Antihypertensive activity and molecular interactions of irbesartan in complex with 2-hydroxypropyl-β-cyclodextrin
Antihypertensive activity and molecular interactions of irbesartan in complex with 2-hydroxypropyl-β-cyclodextrin
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DOI：
10.1111/cbdd.13664
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发表时间：
2020-07-01
影响因子：
3
通讯作者：
Liapakis, Georgios
中科院分区：
文献类型：
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作者：
Leonis, Georgios;Christodoulou, Eirini;Liapakis, Georgios
厄贝沙坦（IRB）单独或与其他药物联合对许多疾病（如癌症、糖尿病和高血压）发挥有益作用。然而，由于其高亲脂性，IRB不具有最佳药理学效率。为了避免这个问题，探索了具有2-羟丙基-β-环糊精（2-HP-β-CD）的药物递送系统。通过ESI QTF HRMS鉴定了IRB与2-HP-β-CD之间的1：1复合物。溶出研究显示，在pH = 1.2时，冻干IRB-2-HP-β-CD复合物的溶出速率高于含有IRB的片剂。DSC结果显示复合物和由两种组分即IRB和2-HP-β-CD组成的各种混合物之间的热性质的差异。有趣的是，根据混合物制备的方式，观察到两种组分之间的不同缔合。分子动力学（MD）模拟预测了上述复合物的有利形成，并确定了IRB与2-HP-β-CD之间的主要相互作用。体外药理学结果证实，包合物不仅保留了IRB与AT 1 R受体的结合亲和力，而且略有增加。我们的方法是一个有前途的新方法，以提高内部评级法的效率。
Irbesartan (IRB) exerts beneficial effects either alone or in combination with other drugs on numerous diseases, such as cancer, diabetes, and hypertension. However, due to its high lipophilicity, IRB does not possess the optimum pharmacological efficiency. To circumvent this problem, a drug delivery system with 2-hydroxypropyl-beta-cyclodextrin (2-HP-beta-CD) was explored. The 1:1 complex between IRB and 2-HP-beta-CD was identified through ESI QTF HRMS. Dissolution studies showed a higher dissolution rate of the lyophilized IRB-2-HP-beta-CD complex than the tablet containing IRB at pH = 1.2. DSC results revealed the differences of the thermal properties between the complex and various mixtures consisting of the two components, namely IRB and 2-HP-beta-CD. Interestingly, depending on the way the mixture preparation was conducted, different association between the two components was observed. Molecular dynamics (MD) simulations predicted the favorable formation of the above complex and identified the dominant interactions between IRB and 2-HP-beta-CD.In vitropharmacological results verified that the inclusion complex not only preserves the binding affinity of IRB for AT1R receptor, but also it slightly increases it. As the complex formulation lacks the problems of the tablet, our approach is a promising new way to improve the efficiency of IRB.