Dudhipala Narendar, Veerabrahma Kishan
a Department of Pharmaceutical Sciences , Laboratory of Nanotechnology, University College of Pharmaceutical Sciences, Kakatiya University , Warangal , Telangana , India.
Drug Dev Ind Pharm. 2015;41(12):1968-77. doi: 10.3109/03639045.2015.1024685. Epub 2015 Apr 1.
Nisoldipine (ND) is a potential antihypertensive drug with low oral bioavailability. The aim was to develop an optimal formulation of ND-loaded solid lipid nanoparticles (ND-SLNs) for improved oral bioavailability and pharmacodynamic effect by using a two-factor, three-level central composite design. Glyceryl trimyristate (Dynasan 114) and egg lecithin were selected as independent variables. Particle size (Y1), PDI (Y2) and entrapment efficiency (EE) (Y3) of SLNs were selected as dependent response variables.
The ND-SLNs were prepared by hot homogenization followed by ultrasonication. The size, PDI, zeta potential, EE, assay, in vitro release and morphology of ND-SLNs were characterized. Further, the pharmacokinetic (PK) and pharmacodynamic behavior of ND-SLNs was evaluated in male Wistar rats.
The optimal ND-SLN formulation had particle size of 104.4 ± 2.13 nm, PDI of 0.241 ± 0.02 and EE of 89.84 ± 0.52%. The differential scanning calorimetry and X-ray diffraction analyses indicated that the drug incorporated into ND-SLNs was in amorphous form. The morphology of ND-SLNs was found to be nearly spherical by scanning electron microscopy. The optimized formulation was stable at refrigerated and room temperature for 3 months. PK studies showed that 2.17-fold increase in oral bioavailability when compared with a drug suspension. In pharmacodynamic studies, a significant reduction in the systolic blood pressure was observed, which sustained for a period of 36 h when compared with a controlled suspension.
Taken together, the results conclusively demonstrated that the developed optimal ND-SLNs caused significant enhancement in oral bioavailability along with pharmacodynamic effect.
尼索地平（ND）是一种口服生物利用度较低的潜在抗高血压药物。本研究旨在通过二因素三水平中心复合设计，开发一种用于提高口服生物利用度和药效学作用的载尼索地平固体脂质纳米粒（ND-SLNs）的优化制剂。选择十四烷酸甘油酯（Dynasan 114）和卵磷脂作为自变量。将SLNs的粒径（Y1）、多分散指数（PDI）（Y2）和包封率（EE）（Y3）作为因变量响应指标。
采用热均质法结合超声法制备ND-SLNs。对ND-SLNs的粒径、PDI、ζ电位、EE、含量测定、体外释放和形态进行表征。此外，在雄性Wistar大鼠中评估ND-SLNs的药代动力学（PK）和药效学行为。
优化后的ND-SLN制剂粒径为104.4±2.13nm，PDI为0.241±0.02，EE为89.84±0.52%。差示扫描量热法和X射线衍射分析表明，载入ND-SLNs的药物为无定形。扫描电子显微镜观察发现ND-SLNs的形态接近球形。优化后的制剂在冷藏和室温下3个月内稳定。PK研究表明，与药物混悬液相比，口服生物利用度提高了2.17倍。在药效学研究中，观察到收缩压显著降低，与对照混悬液相比，这种降低持续了36小时。
综上所述，结果确凿地表明，所开发的优化ND-SLNs显著提高了口服生物利用度并增强了药效学作用。
