U.S. patent application number 15/778343 was filed with the patent office on 2018-12-06 for use of 1,3 diglyceride in a topical composition for countering the weakening of the skin barrier.
This patent application is currently assigned to PIERRE FABRE DERMO-COSMETIQUE. The applicant listed for this patent is PIERRE FABRE DERMO-COSMETIQUE. Invention is credited to Gwendal JOSSE, Daniel REDOULES.
Application Number | 20180344599 15/778343 |
Document ID | / |
Family ID | 55236735 |
Filed Date | 2018-12-06 |
United States Patent
Application |
20180344599 |
Kind Code |
A1 |
REDOULES; Daniel ; et
al. |
December 6, 2018 |
USE OF 1,3 DIGLYCERIDE IN A TOPICAL COMPOSITION FOR COUNTERING THE
WEAKENING OF THE SKIN BARRIER
Abstract
This invention relates to a topical, cosmetic or dermatological
composition, comprising a 1,3 diglyceride having the general
formula (I), in which the radicals R1 and R2 represent,
independently of one another, a C13 to C40 saturated and linear
alkyl radical, and at least one cosmetic or dermatological
excipient for a topical application on the skin. This invention
also relates to such a composition, or a 1,3 diglyceride having the
formula (I), for its use in protecting the skin, in countering the
weakening of the skin barrier and in preventing or reducing the
penetration of exogenous molecules into the skin following a
weakening of the skin barrier. ##STR00001##
Inventors: |
REDOULES; Daniel; (Toulouse,
FR) ; JOSSE; Gwendal; (Toulouse, FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
PIERRE FABRE DERMO-COSMETIQUE |
Boulogne-Billancourt |
|
FR |
|
|
Assignee: |
PIERRE FABRE
DERMO-COSMETIQUE
Boulogne-Billancourt
FR
|
Family ID: |
55236735 |
Appl. No.: |
15/778343 |
Filed: |
December 8, 2016 |
PCT Filed: |
December 8, 2016 |
PCT NO: |
PCT/EP2016/080295 |
371 Date: |
May 23, 2018 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 17/00 20180101;
A61K 8/06 20130101; A61K 8/37 20130101; A61Q 19/00 20130101; A61Q
19/005 20130101; A61Q 17/00 20130101 |
International
Class: |
A61K 8/37 20060101
A61K008/37; A61Q 17/00 20060101 A61Q017/00; A61Q 19/00 20060101
A61Q019/00; A61K 8/06 20060101 A61K008/06 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 8, 2015 |
FR |
1561994 |
Claims
1-19. (canceled)
20. A topical, cosmetic or dermatological composition comprising a
1,3 diglyceride having the general formula (I): ##STR00016## in
which the radicals R.sub.1 and R.sub.2 represent, independently of
one another, a C13 to C40 saturated and linear alkyl radical, and
at least one cosmetic or dermatological excipient for a topical
application on the skin.
21. The composition according to claim 20, wherein the radicals
R.sub.1 and R.sub.2 represent, independently of one another, a C15
to C23 saturated and linear alkyl radical.
22. The composition according to claim 20, wherein the radicals
R.sub.1 and R.sub.2 represent, independently of one another, a C15
to C19 saturated and linear alkyl radical.
23. The composition according to claim 20, wherein R.sub.1 and
R.sub.2 are identical.
24. The composition according to claim 20, wherein the 1,3
diglyceride is glyceryl 1,3 dipalmitate, glyceryl 1,3 distearate or
a mixture thereof.
25. The composition according to claim 20, wherein the quantity of
1,3 diglyceride is between 0.5% and 10% by weight with respect to
the total weight of said composition.
26. The composition according to claim 20, wherein the 1,3
diglyceride is present in the composition in the form of dispersed
solid particles.
27. A method for protecting the skin comprising the administration
to a person in need thereof of an effective quantity of a
composition according to claim 20.
28. A method for countering the weakening of skin barrier
comprising the administration to a person in need thereof of an
effective quantity of a composition according to claim 20.
29. The method according to claim 28, wherein the skin barrier is
weakened under the effect of environmental factors.
30. The according to claim 29, wherein the environmental factor is
the cold or heat.
31. A method for preventing or for reducing the penetration of
exogenous molecules into the skin following a weakening of skin
barrier comprising the administration to a person in need thereof
of an effective quantity of a composition according to claim
20.
32. The method according to claim 31, wherein the skin barrier is
weakened under the effect of environmental factors.
33. The method according to claim 32, wherein the environmental
factor is the cold or heat.
34. A method for protecting the skin comprising the administration
to a person in need thereof of an effective quantity of a 1,3
diglyceride having the general formula (I): ##STR00017## in which
the radicals R.sub.1 and R.sub.2 represent, independently of one
another, a C13 to C40 saturated and linear alkyl radical.
35. A method for countering the weakening of skin barrier
comprising the administration to a person in need thereof of an
effective quantity of a 1,3 diglyceride having the general formula
(I): ##STR00018## in which the radicals R.sub.1 and R.sub.2
represent, independently of one another, a C13 to C40 saturated and
linear alkyl radical.
36. The method according to claim 35, wherein the skin barrier is
weakened under the effect of environmental factors.
37. The method according to claim 36, wherein the environmental
factor is the cold or heat.
38. A method for preventing or for reducing the penetration of
exogenous molecules into the skin following a weakening of skin
barrier comprising the administration to a person in need thereof
of an effective quantity of a 1,3 diglyceride having the general
formula (I): ##STR00019## in which the radicals R.sub.1 and R.sub.2
represent, independently of one another, a C13 to C40 saturated and
linear alkyl radical.
39. The method according to claim 38, wherein the skin barrier is
weakened under the effect of environmental factors.
40. The method according to claim 39, wherein the environmental
factor is the cold or heat.
Description
[0001] This invention relates to a cosmetic or dermatological
composition, intended to be administered topically, comprising at
least one 1,3 diglyceride defined hereinafter, as well as its use
for improving the resistance of the stratum corneum, in particular
to environmental factors such as the cold or heat, and as such
preserve its properties as a skin barrier.
[0002] One of the main functions of the skin is to form a physical
barrier that, in addition to its protective role with respect to
the environment by preventing the penetration of aggressive
microbial or chemical elements, must provide the maintaining of the
physiological medium of the organism by limiting water loss, thanks
to a relative hydrophobicity. Although there is still controversy
concerning the various paths of transcutaneous passage, it is
admitted for the most part that the penetration via the
intercorneocytory spaces also serves as an element for regulating
the permeability of the skin [1]. The substantial number of
adsorption-desorption sequences associated with the diffusion of
molecules through lamellar layers of the corneum determines the
effectiveness of the skin barrier. The diffraction of X-rays, used
for the characterisation of the latter, reveals the presence of two
lamellar phases with repetition distances of 6 and 13 nm which are
mostly located in crystalline lateral phases (orthorhombic lateral
arrangement) [2, 3, 4]. Indeed, at physiological temperature, the
aliphatic long chains of ceramides and of fatty acids form with the
cholesterol and the esters thereof gelled states that are
impermeable to the transepidermal flow of water.
[0003] In subjects whose skin barrier is intact, the transepidermal
flow of water, (also called TransEpidermal Water Loss--TEWL) is
about 5 mg/cm.sup.2 [5] but it can reach higher values in case of
external aggressions due to various environmental factors such as
the cold or heat. In this respect, it has been shown that a simple
exposure for an average of 3 hours in conditions of average outdoor
sunshine (outside temperature of 26.6.degree. C.) was sufficient to
induce an increase of 4.7.degree. C. in the skin temperature
(initially at 31.7.degree. C.) [6] and that the latter can exceed
40.degree. C. after only 20 minutes of exposure to the sun at solar
noon in the summer [7]. Such an elevation in the skin temperature
then causes a fluidification of the lipids of the intercorneocytory
spaces, which change to a state of the liquid crystal type giving
rise to a substantial increase in transepidermal water loss
[4].
[0004] As such, the altering/weakening of the skin barrier allows
for an increased penetration of exogenous substances (polluting
agents, irritant agents or allergenic substances (also called
allergens)), preferably lipophilic exogenous substances, which can
sometimes cause irritations or allergic reactions or oxidative
stress.
[0005] In addition to being allergenic, certain volatile organic
polluting agents, such as benzo[a]pyrene released from exhaust
gases, are also considered to be carcinogenic (carcinogen of Group
1).
[0006] Diglycerides are known in literature and have biological,
cosmetics and/or therapeutic activities. It is known in document KR
2013058299 the use of a composition comprising 1,3-diolein or
1,3-dilinoleoyl-rac-glycerol for preventing or treating
hyperpigmentation. Likewise, preparations with a fatty acid
derivative base among which diglycerides have been able to be
claimed for countering the ageing of the skin (WO 03/014073 A1), as
an emollient (JP02115117 A) or used in sticks for caring for lips
(JP52061240A). Certain diglycerides are used at a low concentration
(<1% by weight) as a texturising agent in cosmetic compositions.
However, to date, no document describes or suggests that 1,3
diglycerides can have interesting properties in order to overcome
the weakening in the skin barrier function, in particular under the
effect of environmental factors (cold, heat).
[0007] This invention as such aims to overcome the disadvantages of
prior art by proposing active stabilisers of the intercorneocytory
spaces and their use in cosmetic or dermatological compositions so
as to counter the weakening of the skin barrier, in particular
under the effect of environmental factors. The obtaining of greater
stability of the intercorneocytory spaces will as such make it
possible to open new perspectives in the fields of cosmetics and
dermatology for skincare and/or make-up products for the skin,
including facial skin, body skin and scalp. Such active agents can
be used in topical cosmetic or dermatological compositions for
protecting the skin, including facial skin, body skin and scalp, in
particular against some deleterious effects (such as allergy,
irritation, etc.) due to the penetration into the skin of exogenous
substances, such a cutaneous penetration being increased under the
effect of environmental factors, such as heat.
[0008] Thus it has been noticed, and this surprisingly and in a
completely unexpectedly manner, that the use of a 1,3 diglyceride
having the general formula (I):
##STR00002##
in which the radicals R.sub.1 and R.sub.2 represent, independently
of one another, a C13 to C40 saturated and linear alkyl radical, in
a cosmetic or dermatological composition made it possible, after
being applied topically, to limit the weakening of the skin barrier
that can be due to environmental factors. The inventors have in
particular revealed that these 1,3 diglycerides, when they are
applied on the skin, stabilise the change in state of the lipids
present in the intercorneocytory spaces; this change in state is
observed in particular under the effect of the temperature.
[0009] In order to evaluate the change in the organisation of the
lipid phases of the stratum corneum, the inventors used infrared
spectroscopy (ATR-FTIR: Attenuated total reflectance-Fourier
transform infrared Spectroscopy) to analyse the variation, under
the effect of the temperature, of the fundamental vibration bands
of the .nu.CH.sub.2 aliphatic chains of these lipids. More
particularly, the position of the absorption band, corresponding to
the stretching of the CH.sub.2, is located around wave number 2848
cm.sup.-1. By way of example, an increase in the temperature of the
surface of the skin causes a displacement of this bands to the
higher wave numbers. This displacement reveals the fact that the
lipids in the stratum corneum adopt, under the effect of the heat,
a less-ordered conformation accompanied by an increase in the
fluidity of the hydrocarbon chains that fill the intercorneocytory
spaces (see example 1).
[0010] In the framework of this invention, it has also been
demonstrated that, on the one hand, the stabilising power of the
1,3 diglycerides, on the heated lipid phase, increases with the
length of the esterified chains (see example 2) and on the other
hand, that the 1,3 diglycerides have a stabilising effect of the
heated lipid phase that is much greater than that observed with
diglycerides 1,2 (see example 3). It is however not excluded in the
framework of this invention to use a 1,3 diglyceride that would be
in a mixture with small quantities of 1,2 diglycerides often
present due to industrial production conditions.
[0011] In addition, a study in vivo on healthy volunteers made it
possible to show that applying glyceryl 1,3 distearate makes it
possible to stabilise the organisation of the intercorneocytory
lipids of the skin heated between 30 and 45.degree. C. This
beneficial effect persists at least 4 hours after application of
the glyceryl 1,3 distearate (see example 4).
[0012] An ex vivo assay allows also demonstrating that applying
glyceryl 1,3 distearate on the skin makes it possible to limit the
increased cutaneous penetration of a polluting agent such as
benzo[a]pyrene due to heat.
[0013] An object of this invention thus relates to a topical
cosmetic or dermatological composition comprising at least one 1,3
diglyceride having the general formula (I),
##STR00003##
in which the radicals R.sub.1 and R.sub.2 represent, independently
of one another, a C13 to C40 saturated and linear alkyl radical;
and further comprising at least one cosmetic or dermatological
excipient for a topical application on the skin.
[0014] The 1,3 diglycerides having the general formula (I)
hereinabove can be prepared in particular as described in the
article of Liu et al. [9]. They are used in the compositions
according to the invention, as an active principle, and more
particularly as a stabilising agent of the intercorneocytory
spaces.
[0015] The term "intercorneocytory spaces" means the spaces
containing a lipid phase which are located between the corneocytes
of the cornea layer (also called stratum corneum--SC in abstract)
which forms the skin barrier.
[0016] In the framework of this patent application, the term
"stabilising agent of the intercorneocytory spaces" will be used
more particularly to designate an agent that limits the
destabilisation of the intercorneocytory spaces, in particular
under the action of environmental factors, and which therefore has
a barrier effect by opposing the penetration of exogenous
substances, such as chemical or microbial agents that can be
irritating and/or allergenic; or polluting agents that can generate
an oxidative stress, in a skin in particular exposed to
environmental factors.
[0017] This effect of stabilisation/destabilisation of the
intercorneocytory spaces can among others be evaluated according to
the protocol of the example 2.
[0018] Concerning the penetration of exogenous substances, an ex
vivo assay (see example 6) allows evidencing the fact that the
bioavailability of benzo[a]pyrene is highly influenced by the skin
temperature: it doubles when the skin temperature passes from
32.degree. C. to 42.degree. C. (increasing from 2.95 to 6.95% of
the dose applied to the skin).
[0019] This illustrates the need to strengthen the skin barrier by
stabilizing the intercorneocytory spaces to limit the penetration
of exogenous substances, in particular when environmental
conditions lead to an increase in outside temperature notably
greater than or equal to about 42.degree. C.
[0020] The ex vivo assay on the bioavailability of benzo[a]pyrene
after application of a 1,3 diglyceride of formula I on the tested
skin also confirms that the 1,3 diglyceride compounds as defined
previously allow this stabilisation and thus the skin
protection.
[0021] Indeed, after application of a 1,3 diglyceride of formula I,
and more particularly glyceryl 1,3 distearate at the dose of 3% or
15%, on a skin maintained in an atmosphere at 42.degree. C., a
significant decrease in the penetration of benzo[a]pyrene compared
to the basal state and the vehicle was observed.
[0022] The term "environmental factors" means, in the terms of this
invention, the external conditions such as heat or cold, preferably
heat, that induce a variation in the skin temperature that can
destabilise the intercorneocytory spaces. In a preferred
embodiment, heat, such as that of a summer period or due to an
exposure to the sun, can induce an elevation in the skin
temperature, notably above about 35.degree. C., in particular above
about 40.degree. C., and cause a fluidification of the lipids of
the intercorneocytory spaces in terms of this invention.
[0023] The impact of the external temperature on the organisation
of the intercorneocytory spaces of the stratum corneum can among
others be evaluated according to the model of example 1 (analysis
via infrared spectroscopy of the variation in the wave number of
the .nu.CH.sub.2 vibration).
[0024] In this respect, as has already been mentioned, it has been
shown that a simple exposure for an average of 3 hours in
conditions of average outdoor sunshine (outside temperature of
26.6.degree. C.) was sufficient to induce an increase of
4.7.degree. C. in the skin temperature (initially at 31.7.degree.
C.) [6] and that the latter can exceed 40.degree. C. after only 20
minutes of exposure to the sun at solar noon in the summer [7].
[0025] Such an elevation in the skin temperature then causes a
fluidification of the lipids of the intercorneocytory spaces, which
develops into a state of the liquid crystal type giving rise to a
substantial increase in transepidermal water loss [4].
[0026] In a particular embodiment of the invention, the radicals
R.sub.1 and R.sub.2 are identical and represent a C13 to C40
saturated and linear alkyl radical.
[0027] According to another embodiment of the invention, the
radicals R.sub.1 and R.sub.2 represent, independently of one
another, a C15 to C23, in particular a C15 to C19, saturated and
linear alkyl radical. The radicals R.sub.1 and R.sub.2 can also be
identical and represent a C15 to C23, in particular a C15 to C19,
saturated and linear alkyl radical.
[0028] The radicals R.sub.1 and R.sub.2, identical or different,
preferably identical, represent in particular the hydrocarbon chain
of palmitic, stearic or arachidic acid, namely a pentadecyle,
heptadecyle or nonadecyle radical.
[0029] The diglyceride 1,3 according to the invention will be more
particularly glyceryl 1,3 dipalmitate, glyceryl 1,3 distearate or a
mixture thereof.
[0030] The 1,3 diglycerides having the formula (I) according to the
invention represent preferably from 0.5 to 10%, more particularly
from 1 to 5%, and even more particularly from 3 to 5% by weight of
the total weight of the composition.
[0031] According to another embodiment, the 1,3 diglycerides having
the formula (I) according to the invention represent from 5 to 10%
by weight of the total weight of the composition.
[0032] The compositions according to this invention can also
contain a 1,2 diglyceride. Indeed, the 1,3 diglycerides used
generally contain small residual quantities of 1,2 diglyceride.
However, the quantity of 1,2 diglyceride in the compositions
according to the invention will not exceed advantageously 10% by
weight, in particular 5% by weight, of the total weight of the 1,3
and 1,2 diglycerides.
[0033] The topical compositions according to the invention are
intended to be applied on the skin. These compositions can be more
or less fluid and have the aspect of a cream, a lotion, a milk, a
serum, an ointment, a gel or a foam. They can also have the form of
a solid, such as a stick or be applied on the skin in the form of
an aerosol. These compositions can in particular have the form of
an oily solution; of an oil-in-water, water-in-oil emulsion, or
multiple emulsions.
[0034] The 1,3 diglycerides having the formula (I) according to the
invention will preferably be introduced into the compositions in
dispersed form.
[0035] By "dispersed form" is meant in the present invention that
the 1,3 diglyceride having the formula (I) according to the
invention is in the form of solid particles which are dispersed in
a dispersing phase.
[0036] Thus, the compositions according to the invention will
comprise advantageously at least one 1,3 diglyceride having the
formula (I) according to the invention in a dispersed form, i.e.
present in the composition in the form of dispersed solid
particles.
[0037] According to a preferred embodiment, the average diameter of
the solid particles of 1,3-diglyceride of formula (I) according to
the invention is greater than 100 nm and less than 50 .mu.m. A
measure of the particle size distribution by laser diffraction
allows obtaining such a value.
[0038] In a particular embodiment, the 1,3-diglycerides of formula
(I) according to the invention will be dispersed in a fatty phase,
for example a silicone and preferably a non-volatile silicone, an
ester, a mineral oil or a vegetable oil, or a mixture thereof.
Among the silicones, dimethicone (non-volatile) can be
mentioned.
[0039] The composition according to the invention provides a
protection of the skin barrier, that remains comfortable all
throughout the day. It can in particular be applied to sensitive,
fragile and/or reactive skin, and in particular to the skin of a
baby.
[0040] This invention also has for object a composition according
to the invention described hereinabove for use in the protection of
the skin, including facial skin, body skin and scalp.
[0041] This invention also relates to the use of a composition
described hereinabove in order to protect the skin, including
facial skin, body skin and scalp.
[0042] This invention also relates to a method for protecting the
skin, including facial skin, body skin and scalp, comprising the
administration to a person in need thereof of an effective quantity
of a composition described hereinabove.
[0043] This invention also has for object a composition according
to the invention described hereinabove for use in countering the
weakening of the skin barrier.
[0044] This invention also relates to the use of a composition
described hereinabove in order to counter the weakening of the skin
barrier.
[0045] This invention also relates to a method for countering the
weakening of the skin barrier comprising the administration to a
person in need thereof of an effective quantity of a composition
described hereinabove.
[0046] This invention also has for object the compositions
described hereinabove for use for preventing or reducing the
penetration of exogenous molecules into the skin following a
weakening of the skin barrier.
[0047] This invention also relates to the use of a composition
described hereinabove for preventing or reducing the penetration of
exogenous molecules into the skin following a weakening of the skin
barrier.
[0048] This invention also relates to a method for preventing or
for reducing the penetration of exogenous molecules following a
weakening of the skin barrier comprising the administration to a
person in need thereof of an effective quantity of a composition
described hereinabove.
[0049] The weakening of the skin barrier can be induced in
particular under the effect of environmental factors such as the
cold or heat, and more particularly heat, in particular in case of
exposure to the sun.
[0050] This weakening results in particular in a destabilisation of
the intercorneocytory spaces, a destabilisation which can among
others be evaluated according to the protocol of the example 1.
[0051] The exogenous molecules can be in particular irritant
substances (hygiene products, solvents, etc.) or allergenic
substances (perfumes, house dust, microbial agents, etc.). In
particular, the exogenous molecules are lipophilic.
[0052] This invention also has for object a 1,3 diglyceride having
the general formula (I) hereinbelow:
##STR00004##
in which the radicals R.sub.1 and R.sub.2 represent, independently
of one another, a C13 to C40 saturated and linear alkyl radical,
for use in the protection of the skin, including facial skin, body
skin and scalp.
[0053] This invention also relates to the use of a 1,3 diglyceride
having the general formula (I) hereinbelow:
##STR00005##
in which the radicals R.sub.1 and R.sub.2 represent, independently
of one another, a C13 to C40 saturated and linear alkyl radical,
for the manufacture of a topical cosmetic or dermatological
composition intended to protect the skin, including facial skin,
body skin and scalp.
[0054] This invention also relates to the use of a 1,3 diglyceride
having the general formula (I) hereinbelow:
##STR00006##
in which the radicals R.sub.1 and R.sub.2 represent, independently
of one another, a C13 to C40 saturated and linear alkyl radical, in
order to protect the skin, including facial skin, body skin and
scalp.
[0055] This invention also relates to a method for protecting the
skin, including facial skin, body skin and scalp, comprising the
administration to a person in need thereof of an effective quantity
of a 1,3 diglyceride having the general formula (I)
hereinbelow:
##STR00007##
in which the radicals R.sub.1 and R.sub.2 represent, independently
of one another, a C13 to C40 saturated and linear alkyl
radical.
[0056] This invention also has for object a 1,3 diglyceride having
the general formula (I) hereinbelow:
##STR00008##
in which the radicals R.sub.1 and R.sub.2 represent, independently
of one another, a C13 to C40 saturated and linear alkyl radical,
for use to counter the weakening of the skin barrier.
[0057] This invention also relates to the use of a 1,3 diglyceride
having the general formula (I) hereinbelow:
##STR00009##
in which the radicals R.sub.1 and R.sub.2 represent, independently
of one another, a C13 to C40 saturated and linear alkyl radical,
for the manufacture of a topical cosmetic or dermatological
composition intended to counter the weakening of the skin
barrier.
[0058] This invention also relates to the use of a 1,3 diglyceride
having the general formula (I) hereinbelow:
##STR00010##
in which the radicals R.sub.1 and R.sub.2 represent, independently
of one another, a C13 to C40 saturated and linear alkyl radical, in
order to counter the weakening of the skin barrier.
[0059] This invention also relates to a method for countering the
weakening of the skin barrier comprising the administration to a
person in need thereof of an effective quantity of a 1,3
diglyceride having the general formula (I) hereinbelow:
##STR00011##
in which the radicals R.sub.1 and R.sub.2 represent, independently
of one another, a C13 to C40 saturated and linear alkyl
radical.
[0060] This invention also has for object a 1,3 diglyceride having
the general formula (I) hereinbelow:
##STR00012##
in which the radicals R.sub.1 and R.sub.2 represent, independently
of one another, a C13 to C40 saturated and linear alkyl radical,
for its topical use in preventing or reducing the penetration of
exogenous molecules following a weakening of the skin barrier.
[0061] This invention also relates to the use of a 1,3 diglyceride
having the general formula (I) hereinbelow:
##STR00013##
in which the radicals R.sub.1 and R.sub.2 represent, independently
of one another, a C13 to C40 saturated and linear alkyl radical,
for the manufacture of a topical cosmetic or dermatological
composition intended to prevent or reduce the penetration of
exogenous molecules following a weakening of the skin barrier.
[0062] This invention also relates to the use of a 1,3 diglyceride
having the general formula (I) hereinbelow:
##STR00014##
in which the radicals R.sub.1 and R.sub.2 represent, independently
of one another, a C13 to C40 saturated and linear alkyl radical,
for preventing or reducing the penetration of exogenous molecules
following a weakening of the skin barrier. In particular, the
exogenous molecules are lipophilic.
[0063] This invention also relates to a method for preventing or
for reducing the penetration of exogenous molecules following a
weakening of the skin barrier comprising the administration to a
person in need thereof of an effective quantity of a 1,3
diglyceride having the general formula (I) hereinbelow:
##STR00015##
in which the radicals R.sub.1 and R.sub.2 represent, independently
of one another, a C13 to C40 saturated and linear alkyl
radical.
[0064] The weakening of the skin barrier can be induced in
particular under the effect of environmental factors such as the
cold or heat, and more particularly heat, in particular in case of
exposure to the sun.
[0065] This weakening results in particular in a destabilisation of
the intercorneocytory spaces, a destabilisation which can among
others be evaluated according to the protocol of the example 1.
[0066] The exogenous molecules can be in particular irritant
substances (hygiene products, solvents, etc.) or allergenic
substances (perfumes, house dust, microbial agents, etc.).
[0067] In a particular embodiment of the invention, the radicals
R.sub.1 and R.sub.2 are identical and represent a C13 to C40
saturated and linear alkyl radical.
[0068] According to another embodiment of the invention, the
radicals R.sub.1 and R.sub.2 represent, independently of one
another, a C15 to C23, in particular a C15 to C19, saturated and
linear alkyl radical. The radicals R.sub.1 and R.sub.2 can also be
identical and represent a C15 to C23, in particular a C15 to C19,
saturated and linear alkyl radical.
[0069] The radicals R.sub.1 and R.sub.2, identical or different,
more preferably identical, represent in particular the hydrocarbon
chain of palmitic, stearic or arachidic acid, namely a pentadecyle,
heptadecyle or nonadecyle radical.
[0070] The 1,3 diglyceride according to the invention shall be more
particularly glyceryl 1,3 dipalmitate, glyceryl 1,3 distearate or a
mixture thereof.
[0071] The following examples and figures show the invention.
FIGURES
[0072] FIG. 1 shows the wave number of the .nu.CH.sub.2 vibration
of the aliphatic chains of the intercorneocytory lipids in function
of temperature.
[0073] FIG. 2 shows the variation in the wave number of the
.nu.CH.sub.2 vibration of the aliphatic chains of the
intercorneocytory lipids, between the situations with or without
1,3 diglyceride, according to the length of the chain of the 1,3
diglyceride.
[0074] FIGS. 3 and 4 represent the CH.sub.2 symmetric stretching
band shift at 28.degree. C. and 43.degree. C. with or without
pre-treatment of the skin.
[0075] FIG. 5 represents the percentage of B(a)P recovered in the
different compartments of the Franz diffusion cell after 24 h
(Mean.+-.SEM; n=8).
EXAMPLES
Example 1: Modification of the Organisation of the
Intercorneocytory Spaces Under the Influence of Heat
[0076] The study was carried out on lipids extracted from the
stratum corneum of the forearm in order to have a model as close as
possible to reality. We have used infrared spectroscopy (ATR-FTIR),
to examine the variation, in function of temperature, of
fundamental .nu.CH.sub.2 vibration bands of aliphatic chains.
[0077] The variation in the wave number of the .nu.CH.sub.2
vibration in function of temperature between 18 and 50.degree. C.
is reported in FIG. 1.
[0078] It is noted that at low temperatures the value of the
.nu.CH.sub.2 stretching vibration of the mixture of pure lipids is
located at 2850.7 cm.sup.-1, which is characteristic of an
Orthorhombic/Hexagonal phase, and that the latter changes at higher
temperatures to higher wave numbers, in order to reach 2852.4
cm.sup.-1, characteristic of a Liquid phase.
[0079] The increase in the wave number observed indeed reveals the
change in state and the fluidification of the intercorneocytory
lipids under the effect of the temperature.
Example 2: Revealing of the Stabilising Effect of 1,3 Diglycerides
and of the Effect of their Chain Length on the Organisation of the
Intercorneocytory Lipids
[0080] The tests were carried out in similar experimental
conditions using lipids extracts from the forearm wherein a
standardized quantity of diglyceride is added (3 .mu.g of
diglyceride for 30 .mu.g of sample). FIG. 2 shows the effect of the
chain length of the 1,3 diglyceride on the .nu.CH.sub.2 parameter,
with the measurements taken at 40.degree. C.
[0081] These results make it possible to reveal the influence of
the length of the aliphatic chains of glycerides. At temperatures
close to living organisms, 1,3-dicaprin (C10) as well as
1,3-dilauroylglycerol (C12) have no influence on the organisation
of the intercorneocytory lipids. As it appears when examining FIG.
2, starting from a C14 chain length, a significant stabilising
effect appears and starting from a C16 chain length, it can be seen
that the stretching frequency of the CH.sub.2 is maintained towards
the low numbers comparatively to the extract devoid of diglyceride.
Furthermore, these results indeed reveal an increase in the
stabilising power with the length of the alkyl chain of the
diglycerides with respect to the fluidification of the skin lipids
under the effect of heat.
Example 3: 1,3 Diglyceride/1,2 Diglyceride Comparison
[0082] The test of the example 2 was reproduced with
1,2-distearoyl-rac-glycerol (1,2 diglyceride) and compared to the
test carried out with glyceryl 1,3-distearate (1,3 diglyceride).
The results obtained are shown in table 1 hereinbelow.
TABLE-US-00001 TABLE 1 variation in the wave number of the
.nu.CH.sub.2 vibration of the aliphatic chains of the
intercorneocytory lipids, between the situations with or without
1,3 diglyceride, for a 1,3 diglyceride and a 1,2 diglyceride.
Glyceride .DELTA. .nu.CH2 (cm.sup.-1) glyceryl 1,3-distearate -1.43
1,2-distearoyl-rac-glycerol -0.65
[0083] These results clearly show the superior effect of 1,3
diglycerides on the stabilisation of intercorneocytory spaces.
Example 4: Revealing of the Stabilising Effect of the Organisation
of the Intercorneocytory Spaces after Application of Glyceryl
1,3-Distearate in Clinical Conditions In Vivo
[0084] This study was carried out on health volunteers. The
collection of infrared data was done through the intermediary of
the ATR-FTIR sensor on the inner face of the forearm on a zone of
10 cm'.
[0085] A treated zone (with application in vivo of glyceryl 1,3
distearate) and a control zone (without application of glyceryl 1,3
distearate) were determined.
[0086] Two concentrations in glyceryl 1,3-distearate were evaluated
(table 2: 0.5 mg/cm.sup.2 and table 3: 0.15 mg/cm.sup.2).
[0087] At T0: the skin is first heated to between 30 and 45.degree.
C.
[0088] Then after application in vivo of glyceryl 1,3-distearate on
the treated zone, an evaluation is made of the variation in the
wave number associated with the .nu.CH.sub.2 vibration
comparatively to the reference measurement without product applied
(control zone) at different times after T0: T 30 minutes, T 1 h30
minutes and T 4 hours.
[0089] The data obtained is gathered together in tables 2 and 3 and
allows several observations to be made.
TABLE-US-00002 TABLE 2 applied quantity of glyceryl 1,3-distearate
= 0.5 mg/cm.sup.2 .DELTA. .nu.CH2 0.5 mg/cm.sup.2 30 min 1 h 30 4 h
Subject 1 -2.56 -2.65 -2.6 Subject 2 -3.02 -2.62 -2.29 Subject 3
-2.71 -2.6 -2.18 Average (cm.sup.-1) -2.46 -2.41 -2.17
TABLE-US-00003 TABLE 3 applied quantity of glyceryl 1,3-distearate
= 0.15 mg/cm.sup.2 .DELTA. .nu.CH2 0.5 mg/cm.sup.2 30 min 1 h 30 4
h Subject 4 -1.87 -1.91 -1.64 Subject 5 -2.16 -2.25 -2.15 Average
(cm.sup.-1) -2.02 -2.08 -1.89
[0090] Tables 2 and 3: express the variation of the wave number
associated with the .nu.CH.sub.2 vibration of the aliphatic chains
of the intercorneocytory lipids at 40.degree. C. in the presence of
glyceryl 1,3-distearate comparatively to the reference measurement
without glyceryl 1,3-distearate.
[0091] Firstly, it is shown without ambiguity that the glyceryl
1,3-distearate in normal conditions of use makes it possible to
stabilise the organisation of the intercorneocytory spaces of the
skin heated between 30 and 45.degree. C.
[0092] Secondly, it is shown that this stabilising effect visible
as soon as the diglyceride is applied lasts for at least 4
hours.
Example 5: Examples of Compositions According to the Invention
Composition 1: O/W Formula
TABLE-US-00004 [0093] Components % by weight Glyceryl 1,3
dipalmitate 1-5 Glycerine 10.0 Na.sub.2EDTA 0.1 Xanthan gum 0.3
C12-C15 alkyl benzoate 10.0 Octyl palmitate 5.0 Preservatives qs
Stearic alcohol 2.5 Glycerol monostearate 2.5 Potassium cetyl
phosphate 1.8 Demineralised water QSP 100
Composition 2: W/O Formula
TABLE-US-00005 [0094] Components % by weight Glyceryl 1,3
distearate 1-5 Glycerine 4.0 Na.sub.2EDTA 0.1 MgSO.sub.4 1.0
Xanthan gum 0.1 C12-C15 alkyl benzoate 12.5 Isohexadecane 3.5
Cyclomethicone 3.0 Preservatives qs Sorbitane and polyglycerol
esters 4.0 Myreth-3 myristate 2.0 Demineralised water Qsp 100
Composition 3: Creamy Gel
TABLE-US-00006 [0095] Components % by weight Glyceryl 1,3
dipalmitate 1-5 Dimethicone 5.0 C8-C18 alkyl ester 5.0 Polyethylene
glycol glyceryl cocoate 2.5 (Cetiol .RTM. HE) Polyacrylate 13 &
Polyisobutene & 3.0 Polysorbate 20 (Sepiplus .TM. 400) Xanthan
gum 0.1 Propylene glycol 3.0 Na.sub.2EDTA 0.2 Preservatives qs
Demineralised water Qsp 100
Composition 4: Cream
TABLE-US-00007 [0096] Components % by weight Glyceryl 1,3
distearate 3-10 Dimethicone 5.0 Glyceryl stearate/PEG-100 stearate
5.0 (Simulsol .TM. 165) Behenic alcohol 1.3 Octyldodecanol 10.0
C8-C18 alkyl ester 5.0 Polyacrylate 13 & Polyisobutene &
2.0 Polysorbate 20 (Sepiplus .TM. 400) Propylene glycol 3.0
Na.sub.2EDTA 0.2 Preservatives qs Demineralised water Qsp 100
Example 6: Evaluation of the Impact of 1,3 Diglycerides on the
Benzo[a]Pyrene Skin Penetration
[0097] In order to evaluate the impact of 1,3-diglycerides on the
organization of stratum corneum lipids and barrier function, in
vitro, skin penetration studies of a known pollutant
(benzo[a]pyrene (B(a)P) has been developed and performed. On the
same donors, FTIR (Fourier transform infrared) measurement and
B(a)P skin penetration were assessed to link lipid organization and
the "outside-in" skin barrier function modulations, when the skin
is heated up to 42.degree. C.
[0098] Firstly, it has been demonstrated that an increase of
temperature from 32.degree. C. to 42.degree. C. at the surface of
the skin modifies the lipid organization and alters the
"outside-in" skin barrier function as evidenced by an increase of
the skin penetration of B(a)P.
[0099] Secondly, the impact of pre-treatment with 3% and 15% of
glyceryl 1,3 distearate formulated in dimethicone on the
modification of the SC (stratum corneum) lipid organization and
B(a)P skin penetration provoked by the temperature elevation has
been evaluated.
[0100] Material and Methods:
[0101] Compounds
Test Items:
TABLE-US-00008 [0102] TEST ITEM NAME SUPPLIER MW STOCK SOLUTION
Glyceryl 1,3 distearate Sigma Aldrich 625.02 3% and 15% in
dimethicone Benzo[a]pyrene Sigma Aldrich 252.31 In acetone at 0.5%
C.sup.14-Benzo[a]pyrene Isobio 252.31 In acetone at 0.5%
Solubility:
[0103] The solubility of B(a)P is well documented in the
literature. Due to its physicochemical properties, B(a)P has a very
poor solubility in water. The software Episuite predict a
solubility of 13.3 .mu.g/L and experimental data confirmed this
result at 25.degree. C. [11]. In the present study, the percentage
of B(a)P found in the receptor fluid reach 0.13% of the applied
dose in the worst case, corresponding to 12.51 .mu.g/L. Based on
these data, we have added 4% of bovine serum albumin (BSA) to
increase the solubility of B(a)P and avoid to damage the skin.
Surfactants and ethanol were prohibited in order to avoid
modification of skin barrier function.
[0104] Guidelines
[0105] The study was performed according to: [0106] OECD Guidelines
for the testing of chemicals: guideline 428, skin absorption: in
vitro method (13 Apr. 2004); [0107] SCCS Guidelines, basic criteria
for the in-vitro assessment of dermal absorption of cosmetics
ingredients, updated March 2006.
[0108] Experimental Design
Set of the Temperatures:
FTIR Measurement:
[0109] The skin samples were heated at the rate of 1.degree.
C./min, and spectra were collected between 28.degree. C. and
43.degree. C.
TABLE-US-00009 Kinetic of heating 1.degree. C./min Minimal
temperature tested 28.degree. C. Maximal temperature tested
43.degree. C.
Skin Delivery Experiment:
[0110] For the skin delivery study, two temperatures were set. The
classical temperature at the surface of the skin for skin delivery
studies is 32.degree. C. This temperature corresponds to the
temperature at the surface of the skin in vivo.
[0111] Previous studies performed by the Biophysic and Imaging Unit
on in vitro lipids with FTIR shown that at 40.degree. C. the
disorganization of the lipids starts to be visible. Based on these
results, a temperature of 42.degree. C. has been chosen to be able
to observe the disorganisation of the lipids during the skin
delivery experiment.
TABLE-US-00010 32.degree. C. Without pre-treatment Dimethicone 3%
Glyceryl 1,3 distearate 15% Glyceryl 1,3 distearate 42.degree. C.
Without pre-treatment Dimethicone 3% Glyceryl 1,3 distearate 15%
Glyceryl 1,3 distearate
Skin Delivery Experiment:
TABLE-US-00011 [0112] Glyceryl 1,3 distearate at 3% and
Pre-treatment 15% in dimethicone Time of pre-treatment 30 min
Formulation B(a)P in acetone Theoretical B(a)P concentration 0.5%
in the formulation Cell system Franz diffusion cell (1.2 cm.sup.2)
Skin Human skin Formulation applied per cell (mg) 10 .mu.l/cm.sup.2
Skin temperature 32.degree. C. .+-. 1.degree. C. Skin integrity
TEWL .ltoreq.13 g/m.sup.2/h Theoretical amount of B(a)P 52
.mu.g/cm.sup.2 applied on skin Thickness of the skin 400 .+-. 50
.mu.m Number of cell per donor 1 Number of donor per condition 8
Total cells 64 Temperature of incubation 32.degree. C. and
42.degree. C. Washing of the formulation 24 hours after application
Surface 2 times with water 2 times with acetonitrile (ACN) 2 times
with 1/2 Whatman discs Receptor fluid NaCl 0.9% + BSA 4% Sampling
of receptor fluid No Separation of epidermis and No dermis Strips
15 strips (D-Squame .RTM.) Solvent used Acetonitrile
[0113] The skin penetration study was carried out on 8 donors, the
same donor was used for all the conditions:
TABLE-US-00012 32.degree. C. Without pre-treatment Dimethicone 3%
Glyceryl 1,3 distearate 15% Glyceryl 1,3 distearate 42.degree. C.
Without pre-treatment Dimethicone 3% Glyceryl 1,3 distearate 15%
Glyceryl 1,3 distearate
Lipids Organization--FTIR Measurement:
[0114] After 30 min of pre-treatment, FTIR measurements were
performed to evaluate the molecular organization of the lipid
matrix in the stratum corneum. The procedure is based on the study
of the position of the CH.sub.2 symmetric stretching band, around
2850 cm.sup.-1, depending on the temperature: the skin samples were
heated at the rate of 1.degree. C./min and spectra were collected
between 28.degree. C. and 43.degree. C. with and without
pre-treatment. The position of the CH.sub.2 symmetric stretching
band is characteristic of the lipid organization and can be related
to the barrier function.
[0115] Read-Out Parameters [0116] FTIR measurement of skin explant
(position of CH.sub.2 symmetric stretching band) depending on the
temperature; [0117] Skin penetration study [0118] Total recovery of
B(a)P [0119] Compartmental repartition in percentage of B(a)P
applied [0120] Compartmental repartition in .mu.g/cm.sup.2
[0121] Data Management
[0122] The study was carried out on 8 donors, the same donor was
used for all the conditions. B(a)P recovery should be comprised
between 85% and 115% of the applied dose, in accordance with OECD
428 and SCCS guidelines.
[0123] Results of B(a)P were presented in Tables and Graphs
expressed as: [0124] % of the applied dose at surface, stratum
corneum, skin and receptor fluid; [0125] .mu.g/cm.sup.2 of B(a)P at
surface, stratum corneum, skin and receptor fluid.
[0126] Results were presented with 2 decimals for the percentages
and the quantities in .mu.g/cm.sup.2. Formula used in this report:
[0127] Standard error of the mean:
[0127] sem=Sd/ n [0128] Bioavailability: [0129] Sum of the
quantities found in the skin and receptor fluid.
[0130] The inter-group comparison was performed by a paired
Student's t-test with Graph Pad Prism software. The statistical
analysis can be interpreted if n>5.
[0131] Results:
[0132] Lipids Organization--FTIR Measurement
[0133] FTIR measurements were performed on human skin explants (8
donors) with or without pre-treatment. The skin samples were heated
at the rate of 1.degree. C./min, and spectra were collected between
28.degree. C. and 43.degree. C.
[0134] FIGS. 3 and 4 show the impact of the temperature on the
CH.sub.2 symmetric stretching band. Without pre-treatment, a
significant difference on lipid organization can be seen when the
skin is heated, with a shift of the CH.sub.2 symmetric stretching
band from 2851.2 cm.sup.-1 at 28.degree. C. to 2852.12 cm.sup.-1 at
43.degree. C. (T test, p value<0.05). The pre-treatment with 3%
or 15% of glyceryl 1,3 distearate permits to decrease significantly
(T tests, p value<0.05) the impact of the heating on the lipid
organization. A shift of the CH.sub.2 symmetric stretching band
from 2852.12 cm.sup.-1 (43.degree. C. basal) to 2848.7 cm.sup.-1
has been observed with 3% glyceryl 1,3 distearate as pre-treatment
at 43.degree. C. The pre-treatment with glyceryl 1,3 distearate
decreases the shift of the CH.sub.2 symmetric stretching band
induced by the heating of the skin: the shift is only 0.05
cm.sup.-1 after pre-treatment with 3% of glyceryl 1,3 distearate
and 0.81 cm.sup.-1 without pre-treatment.
[0135] Skin Penetration Study
Total Recovery:
[0136] The total recovery for all the diffusion cells was in the
acceptance criteria, ranging between 94.9% and 97.6% of the applied
dose, and permits to validate the study.
[0137] Compartmental repartition in percentage of the applied
dose:
[0138] The results obtained are presented in Table 4 below and on
FIG. 5.
TABLE-US-00013 TABLE 4 Summary results in percentage of the applied
dose (Mean .+-. SEM; n = 8) 32.degree. C Without 3% 15%
pretreatment Dimethicone Diglyceride Diglyceride Mean SEM Mean SEM
Mean SEM Mean SEM Surface 89.38 1.49 94.42 0.70 94.66 0.47 94.99
0.47 Stratum 3.05 0.63 0.72 0.12 0.82 0.16 0.77 0.15 corneum Skin
2.91 0.58 2.28 0.34 2.09 0.32 1.87 0.30 Receptor fluid 0.04 0.01
0.04 0.01 0.05 0.01 0.04 0.01 Bioavailability 2.95 1.64 2.32 0.95
2.14 0.91 1.91 0.84 Mass balance 95.37 1.19 97.45 0.74 97.62 0.57
97.67 0.58 42.degree. C. Without 3% 15% pretreatment Dimethicone
Diglyceride Diglyceride Mean SEM Mean SEM Mean SEM Mean SEM Surface
86.55 1.28 86.80 2.09 90.39 1.21 92.68 0.68 Stratum 2.90 0.83 1.74
0.56 0.90 0.11 0.75 0.07 corneum Skin 6.79 0.88 7.37 1.01 5.18 0.77
4.40 0.60 Receptor fluid 0.15 0.03 0.20 0.07 0.17 0.05 0.15 0.05
Bioavailability 6.95 2.45 7.57 2.81 5.35 2.15 4.55 1.71 Mass
balance 96.40 0.59 96.11 1.44 96.64 0.90 97.99 0.57
[0139] The majority of the applied dose of B(a)P was recovered at
the surface (up to 94.5% of the applied dose).
[0140] B(a)P bioavailability (skin+receptor fluid) is low at
32.degree. C., i.e. up to 2.95% of the applied dose. B(a)P
bioavailability increases significantly and reaches 6.95% of the
applied dose when the skin is heated at 42.degree. C. (T test, p
value<0.05).
[0141] The pre-treatment with the vehicle alone (dimethicone) does
not modify significantly the bioavailability of B(a)P whatever the
temperature of the skin (T test, p value<0.05). After
pre-treatment with glyceride 1,3 distearate as diglyceride at 3% or
15%, a significant decrease of the bioavailability of B(a)P is
observed at 43.degree. C. Indeed, 7.57% of the applied dose is
bioavailable with the vehicule (dimethicone) and decreases to 5.35%
and 4.35% of the applied dose after pre-treatment with 3% and 15%
of glyceride 1,3 distearate, respectively.
[0142] At 42.degree. C., the percentage of B(a)P found in the
stratum corneum decreases after application of glyceride 1,3
distearate. For compounds with physicochemical properties as B(a)P
(lipophilic compounds), stratum corneum, which is a lipophilic
compartment, acts as a reservoir. Decreasing the percentage of
B(a)P recovered in the stratum corneum thus prevents the diffusion
of this compound in the deeper layers of the skin even if the skin
is not heated.
[0143] The results obtained for the skin penetration of B(a)P
correlate well with the results obtained from the FTIR
measurement.
CONCLUSION
[0144] The results obtained for the skin penetration of B(a)P after
24 h skin application correlate well with the results obtained from
the FTIR measurements. These data showed that the modification of
the organisation of the lipids around 42.degree. C. induces a
weaker barrier function and increases the bioavailability of
compounds like outdoor pollutants such as B(a)P. This shows that
the use of 1,3-diglycerides improves significantly the barrier
function; both pre-treatments with 3% and 15% of glyceride 1,3
distearate formulated in dimethicone have been evaluated. The
pre-treatment with glyceride 1,3 distearate permits to stabilize
the lipids organization (FTIR measurement) and improves the
"outside-in" barrier function as demonstrated by the B(a)P skin
penetration study. Even with 3% of glyceride 1,3 distearate as
pre-treatment, a significant improvement of the barrier function
and lipid stabilization is observed.
BIBLIOGRAPHIC REFERENCES
[0145] [1] Fabienne Berthaud, Mila Boncheva. Correlation between
the properties of the lipid matrix and the degrees of integrity and
cohesion in healthy human stratum corneum. Exp Dermatol,
20(3):255-262, March 2011. [0146] [2] Mila Boncheva, Fabienne
Damien, Valery Normand. Molecular organization of the lipid matrix
in intact stratum corneum using atr-ftir spectroscopy. Biochim
Biophys Acta, 1778(5):1344-1355, May 2008. [0147] [3] Fabienne
Damien, Mila Boncheva. The extent of orthorhombic lipid phases in
the stratum corneum determines the barrier efficiency of human skin
in vivo. J Invest Dermatol, 130(2):611-614, February 2010. [0148]
[4] Daniel Groen, Dana S. Poole, Gert S. Gooris, Joke A. Bouwstra.
Is an orthorhombic lateral packing and a proper lamellar
organization important for the skin barrier function? Biochimica
and Biophysica Acta (BBA)--Biomembranes, 1808(6):1529-1537, 2011.
[0149] [5] Coderch L, Lopez O, de la Maza A, Parra J L. Ceramides
and skin function. Am J Clin Dermatol. 2003, 4(2):107-29. [0150]
[6] Cho S, Lee M J, Kim M S, Lee S, Kim Y K, Lee D H, Lee C W, Cho
K H, Chung J H. Infrared plus visible light and heat from natural
sunlight participate in the expression of MMPs and type
Iprocollagen as well as infiltration of inflammatory cell in human
skin in vivo. Journal of Dermatological Science (2008) 50, 123-133
[0151] [7] Jin Young Seo, Jin Ho Chung. Thermal aging: A new
concept of skin aging. Journal of Dermatological Science
Supplement, 2(1):S13-S22, 2006. Proceedings of the 5th Annual
Meeting of the Japanese Photoaging Research Society. [0152] [8]
Scalia S, Mezzena M, Ramaccini D. Encapsulation of the UV filters
ethylhexyl methoxycinnamate and butyl methoxydibenzoylmethane in
lipid microparticles: effect on in vivo human skin permeation. Skin
Pharmacol Physiol. 2011, 24(4):182-9. [0153] [9] Ning Liu, Yong
Wang, Qiangzhong Zhao, Qingli Zhang, Mouming Zhao. Fast synthesis
of 1,3-DAG by Lecitase.RTM. Ultra-catalyzed esterification in
solvent-free system. Eur. J. Lipid Sci. Technol. 2011, 113,
973-979. [0154] [10] KR 2013058299, WO 03/014073 A1, JP02115117 A,
JP52061240A [0155] [11] May W E et al. J. Chem. Ref. Data 1983, 28:
197-200
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