title: Use of in vitro release tests for the prediction of the in vivo behavior and the development of flucytosine controlled-release capsules.
abstract: The antifungal substance flucytosine (5-fluorocytosine) was chosen as a model drug for studying the development of a controlled-release capsule dosage form based mainly on in vitro drug release tests. A solution and various capsule formulations of flucytosine were orally administered to beagle dogs, and the resulting plasma concentration-time profiles were determined. Special attention was directed to multiple-unit hard-gelatin capsules that exhibited a controlled-release effect in vitro, but not in vivo. The respective plasma profile was treated by the technique of numerical deconvolution to obtain the corresponding in vivo release profile (i.e., the drug release from the dosage form in the gastrointestinal tract of the dog). The influence of different experimental conditions of the USP paddle method on the release profile was investigated. By adding surfactant to the dissolution medium and omission of the sinker device, which is used to prevent the capsule from floating, the in vitro release rate markedly increased and correlated well with the in vivo release. Based on this adjusted in vitro test, the formulation was modified to achieve a more pronounced controlled-release effect. The plasma profile resulting from the reformulated multiple-unit capsules was in good agreement with the predictions made by numerical convolution of the in vitro release profile.
authors.affiliation: Department of Galenical Research and Development, Nippon Roche Research Center, Kanagawa Prefecture, Japan.
authors.forename: J D
authors.initials: JD
authors.lastname: Bonny
authors.forename: M
authors.initials: M
authors.lastname: Kyowa
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002214:Capsules; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D004285:Dogs; D005437:Flucytosine / Q000097:blood / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D007700:Kinetics; D013997:Time Factors
chemical_list: D002214:Capsules; D003692:Delayed-Action Preparations; D005437:Flucytosine