Abstract
In this work, two different approaches have been developed to predict the food effect and the bioequivalence of marketed itraconazole (ITRA) formulations. Kinetic solubility and simultaneous dissolution-permeation tests of three (ITRA) formulations (Sporanox capsules and solution and SUBA-ITRA capsules) were carried out in simulated fasted and fed states. Fraction of dose absorbed ratios estimating food effect and bioequivalence were calculated based on these results and were compared to the in vivo study results published by Medicines Agencies. The comparison demonstrated that kinetic solubility and flux values could be used as input parameters for biopharmaceutics modeling and simulations to estimate food effect and bioequivalence. Both prediction methods were able to determine a slightly negative food effect in the case of the Sporanox solution and also a pronounced positive food effect for the Sporanox capsule. Superior bioavailability was predicted when the Sporanox solution was compared to the Sporanox capsule (in agreement with in vivo data).
Highlights
IntroductionPart of the gastrointestinal unified theoretical (GUT) framework mathematical model, assuming that both free drug and micelle bound drug permeate through the unstirred water layer (UWL) by self-diffusion was found to be appropriate for the prediction of the fraction of dose absorbed (Fa) in the cases of lipophilic drugs with UWL limited absorption, by Sugano et al.[10,27]
In cases of lipophilic compounds where cellular membrane permeation is very fast, unstirred water layer (UWL) permeation is often the rate-limiting step of absorption.[11−15] While the bile micelles and CDs usually increase the solubility of lipophilic compounds it has been realized that they decrease the effective permeability (Peff) due to a reduction of the fraction of free drug at the epithelial membrane surface and/or the reduction of the diffusion coefficient in the UWL caused by the enlarged hydrodynamic radius of the micelle or CD complex as compared to the pure active pharmaceutical ingredients (API).[16−26] the balance of the solubility increase and the Peff decrease determines the direction and the extent of the food or CD effect.[17]
In these cases, kinetic solubility measurements, which were expected to result in several times higher solubility values than the equilibrium thermodynamic solubility,[28] were chosen to determine the solubilizing effect of bile micelles and formulation additives on ITRA
Summary
Part of the gastrointestinal unified theoretical (GUT) framework mathematical model, assuming that both free drug and micelle bound drug permeate through the UWL by self-diffusion was found to be appropriate for the prediction of the fraction of dose absorbed (Fa) in the cases of lipophilic drugs with UWL limited absorption, by Sugano et al.[10,27].
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