Ingunn Tho

• Svendsen, Randi Maria Hamre; Hagesæther, Ellen; Fischer, Sarah Maud; Bjerknes, Kathrin; Brustugun, Jørgen & Tho, Ingunn (2026). Manipulating prednisolone tablets for paediatric adjustments – dose accuracy and precision. European Journal of Hospital Pharmacy (EJHP). ISSN 2047-9956. doi: 10.1136/ejhpharm-2025-004873. Full text in Research Archive
• Korelc, Karin; Arumughan, Vishnu; Henrik-Klemens, Åke; Larsson, Anette & Tho, Ingunn (2026). Early-stage pharmaceutical development of bilayer buccal films with a chitosan backing layer for local pain management in oral mucositis. European Journal of Pharmaceutical Sciences. ISSN 0928-0987. 221. doi: 10.1016/j.ejps.2026.107530. Full text in Research Archive
• Svendsen, Randi Maria Hamre; Andersen, Jennifer Kathleen Neily; Sporrong, Sofia Kälvemark; Andersson, Yvonne & Tho, Ingunn (2026). Off-Label Manipulation of Paediatric Medication Remains a Challenge in Clinical Practice: An Observational Study. Acta Paediatrica. ISSN 0803-5253. doi: 10.1111/apa.70523. Full text in Research Archive
• Arumughan, Vishnu; Korelc, Karin; Tho, Ingunn & Larsson, Anette (2026). The influence of substituents of cellulose ethers on their interaction with chitosan surfaces. Colloid and Interface Science Communications. 70. doi: 10.1016/j.colcom.2025.100867. Full text in Research Archive
• Paulsson, M.; Svendsen, Randi Maria Hamre; Andersen, Jennifer Kathleen Neily; Sporrong, S. Kälvemark; Andersson, Yvonne & Tho, Ingunn (2025). Challenges and Considerations in Manipulating Oral Dosage Forms in Paediatric Healthcare Settings: A Narrative Review. Acta Paediatrica. ISSN 0803-5253. 114(10), p. 2480–2489. doi: 10.1111/apa.70199. Full text in Research Archive Show summary

  Aim To explore the challenges and risks associated with the manipulation of solid oral dosage forms in paediatric healthcare. To compile recommendations to support the safety, efficacy and patient outcomes in paediatric patients. Methods A narrative review was conducted based on literature searches in PubMed, Scopus and Web of Science (2000–2024), including regulatory guidelines and clinical case reports. Selection focused on studies involving oral drug manipulation in children, particularly dose extraction, dispersing tablets, and administration via enteral tubes. Results Between 15%–37% of paediatric oral drug administrations require manipulation due to lack of age-appropriate formulations. Common manipulations include tablet splitting, crushing or dispersing, often resulting in dose inaccuracies, variable solubility and inconsistent pharmacokinetics. Risks are elevated in children using enteral feeding tubes or when manipulating poorly soluble drugs. Studies show manipulation can lead to dosing errors with potential harm. Conclusion Oral drug manipulation in paediatrics is widespread but often unsupported by evidence. Safer practices require improved access to licensed formulations, better training and clinical support tools. Pharmacy compounding, personalised manufacturing and technologies like 3D printing may reduce risks. Regulatory alignment and interdisciplinary collaboration are critical to improving drug safety and outcomes for paediatric patients.

• 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. Full text in Research Archive
• Hagesæther, Ellen; Karbø, Ingeborg; Tho, Ingunn; Teimori, Kaveh & Nilsson, Carl Niklas (2025). Using Raman spectroscopy to analyse in situ a precipitate appearing in a catheter line after drug co-administration. European Journal of Hospital Pharmacy (EJHP). ISSN 2047-9956. 0, p. 1–5. doi: 10.1136/ejhpharm-2025-004664. Full text in Research Archive
• Korelc, Karin; Tzanova, Martina Martin; Larsson, Anette; Grassi, Mario; Cagno, Massimiliano Pio Di & Tho, Ingunn (2025). A simplified method to interpret the mechanism of drug release from thin polymeric films by drug diffusivity measurements. International Journal of Pharmaceutics. ISSN 0378-5173. 675. doi: 10.1016/j.ijpharm.2025.125491. Full text in Research Archive
• 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. Full text in Research Archive Show summary

  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 [Show all 9 contributors for this article] (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. Full text in Research Archive Show summary

  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. [Show all 11 contributors for this article] (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), p. 1319–1329. doi: 10.1016/j.xphs.2023.12.012. Full text in Research Archive Show summary

  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. Full text in Research Archive Show summary

  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 [Show all 8 contributors for this article] (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. Full text in Research Archive Show summary

  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 [Show all 8 contributors for this article] (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), p. 2853–2863. doi: 10.1021/acs.molpharmaceut.2c00983. Full text in Research Archive Show summary

  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. Full text in Research Archive Show summary

  <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 [Show all 7 contributors for this article] (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. Full text in Research Archive Show summary

  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.

• Nezvalova-Henriksen, Katerina; Holm, Tone Huseby; Nilsson, Niklas; Kjønniksen, Inge & Tho, Ingunn (2022). Frequently acquired drugs in neonatal intensive care and their physical compatibility. Acta Paediatrica. ISSN 0803-5253. 111(12), p. 2307–2314. doi: 10.1111/apa.16526. Full text in Research Archive
• 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. Full text in Research Archive Show summary

  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.

• Nilsson, Niklas; Nguyen, Vivian; Nezvalova-Henriksen, Katerina & Tho, Ingunn (2022). Exploring a case of incompatibility in a complex regimen containing Plasma-Lyte 148 in the pediatric intensive care. Pediatric Anaesthesia. ISSN 1155-5645. 33(3), p. 211–218. doi: 10.1111/pan.14598. Full text in Research Archive
• Nilsson, Niklas; Storesund, Ingebjørg; Tho, Ingunn & Nezvalova-Henriksen, Katerina (2022). Co-administration of drugs with parenteral nutrition in the neonatal intensive care unit—physical compatibility between three components. European Journal of Pediatrics. ISSN 0340-6199. 181, p. 2685–2693. doi: 10.1007/s00431-022-04466-z. Full text in Research Archive Show summary

  There is a lack of compatibility data for intravenous therapy to neonatal intensive care unit (NICU) patients, and the purpose of this study was to contribute with documented physical compatibility data to ensure safe co-administration. We selected Numeta G13E, the 3-in-1 parenteral nutrition (PN) used at our NICU, together with the frequently used drugs morphine, dopamine and cefotaxime in two- but also three-component combinations. Incompatibility may lead to particle formation (precipitation) and oil-droplet growth (emulsion destabilisation), both which are undesirable and pose a safety risk to already unstable patients. We assessed potential particle formation of three mixing ratios for each combination (always including 1 + 1 ratio) using light obscuration, turbidity and pH measurements combined with visual inspection by focused Tyndall beam. Potential droplet-growth and emulsion destabilisation was assessed by estimating PFAT5 from droplet size measurements and counts, mean droplet diameter and polydispersity index from dynamic light scattering, and pH measurements. Mixed samples were always compared to unmixed controls to capture changes as a result of mixing and samples were analysed directly after mixing and after 4 h to simulate long contact time. None of the samples showed any sign of precipitation, neither in the drug-drug nor in the two- or three-component mixture with PN. Neither did we detect any form of emulsion destabilisation. Conclusion: Dopamine, morphine and cefotaxime were found to be compatible with NumetaG13E, and it is safe to co-administer these drugs together with this PN in NICU patients.

• Govender, Rydvikha; Kissi, Eric Ofosu; Larsson, Anette & Tho, Ingunn (2021). Polymers in Pharmaceutical Additive Manufacturing: A Balancing Act Between Printability and Product Performance. Advanced Drug Delivery Reviews. ISSN 0169-409X. 177. doi: 10.1016/j.addr.2021.113923. Full text in Research Archive
• Kissi, Eric Ofosu; Nilsson, Robin; Nogueira, Liebert Parreiras; Larsson, Anette & Tho, Ingunn (2021). Influence of Drug Load on the Printability and Solid-State Properties of 3D-Printed Naproxen-Based Amorphous Solid Dispersion. Molecules. ISSN 1431-5157. 26(15). doi: 10.3390/molecules26154492. Full text in Research Archive Show summary

  Fused deposition modelling-based 3D printing of pharmaceutical products is facing challenges like brittleness and printability of the drug-loaded hot-melt extruded filament feedstock and stabilization of the solid-state form of the drug in the final product. The aim of this study was to investigate the influence of the drug load on printability and physical stability. The poor glass former naproxen (NAP) was hot-melt extruded with Kollidon® VA 64 at 10–30% w/w drug load. The extrudates (filaments) were characterised using differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA), and thermogravimetric analysis (TGA). It was confirmed that an amorphous solid dispersion was formed. A temperature profile was developed based on the results from TGA, DSC, and DMA and temperatures used for 3D printing were selected from the profile. The 3D-printed tablets were characterised using DSC, X-ray computer microtomography (XµCT), and X-ray powder diffraction (XRPD). From the DSC and XRPD analysis, it was found that the drug in the 3D-printed tablets (20 and 30% NAP) was amorphous and remained amorphous after 23 weeks of storage (room temperature (RT), 37% relative humidity (RH)). This shows that adjusting the drug ratio can modulate the brittleness and improve printability without compromising the physical stability of the amorphous solid dispersion.

• Gulin-Sarfraz, Tina; Kalantzopoulos, Georgios N.; Pettersen, Marit Kvalvåg; Åsli, Anette Wold; Tho, Ingunn & Axelsson, Lars Torsten [Show all 7 contributors for this article] (2021). Inorganic Nanocarriers for Encapsulation of Natural Antimicrobial Compounds for Potential Food Packaging Application: A Comparative Study. Nanomaterials. 11(2). doi: 10.3390/nano11020379. Full text in Research Archive Show summary

  Design and development of novel inorganic nanocarriers for encapsulation of natural antimicrobial substances for food packaging applications have received great interest during the last years. Natural nanoclays are the most investigated nanocarriers and recently interest has also grown in the synthetically produced porous silica particles. However, these different carrier matrices have not been compared in terms of their loading capability and subsequent release. In this study, the feasibility of porous silica particles (with different pore structures and/or surface functionalities) and commercially available nanoclays were evaluated as encapsulation matrices. Two well-studied antimicrobial substances, thymol and curcumin, were chosen as volatile and non-volatile model compounds, respectively. The encapsulation efficiency, and the subsequent dispersibility and release, of these substances differed significantly among the nanocarriers. Encapsulation of the volatile compound highly depends on the inner surface area, i.e., the protective pore environment, and an optimal nanocarrier can protect the encapsulated thymol from volatilization. For the non-volatile compound, only the release rate and dispersibility are affected by the pore structure. Further, water-activated release of the volatile compound was demonstrated and exhibited good antimicrobial efficacy in the vapor phase against Staphylococcus aureus. This comparative study can provide a base for selecting the right nanocarrier aimed at a specific food packaging application. No nanocarrier can be considered as a universally applicable one.

• Nezvalova-henriksen, Katerina; Nilsson, Niklas; Holvik, Camilla Tomine; Berge, Vigdis Staven & Tho, Ingunn (2020). Y-site physical compatibility of numeta g13e with drugs frequently used at neonatal intensive care. Pharmaceutics. 12(7). doi: 10.3390/pharmaceutics12070677. Full text in Research Archive Show summary

  Preterm neonates require parenteral nutrition (PN) in addition to intravenous drug therapy. Due to limited venous access, drugs are often co-administered with PN via the same lumen. If incompatible, precipitation and emulsion destabilization may occur with the consequent risk of embolism and hyper-immune reactions. Information on intravenous compatibility is scarce. Our aim was to analyse the compatibility of Numeta G13E with paracetamol, vancomycin and fentanyl because of the frequency of their use. A panel of methods was chosen to assess precipitation (sub-visual particle counting, turbidity measurement, Tyndall beam effect and pH measurement) and emulsion destabilization (mean droplet diameter measurement and sub-visual counting of oil droplets, followed by estimation of PFAT5 (percentage of fat residing in globules larger than 5 µm) and pH measurement). Samples in clinically relevant mixing ratios were tested immediately and after 4 h. All samples of drugs mixed with Numeta G13E were compared to unmixed controls. None of the tested drugs precipitated in contact with Numeta G13E, and we did not see any sign of emulsion destabilization when clinically relevant mixing ratios were applied. These results are reassuring. However, when contact time exceeds the established norm, caution in the form of filter utilisation and close inspection is advised.

• Hagesæther, Ellen; Adamczak, Malgorzata Iwona; Hiorth, Marianne & Tho, Ingunn (2020). Characterization of Bioadhesion, Mucin‐interactions and Mucosal Permeability of Pharmaceutical Nano‐ and Microsystems. In Peltonen, Leena (Eds.), Characterization of Pharmaceutical Nano and Microsystems. John Wiley & Sons. ISSN 9781119414018. p. 171–205. doi: 10.1002/9781119414018.ch5. Full text in Research Archive
• Tzanova, Martina; Hagesæther, Ellen & Tho, Ingunn (2020). Solid lipid nanoparticle-loaded mucoadhesive buccal films – Critical quality attributes and in vitro safety & efficacy. International Journal of Pharmaceutics. ISSN 0378-5173. 592. doi: 10.1016/j.ijpharm.2020.120100. Full text in Research Archive Show summary

  The objective of this work was to develop and characterize solid lipid nanoparticle (SLN)-loaded mucoadhesive films to reveal their potential as successful drug formulations. SLNs based on lipid (Lipoid S100) and surfactant (polysorbate 80) were prepared using the solvent-injection method, and their properties examined using experimental designs. Further, the marker coumarin 6 (C6) was solubilized in the particles as a model for a lipophilic drug. Lipid and surfactant concentrations influenced the particle size, while C6 had minor impact. The particle size distribution was narrow and the storage stability satisfactory for 4 months (4 ℃). The incorporation of the nanoparticles into a film matrix consisting of HPMC and glycerol, increased film thickness and flexibility, and slightly decreased the mechanical strength. The mucin interaction and disintegration time of the films were unimpaired. Film uniformity was satisfactory. Solubilisation in SLNs reduced the rate and extent of permeation of C6 through a monolayer of mucus-producing HT29-MTX cells. When the particles were incorporated into the mucoadhesive film, this effect was compensated for. In conclusion, this project was a first step in the successful development of an SLN-loaded mucoadhesive film formulation and served its purpose in revealing the formulation’s uniformity, mucoadhesiveness and biocompatibility

• Liu, JingWen; Rades, Thomas; Tho, Ingunn & Kissi, Eric Ofosu (2020). Functionalised calcium carbonate as a coformer to stabilize amorphous drugs by mechanochemical activation. European journal of pharmaceutics and biopharmaceutics. ISSN 0939-6411. 155, p. 22–28. doi: 10.1016/j.ejpb.2020.07.029. Full text in Research Archive
• Alopaeus, Julia Fredrika; Göbel, Anja; Breitkreutz, Jörg; Sande, Sverre Arne & Tho, Ingunn (2020). Investigation of hydroxypropyl-β-cyclodextrin inclusion complexation of two poorly soluble model drugs and their taste-sensation - Effect of electrolytes, freeze-drying and incorporation into oral film formulations. Journal of Drug Delivery Science and Technology. ISSN 1773-2247. 61. doi: 10.1016/j.jddst.2020.102245. Full text in Research Archive
• Brustugun, Jørgen; Aas, Elisabeth Birkedal; Tho, Ingunn & Bjerknes, Kathrin (2020). Comparing Two Methods of Tablet Manipulation to Adjust the Warfarin Dose in Paediatric Care. Pharmaceutics. 12(4), p. 1–13. doi: 10.3390/pharmaceutics12040375. Full text in Research Archive Show summary

  Tablets containing prescribed doses are not always available, and this is of particular importance in paediatric care where suitable age-appropriate formulations are generally lacking. To obtain a child-adjusted dose, tablets are manipulated in several ways; e.g., they may be dispersed in water before a fraction is extracted, or they may be split before the resulting fragment is dispersed. In this study, the accuracy attained through these manipulation methods was investigated for two generic tablets containing the anticoagulant warfarin. Tablets were dispersed in water (10 mL) before a fraction (10%) was withdrawn, alternatively tablets were split in half or quarter fragments before the fragments were dispersed in water. To investigate the contribution of variability from the different steps in the manipulation processes, the amount of warfarin recovered from the various dispersions was determined, as was the accuracy of the splitting. A validated UHPLC-method was used for quantitative determination of warfarin. Splitting of the tablets could result in deviation &gt;30% from the ideal, theoretical weight. The amount of drug substance extracted as a fraction from the dispersed tablets deviated no more than 10% from the intended amount. To obtain the most accurate child-adjusted fraction dose of warfarin, the tablets investigated in this study should be dispersed and the desired proportion extracted. Practices that involve splitting tablets are likely to increase the variation, and should be avoided.

• Brustugun, Jørgen; Notaker, Nikolai; Paetz, Lasse Holtan; Tho, Ingunn & Bjerknes, Kathrin (2020). Adjusting the dose in paediatric care by dispersing fragments of four different aspirin tablets. Acta Paediatrica. ISSN 0803-5253. 109(11), p. 2394–2401. doi: 10.1111/apa.15216. Full text in Research Archive
• Adrover, Alessandra; Paolicelli, Patrizia; Petralito, Stefania; Muzio, Laura Di; Trilli, Jordan & Cesa, Stefania [Show all 8 contributors for this article] (2019). Gellan Gum/Laponite Beads for the Modified Release of Drugs: Experimental and Modeling Study of Gastrointestinal Release. Pharmaceutics. 11(4), p. 187–187. doi: 10.3390/pharmaceutics11040187. Full text in Research Archive Show summary

  In this study, gellan gum (GG), a natural polysaccharide, was used to fabricate spherical porous beads suitable as sustained drug delivery systems for oral administration. GG was cross-linked with calcium ions to prepare polymeric beads. Rheological studies and preliminary experiments of beads preparation allowed to identify the GG and the CaCl2 concentrations suitable for obtaining stable and spherical particles. GG beads were formed, through ionotropic gelation technique, with and without the presence of the synthetic clay laponite. The resultant beads were analyzed for dimensions (before and after freeze-drying), morphological aspects and ability to swell in different media miming biological fluids, namely SGF (Simulated Gastric Fluid, HCl 0.1 M) and SIF (Simulated Intestinal Fluid, phosphate buffer, 0.044 M, pH 7.4). The swelling degree was lower in SGF than in SIF and further reduced in the presence of laponite. The GG and GG-layered silicate composite beads were loaded with two model drugs having different molecular weight, namely theophylline and cyanocobalamin (vitamin B12) and subjected to in-vitro release studies in SGF and SIF. The presence of laponite in the bead formulation increased the drug entrapment efficiency and slowed-down the release kinetics of both drugs in the gastric environment. A moving-boundary swelling model with “diffuse” glassy-rubbery interface was proposed in order to describe the swelling behavior of porous freeze-dried beads. Consistently with the swelling model adopted, two moving-boundary drug release models were developed to interpret release data from highly porous beads of different drugs: drug molecules, e.g., theophylline, that exhibit a typical Fickian behavior of release curves and drugs, such as vitamin B12, whose release curves are affected by the physical/chemical interaction of the drug with the polymer/clay complex. Theoretical results support the experimental observations, thus confirming that laponite may be an effective additive for fabricating sustained drug delivery systems.

• Alopaeus, Julia Fredrika; Hellfritzsch, Marie; Gutowski, Tobias; Scherließ, Regina; Almeida, Andreia F & Sarmento, Bruno [Show all 8 contributors for this article] (2019). Mucoadhesive buccal films based on a graft co-polymer – A mucin-retentive hydrogel scaffold. European Journal of Pharmaceutical Sciences. ISSN 0928-0987. 142:105142, p. 1–15. doi: 10.1016/j.ejps.2019.105142. Full text in Research Archive Show summary

  From a patient-centric perspective, oromucosal drug delivery is highly attractive due to the ease of administration without the need of swallowing, and improved patient safety. The aim of the presented work was to prepare a buccal film using a self-forming micellar drug solubiliser as the film matrix, combining it with a mucoadhesive polymer for an enhanced retention on the buccal mucosa. Specifically, we propose the use of a graft co-polymer (Soluplus®), as a solubiliser and film former, supplemented with polymers with more hydrophilic properties and known mucoadhesive properties; hydroxypropyl methylcellulose (HPMC) or modified hydroxypropyl pea starch (Lycoat®). The film was manufactured by the solvent casting method. The resulting dual polymer film containing HPMC exhibited resistance to erosion and mucoadhesive properties superior to the control films of single polymers. In an <i>in vitro</i> oral cavity model, these properties were shown to correlate with increased residence time on simulated oral mucosa. Furthermore, all films containing the graft co-polymer showed similar permeability characteristics of furosemide towards buccal TR146 epithelial cells. This work illustrated that it is possible to manufacture dry, solid, dual polymer films containing an advanced drug delivery system with a cheap and simple method. The combination of a graft co-polymer with a mucoadhesive polymer transform into drug solubilising micelles in a mucin-retentive hydrogel scaffold with longer retention time on buccal mucosa for safe and enhanced advanced formulation.

• Brustugun, Jørgen; Notaker, Nikolai; Paetz, Lasse Holtan; Tho, Ingunn & Bjerknes, Kathrin (2019). Adjusting the dose in paediatric care: dispersing four different aspirin tablets and taking a proportion. European Journal of Hospital Pharmacy (EJHP). ISSN 2047-9956. doi: 10.1136/ejhpharm-2019-001903. Full text in Research Archive Show summary

  Objectives: When caring for children in a hospital setting, tablets are often manipulated at the ward to obtain the right dose. One example is manipulation of tablets containing the slightly water-soluble substance aspirin, used in paediatric care as an antiplatelet agent. The evidence base, however, for choosing certain tablet formulations and manipulation methods over others for extraction of proportions is lacking. The aim of this study was to investigate the effect of tablet formulation and manipulation technique on the dose accuracy and precision attained when dispersing different commercially available aspirin tablets and extracting a small proportion suitable for children. Methods: The manipulation methods investigated simulated those observed in the paediatric clinic. Four tablet formulations—one chewable, one conventional and two dispersible—were dispersed in 10 mL water in a medicine measure. On (1) passive dispersion, (2) mixing by stirring with the syringe, or (3) stirring and pumping the dispersion in and out of the syringe, respectively, proportions (1 mL or 2 mL) were extracted and the doses recovered were determined using a validated UHPLC (ultra high-pressure liquid chromatography) method. Results: Fractions from the four different dispersed aspirin tablet formulations varied from 99% to 3% of that intended with the lowest degree of mixing, and from 96% to 34% of that intended with the highest degree of mixing. Only the dispersible tablets gave average doses within 20% of the intended dose. Conclusions: Fraction extraction from dispersed aspirin tablets only gave doses within 20% of intended for the dispersible tablets, and then only for some of the manipulation methods: ‘passive dispersion’ for the 75 mg dispersible tablet and ‘stirring and pumping’ for the 300 mg dispersible tablet. The tablets not intended for dispersion gave unsatisfactory results, outside 20%, regardless of manipulation method. The findings underline the importance of considering both tablet formulation and dose extraction technique when manipulations are required.

• Nilsson, Niklas; Nezvalova-Henriksen, Katerina & Tho, Ingunn (2019). Emulsion Stability of Different Intravenous Propofol Formulations in Simulated Co-Administration with Remifentanil Hydrochloride. Pharmaceutical Technology in Hospital Pharmacy (PTHP). ISSN 2365-2411. 4(2), p. 77–87. doi: 10.1515/pthp-2019-0014. Full text in Research Archive Show summary

  Background Propofol and remifentanil often need to be co-administered via the same intravenous catheter line, which predisposes to potential compatibility issues. Our aim was to determine and compare the emulsion stability of three propofol formulations, two with medium chain triglycerides and one with long chain triglycerides, when administered together with remifentanil hydrochloride. Methods Remifentanil hydrochloride (Ultiva ®) 50 µg/mL was mixed with two concentrations (10 and 20 mg/mL) of each propofol formulation in mixing ratios 10+1, 20+1, 1+1 and 1+20. Emulsion stability was assessed immediately after mixing and 4 hours later by measurements of pH, mean droplet diameter, polydispersity index, and calculating percentage of fat residing in globules>5 µm (PFAT5). Results High PFAT5 values were observed in certain mixing ratios. The correlation between elevated PFAT5 and high propofol concentration (20 mg/mL), when remifentanil was in abundance and for long contact time indicated that these factors influenced the stability of the propofol emulsions. Conclusions Stability differences between the propofol formulations were identified under extreme test conditions. Co-administration of remifentanil and propofol in the same i.v. line is safe when propofol is in abundance. Caution is advised when remifentanil is present in equal parts or in abundance when co-administered with propofol 20 mg/mL.

• Alopaeus, Julia Fredrika; Hagesæther, Ellen & Tho, Ingunn (2019). Micellisation Mechanism and Behaviour of Soluplus®–Furosemide Micelles: Preformulation Studies of an Oral Nanocarrier-Based System. Pharmaceuticals. 12(1). doi: 10.3390/ph12010015. Full text in Research Archive Show summary

  In this study, self-assembling Soluplus® micelles were examined for inherent properties. Through calorimetric analysis, the critical micelle concentration (CMC) could be determined at 25 and 37 °C, and the influence of three media (Milli-Q water, phosphate-buffered saline (PBS) with a pH of 7.4 and 0.1 M HCl) on the lower critical solution temperature (LCST) was detected. Furthermore, the solubilisation of a poorly soluble drug, furosemide, into the Soluplus® micelles was studied. The concentration-dependent properties of the micellar system were assessed through an examination of the micellar size, polydispersity, morphology, viscosity and solubilising properties, which were all found to be affected by the concentration, but temperature, pH and the composition of the test medium were also found to have an effect. Homogeneity in the estimated micellar size and morphology was shown for monophasic micelle dispersions in lower concentrations and with a shift towards more complex structures or aggregates in higher concentrations. The micelles were further investigated in terms of drug release and biocompatibility with mucus-producing HT29-MTX cells, where no biocompatibility issues were found. In this research, the implications for oral drug delivery are discussed and valuable preformulation information is provided on the micellar properties of a Soluplus® drug system in a liquid or semi-solid form.

• Roque, Luis; Castro, Pedro; Molpeceres, Jesus; Viana, Ana S.; Roberto, Amilcar & Reis, Cláudia [Show all 10 contributors for this article] (2018). Bioadhesive polymeric nanoparticles as strategy to improve the treatment of yeast infections in oral cavity: in-vitro and ex-vivo studies. European Polymer Journal. ISSN 0014-3057. 104, p. 19–31. doi: 10.1016/j.eurpolymj.2018.04.032. Full text in Research Archive
• Staven, Vigdis; Wang, Siri; Grønlie, Ingrid & Tho, Ingunn (2018). Physical stability of an all-in-one parenteral nutrition admixture for preterm infants upon mixing with micronutrients and drugs. European Journal of Hospital Pharmacy (EJHP). ISSN 2047-9956. 27, p. 36–42. doi: 10.1136/ejhpharm-2018-001562. Full text in Research Archive Show summary

  <p><I>Objectives</I>: The main objective was to investigate Y-site compatibility of intravenous drugs with one standard total parenteral nutrition (TPN) admixture for preterm infants. Since micro-precipitation was observed in the water phase after addition of trace elements, the concentration effect on micro-precipitation formation developed as a sub-goal.</p> <p><I>Methods</I>: Seven drugs (ampicillin, ceftazidime, fluconazole, fosphenytoin, furosemide, metronidazole and paracetamol) were mixed in three mixing ratios with one preterm TPN admixture. Samples were investigated within 1 hour and again after 4 hours. Precipitation was studied in a lipid-free version called TPNaq by light obscuration, turbidimetry and visual examination. Emulsion stability data were assessed by light obscuration and laser diffraction. pH was measured to assess the theoretical risk of precipitation and emulsion destabilisation. The influence of different concentrations of trace elements on precipitation was investigated by visual examination, turbidimetry and light obscuration.</p> <p><I>Results</I>: Ampicillin, ceftazidime, fosphenytoin and furosemide led to precipitation after mixing with TPNaq. In some samples of TPN and fluconazole, metronidazole and paracetamol, the emulsion droplet size was above the acceptance limit, although this might also be inherent to the TPN admixture. An unexpected formation of micro-precipitate correlating with increasing amounts of added trace elements might be caused by an interaction of cysteine and copper, and complicated the compatibility assessment with drugs.</p> <p><I>Conclusions</I>: The micro-precipitate resulting from the addition of trace elements should be investigated further. This study did not provide sufficient evidence to recommend Y-site infusion of the tested drugs and the preterm admixture; however, it might offer some additional support to other compatibility data.

• Roque, Luis; Duarte, Noelia; Bronze, Maria Rosario; Garcia, Catarina; Alopaeus, Julia Fredrika & Molpeceres, Jesus [Show all 10 contributors for this article] (2018). Development of a bioadhesive nanoformulation with Glycyrrhiza glabra L. extract against Candida albicans. Biofouling (Print). ISSN 0892-7014. 34(8), p. 880–892. doi: 10.1080/08927014.2018.1514391. Full text in Research Archive
• Adrover, Alessandra; Varani, Gabriele; Paolicelli, Patrizia; Petralito, Stefania; Muzio, Laura Di & Casadei, Maria Antonietta [Show all 7 contributors for this article] (2018). Experimental and Modeling Study of Drug Release from HPMC-Based Erodible Oral Thin Films. Pharmaceutics. 10(4). doi: 10.3390/pharmaceutics10040222. Full text in Research Archive Show summary

  In this work hydroxypropyl methylcellulose (HPMC) fast-dissolving thin films for oral administration are investigated. Furosemide (Class IV of the Biopharmaceutical Classification System) has been used as a model drug for in vitro release tests using three different set-ups: the Franz cell, the millifluidic flow-through device, and the paddle type dissolution apparatus (USP II). In order to enable drug incorporation within HPMC films, a multifunctional excipient, hydroxypropyl- β -cyclodextrin (HP- β -CD) has been included in the formulation, and the influence of HP- β -CD on film swelling, erosion, and release properties has been investigated. Mathematical models capable of describing the swelling and release processes from HPMC erodible thin films in different apparatuses have been developed. In particular, we propose a new model for the description of drug transport and release in a Franz cell that accounts for the effect of the unavoidable imperfect mixing of the receptor chamber.

• Tovsen, Marianne Lilletvedt; Tho, Ingunn & Tønnesen, Hanne Hjorth (2018). Viscosity reduction of isotonic solutions of the photosensitizer TPCS2a by cyclodextrin complexation. Drug Development and Industrial Pharmacy. ISSN 0363-9045. 44(2), p. 261–265. doi: 10.1080/03639045.2017.1386210. Full text in Research Archive
• Roque, Luis; Alopaeus, Julia Fredrika; Reis, Cláudia; Rijo, Patricia; Molpeceres, Jesus & Hagesæther, Ellen [Show all 8 contributors for this article] (2018). Mucoadhesive assessment of different antifungal nanoformulations. Bioinspiration & Biomimetics. ISSN 1748-3182. 13(5). doi: 10.1088/1748-3190/aad488. Full text in Research Archive
• Andersen, Toril; Mishchenko, Ekaterina; Flaten, Gøril Eide; Sollid, Johanna U Ericson; Mattsson, Sofia & Tho, Ingunn [Show all 7 contributors for this article] (2017). Chitosan-based nanomedicine to fight genital Candida infections: Chitosomes. Marine Drugs. 15:64(3), p. 1–12. doi: 10.3390/md15030064. Full text in Research Archive Show summary

  Vaginal infections are associated with high recurrence, which is often due to a lack of efficient treatment of complex vaginal infections comprised of several types of pathogens, especially fungi and bacteria. Chitosan, a mucoadhesive polymer with known antifungal effect, could offer a great improvement in vaginal therapy; the chitosan-based nanosystem could both provide antifungal effects and simultaneously deliver antibacterial drugs. We prepared chitosan-containing liposomes, chitosomes, where chitosan is both embedded in liposomes and surface-available as a coating layer. For antimicrobial activity, we entrapped metronidazole as a model drug. To prove that mucoadhesivness alone is not sufficient for successful delivery, we used Carbopol-containing liposomes as a control. All vesicles were characterized for their size, zeta potential, entrapment efficiency, and in vitro drug release. Chitosan-containing liposomes were able to assure the prolonged release of metronidazole. Their antifungal activity was evaluated in a C. albicans model; chitosan-containing liposomes exhibited a potent ability to inhibit the growth of C. albicans. The presence of chitosan was crucial for the system’s antifungal activity. The antifungal efficacy of chitosomes combined with antibacterial potential of the entrapped metronidazole could offer improved efficacy in the treatment of mixed/complex vaginal infections.

• Staven, Vigdis; Iqbal, Herra; Wang, Siri; Grønlie, Ingrid & Tho, Ingunn (2016). Physical compatibility of total parenteral nutrition and drugs in Y-site administration to children from neonates to adolescents. Journal of Pharmacy and Pharmacology (JPP). ISSN 0022-3573. 69(4), p. 448–462. doi: 10.1111/jphp.12647. Full text in Research Archive
• Staven, Vigdis; Wang, Siri; Grønlie, Ingrid & Tho, Ingunn (2016). Development and evaluation of a test program for Y-site compatibility testing of total parenteral nutrition and intravenous drugs. Nutrition Journal. 15. doi: 10.1186/s12937-016-0149-x. Full text in Research Archive Show summary

  Background: There is no standardized procedure or consensus to which tests should be performed to judge compatibility/ incompatibility of intravenous drugs. The purpose of this study was to establish and evaluate a test program of methods suitable for detection of physical incompatibility in Y-site administration of total parenteral nutrition (TPN) and drugs. Methods: Eight frequently used methods (dynamic light scattering, laser diffraction, light obscuration, turbidimetry, zeta potential, light microscopy, pH-measurements and visual examination using Tyndall beams), were scrutinized to elucidate strengths and weaknesses for compatibility testing. The responses of the methods were tested with samples containing precipitation of calcium phosphate and with heat destabilized TPN emulsions. A selection of drugs (acyclovir, ampicillin, ondansetron and paracetamol) was mixed with 3-in-1 TPN admixtures (Olimel® N5E, Kabiven® and SmofKabiven®) to assess compatibility (i.e. potential precipitates and emulsion stability). The obtained compatibility data was interpreted according to theory and compared to existing compatibility literature to further check the validity of the methods. Results: Light obscuration together with turbidimetry, visual inspection and pH-measurements were able to capture signs of precipitations. For the analysis of emulsion stability, light obscuration and estimation of percent droplets above 5 μm (PFAT5) seemed to be the most sensitive method; however laser diffraction and monitoring changes in pH might be a useful support. Samples should always be compared to unmixed controls to reveal changes induced by the mixing. General acceptance criteria are difficult to define, although some limits are suggested based on current experience. The experimental compatibility data was supported by scattered reports in literature, further confirming the suitability of the test program. However, conflicting data are common, which complicates the comparison to existing literature. Conclusions: Testing of these complex blends should be based on a combination of several methods and accompanied by theoretical considerations.

• Hagen, Eirik; Løding, Fredrik Sandberg; Mattsson, Sofia & Tho, Ingunn (2016). Use of interactive mixtures to obtain mini-tablets with high dose homogeneity for paediatric drug delivery. Journal of Drug Delivery Science and Technology. ISSN 1773-2247. 34, p. 51–59. doi: 10.1016/j.jddst.2016.03.006. Full text in Research Archive
• Andersen, Toril; Bleher, Stefan; Flaten, Gøril Eide; Tho, Ingunn; Mattsson, Sofia & Skalko-Basnet, Natasa (2015). Chitosan in Mucoadhesive Drug Delivery: Focus on Local Vaginal Therapy. Marine Drugs. 13(1), p. 222–236. doi: 10.3390/md13010222. Full text in Research Archive Show summary

  Mucoadhesive drug therapy destined for localized drug treatment is gaining increasing importance in today’s drug development. Chitosan, due to its known biodegradability, bioadhesiveness and excellent safety profile offers means to improve mucosal drug therapy. We have used chitosan as mucoadhesive polymer to develop liposomes able to ensure prolonged residence time at vaginal site. Two types of mucoadhesive liposomes, namely the chitosan-coated liposomes and chitosan-containing liposomes, where chitosan is both embedded and surface-available, were made of soy phosphatidylcholine with entrapped fluorescence markers of two molecular weights, FITC-dextran 4000 and 20,000, respectively. Both liposomal types were characterized for their size distribution, zeta potential, entrapment efficiency and the in vitro release profile, and compared to plain liposomes. The proof of chitosan being both surface-available as well as embedded into the liposomes in the chitosan-containing liposomes was found. The capability of the surface-available chitosan to interact with the model porcine mucin was confirmed for both chitosan-containing and chitosan-coated liposomes implying potential mucoadhesive behavior. Chitosan-containing liposomes were shown to be superior in respect to the simplicity of preparation, FITC-dextran load, mucoadhesiveness and in vitro

• Vanic, Zeljka; Planinsek, Odon; Skalko-Basnet, Natasa & Tho, Ingunn (2014). Tablets of pre-liposomes govern in situ formation of liposomes: Concept and potential of the novel drug delivery system. European journal of pharmaceutics and biopharmaceutics. ISSN 0939-6411. 88(2), p. 443–454. doi: 10.1016/j.ejpb.2014.06.003. Full text in Research Archive
• Hiorth, Marianne; Nilsen, Susanne & Tho, Ingunn (2014). Bioadhesive Mini-Tablets for Vaginal Drug Delivery. Pharmaceutics. 6(3), p. 494–511. doi: 10.3390/pharmaceutics6030494. Full text in Research Archive Show summary

  Different non-ionic cellulose ethers (methyl cellulose, MC; hydroxyethyl cellulose, HEC; hydroxypropyl cellulose, HPC; hydroxypropylmethyl cellulose, HPMC) and microcrystalline cellulose (MCC) were investigated as matrix formers for preparation of mini-tablets targeting vaginal drug delivery. Hexyl aminolevulinat hydrochloridum (HAL) was used as a model drug. The mini-tablets were characterized with respect to their mechanical strength, bioadhesion towards cow vaginal tissue in two independent tests (rotating cylinder test, detachment test using texture analyzer), and dissolution rate in two media mimicking the pH levels of fertile, healthy and post-menopausal women (vaginal fluid simulant pH 4.5, phosphate buffer pH 6.8). Mini-tablets with a matrix of either HPMC or HPC were found to possess adequate mechanical strength, superior bioadhesive behavior towards vaginal tissue, and pH independent controlled release of the model drug, suggesting that both systems would be suited for the treatment of women regardless of age, i.e., respective of their vaginal pH levels. Bioadhesive mini-tablets offer a potential for improved residence time in the vaginal cavity targeting contact with mucosal tissue and prolonged release of the drug.

• Staven, Vigdis; Waaseth, Marit; Wang, Siri; Grønlie, Ingrid & Tho, Ingunn (2014). Utilization of the Tyndall effect for enhanced visual detection of particles in compatibility testing of intravenous fluids: Validity and reliability. PDA journal of pharmaceutical science and technology. ISSN 1079-7440. 69(2), p. 270–283. doi: 10.5731/pdajpst.2015.01020. Full text in Research Archive
• Jøraholmen, May Wenche; Vanić, Željka; Tho, Ingunn & Škalko-Basnet, Nataša (2014). Chitosan-coated liposomes for topical vaginal therapy: Assuring localized drug effect. International Journal of Pharmaceutics. ISSN 0378-5173. 472(1-2), p. 94–101. doi: 10.1016/j.ijpharm.2014.06.016. Full text in Research Archive Show summary

  The choice of drug therapy in pregnant patients suffering from vaginal infections is limited by the safety profile of the drug. Assuring the efficient topical therapy to avoid systemic absorption is considered the best therapy option. Chitosan-coated liposomes have been developed and optimized to assure localized therapy of clotrimazole. Chitosan was selected as mucoadhesive polymer both to prolong system's retention at the vaginal site and act on biofilms responsible for high recurrence of infections. Sonicated liposomes were coated with chitosan in three different concentrations, namely 0.1, 0.3 and 0.6% (w/v). Clotrimazole-containing (22 μg/mg lipid) chitosan-coated liposomes were in the size range of 100–200 nm. The <i>in vitro</i> release studies confirmed prolonged release of clotrimazole from both non-coated and chitosan-coated liposomes as compared to control. The <i>ex vivo</i> penetration experiments performed on the pregnant sheep vaginal tissue showed that coated liposomes assured increased clotrimazole tissue retention and reduced its penetration as compared to the control. Mucin studies revealed that the coating with lower chitosan concentration increased the system's mucoadhesive potential, as compared to coating with higher concentrations. These results provide a good platform for further <i>in vivo</i> animal studies on mucoadhesive liposomes destined to localized vaginal therapy.

• Andersen, Toril; Vanic, Zeljka; Flaten, Gøril Eide; Mattsson, S.; Tho, Ingunn & Skalko-Basnet, Natasa (2013). Pectosomes and Chitosomes as Delivery Systems for Metronidazole: The One-Pot Preparation Method. Pharmaceutics. 5, p. 445–456. doi: 10.3390/pharmaceutics5030445. Full text in Research Archive Show summary

  Mucoadhesive liposomes offer a potential for improved residence time of liposomal systems targeting contact with mucosal tissues, such as in buccal, oral, colon, and vaginal drug delivery. Most of the currently available methods rely on the coating of preformed liposomes by various mucoadhesive polymers. The aim of this study was to develop novel mucoadhesive system by the one-pot preparation method. The pectin- and chitosan-containing liposomes, namely pectosomes and chitosomes, were prepared by the modified solvent injection method. In order to optimize this novel delivery system, we used pectins and chitosans of both high and low degree of esterification/deacetylation (DE/DD), respectively. Sonication was applied to reduce the original vesicle size. All vesicles were characterized for their size, zeta potential, metronidazole entrapment, and stability. Both pectosomes and chitosomes were found to entrap more metronidazole than conventional plain liposomes. Preliminary data indicate that the polymer is present on the liposomal surface, embedded within inner liposomal bilayers, and entrapped inside the aqueous compartment. The next step in the evaluation of this system is the testing of its mucoadhesiveness.

• Hiorth, Marianne; Liereng, Linda; Selmer, Reidun Reinertsen & Tho, Ingunn (2013). Formulation of bioadhesive hexylaminolevulinate pellets intended for photodynamic therapy in the treatment of cervical cancer. International Journal of Pharmaceutics. ISSN 0378-5173. 441(1-2), p. 544–554. doi: 10.1016/j.ijpharm.2012.10.046. Full text in Research Archive
• Basnet, Purusotam; Hussain, Haider; Tho, Ingunn & Skalko-Basnet, Natasa (2012). Liposomal delivery system enhances anti-inflammatory properties of curcumin. Journal of Pharmaceutical Sciences. ISSN 0022-3549. 101(2), p. 598–609. doi: 10.1002/jps.22785. Full text in Research Archive
• Tho, Ingunn & Bauer-Brandl, Annette (2012). Chemometrics (PCA)in Pharmaceutics: Tablet Development, Manufacturing and Quality Assurance. In Sanguansat, Parinya (Eds.), Principal component analysis - multidisciplinary applications. IntechOpen. ISSN 9789535101291. p. 43–58. doi: 10.5772/37185. Full text in Research Archive
• Martins, Susana; Tho, Ingunn; Reimold, Isolde; Fricker, Gert; Souto, Eliana & Ferreira, Domingos C. [Show all 7 contributors for this article] (2012). Brain delivery of camptothecin by means of solid lipid nanoparticles: Formulation design, in vitro and in vivo studies. International Journal of Pharmaceutics. ISSN 0378-5173. 439(1-2), p. 49–62. doi: 10.1016/j.ijpharm.2012.09.054. Full text in Research Archive
• Martins, Susana; Tho, Ingunn; Souto, Eliana; Ferreira, Domingos C. & Brandl, Martin (2012). Multivariate design for the evaluation of lipid and surfactant composition effect for optimisation of lipid nanoparticles. European Journal of Pharmaceutical Sciences. ISSN 0928-0987. 45(5), p. 613–623. doi: 10.1016/j.ejps.2011.12.015. Full text in Research Archive
• Tho, Ingunn; Picker-Freyer, Katharina M.; Salbu, Linda & Bauer-Brandl, Annette (2012). On the Drug-Loading Capacity of Pectin Powder for Direct Compression. AAPS PharmSciTech. 13(2), p. 601–604. doi: 10.1208/s12249-012-9785-4. Full text in Research Archive
• Salbu, Linda; Picker-Freyer, Katharina M.; Schmid, Wolfgang; Bauer-Brandl, Annette & Tho, Ingunn (2012). Use of 3-D modelling in early development phase of pectin tablets. Journal on Excipients and Food Chemicals. 3, p. 5–16. Full text in Research Archive Show summary

  This study examines the contribution of the 3-D model in an early development set-up for pectin tablets. Therefore, the aim of this work is to extract as much information on the compression behaviour from as few tablets as possible. Pectins with various degrees of methoxylation (DM) were studied (4-72%). The compressibility was evaluated by classical “in-die” Heckel and Kawakita analyses in addition to the 3-D modelling. For validation purposes well-known reference materials were included. 3-D modelling applied on data of single tablets yielded a certain degree of information on the compressibility. When several tablets with different maximum relative densities were included, no additional information was gained in the classical evaluation, whereas the 3D-model provided additional information through the shape of the 3-D parameter plot: pectins with a DM ? 25% consolidated predominantly by elastic deformation similarly to the 3-D parameter plot of pregelatinized starch (PGS). The 3-D analysis also suggests some degree of fragmentation, and for some of the low-methoxylated pectins (DM ? 10%) viscoelastic deformation. This study showed that by application of 3-D modelling it is possible to differentiate elastic and viscoelastic materials, if tablets of different maximum relative densities are evaluated.

• Salbu, Linda; Bauer-Brandl, Annette; Alderborn, Göran & Tho, Ingunn (2012). Effect of degree of methoxylation and particle size on compression properties and compactibility of pectin powders. Pharmaceutical development and technology (Print). ISSN 1083-7450. 17, p. 333–343. doi: 10.3109/10837450.2010535831. Full text in Research Archive
• Tho, Ingunn & Bauer-Brandl, Annette (2011). Quality by design (QbD) approaches for the compression step of tableting. Expert Opinion on Drug Delivery. ISSN 1742-5247. 8(12), p. 1631–1644. doi: 10.1517/17425247.2011.633506. Full text in Research Archive
• Cavalcanti, Leide Passos; Tho, Ingunn; Konovalov, Oleg; Fossheim, Sigrid L & Brandl, Martin (2011). Compressibility study of quaternary phospholipid blend monolayers. Colloids and Surfaces B: Biointerfaces. ISSN 0927-7765. 85(2), p. 153–160. doi: 10.1016/j.colsurfb.2011.02.015. Full text in Research Archive
• Martins, Susana; Tho, Ingunn; Ferreira, D.C; Souto, Eliana B & Brandl, Martin (2011). Physicochemical properties of lipid nanoparticles: Effect of lipid and surfactant composition. Drug Development and Industrial Pharmacy. ISSN 0363-9045. 37(7), p. 815–824. doi: 10.3109/03639045.2010.545414. Full text in Research Archive
• Tho, Ingunn; Liepold, Bernd; Rosenberg, Jürg; Maegerlein, Markus; Brandl, Martin & Fricker, Gert (2010). Formation of nano/micro-dispersions with improved dissolution properties upon dispersion of ritonavir melt extrudate in aqueous media. European Journal of Pharmaceutical Sciences. ISSN 0928-0987. 40(1), p. 25–32. doi: 10.1016/j.ejps.2010.02.003. Full text in Research Archive

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• Tho, Ingunn & Basnet, Natasa Skalko (2024). Cell-based in vitro models for vaginal permeability studies. In Sarmento, Bruno; Pereira, Catarina Leite & Neves, José Das (Ed.), Concepts and Models for Drug Permeability Studies: Cell and Tissue Based In Vitro Culture Models, 2nd Eds.. Elsevier. ISSN 9780443155109. p. 169–186. doi: 10.1016/B978-0-443-15510-9.00021-9. Full text in Research Archive
• 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. Full text in Research Archive
• Alopaeus, Julia Fredrika & Tho, Ingunn (2019). The micellisation mechanism of Soluplus: effect of temperature, concentration and disperse media. Full text in Research Archive
• Valen, Håkon; Dragland, Inger Sofie; Blomqvist, Brianna; Tho, Ingunn; Bruzell, Ellen Merete & Tønnesen, Hanne Hjorth (2018). Antibacterial and anti-adhesive properties of Pluronic® F127 solutions in the absence or presence of photoactivation. Full text in Research Archive
• Valen, Håkon; Blomqvist, Brianna; Dragland, Inger Sofie; Tho, Ingunn; Bruzell, Ellen Merete & Tønnesen, Hanne Hjorth (2018). Antibacterial and anti-adhesive Properties of Pluronic F127 solutions in the abscence and presence of photoactivation. Full text in Research Archive
• Roque, Luis; Castro, P; Fonte, P; Hagesæther, Ellen; Molpeceres, J & Rijo, P [Show all 8 contributors for this article] (2018). Mucoadhesive assessment of different antifungal nanoformulations. Full text in Research Archive
• Roque, Luis; Castro, P; Tho, Ingunn; Hagesæther, Ellen; Molpeceres, J & Rijo, P [Show all 7 contributors for this article] (2018). Mucoadhesive assessment of different antifungal nanoformulations for the Treatment of Yeast Infections in oral mucosa. Full text in Research Archive
• Alopaeus, Julia Fredrika; Nguyen, Lina Mai; Pohjavirta, Jennie; Hagesæther, Ellen; Tønnesen, Hanne Hjorth & Tho, Ingunn (2018). Evaluation of concentration-dependent self-assembling structures of Soluplus and their properties in oral drug delivery. Full text in Research Archive
• Tho, Ingunn (2016). Nano-particulate drug delivery to various targets. Full text in Research Archive
• Tho, Ingunn & Skalko-Basnet, Natasa (2015). Cell-based in vitro models for vaginal permeability studies. In Bruno, Sarmento (Eds.), Concepts and Models for Drug Permeability Studies. Cell and Tissue based In Vitro Culture Models. Elsevier. ISSN 9780081000946. p. 115–128. doi: 10.1016/B978-0-08-100094-6.00008-0. Full text in Research Archive
• Louis, Betoko; Skalko-Basnet, Natasa & Tho, Ingunn (2015). Orodispersible films containing inclusion complexes of HP-β-CD furosemide for taste-masking. Full text in Research Archive
• Tho, Ingunn; Vanic, Zeljka & Skalko-Basnet, Natasa (2015). Compaction of pre-liposomal tablets that governing in situ formation of liposomes. Full text in Research Archive
• Blomqvist, Brianna; Kvam, Ketil; Dragland, Inger Sofie; Tho, Ingunn; Bruzell, Ellen Merete & Tønnesen, Hanne Hjorth (2015). Evaluation of Material Suitability for Nanoparticle-Based Coatings and Further Antimicrobial Treatment. Full text in Research Archive
• Vanic, Zeljka; Skalko-Basnet, Natasa & Tho, Ingunn (2015). In situ liposomes from novel pre-liposome tablets for vaginal drug delivery. Full text in Research Archive
• Tho, Ingunn (2015). Kvinner og legemidler. Norsk Farmaceutisk Tidsskrift (NFT). ISSN 0029-1935. 4, p. 11–11. Full text in Research Archive
• Tho, Ingunn (2015). Dosage forms today and in the future. Full text in Research Archive
• Alopaeus, Julia Fredrika; Tønnesen, Hanne Hjorth & Tho, Ingunn (2015). The influence of drug-cyclodextrin inclusion complexes on properties of hydroxypropyl cellulose based orodispersible films. Full text in Research Archive
• Staven, Vigdis; Waaseth, Marit; Wang, Siri; Grønlie, Ingrid & Tho, Ingunn (2014). Visual examination for compatibility testing of parenterals: experiences with two different light sources. Full text in Research Archive
• Tho, Ingunn & Bauer-Brandl, Annette (2013). Principal component analysis as a useful tool in tableting. Full text in Research Archive
• Jøraholmen, May Wenche; Vanic, Zeljka; Tho, Ingunn & Skalko-Basnet, Natasa (2013). Chitosan-coating as a mean to prolong vaginal residence time: Liposomes with clotrimazole. Full text in Research Archive
• Tho, Ingunn (2012). Nye legemiddelformer for barn – er minitabletter løsningen? Full text in Research Archive
• Tho, Ingunn (2012). New dosage forms for children: Mini-tablets. Full text in Research Archive
• Tho, Ingunn (2012). Smeltetabletter - brukervennlige og kjappe. [Internet]. Podkast. Full text in Research Archive
• Jøraholmen, May Wenche; Vanic, Zeljka; Tho, Ingunn & Skalko-Basnet, Natasa (2012). Vaginal penetration of chitosan-coated liposomes with clotrimazole: The effect of vesicle size. Full text in Research Archive
• Vanic, Zeljka; Duvnjak, Marieta; Skalko-Basnet, Natasa & Tho, Ingunn (2012). Tableting of spray-dried liposomes - concept and possibilities. Full text in Research Archive
• Andersen, Toril; Vanic, Zeljka; Tho, Ingunn & Skalko-Basnet, Natasa (2012). mucoadhesive lipsoomes for vaginal therapy: Chitosan vs pectin. Full text in Research Archive
• Tho, Ingunn (2012). Smeltetabletter – fordeler og ulemper. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 132, p. 424–425. doi: 10.4045/tidsskr.10.1464. Full text in Research Archive
• Tho, Ingunn (2012). Formulering av bedre legemidler til barn. Norsk Farmaceutisk Tidsskrift (NFT). ISSN 0029-1935. p. 6–6. Full text in Research Archive
• Meland, H-G; Pflaumer, H; Skalko-Basnet, Natasa & Tho, Ingunn (2012). Choice of polymer matrix for development of bioadhesive mini-tablets for vaginal delivery of metronidazole. Full text in Research Archive
• Staven, Vigdis; Aasarød, Kristin; Grønlie, Ingrid & Tho, Ingunn (2011). Innledende Studie av Kompatibilitet mellom Legemidler og en Standard Trekammer-TPN-Pose til Pediatriske Pasienter. Full text in Research Archive
• Tho, Ingunn; Aasarød, Kristin; Staven, Vigdis; Fjellaksel, Richard & Grønlie, Ingrid (2011). Compatibility of Y-site Administration of Medications with a Standard 3-in-1 Parenteral Nutriton Admixture for Paediatrics. Full text in Research Archive
• Tho, Ingunn; Aasarød, Kristin; Staven, Vigdis; Fjellaksel, Richard & Grønlie, Ingrid (2011). Compatibility of Y-site Administration of Medications with a Standard 3-in-1 Parenteral Nutrition Admixture for Paediatrics. Full text in Research Archive
• Pistone, Sara; Tho, Ingunn; Fini, Adamo & Skalko-Basnet, Natasa (2010). Vescicle-based mucoadhesive hydrogels for vaginal delivery of metronidazole. Full text in Research Archive
• Basnet, Purusotam; Tho, Ingunn & Skalko-Basnet, Natasa (2010). Curcumin, a wonder drug of 21st century: liposomal delivery system targeting vaginal inflammation. Full text in Research Archive
• Basnet, Purusotam; Tho, Ingunn & Skalko-Basnet, Natasa (2010). Curcumin: Liposomal delivery system enhances anti-inflammatory property. Full text in Research Archive
• Staven, Vigdis & Tho, Ingunn (2016). Y-site compatibility testing of intravenous drugs and total parenteral nutrition. Establishment of a test program and study of mixtures relevant for children. UiT Norges arktiske universitet. ISSN 9788275894920. Full text in Research Archive
• Salbu, Linda & Tho, Ingunn (2011). Compressibility and compactibility of pectin powders: A study of their potential as direct compression excipients in tablets. UiT Norges arktiske universitet. ISSN 9788275893114. Full text in Research Archive

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