International Journal of Pharmaceutics 269 (2004) 373–383 Development of a perillyl alcohol topical cream formulation Abhishek Gupta ∗ , Paul B. Myrdal College of Pharmacy, University of Arizona, 1703 E. Mabel St., Tucson, AZ 85721, USA Received 24 April 2003; received in revised form 17 September 2003; accepted 17 September 2003 Abstract Perillyl alcohol (POH) is a relatively non-toxic agent that has been shown to be a promising anticancer monoterpene in preclin- ical models. Studies have indicated that topical application of POH may prove to be effective as a skin cancer chemoprevention therapy. The main aim of this study was to determine the influence of several factors on the stability of POH in solution and develop a topical formulation of POH. During preformulation, the influence of pH, temperature, ionic strength, and organic sol- vents, on the stability of POH was evaluated at four different temperatures: 4, 25, 37, and 48 ◦ C. POH was found to degrade under acidic conditions with degradation following apparent first-order kinetics. A hydrophilic topical cream formulation of POH was developed and prepared for toxicology and clinical studies. A reverse phase gradient HPLC method was developed to quantitate POH in the complex formulation. Stability studies of the formulation and a placebo were performed and the formulation was found to be physically and chemically stable over a period of 1 year at 4 and 25 ◦ C. © 2003 Elsevier B.V. All rights reserved. Keywords: Perillyl alcohol; Stability; Topical cream formulation; Reverse phase HPLC assay 1. Introduction Perillyl alcohol (POH) (Fig. 1), is a cyclic monoter- pene (p-metha, 1, 7-diene-6-ol or 4-isoprophenyl- cylcohexenecarbinol) and is found in the essential oils of lavendin, peppermint, spearmint, sage, cherries, lemongrass, caraway, and celery seeds. Perillyl alco- hol has a calculated octanol/water partition coefficient of 2.38 and is an oil at room temperature. The intrinsic solubility of POH in water is about 115 g/ml. POH is a relatively non-toxic agent that has been shown in preclinical trials to have therapeutic and chemo- preventive activity against a wide variety of cancers. In animal studies it has been shown to regress pan- creatic, mammary, and liver tumors, and as a chemo- ∗ Corresponding author. Tel.: +1-520-626-3847; fax: +1-520-626-4063. E-mail address: gupta@pharmacy.arizona.edu (A. Gupta). preventive agent for colon, skin, and lung cancers (Wattenberg, 1983; Elson et al., 1988; Haag et al., 1992; Crowell and Gould, 1994; Mills et al., 1995). It has also been shown to inhibit photocarcinogenesis in a non-melanoma model of mouse skin carcinogenesis and UVB-induced skin carcinogenesis. Barthelman et al. (1998), have shown that POH causes a reduction in UVB-induced non-melanoma tumors. Prevatt et al. (2002), found that topically applied POH is effective as a chemopreventive agent in melanoma. As a result, the topical application of POH may prove to be a safe and effective skin cancer chemoprevention therapy. Because of the increasing incidence of skin can- cer, effective chemoprevention strategies need to be developed. There is a need to develop oral and topi- cal agents that will complement primary skin cancer prevention. Despite the promise of POH as a ther- apeutic agent for many applications, there is little data available concerning the stability of POH under 0378-5173/$ – see front matter © 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2003.09.026