Promoting mechanism of menthol derivative, 1-O-ethyl-3-buthylcyclohexanol,on the percutaneous absorption of ketoprofen

Citation
Cj. Li et al., Promoting mechanism of menthol derivative, 1-O-ethyl-3-buthylcyclohexanol,on the percutaneous absorption of ketoprofen, BIOL PHAR B, 24(9), 2001, pp. 1044-1048
Citations number
13
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BIOLOGICAL & PHARMACEUTICAL BULLETIN
ISSN journal
09186158 → ACNP
Volume
24
Issue
9
Year of publication
2001
Pages
1044 - 1048
Database
ISI
SICI code
0918-6158(200109)24:9<1044:PMOMD1>2.0.ZU;2-S
Abstract
Menthol derivatives were synthesized and evaluated for their promoting acti vity on the percutaneous absorption of ketoprofen and skin irritation in vi vo, choosing O-ethylmenthol (MET) as the mother compound. The compound havi ng a C-3 positionned n-butyl group (1-O-ethyl-3-n-buthyleyclohexanol, OEBC) indicated the most promoting activity and caused relatively little skin ir ritation. In order to understand enhancement mechanism of OEBC an ht vitro permeation study of ketoprofen was performed. The time course of the cumula tive amounts of drug permeated through the rat skin exhibited a linear rela tion after an initial lag time. This was analyzed in membrane diffusion mod el and the diffusion and partition parameters of ketoprofen were estimated. Both parameters were remarkably enhanced when a hydrogel containing a smal l quantity of OEBC (0.5%) was applied. Furthermore, to clarify the site of action of OEBC, we also investigated in vitro permeation study of ketoprofe n employing different skins of state, reversed skin and stratum corneum str ipped skin. When OEBC was added to the hydrogels which were applied to the reversed and stripped skins, almost no changes of the flux were observed co mpared with the control (without OEBC). These results suggested that the si te of action of OEBC was stratum corneum. Morphological changes of the stra tum corneum surface were microscopically observed with 0-2% OEBC. The space s between the stratum corneum cells treated with 0.5-2% OEBC became extende d and the shape of each cell became clear. This may suggest that the site o f action of OEBC was the intercellular of stratum corneum. Furthermore, an electron spin resonance study was performed to investigate the effect of OE BC on the intercellular lipid bilayer fluidity of the stratum corneum and t he rotational correlation times were calculated. 2,2,6,6-Tetramethylpiperid ine-1-oxyl (TEMPO) and 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMP OL) were used as the spin label. In use of OEBC, the fluidity of TEMPO labe led the stratum corneum lipid increased as the addition of OEBC. The result s suggested that OEBC promote the penetration of drugs by enhancing fluidit y of the local lipid bilayers around TEMPO.