The
process of disintegration is a crucial step in oral drug delivery
with immediate release dosage forms. In this work, the salivary tracer
technique was applied as a simple and inexpensive method for the investigation
of the in vivo disintegration time of hard gelatin
capsules filled with caffeine. The disintegration times observed with
the salivary tracer technique were verified by magnetic resonance
imaging (MRI). After an overnight fast of at least 10 h and caffeine
abstinence of minimum 72 h, conventional hard gelatin capsules containing
50 mg caffeine and 5 mg iron oxide were administered to 8 healthy
volunteers. For the period of 1 h after capsule intake, subjects were
placed in supine position in the MRI scanner, and scans were performed
in short time intervals. Each MRI measurement was directly followed
by saliva sampling by drooling. Salivary caffeine concentrations were
determined by high performance liquid chromatography followed by mass
spectrometric detection (LC/MS-MS). The time point of capsule disintegration
was determined by visual inspection of the MR images as well as by
an increase in the salivary caffeine concentration. The results indicated
that the difference in mean disintegration times of the capsules as
determined by the two in vivo methods was around
4 min (8.8 min for MRI vs 12.5 min for saliva). All disintegration
times determined by the salivary tracer technique were slightly higher.
This delay could be explained by the fact that the appearance of caffeine
in saliva required drug absorption in the small intestine. Because
capsule disintegration happened mainly in the stomach, the exact site
of disintegration as well as the processes of gastric mixing and gastric
emptying contributed to the delay between the two methods. This work
demonstrated the feasibility of the salivary tracer technique to investigate
the in vivo disintegration of immediate release dosage
forms in a simple and reliable manner.
In the postprandial stomach, processes such as secretion, digestion, and gastric emptying all occur simultaneously. Therefore, the system is highly heterogeneous and dynamically changing, for instance, in terms of various physicochemical parameters such as pH value or viscosity. Thus, the administration of a drug together with food can result in highly variable drug plasma concentrations, which may affect the efficacy and safety of the pharmacotherapy. In this work, the pharmacokinetic (PK) data obtained from two fed-state bioequivalence studies with the immediate release (IR) drug products Viagra (sildenafil) and Adenuric (febuxostat) have been analyzed. This evaluation revealed that basically three characteristic types of onset behaviors of drug plasma concentration can be distinguished. It was hypothesized that the different types of onset behaviors were mainly caused by the interplay between gastric drug dissolution and gastric emptying. To study this interplay in vitro, a biopredictive dissolution toolGastroDuowas developed and used for both drug products. Therefore, three different test programs have been applied to simulate certain aspects of the postprandial human stomach, which included dynamic pH changes, gastric peristalsis, and the kinetics of gastric emptying. Specifically, the behavior of noncaloric fluids by the so-called "Magenstrasse" was taken into deeper consideration. The experiments revealed that the dissolution and emptying behavior of the two drug products were affected in different ways by the three test programs. The in vitro data nicely explained the tendencies of the drug products for certain types of onset behaviors observed in the PK data. While Viagra was strongly affected by simulated peristalsis, Adenuric was more sensitive to the simulated emptying kinetics. This work clearly demonstrated the important role of gastric fluid emptying for the onset of drug plasma concentration after oral administration of IR formulations in the fed state. Moreover, this was the first study in which GastroDuo was applied as a biopredictive in vitro model which is able to simulate crucial parameters of the human stomach (e.g., pH profiles and gastric emptying) in a realistic manner.
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