Purpose: Complex in vitro models of the upper gastro-intestinal (GI) tract that mimic the dynamic GI environment (in terms of hydrodynamics and fluid composition/characteristics) are potentially of high value for the development and understanding of new oral pharmaceutical products as they may be capable of providing a similar or better predictive ability than animal models. The dynamic gastric model (DGM) is one such model that simulate the pH profile and emptying time of the fed or fasted stomach and it can accommodate a glass of water as well as a full meal. Thus, the DGM can be used to evaluate the in vivo behavior of a dosage form in both the fasted and fed state. The aim of the current study was to evaluate if the DGM followed by a duodenal module, is able simulate the performance of diclofenac in the human gastro-intestinal (GI) tract, as reported in a previously published clinical study.
Methods: For both the fasted and the fed state, one Cataflam® tablet (50 mg diclofenac potassium) was pre-dissolved in 240 mL tap water to mimic the clinical study. For the fasted state studies, the 240 mLdiclofenac solution then was added to 50 mL gastric fluid with the DGM initially set to mimic the in vivo fasted state pH profile and gastric emptying time. Subsequently, the gastric volume was maintained at 50 mL throughout the experiment by balancing the gastric juice flow and gastric emptying volume. For the fed state studies, 400 ml Ensure Plus® was added to the DGM set to the in vivo fed state pH profile and gastric emptying time, and after 20 min of digestion the 240 mL diclofenac solution was added. For both the fed and fasted state experiments, the fraction of dissolved/solubilized and total diclofenac was determined using RP-HPLC. The samples ejected from the DGM was further added to a duodenal module for an additional 60 min.
Results: In the fasted state, the data from the DGM experiments simulated well the fraction of dissolved vs. total diclofenac observed in the in vivo study where the majority of the drug at fasted state low pH was in suspension. Furthermore, similar to the in vivo study, the following duodenal module indicated that the majority of the drug in the fasted state is then solubilize when the pH is increased in the small intestine (please note the lack of absorption/transit in the DGM results in a constant drug level). In the fed state, the data from the DGM experiments also simulated well the fraction of dissolved vs. total diclofenac observed in the in vivo study where the majority of the drug was in solution throughout. Furthermore, decreasing the pH did not lead to precipitation of diclofenac, probably due to solubilization caused by the lipids/surfactants present from the Ensure Plus® “meal”. In the following duodenal model, most drug was not surprisingly in solution, which was also observed in vivo.
Conclusion: The study showed that the DGM is able mimic the mass balance of a diclofenac formulation in vivo probably because the volume, gastric emptying and pH can be accurately programmed to simulate human conditions. These findings indicate that the DGM has the potential to enable an assessment of the behavior and performance of any given drug delivery system during transit in the GI tract.
Mathias Fanø– Senior Pharmaceutical Scientist, Bioneer:FARMA, Copenhagen
Preben Olesen– Senior Pharmaceutical Scientist, Bioneer:FARMA, Copenhagen
James Butler– GSK
Anette Mullertz– Professor, University of Copenhagen, Copenhagen