Listen
89 Ergebnisse
Ergebnisse nach Hochschule und Institut
Publikation Validation of UHPLC–MS/MS methods for the determination of kaempferol and its metabolite 4-hydroxyphenyl acetic acid, and application to in vitro blood-brain barrier and intestinal drug permeability studies(Elsevier, 05.09.2016) Moradi-Afrapoli, Fahimeh; Oufir, Mouhssin; Walter, Fruzsina R.; Deli, Maria A.; Smiesko, Martin; Zabela, Volha; Butterweck, Veronika; Hamburger, Matthias01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Predictive Toxicology: Genetics, Genomics, Epigenetics, and Next-Generation Sequencing in Toxicology(Wiley, 2015) Heckel, Tobias; Suter-Dick, Laura; Pfannkuch, Friedlieb; Suter-Dick, Laura04A - Beitrag SammelbandPublikation Predictive Toxicology: From Vision to Reality(Wiley, 2015) Suter-Dick, Laura03 - SammelbandPublikation Omics in Toxicology(Wiley, 2019) Suter-Dick, Laura; Greim, Helmut; Snyder, Robert04A - Beitrag SammelbandPublikation Combining biorelevant in vitro and in silico tools to simulate and better understand the in vivo performance of a nano-sized formulation of aprepitant in the fasted and fed states(Elsevier, 01.10.2019) Litou, Chara; Kuentz, MartinINTRODUCTION: When developing bio-enabling formulations, innovative tools are required to understand and predict in vivo performance and may facilitate approval by regulatory authorities. EMEND® is an example of such a formulation, in which the active pharmaceutical ingredient, aprepitant, is nano-sized. The aims of this study were 1) to characterize the 80 mg and 125 mg EMEND® capsules in vitro using biorelevant tools, 2) to develop and parameterize a physiologically based pharmacokinetic (PBPK) model to simulate and better understand the in vivo performance of EMEND® capsules and 3) to assess which parameters primarily influence the in vivo performance of this formulation across the therapeutic dose range. METHODS: Solubility, dissolution and transfer experiments were performed in various biorelevant media simulating the fasted and fed state environment in the gastrointestinal tract. An in silico PBPK model for healthy volunteers was developed in the Simcyp Simulator, informed by the in vitro results and data available from the literature. RESULTS: In vitro experiments indicated a large effect of native surfactants on the solubility of aprepitant. Coupling the in vitro results with the PBPK model led to an appropriate simulation of aprepitant plasma concentrations after administration of 80 mg and 125 mg EMEND® capsules in both the fasted and fed states. Parameter Sensitivity Analysis (PSA) was conducted to investigate the effect of several parameters on the in vivo performance of EMEND®. While nano-sizing aprepitant improves its in vivo performance, intestinal solubility remains a barrier to its bioavailability and thus aprepitant should be classified as DCS IIb. CONCLUSIONS: The present study underlines the importance of combining in vitro and in silico biopharmaceutical tools to understand and predict the absorption of this poorly soluble compound from an enabling formulation. The approach can be applied to other poorly soluble compounds to support rational formulation design and to facilitate regulatory assessment of the bio-performance of enabling formulations.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Benefits of Fractal Approaches in Solid Dosage Form Development(Springer, 06.09.2019) Abreu-Villela, Renata; Kuentz, MartinPharmaceutical formulations are complex systems consisting of active pharmaceutical ingredient(s) and a number of excipients selected to provide the intended performance of the product. The understanding of materials' properties and technological processes is a requirement for building quality into pharmaceutical products. Such understanding is gained mostly from empirical correlations of material and process factors with quality attributes of the final product. However, it seems also important to gain knowledge based on mechanistic considerations. Promising is here to study morphological and/or topological characteristics of particles and their aggregates. These geometric aspects must be taken into account to better understand how product attributes emerge from raw materials, which includes, for example, mechanical tablet properties, disintegration or dissolution behavior. Regulatory agencies worldwide are promoting the use of physical models in pharmaceutics to design quality into a final product. This review deals with pharmaceutical applications of theoretical models, focusing on percolation theory, fractal, and multifractal geometry. The use of these so-called fractal approaches improves the understanding of different aspects in the development of solid dosage forms, for example by identifying critical drug and excipient concentrations, as well as to study effects of heterogeneity on dosage form performance. The aim is to link micro- and macrostructure to the emerging quality attributes of the pharmaceutical solid dosage forms as a strategy to enhance mechanistic understanding and to advance pharmaceutical development and manufacturing processes.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Ultra-sub-stoichiometric “Dynamic” Bioconjugation Reduces Viscosity by Disrupting Immunoglobulin Oligomerization(American Chemical Society, 09.09.2019) Gong, Yuhui; Niederquell, Andreas; Kuentz, MartinMonoclonal antibodies (mAb) are a major focus of the pharmaceutical industry, and polyclonal immunoglobulin G (IgG) therapy is used to treat a wide variety of health conditions. As some individuals require mAb/IgG therapy their entire life, there is currently a great desire to formulate antibodies for bolus injection rather than infusion. However, to achieve the required doses, very concentrated antibody solutions may be required. Unfortunately, mAb/IgG self-assembly at high concentration can produce an unacceptably high viscosity for injection. To address this challenge, this study expands the concept of "dynamic covalent chemistry" to "dynamic bioconjugation" in order to reduce viscosity by interfering with antibody-antibody interactions. Ultra-sub-stoichiometric amounts of dynamic PEGylation agents (down to the nanomolar) significantly reduced the viscosity of concentrated antibody solutions by interfering with oligomerization.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation From Quantum Chemistry to Prediction of Drug Solubility in Glycerides(American Chemical Society, 04.11.2019) Alsenz, Jochem; Kuentz, Martin01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Successful oral delivery of poorly water-soluble drugs both depends on the intraluminal behavior of drugs and of appropriate advanced drug delivery systems(Elsevier, 01.09.2019) Boyd, Ben J.; Kuentz, Martin01A - Beitrag in wissenschaftlicher ZeitschriftPublikation A Relative Permittivity Approach for Fast Drug Solubility Screening of Solvents and Excipients in Lipid-Based Delivery(Elsevier, 2019) Niederquell, Andreas; Kuentz, MartinDrug solubility screening in solvents and lipids is central for the development of lipid-based formulations (LBFs), and any guidance to reduce the experimental workload would be highly desirable. Solubility parameters are interesting as they can be predicted in silico for a drug but they are hardly predictable for complex lipids. This paper uses a new approach to convert an in silico drug solubility parameter to an estimated relative permittivity, εr. Diverse solvents and lipid-based excipients were then experimentally tested for εr and solubility using fenofibrate as model. The typical excipients and solvents used in LBFs showed an εr range of about 2-24, and good solubility of fenofibrate was indeed evidenced in vicinity of its estimated relative permittivity 13.2 ± 2.7. Mixtures of promising excipients were studied subsequently, and the obtained εr was predictable based on the known values of the individual components. The novel permittivity approach has demonstrated its usefulness, it has much potential in early development for ranking of suitable excipients, and it gives an initial orientation to design formulations. Future research may clarify further opportunities and limits of the novel approach for LBFs.01A - Beitrag in wissenschaftlicher Zeitschrift