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IN VITRO DISSOLUTION OF POORLY SOLUBLE DRUGS IN THE PRESENCE OF SURFACE ACTIVE AGENTS – IN VIVO PHARMACOKINETICS CORRELATIONS. II. NIMESULIDE

ION MIRCIOIU², VALENTINA ANUTA^1*, STEFANA-OANA PURCARU³, FLAVIAN RADULESCU¹, DALIA MIRON¹, ION-BOGDAN DUMITRESCU¹, NAGWA IBRAHIM², CONSTANTIN MIRCIOIU¹

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A cross-over two-periods, two sequences clinical study concerned pharmacokinetics of Nimesulide and its active metabolite 4’-hydroxy-Nimesulide after oral administration of 100 mg AULIN® tablets (HELSSIN BIREX) was performed on 24 healthy volunteers. The assay of plasma levels was undertaken using a HPLC validated method. Modelling of data was performed using mono- and bicompartmental models. Application of information and statistical criteria indicated the monocompartmental model was efficient enough in describing time course of concentration of both parent drug and metabolite. In vitro dissolution of tablets was undertaken using USP apparatus 2 and different experimental conditions, by varying the concentration of the surface active agent Tween 80. Modelling of release data was possible only for the initial kinetics, since a saturation phase appeared as consequence of the poor solubility of nimesulide. Extent of release increased approximately linear with Tween concentration at levels just above critical micellar concentration and strongly linear at much higher concentrations. In order to establish the most relevant in vitro tests, correlation of mean plasma levels with in vitro dissolution results was undertaken, by applying Nelson-Wagner method. The experimental set of results was enriched based on models in order to match the in vitro and in vivo sampling times. Neglecting the concentration term in Nelson Wagner formula, an approximate formula [ ] [ ] 0 0 ( ) / t FRA t AUC AUC ∞ = was derived, which represents rather the „eliminated fraction” than the „absorption fraction”. In spite of simplification, the pointwise correlation with in vitro released fraction remained practically the same. Extrapolation of the correlations concerning parent drug to rate of appearance of metabolites in plasma proved that this kinetics also could be well with dissolution. By comparing the hierarchy of biorelevance of the dissolution tests, higher the Tween 80 concentration, better in vitro – in vivo correlation (IVIVC) was obtained. High bioavailability observed in vivo and higher concentrations of Tween required for good correlation suggested a possible critical dependence of in vivo absorption on physiological surface active agents.