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
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.