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Published on: February 6, 2015
Development of an extended-release formulation of capecitabine making use of in vitro-in vivo correlation modelling
Jelte Meulenaar1, Ron J Keizer, Jos H Beijnen
1Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands; Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Abstract:
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.
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