Synthetic polymers have enabled amorphous solid dispersions to emerge as a strategy for overcoming poor solubility and bioavailability of intractable drugs via oral administration. In such formulations, polymeric carriers generate and maintain supersaturation of drugs via noncovalent interactions, which serve to increase the apparent drug solubility upon dissolution and enhance gastrointestinal absorption and oral bioavailability. In this work, we use controlled polymerization to create a family of multicomponent copolymers containing numerous functional groups that promote hydrogen bonding and hydrophobic interactions with several drug structures such as phenytoin and nilutamide. Through systematic characterization and screening we show that macromolecular design parameters with comomoners significantly improve efficacy by using: i) one monomer to serve as a precipitation inhibitor that discourages drug recrystallization and ii) another comonomer to provide hydrophilicity and solubility of the hierarchical system. Systems that maintained drug supersaturation in amorphous solid dispersions were identified with molecular-level understanding of noncovalent interactions using NOESY and DOSY NMR spectroscopy. Through this approach, effective polymers have been discovered that promote high drug solubilization and in vivo efficacy such as a Poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (poly(NIPAm-co-DMA)). In vitro dissolution tests and in vivo pharmacokinetics of select spray-dried dispersions created via this approach have shown polymer chemical composition and solubilization performance relationships, which will be discussed in detail.

Synthetic and compositional control of multicompontent copolymers to promote drug solubility, bioavailability, and delivery

2019 Spring National Meeting

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