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

Abstract

Controlling the time point and site of the release of active ingredients within the gastrointestinal tract after administration of oral delivery systems is still a challenge. In this study, the effect of the combination of small capsules (size 3) and large capsules (size 00) on the disintegration site and time was investigated using magnetic resonance imaging (MRI) in combination with a salivary tracer technique. As capsule shells, Vcaps® HPMC capsules, Vcaps® Plus HPMC capsules, gelatin and DRcaps® designed release capsules were used. The three HPMC-based capsules (Vcaps®, Vcaps® Plus and DRcaps® capsules) were tested as single capsules; furthermore, seven DUOCAP® capsule-in-capsule combinations were tested in a 10-way crossover open-label study in six healthy volunteers. The capsules contained iron oxide and hibiscus tea powder as tracers for visualization in MRI, and two different caffeine species (natural caffeine and 13C3) to follow caffeine release and absorption as measured by salivary levels. Results showed that the timing and location of disintegration in the gastrointestinal tract can be measured and differed when using different combinations of capsule shells. Increased variability among the six subjects was observed in most of the capsule combinations. The lowest variability in gastrointestinal localization of disintegration was observed for the DUOCAP® capsule-in-capsule configuration using a DRcaps® designed release capsule within a DRcaps® designed release outer capsule. In this combination, the inner DRcaps® designed release capsule always opened reliably after reaching the ileum. Thus, this combination enables targeted delivery to the distal small intestine. Among the single capsules tested, Vcaps® Plus HPMC capsules showed the fastest and most consistent disintegration.

Comparing Salivary Caffeine Kinetics of 13C and 12C Caffeine for Gastric Emptying of 50 mL Water

“…In this regard, caffeine might be favorable due to its higher solubilization rate and lower doses needed. Furthermore, the salivary sampling technique utilizing caffeine can also be applied to investigate the onset of dosage form disintegration, due to its rapid dissolution [ 14 , 15 , 16 , 17 ].…”

In Vivo Evaluation of a Gastro-Resistant HPMC-Based “Next Generation Enteric” Capsule

“…The newly developed “Next Generation Enteric” (NGE) capsules composed of Hypromellose (HPMC) and HPMC Acetate Succinate (HPMC-AS) are a promising approach for this goal. DRcaps ® designed release capsules are regularly used for enteric purposes [ 4 ], but show more time-dependent disintegration which might not be sufficient if an enteric formulation is necessary [ 5 ]. Furthermore, the NGE capsules have an improved manufacturing process compared to their predecessors, which enables an efficient industrial production.…”

“…There are different ways to detect the gastrointestinal transit of a dosage form, i.e., the labeling with olive oil and application of an mDIXON sequence [ 6 ]. However, for this study, two independent and established methods were used, that have already proven their capabilities [ 5 ]. Magnetic Resonance Imaging (MRI) observation and caffeine detection in saliva were used as they offer complementary advantages.…”

“…Hence, disintegration evaluated by caffeine appearance correlates with the time point from which the capsules integrity is disrupted, in a way that its infill can get in contact with the surrounding media or vice versa. These two complementary techniques have already proven their value to evaluate immediate release capsules [ 8 ] as well as DUOCAP ® combinations of capsules [ 5 ]. However, this is the first time these techniques were used to assess the performance of gastro-resistant capsules in fasted conditions.…”

Drug-Release Mechanisms Elucidated by Imaging Techniques: Visualizing the Invisible!

“…A capsule-in-capsule drug delivery device was analyzed in terms of the disintegration time and location as a function of the capsule material [3]. The MRI images of black iron oxide (in the inner capsule) revealed capsule disintegration in different regions of the gastrointestinal (GI) tract and have been compared to the established method of tracing salivary caffeine (radio-labeled in the inner capsule and natural caffeine in the outer capsule).…”