J. Soc. Cosmet. them., 39, 139-157 (1988) Effect of phase-volume ratio of o/w emulsion vehicles on the activity of a topically applied vasoconstrictor JONAS C. T. WANG, S. R. WINARNA, J. L. LICHTIN, and B. G. PATEL, Pharmaceutical Research & Development Division, Bristol-Myers Co., Buffalo, NY 14213 (J.C.T.W., B.G.P.), and College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267 (S.R.W.,J.L.L.). Received July 30, 1987. Synopsis This study was intended to test the relationships among phase-volume ratio, transepidermal water loss (TEWL) and skin permeation with the activity of vasoconstrictor emulsions containing hydrocortisone 17-valerate (HCV). Formulas with a phase-volume ratio of 3.59 provide the highest occlusivity (lower TEWL values), while formulas with phase-volume ratio of 0.06 or 0.19 were not occlusive. The major ingredient affecting occlusivity of the o/w emulsion systems is petrolatum, not mineral oil. In vivo vasocon- striction activity of a selected HCV 0.2% emulsion relative to several marketed intermediate or moderate corticosteroids was also assessed in 24 normal subjects. The results suggest that the vasoconstriction ac- tivity of the newly developed HCV 0.2% emulsion was greater than that of the HCV 0.2% cream, consis- tent with the in vitro skin permeation data. This study also reveals that the permeation rate of o/w emul- sions can be increased by increasing occlusivity while still maintaining the cosmetic elegance of o/w emul- sions. INTRODUCTION If a drug candidate intended for topical medication is to be a useful therapeutic agent, the active moiety must be formulated in a vehicle that is medically rational, physico- chemically stable, cosmetically acceptable to the patient, and, above all, able to en- hance the drug's biologic activity (1-3). It is known that the clinical efficacy of a topical medication is determined as much by its ability to reach the inflamed tissue as by its inherent activity and the characteristics of the molecule itself. Vehicle design plays a crucial role in the development of an active molecule. In fact, an inappropriate vehicle will diminish a drug's therapeutic potential. Conversely, a suitable base can significantly increase the penetration rate in skin and thereby improve the drug's bio- availability and activity (4,5). In theory, the ideal vehicle should act as an inert me- dium in which the drug is incorporated in a homogeneous phase. In this study hydrocortisone 17-valerate (HCV), a nonhalogenated derivative of hydro- cortisone shown by Cornell and Stoughton (6) in their clinical evaluation and vasocon- strictor assay to be a mid-potent steroid with superior biological activity over its parent compound, was selected as the candidate molecule. Hydrocortisone 17-valerate 0.2% 139

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