Stabilizing and Solubilizing Effects of Sulfobutyl Ether β-Cyclodextrin on Prostaglandin E1 Analogue
Stabilizing and Solubilizing Effects of Sulfobutyl Ether β-Cyclodextrin on Prostaglandin E1 Analogue
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磺丁基醚β-环糊精对前列腺素E1类似物的稳定和增溶作用
DOI：
10.1023/a:1013034615464
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发表时间：
2001
影响因子：
3.7
通讯作者：
H. Terashima
中科院分区：
文献类型：
--
作者：
K. Uekama;Yukako Hieda;F. Hirayama;H. Arima;M. Sudoh;A. Yagi;H. Terashima
用途：已知母体环糊精在中性和碱性溶液中能加速E型洋地黄素的降解，如脱水和异构化。本研究的目的是尝试通过生物相容性环糊精衍生物稳定和增溶E1型前列腺素类似物在水溶液中。方法。E1型前列腺素甲基7-[（1R、2R、3R）-3-羟基-2-[（E）-（3S）-3-羟基-4-用光谱法和溶解度法研究了1-丁烯基]-5-氧代环戊基]-5-硫代庚酸酯（MEester）与环糊精（CyDs）的相互作用。结果：1H-NMR研究表明，MEester与α-、β-和γ-CyD在溶液中形成1：1的包合物，其中α-CyD与药物的含甲酯基的α-侧链相互作用，而β-和γ-CyD优先包合在药物的五元环周围和两侧链。母体α-CyD和亲水性衍生物如2-羟丙基-α-和-β-CyD、磺丁基醚β-CyD（SBE-β-CyD）和麦芽糖基β-CyD对MEester的增溶能力高于母体β-和γ-CyD。在中性和碱性条件下，SBE-β-CyD和2，6-二甲基-β-CyD（DM-β-CyD）能显著减缓MEester的降解，尤其是碱催化脱水，而其他CyD则能加速MEester的降解。结论：SBE-β-CyD对MEester有较好的稳定性和增溶作用，具有较低的溶血活性和较低的毒性，可作为MEester注射剂的药物载体。此外，SBE-β-CyD可以用作药物的稳定剂，所述药物经受碱催化降解，这可能是因为磺丁基部分的阴离子电荷与催化阴离子物质如氢氧根离子之间的电排斥。
Purpose.Parent cyclodextrins are known to accelerate the degradations such as dehydration and isomerization of E-type prostaglandins in neutral and alkaline solutions. The objective of this study was to attempt the stabilization and solubilization of E1-type prostaglandin analogue in aqueous solution by biocompatible cyclodextrin derivatives.Methods.The interaction of an E1-type prostaglandin, methyl 7-[(1R,2R,3R)-3-hydroxy-2-[(E)-(3S)-3-hydroxy-4-(m-methoxymethylphenyl)1-butenyl]-5-oxocyclopentyl]-5-thiaheptanoate (MEester) with cyclodextrins (CyDs) was studied by spectroscopies and the solubility method. The degradation of MEester was monitored by high-performance liquid chromatography.Results.1H-nuclear magnetic resonance spectroscopic studies indicated that MEester forms 1:1 inclusion complexes with α-, β-, and γ-CyDs in solutions, where α-CyD interacts with the α-side chain containing methyl ester moiety of the drug, whereas β- and γ-CyDs preferentially include around the five-membered ring and both side chains of the drug. Parent α-CyD and hydrophilic derivatives, such as 2-hydoxypropyl-α- and -β-CyDs, sulfobutyl ether β-CyD (SBE-β-CyD) and maltosyl β-CyD showed higher solubilizing abilities against MEester over parent β- and γ-CyDs. SBE-β-CyD and 2,6-dimethyl-β-CyD (DM-β-CyD) significantly decelerated the degradation of MEester, particularly the base-catalyzed dehydration, in neutral and alkaline solutions, whereas other CyDs accelerated the degradation. The acid-catalyzed degradation of MEester (pH < 3) was decelerated by the addition of CyDs, especially α-CyD.Conclusions.SBE-β-CyD with low hemolytic activity and low toxicity is useful as a pharmaceutical carrier for the preparation of injectable MEester, because of its higher stabilizing and solubilizing effects on MEester. Furthermore, SBE-β-CyD can be useful as a stabilizing agent for drugs, that are subject to base-catalyzed degradations, probably because of the electric repulsion between anionic charges of the sulfobutyl moiety and catalytic anionic species such as hydroxide ion.
DOI：
10.1248/bpb1978.4.879
发表时间：
1981-01-01
期刊：
JOURNAL OF PHARMACOBIO-DYNAMICS
影响因子：
--
作者：
YAMAOKA, K;TANIGAWARA, Y;UNO, T
通讯作者：
UNO, T