J. Cosmet. Sci., 55, 65-80 CTanuary/February 2004) Targeted delivery of salicylic acid from acne treatment products into and through skin: Role of solution and ingredient properties and relationships to irritation LINDA RHEIN, BHASKAR CHAUDHURI, NUR JIVANI, HANI FARES, and ADRIAN DAVIS, GlaxoSmithKline Consumer Healthcare, Parsippany, NJ (L.R., H.F., A.D.), and Bertek Corporation, Foster City, CA (B.C., NJ.). Accepted for publication October 18, 2003. Synopsis Salicylic acid (SA) is a beta hydroxy acid and has multifunctional uses in the treatment of various diseases in skin such as acne, psoriasis, and photoaging. One problem often cited as associated with salicylic acid is that it can be quite irritating at pH 3-4, where it exhibits the highest activity in the treatment of skin diseases. We have identified strategies to control the irritation potential of salicylic acid formulations and have focused on hydroalcoholic solutions used in acne wipes. One strategy is to control the penetration of SA into the skin. Penetration of the drug into various layers of skin, i.e., epidermis, dermis, and receptor fluid, was measured using a modified Franz in vitro diffusion method after various exposure times up to 24 hours. A polyurethane polymer (polyolprepolymer-15) was found to be an effective agent in controlling delivery of SA. In a dose-dependent fashion it targeted delivery of more SA to the epidermis as compared to penetration through the skin into the receptor fluid. It also reduced the rapid rate of permeation of a large dose of SA through the skin in the first few hours of exposure. A second strategy that proved successful was incorporation of known mild nonionic surfactants like isoceteth-20. These surfactants cleanse the skin, yet clue to their inherent mildness (because of their reduced critical micelle concentration and monomer concentration), keep the barrier intact. Also, they reduce the rate of salicylic acid penetration, presumably through micellar entrapment (either in solution or on the skin surface after the alcohol evaporates). Cu­ mulative irritation studies showed that targeting delivery of SA to the epidermis and reducing the rapid early rate of penetration of large amounts of drug through the skin resulted in a reduced irritation potential. In vivo irritation studies also showed that the surfactant system is the most important factor controlling irritancy. SA delivery is secondary, as formulations with less SA content reduced the rate of delivery to the receptor and yet were some of the most irritating formulations tested, presumably clue to the action of the specific anionic surfactant on the barrier. Alcohol content also did not appreciably affect irritation and SA delivery formulations with considerably lower alcohol content but containing anionic versus nonionic surfactant systems exhibited considerably higher irritancy. Thus the surfactant type was again the predomi­ nant factor in those studies, although arguably alcohol plays some role (solubilization of SA). Results showed that both polymers and mild surfactants work in concert to provide the optimal formulation benefits of targeted delivery and reduced irritation. Synergistic relationships among hydroalcoholic formulation com­ ponents will be discussed along with the mechanisms likely involved in controlling delivery of SA to skin. INTRODUCTION Various strategies are being used to control delivery of active substances to the skin. The use of polymers to control the delivery of actives from semisolid preparations has 65

66 JOURNAL OF COSMETIC SCIENCE numerous advantages. Acrylic, cellulosic, block copolymers and, more recently, polyes­ ters are among the polymers that received most of the attention from investigators ( 1-S). In semisolid preparations, these polymers usually increase the viscosity of the system (2,6) without effect on the rate of delivery of actives (7). Other polymeric systems studied used polymer microparticles that contained the drug and were capable of re­ leasing it over an extended period of time. Won (8) introduced porous solid microspheres into which the drug could be incorporated. Mathiowitz et al. (9) presented non­ bioerodable and erodable microspheres that were capable of reducing the release rate of actives. Additional patents reference incorporation of cationic polymers (acrylates) and skin-depositing polyurethanes. These polymers are reported to deposit the active drug salicylic acid onto the skin surface or to target penetration into the epidermis from cleansers and emulsions (10,11). The use of the polyurethane polymer polyethylene glycol-8/SMDI copolymer (polyol­ prepolymer-15) in controlling the delivery of salicylic acid and lactic acid from topical preparations was recently studied by Fares and Zatz (12). The effect of this polyurethane polymer, polyolprepolymer-15, on permeation was measured in vitro using flow-through diffusion cells and dermatomed pig skin. Skin uptake was also evaluated over time using tape-stripping and tissue analysis. The polymer decreased the flux of salicylic acid through pig skin but did not affect the delivery of lactic acid. The polymer increased the overall deposition of salicylic acid in the stratum corneum but did not change the levels of salicylic acid in the viable skin significantly. Skin uptake of lactic acid was not affected by the presence of the polymer. Based on dialysis and cloud point measurements, it was found that polyolprepolymer-15 reduced the activity of salicylic acid in the vehicle via binding, leading to a decrease in permeation. The binding mechanism accounts for the effect of polyolprepolymer-15 on the solutes investigated salicylic acid was found to bind to the polymer but lactic acid did not. Because of binding, the thermodynamic activity of salicylic acid is reduced in the presence of the polymer and the stratum corneum/vehicle partition coefficient is reduced. As a consequence, the transfer rate into stratum corneum is lower than for a control system without polymer, which also results in a lower rate of passage through the skin. Another strategy frequently used to control delivery of active compounds to skin is entrapment in surfactant micelles. For topical treatment products this strategy can become problematic since surfactants are used for cleansing but are generally too irri­ tating to be in contact with skin for an extended period of time. Several patents have recently been issued that show the use of surfactant complexes to control delivery of actives (13,14) while maintaining the gentleness of formulations. This technology refers to the formulation of surfactant complexes that produce milder formulations and en­ hance deposition of salicylic acid onto the skin surface layers. In the first technology (13), an anionic-amine oxide complex was carefully preformed to end up with a charge density of zero, meaning complexation is complete. Thus the system no longer is comprised of anionics or zwitterionics rather, the complex is "pseudononionic." The irritation potential of the pseudononionic will likely be as mild as typical nonionics. The critical micelle concentration would be very low, thus producing a large micelle reservoir to trap the drug. The irritating anionic moiety is tied up in the complex. A similar technology strategy incorporates complexes of anionics with traditional cationic surfac­ tants (14). The result is also a pseudononionic complex with similar consequences, providing complexation is complete.