In Vitro–In Vivo Relationship in Mini-Scale—Enabling Formulations of Corallopyronin A

In vivo studies in mice provide a valuable model to test novel active pharmaceutical ingredients due to their low material need and the fact that mice are frequently used as a species for early efficacy models. However, preclinical in vitro evaluations of formulation principles in mice are still lacking. The development of novel in vitro and in silico models supported the preclinical formulation evaluation for the anti-infective corallopyronin A (CorA). To this end, CorA and solubility-enhanced amorphous solid dispersion formulations, comprising povidone or copovidone, were evaluated regarding biorelevant solubilities and dissolution in mouse-specific media. As an acidic compound, CorA and CorA-ASD formulations showed decreased solubilities in mice when compared with human-specific media. In biorelevant biphasic dissolution experiments CorA-povidone showed a three-fold higher fraction partitioned into the organic phase of the biphasic dissolution, when compared with CorA-copovidone. Bioavailabilities determined by pharmacokinetic studies in BALB/c mice correlated with the biphasic dissolution prediction and resulted in a Level C in vitro–in vivo correlation. In vitro cell experiments excluded intestinal efflux by P-glycoprotein or breast cancer resistance protein. By incorporating in vitro results into a physiologically based pharmacokinetic model, the plasma concentrations of CorA-ASD formulations were predicted and identified dissolution as the limiting factor for bioavailability.

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Chemicals and Materials

CorA was provided by the Helmholtz Centre for Infection Research (Braunschweig, Germany). Polyvinylpyrrolidone (Kollidon^® 30 LP) and vinylpyrrolidone-vinyl acetate copolymer (Kollidon^® VA 64) were kindly provided by BASF SE (Ludwigshafen, Germany). Ethanol 99.8% and tri-potassium citrate were purchased from Carl Roth GmbH & Co. KG (Karlsruhe, Germany). Tri-potassium phosphate, lecithin, 1-decanol and sodium taurocholate were purchased from Thermo Fisher GmbH (Kandel, Germany). Sodium oleate was purchased from Sigma (Darmstadt, Germany). Glycerol mono-oleate was kindly provided by Gattefosseé SAS (Saint-Priest, France). In addition, 1-micron full-flow polyethylene filters were purchased from Cole-Parmer GmbH. Acetic acid was purchased by Sigma Aldrich Chemie GmbH (Steinheim, Germany). Sodium hydroxide was purchased from VWR International, LLC (Darmstadt, Germany). Water for injection was purchased from Fresenius Kabi Deutschland GmbH (Bad Homburg, Germany). LC-MS grade acetonitrile and water were purchased from Bernd Kraft GmbH (Duisburg, Germany), and LC-MS grade ammonium acetate from Merck KGaA (Darmstadt, Germany). Cell culture reagents were purchased from Sigma Aldrich (Taufkirchen, Germany).

Becker, T.; Krome, A.K.; Vahdati, S.; Schiefer, A.; Pfarr, K.; Ehrens, A.; Aden, T.; Grosse, M.; Jansen, R.; Alt, S.; Hesterkamp, T.; Stadler, M.; Hübner, M.P.; Kehraus, S.; König, G.M.; Hoerauf, A.; Wagner, K.G. In Vitro–In Vivo Relationship in Mini-Scale—Enabling Formulations of Corallopyronin A. Pharmaceutics 2022, 14, 1657. https://doi.org/10.3390/pharmaceutics14081657