308 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Table V Vasoconstriction Scores at Eight Hours* Steroid None Mild Moderate Maximum Average Vehicle (0) (1) (2) (3) Score p Value Hydrocortisone 17-butyrate Desonide Diflorasone Diacetate 1-Propylene glycol 1 (3.3%) 5 (16.7%) 11 (36.7%) 13 (43.3%) 2.20 0.05 2-Caprylic/Capric 1 (3.3%) 1 (3.3%) 14 (46.7%) 14 (46.7%) 2.37 1-Propylene glycol 1 (3.3%) 8 (26.7%) 16 (53.3%) 5 (16.7%) 1.83 0.05 2-Caprylic/Capric Triglyceride 2 (6.7%) 10 (33.3%) 12 (40.0%) 6 (20.0%) 1.73 1-Propylene glycol 3 (10.0%) 11 (36.7%) 10 (33.3%) 6 (20.0%) 1.63 0.05 2-Caprylic/Capric 2 (6.7%) 11 (36.7%) 7 (23.3%) 10(33.3%) 1.83 * 30 Subjects. RESULTS AND DISCUSSION The flux of hydrocortisone, hydrocortisone 17-butyrate, and desonide from the caprylic/ capric triglyceride vehicle was found to be similar to that from propylene glycol vehicle (Table IV). The flux of diflorasone diacetate was higher from the caprylic/capric tri- glyceride vehicle. Theoretically, if there are no skin-solvent interactions, the steady- state penetration flux of a given steroid from different vehicles should be the same, regardless of the solvents used (1). The results suggest that there is little or no inter- action between the skin and the two vehicles used in this study. The results of the vasoconstriction assay are summarized in Tables V and VI. The vasoconstrictor scores were evaluated using Wilcoxoh's signed ranks test. There were Table VI Vasoconstriction Scores at Twenty-four Hours* None Mild Moderate Maximum Average Steroid Vehicle (0) (1) (2) (3) Score p Value Hydrocortisone 17-butyrate 1-Propylene glycol 18 (60.0%) 12 (40.0%) -- -- 0.40 2-Caprylic/Capric Triglyceride 16 (53.3%) 12 (40.0•) 2 (6.7%) -- 0.53 Desonide 1-Propylene glycol 17 (56.7%) 12 (40.0%) 1 (3.3%) -- 0.47 Diflorasone Diacetate 2-Caprylic/Capric Triglyceride 13 (43.3%) 14 (46.7%) 3 (10.0%) 1-Propylene glycol 16 (53.3%) 10 (33.3%) 4 (13.3%) -- 1-Caprylic/Capric Triglyceride 14 (46.7%) 14 (46.7%) 2 (6.7%) -- 0.67 0.60 0.60 0.05 0.05 * 30 Subjects.

COMPARISON OF TOPICAL VEHICLES 309 Table VII Twenty-One Day Cumulative Irritancy Grade* Test Material Total Mean + S.D. p Value Caprylic/Capric Triglyceride 4.0 0.16 + 0.47 Propylene Glycol 72.0 2.88 + 7.31 0.0077 * 25 Subjects. no statistically significant differences between the effects of different vehicles on the bioactivity of the steroids at either the eight-hour or the 24-hour evaluations. Caprylic/capric triglyceride demonstrated a minimal potential compared to propylene glycol for causing irritation. When applied under occlusion for 21 days in 25 volunteers, caprylic/capric triglyceride elicited a total cumulative irritation score of 4, whereas propylene glycol had a total cumulative score of 72 (Table VII). This difference was statistically significant (p 0.01). Bioactivity of a topical dosage form can be optimized by using the minimum amount of solvent necessary to completely dissolve the drug. For several hydrophobic steroids, this requires high concentrations of propylene glycol. However, propylene glycol has been reported to be an irritant and/or sensitizer at high concentrations (10% or more). The in vitro and in vivo data show that caprylic/capric triglyceride is an acceptable vehicle for topical formulations, exhibiting an efficacy equal to that achieved with propylene glycol. Further, since caprylic/capric triglyceride is not an irritant and/or sensitizer, it can be safely used in place of propylene glycol in optimized formulations requiring high solvent concentration. CONCLUSIONS 1. The in vitro steady-state penetration flux of difiorasone diacetate from the caprylic/ capric triglyceride vehicle was higher than that from the propylene glycol vehicle. For the other steroids used in this study, no differences were observed in the in vitro penetration from the two vehicles. 2. There are no statistically significant differences between the vehicles in the in vivo vasoconstriction assay of selected corticosteroids. 3. Caprylic/capric triglyceride has significantly less potential for causing irritation (p 0.01) than propylene glycol. 4. Caprylic/capric triglyceride is a suitable vehicle for topical formulations and, due to lack of irritancy, is preferred over propylene glycol in optimized formulations requiring high solvent concentrations. ACKNOWLEDGEMENT The 21-Day Cumulative Irritancy Assay was performed by Derma Test Labs, Inc., Long Island, New York.