Jain Sanyog, Patel Kamlesh, Arora Sumit, Reddy Venkata Appa, Dora Chander Parkash
Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S, Nagar, Punjab, 160062, India.
Drug Deliv Transl Res. 2017 Apr;7(2):292-303. doi: 10.1007/s13346-016-0355-2.
The aim of the present study is to increase the saturation solubility and oral bioavailability of olmesartan medoxomil (OLM) using nano-sized crystals produced using a combination of antisolvent precipitation and high-shear homogenization. A response surface design comprising 46 runs was used to optimize the OLM nanocrystal formulation. The optimized formulation was produced using a combination of D-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS) (0.7% w/v), Pluronic F-68® (0.5% w/v), and drug concentration (0.2% w/v) and subjected to 10 and 15 homogenization cycles at 1000 and 1700 bar, respectively. The particle size, polydispersity index (PDI), and zeta potential of optimized formulation were found to be 140 ± 10.34 nm, 0.07 ± 0.016, and -21.43 ± 2.33 mV, respectively. The optimized formulation exhibited irregular morphology as evaluated by scanning electron microscopy and was crystalline as determined by thermal analysis and powder X-ray diffraction studies. OLM nanocrystals showed a marked increase in the saturation solubility as well as rapid dissolution rate in comparison with the pure drug. No significant change in the particle size, PDI, and zeta potential was observed when optimized formulation was stored at room and refrigeration conditions for 3 months. Lastly, in vivo pharmacokinetic studies in Sprague-Dawley rats substantiate the ability of OLM nanocrystal formulation to significantly improve (∼4.6-fold) the oral bioavailability of OLM in comparison with the free drug. This study has established a potential and commercial viable OLM formulation with enhanced saturation solubility and in vivo oral bioavailability.
本研究的目的是通过结合反溶剂沉淀法和高剪切均质法制备纳米晶体，来提高奥美沙坦酯（OLM）的饱和溶解度和口服生物利用度。采用包含46次实验的响应面设计来优化OLM纳米晶体制剂。优化后的制剂是通过将聚乙二醇1000维生素E琥珀酸酯（TPGS）（0.7% w/v）、普朗尼克F-68®（0.5% w/v）和药物浓度（0.2% w/v）相结合制备而成，并分别在1000和1700巴的压力下进行10次和15次均质循环。优化制剂的粒径、多分散指数（PDI）和zeta电位分别为140±10.34 nm、0.07±0.016和-21.43±2.33 mV。通过扫描电子显微镜评估，优化后的制剂呈现不规则形态，通过热分析和粉末X射线衍射研究确定其为晶体。与纯药物相比，OLM纳米晶体的饱和溶解度显著增加，溶解速度也更快。当优化后的制剂在室温和冷藏条件下储存3个月时，未观察到粒径、PDI和zeta电位有显著变化。最后，在Sprague-Dawley大鼠体内进行的药代动力学研究证实，与游离药物相比，OLM纳米晶体制剂能够显著提高（约4.6倍）OLM的口服生物利用度。本研究建立了一种具有增强饱和溶解度和体内口服生物利用度的潜在且具有商业可行性的OLM制剂。
