Department of Drug Absorption and Pharmacokinetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Int J Pharm. 2013 Sep 10;453(2):363-70. doi: 10.1016/j.ijpharm.2013.05.055. Epub 2013 Jun 3.
Pharmaceutical excipients should not disturb the effects of drug therapy. In recent years, however, it has been reported that excipients induce some changes to the tight junction (TJ) and P-glycoprotein (P-gp), which can affect drug disposition. In this study, we examined the effects of 20 common pharmaceutical excipients from different classes on mucosal membrane and the differences of such effects among regions of the small intestine. We used the in vitro sac method in rat jejunum and ileum to study the effects of excipients on the membrane permeation of 5(6)-carboxyfluorescein (5-CF). 5-CF was used as a model of water-soluble compounds. In some dosage conditions of methyl-β-cyclodextrin, the membrane permeability of 5-CF was significantly increased in the jejunum, but such change was not observed in the ileum. Similarly, in the cases of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and croscarmellose sodium, the membrane permeability of 5-CF was significantly increased in the jejunum, but no change was observed in the ileum. On the other hand, in both the jejunum and the ileum, the membrane permeation of 5-CF was decreased with 0.02% (w/v) hydroxypropyl cellulose, but significantly increased with it at 0.20% (w/v). It was shown that excipients affected the membrane permeability of water-soluble compounds via the paracellular route, and these effects on absorption differed among regions of the small intestine. Moreover, in the case of 20 excipients, not only an increase in membrane permeability but also a decrease was observed. Therefore, it was suggested that a more effective formulation could be designed by changing the combination of excipients.
药用辅料不应干扰药物治疗效果。然而，近年来有报道称辅料会引起紧密连接（TJ）和 P-糖蛋白（P-gp）的一些变化，从而影响药物分布。在这项研究中，我们研究了来自不同类别的 20 种常见药用辅料对粘膜的影响，以及这些影响在小肠不同区域的差异。我们使用大鼠空肠和回肠的体外囊方法研究了辅料对 5(6)-羧基荧光素（5-CF）膜透过性的影响。5-CF 被用作水溶性化合物的模型。在甲基-β-环糊精的某些剂量条件下，5-CF 的膜透过性在空肠中显著增加，但在回肠中未观察到这种变化。同样，在羧甲基淀粉钠、低取代羟丙基纤维素和交联羧甲基纤维素钠的情况下，5-CF 的膜透过性在空肠中显著增加，但在回肠中没有变化。另一方面，在空肠和回肠中，0.02%（w/v）羟丙基纤维素降低了 5-CF 的膜透过性，但在 0.20%（w/v）时显著增加。结果表明，辅料通过细胞旁途径影响水溶性化合物的膜透过性，这些吸收差异存在于小肠的不同区域。此外，在 20 种辅料的情况下，不仅观察到膜透过性增加，还观察到膜透过性降低。因此，通过改变辅料的组合，可以设计出更有效的配方。
