Ueda Keisuke, Higashi Kenjirou, Moribe Kunikazu
Graduate School of Pharmaceutical Sciences, Chiba University , 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
Mol Pharm. 2017 Jul 3;14(7):2314-2322. doi: 10.1021/acs.molpharmaceut.7b00178. Epub 2017 Jun 6.
We investigated the phase separation behavior and maintenance mechanism of the supersaturated state of poorly water-soluble nifedipine (NIF) in hypromellose (HPMC) derivative solutions. Highly supersaturated NIF formed NIF-rich nanodroplets through phase separation from aqueous solution containing HPMC derivative. Dissolvable NIF concentration in the bulk water phase was limited by the phase separation of NIF from the aqueous solution. HPMC derivatives stabilized the NIF-rich nanodroplets and maintained the NIF supersaturation with phase-separated NIF for several hours. The size of the NIF-rich phase was different depending on the HPMC derivatives dissolved in aqueous solution, although the droplet size had no correlation with the time for which NIF supersaturation was maintained without NIF crystallization. HPMC acetate and HPMC acetate succinate (HPMC-AS) effectively maintained the NIF supersaturation containing phase-separated NIF compared with HPMC. Furthermore, HPMC-AS stabilized NIF supersaturation more effectively in acidic conditions. Solution H NMR measurements of NIF-supersaturated solution revealed that HPMC derivatives distributed into the NIF-rich phase during the phase separation of NIF from the aqueous solution. The hydrophobicity of HPMC derivative strongly affected its distribution into the NIF-rich phase. Moreover, the distribution of HPMC-AS into the NIF-rich phase was promoted at lower pH due to the lower aqueous solubility of HPMC-AS. The distribution of a large amount of HPMC derivatives into NIF-rich phase induced the strong inhibition of NIF crystallization from the NIF-rich phase. Polymer distribution into the drug-rich phase directly monitored by solution NMR technique can be a useful index for the stabilization efficiency of drug-supersaturated solution containing a drug-rich phase.
我们研究了难溶性硝苯地平（NIF）在羟丙甲纤维素（HPMC）衍生物溶液中的相分离行为及过饱和状态的维持机制。高度过饱和的NIF通过从含有HPMC衍生物的水溶液中相分离形成富含NIF的纳米液滴。本体水相中可溶解的NIF浓度受NIF从水溶液中相分离的限制。HPMC衍生物使富含NIF的纳米液滴稳定，并使相分离的NIF的NIF过饱和度维持数小时。尽管液滴大小与NIF过饱和状态在无NIF结晶情况下维持的时间无关，但富含NIF相的大小因溶解在水溶液中的HPMC衍生物不同而有所差异。与HPMC相比，醋酸羟丙甲纤维素和醋酸琥珀酸羟丙甲纤维素（HPMC-AS）能有效维持含有相分离NIF的NIF过饱和度。此外，HPMC-AS在酸性条件下能更有效地稳定NIF过饱和度。对NIF过饱和溶液的溶液1H NMR测量表明，在NIF从水溶液中相分离过程中，HPMC衍生物分布到富含NIF的相中。HPMC衍生物的疏水性强烈影响其向富含NIF相中的分布。此外，由于HPMC-AS在水中的溶解度较低，在较低pH值下HPMC-AS向富含NIF相中的分布会增加。大量HPMC衍生物分布到富含NIF的相中会强烈抑制NIF从富含NIF的相中结晶。通过溶液NMR技术直接监测聚合物在富含药物相中的分布，可作为含有富含药物相的药物过饱和溶液稳定效率的有用指标。
