A Mechanistic Study of Drug Mass Transport from Supersaturated Solutions Across PAMPA Membranes

Hate, Siddhi S.; Mosquera-Giraldo, Laura I.; Taylor, Lynne S.

doi:10.1016/j.xphs.2021.07.003

Cited by 13 publications

(8 citation statements)

References 65 publications

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“…Therefore, solute activity remained constant due to the formation of a second phase in the form of amorphous aggregates above amorphous solubility. , As a result, membrane flux remained constant above amorphous solubility. Similar results were previously reported in various hydrophilic membrane setups. ,− In contrast, for lipophilic membranes, due to high drug partitioning in the membrane, the contribution to diffusion by UWLs is dominant, enabling a significant particle drifting effect to be observed (Figure D). With increasing lecithin coverage from 0 to 100%, increased flux enhancement by particles was observed above the amorphous solubility (Figure A-D, Figure S8).…”

Section: Discussionsupporting

confidence: 88%

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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Section: Discussionsupporting

confidence: 88%

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

et al. 2022

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“…Naporafenib’s diffusion was also sensitive to the presence of TC/L (Table , Figures S13 and S14), but more drug in solution stillled to increased mass transport across the cellulose membrane at given PSOs (Figures S17 and S18). Previous contributions support such findings and describe the enhanced permeability via an apparent thinning of the unstirred water layer (UWL) or, more precisely, as bile colloid-mediated additive flux through the UWL. − Using the diffusion coefficients and flux values for PBS and 5× TC/L (Table and Figure S17), we have solved the diffusion equation (based on Fick’s first law , ). The obtained estimate for the UWL thickness was about 1000 μm (each donor and acceptor).…”

Section: Discussionmentioning

confidence: 66%

Harnessing Bile for Drug Absorption through Rational Excipient Selection

Schlauersbach,

Werthmüller,

Harlacher

et al. 2023

Mol. Pharmaceutics

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Bile solubilization and apparent solubility at resorption sites critically affect the bioavailability of orally administered and poorly water-soluble drugs. Therefore, identification of drug-bile interaction may critically determine the overall formulation success. For the case of the drug candidate naporafenib, drug in solution at phase separation onset significantly improved with polyethylene glycol-40 hydrogenated castor oil (RH40) and amino methacrylate copolymer (Eudragit E) but not with hydroxypropyl cellulose (HPC) in both phosphate-buffered saline (PBS) and PBS supplemented with bile components. Naporafenib interacted with bile as determined by 1 H and 2D 1 H− 1 H nuclear magnetic resonance spectroscopy and so did Eudragit E and RH40 but not HPC. Flux across artificial membranes was reduced in the presence of Eudragit E. RH40 reduced the naporafenib supersaturation duration. HPC on the other side stabilized naporafenib's supersaturation and did not substantially impact flux. These insights on bile interaction correlated with pharmacokinetics (PK) in beagle dogs. HPC preserved naporafenib bile solubilization in contrast to Eudragit E and RH40, resulting in favorable PK.

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“…Mechanism 1 was previously reported in bile micelle systems 34 and was quantitatively demonstrated in systems containing amorphous drug particles. 33 In this study, we conducted diffusion experiments using clotrimazole as a model drug, which has a low amorphous solubility and provides a large concentration window of particle formation, to allow direct visualization of the flux plateau.…”

Section: Resultsmentioning

confidence: 99%

“…For lipophilic drugs that easily permeate lipid cell membranes, the otherwise negligible diffusional resistance from the UWL dominates the total resistance of permeation. 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%

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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A Mechanistic Study of Drug Mass Transport from Supersaturated Solutions Across PAMPA Membranes

Cited by 13 publications

References 65 publications

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

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

Harnessing Bile for Drug Absorption through Rational Excipient Selection

Mechanisms and Extent of Enhanced Passive Permeation by Colloidal Drug Particles

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