The ability of two in vitro lipolysis models reflecting the human and rat gastro-intestinal conditions to predict the in vivo performance of SNEDDS dosing regimens

Jørgensen, Scheyla Daniela Siqueira; Sawaf, Malak Al; Gräeser, Kirsten; Mu, Huiling; Müllertz, Anette; Rades, Thomas

doi:10.1016/j.ejpb.2017.12.014

Cited by 43 publications

(19 citation statements)

References 34 publications

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“…This finding would suggest that in vivo , the Chasing Principle would provide higher absorption of CIN than for R3040. This hypothesis is supported by two previous pharmacokinetic studies in rats where R3040 26 or CIN 5 were dosed in SNEDDS (same composition as F55) using different drug loads and physical states of the drug, i.e. , dissolved in SNEDDS with a drug load of 80% of S eq (SNEDDS 80%), supersaturated in SNEDDS at 200% S eq (Super-SNEDDS solution), and suspended in SNEDDS containing R3040 or CIN at 200% S eq (Super-SNEDDS suspension), as the Chasing Principle and aqueous suspension 5 .…”

Section: Resultssupporting

confidence: 72%

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Exploring the utility of the Chasing Principle: influence of drug-free SNEDDS composition on solubilization of carvedilol, cinnarizine and R3040 in aqueous suspension

Jørgensen

Rades

et al. 2019

Acta Pharmaceutica Sinica B

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This study assessed the influence of the composition of drug-free SNEDDS co-dosed with aqueous suspensions of carvedilol (CAR), cinnarizine (CIN) or R3040 on drug solubilization in a two-compartment in vitro lipolysis model. Correlation of drug logP or solubility in SNEDDS with drug solubilization during in vitro lipolysis in the presence of drug-free SNEDDS was assessed. SNEDDS with varying ratios of soybean oil:Maisine 35-1 (1:1, w/w) and Kolliphor RH40, with ethanol at 10% (w/w) were used. SNEDDS were named F65, F55 and F20 (numbers refer to the percentage of lipids) and aqueous suspensions without drug-free SNEDDS (F0) were also analyzed. While the ranking order of drug solubilization was F65=F55=F20>F0 for CAR; F65=F55>F20>F0 for CIN and F65=F55=F20>F0 for R3040 - with higher CAR solubilization than for R3040 and CIN - the ranking of Seq of CAR, CIN and R3040 in SNEDDS was F65F20 and F65>F55>F20, respectively. Therefore, the composition of SNEDDS influenced the solubilization of CIN, but not CAR and R3040. Furthermore, high Seq in SNEDDS did not reflect high drug solubilization. As CAR (logP 3.8) showed higher solubilization than CIN (logP 5.8) and R3040 (logP 10.4), a correlation between drug logP and drug solubilization was observed.

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Section: Resultssupporting

confidence: 72%

“…Thus, CIN dosed in the Chasing Principle produced similar absorptions profiles to CIN dosed dissolved in SNEDDS, while R3040 did not show significant absorption improvement upon dosing in the Chasing Principle 5. , 26. .…”

Section: Resultsmentioning

confidence: 99%

Exploring the utility of the Chasing Principle: influence of drug-free SNEDDS composition on solubilization of carvedilol, cinnarizine and R3040 in aqueous suspension

Jørgensen

Rades

et al. 2019

Acta Pharmaceutica Sinica B

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“…The % increases in drug loading in lipids observed for venetoclax were higher compared to typical dose loadings reported for other drugs in sLBFs [ 11 , 12 , 15 , 17 ]. For example, in the case of halofantrine [ 12 ] and fenofibrate [ 15 ], dose loading increased to 150% compared to solubility at 37 °C, whereas for simvastatin [ 11 ] and R4040 [ 17 ], dose loading was increased to 200% compared to solubility at 37 °C. This indicates that many model drugs already show a reasonably high solubility in the lipid vehicles or a lower therapeutic dose compared to venetoclax.…”

Section: Discussionmentioning

confidence: 63%

“…A consequence of these particular hydrophobic drugs is an overall lower aqueous and lipid solubility, which may come with lower permeability due to molecular bulkiness and, therefore, the applicability of the classical LBF solutions is limited. As a consequence, strategies such as lipophilic salts/ionic liquids [ 9 , 10 , 29 ], supersaturated lipid solutions [ 11 , 12 , 13 , 15 , 17 ] or hybrid systems [ 30 , 31 ] were proposed that focus on increasing the drug load in LBFs. Nevertheless, it remains unclear whether LBFs offer biopharmaceutical benefits to enhance the bioavailability of these beyond Rule-of-Five drugs which display high lipophilicity and molecular weight as well as moderate hydrophobicity.…”

Section: Discussionmentioning

confidence: 99%

“…sLBFs offer significant advantages in a pre-clinical drug product development setting, offering a balance between the potential to maximise oral exposure and facilitating ease of preparation and administration in pre-clinical models, which is particularly relevant in early toxicological drug evaluations [ 14 ]. In the literature, sLBFs of small and highly lipophilic drugs such as halofantrine [ 12 ], simvastatin [ 11 ], fenofibrate [ 15 ], cinnarizine [ 16 ] and R3040 [ 17 ] have been reported. In most cases, a higher oral bioavailability was observed in comparison to either an aqueous suspension, commercial product or an undersaturated lipid solution.…”

Section: Introductionmentioning

confidence: 99%

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Supersaturated Lipid-Based Formulations to Enhance the Oral Bioavailability of Venetoclax

et al. 2020

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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.

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Particle degradation and nutrient bioavailability of soybean milk during in vitro digestion

Ritzoulis

Han

et al. 2020

Food Biophysics

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The ability of two in vitro lipolysis models reflecting the human and rat gastro-intestinal conditions to predict the in vivo performance of SNEDDS dosing regimens

Cited by 43 publications

References 34 publications

Exploring the utility of the Chasing Principle: influence of drug-free SNEDDS composition on solubilization of carvedilol, cinnarizine and R3040 in aqueous suspension

Exploring the utility of the Chasing Principle: influence of drug-free SNEDDS composition on solubilization of carvedilol, cinnarizine and R3040 in aqueous suspension

Supersaturated Lipid-Based Formulations to Enhance the Oral Bioavailability of Venetoclax

Particle degradation and nutrient bioavailability of soybean milk during in vitro digestion

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