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用于口服给药的坎地沙坦酯固体脂质纳米粒:表征、药代动力学和药效学评价

Candesartan cilexetil loaded solid lipid nanoparticles for oral delivery: characterization, pharmacokinetic and pharmacodynamic evaluation.

作者信息

Dudhipala Narendar, Veerabrahma Kishan

机构信息

a Department of Nanotechnology , University College of Pharmaceutical Sciences, Kakatiya University , Warangal , Andra Pradesh , India.

出版信息

Drug Deliv. 2016;23(2):395-404. doi: 10.3109/10717544.2014.914986. Epub 2014 May 28.

Abstract

Candesartan cilexetil (CC) is used in the treatment of hypertension and heart failure. It has poor aqueous solubility and low oral bioavailability. In this work, CC loaded solid lipid nanoparticles (CC-SLNs) were developed to improve the oral bioavailability. Components of the SLNs include either of trimyristin/tripalmitin/tristearin, and surfactants (Poloxamer 188 and egg lecithin E80). The CC loaded nanoparticles were prepared by hot homogenization followed by ultrasonication method. The physicochemical properties, morphology of CC-SLNs were characterized, the pharmacokinetic and pharmacodynamic behaviour of CC-SLNs were evaluated in rats. Stable CC-SLNs having a mean particle size of 180-220 nm with entrapment efficiency varying in between 91-96% were developed. The physical stability of optimized formulation was studied at refrigerated and room temperature for 3 months. Further, freeze drying was tried for improving the physical stability. DSC and XRD analyses indicated that the drug incorporated into SLN was in amorphous form but not in crystalline state. The SLN-morphology was found to be nearly spherical by electron microscopic studies. Pharmacokinetic results indicated that the oral bioavailability of CC was improved over 2.75-fold after incorporation into SLNs. Pharmacodynamic study of SLNs in hypertensive rats showed a decrease in systolic blood pressure for 48 h, while suspension showed a decrease in systolic blood pressure for only 2 h. Taken together, these effects are due to enhanced bioavailability coupled with sustained action of CC in SLN formulation. Thus, the results conclusively demonstrated the role of CC-SLNs for a significant enhancement in oral bioavailability along with improved pharmacodynamic effect.

摘要

坎地沙坦酯(CC)用于治疗高血压和心力衰竭。它的水溶性差,口服生物利用度低。在本研究中,开发了载有CC的固体脂质纳米粒(CC-SLNs)以提高口服生物利用度。SLNs的成分包括肉豆蔻酸甘油三酯/棕榈酸甘油三酯/硬脂酸甘油三酯中的任何一种,以及表面活性剂(泊洛沙姆188和蛋黄卵磷脂E80)。通过热均质化结合超声法制备了载有CC的纳米粒。对CC-SLNs的理化性质、形态进行了表征,并在大鼠体内评价了CC-SLNs的药代动力学和药效学行为。制备出了平均粒径为180-220nm、包封率在91%-96%之间的稳定的CC-SLNs。在冷藏和室温下对优化后的制剂进行了3个月的物理稳定性研究。此外,尝试了冷冻干燥以提高物理稳定性。DSC和XRD分析表明,掺入SLN中的药物为无定形而非结晶态。通过电子显微镜研究发现SLN的形态近乎球形。药代动力学结果表明,CC掺入SLNs后口服生物利用度提高了2.75倍以上。对高血压大鼠的SLNs药效学研究表明,收缩压降低了48小时,而混悬液仅使收缩压降低了2小时。综上所述,这些效果归因于生物利用度的提高以及CC在SLN制剂中的持续作用。因此,结果确凿地证明了CC-SLNs在显著提高口服生物利用度以及改善药效学方面的作用。

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