Development and Characterization of Gastro-Intestinal Simulator (GIS)

Abstract

For oral drug formulations, the efficacy of a formulation in an individual is dependent on many physiological processes and variables. For most immediate release drug products, the formulation must disintegrate and dissolve, undissolved mass must empty from the stomach into the upper gastrointestinal (GI) tract, and remaining undissolved drug must dissolve and be absorbed across the intestinal wall to reach systemic circulation. Despite understanding the relevant processes, conventional in vitro methods only capture a part of these processes by performing dissolution at one pH without any other processes acting on the formulation. In this work, a dissolution device is developed that simulates the relevant in vivo processes that can affect drug dissolution. This device is called the Gastro-Intestinal Simulator or (GIS) and is designed to simulate in vivo conditions in a way that maintains ease of use. Compared to other multi-vessel dissolution devices, the GIS can be run multiple times in a day by just one analyst. The device has been designed with customizability in mind, with the ability for vessel geometry to be easily selected, a variety of gastric emptying rates applied, and a titration function to maintain pH in the chamber representing the upper intestine (e.g. duodenum) when using biorelevant media. Applications of the device were evaluated with two sets of experiments: determination of in vitro – in vivo correlations (IVIVC), and formulation screening tests to determine sensitivity to formulation variables and results compared to conventional testing procedures. IVIVCs are a valuable tool in quantifying drug release into systemic circulation but require physiologically relevant dissolution data. The dissolution data generated for two ibuprofen formulations in the GIS did not produce a successful IVIVC. Although the results of this work failed to meet strict FDA requirements for an IVIVC, the results showed promise and provide a framework for future correlative dissolution. The GIS system has the capability for further optimization to better represent the conditions of the human intestine, which could allow for improved correlations including biorelevant media selection, gastric emptying, and introduction of an absorption compartment. For formulation optimization, a similar framework as other industrial process optimizations can be applied. However, multiple process and formulation variables increases the challenge of developing an understanding of these effects and therefore benefits from an appropriate experimental design. This empirical approach requires a statistical design of experiments and a Plackett-Burman design was selected as a screening approach designed to limit the number of experiments to determine the main effects of interest. The GIS results showed the most statistically significant factors compared to compendial disintegration and dissolution methods. In both applications, the GIS, when configured to simulate the relevant conditions of the human intestine showed significant promise for assessing formulations and mechanisms that lead to improved in vivo drug dissolution.