Note: Descriptions are shown in the official language in which they were submitted.
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WO 00/38658 PCT/FR99/03051
SPRAYABLE COSMETIC COMPOSITION AND MATRIX WHICH MAY BE
USED IN THIS COMPOSITION FOR DERMAL ADMINISTRATION
The present invention relates to a novel
composition for dermal administration of an active
substance or active principle. This composition may be
a cosmetic composition, for example a slimming
composition.
The terms "active principle" and "active
substance(s)" mean one or more medicinal or non-
medicinal active principles. It may thus be, for
example, a peptide or non-peptide compound, a cell or
tissue extract of animal or plant origin or a product
obtained by fermenting a microorganism, for example a
bacterium or a fungus. Thus, in the present
description, the terms "active principles" and "active
substance(s)" will be used without discrimination,
according to the definitions given above.
More specifically, the invention relates to a
composition for dermal administration which is capable
of forming a supple film after drying on the skin, and
also to a matrix which may be used in such a
composition.
The dermal administration of active
substances is an advantageous technique, endowed with
certain advantages such as the absence of side effects.
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However, in order to be effective, this
technique must allow penetration into the skin over a
prolonged period and in a manner which is sufficient to
reach the intended cells and obtain the desired effect.
To date, various systems or devices for this
type of administration have been proposed. They make it
possible to introduce controlled doses of active
substances.
For example, the transdermal administration
device known commonly as a "patch" is known, this
device consisting of a reservoir formed from synthetic
plastics containing the active principle. This
reservoir may be covered, on its face in contact with
the skin, with a microporous membrane whose
permeability to the active substance regulates its
diffusion and consequently its dosage.
Despite the genuine possibilities offered by
this device, in particular for an application, other
systems may be preferred to it. The reason for this is
that it is known that the patch may become detached
from the skin and that it may moreover often have an
unsightly appearance.
Gels containing active substances have also
been proposed. However, this mode of use may have
certain drawbacks in practice, generally a sticky feel
which is unpleasant for the person using it, and also
difficulty in controlling the dose administered.
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Other systems which help in transdermally
administering active substances have also been
reported.
In this respect, mention may be made of
sprayable compositions especially comprising polymers
capable of forming a film on contact with the skin and
of releasing the active principle, for transcutaneous
administration. Compositions of this type, disclosed,
for example, in patent EP 319 555, comprise an active
principle, a polymer matrix forming a supple film after
drying, a solvent for controlling the release of the
active substance, namely a sorbitan macrogollaurate, a
parrafin, a medium-chain fatty acid diglyceride or
triglyceride or propylene carbonate, and also a
solvent, for the matrix, which is capable of
evaporating on the skin, and finally a propellant for
spraying this composition contained in a suitable
device.
Furthermore, due to the presence of
polymethacrylic derivatives, the compositions of patent
EP 319 555 give a characteristic odor which is
relatively unpleasant for the user and those in his or
her vicinity.
Other pharmaceutical compositions for topical
administration containing an active principle, a
solvent and various other ingredients are also known.
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By way of example, mention may be made of
patent EP 55396 which discloses antimycotic
compositions formed:
~ from a cellulose ether
~ from 2o to 10% of a spreading agent such as
isopropyl myristate or isopropyl palmitate
~ from 1o to 80 of a solubilizing agent
~ from 0.05% to 10 of active principle, and
~ from a solvent such as isopropanol.
However, although these compositions may be
used for dermatological topical applications, they are
found to be entirely unsuitable for application by
spraying, even after adding from 10o to 400 of a
propellent gas as recommended, since they appear to be
too viscous and liable to have various drawbacks such
as blockage of the spraying device.
Mention may also be made of patent EP 319 964
which discloses antifungal compositions capable of
forming a film, comprising:
~ from 0.1% to 1.5% of tolnaphthalate
~ from 10o to 20% of a dimethylaminoethyl
methacrylate/methacrylate copolymer
~ from 0.5o to 10% of a fatty acid ester
~ a solvent of alcohol type and optionally from 0.1%
to 5% of a cellulose derivative.
This composition does not appear to be
suitable for spraying either. In addition, as already
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mentioned previously, the presence of methacrylic
derivatives gives it an acceptable odor.
Mention may also be made of patent EP 289 900
which relates to antibacterial compositions for topical
5 use, comprising:
~ from 0.5o to 100 of an antibacterial active
principle
~ from 1o to 300 of a water-insoluble polymer, in
particular ethylcellulose or a
polyvinylpyrrolidone copolymer
~ from 0.5% to 40% of a plasticizer, generally an
essential oil, which also acts as a transcutaneous
absorption promoter
~ from 50o to 950 of a solvent such as ethanol.
Finally, mention may be made of patent
application WO 96/30000, the main subject of which is a
pharmaceutical composition for transdermal
administration, comprising:
1) a polymeric release matrix capable of forming a
supple film after drying
2) an active principle
3) a promoter of transcutaneous absorption of the
active principle
4) a physiologically acceptable non-aqueous solvent
capable of dissolving the release matrix, the
active principle and the transcutaneous absorption
promoter, and also of being rapidly removed by
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evaporation on contact with the skin, which is
intended, after administration of the medicinal
substance, to bring about a preventive or
therapeutic response.
The medicinal product particularly used in
said patent application is estradiol.
The search for a composition allowing the
diffusion of active substances through the dermis, from
an area of low coverage and at rates that are
compatible with a treatment while at the same time
being free of the drawbacks reported previously, thus
remains of major interest.
Now, it has been discovered, surprisingly,
according to the invention, that it is possible to
provide compositions, more particularly cosmetic
compositions for dermal administration, using a film
formed on the skin, these compositions lacking the
drawbacks mentioned above but being capable, using a
small and controllable area of coverage, of delivering
the active substance uniformly, continuously and at
rates largely reaching the possibility of achieving the
desired effect.
Thus, one subject of the invention is a
cosmetic composition for dermal administration,
comprising:
1) a polymeric release matrix capable of forming a
supple film after drying,
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2) one or more active substances,
3) a promoter of cutaneous absorption of the active
principle,
4) a non-aqueous solvent capable of dissolving the
release matrix, the active principle and the
cutaneous absorption promoter and also of being
rapidly removed by evaporation on contact with the
skin,
5) at least one propellent gas.
In the present context, both in the
description and in the claims, the term "[lacuna]"
means either a substance which is intended, after
administration, to bring about a preventive or curative
response, or a combination of two or more substances of
this type.
The polymeric matrix is generally chosen from
polymeric or copolymeric substances capable both of
forming a supple film after evaporation of the solvent
and of releasing the active substance.
This matrix is formed in the stratum corneum
after evaporation of the solvent capable of releasing
the active substances.
This matrix is generally present in a
proportion of from 0% to 7% relative to the weight of
the composition according to the invention, for
instance from 4% to 70, for example 30. From 1% to 5%
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by weight of matrix and in particular 3o is preferably
used.
The choice of this matrix will relate mainly
to polymeric or copolymeric substances that are soluble
in the physiologically acceptable solvent so as to form
a homogeneous solution.
Among the polymers or copolymers capable of
satisfying the above criteria, those more particularly
selected are cellulose polymers or copolymers,
especially because they have a suitable abrasion
strength and mechanical stability after drying. For
this reason, cellulose matrices of this type may be
placed in contact with water without any fear of
deterioration.
As examples of cellulose polymers or
copolymers which may be used in the compositions of the
invention, mention may be made of ethylcellulose,
cellulose acetate butyrate, cellulose acetate
propionate or a hydroxypropylmethylcellulose which may
or may not be grafted, such as
hydroxypropylmethylcellulose acetate succinate.
However, ethylcellulose represents the
preferred cellulose polymer and, consequently, the
polymeric release matrix of choice for the formation of
a film which is supple on contact with the skin.
In addition, the polymeric matrix may consist
of a vinylpyrrolidone/vinyl acetate copolymer such as
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polyvinylpyrrolidone/vinyl acetate, referred to
hereinbelow as PVP/VA.
Consequently, according to another of its
aspects, a subject of the invention is a cosmetic
composition for dermal administration, comprising:
1) a polymeric release matrix capable of forming a
supple film after drying, chosen from cellulose
polymers or copolymers and vinylpyrrolidone/vinyl
acetate copolymers,
2) active substances,
3) a promoter of cutaneous absorption of the active
principle,
4) a non-aqueous solvents) capable of dissolving the
release matrix, the active principle and the
cutaneous absorption promoter and also of being
rapidly removed by evaporation on contact with the
skin,
5) at least one propellent gas.
As regards the active substance, it will be
chosen from substances that are soluble in the solvent
and capable of continuously crossing the epidermis
and/or the dermis with a flow which is sufficient to
give an effective concentration using a small but
sufficient area of skin.
These active substances will be incorporated
into the compositions of the invention in a proportion,
in particular, of from 0.1% to 20o relative to the
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weight of these compositions, it being understood that
each active substance will be introduced at
individualized concentrations known in the art for
dermal administration or at concentrations adapted to
5 this route of administration.
In order to achieve an effective
concentration of active principle without, however,
using too large an area of skin, a cutaneous absorption
promoter is combined with the polymeric matrix and the
10 active principle. This promoter is advantageously
incorporated in the compositions of the invention in a
proportion of from 15o to 30o relative to the weight of
this composition, preferably from 15o to 250, for
example 20%.
This absorption promoter is chosen such that
it can bring large dermal flows in order to obtain the
desired effects by means of an acceptable skin
coverage, i.e. a coverage of less than 150 cmz but
preferably between 10 and 40 cm2, for example 30 cmz.
In order to be effective, the skin absorption
promoter under consideration must be capable of
transiently disorganizing the skin barrier so as to
increase the permeability of the skin without
irritating it, while at the same time promoting the
diffusion of the active principle chosen according to
kinetics and a concentration which are sufficient and
which may be maintained for a certain amount of time.
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This skin absorption promoter will be
selected from substances that are compatible with the
non-aqueous solvent capable of rapidly evaporating on
contact with the skin. It will preferably be selected
from the following compounds which have the required
degree of solubility in the physiological solvent under
consideration and which combine the best qualities
reported above, that is to say:
~ esters of aliphatic fatty acids, essentially
esters containing in total from 10 to 30 carbon
atoms optionally substituted with one or two
hydroxyl, carboxylic or C1-C4 acyloxy groups such
as acetoxy, or optionally interrupted with one or
two ethylenic bonds or with one or two ether
oxygens,
~ aliphatic fatty alcohols, essentially C1o-C3o
alcohols optionally substituted with one or two
hydroxyl, carboxylic or C1-C4 acyloxy groups such
as acetoxy, or optionally interrupted with one or
two ethylenic bonds or with one or two ether
oxygens.
Absorption promoters that are particularly
preferred, which may be selected from the esters of
aliphatic fatty acids and aliphatic fatty alcohols
mentioned above, are given below, namely:
a) aliphatic fatty acid esters of general formula:
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Q
c--
1
in which R represents a linear or branched C2-C~
alkyl or alkenyl group optionally substituted with
a hydroxyl, carboxylic or C1-C4 acyloxy group and
R1 represents a linear or branched C3-C8 alkyl
group optionally substituted with one or two
hydroxyl groups such as, for example, an isopropyl
or 2-ethyldihydroxyethyl group or R1 represents a
-CH2-CH2-0- (CH2) 2-O-CH2-CH3 group, the aliphatic
fatty acid ester comprising a minimum of 10 carbon
atoms and a maximum of 2 hydroxyl groups;
b) aliphatic fatty acid alcohols of general formula:
R2-OH II
in which RZ represents a Clo-Cao alkyl group.
As examples of specific compounds which have
shown the best potential for promoting the cutaneous
absorption of active substances, mention may be made
of
2-ethylhexyl 2-ethylhexanoate
isopropyl myristate
diethylene glycol monoethyl ether myristate
isopropyl palmitate
2-octyldecanol
2-ethylhexyl undecylenate
2-ethylhexyl succinate
2-ethylhexyl 12-hydroxystearate
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2-ethylhexyl 12-acetoxystearate
glyceryl isostearate
hexyl laurate
isononyl isononanoate
2-ethylhexyl palmitate
2-ethylhexyl stearate
diethylene glycol monoethyl ether
2-ethylhexyl 2-ethylhexanoate represents the
preferred absorption promoter, in particular for
cosmetic compositions according to the invention. This
compound is sold under the name Dragoxat° and is also
known as octyl octanoate.
As regards the non-aqueous solvent capable of
dissolving the release matrix, the active principle and
the cutaneous absorption promoter, it will be selected
from compounds with a relatively low boiling point,
that is to say a boiling point of less than 100°C at
atmospheric pressure, such that it can be rapidly
removed by evaporation on contact with the skin and
similarly help to form a film by drying without,
however, causing any local irritation.
Such solvents are generally used in a
proportion of from 44o to 84.90 relative to the weight
of the final composition and may be selected from
volatile compounds such as dichloromethane, ethanol,
isopropanol and ethyl acetate.
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Ethanol and isopropanol are solvents of
choice. However, ethanol is a preferred solvent
according to the invention since it efficiently
contributes toward the formation of films on the skin
while at the same time rapidly evaporating on contact
with the skin.
The propellent gases which may be used
according to the invention are chosen from:
butane
propane
isobutane
carbon dioxide
dimethyl ether
hydrochlorofluorocarbon
hydrofluorocarbon
nitrogen
isopentane
nitrogen oxide
pentane
Butane or propane is preferred.
Consequently, according to one of its
particular aspects, the invention relates to a cosmetic
composition comprising:
1) from Oo to 7% of a polymeric release matrix
capable of forming a supple film after drying,
chosen in particular from cellulose polymers or
copolymers such as ethylcellulose
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2) from 0.1o to 200 of an active substance
3) from 15o to 30~ of a promoter of cutaneous
absorption of the active principle, in particular
from 15% to 250 of a fatty acid ester or of a
5 fatty alcohol chosen from:
2-ethylhexyl 2-ethylhexanoate
isopropyl myristate
diethylene glycol monoethyl ether myristate
isopropyl palmitate
10 2-octyldecanol
2-ethylhexyl undecylenate
2-ethylhexyl succinate
2-ethylhexyl 12-hydroxystearate
2-ethylhexyl 12-acetoxystearate
15 glyceryl isostearate
hexyl laurate
4) from 44o to 84.90 of a non-aqueous solvent capable
of dissolving the release matrix, the active principle
and the cutaneous absorption promoter, and also of
being rapidly removed by evaporation on contact with
the skin, in particular ethanol or isopropanol
5) at least one propellent gas.
In the context of the present invention, a
sprayable composition to be applied from a dosing
vaporizer bottle onto the skin, which is cosmetically
satisfactory and whose application area and dose
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characteristics are controlled and reproducible, has
been investigated more particularly.
There is thus formation of a "film" on the
skin. Active substances may thus be applied according
to the invention to the skin in the form of a film.
Several biocompatible formulations which
promote cutaneous penetration were prepared.
The active substances used may be intended
for the manufacture of a film, for example a film
intended for slimming purposes.
In particular, the film according to the
present invention relates to a cosmetic composition
containing slimming substances. This slimming substance
may be a neuropeptide Y receptor antagonist.
Neuropeptide Y, referred to hereinbelow as "NPY" for
short, is a neuromediator which participates in a
certain number of physiological processes and for which
an involvement in regulating lipolysis has been
demonstrated (P. Valet. J. Clin. Invest. 1990, 85, 291-
295).
It has been disclosed in EP 838 217 that NPY
antagonists may be used to prepare cosmetic
compositions.
These cosmetic compositions containing an
NPY-antagonist component may be used as
lipolysis/lipogenesis regulators on the skin without,
however, interfering with the skin's natural functions.
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It has also been disclosed that cosmetic
slimming compositions containing an NPY-antagonist
component and an a2-antagonist component are
particularly advantageous.
Thus, according to one of its aspects, the
present invention relates to a film containing a
cosmetic slimming composition containing at least one
NPY-antagonist component with another active substance
such as an a2-antagonist. The NPY antagonist contained
in the cosmetic composition may be a non-peptide
compound, a peptide, a cell or tissue extract of animal
or plant origin or a product obtained by fermenting a
microorganism, for example a bacterium or a fungus.
These components are themselves non-peptide
synthetic compounds, peptides or products obtained by
fermenting a microorganism, for example a bacterium or
a fungus, or by extracting cells or tissues of animal
or plant origin.
Of course, the applied film needs to be well
tolerated, but also needs to have an appealing cosmetic
appearance with rapid evaporation of the vehicles,
leaving little in the way of residues on the surface of
the skin.
The cosmetic evaluation of a series of
formulations applied as a film to the skin was carried
out.
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More particularly, the objective was to
characterize all of the cosmetic properties of the
spray solutions by means of a sensory analysis study.
This is a sensory study according to six
criteria identified as being favorable (the
implementation of the protocols and the type of
calculation adopted correspond to the AFNOR standards
published for the agrifood sector).
These criteria are as follows:
~ ease of penetration: absorption and evaporation
~ the residue: greasy/dry (the feel is evaluated by
sliding the index finger over the film
deposited)
gloss (visual presence of the residue)
stickiness (the feel is observed by
tapping the film with the index finger)
odor
~ overall assessment of the product: taking into
account only the above criteria.
The application method is as follows:
After priming the pump by pressing several
times, the formulation is sprayed onto the skin at a
measured distance of 10 cm. The observations begin
10 minutes after the application, and this duration is
standardized for the sensory analysis protocols.
One spray corresponds to 130 ~l of
formulation onto an area of about 35 to 40 cmz.
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The excipients used are as follows:
~ film-forming agent: ethylcellulose 99 N7NF
(7 mPa.s: Aqualon)
~ solvent: isopropanol (SDS), ethanol (Labover),
~ promoter and texture agent: Dragoxat ° E.H.
(penetrating cosmetic oil: Dragoco), Dow
Corning 556 silicone, light liquid paraffin
( Sano f i V~linthrop Genti f ly ) .
The spray system used is as follows:
~ VP7/130 pump: Valois
~ push-button dispenser IN3 GP4/5: Valois
~ 20 ml ONC varnished aluminium can.
The formulations contain:
~ 66o to 67% solvent: ethanol, isopropanol or a
combination of the two.
~ 20% to 30o promoter: Dragoxat~ E.H.
~ 3% to 5o ethylcellulose
The formulation disclosed in WO 98/30000,
which was the subject of studies with estradiol as
medicinal agent, serves as reference and will be
referred to hereinbelow as (R).
The details of the compositions are given in
Table A.
All the criteria measured and the overall
assessment for each formulation are evaluated on a
scale ranging from +3 to -4 and reported in the form of
histograms.
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The average values obtained for the ten
experimenters are accompanied by the high and low
values.
The evaluation of the formulations is
5 detailed herein relative to the reference formulation
(R) by demonstrating the changes in composition which
affect or improve its cosmetic appearance.
Table B summarizes the main interpretations
regarding the effect of the various excipients relative
10 to the reference formulation.
The perception of the reference formulation
(R) is improved by limiting the amount of
ethylcellulose to 3% (A) (less greasy, less sticky and
less residue). An improved sprayability by means of
15 better dispersion of the formulation by the pump of the
device is thus obtained. With these 3%, it is even
possible to increase the Dragoxat° incorporated to 300
while at the same time maintaining very good perception
of the sprayed formulation (C).
20 The formulation which is classified
immediately after (E) has a slightly larger amount of
residue. It still contains 3o ethylcellulose, but the
solvent comprises a fraction of isopropanol which is
more difficult to spray. The application area must be
smaller for the same volume of solution and thus the
residue must be thicker on the skin. The formulations
which found least favor (B, R, F and G) because they
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were too greasy or sticky all contain 4 to 50
ethylcellulose. The result is the same with ethanol or
isopropanol. No improvement is observed by adding 10 of
compound described as optimizing the spraying (silicone
or liquid paraffin) (F and G). Formulation (D) gave
very dispersed results. It comprises 4a ethylcellulose
and 30o Dragoxat~. The solution is not easy to spray.
The use of ethanol or isopropanol is
equivalent in overall terms.
The reference formulation is slightly greasy
and sticky. By limiting only the amount of
ethylcellulose to 0.5 to 30, the results are much
improved and satisfactory.
There is little to very little residue, which
is rather glossy but is not greasy and is hardly sticky
at all.
The penetration is quite rapid to very rapid.
More particularly, according to the
invention, a film formulation containing slimming
active agents was developed.
These slimming active agents are preferably
neuropeptide Y (NPY) receptor antagonists or a2
receptor antagonists. A large number of them are
disclosed in patent application EP 838 217.
In cosmetology and also in the slimming
sector, the cutaneous absorption of an active principle
is similar to a passive diffusion, the limiting step
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being the moment of crossing the horny layer, which is
1000 times more impermeable than the epidermis or the
dermis.
One of the main advantages expected of the
films according to the invention is that of removing
this cutaneous resistance to diffusion. This increase
in cutaneous absorption is the result of an increase in
the moisturization and the temperature of the horny
layer, following the semi-occlusion of the site of
application, brought about by the film.
The expected benefits of slimming films
relate mainly to the areas of the body characterized by
the presence of stubborn cellulite.
For these sites in which cellulite is firmly
established, it is necessary to be able to renew and
maintain the action of the active substances before
they are naturally metabolized by the adipocytes.
The technology of films makes it possible,
using active substances, to create on the horny layer a
reservoir effect, from which a uniform and continuous
diffusion of the active agents into the lower layers of
the skin is exerted. On account of this continuous
diffusion, permanent presence of active agents in the
region of the adipocytes is ensured.
This results in a constant saturation of the
storage receptors, which will make it possible to act
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on reducing the orange peel effect present in the areas
of stubborn cellulite.
The advantageous aspect of the films results
firstly from the structure of the matrix containing the
active substances and secondly from its application
system.
Since it can be sprayed directly onto the
skin, the film forms a thin, supple and invisible film,
from which the active substances are diffused.
The low thickness of the film formed makes it
possible not to disrupt the gaseous and aqueous
exchanges existing between the skin and the external
environment, thereby further improving the tolerability
of the product. The suppleness of the film moreover
offers a greater sensation of comfort.
As regards the active substances, the film
contains NPY antagonist and a2 antagonist active
agents, in a concentration 10 times greater than that
used in the conventional fluid as disclosed in
EP 838 217.
Thus, by virtue of its bioavailability which
is subject to two-fold control over time, by means of
continuous diffusion of the active substances and
locally by means of an activity strictly limited to the
sites of spraying, the film makes it possible to
provide effective and long-lasting saturation of the
adipocyte storage receptors by the NPY receptor
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antagonist and the a2 receptor antagonist, resulting in
a reduction of the areas that are traditionally
resistant to slimming treatments.
The compositions according to the invention
for dermal administration may be prepared in a
conventional manner, by a person skilled in the art, by
mixing together the various constituents in the chosen
proportions.
For example, the cutaneous absorption
promoter may be dissolved, with stirring, in the
solvent, followed by addition of the active principle
and finally the release matrix.
All of the substances forming part of the
compositions of the invention are known products or may
be prepared by known methods, some of these products
being commercially available.
The dermal compositions of the invention thus
obtained may be applied by any means to an area of
skin, for example to an area of between 10 and 40 cm2,
for example 30 cm2, in particular and preferably by
direct spraying using a dosing pump of a type which is
known and sold, with the aid of a propellant such as a
compressed or liquefied gas.
Although the prior art asserts the contrary,
it has been found, surprisingly, that a release matrix
formed from ethylcellulose does not, with the
composition used, cause any obstruction by blocking the
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outlet of the spraying head nozzle, such that the
compositions of the invention may be sprayed in the
presence of a propellent gas without any fear of
deterioration of the spray container.
5 The compositions of the invention may thus be
administered by spraying using a container fitted with
metering valve, also containing a propellent gas such
as nitrogen or nitrous oxide, or a liquefied gas such
as butane or propane.
10 According to another subject, the invention
relates to a matrix intended for cosmetic compositions
for dermal administration, comprising:
a) a polymeric matrix, for releasing an active
principle, which is capable of forming a supple
15 film after drying
b) a promoter of cutaneous absorption of an active
principle
c) a non-aqueous solvent capable of dissolving the
release matrix and the cutaneous absorption
20 promoter and also of being rapidly removed by
evaporation on contact with the skin
d) a propellent gas
The polymeric matrix will be selected from
polymeric and copolymeric substances, in particular
25 from cellulose polymers or copolymers as specified
previously, while the cutaneous absorption promoter
will be selected from aliphatic fatty acid esters or
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from aliphatic fatty alcohols as described above, in
particular esters of formula I or alcohols of formula
II.
As regards the non-aqueous solvent, it is a
compound with a boiling point of less than 100°C at
atmospheric pressure, as mentioned previously.
These various components of the matrix for
the dermal cosmetic composition will be distributed
such that, in the cosmetic composition under
consideration containing the active principle, the
release matrix represents from 0% to 70, the cutaneous
absorption promoter represents from 15o to 30o and the
non-aqueous solvent represents from 44o to 84.90, these
percentages being expressed relative to the weight of
the final cosmetic composition.
These matrices for dermal compositions
according to the invention may be conventionally
prepared by mixing together the various ingredients of
which they are made in the selected proportions.
The propellent gases are advantageously
chosen from propanol and butanol.
The film-forming compositions of the
invention and the matrices for dermal compositions
according to the invention have unquestionable
advantages since they are capable of bringing about the
cutaneous diffusion of an active substance, so as to
produce constant and controlled effective levels over a
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prolonged period of at least 12 hours from an area of
skin coverage of about from 10 to 40 cm2.
In addition, the compositions and matrices
for dermal compositions according to the invention,
while lacking any unpleasant odor, spread out to form a
uniform film over the entire area of skin selected.
These films are sufficiently supple and
abrasion resistant to avoid any deterioration on the
skin of the user and exhibit better tolerability than
the known dermal devices since, on account of their
thinness and the absence of any coverage, gaseous and
aqueous exchanges with the external environment are not
disrupted.
Finally, the compositions of the invention,
in the form of a supple film, afford the user a greater
sensation of comfort and, by virtue of their
transparency, are entirely invisible.
Various tests were performed both in vitro
and in vivo so as to demonstrate the characteristics
and particular features of the compositions of the
invention.
The cosmetic compositions according to the
invention preferably contain slimming active
substances.
The slimming active substances are preferably
chosen from NPY or a2 receptor antagonists.
, , CA 02350685 2001-05-15
28
In this case, the active substances used are,
for example, the extracts of the Streptomyces sp strain
SEBR 2794, filed at the C.N.C.M. of the Institut
Pasteur under No. I-1332 and the extracts of the
Bacillus Iicheniformis strain SEBR 2464 filed at the
C.N.C.M. of the Institut Pasteur under No. I-1778. They
will be referred to hereinbelow as slimming active
substance.
A clinical efficacy study was carried out
with a slimming composition containing NYP and a2
receptor antagonists. The object of this study was to
evaluate the efficacy of the film used in combination
with Lipofactor° fluid (Lipofactor: registered
trademark of Sanofi).
a) Protocol
The test is carried out over a period of
28 days and is performed on 31 women. The individuals
were included after a clinical examination and
verification of the presence of areas of established
cellulite. The individuals applied the fluid and the
film to the same leg, defined randomly, the other leg
being used as the untreated control.
The fluid is applied in the desired amount to
the entire thigh, from the knee to the buttock fold.
The application is carried out in the evening, with no
massaging beyond that required for penetration of the
product.
z CA 02350685 2001-05-15
29
The film is applied in the morning in a
highly localized manner to the following 4 sites:
~ outer superior lateral face of the thigh,
~ inner superior face of the thigh,
~ posterior face (buttock fold),
~ inner face of the knee.
The amount of film used per day corresponds
to two adjacent sprayings so as to cover the area
concerned.
The evaluation of the efficacy is performed
at To (before treatment) and at Tza aays and uses three
different methods:
~ echography to measure the thickness of the
adipose tissue taken at three locations on
the thigh plus one on the knee;
~ clinical evaluation of the macrorelief
(orange peel effect) of the outer face of
the thighs;
~ analysis of images of the relief of the
orange peel effect.
b) Results
Echography
Table 1 shows the main characteristics of the
individuals.
The weight of the individuals was measured at
the end of the 28 days of the test. No significant
changes were observed, which will thereby make it
r CA 02350685 2001-05-15
possible to confirm the attribution of the results
observed to the activity of the test products.
Table 1: Characteristics of the individuals
Criteria Average Maximum values Minimum values
Age 37 years old 53 years old 19 years old
BMI (a) 21.8 26.9 18.5
(a) Body Mass Index
5 Table 2 and Figure 1 show the average
reduction in thickness of the adipose tissue after
one month of testing.
Depending on the area, a marked reduction in
the thickness of the adipose tissue, of the order of
10 -10o compared with the values measured at To, is
observed.
Table 2: Average reductions of the adipose tissue as a
function of the sites treated
(expressed as a % change relative to To)
Location Treated Control Tr-control Standard
deviation
Outer thigh -10.1% 0.50 -19,50* 2.8~
Back of the thigh -11.60 0.80 -12.4%* 2.40
Inner thigh -ll.Oo -0.70 -10.30* 20
Inner side of the -10.60 -1.50 -9.10 1.90
knee
15 *S (p«0 . 05 )
r CA 02350685 2001-05-15
31
Figure 1: Percentage change between To and T28 days for
each location
2.I3%
U.0%
-2.0%
-4.0%
-8.0%
-~.~°/P
-~ 2.0'Y°
-'14.0%
Outer Back of Inner Inner side
thigh the thigh thigh of the knee
These results appear to be very significant
and concern only the treated side. At the same time,
good stability of the controlateral control locations,
which show non-significant variations ranging from -0.3
to ~0.1 mm, is observed.
Clinical evaluation and image analysis
The clinical evaluation of the macrorelief is
carried out using photographic negatives by five
evaluators. After random distribution, all the
negatives are graded by the evaluators by comparison
with a calibration range (reference photographs),
structured around 7 degrees of intensity.
For five individuals, a preliminary
profilometric analysis was carried out so as to
calculate the average relief of a defined area on each
s CA 02350685 2001-05-15
32
image and corresponding to an area of skin equivalent
to 3 x 130 mm.
The negatives of the outer sides of the
treated and control thighs of the 31 volunteers made it
possible to confirm clinically, after analysis by the
5 evaluators, an improvement in the skin relief.
This improvement is significant (p«0.05) for
the thighs treated between To and Tz$ d, whereas, in the
same period, no significant result is obtained on the
untreated sides.
Table 3: Results compared on 5 individuals between the
clinical change and the image analysis
Individual Clinical change Image analysis (attenuation
(improvement) of the skin relief)
1 30% -35%
2 43 0 -24 0
3 18% -14%
4 180 -220
5 52 0 -11%
The concept of the film was evaluated in the
course of the study carried out on 113 women recruited
for having cellulite.
The film is applied for 4 weeks at a rate of
two adjacent sprayings so as to cover the area
concerned. The efficacy of the film is evaluated at the
end of the study.
r CA 02350685 2001-05-15
33
It emerges from this study, as regards the
efficacy, that the film generally allows a significant
improvement in the orange peel effect located on the
lower limbs.
EXAMPLE 1
Dermal composition containing [lacuna]
100 g of a dermal composition having the
formulation below is prepared:
o by weight
Ethylcellulose 6 mPa.s 50
Slimming active substance 20
2-Ethylhexyl 2-ethylhexanoate 20%
Ethanol 730
Propylene glycol 0.5%
Propellent gas
by mixing together, for 30 seconds and with magnetic
stirring, 73 g of ethanol and 20 g of 2-ethylhexyl
2-ethylhexanoate. 2 g of slimming active substances)
are then added portionwise to the mixture obtained and,
after complete dissolution (5 minutes), 5 g of
ethylcellulose 6 mPa.s are added with vigorous
stirring, so as to avoid the formation of lumps. The
final solution obtained is homogeneous and slightly
opalescent. For the purpose of administration by
spraying, aluminum cans are filled with 5 ml of the
solution obtained above and are fitted with a crimping
vasopump comprising a push-button dispenser. The pump
o CA 02350685 2001-05-15
34
is actuated twice to prime it before its first use.
EXAMPLE 2
Matrix for a dermal composition
98 g of a dermal matrix are prepared by
mixing together 73 g of ethanol and 20 g of
2-ethylhexyl 2-ethylhexanoate for 30 seconds. 5 g of
ethylcellulose 6 mPa.s are then added with vigorous
stirring, so as to avoid the formation of lumps. The
matrix thus obtained is ready to receive an active
agent, by incorporation, so as to form a cosmetic
composition containing 2% by weight of this active
agent, which may be applied by spraying.
EXAMPLE 3
Matrix for a dermal composition
The process is performed according to
Example 2, by mixing together:
Ingredients o by weight
Ethanol 75
Isononyl isononanoate 20
Ethylcellulose 5
EXAMPLE 4
Matrix for a dermal composition
The process is performed as in Example 2, by
mixing together:
Ingredients o by weight
Ethanol 80
Isononyl isononanoate 15
Ethylcellulose 5
CA 02350685 2001-05-15
EXAMPLE 5
Matrix for a dermal composition
The process is performed as in Example 2, by
mixing together:
Ingredients % by weight
Ethanol 75
Isononyl isononanoate 15
Ethylcellulose 5
Diethylene glycol monoethyl ether 5
5 EXAMPLE 6
Matrix for a dermal composition
The process is performed as in Example 2, by
mixing together:
Ingredients o by weight
Ethanol 70
Isononyl isononanoate 15
Ethylcellulose 5
Diethylene glycol monoethyl ether 10
EXAMPLE 7
10 The following composition is prepared:
Ingredients o by weight
Alcohol 44.016
Butane 23.20
Octyl octanoate 12.00
Propane 11.20
Isobutane 5.60
Ethylcellulose 3.00
Panthenol 0.30
Propylene glycol 0.30
Diethyl phthalate 0.258
Slimming active substances) 0.126
t CA 02350685 2001-05-15
36
Table A: Composition of the formulations
Reference formulation: A B R C D E F G
Percentage
Ethanol 95 77 76 75 67 66 18
Isopropanol 54 74 74
Dragoxat~ EH 20 20 20 30 30 25 20 20
Ethylcellulose 7 mPa.s 3 4 5 3 4 3 5 5
Silicone DC 556 1
Light liquid paraffin 1
Reminder of the reference formulation: 95° ethanol:
75%; Dragoxat~: 200; ethylcellulose: 5%.
Table B: Classification of the evaluation of the
excipients relative to the reference formulation
Criteria OverallStickyPenetra- Gloss Greasi-Resi- Odor
assess-skin tion mess due
meet
EFFECT
RELATIVE
TO
THE
REFERENCE
(+ Better,
- Worse,
- equivalent)
EXCIPIENTS -
Isopropanol- - - - - - -
3 o ethyl-
cellulose + + + + + + +
4o ethyl-
cellulose - - - - - - -
250
Dragoxat~ - - - - - - -
300
Dragoxat~ - - - - - - -
