Nagaraj K, Narendar D, Kishan V
a Department of Pharmaceutical Sciences , Laboratory of Nanotechnology, University College of Pharmaceutical Sciences, Kakatiya University , Warangal , India.
Drug Dev Ind Pharm. 2017 Jul;43(7):1186-1196. doi: 10.1080/03639045.2017.1304955. Epub 2017 Mar 27.
The aim of the present investigation was to enhance the oral bioavailability of olmesartan medoxomil by improving its solubility and dissolution rate by preparing nanosuspension (OM-NS), using the Box-Behnken design. In this, four factors were evaluated at three levels. Independent variables include: concentration of drug (X), concentration of surfactant (X), concentration of polymer (X) and number of homogenization cycles (X). Based on preliminary studies, the size (Y), zeta potential (ZP) (Y) and % drug release at 5 min (Y) were chosen as dependent responses. OM-NS was prepared by high pressure homogenization method. The size, PDI, ZP, assay, in vitro release and morphology of OM-NS were characterized. Further, the pharmacokinetic (PK) behavior of OM-NS was evaluated in male wistar rats. Statistically optimized OM-NS formulation exhibited mean particle size of 492 nm, ZP of -27.9 mV and 99.29% release in 5 min. OM-NS showed more than four times increase in its solubility than pure OM. DSC and XRD analyses indicated that the drug incorporated into OM-NS was in amorphous form. The morphology of OM-NS was found to be nearly spherical with high dispersity by scanning electron microscopic studies. The PK results showed that OM lyophilized nanosuspension (NS) exhibited improved PK properties compared to coarse powder suspension and marketed tablet powder suspension (TS). Oral bioavailability of lyophilized NS was increased by 2.45 and 2.25 folds when compared to marketed TS and coarse powder suspension, respectively. Results of this study lead to conclusion that NS approach was effective in preparing OM formulations with enhanced dissolution and improved oral bioavailability.
本研究的目的是通过采用Box-Behnken设计制备纳米混悬液（OM-NS）来提高奥美沙坦酯的溶解度和溶出速率，从而增强其口服生物利用度。在此过程中，对四个因素在三个水平上进行了评估。自变量包括：药物浓度（X1）、表面活性剂浓度（X2）、聚合物浓度（X3）和匀化循环次数（X4）。基于初步研究，选择粒径（Y1）、zeta电位（ZP）（Y2）和5分钟时的药物释放率（Y3）作为因变量。OM-NS采用高压匀化法制备。对OM-NS的粒径、多分散指数（PDI）、ZP、含量测定、体外释放和形态进行了表征。此外，在雄性Wistar大鼠中评估了OM-NS的药代动力学（PK）行为。经统计学优化的OM-NS制剂的平均粒径为492 nm，ZP为-27.9 mV，5分钟内释放率为99.29%。OM-NS的溶解度比纯OM增加了四倍多。差示扫描量热法（DSC）和X射线衍射（XRD）分析表明，掺入OM-NS中的药物为无定形形式。通过扫描电子显微镜研究发现，OM-NS的形态近乎球形，分散性高。PK结果表明，与粗粉混悬液和市售片剂粉末混悬液（TS）相比，冻干纳米混悬液（NS）表现出更好的PK性质。与市售TS和粗粉混悬液相比，冻干NS的口服生物利用度分别提高了2.45倍和2.25倍。本研究结果得出结论，纳米混悬液方法有效地制备了具有增强溶出度和改善口服生物利用度的OM制剂。
