Characteristics of contents in the upper gastrointestinal lumen after a standard high-calorie high-fat meal and implications for the in vitro drug product performance testing conditions

Abstract

Objectives: To measure the pH, buffer capacity, lipid content, bile acid content, and viscosity in the upper gastrointestinal (GI) lumen after a standard high-calorie, high-fat meal as well as the osmolality, lipid content and bile acid content in the aqueous phase of the gastric contents and the micellar phase of contents of the upper small intestine. To evaluate the implications of these findings for the composition of biorelevant media employed in vitro oral drug product performance testing representing the upper GI conditions after ingestion of the standard meal.

Methods: Eight healthy male adult volunteers participated in a two-phase, crossover study in which a homogenized standard meal was administered to the antrum via the gastric port of a naso-gastro-intestinal tube. A glass of tap water and single paracetamol and danazol doses were administered to the antrum of the stomach 30 min after the initiation of meal administration (Pentafragka et al., 2020). Samples were aspirated from the antrum and the upper small intestine over the next four hours. The pH and the buffer capacity of the samples were measured immediately upon aspiration, while viscosity, osmolality, and presence of solubilizing agents were measured after storage at -70 °C.

Results: The composition of gastric contents over time fluctuated less after the homogenized standard meal than after liquid meals with similar composition. Intra-subject variability of pH and buffer capacity in the stomach and in the upper small intestine was low. Mean viscosity values in the stomach at 100 s^-1 were 80-800 times higher than in the fasted state for more than 3 h after the standard meal. In the upper small intestine, mean viscosity values at 100 s^-1 were at least 100 times higher than in the fasted state for 4 h after the standard meal.

Conclusions: Based on data collected in this study, Level I and Level II biorelevant media simulating the intragastric conditions after ingestion of a standard meal could be simplified whereas FeSSIF-V2 composition was confirmed to be representative of the composition of contents in the upper small intestine. Representative values of viscosity in the stomach and the upper small intestine and Level II composition of the aqueous phase of gastric contents, after the standard meal, are proposed for first time.

Keywords: Biorelevant media; Fed state; Micellar phase; Physicochemical characteristics; Upper gastrointestinal lumen; Viscosity.