Physiologically based mathematical modelling of solute transport within the epidermis and dermis

Calcutt, Joshua J.; Anissimov, Yuri German

doi:10.1016/j.ijpharm.2019.118547

Cited by 10 publications

(22 citation statements)

References 40 publications

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“…This work showed that convection could dominate axial dermal and deeper tissue transport for the highly plasma protein bound corticosteroids (3) and non-steroidal anti-inflammatory drugs (4). However, dermal capillary loops should also be considered in optimising viable skin modelling as we and others have shown using capillary models (1,2,7). In particular, we found that convectional transport in the dermal capillaries has a profound effect on the time course of dermal drug concentrations, including the time taken to reach a steady state concentration (1).…”

Section: Introductionmentioning

confidence: 54%

“…While systemic toxicity in this case is determined by the flux of the substance though the skin into the systemic circulation, and is relatively well studied, the skin toxicity after topical application depends on the substance concentration at reactive skin sites. This concentration, in turn, is dependent on the flux of solute through the stratum corneum, clearance from those sites and, where the target site is the superficial dermis, drug transport in the dermal tissues (1)(2)(3)(4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

“…In this paper, we applied our previously published COM-SOL based detailed computational models (1,2) to develop the more sophisticated and realistic physiological representation of dermal transport described in this paper. Here, we refine the modelling of the dermal capillary network to account for a highly anastomotic network of blood vessels in the superficial dermis, the subpapillary plexus.…”

Section: Introductionmentioning

confidence: 99%

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Predicting Viable Skin Concentration: Modelling the Subpapillary Plexus

2022

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The skin concentration of a substance after a topical application or exposure determines both local treatment outcomes and the dermal toxicity assessment of various products. However, quantifying the time course of those concentrations at skin effect sites, such as the viable epidermal, superficial dermis and appendages in humans is especially problematic in vivo, making physiologically based mathematical modelling an essential tool to meet this need. This work further develops our published physiologically based pharmacokinetic and COMSOL based dermal transport modelling by considering the impact of the superficial subpapillary dermal plexus, which we represent as two well stirred compartments. The work also studied the impact on dermal concentrations of subpapillary plexus size, depth, blood velocity and density of subpapillary plexus vessels. Sensitivity analyses are used to define the most important transport determinants of skin concentrations after topical application of a substance, with previously published results used to validate the resulting analyses. This resulting model describes the available experimental data better than previous models, especially at deeper dermal depths.

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Section: Introductionmentioning

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Predicting Viable Skin Concentration: Modelling the Subpapillary Plexus

2022

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“…The dermis could also play a role in drug transport and drug retention during transdermal delivery [50]. Previous works modeled the dermis (1) as an additional depot in which drugs can be stored [51]; (2) as an additional layer in which only diffusion and no drug removal by the blood flow was modeled [52]; (3) by adding a sink condition to the system [53]; (4) by modeling simplified capillary loops in the dermis [54]. An even more realistic model of dermis would require modeling the patient's blood flow since capillaries and vessels are present in the papillary and reticular dermis, respectively.…”

Section: Figure 2 3d and 1d Geometrical Models Of Square-shaped Drugmentioning

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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“…The dermis could also play a role in drug transport and drug retention during transdermal delivery (Menczel and Maibach, 1970). Previous works modeled the dermis 1) as an additional depot in which drugs can be stored (Heikkinen et al, 2015); 2) as an additional layer in which only diffusion and no drug removal by the blood flow was modeled (Manitz et al, 1998); 3) by adding a sink condition to the system (Grassi et al, 2011); 4) by modeling simplified capillary loops in the dermis (Calcutt and Anissimov, 2019). An even more realistic model of dermis would require modeling the patient's blood flow since capillaries and vessels are present in the papillary and reticular dermis, respectively.…”

Section: Continuum Model For Transdermal Fentanyl Deliverymentioning

confidence: 99%

Predicting Transdermal Fentanyl Delivery Using Mechanistic Simulations for Tailored Therapy

et al. 2020

View full text Add to dashboard Cite

Transdermal drug delivery is a key technology for administering drugs. However, most devices are "one-size-fits-all", even though drug diffusion through the skin varies significantly from person-to-person. For next-generation 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 micron-sized 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.

show abstract

Physiologically based mathematical modelling of solute transport within the epidermis and dermis

Cited by 10 publications

References 40 publications

Predicting Viable Skin Concentration: Modelling the Subpapillary Plexus

Predicting Viable Skin Concentration: Modelling the Subpapillary Plexus

Predicting transdermal fentanyl delivery using mechanistic simulations for tailored therapy

Predicting Transdermal Fentanyl Delivery Using Mechanistic Simulations for Tailored Therapy

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