72 JOURNAL OF COSMETIC SCIENCE Table II Distribution of Salicylic Acid From Various Formulations in the Epidermis, Dermis, and Receptor After Incubation for 24 Hours Formulation Tape strip Epidermis Dermis Receptor µg salicyclic acid/cm 2 Experiment one Reference anionic formulation 3.30 ± 0.97 16.5 ± 2.19a 4.49 ± 1.42 65.1 ± 2.346 Reference nonionic formulation 12.1 ± 8.72 25.4 ± 5.92 4.55 ± 1.87 25.8 ± 4.65 Formulation 1 10.1 ± 4.28 22.l ± 3.48 6.14±2.12 39.6 ± 2.56g Formulation 2 15.2 ± 4.42 24.4 ± 4.57 5.34 ± 2.83 32.4 ± 2.56h Formulation 4 12.1 ± 6.60 37.1±7.98c 6.69 ± 4.03 18.2 ± 3.40i Formulation 5 10.3 ± 2.50 31.1 ± 7.67d 6.60 ± 1.62 26.6 ± 6.13 Formulation 6 10.2 ± 5.46 27.8 ± 4.20 8.68 ± 5.01 26.2 ± 4.13 Formulation 7 9.66 ± 2.55 18.5 ± 2.09c 5.35 ± 2.43 48.6 ± 4.2l f Experiment two Reference anionic formulation ND ND ND 53.5 ± 13_3i Reference nonionic formulation ND ND ND 34.4 ± 7.59 Formulation 1 ND ND ND 41.2 ± 8.54 Formulation 3 ND ND ND 29.7±11.0 Formulation 4 ND ND ND 22.6 ± 5.77k Values are µg salicylic acid/cm2• Mean ± standard deviation. ND: not done. Statistics (all testing done at p 0.05 by Student-Neuman-Keuls) compared within each experiment and within each part of skin: Experiment one: a Epidermal levels significantly lower compared to all other formulations except formula 7. 6 Penetration into receptor significantly higher than for all other formulations. c Epidermal levels significantly higher compared to all other formulations. d Epidermal levels significantly higher compared to formulas 1, 7, and reference anionic. e Epidermal levels significantly lower compared to formulas 4, 5, and 6. f Penetration into receptor significantly higher compared to all other formulations except reference anionic. g Penetration into receptor significantly higher compared to all other formulations except formulation 7 and reference anionic. h Penetration into receptor significantly higher compared to all other formulations except formulations 1, 7, and reference anionic. i Penetration into receptor significantly lower than for all other formulations. Experiment two: i Penetration into receptor significantly higher than for all other formulations. k Penetration into receptor significantly lower compared to reference anionic, nonionic, and formula 1. formulation. The nonionic formulation without the polymer exhibited the next highest maximum of drug penetration through the skin. When 2% polymer was incorporated, the maximum was two thirds (14 out of 21 µg/cm2) that of the same formulation without the polymer and only about one half (14/29 or 48%) that of the anionic formula. The highest dose of polymer tested exhibited a maximum salicylic penetration that was only about one third that of the anionic. Thus all the polymer-containing nonionic formulations and even the nonionic formulation without polymer successfully reduced the initial delivery of high amounts of salicylic acid through the skin. Delivery of the drug into the various skin layers was also examined. Figure 3 compares entrapment of salicylic acid in skin layers, again from the same isoceteth-20 formula­ tions, with and without polymer (Table IA). What we found was that as the polymer

TARGETED DELIVERY OF SALICYLIC ACID 73 .c 35 l'I .... 30 l'I +:N 25 l! E _______ _,_ __ ..__ _______ .__ +----�---': .,.. _____ .....,_,. ______________�I --Anionic 1j -2 a 20 -9-Commercial G) a. .... c.5 2 0 15 C a. ... m '2 E Cl) .= 10 :I � C 0 0 6 12 18 Incubation Time, hours *All formulations contained 2% Salicylic Acid and are in table IA. -Anionic is a reference sodium lauryl sulfate hydroalcoholic formulation --tl-0% polymer -M-2% polymer ......,.3% polymer 24 -0% polymer formula 1 is the nonionic Isoceteth-20 hydroalcoholic system with 0% polymer -2% polymer formula 3 is the nonionic Isoceteth-20 hydroalcoholic system with 2% polymer -3% polymer formula 4 is the nonionic lsoceteth-20 hydroalcoholic system with 3% polymer -Commercial is a reference nonionic hydroalcoholic formulation (most ormulation details not available) Figure 2. Delta values indicating amount of additional salicylic acid penetrating the receptor at each incubation time for various products: Effect of polymer dose. dose was increased, consistently less drug was found in the receptor fluid, in agreement with the findings discussed above. However, we also found that as the polymer dose increased, more drug tended to accumulate in the epidermis [e.g., in Table II, formu­ lation 4 with 3% polymer left significantly more (p 0.05) drug in the epidermis than all other formulations in Figure 3}. Thus when the polymer is present, the drug tends to stay in the epidermis and does not penetrate through the skin as readily. The polymer is able to provide targeted delivery of the drug to the epidermal tissue rather than through the epidermis into the viable tissue where, as discussed below, it can cause increased irritation. The phenomenon of targeted delivery was examined in another way. Table III compares the ratio of the drug in the receptor to that in the epidermis. This shows a higher ratio of drug in the receptor for the anionic formulation than for any other formulation. Results also show that the nonionic formulation with 3% polymer exhibited consider­ ably less drug in the receptor and more in the receptor than any other formulation. This again confirms that the polymer can target salicylic acid to the epidermis, but it also indicates that the nonionic surfactant can target more drug to the epidermis as compared to the anionic formulation. The polymer also has the same effect in the anionic surfactant formulation that it does in the nonionic isoceteth-20 type formulation. For example, in Figure 4, significantly more (p 0.05) salicylic acid is deposited in the receptor from the formulation containing 2% ,_