Hu Lian-Dong, Liu Yang, Tang Xing, Zhang Qian
College of Pharmacy, Hebei University, Baoding, PR China.
Eur J Pharm Biopharm. 2006 Oct;64(2):185-92. doi: 10.1016/j.ejpb.2006.04.004. Epub 2006 May 10.
In this study, metformin hydrochloride (MH) sustained-release pellets were successfully prepared by centrifugal granulation. Seed cores preparation, drug layering, talc modification and coating of polymeric suspensions were carried out in a centrifugal granulator. Talc modification was performed before coating in order to overcome the high water solubility of metformin. The influence of surface modification by talc, the effects of Eudragit types and ratios, as well as the correlation between in vitro release and in vivo absorption were investigated in detail. Experimental results indicated that talc modification made a decisive contribution to controlling the drug release by avoiding drug dumping. Three dissolution media: 0.1 M HCl, distilled water and pH 6.8 phosphate buffer were employed to determine the in vitro release behaviors of the above metformin hydrochloride pellets. The relative bioavailability of the sustained-release pellets was studied in 12 healthy volunteers after oral administration in a fast state using a commercially available immediate release tablet (Glucophage) as a reference. Following coating with a blend of Eudragit L30D-55 and Eudragit NE30D (1:20), at 7% or 10% coating level, respectively (referred to as F-2, F-3), the pellets acquired perfect sustained-release properties and good relative bioavailability. The Cmax, Tmax and relative bioavailability for F-2 and F-3 coated pellets were 1.21 microg/ml, 6 h, 97.6% and 1.65 microg/ml, 8 h, 165%, respectively. Combined use of two Eudragit polymers with different features as coating materials produced the desired results. Restricted delivery of metformin hydrochloride to the small intestine from differently coated pellets resulted in increased relative bioavailability and a sustained release effect. The adoption of several different pH dissolution media established a better relationship between the in vitro release and in vivo absorption of the sustained-release pellets.
在本研究中，通过离心造粒成功制备了盐酸二甲双胍（MH）缓释微丸。在离心造粒机中进行了种子核制备、药物层积、滑石粉改性以及聚合物混悬液包衣。为克服二甲双胍的高水溶性，在包衣前进行滑石粉改性。详细研究了滑石粉表面改性的影响、丙烯酸树脂类型及比例的影响以及体外释放与体内吸收之间的相关性。实验结果表明，滑石粉改性通过避免药物突释对控制药物释放起决定性作用。采用三种溶出介质：0.1 M盐酸、蒸馏水和pH 6.8磷酸盐缓冲液来测定上述盐酸二甲双胍微丸的体外释放行为。以市售速释片（格华止）为参比，在12名健康志愿者处于禁食状态下口服给药后，研究了缓释微丸的相对生物利用度。分别用7%或10%包衣水平的丙烯酸树脂L30D - 55和丙烯酸树脂NE30D（1:20）的混合物包衣后（分别称为F - 2、F - 3），微丸获得了理想的缓释性能和良好的相对生物利用度。F - 2和F - 3包衣微丸的Cmax、Tmax和相对生物利用度分别为1.21 μg/ml、6 h、97.6%和1.65 μg/ml、8 h、165%。联合使用两种具有不同特性的丙烯酸树脂聚合物作为包衣材料产生了预期效果。不同包衣微丸使盐酸二甲双胍在小肠中的释放受限，导致相对生物利用度增加和缓释效果。采用几种不同pH的溶出介质建立了缓释微丸体外释放与体内吸收之间更好的关系。
