Bottlebrush polymers have great potential as vehicles to noncovalently sequester, stabilize, and deliver active pharmaceutical ingredients for oral drug delivery. To this end, bottlebrush copolymers of poly(N-isopropylacrylamide-stat-N,N-dimethylacrylamide) (PND) have been synthesized to be used as polymer excipients to promote the solubilization and prevent the crystallization of small molecule therapeutics using polymer amorphous spray-dried dispersions (PASDs). Post-polymerization end-group modification of the PND bottlebrush copolymer side chains, modulated the hydrophilicity and thermoresponsive properties that were optimized to solubilize an orally administered antiseizure medication and breast cancer therapeutic. The bottlebrushes were observed to solubilize the drugs in solution as unimolecular drug-loaded nanoparticles at drug loadings of 25wt% and higher using dynamic light scattering and cryogenic transmission electron microscopy. It has been widely observed that effective PASDs assemble into amorphous nanostructures in solution to solubilize small-molecule actives. However, it has yet to be well understood how the formation of liquid-liquid phase separated nanodroplets vs. amorphous drug-polymer nanoparticles impacts the bioavailability of small molecule actives. Therefore, we thoroughly characterized the phenotype of amorphous nanostructures formed in solution during ASD dissolution between an orally administered breast cancer therapeutic, GDC-0810, and a library of commercial linear polymer and end-group modified bottlebrush copolymer excipients. The resulting insight was then used to interpret the differences in bioavailability observed through in vivo pharmacokinetic studies and in vitro permeation assays as a function of nanostructure formation.

End-Group modified bottlebrush copolymers to deliver active pharmaceutical ingredients

ACS Spring 2022

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