Drug Targeting to the Hair Follicles: A Cyclodextrin-Based Drug Delivery

Abstract

Topical drug delivery systems that selectively target hair follicles and sweat glands are of interest to both the pharmaceutical and the cosmetic industry not only to treat dermal complications but also for systemic drug delivery (1,2). Possible dermal applications include treatment of acne, inflammation, and hair growth disorders. Hair follicles are tube-like pockets of the epidermis that extend through most or all of the depth of the skin and enclose a small papilla of dermis in their base. The hair bulb, which lies at the base of the hair follicle, is a structure of actively growing cells that eventually produce the long fine cylinder of a hair. Attached to the follicle are one or more sebaceous glands. The hair shaft is enveloped in an inner root sheath that consists of keratin-rich cells that have migrated from the growing cells that line the inside of the hair follicles (Fig. 1). Microparticulate vehicles, like liposomes (2,3) and nanoparticles (4), have been shown to deliver drug molecules much deeper into the hair follicles than conventional formulations like creams and ointments. It has been shown that liposomes and nanoparticles with diameter between 300 and 750 nm penetrate preferentially into the hair follicles (5) and that titanium dioxide particles with a diameter of about 100 nm penetrate into the hair follicles (6). Fig. 1 A schematic drawing of a hair follicle Cyclodextrins (CDs) are cyclic oligosaccharides that have in recent years been introduced to the pharmaceutical industry as novel enabling excipients, mainly as solubilizing complexing agents for enhanced drug bioavailability (7,8). CDs consist of six (αCD), seven (βCD), eight (γCD), or more α-1,4-linked α-d-glucopyranose units forming a somewhat truncated cone. The hydroxy groups are oriented towards the cone exterior, making the external surface hydrophilic, while the central cavity is lined by the carbons and ethereal oxygens of the carbohydrate skeleton, making it somewhat hydrophobic. CDs form inclusion complexes by taking up a lipophilic drug molecule, or more frequently some lipophilic moiety on the drug molecule, into the lipophilic central cavity. Although such inclusion complexes are probably the most common form of drug/CD complexes, the hydroxy groups on the outer surface of the CD molecule are able to form hydrogen bonds with other molecules, and CDs can, like non-cyclic oligosaccharides and polysaccharides, form water-soluble non-inclusion complexes with lipophilic water-insoluble drugs (9–11). In saturated aqueous solutions, drug/CD complexes frequently consist of a mixture of inclusion and non-inclusion complexes. CDs and CD complexes are also known to self-associate to form nanoscale aggregates (12–14), and these aggregates are thought to be able to solubilize lipophilic drug molecules in micellar-like fashion (15). The diameter of these cyclodextrin aggregates has been determined to be about 100 to 600 nm (13,14,16). Thus, it is possible that drug/CD complexes will, like liposomes and nanoparticles, selectively target the hair follicles. The purpose of this study was to evaluate follicular targeting potential of drug/CD complexes using curcumin as a sample compound. Curcumin, a lipophilic fluorescent dye, is a non-toxic natural compound with very limited solubility in water. Curcumin forms water-soluble cyclodextrin complexes (17). Previously, curcumin has been used to detect follicular penetration from liposome formulations by laser scanning microscopy using pig skin as a model tissue (3,18,19).