(185j) Design of Tunable Hpmcas-Inspired Polymers As Modular Oral Excipients to Deliver Poorly Water-Soluble Drugs

Authors: 
Ting, J. M., University of Minnesota
Navale, T. S., University of Minnesota
Bates, F. S., University of Minnesota
Reineke, T. M., University of Minnesota

Spray-dried dispersions (SDDs) have emerged as remarkable drug delivery materials for improving limited oral bioavailability and providing therapeutic safety with high patient compliance. In this approach, synthetic and natural polymers hold tremendous potential as excipients to solubilize potent but highly lipophilic drugs in pharmaceutical formulation by maintaining drug molecules in an amorphous state. Unfortunately, excipient selection currently takes an Edisonian trial-and-error approach with little to no potential of accurately predicting key thermodynamic and kinetic phenomena. Herein, we explore fundamental polymer-drug interactions through the controlled synthesis and study of a multicomponent acrylic polymer, inspired by hydroxypropyl methylcellulose acetate succinate (HPMCAS). By strategically varying the precise monomeric incorporation and chemistry of these modular HPMCAS analogs, we comprehensively examined the role of polymers in producing stable amorphous SDDs with a model hydrophobic drug (probucol) at 10, 25, and 50 wt % drug loadings. To assess the overall amorphicity and miscibility, a combination of scanning electron microscopy imaging, powder X-ray diffraction, modulated differential scanning calorimetry, and Fourier transform infrared spectroscopy was utilized. Dissolution experiments of these HPMCAS-based SDDs in solution revealed dramatic difference in drug release kinetics, supersaturation generation, and bioavailability as a function of polymeric chemical specificity. The solubility of unprocessed probucol was increased from 0.5% to ~100% drug release in the presence of engineered polymers, comparable to HPMCAS. We identify chemically-driven interactions as crucial ingredients for facilitating high initial release and supersaturation maintenance. In particular, modulating polymer swelling in aqueous media by (1) increasing the ionizable carboxylic acid moieties and (2) applying selective chemical deprotection of hydrophobic acetate groups provided electrostatic stability and access towards polymer-drug hydrogen bonding with complementary hydrophobic interactions. Our results show the practical utility of tunable polymeric excipients for elucidating important structure-property relationships to effectively solubilize and deliver otherwise intractable drugs.