i j. $oc. Cosmet. Chem., 34, 327-334 (September/October 1983) Evaluation of solvent-skin interaction in percutaneous absorption JOEL L. ZATZ, Department of Pharmacy, Rutgers College of Pharmacy, P.O. Box 789, Piscataway, NJ 08854 and UMESH G. DALVI, E. R. Squibb and Sons, Inc., P.O. Box 191, New Brunswick, ?qj 08903. Received May 6, 1983. Presented at the 12th Congress of the International Federation of Societies of Cosmetic Chemists, Paris, September 1982. Synopsis A method for quantitating solvent-skin interaction in percutaneous absorption under steady state conditions has been developed. In the absence of interactions with the membrane, the maximal flux from saturated solution,Js, is independent of the solvent. Differences in value of Js are taken as a measure of the effect of interaction on percutaneous absorption. Js may be determined experimentally or calculated from the slope of a plot of flux against the ratio of concentration to solubility. The validity of the method was verified by penetration experiments through an inert polypropylene membrane. Data for benzocaine penetration through hairless mouse skin showed that, with water as standard, interaction effects were not significant when propylene glycol was the solvent. However, interaction resulted in a tenfold decrease in benzocaine permeability from solution in polyethylene glycol 400. INTRODUCTION One of the major factors influencing percutaneous absorption is the nature of the vehicle. A change in solvent character causes alteration in affinity of permeant for the solvent. As a result, partitioning into the membrane, and consequently, the transport rate are changed. An example is the dependence of permeability coefficient of a series of alkanols on carbon number (1). When the solvent was water, an increase in carbon number caused an increase in permeability coefficient. With isopropyl palmitate as solvent, the opposite trend was found. In each series, an increase in permeant affinity for the solvent resulted in a reduction in transport rate. The effect of solvent on partitioning of a permeant to the outer layer of the skin is a noninteractive influence because the properties of the barrier are not altered. It is also possible for solvents to interact with the stratum corneum so as to change its resistance to diffusion. The effect may be of an irreversible nature, in which damage to membrane integrity takes place, or it may be less drastic, involving solvent penetration followed by temporary alteration of barrier properties (2). The replacement of water molecules in the stratum corneum by those of another solvent can affect drug solubility, thereby influencing partitioning behavior. 327

328 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Interpretation of solvent effects with regard to skin permeation can become very complicated when both interactive and noninteractive influences are operating simultaneously. Simple comparison of permeation rates from different solvents can be quite misleading. In their study of phenol penetration through rat skin, Roberts and Anderson (3) found that use of dimethyl sulfoxide (an interactive solvent) yielded lower flux levels than did light liquid petrolatum (a noninteractive solvent). Although dimethyl sulfoxide increased.the diffusivity of phenol, this was more than offset by decreased partitioning of phenol into the stratum corneum. A more complete understanding of the role of solvents in percutaneous absorption requires separation and evaluation of interactive and noninteractive solvent effects. In this paper, we describe a proposed technique for doing so. Our approach is to assume that no interaction occurs and to apply the equations describing diffusion through an inert membrane to the experimental results. These equations take differences in solvent-permeant affinity into account. Thus, agreement of our calculations with experiment indicates that membrane interaction is not significant. On the other hand, large differences between theoretical and measured values mean that interactive effects are important. This approach is first tested on a series of penetration studies in which an inert membrane is used as a barrier. We then apply our technique to studies of penetration through hairless mouse skin. EXPERIMENTAL MATERIALS Benzocaine was the same material used in previous studies (4-5). Propylene glycol (J. T. Baker Co.) and polyethylene glycol 400 (Ruger Chemical) were USP grade and used as received. Distilled water was boiled and cooled before each use to eliminate dissolved gases. SOLUBILITY DETERMINATION A moderate excess of benzocaine was added to premeasured solvent system in an Erlenmeyer flask with a screw top. The flask was shaken in a temperature controlled water bath at 30 ø _+ 1 ø C. This temperature was chosen to conform to conditions in the donor portion of the diffusion cells, since only the receptor portion of the cells was jacketed. With the receptor maintained at 37 ø C., skin surface temperature was found to be 30 ø _+ 0.5 ø C. with a thermocouple probe. Solution samples were withdrawn and filtered at 30 ø C., first through a filter paper and then through a 3/xm membrane filter. After dilution, benzocaine concentration was determined spectrophotometrically at 286 nm using a control blank without benzo- caine. The procedure was repeated every 24 hours until the system reached equilibrium. This required one day for the aqueous system, and seven days in the case of polyethylene glycol 400. MEMBRANE PREPARATION The excised hairless mouse skin samples were prepared as previously described (4). Only fresh skin samples were used.