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We review experimental studies that address age-related changes in cutaneous barrier function and dermal blood vessel function. These differences have important implications in the understanding of age-related changes in the inflammatory process and topical drug delivery systems.
It is a given fact that hair follicles play an important role in the penetration process of topically applied drugs and cosmetics. Since exact knowledge of the potential follicular reservoir is essential for understanding and calculating the penetration process, this knowledge may indeed help to optimize the development of topically applied drugs and cosmetic products. We know that variability in skin properties exists among the human population, but it is the deciphering and quantification of these differences that may help to explain racial disparities in dermatological disorders and provide a basic approach for treatment and prevention. Data pertaining to structural and functional differences within ethnic skin types (reviewed in this paper) support the assumption that hair follicles in the various skin types are not equal. Thus, the need to investigate follicular morphology in non-Caucasian skin types becomes more than apparent. The aim of the present study was to determine the potential reservoir of vellus hair follicles in non-Caucasian skin types in order to estimate their contribution to the penetration of topically applied substances. Cyanoacrylate skin surface biopsies were taken from seven body sites of Asians and African-Americans. To determine the follicular reservoir, the samples were evaluated under the light microscope. Follicular parameters were measured with the help of a digital imaging software program. In the evaluation and comparison of the results with those of Caucasians, significant differences were detected. Compared with Whites, follicular density on the forehead is significantly lower in Asians and African-Americans. Smaller values were detected for volume, surface, follicular orifice and hair shaft diameter on the thigh and in calf regions in Asians and African-Americans. Furthermore, the follicular reservoir, characterized by follicular volume, is generally higher in Caucasians. In comparison to African-Americans, larger follicular volumes on the forehead, back and on the upper arm were determined in Asians. The fairly similar density in these sites revealed that Asians have a higher follicular reservoir in these sites. Due to significant ethnic differences in the follicular reservoir, particularly on the calf and forehead, prospective skin absorption experiments need to be performed on different skin types in order to be representative. Likewise, the development of topically applied drugs should take place under adequate consideration of ethnic differences in skin physiology.
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Previously we have shown that the diacyl glyceryl ester of naproxen is absorbed into excised mouse skin and slowly degraded to release naproxen. In the present work we have synthesised some organic acid and fatty acid derivatives of metronidazole, and studied the in-vitro degradation in aqueous buffer solutions and serum as well as their permeation through hairless mouse skin. The derivatives were enzymatically degraded in serum to form metronidazole. Only the acetic acid and butyric acid derivatives were able to permeate hairless mouse skin intact. The fatty acid derivatives released metronidazole within the skin. The metronidazole delivery through the skin was significant when the metronidazole oleate was used. This compound could therefore be considered as a suitable pro drug for dermal applications.
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Collagen microparticles (CMPs) were manufactured with the objective to enhance the dermal delivery of all-trans retinol. The influence of CMPs on the stability of retinol was investigated after a long-term storage of two hydrogel preparations (hydroxyethylcellulose). The retinol in the first preparation was adsorbed onto the surface of CMPs, whereas the retinol in the second preparation was freshly precipitated. Retinol was not protected from oxidization by adsorption to CMPs. However, the sorption on the surface of CMPs prevented the retinol from crystallization. On the other hand, significant crystallization occurred with the freshly precipitated retinol. For the study of the in vitro penetration of retinol into hairless mouse skin three preparations for topical application were used. Beside the two hydrogel preparations mentioned above, an O/W-creme was tested. The study of the in vitro penetration was performed by using Franz diffusion cells and tritium labelled retinol. Both hydrogel preparations yielded significantly higher quantities of penetrated retinol than the O/W-creme. The amounts of radioactive retinol in the stratum corneum and in the epidermis and dermis were in all cases more than ten times higher for the hydrogel preparations. The other remarkable result was that the presence of CMPs led to a faster and higher transport of retinol into the skin than the freshly precipitated drug. With the CMP preparation a statistically significant increase of penetrated retinol was found during the first 4 h after application in the stratum corneum. In the residual epidermis and dermis a clear tendency towards enhanced quantities of penetrated retinol also were observed with the CMPs compared to the freshly precipitated drug in the hydrogel.
This paper reviews the literature to determine the importance of the dermal route of exposure for swimmers and bathers using Great Lakes waters and summarizes the chemical water contaminants of concern in the Great Lakes along with relevant dermal absorption data. We detail in vivo and in vitro methods of quantifying the degree of dermal absorption and discuss a preference for infinite dose data as opposed to finite dose data. The basic mechanisms of the dermal absorption process, routes of chemical entry, and the environmental and physiological factors affecting this process are also reviewed, and we discuss the concepts of surface slick exposure to lipophilic compounds and the adsorption of contaminants to water sediment. After presenting mathematical constructs for calculating the degree of exposure, we present in vitro data concerning skin absorption of polyaromatic hydrocarbons adsorbed to Great Lakes water sediment to show that in a worst-case scenario exposure via the dermal route can be equally important to the oral route. We have concluded that prolonged exposure of the skin, especially under conditions that may enhance dermal absorption (e.g., sunburn) may result in toxicologically significant amounts of certain water contaminants being absorbed. It is recommended that swimming should be confined to public beaches, people should refrain from swimming if they are sunburned, and skin should be washed with soap as soon as possible following exposure. Future studies should be conducted to investigate the importance of the dermal exposure route to swimmers and bathers.
This study assessed the in vitro percutaneous absorption and metabolism of 3-indolylacetic acid after topical dosing to human skin from four sources. The metabolism of the compound during percutaneous absorption was assessed. The absorbed and metabolized chemicals were analyzed by radioactive scintillation counting and thin-layer chromatography: 1.2% +/- 0.04%, 1.4% +/- 0.07%, 3.0% +/- 1.0%, and 0.1% +/- 0.02% of the applied doses permeated through human skin samples from sources A to D, respectively, whereas 3.4% +/- 0.5% to 20.0% +/- 0.2% of the applied doses were retained by the skin. Of the absorbed dose, 2.1% +/- 1.0% to 12.1% +/- 3.5% was present as metabolites in the receptor fluid, and 2.2% +/- 0.5% to 5.2% +/- 0.1% was present as metabolites retained in the skin. Microsomal fractions were prepared from the skin samples, and the actions of these preparations on 3-indolylacetic acid were estimated. 5'-Hydroxyl-3-indolylacetic acid, 5',6'-dihydroxy-3-indolylacetic acid, and 5,6-dihydroxyindole were formed both during percutaneous absorption and by skin microsomal preparations. In addition, the skin samples biotransformed the acid to metabolic indican (3-indoxylsulfuric acid) and to the glucuronide conjugate of indole. The possible functional significance of the metabolism is discussed.
For many years, hairless and rhino mouse mutants have provided a useful and extensively exploited model for studying different aspects of skin physiology, including skin aging, pharmacokinetic evaluation of drug activity and cutaneous absorption, skin carcinogenesis, and skin toxicology. Interestingly, however, hairless and rhino mice have rarely been studied for their primary cellular defect - hairlessness - and thus, the hairless gene itself and its physiological functions have been largely overlooked for decades. The recent identification of the human homolog of the hairless gene on human Chromosome 8p12 confirmed the clinical significance of the phenomenon of "hairlessness" in humans, which was predicted on the basis of similarities between hairless mice and a congenital hair disorder characterized by atrichia with papules. Mutations in the hairless gene of mice provide instructive models for further studies of hr gene function, and may facilitate insights into the pathophysiology of different human disorders associated with the disruption of hr gene activity. We provide an overview of current data on the structure and expression patterns of the hr gene, and of mutations at the hairless locus in mice and humans, including the genetic basis of different alleles, the pathology of hairlessness, reproductive and immunological defects, and susceptibility to dioxin toxicity. On the basis of our current understanding of hairlessness, we speculate on the putative functions of the hr gene product in skin physiology, and particularly, in hair follicle biology.
A knowledge of the rate and extent of chemical absorption across the skin is central to both transdermal drug delivery and cutaneous toxicology. Toward gaining sufficient insight into the relevant mechanisms involved in percutaneous absorption of topically applied agents in solution to validate a predictive model, we have 1) estimated porcine stratum corneum/water partition coefficients of two 14C-labeled compounds of interest (phenol and p-nitrophenol), and 2) measured dynamic surface evaporation from dosed excised porcine skin of these two radiolabeled compounds and two 14C-labeled commonly employed vehicles (acetone and ethanol). The surface evaporation profiles were fit to a kinetic model designed to estimate the liquid/vapor parameters for application to a general biophysically-based model of percutaneous absorption. In an effort to obtain more robust estimates of model parameters, corresponding evaporation experiments were effected on the isolated perfused porcine skin flap (IPPSF) under the same experimental conditions. Stratum corneum/water partition coefficients were determined for phenol and p-nitrophenol using a stratum corneum preparation from excised porcine integument.
The purpose of this study was to evaluate the in vitro cutaneous penetration of five terpenes--linalool, linalyl acetate, terpinen-4-ol, citronellol and alpha-pinene--applied in pure essential oils or in dermatological formulations (o/w emulsion, oily solution or hydrogel) containing 0.75 % w/w of the essential oils. Different skin absorption was observed depending on the type of the vehicle and terpenes' log P values. Cutaneous accumulation of terpenes is several times higher when they are applied in pure essential oils than in topical vehicles. Penetration of terpinen-4-ol to the skin was better from an oily solution (approximately 90 microg/cm (2)) than from an emulsion (60 microg/cm (2)). No penetration of linalyl acetate from topical vehicles into viable skin was observed, but also for this terpene penetration to the upper layers of the stratum corneum was 2-times higher when an oily solution was used. In contrast, the cutaneous absorption of linalool was the same from both vehicles (50-60 microg/cm (2)). The skin penetration of alpha-pinene was not traceable when it was applied in an oily solution. Only a small amount (approximately 5 microg/cm (2)) of this terpene was determined in viable skin after application as a hydrogel. Citronellol applied in a hydrogel penetrated into all skin layers in a total amount of 25 microg/cm (2), while no penetration into viable skin layers after application of an oily solution was noted. Only citronellol permeated into the acceptor medium.
Salicylic acid (SA) and urea are widely used in topical preparations. Using a simple tape stripping technique the effect on the binding forces within the stratum corneum and the skin absorption of SA and urea were studied. The degree of stratum corneum removal was recorded by measuring the transmission through the tape with a digital light-measuring instrument. With successive stripping of the skin the amount of tissue adhering to the tape decreased. Exposure of the upper arm to 2% SA for 6 h increased the skin material on the tape strips significantly. No significant increase was recorded after 3-hour exposure, or after exposure to 0.5% SA. Neither did the exposure to 10% urea for 3 or 6 h influence the amount of skin adhering to the tape significantly. Radiochemical analyses showed that the amount of SA and urea in each of the first 6 tape strips was about 5-15 micrograms/cm2. This technique provides a useful tool to evaluate the binding forces within the stratum corneum in relation to absorption of topically applied substances.
Literature from the first half of this century report concern for toxicity from topical use of boric acid, but assessment of percutaneous absorption has been impaired by lack of analytical sensitivity. Analytical methods in this study included inductively coupled plasma-mass spectrometry which now allows quantitation of percutaneous absorption of 10B in 10B-enriched boric acid, borax, and disodium octaborate tetrahydrate (DOT) in biological matrices. This made it possible, in the presence of comparatively large natural dietary boron intakes for the in vivo segment of this study, to quantify the boron passing through skin. Human volunteers were dosed with 10B-enriched boric acid, 5.0%, borax, 5.0%, or disodium octaborate tetrahydrate, 10%, in aqueous solutions. Urinalysis, for boron and changes in boron isotope ratios, was used to measure absorption. Boric acid in vivo percutaneous absorption was 0.226 (SD = 0.125) mean percentage dose, with flux and permeability constant (Kp) calculated at 0.009 microgram/cm2/h and 1.9 x 10(-7) cm/h, respectively. Borax absorption was 0.210 (SD = 0.194) mean percentage of dose, with flux and Kp calculated at 0.009 microgram/cm2/h and 1.8 x 10(-7) cm/h, respectively. DOT absorption was 0.122 (SD = 0.108) mean percentage, with flux and Kp calculated at 0.01 microgram/cm2/h and 1.0 x 10(-7) cm/h, respectively. Pretreatment with the potential skin irritant 2% sodium lauryl sulfate had no effect on boron skin absorption. In vitro human skin percentage of doses of boric acid absorbed were 1.2 for a 0.05% solution, 0.28 for a 0.5% solution, and 0.70 for a 5.0% solution. These absorption amounts translated into flux values of, respectively, 0.25, 0.58, and 14.58 micrograms/cm2/h and permeability constants (Kp) of 5.0 x 10(-4), 1.2 x 10(-4), and 2.9 x 10(-4) cm/h for the 0.05, 0.5, and 5.0% solutions. The above in vitro doses were at infinite, 1000 microliters/cm2 volume. At 2 microliters/cm2 (the in vivo dosing volume), flux decreased some 200-fold to 0.07 microgram/cm2/h and Kp of 1.4 x 10(-6) cm/h, while percentage of dose absorbed was 1.75%. Borax dosed at 5.0%/1000 microliters/cm2 had 0.41% dose absorbed, flux at 8.5 micrograms/cm2/h, and Kp was 1.7 x 10(-4) cm/h. Disodium octaborate tetrahydrate (DOT) dosed at 10%/1000 microliters/cm2 was 0.19% dose absorbed, flux at 7.9 micrograms/cm2/h, and Kp was 0.8 x 10(-4) cm/h. These in vitro results from infinite doses (1000 microliters/cm2) were 1000-fold greater than those obtained in the companion in vivo study. The results from the finite (2 microliters/cm2) dosing were closer (10-fold difference) to the in vivo results. General application of infinite dose percutaneous absorption values for risk assessment is questioned by these results. These in vivo results show that percutaneous absorption of boron, as boric acid, borax, and disodium octaborate tetrahydrate, through intact human skin, is low and is significantly less than the average daily dietary intake. This very low boron skin absorption makes it apparent that, for the borates tested, the use of gloves to prevent systemic uptake is unnecessary. These findings do not apply to abraded or otherwise damaged skin.
Various concentrations of salicylic acid in hydrophilic ointment were applied repeatedly at daily or weekly intervals to rats in vivo. Salicylic acid absorption through treated skin was monitored by determining the penetration fluxes of salicylic acid through skin excised at various times. A gradual decrease in the salicylic acid penetration flux was observed following weekly applications of either 5 or 10% salicylic acid in hydrophilic ointment. The penetration flux of 1% salicylic acid remained constant. In the daily applications of 5 and 10% salicylic acid, the penetration flux increased after approximately 2 days of treatment and declined thereafter. The penetration flux of salicylic acid from the 1% salicylic acid increased slightly after 3--4 days of treatment.