TY - JOUR
T1 - In vivo in vitro correlations for a poorly soluble drug, danazol, using the flow-through dissolution method with biorelevant dissolution media
AU - Sunesen, Vibeke Hougaard
AU - Pedersen, Betty Lomstein
AU - Kristensen, Henning Gjelstrup
AU - Müllertz, Anette
N1 - Keywords: Animals; Bile Acids and Salts; Biological Availability; Danazol; Models, Biological; Particle Size; Solubility; Swine; Technology, Pharmaceutical
PY - 2005
Y1 - 2005
N2 - 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 100mg danazol capsules was performed using the flow-through dissolution method. Flow rates were 8, 16 or 32 ml/min, corresponding to total volumes dissolution medium of 960, 1920 and 3840 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 6.3 mM bile salts and 1.25 mM phospholipids (8 ml/min). A medium containing 18.8 mM bile salts, 3.75 mM phospholipids, 4.0 mM monoglycerides and 30 mM fatty acids (8 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.
AB - 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 100mg danazol capsules was performed using the flow-through dissolution method. Flow rates were 8, 16 or 32 ml/min, corresponding to total volumes dissolution medium of 960, 1920 and 3840 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 6.3 mM bile salts and 1.25 mM phospholipids (8 ml/min). A medium containing 18.8 mM bile salts, 3.75 mM phospholipids, 4.0 mM monoglycerides and 30 mM fatty acids (8 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.
U2 - 10.1016/j.ejps.2004.11.007
DO - 10.1016/j.ejps.2004.11.007
M3 - Journal article
C2 - 15734297
SN - 0928-0987
VL - 24
SP - 305
EP - 313
JO - European Journal of Pharmaceutical Sciences
JF - European Journal of Pharmaceutical Sciences
IS - 4
ER -