THE PERCUTANEOUS ABSORPTION OF SALICYLATES 97 gradient is in the applied phase, skin properties play no part. For these systems drug concentration in the base, diffusion coefficient of the drug molecule in the vehicle, and solubility of the drug in the same are the im- portant factors. For the remaining cases these formulation variables are not directly important, the only significant factor involving the vehicle being the thermodynamic activity of the penetrating agent contained in it. More information concerning the exact route of penetration would be of considerable aid, however, in devising methods of increasing the perme- ability of the rate limiting barriers. Certain solvents significantly lower the resistance of the skin to penetration. Whether this is due to changes produced in the transepidermal barrier layer or to modification of the follicular and sebaceous route apparently has not been unequivocally established. Present treatment is not meant to discount the importance of studies along this line but to show what can be still done without them. THE PERCUTANEOUS ABSORPTION OF SALICYLATES AS MEASURED BY BLOOD PLASMA LEVELS IN THE RABBIT By VAn F. COTT¾, John SKERPAC, HEINZ M. EDERMA, FRANK ZURZOLA and MARTIN KUNA* Presented September 23-24, 1959, Seminar, New York City T,E PERCUTANEOUS ABSORPTION Of salicylates has been reviewed by Gross and Greenberg (1), by Valette and Cavier (2) and more recently by Rothman (3). Most of the studies ofpercutaneous absorption ofsalicylates have been carried out by measuring the total urinary excretion of salicyl- ates over relatively long periods of time following the topical application of the salicylate preparation. The validity of this method may be ques- tioned on the basis that a considerable proportion of administered salicylate is conjugated by the time it appears in the urine (Schachter and Manis) (4) and that this method does not take into account the loss of the drug from the skin surface (e.g., by evaporation). One may seriously question whether it is possible to make conclusions about the relative rates of ab- sorption of salicylates by measuring their excretion. In measuring the ab- sorption of a drug by its blood levels one is usually interested in its fate when it gets into the circulatory system. For this reason the changes in plasma level following the intravenous injection of methyl salicylate dis- solved in saline were studied. * Bristol-Myers Products Division, Hillside 5, N.J.

98 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS METHODS AND MATERIALS During the last two years a large number of measurements of percutane- ous absorption of salicylates were made employing rabbit preparations. Most of our tests were done with methyl salicylate because it is widely used in analgesic ointments and lotions. In this method the rabbit was anesthe- tized by the oral administration of 5 g. urethane per animal and the ventral surface was carefully clipped but not shaved. An incision was made in the neck to permit the insertion of a glass cannula into the common carotid in order to facilitate the drawing of blood samples. The various preparations tested were applied with a spatula without rubbing at the rate of 2 g./Kg. to an area of 75 cm.2/kg. Male and female rabbits averaging 3 kg. in weight were employed. A minimum of five rabbit preparations were used for each test. The statistical significance level on all comparisons in this study was set at a = 0.05. At this probability level, the experimenter may erroneously assert a real difference exists between points about 5 per cent of the times. In some cases, however, a was much smaller than 0.05. In this study some special vehicles were employed. These were obtained as follows: alkyl phosphates [including "LNa" trilauryl (tetraglycol- ether) phosphate] and alkyl sulfates from Farbwerke Hoechst AG. "Trans- dermine," an alkyl phosphate, from van Ameringen Haebler Co. "Lantrol," a purified lanolin derivative, from Maimstrom Chemical Corporation "Polylan" and "Acetulan," lanolin derivatives, from American Cholesterol Products, Inc. and silicone, designated Fluid//200, from Dow Corning Cor- poration. 6.0 5.0 4..0 3.0 2.0 1.0 o I I 5 15 30 (MIN.) I I I 2 TIME (HOURS) Fig. 1.--/•g salicylic acid/mi. plasma subsequent to intravenous re- jection of 10 ml. of 55 rag. methyl sal./100 ml. 0.9% NaC1 solution.