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bonding ability as observed previously10 but requires a certain
optimum.
Fumaric acid derivative F even decreased the skin permeability
with ER = 0.6, 0.1, and 0.7 from an aqueous, PG, and IPM suspen-
sion, respectively (Fig. 2). Although the differences were not signif-
icant, similar trans double bond-containing amphiphiles may serve
as a lead for designing potential permeation retardants. These
compounds are currently widely discussed for their potential to
prevent absorption of hazardous substances through the skin.15
Single-chain compounds. The removal of one dodecyl chain re-
sulted in a markedly increased activity (Fig. 2). The most active
compound was MOH, which increased the flux of theophylline 26
times from the PG vehicle. The higher activity of the monoesters
compared to the double-chain compounds cannot only be caused
by the free carboxyl group; for example, lauric acid enhanced the-
ophylline permeation only twice under the same conditions.7
Moreover, the dodecyl methyl ester M1 showed significant activi-
ties as well. To our knowledge, this is the first report of such an ef-
fect. The possible explanation is that these double-chain
amphiphiles may incorporate into the stratum corneum lipid bilay-
ers without causing any significant disturbance. On the other hand,
their single-chain counterparts possess a polar head of the same
size but only one chain, which may prevent tight association of
the chains via hydrophobic interactions. Interestingly, the activity
of the enhancers in lipophilic IPM was negligible except for MOH
and FOH showing ER = 7.5 and 4.5, respectively.
Geometric isomers. The higher permeation-enhancing activity of
the single-chain compounds allowed for a comparison of the cis (Z)
and trans (E) derivatives. The activities of the dodecyl methyl esters
M1 and F1 were comparable. However, monoester MOH, that is a
cis derivative, was significantly more active than the corresponding
trans isomer FOH in all of the evaluated donor vehicles (Fig. 2).
These monoesters differ in acidity but not to such an extent as
the parent maleic and fumaric acid—the dissociation constants of
MOH and FOH are 4.87 and 4.40, respectively.16 Moreover, the dif-
ferent acidity cannot fully explain the difference in activity of the
monoesters, since the less acidic SOH is inactive in aqueous and
IPM vehicle but its activity is similar to MOH in PG.
Thus, the most likely explanation for the observed difference in
permeation-enhancing activity of MOH and FOH is a different pack-
ing of the geometric isomers. Such behavior was described in unsat-
urated fatty acids with a double bond situated approximately in the
center of the hydrophobic chain. For example, oleic acid was much
more effective enhancer than elaidic acid, its trans isomer.5,17 This
was attributed to the presence of a ‘kink’ in the chain caused by
cis double bond18 leading to disruption of the stratum corneum li-
pid packing or phase separation. Although the double bond in
MOH and FOH was situated in their polar head and not in the hydro-
phobic chains where the influence on the lipid packing is obvious,
the difference in spatial arrangement may explain the higher activ-
ity of the maleate as well. Generally, the straighter-shaped trans
isomers pack better than the U-shaped cis isomers as reflected,
for example by their higher melting points (for example, mp of
FOH and MOH were 82 and 58 °C, respectively, see Supporting
Information). The shape of the polar head of the cis isomer does
not allow for close packing of its hydrophobic chain with those of
the stratum corneum lipids. That means that the intermolecular
forces between the hydrophobic chains are not as effective so the
drug can cross the lipid matrix more easily. The lesser ability of
trans isomers to promote skin permeability seen in this study is fur-
ther supported by the fact that the natural skin barrier constituents,
that is sphingosine and 6-hydroxysphingosine-type ceramides,
contain trans double bond in close proximity to their polar head
too. Moreover, this C4-trans double bond was found to promote clo-
ser packing of ceramide in monomolecular films at the argon–buf-
fer interface relative to comparable saturated species.19
Scheme 2. Reagents and conditions: (i) C12H25OH, H+, toluene, reflux, 4 h; (ii)
C12H25OH, DCC, DMAP, 0 °C to rt, 24 h; (iii) I2, 150 °C, 1 h.
not successful in case of F1, where a preferential formation of F was
observed. Thus, the asymmetric diester F1 was prepared via carbo-
diimide coupling of methyl fumarate with dodecanol (Scheme 2).
The tartaric and meso-tartaric acid esters, T and mT, respec-
tively, were prepared by esterification of the pertinent dicarboxylic
acid. For the preparation of the acetonides AT and AmT, either T or
mT reacted with 2,2-dimethoxypropane under acid catalysis. The
analogous carbonates CT and CmT were synthesized from T and
mT, respectively, with dimethylcarbonate and sodium metal. The
monoester TOH was prepared by partial hydrolysis of T. This pro-
cedure was not successful in case of mTOH; thus it was prepared
by syn dihydroxy addition to MOH (Scheme 3).
The transdermal permeation-enhancing activity of the prepared
compounds was evaluated in vitro using Franz diffusion cell and
porcine skin. Theophylline was selected as a model permeant of
medium lipophilicity and to allow for the comparison with our
previous results. All the prepared enhancers were evaluated in
three donor vehicles of different polarity: water, 60% propylene
glycol (PG), and isopropyl myristate (IPM). Theophylline was pres-
ent at its maximum thermodynamic activity in all the donor sam-
ples either with or without the enhancer. The potencies of the
individual enhancers are reported as the enhancement ratio values
(ER), that is a ratio of the flux of theophylline through the skin with
and without the studied enhancer.
Double-chain compounds. The activity of the first series, that is
maleic, fumaric, and succinic acid derivatives is outlined in Fig-
ure 2. The didodecyl esters M, F, and S, that is the double-chain
enhancers, did not increase theophylline permeation from either
vehicle. This finding was rather surprising as the previously de-
scribed maleic acid derivative 12GM12 was a relatively potent en-
hancer.10 The difference between M and 12GM12 is an absence of
glycyl linker. This suggests that the permeation-enhancing activity
is not simply inversely related to the polar head size and hydrogen
Scheme 3. Reagents and conditions: (i) C12H25OH, H+, 100 °C, 2 h; (ii)
(CH3O)2C(CH3)2, H+, CH2Cl2, rt, 2 h; (iii) (CH3O)2CO, Na, toluene, 90 °C, 3 h; (iv) 1—
OHÀ/H2O, 2—H+; (v) 1—KMnO4/acetone/H2O, 2—Na2SO3, H+.