Percutaneous absorption and histopathology of a poloxamer-based formulation of capsaicin analog

Abstract

A new synthetic capsaicin analog (CA) modified with 4-hydroxyl and alkyl chain of capsaicin was synthesized as a potent anti-inflammatory analgesic drug and is now on clinical trial in Korea. The purpose of this study was to investigate the percutaneous absorption and histopathology of a poloxamer-based formulation of CA. A poloxamer-based gel was prepared by cold method using poloxamer 407. Vertical Franz type diffusion cells were used for skin penetration of drug against receptor phase filled with about 10 ml of 0.9% isotonic saline at 32°C. The concentration of drug was determined by the reverse phased HPLC (C18, Symmetry ®) with fluorometeric detector. Total amount of CA free base permeated was higher than that of the CA salt form. Percutaneous absorption of CA was greatly enhanced in ethanol and PG than that in water, 2-hydroxypropy- β-cyclodextrin and PEG400. As ethanol concentration increased, percutaneous absorption greatly increased. The flux rate of CA increased slightly when PG was added to ethanol solution. The marked enhancing effect of the 5% fatty acid IPM in cosolvents was also noted on the percutaneous absorption of a poloxamer-based formulation of CA. Addition of 5% OA and 5% LA into the gel containing 5% IPM resulted in a slight increase in skin permeation. No significant difference in skin permeation was observed as a function of poloxamer content (20, 25 and 30%). The buffer system of 30% poloxamer-based gel slightly changed the cumulative amounts of CA penetrated for 24 h. The flux of poloxamer-based gels increased linearly as the drug concentration increased. There was a variation of percutaneous absorption of the drug, depending on the species used. The flux of a poloxamer-based formulation of CA was the highest in case of hairless mice but the lowest in hamsters. No skin erythema and histopathologic changes were observed on the dorsal site of hairless mice in six groups after a week or two months application, suggesting no skin toxicity of the poloxamer-based gel. Based on these findings, the current poloxamer-based formulation appears useful in the systemic delivery of CA as topical or transdermal patch formulations.