Development of an Extended‐Release Formulation of Capecitabine Making Use of In Vitro–In Vivo Correlation Modelling. Issue 2 (5th December 2013)

• Record Type: Journal Article
• Authors: Meulenaar, Jelte; Keizer, Ron J.; Beijnen, Jos H.; Schellens, Jan H. M.; Huitema, Alwin D. R.; Nuijen, Bastiaan
• Is Part Of: Journal of pharmaceutical sciences. Volume 103:Issue 2(2014:Feb.)
• Page Start: 478
• Page End: 484
• Publication Date: 2013-12-05
• Subjects: Pharmacy -- Periodicals; 615.1
• DOI: 10.1002/jps.23779
• Languages: English
• ISSNs: 0022-3549

Abstract

<abstract abstract-type="main" xml:lang="en"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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<sup>®</sup>). The target 12‐hour <italic>in vivo</italic> release profile was correlated to an <italic>in vitro</italic> dissolution profile using an <italic>in vitro–in vivo</italic> correlation model based on the pharmacokinetic (PK) and dissolution characteristics of Xeloda<sup>®</sup>. 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<sup>®</sup> SR induced the most prominent ER. Moreover, it was shown that tablets prepared from CoSD capecitabine and Kollidon<sup>®</sup> 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<sup>®</sup> 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 <italic>in vivo</italic> PK of our designed ER capecitabine formulations is investigated in a clinical study. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:478–484, 2014</p> </abstract>