1. Simultaneous Evaluation of Dissolution and Permeation of Oral Drug Solid Formulations for Predicting Absorption Rate–Limiting Factors and In Vitro–In Vivo Correlations: Case Study Using a Poorly Soluble Weakly Basic Drug
- Author
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Mingjin Xun, Ziqiang Li, Zengguang Wu, Guo Feng, Xin He, Yangyang Wang, Shuang Tian, and Cong Huang
- Subjects
Male ,Drug Compounding ,Drug Evaluation, Preclinical ,Administration, Oral ,Pharmaceutical Science ,02 engineering and technology ,Aquatic Science ,030226 pharmacology & pharmacy ,Dosage form ,Rats, Sprague-Dawley ,03 medical and health sciences ,Dogs ,0302 clinical medicine ,IVIVC ,Pharmacokinetics ,Drug Discovery ,medicine ,Animals ,Dissolution testing ,Dissolution ,Antihypertensive Agents ,Ecology, Evolution, Behavior and Systematics ,Chromatography ,Ecology ,Elution ,Chemistry ,Indapamide ,General Medicine ,Permeation ,021001 nanoscience & nanotechnology ,Rats ,Drug Liberation ,Jejunum ,Intestinal Absorption ,Solubility ,0210 nano-technology ,Agronomy and Crop Science ,Forecasting ,Tablets ,medicine.drug - Abstract
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 FaSSIFmod 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 FaSSIFmod is suitable to predict the possible absorption rate-limiting steps of poorly soluble drugs in DDASS.
- Published
- 2019
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