Nanoemulsion improves the oral absorption of candesartan cilexetil in rats: Performance and mechanism.
Candesartan cilexetil (CC), an inactive prodrug of candesartan, was rapidly hydrolyzed into active candesartan during absorption in the gastrointestinal (GI) tract to achieve antihypertensive effects. However, CC exhibited incomplete intestinal absorption with low oral bioavailability due to its poor aqueous solubility. In this work, a novel CC loaded nanoemulsion (CCN) was designed to improve the intestinal absorption. CCN was prepared by a modified emulsification-solvent evaporation technique. The physicochemical characteristics of CCN were characterized, and the intestinal absorption was investigated as well. The experimental results indicated that CCN was nanometer-sized droplets (35.5±5.9nm) with negative potential (-6.45±0.36mV), and the absorption of CCN was significantly improved in total intestinal tract compared with free CC solution. Moreover, CCN could be internalized into the enterocytes by clathrin-mediated endocytosis pathway, and thereafter transported into systemic circulation via both portal vein and lymphatic pathway. The concentration of active candesartan in rat plasma was determined by LC-MS-MS method. The experimental results showed that the area under the concentration-time curve (AUC(0-t)) of candesartan was improved over 10-fold after CC was incorporated into CCN. The overall results implicated that the nanoemulsion was very effective for enhancing the oral absorption of insoluble CC, and CCN showed the great potential for clinical application.
Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Fang
F
Gao
Zhiwen
Z
Zhang
Huihui
H
Bu
Yan
Y
Huang
Zhiwei
Z
Gao
Jianan
J
Shen
Chunjie
C
Zhao
Yaping
Y
Li
D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D001682:Biological Availability; D001692:Biological Transport; D001713:Biphenyl Compounds / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D018938:Caco-2 Cells; D002851:Chromatography, High Pressure Liquid; D004337:Drug Carriers / Q000737:chemistry*; D004386:Duodenum / Q000378:metabolism; D004655:Emulsions; D004705:Endocytosis / Q000187:drug effects; D006801:Humans; D007082:Ileum / Q000378:metabolism; D007408:Intestinal Absorption; D007583:Jejunum / Q000378:metabolism; D008297:Male; D046529:Microscopy, Electron, Transmission; D009061:Mouth Mucosa / Q000378:metabolism*; D049329:Nanostructures / Q000737:chemistry*; D011355:Prodrugs / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013499:Surface Properties; D053719:Tandem Mass Spectrometry; D013777:Tetrazoles / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics
D001562:Benzimidazoles; D001713:Biphenyl Compounds; D004337:Drug Carriers; D004655:Emulsions; D011355:Prodrugs; D013777:Tetrazoles; C077793:candesartan cilexetil; C081643:candesartan