Periodic Reporting for period 1 - FREJA (Foldable, REconfigurable & Jagged devices for enhanced drug Absorption/seeding)
Berichtszeitraum: 2022-10-01 bis 2025-03-31
Oral delivery of peptide drugs is extremely challenging and most research in the field is based on exploring new formulations. We propose an entirely new approach based on what we have named Self-configurable Proximity Enabling Devices (SPEDs). The idea is that these devices will unfold in the gut, embed in the mucus layer covering the wall of the intestine and align to the intestinal wall. It is essential that the SPED has proximity to the intestinal wall and is retained for a while to ensure efficient drug delivery. Proximity will additionally allow us to study and explore the influence of nanotextures on the interaction with the intestinal wall and micromotor-based delivery. The SPEDs are developed and characterized with the following specific objectives: (i) understanding the SPED properties needed to penetrate mucus, (ii) investigating the mechanisms for enhanced retention time, (iii) exploring the SPED as a carrier for self-propelling cargo, (iv) unraveling the overall behavior of SPED and (v) demonstrating anti-diabetic drug formulation delivery with at least 5 % systemic uptake and show the feasibility of a wider range of applications.
Our foil-type devices show great potential for delivering poorly permeable macromolecules by enabling unidirectional release of the loaded pharmaceutical composition near the epithelium in the small intestine or colon. The foil devices have shown great potential for delivering peptides, with a significant increase in the absorption of solid insulin dosage by ∼12 times and nisin by ∼4 times in rats and pigs, respectively. (Mahdi Ghavami et al., Journal of Controlled Release, 2023).
The foils are loaded with a solid-state formulation containing the active pharmaceutical ingredient and then coated and rolled into enteric capsules. The coated lid must remain intact to ensure drug protection in the rolled state until the targeted release in the small intestine after capsule disintegration. We have done a study to compare different mixtures of enteric polymers and a plasticizer, PEG 6000, as potential coating materials. We evaluated mechanical properties as well as drug protection and targeted release in gastric and intestinal media, respectively. Commercially available Eudragit® FL30D-55 is the most suitable material due to its high strain at failure and integrity after capsule fitting. In vitro studies of coated foils in gastric and intestinal media confirmed successful pH-triggered drug release (Carmen Milan-Guimera et al., Pharmaceutics, 2024).
To visualize the behaviors of our devices in animal studies we have explored how to magnetically and/or radiopaque functionalize the foils by adding BaSO4 or Fe3O4 nanoparticles. The resulting foils have been characterized by surface characterization, mechanical testing, and X-ray imaging. Unfolding of the foil and its very close proximity to the small intestine can be observed 2 h post-administration by applying both computed tomography scanning and planar X-ray imaging (Rolf Bech Kjeldsen et al, ACS Biomaterials Science and Engineering, 2023).
One of the primary concerns associated with the use of our foil-type devices so far has been the utilization of nonbiodegradable elastomers (PDMS) in the fabrication of the devices. Therefore, we have synthesized a biodegradable elastomer, polyoctanediol citrate (POC), via a one-pot reaction, with subsequent purification and microscale pattern replication via casting. The microstructure geometry was designed to enable fabrication of foil-type devices with the selected elastomer, which has a high intrinsic surface free energy. The realized foil devices have been tested for drug release and show promising properties based on mechanical testing, and degradation studies (Reece McCabe et al., ACS Applied Biomaterials, 2024).
To get closer to the epithelium, we are exploring micromotors loaded into the foil structure. We are following an approach where microcontainers are loaded with magnesium micromotors and coated with a pH-responsive lid (Tijana Maric et al., Small 2023). We also explore needle shaped micromotors to be ejected from the foil. We additionally study delivery of a variety of new ‘cargos’. One of these is so-called polymersomes, that can be loaded with drugs and where the release can be triggered by e.g oxygen content. In a recent study, we explored a novel approach using oxygen-producing enzymatic reactions within biodegradable PEG-p(CL-g-TMC) polymersomes to modulate drug release. These polymersomes enhance the release of hydrophobic drugs while retaining hydrophilic drugs (Matteo Tollemeto et al, Angewandte Chemie, 2024).
The foils are loaded with a solid-state formulation containing the active pharmaceutical ingredient and then coated and rolled into enteric capsules. The coated lid must remain intact to ensure drug protection in the rolled state until the targeted release in the small intestine after capsule disintegration. We have done a study to compare different mixtures of enteric polymers and a plasticizer, PEG 6000, as potential coating materials. We evaluated mechanical properties as well as drug protection and targeted release in gastric and intestinal media, respectively. Commercially available Eudragit® FL30D-55 is the most suitable material due to its high strain at failure and integrity after capsule fitting. In vitro studies of coated foils in gastric and intestinal media confirmed successful pH-triggered drug release (Carmen Milan-Guimera et al., Pharmaceutics, 2024).
To visualize the behaviors of our devices in animal studies we have explored how to magnetically and/or radiopaque functionalize the foils by adding BaSO4 or Fe3O4 nanoparticles. The resulting foils have been characterized by surface characterization, mechanical testing, and X-ray imaging. Unfolding of the foil and its very close proximity to the small intestine can be observed 2 h post-administration by applying both computed tomography scanning and planar X-ray imaging (Rolf Bech Kjeldsen et al, ACS Biomaterials Science and Engineering, 2023).
One of the primary concerns associated with the use of our foil-type devices so far has been the utilization of nonbiodegradable elastomers (PDMS) in the fabrication of the devices. Therefore, we have synthesized a biodegradable elastomer, polyoctanediol citrate (POC), via a one-pot reaction, with subsequent purification and microscale pattern replication via casting. The microstructure geometry was designed to enable fabrication of foil-type devices with the selected elastomer, which has a high intrinsic surface free energy. The realized foil devices have been tested for drug release and show promising properties based on mechanical testing, and degradation studies (Reece McCabe et al., ACS Applied Biomaterials, 2024).
To get closer to the epithelium, we are exploring micromotors loaded into the foil structure. We are following an approach where microcontainers are loaded with magnesium micromotors and coated with a pH-responsive lid (Tijana Maric et al., Small 2023). We also explore needle shaped micromotors to be ejected from the foil. We additionally study delivery of a variety of new ‘cargos’. One of these is so-called polymersomes, that can be loaded with drugs and where the release can be triggered by e.g oxygen content. In a recent study, we explored a novel approach using oxygen-producing enzymatic reactions within biodegradable PEG-p(CL-g-TMC) polymersomes to modulate drug release. These polymersomes enhance the release of hydrophobic drugs while retaining hydrophilic drugs (Matteo Tollemeto et al, Angewandte Chemie, 2024).
We have started to explore the use of mycelium in the production of drug delivery devices. Currently, we are loading drugs into the mycelium. A possible future step is to modify the fungi strains to produce the needed drug(s).
We are implementing kirigami structures into our foil-devices to improve retention. We are also exploring cone-shaped devices that like a pinecone will open in the case of change of humidity. The devices have been successfully fabricated and are now being tested in vitro.
Our work on enhancing the absorption by ‘tickling’ the cells in the intestine has started. We fabricate surfaces with micro and nano texturing and study how the textures affect the opening of tight junctions. Using Coherent anti-Stokes Raman spectroscopy (CARS), we can study cell behavior in a label-free manner. We are unveiling new mechanisms of action for known chemical permeation enhancers. We have found that adding lipids can open the tight junctions in a reproducible and reversible manner.
Using ionic liquids, we will soon be able to publish an oral bioavailability of 15% using our foil device. Without the devices, the bioavailability is around 4%. The foil clearly provides better contact with the epithelium and secures a unidirectional release of the formulation.
Most significant results:
•The foil devices have shown great potential for delivering peptides, with a significant increase in the absorption of solid dosage of insulin by ∼12 times and nisin by ∼4 times in rats and pigs, respectively. This, we have recently improved further by using ionic liquids.
•We can now replace our PDMS, used to make our foils, with a biodegradable substitute with similar characteristics. We have synthesized biodegradable elastomer, POC, via a one-pot reaction, with subsequent purification and microscale pattern replication via casting.
•We can, in a label-free manner using CARS, study drug transport through cell layers mimicking the epithelium. This allows us to study chemical permeation enhancers already in use and new mechanical triggering mechanisms.
•We have filed a notification of the invention on our pine-cone design as well as our mycelium devices.
During our studies of drug permeation using CARS we were investigating lipid coated microparticles. We see that the lipid has a dramatic transient effect on the tight junctions that we will explore further. It could potentially be an important finding since there is a need for safe and reversible permeation enhancers. Also, the work on mycelium has the potential of significantly advancing state-of-the art. We have demonstrated the fabrication of mycelium patches loaded with drugs. The most interesting aspect is that the mycelium can be shaped into intricate 3D structures, as we can let the mycelium grow inside sacrificial moulds.
We are implementing kirigami structures into our foil-devices to improve retention. We are also exploring cone-shaped devices that like a pinecone will open in the case of change of humidity. The devices have been successfully fabricated and are now being tested in vitro.
Our work on enhancing the absorption by ‘tickling’ the cells in the intestine has started. We fabricate surfaces with micro and nano texturing and study how the textures affect the opening of tight junctions. Using Coherent anti-Stokes Raman spectroscopy (CARS), we can study cell behavior in a label-free manner. We are unveiling new mechanisms of action for known chemical permeation enhancers. We have found that adding lipids can open the tight junctions in a reproducible and reversible manner.
Using ionic liquids, we will soon be able to publish an oral bioavailability of 15% using our foil device. Without the devices, the bioavailability is around 4%. The foil clearly provides better contact with the epithelium and secures a unidirectional release of the formulation.
Most significant results:
•The foil devices have shown great potential for delivering peptides, with a significant increase in the absorption of solid dosage of insulin by ∼12 times and nisin by ∼4 times in rats and pigs, respectively. This, we have recently improved further by using ionic liquids.
•We can now replace our PDMS, used to make our foils, with a biodegradable substitute with similar characteristics. We have synthesized biodegradable elastomer, POC, via a one-pot reaction, with subsequent purification and microscale pattern replication via casting.
•We can, in a label-free manner using CARS, study drug transport through cell layers mimicking the epithelium. This allows us to study chemical permeation enhancers already in use and new mechanical triggering mechanisms.
•We have filed a notification of the invention on our pine-cone design as well as our mycelium devices.
During our studies of drug permeation using CARS we were investigating lipid coated microparticles. We see that the lipid has a dramatic transient effect on the tight junctions that we will explore further. It could potentially be an important finding since there is a need for safe and reversible permeation enhancers. Also, the work on mycelium has the potential of significantly advancing state-of-the art. We have demonstrated the fabrication of mycelium patches loaded with drugs. The most interesting aspect is that the mycelium can be shaped into intricate 3D structures, as we can let the mycelium grow inside sacrificial moulds.