STRUCTURE AND PERMEABILITY OF HUMAN NAIL 375 100.00 90.00 80.00 70.00 60.00 o.oo 40.00 30.00 20.00 [] Benzoic acid 1Pyridine 1o.oo 0.00 2.0 7.4 pll Figure 4. Effect of pH on the permeability coefficients of benzoic acid and pyridine through a bovine hoof membrane. Mean + S.D., n= 4. Adapted from reference 36. pH 7.4. The authors suggest that the hindered permeation is a result of the exclusion of the dissociated substance from the membrane due to the Donnan equilibrium effect. Thus, although the studies by Walters et al. (39) showed that the permeability of miconazole was essentially pH-independent, the other studies described above suggest that the undissociated drug is preferentially transported through the nail plate. EFFECT OF VEHICLE COMPOSITION The penetration of chloramphenicol from an aqueous vehicle (phosphate buffer, pH 7.4) and two lipophilic vehicles (n-octanol, and one comprising medium chain triglycerides) through human nail and bovine hoof membranes was studied (40). For the lipophilic vehicles, chloramphenicol was used in a suspended form to ensure maximum thermo- dynamic activity. Permeation studies were conducted using a modified Franz-type dif- fusion cell, with temperature maintained at 32øC. The analytical technique used to measure drug concentrations was HPLC. The maximum flux of chloramphenicol (stan- dardized to a barrier thickness of 1000 pm) through the hoof membrane and the nail plate, as a function of vehicle composition, is shown in Table III. It was found that the maximum flux of chloramphenicol through both the human nail plate and the bovine hoof membrane was essentially independent of the nature of the vehicle. Also, from Table III, we see that fluxes through the hoof membrane are at least an order of magnitude higher than those through the nail plate. These results indicate, once again,

376 JOURNAL OF COSMETIC SCIENCE Table III Maximum Flux of Chloramphenicol (standardized to a barrier thickness of 1000 i•m) [J ...... (1000 •m)] Through a Bovine Hoof Membrane and the Human Nail Plate, as a Function of Vehicle Composition Vehicle Maximum flux for chloramphenicol J ....... (1000 lain) (x 1½) •') (mg/cm2/s) Hoof membrane Human nail plate Phosphate buffer, pH 7.4 n-Octanol Medium chain triglycerides 4.07 _+ 1.18 3.40 _ 0.68 4.06 ñ 1.00 0.821 * 0.211 0.913 •: 0.063 n.d. 1 Values represent mean _+ S.D. (n = 3-4). • Not determined. Adapted f}om reference 40. that caution must be exercised in interpreting data from other keratinous membranes when information on human nail permeability is required. In the same study, a nail lacquer composed of Eudragit RL [quarternary poly (methyl methacrylate)] and varying chloramphenicol concentrations was investigated. It was found that the lacquer allowed the formation of a supersaturated layer of the drug on the nail plate/hoof membrane and that this resulted in relatively large drug fluxes, particularly with high drug concen- trations (up to 31%). Thus, a lacquer-type formulation appears to be especially suitable for topical treatment of nail infections, as it allows sufficient adherence of the formu- lation to the nail plate. In another study, it was reported that the absorption of amorolfine through the human nail was affected by the composition of the lacquer in which it was present (41). In this study, the permeation rate of 5% amorolfine (radiolabeled) from an ethanol or methylene chloride lacquer was investigated. The fluxes were f•)und to be higher from the meth- ylene chloride lacquer than from the ethanolic vehicle, with peak fluxes approaching 100 ng/cm2/h. Also, drug uptake by nails (measured by soaking nail pieces in the test formulation for 48 h) was found to be 2.9 _+ 0.6 lag/g nail for the methylene chloride lacquer, as opposed to 1.2 + 0.4 !ag/g nail for the ethanol lacquer. However, the topical efficacy of these amorolfine lacquers in the treatment of OM was not reported. Thus, although the composition of the vehicle may impact the rate of permeation of an antifungal drug and its uptake by nail, topical therapy is not yet effective enough to treat nail disease. PENETRATION ENHANCEMENT The limited success of topical therapy is due to the poor penetration rates of the active, which results in prolonged treatment periods. Thus, there is a need to enhance pen- etration rates with a view towards achieving significant drug concentrations at the site of infection and reducing the duration of treatment. An efficacy coefficient, E, was recently introduced (37) to predict the topical effectiveness of an antimycotic formula- tion. This efficacy coefficient (which should be maximum for high therapeutic effec- tiveness) takes into account the fact that both the maximum flux and the antifungal potency (expressed as minimum inhibitory concentration) play a role in determining the