Molecular size as the main determinant of solute maximum flux across the skin

One of the most important determinants of dermatological and systemic penetration after topical application is the delivery or flux of solutes into or through the skin. The maximum dose of solute able to be delivered over a given period of time and area of application is defined by its maximum flux (J(max), mol per cm(2) per h) from a given vehicle. In this work, J(max) values from aqueous solution across human skin were acquired or estimated from experimental data and correlated with solute physicochemical properties. Whereas epidermal permeability coefficients (k(p)) are optimally correlated to solute octanol-water partition coefficient (K-ow) and molecular weight (MW) was found to be the dominant determinant of J(max) for this literature data set: log J(max)=-3.90-0.0190MW (n=87, r(2)=0.847, p

Percutaneous absorption of steroids: Determination of in vitro permeability and tissue reservoir characteristics in human skin layers

The skin localization of steroids following topical application is largely unknown. We determined the distribution of five steroids in human skin using excised epidermal, dermal, and full-thickness membranes in vitro. There was no significant difference in steroid maximum flux through epidermal and full-thickness membranes, other than significantly lower fluxes for the most polar steroid, aldosterone. Hydrocortisone had the highest dermal diffusivity and dermal penetration, and the accumulation of hydrocortisone and corticosterone was higher than that of the other steroids. Slower penetration and higher accumulation in the viable epidermis of progesterone in full-thickness skin were consistent with dermal penetration limitation effects associated with high lipophilicity. Copyright (c) 2006 S. Karger AG, Basel

Effects of vehicle and region of application on absorption of hydrocortisone through canine skin

Objective-To determine the effects of various vehicles on the penetration and retention of hydrocortisone applied to canine skin. Sample Population-20 canine skin samples obtained from the thorax, neck, and groin regions of 5 Greyhounds. Procedure-Skin was harvested from dogs after euthanasia and stored at -20 degrees C until required. The skin was then defrosted and placed into diffusion cells, which were maintained at approximately 32 degrees C by a water bath. Saturated solutions of hydrocortisone that contained trace amounts of radiolabelled [C-14]-hydrocortisone in each vehicle (ie, PBS solution [PBSS] alone, 50% ethanol [EtOH] in PBSS [wt/wt], and 50% propylene glycol in PBSS [wt/wt]) were applied to the outer (stratum corneum) surface of each skin sample, and aliquots of receptor fluid were collected for 24 hours and analyzed for hydrocortisone. Results-The maximum flux of hydrocortisone was significantly higher for all sites when dissolved in a vehicle containing 50% EtOH, compared with PBSS alone or 50% propylene glycol, with differences more prominent in skin from the neck region. In contrast, higher residues of hydrocortisone were found remaining within the skin when PBSS alone was used as a vehicle, particularly in skin from the thorax and neck. Conclusions and Clinical Relevance-Penetration of topically applied hydrocortisone is enhanced when EtOH is used in vehicle formulation. Significant regional differences (ie, among the thorax, neck, and groin areas) are also found in the transdermal penetration and skin retention of hydrocortisone. Variability in clinical response to hydrocortisone can be expected in relation to formulation design and site of application.

Vehicle effects on the in vitro penetration of testosterone through equine skin

The effects of three vehicles, phosphate-buffered saline (PBS), ethanol (50% in PBS w/w) and propylene glycol (50% in PBS w/w) on in vitro transdermal penetration of testosterone was investigated in the horse. Skin was harvested from the thorax of five Thoroughbred horses after euthanasia and stored at -20 degrees C until required. The skin was then defrosted and placed into Franz-type diffusion cells, which were maintained at approximately 32 degrees C by a water bath. Saturated solutions of testosterone, containing trace amounts of radiolabelled [C-14]testosterone, in each vehicle were applied to the outer (stratum corneum) surface of each skin sample and aliquots of receptor fluid were collected at 0, 2, 4, 8, 16, 20, 22 and 24 h and analysed for testosterone by scintillation counting. The maximum flux (J(max)) of testosterone was significantly higher for all sites when testosterone was dissolved in a vehicle containing 50% ethanol or 50% propylene glycol, compared to PBS. In contrast, higher residues of testosterone were found remaining within the skin when PBS was used as a vehicle. This study shows that variability in clinical response to testosterone could be expected with formulation design.

Particle flux in the NE Atlantic as recorded by sediment traps

Downward particle flux was measured using sediment traps at various depths over the Porcupine Abyssal Plain (water depth ab. 4850 m) for prolonged periods from 1989 to 1999. A strong seasonal pattern of flux was evident reaching a maximum in mid-summer. The composition of the material changed with depth, reflecting the processes of remineralisation and dissolution as the material sank through the water column. However, there was surprisingly little seasonal variation in its composition to reflect changes in the biology of the euphotic zone. Currents at the site have a strong tidal component with speeds almost always less than 15 cm/sec. In the deeper part of the water column they tend to be northerly in direction, when averaged over periods of several months. A model of upper ocean biogeochemistry forced by meteorology was run for the decade in order to provide an estimate of flux at 3000 m depth. Agreement with measured organic carbon flux is good, both in terms of the timings of the annual peaks and in the integrated annual flux. Interannual variations in the integrated flux are of similar magnitude for both the model output and sediment trap measurements, but there is no significant relationship between these two sets of estimates. No long-term trend in flux is evident, either from the model, or from the measurements. During two spring/summer periods, the marine snow concentration in the water column was assessed by time-lapse photography and showed a strong peak at the start of the downward pulse of material at 3000 m. This emphasises the importance of large particles during periods of maximum flux and at the start of flux peaks. Time lapse photographs of the seabed show a seasonal cycle of coverage of phytodetrital material, in agreement with the model output both in terms of timing and magnitude of coverage prior to 1996. However, after a change in the structure of the benthic community in 1996 no phytodetritus was evident on the seabed. The model output shows only a single peak in flux each year, whereas the measured data usually indicated a double peak. It is concluded that the observed double peak may be a reflection of lowered sediment trap efficiency when flux is very high and is dominated by large marine snow particles. Resuspension into the trap 100 m above the seabed, when compared to the primary flux at 3000 m depth (1800 mab) was lower during periods of high primary flux probably because of a reduction in the height of resuspension when the material is fresh. At 2 mab, the picture is more complex with resuspension being enhanced during the periods of higher flux in 1997, which is consistent with this hypothesis. However there was rather little relationship to flux at 3000 m in 1998. At 3000 m depth, the Flux Stability Index (FSI), which provides a measure of the constancy of the seasonal cycle of flux, exhibited an inverse relationship with flux, such that the highest flux of organic carbon was recorded during the year with the greatest seasonal variation.

Diffusion modeling of percutaneous absorption kinetics: 2. Finite vehicle volume and solvent deposited solids

The diffusion model for percutaneous absorption is developed for the specific case of delivery to the skin being limited by the application of a finite amount of solute. Two cases are considered; in the first, there is an application of a finite donor (vehicle) volume, and in the second, there are solvent-deposited solids and a thin vehicle with a high partition coefficient. In both cases, the potential effect of an interfacial resistance at the stratum corneum surface is also considered. As in the previous paper, which was concerned with the application of a constant donor concentration, clearance limitations due to the viable eqidermis, the in vitro sampling rate, or perfusion rate in vivo are included. Numerical inversion of the Laplace domain solutions was used for simulations of solute flux and cumulative amount absorbed and to model specific examples of percutaneous absorption of solvent-deposited solids. It was concluded that numerical inversions of the Laplace domain solutions for a diffusion model of the percutaneous absorption, using standard scientific software (such as SCIENTIST, MicroMath Scientific software) on modern personal computers, is a practical alternative to computation of infinite series solutions. Limits of the Laplace domain solutions were used to define the moments of the flux-time profiles for finite donor volumes and the slope of the terminal log flux-time profile. The mean transit time could be related to the diffusion time through stratum corneum, viable epidermal, and donor diffusion layer resistances and clearance from the receptor phase. Approximate expressions for the time to reach maximum flux (peak time) and maximum flux were also derived. The model was then validated using reported amount-time and flux-time profiles for finite doses applied to the skin. It was concluded that for very small donor phase volume or for very large stratum corneum-vehicle partitioning coefficients (e.g., for solvent deposited solids), the flux and amount of solute absorbed are affected by receptor conditions to a lesser extent than is obvious for a constant donor constant donor concentrations. (C) 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:504-520, 2001.

Determination of the effect of lipophilicity on the in vitro permeability and tissue reservoir characteristics of topically applied solutes in human skin layers

In order to establish the relationship between solute lipophilicity and skin penetration (including flux and concentration behavior), we examined the in vitro penetration and membrane concentration of a series of homologous alcohols (C2-C10) applied topically in aqueous solutions to human epidermal, full-thickness, and dermal membranes. The partitioning/distribution of each alcohol between the donor solution, stratum corneum, viable epidermis, dermis, and receptor phase compartments was determined during the penetration process and separately to isolated samples of each tissue type. Maximum flux and permeability coefficients are compared for each membrane and estimates of alcohol diffusivity are made based on flux/concentration data and also the related tissue resistance (the reciprocal of permeability coefficient) for each membrane type. The permeability coefficient increased with increasing lipophilicity to alcohol C8 (octanol) with no further increase for C10 (decanol). Log vehicle:stratum corneum partition coefficients were related to logP , and the concentration of alcohols in each of the tissue layers appeared to increase with lipophilicity. No difference was measured in the diffusivity of smaller more polar alcohols in the three membranes; however, the larger more lipophilic solutes showed slower diffusivity values. The study showed that the dermis may be a much more lipophilic environment than originally believed and that distribution of smaller nonionized solutes into local tissues below a site of topical application may be estimated based on knowledge of their lipophilicity alone.

Effect of solute lipophilicity on penetration through canine skin

Objective To investigate the effect of lipophilicity on the percutaneous penetration of a homologous series of alcohols through canine skin Design Skin harvested from Greyhound thorax was placed in Franz-type diffusion cells and the in vitro passage of radio-labelled (C-14) alcohols (ethanol, butanol, hexanol and octanol (Log P 0.19 - 3.0)) through separate skin sections was measured in replicates of five. Permeability coefficient (k(P), cm/h), maximum flux (J(max), mol/cm(2)/h) and residue remaining within the skin were determined. Results The k(P) increased with increasing lipophilicity (6.2 x 10(-4) +/- 1.6 x 10(-4) cm/h for ethanol to 1.8 x 10(-2) 3.6 x 10(-3) cm/h for octanol). Alcohol residues remaining within each skin sample followed a similar pattern. An exponential decrease in Jmax with increasing lipophilicity was observed. Conclusion Changes in canine skin permeability occur with increasing alcohol lipophilicity. This finding has practical consequences for the design of topical formulations and optimisation of drug delivery through animal skin.

The free escape continuum of diffuse ions upstream of the Earth's quasi-parallel bow shock

The Earth's bow shock is very efficient in accelerating ions out of the incident solar wind distribution to high energies (≈ 200 keV/e). Fluxes of energetic ions accelerated at the quasi-parallel bow shock, also known as diffuse ions, are best represented by exponential spectra in energy/charge, which require additional assumptions to be incorporated into these model spectra. One of these assumptions is a so-called "free escape boundary" along the interplanetary magnetic field into the upstream direction. Locations along the IBEX orbit are ideally suited for in situ measurements to investigate the existence of an upstream free escape boundary for bow shock accelerated ions. In this study we use 2 years of ion measurements from the background monitor on the IBEX spacecraft, supported by ACE solar wind observations. The IBEX Background Monitor is sensitive to protons > 14 keV, which includes the energy of the maximum flux for diffuse ions. With increasing distance from the bow shock along the interplanetary magnetic field, the count rates for diffuse ions stay constant for ions streaming away from the bow shock, while count rates for diffuse ions streaming toward the shock gradually decrease from a maximum value to ~1/e at distances of about 10 RE to 14 RE. These observations of a gradual decrease support the transition to a free escape continuum for ions of energy >14 keV at distances from 10 RE to 14 RE from the bow shock.

Comparison of 3D kinetic and hydrodynamic models to ROSINA-COPS measurements of the neutral coma of 67P/Churyumov-Gerasimenko

67P/Churyumov-Gerasimenko (67P) is a Jupiter-family comet and the object of investigation of the European Space Agency mission Rosetta. This report presents the first full 3D simulation results of 67P’s neutral gas coma. In this study we include results from a direct simulation Monte Carlo method, a hydrodynamic code, and a purely geometric calculation which computes the total illuminated surface area on the nucleus. All models include the triangulated 3D shape model of 67P as well as realistic illumination and shadowing conditions. The basic concept is the assumption that these illumination conditions on the nucleus are the main driver for the gas activity of the comet. As a consequence, the total production rate of 67P varies as a function of solar insolation. The best agreement between the model and the data is achieved when gas fluxes on the night side are in the range of 7% to 10% of the maximum flux, accounting for contributions from the most volatile components. To validate the output of our numerical simulations we compare the results of all three models to in situ gas number density measurements from the ROSINA COPS instrument. We are able to reproduce the overall features of these local neutral number density measurements of ROSINA COPS for the time period between early August 2014 and January 1 2015 with all three models. Some details in the measurements are not reproduced and warrant further investigation and refinement of the models. However, the overall assumption that illumination conditions on the nucleus are at least an important driver of the gas activity is validated by the models. According to our simulation results we find the total production rate of 67P to be constant between August and November 2014 with a value of about 1 × 10²⁶ molecules s⁻¹.

Partial pressure of carbon dioxide along the Transatlantic section from 7 November till 19 December 2000

Along a transatlantic section from 57°N to 60°S that was carried out from November 7 till December 19, 2000 on board R/V Horizont II concentrations of CO2 were measured in the near-water layer of the air and differences between partial pressures in water and air in various climatic zones were calculated. It was shown that variations of CO2 concentrations in the near-water layer of air and those of values of water-air partial pressure difference were from 324x10**-6 to 426x10**-6 and from 150x10**-6 to 100x10**-6 atm, respectively. Maximum value of CO2 partial pressure in air in the near-water layer (426x10**-6 atm) was noted at 45°-47°N; minimum of 324x10**-6 atm was found in Antarctica at 59°S. During measurenents maximum value of CO2 partial pressure difference in water and air (150 x10**-6) was observed at 45°-48°N; maximum flux in this case was directed from the atmosphere to water. Maximum value of CO2 partial pressure difference in water and air for flux directed from the ocean to air (100 x10**-6) was observed at 59°-60°S. Comparison of calculated values of partial pressure difference in water and air with previous data points to more intense exchange of CO2 between the ocean and atmosphere during the survey period was considered. According to values of CO2 partial pressure difference in air and water as compared to 1975, exchange intensity in the Northern Hemisphere (absorption from the atmosphere) increased. A well-pronounced latitudinal effect of distribution of CO2 partial pressure in air was observed. Along the route variations in CO2 concentrations in zones of water divergence and convergence were registered.

Quasi-cylindrical approximation to the swirling flow in an atomizer chamber

A quasi-cylindrical approximation is used to analyse the axisymmetric swirling flow of a liquid with a hollow air core in the chamber of a pressure swirl atomizer. The liquid is injected into the chamber with an azimuthal velocity component through a number of slots at the periphery of one end of the chamber, and flows out as an anular sheet through a central orifice at the other end, following a conical convergence of the chamber wall. An effective inlet condition is used to model the effects of the slots and the boundary layer that develops at the nearby endwall of the chamber. An analysis is presented of the structure of the liquid sheet at the end of the exit orifice, where the flow becomes critical in the sense that upstream propagation of long-wave perturbations ceases to be possible. This nalysis leads to a boundary condition at the end of the orifice that is an extension of the condition of maximum flux used with irrotational models of the flow. As is well known, the radial pressure gradient induced by the swirling flow in the bulk of the chamber causes the overpressure that drives the liquid towards the exit orifice, and also leads to Ekman pumping in the boundary layers of reduced azimuthal velocity at the convergent wall of the chamber and at the wall opposite to the exit orifice. The numerical results confirm the important role played by the boundary layers. They make the thickness of the liquid sheet at the end of the orifice larger than predicted by rrotational models, and at the same time tend to decrease the overpressure required to pass a given flow rate through the chamber, because the large axial velocity in the boundary layers takes care of part of the flow rate. The thickness of the boundary layers increases when the atomizer constant (the inverse of a swirl number, proportional to the flow rate scaled with the radius of the exit orifice and the circulation around the air core) decreases. A minimum value of this parameter is found below which the layer of reduced azimuthal velocity around the air core prevents the pressure from increasing and steadily driving the flow through the exit orifice. The effects of other parameters not accounted for by irrotational models are also analysed in terms of their influence on the boundary layers.

Fresnel-based modular solar fields for performance/cost optimization in solar thermal power plants: A comparison with parabolic trough collectors.

Linear Fresnel collectors are identified as a technology that should play a main role in order to reduce cost of Concentrating Solar Power. An optical and thermal analysis of the different blocks of the solar power plant is carried out, where Fresnel arrays are compared with the most extended linear technology: parabolic trough collectors. It is demonstrated that the optical performance of Fresnel array is very close to that of PTC, with similar values of maximum flux intensities. In addition, if the heat carrier fluid flows in series by the tubes of the receiver, relatively high thermal efficiencies are achieved. Thus, an annual solar to electricity efficiency of 19% is expected, which is similar to the state of the art in PTCs; this is done with a reduction of costs, thanks to lighter structures, that drives to an estimation of LCOE of around 6.5 c€/kWh.

The effect of region of application on absorption of ethanol and hexanol through canine skin

The effect of region of application on the percutaneous penetration of solutes with differing lipophilicity was investigated in canine skin. Skin from the thorax, neck, back, groin, and axilla regions was harvested from Greyhound dogs and placed in Franz-type diffusion cells. Radiolabelled (C-14) ethanol (Log P 0.19) or hexanol (Log P 1.94) was applied to each skin section for a total of 5 h. The permeability coefficient (k(P), cm h(-1)) and residue of alcohol remaining in the skin were significantly (P = 0.001) higher for hexanol compared to ethanol. In contrast, ethanol had a far greater maximum flux (J(max), mol (cm(2))(-1) h(-1)) than hexanol (P = 0.001). A comparison of regional differences shows the k(P) and Jmax for ethanol in the groin was significantly lower (P = 0.035) than the back. The k(P) and Jmax for hexanol were significantly higher (P = 0.001) in the axilla than the other four skin sites. An understanding of factors influencing percutaneous drug movement is important when formulating topical preparations for the dog. (C) 2003 Elsevier Ltd. All rights reserved.

Regional differences in the in vitro penetration of hydrocortisone through equine skin

Little is known about the transdermal penetration of hydrocortisone in the horse and, although commercial formulations containing hydrocortisone are registered for topical use in the horse, there have been no studies investigating the movement of this glucocorticoid through different regions of equine skin. Skin was harvested from the thorax, groin and leg (dorsal metacarpal) regions of five Thoroughbred geldings and frozen (-20 degrees C) until required. Defrosted skin was placed in Franz-type diffusion cells and the amount of radiolabelled (H-3) hydrocortisone, in a saturated solution of unlabelled hydrocortisone in 50% ethanol (w/w), which penetrated through and remained within skin samples was measured over 24 h. Significantly higher (P < 0.001) maximum flux (J(max); mol/cm(2)/h) was measured when hydrocortisone was applied to skin from the leg, compared to thorax and groin, although significantly less hydrocortisone (P < 0.001) was retained within skin from the leg at 24 h. Topical application of hydrocortisone in a vehicle containing ethanol would penetrate faster through leg skin from the lower leg when compared with the thorax or groin, which depending on cutaneous blood flow, may result in higher systemic drug concentrations or greater efficiency in treating local inflamed tissue.