Pradines Bénédicte, Gallard Jean-François, Iorga Bogdan I, Gueutin Claire, Ponchel Gilles, Loiseau Philippe M, Bouchemal Kawthar
Institut Galien Paris Sud, UMR CNRS 8612, Université Paris-Sud, Faculté de Pharmacie, 5, rue J-B. Clément, 92296, Chatenay-Malabry cedex, France; BioCis, Biomolécules : conception, isolement, synthèse-Chimiothérapie Antiparasitaire, UMR CNRS 8076, Université Paris-Sud, Faculté de Pharmacie, 5, rue J-B. Clément, 92296, Châtenay-Malabry cedex, France.
J Mol Recognit. 2015 Feb;28(2):96-102. doi: 10.1002/jmr.2432. Epub 2015 Jan 21.
Clotrimazole (CTZ) and cyclodextrin (CD) inclusion complexes having improved apparent water solubility were obtained from phase solubility diagrams. β-CD (1.5% w/w) and hydroxypropyl-β-CD (40% w/w) offered poor CTZ solubility enhancements (12 and 384 times, respectively). Unexpectedly, the apparent solubility of CTZ was 9980 times increased from 0.4 µg.mL(-1) (1.42 μM) without CD to 4.89 mg.mL(-1) (14.9 mM) using randomly-methylated β-CD (Me-β-CD) (40% w/w). This is the highest apparent CTZ solubility improvement ever reported in the literature using conventional CDs. Quantitative nuclear magnetic resonance ((1) H-NMR) coupled with two-dimensional nuclear Overhauser effect (NOESY) experiments and molecular docking calculations showed that the highest interactions with Me-β-CD were reported for CTZ two phenyl groups. A lower interaction was reported for chlorophenyl, while imidazole had the weakest interaction with Me-β-CD.
从相溶解度图中获得了具有改善的表观水溶性的克霉唑（CTZ）与环糊精（CD）包合物。β-环糊精（1.5% w/w）和羟丙基-β-环糊精（40% w/w）对CTZ溶解度的提高效果较差（分别为12倍和384倍）。出乎意料的是，使用随机甲基化β-环糊精（Me-β-CD）（40% w/w）时，CTZ的表观溶解度从无CD时的0.4 µg.mL(-1)（1.42 μM）增加到4.89 mg.mL(-1)（14.9 mM），提高了9980倍。这是文献中使用传统环糊精报道的CTZ表观溶解度提高的最高值。定量核磁共振（(1) H-NMR）结合二维核Overhauser效应（NOESY）实验和分子对接计算表明，CTZ的两个苯基与Me-β-CD的相互作用最强。氯苯基的相互作用较弱，而咪唑与Me-β-CD的相互作用最弱。
