Measurement, analysis and prediction of topical UV filter bioavailability.

The aim of the present study was to objectively quantify and predict bioavailability of three sunscreen agents (i.e., benzophenone-3, 2-ethylhexylsalicylate, and 2 ethylhexyl-4-methoxycinnamate) in epidermis treated by petrolatum and emulsion-based formulations for 7 and 30min on four human volunteers. Profiles of sunscreen agents through stratum corneum (SC), derived from the assessment of chemical amounts in SC layers collected by successive adhesive tape-stripping, were successfully fitted to Fick's second law of diffusion. Therefore, permeability coefficients of sunscreen agents were found lower with petrolatum than with emulsion based formulations confirming the crucial role of vehicle in topical delivery. Furthermore, the robustness of that methodology was confirmed by the linear relationship between the chemical absorption measured after 30min and that predicted from the 7-min exposure experiment. Interestingly, in this dermatopharmacokinetic method, the deconvolution of permeability coefficients in their respective partition coefficients and absorption constants allowed a better understanding of vehicle effects upon topical bioavailability mechanisms and bioequivalence of skin products.

Removal of internally deposited gold by 2,3-dimercaptopropane sodium sulphonate (Dimaval).

1 Orally administered 2,3-dimercaptopropane sodium sulphonate (DMPS, Dimaval) reduced the concentration of gold in rats treated with Auro-Detoxin and increased the urinary excretion of the metal. 2 In a long-term experiment, DMPS decreased significantly the concentration of gold in the kidneys and in the skin and increased it in plasma. 3 DMPS appears to be of interest as a possible antidote to gold, which could replace the more toxic 2,3-dimercaptopropanol (BAL).

There is no influence of a temperature rise on in vivo adsorption of UV filters into the stratum corneum.

Temperature influences the stratum corneum adsorption of several topically applied compounds. This study was designed to evaluate the influence of the temperature on the stratum corneum adsorption of 3 UV filters. The UV filters were solubilized in two vehicles, an emulsion gel and petroleum jelly and applied at respectively, 31 and 40 degrees C during 30 min. In vivo stratum corneum UV filter content was measured using the tape stripping method. Similar amounts of UV filter were detected in the stratum corneum when comparing applications at the different temperatures. Application of the UV filters in the emulsion gel resulted in higher stratum corneum UV filter concentrations compared with application in the petroleum jelly. The application temperature did not influence the stratum corneum adsorption of the tested UV filters while the nature of the vehicle significantly influenced the amount of UV filters recovered from the stratum corneum.

Photostabilization of butyl methoxydibenzoylmethane (Avobenzone) and ethylhexyl methoxycinnamate by bis-ethylhexyloxyphenol methoxyphenyl triazine (Tinosorb S), a new UV broadband filter.

It is now well documented that chronic UVA exposure induces damage to human skin. Therefore, modern sunscreens should not only provide protection from both UVB and UVA radiation but also maintain this protection during the entire period of exposure to the sun. UVA filters, however, are rare and not sufficiently photostable. We investigated the effect of the introduction of a new UV filter, bis-ethylhexyloxyphenol methoxyphenyl triazine (Tinosorb S), in oil in water sunscreen formulations on the photostability of butyl methoxydibenzoylmethane (Avobenzone [AVB]) after irradiation with an optically filtered Xenon arc source (UV irradiance adjusted at 1 mean effective dose [MED]/min). With spectrophotometrical methods to assess the sun protection factor (SPF) and UVA ratio and chromatographical methods to determine the amount of UV filters recovered after irradiation we showed that Tinosorb S prevented the photodegradation of AVB in a concentration-dependent way, leading to a sustained SPF and UVA ratio even after irradiation with doses of up to 30 MED. Since AVB was shown to destabilize ethylhexyl methoxycinnamate (EHM) we tested the effect of Tinosorb S in sunscreens containing this UV filter combination. Here too Tinosorb S showed photoprotective properties toward both UV filters. Thus, Tinosorb S can be used successfully to improve the photostability and efficiency of sunscreens containing AVB and EHM.

The excretion of trace elements in rat urine after treatment with 2,3-dimercaptopropane sodium sulfonate.

Administration of various doses of the chelating agent 2,3-dimercaptopropane sodium sulfonate (Dimaval, DMPS) leads to a greatly enhanced excretion of Zn and Cu. The excretion of Co, Mn, Ni and Fe remains unchanged. The relevance of these findings to the toxicity of DMPS is discussed.

Stratum corneum dynamic function measurements after moisturizer or irritant application.

Two simple tests were conducted which allowed the quantification of parameters that characterize the stratum corneum (SC) dynamic functions in vivo under physiological conditions after moisturizer applications for 1 h and after irritation with different concentrations of sodium lauryl sulphate (SLS; 0.5-4%) applied under occlusion for 15 min or 24 h. Both tests, the sorption-desorption test (SDT) and the moisture accumulation test (MAT), were performed with a Nova Dermal Phase Meter 9003. The following parameters were quantified: prehydration state (SDT, MAT), hygroscopicity, water-holding capacity (SDT), water accumulation velocity and water accumulation (MAT). These procedures allowed the demonstration of the water-holding effect of urea contained in moisturizers. Differences between the long and the short application time of SLS were characterized by differences in SC dynamic functions while the hydration state was not changed. An effect on transepidermal water loss (TEWL) was noted only after the long application time, although the MAT clearly showed dynamic parameters to be changed after 15 min of treatment. These tests were simple in practice and allowed the demonstration of functional modifications of the SC while other parameters remained unchanged. They gave insight into possible action mechanisms of urea and SLS in the SC.

Distribution and excretion of the mercury chelating agent sodium 2,3-dimercaptopropane-1-sulfonate in the rat.

The distribution and excretion of sodium 2,3-dimercapto-1,3 14C-propane-1-sulfonate as dependent on time has been studied in the rat. The highest concentration is found in the kidneys, the lowest in the brain. The excretion is very rapid (T1/2 = 19 min) and follows a monoexponential curve during the first hour after administration. This holds for plasma and most of the organs too. The apparent distribution volume of the radioactivity is equivalent to the volume of the extracellular water. After oral administration, 30-40% is absorbed from the gut. The results lead to the conclusion that a fraction of the drug is weakly bound to plasma- and membrane-proteins. They are discussed with respect to the treatment of heavy metal poisoning.

The excretion and distribution of inorganic mercury in the rat as influenced by several chelating agents.

Among 15 chelating agents tested, sodium-2,3-dimercaptopropane 1 sulfonate (DMPS), 2,3-dimercaptopropanol (BAL), sodium-mercaptoethyliminodiacetate (MEIDA), and D-penicillamine (PA) exerted an influence on the excretion of Hg and its distribution in the organs. The excretion pattern however, is different for these compounds, and, from the practical point of view, a favourable effect is exhibited only by DMPS which enhances the urinary excretion rate and lowers the Hg-concentration in all organs.

Ibuprofen epidermal levels after topical application in vitro: effect of formulation, application time, dose variation and occlusion.

The influence of vehicle (two oil-in-water emulsions and two gels, each containing 10% or 5% ibuprofen) application time (0.5, 1, 2 h), applied dose (1.5, 3, 6, 12 mg/cm2), time (24 h after an 0.5 h application time), and occlusion on the epidermal concentration of ibuprofen was investigated. The drug concentration in the epidermis was measured by HPLC. All results were expressed as microgram drug/mg epidermal protein. The application time had no influence on the epidermal drug concentration, whereas the two gel formulations produced concentrations approximately twice those obtained with the emulsions. A significant positive correlation was found between the applied dose and the epidermal concentration for each formulation. After 24 h the amount of drug remaining in the epidermis was low (reduced by factors of 10-20). Occlusion produced higher concentrations, but only with the 2-h application time. The methods are reliable, and useful in ranking vehicles according to their ability to release ibuprofen into the epidermis. Future investigations should explore the relationship between epidermal concentration and anti-inflammatory efficacy in vivo.

Feasibility of measuring the bioavailability of topical ibuprofen in commercial formulations using drug content in epidermis and a methyl nicotinate skin inflammation assay.

A method has been developed which simultaneously compares the inhibition of an inflammation induced by a methyl nicotinate assay with the concentration of drug in the human epidermis determined in vitro following topical application of two 10% ibuprofen formulations. The bioavailability of drug from commercial gel and emulsion was assessed after the application of various doses (3, 6 and 12 mg/cm2) and an application time of 0.5 h at two time points: 0.5 and 24 h (only with the 12 mg/cm2 dose) after the removal of the non-steroidal anti-inflammatory drug (NSAID) from the skin. In parallel, we assessed the epidermal concentration of the drug in vitro and evaluated the anti-inflammatory effect of the topicals in vivo. A correlation (r = 0.9603, p < 0.001) between the amount of drug in the epidermis expressed as micrograms per milligram of epidermal protein and the corresponding inhibition of the inflammation was observed. Increasing the amount of drug in the epidermis correlated with an increased inhibition of the inflammation. The gel formulation released more drug to the skin and produced a greater anti-inflammatory effect. Topical NSAID concentration in treated skin can therefore be determined and correlates well with the resulting pharmacodynamic activity. This approach will likely have utility in optimizing topical NSAIDs.

Endogenous plasma N-acetylcysteine and single dose oral bioavailability from two different formulations as determined by a new analytical method.

A method to quantitate N-acetylcysteine in plasma using reductive cleavage with tributylphosphine and post-HPLC column derivatisation with omicron-phthalaldehyde is described. Using this method, endogenous average concentrations of 0.08 microM were measured in 10 volunteers participating in a crossover study to compare the bioavailability of two different formulations of N-acetylcysteine. The drug was detected in plasma for up to 12 h after administration of a single oral dose (200 mg); the Cmax values were up to 20 times the endogenous levels. The sensitivity and selectivity of the method should thus enable the behaviour of N-acetylcysteine after oral administration to be properly described and bioavailability studies to be performed.

Skin penetration and sun protection factor of ultra-violet filters from two vehicles.

PURPOSE: In order to improve our knowledge on the efficacy and safety of sunscreen products, we measured the skin penetration profiles of ultra-violet (UV) filters in vitro and in vivo, and the corresponding sun protection factors (SPF) from two vehicles (an O/W emulsion-gel and petroleum jelly). METHODS: The UV filters tested were oxybenzone (5%, A), 2-ethylhexyl 4-methoxycinnamate (7.5%,B), and 2-ethylhexylsalicylate (3%,C). Two mg/cm(2) were applied for 2 min to 6 h. In vitro penetration measurements were performed with static diffusion cells. In vivo, horny layer concentrations were measured after stripping and the SPF evaluated as recommended by the COLIPA-guidelines. RESULTS: Significant differences between vehicles were noticed in vitro as well as in vivo. In vitro, the emulsion-gel generated higher epidermal concentrations than petroleum jelly. Values at 6 h, expressed as percent of the applied dose for A, B, and C were 4, 9, and 7% for the emulsion-gel and 2, 1, and 2% for petroleum jelly. An opposite trend was noticed, mainly for A, in the deeper skin layers with concentrations of 2% in the dermis and 5% in the receptor fluid for petroleum jelly and 0.6% and 1% for the emulsion-gel respectively. In vivo, for each UV filter, maximal stratum corneum levels (15 strips) were obtained at 0.5 h with percentages of the applied doses of 50% for the emulsion-gel and 15 percent for petroleum jelly. SPFs, measured 0.5 h after application amounted to 14 for the emulsion-gel and 5 for petroleum jelly, and decreased in both cases by a factor 2.2 after removal of non penetrated product. CONCLUSIONS: These preliminary results demonstrated that UV filters penetration and retention as well as expected SPF could be optimized by a suitable vehicle.

Measurement of sodium lauryl sulfate-induced skin irritation.

Besides visual evaluation, skin irritation induced by sodium lauryl sulfate (SLS) may be characterized by bioengineering measurements, such as skin colour reflectance, transepidermal water loss (TEWL) or hydration. Short application times or low concentrations of the irritant usually do not modify the visual aspect of the skin, and the measurements described above are unchanged or only slightly altered. We were looking for a suitable method to measure cutaneous changes not detectable by usual bioengineering procedures. Therefore these measurements were compared to those of dynamic function testing of the stratum corneum, namely sorption-desorption and moisture accumulation tests. Different concentrations of SLS (0.1%, 0.5%, 2.5%), application times (15 min, 24 h) and times of testing (1 h, 24 h after patch removal) were investigated on the ventral forearm of human subjects. When SLS was applied for a short period (15 min), 1 h after patch removal skin colour, TEWL and hydration were not modified, while increases in hygroscopicity, water-holding capacity and water accumulation were detected depending on the applied concentration. Increase of hygroscopicity was closely correlated with the alteration of epidermal barrier function (TEWL). We demonstrated that sorption-desorption and moisture accumulation tests performed on SLS-treated areas for a short period, without visible modifications, could evaluate changes of the stratum corneum properties. We consider these tests as useful complementary methods to skin colour, TEWL and hydration measurements, particularly in the detection of subclinical skin injuries.

Bioengineering measurements of barrier creams efficacy against toluene and NaOH in an in vivo single irritation test.

BACKGROUND/AIMS: By now, only a few models have been published with the goal of testing barrier creams in vivo in humans. The aim of this study was to evaluate with a single irritation test, barriers creams in humans against a lipophilic and a hydrophilic irritant, toluene and NaOH, respectively. METHODS: Both irritants were applied for 15 min after pretreatment of the skin with barrier creams. Non-invasive bioengineering methods, such as skin colorimetry (a*) and cutaneous blood flow (CBF) measurements were used to assess product protection. RESULTS: After toluene application on control sites, the irritation appeared quickly (Tmax =3 min after patch removal), was significant (+5-6 units for a* and+80% for CBF) and did not return to base value within 1 h. Skin irritation after NaOH application, as measured by a*, was less important (+2 units) and occurred later (T"max=40 min after patch removal). For this irritant, CBF response was minor and variable. When testing barrier properties of the products, none of them were able to prevent the skin erythema induced by toluene. Against NaOH, one barrier cream as well as petrolatum and a fatty cream protected the skin significantly. CONCLUSION: The present study points out the unsatisfactory effectiveness of several commercially available barrier creams claimed to protect against lipophilic or hydrophilic irritants.

Note on the metabolism of the mercury chelating agent sodium 2,3-dimercaptopropane-1-sulfonate.

Chromatographic analysis of the radioactive urine obtained after injection into rats of [1,3-(14)C] dimercaptopropane sodium sulfonate (DMPS, Dimaval) showed that part of the administered chelating agent is excreted unchanged. This was confirmed by the results of studies of sulfur excretion in the different fractions of the urine as well as by titration of the excreted thiol groups. The results show that, at least in rats, DMPS is not involved in important metabolic reactions.

Lip sun protection factor of a lipstick sunscreen.

BACKGROUND AND OBJECTIVE: There is a well-documented need for effective human UVA and UVB photoprotection. Since there are important anatomical variations, the sun protection factor (SPF) of a lipstick sunscreen was measured on the anatomical site intended for use. METHODS: The SPF tests were performed according to Federal US and European COLIPA guidelines. Prior to performing a test on the lip, the minimal erythemal dose (MED) of the unprotected back skin was determined. Subsequently, the sunscreen SPF was measured on the anatomical target site (lip). The evaluator was blinded with respect to scoring the SPF of each sunscreen treatment. Individual test sites were assigned to one of the following treatment conditions: (1) no treatment (MED of unprotected skin); (2) test formulation; (3) reference standard. RESULTS: The MED on unprotected back skin was found to be 25% lower than on unprotected lip skin. The SPF of the lipstick sunscreen was measured 2 units lower than the SPF determined in the classical way on the back skin. CONCLUSION: It was hypothesized that the higher MED of the lower lip compared with back skin was due to the adaptation of this tissue to the continuous exposure to UV radiation.

[Salicylic acid and urea--possible modification of the keratolytic effect of salicylic acid by urea]. / Salizylsäure und Harnstoff--mögliche Beeinflussung der keratolytischen Wirkung von Salizylsäure durch Harnstoff.

The keratolytic effect of salicylic acid was measured with a colorimeter after staining the outer layers of the stratum corneum with silver nitrate. Salicylic acid was used in a concentration of 5% or 10% in vaseline or of 5% in an improved vehicle. The results of two experiments showed that improvement of the vehicle increased the keratolytic effect of salicylic acid and that urea played a major role in this improvement.

Skin penetration and sun protection factor of five UV filters: effect of the vehicle.

To gain information about efficacy and safety of sunscreens, we compared the skin penetration of ultraviolet (UV) filters from two vehicles, i.e. an oil-in-water (O/W) emulsion gel and petrolatum jelly both in vitro and in vivo, as well as the corresponding pharmacological effect, i.e. the sun protection factor (SPF) in vivo. The UV filters studied were benzophenone-3 (BPH), ethylhexyl methoxycinnamate (EHM), butyl methoxydibenzoyl methane, ethylhexyl salicylate and homosalate. The human skin penetration of these five chemicals from the two vehicles was determined both in vitro using Franz cells and in vivo using a standardized tape-stripping method. The SPF of the two sunscreens was determined in vivo following the COLIPA guidelines. In vitro none of the filters permeated through the skin after 6 h of product application and very little could be found in the skin. BPH and EHM were the only UV filters found in the dermis (both after 30 min and 6 h). An effect of the vehicle could be noticed only for BPH after 30 min in the dermis and 6 h in both dermis and epidermis. In vivo, no differences in the amount of individual UV filters (in % of the applied dose) in the 15 first strips of the stratum corneum (SC) were found following 30 min of application of the formulations; however, the amount of UV filters that were retained in the SC was significantly higher (around 3 times) with the O/W emulsion gel than with the petrolatum jelly. This difference between the two vehicles was also of consequence for the SPF in vivo measured 30 min after application of the products (SPF congruent with 18 with the O/W emulsion gel compared to SPF congruent with 10 with the petrolatum jelly). By choosing the right vehicle or optimizing it, not only sunscreen products can be significantly improved in terms of pharmacological efficacy but the potential toxicological risk associated with the skin penetration of UV filters may be significantly reduced.

Barrier function of the skin in a repetitive irritation model and influence of 2 different treatments.

BACKGROUND/AIMS: The aim of this study was to develop and characterize an experimental model of cumulative irritant contact dermatitis using the repetitive application over 2 weeks of 2 different irritative stimuli, sodium lauryl sulphate (SLS) in low concentration and toluene. Further, it was intended to look at the effect of 2 different treatments which could influence the regeneration of the skin barrier, as already investigated in preliminary short-term experiments. METHODS: Occlusive short-time daily application of the irritants (SLS 30 min; toluene 10 min) was performed. After removal of the occlusive patch, the irritated areas were treated with 2 different preparations, Lotio Alba Aquosa and vaseline (white petroleum jelly). Bioengineering techniques were used to precisely measure the skin condition. RESULTS: A mild irritation was obtained under these experimental conditions. The bioengineering measurements allowed us to differentiate both irritants through their different influences on trans-epidermal water loss and skin hydration. Treatment with vaseline did not significantly influence the course of the irritation, but Lotio Alba Aquosa clearly potentiated it, whereby different effects were noticed for both irritative stimuli. CONCLUSIONS: The use of bioengineering techniques in this model of mild cumulative irritation allowed us to differentiate the action of both irritants, showing that they act through different mechanisms. The results of the treatments pointed out the need to treat an irritation with the right product for the right time period.