Säkkinen Mia, Tuononen Tiina, Jürjenson Heidi, Veski Peep, Marvola Martti
Division of Biopharmaceutics and Pharmacokinetics, Department of Pharmacy, University of Helsinki, P.O. Box 56, FIN-00014, Helsinki, Finland.
Eur J Pharm Sci. 2003 Aug;19(5):345-53. doi: 10.1016/s0928-0987(03)00121-0.
In vivo absorption studies were carried out in human volunteers to evaluate whether microcrystalline chitosan (MCCh) granules would be gastro-retentive. Furosemide, which is site-specifically absorbed from the upper gastrointestinal tract, was used as model drug. The rate of release of furosemide in vitro could be prolonged by increasing the molecular weight (M(w)) or amount of MCCh (150 to 240 kDa; 80 to 95%) in the granules, and also by addition of acidic excipients to the formulations. No marked changes in the in vivo absorption rate (t(max)) were noted, but the amounts of furosemide absorbed (AUC(0- infinity ) and C(max)) decreased as the in vitro release rate decreased, although this was not statistically significant in the case of AUC. The highest AUC(0- infinity ) (3050 micro g l(-1) h) for furosemide (40 mg) was achieved with granules containing 80% MCCh of 150 kDa M(w). With MCCh of 240 kDa M(w) AUC(0- infinity ) was 1890 micro g l(-1) h. This kind of pharmacokinetic profile of furosemide suggests that the gastric retention time of the granules is too short in relation to the release rate, and a large amount of the drug passes its "absorption window" before being released. The in vivo study produced no evidence that the chitosan formulations studied can be used as mucoadhesive gastro-retentive drug delivery systems. The results of in vitro mucoadhesion studies did not predict the results of in vivo studies.
在人体志愿者中进行了体内吸收研究，以评估微晶壳聚糖（MCCh）颗粒是否具有胃滞留性。将从上消化道进行部位特异性吸收的呋塞米用作模型药物。通过增加颗粒中MCCh的分子量（M(w)）或用量（150至240 kDa；80至95%），以及在制剂中添加酸性辅料，可延长呋塞米的体外释放速率。体内吸收速率（t(max)）未见明显变化，但随着体外释放速率降低，呋塞米的吸收量（AUC(0-∞)和C(max)）减少，不过AUC的情况在统计学上无显著差异。对于40 mg呋塞米，含80% 150 kDa M(w) MCCh的颗粒实现了最高的AUC(0-∞)（3050 μg l(-1) h）。对于240 kDa M(w)的MCCh，AUC(0-∞)为1890 μg l(-1) h。呋塞米的这种药代动力学特征表明，颗粒的胃滞留时间相对于释放速率过短，大量药物在释放前就已通过其“吸收窗”。体内研究未提供证据表明所研究的壳聚糖制剂可作为黏膜黏附性胃滞留药物递送系统。体外黏膜黏附研究结果无法预测体内研究结果。
