Hair loss abstract
The invention relates to the use of Medicago saponins for the preparation
of cosmetic or pharmaceutical compositions. The invention provides
for the incorporation of 0.01% to 5% by weight of a saponin or a
corresponding sapogenin, or a plant extract in which it is present,
originating in particular from lucerne leaves or roots. The invention
makes it possible to promote renewal of the epidermis, stimulate
hair regrowth or delay hair loss, or else to combat the effects
of ageing on the state of the skin and scalp, as is evident from
the FIGURE.
Hair loss claims
We claim:
1. A method for promoting hair growth, combating seborrheic alopecia,
and delaying hair loss, comprising the topical application on the
desired area to be treated comprising hair, and scalp, an amount
effective for achieving said topical treatment of an active ingredient
consisting essentially of at least one Medicago component selected
from the group consisting of Medicago triterpene saponins, the corresponding
sapogenins, Medicago plant extracts containing at least one of said
triterpene saponins, and Medicago plant extracts containing at least
one of said sapogenins.
2. The method of claim 1, wherein said method is for promoting
eye lash growth.
3. The method according to claim 1 wherein the Medicago component
is at least partially incorporated into a hydrated lipidic lamellar
phase or into liposomal vesicles.
4. The method according to claim 1 wherein the Medicago component
is obtained by extraction from a Medicago plant part selected from
the group consisting of aerial parts and roots.
5. The method according to claim 1 wherein the sapogenin and Medicago
plant extract are obtained from calluses obtained by the in vitro
culture of tissue of Medicago.
6. The method according to claim 1 wherein the saponin is a saponin
containing a carboxyl group.
7. The method according to claim 1 wherein the Medicago plant extract
is obtained from a Medicago plant selected from the group consisting
of Medicago satira, Medicago lupulina, Medicago truncatula, Medicago
laciniata, Medicago littoralis, Medicago falcata, Medicago media,
Medicago minima, Medicago varia, Medicago arborea and Medicago romanica.
8. The method according to claim 1 wherein the Medicago plant extract
is obtained from a Medicago plant part in dry form, by contacting
said Medicago plant part in dry form with a solvent selected from
the group consisting of water, alcohols containing from 1 to 4 carbon
atoms, and organic esters containing from 3 to 6 carbon atoms, and
a mixed solvent based on a mixture of said solvents.
9. The method according to claim 7 wherein the extraction solvent
is selected from the group consisting of methanol, ethanol, a methanol/water
mixture, or an ethanol/water mixture.
10. The method according to claim 1 wherein a mixture of saponins
is used and wherein the mixture is obtained by precipitation of
the plant extract on an apolar solvent.
11. The method according to claim 10 wherein the apolar solvent
is miscible with the extraction solvent.
12. The according to claim 10 wherein the mixture of saponins is
subjected to a treatment converting to the acid form those saponins
which contain a carboxyl group as a salt.
13. The method according to claim 1 wherein the sapogenins are
obtained from the saponins by hydrolysis of the glycosidic linkages
of the saponins.
14. The method according to claim 13 wherein the hydrolysis is
an acid hydrolysis.
15. The method according to claim 14 wherein the above-mentioned
sapogenin is selected from the group consisting of lucernic acid,
medicagenic acid, zanhic acid, bayogenin, hederagenin and soyasapogenols
A, B, C and E.
16. The method according to claim 3 wherein the above-mentioned
saponin is introduced into the aqueous phase of the hydrated lipidic
lamellar phase or the liposomes at a concentration of between 0.01%
and 5% by weight, based on the total weight of said aqueous phase.
17. The method according to claim 3 wherein the sapogenin is incorporated
into the lipidic phase of the hydrated lamellar phase or the liposomes
at a concentration of between 0.01% and 30% by weight of said lipidic
phase.
18. The method according to claim 17 wherein the sapogenin is incorporated
at a concentration of between 0.01% and 10% by weight of this lipidic
phase.
19. The method according to claim 4, wherein said aerial part is
selected from the group consisting of leaves and stems.
20. A method according to claim 5, wherein said calluses are obtained
by the in vitro culture of root tissues of a Medicago plant.
21. The method according to claim 8, wherein said Medicago plant
extract is obtained from Medicago plant roots.
22. The method according to claim 14, wherein said hydrolysis comprises
using as an acid a halogen-containing acid.
23. The method according to claim 22, wherein said halogen-containing
acid is selected from the group consisting of perchloric acid, fluoboric
acid and trifluoroacetic acid.
Hair loss description
The present invention relates essentially to the use of Medicago
saponins or corresponding sapogenins for the preparation of cosmetic
or pharmaceutical compositions, especially dermatological compositions,
intended in particular for promoting renewal of the epidermis, stimulating
hair regrowth or delaying hair loss, and for combating the effects
of ageing on the state of the skin and scalp.
The plants of the genus Medicago, often designated by the generic
term "lucernes", are Leguminosae which are widespread
on the planet in temperate zones and in certain arid regions, either
in the wild state or in the cultivated state as animal fodder.
Medicago sativa or alfalfa, correctly called lucerne, is the principal
representative of this family. By plants of the genus Medicago are
present on the five continents, especially in France, in the mediterranean
basin, in the United States, in Canada and in Australia. The following
may be mentioned among the other Medicago species: M. lupulina (Canada),
M. truncatula (Australia, South Africa), M. laciniata (arid and
semi-arid zones of Australia, Saudi Arabia, Libya), M. littoralis
(Australia), M. minima (Algeria), M. falcata (USSR, Canada), M.
media (Alaska) and M. arborea (Greece).
The lucernes contain a large variety of substances useful for feeding
animals and humans, especially proteins, vitamins, carotenoids and
mineral salts (J. G. COORS et al., Crop Science, 1986, vol. 26,
no. 5, p. 843-848; E. M. BICKOFF et al. in Alfalfa Science and Technology,
ed. C. H. HANSON, published by The American Society of Agronomy,
Madison, Wis., USA, 1972, p. 247-282). The leaves and especially
the roots also contain glycosylated compounds consisting essentially
of triterpene saponins described in particular by G. MASSIOT et
al., J. Chem. Soc. Perkin Trans. I (1988) p. 3071-3079. Hydrolysis
of the glycosidic linkages of these saponins yields the corresponding
triterpene sapogenins, the most abundant of which is medicagenic
acid (G. Massiot et al., J. Agric. Food Chem., 1988, vol. 36, p.
902-909). Finally, sterol glycosides, present in very small amounts,
have been identified by S. ITO et al., Nippon Nogei Kagaku Kaishi
1973, vol. 47, no. 3, p. 229-230, in particular beta-sitosteryl
glucoside and stigmasteryl glucoside.
A number of therapeutic uses of extracts or substances extracted
from lucerne--Medicago sativa--have been described.
Thus it has been recommended to administer lucerne sap in order
to treat avitaminosis and decalcification (Aldo Poletti, "Fleurs
et Plantes medicinales" ("Medicinal Flowers and Plants"),
ed. Delachaux and Niestle, p. 126) and the seed extract has been
described in the document SU-624 634 as possessing an antiinflammatory
activity. Also, a lucerne extract has been described in the document
FR-2 571 256 as possessing an estrogenic activity, its application
being in the treatment of cellulitis. The above-mentioned medicagenic
acid possesses a hemolytic activity (B. GESTETNER et al., Experientia,
1971, 27(1), 40-41) and an antifungal activity (DE-3 717 280).
Finally, the use in cosmetics of the sterol glucosides present
in the leaves has been described in the document JP-62-72 604 as
promoting hydration of the skin.
The above-mentioned effects of ageing on the skin are characterized
in particular by a slowing-down of the cell differentiation of the
epidermis, especially the keratinocytes, leading to a slowing-down
of their renewal and their activity, which gives the skin a duller,
dry and more wrinkled appearance. Ageing also has adverse effects
on the hair follicles. For the keratinocytes of the follicles, as
for those of the epidermis, these effects cause a reduction in activity,
leading to a slowing-down of hair growth and, ultimately, a degeneration
of the follicle and the definitive loss of the hair.
One object of the present invention is to solve the novel technical
problem which consists in providing a novel formulation of a cosmetic
or pharmaceutical composition, especially a dermatological composition,
which is effective in respect of renewal of the epidermis, hair
regrowth and the prevention or slowing-down of hair loss, as well
as in combating the effects of ageing on the state of the skin and
scalp.
A further object of the present invention is to solve this novel
technical problem in a particularly simple manner which can be used
on the industrial scale.
The present invention makes it possible to solve this technical
problem for the first time in a satisfactory manner which can be
used on the industrial scale.
Thus, according to a first feature, the present invention relates
to the use of at least one Medicago triterpene saponin or at least
one corresponding sapogenin, or a plant extract in which it is present,
for the manufacture of a cosmetic or pharmaceutical composition,
especially a dermatological composition, intended in particular
for promoting renewal of the epidermis, stimulating hair regrowth
or delaying hair loss, and for combating the effects of ageing on
the state of the skin and scalp.
In one particular variant, the above-mentioned saponin and plant
extract are obtained by extraction from aerial parts, such as leaves
or stems, or roots of Medicago, preferably from roots of this plant.
Particularly preferably, the parts of the plant which are used are
dried prior to the extraction treatment.
In another variant, the above-mentioned saponin and plant extract
are obtained by extraction from calluses obtained by the in vitro
culture of tissues of Medicago, in particular from root tissues
of this plant, for example by the technique described by BESSON
V. et al. in Phytochemistry 1989, vol. 28, no. 5, pages 1379 and
1380.
In one advantageous variant, the above-mentioned saponin is selected
from those containing a carboxyl group and is used in the acid form
for carrying out the present invention.
In another embodiment, the above-mentioned sapogenin is preferably
selected from the group consisting of lucernic acid, medicagenic
acid, zanhic acid, bayogenin, hederagenin and soyasapogenols A,
B, C and E.
In yet another variant of the invention, the above-mentioned Medicago
plant is selected from the group consisting of: Medicago sativa,
Medicago lupulina, Medicago truncatula, Medicago laciniata, Medicago
littoralis, Medicago falcata, Medicago media, Medicago minima, Medicago
varia, Medicago arborea and Medicago romanica.
In yet another particular embodiment of the invention, the above-mentioned
plant extract is obtained by the method which is described below
by way of indication but without implying any limitation. The dry
matter, preferably consisting of Medicago roots, is extracted by
means of a solvent selected from the group consisting of: water,
alcohols preferably containing from 1 to 4 carbon atoms, and organic
esters preferably containing from 3 to 6 carbon atoms, or by means
of a mixed solvent based on any mixture of the above-mentioned solvents.
Advantageously, the primary extraction solvent is methanol, ethanol,
a methanol/water mixture or an ethanol/water mixture.
The ratio of the plant material to the extraction agent is not
critical and will generally be between 1:5 and 1:20 parts by weight.
The above-mentioned primary extraction is effected at temperatures
between room temperature and the boiling point of the solvent used
for the extraction.
Preferably, the primary extraction is effected under reflux for
a period of 2 to 4 h under atmospheric pressure. Also, it is advantageously
preceded by cold maceration for 2 to 4 h in the extraction solvent.
When extraction has ended, the solvent phase containing the extract
is filtered and then concentrated and/or evaporated to dryness under
reduced pressure to give a first, saponin-rich extract according
to the invention.
In one particular variant, the use according to the invention relates
to a mixture of above-mentioned saponins. A mixture of saponins
according to the invention is obtained in particular from the above-mentioned
first concentrated or dry extract by the procedure indicated below.
The above-mentioned first extract is introduced into and then agitated
in an apolar solvent which is preferably miscible with the primary
extraction solvent, such as an ether or a ketone of low molecular
weight, in particular ethyl or isopropyl ether, acetone or methyl
ethyl ketone. The amount by weight of apolar solvent is generally
5 to 100 parts to one part of primary extract. The insoluble material
and/or the precipitate formed contains principally a mixture of
saponins according to the invention.
Advantageously, the mixture of saponins obtained above is purified
by any method accessible to those skilled in the art.
In particular, the above-mentioned insoluble material and/or precipitate
is redissolved in about 20 times its weight of water. The aqueous
solution is then extracted 3 to 4 times with a sparingly water-soluble
alcohol, such as butanol, saturated with water, for example in proportions
of 1/1 by volume for each extraction operation. The alcohol phases
are combined and evaporated under reduced pressure. The residue
is dissolved in about 10 times its weight of water and the solution
is then dialyzed against pure water for 4 to 5 days. The contents
of the dialysis cell are lyophilized. If it is appropriate to further
improve the purification of the mixture of saponins obtained, the
lyophilizate is dissolved in methanol and then discharged into ethyl
ether. The precipitate formed is collected.
Advantageously, the mixture of saponins obtained is subjected to
an additional treatment consisting for example in passing an aqueous
solution of said mixture over an acid cation exchange resin and
then eluting it with water or a methanol/water mixture, the purpose
of said additional treatment being to convert to the acid form those
saponins which contain a salified carboxyl group.
The above-mentioned sapogenins according to the invention are preferably
obtained from the saponins extracted by the method described above.
This is done by hydrolyzing the glycosidic linkages of said saponins.
Advantageously, acid hydrolysis is carried out, especially with
halogen-containing acids such as perchloric acid, fluoboric acid
or trifluoroacetic acid, in the manner described for example in
the publication by G. Massiot et al. in Journal of Agricultural
and Food Chemistry 1988, vol. 36, p. 902-909.
In another advantageous variant of the invention, the above-mentioned
saponin or the above-mentioned corresponding sapogenin, or the above-mentioned
lucerne extract, is at least partially incorporated into a hydrated
lipidic lamellar phase or into vesicles of the liposome type.
The term "lipidic" in the expression "lipidic lamellar
phase" covers all substances comprising a so-called fatty hydrocarbon
chain generally containing more than 5 carbon atoms, this substance
usually being called a "lipid".
According to the invention, the lipids used to form the lipidic
lamellar phase or the vesicles of the liposome type are amphiphilic
lipids, i.e. lipids consisting of molecules possessing a hydrophilic
group, which can equally well be ionic or non-ionic, and a lipophilic
group, these amphiphilic lipids being capable of forming a lipidic
lamellar phase or vesicles of the liposome type, in the presence
of an aqueous phase, according to the amount of water in the mixture.
The following may be mentioned in particular among these lipids:
phospholipids, phosphoaminolipids, glycolipids, polyoxyethyleneated
fatty alcohols and optionally polyoxyethyleneated polyol esters.
Such substances consist for example of an egg or soya lecithin,
a phosphatidylserine, a sphingomyelin, a cerebroside, a glycosyl
ceramide or an oxyethyleneated polyglycerol stearate.
It is preferred according to the invention to use a lipid mixture
consisting of at least one amphiphilic lipid and at least one hydrophobic
lipid such as a sterol like cholesterol or beta-sitosterol. The
amount of hydrophobic compounds, expressed by weight, must not generally
exceed the amount of amphiphilic lipids and preferably must not
exceed 0.5 times this amount.
In one preferred variant, the above-mentioned saponin is introduced
into the aqueous phase of the hydrated lipidic lamellar phase or
the liposomes at a concentration of between 0.01% and 5% by weight,
based on the total weight of said aqueous phase.
In yet another preferred variant, the above-mentioned sapogenin
is incorporated into the lipidic phase of the hydrated lipidic lamellar
phase or the liposomes at a concentration preferably of between
0.01% and 30% by weight of said lipidic phase. In this case, it
is not generally necessary to add another hydrophobic constituent,
such as a sterol, to the lipidic phase. The above-mentioned concentration
is particularly preferably between 0.01% and 10% by weight of this
lipidic phase.
The incorporation of the above-mentioned saponins or sapogenins
or the above-mentioned extracts according to the invention into
hydrated lipidic lamellar phases or into liposomes can be carried
out by the known preparative techniques described for example in
the document EP-B1-0 087 993=U.S. Pat. No. 4,508,703, if appropriate
in combination with the document EP-B1-0 101 559=U.S. Pat. No. 4,621,023.
According to a second feature, the present invention further relates
to a cosmetic or pharmaceutical composition, especially a dermatological
composition, intended in particular for promoting renewal of the
epidermis, stimulating hair regrowth or delaying hair loss, and
for combating the effects of ageing on the state of the skin and
scalp, which composition comprises, as the active ingredient, an
effective amount of at least one Medicago triterpene saponin or
at least one corresponding sapogenin, or at least one plant extract
in which it is present, if appropriate in a cosmetically or pharmaceutically
acceptable excipient, carrier or vehicle.
Preferably, the above-mentioned saponin, the above-mentioned sapogenin
or the above-mentioned extract is obtained from aerial parts, such
as leaves or stems, or roots of Medicago, preferably from roots
of this plant.
Diverse variants of the composition are clearly apparent from the
above description relating to the use.
In particular, the above-mentioned saponin or sapogenin or the
above-mentioned plant extract can advantageously be at least partially
incorporated into hydrated lipidic lamellar phases or into vesicles
of the liposome type.
Furthermore, in one advantageous variant, the concentration of
above-mentioned saponin or sapogenin or above-mentioned plant extract
is preferably between 0.001% and 5% and particularly preferably
between 0.01 and 2% by weight, based on the total weight of the
cosmetic or pharmaceutical composition.
These proportions are understood as being by dry weight where plant
extracts are concerned.
In another advantageous variant of the invention, the cosmetic
or pharmaceutical composition, especially the dermatological composition,
according to the invention also comprises an effective concentration
of at least one other active substance selected from xanthines,
vitamins, in particular vitamins A, B and E, tyrosine or its derivatives,
for example glucose tyrosinate and malyltyrosine, quinine or its
derivatives, rubefacients such as methyl nicotinate, a papilla fibroblast
culture supernatant such as that described in the document EP-A-272
920, keratin hydrolyzates, trace elements such as zinc, selenium
and copper, 5-.alpha.-reductase inhibitors such as: progesterone,
cyproterone acetate and Minoxidil.RTM., azelaic acid and its derivatives,
a 1,4-methyl-4-azasteroid, in particular 17-.beta.-N,N-diethylcarbamoyl-4-methyl-4-aza-5-.alpha.-androstan-3-one,
or else an extract of Serenoa repens. Advantageously, this active
substance can be at least partially incorporated into hydrated lipidic
lamellar phases or into vesicles of the liposome type.
The cosmetic or pharmaceutical compositions, especially the dermatological
compositions, according to the present invention can be applied
topically, in particular for promoting renewal of the epidermis,
stimulating hair regrowth or delaying hair loss, and for combating
the effects of ageing on the state of the skin and scalp, in particular
in compositions presented in the form of creams, gels or lotions
for topical application.
Within this feature, the present invention further provides a method
of treating the epidermis, intended especially for promoting its
renewal, or a method of treating the hair, intended for promoting
its regrowth or delaying its loss, which method comprises the topical
application, in an amount effective for achieving said desired effect,
of at least one Medicago saponin or at least one corresponding sapogenin,
or a plant extract in which it is present. In one advantageous variant,
said above-mentioned saponin or sapogenin or said plant extract
is at least partially incorporated into a hydrated lipidic lamellar
phase or into vesicles of the liposome type.
It should be noted that, in the present description and in the
claims, the expression "at least partially into hydrated lipidic
lamellar phases or into vesicles of the liposome type" is understood
as meaning that the above-mentioned active ingredient is combined
with hydrated lipidic lamellar phases or with vesicles of the liposome
type, whatever form this combination may take.
However, it is clear that such a combination can constitute incorporation
or even encapsulation in the hydrated lipidic lamellar phases or
in the vesicles of the liposome type, although it is not necessary
for all this active ingredient to be incorporated or encapsulated
in order to obtain the desired effect, especially on the epidermis
and on the scalp.
According to another feature, the invention further provides a
method of manufacturing a cosmetic or pharmaceutical composition,
especially a dermatological composition, intended in particular
for promoting renewal of the epidermis, stimulating hair regrowth
or delaying hair loss, and for combating the effects of ageing on
the state of the skin and scalp, which method comprises using at
least one Medicago saponin or at least one corresponding sapogenin,
or a plant extract in which it is present, and mixing it with a
pharmaceutically or cosmetically acceptable excipient, vehicle or
carrier. In one variant, this method comprises firstly at least
partially incorporating at least one above-mentioned saponin or
at least one corresponding sapogenin, or a plant extract in which
it is present, into hydrated lipidic lamellar phases or into vesicles
of the liposome type and then mixing them with a pharmaceutically
or cosmetically acceptable excipient, vehicle or carrier.
Other objects, characteristics and advantages of the invention
will become clearly apparent from the following explanatory description
referring to several Examples which are given solely by way of illustration
and which consequently cannot limit the scope of the invention in
any way.
BRIEF DESCRIPTION OF THE DRAWING
The accompanying single FIGURE reports test results on the pilary
cycle of Sprague Dawley rats with the percentage of hairs in anagenetic
phase comprising the Y-axis as a function of the number of days
on the X-axis as reported in detail in Example 13, the curve joining
the squares corresponding to the results obtained with the mixture
of saponins extracted from lucerne roots, of Example 2, according
to the invention, the curve joining the crosses being obtained with
the excipient and finally the curve joining the dots being obtained
with the control group not receiving any product.
In the Examples, the percentages are expressed by weight, unless
indicated otherwise. In the case of extracts, the percentages are
expressed by dry weight of the extract. |