Kuentz, Martin

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Martin
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Kuentz, Martin

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2016 - 201982020 - 20226
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    Publikation
    Lipophilic salts and lipid-based formulations for bridging the food effect gap of venetoclax
    (Elsevier, 01/2022) Koehl, Niklas; Henze, Laura; Holm, Rene; Kuentz, Martin; Keating, John; De Vijlder, Thomas; Marx, Andreas; Griffin, Brendan [in: Journal of Pharmaceutical Sciences]
    Lipid based formulations (LBF) have shown to overcome food dependent bioavailability for some poorly water-soluble drugs. However, the utility of LBFs can be limited by low dose loading due to a low drug solubility in LBF vehicles. This study investigated the solubility and drug loading increases in LBFs using lipophilic counterions to form lipophilic salts of venetoclax. Venetoclax docusate was formed from venetoclax free base and verified by 1H NMR. Formation of stable venetoclax-fatty acid associations with either oleic acid or decanoic acid were attempted, however, the molecular associations were less consistent based on 1H NMR. Venetoclax docusate displayed a up to 6.2-fold higher solubility in self-emulsifying drug delivery systems (SEDDS) when compared to the venetoclax free base solubility resulting in a higher dose loading. A subsequent bioavailability study in landrace pigs demonstrated a 2.5-fold higher bioavailability for the lipophilic salt containing long chain SEDDS compared to the commercially available solid dispersion Venclyxto® in the fasted state. The bioavailability of all lipophilic salt SEDDS in the fasted state was similar to Venclyxto® in the fed state. This study confirmed that lipophilic drug salts increase the dose loading in LBFs and showed that lipophilic salt-SEDDS combinations may be able to overcome bioavailability limitations of drugs with low inherent dose loading in lipid vehicles. Furthermore, the present study demonstrated the utility of a LBF approach, in combination with lipophilic salts, to overcome food dependent variable oral bioavailability of drugs.
    01A - Beitrag in wissenschaftlicher Zeitschrift
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    Publikation
    Artificial neural networks to predict the apparent degree of supersaturation in supersaturated lipid-based formulations. A pilot study
    (MDPI, 05.09.2021) Bennett-Lenane, Harriett; O'Shea, Joseph; Murray, Jack; Ilie, Alexandra Roxana; Holm, Rene; Kuentz, Martin; Griffin, Brendan [in: Pharmaceutics]
    In response to the increasing application of machine learning (ML) across many facets of pharmaceutical development, this pilot study investigated if ML, using artificial neural networks (ANNs), could predict the apparent degree of supersaturation (aDS) from two supersaturated LBFs (sLBFs). Accuracy was compared to partial least squares (PLS) regression models. Equilibrium solubility in Capmul MCM and Maisine CC was obtained for 21 poorly water-soluble drugs at ambient temperature and 60 °C to calculate the aDS ratio. These aDS ratios and drug descriptors were used to train the ML models. When compared, the ANNs outperformed PLS for both sLBFCapmulMC (r2 0.90 vs. 0.56) and sLBFMaisineLC (r2 0.83 vs. 0.62), displaying smaller root mean square errors (RMSEs) and residuals upon training and testing. Across all the models, the descriptors involving reactivity and electron density were most important for prediction. This pilot study showed that ML can be employed to predict the propensity for supersaturation in LBFs, but even larger datasets need to be evaluated to draw final conclusions.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    Rational selection of bio-enabling oral drug formulations. A PEARRL commentary
    (Elsevier, 05/2021) Kuentz, Martin; Kronseder, Christian; Holm, Rene; Saal, Christoph; Griffin, Brendan [in: Journal of Pharmaceutical Sciences]
    New drug candidates often require bio-enabling formation technologies such as lipid-based formulations, solid dispersions, or nanosized drug formulations. Development of such more sophisticated delivery systems generally requires higher resource investment compared to a conventional oral dosage form, which might slow down clinical development. To achieve the biopharmaceutical objectives while enabling rapid cost effective development, it is imperative to identify a suitable formulation technique for a given drug candidate as early as possible. Hence many companies have developed internal decision trees based mostly on prior organizational experience, though they also contain some arbitrary elements. As part of the EU funded PEARRL project, a number of new decision trees are here proposed that reflect both the current scientific state of the art and a consensus among the industrial project partners. This commentary presents and discusses these, while also going beyond this classical expert approach with a pilot study using emerging machine learning, where the computer suggests formulation strategy based on the physicochemical and biopharmaceutical properties of a molecule. Current limitations are discussed and an outlook is provided for likely future developments in this emerging field of pharmaceutics.
    01A - Beitrag in wissenschaftlicher Zeitschrift
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    Publikation
    In Silico, In Vitro, and In Vivo evaluation of precipitation inhibitors in supersaturated lipid-based formulations of venetoclax
    (American Chemical Society, 23.04.2021) Koehl, Niklas; Henze, Laura; Bennett-Lenane, Harriett; Faisal, Waleed; Price, Daniel J.; Holm, Rene; Kuentz, Martin; Griffin, Brendan [in: Molecular Pharmaceutics]
    The concept of using precipitation inhibitors (PIs) to sustain supersaturation is well established for amorphous formulations but less in the case of lipid-based formulations (LBF). This study applied a systematic in silico–in vitro–in vivo approach to assess the merits of incorporating PIs in supersaturated LBFs (sLBF) using the model drug venetoclax. sLBFs containing hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinylpyrrolidone (PVP), PVP-co-vinyl acetate (PVP/VA), Pluronic F108, and Eudragit EPO were assessed in silico calculating a drug–excipient mixing enthalpy, in vitro using a PI solvent shift test, and finally, bioavailability was assessed in vivo in landrace pigs. The estimation of pure interaction enthalpies of the drug and the excipient was deemed useful in determining the most promising PIs for venetoclax. The sLBF alone (i.e., no PI present) displayed a high initial drug concentration in the aqueous phase during in vitro screening. sLBF with Pluronic F108 displayed the highest venetoclax concentration in the aqueous phase and sLBF with Eudragit EPO the lowest. In vivo, the sLBF alone showed the highest bioavailability of 26.3 ± 14.2%. Interestingly, a trend toward a decreasing bioavailability was observed for sLBF containing PIs, with PVP/VA being significantly lower compared to sLBF alone. In conclusion, the ability of a sLBF to generate supersaturated concentrations of venetoclax in vitro was translated into increased absorption in vivo. While in silico and in vitro PI screening suggested benefits in terms of prolonged supersaturation, the addition of a PI did not increase in vivo bioavailability. The findings of this study are of particular relevance to pre-clinical drug development, where the high in vivo exposure of venetoclax was achieved using a sLBF approach, and despite the perceived risk of drug precipitation from a sLBF, including a PI may not be merited in all cases.
    01A - Beitrag in wissenschaftlicher Zeitschrift
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    Publikation
    Exploring precipitation inhibitors to improve in vivo absorption of cinnarizine from supersaturated lipid-based drug delivery systems
    (Elsevier, 01.04.2021) Kuentz, Martin; Ilie, Alexandra Roxana; Griffin, Brendan; Vertzoni, Maria; Kolakovic, Ruzica; Prudic-Paus, Anke; Malash, Ahmed; Bohets, Hugo; Herman, Jilly; Holm, Rene [in: European Journal of Pharmaceutical Sciences]
    Supersaturated lipid-based drug delivery systems are increasingly being explored as a bio-enabling formulation approach, particularly in preclinical evaluation of poorlywater-soluble drugs. While increasing the drug load through thermally-induced supersaturation resulted in enhanced in vivo exposure for some drugs, for others, such as cinnarizine, supersaturated lipid-based systems have not been found beneficial to increase the in vivo bioavailability. We hypothesized that incorporation of precipitation inhibitors to reduce drug precipitation may address this limitation. Therefore, pharmacokinetic profiles of cinnarizine supersaturated lipid-based drug delivery systems with or without precipitation inhibitors were compared. Five precipitation inhibitors were selected for investigation based on a high throughput screening of twenty-one excipients. In vivo results showed that addition of 5% precipitation inhibitors to long chain monoglyceride (LCM) or medium chain monoglyceride (MCM) formulations showed a general trend of increases in cinnarizine bioavailability, albeit only statistically significantly increased for Poloxamer 407 + LCM system (i.e. 2.7-fold increase in AUC0-24h compared to LCM without precipitation inhibitors). It appeared that precipitation inhibitors mitigated the risk of in vivo precipitation of cinnarizine from sLBDDS and overall, bioavailability was comparable to that previously reported for cinnarizine after dosing of non-supersaturated lipid systems. In summary, for drugs which are prone to precipitation from supersaturated lipid-based drug delivery systems, such as cinnarizine, inclusion of precipitation inhibitors mitigates this risk and provides the opportunity to maximize exposure which is ideally suited in early efficacy and toxicology evaluation.
    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
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    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
    Publikation
    Modified Polymer Matrix in Pharmaceutical Hot Melt Extrusion by Molecular Interactions with a Carboxylic Coformer
    (American Chemical Society, 2019) Ditzinger, Felix; Scherer, Uta Maria; Schönenberger, Monica; Holm, Rene; Kuentz, Martin [in: Molecular Pharmaceutics]
    Hot melt extrusion (HME) has become an essential technology to cope with an increasing number of poorly soluble drug candidates. However, there is only a limited choice of pharmaceutical polymers for obtaining suitable amorphous solid dispersions (ASD). Considerations of miscibility, stability, and biopharmaceutical performance narrow the selection of excipients, and further technical constraints arise from needed pharmaceutical processing. The present work introduces the concept of molecularly targeted interactions of a coformer with a polymer to design a new matrix for HME. Model systems of dimethylaminoethyl methacrylate copolymer, Eudragit E (EE), and bicarboxylic acids were studied, and pronounced molecular interactions were demonstrated by 1H, 13C NMR, FTIR spectroscopy, as well as by different techniques of microscopic imaging. A difference was shown between new formulations exploiting specifically the targeted molecular interactions and a common drug−polymer formulation. More specifically, a modified matrix with Malic acid exhibited a technical extrusion advantage over polymer alone, and there was a benefit of improved physical stability revealed for the drug fenofibrate. This model compound displayed greatly enhanced dissolution kinetics from the ASD formulations. It can be concluded that harnessing molecularly designed polymer modifications by coformers has much potential in solid dispersion technology and in particular regarding HME processing.
    01A - Beitrag in wissenschaftlicher Zeitschrift
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    Publikation
    Lipophilicity and hydrophobicity considerations in bio‐enabling oral formulations approaches – a PEARRL review
    (Wiley, 08/2018) Ditzinger, Felix; Price, Daniel; 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]
    Objectives This review highlights aspects of drug hydrophobicity and lipophilicity as determinants of different oral formulation approaches with specific focus on enabling formulation technologies. An overview is provided on appropriate formulation selection by focussing on the physicochemical properties of the drug. Key findings Crystal lattice energy and the octanol–water partitioning behaviour of a poorly soluble drug are conventionally viewed as characteristics of hydrophobicity and lipophilicity, which matter particularly for any dissolution process during manufacturing and regarding drug release in the gastrointestinal tract. Different oral formulation strategies are discussed in the present review, including lipid‐based delivery, amorphous solid dispersions, mesoporous silica, nanosuspensions and cyclodextrin formulations. Summary Current literature suggests that selection of formulation approaches in pharmaceutics is still highly dependent on the availability of technological expertise in a company or research group. Encouraging is that, recent advancements point to more structured and scientifically based development approaches. More research is still needed to better link physicochemical drug properties to pharmaceutical formulation design.
    01A - Beitrag in wissenschaftlicher Zeitschrift
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    Publikation
    Application of the solubility parameter concept to assist with oral delivery of poorly water-soluble drugs – a PEARRL review
    (Wiley, 07/2018) Jankovic, Sandra; Tsakiridou, Georgia; Ditzinger, Felix; Koehl, Niklas; Price, Daniel; Ilie, Alexandra Roxana; Kalantzi, Lida; Kimpe, Kristof; Holm, Rene; Nair, Anita; Griffin, Brendan; Saal, Christoph; Kuentz, Martin [in: Journal of Pharmacy and Pharmacology]
    Objectives Solubility parameters have been used for decades in various scientific fields including pharmaceutics. It is, however, still a field of active research both on a conceptual and experimental level. This work addresses the need to review solubility parameter applications in pharmaceutics of poorly water‐soluble drugs. Key findings An overview of the different experimental and calculation methods to determine solubility parameters is provided, which covers from classical to modern approaches. In the pharmaceutical field, solubility parameters are primarily used to guide organic solvent selection, cocrystals and salt screening, lipid‐based delivery, solid dispersions and nano‐ or microparticulate drug delivery systems. Solubility parameters have been applied for a quantitative assessment of mixtures, or they are simply used to rank excipients for a given drug. Summary In particular, partial solubility parameters hold great promise for aiding the development of poorly soluble drug delivery systems. This is particularly true in early‐stage development, where compound availability and resources are limited. The experimental determination of solubility parameters has its merits despite being rather labour‐intensive because further data can be used to continuously improve in silico predictions. Such improvements will ensure that solubility parameters will also in future guide scientists in finding suitable drug formulations.
    01A - Beitrag in wissenschaftlicher Zeitschrift