Use of at least one sulphonic acid for stimulating renewal and/or epidermal repair and for combatting cutaneous aging and conditions

The use of specific sulphonic acids or hydrates thereof in or for the preparation of a cosmetic or dermatological composition for achieving various effects on the skin, such as promoting desquamation of the skin, stimulating epidermal renewal, combatting intrinsic and extrinsic cutaneous aging. A process for the non-therapeutic treatment of the skin intended to achieve such effects, such as to promote the desquamation of the skin.

The present invention is directed to the use of specific sulphonic acids in
 or for the preparation of a cosmetic and/or dermatological composition for
 such purposes as promoting desquamation of the skin and/or for combatting
 intrinsic and extrinsic aging of the skin, as well as treating various
 skin conditions. The present invention is also directed to a process for
 the non-therapeutic treatment of the skin for purposes such as
 desquamating the skin and treating the skin for cutaneous aging and
 various skin conditions.
 Cutaneous aging resulting from the effects on the skin of intrinsic or
 extrinsic factors is reflected, for example, by the appearance of wrinkles
 and fine lines, by the yellowing of the skin, which develops a wizened
 appearance, by the appearance of pigmentary blemishes, by disorganization
 of the elastin and collagen fibres, which results in a loss of elasticity,
 suppleness and firmness, and by the appearance of telangiectasias.
 Some of these signs of aging are more particularly related to intrinsic or
 physiological aging, that is to say, to the "normal" effects of age,
 whereas others are more specific to extrinsic aging, that is to say, aging
 generally caused by the environment, more particularly photoaging due to
 exposure to the sun, to light or to any other radiation. The present
 invention is concerned with both intrinsic or physiological aging and with
 extrinsic aging of the skin.
 The changes in the skin due to intrinsic aging are the consequence of a
 genetically programmed senescence involving endogenous factors. This
 intrinsic aging causes, in particular, a slowing down in the renewal of
 the cells of the skin, which is essentially reflected by the appearance of
 undesirable clinical changes, such as the reduction in the subcutaneous
 adipose tissue and the appearance of fine lines or wrinkles, and by
 histopathological changes, such as an increase in the number and thickness
 of the elastic fibres, the loss of vertical fibres in the membrane of the
 elastic tissue and the presence of large irregular fibroblasts in the
 cells of this elastic tissue.
 In contrast, extrinsic aging results in undesirable clinical changes, such
 as thick wrinkles and the formation of a flabby and tanned skin, and in
 histopathological changes, such as excessive accumulation of elastic
 matter in the upper dermis and degeneration of the collagen fibres.
 Various agents intended for combatting cutaneous aging are known in the
 prior art. In this regard, U.S. Pat. No. 4,603,146 describes the use of
 retinoic acid and its derivatives in cosmetic compositions for the purpose
 of controlling cutaneous aging.
 Further, many patents and publications, for example, European Patent
 application EP-A-413,528, and many commercial cosmetic compositions teach
 the use of .alpha.-hydroxy acids, such as lactic acid, glycolic acid or
 citric acid, for treating cutaneous aging.
 Finally, .beta.-hydroxy acids, and more particularly salicylic acid and its
 derivatives, are known for their desquamating properties, see, for
 example, International patent application WO-A-93/10756 and U.S. Pat. No.
 4,767,750.
 All these compounds have an action against aging of the skin which includes
 a desquamation, that is to say the removal of the "dead" cells situated at
 the surface of the stratum corneum. This desquamating property is also
 known, often wrongly, as a keratolytic property. However, these compounds
 also exhibit side effects, which consist of stinging, tightness,
 overheating and redness, which the user often finds unpleasant.
 It can thus be seen that there is still a need for anti-aging agents which
 act on the skin, at least as effectively as that of the compounds of the
 prior art, but which do not exhibit their disadvantages.
 The Inventor has unexpectedly discovered that the topical application of
 cysteic or homocysteic acid or of one of their derivatives makes it
 possible to desquamate the skin as well as to stimulate epidermal cell
 renewal and epidermal repair.
 Cysteic and homocysteic acids are certainly already known in the
 pharmaceutical field for the treatment of dry skin, warts, actinic or
 non-actinic keratoses, acne, ichthyoses and palmar and plantar
 hyperkeratoses, see, for example, U.S. Pat. No. 4,224,339. However, no
 one, until now, has envisaged or suggested the use of these acids for
 desquamation of the skin, stimulation of epidermal renewal, epidermal
 repair and/or the treatment of cutaneous aging.
 A subject of the present invention is consequently the use of at least one
 sulphonic acid or a hydrate thereof, in the free state or at least
 partially neutralized, in or for the preparation of a cosmetic or
 dermatological composition for promoting desquamation of the skin and/or
 for stimulating epidermal renewal and/or epidermal repair. This at least
 one sulphonic acid has the formula (I):
 ##STR1##
 wherein p is 1 or 2 and R.sub.1 represents a hydrogen atom or an acyl
 residue having the structure --COR.sub.2 wherein R.sub.2 is a linear or
 branched C.sub.1 -C.sub.19 alkyl or alkenyl group. which is unsubstituted
 or substituted by at least one hydroxyl functional group.
 Desquamation of the skin is associated with a clinical improvement in the
 quality of the skin which becomes more radiant, less wrinkled and
 generally younger in appearance. Moreover, the above sulphonic acids or
 hydrates thereof can be used to treat imperfections of the skin, such as
 blemishes, cutaneous dyschromias, dermatites, actinic lentigines, scars
 and cicatricial pigmentations.
 A further subject of the invention is consequently the use of at least one
 sulphonic acid or hydrate thereof, in the free state or at least partially
 neutralized, for the preparation of a cosmetic or dermatological
 composition useful as an anti-aging agent, in particular for combatting at
 least one condition selected from wrinkles, fine lines, actinic blemishes,
 cutaneous dyschromias, dermatites, and scars.
 The Inventor has, in particular, observed, without a full explanation for
 this being available, that these compounds can have an anti-aging action
 which is at least as effective as the compounds of the prior art which are
 all carboxylic acids. It has also been observed that, compared to
 compounds of the prior art, this action can also be milder, insofar as
 little or no irritation is experienced and little or no redness is
 observed, when a cosmetic or dermatological composition containing them is
 applied to the skin.
 In particular, the acids of the invention include cysteic and homocysteic
 acids. These two acids have the advantage of being commercially available.
 The other acids of the invention can be prepared according to known
 methods. For example, the products of formula (I), wherein R.sub.1
 represents H, can be reacted with an activated form of an acid having the
 formula R.sub.2 --COOH, with R.sub.2 being defined as indicated above,
 which can be an anhydrous product, a mixed anhydride (obtained from a
 chloroformate) or an acid chloride (CICOR.sub.2), the pH being maintained
 at a value within the range from 7 to 9 (i.e., a Schotten-Baumann
 reaction). At the end of the reaction, the product obtained is
 precipitated at an acidic pH (pH=1) or extracted according to conventional
 techniques.
 All or part of the acids of the invention can be neutralized to form a
 salt, in particular by sodium hydroxide, potassium hydroxide, ammonia,
 monoethanolamine, triethanolamine and isopropanolamine.
 In the compositions according to the invention, the sulphonic acid or the
 mixture of sulphonic acids, including the hydrates thereof, are used in an
 amount effective to achieve the purpose desired, and are preferably used
 in an amount ranging from 0.2 to 20% by weight with respect to the total
 weight of the composition, more preferably in an amount ranging from 0.5
 to 10% and, most preferably, in an amount ranging from 0.5 to 5% by weight
 with respect to the total weight of the composition.
 The acids of the invention can be combined with other active agents known
 for their desquamating properties, such as hydroxy acids, .alpha.- or
 .beta.-keto acids or retinoids. Such a combination makes it possible to
 decrease the active concentration of these latter active agents, due to
 additive effects. It is thus possible to obtain a less irritating and less
 toxic composition as well as a composition which is more effective than
 those of the prior art in which only these active agents are used.
 The hydroxy acids which can be used in accordance with the present
 invention include, for example, .alpha.-hydroxy acids and .beta.-hydroxy
 acids, which can be linear, branched or cyclic, and saturated or
 unsaturated. The hydrogen atoms of the carbon chain can, in addition, be
 substituted by halogens or alkyl, acyl, acyloxy, alkoxycarbonyl or alkoxy
 radicals having from 2 to 18 carbon atoms.
 These hydroxy acids are, in particular, glycolic, lactic, malic, tartaric
 and citric acids, and generally fruit acids, or 2-hydroxyalkanoic,
 mandelic and salicylic acids and their alkyl or acyl derivatives, such as
 5-(n-octanoyl)salicylic acid, 5-(n-dodecanoyl)salicylic acid,
 5-(n-decanoyl)salicylic acid, 5-(n-octyl)salicylic acid, 5- or
 4-(n-heptyloxy)salicylic acid or 2-hydroxy-3-methylbenzoic acid, or
 alternatively their alkoxy derivatives, such as 2-hydroxy-3-methoxybenzoic
 acid.
 The retinoids which can be used in accordance with the present invention
 include, in particular, retinoic acid (all trans or 13-cis) and its
 derivatives, retinol (vitamin A) and its esters, such as retinol
 palmitate, retinol acetate and retinol propionate, and their salts, or
 alternatively retinal.
 By way of example, the hydroxy acids, the keto acids and the retinoids can
 be used in the compositions according to the invention in an amount
 preferably representing from 0.1 to 5% by weight of the total weight of
 the composition and, more preferably, from 0.5 to 3%.
 For the purpose of effectively combatting photoaging, it is additionally
 possible to add, to the composition of the invention, one or a number of
 additional hydrophilic or lipophilic sunscreening agents which are active
 in the UVA and/or the UVB range.
 An in vitro test of the effectiveness of the desquamation achieved in
 accordance with the present invention has been carried out on
 keratinocytes by using 5-(n-octanoyl)salicylic acid (compound 1), cysteic
 acid (compound 2, in accordance with the invention), the
 bis[1-(ethoxycarbonyl)ethyl] ester of nonanedioic acid (compound 3),
 2-acetoxy-5-octanoylbenzoic acid (compound 4) and
 5-oxothiomorpholine-3-carboxylic acid (compound 5).
 The principle of the test, which is art-recognized and thus accepted by
 those skilled in the art, is based on the fact that desquamation induces
 the release of corneocytes. The greater the desquamating power of the
 tested product, the greater the number of corneocytes released.
 The protocol of the test was as follows: keratinocytes were obtained from
 skin biopsies by separation from the epidermis, were dissociated by
 enzymatic action with trypsin and cultured at a concentration of
 2.times.10.sup.-5 cells/ml. Growth and differentiation of the
 keratinocytes were obtained by culturing for 10 to 20 days in a specific
 medium.
 After removal of the culture medium, the test product was then added and
 the activity of the product evaluated. To do this, two samples were taken
 at T.sub.0 and T.sub.60, that is to say before the addition of the product
 and 60 minutes after this addition, and the samples thus taken were
 analyzed in a flow cytometer in order to count the population of
 corneocytes. The corneocyte and keratinocyte populations are
 differentiated in the flow cytometer by treatment with acridine orange
 (which is specific for the DNA of the cells) which binds to the nuclei of
 the cells and thus reveals the presence of the keratinocytes exclusively.
 The cell detachment index is determined by the differences between T.sub.60
 and T.sub.0.
 The same measurement, i.e., the cell detachment index, was determined for a
 control which contained no test product because the experiment inevitably
 results in the release of corneocytes, even in the absence of active
 agent.
 The results are collated in the table below:

Com- Com- Com- Com- Com-
 pound pound pound pound pound
 Control 1 2 3 4 5
 0% 106% 206% 59% inactive inactive
 These results clearly show that Compound 2, cysteic acid, at the same
 concentration as Compound 1, 5-(n-octanoyl)salicylic acid, which is known
 to be a powerful desquamating active agent, is much more active than the
 latter and that the other compounds have significantly lower activities
 than cysteic acid.
 A further subject of the invention is a process for the cosmetic or
 dermatological treatment of the skin for the purpose of desquamation of
 the skin, which comprises applying to the skin a composition containing at
 least one sulphonic acid of formula (I) or a hydrate thereof, in the free
 state or partially neutralized, preferably in a cosmetically and/or
 dermatologically acceptable medium.
 Another subject of the invention is a process for the cosmetic or
 dermatological treatment of aging of the skin, which comprises applying to
 the skin a composition containing at least one sulphonic acid or a hydrate
 thereof as defined above, preferably in a cosmetically and/or
 dermatologically acceptable medium.
 A still further subject of the invention is a process for the cosmetic or
 dermatological treatment of various conditions of the skin including, but
 not limited to, wrinkles, fine lines, actinic blemishes, cutaneous
 dyschromias, scars and dermatites, which comprises applying to the skin a
 composition containing at least one sulphonic acid or a hydrate thereof as
 defined above, preferably in a cosmetically and/or dermatologically
 acceptable medium.
 The compositions of the invention preferably contain a cosmetically or
 dermatologically acceptable medium, that is to say a medium compatible
 with the skin, the nails, the mucous membranes, the tissues and the hair.
 The composition containing sulphonic acid can be applied topically to the
 face, the neck, the hair, the mucous membranes and the nails or any other
 cutaneous region of the body.
 The compositions according to the invention can be provided in any form
 appropriate for topical application, in particular in the form of aqueous,
 aqueous/alcoholic or oily solutions; dispersions of the lotion or serum
 type; aqueous, anhydrous or oily gels; emulsions with a liquid or
 semi-liquid consistency of the milk type, obtained by dispersion of a
 fatty phase in an aqueous phase (O/W) or vice versa (W/O); suspensions or
 emulsions with a soft, semi-solid or solid consistency of the cream or gel
 type; microemulsions, microcapsules, microparticles or vesicular
 dispersions of the ionic and/or nonionic type. These compositions can be
 prepared according to conventional methods.
 The compositions of the invention can also be used for the hair in the form
 of aqueous, alcoholic or aqueous/alcoholic solutions or in the form of
 creams, gels, emulsions or foams or in the form of aerosol compositions
 also containing a pressurized propellant agent.
 The amounts of the various other constituents of the compositions according
 to the invention are those conventionally used in the fields under
 consideration.
 These compositions preferably constitute protective, treatment or care
 creams for the face, for the hands or for the body, protective or care
 body milks, lotions, gels or foams for caring for the skin and mucous
 membranes or for cleansing the skin.
 The compositions can also comprise solid preparations comprising cleansing
 bars or soaps.
 When the composition of the invention is an emulsion, the proportion of the
 fatty phase preferably ranges from 5% to 80% by weight, and more
 preferably ranges from 5% to 50% by weight, with respect to the total
 weight of the composition. The oils, the emulsifiers and the coemulsifiers
 used in the composition in the emulsion form are chosen from those
 conventionally used in the cosmetics or dermatological field.
 The emulsifier and the coemulsifier are preferably present, in the
 composition, in a proportion ranging from 0.3% to 30% by weight, and more
 preferably ranging from 0.5 to 20% by weight, with respect to the total
 weight of the composition. The emulsion can, in addition, contain lipid
 vesicles.
 When the composition is an oily solution or an oily gel, the amount of oil
 preferably ranges up to more than 90% by weight of the total weight of the
 composition.
 In a known way, the composition of the invention can also contain adjuvants
 which are conventional in the cosmetics and dermatological fields, such as
 hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic active
 agents, preservatives, antioxidants, solvents, fragrances, fillers and
 colouring materials.
 The amounts of these various adjuvants are those conventionally used in the
 fields under consideration, for example from 0.01% to 20% of the total
 weight of the composition. These adjuvants, depending on their nature, can
 be introduced into the fatty phase, into the aqueous phase and/or into the
 lipid spherules.
 Mention may be made, as oils which are preferably used in accordance with
 the invention, of mineral oils (liquid petrolatum), vegetable oils (karite
 oil, sweet almond oil), animal oils, synthetic oils, silicone oils
 (cyclomethicone) and fluorinated oils (perfluoropolyethers). It is also
 possible to use, as fatty substances, fatty alcohols, fatty acids (stearic
 acid) and waxes (paraffin wax, carnauba wax, beeswax).
 Mention may be made, as emulsifiers which can preferably be used in
 accordance with the invention, of Polysorbate 60 and sorbitan stearate
 sold respectively under the trade names Tween 60 and Span 60 by the
 Company ICI. Coemulsifiers, such as PPG-3 myristyl ether sold under the
 trade name Emcol 249-3K by the company Witco, can be added thereto.
 Mention may be made, as solvents which can preferably be used in the
 invention, of lower alcohols, in particular ethanol and isopropanol, or
 propylene glycol.
 Mention may be made, as hydrophilic gelling agents, of carboxyvinyl
 polymers (carbomer), acrylic copolymers, such as acrylate/alkyl acrylate
 copolymers, polyacrylamides, polysaccharides, such as
 hydroxypropylcellulose, natural gums (xanthan gum) and clays; mention may
 be made, as lipophilic gelling agents, of modified clays, such as
 bentones, metal salts of fatty acids, such as aluminium stearates,
 hydrophobic silica, polyethylenes and ethylcellulose.
 It is possible to use, as hydrophilic active agents, proteins or protein
 hydrolysates, amino acids, polyols, urea, allantoin, sugars and sugar
 derivatives, water-soluble vitamins, starch, or bacterial or plant
 extracts, in particular, Aloe vera.
 It is possible to use, as lipophilic active agents, tocopherol (vitamin E)
 and its derivatives, essential fatty acids, ceramides or essential oils.
 It is possible, inter alia, to combine the sulphonic acids with active
 agents intended in particular for the prevention and/or the treatment of
 cutaneous ailments. Mention may be made, among these active agents, by way
 of example, of:
 agents which modify cutaneous differentiation and/or proliferation and/or
 pigmentation, such as vitamin D and its derivatives, oestrogens, such as
 oestradiol, kojic acid or hydroquinone;
 agents for combatting free radicals, such as a-tocopherol or its esters,
 superoxide dismutases, certain metal chelating agents or ascorbic acid and
 its esters.
 The cosmetic or dermatological treatment processes of the invention can be
 implemented in particular by applying the hygienic, cosmetic or
 dermatological compositions as defined above according to the usual
 technique for the use of these compositions, for example: application of
 creams, gels, serums, ointments, lotions or milks to the skin, the scalp,
 the nails and/or the mucous membranes.
 The following examples illustrate the invention. In these examples, the
 proportions shown are percentages by weight.

EXAMPLE 1
 Preparation of an Oil-in-Water Emulsion

Phase A:
 Cysteic acid 2.5
 Sweet almond oil 14.5
 Karite oil 7.0
 PPG-3 myristyl ether (Emcol 249-3K) 5.0
 Preservative (propylparaben) 0.1
 Polysorbate 60 (Tween 60) 2.5
 Sorbitan stearate (Span 60) 2.5
 Phase B:
 Cyclomethicone 4.0
 Xanthan gum 0.2
 Carboxyvinyl polymer 0.5
 Phase C:
 Triethanolamine (neutralizing agent) 0.5
 Water 2.0
 Phase D:
 Preservative (methylparaben) 0.2
 Glycerol 5.0
 Water q.s. for 100
 Procedure:
 The constituents of phase A were melted at 85.degree. C., phase A was then
 cooled to 70.degree. C. and phases B, and then C and D, were introduced
 therein with stirring. Cooling was carried out to room temperature. A day
 cream was obtained which caused desquamation of the skin and thus
 conferred a smoother and younger appearance on the skin than existed
 before the treatment.
 EXAMPLE 2
 Preparation of a Gel

Homocysteic acid 5.0
 Hydroxypropylcellulose (Klucel H from the 1.0
 company Hercules)
 Antioxidant 0.05
 Isopropanol 40.0
 Preservative 0.3
 Water q.s. for 100
 A gel was obtained which, on regular application, toned down blemishes of
 the skin by desquamation.
 EXAMPLE 3
 Preparation of a Solution for Dermatological Application

Cysteic acid 5.00
 Antioxidant 0.05
 Ethyl alcohol 10.00
 Preservative 0.30
 Water q.s. for 100
 The application under dermatological control of this solution brought-about
 deep desquamation of the corneal layer and, thus, instigated an epidermal
 repair process which resulted in, as final therapeutic effect, an erasing
 of blemishes and dyschromias, a toning down of wrinkles and fine lines and
 an improvement in the clinical condition of the skin, the appearance of
 which became that of a younger skin. This application was carried out one
 to three times weekly for 4 to 6 weeks.