Stabilizing Effect of β-Cyclodextrin on Limaprost, a PGE1 Derivative, in Limaprost Alfadex Tablets (Opalmon®) in Highly Humid Conditions
Stabilizing Effect of β-Cyclodextrin on Limaprost, a PGE1 Derivative, in Limaprost Alfadex Tablets (Opalmon®) in Highly Humid Conditions
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DOI：
10.1248/cpb.c14-00150
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发表时间：
2014-08-01
影响因子：
1.7
通讯作者：
Uekama, Kaneto
中科院分区：
文献类型：
--
作者：
Inoue, Yasuo;Sekiya, Noboru;Uekama, Kaneto
目前以 Opalmon (R) 名义销售的利马前列素（一种前列腺素 E-1 衍生物）的湿度稳定性是使用 β-环糊精 (β-CD) 进行的。将利马前列素阿法葡聚糖/葡聚糖 40 的水溶液在有或没有β-CD的情况下冻干。含有 β-CD 的利马前列素阿法葡糖冻干粉在潮湿条件下比不含 β-CD 的冻干粉更稳定。此外，在这些冻干复合材料片剂中添加β-CD作为赋形剂显着提高了利马前列素的稳定性，并且这种防潮制剂中的利马前列素在30℃、75%相对湿度(R.H.)下化学稳定19周。利马前列素及其降解产物的化学分析表明，降解以包涵体形式进行（即在 CD 腔内）。固体 H-2-NMR 光谱研究表明，β-CD 限制了固态水的分子迁移率。这些结果表明，β-CD 对利马前列素的稳定作用至少部分归因于水的分子流动性受限，水充当降解的催化物质，并且还通过与 β-CD 形成包合络合物来保护利马前列素的五元环免受水催化脱水。
Stabilization against humidity of Limaprost (a prostaglandin E-1 derivative), which is currently marketed as Opalmon (R), was undertaken using beta-cyclodextrin (beta-CD). Aqueous solutions of Limaprost alfadex/dextran 40 were lyophilized with and without beta-CD. Limaprost alfadex lyophilized with beta-CD was more chemically stable in humid conditions than that without beta-CD. Moreover, the addition of beta-CD as an excipient to tablets of these lyophilized composites remarkably improved the stability of Limaprost, and Limaprost in this moisture-resistant formulation was chemically stable for 19 weeks at 30 degrees C, 75% relative humidity (R.H.). Chemical analysis of Limaprost and its degradation products indicated that degradation proceeded in the inclusion form (i.e., within the CD cavity). Solid H-2-NMR spectroscopic studies showed that beta-CD constrained the molecular mobility of water in the solid state. These results suggested that the stabilization of Limaprost by beta-CD was at least partly due to the restricted molecular mobility of water, which acted as a catalytic species for the degradation, and also to the protection of the five-membered ring of Limaprost from water catalytic dehydration through inclusion complex formation with beta-CD.