Kuentz, Martin

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Martin
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Kuentz, Martin

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  • Vorschaubild nicht verfügbar
    Publikation
    Synergistic Computational Modeling Approaches as Team Players in the Game of Solubility Predictions
    (Elsevier, 17.11.2020) Kuentz, Martin [in: Journal of Pharmaceutical Sciences]
    Several approaches to predict and model drug solubility have been used in the drug discovery and development processes during the last decades. Each of these approaches have their own benefits and place, and are typically used as standalone approaches rather than in concert. The synergistic effects of these are often overlooked, partly due to the need of computational experts to perform the modeling and simulations as well as analyzing the data obtained. Here we provide our views on how these different approaches can be used to retrieve more information on drug solubility, ranging from multivariate data analysis over thermodynamic cycle modeling to molecular dynamics simulations. We are discussing aqueous solubility as well as solubility in more complex mixed solvents and media with colloidal structures present. We conclude that the field of computational pharmaceutics is in its early days but with a bright future ahead. However, education of computational formulators with broad knowledge of modeling and simulation approaches is imperative if computational pharmaceutics is to reach its full potential.
    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
  • Vorschaubild nicht verfügbar
    Publikation
    Relevance of the theoretical critical pore radius in mesoporous silica for fast crystallizing drugs
    (Elsevier, 26.10.2020) Vraníková, Barbora; Niederquell, Andreas; Kuentz, Martin [in: International Journal of Pharmaceutics]
    Formulation of poorly water-soluble drugs with mesoporous silica has become a thriving field of pharmaceutics. The theoretical critical pore diameter has been introduced as a maximum value below which an undesired drug crystallization is suppressed by spatial confinement. Currently, only few values have been reported and study of fast crystallising drugs is missing especially at relevant storage temperatures. This study investigated the critical pore diameter of three model drugs with a poor glass-forming ability (i.e. haloperidol, carbamazepine and benzamide) using different mesoporous carriers (Parteck® SLC 500, Neusilin® US2, Syloid® XDP 3050 and Aeroperl® 300 Pharma) and subsequently monitored physical formulation stability over three months by X-ray powder diffraction. The selected drugs showed clear differences in their estimated critical pore diameters, whereas a temperature dependence was barely relevant for pharmaceutical storage conditions. Superior stability was noted for the formulations containing benzamide in line with its predicted relatively large critical pore diameter of 29.5 nm. Contrarily, impaired physical stability depending on drug loading was observed in the case of haloperidol representing a compound with a rather small critical pore diameter (8.4 nm). These findings confirm the importance of estimating the critical pore diameter, especially for poor glass-forming drugs.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    Introduction of the energy to break an avalanche as a promising parameter for powder flowability prediction
    (Elsevier, 20.09.2020) Trpělková, Žofie; Kuentz, Martin [in: Powder Technology]
    Dynamic avalanche testing is a newer method useful even with cohesive powder samples. To evaluate flow properties of pharmaceutical powder excipients, break energy (BE) is introduced as a new promising avalanche parameter. Conventional pharmacopoeial methods and an annular shear cell were utilized to characterize 23 pharmaceutical powder samples including binary mixtures. Subsequently, rotating drum avalanching was studied to better understand behaviour of powders. A good linear regression between the energy to break a powder avalanche and powder cohesion with R2 = 0.823 was detected. The relationship between BE and the flow function value, estimated by shear testing, allowed to identify two samples with excellent flow functions: Cellets 100 and Neusilin US2. The latter sample also had very low BE although the mass flow rate was the poorest observed out of 23 samples. Therefore, the BE from avalanching testing seems to be a sensitive measure of cohesion and flow function behaviour.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    Exploring the Impact of Surfactant Type and Digestion: Highly Digestible Surfactants Improve Oral Bioavailability of Nilotinib
    (American Chemical Society, 08.09.2020) Koehl, Niklas; Kuentz, Martin [in: Molecular Pharmaceutics]
    The scientific rationale for selection of the surfactant type during oral formulation development requires an in-depth understanding of the interplay between surfactant characteristics and biopharmaceutical factors. Currently, however, there is a lack of comprehensive knowledge of how surfactant properties, such as hydrophilic-lipophilic balance (HLB), digestibility, and fatty acid (FA) chain length, translate into in vivo performance. In the present study, the relationship between surfactant properties, in vitro characteristics, and in vivo bioavailability was systematically evaluated. An in vitro lipolysis model was used to study the digestibility of a variety of nonionic surfactants. Eight surfactants and one surfactant mixture were selected for further analysis using the model poorly water-soluble drug nilotinib. In vitro lipolysis of all nilotinib formulations was performed, followed by an in vivo pharmacokinetic evaluation in rats. The in vitro lipolysis studies showed that medium-chain FA-based surfactants were more readily digested compared to long-chain surfactants. The in vivo study demonstrated that a Tween 20 formulation significantly enhanced the absolute bioavailability of nilotinib up to 5.2-fold relative to an aqueous suspension. In general, surfactants that were highly digestible in vitro tended to display higher bioavailability of nilotinib in vivo. The bioavailability may additionally be related to the FA chain length of digestible surfactants with an improved exposure in the case of medium-chain FA-based surfactants. There was no apparent relationship between the HLB value of surfactants and the in vivo bioavailability of nilotinib. The impact of this study's findings suggests that when designing surfactant-based formulations to enhance oral bioavailability of the poorly water-soluble drug nilotinib, highly digestible, medium chain-based surfactants are preferred. Additionally, for low-permeability drugs such as nilotinib, which is subject to efflux by intestinal P-glycoprotein, the biopharmaceutical effects of surfactants merit further consideration.
    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
    Exploring impact of supersaturated lipid-based drug delivery systems of celecoxib on in vitro permeation across Permeapad Ⓡ membrane and in vivo absorption
    (Elsevier, 03.07.2020) Ilie, Alexandra Roxana; Kuentz, Martin [in: European Journal of Pharmaceutical Sciences]
    Supersaturated lipid-based drug delivery systems have recently been investigated for oral administration for a variety of lipophilic drugs and have shown either equivalent or superior oral bioavailability compared to conventional non-supersaturated lipid-based drug delivery systems. The aim of the present work was to explore supersaturated versus non-supersaturated lipid-based systems at equivalent lipid doses, on in vivo bioavailability in rats and on in vitro permeation across a biomimetic PermeapadⓇ membrane to establish a potential in vivo - in vitro correlation. A secondary objective was to investigate the influence of lipid composition on in vitro and in vivo performance of lipid systems. Results obtained indicated that increasing the celecoxib load in the lipid-based formulations by thermally-induced supersaturation resulted in increased bioavailability for medium and long chain mono-/di-glycerides systems relative to their non-supersaturated (i.e. 85%) reference formulations, albeit only significant for the medium chain systems. Long chain systems displayed higher celecoxib bioavailability than equivalent medium chain systems, both at supersaturated and non-supersaturated drug loads. In vitro passive permeation of celecoxib was studied using both steady-state and dynamic conditions and correlated well with in vivo pharmacokinetic results with respect to compositional effects. In contrast, permeation studies indicated that flux and percentage permeated of supersaturated systems, either at steady-state or under dynamic conditions, decreased or were unchanged relative to non-supersaturated systems. This study has shown that by using two cell-free PermeapadⓇ permeation models coupled with rat-adapted gastro-intestinal conditions, bio-predictive in vitro tools can be developed to be reflective of in vivo scenarios. With further optimization, such models could be successfully used in pharmaceutical industry settings to rapidly screen various prototype formulations prior to animal studies.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    Supersaturated Lipid-Based Formulations to Enhance the Oral Bioavailability of Venetoclax
    (Elsevier, 18.06.2020) Koehl, Niklas; Kuentz, Martin [in: Pharmaceutics]
    Increasing numbers of beyond Rule-of-Five drugs are emerging from discovery pipelines, generating a need for bio-enabling formulation approaches, such as lipid-based formulations (LBF), to ensure maximal in vivo exposure. However, many drug candidates display insufficient lipid solubility, leading to dose-loading limitations in LBFs. The aim of this study was to explore the potential of supersaturated LBFs (sLBF) for the beyond Rule-of-Five drug venetoclax. Temperature-induced sLBFs of venetoclax were obtained in olive oil, Captex® 1000, Peceol® and Capmul MCM®, respectively. A Peceol®-based sLBF displayed the highest drug loading and was therefore evaluated further. In vitro lipolysis demonstrated that the Peceol®-based sLBF was able to generate higher venetoclax concentrations in the aqueous phase compared to a Peceol®-based suspension and an aqueous suspension. A subsequent bioavailability study in pigs demonstrated for sLBF a 3.8-fold and 2.1-fold higher bioavailability compared to the drug powder and Peceol®-based suspension, respectively. In conclusion, sLBF is a promising bio-enabling formulation approach to enhance in vivo exposure of beyond Rule-of-Five drugs, such as venetoclax. The in vitro lipolysis results correctly predicted a higher exposure of the sLBF in vivo. The findings of this study are of particular relevance to pre-clinical drug development, where maximum exposure is required.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    Chase Dosing of Lipid Formulations to Enhance Oral Bioavailability of Nilotinib in Rats
    (Springer, 10.06.2020) Koehl, Niklas; Kuentz, Martin [in: Pharmaceutical Research]
    Conclusion: Chase dosed LBF enhanced the in vivo bioavailability of nilotinib. Long chain lipids showed superior performance compared to medium chain lipids. Chase dosing appeared to prolong the absorption phase of the drug. Therefore, chase dosing of LBF is favourable compared to lipid suspensions for 'brick dust' molecules such as nilotinib. Graphical Abstract The potential of bio-enabling lipid vehicles, administered via chase dosing and lipid suspensions, has been evaluated as an approach to enhance oral bioavailability of nilotinib.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    Machine Estimation of Drug Melting Properties and Influence on Solubility Prediction
    (American Chemical Society, 04.06.2020) Wyttenbach, Nicole; Niederquell, Andreas; Kuentz, Martin [in: Molecular Pharmaceutics]
    There has been much recent interest in machine learning (ML) and molecular quantitative structure property relationships (QSPR). The present research evaluated modern ML-based methods implemented in commercial software (COSMOquick and Molecular Modeling Pro), compared to a classical group contribution approach (Joback and Reid method), to estimate melting points and enthalpy of fusion values. A broad data set of market compounds was gathered from the literature, together with new data measured by differential scanning calorimetry for drug candidates. The highest prediction accuracy was achieved by QSPR using stochastic gradient boosting. The model deviations were discussed, particularly the implications on thermodynamic solubility modeling, as this typically requires estimation of both melting point and enthalpy of fusion. The results suggested that despite considerable advancement in prediction accuracy, there are still limitations especially with complex drug candidates. It is recommended that in such cases, melting properties obtained in silico should be used carefully as input data for thermodynamic solubility modeling. Future research will show how the prediction limits of thermophysical drug properties can be further advanced by even larger data sets and other ML algorithms or also by using molecular simulations.
    01A - Beitrag in wissenschaftlicher Zeitschrift