Bjarke Strøm Larsen

• Mrsa, Ago; Larsen, Bjarke Strøm; Halvorsen, Trine Grønhaug & Reubsaet, Leon (2026). Dual Functionality in Whole Blood Microsampling: Combining Plasma Separation and Immunoaffinity Cleanup for LC-MS Based Targeted Protein Analysis. Journal of Proteome Research. ISSN 1535-3893. 25(9), s. 4665–4675. doi: 10.1021/acs.jproteome.6c00092. Fulltekst i vitenarkiv
• Teimori, Kaveh; Larsen, Bjarke Strøm; Austli, Mathias Buaas; Nilsson, Carl Niklas; Tho, Ingunn & Nezvalova-Henriksen, Katerina (2025). Strategies for Assessing Physical Compatibility of Calcium Folinate with Bicarbonate During Methotrexate Rescue Therapy in Pediatric Patients with Acute Lymphoblastic Leukemia. Pharmaceutics. 17(9). doi: 10.3390/pharmaceutics17091155. Fulltekst i vitenarkiv
• Larsen, Bjarke Strøm; Meiland, Peter; Tzdaka, Eidan; Tho, Ingunn & Rades, Thomas (2024). A unifying approach to drug-in-polymer solubility prediction: Streamlining experimental workflow and analysis. European journal of pharmaceutics and biopharmaceutics. ISSN 0939-6411. 203. doi: 10.1016/j.ejpb.2024.114478. Fulltekst i vitenarkiv Vis sammendrag

  This method paper describes currently used experimental methods to predict the drug-in-polymer solubility of amorphous solid dispersions and offers a combined approach for applying the Melting-point-depression method, the Recrystallization method, and the Melting-and-mixing method. It aims to describe and expand on the theoretical basis as well as the analytical methodology of the recently published Melting-and-mixing method. This solubility method relies on determining the relationship between drug loads and the enthalpy of melting and mixing of a crystalline drug in the presence of an amorphous polymer. This relationship is used to determine the soluble drug load of an amorphous solid dispersion from the recorded enthalpy of melting and mixing of the crystalline drug portion in a drug-polymer sample at equilibrium solubility. Due to the complex analytical methodology of the Melting-and-mixing method, a software solution called the Glass Solution Companion app was developed. Using this new tool, it is possible to calculate the predicted drug-in-polymer solubility and Flory-Huggins interaction parameter from experimental samples, as well as to generate the resulting solubility-temperature curve. This software can be used for calculations for all three experimental methods, which would be useful for comparing the applicability of the methods on a given drug-polymer system. Since it is difficult to predict the suitability of these drug-in-polymer solubility methods for a specific drug-polymer system in silico, some experimental investigation is necessary. By optimizing the experimental protocol, it is possible to collect data for the three experimental methods simultaneously for a specific drug-polymer system. These results can then be readily analyzed using the Glass Solution Companion app to find the most appropriate method for the drug-polymer system, and therefore, the most reliable drug-in-polymer solubility prediction.

• Petersen, Emilie Fynbo; Larsen, Bjarke Strøm; Nielsen, Rasmus Blaaholm; Pijpers, Ils; Versweyveld, Dries & Holm, René [Vis alle 9 forfattere av denne artikkelen] (2024). Co-release of paclitaxel and encequidar from amorphous solid dispersions increase oral paclitaxel bioavailability in rats. International Journal of Pharmaceutics. ISSN 0378-5173. 654. doi: 10.1016/j.ijpharm.2024.123965. Fulltekst i vitenarkiv Vis sammendrag

  The oral bioavailability of paclitaxel is limited due to low solubility and high affinity for the P-glycoprotein (P-gp) efflux transporter. Here we hypothesized that maximizing the intestinal paclitaxel levels through apparent solubility enhancement and controlling the simultaneous release of both paclitaxel and the P-gp inhibitor encequidar from amorphous solid dispersions (ASDs) would increase the oral bioavailability of paclitaxel. ASDs of paclitaxel and encequidar in polyvinylpyrrolidone K30 (PVP-K30), hydroxypropylmethylcellulose 5 (HPMC-5), and hydroxypropylmethylcellulose 4 K (HPMC-4K) were hence prepared by freeze-drying. In vitro dissolution studies showed that both compounds were released fastest from PVP-K30, then from HPMC-5, and slowest from HPMC-4K ASDs. The dissolution of paclitaxel from all polymers resulted in stable concentration levels above the apparent solubility. The pharmacokinetics of paclitaxel after oral administration to male Sprague-Dawley rats was investigated with or without 1 mg/kg encequidar, as amorphous solids or polymer-based ASDs. The bioavailability of paclitaxel increased 3- to 4-fold when administered as polymer-based ASDs relative to solid amorphous paclitaxel. However, when amorphous paclitaxel was co-administered with encequidar, either as an amorphous powder or as a polymer-based ASD, the bioavailability increased 2- to 4-fold, respectively. Interestingly, a noticeable increase in paclitaxel bioavailability of 24-fold was observed when paclitaxel and encequidar were co-administered as HPMC-5-based ASDs. We, therefore, suggest that controlling the dissolution rate of paclitaxel and encequidar in order to obtain simultaneous and timed release from polymer-based ASDs is a strategy to increase oral paclitaxel bioavailability.

• Tzanova, Martina Martin; Larsen, Bjarke Strøm; Birolo, Rebecca; Cignolini, Sara; Tho, Ingunn & Chierotti, Michele R. [Vis alle 11 forfattere av denne artikkelen] (2024). Shifting the Focus from Dissolution to Permeation: Introducing the Meso-fluidic Chip for Permeability Assessment (MCPA). Journal of Pharmaceutical Sciences. ISSN 0022-3549. 113(5), s. 1319–1329. doi: 10.1016/j.xphs.2023.12.012. Fulltekst i vitenarkiv Vis sammendrag

  In response to the growing ethical and environmental concerns associated with animal testing, numerous in vitro tools of varying complexity and biorelevance have been developed and adopted in pharmaceutical research and development. In this work, we present one of these tools, i.e., the Meso-fluidic Chip for Permeability Assessment (MCPA), for the first time. The MCPA combines an artificial barrier (PermeaPad®) with an organ-on-chip device (MIVO®) and real-time automated concentration measurements, to yield a sustainable, yet effortless method for permeation testing. The system offers three major physiological aspects, i.e., a biomimetic membrane, an optimal membrane interfacial area-to-donor-volume-ratio (A/V) and a physiological flow on the acceptor/basolateral side, which makes the MPCA an ideal candidate for mechanistic studies and excellent in vivo bioavailability predictions. We validated the method with a handful of assorted drug compounds in unstirred and stirred donor conditions, before exploring its applicability as a tool for dissolution/permeation testing on a BCS class III/I drug (pyrazinamide) crystalline adducts and BCS class II/IV (hydrocortisone) amorphous solid dispersions. The results were highly reproducible and clearly displayed the method's potential for evaluating the performance of enabling formulations, and possibly even predicting in vivo performance. We believe that, upon further development, the MCPA will serve as a useful in vitro tool that could push sustainability into pharmaceutics by refining, reducing and replacing animal testing in early-stage drug development.

• Korelc, Karin; Larsen, Bjarke Strøm; Gašperlin, Mirjana & Tho, Ingunn (2023). Water-soluble chitosan eases development of mucoadhesive buccal films and wafers for children. International Journal of Pharmaceutics. ISSN 0378-5173. 631. doi: 10.1016/j.ijpharm.2022.122544. Fulltekst i vitenarkiv Vis sammendrag

  Oromucosal films and wafers are user-friendly solid dosage forms offering easy and convenient administration, as well as rapid or controlled drug delivery. The aim of this study was to develop prednisolone containing child-friendly chitosan-based mucoadhesive films and wafers with a prolonged residence time on the buccal mucosa. Four different chitosan types (different molecular weights, degree of deacetylation (DDA), pattern of deacetylation) were studied for films prepared by solvent-cast-evaporation and wafers by freeze-drying. Mucoadhesive properties correlated with swelling abilities and were dependent on the chitosan type, the solvent, and the preparation method. Mucoadhesive forces were higher for formulations containing chitosan with higher DDA and for wafers compared to films. The drug release was relatively fast, especially for films (approx. 90 % in 15 minutes) and steadier for wafers (90 % in 45–120 minutes). Permeability was evaluated using artificial membranes and HT29-MTX cell-monolayers. The developed formulations exhibited good biocompatibility. Organoleptic properties can be improved by choosing a homogenously deacetylated chitosan type that provides a more neutral pH. Using hydroxypropyl-beta-cyclodextrin-complexation for taste masking of bitter drugs also reduced wafers’ drug release rate. Mucoadhesive wafers are promising alternatives to films with a slower drug release rate and stronger mucoadhesion.

• Nielsen, Rasmus Blaaholm; Larsen, Bjarke Strøm; Holm, René; Pijpers, Ils; Snoeys, Jan & Nielsen, Ulla Gro [Vis alle 8 forfattere av denne artikkelen] (2023). Increased bioavailability of a P-gp substrate: Co-release of etoposide and zosuquidar from amorphous solid dispersions. International Journal of Pharmaceutics. ISSN 0378-5173. 642. doi: 10.1016/j.ijpharm.2023.123094. Fulltekst i vitenarkiv Vis sammendrag

  P-glycoprotein (P-gp) inhibitors, like zosuquidar, partly increase oral bioavailability of P-gp substrates, such as etoposide. Here, it was hypothesised that co-release of etoposide and zosuquidar from amorphous solid dispersions (ASDs) may further increase oral etoposide bioavailability. This was envisioned through simultaneous co-release and subsequent spatiotemporal association of etoposide and zosuquidar in the small intestinal lumen. To further achieve this, ASDs of etoposide and zosuquidar in polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC) 5, and HPMC 4 k were prepared by freeze-drying. From these ASDs, etoposide release was fastest from PVP, then HPMC 5 and slowest from HPMC 4. Release from PVP and HPMC 5 resulted in stable supersaturations of etoposide. In transcellular permeability studies across MDCKII-MDR1 cell monolayers, the accumulated amount of etoposide increased 3.7–4.9-fold from amorphous etoposide or when incorporated into PVP- or HPMC 5-based ASDs, compared to crystalline etoposide. In vivo, the oral bioavailability in Sprague Dawley rats increased from 1.0 to 2.4–3.4 %, when etoposide was administered as amorphous drug or in ASDs. However, when etoposide and zosuquidar were co-administered, the oral bioavailability increased further to 8.2–18 %. Interestingly, a distinct increase in oral etoposide bioavailability to 26 % was observed when etoposide and zosuquidar were co-administration in HPMC 5-based ASDs. The supersaturation of etoposide as well as the simultaneous co-release of etoposide and zosuquidar in the small intestinal lumen may explain the observed bioavailability increase. Overall, this study suggested that simultaneous co-release of an amorphous P-gp substrate and inhibitor may be a novel and viable formulation strategy to increase the bioavailability P-gp substrates.

• Nilsson, Carl Niklas; Nezvalova-Henriksen, Katerina; Bøtker, Johan P.; Andersen, Niels Højmark; Larsen, Bjarke Strøm & Rantanen, Jukka [Vis alle 8 forfattere av denne artikkelen] (2023). Co-administration of Intravenous Drugs: Rapidly Troubleshooting the Solid Form Composition of a Precipitate in a Multi-drug Mixture Using On-Site Raman Spectroscopy. Molecular Pharmaceutics. ISSN 1543-8384. 20(6), s. 2853–2863. doi: 10.1021/acs.molpharmaceut.2c00983. Fulltekst i vitenarkiv Vis sammendrag

  Intravenous drugs are often co-administrated in the same intravenous catheter line due to which compatibility issues, such as complex precipitation processes in the catheter line, may occur. A well-known example that led to several neonatal deaths is the precipitation due to co-administration of ceftriaxone- and calcium-containing solutions. The current study is exploring the applicability of Raman spectroscopy for testing intravenous drug compatibility in hospital settings. The precipitation of ceftriaxone calcium was used as a model system and explored in several multi-drug mixtures containing both structurally similar and clinically relevant drugs for co-infusion. Equal molar concentrations of solutions containing ceftriaxone and calcium chloride dihydrate were mixed with solutions of cefotaxime, ampicillin, paracetamol, and metoclopramide. The precipitate formed was collected as an “unknown” material, dried, and analyzed. Several solid-state analytical methods, including X-ray powder diffraction, Raman spectroscopy, and thermogravimetric analysis, were used to characterize the precipitate. Raman microscopy was used to investigate the identity of single sub-visual particles precipitated from a mixture of ceftriaxone, cefotaxime, and calcium chloride. X-ray powder diffraction suggested that the precipitate was partially crystalline; however, the identity of the solid form of the precipitate could not be confirmed with this standard method. Raman spectroscopy combined with multi-variate analyses (principal component analysis and soft independent modelling class analogy) enabled the correct detection and identification of the precipitate as ceftriaxone calcium. Raman microscopy enabled the identification of ceftriaxone calcium single particles of sub-visual size (around 25 μm), which is in the size range that may occlude capillaries. This study indicates that Raman spectroscopy is a promising approach for supporting clinical decisions and especially for compatibility assessments of drug infusions in hospital settings.

• Larsen, Bjarke Strøm; Kissi, Eric Ofosu; Nogueira, Liebert Parreiras; Genina, Natalja & Tho, Ingunn (2023). Impact of drug load and polymer molecular weight on the 3D microstructure of printed tablets. Journal of Pharmaceutical Sciences. ISSN 0022-3549. 192. doi: 10.1016/j.ejps.2023.106619. Fulltekst i vitenarkiv Vis sammendrag

  <p>This study investigates the influence of drug load and polymer molecular weight on the structure of tablets three-dimensionally (3D) printed from the binary mixture of prednisolone and hydroxypropyl methylcellulose (HPMC). Three different HPMC grades, (AFFINISOLTM HPMC HME 15LV, 90 Da (HPMC 15LV); 100LV, 180 Da (HPMC 100LV); 4M, 500 Da (HPMC 4M)), which are suitable for hot-melt extrusion (HME), were used in this study. HME was used to fabricate feedstock material, i.e., filaments, at the lowest possible extrusion temperature. Filaments of the three HPMC grades were prepared to contain 2.5, 5, 10 and 20 % (w/w) prednisolone. The thermal degradation of the filaments was studied with thermogravimetric analysis, while solid-state properties of the drug-loaded filaments were assessed with the use of X-ray powder diffraction. Prednisolone in the freshly extruded filaments was determined to be amorphous for drug loads up to 10%. It remained physically stable for at least 6 months of storage, except for the filament containing 10% drug with HPMC 15LV, where recrystallization of prednisolone was detected. <p>Fused deposition modeling was utilized to print honeycomb-shaped tablets from the HME filaments of HPMC 15LV and 100LV. The structural characteristics of the tablets were evaluated using X-ray microcomputed tomography, specifically porosity and size of structural elements were investigated. The tablets printed from HPMC 15LV possessed in general lower total porosity and pores of smaller size than tablets printed from the HPMC 100LV. The studied drug loads were shown to have minor effect on the total porosity of the tablets, though the lower the drug load was, the higher the variance of porosity along the height of the tablet was observed. It was found that tablets printed with HPMC 15LV showed higher structural similarity with the virtually designed model than tablets printed from HPMC 100LV. These findings highlight the relevance of the drug load and polymer molecular weight on the microstructure and structural properties of 3D printed tablets.

• Korelc, Karin; Larsen, Bjarke Strøm; Heintze, Anna-Lena; Henrik-Klemens, Åke; Karlsson, Jakob & Larsson, Anette [Vis alle 7 forfattere av denne artikkelen] (2023). Towards personalized drug delivery via semi-solid extrusion: Exploring poly(vinyl alcohol-co-vinyl acetate) copolymers for hydrochlorothiazide-loaded films. European Journal of Pharmaceutical Sciences. ISSN 0928-0987. 192. doi: 10.1016/j.ejps.2023.106645. Fulltekst i vitenarkiv Vis sammendrag

  The increasing need for personalized drug delivery requires developing systems with tailorable properties. The copolymer poly(vinyl alcohol-co-vinyl acetate) (PVA/PVAc) allows for adjusting the monomer ratio. This study explored the effect of vinyl alcohol (VA) and vinyl acetate (VAc) monomer ratio on the properties of hydrochlorothiazide (HCT) films. Five copolymers with different VA/VAc ratios were selected and characterized. Semi-solid extrusion was employed as a method for the preparation of HCT-PVA/PVAc films to address the challenges of HCT´s low water solubility, high melting point, and low permeability. All copolymers were suitable for semi-solid extrusion, however, the mechanical properties of films with higher VA proportions were more suitable. The drug was found to be homogeneously distributed on a micrometer level throughout the prepared films. It was found that using different monomer ratios in the copolymer allows for drug release tuning – higher VA proportions showed an increased rate of drug release. Experiments through HT29-MTX cell monolayers revealed differences in HCT permeability between the different formulations. In addition, no cytotoxicity was observed for the tested formulations. The results highlight the effect of monomer ratio on film properties, providing valuable guidance for formulators in selecting PVA/PVAc copolymers for achieving desired high-quality films. In addition, varying the monomer ratio allows tuning of the film properties, and can be applied for personalization, with flexible-dose adjustment and design of appealing shapes of the pharmaceutics, not least attractive for pediatric drug delivery.

• Meiland, Peter; Larsen, Bjarke Strøm; Knopp, Matthias Manne; Tho, Ingunn & Rades, Thomas (2022). A new method to determine drug-polymer solubility through enthalpy of melting and mixing. International Journal of Pharmaceutics. ISSN 0378-5173. 629. doi: 10.1016/j.ijpharm.2022.122391. Fulltekst i vitenarkiv Vis sammendrag

  In this study, a new method to determine the solubility of crystalline drugs in (amorphous) polymers is proposed. The method utilizes annealing of supersaturated amorphous solid dispersions to achieve equilibrium between dissolved and recrystallized drug. By measuring the enthalpy of melting and mixing (Hm+mix) of the recrystallized drug, the equilibrium solubility of the drug in the polymer at the annealing temperature is determined. The equilibrium solubilities at these elevated temperatures were used to extrapolate to room temperature using the Flory-Huggins model. The new Hm+mix method showed solubility predictions in line with the melting point depression (MPD) and recrystallization (RC) methods for indomethacin (IMC) -polyvinylpyrrolidone (PVP). For IMC-hydroxypropyl methylcellulose (HPMC), the MPD method plateaued rapidly, leaving only one usable data point. The RC method showed large variations in the solubility predictions possibly due to a narrow glass transition temperature (Tg) window or inaccurate Tg determination. In contrast, the new Hm+mix method showed robust solubility prediction over the entire annealing temperature range with low variation and narrow error margins after extrapolation for both drug-polymer systems. The new Hm+mix method was able to accurately determine the drug-polymer solubility of IMC-HPMC, showing promise as a new tool to determine the solubility of problematic drug-polymer systems.

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• Meiland, Peter; Larsen, Bjarke Strøm; Knopp, Matthias Manne; Tho, Ingunn & Rades, Thomas (2024). Corrigendum to “A new method to determine drug-polymer solubility through enthalpy of melting and mixing” (International Journal of Pharmaceutics (2022) 629, (S0378517322009462), (10.1016/j.ijpharm.2022.122391)). International Journal of Pharmaceutics. ISSN 0378-5173. 662. doi: 10.1016/j.ijpharm.2024.124554. Fulltekst i vitenarkiv

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