オキシブチニンの皮膚透過におけるメントール誘導体の影響

Abstract

Oxybutynin (OB) is widely used for the treatment of incontinence due to neurogenic bladder dysfunction. In order to reduce side effects and increase therapeutic efficiency, we investigated transdermal therapeutic system of OB. in vitro skin permeation study was performed by employing the vertical diffusion cell in which the excised rat abdominal skin was mounted, and menthol derivatives were selected as effective enhancers. The flux of OB was remarkably increased by the addition of several kind of menthol derivatives (e.g. O-ethylether (MET), O-allylether, O-2-propynylether, O-methylester, O-propylester, O-isopropylester, and O-cyclopropylester). Among these compounds, the skin irritancy of MET was significantly low compared with the other compounds. Therefore, MET is thought to be a promising compound as effective absorption enhancer for the transdermal drug delivery of OB. The data obtained from in vitro skin permeation study were analyzed by a membrane diffusion model derived from Fick's second law, and the diffusion and partition parameters of OB were estimated. The diffusion parameters were increased when the menthol derivatives were incorporated in hydrogel. On the other hand, partition parameters were almost constant. The flux of OB increased with increase of the concentration of MET. Maximum flux was observed when the hydrogel containing 0.5% MET was applied. No further increase of flux was obtained when the amount of MET was increased. In in vivo percutaneous absorption, the excretion of urine was restrained until 8h by the administration of OB hydrogel containing 0.5% MET. It was suggested that OB was delivered through the skin from hydrogel containing 0.5% MET. In conclusion, it was suggested that OB hydrogels containing menthol derivatives, especially MET, were available as a new dosage form for the treatment of incontinence due to neurogenic bladder dysfunction.