Supersaturated Lipid-Based Formulations to Enhance the Oral Bioavailability of Venetoclax
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 t...
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doaj-e8396e284ac84c49a16691b9fa38b9522020-11-25T03:32:54ZengMDPI AGPharmaceutics1999-49232020-06-011256456410.3390/pharmaceutics12060564Supersaturated Lipid-Based Formulations to Enhance the Oral Bioavailability of VenetoclaxNiklas J. Koehl0Laura J. Henze1Martin Kuentz2René Holm3Brendan T. Griffin4School of Pharmacy, University College Cork, College Road, T12 YN60 Cork, IrelandSchool of Pharmacy, University College Cork, College Road, T12 YN60 Cork, IrelandInstitute of Pharma Technology, University of Applied Sciences and Arts Northwestern Switzerland, Hofackerstrasse 30, 4132 Muttenz, SwitzerlandDrug Product Development, Janssen Research and Development, Johnson & Johnson, Turnhoutseweg 30, 2340 Beerse, BelgiumSchool of Pharmacy, University College Cork, College Road, T12 YN60 Cork, IrelandIncreasing 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<sup>®</sup> 1000, Peceol<sup>®</sup> and Capmul MCM<sup>®</sup>, respectively. A Peceol<sup>®</sup>-based sLBF displayed the highest drug loading and was therefore evaluated further. In vitro lipolysis demonstrated that the Peceol<sup>®</sup>-based sLBF was able to generate higher venetoclax concentrations in the aqueous phase compared to a Peceol<sup>®</sup>-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<sup>®</sup>-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.https://www.mdpi.com/1999-4923/12/6/564lipid-based formulationvenetoclaxSuper-SNEDDSsupersaturationamorphous solubilitylandrace pigs |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Niklas J. Koehl Laura J. Henze Martin Kuentz René Holm Brendan T. Griffin |
spellingShingle |
Niklas J. Koehl Laura J. Henze Martin Kuentz René Holm Brendan T. Griffin Supersaturated Lipid-Based Formulations to Enhance the Oral Bioavailability of Venetoclax Pharmaceutics lipid-based formulation venetoclax Super-SNEDDS supersaturation amorphous solubility landrace pigs |
author_facet |
Niklas J. Koehl Laura J. Henze Martin Kuentz René Holm Brendan T. Griffin |
author_sort |
Niklas J. Koehl |
title |
Supersaturated Lipid-Based Formulations to Enhance the Oral Bioavailability of Venetoclax |
title_short |
Supersaturated Lipid-Based Formulations to Enhance the Oral Bioavailability of Venetoclax |
title_full |
Supersaturated Lipid-Based Formulations to Enhance the Oral Bioavailability of Venetoclax |
title_fullStr |
Supersaturated Lipid-Based Formulations to Enhance the Oral Bioavailability of Venetoclax |
title_full_unstemmed |
Supersaturated Lipid-Based Formulations to Enhance the Oral Bioavailability of Venetoclax |
title_sort |
supersaturated lipid-based formulations to enhance the oral bioavailability of venetoclax |
publisher |
MDPI AG |
series |
Pharmaceutics |
issn |
1999-4923 |
publishDate |
2020-06-01 |
description |
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<sup>®</sup> 1000, Peceol<sup>®</sup> and Capmul MCM<sup>®</sup>, respectively. A Peceol<sup>®</sup>-based sLBF displayed the highest drug loading and was therefore evaluated further. In vitro lipolysis demonstrated that the Peceol<sup>®</sup>-based sLBF was able to generate higher venetoclax concentrations in the aqueous phase compared to a Peceol<sup>®</sup>-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<sup>®</sup>-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. |
topic |
lipid-based formulation venetoclax Super-SNEDDS supersaturation amorphous solubility landrace pigs |
url |
https://www.mdpi.com/1999-4923/12/6/564 |
work_keys_str_mv |
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