Oral drug delivery is the most common form of medication administration worldwide. However, very few small molecule therapeutics can be successfully formulated for oral administration without the use of polymer additives called excipients. Recent work has discovered a linear statistical copolymer excipient, composed of 70 mol% N-isopropylacrylamide (NIPAm) and 30 mol% N,N-dimethylacrylamide (DMA), able to efficiently maintain the aqueous solubility of poorly water-soluble active pharmaceutical ingredients (APIs). While this excipient out performs current excipients on the market, it is unable to accommodate high drug loadings and the mechanism of solubilization is not well understood. Therefore, to further probe the mechanism of API solubilization and determine key variables to optimize the performance at higher drug loadings, bottlebrush polymers were used as a robust synthetic platform to investigate the roles of nanoparticle formation and end-group composition. Herein, 70 mol% NIPAm containing poly(NIPAm-co-DMA) bottlebrush copolymers were synthesized using grafting-through methods. Norbornene functionalized linear macromonomers were synthesized using radical addition-fragmentation chain transfer polymerization and stitched together using ring-opening metathesis polymerization to form the bottlebrush architecture. Post-polymerization modification was used to install increasingly hydrophilic moieties at the ω-terminus of each side chain (-H, -OH, -methyl-PEG, -hydroxy-PEG, and -COOH). The increasing hydrophilicity of the bottlebrush polymers was shown to directly modulate the thermoresponsive behavior which was manifested as increasing dissolution effectiveness of the bottlebrush polymer excipients with a poorly-water soluble API. The top performing end-group modified bottlebrush was also tested at higher drug loadings and shown to out-perform the linear copolymer control. In this talk, the influence of each end-group functionality will be discussed in the context of bottlebrush polymer colloidal stability, thermoresponsiveness, and ultimately, solubility enhancement of the antiseizure medication, phenytoin, using polymer amorphous spray-dried dispersions.

Thermoresponsive bottlebrush polymers for oral drug delivery: Influence of end-group hydrophobicity and hydrophilicity

ACS Spring Meeting 2021

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