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M. Novotny et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2726–2728
2728
This hypothesis that both the polar groups are positioned with-
in the polar layer of the lipid membranes and probably close to
each other agrees well the previously suggested formation of an
intramolecular hydrogen bond between the ester carbonyl and
N–H of transkarbams.15,16 Such interaction would lead to a ‘cyclic’
polar head similar to Azone, which is a well described permeation
enhancer having a dodecyl chain attached to a seven-membered
azepan-2-one ring.25,26
Another possible explanation of these results, that is, that trans-
karbams are only pro-enhancers releasing the respective fatty alco-
hols, was excluded previously.10,13
In conclusion, transkarbams, which are highly potent ammo-
nium carbamate transdermal permeation enhancers, probably act
by a dual mechanism. First, a part of their activity is associated
with the carbamic acid salt and/or with its decomposition in the
acidic stratum corneum. Consequently, the ammonium esters
thereby released possess transdermal permeation-enhancing
activity as well. Further investigation on the mechanism of action
of these unusual enhancers is in progress.
Figure 4. Effects of the ammonium chloride 1d and the corresponding ammonium
carbamate 2d on the in vitro permeation profiles of theophylline (A) and
hydrocortisone (B) at pH 7.0.
Acknowledgements
tures, they are relatively stable at neutral or slightly alkaline pH or,
more precisely, equilibrium between carbamate, bicarbonate and
carbonate is formed in aqueous solutions.17 Thus, the ammonium
carbamate concentration in the donor sample did not significantly
change over time as reflected by stable flux values (and the ratios
of flux values of the carbamates and ammonium salts) during the
assay. To illustrate this, Figure 4 shows the permeation profiles
of theophylline (Fig. 4A) and hydrocortisone (Fig. 4B) in the pres-
ence of 1d and 2d.
This work was supported by the Ministry of Education of the
Czech Republic (Centre for New Antivirals and Antineoplastics
1M0508 and a Research Project MSM0021620822).
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