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- Wanselius, Marcus
(författare)
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Development and characterization of an in vitro method for interaction studies between polymers and pharmaceuticals : Aiding in the development of new drug delivery systems
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Polymers are a group of macromolecules used in formulations of pharmaceuticals, one example being the delivery system DC Bead™. Further, some of the most abundant and for drug delivery important constituents of the subcutaneous tissue are charged polymers (polyelectrolytes), e.g. collagen, hyaluronic acid, and chondroitin sulfate. The interactions between these subcutaneous polyelectrolytes and drug molecules are believed to heavily affect the transport and absorption of subcutaneously injected drugs. To increase the understanding of how the interactions between subcutaneous polymers and drug molecules affect the pharmaceutical behavior in subcutaneous tissue, we developed a new microfluidic-based platform. The platform is used to study interactions between polyelectrolytes and drug molecules, and can beyond the investigation of subcutaneous interactions be used to develop polyelectrolyte-based microgel formulations. In this thesis, the microfluidic method denoted “Microfluidic chip for interactions studies” (MIS) is presented, and the design, validation, and several examples of usage are described. The method which is based on microfluidic instrumentation, utilizes spherical microgels created using different types of polymers/polyelectrolytes. These hydrogels collapse when experiencing attractive interactions with drug molecules making it possible to investigate drug binding by studying the volume change of the microgels. We prove that the interactions are strongly affected by charges both on the gel networks and the drug molecules. Further, the aggregation behavior of drugs in a polyelectrolyte-rich environment is studied in detail. Results show that both a strong aggregation behavior and a high charge on the drugs may affect the transport through a network of polyelectrolytes. The behavior of drugs in subcutaneous polyelectrolyte-rich environments such as hyaluronic acid networks, can partly explain bioavailability and absorption rates of the drugs in vivo. Several potential drug delivery systems in the form of microgels were investigated together with both small amphiphilic molecules and larger peptides exhibiting a wide range of physicochemical properties. The results indicate a possibility of delivering large amounts of drug in low volumes of microgel suspensions but with varying release times, ranging from seconds to days. The MIS was able to provide information about the interactions in a large number of polyelectrolyte-drug systems. The studies were performed in a highly efficient and cost-effective way, with experiments being mostly automated. This makes it a suitable method for rapid screening experiments in the development of new microgel formulations, and as part of larger studies utilizing several different methods to better understand and predict the behavior and absorption profiles of potential subcutaneously administrated drugs.
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- Wanselius, Marcus, et al.
(författare)
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Microfluidics platform for studies of peptide - polyelectrolyte interaction
- 2022
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Ingår i: International Journal of Pharmaceutics. - : Elsevier. - 0378-5173 .- 1873-3476. ; 621
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Tidskriftsartikel (refereegranskat)abstract
- Subcutaneous injection is one of the most common approaches for administering biopharmaceuticals unsuitable for oral delivery. However, there is a lack of methods to predict the behavior of biopharmaceuticals within the extracellular matrix of the subcutaneous tissue. In this work, we present a novel miniaturized microfluidic-based in vitro method able to investigate interactions between drug molecules and the polymers of the subcutaneous extracellular matrix. To validate the method, microgels consisting of, respectively, covalently cross-linked hy-aluronic acid, polyacrylic acid, and commercially available DC BeadTM, were exposed to three model substances: cytochrome C, protamine sulfate and amitriptyline hydrochloride. These components were chosen to include systems with widely different physiochemical properties (charge, size, self-assembly, etc.) The experimental results were compared with theoretical predictions from a gel model developed earlier. The results show that the method is suitable as a rapid screening method for automated, large-scale, probing of interactions between biopolymers and drug molecules, with small consumption of material.
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| 5. |
- Wanselius, Marcus, et al.
(författare)
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Responsive Hyaluronic Acid-Ethylacrylamide Microgels Fabricated Using Microfluidics Technique
- 2022
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Ingår i: Gels. - : MDPI. - 2310-2861. ; 8:9
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Tidskriftsartikel (refereegranskat)abstract
- Volume changes of responsive microgels can probe interactions between polyelectrolytes and species of opposite charges such as peptides and proteins. We have investigated a microfluidics method to synthesize highly responsive, covalently crosslinked, hyaluronic acid microgels for such purposes. Sodium hyaluronate (HA), pre-modified with ethylacrylamide functionalities, was crosslinked in aqueous droplets created with a microfluidic technique. We varied the microgel properties by changing the degree of modification and concentration of HA in the reaction mixture. The degree of modification was determined by H-1 NMR. Light microscopy was used to investigate the responsiveness of the microgels to osmotic stress in aqueous saline solutions by simultaneously monitoring individual microgel species in hydrodynamic traps. The permeability of the microgels to FITC-dextrans of molecular weights between 4 and 250 kDa was investigated using confocal laser scanning microscopy. The results show that the microgels were spherical with diameters between 100 and 500 mu m and the responsivity tunable by changing the degree of modification and the HA concentration. Microgels were fully permeable to all investigated FITC-dextran probes. The partitioning to the microgel from an aqueous solution decreased with the increasing molecular weight of the probe, which is in qualitative agreement with theories of homogeneous gel networks.
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- Wanselius, Marcus, et al.
(författare)
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Utilizing a Microfluidic Platform to Investigate Drug-Eluting Beads : Binding and Release of Amphiphilic Antidepressants
- 2023
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Ingår i: International Journal of Pharmaceutics. - : Elsevier. - 0378-5173 .- 1873-3476. ; 647
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Tidskriftsartikel (refereegranskat)abstract
- Drug-eluting beads made of responsive polyelectrolyte networks are used in the treatment of liver cancer. Aggregates of loaded drugs in complex with the networks dissolve upon release, causing swelling of the network. According to a recent mechanism the release and swelling rates are controlled by the mass transport of drug through a depletion layer created in the microgel. We hypothesise that the mechanism, in which the stability of the drug aggregates and the swelling properties of the network play crucial roles, offers means to control the release profile also for other drugs. To test this, we investigated the loading and release properties of amitriptyline, chlorpromazine and doxepin in polyacrylate, hyaluronate and DCbeadTM microgels in a microfluidic setup. Loaded drugs could be released to a medium with physiological ionic strength and pH. The binding strength increased with decreasing critical micelle concentration of the drugs and increasing linear charge density of network chains. Microgels displayed drug-rich core/swollen shell coexistence, and swelled during release at a rate in agreement with the depletion layer mechanism, indicating its generality. The results demonstrate the potential of microgels as vehicles for amphiphilic drugs and the usefulness of the microfluidics method for in vitro studies of such systems.
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