaces were sampled to identify an optimal excipient synthon among 70 copolymers to solubilize phenytoin. The leading system contained N-isopropylacrylamide (NIPAm, responsible for inhibiting phenytoin crystallization) and N,N-dimethylacrylamide (DMA, providing polymer hydrophilicity), and polymer-drug interactions were revealed using NOESY and DOSY NMR spectroscopy. Complementary all-atom molecular dynamic simulations corroborated experimental evidence of NIPAm synthons strongly binding to phenytoin. When administered to rats, we observed a record 23-fold increase in area-under-the-curve bioavailability over neat drug with excellent in vitro-in vivo correlations. Altogether, these discoveries demonstrate how existing synthesis tools in the polymer chemistry landscape can accelerate the translation of new drug candidates (or even failed compounds) into more effective and accessible therapeutic treatments.