Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands; Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
J Pharm Sci. 2014 Feb;103(2):478-84. doi: 10.1002/jps.23779. Epub 2013 Dec 5.
An oral extended-release (ER) formulation of capecitabine was developed for twice daily dosing, theoretically providing a continuous exposure to capecitabine, thus avoiding the undesirable in-between dosing gap inherent to the dosing schedule of the marketed capecitabine immediate-release formulation (Xeloda(®)). The target 12-hour in vivo release profile was correlated to an in vitro dissolution profile using an in vitro-in vivo correlation model based on the pharmacokinetic (PK) and dissolution characteristics of Xeloda(®). Making use of the slow dissolution characteristics of amorphous capecitabine as reported previously and screening of a panel of ER excipients, an ER formulation was designed. Kollidon(®) SR induced the most prominent ER. Moreover, it was shown that tablets prepared from CoSD capecitabine and Kollidon(®) SR have an additional threefold delay in dissolution compared with tablets prepared from the same but only physically mixed components. Therefore, a prototype tablet formulation composed of co-spray-dried capecitabine and Kollidon(®) SR (98/2%, w/w) mixed with colloidal silicon dioxide (0.5%, w/w) and magnesium stearate (2.5%, w/w) was defined. This prototype shows similar dissolution characteristics as the modelled dissolution profile. Currently, the in vivo PK of our designed ER capecitabine formulations is investigated in a clinical study.
卡培他滨的一种口服延长释放（ER）制剂被开发用于每日两次给药，理论上提供了对卡培他滨的持续暴露，从而避免了市售卡培他滨即释制剂（Xeloda(®)）给药方案固有的不理想的两次给药之间的间隔。目标 12 小时体内释放曲线与基于 Xeloda(®)的药代动力学（PK）和溶解特性的体外-体内相关性模型的体外溶解曲线相关。利用先前报道的无定形卡培他滨的缓慢溶解特性并筛选 ER 赋形剂，设计了一种 ER 制剂。Kollidon(®) SR 诱导了最明显的 ER。此外，还表明与由相同但仅物理混合的成分制备的片剂相比，由 CoSD 卡培他滨和 Kollidon(®) SR 制备的片剂的溶解延迟了三倍。因此，定义了由共喷雾干燥的卡培他滨和 Kollidon(®) SR（98/2%，w/w）与胶体二氧化硅（0.5%，w/w）和硬脂酸镁（2.5%，w/w）混合组成的原型片剂制剂。该原型与模拟的溶解曲线具有相似的溶解特性。目前，正在临床研究中研究我们设计的 ER 卡培他滨制剂的体内 PK。
