PREPRINTS OF THE 1998 ANNUAL SCIENTIFIC MEETING 73 shown in the reaction below. Both cysteine and acetylcysteine have been used in Japan as hair-waving agents (15). Chemical Reaction Sequence: Nail-S-S-Nail + 2HSCH2t2qH2)COOH -• Cysteine -- 2 Nail-SH + HOOCH0qH2) CH•-S-S-CH(NH•)COOH Cysfine Reducing the disulfide bonds in the nail along with softening the nail plate could serve to open up the nail plate to drag penetration. To demonstrate enhanced penetration of anti-fungals into nail, in vitro methodologies such as nail swelling test, drug partitioning test, and drug permeation through human nails were used. The ability of a drug in a formulation to penetrate nail plate should be reflected by the rate and extent of the nail uptake of the formulation (i.e., nail swelling in the formulation), as well as by the amount of the drug migration into the nail (drug partitioning). Nail swelling and drug partitioning tests were conducted by immersing human nail clippings in a topical drug formulation at 32øC for two days. After washing off the surface-bond formulation, the nail clippings were first examined for weight gain, then digested and analyzed for drug analysis with a high pressure liquid chromatography method. Figures 3 and 4 show the effect of NAC and urea as penetration enhancers on the nail swelling and itraconazole partitioning. All four itraconazole formulations contained 1% itraconazole and different enhancer compositions: Formulation A was the control, containing neither NAC nor urea Formula B contained 10% urea but no NAC Formula C contained 5% NAC but no urea and Formulation D contained both 5% NAC and 10% urea. The numbers over the bars are the enhancement factors, i.e., the ratio of the nail weight gain (Figure 3) or nail itraconazole content (Figure 4) from the test formulations to those from the control (Formulation A). Figure 3 shows that Formulation D produced the highest nail swelling, which corresponds to the highest drug uptake into the nail, 93.6 fold higher than the control. The benefits of incorporating nail penetration enhancers into topical antifungal formulations are clearly demonstrated by these examples. The amount of antifungal drags penetrated through the nail in these in vitro studies are over a thousand fold higher than that required to have therapeutic effect. Conclusions In summary, the chemical composition of human nail is significantly different from the other body membranes such as the skin, vaginal and gastrointestinal membranes. In topical delivery of actives to the nail, the nail plate does not mimic the behavior of a

74 JOURNAL OF COSMETIC SCIENCE lipophilic membrane, which has been the case for almost all the other body membranes, including the skin. Instead, a nail plate behaves more like a hydrogel membrane in its barrier properties. Effectiveness of topical formulation at treating nail disease is increased dramatically by enhancers that disrupt protein structure of the nail plate. REFERENCES 1. Fleckman, P. (1990). Basic science of the nail unit. In Nails: therapy, diagnosis, surgery. edited by Scher, R.K. and Daniel, C.R.W.B. Saunders Company, Philadelphia, pp. 42-43. 2. Walters, K.A., Flynn, G.L., and Marvel, J.R. (1983b). Physiochemical chemical characterization of the human nail: permeation pattern for water and the homologous alcohols and difference with respect to the stratum corneum. J.Pharrn. Pharmcol. 35:28-33. 3. Baden, H.P., Goldsmith, L.A., and Fleming, B. (1973). A comparative study of the physicochemical properties of human keratinized tissues. Biochim. Biophys. Acta. 322:269-278. 4. Scheuplein, R.J. and Morgan, L.J. (1967). Bound water in keratin membranes measured by a microbalance technique. Nature. 214:456. 5. Haneke, E. (1991). Fungal infections of the nail. Seminars in Dermtol. 10:41-53. 6. Walters, K.A., Flynn, F.L., and Marvel, J.R. (1985a). Penetration of the human nail plate: the effects of vehicle pH on the permeation ofmiconazole. J. Pharrn. Pharrncol. 37:498-499. 7. Mertin, D. and Lippold, B.C. (1997b). In-vitro permeability of the human nail and a keratin membrane from bovine hooves: penetration of chloramphenicol from lipophilic vehicles and a nail lacquer. J. Pharm. Pharmacol. 49:241-245. 8. Mertin, D. and Lippold, B.C. (1997a). In-vitro permeability of the human nail and a keratin membrane from bovine hooves: influence of the partition coefficient octanol/water and the water solubility of drugs on their permeability and maximum flux. J. Pharrn. Pharrnacol. 49:30-34. 9. Mertin, D. and Lippold, B.C. (1997c). In-vitro permeability of the human nail and a keratin membrane from bovine hooves: prediction of the penetration rate of antimycotics through the nail plate and their efficacy. J.Pharm. Pharmacol. 49:866- 872. 10. Farbet, E.M. and South, D.A. (1978). Urea ointment in the nonsurgical avulsion of nail dystrophies. CUTIS.22:689-692. 11. South, D.A. and Farbet, E.M. (1980). Urea ointment in the nonsurgical avulsion of nail dystrophies - a reappraisal. CUTIS.25.609-612. 12. Buselmeier, T.J. (1980). Combination urea and salicylic acid ointment nail avulsion in nondystrophic nails: a follow-up observation. CUTIS.25:397-405. 13. Lauharanta, J. (1992). Comparative efficacy and safety of amorolfine nail lacquer 2% and 5% once weekly. Clin. Exp. Dermatol. 17 (Suppl. 1): 41-43. 14. Sun, Y., Liu, J.C., Kimbleton, E. and Wang, J. (1977). Antifungal treatment of nails. US patent No. 5,696,164. 15. Iwaski, A. (1994). Cysteine Waving Lotions - Past Improvement and Future Prospects. Cosmetics & Toiletdes. 109:69-78.