STRUCTURE AND PERMEABILITY OF HUMAN NAIL 383 of drugs across the nail plate and the extremely long treatment periods required to achieve reasonable drug concentrations in the nail. The highly cross-linked nature of the keratin network makes it difficult for actives to reach the site of infection inside the nail and in the nail bed. The nail lipid content is found to be low. Recent experiments suggest that the dorsal layer of the nail is the main barrier to penetration of actives. The water content and flexibility of the nail are seen to increase after immersion in water, and the nail is found to be much more porous to water than is stratum corneum. The nail plate has been found to favor the permeation of small molecules and is pos- tulated to behave as a hydrogel barrier in some instances. Some studies indicate that pH at•cts nail permeation since the unionized form of the drug seems to preferentially permeate, although contradictory results have been reported. It has generally been found that water-soluble drugs permeate the nail in higher quantities, compared with water- insoluble compounds. Due to the extremely poor permeability of drugs (including antimycotics) across the nail plate, recent research has focused on nail penetration enhancement. A potential method for enhancing drug transport across the nail plate may be to treat the nail with an agent capable of reducing disulfide linkages (-S-S-) in the keratin matrix. Several researchers have reported the utility of N-acetyl-l-cysteine as an effective reducing agent for im- proving topical penetration of drugs through the nail. Urea has also been reported to have a beneficial effect on nail penetration enhancement. It is necessary to balance factors such as molecular size, charge, and lipophilicity of the permeant when designing topical products for nails. One must also ensure that the formulation adheres fairly well to the nail plate in order to achieve effective drug concentrations in the nail for a sufficient length of time. Inclusion of compounds that can directly interact with sites on nail keratin can improve drug penetration. Thus, recent studies have allowed to us to better understand the structural and permeability prop- erties of the nail. However, there is still a need for further research so that effective topical treatment for nail disorders can be achieved in the near future. REFERENCES (1) P.J. Basuk, R. K. Scher, and A. R. Ricci, "Dermatological Diseases of The Nail Unit," in Nails: Therapy, DiagnosE, Surgery, R. K. Scher and C. R. Daniel, Eds. (W. B. Saunders, Philadelphia, 1990), pp. 127-152. (2) C.R. Daniel, "Nonfungal Infections," in Nails: Therapy, DiagnosE, Surgery, R.K. Scher and C. R. Daniel, Eds. (W. B. Saunders, Philadelphia, 1990), pp. 120-126. (3) L. Haley and C. R. Daniel, "Fungal Infections," in Nails: Therapy, Diagnosis, Surgery, R. K. Scher and C. R. Daniel, Eds. (W. B. Saunders, Philadelphia, 1990), pp. 106-119. (4) R. Baran and R. P. R. Dawber, "The Nail and Cosmetics," in The Nails in Disease, 4th ed., P. D. Samman and D. A. Fenton, Eds. (Year Book Medical Publishers, Chicago, 1986), pp. 126-134. (5) J. T. Wang and Y. Sun, Human nail and its topical treatment: Brief review of current research and development of topical antifungal drug delivery for onychomycosis treatment, J. Cosmet. Sci., 50, 71-76 (1999). (6) P. D. Samman, "Principal Nail Symptoms," in The Nails in Disease, 4th ed., P. D. Samman and D. A. Fenton, Eds. (Year Book Medical Publishers, Chicago, 1986), pp. 20-26. (7) C. M. Tom and M.P. Kane, Management of toenail onychomycosis, Am. J. Health Syst. PEarre., 56, 865-871 (1999). (8) H. P. Baden, andJ. C. Kvedar, "Biology of Nails," in Dermatology in Genera/Medicine, T. B. Fitzpatrick, A. Z. Eisen, K. Wolff, and K. F. Austin, Eds. (McGraw-Hill, New York, 1993), Vol. 1, pp. 294-297.

384 JOURNAL OF COSMETIC SCIENCE (9) U. Runne and C. E. Orfanos, The human nail: Structure, growth and pathological changes, Curr. Probl. Dermatol., 9, 102-149 (1981). (10) P. D. Samman, "Anatomy and Physiology," in The Nails in Disease, 4th ed., P. D. Samman and D. A. Fenton, Eds. (Year Book Medical Publishers, Chicago, 1986), pp. 1-19. (11) T. Kitihara and H. Ogawa, Coexpression of keratins characteristic of skin and hair differentiation in nail cells, J. Invest. Dermatol., 100, 171-175 (1993). (12) T. Kitihara and H. Ogawa, Cellular features of differentiation in the nail, Microscopy Res. Tech., 38, 436•442 (1997). (13) H. P. Baden, L. A. Goldsmith, and B. Fleming, A comparative study of the physicochemical properties of human keratinized tissues, Blochim. Biophys. Acta, 322, 269-278 (1973). (14) R. C. Marshall and J. M. Gillespie, The keratin proteins of wool, horn and hoof from sheep, Aust. J. Biol. Sci., 30, 389•400 (1977). (15) M. S. Greaves and J. M. H. Moll, Amino acid composition of human nail, as measured by gas-liquid chromatography, C/in. Chem., 22, 1608-1613 (1976). (16) S. Shono and K. Toda, The structure proteins of the human nail, Curt. ProbL Dermatol., 11, 317-326 (1983). (17) A. K. Allen, J. Ellis, and D. E. Rivett, The presence of glycoproteins in the cell membrane complex of a variety of keratin fibers, Biochim. Biophys. Acta, 1074, 331-333 (1991). (18) O. D. Vellar, Composition of the human nail substance, Am. J. C/in. Nutrit., 23, 1272-1274 (1970). (19) A. Jarrett and R. I. C. Spearman, The histochemistry of the human nail, Arch. Dermatol., 94, 652-657 (1966). (20) E. L. Kanabrocki, J. A. Kanabrocki, J. Greco, E. Kaplan, Y. T. Oester, S.S. Brar, P.S. Gustafson, D.M. Nelson, and C. E. Moore, Instrumental analysis of trace elements in thumbnails of human subjects, Sci. Tot. Env., 13, 131-140 (1979). (21) M. Feughelman, "Morphology and Properties of Hair," in Hair and Hair Care, D. H. Johnson, Ed. (Marcel Dekker, New York, 1997), pp. 1-12. (22) J. Bersaques, Keratin and its formation, Curr. Prob. Dermatol., 6, 34-86 (1976). (23) J. M. Steinert and J. S. Cantieri, "Epidermal Keratins," in Biochemistry and Physiology of the Skin, L. A. Goldsmith, Ed. (Oxford University Press, New York, 1983), pp. 135-169. (24) R. C. Marshall, Characterization of the proteins of human hair and nail by electrophoresis, J. Invest. DermatoL, 80, 519-524 (1983). (25) R. Caputo, G. Gasparini, and D. Contini, A freeze-fracture study of the human nail plate, Arch. Dermatol. Res., 272, 117-125 (1982). (26) G. E. Burch and T. Winsor, Diffusion of water through dead plantar, palmar and torsal human skin, and through toenails, Arch. Dermatol. Syph., 51, 39-41 (1946). (27) H. P. Baden, The physical properties of nail, J. Invest. DermatoL, 55, 115-122 (1970). (28) B. Forslind, G. Nordstrom, D. Toijer, and K. Eriksson, The rigidity of human fingernails: A bio- physical investigation on influencing parameters, Acta Derre. VenereoL, 60, 217-222 (1980). (29) D. Spruit, Measurement of water vapor loss through human nail in vivo, J. Invest. Dermatol., 56, 359-361 (1971). (30) A. Y. Finlay, P. Frost, A.D. Keith, and W. Snipes, An assessment of the factors influencing flexibility of human fingernails, Br. J. DermatoL, 103, 357-365 (1980). (31) G. B. E. Jemec, T. Agner, and J. Serup, Transonychial water loss: Relation to sex, age and nail-plate thickness, Brit. J. DermatoL, 121,443•446 (1989). (32) K. A. Walters, G. L. Flynn, and J. R. Marvel, Physicochemical characterization of the human nail. I. Pressure sealed apparatus for measuring nail plate permeabilities, J. Invest. Dermatol., 76, 76-79 (1981). (33) K. A. Walters, G. L. Flynn, and J. R. Marvel, Physicochemical characterization of the human nail: Permeation pattern for water and the homologous alcohols and differences with respect to stratum corneum, J. Pharm. PharmacoL, 35, 28-33 (1983). (34) K.A. Walters, G. L. Flynn, and J. R. Marvel, Physicochemical characterization of the human nail: Solvent effects on the permeation of homologous alcohols,J. Pharm. PharmacoL, 37,771-775 (1985). (35) M. H. Soong, Transport properties of drugs and model compounds across the human nail, Ph.D. dissertation, University of Minnesota (1991). (36) D. Mertin and B.C. Lippold, In-vitro permeability of the human nail and of a keratin membrane from bovine hooves: Influence of the partition coefficient octanol/water and the water solubility of drugs on their permeability and maximum fiux, J. Pharm. Pharmacol., 49, 30-34 (1997).