Food-dependent disintegration of immediate release fosamprenavir tablets: In vitro evaluation using magnetic resonance imaging and a dynamic gastrointestinal system

• DOI: 10.1016/j.ejpb.2010.10.009
• Publication Date: 2010-11-04T08:34:18Z
• Authors: Joachim Brouwers; Bart Anneveld; Gert-Jan Goudappel; Guus Duchateau; Pieter Annaert; Patrick Augustijns; Evelijn Zeijdner
• Keywords: 0301 basic medicine; Sulfonamides; Fasting; HIV Protease Inhibitors; Postprandial Period; Magnetic Resonance Imaging; Organophosphates; 3. Good health; Gastrointestinal Tract; Food-Drug Interactions; 03 medical and health sciences; Solubility; Humans; Carbamates; Furans; Tablets

In the present study, we demonstrated the value of two advanced tools, the TNO gastric and small Intestinal Model (TIM-1) and magnetic resonance imaging (MRI), for the in vitro evaluation of food-dependent disintegration of immediate release fosamprenavir tablets. Upon introduction of a tablet with the nutritional drink Scandishake Mix® in the stomach compartment of TIM-1, simulating the fed state, disintegration and fosamprenavir dissolution were significantly postponed compared to the fasted state (lag time 80 ± 23 min). This resulted in a lag in the appearance of bioaccessible fosamprenavir (<5% during the first 2h), even though the nutritional state did not significantly alter the cumulative bioaccessibility after 5h. These results were in agreement with the previously observed postprandial delay in gastric fosamprenavir tablet disintegration and subsequent amprenavir absorption in healthy volunteers. Therefore, TIM-1 can be used in tablet development to identify food-induced disintegration issues causing unexpected clinical behavior. From a mechanistic perspective, we applied MRI to illustrate impaired water ingress in fosamprenavir tablets immersed in the nutritional drink compared to simulated gastric fluid. This effect may be attributed to both competition between nutritional components and the tablet for the available water (indicated by reduced rotational and translational diffusion) as well as the possible formation of a food-dependent precipitation layer on the HPMC-coated tablet.