140 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS cream is a mid-potent steroid used for dermatological disease, e.g., inflammation, pso- riasis, and contact dermatitis. This study was conducted in an attempt to achieve the maximum therapeutic benefit of hydrocortisone 17-valerate by optimizing the vehicle. A standard o/w emulsion system similar to USP XXI Hydrophilic Ointment was adopted as the model formulation. Some modifications were made according to previous kinetic studies (7,8) to ensure that ideal conditions providing maximum thermodynamic activity and chemical stability of hydrocortisone 17-valerate were achieved. Previous studies indicated that 12% pro- pylene glycol in combination with 0.1- 0.5 % sodium lauryl sulfate at pH 4.7 offers the ideal environment for hydrocortisone 17-valerate 0.2% cream. Clinically, it is well recognized that an occlusive vehicle enhances the therapeutic effi- cacy of topical corticosteroids (9- 12), possibly by increasing skin hydration which then enhances the penetration of the active drug through the skin. Traditionally, o/w emul- sions have been known to be non-occlusive vehicles which provide little or no hydration to the skin as compared to other vehicles, i.e., petrolatum ointments, oils, greases, and w/o emulsions (10-12). Despite the disadvantage of low occlusivity, however, o/w emulsions are still the most popular topical vehicles because of their cosmetic elegance. The main objective of the study is to explore the possibility of enhancing the clinical efficacy of hydrocortisone 17-valerate by increasing the occlusivity of the o/w emulsion while maintaining its cosmetic elegance. EXPERIMENTAL REAGENTS AND MATERIALS Purified water processed with Milli-Q Water Purification System from Millipore Corp., Bedford, MA, was used throughout the study. USP grade hydrocortisone 17-valerate from Upjohn-Roussel Co., Kalamazoo, MI, was used as active ingredient in formula- tion design, while the reference standard hydrocortisone 17-valerate for HPLC analysis was obtained from Lark Chemical, Milan, Italy. Internal standard ethyl benzoate was obtained from Aldrich Chemical Co., Milwaukee, WI. HPLC grade acetonitrile pur- chased from J. T. Baker Chemical Co., Phillipsburg, NJ, was used in the mobile phase during HPLC analysis. ACS grade methanol, octanol, sodium chloride, lithium chlo- ride, magnesium nitrate, and potassium sulfate were obtained from Fisher Scientific Co., Fair Lawn, NJ. Ingredients used in the formulation study were USP grade pro- pylene glycol from Dow Chemical Co., Midland, MI NF grade sodium lauryl sulfate from Onyx Chemical Co., Jersey City, NJ NF grade stearyl alcohol from Sherex Chem- ical Co., Dublin, OH non-ionic emulsifiers from ICI United States Inc., Wilmington, DE USP grade dried sodium phosphate from FMC Corp., Philadelphia, PA NF grade sorbic acid from American Hoechst Corp., New York, NY and USP grade white petrolatum and mineral oil from Witco Co., Sonneborn Division, New York, NY. EQUIPMENT An HP 1090 Liquid Chromatograph with HP 3390 Integrator Recorder from Hewlett Packard, Fairport, NY, was used in the study. A Ix-Bondapak C-18 reverse phase column of 30 cm length and 3.9 mm inside diameter with 10 Ix particle size from

EMULSION VEHICLES AND VASOCONSTRICTOR ACTIVITY 141 Waters Associates, Milford, MA, was used. A Metrohn 632 pH meter from Brinkmann Co., Switzerland, was used for pH determination. A Precision penetrometer with 1/10 mm divisions from Precision Scientific Co., Chicago, IL, was used for consistency de- termination. Evaporimeter EP1 from ServoMed AB, Stockholm, Sweden, equipped with model SR-206 Dual Pen Chart Recorder of Heath Co., Benton Harbor, MI, was used to determine water volatility and transepidermal water loss in the prepared for- mulas. FORMULATION DESIGN Hydrocortisone 17-valerate 0.2%, formulated in a vehicle base similar to USP XXI Hydrophilic Ointment, was chosen as the model formulation. The formula contains 0.2% hydrocortisone 17-valerate as active, 12% propylene glycol as solubilizer, 0.1% sodium lauryl sulfate and 3% non-ionic surfactant as emulsifier, 5% stearyl alcohol as vehicle stabilizer, 0.5% carbopol as thickening agent, and 0.3% sorbic acid as preser- vative. Other additives were added as needed. Petrolatum, mineral oil, and water were the three variables in the formulation, while the total concentration of the three vari- ables was maintained constant at 78.9%. Each formula was adequately phosphate buff- ered at its optimal pH 4.70. The variables and the o/w phase-volume ratios (0) of thirty-six formulas are listed in Table I. The procedure of USP XXI Hydrophilic Ointment was adopted to prepare all the for- mulations. All prepared formulations were chemically assayed by HPLC method de- scribed in USP XXI immediately after preparation. PHYSICAL STABILITY EVALUATION Each formula was filled into five 1-oz transparent glass jars and stored at 55øC, 45øC, 35øC, RT (23øC), and - 20øC. The samples were examined for physical stability every day for the first seven days, then every week until four months. The judgment used for this evaluation was a self-designed rating scale (see Table II) similar to the method described by Wittern et al. (13). CONSISTENCY DETERMINATION The consistency of the formula was determined by means of a penetrometer fitted with a polished cone-shaped metal plunger (14). Before measurements were taken, the surface of the formula in each container was made flat with a spatula and then allowed to stand for about « hr. Measurements were taken at three different spots, and the resulting values were averaged. VOLATILITY DETERMINATION Two methods were used in this study: Evaporimeter method. This method was based upon water evaporation rate. The evaporim- eter was first calibrated by placing the measurement probe in three different humidity standard solutions: lithium chloride (11% relative humidity), magnesium nitrate