Formulation Technology Research Laboratories, Daiichi Sankyo., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.
Formulation Technology Research Laboratories, Daiichi Sankyo., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.
Colloids Surf B Biointerfaces. 2020 Nov;195:111215. doi: 10.1016/j.colsurfb.2020.111215. Epub 2020 Jul 1.
We quantitatively evaluated the properties of aggregates of amphiphilic polymers formed in an aqueous medium and clarified the effect of the inside polarity and viscosity of the polymer aggregate on the solubilization of poorly water-soluble drugs. Three water-soluble amphiphilic 2-methacryloyloxyethyl phosphorylcholine (MPC) polymers with various hydrophobic monomer units, namely, n-butyl methacrylate (BMA), 2-methacryloyloxyethyl butylurethane (MEBU), and 2-methacryloyloxyethyl benzylurethane (MEBZU), were synthesized. The different molecular interactions between the hydrophobic monomer units, such as hydrophobic interactions, hydrogen bonding, and dispersion force between the aromatic rings, were considered. Fluorescence spectroscopic measurements revealed that every polymer aggregate had almost the same polarity as that of ethanol. Also, the polymers with urethane bonds, poly(MPC-co-MEBU) and poly(MPC-co-MEBZU) had slightly higher polarity and viscosity inside the polymer aggregate than that of poly(MPC-co-BMA). The water solubility of nifedipine and indomethacin was clearly enhanced in the MPC polymer aqueous solution depending on the polymer structure. As indomethacin is less soluble in polar solvents than is nifedipine, it needed to be transferred deeper into the polymer aggregates for stable solubilization. It is plausible that the high viscosity inside the polymer aggregate prevented the diffusion of drug molecules. We concluded that not only the polarity inside the polymer aggregates and the strength of the interaction force between the polymer and drug, but also the viscosity inside the polymer aggregates were responsible for enhancing the solubilization of poorly water-soluble drugs.
我们定量评估了在水介质中形成的两亲聚合物聚集体的性质，并阐明了聚合物聚集体内部极性和粘度对难溶性药物增溶的影响。合成了三种水溶性两亲性 2-甲基丙烯酰氧乙基磷酰胆碱（MPC）聚合物，它们具有不同的疏水性单体单元，分别为甲基丙烯酸正丁酯（BMA）、2-甲基丙烯酰氧乙基丁基脲（MEBU）和 2-甲基丙烯酰氧乙基苄基脲（MEBZU）。考虑了疏水性单体单元之间的不同分子相互作用，如疏水相互作用、氢键和芳环之间的分散力。荧光光谱测量表明，每个聚合物聚集体的极性几乎与乙醇相同。此外，具有脲键的聚合物，聚（MPC-co-MEBU）和聚（MPC-co-MEBZU）的聚合物聚集体内部的极性和粘度略高于聚（MPC-co-BMA）。根据聚合物结构，硝苯地平和吲哚美辛在 MPC 聚合物水溶液中的溶解度明显提高。由于吲哚美辛在极性溶剂中的溶解度低于硝苯地平，因此需要更深地转移到聚合物聚集体中以实现稳定增溶。聚合物聚集体内部的高粘度可能阻止了药物分子的扩散。我们得出结论，不仅聚合物聚集体内部的极性和聚合物与药物之间相互作用力的强度，而且聚合物聚集体内部的粘度都负责增强难溶性药物的增溶。
