期刊
AAPS PHARMSCITECH
卷 20, 期 8, 页码 -出版社
SPRINGER
DOI: 10.1208/s12249-019-1544-3
关键词
poorly water-soluble drugs; in vitro-in vivo correlation; indapamide; pharmacokinetic; drug dissolution; absorption simulating system
资金
- Key Support Projects of Tianjin Science and Technology [16YFZCSY00440]
- Changjiang Scholars and Innovative Research Team [IRT_14R41]
- Tianjin Natural Science Foundation [18JCQNJC83800]
Combined dissolution and permeation systems are designed to simultaneously assess the dissolution of a pharmaceutical dosage form and the permeation of dissolved drugs therefrom. However, there were still some limitations on predicting the possible absorption rate-limiting steps and improving the in vitro-in vivo correlation (IVIVC) of a complete dosage form. In this study, the modified biorelevant media with some solubilizers and pH modifiers were integrated into the drug dissolution/absorption simulating system (DDASS). Indapamide, a poorly soluble compound (pKa = 8.8), was selected to validate the applicability of the modified biorelevant media. The elution and permeation dynamics of indapamide were investigated by using appropriate solubilizing agents in the DDASS. The absorption behaviors were analyzed after oral administration of indapamide in beagle dogs. The absorption rate-limiting steps and IVIVCs were predicted from the dissolution-permeation-absorption dynamic parameters. As a result, the absorption fraction of indapamide in the FaSSIF(mod) of DDASS was estimated to be approximately 100%, in accordance with its high permeability. The ratios of permeation rate to elution rate were 2.55 and 3.34 for the immediate- and sustained-release tablets of indapamide, respectively, suggesting a dissolution rate-limiting absorption for indapamine. In addition, point-to-point correlations were established between in vitro elution and in vivo absorption by the nonlinear and linear regression analysis ways (r > 0.85). The findings indicate that DDASS is a promising technique to develop improved IVIVCs of a complete dosage form, and the FaSSIF(mod) is suitable to predict the possible absorption rate-limiting steps of poorly soluble drugs in DDASS.
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