Lipophilic Salts and Lipid-Based Formulations for Bridging the Food Effect Gap of Venetoclax
| Autor: | Andreas Marx, Niklas J. Koehl, René Holm, Brendan T. Griffin, John J. Keating, Thomas De Vijlder, Martin Kuentz, Laura J. Henze |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Drug
Salt formation Co-crystals Swine media_common.quotation_subject Drug Compounding Pharmaceutical Science Administration Oral Biological Availability Lipophilic salts Venetoclax chemistry.chemical_compound Drug Delivery Systems Animals Solubility media_common Sulfonamides Chromatography Free base Decanoic acid Bridged Bicyclo Compounds Heterocyclic Lipids Bioavailability Oleic acid Lipid based formulations chemistry Drug delivery Emulsions Salts |
| Zdroj: | Koehl, N J, Henze, L J, Holm, R, Kuentz, M, Keating, J J, De Vijlder, T, Marx, A & Griffin, B T 2022, ' Lipophilic Salts and Lipid-Based Formulations for Bridging the Food Effect Gap of Venetoclax ', Journal of Pharmaceutical Sciences, vol. 111, no. 1, pp. 164-174 . https://doi.org/10.1016/j.xphs.2021.09.008 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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