背景:Empagliflozin(EMPA)是SGLT2抑制剂,一类新的抗糖尿病药物,用于治疗2型糖尿病。它的低渗透性,较差的溶解度和生物利用度限制了其在糖尿病治疗中的应用.该研究旨在配制负载EMPA的聚合物胶束(PM)以克服口服吸收中的这些障碍。
方法:计算机模拟研究-分子对接,分子动态模拟(MDS),通过量子化学计算研究了EMPA与不同聚合物的相互作用。通过直接溶解法配制了负载EMPA的TPGS聚合物胶束(EMPA-TPGS-PMs),并在表面形态方面进行了表征。诱捕,颗粒大小,体外药物释放,和体外细胞毒性(HEK293细胞)。还进行了体内药代动力学和药效学研究。
结果:结果表明,与其他聚合物相比,TPGS和EMPA之间的良好相互作用具有最低的结合能。进一步的MDS结果和DFT计算验证了复合物的稳定结合,因此选择TPGS用于进一步的湿实验室实验。EMPA-TPGS复合物显示的总能量(T.E.)值低于其单个组件,表明复合物的整体稳定性,两个单独分子之间的能带隙(ΔE)值,表示配合物的HOMO和LUMO之间更好的电子转移。基于溶解度,包埋和细胞毒性研究,选择5%TPGS用于配制载药胶束。EMPA-TPGS5-PM的尺寸为9.008±1.25nm,多分散指数(PDI)为0.254±0.100,控释行为长达24小时。纳米制剂的SEM和AFM图像表明球形颗粒,而DSC,和PXRD研究证实了EMPA结晶度的损失。与小鼠模型中的EMPA-SUSP相比,EMPA-TPGS5-PM表现出3.12倍高的AUC和更大的血糖水平降低。
结论:EMPA-TPGS-PMs在糖尿病治疗中表现出更好的生物吸收和治疗效果。这种改进的性能将打开剂量减少的可能性,减少给药频率和剂量相关的副作用,改善药物经济学,从而提高患者的总体依从性。然而,这种从长凳到床边的翻译需要在高等动物和人类志愿者中进行研究。
BACKGROUND: Empagliflozin (EMPA) is an SGLT2 inhibitor, a new class of anti-diabetic medication, indicated for treating type-2 diabetes. Its low permeability, poor solubility and bioavailability limits its use in management of diabetes. The study was aimed to formulate EMPA loaded polymeric micelles (PMs) to overcome these obstacles in oral absorption.
METHODS: In silico studies-molecular docking, molecular dynamic simulation (MDS), and quantum chemical calculation were employed to study the interaction of EMPA with different polymers. EMPA loaded TPGS polymeric micelles (EMPA-TPGS-PMs) were formulated by direct dissolution method and characterized in terms of surface morphology, entrapment, particle size, in vitro drug release, and in vitro cytotoxicity (HEK293 cells). In vivo pharmacokinetic and pharmacodynamic studies were also performed.
RESULTS: The results suggested a good interaction between TPGS and EMPA with lowest binding energy compared to other polymers. Further MDS results and DFT calculations validated the stable binding of the complex hence TPGS was selected for further wet lab experiments. The EMPA-TPGS complex displayed lower value of Total energy (T.E.) than its individual components, indicating the overall stability of the complex while, the energy band gap (∆E) value lied between the two individual molecules, signifying the better electron transfer between HOMO and LUMO of the complex. Based on the solubility, entrapment and cytotoxicity studies, 5% TPGS was selected for formulating drug loaded micelles. EMPA-TPGS5-PMs presented a size of 9.008 ± 1.25 nm, Polydispersity index (PDI) of 0.254 ± 0.100, a controlled release behaviour upto 24 h. SEM and AFM images of the nanoformulation suggested spherical particles whereas, DSC, and PXRD studies confirmed the loss of crystallinity of EMPA. A 3.12-folds higher AUC and a greater reduction in blood glucose levels was exhibited by EMPA-TPGS5-PMs in comparison to EMPA-SUSP in mice model.
CONCLUSIONS: EMPA-TPGS-PMs has exhibited better bio absorption and therapeutic effectiveness in diabetes treatment. This improved performance would open the possibility of dose reduction, reduced dosing frequency & dose-related side effects, improving pharmaco-economics and thereby improved overall compliance to the patient. However, this translation from bench to bedside would necessitate studies in higher animals and human volunteers.