Lipophilic salts and lipid-based formulations for bridging the food effect gap of venetoclax
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Authors
Koehl, Niklas
Henze, Laura
Holm, Rene
Keating, John
De Vijlder, Thomas
Marx, Andreas
Griffin, Brendan
Author (Corporation)
Publication date
01.2022
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Type
01A - Journal article
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Parent work
Journal of Pharmaceutical Sciences
Special issue
DOI of the original publication
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Volume
111
Issue / Number
1
Pages / Duration
164-174
Patent number
Publisher / Publishing institution
Elsevier
Place of publication / Event location
Edition
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Abstract
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.
Keywords
Lipophilic salts, Lipid based formulations, Venetoclax, Salt formation, Co-crystals
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ISBN
ISSN
0022-3549
1520-6017
1520-6017
Language
English
Created during FHNW affiliation
Yes
Strategic action fields FHNW
Publication status
Published
Review
Peer review of the complete publication
Open access category
Closed
License
Citation
Koehl, N., Henze, L., Holm, R., Kuentz, M., Keating, J., De Vijlder, T., Marx, A., & Griffin, B. (2022). Lipophilic salts and lipid-based formulations for bridging the food effect gap of venetoclax. Journal of Pharmaceutical Sciences, 111(1), 164–174. https://doi.org/10.1016/j.xphs.2021.09.008