Hayashi Tetsuo, Kanbe Hideyoshi, Okada Minoru, Kawase Ichiro, Ikeda Yasuo, Onuki Yoichi, Kaneko Tetsuo, Sonobe Takashi
Life Science Institute, SSP Co., Ltd., Nanpeidai 1143, Narita-shi, Chiba 286-1511, Japan.
Int J Pharm. 2007 Aug 16;341(1-2):105-13. doi: 10.1016/j.ijpharm.2007.03.048. Epub 2007 Apr 5.
We compared the in vitro/in vivo properties of theophylline between two sustained-release preparations, which are administered once a day. Tablet A is a swelling/disintegration-type matrix tablet consisting of hydrophobic wax granules and hydrophilic polymer granules (cluster tablets). Tablet B is a matrix tablet consisting of hydrophilic polymer granules. We conducted a dissolution test with JPXIV in vitro, and compared the results between the two preparations. Neither pH nor agitation intensity influenced these preparations. After they were immersed in oleic acid, there were no marked changes in the dissolution properties in the dissolution test. After administration of Tablets A and B containing theophylline at 200mg to fasted dogs, we compared plasma level profiles of theophylline. The mean plasma level of theophylline gradually increased to a maximum (7.17microg/mL) 4h after administration of Tablet A. After administration of Tablet B, a similar finding was noted, with a maximum of 6.09microg/mL. Tablet B showed a higher coefficient of variation (CV) for the plasma level at each point. Subsequently, we administered two tablets of preparations A and B containing theophylline at 200mg to healthy volunteers who had not been fasted, and compared plasma level concentration of theophylline. The mean plasma level of theophylline gradually increased to a maximum (6.09microg/mL) 12h after administration of Tablet A, but then decreased, with a half-life of 9.10h. After administration of Tablet B, a similar finding was noted, with a maximum of 7.87microg/mL and a half-life of 7.76h. Tablet A showed a significantly higher plasma concentration 1 and 2h after administration; however, there were no significant differences at other points. The C(max) of Tablet B was significantly higher than that of Tablet A. However, there were no significant differences in other pharmacokinetic parameters between the two preparations. The T(max) of Tablet A was 10-12h after administration, relatively constant. However, that of Tablet B was 10-18h after administration. The CV for T(max) was 9.8% for Tablet A and 22.0% for Tablet B. After administration of Tablet B, the plasma level of theophylline varied at each point. Based on these results, inter-subject variations after administration of Tablet A may be less marked than those after administration of Tablet B. It is concluded that, the cluster tablets A developed in this study showed significantly less inter-subject variation of theophylline plasma levels than the conventional matrix tablets B.
我们比较了两种每日给药一次的缓释制剂中茶碱的体外/体内特性。片剂A是一种溶胀/崩解型骨架片，由疏水蜡颗粒和亲水聚合物颗粒组成（聚粒片）。片剂B是一种由亲水聚合物颗粒组成的骨架片。我们在体外采用日本药局方第十四改正版进行了溶出度试验，并比较了两种制剂的结果。pH值和搅拌强度均未对这些制剂产生影响。将它们浸入油酸中后，溶出度试验中的溶出特性没有明显变化。给禁食犬口服含200mg茶碱的片剂A和B后，我们比较了茶碱的血浆浓度曲线。口服片剂A后，茶碱的平均血浆浓度在给药后4小时逐渐升高至最高值（7.17μg/mL）。口服片剂B后，也观察到类似结果，最高值为6.09μg/mL。片剂B在各时间点血浆浓度的变异系数（CV）较高。随后，我们给未禁食的健康志愿者口服两片含200mg茶碱的制剂A和B，并比较了茶碱的血浆浓度。口服片剂A后，茶碱的平均血浆浓度在给药后12小时逐渐升高至最高值（6.09μg/mL），随后下降，半衰期为9.10小时。口服片剂B后，也观察到类似结果，最高值为7.87μg/mL，半衰期为7.76小时。给药后1小时和2小时，片剂A的血浆浓度显著更高；然而，在其他时间点没有显著差异。片剂B的C(max)显著高于片剂A。然而，两种制剂在其他药代动力学参数上没有显著差异。片剂A给药后的T(max)为10 - 12小时，相对恒定。然而，片剂B给药后的T(max)为10 - 18小时。片剂A的T(max)的CV为9.8%，片剂B为22.0%。口服片剂B后，茶碱的血浆浓度在各时间点有所变化。基于这些结果，口服片剂A后的个体间差异可能比口服片剂B后的个体间差异不那么明显。得出的结论是，本研究中开发的聚粒片A与传统骨架片B相比，茶碱血浆水平的个体间差异显著更小。
