Percutaneous drug delivery to the hair follicle

Unique biochemical and immunological events dictate the complex cyclic growth and differentiation patterns of hair follicles and their associated sebaceous glands (1), structures that are collectively referred to as pilosebaceous units. Once regarded as mere evolutionary remnants, hair follicles and sebaceous glands have been recognized increasingly as significant pathways for percutaneous transport (2). Percutaneous transport routes via the lipoidal domains of the stratum corneum have been well established (3,4), whereas comparatively less is known about the specific roles of hair follicles and sebaceous glands. Determination of the roles of these structures is complicated by the lack of adequate animal models and methodologies that can distinctly distinguish follicular and stratum corneumpathways.Moreover, it may be possible that a topically applied compound traverses more than one pathway simultaneously. The stratum corneum is acknowledged not only as the main barrier to skin penetration, but also as the major permeation pathway. The tightly packed, semicrystalline intercellular lipid domains and the extremely compact corneocytes of the stratum corneum create a barrier highly resistant to percutaneous transport (3,4). Modulation of stratum corneum lipid fluidity by topical agents has been thoroughly studied and is generally acknowledged as the major mechanism of percutaneous delivery (5). Passive percutaneous transport depends on several factors, including penetrant lipophilicity, charge, and molecular size (6). The upper limit of molecular size for permeation through the stratum corneum is still unknown. Early suggestions of a follicular pathway were based on the hypothesis that hair follicles act as shunts, resulting in the rapid transport of ions and large polar molecules. Scheuplein (7) and Scheuplein et al. (8) first described transient follicular delivery for small polar molecules and large polar steroids that ordinarily would not be expected to traverse the skin rapidly due to their charge or restrictive molecular size. Feldmann and Maibach (9) and Maibach et al. (10) observed increases in percutaneous transport through skin areas with greatest follicular densities in both animals and humans, which also hinted at the possibility of follicular delivery.