An in vitro dissolution–digestion–permeation assay for the study of advanced drug delivery systems

Alvebratt, Caroline; Keemink, Janneke; Edueng, Khadijah; Cheung, Ocean; Strömme, Maria; Bergström, Christel A. S.

doi:10.1016/j.ejpb.2020.01.010

Cited by 24 publications

(18 citation statements)

References 48 publications

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“…However, in the in vivo situation, such a lipid phase may be critical to maintain bio-enhancing effects by sustaining the aqueous phase concentration as venetoclax partitions from the lipid into the aqueous phase. An adjustment of the in vitro model to species-specific parameters such as enzyme activity, gastrointestinal volumes [ 33 ] and the addition of a gastric step [ 34 , 35 ] and an absorptive sink [ 36 , 37 ] may have offered additional insights into reliably correlating in vitro formulation characteristics with in vivo performance.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…These include the following. Fundamental flaws exist with in vitro lipolysis assays, which limit the ability to predict in vivo lipid metabolism. Despite recent efforts in improving the biological relevancy of in vitro lipolysis models, for simulating both food and drug absorption, − significant limitations still exist, largely due to the complex physiological processes involved in lipid metabolism . Subsequently, it is proposed that future studies utilize lipolysis models that extend beyond 60 min to ensure a plateau in fatty acid release, harness dynamic changes in pH, calcium ion and bile salt concentrations, and include an absorption step to elucidate the impact of biomaterial supplementation on lipid absorption across intestinal epithelium …”

Section: Resultsmentioning

confidence: 99%

Contrasting Anti-obesity Effects of Smectite Clays and Mesoporous Silica in Sprague-Dawley Rats

Joyce

Dening

Meola

et al. 2020

ACS Appl. Bio Mater.

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Porous colloids have been shown to exert unique bioactivities for mediating lipid (fat) metabolism and thereby offer significant potential as anti-obesity therapies. In this study, we compare the capacity for two classes of colloids, that is, smectite clays (Laponite XLG, LAP; montmorillonite, MMT) and mesoporous silica (SBA-15 ordered silica; MPS), to impede intestinal lipid hydrolysis and provoke lipid and carbohydrate excretion through adsorption within their particle matrices. A two-stage in vitro gastrointestinal lipolysis model revealed the capacity for both smectite clays and MPS to inhibit the rate and extent of lipase-mediated digestion under simulated fed state conditions. Each system adsorbed more than its own weight of organic media (i.e., lipid and carbohydrates) after 60 min lipolysis, with MMT adsorbing >10% of all available organics through the indiscriminate adsorption of fatty acids and glycerides. When co-administered with a high-fat diet (HFD) to Sprague-Dawley rats, treatment with MMT and MPS significantly reduced normalized rodent weight gain compared to a negative control, validating their potential to restrict energy intake and serve as anti-obesity therapies. However, in vitro–in vivo correlations revealed poor associations between in vitro digestion parameters and normalized weight gain, indicating that additional/alternate anti-obesity mechanisms may exist in vivo, while also highlighting the need for improved in vitro assessment methodologies. Despite this, the current findings emphasize the potential for porous colloids to restrict weight gain and promote anti-obesity effects to subjects exposed to a HFD and should therefore drive the development of next-generation food-grade biomaterials for the treatment and prevention of obesity.

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“…A potential solution could be to use a stronger buffer in the digestion chamber instead of the pH-stat, a strategy we have successfully used in a different experimental setup. 30 A stronger buffer would also allow for reduction of the donor volume in the current setup by up to 67% and therefore increasing the surface-area to donor volume ratio (A/V) by the same amount.…”

Section: Discussionmentioning

confidence: 99%

“…Based on the current and previous studies, the Caco-2 cells seem more suitable than the MDCK monolayers for (dissolution-)permeation systems that evaluate the performance of enabling formulations and LBFs in particular. 17,30,43,44 A strategy to protect the MDCK cells from potentially detrimental effects of the digestion medium could be a mucus layer on top of the membrane, as has been done with Caco-2 cells. 25 Falavigna et al applied biosimilar mucus to an artificial PVPA barrier with the aim of simulating the intestinal mucosa.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Cellular Monolayers and an Artificial Membrane as Absorptive Membranes in the in vitro Lipolysis-permeation Assay

Keemink

Hedge

Bianco

et al. 2022

Journal of Pharmaceutical Sciences

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Permeation across Caco-2 cells in lipolysis-permeation setups can predict the rank order of in vivo drug exposure obtained with lipid-based formulations (LBFs). However, Caco-2 cells require a long differentiation period and do not capture all characteristics of the human small intestine. We therefore evaluated two in vitro assays with artificial lecithin-in-dodecane (LiDo) membranes and MDCK cells as absorptive membranes in the lipolysis-permeation setup. Fenofibrate-loaded LBFs were used and the results from the two assays compared to literature plasma concentrations in landrace pigs administered orally with the same formulations. Aqueous drug concentrations, supersaturation, and precipitation were determined in the digestion chamber and drug permeation in the receiver chamber. Auxiliary in vitro parameters were assessed, such as permeation of the taurocholate, present in the simulated intestinal fluid used in the assay, and size of colloidal structures in the digestion medium over time. The LiDo membrane gave a similar drug distribution as the Caco-2 cells and accurately reproduced the equivalent rank-order of fenofibrate exposure in plasma. Permeation of fenofibrate across MDCK monolayers did not, however, reflect the in vivo exposure rankings. Taurocholate flux was negligible through either membrane. This process was therefore not considered to significantly affect the in vitro distribution of fenofibrate. We conclude that the artificial LiDo membrane is a promising tool for lipolysis−permeation assays to evaluate LBF performance.

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An in vitro dissolution–digestion–permeation assay for the study of advanced drug delivery systems

Cited by 24 publications

References 48 publications

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

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

Contrasting Anti-obesity Effects of Smectite Clays and Mesoporous Silica in Sprague-Dawley Rats

Comparison of Cellular Monolayers and an Artificial Membrane as Absorptive Membranes in the in vitro Lipolysis-permeation Assay

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