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

Abstract

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.

Bionanotechnology and bioMEMS (BNM): state-of-the-art applications, opportunities, and challenges

“…Microengineering has been demonstrated to be a useful technique for improving the efficacy of orally delivered drugs and has been utilized in a number of ways. This includes the integration of miniaturized devices within capsules 37 or the microfabrication of the drug delivery form factor itself, leading to novel methods of delivery such as microneedles, 38 microcontainers, 39,40 microgrippers 41 or nanostraws, 42 some of which are represented in Fig. 2.…”

“…Smaller patches with lateral dimensions of 50-150 μm and thicknesses of a few microns have also been created using photolithography. 39,40 These micropatches, also known as microcontainers, can contain multiple reservoirs filled with different drugs for combination therapy, the release profile of these micropatches can be adjusted through hydrogel or bioresorbable films.…”

Delivery of E. coli Nissle to the mouse gut by mucoadhesive microcontainers does not improve its competitive ability against strains linked to ulcerative colitis

“…Microcontainers have been fabricated in various shapes and sizes from 60 to 450 µM (Abid et al 2019 , Dalskov Mosgaard et al 2019 , Christfort et al 2020 , Chang et al 2023 , Petersen et al 2015 ), but in this study, cylindrical devices with an inner diameter of 236 ± 1 µm (mean ± SD) and height of 218 ± 1 µm (mean ± SD) was used. The microcontainers were sealed with a polymeric lid, which protected from the acidic environment in the stomach and facilitated targeted release in the distal small intestine when encountering a pH above 6 in the environment (Shimizu et al 2021 , Christfort, Milián-Guimerá et al 2022 ). Prior observations suggest that microcontainers will spread in the intestine and embed into the mucus layer enabling a dispersed and sustained release of drugs (Nielsen et al 2016b , Mazzoni et al 2017 ).…”