What is already known about this subject • In recent years, it has been suggested that hair follicles represent important shunt routes into the skin for drugs and chemicals [ 1-3 ]. • In vitro studies have shown the importance of skin appendages for skin penetration by hydrophilic compounds [ 4 ]. Investigation of follicular penetration in vivo has been difficult due to the absence of appropriate analytical methods or suitable animal model systems. • Recently, a new method was described that quantifies follicular penetration in vivo by using selective closure of hair follicles [ 5 ]. • Caffeine is frequently used in skin penetration experiments as a model for highly water‐soluble compounds. Occlusion [ 6 ] and skin thickness [ 7 ] seem to have little influence on the penetration of caffeine. However, percutaneous absorption rates for caffeine exhibit regional skin differences in humans in vivo[ 1 ]. What this study adds • The results of the present study demonstrate that a fast drug delivery of caffeine occurs through shunt routes. Therefore, hair follicles are considerable weak spots in our protective sheath against penetration into the body by hydrophilic substances. • We showed that there is a quantitative distinction between follicular penetration and interfollicular diffusion of caffeine in vivo. • These findings are of importance for the development and optimization of topically applied drugs and cosmetics. In addition, such properties must be considered in the development of skin protection measures. Aims The skin and its appendages are our protective shield against the environment and are necessary for the maintenance of homeostasis. Hypotheses concerning the penetration of substances into the skin have assumed diffusion through the lipid domains of the stratum corneum. It is believed that while hair follicles represent a weakness in the shield, they play a subordinate role in the percutaneous penetration processes. Previous investigation of follicular penetration has mostly addressed methodical and technical problems. Our study utilized a selective closure technique of hair follicle orifices in vivo, for the comparison of interfollicular and follicular absorption rates of caffeine in humans. Methods Every single hair follicle within a delimited area of skin was blocked with a microdrop of a special varnish‐wax‐mixture in vivo. Caffeine in solution was topically applied and transcutaneous absorption into the blood was measured by a new surface ionization mass spectrometry (SI/MS) technique, which enabled a clear distinction to be made between interfollicular and follicular penetration of a topically applied substance. Results Caffeine (3.75 ng ml⁻¹) was detected in blood samples, 5 min after topical application, when the follicles remained open. When the follicles were blocked, caffeine was detectable after 20 min (2.45 ng ml⁻¹). Highest values (11.75 ng caffeine ml⁻¹) were found 1 h after application when the follicles were open. Conclusions Our findings demonstrate that hair follicles are considerable weak spots in our protective sheath against certain hydrophilic drugs and may allow a fast delivery of topically applied substances.

The optimization of drug delivery to and via the hair follicles is gaining more and more importance as it has been recognized that the hair follicles are an interesting target site for topical applications. They are closely surrounded by capillaries and antigen-presenting cells, are associated with the sebaceous glands and are the host of stem cells in the bulge region of the hair follicle. The present review shortly summarizes the complexity of the structure, biology and functions of the hair follicle and presents the models and methods suitable to investigate follicular penetration. Drug delivery to hair follicles was clearly shown to be dependent on the physicochemical properties of the applied substances and vehicles as well as on the activity status, size and density of the hair follicles. Especially particulate substances were demonstrated to be proficient drug carriers into the hair follicles, whereas dependent data for transfollicular penetration into the deeper viable skin layers could only be found for non-particulate substances which then, however, received rapid access to the circulation when the follicular pathway was accessible. Promising concepts to optimize hair follicle delivery and to beneficially utilize particulate substances for efficient follicular drug delivery are the application of external or internal stimuli for controlled drug release from the particles such as the combined application with protease or the usage of gold nanoparticles in combination with near-infrared irradiation.