(51c) Simulation of In-Vitro Gastrointestinal Digestion for Understanding Food Effect On Oral Drug Delivery

Oral delivery is preferred by the pharmaceutical industry, in large part due to patient convenience and compliance, but is not always possible due to low oral bioavailability. It has been observed that the presence of food can positively or negatively affect oral drug absorption, but these effects are not currently amenable to quantitative prediction. To understand food-drug interactions, it is crucial to develop an in-vitro system that simulates the digestion process in the stomach and intestine. Many in-vitro models have been developed that mimic digestion events in the gastrointestinal (GI) tract. However, they fail to accurately represent this dynamic environment, to a large extent because the majority of these models only take into account intestinal digestion, disregarding the fact that a significant portion of food is first digested as it passes through the stomach. Little information is available for gastric digestion. Hence, it has either been ignored or simulated via an extremely simplified in-vitro gastric digestion process that does not nearly match in-vivo events. Here we present an effort to simulate gastric digestion of milk as a relatively simple representative food model containing  major components (protein, carbohydrate, fat) of a normal diet. We have designed model milk containing 33 g/L triolein, 32 g/L casein, and 53 g/L lactose. The simulated gastric fluid contains a mixture of phospholipids, specifically phosphatidylcholine at 0.133 g/L, and salts, specifically NaCl (67 mM), KCl (14 mM), and CaCl₂ (0.6 mM). Moreover, it also contains the two major gastric enzymes, pepsin and lipase, the concentrations of which are determined based on reported in-vivo activity data. Gastric digestion is mimicked via concurrent lipolysis and proteolysis while dropping pH stepwise every 5 min over a 1h timeframe from pH 6.5 to 1.7. The extent of digestion achieved (~30%) agrees with reported in-vivo gastric digestion. Some protein precipitation occurs as the pH of the solution approaches the isoelectric point of caseins (pI = 4.6). Dynamic light scattering analysis of particle size reveals the formation of relatively large (~900 nm – 1 um) emulsions in solution as well as micellar size (~1-5 nm) particles which are believed to include phospholipids. As the colloidal structures present during digestion serve as carriers for lipophilic drugs, impacting dissolution and absorption, analysis of structure, composition, and kinetics of partitioning of compounds within them will be useful for mechanistic and predictive models of the impact of food on bioavailability.