title: Development of an extended-release formulation of capecitabine making use of in vitro-in vivo correlation modelling.
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.
authors: Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands; Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Jelte
authors: J
authors: Meulenaar
authors: Ron J
authors: RJ
authors: Keizer
authors: Jos H
authors: JH
authors: Beijnen
authors: Jan H M
authors: JH
authors: Schellens
authors: Alwin D R
authors: AD
authors: Huitema
authors: Bastiaan
authors: B
authors: Nuijen
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry; D019540:Area Under Curve; D002152:Calorimetry, Differential Scanning; D000069287:Capecitabine; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D003890:Desiccation; D004339:Drug Compounding; D005079:Excipients; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D008956:Models, Chemical; D011205:Povidone; D012822:Silicon Dioxide / Q000737:chemistry; D012995:Solubility; D013229:Stearic Acids / Q000737:chemistry; D013607:Tablets; D014961:X-Ray Diffraction
chemical_list: D000964:Antimetabolites, Antineoplastic; D003692:Delayed-Action Preparations; D005079:Excipients; D013229:Stearic Acids; D013607:Tablets; D003841:Deoxycytidine; C031183:stearic acid; D000069287:Capecitabine; D012822:Silicon Dioxide; D011205:Povidone; D005472:Fluorouracil
keywords: IVIVC modelling; amorphous; capecitabine; co-spray drying; extended release