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Publikation Hydroxypropyl Cellulose for Drug Precipitation Inhibition: From the Potential of Molecular Interactions to Performance Considering Microrheology(American Chemical Society, 10.01.2022) Stoyanov, Edmont; Niederquell, Andreas; Kuentz, MartinThere has been recent interest in using hydroxypropyl cellulose (HPC) for supersaturating drug formulations. This study investigated the potential for molecular HPC interactions with the model drug celecoxib by integrating novel approaches in the field of drug supersaturation analysis. Following an initial polymer characterization study, quantum-chemical calculations and molecular dynamics simulations were complemented with results of inverse gas chromatography and broadband diffusing wave spectroscopy. HPC performance was studied regarding drug solubilization and kinetics of desupersaturation using different grades (i.e., HPC-UL, SSL, SL, and L). The results suggested that the potential contribution of dispersive interactions and hydrogen bonding depended strongly on the absence or presence of the aqueous phase. It was proposed that aggregation of HPC polymer chains provided a complex heterogeneity of molecular environments with more or less excluded water for drug interaction. In precipitation experiments at a low aqueous polymer concentration (i.e., 0.01%, w/w), grades L and SL appeared to sustain drug supersaturation better than SSL and UL. However, UL was particularly effective in drug solubilization at pH 6.8. Thus, a better understanding of drug–polymer interactions is important for formulation development, and polymer blends may be used to harness the combined advantages of individual polymer grades.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Supersaturated Lipid-Based Formulations to Enhance the Oral Bioavailability of Venetoclax(Elsevier, 18.06.2020) Koehl, Niklas; Kuentz, MartinIncreasing 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 ZeitschriftPublikation In vitro methods to assess drug precipitation in the fasted small intestine – a PEARRL review(Wiley, 06/2018) O'Dwyer, Patrick J.; Litou, Chara; Box, Karl, J.; Dressman, Jennifer; Kostewicz, Edmund, S.; Kuentz, Martin; Reppas, ChristosObjectives Drug precipitation in vivo poses a significant challenge for the pharmaceutical industry. During the drug development process, the impact of drug supersaturation or precipitation on the in vivo behaviour of drug products is evaluated with in vitro techniques. This review focuses on the small and full scale in vitro methods to assess drug precipitation in the fasted small intestine. Key findings Many methods have been developed in an attempt to evaluate drug precipitation in the fasted state, with varying degrees of complexity and scale. In early stages of drug development, when drug quantities are typically limited, small‐scale tests facilitate an early evaluation of the potential precipitation risk in vivo and allow rapid screening of prototype formulations. At later stages of formulation development, full‐scale methods are necessary to predict the behaviour of formulations at clinically relevant doses. Multicompartment models allow the evaluation of drug precipitation after transfer from stomach to the upper small intestine. Optimisation of available biopharmaceutics tools for evaluating precipitation in the fasted small intestine is crucial for accelerating the development of novel breakthrough medicines and reducing the development costs. Summary Despite the progress from compendial quality control dissolution methods, further work is required to validate the usefulness of proposed setups and to increase their biorelevance, particularly in simulating the absorption of drug along the intestinal lumen. Coupling results from in vitro testing with physiologically based pharmacokinetic modelling holds significant promise and requires further evaluation.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Trends in the Assessment of Drug Supersaturation and Precipitation In Vitro Using Lipid-Based Delivery Systems(Elsevier, 2016) Stillhart, Cordula; Kuentz, MartinThe generation of drug supersaturation close to the absorptive site is an important mechanism of how several formulation technologies enhance oral absorption and bioavailability. Lipid-based formulations belong to the supersaturating drug delivery systems although this is not the only mechanism of how drug absorption is promoted in vivo. Different methods to determine drug supersaturation and precipitation from lipid-based formulations are described in the literature. Experimental in vitro setups vary according to their complexity and proximity to the in vivo conditions and, therefore, some tests are used for early formulation screening, while others better qualify for a later stage of development. The present commentary discusses this rapidly evolving field of in vitro testing with a special focus on the advancements in analytical techniques and new approaches of mechanistic modeling. The importance of considering a drug absorption sink is particularly emphasized. This commentary should help formulators in the pharmaceutical industry as well as in academia to make informed decisions on how to conduct in vitro tests for lipid-based delivery systems and to decide on the implications of experimental results.01A - Beitrag in wissenschaftlicher Zeitschrift