Pharmacy - Journal Articles

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    Mechanistic investigation into the phase separation behavior of soluplus in the presence of biorelevant media
    (ACS American Chemical Society, 2025) Lange, Justus Johann; Senniksen, Malte Bøgh; Wyttenbach, Nicole; Page, Susanne; Bateman, Lorraine M.; O’Dwyer, Patrick J.; Saal, Wiebke; Kuentz, Martin; Griffin, Brendan T.; Horizon 2020
    More than a decade since its introduction, the polymeric excipient Soluplus continues to receive considerable attention for its application in the development of amorphous solid dispersions (ASDs) and its utility as a solubilizer for drugs exhibiting solubility limited absorption. While it is well-recognized that Soluplus forms micelles, the impact of its lower critical solution temperature of approximately 40 °C remains an underexplored aspect. This study investigated the phase behavior of Soluplus in fasted-state simulated intestinal fluid (FaSSIF-V1). It was demonstrated that Soluplus forms a dispersed polymer-rich coacervate phase, which coexists with Soluplus micelles at 37 °C. This behavior was confirmed by cloud point measurements, visually discernible phases after centrifugation, as well as multi-angle dynamic light scattering (MADLS) measurements, and quantitative 1H-nuclear magnetic resonance (NMR) spectroscopy of Soluplus concentrations in the supernatant pre- and post-centrifugation. The practical relevance of these findings was contextualized by solvent shift experiments and dissolution testing of spray-dried ASD. The results demonstrated that the poorly water-soluble drug RO6897779 resided in a polymer-rich coacervate phase and was spun down during centrifugation, which resulted in an amorphous pellet exhibiting the characteristics of a viscous liquid. The entrapment of the drug within the polymer-rich phase was further analyzed by temperature- and time-dependent MADLS experiments. The findings of this study are of particular relevance for a mechanistic understanding, relevant to comprehending in vitro-in vivo relationships of Soluplus-based ASDs. Low sampled drug concentrations in FaSSIF-V1 at 37 °C may originate not only from limited drug release and precipitation but also from the formation of a drug-containing, polymer-rich Soluplus phase. Therefore, a liquid–liquid phase separation occurring from Soluplus-based formulations in a biorelevant medium can be excipient-driven, which is different from the common perception that phase separation in the solution state is triggered primarily by high drug concentrations exceeding their amorphous solubility.
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    Medication management: supportive care medications in older adults with cancer
    (Wolters Kluwer Health, Inc., 2025-03) Walsh, Darren J.; Herledan, Chloé
    Purpose of review: This review raises awareness regarding the lack of data available for healthcare professionals caring for older adults with cancer when using supportive care medications. Recent findings: Guidelines for supportive cancer care lack concrete recommendations on the appropriate use of medications in older adults with cancer. Some guidelines, such as the National Comprehensive Cancer Network Older Adult Oncology guideline, contain vital information for prescribers to consider when choosing a supportive care medication. Information at present in most guidelines is generally vague, identifying areas where caution is required in older adults, without specific details. Summary: Research is needed to assess the efficacy and safety of supportive cancer care medications in older adults.
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    Exploration of solubilisation effects facilitated by the combination of Soluplus® with ionic surfactants
    (Elsevier Ltd., 2025-02-01) Lange, Justus Johann; Enzner, Lukas; Kuentz, Martin; O’Dwyer, Patrick J.; Saal, Wiebke; Griffin, Brendan T.; Wyttenbach, Nicole; Horizon 2020
    Preclinical testing of new drug candidates frequently necessitates high-dose solution formulations to support robust testing in rodent models. This study aimed to expand the range of high solubilisation capacity formulations by exploring the solubilisation effects of the polymeric surfactant Soluplus® in combination with ionic surfactants. The interactions between Soluplus® and three ionic surfactants, sodium dodecyl sulphate, dioctyl sodium succinate, and sodium oleate, with a primary focus on solubility enhancement were investigated over a range of ionic surfactant concentrations. The solubilisation profiles for seven model drugs were obtained, and the vehicles were characterised by their visual characteristics, dynamic light scattering, and viscosity measurements. The solubilisation profiles were non-linear, indicating the formation of different colloidal species with individual solubilisation strengths depending on surfactant type and concentration, demonstrating substantial solubility enhancement. For certain drugs more than additive solubilisation, facilitated by synergistic interactions between Soluplus® and the ionic surfactants, was obtained. Overall, the solubility increase provided by the excipient combinations resulted in non-linear and drug specific solubilisation profiles. The non-linearities observed were reflected in visual observations of the vehicles appearance, DLS and viscosity measurements, which collectively indicated a change in polymer aggregation with increasing concentration of anionic surfactant. This investigation highlights that already low quantities of ionic surfactants introduced to Soluplus® may substantially enhance solubility, which offers a promising approach for further exploration in preclinical drug development where more conventional solubilising formulation strategies may fall short.
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    Predictions of biorelevant solubility change during dispersion and digestion of lipid-based formulations
    (Elsevier Ltd., 2024-06-21) Ejskjær, Lotte; Holm, René; Kuentz, Martin; Box, Karl J.; Griffin, Brendan T.; O'Dwyer, Patrick J.; Horizon 2020
    Computational approaches are increasingly explored in development of drug products, including the development of lipid-based formulations (LBFs), to assess their feasibility for achieving adequate oral absorption at an early stage. This study investigated the use of computational pharmaceutics approaches to predict solubility changes of poorly soluble drugs during dispersion and digestion in biorelevant media. Concentrations of 30 poorly water-soluble drugs were determined pre- and post-digestion with in-line UV probes using the MicroDISS Profiler™. Generally, cationic drugs displayed higher drug concentrations post-digestion, whereas for non-ionized drugs there was no discernible trend between drug concentration in dispersed and digested phase. In the case of anionic drugs there tended to be a decrease or no change in the drug concentration post-digestion. Partial least squares modelling was used to identify the molecular descriptors and drug properties which predict changes in solubility ratio in long-chain LBF pre-digestion (R2 of calibration = 0.80, Q2 of validation = 0.64) and post-digestion (R2 of calibration = 0.76, Q2 of validation = 0.72). Furthermore, multiple linear regression equations were developed to facilitate prediction of the solubility ratio pre- and post-digestion. Applying three molecular descriptors (melting point, LogD, and number of aromatic rings) these equations showed good predictivity (pre-digestion R2 = 0.70, and post-digestion R2 = 0.68). The model developed will support a computationally guided LBF strategy for emerging poorly water-soluble drugs by predicting biorelevant solubility changes during dispersion and digestion. This facilitates a more data-informed developability decision making and subsequently facilitates a more efficient use of formulation screening resources.
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    Akkermansia muciniphila in infectious disease: A new target for this next-generation probiotic?
    (SAGE Publishing, 2024-03-15) Keane, Jonathan M.; Cazzaniga, Monica; Gahan, Cormac G. M.; Science Foundation Ireland; Horizon 2020
    The common gastrointestinal commensal Akkermansia muciniphila is a mucin-degrading bacterium that is greatly reduced in individuals consuming a high-fat diet. Increasing evidence from a variety of clinical and pre-clinical studies suggests that oral supplementation with Akkermansia can improve metabolic health and moderate systemic inflammation. We and others have demonstrated a role for Akkermansia administration in protection against infectious disease and the outcome from sepsis. Very recent studies have indicated the molecular mechanisms by which A. muciniphila may interact with the host to influence systemic immune-regulation and control of microbial pathogenesis. Here we consider recent studies which demonstrate the efficacy of this potential next-generation probiotic in animal models of Salmonella Typhimurium, Listeria monocytogenes and Clostridioides difficile as well as influenza virus and phlebovirus. The potential mechanisms by which A. muciniphila may influence local and systemic immune responses are discussed.