Multi-phase multi-layer mechanistic dermal absorption (MPML MechDermA) model to predict local and systemic exposure of drug products applied on skin.

Physiologically-based pharmacokinetic models combine knowledge about physiology, drug product properties, such as physicochemical parameters, absorption, distribution, metabolism, excretion characteristics, formulation attributes, and trial design or dosing regimen to mechanistically simulate drug pharmacokinetics (PK). The current work describes the development of a multiphase, multilayer mechanistic dermal absorption (MPML MechDermA) model within the Simcyp Simulator capable of simulating uptake and permeation of drugs through human skin following application of drug products to the skin. The model was designed to account for formulation characteristics as well as body site- and sex- population variability to predict local and systemic bioavailability. The present report outlines the structure and assumptions of the MPML MechDermA model and includes results from simulations comparing absorption at multiple body sites for two compounds, caffeine and benzoic acid, formulated as solutions. Finally, a model of the Feldene (piroxicam) topical gel, 0.5% was developed and assessed for its ability to predict both plasma and local skin concentrations when compared to in vivo PK data.

Foam drainage placed on a thin porous layer.

Drainage of foams placed on porous substrates has only recently been theoretically investigated (O. Arjmandi-Tash, N. Kovalchuk, A. Trybala, V. Starov, Foam Drainage Placed on a Porous Substrate, Soft Matter, 2015, 11(18), 3643-3652), where an equation describing foam drainage (with non-slip boundary conditions on the liquid-air interfaces) was combined with that of imbibition of liquid into the thick porous substrate. Foam-based applications have been used as a method of drug delivery, which is a recent and promising area of research related to application of medicinal products onto the skin or hair, which are both thin porous layers. A theory of foam drainage (taking into account surface viscosity) placed on a completely wettable thin porous layer is developed: the rate of foam drainage and imbibition inside the porous layer and other characteristics of the process are predicted. The "effective slip" caused by the surface viscosity increased a movement of the top boundary of the foam. The theoretical predictions are compared with experimental observations of foam drainage placed on thin porous layers. The comparison showed a reasonable agreement between the theoretical predictions and experimental observations. One of the phenomena during foam application is the possibility of a build-up of a free liquid layer on the foam/porous layer interface, which can be very useful for applications. Three different regimes of spreading/imbibition process have been predicted. Conditions and durations of free liquid layer formation have been theoretically predicted and compared with experimental observations.

Prediction and control of drop formation modes in microfluidic generation of double emulsions by single-step emulsification.

HYPOTHESIS: Predicting formation mode of double emulsion drops in microfluidic emulsification is crucial for controlling the drop size and morphology. EXPERIMENTS AND MODELLING: A three-phase Volume of Fluid-Continuum Surface Force (VOF-CSF) model was developed, validated with analytical solutions, and used to investigate drop formation in different regimes. Experimental investigations were done using a glue-free demountable glass capillary device with a true axisymmetric geometry, capable of readjusting the distance between the two inner capillaries during operation. FINDINGS: A non-dimensional parameter (ζ) for prediction of double emulsion formation mode as a function of the capillary numbers of all fluids and device geometry was developed and its critical values were determined using simulation and experimental data. At logζ>5.7, drops were formed in dripping mode; the widening jetting occurred at 5

Kinetics of Wetting and Spreading of Droplets over Various Substrates.

There has been a substantial increase in the number of publications in the field of wetting and spreading since 2010. This increase in the rate of publications can be attributed to the broader application of wetting phenomena in new areas. It is impossible to review such a huge number of publications; that is, some topics in the field of wetting and spreading are selected to be discussed below. These topics are as follows: (i) Contact angle hysteresis on smooth homogeneous solid surfaces via disjoining/conjoining pressure. It is shown that the hysteresis contact angles can be calculated via disjoining/conjoining pressure. The theory indicates that the equilibrium contact angle is closer to a static receding contact angle than to a static advancing contact angle. (ii) The wetting of deformable substrates, which is caused by surface forces action in the vicinity of the apparent three-phase contact line, leading to a deformation on the substrate. (iii) The kinetics of wetting and spreading of non-Newtonian liquid (blood) over porous substrates. We showed that in spite of the enormous complexity of blood, the spreading over porous substrate can be described using a relatively simple model: a power low-shear-thinning non-Newtonian liquid. (iv) The kinetics of spreading of surfactant solutions. In this part, new results related to various surfactant solution mixtures (synergy and crystallization) are discussed, which shows some possible direction for the future revealing of superspreading phenomena. (v) The kinetics of spreading of surfactant solutions over hair. Fundamental problems to be solved are identified.

Spreading of blood drops over dry porous substrate: complete wetting case.

HYPOTHESIS: The process of dried blood spot sampling involves simultaneous spreading and penetration of blood into a porous filter paper with subsequent evaporation and drying. Spreading of small drops of blood, which is a non-Newtonian liquid, over a dry porous layer is investigated from both theoretical and experimental points of view. EXPERIMENTS AND THEORY: A system of two differential equations is derived, which describes the time evolution of radii of both the drop base and the wetted region inside the porous medium. The system of equations does not include any fitting parameters. The predicted time evolutions of both radii are compared with experimental data published earlier. FINDINGS: For a given power law dependency of viscosity of blood with different hematocrit level, radii of both drop base and wetted region, and contact angle fell on three universal curves if appropriate scales are used with a plot of the dimensionless radii of the drop base and the wetted region inside the porous layer and dynamic contact angle on dimensionless time. The predicted theoretical relationships are three universal curves accounting satisfactorily for the experimental data.

Numerical investigation of pulsatile blood flow in a bifurcation model with a non-planar branch: the effect of different bifurcation angles and non-planar branch.

INTRODUCTION: Atherosclerosis is a focal disease that susceptibly forms near bifurcations, anastomotic joints, side branches, and curved vessels along the arterial tree. In this study, pulsatile blood flow in a bifurcation model with a non-planar branch is investigated. METHODS: Wall shear stress (WSS) distributions along generating lines on vessels for different bifurcation angles are calculated during the pulse cycle. RESULTS: The WSS at the outer side of the bifurcation plane vanishes especially for higher bifurcation angles but by increasing the bifurcation angle low WSS region squeezes. At the systolic phase there is a high possibility of formation of a separation region at the outer side of bifurcation plane for all the cases. WSS peaks exist on the inner side of bifurcation plane near the entry section of daughter vessels and these peaks drop as bifurcation angle is increased. CONCLUSION: It was found that non-planarity of the daughter vessel lowers the minimum WSS at the outer side of the bifurcation and increases the maximum WSS at the inner side. So it seems that the formation of atherosclerotic plaques at bifurcation region in direction of non-planar daughter vessel is more risky.

Simulation of blood flow coronary artery with consecutive stenosis and coronary-coronary bypass.

INTRODUCTION: In this research the behavior of coronary arteries has been studied with symmetric and asymmetric consecutive stenosis, and grafted vessels. METHODS: The incompressible Navier-Stokes and energy equations were discretized with second-order upwind method. Assumptions such as Newtonian fluid, wall rigidity and steady-flow were used. RESULTS: All the calculations showed the same results with Newtonians and non- Newtonian fluids. It was found that the possibility of stenosis be reduced by increasing the graft angle. However, there exists further stenosis possibility. Among the three graft angles 20, 30 ˚ and 40, the 30 ˚ was found to be the reliable ones. CONCLUSION: Based on these findings, it can be deduced that there would be a high risk of further atherosclerosis when the first stenose has the maximum percentage.

Possibility of atherosclerosis in an arterial bifurcation model.

INTRODUCTION: Arterial bifurcations are susceptible locations for formation of atherosclerotic plaques. In the present study, steady blood flow is investigated in a bifurcation model with a non-planar branch. METHODS: The influence of different bifurcation angles and non-planar branch is demonstrated on wall shear stress (WSS) distribution using three-dimensional Navier-Stokes equations. RESULTS: The WSS values are low in two locations at the top and bottom walls of the mother vessels just before the bifurcation, especially for higher bifurcation angles. These regions approach the apex of bifurcation with decreasing the bifurcation angle. The WSS magnitudes approach near to zero at the outer side of bifurcation plane and these locations are separation-prone. By increasing the bifurcation angle, the minimum WSS decreases at the outer side of bifurcation plane but low WSS region squeezes. WSS peaks exist on the inner side of bifurcation plane near the entry section of daughter vessels and these initial peaks drop as bifurcation angle is increased. CONCLUSION: It is concluded that the non-planarity of the daughter vessel lowers the minimum WSS at the outer side of bifurcation and increases the maximum WSS at the inner side. So it seems that the formation of atherosclerotic plaques at bifurcation region in direction of non-planar daughter vessel is more risky.