University College London LONDON, England, United Kingdom
Purpose: Skin cancer is the most common cancer in Caucasian populations1. Damage of skin cell deoxyribonucleic acid (DNA) by ultraviolet (UV) radiation followed by failure of DNA repair mechanisms is the primary cause of these neoplasms. An actinic keratosis (AK) or solar keratosis is a scaly or crusty growth on the skin indicative of sustained damage by the sun. AK may progress to invasive neoplasms and has been interpreted as the earliest sign of skin cancer2. To date, a very limited number of molecules has been administered topically to skin cancer lesions or AK. 5-fluorouracil (5-FU) is approved for the topical treatment of AK, superficial Basal Cell Carcinomas and Bowen’s disease. Creams and solution formulations of 5-FU are currently available in a range of strengths. Systemic absorption of 5-FU has been reported for a number of topical preparations but has not been investigated in detail. Therefore, the aim of the present work was to conduct pre-formulation and permeation studies with 5-FU in order to identify vehicles that would preferentially deliver 5-FU to the skin rather than through the skin. Methods: The solubility parameter for 5-FU was calculated used Molecular Modelling Pro (NGMSI, USA). Subsequently the following solvents were investigated as potential carriers for 5-FU: ethyl acetate (EA), propylene glycol (PG), propylene glycol monolaurate (PGML), glycerol (GLY), dimethyl isosorbide (DMI), polyethylene glycol (PEG) 200 and 400, hexylene glycol (HEX), dipropylene glycol (DPG), Transcutol™ (TC) and 1,5-pentanediol (PENT). Solubility was determined in all vehicles and also in water and phosphate buffered saline to identify an appropriate receptor medium for skin permeation studies. Franz cell studies were subsequently conducted with 5-FU 1% (w/v) in selected vehicles (PG, TC, PEG 200 and 400, GLY) using porcine skin for 24 h followed by a full mass balance evaluation of the active. Results: The solubility parameter of 5-FU was determined to be 16.3 (cal/cm3)1/2. Solubility of 5-FU in the selected vehicles ranged from 0.93±0.09 mg/ ml (EA) to 81.27 ± 3.36 mg/ mL (DMSO). Solubility values of 5-FU were also higher for PEG 200 (36.39±1.04 mg/mL) and 400 (35.26±1.00 mg/mL) compared with PG 17.56±0.38 and TC (23.25±0.12 mg/mL). For GLY, the solubility of 5- FU was observed to be 15.6±0.64 mg/mL. Interestingly, no correlation was observed for 5-FU solubility results with vehicle solubility parameter values. Results for the skin permeation studies confirmed that 5-FU did not permeate though the skin from any of the vehicles. The percentage of 5-FU deposited in the skin ranged from 0.70 – 1.54% with most of the active deposited on the skin. Mass balance values also ranged from 90-100%, consistent with OECD guidelines for recovery of actives following skin permeation studies3. Conclusion: Future studies will focus on expanding the range of solvents and vehicles for 5-FU as well as investigation of combination formulations of the drug with other actives. References: 1. Byrd-Miles, K., Toombs, E.L., Peck, G.L., 2007. Skin cancer in individuals of African, Asian, Latin–American, and American–Indian descent: differences in incidence, clinical presentation, and survival compared to Caucasians. J. Drugs Dermatol. 6, 10–16. 2. Ibrahim, S.F., Brown, M.D., 2009. Actinic keratoses: a comprehensive update. J. Clin.Aesthet. Dermatol. 2, 43–48. 3. Test No. 428: skin absorption: in vitro method, in OECD Guidelines for the Testing of Chemicals. 2004, OECD Publishing. p. 8.
