Kuentz, Martin

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Martin
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Kuentz, Martin

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2015 - 201957
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Anfangsdatum: 2015 × Enddatum: 2019 ×

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  • Vorschaubild
    Publikation
    Opportunities for Successful Stabilization of Poor Glass-Forming Drugs: A Stability-Based Comparison of Mesoporous Silica Versus Hot Melt Extrusion Technologies
    (Elsevier, 04.11.2019) Ditzinger, Felix; Price, Daniel J.; Nair, Anita; Becker-Baldus, Johanna; Glaubitz, Clemens; Dressman, Jennifer; Saal, Christoph; Kuentz, Martin [in: Pharmaceutics]
    Amorphous formulation technologies to improve oral absorption of poorly soluble active pharmaceutical ingredients (APIs) have become increasingly prevalent. Currently, polymer-based amorphous formulations manufactured by spray drying, hot melt extrusion (HME), or co-precipitation are most common. However, these technologies have challenges in terms of the successful stabilization of poor glass former compounds in the amorphous form. An alternative approach is mesoporous silica, which stabilizes APIs in non-crystalline form via molecular adsorption inside nano-scale pores. In line with these considerations, two poor glass formers, haloperidol and carbamazepine, were formulated as polymer-based solid dispersion via HME and with mesoporous silica, and their stability was compared under accelerated conditions. Changes were monitored over three months with respect to solid-state form and dissolution. The results were supported by solid-state nuclear magnetic resonance spectroscopy (SS-NMR) and scanning electron microscopy (SEM). It was demonstrated that mesoporous silica was more successful than HME in the stabilization of the selected poor glass formers. While both drugs remained non-crystalline during the study using mesoporous silica, polymer-based HME formulations showed recrystallization after one week. Thus, mesoporous silica represents an attractive technology to extend the formulation toolbox to poorly soluble poor glass formers.
    01A - Beitrag in wissenschaftlicher Zeitschrift
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    Publikation
    From Quantum Chemistry to Prediction of Drug Solubility in Glycerides
    (American Chemical Society, 04.11.2019) Alsenz, Jochem; Kuentz, Martin [in: Molecular Pharmaceutics]
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    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, Martin [in: European Journal of Pharmaceutical Sciences]
    INTRODUCTION: 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 Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    Ultra-sub-stoichiometric “Dynamic” Bioconjugation Reduces Viscosity by Disrupting Immunoglobulin Oligomerization
    (American Chemical Society, 09.09.2019) Gong, Yuhui; Niederquell, Andreas; Kuentz, Martin [in: Biomacromolecules]
    Monoclonal 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 Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    Benefits of Fractal Approaches in Solid Dosage Form Development
    (Springer, 06.09.2019) Abreu-Villela, Renata; Kuentz, Martin [in: Pharmaceutical Research]
    Pharmaceutical 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 Zeitschrift
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    Publikation
    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, Martin [in: European Journal of Pharmaceutical Sciences]
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild
    Publikation
    Lipophilicity and hydrophobicity considerations in bio-enabling oral formulations approaches | a PEARRL review
    (Wiley, 04/2019) Ditzinger, Felix; Price, Daniel J.; Ilie, Alexandra Roxana; Koehl, Niklas; Jankovic, Sandra; Tsakiridou, Georgia; Aleandri, Simone; Kalantzi, Lida; Holm, Rene; Nair, Anita; Saal, Christoph; Griffin, Brendan; Kuentz, Martin [in: Journal of Pharmacy and Pharmacology]
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    Predicting the Angle of Internal Friction from Simple Dynamic Consolidation Using Lactose Grades as Model
    (Springer, 28.03.2019) Trpělková, Žofie; Kuentz, Martin [in: Journal of Pharmaceutical Innovation]
    Powder flow and packing behavior are among other factors determined by particle friction, which is traditionally measured in shear cells as the angle of internal friction (AIF). Considering that an AIF at a normal stress should be comparable to friction during tapping consolidation, this work aims at whether dynamic consolidation under gravity can be used to estimate an AIF.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    Calculation of drug-polymer mixing enthalpy as a new screening method of precipitation inhibitors for supersaturating pharmaceutical formulations
    (Elsevier, 12.03.2019) Kuentz, Martin [in: European Journal of Pharmaceutical Sciences]
    Supersaturating formulations are widely used to improve the oral bioavailability of poorly soluble drugs. However, supersaturated solutions are thermodynamically unstable and such formulations often must include a precipitation inhibitor (PI) to sustain the increased concentrations to ensure that sufficient absorption will take place from the gastrointestinal tract. Recent advances in understanding the importance of drug-polymer interaction for successful precipitation inhibition have been encouraging. However, there still exists a gap in how this newfound understanding can be applied to improve the efficiency of PI screening and selection, which is still largely carried out with trial and error-based approaches. The aim of this study was to demonstrate how drug-polymer mixing enthalpy, calculated with the Conductor like Screening Model for Real Solvents (COSMO-RS), can be used as a parameter to select the most efficient precipitation inhibitors, and thus realize the most successful supersaturating formulations. This approach was tested for three different Biopharmaceutical Classification System (BCS) II compounds: dipyridamole, fenofibrate and glibenclamide, formulated with the supersaturating formulation, mesoporous silica. For all three compounds, precipitation was evident in mesoporous silica formulations without a precipitation inhibitor. Of the nine precipitation inhibitors studied, there was a strong positive correlation between the drug-polymer mixing enthalpy and the overall formulation performance, as measured by the area under the concentration-time curve in in vitro dissolution experiments. The data suggest that a rank-order based approach using calculated drug-polymer mixing enthalpy can be reliably used to select precipitation inhibitors for a more focused screening. Such an approach improves efficiency of precipitation inhibitor selection, whilst also improving the likelihood that the most optimal formulation will be realized.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    New Insights into Using Lipid Based Suspensions for 'Brick Dust' Molecules: Case Study of Nilotinib
    (Springer, 22.02.2019) Koehl, Niklas; Kuentz, Martin [in: Pharmaceutical Research]
    PurposeLipid suspensions have been shown to be a suitablebio-enabling formulation approach for highly lipophilic or‘grease ball’drug molecules, but studies on‘brick dust’drugsare lacking. This study explored the utility of lipid suspensionsfor enhancing oral bioavailability of the rather hydrophobicdrug nilotinibin vivoin rats.MethodsFour lipid suspensions were developed containinglong chain triglycerides, medium chain triglyceride, longchain monoglycerides and medium chain monoglyceridesandin vivobioavailability was compared to an aqueous suspen-sion. Additionally,in vitrolipolysis and wettability tests wereconducted.ResultsNilotinib lipid suspensions did not show a bioavail-ability increase compared to an aqueous suspension. The bio-availability was lower for triglyceride suspensions, relative toboth monoglyceride and an aqueous suspension. The longchain monoglyceride displayed a significantly higher bioavail-ability relative to triglycerides.In vitrolipolysis results suggestedentrapment of nilotinib crystals within poorly dispersible tri-glycerides, leading to slower nilotinib release and absorption.This was further supported by higher wettability of nilotinibby lipids.ConclusionMonoglycerides improved oral bioavailability ofnilotinib in rats, relative to triglycerides. For‘brick dust’drugsformulated as lipid suspensions, poorly dispersible formula-tions may delay the release of drug crystals from the formula-tion leading to reduced absorption.
    01A - Beitrag in wissenschaftlicher Zeitschrift