The Effect of Perfusion Rate on In Vitro Percutaneous Penetration**From the Division of Dermatology, University of California School of Medicine, San Francisco, California 94122.

This study presents data on the effect of varying dermal perfusion rates in an in vitro chamber on percutaneous penetration. Increasing the perfusion flow rates significantly increases the penetration rate with the compounds studied. This suggests that the data obtained in in vitro studies will be more meaningful when ideal flow rates are determined for such chambers and validated with in vivo data

Relevance of Skin Enzymes for Rational Drug Design

Transdermal therapeutic systems (TTS) have numerous pharmacological benefits. Drug release, for example, is independent of whether a patient is in a fed or a fasted state, and lower doses can be given as gastrointestinal and hepatic first-pass metabolism is avoided. In addition, inter- and intrapatient variability is minimized as the release of the drug is mainly controlled by the system. This makes TTS interesting as alternative systems to the most common dosage form of oral tablets. The difficulty with the dermal administration route is transporting the drug through the skin, since the skin is an efficient barrier against foreign bodies. Various strategies have been reported in the literature of how drug penetration can be improved. Most of them, however, focus on overcoming the stratum corneum as the first (mechanical) skin barrier. However, penetration is much more complex, and the skin’s barrier function does not only depend on the stratum corneum; what has been underestimated is the second (biological) skin barrier formed of enzymes. Compared to the stratum corneum, very little is known about these enzymes, e.g., which enzymes are present in the skin and where exactly they are localized. Hence, very few strategies can be found for how to bypass or even use the skin enzyme barrier for TTS development. This review article provides an overview of the skin enzymes considered to be relevant for the biotransformation of dermally applied drugs. Also, we discuss the use of dermal prodrugs and soft drugs and give the stereoselectivity of skin metabolism careful consideration. Finally, we provide suggestions on how to make use of the current knowledge about skin enzymes for rational TTS design

The Hairless Rat: A Relevant Animal Model to Predict In Vivo Percutaneous Absorption in Humans?

Percutaneous absorption of 4 radiolabeled molecules was compared in the hairless rat (back) and in different anatomic sites in human (arm, abdomen, postauricular, forehead). The conditions under which these 4 compounds were administered (area treated, dose, vehicle, contact time, etc.) were similar in both species. The results showed that, in humans and rats, there exists the same rank order in total absorption: benzoic acid sodium salt < caffeine < benzoic acid < acetylsalicylic acid. In both species there was a factor of 3 between the most and the least absorbed molecule. Although skin permeability varied significantly with the physicochemical nature of the compound administered, it also depended on the anatomic site involved. Independent of the molecule studied, the rank order of permeability of the sites tested in humans appeared as follows: arm ≤ abdomen < postwar < forehead. There was a factor of 3 between the most and the least permeable sites. For each molecule and each anatomic site, the ratios of total percutaneous absorption human/hairless rat (back) were determined. For a given anatomic site and whatever the molecule tested, these ratios were constant. It thus appears that when conditions are carefully controlled, it may be possible, by measurements on animals, to predict the absorption of a compound in humans. Further experimentation with chemicals of varied physicochemical properties will be required for validation of the model

Human skin retention and penetration of a copper tripeptide in vitro as function of skin layer towards anti-inflammatory therapy

The skin retention and penetration characteristics of copper applied as glycyl-l-histidyl-l-lysine cuprate diacetate were evaluated in vitro in order to assess the potential for its transdermal delivery as anti-inflammatory agent. Flow-through diffusion cells with 1 cm2 exposure area were used under infinite dose conditions. 0.68% aq. Copper as a tripeptide was applied on isolated stratum corneum, on heat-separated epidermis and on dermatomed skin. Receptor fluid collected over 48 h in 4 h intervals was analyzed by inductively coupled plasma mass spectrometry for copper in tissues and receptor fluid. The permeability coefficient of the compound through dermatomed skin was 2.43 ± 0.51 × 10−4 cm/h; 136.2 ± 17.5 μg/cm2 copper permeated 1 cm2 of that tissue over 48 h, while 82 ± 8.1 μg/cm2 of copper were retained there as depot. Applied tansdermally as the tripeptide on human skin ex vivo, copper permeated the skin and was also retained in skin tissue in amounts potentially effective for the treatment of inflammatory diseases

Skin Permeability In Vivo: Comparison in Rat, Rabbit, Pig and Man

A comparative study was undertaken in rats, rabbits, miniature swine and man, in which the percutaneous absorption of the following compounds, labeled with 14C or 35S, were studied: haloprogin, N-acetylcysteine, cortisone, testosterone, caffeine and butter yellow. The amount of radioactivity excreted in urine for 5 days following application of the test compound to the skin was employed as the index for quantifying skin penetration. A special nonocclusive foam pad device for rabbits and miniature swine was developed to prevent artifacts resulting from transfer of drug to the urine by any route other than percutaneous absorption. The dose was 4 μg/cm2 of skin surface. The excretion data obtained from the topical studies were adjusted for recovery of radioactivity following intravenous administration of the radioactive drug. The results obtained in this study indicated that skin permeability decreases in the following order: rabbit, rat, pig and man. Overall, skin of miniature swine has the closest permeability characteristics to that of human skin with this series of compounds

Deep Percutaneous Penetration into Muscles and Joints: Update

Transdermal drug delivery is a multifactorial process with variable penetration mechanisms.  Adverse effects associated with nonsteroidal anti-inflammatory drugs’ (NSAIDs) use in treatment for joint and muscle diseases are sufficiently severe to consider topical application.  A drug's lipophilicity, fraction unbound and permeability found in the viable skin are some of the physiochemical factors influencing the delivery mechanism of transdermal absorption. These and other variables play a role in determining if the drug reaches the deep tissues via direct penetration from dermal or systemic blood redistribution.  Pharmacokinetic models have been developed to help elucidate penetration routes and efficacy for various drugs. Improvements in modes of transdermal delivery through active research projects including relevant animal models and human translational research may introduce advances in clinical development of treatments

A Systematic Search for Structure-Activity Relationships of Skin Contact Sensitizers: Methodology

A computerized resource for the systematic evaluation of the structure-activity relationships and other aspects of contact allergens is described. This resource consists of a data base of results of contact dermatitis tests and a structural classification scheme for contact allergens that is called a Structure-Activity (S/A) Tree. The data base now contains approximately 2200 test results extracted from the journal Contact Dermatitis (1975–1982) and is continually being expanded. The S/A Tree is being developed to provide an index to structure-activity relationships of contact allergens; 63 structural groups are currently indexed. Analyses of benzoquinones and gallic acid esters are presented as examples of the potential application of this resource to such problems as the identification of potential cross-reactants, appropriate test concentrations and vehicles, and the reliability of available test results