A fundamental understanding of the effects of polymer microstructure and polymer-drug interactions on in vitro drug release kinetics in bioerodible polyanhydrides

This research aims to create an experimental and theoretical framework to investigate the effects of polymer microstructure on controlled drug delivery from bioerodible polyanhydride copolymers of poly(l,6-bis-p-carboxyphenoxy hexane-co-sebacic anhydride) (CPH:SA). The central hypothesis is that microphase separation is driven by both copolymer composition and difference in hydrophobicity of the two monomers, and drugs will thermodynamically partition into the phase-separated micro-domains. Four specific areas were investigated to fulfill the overall objective: microstructural characterization; in vitro release kinetics; mathematical modeling; and microsphere fabrication.; Several characterization methods (DSC, WAXD, SAXS, AFM, 1NMR) were used to study polyanhydride microstructure, and showed that both 20:80 and 80:20 CPH:SA copolymers exhibit microphase separation driven by differences in hydrophobicity and tend toward a “block-like” microstructure. The model drugs p-nitroaniline (PNA), disperse yellow 3 (DY), and brilliant blue (BB) were found to thermodynamically partition into the micro-domains according to compatibility with the phases in the microphase-separated copolymers.; The kinetics of in vitro monomer and drug release revealed that for homogeneous polymers, excellent correlation between polymer degradation and drug release was observed for both PNA and DY. In heterogeneous copolymers, a burst effect was observed when incompatible drugs were loaded into the microphase-separated polymer. Based on these results, the following mechanism was proposed: A drug molecule, when loaded into a polymer, will distribute itself into compatible regions (based on the relative hydrophobicity) until saturation is reached; excess drug will disperse itself into less compatible regions, resulting in a pronounced burst effect.; A mathematical model was developed to describe drug and monomer release from the microphase-separated copolymers. The model hypothesizes that the erosion rate constant for each monomer controls the evolution of the polymer microstructure, and hence monomer and drug release. Monomer and drug release predictions were compared with experimental data and provided promising results.; Finally, microsphere formulations were prepared to obtain a specific release profile consisting of an initial burst followed by zero-order release within the therapeutic range. Microsphere morphology and size was characterized by SEM and particle size analysis. Tailored release profiles were obtained by creating microsphere “cocktails,” given microspheres of varying timescales of release.