Mechanistic Transport Analysis to Predict In Vivo Oral Bioperformance.

Abstract

Oral delivery of solid dosage forms is the most frequently used route of administration for pharmaceutical drug products. Despite their ubiquity, development of robust oral dosage forms can be challenging due to the complex nature of dissolution and absorption in the gastrointestinal tract. The goal of this research was to set a basis for development of practical in vitro physiological dissolution methodologies that could be used to design drug product formulations and scientifically justify reduced regulatory requirements for product approval (e.g. introduction of generic products). While existing methodologies can be used as benchmarks for development of new dosage forms, no single in vitro apparatus captures the range of key physiological conditions that can impact in vivo bioperformance of a diverse range of drug products. In this work we provide a comprehensive and up-to-date summary of the critical physiological parameters affecting dissolution and absorption of oral dosage forms in humans and dogs, including average values and ranges for each parameter from the literature. Next, we developed a mechanistic transport model that successfully described the kinetics of partitioning of weak acids in solution from aqueous to organic medium, and proposed scaling factors for establishing physiological relevance of the in vitro two-phase dissolution apparatus. In contrast to previous kinetically derived mathematical models, our model uses physical input parameters that are known or can be estimated a priori. Next, we developed a mechanistic transport model for predicting the rate and extent of dissolution of solid drug particles under physiological conditions (e.g. low buffer capacity and moderate drug saturation), extending previously published models by taking into account the impact of dissolved drug concentration on pH change and dissolution performance as a function of time. Finally, we developed an in vivo transport analysis to identify practical in vitro dissolution methodologies that could be used to predict in vivo performance of oral formulations of the BCS II weak acid, Ibuprofen, in dogs. Taken as a whole, this work sets a basis for determination of the key, rate-determining factors driving in vivo oral drug product bioperformance, and selection of appropriate in vitro predictive dissolution methodologies.