An in vitro skin penetration model for compromised skin: estimating penetration of polyethylene glycol [¹4C]-PEG-7 phosphate.

BACKGROUND/AIMS: Establishing dermal penetration rates is important to better understand the safety of topically applied materials, especially for premature infant skin with compromised skin barrier function. Skin prematurity involves thinner stratum corneum and underdeveloped epidermis/dermis resulting in decreased barrier function, higher transepidermal water loss and greater chemical penetration, when compared to healthy full-term neonate/adult skin. METHODS: We developed an in vitro skin penetration model using human ex vivo skin to estimate penetration for premature/compromised skin barrier conditions by tape stripping. Skin barrier deficiency was characterized by transepidermal water loss. Baby wipe lotion containing 5 mg/cm(2) [(14)C]-PEG-7 phosphate was applied 5 times to human skin samples of intact, moderately or highly compromised skin barrier and once at 25 mg/cm(2) over 24 h. RESULTS: Overall penetration of [(14)C]-PEG-7 phosphate was low (<5%) even for highly compromised skin. The absorption rate was higher (p < 0.001) for compromised skin versus intact skin. No significant difference was seen between moderately and highly compromised skin by repeated dosing. Under single-dose conditions, penetration through highly compromised skin was significantly higher compared to intact skin (p = 0.001). CONCLUSION: Our model demonstrates that even under highly compromised skin conditions, penetration of [(14)C]-PEG-7 phosphate is low (<5%) and only 4-6 times higher compared to mature/intact skin and does not approach 100%. Penetration was unaffected by single or multiple dosing conditions.

Effect of essential oils, hydrating agents, and ethanol on hair removal efficiency of thioglycolates.

BACKGROUND: The required time for hair removal by chemical depilatories has always been a concern and depends on different parameters including permeation into the hair shaft. OBJECTIVES: In an attempt to improve this process, it was decided here to investigate the possibility of decreasing depilation time of thioglycolates, widely used depilatories, using penetration enhancers. METHODS: Urea, sodium dodecyl sulfate, dimethylsulfoxide (DMSO), ethanol (75 and 96%), NaCl, and peppermint and orange oils were used as penetration enhancers, and their effect on depilatory time of thioglycolates, represented as tear resistance time (TRT) of hair shaft under a constant tensile stress, was studied. The effects of temperature and hydration on TRT were also investigated. RESULTS: Results showed that ethanol (75%), DMSO, and peppermint oil (ethanolic solution) were able to significantly reduce TRT up to two times from about 6 to 3.5 min. Other enhancers were not able to change TRT. Results also revealed that increase in temperature from 20 to 37 °C reduces TRT by about 4 times. Hydration in boiling water also reduced TRT significantly about 1.5 times. CONCLUSIONS: Present results show that it is possible to reduce depilation time by penetration enhancers. Such improvement can increase users' compliance and might provide other advantages like decreased skin irritation.

Measuring transepidermal water loss: a comparative in vivo study of condenser-chamber, unventilated-chamber and open-chamber systems.

BACKGROUND/AIMS: Two main systems have been utilized for measuring transepidermal water loss (TEWL): open chamber and closed chamber. Yet, further validation and standardization studies may be necessary to reveal the sensitivity, precision, and robustness of these instruments. METHODS: Three instruments are compared for their applicability to assess TEWL: unventilated chamber, open chamber and condenser chamber. The comparative study was performed on human forearm skin (n=6), in the normal condition (baseline), and after (1) 10 tape strippings on both arms, (2) moisturizer cream (Eucerin) and petrolatum application for 1 h, and (3) 1% sodium lauryl sulfate (SLS) aqueous solution and distilled water (as control) application for 20 min. RESULTS: The condenser-chamber system, was the only device among these three that could show the effect of tape stripping on TEWL values as compared with baseline (P<0.001). The effect of moisturization, in terms of % change of TEWL values after application of cream and petrolatum, did not show significant difference between devices (P>0.05). However, only the values obtained from condenser-chamber device revealed a highly significant change as compared with baseline (P<0.001). Condenser-chamber system could also discriminate between the effect of moisturizer and petrolatum on TEWL values (P<0.05). The change of TEWL values after SLS application was shown to be significant by unventilated and condenser-chamber systems (P<0.05). However, none of the devices differentiated between the effect of water and 1% SLS solution applied for 20 min. The values obtained from all three instruments correlate well with each other (P<0.001). CONCLUSION: Our results highlight the differences between two closed-chamber TEWL measurement instruments, which are designed based on different measurement principles. This may provide insights to find the best practice to improve the quality, precision and sensitivity of the measurements.

Measuring human skin buffering capacity: an in vitro model.

BACKGROUND/PURPOSE: It has been thought that skin possesses buffering capacity. This study measured the skin buffering capacity against two model solutions of acid and base at three concentrations with an in vitro system. METHODS: Ten microliters of model base (sodium hydroxide--NaOH) and acid (hydrochloric acid--HCl) solutions at concentrations of 0.025, 0.05, and 0.1 N was applied to human cadaver skin (3.18 microL/cm(2)) placed onto glass diffusion cells. Phosphate-buffered saline (PBS) was used as a standard buffer solution. Deionized water served as the negative control, whereas untreated skin served as the blank control. Skin pH was read and recorded immediately following dosing (0 time), and at 10 and 30 min of post-dosing. After the 30 min of dosing, each skin, except untreated skin (blank control), was then washed by applying 1 cm(3) of deionized water. The pH on each washed skin was measured immediately following washing, and the pH measurement was repeated at 10 and 30 min of post-washing. Six replicates were conducted. RESULTS: The pH values sharply significantly increased (P<0.05) immediately following dosing with NaOH at all concentrations (the highest concentration, caused the highest pH), and then decreased closely to baselines within 30 min post-application but still remained at significantly (P<0.05) higher values when compared with the blank control (untreated skin). HCl (acid) significantly (P<0.05) decreased skin pH immediately following dosing with all concentrations (the highest concentration, caused the lowest pH) and then restored rapidly to baseline. There was no significant difference in post-washing procedures on the skins that were pre-treated with the acid (HCI) solutions. However, with all base solutions (NaOH) pre-treated skin, pH values were significantly higher (P<0.05) at all time points post-washing. Furthermore, both PBS and water controls significantly elevated (P<0.05) the pH values following washing. CONCLUSION: Skin pH and its buffering capacity can be measured on human cadaver skin in vitro, which may partially replicate the response of in vivo skin. Dose-response was noted; i.e. the higher concentration caused larger changes in skin pH. In addition, the restoration of skin pH is relatively faster with acid when compared with base treatment. Clinical implications are offered.

Estimating skin permeability from physicochemical characteristics of drugs: a comparison between conventional models and an in vivo-based approach.

This study evaluates the correlation of some widely used skin permeability predictive models with a recently proposed empirical model based on human in vivo dermatopharmacokinetic data. Drug fluxes through the skin have been calculated using in vitro- and in vivo-based models, and observed in vivo data, and the values compared. Most in vitro-based models underestimate the in vivo data by 1-100-fold. The discrepancy between observed data and prediction reaches the maximum (1000-10,000-fold underestimation) for nicotine (with the smallest molecular weight and logK(oct)), nitroglycerin (with the largest number of hydrogen bond acceptor groups), and for oxybutynin (with the largest molecular weight and logK(oct)) where there was a 1000-fold flux overestimation. However, most models correlated well with the in vivo data and the in vivo-based model (p<0.05). The vehicle effect and using non-steady state in vivo data in the flux calculations partly account for the observed discrepancies between predicted and observed values. Nevertheless, these results reveal the need for further refinement of skin permeability predictive equations, using the steady state in vivo data, and consideration of formulation effect.

Correlating percutaneous absorption with physicochemical parameters in vivo in man: agricultural, steroid, and other organic compounds.

In vitro data are currently used to predict cutaneous chemical exposure based on physicochemical parameters. However, this in vitro data may not sufficiently account for what occurs in vivo. Previously, we modeled (via multivariate analysis) percutaneous absorption with physicochemical parameters using in vivo human transdermal patch-based data. In our current study, we correlated absorption data from three human in vivo data sets to physicochemical parameters. Most univariate and multivariate analyses did not provide satisfactory fits, and only steroids demonstrated significant relationships, where: (1) total percentge absorption inversely correlated with molecular weight and number of hydrogen bond acceptor groups on the molecule; and (2) maximal absorption rate inversely correlated with molecular weight, and number of hydrogen bond donor and acceptor groups on the molecule. For the most part, however, disparities exist between our previous results with transdermal patches and our current results with acetone as the solvent. Reasons for this discordance may include: drug-vehicle interactions, compound variability and endpoint differences. With such variability between in vivo human data, current in vitro predictive models should be critically scrutinized.

Cutaneous bioengineering instrumentation standardization: the Tissue Viability Imager.

BACKGROUND: Tissue Viability Imaging (TiVi) is a new bioengineering technology intended for remote two-dimensional mapping of skin red blood cell concentration (RBC(conc)). Before use in the laboratory, work-site and dermatology clinic, critical performance parameters of this emerging technology require careful evaluation. OBJECTIVE: To assess short- and long-term stability, image uniformity, distance and image size dependence, ambient light and curvature influence in a production batch of Tissue Viability Imagers. METHODS: Four Tissue Viability Imagers from the same production batch were evaluated at two laboratories (one industrial and one dermatological) with respect to critical parameter performance. RESULTS: The average systematic drift in sensitivity over time was 0.27% and <1.02% for all four units tested. Difference in sensitivity between units was limited to 4.1% and was due to offset rather than gain deviation. Spatial variation in image uniformity was below 3.08% and 1.93% in the corners and centre of an individual image, respectively. This spatial variation could be further reduced to 0.25% and 0.13%, respectively by image normalization. Ambient light from a 40 W bulb or a 11 W fluorescent light source at a distance of 50-60 cm above the object, reduced the recorded values by about 10%, while the camera to object distance and image size had no detectable influence on sensitivity. Curved objects, such as human forearm, demonstrated an edge effect limited to below 10%. CONCLUSION: The critical TiVi performance parameters evaluated proved stable in relation to expected variations in skin RBC(conc) over time. Calibration by way of a two-point method may reduce differences in sensitivity between instruments to further facilitate inter-laboratory comparison of results.

Tissue viability imaging: mapping skin erythema.

BACKGROUND: Tissue Viability Imaging (TiVi) is an emerging bioengineering technology intended for two-dimensional mapping of skin erythema and blanching. Before TiVi can be effectively used in studies of diseased or damaged skin, the variability in normal skin red blood cell concentration (RBC(conc)) requires evaluation. OBJECTIVE: To demonstrate how TiVi maps spatial and temporal variations in normal skin RBC(conc) at the dorsal side of the hand at rest and during post-occlusive hyperemia. METHODS: Short-term and day-to-day variations in skin RBC(conc) were quantified at the dorsal side of the hand in four healthy volunteers at rest. In a separate study, the increase in skin RBC(conc) was recorded during post-occlusive hyperemia. RESULTS: A lower skin RBC(conc) (179-184 TiVi units) was observed at the back of the hand and base of the thumb compared with areas adjacent to the nailfoldfold region of the fingers (190-213 TiVi units). The short-term variation (within 70 s) was <2% in all areas of the dorsal side of the hand, while day-to-day variations were in the range 5-7% in the back of the hand and up to 10% in areas adjacent to the nailfold region. In the post-occlusive hyperemia phase, up to a 60% increase in skin RBC(conc) was observed in the early part of the reactive hyperemia phase. This increase in skin RBC(conc) successively decreased but remained about 18% above the pre-occlusion level after 30 min. CONCLUSION: Establishment of healthy skin RBC(conc) reference values is important for the design of versatile test procedures for assessment of skin damage caused by vibration tools, chemical exposure or peripheral vascular disease.

Comparison of tissue viability imaging and colorimetry: skin blanching.

BACKGROUND: Operator-independent assessment of skin blanching is important in the development and evaluation of topically applied steroids. Spectroscopic instruments based on hand-held probes, however, include elements of operator dependence such as difference in applied pressure and probe misalignment, while laser Doppler-based methods are better suited for demonstration of skin vasodilatation than for vasoconstriction. OBJECTIVE: To demonstrate the potential of the emerging technology of Tissue Viability Imaging (TiVi) in the objective and operator-independent assessment of skin blanching. METHODS: The WheelsBridge TiVi600 Tissue Viability Imager was used for quantification of human skin blanching with the Minolta chromameter CR 200 as an independent colorimeter reference method. Desoximetasone gel 0.05% was applied topically on the volar side of the forearm under occlusion for 6 h in four healthy adults. In a separate study, the induction of blanching in the occlusion phase was mapped using a transparent occlusion cover. RESULTS: The relative uncertainty in the blanching estimate produced by the Tissue Viability Imager was about 5% and similar to that of the chromameter operated by a single user and taking the a(*) parameter as a measure of blanching. Estimation of skin blanching could also be performed in the presence of a transient paradoxical erythema, using the integrated TiVi software. The successive induction of skin blanching during the occlusion phase could readily be mapped by the Tissue Viability Imager. CONCLUSION: TiVi seems to be suitable for operator-independent and remote mapping of human skin blanching, eliminating the main disadvantages of methods based on hand-held probes.

Transdermal drug pharmacokinetics in man: Interindividual variability and partial prediction.

A database of human dermatopharmacokinetic parameters of 12 transdermal patches is established. The effect of system design, application site, and metabolism on pharmacokinetic data is discussed, and interindividual variability of data and its possible sources evaluated. Using multiple regression analysis, two equations based on drugs physicochemical characteristics are suggested for partial prediction of peak plasma concentration (C(max)) after patch application. Patch application presumably decreases variance as rub-off, wash and exfoliation steps are diminished. The results showed that interindividual variation, in terms of coefficient of variation (CV) of C(max), is inversely correlated with drugs molecular weight and lipophilicity in the range of 200