title: Enhanced Performance of Blended Polymer Excipients in Delivering a Hydrophobic Drug through the Synergistic Action of Micelles and HPMCAS.
abstract: Blends of hydroxypropyl methylcellulose acetate succinate (HPMCAS) and dodecyl (C12)-tailed poly(N-isopropylacrylamide) (PNIPAm) were systematically explored as a model system to dispense the active ingredient phenytoin by rapid dissolution, followed by the suppression of drug crystallization for an extended period. Dynamic and static light scattering revealed that C12-PNIPAm polymers, synthesized by reversible addition-fragmentation chain-transfer polymerization, self-assembled into micelles with dodecyl cores in phosphate-buffered saline (PBS, pH 6.5). A synergistic effect on drug supersaturation was documented during in vitro dissolution tests by varying the blending ratio, with HPMACS primarily aiding in rapid dissolution and PNIPAm maintaining supersaturation. Polarized light and cryogenic transmission electron microscopy experiments revealed that C12-PNIPAm micelles maintain drug supersaturation by inhibiting both crystal nucleation and growth. Cross-peaks between the phenyl group of phenytoin and the isopropyl group of C12-PNIPAm in 2D1H nuclear Overhauser effect (NOESY) spectra confirmed the existence of drug-polymer intermolecular interactions in solution. Phenytoin and polymer diffusion coefficients, measured by diffusion-ordered NMR spectroscopy (DOSY), demonstrated that the drug-polymer association constant increased with increasing local density of the corona chains, coincident with a reduction in C12-PNIPAm molecular weight. These findings demonstrate a new strategy for exploiting the versatility of polymer blends through the use of self-assembled micelles in the design of advanced excipients.
authors.affiliation: Department of Chemical Engineering and Materials Science and ‡Department of Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Ziang
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Chemical Engineering and Materials Science and ‡Department of Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Lindsay M
authors.identifier: 0000-0001-6702-6406
authors.initials: LM
authors.lastname: Johnson
authors.affiliation: Department of Chemical Engineering and Materials Science and ‡Department of Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Ralm G
authors.initials: RG
authors.lastname: Ricarte
authors.affiliation: Department of Chemical Engineering and Materials Science and ‡Department of Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Letitia J
authors.initials: LJ
authors.lastname: Yao
authors.affiliation: Department of Chemical Engineering and Materials Science and ‡Department of Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Marc A
authors.identifier: 0000-0001-8255-3853
authors.initials: MA
authors.lastname: Hillmyer
authors.affiliation: Department of Chemical Engineering and Materials Science and ‡Department of Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Frank S
authors.identifier: 0000-0003-3977-1278
authors.initials: FS
authors.lastname: Bates
authors.affiliation: Department of Chemical Engineering and Materials Science and ‡Department of Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Timothy P
authors.identifier: 0000-0001-5916-8834
authors.initials: TP
authors.lastname: Lodge
mesh_terms: D000178:Acrylamides / Q000737:chemistry; D000180:Acrylic Resins / Q000737:chemistry; D005079:Excipients / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D008747:Methylcellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D008823:Micelles; D010672:Phenytoin / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*
chemical_list: D000178:Acrylamides; D000180:Acrylic Resins; D005079:Excipients; D008823:Micelles; D011108:Polymers; C052970:poly-N-isopropylacrylamide; D010672:Phenytoin; C048331:hydroxypropylmethylcellulose acetate succinate; D008747:Methylcellulose; C067295:N-isopropylacrylamide