Influence of drug release properties of conventional solid dosage forms on the systemic exposure of highly soluble drugs
Journal Title: The AAPS Journal - Year 2001, Vol 3, Issue 3
Abstract
This study was designed to theoretically investigate the influence of drug release properties, characterized by the disintegration of a solid dosage form and dissolution of drug particles, on the systemic exposure of highly soluble drugs in immediate release products. An absorption model was developed by considering disintegration of a solid dosage form, dissolution of drug particles, gastrointestinal transit flow, and intestinal absorption processes. The absorption model was linked to a conventional pharmacokinetic model to evaluate the effect of disintegration and dissolution on the peak exposure (Cmax) and total exposure of area under the curve (AUC). Numerical methods were used to solve the model equations. The simulations show that the effect of disintegration of a dosage form and dissolution of drug particles depend on the permeability of a drug, with a low-permeability drug having a greater effect. To provide similar exposure to an oral solution formulation, a solid dosage form containing a low-permeability drug would need to dissolve more rapidly than a solid dosage form containing a high-permeability drug. It was shown theoretically for poorly permeable drugs that the disintegration rate constant has to be greater than 9 hour−1 (equivalent to approximately 90% in 30 minutes) to make both AUC and Cmax ratios higher than .9, ensuring the confidence interval of .80 to 1.25. The rapid in vitro release requirement of at least 85% dissolved in 30 minutes is sufficient for highly soluble and highly permeable drugs. However, for highly soluble and poorly permeable drugs, the appropriate in vitro release requirement seems to be 90% dissolved in 30 minutes.
Authors and Affiliations
Lawrence X. Yu, Christopher D. Ellison, Dale P. Conner, Larry J. Lesko, Ajaz S. Hussain
Keywords
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- EP ID EP682069
- DOI 10.1208/ps030324
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