Lipophilic Salts and Lipid-Based Formulations for Bridging the Food Effect Gap of Venetoclax
Copyright © 2021 American Pharmacists Association. Published by Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:111 |
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| Enthalten in: |
Journal of pharmaceutical sciences - 111(2022), 1 vom: 15. Jan., Seite 164-174 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Koehl, Niklas J [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 16.03.2022 Date Revised 16.03.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.xphs.2021.09.008 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM330591428 |
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| 100 | 1 | |a Koehl, Niklas J |e verfasserin |4 aut | |
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| 500 | |a Date Revised 16.03.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 American Pharmacists Association. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Lipid based formulations | |
| 650 | 4 | |a Lipophilic salts | |
| 650 | 4 | |a Salt formation, Co-crystals | |
| 650 | 4 | |a Venetoclax | |
| 650 | 7 | |a Bridged Bicyclo Compounds, Heterocyclic |2 NLM | |
| 650 | 7 | |a Emulsions |2 NLM | |
| 650 | 7 | |a Lipids |2 NLM | |
| 650 | 7 | |a Salts |2 NLM | |
| 650 | 7 | |a Sulfonamides |2 NLM | |
| 650 | 7 | |a venetoclax |2 NLM | |
| 650 | 7 | |a N54AIC43PW |2 NLM | |
| 700 | 1 | |a Henze, Laura J |e verfasserin |4 aut | |
| 700 | 1 | |a Holm, René |e verfasserin |4 aut | |
| 700 | 1 | |a Kuentz, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Keating, John J |e verfasserin |4 aut | |
| 700 | 1 | |a De Vijlder, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Marx, Andreas |e verfasserin |4 aut | |
| 700 | 1 | |a Griffin, Brendan T |e verfasserin |4 aut | |
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