Review
Transfollicular drug delivery—Is it a reality?

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Abstract

Once regarded as merely evolutionary remnants, the hair follicles and sebaceous glands are increasingly recognised as potentially significant elements in the percutaneous drug delivery paradigm. Interest in pilosebaceous units has been directed towards their use as depots for localised therapy, particularly for the treatment of follicle-related disorders such as acne or the alopecias. Furthermore, considerable attention has also been focused on exploiting the follicles as transport shunts for systemic drug delivery. This paper reviews various key facets of this field including; relevant aspects of pilosebaceous anatomy and physiology, the design and efficacy of follicle-targeting formulations and the emergence of quantitative modeling systems. Several novel developments in this area promise to greatly expand our understanding of this field in the near future.

Introduction

For several decades, researchers working with human skin have questioned the relative importance of drug transport through the continuous stratum corneum versus drug penetration through the follicular shunts of the pilosebaceous units. Although very early work suggested that follicles played a negligible role in facilitating steady state drug penetration (Scheuplein, 1965), the results of subsequent investigations began to cast some doubt on this concept. Specifically, qualitative dye and stain localisation studies provided evidence for penetrant accumulation in the hair follicles (Scheuplein, 1967, Rutherford and Black, 1969) while the greatest absorption of some compounds was observed in regions exhibiting the highest follicular densities (Feldman and Maibach, 1967, Tur et al., 1991). However, these findings subsequently proved difficult to interpret since the most follicle-rich regions were also associated with small corneocyte size, which would influence non-follicular absorption. Despite these caveats and the fact that the nature of pilosebaceous transport mechanisms has yet to be established, recent years have tended to yield progressively more data suggesting that follicular drug penetration could be more significant than previously believed (Lademann et al., 2001, Essa et al., 2002, Grams et al., 2004a). Within this context, it is important to distinguish between two largely distinct drug delivery paradigms. These are pilosebaceous drug depot applications for localised therapeutic targeting versus transfollicular shunt transport for accelerated systemic drug delivery.

After reviewing the anatomic, physiological and site distributions of hair follicles, this paper considers the potential therapeutic rationale of targeting drugs to these structures. Subsequently, there is a discussion of pilosebaceous drug delivery barriers as well as the literature pertaining to distinct drug carrier systems. Finally, emerging methodologies are discussed that should reveal more about this intriguing and complex delivery route.

Section snippets

The pilosebaceous units: anatomy and physiology

The pilosebaceous unit is a term used to describe the integrated structure of the hair follicle, hair shaft, adjoining arrector pili muscle and associated sebaceous gland(s). Since the anatomy and biology of these structures have been reviewed extensively in the literature (Whiting, 2000), these details are discussed relatively briefly here.

The hair follicle consists of a hair bulb and shaft enveloped in an inner root sheath, an outer root sheath and an outermost acellular basement membrane

Regional variations in follicular densities

It is noteworthy that the skin density of pilosebaceous units varies greatly according to body region. On the face and scalp, there are 500–1000 pilosebaceous units per square centimeter with each follicular opening exhibiting a diameter of some 50–100 μm. The combined areas of these orifices may represent as much as 10% of the total surface area of the face and scalp. In other parts of the body, the follicular openings constitute only about 0.1% of the total skin area (Schaefer and Redelmeier,

Drug targeting sites

The sebaceous glands, implicated in the aetiology of both androgenetic alopecia (Meidan and Touitou, 2001) and acne (Thiboutot, 2004), represent an obvious therapeutic target site. Considerable effort has been directed towards maximizing the accumulation of various bio-molecules in these androgen-responsive glands. Examples of investigated drugs include adapalene (Rolland et al., 1993), an erythromycin–zinc complex (Morgan et al., 1993), isotretinoin (Tschan et al., 1997), and the anti-androgen

Barriers to follicular drug delivery

Although the pilosebaceous units may be desirable as either target sites or shunts for drug delivery, access to these structures can be problematic due to architectural and physicochemical constraints. Table 1 lists these potential barriers and the corresponding resolving strategies.

In the case of particulate delivery systems, the size selectivity of the follicular openings can represent a potential barrier. Schaefer's group (Schaefer et al., 1990) found that the follicular deposition of

Strategies for enhanced follicular delivery

Numerous studies have suggested that the extent of follicular delivery may be modulated by applying certain approaches. Adopted strategies have included; the use of optimised vehicles, microspheres, liposomes, lipoplexes as well as iontophoresis. The literature pertaining to each of these approaches is sequentially discussed below.

Emerging follicular methodologies

To date, a major problem in evaluating transfollicular drug delivery has been the lack of a quantitative model system that is truly follicle-free but retains the structural, biochemical and barrier properties of normal skin. Previously employed models such as the Syrian hamster ear, the fuzzy rat, the macaque monkey and the regrown scar tissue system have proved extremely useful for studying follicular penetration (Lauer et al., 1995). However, these systems do not fulfill the criteria stated

Conclusions

It can be concluded that transfollicular drug delivery is indeed a reality but that at present its therapeutic value is still under question. It appears that this delivery route is quite complex in nature and that drug transport through the appendages is probably modulated by an array of different variables. To date, most of the work in this field has been undertaken using a multiplicity of; drugs, skin models, application protocols and end-point evaluation modes. As a result, it has been

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