A biopharmaceutics design model for oral delivery: Predicting intestinal drug absorption.

Abstract

An integrated absorption model was developed to describe the small intestinal transit, dissolution, and permeation processes of drugs. Based on this integrated model and the drug classification system, we presented a biopharmaceutics design model for oral delivery. The design model essentially states that oral drug absorption can be limited by dissolution, solubility, permeability or any combination of them. Using digoxin, griseofulvin, and panadiplon as model drugs, we demonstrated the applications of the design model to support formulation strategies with emphasis on micronization. The model may be used in facilitating lead drug candidate selection, identifying critical factors, and supporting formulation strategies. For nonabsorbable drugs, the integrated absorption model can be reduced into the compartmental transit model. The transit model has been used to characterize the human small intestinal transit flow. A dispersion model and a single-compartment model were also employed to depict the dispersion and fluid flow in the human small intestine. It was found that the small intestinal transit flow profile was well characterized by the compartmental transit and dispersion models, but not by the single-compartment model. We concluded that the transit model might be superior to the single-compartment model and less complex than the dispersion model. For highly soluble drugs dosed in immediate release products, the integrated absorption model can be simplified into the compartmental absorption and transit (CAT) model. In this case the fraction of dose absorbed could be estimated by $\rm F\sb{a}=1{-}(1+0.54\ P\sb{eff})\sp{-7},$ where $\rm P\sb{eff}$ is the effective permeability in cm/hr. A good correlation was obtained between the fraction of dose absorbed and the effective permeability for ten drugs covering a wide range of absorption characteristics. Unlike the mass balance approaches and the dispersion models, the CAT model can relate to pharmacokinetic models to estimate plasma concentration profiles for drugs with passive diffusion or carrier-mediated absorption mechanisms. Using atenolol and cefatrizine as model drugs, it was shown that the CAT model, coupling with intravenous kinetics and gastric emptying, was able to estimate the oral plasma concentration profiles.