Abstract
The fasted state administration of immediate release (IR) dosage forms is often regarded as uncritical since physiological aspects seem to play a minor role for disintegration and drug release. However, recent in vivo studies in humans have highlighted that fasted state conditions are in fact highly dynamic. It was therefore the aim of this study to investigate the disintegration and drug release behavior of four different IR formulations of the probe drug caffeine under physiologically relevant conditions with the aid of the GastroDuo. One film-coated tablet and three different capsule formulations based on capsule shells either made from hard gelatin or hydroxypropylmethyl cellulose (HPMC) were tested in six different test programs. To evaluate the relevance of the data generated, the four IR formulations were also studied in a four-way cross-over study in 14 healthy volunteers by using the salivary tracer technique (STT). It could be shown that the IR formulations behaved differently in the in vitro test programs. Thereby, the simulated parameters affected the disintegration and dissolution behavior of the four IR formulations in different ways. Whereas drug release from the tablet started early and was barely affected by temperature, pH or motility, the different capsule formulations showed a longer lag time and were sensitive to specific parameters. However, once drug release was initiated, it typically progressed with a higher rate for the capsules compared to the tablet. Interestingly, the results obtained with the STT were not always in line with the in vitro data. This observation was due to the fact that the probability of the different test programs was not equal and that certain scenarios were rather unlikely to occur under the controlled and standardized conditions of clinical studies. Nonetheless, the in vitro data are still valuable as they allowed to discriminate between different formulations.
Highlights
It is generally assumed that the fasted state administration of immediate release (IR) drug products results in less variable drug plasma concentrations as compared to fed state administration
This conception is based on two main assumptions: (1) drug release from IR formulations is fast and, (2) the physiological parameters of the human gastrointestinal (GI) tract which are important for oral drug delivery are less variable
Several physiological factors such as luminal fluid volumes present in stomach and small intestine, mechanical stresses resulting from peristalsis, luminal pH values, and temperature can be relevant for drug release from IR formulations
Summary
It is generally assumed that the fasted state administration of immediate release (IR) drug products results in less variable drug plasma concentrations as compared to fed state administration This conception is based on two main assumptions: (1) drug release from IR formulations is fast and, (2) the physiological parameters (e.g., gastric emptying, gastric pH) of the human gastrointestinal (GI) tract which are important for oral drug delivery are less variable. [2] was gained in recent years through different in vivo investigations that aimed at characterizing the physiological conditions in the stomach and the small intestine [3,4,5,6] These studies revealed that the conditions in the human GI tract can be highly variable and in particular, gastric emptying was shown to be largely dynamic [5]. Grimm et al investigated the inter and intrasubject variability in gastric emptying [6]
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