Imaging of Microcontainers Used for Oral Drug Delivery

Among patients, the most convenient and preferred route for administration of drugs is oral and thus, it is the ultimate goal when developing new types of drug delivery systems. However, oral drug delivery is challenging because of chemical, physical and biological barriers found throughout the gastrointestinal (GI) tract. Microscale devices have generally shown great promise to overcome these environmental challenges and during the past years, cylindrical polymeric microdevices, directly referred to as microcontainers (MCs), have been fabricated and tested for oral drug delivery. Overall, MCs are loaded with a drug and closed off with an enteric lid before oral administration. Prior to performing clinical trials on targeted oral drug delivery to the human small or large intestine using MCs, pre-clinical studies with laboratory animals should be performed to better understand the drug absorption and the GI behavior of the MCs. In order to investigate GI behavior, like mucoadhesion and retention and transit time, of MCs after oral administration, imaging with biomedi­cal techniques based on magnetic resonance, ultrasound or x-rays is useful. Imaging with these techniques might include contrast strategies for creating or enhancing the image signal from the MCs. Loading of contrast agents into the MCs or incorporating them into the shell of the MCs could be advantageous contrast strategies.
In this PhD project, magnetic resonance imaging, ultrasound imaging and x-ray imaging have been evalu­ated for investigating GI behavior of MCs. Initial proof-of-concept studies were carried out with all three techniques, from which x-ray imaging seemed to be the most ideal. Thus, x-ray imaging was applied in more extensive studies regarding GI behavior. These included the MCs to be loaded with a contrast agent, barium sulfate (BaS04), and coated with poly(lactic-co-glycolic acid) (PLGA) to retain the BaS04 inside the MCs.
X-ray imaging, both planar x-ray imaging and computed tomography scanning, was used to qualitatively and
quantitatively track BaS04-loaded MCs following to an in vivo study with rats. This x-ray imaging approach was further used for studies investigating how GI behavior is affected by chemical functionalization (material composition) and physical functionalization (morphology and topography) of the MCs. Results from these studies suggested that some sort of dynamic physical functionalization seems to be necessary in order to sig­nificantly improve mucoadhesion and retention and transit time of MCs in the presence of peristaltic forces and the flow of digestive products and water. Furthermore, different approaches for incorporating BaS04 into the shell of MCs were developed. This involved mixing of BaS04 with SU-8, PLGA or 3D print resin for photolithography, mold casting and microscale 3D printing, respectively. Subsequent characterization and testing of the devices were carried out, and, especially, 3D-printed radiopaque MCs showed promising results in terms of being visible and quantifiable in the GI tract of rats. In conclusion, x-ray imaging has been successfully utilized for GI tracking of MCs and for future studies regarding oral drug delivery, MCs with BaS04 incorporated into the shell could be used to advance and thus leaving space for the actual drug.