Overcoming the Bile Salt-Mediated Formation of Nanocolloids That Inhibit Oral Absorption of VX-985

Song, Bin; Bransford, Philip; Peresypkin, Andrey; Medek, A; Mudunuri, Praveen; Randles, Edward G.; Dworakowski, Wojciech; Kumar, Santosh; Snyder, Phillip W.

doi:10.1016/j.xphs.2018.10.036

Cited by 3 publications

(6 citation statements)

References 29 publications

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“…The use of colloidal particles, including nanocrystals, amorphous drug aggregates, ,, as well as surfactant and bile salt micelles, − is drawing increasing attention in the pharmaceutical industry due to their associated effective permeability and bioavailability enhancements. However, unpredictable absorption and nonlinear pharmacokinetics often observed in these formulations have greatly limited their wide use. Understanding key factors affecting the particle drifting effect in vitro is likely essential to help us to predict absorption enhancement by particles more accurately in vivo .…”

Section: Discussionmentioning

confidence: 99%

“…However, key factors affecting the UWL thickness and the extent of particle drifting effect remain less understood, and a lack of linear pharmacokinetics was often found in formulations containing these drug colloids. 16,37 Several attempts were made to understand the particle drifting effect quantitatively. Recently, Stewart et al developed a mathematical model based on Fick's law of diffusion to predict the extent of particle drifting effect by amorphous drug aggregates in vitro 26 and incorporated this model in physiologically based pharmacokinetic models using the Gastroplus platform to predict oral absorption in vivo.…”

Section: T H Imentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…For these drugs, colloidal species such as nanocrystals, amorphous aggregates, , and micelles − can move into the UWL, deliver a high payload of drug near the membrane surface, and thus increase membrane drug concentration and passive permeation rate across the membrane. However, key factors affecting the UWL thickness and the extent of particle drifting effect remain less understood, and a lack of linear pharmacokinetics was often found in formulations containing these drug colloids. , …”

Section: Introductionmentioning

confidence: 99%

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Mechanisms and Extent of Enhanced Passive Permeation by Colloidal Drug Particles

Narula

Sabra

2022

Mol. Pharmaceutics

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Formulations containing nanosized drug particles such as nanocrystals and nanosized amorphous drug aggregates recently came into light as promising strategies to improve the bioavailability of poorly soluble drugs. However, the increased solubility due to the reduction in particle size cannot adequately explain the enhanced bioavailability. In this study, the mechanisms and extent of enhanced passive permeation by drug particles were investigated using atazanavir, lopinavir, and clotrimazole as model drugs. Franz diffusion cells with lipid-infused membranes were utilized to evaluate transmembrane flux. The impact of stirring rate, receiver buffer condition, and particle size was investigated, and mass transport analyses were conducted to calculate transmembrane flux. Flux enhancement by particles was found to be dependent on particle size as well as the partitioning behavior of the drug between the receiver solution and the membrane, which is determined by both the drug and buffer used. A flux plateau was observed at high particle concentrations above amorphous solubility, confirming that mass transfer of amorphous drug particles from the aqueous solution to the membrane occurs only through the molecularly dissolved drug. Mass transport models were used to calculate flux enhancement by particles for various drugs at different conditions. Good agreements were obtained between experimental and predicted values. These results should contribute to improved bioavailability prediction of nanosized drug particles and better design of formulations containing colloidal drug particles.

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Section: Discussionmentioning

confidence: 99%

Section: T H Imentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Mechanisms and Extent of Enhanced Passive Permeation by Colloidal Drug Particles

Narula

Sabra

2022

Mol. Pharmaceutics

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“…Since only solubilized drug can be absorbed, passive diffusion is usually considered to be limited by solubility. However, in recent years, the use of nanosized drug particles, including nanocrystals and amorphous drug aggregates, is drawing increasing attention due to permeation and bioavailability enhancement through the particle drifting effect. − ,,− Although linear pharmacokinetics were often observed in the particle region above amorphous solubility, it remains challenging to predict the extent of flux enhancement by drug particles relative to that of the free drug . This makes it challenging for formulation design without conducting in vivo bioavailability studies.…”

Section: Discussionmentioning

confidence: 99%

Comparisons of in Vitro Models to Evaluate the Membrane Permeability of Amorphous Drug Nanoparticles

et al. 2022

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The spontaneous formation of amorphous drug nanoparticles following the release of a drug from a supersaturating formulation is gaining increasing attention due to their potential contribution to increased oral bioavailability. The formation of nanosized drug particles also has considerable implications for the interpretation of in vitro and in vivo data. However, the membrane transport properties of these drug particles remain less well understood. Herein, the membrane permeation of nanosized amorphous drug particles of a model drug atazanavir was evaluated using different artificial membrane-based, cell-based, and animal tissue-based models. Results showed that flux enhancement by particles was different for the various systems used. Generally, good agreement was obtained among experiments performed using the same apparatus with different model membranes, with the exception of the Madin-Darby canine kidney cell monolayer and the Long-Evans rat intestine tissue, which showed lower flux enhancements. Franz cell-based models showed slightly higher flux enhancements by particles compared to Transwell and intestinal tissue sac models. Mass transport analysis suggested that the extent of flux enhancement by particles is dependent on the geometry of the apparatus as well as the properties of the membrane and buffer used, whereas the flux plateau concentration is dependent on the unstirred water later (UWL) asymmetry. These results highlight the complexity in characterizing the permeability advantage of these nonmembrane permeable drug particles and suggest that caution should be used in selecting the appropriate in vitro model to evaluate the overall permeability of colloidal drug particles.

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Changes in aggregation properties of TPGS micelles in the presence of sodium cholate

Rathod

Joshi

Ray

et al. 2021

Colloids and Surfaces A: Physicochemical and Engineering Aspect

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Overcoming the Bile Salt-Mediated Formation of Nanocolloids That Inhibit Oral Absorption of VX-985

Cited by 3 publications

References 29 publications

Mechanisms and Extent of Enhanced Passive Permeation by Colloidal Drug Particles

Mechanisms and Extent of Enhanced Passive Permeation by Colloidal Drug Particles

Comparisons of in Vitro Models to Evaluate the Membrane Permeability of Amorphous Drug Nanoparticles

Changes in aggregation properties of TPGS micelles in the presence of sodium cholate

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