Percutaneous absorption of hydrocortisone and testosterone on the vulva and forearm: effect of the menopause and site

Summary The percutaneous absorption of hydrocortisone and testosterone was studied following their application to the vulvar and ventral forearm regions of pre- and post-menopausal women. Percutaneous absorption of hydrocortisone was significantly greater in vulvar skin than forearm skin in both pre- and post-menopausal women (P <0·05. respectively), whereas the percutaneous absorption of testosterone was significantly increased (P<0·01) on the vulva compared with the arm only in post-menopausal women.
The effect of age on the percutaneous absorption of hydrocortisone and testosterone was evaluated by using the menopause as a biological chronometric end point. It is a common misconception that older skin has a diminished barrier capacity, and that percutaneous absorption is therefore greater. Our studies showed that absorption of hydrocortisone vulval skin of pre-menopatisal women was significantly greater (P<0·01) than in post-menopausal women. The ventral forearm skin of pre-menopausal women tended to show increased absorption compared with post-menopausal women, but statistical significance was not reached. No significant differences (P > 0· 05) in the percutaneous absorption of testosterone in vulval or forearm skin were observed between the two age groups.     

Age-related percutaneous penetration part 1: skin factors

Changes in the skin that occur in the elderly may put them at increased risk for altered percutaneous penetration from pharmacotherapy along with potential adverse effects. Skin factors that may have a role in age-related percutaneous penetration include blood flow, pH, skin thickness, hair and pore density, and the content and structure of proteins, glycosaminoglycans (GAGs), water, and lipids. Each factor is examined as a function of increasing age along with its potential impact on percutaneous penetration. Additionally, topical drugs that successfully overcome the barrier function of the skin can still fall victim to cutaneous metabolism, thereby producing metabolites that may have increased or decreased activity. This overview discusses the current data and highlights the importance of further studies to evaluate the impact of skin factors in age-related percutaneous penetration.     

Percutaneous penetration through slightly damaged skin

Guidelines for experimental studies of percutaneous penetration prescribe optimal barrier integrity of the skin. The barrier integrity of the skin exposed in occupational or household situations is, however, not always ideal, and skin problems are among the most dominant reasons for absence from work. We have therefore evaluated an experimental model for percutaneous penetration through slightly damaged skin. The influence of a slight damage to the skin was evaluated using five pesticides covering a wide range of solubilities. We used an experimental model with static diffusion cells mounted with human skin. A slight damage to the barrier integrity was induced by pre-treatment of the skin with sodium lauryl sulphate (SLS) before pesticide exposure. The experimental model with 3 h pre-treatment with SLS (0.1% or 0.3%) assured a significant but controlled damage to the barrier integrity, a damage that remained unchanged for an experimental period of 48 h. Based on the percutaneous penetration of five pesticides, we conclude that a slightly damaged skin may significantly affect the rate, lag-time as well as total penetration of chemicals covering a wide range of solubilities. The percutaneous penetration of the most hydrophilic compounds will be those most affected. These findings should be considered when setting standards for dermal exposure to chemicals.     

Barrier function of intact and impaired skin: percutaneous penetration of caffeine and salicylic acid

Background Normally, percutaneous absorption tests are carried out using skin biopsies for an apparent and acceptable physiological condition. However, under different pathological conditions, the stratum corneum (SC) barrier function is impaired. Methods The barrier function of the SC was assessed by correlation between the number of repeated applications of tape strips on the skin and its transepidermal water loss (TEWL), as well as by in vitro percutaneous absorption studies of different compounds, using Franz diffusion cells and porcine skin previously stripped. Results A progressive diminution of the skin barrier function has been detected by TEWL both in vitro and in vivo as the number of skin tape strips increases. On the other hand, the percutaneous absorption of the compounds tested increases in a different way as the number of strips increases. Salicylic acid increases linearly depending on the barrier disturbance. However, percutaneous absorption of caffeine exponentially increased with barrier disturbance. Our results indicate that the barrier impairment of skin always increases the penetration behavior of a given compound; however, the hydrophilic–lipophilic balance of the compounds or formulations used could greatly modify its penetration profile, especially when a modified skin is used. Conclusions This in vitro protocol may be useful to simulate the percutaneous absorption profile of some drugs applied onto skin with an impaired SC barrier function and could be used to avoid, to some extent, the use of in vivo experimental animal models in the dermopharmaceutical field.     

Qualitative and quantitative comparison of heat separated epidermis and dermatomed skin in percutaneous absorption studies

Transepidermal water loss (TEWL), mainly regulated by the stratum corneum, was quantitatively correlated to percutaneous absorption of compounds in human and suggested for the ex vivo assessment of skin integrity. The present study investigated qualitatively and quantitatively the relevance of 100-μm heat separated epidermis (HSE) in percutaneous absorption studies as compared to 500-μm dermatomed skin by dual complementary approaches. Percutaneous absorption of caffeine delivered from aqueous solution through dermatomed skin or HSE specimens (n = 9) was measured using vertical static diffusion cells coupled with an unventilated evaporimeter enabling the assessment of TEWL and skin integrity for 21 h. Permeation of caffeine exhibited different finite dose-like profiles ranged according to the thickness of skin specimens (cumulative dose absorbed up to 21 h: 11.5 ± 11.5 μg/cm² and 29.4 ± 36.2 μg/cm² through dermatomed skin and HSE, respectively). Normalized TEWL and caffeine fluxes were similar through dermatomed skin and HSE suggesting that the intrinsic permeability properties of both models were undifferentiated over time. Interestingly, a significant relationship was shown between TEWL and caffeine fluxes, suggesting the usefulness of TEWL measurement as an element in the estimation of percutaneous drug absorption. In conclusion, the present showed that percutaneous absorption through HSE was qualitatively and quantitatively similar to dermatomed skin when TEWL as endogenous standard and skin thickness were considered in permeability data comparisons.     

Children and newborn skin care and prevention

Neonatal skin suffers a progressive adaptation to the extrauterine environment and special care is needed during this period. This skin is very sensitive, thin and fragile. Immaturity of the epidermal barrier reduces the defense against the excessive proliferation of microbes and makes the skin more vulnerable to trauma and percutaneous drug toxicity. Because of the peculiar characteristics of newborn, infant and children's skin, the use of cosmetic products designed for hygiene and protection requires caution. In order to preserve the integrity of neonatal and child's skin, this article reviewed basic preventive care practices in relation to hygiene, bathing, cleansing agents, topical products and their percutaneous toxicity.     

Percutaneous Absorption in Preterm Infants

The skin of preterm infants varies considerably in its level of maturity. To understand skin absorption in premature infants better, we report a technique for the assessment of percutaneous absorption at various gestational and postnatal ages using stable, isotope-labeled (13C6) benzoic acid. Our results indicate that in the preterm infant, this method detects enhanced skin absorption in the first postnatal days, which declines over three weeks to that expected of a full-term infant. This approach also indicates an inverse relationship between gestational age and skin absorption, as well as postnatal age and skin absorption. The reported technique is a safe and noninvasive method using a model skin penetrant for the study of percutaneous absorption in preterm infants from which basic data may be derived to add to our understanding of skin barrier function.     

Defense against dermal exposures is only skin deep: significantly increased penetration through slightly damaged skin

The OECD guideline for studies on percutaneous penetration to be used in hazard and risk evaluations prescribes experimental conditions with optimal barrier integrity of the skin, which in many occupational settings probably is not true. Thus, workers may have compromised skin due to chemical or mechanical damage, due to different medical conditions (eczema, dermatitis, skin irritation) or related to occupational scenarios involving prolonged wet work. The present study used the OECD guideline procedures to study the in vitro percutaneous penetration through human skin of a number of model substances (glyphosat, caffeine, benzoic acid, malathion) covering a range of solubilities. Further, we studied the extent to which a slightly damaged skin would change the rate, the amount absorbed during dermal exposure and the distribution of chemical deposition between epidermis and dermis. The present study demonstrates that a limited damage to the skin significantly increases the permeability coefficient (K _p) as well as total percutaneous penetration of chemicals, and most significantly for those compounds that due to their physicochemical characteristics (the most hydrophilic as well as the most lipophilic) have low penetration rates through intact skin. The present experiment not only confirms the proportionality between lipophilicity and potential for percutaneous penetration, but also illustrates that at a certain degree of lipophilicity of a model compound, the different skin compartments become more attractive for temporary deposition of model compounds. Moreover, a clear change from epidermal deposition towards a dominating dermis deposition of chemicals temporarily deposited within the skin is seen following damage to the skin barrier. Thus, the distribution of chemicals within the skin compartments is affected by the physicochemical characteristics of the chemicals as well as by the integrity of the skin. This observation may have implications when evaluating the possibility of removing chemicals from the skin through different cleansing procedures following unintended dermal exposures.     

Percutaneous absorption of sunscreens in vitro: interspecies comparison, skin models and reproducibility aspects

Appropriate evaluation of sunscreens is required to provide better knowledge of their safety and efficacy. One of the most important elements of this evaluation is the assessment of percutaneous absorption. In vitro methods are largely used for such assessments, and the accuracy of the measurements generated with these methods depends on the use of a proper methodology. This study was designed to evaluate an in vitro protocol for investigating the percutaneous absorption of two sunscreens under standardized experimental conditions. Octyl methoxycinnamate and benzophenone 4 were each incorporated in a typical oil-in-water emulsion and tested separately. Salicylic acid was tested as a reference compound. In vitro percutaneous absorption was evaluated using two species, the pig and human, and two models, full-thickness and split-thickness skin. The reproducibility of study results was evaluated by comparing the data generated by two industrial laboratories, L'Oréal and Hoffmann-La Roche. The correlation of quantitative data between pig skin and human skin was very good, and the split-thickness skin model seemed to be more appropriate for measuring the absorption of sunscreens. Results obtained for salicylic acid demonstrated the relevance of the protocol in terms of prediction of in vivo percutaneous absorption. Finally, the comparison of pig skin data between the two laboratories demonstrated a good correlation and underlined the need for a standardized in vitro procedure.     

AN AUTORADIOGRAPHIC STUDY ON THE PERCUTANEOUS ABSORPTION OF A TOPICAL CORTICOSTEROID,WITH REFERENCE TO THE EFFECTS OF OCCLUSIVE TREATMENT AND STRIPPING

The effects of occlusive treatment and stripping on the percutaneous absorption of a topical corticosteroid (17-α-desoxymethasone) were studied on human skin by means of a direct mounting method of autoradiography. A greater density of developed silver grains was found in the epithelium of occluded skin than in non-occluded skin. The influence of occlusion on trans-appendageal absorption was demonstrated by a greater density of grains in the cutaneous appendages of occluded skin as compared to non-occluded skin. Further, a step-wise increase in grain deposition was seen in specimens stripped repeatedly with adhesive tape. A partial removal of keratin by stripping was detected histologically, this suggests that the entire horny layer acts as a limiter of percutaneous absorption.     

Use of various models for in vitro percutaneous absorption studies of ultraviolet filters

Background: The percutaneous absorption test aims to estimate the passage of a substance across the skin. The absorption process can be described in three steps: (a) penetration of a substance into the skin layer, followed by (b) penetration from one layer into another (permeation) and finally (c) resorption into the vascular system. In vivo and in vitro models are available but owing to ethical reasons as well as the latter providing greater feasibility, in vitro models are preferred.
Aims: This present study reviews the natural membranes (human skin and animal models: pig, rabbit, rat, hairless mouse, guinea-pig and mouse), artificial skin equivalents and synthetic membranes that are currently being used for in vitro percutaneous absorption studies of UV filters, in order to provide the researcher with a greater insight when selecting membrane models for given experimental conditions.     

New easy handling and sampling device for bioavailability screening of topical formulations

Biopharmaceutical assessment of topical drug formulations is widely carried out by using vertical diffusion cells (Franz type cell). Although Franz diffusion cell model is well designed for percutaneous absorption studies, the extent of drug penetration within the skin requires more adapted device. Recently, we have developed a new patented versatile, easy-to-use, and disposable diffusion cell called VitroPharma. In this study we have assessed the cutaneous bioavailability of caffeine as hydrophilic compound model using Franz diffusion cell and VitroPharma. The percutaneous absorption of caffeine assessed with Franz diffusion cell andVitroPharmawas characterized by using (i) finite dose model and (ii) classical pharmacokinetic analysis. Furthermore, the follow-up of caffeine penetration within the skin was determined by sequential measurements of tissular drug concentration throughout the time of skin exposure with VitroPharma. However, classical experimental design using Franz diffusion cell involved unique determination of tissular concentration at the final point of skin exposure protocol. Finally, device equivalence between Franz diffusion cell and VitroPharma was claimed from percutaneous absorption data analysis. Concomitant assessment of dual penetration and permeation kinetics by using VitroPharma reinforced the understanding of skin drug delivery.     

Pentane-1,5-diol as a percutaneous absorption enhancer

Propylene glycol (propane-1,2-diol) is the only diol widely used in dermatology. Pentane-1,5-diol is mainly used as a plasticizer in cellulose products and adhesives, in dental composites and in brake fluid compositions and as a preservative for grain. However, pentane-1,5-diol is also an effective solvent, water-binding substance, antimicrobial agent and preservative and may therefore replace several ingredients in a skin composition. The release of tri-iodothyroacetic acid (TRIAC) and percutaneous absorption of hydrocortisone and mometasone furoate with either pentane-1,5-diol or propane-1,2-diol and 2-methyl-pentane-2,4-diol (hexylene glycol), respectively, as enhancers was compared. The release of TRIAC was 21% higher when pentane-1,5-diol was used as an enhancer instead of propane-1,2-diol. The percutaneous absorption of hydrocortisone through the skin was increased 12 times with propane-1,2-diol compared to 4.4 times with pentane-1,5-diol. However, the percutaneous absorption of hydrocortisone into the skin was 50% higher with pentane-1,5-diol compared to propane-1,2-diol. There was no significant difference, between the original mometasone furoate cream, with 2-methyl-pentane-2,4-diol, and the new cream with pentane-1,5-diol in the amount of mometasone furoate that was absorbed into the skin and through the skin. However, the cosmetic properties of the new mometasone furoate cream was superior to the original mometasone furoate cream, for examples, no bad odour, more even texture, goes better into the skin and has less greasiness. Pentane-1,5-diol can be used as a technology platform, which adds a series of desirable properties to dermatological preparations and enhances product usability. This will result in improved formulations for a series of major and commonly used dermatological drugs. When used in pharmaceutical topical preparations, pentane-1,5-diol will increase the percutaneous absorption of the active substance and it is an efficient antimicrobial agent that will act as an effective preservative in topical formulations. Pentane-1,5-diol is cosmetically attractive, has low risk for skin and eye irritation compared to other diols, low toxicity risk and no bad odour.     

Skin strain and its influence on systemic exposure to a glycol ether in offset printing workers

Under workplace conditions, it is difficult to prove the influence of skin lesions on skin penetration by chemical substances. The aim of the present study was to show whether systemic exposure to glycol ether increases due to lesions of the skin in printing workers. 28 male printers, exposed to 2-(2-butoxyethoxy)ethanol (BEE), were interviewed about the workplace exposure by a standardized questionnaire. The systemic exposure in printers was determined by biological monitoring of the main metabolite of BEE butoxyethoxyacetic acid (BEAA) in urine. Furthermore, clinical examination of the skin, transepidermal water loss, capacitance and skin surface pH measurements were carried out. Erythema and scaliness were the most important factors showing an effect on dermal absorption. The mean urinary BEAA excretions for printers with skin lesions on the hands were higher (20.62 mg/l for scaliness and 14.40 mg/l for erythema) compared to that for printers without detectable skin lesions (12.08 mg/l for scaliness and 13.03 mg/l for erythema). Bioengineering measurements to predict skin strain and percutaneous absorption were only supportive. We were able to show that by using a multiple spectrum of methods an enhancement of percutaneous absorption of BEE could be demonstrated in workers with skin lesions.     

Comparison of stratum corneum thickness in children and adults

We compared the thickness of the stratum corneum from abdominal skin in infants less than 3 months of age, children between 3 months and 11 years, and adults. Measurements were made with a filar micrometer eyepiece on histologic sections obtained at autopsy. No significant differences were seen; therefore, a stratum corneum of different thickness cannot be used to explain differences in percutaneous absorption, supporting previous work which suggested that term infants and children have an efficient skin barrier. The greater toxicity from percutaneous absorption of topical compounds sometimes seen in children is more likely due to their increased surface to volume ratio and/or metabolic differences.     

Effect of sodium lauryl sulfate-induced skin irritation on in vivo percutaneous penetration of four drugs.

The influence of sodium lauryl sulfate-induced irritant contact dermatitis on in vivo percutaneous penetration was investigated for four 14C-labeled compounds with diverse physicochemical properties: hydrocortisone (HC), indomethacin (IM), ibuprofen (IB), and acitretin (AC). Hairless guinea pigs were pretreated for 24 h with either 0.5% sodium lauryl sulfate (SLS) to induce irritant contact dermatitis or with water (controls). Twenty-four hours after pretreatment, 450 microliters saturated solutions of HC, IM, IB, or AC in isopropylmyristate were applied to the pretreated skin for 24 h. Systemic absorption was determined by urinary and fecal excretion of compounds. Drug concentrations in stratum corneum (obtained by tape cellophane stripping after decontamination of the application site) and in epidermis/dermis (punch biopsy) were also investigated. Systemic absorption of topically applied drugs (as evaluated by urinary and fecal excretion) in SLS-irritated skin was significantly increased for HC (factor 2.6) followed by IB (1.9 times) and IM (1.6 times) but not increased for AC. However, drug concentrations in the viable epidermis and dermis were 70% lower in SLS-irritated than normal skin for HC, but not different for IB, IM, and AC. Thus, the influence of the state of the skin (irritant dermatitis versus healthy) on percutaneous penetration was different for diverse drugs. The general assumption that percutaneous penetration and drug tissue concentrations were higher in diseased versus healthy skin was not found to be true in our irritated-skin model.     

三种香料皮肤刺激和皮肤变态反应及离体皮肤渗透的研究

为探讨化妆品皮炎的发病机制,对3种香料(异丁香酚、肉桂醛、羟基香茅醛)进行皮肤刺激、皮肤变态反应及离体皮肤渗透的动物实验研究.结果显示:3种香料均是强致敏原,其中肉桂醛还具刺激性.三种香料均能经皮渗透,其中肉桂醛的皮肤渗透性最强;提示化妆品引起的接触性皮炎可能原发刺激与变态反应两种机制同时存在;皮肤渗透性与致敏性有相关关系.     

Percutaneous absorption in the aged

The work described in this article reveals a remarkable lack of consensus as to whether percutaneous absorption changes as humans grow older. The data that have been recorded point to possible significant alterations in the barrier function with age. The importance of these observations with respect to dermatopharmacology and dermatotoxicology is clear. The absence of a clearly defined relationship between aging, percutaneous penetration, and the properties of the molecules crossing the skin barrier represents an unacceptable gap in fundamental dermatologic knowledge. With the changing demographic pattern of Western civilization and the increasing awareness of human subjects for the condition of their skin, and the potential for drug delivery via their skin, it is crucial that we begin to establish precisely how the barrier function alters with increasing age. The answer to this question may permit unique improvements in the quality of both local and systemic health in aging populations.     

A pilot study on the percutaneous absorption of microfine titanium dioxide from sunscreens

Many Australians are being advised to apply microfine titanium dioxide sunscreen daily from the cradle to the grave. However, there is a surprising lack of data on the percutaneous absorption of microfine titanium dioxide. A prospective pilot study was conducted to analyse the percutaneous absorption of microfine titanium dioxide from sunscreens. Selected patients scheduled to have skin surgery, applied titanium dioxide sunscreen to the skin daily for 2–6 weeks prior to their operation. After excision, the stratum corneum of the sample was stripped and the titanium concentration of the remaining epidermis and dermis was measured by inductively coupled plasma-mass spectrometry. The results from this pilot study showed that levels of titanium in the epidermis and dermis of subjects who applied microfine titanium dioxide to their skin were higher than the levels of titanium found in controls. Studies with larger cohorts are necessary to establish if this absorption is statistically significant.     

Permeation and skin absorption: reproducibility of various industrial reconstructed human skin models

Human reconstructed skin models could be very useful tools to quantify percutaneous permeation and absorption. Before using such models, the reproducibility in the same batch and/or various batches, i.e. the relevance of the results obtained, must be verified. The reproducibility of 3 industrial models--EpiDerm, Episkin and SkinEthic--was tested regarding the permeation and skin absorption of 3 topically applied compounds (with a large range of physicochemical properties): lauric acid, caffeine and mannitol. For all the models, the intrabatch reproducibility was greater than the interbatch reproducibility. According to the batches tested, the larger difference in terms of reproducibility between the 3 models was observed in the case of mannitol, a very poor permeant. In this case, the best reproducibility was observed with EpiDerm and Episkin. Moreover, the rank order of the 3 compounds applied, in terms of permeation and skin absorption, was the same as that expected from ex vivo human skin. Such results revealed human skin models as a promising means to test in vitro permeation and percutaneous absorption of topical products.