Department of Chemical Engineering and Materials Science and ‡Department of Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
Langmuir. 2017 Mar 21;33(11):2837-2848. doi: 10.1021/acs.langmuir.7b00325. Epub 2017 Mar 10.
Blends of hydroxypropyl methylcellulose acetate succinate (HPMCAS) and dodecyl (C)-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 C-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 C-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 C-PNIPAm in 2D H 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 C-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.
羟丙甲纤维素醋酸琥珀酸酯（HPMCAS）和十二烷基（C）尾聚（N-异丙基丙烯酰胺）（PNIPAm）的混合物被系统地探索为一种模型体系，通过快速溶解来分配活性成分苯妥英，并随后抑制药物结晶延长时间。动态和静态光散射表明，通过可逆加成-断裂链转移聚合合成的 C-PNIPAm 聚合物在磷酸盐缓冲盐水（PBS，pH6.5）中自组装成具有十二烷基核的胶束。通过改变共混比，在体外溶解试验中记录到药物过饱和度的协同效应，其中 HPMACS 主要有助于快速溶解，而 PNIPAm 则维持过饱和度。偏光和低温透射电子显微镜实验表明，C-PNIPAm 胶束通过抑制晶体成核和生长来维持药物过饱和度。在二维 H 核 Overhauser 效应（NOESY）谱中，苯妥英的苯基和 C-PNIPAm 的异丙基之间的交叉峰证实了溶液中药物-聚合物分子间相互作用的存在。通过扩散排序 NMR 光谱（DOSY）测量的苯妥英和聚合物扩散系数表明，药物-聚合物缔合常数随冠链局部密度的增加而增加，与 C-PNIPAm 分子量的降低一致。这些发现证明了一种通过使用自组装胶束设计先进赋形剂来利用聚合物共混物多功能性的新策略。
