Basit Abdul W, Podczeck Fridrun, Newton J Michael, Waddington Wendy A, Ell Peter J, Lacey Larry F
Department of Pharmaceutics, The School of Pharmacy, University of London, 29/39 Brunswick Square, London WC1N 1AX, UK.
Eur J Pharm Sci. 2004 Feb;21(2-3):179-89. doi: 10.1016/j.ejps.2003.10.003.
The aim of this study was to assess the feasibility of using oral modified-release formulations for the purposes of site-specific targeting and regional drug absorption assessment in man. An immediate release pellet formulation containing ranitidine as the model drug of choice for the study was fabricated by extrusion-spheronisation, and then film coated with either the enteric polymer polyvinyl acetate phthalate or the bacteria-degradable polymer amylose, in combination with ethylcellulose, to effect drug release within the small intestine and colon, respectively. Optimised formulations were evaluated in vivo in ten healthy volunteers, who each received, on four separate occasions, the immediate release, small intestinal release and colonic release formulations (each equivalent to 150mg ranitidine), and an intravenous injection of ranitidine (equivalent to 50mg ranitidine). Blood samples were collected and assessed for ranitidine concentration, and radiolabelled placebo pellets were co-administered with the coated ranitidine pellets to monitor their gastrointestinal transit using a gamma camera. Ranitidine was rapidly released and absorbed from the immediate release formulation, whereas the enteric formulation (10% coat weight gain) delayed drug release until some or all of the pellets had emptied into the small intestine. The amylose-ethylcellulose coated formulation (coat ratio 1:3, coat weight gain 25%) retarded ranitidine release until the pellets had reached the colon. The mean absolute bioavailability of ranitidine from the immediate release, small intestinal release and colonic release formulations were 50.6, 46.1 and 5.5%, respectively. These data are in general agreement to those obtained from a previous regional intubation study. The present study therefore demonstrates the practical potential of utilising a non-invasive, formulation-based approach to assess drug absorption from different regions of the human gastrointestinal tract.
本研究的目的是评估使用口服缓释制剂实现人体部位特异性靶向和区域药物吸收评估的可行性。通过挤出滚圆法制备了一种含雷尼替丁的速释微丸制剂作为本研究的首选模型药物，然后分别用肠溶聚合物邻苯二甲酸聚乙烯酯或可被细菌降解的聚合物直链淀粉与乙基纤维素混合进行薄膜包衣，以使药物分别在小肠和结肠内释放。在10名健康志愿者体内对优化后的制剂进行了评估，每位志愿者在四个不同的场合分别接受速释、小肠释放和结肠释放制剂（每种制剂相当于150mg雷尼替丁），以及静脉注射雷尼替丁（相当于50mg雷尼替丁）。采集血样并评估雷尼替丁浓度，同时将放射性标记的安慰剂微丸与包衣的雷尼替丁微丸共同给药，使用γ相机监测其胃肠道转运情况。雷尼替丁从速释制剂中迅速释放并吸收，而肠溶制剂（包衣增重10%）会延迟药物释放，直到部分或全部微丸排空进入小肠。直链淀粉-乙基纤维素包衣制剂（包衣比例1:3，包衣增重25%）会延缓雷尼替丁释放，直到微丸到达结肠。雷尼替丁从速释、小肠释放和结肠释放制剂中的平均绝对生物利用度分别为50.6%、46.1%和5.5%。这些数据与先前区域插管研究获得的数据总体一致。因此，本研究证明了利用基于制剂的非侵入性方法评估人体胃肠道不同区域药物吸收的实际潜力。
