Lucio David, Irache Juan Manuel, Font María, Martínez-Ohárriz María Cristina
Department of Chemistry, Faculty of Sciences, University of Navarra, Irunlarrea s/n. Pamplona, 31080, Navarra, Spain.
Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy. University of Navarra. Irunlarrea s/n. Pamplona 31080, Navarra, Spain.
Int J Pharm. 2017 Mar 15;519(1-2):263-271. doi: 10.1016/j.ijpharm.2017.01.028. Epub 2017 Jan 19.
Glibenclamide is a sulfonylurea used for the oral treatment of type II diabetes mellitus. This drug shows low bioavailability as consequence of its low solubility. In order to solve this problem, the interaction with cyclodextrin has been proposed. This study tries to provide an explanation about the processes involved in the formation of GB-βCDs complexes, which have been interpreted in different ways by several authors. Among native cyclodextrins, βCD presents the most appropriate cavity to host glibenclamide molecules showing A solubility diagrams (K≈1700M). However, [Formula: see text] solubility profiles were found for βCD derivatives, highlighting the coexistence of several phenomena involved in the drug solubility enhancement. At low CD concentration, the formation of inclusion complexes can be studied and the stability constants can be calculated (K≈1400M). Whereas at high CD concentration, the enhancement of GB solubility would be mainly attributed to the formation of nanoaggregates of CD and GB-CD complexes (sizes between 100 and 300nm). The inclusion mode into βCD occurs through the cyclohexyl ring of GB, adopting a semi-folded conformation which maximizes the hydrogen bond network. As consequence of all these phenomena, a 150-fold enhancement of drug solubility has been achieved using β-cyclodextrin derivatives. Thus, its use has proven to be an interesting tool to improve the oral administration of glibenclamide in accordance with dosage bulk and dose/solubility ratio requirements.
格列本脲是一种用于口服治疗II型糖尿病的磺酰脲类药物。由于其低溶解度，该药物的生物利用度较低。为了解决这个问题，有人提出了其与环糊精的相互作用。本研究试图对格列本脲-β-环糊精复合物形成过程中涉及的机制作出解释，几位作者对这些机制有不同的解读。在天然环糊精中，β-环糊精具有最合适的空腔来容纳格列本脲分子，溶解度图显示（K≈1700M）。然而，对于β-环糊精衍生物，发现了[公式：见原文]溶解度曲线，突出了药物溶解度提高过程中涉及的几种现象的共存。在低环糊精浓度下，可以研究包合物的形成并计算其稳定常数（K≈1400M）。而在高环糊精浓度下，格列本脲溶解度的提高主要归因于环糊精和格列本脲-β-环糊精复合物纳米聚集体的形成（尺寸在100至300nm之间）。格列本脲进入β-环糊精的包合模式是通过其环己基环实现的，采用半折叠构象，使氢键网络最大化。由于所有这些现象，使用β-环糊精衍生物可使药物溶解度提高150倍。因此，根据剂量体积和剂量/溶解度比的要求，其应用已被证明是改善格列本脲口服给药的一种有效手段。
