Predicting drug permeability through skin using molecular dynamics simulation

Lundborg, Magnus; Wennberg, Christian L.; Narangifard, Ali; Lindahl, Erik; Norlén, Lars

doi:10.1016/j.jconrel.2018.05.026

Cited by 108 publications

(111 citation statements)

References 62 publications

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“…1F), the permeability of a strongly hydrophilic species such as mannitol using the above parameters is strongly underestimated (1.6×10 -7 cm/h vs. 3.7×10 -5 cm/h). Such discrepancy is in line with similar computations across other model skin lipid systems (Lundborg et al, 2018), and is a known limitation of models based on homogeneous lipid lamellae (Mitragotri et al, 2011).…”

Section: Permeability Calculations Of Small Moleculessupporting

confidence: 86%

“…The most significant limitation of the models described above, particularly the lamellar phases, is that they do not explain all available experimental permeability data. For small lipophilic molecules, permeability measurements from skin samples led to the development of empirical models (Potts & Guy, 1992) whose accuracy is comparable to atomistic computations (Lundborg et al, 2018). On the other hand, hydrophilic molecules and macromolecules are found to permeate through the skin many orders of magnitude more quickly than through lipid bilayers (Mitragotri et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Coexistence of lipid phases stabilizes interstitial water in the outer layer of mammalian skin

MacDermaid¹,

Hall²,

DeVane

et al. 2019

Preprint

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The lipid matrix in the outer layer of mammalian skin, the stratum corneum, has been previously investigated by multiple biophysical techniques, aimed at identifying hydrophilic and lipophilic pathways of permeation. While consensus is developing over the microscopic structure of the lipid matrix, no molecular-resolution model describes the permeability of all chemical species simultaneously. Using molecular dynamics simulations of a model mixture of skin lipids, the self-assembly of the lipid matrix lamellae has been studied. At higher humidity, the resulting lamellar phase is maintained by partitioning excess water into isolated droplets of controlled size and spatial distribution. The droplets may fuse together to form intra-lamellar water channels, thereby providing a pathway for the permeation of hydrophilic species. These results reconcile competing data on the outer skin's structure and broaden the scope of molecular-based methods to improve the safety of topical products and to advance transdermal drug delivery.

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Section: Permeability Calculations Of Small Moleculessupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Coexistence of lipid phases stabilizes interstitial water in the outer layer of mammalian skin

MacDermaid¹,

Hall²,

DeVane

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Finally, diffusion and partition coefficients that are a function of drug concentration (rather than constant values) should be used, especially if there are large variations for the drug of interest. For example, when increasing the Azone concentration from 0 to 9 wt%, the partition coefficient changed from -4.0 to 2.1 [25]. This alteration significantly changes its equilibrium distribution.…”

Section: Modeled Transport Processesmentioning

confidence: 98%

“…(1) Mechanistic models that solve partial differential equations, for example at the macroscale, mesoscale [23] and even cellular level (microscale; Figure 1 a, b, c) with finite elements [24]. (2) Molecular dynamics at the subcellular level (e.g., lipid layers) to obtain transport properties and thermodynamic values of the system (e.g., partition coefficients) [25] that could then be used in a multiscale approach [26], [27] (Figure 1d). Additionally, alternative modeling strategies have been proposed that account for interactions at the molecular level [28] to calculate the skin permeability.…”

Section: Introductionmentioning

confidence: 99%

Predicting transdermal fentanyl delivery using mechanistic simulations for tailored therapy

Defraeye

Bahrami

Ding

et al. 2020

Preprint

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Transdermal drug delivery is a key technology for administering drugs. However, most devices are "one-sizefits-all", even though drug diffusion through the skin varies significantly from person-to-person. For nextgeneration devices, personalization for optimal drug release would benefit from an augmented insight into the drug release and percutaneous uptake kinetics. Our objective was to quantify the changes in transdermal fentanyl uptake with regards to the patient's age and the anatomical location where the patch was placed. We also explored to which extent the drug flux from the patch could be altered by miniaturizing the contact surface area of the patch reservoir with the skin. To this end, we used validated mechanistic modeling of fentanyl diffusion, storage, and partitioning in the epidermis to quantify drug release from the patch and the uptake within the skin. A superior spatiotemporal resolution compared to experimental methods enabled in-silico identification of peak concentrations and fluxes, and the amount of stored drug and bioavailability. The patients' drug uptake showed a 36% difference between different anatomical locations after 72 h, but there was a strong interpatient variability. With aging, the drug uptake from the transdermal patch became slower and less potent. A 70-year-old patient received 26% less drug over the 72-h application period, compared to an 18-year-old patient. Additionally, a novel concept of using micron-sized drug reservoirs was explored in silico. These reservoirs induced a much higher local flux (µg cm -2 h -1 ) than conventional patches. Up to a 200-fold increase in the drug flux was obtained from these small reservoirs. This effect was mainly caused by transverse diffusion in the stratum corneum, which is not relevant for much larger conventional patches. These micronsized drug reservoirs open new ways to individualize reservoir design and thus transdermal therapy. Such computer-aided engineering tools also have great potential for in-silico design and precise control of drug delivery systems. Here, the validated mechanistic models can serve as a key building block for developing digital twins for transdermal drug delivery systems.

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“…To collect datasets of molecule-membrane interactions, a manual inspection of articles (15)(16)(17)(18)(19)(20)(21)(22)(23) and already existing databases (e.g., PerMM database (10)) with the focus on expressions like 'membrane partition coefficient', 'membrane permeability' or 'permeability coefficient' was performed ( Figure 1). Primarily, we focused on high-throughput experimental setups like Black Lipid Membrane (BLM) (24), Parallel Artificial Membrane Permeability Assay (PAMPA) (17,25), Caco-2 permeability assay (22), liposomal fluorescence assay (20), n-hexane passive dosing (26), and polydimethylsiloxane (PDMS) based permeabilities (19,27) that provide partition coefficients of compounds on a variety of natural and artificial membranes.…”

Section: Data Collectionmentioning

confidence: 99%

MolMeDB: Molecules on Membranes Database

Juračka

Šrejber

Melíková

et al. 2018

Preprint

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Biological membranes act as barriers or reservoirs for many compounds within the human body. As such, they play an important role in pharmacokinetics and pharmacodynamics of drugs and other molecular species. Until now, most membrane/drug interactions have been inferred from simple partitioning between octanol and water phases. However, the observed variability in membrane composition and among compounds themselves stretches beyond such simplification as there are multiple drug-membrane interactions. Numerous experimental and theoretical approaches are used to determine the molecule-membrane interactions with variable accuracy, but there is no open resource for their critical comparison. For this reason, we have built Molecules on Membranes Database (MolMeDB), which gathers data about over 3600 compound-membrane interactions including partitioning, penetration, and positioning. The data have been collected from scientific articles published in peer-reviewed journals and complemented by inhouse calculations from high-throughput COSMOmic approach to set up a baseline for further comparison. The data in MolMeDB are fully searchable and browsable by means of name, SMILES, membrane, method, or dataset and we offer the collected data openly for further reuse and we are open to further additions. MolMeDB can be a powerful tool that could help researchers better understand the role of membranes and to compare individual approaches used for the study of molecule/membrane interactions.Database URL: http://molmedb.upol.cz.

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Predicting drug permeability through skin using molecular dynamics simulation

Cited by 108 publications

References 62 publications

Coexistence of lipid phases stabilizes interstitial water in the outer layer of mammalian skin

Coexistence of lipid phases stabilizes interstitial water in the outer layer of mammalian skin

Predicting transdermal fentanyl delivery using mechanistic simulations for tailored therapy

MolMeDB: Molecules on Membranes Database

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