Development of a Clinically Relevant Dissolution Approach to Simulate Physiological Forces with a USP 2 Apparatus: “Peristaltic Dissolution”

Abstract

Gastrointestinal hydrodynamics are poorly replicated in vitro and can significantly alter the release kinetics of drug products due to compressive forces in the stomach and peristaltic movement in the intestines. In this work, we describe the development and application of a predictive in vitro dissolution device that simulates gastrointestinal forces for the testing of oral drug products. The peristaltic dissolution device developed herein is designed as an addition to the common USP Apparatus 2 that applies repetitive compressive forces via a piston during dissolution testing of a product to replicate in vivo conditions. A dissolution testing device was designed, fabricated, and evaluated against human in vivo pharmacokinetic data to better mimic the physical forces present in the gastrointestinal tract. An optimized compression protocol to predict in vivo dissolution was developed using clinical data from two modified release carvedilol drug products. The apparatus was further evaluated using data from an additional modified release drug product. Finally, additional dissolution studies were performed to evaluate the utility of the apparatus for in vitro analysis of medicated gums, gastric retentive formulations, and long-acting injectable drug depots. The device was successfully implemented and the protocol to use the device was optimized using two initial drug products and further evaluated using an additional three drug products. The optimized protocol included a 1-h lag time (applicable in the fed state), followed by a cycle of 3 s of compression with 6 s intervals between compressions. Additional applications of the peristaltic dissolution device were also demonstrated through small exploratory studies, with continued potential for further optimization of the testing protocols following further research. This simple compressive device referred to as the “peristaltic dissolution device” was successfully proven to better predict in vivo performance of modified release drug products, as gastrointestinal mechanical forces have been observed to significantly impact and occasionally cause complete dose dumping of controlled release formulations. In addition, it has proven to be easily adapted for evaluation of other drug products such as medicated gums, gastric retentive formulations, and ex vivo long-acting injectable drug depots.