Evaluation of derivatives of 3-(2-oxo-1-pyrrolidine) hexahydro-1H-azepine-2-one as dermal penetration enhancers: side chain length variation and molecular modeling
N. Kim et al., Evaluation of derivatives of 3-(2-oxo-1-pyrrolidine) hexahydro-1H-azepine-2-one as dermal penetration enhancers: side chain length variation and molecular modeling, J CONTR REL, 73(2-3), 2001, pp. 183-196
The present study examined the enhancement effect of two series of compound
s derived from 3-(2-oxo-1-pyrrolidine)hex ahydro-1H-azepine-2-one. One seri
es possessed alkyl side chains (series I) and the other alkyl ester side ch
ains (series II). An in vitro diffusion study was performed to investigate
the effect of variation in alkyl/alkyl ester side chain length of two serie
s of compounds on the permeation of hydrocortisone (HC) across hairless mou
se skin. The permeability coefficient (P), 24 h receptor concentration (Q,,
) and skin content (SC), as well as the enhancement ratios (ER) for each pa
rameter were recorded, A parabolic relationship was observed between the ER
,, and the alkyl side chain length of the enhancers. The relationship betwe
en the length of ester side chains and ER, appeared to be relatively linear
with R-2 of 0.9676. The relationship between the calculated lipophilicity
(CL) and enhancement activity of the enhancers showed that for CL 5-9, seri
es I showed higher P values compared with Azone((R)), but this was not obse
rved with series II. For CL values 4.57-7.75, a significant correlation exi
sted between P of HC and CL of series II compounds (R-2 = 0.9967). 1-Tetrad
ecyl-3-( 2-oxo-1-pyrrolidine)-epsilon -caprolactam showed the highest P and
Q(24), with 40.5- and 18.6-fold increases over the control. In conclusion.
the alkyl side chain series of compounds showed more enhancing activity th
an the alkyl eater side chain series. (C) 2001 Published by Elsevier Scienc
e B.V.