Supersaturation induced by Itraconazole/Soluplus^® micelles provided high GI absorption in vivo

详细信息    查看全文

• 作者：Yue Zhong ; Guanghui Jing ; Bin Tian ; Hao Huang ; Yuanyuan Zhang ; Jingxin Gou ; Xing Tang ; Haibing He ; ^{emily_hehaibing@hotmail.com" class="auth_mail" title="E-mail the corresponding author} ; Yanjiao Wang ; ^{tanglab@126.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Solid dispersion ; Itraconazole tablets ; Hot melt extrusion ; Supersaturation ; Micelles ; Bioavailability
• 刊名：Asian Journal of Pharmaceutical Sciences
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：11
• 期：2
• 页码：255-264
• 全文大小：2229 K

文摘

To investigate the effect of supersaturation induced by micelle formation during dissolution on the bioavailability of itraconazole (ITZ)/Soluplus^® solid dispersion. Solid dispersions prepared by hot melt extrusion (HME) were compressed into tablets directly with other excipients. Dissolution behavior of ITZ tablets was studied by dissolution testing and the morphology of micelles in dissolution media was studied using transmission electron microscopy (TEM). Drug transferring from stomach into intestine was simulated to obtain a supersaturated drug solution. Bioavailability studies were performed on the ITZ tablets and Sporanox^® in beagle dogs. The morphology of micelles in the dissolution media was observed to be spherical in shape, with an average size smaller than 100 nm. The supersaturated solutions formed by Soluplus^® micelles were stable and no precipitation took place over a period of 180 min. Compared with Sporanox^®, ITZ tablets exhibited a 2.50-fold increase in the AUC_(0–96) of ITZ and a 1.95-fold increase in its active metabolite hydroxyitraconazole (OH-ITZ) in the plasma of beagle dogs. The results obtained provided clear evidence that not only the increase in the dissolution rate in the stomach, but also the supersaturation produced by micelles in the small intestine may be of great assistance in the successful development of poorly water-soluble drugs. The micelles formed by Soluplus^® enwrapped the molecular ITZ inside the core which promoted the amount of free drug in the intestinal cavity and carried ITZ through the aqueous boundary layer (ABL), resulting in high absorption by passive transportation across biological membranes. The uptake of intact micelles through pinocytosis together with the inhibition of P-glycoprotein-mediated drug efflux in intestinal epithelia contributed to the absorption of ITZ in the gastrointestinal tract. These results indicate that HME with Soluplus^®, which can induce supersaturation by micelle formation, may be of great assistance to the successful development of poorly water-soluble drugs.