Moribe Kunikazu, Sekiya Noboru, Fujito Takayuki, Yamamoto Masanobu, Higashi Kenjiro, Yokohama Chihiro, Tozuka Yuichi, Yamamoto Keiji
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan.
Int J Pharm. 2007 Jun 29;338(1-2):1-6. doi: 10.1016/j.ijpharm.2006.12.047. Epub 2007 Feb 12.
The effect of polymeric pharmaceutical excipients on the degradation of limaprost by hydrolysis was assessed by near infrared (NIR) spectroscopy and spin-spin relaxation time (T(2)) measurements of proton NMR. Freeze-dried limaprost-alfadex formulated with various polymeric pharmaceutical excipients was exposed under humidified condition at 25 degrees C and 75% relative humidity. The freeze-dried limaprost-alfadex formulated with cellulose derivatives, hydroxypropylmethylcellulose (HPMC) and hydroxypropylcellulose (HPC-L), degraded easily. However, degradation was suppressed in samples formulated with polysaccharides, dextran40, dextrin, and pullulan, although the water sorption was more than 10% (w/w). A second-derivative NIR study showed the changes in the water mobility in the mixtures. The absorption peak near 1900nm, which was assigned to water with high mobility, was observed in the humidified HPMC and HPC-L. The proton NMR spin-spin relaxation time measurements indicated that the structural relaxation of a polymeric excipient changed upon humidification. The polysaccharides showed only Gaussian relaxations, but the cellulose derivatives showed Lorentzian relaxations and Gaussian relaxations. The T(2) values of the Gaussian relaxation in HPMC and HPC-L were higher than those in dextran40, dextrin, and pullulan throughout the humidifying period. The higher molecular mobility of HPMC and HPC-L is related to the mobility of water, which may accelerate limaprost degradation.
通过近红外（NIR）光谱和质子核磁共振的自旋-自旋弛豫时间（T(2)）测量，评估了高分子药用辅料对利马前列素水解降解的影响。将用各种高分子药用辅料配制的冻干利马前列素-阿尔法环糊精在25℃和75%相对湿度的潮湿条件下暴露。用纤维素衍生物羟丙基甲基纤维素（HPMC）和羟丙基纤维素（HPC-L）配制的冻干利马前列素-阿尔法环糊精很容易降解。然而，在用多糖、右旋糖酐40、糊精和支链淀粉配制的样品中，降解受到抑制，尽管吸水量超过10%（w/w）。二阶导数近红外研究显示了混合物中水流动性的变化。在潮湿的HPMC和HPC-L中观察到1900nm附近的吸收峰，该峰归属于高流动性的水。质子核磁共振自旋-自旋弛豫时间测量表明，高分子辅料的结构弛豫在加湿时发生了变化。多糖仅表现出高斯弛豫，而纤维素衍生物表现出洛伦兹弛豫和高斯弛豫。在整个加湿期间，HPMC和HPC-L中高斯弛豫的T(2)值高于右旋糖酐40、糊精和支链淀粉中的T(2)值。HPMC和HPC-L较高的分子流动性与水的流动性有关，这可能会加速利马前列素的降解。
