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Cosmetic Ingredients: Guidelines for Percutaneous Absorption / Penetration

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... The purpose of our study was to clarify any penetration properties of micronized TiO 2 . Our experimental approach was to use the ex vivo/in vitro penetration model [14,15], employing pig skin in Franz-type diffusion cells. This assay is widely accepted to properly predict the in vivo penetration potential of test materials on human skin, where porcine skin is said to slightly overestimate the absorption of lipophilic compounds [19]. ...
... With the SC being the crucial barrier towards invading chemicals, any uptake into the SC needs to be assessed with great care. This has been done traditionally by tape stripping and chemical analysis [15]. Earlier van der Molen et al. [13] pointed out that the skin topography may create an inherent problem for this experimental design. ...
In order to help clarify the controversially discussed dermal uptake properties of micronized titanium dioxide (TiO ), we conducted extensive in vitro dermal absorption studies with ’Franz-type’ diffusion cells on excised porcine skin. After biopsies and chemical fixation, the overall localization of TiO in the skin was analyzed by means of transmission electron microscopy (TEM). The lateral and vertical distribution of TiO within the stratum corneum (SC) was investigated by tape stripping and subsequent scanning electron microscopy (SEM) in combination with energy dispersive X-ray analysis (EDXA).
... Furthermore, the application of solutions prior to each experiment limited the use of the TER, since a complete removal of the solution, especially of lipophilic preparations, could not be ensured. Finally, the use of tritiated water was not regarded as suitable, since its application for 5 hours prior to each experiment might affect the quality of the skin samples (50). Moreover, the ³Hlabel might result in an overestimation of the quantity of permeated test compound, due to radioactive contamination. ...
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Exposure to chemicals absorbed by the skin can threaten human health. In order to standardise the predictive testing of percutaneous absorption for regulatory purposes, the OECD adopted guideline 428, which describes methods for assessing absorption by using human and animal skin. In this study, a protocol based on the OECD principles was developed and prevalidated by using reconstructed human epidermis (RHE). The permeation of the OECD standard compounds, caffeine and testosterone, through commercially available RHE models was compared to that of human epidermis and animal skin. In comparison to human epidermis, the permeation of the chemicals was overestimated when using RHE. The following ranking of the permeation coefficients for testosterone was obtained: SkinEthic > EpiDerm, EPISKIN > human epidermis, bovine udder skin, pig skin. The ranking for caffeine was: SkinEthic, EPISKIN > bovine udder skin, EpiDerm, pig skin, human epidermis. The inter-laboratory and intra-laboratory reproducibility was good. Long and variable lag times, which are a matter of concern when using human and pig skin, did not occur with RHE. Due to the successful transfer of the protocol, it is now in the validation process.
Developing topical sildenafil for local treatment of erectile dysfunction has been of great interest in pharmaceutical research. Sildenafil citrate (SC) exhibited a well-documented success for treatment of several types of erectile dysfunction. However, its oral use is limited by serious adverse effects, poor bioavailability, delayed onset, and drug-drug interactions. This work is the first to design and assess sildenafil-loaded bilosomes for topical local treatment of erectile dysfunction. Different sildenafil-loaded bilosomes were prepared and characterized. Permeability of selected formulations was conducted through full-thickness human skin. Optimized bilosomes integrating sodium tauroglycocholate (STGC) showed spherical shape with good particle size (133 nm), high zeta potential (-53.6 mV) and high entrapment efficiency (87.45%). Ex-vivo permeability study revealed that about 39% of the applied dose permeated within 15 min. Furthermore, in-vivo appraisal of therapeutic efficacy was performed using aged male Sprague-Dawley rats. After single application of 2 mg/kg sildenafil loaded in STGC-bilosomes, behavioral and biochemical evaluation was carried out. Behavioral assessment recorded an increased rats’ potency manifested as 2 folds increase in intromission frequency and intromission ratio compared to untreated group. That was accompanied by significant increase in cGMP concentration in corpora cavernosa (P < 0.0001) confirming increased potency. In conclusion, STGC-bilosomes could provide topical treatment of impotence with 20% of the oral dose and fast onset of action (10 min).
The transient dermal exposure is one where the skin is exposed to chemical for a finite duration, after which the chemical is removed and no residue remains on the skin's surface. Chemical within the skin at the end of the exposure period can still enter the systemic circulation. If it has some volatility, a portion of it will evaporate from the surface before it has a chance to be absorbed by the body. The fate of this post-exposure "skin depot" is the focus of this theoretical study. Laplace domain solutions for concentration distribution, flux, and cumulative mass absorption and evaporation are presented, and time domain results are obtained through numerical inversion. The Final Value Theorem is applied to obtain the analytical solutions for the total fractional absorption by the body and evaporation from skin at infinite time following a transient exposure. The solutions depend on two dimensionless variables: χ, the ratio of evaporation rate to steady-state dermal permeation rate; and the ratio of exposure time to membrane lag time. Simple closed form algebraic equations are presented that closely approximate the complete analytical solutions. Applications of the theory to the dermal risk assessment of pharmaceutical, occupational, and environmental exposures are presented for four example chemicals. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.
An in vitro technique for the prediction of percutaneous penetration/dermal absorption is recommended by the European SCCNFP (The Scientific Committee on Cosmetic Products and Non-Food Products intended for consumers) for the safety evaluation of particular ingredients. In 2002, this in vitro method became officially accepted at the OECD level and will be published as OECD Guideline 428. Examples are given for its routine application, demonstrating the bioavailability of cationic azo hair dyes out of an aqueous solution compared to data from a realistic standard hair dye formulation. Data from two direct hair dyes, BASIC BROWN 17 and BASIC YELLOW 57, demonstrate the results of applying this new in vitro technique without radiolabelled material. Direct hair dyes are frequently used in semi-permanent cosmetic hair colourations without the additional need for hydrogen peroxide. In the light of the in-house experience over about 5 years in using excised pig skin for measurements of the percutaneous penetration and dermal absorption of hair dyes, the technique was found to be successful and appropriate for reducing the number of test animals normally used for toxicological assessments.
COLIPA (the European Federation of the Cosmetics Industry) represents 24 international companies and 2000 small and medium-sized enterprises. Together with ECVAM, COLIPA has been involved in the development and validation of alternative methods since the beginning of the validation efforts. The work of the Steering Committee on Alternatives to Animal Testing (SCAAT) is based on collaboration between companies, but also with academia, trade associations, the Scientific Committee on Cosmetics and Non-Food Products (SCCNFP), European Commission Directorates General, and ECVAM. Some success has been achieved, but some validation efforts have failed. One lesson is that the search for alternatives requires a lot of humility.
The aim of this study was to investigate the cutaneous penetration and metabolism of the new vitamin E prodrug delta-tocopherol glucoside (delta-TG), as compared to those of common vitamin E acetate, in vitro, both in reconstituted human epidermis and in viable human skin. Better diffusion was observed with alpha-tocopherol acetate (alpha-TAc) than with delta-tocopherol glucoside in both skin models, at 0.1% and 0.05% in a myritol solution; however, no metabolism was detected with alpha-tocopherol acetate. In all conditions tested (two skin models, two concentrations, three test times, and compartmental analysis) the delta-tocopherol glucoside was metabolized into free tocopherol. In the reconstituted human epidermis, after 18 h, over 90% of the delta-tocopherol glucoside was bioconverted. In the viable human skin, the extent of metabolism was about 20%, with 0.12 and 0.10 microg/cm2 of delta-tocopherol glucoside in the stratum corneum and epidermis, respectively. After topical application, the delta-tocopherol glucoside had a considerable reservoir effect, associated with gradual delivery of free tocopherol. The use of this gluco-conjugated vitamin E at a low concentration shows the capability of the skin to metabolize the prodrug in a slow and prolonged manner, making this gluco-conjugated vitamin E an excellent candidate for continuous reinforcement of antioxidants in the skin.
Following an in-house comparison of permeation data from rats in vivo and pig skin in vitro, which resulted in very good correlations, in this series of experiments we compare the skin permeability of a number of hair dyes obtained in two different laboratories. Despite the fact that in vivo and in vitro experiments, although performed under very similar conditions, were in general spaced by several years, performed by different personnel, and with different chamber systems for in vitro experiments, the comparisons again gave good correlations. In general, the results demonstrate that rat skin is moire permeable than pig skin. The results presented, with the excellent correlations among species, further suggest that pig skin can favorably replace skin from laboratory animals for in vitro experiments and thus contribute to reducing the number of laboratory animals required.
Synopsis The percutaneous permeation of two oxidative hair dyes was measured by means of pig skin in a flow-through diffusion cell system entirely constructed from Teflon. Pig skin membranes were prepared by reducing full thickness skin with a dermatome to a more in vivo-like barrier layer and their integrity was checked by measuring the steady-state permeation of tritiated water. Initially, the inter- and intraindividual variability of percutaneous permeation was determined with an aqueous solution of 1-(2'-hydroxyethyl)-amino-3,4-methylenedioxybenzene-hydrochloride, an oxidative hair dye component. In the same way the proper flow rate of elution fluid through the receptor cell was found to be most favourable at 10 ml h(-1), the thickness of permeation membranes was fixed at 1 mm, and it was shown that storage of the skin at -20 degrees C for up to 35 days did not change the permeability. The percutaneous permeation of the same hair dye component and of 4-amino-2-hydroxymethylphenol-hydrochloride was determined after application to pig skin membranes under practical conditions of hair dyeing. The in vitro skin permeation was in the same order of magnitude as results from comparable in vivo skin absorption studies in rats. Perméation percutanée in vitro de colorants d'oxydation pour cheveux.
In vitro absorptionlpenetration with pig skin: Instrumentation and comparison 0/ jlow-through versus static-diffusion protocol
  • Ek Noser
  • C Faller
  • M Bracher
Noser EK., Faller C. & Bracher M., In vitro absorptionlpenetration with pig skin: Instrumentation and comparison 0/ jlow-through versus static-diffusion protocol, 1. AppL Cosmetol. 6, pp. 111-122, 1988.
Companson 0/ in vitro and in vivo skin absorption/penetration 0/ dyes in: Prediction 0/ Percutaneous Penetration-Methods, Measurements, Modelling (Ed
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Comparison 0/ in vitro and in vivo skin absorption
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Beck H. Bracher M., Faller e. & Hofer H., Comparison 0/ in vitro and in vivo skin absorption/penetration 0/ hair dyes, Cosmetics & Toiletries, 108, pp. 76-83, 1993.
Bandrowski's Base: HPLC Analysis and cutaneous absorptionlpenetration
  • H Beek
  • M Bracher
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Beek H., Bracher M. & Spengler J., Bandrowski's Base: HPLC Analysis and cutaneous absorptionlpenetration, Conference Proceedings 16th IFSCC Int. Congress, New York, pp. 250-262, 1990.
Dermal and transdermal absorption
  • R Brandau
  • B H Lippold
Brandau R., Lippold B.H., Dermal and transdermal absorption, Wissenschaftliche Verlagsgesellschaft GmbH, Stuttgart, 1982.
Prediction 01 percutaneous penetration: methods, measurements, modelling, mc
  • Scott R C Guy
  • R H Hadgraft
Scott R.C., Guy R.H., Hadgraft J., Prediction 01 percutaneous penetration: methods, measurements, modelling, mc, 1990.
Percutaneous absorption: mechanisms, methodology, drug delivery
  • Rl Bronaugh
  • Rl Maibach
Bronaugh RL., Maibach RL, Percutaneous absorption: mechanisms, methodology, drug delivery, Mareell Dekker Ine., 1989.