Kuentz, Martin

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Martin
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Kuentz, Martin

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    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
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    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
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    Publikation
    Current challenges and future perspectives in oral absorption research. An opinion of the UNGAP network
    (Elsevier, 04/2021) Kuentz, Martin; Vinarov, Zahari; Bertil, Abrahamsson; Artursson, Per; Batchelor, Hannah; Berben, Philippe; Bernkop-Schnürch, Andreas; Butler, James; Ceulemans, Jens; Davies, Nigel; Dupont, Didier; Eide Flaten, Goril; Fotaki, Nikoleta; Jannin, Vincent; Keemink, Janneke; Kesisoglou, Filippos; Koziolek, Mirko; Augustijns, Patrick; Griffin, Brendan [in: Advanced Drug Delivery Reviews]
    Although oral drug delivery is the preferred administration route and has been used for centuries, modern drug discovery and development pipelines challenge conventional formulation approaches and highlight the insufficient mechanistic understanding of processes critical to oral drug absorption. This review presents the opinion of UNGAP scientists on four key themes across the oral absorption landscape: (1) specific patient populations, (2) regional differences in the gastrointestinal tract, (3) advanced formulations and (4) food-drug interactions. The differences of oral absorption in pediatric and geriatric populations, the specific issues in colonic absorption, the formulation approaches for poorly water-soluble (small molecules) and poorly permeable (peptides, RNA etc.) drugs, as well as the vast realm of food effects, are some of the topics discussed in detail. The identified controversies and gaps in the current understanding of gastrointestinal absorption-related processes are used to create a roadmap for the future of oral drug absorption research.
    01A - Beitrag in wissenschaftlicher Zeitschrift
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    Publikation
    A diffusing wave spectroscopy study of pharmaceutical emulsions for physical stability assessment
    (Elsevier, 2017) Niederquell, Andreas; Machado, Alexandra H.E.; Kuentz, Martin [in: International Journal of Pharmaceutics]
    Emulsions are broadly used in pharmaceutics either as intermediate products or as final dosage forms. Such disperse systems are only kinetically stabilized and therefore early detection of physical instability is highly desirable. This work employed diffusing wave spectroscopy (DWS) to study a series of model emulsions that were categorized, based on their composition, as either “simple” or “complex”. DWS data were compared with results of droplet size imaging, apparent viscosity obtained by microfluidics, and near-infrared (NIR) analytical centrifugation. A mathematical model of the droplet mean square displacement (MSD) was modified by us regarding improved fitting of experimental data. Although the emulsions showed different types of instability like creaming and sedimentation, a good rank correlation was found between the DWS parameters and results from the comparative stability methods. Our findings indicate that DWS provides a highly attractive method for stability analysis of pharmaceutical emulsions because it requires only low sample volumes, is rapid and non-invasive. The proposed data modeling provides the means for a better understanding of emulsion microstructure that in turn will help designing quality into pharmaceutical dispersions.
    01A - Beitrag in wissenschaftlicher Zeitschrift
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    Publikation
    In Vivo Performance of Innovative Polyelectrolyte Matrices for Hot Melt Extrusion of Amorphous Drug Systems
    (American Chemical Society, 2020) Ditzinger, Felix; Wieland, Rebecca; Statelova, Marina; Vertzoni, Maria; Holm, Rene; Kuentz, Martin [in: Molecular Pharmaceutics]
    Hot melt extrusion of amorphous systems has become a pivotal technology to cope with challenges of poorly water-soluble drugs. Previous research showed that small molecular additives with targeted molecular interactions enabled introduction of a polyelectrolyte matrix into hot melt extrusion that would otherwise not be possible to process due to the unfavorable properties upon heating of the pure polymer. Carboxymethyl cellulose sodium (NaCMC) with lysine or alternatively meglumine led to modified polymeric matrices that showed adequate processability by hot melt extrusion and yielded stable amorphous formulations. The investigated formulations, including fenofibrate as a model drug, were characterized by attenuated total reflectance Fourier transform infrared spectroscopy, differential scanning calorimetry, and viscosity measurements after aqueous dispersion. Further biopharmaceutical assessment started with biorelevant nonsink dissolution testing followed by a pharmacokinetic in vivo study in rats. The in vitro assessment showed superiority of the lysine-containing formulation in the extent of in vitro supersaturation and overall drug release. In accordance with this, the in vivo study also demonstrated increased exposure of the amorphous formulations and in particular for the system containing lysine. In summary, the combination of polyelectrolytes with interacting additives presents a promising opportunity for the formulation of poorly water-soluble drugs.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    Novel Biphasic Lipolysis Method To Predict in Vivo Performance of Lipid-Based Formulations
    (American Chemical Society, 21.08.2020) O'Dwyer, Patrick J.; Kuentz, Martin [in: Molecular Pharmaceutics]
    The absence of an intestinal absorption sink is a significant weakness of standard in vitro lipolysis methods, potentially leading to poor prediction of in vivo performance and an overestimation of drug precipitation. In addition, the majority of the described lipolysis methods only attempt to simulate intestinal conditions, thus overlooking any supersaturation or precipitation of ionizable drugs as they transition from the acidic gastric environment to the more neutral conditions of the intestine. The aim of this study was to develop a novel lipolysis method incorporating a two-stage gastric-to-intestinal transition and an absorptive compartment to reliably predict in vivo performance of lipid-based formulations (LBFs). Drug absorption was mimicked by in situ quantification of drug partitioning into a decanol layer. The method was used to characterize LBFs from four studies described in the literature, involving three model drugs (i.e., nilotinib, fenofibrate, and danazol) where in vivo bioavailability data have previously been reported. The results from the novel biphasic lipolysis method were compared to those of the standard pH-stat method in terms of reliability for predicting the in vivo performance. For three of the studies, the novel biphasic lipolysis method more reliably predicted the in vivo bioavailability compared to the standard pH-stat method. In contrast, the standard pH-stat method was found to produce more predictive results for one study involving a series of LBFs composed of the soybean oil, glyceryl monolinoleate (Maisine CC), Kolliphor EL, and ethanol. This result was surprising and could reflect that increasing concentrations of ethanol (as a cosolvent) in the formulations may have resulted in greater partitioning of the drug into the decanol absorptive compartment. In addition to the improved predictivity for most of the investigated systems, this biphasic lipolysis method also uses in situ analysis and avoids time- and resource-intensive sample analysis steps, thereby facilitating a higher throughput capacity and biorelevant approach for characterization of LBFs.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    Early stages of drug crystallization from amorphous solid dispersion via fractal analysis based on chemical imaging
    (Elsevier, 12/2018) Kuentz, Martin; Abreu-Villela, Renata; Schönenberger, Monica; Caraballo, Isidoro [in: European Journal of Pharmaceutics and Biopharmaceutics]
    Early stages of crystallization from amorphous solid dispersion (ASD) are typically not detected by means of standard methods like powder X-ray diffraction (XRPD). The aim of this study is therefore to evaluate if fractal analysis based on energy dispersive X-ray imaging can provide the means to identify early signs of physical instability. ASDs of the poorly water-soluble compound, felodipine (FEL) were prepared by solvent evaporation using different grades of HPMCAS, at 50 wt% drug loading. Samples were stored at accelerated conditions of 40 °C. Scanning electron microscopy equipped with an energy-dispersive X-ray spectroscopy (SEM-EDS) was used for elemental mapping of tablet surfaces. Comparative data were generated with a standard XRPD and with more sensitive methods for detection of early instability, i.e. laser scanning confocal microscopy (LSM) and atomic force microscopy (AFM). The SEM-EDS identified changes of drug-rich domains that were confirmed by LSM and AFM. Early changes in drug clusters were also revealed by a multifractal analysis that indicated a beginning phase separation and drug crystallization. Therefore, the presented fractal cluster analysis based on chemical imaging bears much promise as a new method to detect early signs of physical instability in ASD, which is of great relevance for pharmaceutical development.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    Toward simplified oral lipid-based drug delivery using mono-/di-glycerides as single component excipients
    (Marcel Dekker, 09.11.2020) Ilie, Alexandra Roxana; Kuentz, Martin [in: Drug Development and Industrial Pharmacy]
    Objective: This study aimed to systematically explore compositional effects for a series of lipid systems, on the in vitro drug solubilization and in vivo bioavailability of three poorly water-soluble drugs with different physico-chemical properties. Significance: While many lipid-based drug products have successfully reached the market, there is still a level of uncertainty on the design guidelines for such drug products with limited understanding on the influence of composition on in vitro and in vivo performance. Methods and results: Lipid-based drug delivery systems were prepared using either single excipient systems based on partially digested triglycerides (i.e. mono- and/or di-glycerides) or increasingly complex systems by incorporating surfactants and/or triglycerides. These lipid systems were evaluated for both in vitro and in vivo behavior. Results indicated that simple single component long chain lipid systems are more beneficial for the absorption of the weak acid celecoxib and the weak base cinnarizine compared to equivalent single component medium chain lipid systems. Similarly, a two-component system produced by incorporating small amount of hydrophilic surfactant yields similar overall pharmacokinetic effects. The lipid drug delivery systems based on medium chain lipid excipients improved the in vivo exposure of the neutral drug JNJ-2A. The higher in vivo bioavailability of long chain lipid systems compared to medium chain lipid systems was in agreement with in vitro dilution and dispersion studies for celecoxib and cinnarizine. Conclusions: The present study demonstrated the benefits of using mono-/di-glycerides as single component excipients in LBDDS to streamline formulation screening and improve oral bioavailability for the three tested poorly water-soluble drugs.
    01A - Beitrag in wissenschaftlicher Zeitschrift
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  • Vorschaubild nicht verfügbar
    Publikation
    Can we estimate the critical micelle concentration of amphiphilic drug bases from molecular connectivity indices?
    (Informa, 2017) Saal, Wiebke; Wyttenbach, Nicole; Alsenz, Jochem; Kuentz, Martin [in: Pharmaceutical Development and Technology]
    Self-aggregation of drugs is since many years an important topic in the pharmaceutical sciences. Drugs can aggregate similar to surfactants and thereby exhibit a critical micelle concentration (CMC). The present work focused on amphiphilic drug bases and it was aimed to predict log(CMC) based on chemical structure alone. A dataset of 35 compounds was gathered mostly form the literature and complemented with own measurements based on ultrasonic resonator technology. The hydrophilic–lipophilic balance (HLB) values of the protonated bases were calculated and provided a range of 22.9–27.4. Based on a hypothesis from surfactant sciences, it was tried to predict log(CMC) with connectivity and shape indices as well as molecular dipole moment. A fairly good model was obtained using the Randix index (RI), 3 D Wiener number (WN) and molecular dipole moment (DM) (R2 = 0.824). Interestingly, a simple linear regression of log(CMC) with the Randic index alone, resulted in an acceptable model (R2 = 0.755). The present work should help with early identification of drug bases that exhibit surfactant-like behavior and an estimation of log(CMC) values is proposed. An improved understanding of drug aggregation and prediction of log(CMC) helps to better cope with physical consequences like, for example, “anomalous” drug solubility in drug discovery and development.
    01A - Beitrag in wissenschaftlicher Zeitschrift