Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
9917745 | European Journal of Pharmaceutical Sciences | 2005 | 9 Pages |
Abstract
The purpose of the study was to design dissolution tests that were able to distinguish between the behaviour of danazol under fasted and fed conditions, by using biorelevant media. In vitro dissolution of 100Â mg danazol capsules was performed using the flow-through dissolution method. Flow rates were 8, 16 or 32Â ml/min, corresponding to total volumes dissolution medium of 960, 1920 and 3840Â ml, respectively. The media used contained bile salt and phospholipid levels relevant for either fasted or fed conditions in vivo. Crude and inexpensive bile components, Porcine Bile Extract and soybean phospholipids, were used as the bile source. The effect of adding different concentrations and molar ratios of monoglycerides and fatty acids to the fed state media was investigated. In vivo release profiles under fasted and fed conditions were obtained from a previous study by deconvolution [Sunesen, V.H., Vedelsdal, R., Kristensen, H.G., Christrup, L., Müllertz, A. 2005. Effect of liquid volume and food intake on the absolute bioavailability of danazol, a poorly soluble drug, Eur. J. Pharm. Sci. 24, 297-303]. In the fasted state, the physiologically most relevant correlation with in vivo results was achieved with a medium containing 6.3Â mM bile salts and 1.25Â mM phospholipids (8Â ml/min). A medium containing 18.8Â mM bile salts, 3.75Â mM phospholipids, 4.0Â mM monoglycerides and 30Â mM fatty acids (8Â ml/min) gave the closest correlation with fed state in vivo results. By using the flow-through dissolution method it was possible to obtain correlations with in vivo release of danazol under fasted and fed conditions. Both hydrodynamics and medium composition were important for the dissolution of danazol. In the fed state an IVIVC could only be obtained by including monoglycerides and fatty acids in the medium.
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Authors
Vibeke Hougaard Sunesen, Betty Lomstein Pedersen, Henning Gjelstrup Kristensen, Anette Müllertz,