X-ray Imaging for Gastrointestinal Tracking of Microscale Oral Drug Delivery Devices

Kjeldsen, Rolf Bech; Kristensen, Maja Nørgaard; Gundlach, Carsten; Thamdrup, Lasse Højlund Eklund; Müllertz, Anette; Nielsen, Line Hagner; Zór, Kinga

doi:10.1021/acsbiomaterials.1c00225

Cited by 16 publications

(13 citation statements)

References 49 publications

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“…Additionally, imaging of intestinal sections from two rats 2.5 h after dosing, revealed the presence of empty, but otherwise intact, DCMCs in the ileum (Figure 5G). These observations confirm that the DCMCs were structurally undamaged and non‐digested as previously observed, [ 51 ] and that the enteric coating was completely dissolved and the drugs successfully released from both compartments.…”

Section: Resultssupporting

confidence: 90%

Sequential Drug Release Achieved with Dual‐Compartment Microcontainers: Toward Combination Therapy

Christfort

Milián‐Guimerá

Kamguyan

et al. 2022

Advanced Therapeutics

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Combination drug therapy is commonly used to treat cancer, diabetes, cardiovascular conditions, and infections. However, these therapies face challenges associated with patient compliance and toxicology. Over the past decades, microdevices have emerged as a promising candidate for oral delivery allowing for targeted drug delivery with a tunable drug release. In the present work, engineered and monodisperse dual‐compartment microdevices are developed to achieve a physical separation of two drugs followed by a sequential release in the gastrointestinal tract. As proof‐of‐concept, the compartments are sealed with two pH‐sensitive polymers of different thicknesses to control the sequential release of propranolol and furosemide. In vitro release studies and in vivo absorption studies in rats confirm a sequential drug release from the two compartments. Unlike other proposed approaches, it is highly advantageous that the drugs can be loaded directly as powders, and that their release can be tuned via optimized coatings to achieve the desired release and absorption profiles. Conclusively, this study lays a strong foundation for the future use of microdevices to enable co‐delivery of drugs followed by a sequential release in close proximity in the gastrointestinal tract.

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Section: Resultssupporting

confidence: 90%

Sequential Drug Release Achieved with Dual‐Compartment Microcontainers: Toward Combination Therapy

Christfort

Milián‐Guimerá

Kamguyan

et al. 2022

Advanced Therapeutics

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“…To evaluate the mucoadhesive properties observed ex vivo for the neutral, pillar, and arrow microcontainer designs, retention and transit times were investigated in an in vivo rat study using planar X-ray imaging for quantitative GI tracking, similarly to what has previously been demonstrated. [15,31] Prior to the study, having n = 2 rats was discussed but chosen in order to reduce the total number of animals needed to look for any apparent differences in GI retention and transit between the different microcon-tainer designs. Furthermore, an appropriate statistical procedure (Gaussian process with a squared exponential kernel and a Poisson likelihood) was going to be applied on the data obtained.…”

Section: Quantitative Gastrointestinal Tracking For Retention and Tra...mentioning

confidence: 99%

3D‐Printed Radiopaque Microdevices with Enhanced Mucoadhesive Geometry for Oral Drug Delivery

Chang

Kjeldsen

Christfort

et al. 2022

Adv Healthcare Materials

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During the past decades, microdevices have been evaluated as a means to overcome challenges within oral drug delivery, thus improving bioavailability. Fabrication of microdevices is often limited to planar or simple 3D designs. Therefore, this work explores how microscale stereolithography 3D printing can be used to fabricate radiopaque microcontainers with enhanced mucoadhesive geometries, which can enhance bioavailability by increasing gastrointestinal retention. Ex vivo force measurements suggest increased mucoadhesion of microcontainers with adhering features, such as pillars and arrows, compared to a neutral design. In vivo studies, utilizing planar X-ray imaging, show the time-dependent gastrointestinal location of microcontainers, whereas computed tomography scanning and cryogenic scanning electron microscopy reveal information about their spatial dynamics and mucosal interactions, respectively. For the first time, the effect of 3D microdevice modifications on gastrointestinal retention is traced in vivo, and the applied methods provide a much-needed approach for investigating the impact of device design on gastrointestinal retention.

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“…For this, MCs were loaded with the contrast agent, BaSO4, then coated with either ZT-80 (the mucoadhesive coating) or EFS100 (the non-mucoadhesive control), loaded into gelatin capsules, and dosed to rats. The movement of the coated MCs after the dosage was tracked and visualized inside the GIT of rats, using a previously reported method [45]. Figure 5A shows representative computed tomography (CT) scan images, while in Figure 5B we can see the corresponding planar X-ray images of the intestines of rats after dosage with the coated MCs.…”

Section: Intestinal Retentionmentioning

confidence: 99%

Bioadhesive Tannic-Acid-Functionalized Zein Coating Achieves Engineered Colonic Delivery of IBD Therapeutics via Reservoir Microdevices

et al. 2022

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The biggest challenge in oral delivery of anti-inflammatory drugs such as 5-aminosalicylic acid (5-ASA) is to (i) prevent rapid absorption in the small intestine and (ii) achieve localized release at the site of inflammation in the lower gut, i.e., the colon. Here, we present an advanced biopolymeric coating comprising of tannic-acid-functionalized zein protein to provide a sustained, colon-targeted release profile for 5-ASA and enhance the mucoadhesion of the dosage form via a mussel-inspired mechanism. To enable localized delivery and provide high local concentration, 5-ASA is loaded into the microfabricated drug carriers (microcontainers) and sealed with the developed coating. The functionality and drug release profile of the coating are characterized and optimized in vitro, showing great tunability, scalability, and stability toward proteases. Further, ex vivo experiments demonstrate that the tannic acid functionalization can significantly enhance the mucoadhesion of the coating, which is followed up by in vivo investigations on the intestinal retention, and pharmacokinetic evaluation of the 5-ASA delivery system. Results indicate that the developed coating can provide prolonged colonic delivery of 5-ASA. Therefore, the here-developed biodegradable coating can be an eco-friendly substitute to the state-of-the-art commercial counterparts for targeted delivery of 5-ASA and other small molecule drugs.

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X-ray Imaging for Gastrointestinal Tracking of Microscale Oral Drug Delivery Devices

Cited by 16 publications

References 49 publications

Sequential Drug Release Achieved with Dual‐Compartment Microcontainers: Toward Combination Therapy

Sequential Drug Release Achieved with Dual‐Compartment Microcontainers: Toward Combination Therapy

3D‐Printed Radiopaque Microdevices with Enhanced Mucoadhesive Geometry for Oral Drug Delivery

Bioadhesive Tannic-Acid-Functionalized Zein Coating Achieves Engineered Colonic Delivery of IBD Therapeutics via Reservoir Microdevices

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