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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, BrendanLipid 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 ZeitschriftPublikation Rational selection of bio-enabling oral drug formulations. A PEARRL commentary(Elsevier, 05/2021) Kuentz, Martin; Kronseder, Christian; Holm, Rene; Saal, Christoph; Griffin, BrendanNew 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