Sulaiman, Sarah
(2023)
Bowel MRI imaging to investigate drug delivery from coated capsules.
PhD thesis, University of Nottingham.
Abstract
Background
Magnetic resonance imaging (MRI) has the potential to provide new physiological insights into oral dosage forms in the undisturbed human GI tract. This potential has been recently shown in the literature, however these initial studies principally focused on the upper GI tract. Applications to the lower GI tract and particularly to MRI imaging of coated capsules remain to be explored to date.
Aims
Building on the available literature, this work therefore aimed to:
1. Design and manufacture coated capsules with the potential to reach the lower human intestine and at the same time to be MRI-visible
2. Develop and demonstrate a new MRI method to track the transit of the coated capsule and its disintegration in the lower human intestine
3. Load the coated capsule with an active pharmaceutical ingredient (API) and correlate the MRI findings with the API’s absorption kinetic
4. Explore additional MRI measurements of GI function of interest for oral dosage forms, such as small bowel motility measurements, by comparing MRI with concomitant perfused manometry
Key results
Size 0 (21 mm × 7 mm) capsules, consisting of a hydroxypropyl methylcellulose (HPMC) shell, dip-coated with different amounts of synthetic polymer Eudragit® S 100 were designed and manufactured manually in house. The capsules were filled with 0.65 mL of olive oil as MRI-visible marker fluid. Standard, basket apparatus disintegration tests showed that the capsules were able to withstand the upper gastrointestinal tract acid conditions and that disintegration time in intestinal condition increased with weight gain due to coating. The capsules could also be visualised in vitro using MRI. The in vivo imaging feasibility study in 10 healthy adult participants showed
that it was possible to track capsules with varying amounts of coating in the human gastrointestinal tract. The capsules’ loss of integrity was imaged exploiting the ability of MRI to image fat and water separately, and in
combination. By the 360 min end of the study, out of the 10 participants, the capsules were imaged in the small bowel in 9 participants, in the terminal ileum in 8 participants and in the colon in 4 participants. Loss of capsule’s
integrity was observed for 8 participants out of 10, occurring predominantly in distal intestinal regions.
After this, 75 mg of caffeine was added in suspension to the olive oil inside the capsules. The selection of this dose was based on literature searches and aimed to provide a safe active pharmaceutical ingredient marker, and also a marker that could be adequately absorbed from the unfavourable
environment of the large intestine and then be detected in saliva. For this purpose, a pre-existing high-performance liquid chromatography (HPLC) assay was used. The conditions, peak shapes and run time for the injections were optimised for this study and the assay’s lower limits of detection
characterised. Nine healthy participants were then administered capsules manufactured with varying amounts of Eudragit® S 100 coating from 0 mg to 36 mg weight gain. The timing of the first loss of capsule integrity detected in
the body using MRI correlated well with the onset of increase in caffeine concentration in the saliva from the baseline level (R2 = 0.76, p = 0.0022). Lastly, the work explored the ability of MRI to monitor small bowel motility
using retrospective data whereby 18 healthy volunteers underwent concomitant MRI and perfused manometry monitoring of duodenal motility. Total of 393 data sets could be compared showing limitations of the MRI protocol and a modest (R2 = 0.1214) but significant (p < 0.0001) correlation between the values of motility indexes derived from MRI and corresponding perfused manometry values. The association between MRI peaks of motility and MMC III events was statistically significant (p < 0.0001).
Conclusion
Building on initial reports in the literature this work has successfully developed and tested in vivo a coated capsule using a new concept for the MRI-visible filling. MRI was able to determine location and disintegration times of these coated capsules in the distal intestine, and this correlated well with absorption kinetics of a model active pharmaceutical ingredient, caffeine in this case. This work adds to the field new methods to study performance of coated
capsules in vivo in an undisturbed bowel. The new data and techniques will in turn help to make in vitro pharmacopoieial tests and kinetic and bench dynamic modelling more in vivo relevant. MRI has also the potential to assess other parameters of gastrointestinal function which are relevant for dosage form transit and disintegration such as small bowel motility. However such
methods have limitations and more work to incorporate them with the MRI tracking of coated capsules remains to be done.
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