Supersaturated Lipid-Based Formulations to Enhance the Oral Bioavailability of Venetoclax.
Issue Date
2020-06-18Keywords
SEDDSSuper-SNEDDS
amorphous solubility
landrace pigs
lipid suspensions
lipid-based formulation
self-emulsifying drug delivery system
supersaturated lipid-based formulations
supersaturation
venetoclax
Metadata
Show full item recordJournal
PharmaceuticsDOI
10.3390/pharmaceutics12060564PubMed ID
32570753Abstract
Increasing numbers of beyond Rule-of-Five drugs are emerging from discovery pipelines, generating a need for bio-enabling formulation approaches, such as lipid-based formulations (LBF), to ensure maximal in vivo exposure. However, many drug candidates display insufficient lipid solubility, leading to dose-loading limitations in LBFs. The aim of this study was to explore the potential of supersaturated LBFs (sLBF) for the beyond Rule-of-Five drug venetoclax. Temperature-induced sLBFs of venetoclax were obtained in olive oil, Captex® 1000, Peceol® and Capmul MCM®, respectively. A Peceol®-based sLBF displayed the highest drug loading and was therefore evaluated further. In vitro lipolysis demonstrated that the Peceol®-based sLBF was able to generate higher venetoclax concentrations in the aqueous phase compared to a Peceol®-based suspension and an aqueous suspension. A subsequent bioavailability study in pigs demonstrated for sLBF a 3.8-fold and 2.1-fold higher bioavailability compared to the drug powder and Peceol®-based suspension, respectively. In conclusion, sLBF is a promising bio-enabling formulation approach to enhance in vivo exposure of beyond Rule-of-Five drugs, such as venetoclax. The in vitro lipolysis results correctly predicted a higher exposure of the sLBF in vivo. The findings of this study are of particular relevance to pre-clinical drug development, where maximum exposure is required.Item Type
ArticleLanguage
enISSN
1999-4923ae974a485f413a2113503eed53cd6c53
10.3390/pharmaceutics12060564
Scopus Count
Collections
Related articles
- In Silico, In Vitro, and In Vivo Evaluation of Precipitation Inhibitors in Supersaturated Lipid-Based Formulations of Venetoclax.
- Authors: Koehl NJ, Henze LJ, Bennett-Lenane H, Faisal W, Price DJ, Holm R, Kuentz M, Griffin BT
- Issue date: 2021 Jun 7
- Lipophilic Salts and Lipid-Based Formulations for Bridging the Food Effect Gap of Venetoclax.
- Authors: Koehl NJ, Henze LJ, Holm R, Kuentz M, Keating JJ, De Vijlder T, Marx A, Griffin BT
- Issue date: 2022 Jan
- Chase Dosing of Lipid Formulations to Enhance Oral Bioavailability of Nilotinib in Rats.
- Authors: Koehl NJ, Holm R, Kuentz M, Griffin BT
- Issue date: 2020 Jun 10
- Correlating in Vitro Solubilization and Supersaturation Profiles with in Vivo Exposure for Lipid Based Formulations of the CETP Inhibitor CP-532,623.
- Authors: McEvoy CL, Trevaskis NL, Feeney OM, Edwards GA, Perlman ME, Ambler CM, Porter CJH
- Issue date: 2017 Dec 4
- The Influence of Solidification on the in vitro Solubilisation of Blonanserin Loaded Supersaturated Lipid-Based Oral Formulations.
- Authors: Møller A, Schultz HB, Meola TR, Müllertz A, Prestidge CA
- Issue date: 2021 Feb 1