Developing Models to Improve Oral Drug Product Delivery in the Human Gastrointestinal Tract

Abstract

Oral drug products must dissolve in the gastrointestinal (GI) tract before being absorbed and reaching the systemic circulation. The rate and extent of drug dissolution and absorption depend on the characteristics of the active ingredient, properties of the drug product, physiological parameters such as buffer species, pH, bile salts, gastric emptying rate, intestinal motility, and hydrodynamic conditions. Drug products may overcome small-molecule drug's low solubility or permeability under the standard and disease conditions of the GI tract by adding compounds called excipients to the formulations. Since the conventional compendial dissolution and absorption tests often fail to predict drug compounds' behavior in the GI tract, designing and testing the newly designed drug formulations remains a challenge for the pharmaceutical industry. Therefore, developing cost-effective, reliable bio-relevant predictive dissolution and absorption models that can improve and accelerate product development is in high demand. This work develops mathematical mass transfer models for drug dissolution in a variety of physiologically-relevant media including bicarbonate buffer, which is the main buffering system in the GI tract. Dissolution in bicarbonate buffer, which takes into account the hydration and dehydration reaction rate constants of carbon dioxide and carbonic acid, is called the reversible non-equilibrium (RNE) model. Also, a mechanistic mass transfer model for weak-base, weak-acid, and non-ionizable drug compounds dissolution is developed; this in silico model, which is called hierarchical mass transfer (HMT) successfully predicts drug dissolution under the in vitro and simulated in vivo conditions by accounting for the effect of drug properties (i.e., solubility, acid/base character, pKa, particle size), GI fluid properties (i.e., bulk pH, buffer species concentration), and fluid hydrodynamics (i.e., shear rate, convection) on drug dissolution through a mathematical transport model. Next, a mass transfer model is developed to quantify the impact of co-administration of acid-reducing agents (ARA) (i.e., proton pump inhibitors (PPI) and antacids) on the bioavailability of weakly basic drugs and provides a rationale for selection of the optimum excipient to improve the weak-base formulation bioavailability by modulating the gastric pH. Finally, this work provides insights into in vitro drug dissolution device design and compares the hydrodynamic conditions in a commonly used in vitro dissolution device with other systems with different stirrer and vessel designs. The selected design can overcome some of the common challenges in the in vitro dissolution apparatuses, such as particle settling and can lead to dissolution testing approaches with higher experimental reproducibility and more robust in vitro- in vivo correlations (IVIVC). To conclude, this thesis sets a basis for the quantification of drug dissolution rate and extent by taking into account for the impact of the rate-determining factors controlling in vivo and in vitro oral drug product bioperformance; compared to other drug dissolution models, our physiologically-realistic model predictions are in a good agreement with the experimental dissolution data with less than 5% error if all of the assumptions associated with the model are met with the experimental conditions. In addition, this work facilitates the design of an in vivo-relevant in vitro device to simulate drug dissolution and absorption in the human GI tract, which is simple, practical, reliable, and useful.