Comparison of In Vitro and In Vivo Results Using the GastroDuo and the Salivary Tracer Technique: Immediate Release Dosage Forms under Fasting Conditions

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.

The Effect of Capsule-in-Capsule Combinations on In Vivo Disintegration in Human Volunteers: A Combined Imaging and Salivary Tracer Study

“…To trace the disintegration by salivary caffeine assessment, natural caffeine was added to the outer capsule and 13 C 3 -labeled caffeine to the inner capsule. This latter procedure has been successfully established in recent years [12,13]. However, visualization of the disintegration using the hibiscus tea powder previously used in vitro was not reproduced in this human trial.…”

“…Capsules consisted of three single capsules (arms I, II, and VII, Table 1) and seven different DUOCAP ® combinations (III, IV, V, VI, VIII, IX and X, Table 1). For each study arm, an observation period was set based on the estimated maximum in vivo disintegration time of the individual capsules or the inner capsule of the DUOCAP ® combinations (Table 1) according to results of previous studies [11][12][13]. All subjects arrived at the study unit in the morning after at least 10 h overnight fast.…”

“…This method met the criteria of the FDA Guidance for Industry "Bioanalytical Method Validation". A detailed description of the analytical method is given elsewhere [13].…”

“…After its release caffeine is quickly absorbed and can be rapidly detected in saliva, thus serving as a non-invasive disintegration marker [10]. To be able to distinguish between the disintegration of the outer and the inner capsules, natural caffeine was added to the infill between outer capsule and inner capsule whilst the inner capsules were filled with 13 C 3 labeled caffeine. This utilization of stable isotope labeled caffeine for determination of dosage form disintegration is first described in this study and might find further applications in the future.…”

In vitro models to evaluate ingestible devices: Present status and current trends

“…Further work with this apparatus has explained in vivo data on fast disintegrating and dissolving aspirin tablets compared to conventional tablets where the rapid emptying of dispersed aspiring in the fed state could be replicated in vitro [180]. Further work exploring the link between this apparatus and in vivo data compared the performance of one film-coated tablet and three different capsule immediate release formulations of caffeine; although the in vitro apparatus discriminated between the performance of these dosage forms the in vivo data was not in line with this in vitro data [181].…”