title: High-Throughput Excipient Discovery Enables Oral Delivery of Poorly Soluble Pharmaceuticals.
abstract: Polymeric excipients are crucial ingredients in modern pills, increasing the therapeutic bioavailability, safety, stability, and accessibility of lifesaving products to combat diseases in developed and developing countries worldwide. Because many early-pipeline drugs are clinically intractable due to hydrophobicity and crystallinity, new solubilizing excipients can reposition successful and even failed compounds to more effective and inexpensive oral formulations. With assistance from high-throughput controlled polymerization and screening tools, we employed a strategic, molecular evolution approach to systematically modulate designer excipients based on the cyclic imide chemical groups of an important (yet relatively insoluble) drug phenytoin. In these acrylamide- and methacrylate-containing polymers, a synthon approach was employed: one monomer served as a precipitation inhibitor for phenytoin recrystallization, while the comonomer provided hydrophilicity. Systems that maintained drug supersaturation in amorphous solid dispersions were identified with molecular-level understanding of noncovalent interactions using NOESY and DOSY NMR spectroscopy. Poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (poly(NIPAm-co-DMA)) at 70 mol % NIPAm exhibited the highest drug solubilization, in which phenytoin associated with inhibiting NIPAm units only with lowered diffusivity in solution. In vitro dissolution tests of select spray-dried dispersions corroborated the screening trends between polymer chemical composition and solubilization performance, where the best NIPAm/DMA polymer elevated the mean area-under-the-dissolution-curve by 21 times its crystalline state at 10 wt % drug loading. When administered to rats for pharmacokinetic evaluation, the same leading poly(NIPAm-co-DMA) formulation tripled the oral bioavailability compared to a leading commercial excipient, HPMCAS, and translated to a remarkable 23-fold improvement over crystalline phenytoin.
authors: Department of Chemistry and Department of Chemical Engineering and Materials Science, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors: Jeffrey M
authors: JM
authors: Ting
authors: Department of Chemistry and Department of Chemical Engineering and Materials Science, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors: Swapnil
authors: S
authors: Tale
authors: Department of Chemistry and Department of Chemical Engineering and Materials Science, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors: Anatolii A
authors: AA
authors: Purchel
authors: Department of Chemistry and Department of Chemical Engineering and Materials Science, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors: Seamus D
authors: SD
authors: Jones
authors: Department of Chemistry and Department of Chemical Engineering and Materials Science, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors: Lakmini
authors: L
authors: Widanapathirana
authors: Department of Chemistry and Department of Chemical Engineering and Materials Science, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors: Zachary P
authors: ZP
authors: Tolstyka
authors: Corporate R&D, The Dow Chemical Company , Midland, Michigan 48674, United States.
authors: Li
authors: L
authors: Guo
authors: Corporate R&D, The Dow Chemical Company , Midland, Michigan 48674, United States.
authors: Steven J
authors: SJ
authors: Guillaudeu
authors: Department of Chemistry and Department of Chemical Engineering and Materials Science, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors: Frank S
authors: FS
authors: Bates
authors: Department of Chemistry and Department of Chemical Engineering and Materials Science, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors: Theresa M
authors: TM
authors: Reineke