Possible routes of penetration through hair follicles could involve the hair fiber itself, through the outer root sheath of the hair into the viable cells of the follicle, or through the air-filled canal and into the sebaceous gland. In addition, the release of sebum by the sebaceous glands may provide a lipoidal pathway that may influence absorption by this route (228). The route for the sweat duct may involve diffusion through either the lumen or walls to below the epidermis and through the thin ring of kera-
tinized cells. Dense capillary networks closely envelop the bases of both the hair follicles and sweat ducts, providing access to the circulation for most molecules reaching these regions. Hueber et al. (229) used the observation that a higher reservoir and permeability barrier function in appendage-free (scar) SC than in normal SC, as supporting evidence for a significant contribution of the appendageal route to overall skin transport.
There are estimated to be close to 500-1000 pilosebaceous units/square centimeter of skin on areas such as the face and scalp, each with an orifice with a diameter of 50-100 ¡m and 4 X 10~5 cm2 surface area. These orifices represent 0.1% of the surface area of the skin in low-density areas and up to 10% in high-density areas, such as those on the face and scalp. The openings lead down to an epithelial surface which does not have a protective SC, and exists only from the ostia of the sebaceous gland upward to the skin surface (Fig. 35). These characteristics have been used to selectively target drugs into the hair follicles and sebaceous glands. Given that the exposed surface area of appendages is much higher than that of the openings used in earlier evaluations and that the current intercellular transport also has a restricted area for transport, the role of the follicle as a pathway for transdermal delivery is being reconsidered. In the hair follicle, for example, the outer
root sheath (see Fig. 35) is thought to be of greatest importance for drug delivery, as this layer is continuous with the epidermis and is indistinguishable from it, which potentially allows for increased surface area for absorption beneath the skin's surface. In addition, there is increasing demand for localized drug delivery to the hair follicle itself, particularly for the treatment of dermatological disorders such as acne, alopecia, areata, and androgenetic hair loss.
One of the most important determinants of targeted follicular transport is the particle size of applied materials. By using fluorescent microspheres, Rolland et al. (230) showed that the degree of penetration into the human hair follicle was inversely related to particle size. The optimum size at which microspheres selectively entered follicles was 3-10 ¡m; below this size, particles were also seen to be distributed in the superficial layers of the SC (see Fig. 35). The depth of penetration into the follicle was also determined by size, with beads of 5-7 ¡m reaching the deeper parts of the upper follicle, though rarely penetrating the superficial SC, and those between 9 and 10 ¡m were observed to concentrate only around the opening of the follicles, but not inside them. No beads larger than 1 ¡m were observed to penetrate as deep as the hair bulb of the follicles.
Recent studies using fluorescence-labeled oligonucleotides and dextrans applied to fresh human scalp skin confirmed earlier findings that follicular penetration was determined by size and also charge (231). These studies also identified that the primary anatomical structures for the pathway(s) of intrafollicular delivery of these molecules were along the junction of the inner root sheath and outer root sheath (see Fig. 35). Although this pattern of distribution was particularly evident with oligomers formulated with cationic lipids, the molecular features that allow a selected agent to move into and through this region await definition. In the same study, it was also noticed that rhodamine-labeled dextran (3000 MW) applied in a hydroalcoholic formulation (40% ethanol) was present in the center of the hair shaft as well as within the follicle. It was speculated that this region of the hair shaft may be more amorphous relative to keratin content compared with the rest of the hair; therefore, it may be more permeable to certain agents, although whether entry occurred by diffusion across the hair shaft or down the cut end of the hair was unclear.
The concept that vehicle and formulation significantly influence the rate of drug localization within hair follicles, following the application of vitamin A in various vehicles to guinea pigs back, was noticed in 1954 by Montagna (232). Reviews covering formulation effects, in particular the use of liposomes, to optimize transfollicular delivery can be found (233,234). Some of the literature in this area pointing to the favoritism for lipophilic vehicles in follicular targeting is outlined in Table 11.
It can be seen from Table 11 that alcoholic vehicles are among those tending to increase transfollicular penetration. Bamba and Wepierre (235) speculated that, as ethanol is primarily a lipid solvent, as well as increasing the fluidity of lipid areas within the SC and extending the hydrophobic domain between polar head groups, it was also acting on the sebum within the follicles and allowing the more rapid migration of solute in the sebaceous glands, thereby making the transfollicular pathway predominant in the initial stages of absorption. DMSO is thought to act on normal SC by creating a ''solvent pathway'' through the skin or fluidizing the lipids (140). However, in the studies of Bamba and Wepierre (235) the concentration was too weak to have this enhancing effect through the whole epidermis, and it was suggested that its solvent properties would favor pilosebaceous migration by incorporating the drug in the sebum.
The contribution of transappendageal transport to systemic clearance, rather than local deposition, was considered by Maibach et al. (236) following the topical application of radiolabeled pesticides to human volunteers. A greater urinary recovery was noted after application to follicle-rich areas, such as the forehead and scalp, than after application to less hairy areas such as the forearm. The authors concluded that transfollicular transport could not be ruled out as a contributing factor to the observed differences. However, studies examining the effect of increasing hair folicle density on percutaneous absorption (237) failed to show any correlation with the amount of solute absorbed, suggesting that the follicles' overall contribution to transdermal delivery is negligible.
In the recent review by Lauer (238), it was concluded that the contribution of the pilosebaceous unit to localized and percutaneous absorption may have been underestimated in the past and that a more detailed understanding of formulation factors, such as drug and vehicle physicochemical properties and particle size, may allow optimization of follicular delivery. The potential clinical significance of the ability to selectively deliver drugs to follicles for the treatment of associated der-matological disorders warrants the pursuit of this area of transdermal research.
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