IN VITRO DISSOLUTION OF POORLY SOLUBLE DRUGS IN THE PRESENCE OF SURFACE ACTIVE AGENTS – IN VIVO PHARMACOKINETICS CORRELATIONS. II. NIMESULIDE
ION MIRCIOIU2, VALENTINA ANUTA1*, STEFANA-OANA PURCARU3, FLAVIAN RADULESCU1, DALIA MIRON1, ION-BOGDAN DUMITRESCU1, NAGWA IBRAHIM2, CONSTANTIN MIRCIOIU1
1University of Medicine and Pharmacy „Carol Davila” Bucharest, Faculty of Pharmacy, 6 Traian Vuia street, 020956, Bucharest, Romania
2 University of Medicine and Pharmacy Tg. Mures, Romania
3 University of Medicine and Pharmacy, Craiova, Romania
Download Full Article PDF
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
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.