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Lipophilic salts and lipid-based formulations for bridging the food effect gap of venetoclax

Autor/Autorin
Koehl, Niklas
Henze, Laura
Holm, Rene
Kuentz, Martin
Keating, John
De Vijlder, Thomas
Marx, Andreas
Griffin, Brendan
Datum
01.2022
Metadata
Zur Langanzeige
Type
01 - Zeitschriftenartikel, Journalartikel oder Magazin
Zusammenfassung
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.
URI
https://irf.fhnw.ch/handle/11654/33404
DOI der Originalausgabe
https://doi.org/10.1016/j.xphs.2021.09.008
Übergeordnetes Werk
Pharmaceutics, Drug Delivery and Pharmaceutical Technology
Jahrgang
111
Ausgabe
1
Seiten
164-174
Verlag / Hrsg. Institution
Elsevier
Zitation

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