Note: Descriptions are shown in the official language in which they were submitted.
201726S
The present invention relates to a cosmetic composition for
combatting ageing of the skin which comprises an ademe~ionine
generating system. The present invention also refers to a method of
treating the skin to counteract ageing by applying the new composition
thereto.
Ademetionine is the International Non-proprietary Name for the
inner salt of (S)-5'-[(3-amino-3-carboxypropyl)methylsulfoniol-S'-
desoxyadenosine hydroxide of the formula:
NH2 CH3 NH2
l N
N ~ ~CH2-' -CH2-CH2-CH-COO Q
OH OH
also indicated as S-adenosyl-L-methionine or, more simply, as SAMe.
Ademetionine is a physiological molecule, almost ubiquitously
distributed within the organism tissues and fluids wherein it
participates in important biological processes as a donor of methyl
groups for a number of transmethylation reactions and as a precursor
of physiological sulfur compounds such as glutathione, cysteine,
taurine, and coenzyme A.
It is known that ademetionine levels are high in the infant and
in the adolescent, they diminish in the adult and lower further in the
pre-senile and senile age.
It is also known that endogenous ademetionine forms at the cell level
starting from methionine by the action of adenosyltransferase, of
betaine as donor of methyl groups, and of adenosyltriphosphoric acid
(ATP), in the presence of magnesium and potassium ions.
It has also been found (FR-A-2623396, published on May 26, 1989)
that ademetionine has a skin anti-ageing action and that it can be
employed for cosmetic purposes directly on the skin.
The anti-ageing effect of ademetinnine is due to its biochemical
properties. Transmethylation takes place on biological molpcllles~
mainly on skin proteins, nucleic acids and phosrhnlipids which are
thereby biotransformed and enter the anabolic and catabolic cycles.
201 7265
This anabolic-catabolic activity at the epidermal cell
level favouræ their regeneration while the action on
methyltransferases, by increasing phospholipids
methylation, make the cell membranes more fluid, thus
slowing down the natural skin ageing process.
This membrane-fluidizing action has been
demonstrated on human epidermal cells. The membrane
microviscosity of human epidermal cells has been studied
by the Shinitzky et al method (J. Biol. Chem. 1974, 249,
2652-2657) using diphenylhexatriene as the fluorescent
marker. The presence of ademetionine, at a molar
concentration of from 106 to 10-4, reduces membrane
viscosity by 10 to 25%.
However, for a cosmetic use, ademetionine has the
disadvantage of being unstable and rather unsuitable to
be handled in the cosmetic industry.
It has now been found, in invitro tests, that betaine,
also at very low concentrations, significantly affects
ademetionine levels in human skin fibroblasts.
It has also been found that it is possible to obtain
the same effects observed with ademetionine by treating
the skin with a mixture of betaine, ATP or an ATP
generating system, a potassium salt and a magnesium salt,
in a cosmetically acceptable vehicle, thus generating
ademetionine in situ.
In accordance with one aspect of the present
invention, there is provided a cosmetic composition which
comprises a mixture of:
(a) "betaine", as defined below,
(b) ATP or an ATP generating system,
(c) a magnesium salt, and
(d) a potassium salt,
in a cosmetically acceptable vehicle for topical
administration. Such mixture is contained in the
composition in an amount effective to improve the
appearance of ageing skin.
~'
3 201 7265
As used herein, the term "betaine" encompasses the
com~ou.-d of formula (CH3)3~CH2-COO as well as the
correspon~i~g addition salts with dermocompatible acids
and the hydrated forms thereof.
The term "ATP generating system" or "ATP-GS" refers
to any biological extract which is capable of increasing
the respiratory cellular activity within the mitho-
condria, thus accelerating the cellular metabolism and
hence the transformation of the products of the
glycolysis and of the Krebs cycle into ATP. By
increasing the respiratory cellular activity in the last
step of the respiratory chain, ATP is generated
immediately and directly via biochemical transformation
of glucose in ATP, and then via the intermediate pyruvic
acid which in its turn produces ATP (T~h~; nger -
Principes biochimiques - Flammarion Medicine Science Ed.,
1985, 497-498).
Among said biological extracts, those derived from
eucaryotic cells, in particular from yeasts, and obtAi~e~
by conventional extraction and purification pror~Cc~s
which maintain the biochemical components of the cells,
mainly amino acids, peptides and enzymes, almost intact,
are preferred.
These yeast extracts are known in the literature and
are also commercially available, e.g. under the trade
mark VITACELL LS 1917 (manufactured by the French company
Laboratoires Sérobiologiques S.A.).
Also preferred are those biological extracts
obtained from bovine spleen, well known in literature and
commercially available, e.g. under the trade marks
K~vllALINE (manufactured by the Swiss company PENTAPHARM)
and OXYDERMINE (manufactured by the French company
SEDERMA). Such extracts are also obtained by convention-
al extraction and purification pror~ss~C which maintain
the biochemical components of the cells almost intact.
As far as the magnesium salt as well as the
potassium salt are concerned, any organic or inorganic
'~aL
3a 2 0 1 7 2 6 5
salt may suitably be employed provided it is dermocom-
patible. Gluconates, pyroglutamates and chlorides are
however the preferred anions.
British patent application GB-A-2,151,924 describes
a cosmetic or dermatological composition-for skin care
which comprises, as essential components, a plant,
extract from Oenv~,erd biennis and a spleen extract. While
Oenothera oil is employed to create a barrier on the
epidermis which controls the loss of water from the skin,
the spleen extract is employed to activate the cellular
respiratory activity, a well known effect also referred
to above.
French patent application FR-A-2,608,393 claims
pharmaceutical or cosmetic compositions, or compositions
useful as bases for the preparation of pharmaceutical or
cosmetic compositions which comprise a nitrogen contain-
ing compound such as an amino acid, an oligo- or poly-
peptide, a protein or a derivative thereof, including
also betaine. According to the teachings of said French
patent application,
P
20~726~
- 4 -
which however does not describe compositions such as those defined in
the present application, said preparations present - depen~;ng on the
particular formulation - different activities : hydrating, nourishing,
regenerating, protecting and stimulating the growth of epidermal and
denmal cells or piliferous bulbs.
The components of the cosmetic preparations of the present
invention may suitably be employed therein in the following
pLoporLions (the percentages are by weight) :
(a) betaine from 0.001 to 1 %
(b) ATP (or ATP-GS) from 0.045 to 4.5 %
(c) Mg from 10 ppb to 0.3 %
(d) K from 0.0001 to 0.6 %
Preferably, said components are employed in the following proportions
(the percentages are by weight) :
(a) betaine from 0.03 to 0.3 %
(b) ATP (or ATP-GS) from 0.15 to 1.5 %
(c) Mg from 15 ppb to 0.1 %
(d) K from QOO1 to 0.2 %
Preferred cosmetic preparations according to the present invention
comprise :
(a) betaine from 0.05 to 0.25 %
(b) ATP-GS (such as yeast extracts such as e.g. VITACELL LS
l9l7 or bovine spleen extracts such as REVITALINE or
OXYDERMINE) from 0.25 to 1 %
(c) Mg from 20 ppb to 0.06 %
(d) K from Q002 to 0.1 %
For the preparation of the cosmetic compositions according to
the present invention, the ~ ~n~nts are mixed with cosmetic
excipients in order to prepare creams, lotions, emNlsions or
solutions.
In particlllAr, the active components are admixed with the
excipients conventionAlly employed in the cosmetic field such as for
example, fats of animal or vegetal origin, vegetable oil, fatty acids,
alcohols, polyalkylene glycols, waxes, petroleum jellies and
polyesters, which can be used in ~CsocjAtion with water and jelling
agents provided they are compatible therewith.
2017265
.
Other ingredients compatible with the active components, such
as preservatives, e.g. 4-hyd~oxybenzoic acid esters, antioxidants,
e.g. butylhydroxytoluene or vitamin E derivatives, or fragrances, can
be added to these preparations.
S Fatty acids employed as adjuvants in the cosmetic compositions of the
present invention may be saturated or unsaturated, may contain from 10
to 22 carbon atoms, be unsubstituted or hydL~y-substituted and in the
form of the free acids or of the ~lkAline salts thereof.
The cosmetic compositions according to the present invention can
be in the form of a cream wherein the active components are associated
with the excipients which are commonly used in cosmetology and which
are compatiblè therewith, such as lanolin or its derivatives.
The cosmetic compositions according to the present invention can
also be in the form of a gel in a suitable excipient such as a cellu-
lose ester, an acrylic polymer, a fatty acid ester, e.g. octyl palmi-
tate or stearate, or other gelling agents.
According to another embodiment of the present invention, the
above active principles are - at least in part - incorporated into
phospholipid vectors, in the form of lamellar phases, spherical vesic-
les or hollow cylinders of phospholipid layers alternated with aqueous
layers, generally designated as "liposomes". The selection of the
phospholipids to be used in the preparation of the liposomes as well
as the methods for the preparation and utilisation thereof in the
liposomal compositions according to the present invention can readily
be carried out by following the literature tea~hings (see for instance
"Liposomes" - M. Ostro Ed., Marcel Decker, New York, 1983).
The cosmetic compositions of the present invention can also be
in the form of a lotion, a solution or a mi~r. l~ion wherein the
active components are dissolved or micro~isr~rsed.
The cosmetic compositions according to the invention can therefore be
in the form of a microdispersion of the components in a liquid conta-
ining water, oil and one or more surfactants. These dispersions have
the same properties as microemulsions and the same appearance as true
solutions. They can be prepared immediately before use. These microem-
ulsions possess a good stability and can be stored for the time
- 6 - 2017265
-
necessary for their use, at temperatures from 0C to 60C without
sedimentation of the constituents or irreversible phase separation.
The surfactants which can suitably be employed in these compositions
are selected from those surface-active agents which can be used in
05 cosmetology.
As non-limiting examples there may be cited: sorbitol esters and their
polyethoxylated derivatives, polyethoxylated castor oils (hydrogenated
or non-hydrogenated), ethylene oxide/propylene oxide block polymers,
polyethoxylated fatty alcohols and sterols, sodium laurylsulfate,
sodium dioctylsulfosuccinate, egg or soya lecithins, and polyeth-
oxylated silicon oils.
The effect of betaine on SAMe formation has been evaluated by
the results obtained with betaine increasing concentrations in cultu-
res of human skin fibroblasts. More particularly human skin fibroblasts
(ATCC No. CRL 1513 - 2.104 cells/ml) have been cultured for 6 days in
Dulbecco's Modified Eagle Medium (DMEM - 250 ml containers) containing
20 % of foetal calf serum, in the presence of increasing concentrations
(from 10 5M to 5.10 4M)) of betaine. Then, the cells were taken off by
treatment with trypsine (0.05 %) and EDTA (0.02 %) and centrifuged. The
supernatant was separated, precipitated by the addition of trichloro-
acetic acid (0.2N, v/v) and centrifuged again. The supernatant was then
recovered and lyophilized. The lyophilized material was taking up in
water and analyzed by HPLC (column : ~ucleosyl C8; Eluent: Solvent A
(Sodium acetate 8.2 g, Sodium octylsulfonate 200 mg, Citric acid
4.2 g, EDTA 50 mg and water q.s. to I 1) 95 % and Solvent B (Methanol)
5 %) using an U.V. detector at 260 nm. The amount of SAMe has been
determined in comparison with a calibration curve prepared under the
same experimental conditions.
Betaine concentration SAMe concentration
30 (10 M) (nMoles/10 cells)
0 0.54
1 0.62
0.94
~.72
1.90
By using the cosmetic compositions according to the present
invention, which contain, in addition to betaine, ATP or an ATP gener-
ating system, a magnesium salt, and a potassium salt, after 30 days of
7 20 1 7265
regular application, a notable improvement in the
appearance of the skin and a slowing down of wrinkle
formation is achieved.
The cosmetic compositions of the present invention
are therefore particularly suitable for:
- slowing down ageing by maintaining an optimum
fluidity of the skin cell membranes, a high membrane
fluidity favouring internal intercellular exchanges
and hence the optimum metabolism;
- improving the conditions of skins prematurely aged
by the action of exogenous factors, via the above
process.
Furthermore the cosmetic compositions according to
the present invention are very well tolerated; they have
no phototoxicity and their application to the skin for
prolonged periods of time does not give rise to any
systemic effect.
Another aspect of the present invention is,
therefore, a method of treating the skin of a living
human to improve the appearance of ageing skin, which
method comprises applying to the skin a cosmetic
preparation comprising a mixture of
(a) "betaine", (as defined above)
(b) ATP or an ATP generating system,
(c) a magnesium salt, and
(d) a potassium salt,
in a cosmetically acceptable vehicle for topical
administration. The mixture is contained in the cosmetic
preparation in an amount effective to improve the
appearance of ageing skin.
The following examples are merely illustrative of
the scope of the present invention and are not intended
as a limitation to the scope thereof.
For the sake of simplification, certain constituents
of the compositions have been indicated by their
tradenames or abbreviations whose meanings are reported
hereinbelow.
~A
8 201 7265
VITACELL LS1917 yeast extract manufactured by
Laboratoires Serobiologiques S.A.
REVITALINE bovine spleen extract marketed by
Pentapharm
5 OXYDERMINE bovine spleen extract marketed by
Sederma
SOLUTOL HS 15 polyethylene glycol 600 12-hydroxy
stearate, marketed by BASF
CETIOL HE polyethylene glycol-7 glyceryl
cocoate marketed by Henkel
LABRAFAC
HYDROPHYLE polyethoxylated triglycerides
containing 7-8 carbon atoms,
marketed by Gattefosse
15 ABIL* 8851 B dimethycone copolyol marketed by
Goldschmidt
CARBOPOL* 934 I carboxypolymethylenes marketed by
CARBOPOL 940 I Goldschmidt
TWEEN* 60 ethoxylated sorbitan monostearate
20 TWEEN 20 ethoxylated sorbitan laurate
EDTA ethylenediaminotetraacetic acid
W B FILTER 2-ethylhexyl 4-methoxycinnamate
(trademark PARSOL MCX)
Example 1
Preparation to be reconstituted before use
A) Solvent
Carboxymethylcellulose 0.30 g
Preservatives in propylene glycol 5.00 g
Phenoxyethanol 0.5 g
Methyl 4-hydroxybenzoate 0.1 g
Ethyl 4-hydroxybenzoate 0.1 g
Propyl 4-hydroxybenzoate 0.1 g
Butyl 4-hydroxybenzoate 0.1 g
Propylene glycol 4.1 g
Ethoxylated hydrogenated castor oil 1.00 g
Fragrance 0.20 g
Demineralized water q.s. to 100.00 g
* - Trade-marks
~A~
20 1 7265
8a
B) Powder
Betaine 0.10 g
Magnesium chloride 0.05 g
Potassium chloride 0.10 g
REVITALINE 0.50 g
Lactose q.s. to 100.00 g
Example 2
Protective day cream
Betaine 0.05 g
Magnesium chloride 0.05 g
Potassium chloride 0.10 g
REVITALINE 0.50 g
201 7265
TWEEN 60 2.60 g
Silicon oil 1.00 g
Cetyl alcohol 2.00 g
Mineral oil 3.00 g
Lanolin alcohol 1.00 g
-Perhydrosqualene 1.00 g
Sorbitan monostearate 2.40 g
Cetyl palmitate 3.00 g
Isopropyl palmitate 4.00 g
UVB FILTER 2.00 g
Tetrasodium EDTA 0.10 g
CARBOPOL 934 0.30 g
Triethanolamine 0.30 g
Butylhyd~oxyLoluene 0.01 g
Preservatives in butylene glycol 5.00 g
Phenoxyethanol 0.5 g
Methyl 4-hydLvxybenzoate 0.1 g
Ethyl 4-hydLvxyLenzoate 0.1 g
Propyl 4-hydLvxy~enzoate 0.1 g
Butyl 4-hydroxyhen7O~te 0.1 g
Butylene glycol 4.1 g
Fragrance 0.30 g
Demineralized waterq.s. to 100.00 g
Example 3
Microemulsion
Betaine 0.10 g
Magnesium chloride0.05 g
Potassium pyroglutamate 0.10 g
REVITALINE 0.50 g
TWEEN 60 20.00 g
Glycerol 28.00 g
Propylene glycol dipelargonate 40.00 g
Ethyl 4-hydLoxyLenzoate0.30 g
Fragrance 0.30 g
~ ;neralized water q.s. to 100.00 g
20172&S
-
-- 10 --
The microemulsion is obtained by mixing all the ingredients together
and stirring until a clear solution is obtained.
Example 4
Microemulsion
Betaine 0.20 g
Magnesium gluconate 0.50 g
Potassium gluconate 0.50 g
OxYv~KMINE 0.50 g
SOLUTOL HS 15 1.00 g
LABRAFAC HYDROPHYLE 0.25 g
CETIOL HE 0.20 g
ABIL 8851 B 0.05 g
Propylene glycol 12.50 g
Ethanol 12.50 g
CaL~uxy~olyvinyl polymer 0.40 g
Fragrance 0.30 g
Preservatives 0.30 g
Colorant q.s.
Demineralized water q.s. to 100.00 g
Triethanolamine q.s. to pH = 6
The microemulsion is prepared as described in Example 3.
Example 5
Fluid make-up foundation
Betaine 0.10 g
Magnesium gluconate 0.90 g
Potassium gluco~Ate 0.60 g
REVITALINE 0.50 g
Ethoxylated soja sterols 4.00 g
Soja sterols 0.50 g
Glycerol monostearate 1.00 g
Vegetable oil 1.50 g
2-Ethylhexyl palmitate 4.00 g
Cetyl alcohol 0.50 g
Capric/caprylic triglycerides 1.50 g
Silicon oil 1.00 g
Mineral oil 1.80 g
2017265
- 11 --
Lanolin alcohols 0.20 g
Propylene glycol dipelargonate 3.00 g
Lecithin 1.00 g
Preservatives in butylene glycol 5.00 g
Phenoxyethanol 0.5 g
Methyl 4-hydLoxybP~o~te 0.1 g
Ethyl 4-hydroxyhPn7-o~te 0.1 g
Propyl 4-hydroxybenzoate 0.1 g
Butyl 4-hydroxybenzoate 0.1 g
Butylene glycol 4.1 g
CARBOPOL 940 0.20 g
Triethanolamine 0.20 g
Tetrasodium EDTA 0.10 g
Butylhydroxytoluene 0.01 g
Fragrance 0.30 g
Example 6
Night cream
Betaine 0.05 g
Magnesium gluconate 0.90 g
Potassium pyroglutamate 0.60 g
REVITALINE 0.50 g
Cetyl alcohol 2.00 g
Stearin 2.50 g
Glycerol monostearate 5.00 g
Isopropyl palmitate 5.00 g
Vegetable oil 3.00 g
Mineral oil 2.00 g
Perhydrosqualene 2.00 g
Silicon oil 1.00 g
Shea butter 2.00 g
Preservatives in butylene glycol 5.00 g
Phenoxyethanol 0.5 g
Methyl 4-hydr~xybenzoate 0.1 g
Ethyl 4-hydL~xyLenzoate 0.1 g
Propyl 4-hyd~oxyLenzoate 0.1 g
Butyl 4-hydLoxybenzoate 0.1 g
201726~
.
- 12 -
Butylene glycol 4.1 g
Triethanolamine 5.50 g
Tetr~s~; EDTA 0.10 g
Fragrance 0.30 g
Water q.s. to 100.00 g
Example 7
Gel
Betaine 0.10 g
Magnesium gluconate 0.90 g
Potassium gluconate 0.60 g
REVITALINE 0.50 g
CARBOPOL 940 0.20 g
Polyethylene glycol 3.00 g
Preservatives in butylene glycol 5.00 g
Phenoxyethanol 0.5 g
Methyl 4-hydLu~ybenzoate 0.1 g
Ethyl 4-hydL~ybenzoate 0.1 g
Propyl 4-hydL~xyLenzoate 0.1 g
Butyl 4-hyd~xybenzoate 0.1 g
Butylene glycol 4.1 g
TWEEN 20 0.50 g
Triethanolamine 0.25 g
Fragrance 0.20 g
D~ ;n~ralized waterq.s. to 100.00 g
Example 8
Serum
Betaine 0.10 g
Magnesium gluconate0.90 g
Potassium gluconate0.60 g
Yeast extract (VITA OE LL LS 1917) 0.50 g
HydLvxy~ropylmethylcellulose 0.30 g
Propylene glycol S.00 g
Glycerin 5-00 g
`'Ethoxylated oleic alcohol 0.50 g
Fragrance 0.30 g
Tetrasodium EDTA 0.10 g
~ 2017265
- 13 -
Preservatives 0.50 g
Bovine albumin 5.00 g
Demineralized waterq.s. to 100.00 g
Example 9
Make-up foundation
Betaine 0.10 g
Magnesium gluconate0.90 g
Potassium pyroglutamate0.60 g
Yeast extract (VITACELL LS 1917) 0.50 g
Tetrasodium EDTA 0.10 g
Carboxymethylcellulose0.20 g
Aluminum magnesium silicate 1.00 g
Ethoxylated sorbitan laurate 1.00 g
Propylene glycol 5.00 g
Titanium oxide 2.00 g
Talc 1.00 g
Pigments 1. ao g
Triethanolamine -a . 50 g
Preservatives 0.50 g
Cetyl alcohol 1.00 g
Lanolin alcohol 3.00 g
Stearic acid 1.80 g
Propylene glycol monostearate 3.00 g
Isopropyl palmitate8.00 g
Vegetable oil 2.00 g
Antioxidants 0.05 g
Fragrance 0.30 g
Demineralized waterq~s. to 100.00 g
