Diffusion of E and Z urocanic amphiphiles through skin and their insertion in a membrane model

Article abstract of DOI:10.1159/000066454

The incorporation of synthetic urocanic amphiphiles into a membrane model is described. A monomolecular film of dipalmitoyl phosphatidylcholine (DPPC) and cholesterol was formed at the air-water interface and used as a model. In parallel, diffusion of these derivatives through the skin was studied using rat skin on flow-through diffusion cells. The flux and the cumulative amount were determined. Although the structure and the composition of the DPPC/cholesterol monolayer differed greatly from multilayers of epidermal lipids, the results obtained in the incorporation and diffusion studies were similar. The structure of the urocanic amphiphiles was very close, but the membranes led to the following flux or insertion classification: Ester E > Ester Z ? Amide E. From the results obtained and for simplicity, the technique of Langmuir monolayers seems to be highly suited to the primary screening of amphiphilic compounds. Copyright

Full text of DOI:10.1159/000066454

Orig in a l Re s e a rc h Art ic le
Skin
Pharmacology
andApplied
Skin
Received: J une 25, 2001
Accepted after revision:
Feb. 28, 2002
Skin Pharm acol Appl Skin Physiol 2002;15:425–433
DOI: 10.1159/000066454
Physiology
Diffu s io n o f E a n d Z Uro c a n ic
Am p h ip h ile s t h ro u g h S k in a n d Th e ir
In s e rt io n in a Me m b ra n e Mo d e l
J . Sirieix-Pléneta J .C. Adera C. Miquelb A. Mavon b
N. Lauth-de Viguerie a
a Laboratoire IMRCP, Université Paul-Sabatier, Toulouse, and
b Institut de Recherche Pierre-Fabre, Vigoulet-Auzil, Castanet Tolosan, France
Ke y Wo rd s
led to the following flux or insertion classifi-
cation: Ester E 1 Ester Z 11 Am ide E. From
the results obtained and for sim plicity, the
technique of Langm uir m onolayers seem s to
be highly suited to the prim ary screening of
Urocanic acid isom ers W Am phiphile W
Monolayer W Flow-through diffusion cells W
Mem brane m odel
am phiphilic com pounds.
Copyright © 2002 S. Karger AG, Basel
Ab s t ra c t
The incorporation of synthetic urocanic am -
phiphiles into a m em brane m odel is de-
scribed. A m onom olecular film of dipalm i-
toyl phosphatidylcholine (DPPC) and choles-
terol was form ed at the air-water interface
and used as a m odel. In parallel, diffusion of
these derivatives through the skin was stud-
ied using rat skin on flow-through diffusion
cells. The flux and the cum ulative am ount
were determ ined. Although the structure and
the com position of the DPPC/cholesterol
m onolayer differed greatly from m ultilayers
of epiderm al lipids, the results obtained in
the incorporation and diffusion studies were
sim ilar. The structure of the urocanic am phi-
philes was very close, but the m em branes
In t ro d u c t io n
The main barrier to the diffusion of drugs
through the skin is the outermost layer of the
skin, the stratum corneum [1]. There has been
an increased interest in percutaneous permea-
tion due to the development of topical drugs
and the increasing presence of potent pharma-
cologically active environmental pollutants
that can penetrate the skin [2]. The elabora-
tion of artificial membrane systems which are
sufficiently simple and bear resemblance to
biological membranes is a crucial step in
screening cosmetic and pharmaceutical active
© 2002 S. Karger AG, Basel
ABC
N. Lauth-de Viguerie
1422–2868/02/0156–0425$18.50/0
Laboratoire IMRCP, Université Paul Sabatier
118, route de Narbonne, F–31062 Toulouse Cedex 04 (France)
Tel. +33 5 61 55 61 35, Fax +33 5 61 55 81 55
E-Mail viguerie@chimie.ups-tlse.fr
Fax + 41 61 306 12 34
E-Mail karger@karger.ch
Accessible online at:
www.karger.com/sph
www.karger.com

Fig . 1 . E-UCA, Z-UCA.
Fig . 2 . Urocanic amphiphiles studied.
principles and also in understanding complex compound having immunosuppressive ef-
biological processes. Models may provide less fects remains very interesting because it can
time-consuming, less expensive and less mo- have clinical applications against transplant
rally objectionable alternatives to carrying out rejection or be used for the treatment of skin
experiments on living animals or humans.
diseases like psoriasis. So, we have envisaged
This paper concerns the comparison of the various amphiphilic derivatives of UCA [8–
diffusion of urocanic derivatives through two 11]. The monopolar amphiphiles (N- and O-
membrane systems: Langmuir monolayers alkylated derivatives) [8, 12] (fig. 2) present
and rat skin. Urocanic acid (UCA) (fig. 1) good photoprotective qualities, may operate
occurs naturally in the stratum corneum of differently on the membranes due to their
the epidermis as the E-isomer where it plays hydrophobic character and, from a pharma-
the role of a photoreceptor [3]. Upon exposure ceutical point of view, be introduced more
to UVB radiation, it converts to Z-UCA, a easily in formulations.
mediator of immunosuppressive phenomena
We studied the incorporation of these
[4–6]. Currently, a debate over the protective compounds into Langmuir monolayers, com-
versus immunomodulatory behaviour of E- posed of phospholipids and sterols [13],
UCA excludes the use of UCA in cosmetic which are stable with time. The main sterol of
formulations [7]. This naturally produced the mammalian cell membrane is cholesterol
Skin Pharmacol Appl Skin Physiol
2002;15:425–433
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E, N-alkyl Z and Amide E in chloroform/methanol 8/2
at a concentration of 2 mM. Solutions of compound
N-alkyl E (30 Ìl), N-alkyl Z (30 Ìl), Ester E (25 Ìl),
Ester E (40 Ìl) and Amide E (30 Ìl) were spread on the
surface. After spreading, 15 min were allowed for sol-
vent evaporation, and the monolayer was compressed
at a rate of 15 mm/min. All isotherms were run at least
three times.
where the average molar ratio phospholipid/
sterol is 70/30 [14]. Thus, we analysed the
modifications caused in the surface pressure-
molecular area (-A) isotherms of dipalmitoyl
phosphatidylcholine (DPPC) and cholesterol
films by different concentrations of urocanic
derivatives. This incorporation was quanti-
fied by the measurement of overpressure (¢)
in the film. In addition, the permeation of
these derivatives through samples of rat skin
using a diffusion cell apparatus was studied.
The results of the two methods are com-
pared.
Stability of Monolayers. The study of film stability
was completed by relaxation and expansion experi-
ments. The films prepared as above were compressed
to 10 or 25 mN/m; then the surface pressure was
recorded until an equilibrium value was reached.
Study of the Incorporation of Urocanic Amphiphiles
in a Film Composed of DPPC and Cholesterol. A 25-Ìl
aliquot of a chloroform solution of DPPC (2.1 mM)/
cholesterol (0.9 mM) was layered on the surface of the
0.9% NaCl solution. After 15 min, the film was com-
pressed to an initial pressure 0 = 5 mN/m. Under this
pressure, the monolayer remained stable. Solutions
(2 mM) of various urocanic amphiphiles were pre-
pared in methanol. The required volume to obtain
concentrations of 10–7, 2.5 ! 10–7, 3.75 ! 10–7, 5 !
10–7, 6.25 ! 10–7, 7.5 ! 10–7, 10–6, 1.125 ! 10–6 and
1.25 ! 10–6 M was injected into the aqueous phase
supporting the DPPC/cholesterol film. Equivalent vol-
umes of methanol injected into the subphase did not
disturb the film. The surface pressure was measured
versus time until an equilibrium state was reached.
Each measurement was repeated three times. Then,
the increase in pressure ¢ = at equilibrium – 0 was cal-
culated versus the concentration of urocanic deriva-
tives in the 0.9% NaCl solution.
Ma t e ria l a n d Me t h o d s
Chemicals
DPPC, cholesterol and stearic acid (199%) were
purchased from Sigma Chemical (St. Louis, Mo.,
USA). E-UCA was purchased from Aldrich and was
used without further purification. Z-UCA was ob-
tained by irradiating (350 nm), for 2 h, a 6 mM solu-
tion of E-UCA in ethanol:water, 2:3 v:v. The solvent
was removed and the isomers (20/80 E/Z) were sepa-
rated by flash chromatography (silica gel, dichlorome-
thane-ethanol, 9:1 v:v). Chloroform, ethanol, metha-
nol and dichloromethane (Chromanorm 199%) were
from Prolabo (Paris, France). The urocanic amphi-
philes were synthesized in our laboratory, using a pro-
cedure previously described [12, 15].
Skin Permeation Study
Langmuir Monolayers
Skin Preparation. Two hairless rats (6–11 weeks;
IFFA Credo, France) were killed by cervical disloca-
tion and dorsal skin removed for experimentation. The
The analyses were carried out on a KSV2200 appa-
ratus, equipped with a Wilhelmy platinum plate, en-
closed in a thermostated box. The pressures were cali-
brated by recording the well-known isotherm of stearic
acid. The Teflon trough of an area of 34,500 mm2 and
a volume of 260 ml was cleaned with chloroform
(Chromanorm, Prolabo) and paper (Kimwipes, 7106,
Kimberly-Clark). The 0.9% NaCl solution, pH = 6.5,
to be in isotonic conditions, was prepared every day by
adding the NaCl (Rectapur, Prolabo) to ultrafiltered
water. All measurements were carried out at 24.5 B
°
skin was stored at –20 C and when required, full-
thickness (800–1,500 Ìm) skin was thawed and used
without further treatment. Each skin sample was then
cut into sections of approximately 1.5 ! 1.5 cm for the
penetration study.
Flow-Through Diffusion Cells. The flow-through
diffusion cells were manufactured from Teflon as de-
scribed by Bronaugh and Stewart [16]. They exposed a
skin area of 0.64 cm2. The lower part of the skin was in
direct contact with the receptor fluid. The upper sec-
tion in contact with the air received the molecule to be
studied. Receptor fluid flow-through was controlled by
peristaltic pump (minipulse 3, Gilson) to approximate-
ly 1.5 ml/h.
°
0.3 C.
Study of Langmuir Layers at the Air/Aqueous
Solution Interface
-A Isotherms. The urocanic amphiphiles Ester E
and Ester Z were dissolved in chloroform and N-alkyl
Skin Pharmacol Appl Skin Physiol
2002;15:425–433
Diffusion of E and Z Urocanic
Amphiphiles through Skin and Their
Insertion in a Membrane Model
427

Ta b le 1 . HPLC conditions
Compound tr, min Mode and mobile phase (v/v) Internal standard
tr, min
Detection Flow rate Injection
Ï, nm
ml
W
min–1 volume, Ìl
Ester E
Ester Z
Amide E
4.58
3.00
5.06
isocratic: CHCl3/EtOH 88/12
290
1
20
tr = 6.06
tr = 10.8
gradient
CHCl3/(CH3)2CHOH
0–4 min: 90/10
4–8 min: 90/10 to 75/25
8–13 min: 90/10
320
300
1.5
1
15
20
isocratic: CHCl3/EtOH 80/20 Ester E
tr = 3.78
Permeation Procedure. Fifteen diffusion cells with
Re s u lt s a n d Dis c u s s io n
rat skin were placed on a heating block to maintain the
°
skin surface temperature at approximately 32 C by
-A Isotherms
We recorded the -A isotherms of the uro-
canic amphiphiles Ester E, Ester Z and Amide
E on a 0.9% NaCl solution at 24.5 B 0.3 C
water circulation. After 1 h of stabilisation, 0.5 ml eth-
anol-water solution (55:45, v:v) at 60% of the solubility
of each compound was deposited on three diffusion
cells per compound. The concentrations of the E-UCA,
Z-UCA, Ester E, Ester Z and Amide E solutions depos-
ited were 1.63, 3.27, 3.06, 1.04 and 1.43 mg/ml,
respectively. The receptor fluid was an ethanol 95%-
water solution (55:45, v:v). It was collected using a Gil-
son 201–202 autosampler at 6, 12, 18 and 24 h. The
compounds diffusing through skin and collected in the
receptor fluid fractions were then analysed using high-
performance liquid chromatography (HPLC).
HPLC Conditions. HPLC was performed using a
system consisting of a Millipore-Waters unit (Model
600E) with an automatic gradient controller, a Waters
Assoc. 991 photodiode-array detector and a Hypersil-
silica (0.5 Ìm) column (250 ! 4.0 mm ID; Bischoff,
ISC). After the reacted sample solution was evapo-
rated, the residue was dissolved in 2 ml of chloroform
in the presence of an internal standard (10–4 M). The
tube containing the sample was placed in an ultrasonic
bath for 2 min and filtered through a Minisart-NML
filter (0.45 Ìm).
°
(fig. 3). For compounds N-alkyl E and N-alkyl
Z, whatever the volume of solution spread on
the surface, no collapse was obtained at the
end of the compression. For each -A iso-
therm, we measured the value of maximum
surface pressure (c) and the area per mole-
cule by extrapolating the condensed region to
zero surface pressure (A0). We also studied the
stability of molecular films submitted to two
different pressures (10 and 25 mN/m). The
films were compressed at a rate of 15 mm/min
until the chosen pressure was reached. Then,
the evolution of the pressure was followed for
30 min. The results given as a percentage of
pressure loss are indicated in table 2.
Esters E and Z formed the most stable
molecular films. However, the -A isotherms
indicate a difference in the molecular area
(A0) between the E and Z isomers (53 and
Different HPLC conditions were used for the uro-
canic derivatives (table 1) and for the two UCA iso-
mers [17].
Skin Pharmacol Appl Skin Physiol
2002;15:425–433
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Lauth-de Viguerie

Fig . 3 . -A isotherms of the uro-
canic amphiphiles Ester E, Ester Z
and Amide E.
Ta b le 2 . Parameters (A0 and c) extracted from the isotherms
Compound
-A isotherm
Pressure loss, %
logP1
A0, Å2/molecule c, mN/m
initial = 10 mN/m initial = 25 mN/m
Nalkyl E
Nalkyl Z
Ester E
Ester
–
–
53
–
–
50
95
84
11
93
80
35
24
3.29
3.29
3.94
3.94
Z
43
482
stable after 5 min
34
stable after 20 min
57
Amide E
25.4
68.8
3.29
Percentages of pressure loss, after 30 min, of compressed amphiphile monolayers.
logP is a molecular index used to classify organic compounds in relation to lipophilicity and corresponds to the
1
distribution coefficient between octanol and water.
43 Å2/molecule, respectively). The substitu- films and moved into the subphase in the
tion of the ester by an amide function caused course of the compression. So, no parameters
a loss of stability of the molecular film. This could be measured for these two compounds.
explains the low value obtained for A0 of For the urocanic amphiphiles, Z isomers
Amide E because under compression, part of formed molecular more stable films than the
this compound preferred the subphase. Com- E isomers.
pounds N-alkyl E and Z did not form stable
Skin Pharmacol Appl Skin Physiol
2002;15:425–433
Diffusion of E and Z Urocanic
Amphiphiles through Skin and Their
Insertion in a Membrane Model
429

Fig . 4 . ¢ (mN/m) measured in a
film of DPPC/cholesterol versus
the concentration of urocanic am-
phiphiles (see experimental sec-
tion).
All these results could be compared with
¢ (see experimental section) in a film of
the logP values. logP is a molecular index used DPPC/cholesterol versus the amphiphile con-
to classify organic compounds in relation to centration is shown in figure 4. In the phos-
their lipophilicity. The calculated logP values pholipid/sterol film, the incorporation of E-
[18] are indicated in table 2. The higher its UCA can be considered as negligible, whereas
value, the higher the lipophilicity of the com- all the amphiphilic derivatives did become
pound. The logP of Ester E and Ester Z were incorporated. A maximum of incorporation
the highest and the films of Ester E and Ester was reached for a concentration of 10–6 M for
Z were the most stable.
Ester E, 7.5 ! 10–7 M for Ester Z, 5 ! 10–7 M
for Amide E and 3.75 ! 10–7 M for com-
pounds N-alkyl E and N-alkyl Z. These values
corresponded to the critical concentration of
incorporation into the monolayer (table 3).
Incorporation of Urocanic Amphiphiles in
a Film Composed of DPPC and
Cholesterol
The choice of the film DPPC associated The ¢ values, which remained constant
with cholesterol was governed not only by its above this critical concentration, indicated
low price and easy use but the system was saturation of the phospholipid/sterol film by
suited to the study of the incorporation of the injected molecule. Moreover, the ¢max
molecules. The results obtained from -A iso- values were linked to the critical incorpora-
therms of DPPC, cholesterol and 70/30 tion concentration: the more amphiphile is
DPPC/cholesterol films were in accordance inserted into the phospholipid/sterol film, the
with the literature [19, 20]. The stability in higher the value of ¢max. The O-alkylated
time of the model film compressed to a pres- urocanic derivatives (Ester E, Ester Z and
sure of 5 mN/m was verified.
Amide E) were inserted into DPPC/cholester-
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Ta b le 3 . Critical concentration of incorporation into
the DPPC/cholesterol monolayer for the studied uro-
canic derivatives and values of ¢max obtained at this
concentration
Indeed, the thermodynamic activity theo-
ries tell us that two permeants in a saturated
solution should permeate at equal rates [22].
As the studied compounds have different so-
lubilities in the vehicle (ethanol-water 55:45,
v:v), and as the maximum flux is reached if
the compounds are saturated in the vehicle,
we assessed their skin diffusion at the same
percentage of solubility compared with the
saturation. To avoid crystallization in the do-
nor phase during the 24-hour study, the same
percentage of saturation, i.e. 60% was re-
tained.
Compound
Critical
incorporation
concentration, M
¢max
mN/m
Ester E
Ester Z
Amide E
N-alkyl E
N-alkyl Z
10–6
47.4
44.8
25.4
8.5
7.5
W
10–7
5
W
10–7
3.75
3.75
W
W
10–7
10–7
8.5
The time course of the flux of the urocanic
derivatives is shown in figure 5.
The two isomers of UCA are not shown in
figure 5 because no permeation was found in
the receptor fluid (under HPLC detection lim-
it). The diffusion flux of Amide E was very
low with a maximum flux at 18 h of about 0.9
Ìg/cm2/h. The diffusion flux increased con-
tinuously with time and reached about 60 Ìg/
cm2/h for Ester E. In Ester Z, the flux slowly
increased to 17 Ìg/cm2/h until 18 h and then
reached a value of about 58 Ìg/cm2/h at 24 h.
Accordingly, in cumulative amounts (corre-
sponding to the area under the curve), this
represents 840, 490 and 17 Ìg/cm2 for Ester E,
Ester Z and Amide E, respectively (fig. 6).
The solubility of Ester Z and Amide E are
similar, thus only changing an oxygen atom
for a nitrogen atom, transforming an ester
function into an amide function, can dramati-
cally modify the diffusion properties of these
two molecules. This can be explained by a
strong spatial modification enhanced by spe-
cific interactions with the skin and probably
the proteins where the amide function is the
base of their structure, retarding the diffusion
of Amide E. For Ester E and Ester Z, with the
ol film more than the N-alkylated (com-
pounds N-alkyl E and N-alkyl Z). It seems
that there is a correlation between the ability
of these molecules to be incorporated and the
stability of the films they form alone (ta-
ble 2).
Diffusion of Urocanic Derivatives through
a Sample Skin
The main barrier for the diffusion of drugs
through the skin is the outermost layer of skin,
the stratum corneum. It is composed of cor-
neocytes embedded in lipid domains consist-
ing alternately of hydrophilic and lipophilic
layers. For rat skin, the stratum corneum is a
10-Ìm thick layer. Thus, for technical rea-
sons, the skin permeation studies were per-
formed using full-thickness skin.
According to equation 1, which defines
maximum flux [21], the skin permeation de-
pends on both partitioning where logP is of
prime importance and thermodynamic ac-
tivity.
Jmax = KP ! Cv,sat
(1)
with Jmax = maximum flux; KP = permeability same functions, only a modification of the
coefficient; Cv,sat = concentration of the stud- spatial form can be at the origin of the differ-
ied compound at the saturation solubility in ence of total diffusion of 490 Ìg/cm2 for Ester
the vehicle.
Z and 840 Ìg/cm2 for Ester E (fig. 6). Previous
Skin Pharmacol Appl Skin Physiol
2002;15:425–433
Diffusion of E and Z Urocanic
Amphiphiles through Skin and Their
Insertion in a Membrane Model
431

Fig . 5 . Diffusion flux through rat
skin of urocanic derivatives (Ìg/
cm2/h) versus time (h).
Fig . 6 . Cumulative amounts of
UCA derivatives through rat skin
in Ìg/cm2 at 24 h.
work studying the skin absorption of quinine two esters differs until 18 h, but the Ester Z
and quinidine shows similar results. The dif- flux increased sharply and joined that of Ester
ferences of configuration are proposed to ex- E at 24 h. Surprisingly, the shapes of the
plain the large variation in diffusion of these curves obtained from the two studies were
two molecules. A greater volume was ex- similar. Indeed, a difference in behaviour of
pected to be the most retarding feature [22].
the two esters with respect to the DPPC/cho-
The results obtained on the cumulative lesterol film was observed for the weaker con-
amounts show important differences between centrations, then the insertion of these two
the two ester isomers. However, if we consid- compounds became comparable from a cer-
er the flux graph (fig. 5), the diffusion of the tain concentration.
Skin Pharmacol Appl Skin Physiol
2002;15:425–433
432
Sirieix-Plénet/Ader/Miquel/Mavon/
Lauth-de Viguerie

The objective of these two methods was to structure of the urocanic amphiphiles was
evaluate the diffusion of various molecules very close but the membranes led to the fol-
through a lipid membrane. Although the lowing flux or insertion classification: Ester E
structure and the composition of these two 1 Ester Z 11 Amide E. From the results
membranes are different, one a DPPC/choles- obtained and for simplicity, the Langmuir
terol monolayer, the other multilayers of epi- film technique seems to be highly suited to the
dermal lipids, the results obtained in incorpo- primary screening of amphiphilic com-
ration and diffusion studies were similar. The pounds.
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