University of Connecticut, School of Pharmacy, Storrs, CT 06269 USA.
University of Connecticut, School of Pharmacy, Storrs, CT 06269 USA.
J Control Release. 2014 Oct 28;192:95-102. doi: 10.1016/j.jconrel.2014.06.059. Epub 2014 Jul 7.
The objective of this study was to formulate nano-amorphous spray-dried powders of itraconazole to enhance its oral bioavailability. A combination approach of solvent-antisolvent precipitation followed by spray drying was used. DoE studies were utilized to understand the critical processing parameters: antisolvent-to-solvent ratio, drug concentration and stabilizer concentration. Particle size was the critical quality attribute. Spray drying of the nano-precipitated formulation was performed with several auxiliary excipients to obtain nano-sized amorphous powder formulations. PLM, DSC and PXRD were utilized to characterize the spray-dried powders. In vitro dissolution and in vivo bioavailability studies of the nano-amorphous powders were performed. The particle size of the nano-formulations was dependent on the drug concentration. The smallest size precipitates were obtained with low drug concentration. All high molecular weight auxiliary excipients and mannitol containing formulations were unstable and crystallized during spray drying. Formulations containing disaccharides were amorphous and non-aggregating. In vitro dissolution testing and in vivo studies showed the superior performance of nano-amorphous formulations compared to melt-quench amorphous and crystalline itraconazole formulations. This study shows superior oral bioavailability of nano-amorphous powders compared to macro-amorphous powders. The nano-amorphous formulation showed similar bioavailability to the nano-crystalline formulation but with a faster absorption profile.
本研究的目的是制备伊曲康唑纳米无定形喷雾干燥粉末以提高其口服生物利用度。采用溶剂-抗溶剂沉淀法结合喷雾干燥法。采用设计实验（DoE）研究来了解关键的工艺参数：反溶剂与溶剂的比例、药物浓度和稳定剂浓度。粒径是关键的质量属性。用几种辅料对纳米沉淀制剂进行喷雾干燥，以获得纳米级无定形粉末制剂。采用 PLM、DSC 和 PXRD 对喷雾干燥粉末进行了表征。进行了纳米无定形粉末的体外溶解和体内生物利用度研究。纳米制剂的粒径取决于药物浓度。低药物浓度下得到的粒径最小。所有高分子量辅料和含有甘露醇的制剂在喷雾干燥过程中不稳定并结晶。含有二糖的制剂是无定形的且不聚集。体外溶解试验和体内研究表明，与熔融淬火无定形和结晶伊曲康唑制剂相比，纳米无定形制剂具有更好的性能。本研究表明，与宏观无定形粉末相比，纳米无定形粉末具有更高的口服生物利用度。纳米无定形制剂的生物利用度与纳米晶制剂相似，但吸收速度更快。
