WO1998024407A1

WO1998024407A1 - Use of paracetamol as depigmenting agent

Info

Publication number: WO1998024407A1
Application number: PCT/FR1997/002084
Authority: WO
Inventors: Albert Duranton; Francis Pruche
Original assignee: L'oreal
Priority date: 1996-12-06
Filing date: 1997-11-19
Publication date: 1998-06-11
Also published as: AU5226798A; FR2756734B1; FR2756734A1

Abstract

The invention concerns the use of paracetamol in a composition as depigmenting and/or bleaching agent for human skin, hairs and/or hair, and a depigmenting composition containing paracetamol. It also concerns a method for depigmenting and/or bleaching the skin, hairs and/or hair, which consists in applying on human skin, hairs and/or hair a composition containing paracetamol.

Description

Use of paracetamol as a depigmenting agent

The present invention relates to the use of paracetamol as a depigmenting or whitening agent in a cosmetic and / or dermatological composition, as well as to a depigmenting and / or whitening composition containing paracetamol.

The color of human skin is a function of various factors, including the seasons of the year, race and sex, and is mainly determined by the nature and concentration of melanin produced by the melanocytes. Melanocytes are the specialized cells which, via particular organelles, the melanosomes, synthesize melanin. In addition, at different periods of their life, some people see appearing on the skin and more particularly on the hands, darker and / or more colored spots, giving the skin a heterogeneity. These spots are also due to a high concentration of melanin in the keratinocytes located on the surface of the skin.

In the same way, the color of the hairs and the hair is due to the melanin, when the hairs or the hair are dark, some people wish to see their lighter. This is particularly interesting for hairs which are less visible when they are light than when they are dark.

The mechanism of formation of the pigmentation of the skin, of the hairs and of the hair, that is to say of the formation of melanin is particularly complex and schematically involves the following main stages:

Tyrosine -> Dopa -> Dopaquinone -> Dopachrome -> Melanin

Tyrosinase (monophenol dihydroxyl phenylalanine: oxygen oxidoreductase EC 1, 14,18,1) is the essential enzyme involved in this sequence of reactions. It catalyzes in particular the reaction of transformation of tyrosine into Dopa (dihydroxyphenylalanine) thanks to its hydroxylase activity and the reaction of transformation of Dopa into dopaquinone thanks to its oxidase activity. This tyrosinase only acts when it is in the maturation state under the action of certain biological factors.

A substance is recognized as depigmenting if it acts directly on the vitality of the epidermal melanocytes where melanogenesis takes place and / or if it interferes with one of the stages of melanin biosynthesis either by inhibiting one of the enzymes involved in melanogenesis or by s intercalating as a structural analogue of one of the chemical compounds in the melanin synthesis chain, a chain which can then be blocked and thus ensure depigmentation.

The substances most used as depigmentants are more particularly hydroquinone and its derivatives, in particular its ethers such as the monomethyl ether and the monoethyl ether of hydroquinone. These compounds, although they have a certain effectiveness, are unfortunately not free from side effects due to their toxicity, which can make their use delicate, even dangerous. This toxicity comes from the fact that they intervene on the fundamental mechanisms of melanogenesis by killing cells which then risk disturbing their biological environment and which consequently oblige the skin to evacuate them by producing toxins.

Thus, hydroquinone is a particularly irritating and cytotoxic compound for the melaπocyte, the replacement of which, total or partial, has been considered by many authors.

We have thus sought substances which do not intervene in the mechanism of melanogenesis but which act upstream on tyrosinase by preventing its activation and are therefore much less toxic. We commonly used as an inhibitor of the activation of tyrosinase kojic acid which complexes the copper present in the active site of this enzyme. Unfortunately, this compound can cause allergy reactions ("Contact allergy to kojic acid in skin care products", Nakagawa M. et al., In Contact Dermatitis, Jan. 95, Vol 42 (1), pp.9-13 ). This compound is also unstable in solution, which somewhat complicates the manufacture of the composition.

The use of harmless topical depigmenting substances with good efficacy is particularly sought in order to treat regional hyperpigmentations by melanocytic hyperactivity such as idiopathic melasmas, occurring during pregnancy ("pregnancy mask" or chloasma) or Estroprogestative contraception, localized hyperpigmentations by hyperactivity and benign melanocytic proliferation, such as senile pigment spots called lentigo actinic, accidental hyperpigmentations or depigmentations, possibly due to photosensitization or post-lesional scarring, as well as certain leukoderma, such than vitiligo. For the latter (scarring which can lead to a scar giving the skin a whiter appearance and leukoderma), failing to be able to repigment the damaged skin, we finish depigmenting the areas of residual normal skin to give the whole of the skin a homogeneous white shade.

Also, there remains the need for a new whitening agent for human skin, hair and / or hair with an action as effective as those known, but not having their drawbacks, that is to say which is not irritant, non-toxic and / or non-allergenic for the skin and stable in a composition.

The Applicant has unexpectedly found that paracetamol has the property of inhibiting tyrosinase, and therefore the synthesis of melanin, and could thus act effectively on pigmentation and dark spots. the skin or on the pigmentation of the hair and / or the hair without any toxicity.

Paracetamol is N- (4-hydroxyphenyl) acetamide (or acetaminophen).

It has been known for many years as an antipyretic and analgesic agent. However, to date no one had considered using it as a depigmenting agent.

The present invention therefore relates to the use of paracetamol in and / or for the manufacture of a cosmetic and / or dermatological composition for depigmenting and / or bleaching human skin and / or removing pigment spots from the skin and / or depigment the hairs and / or hair.

The present invention also relates to the use of paracetamol in and / or for the manufacture of a cosmetic and / or dermatological composition, as an inhibitor of tyrosinase and / or of the synthesis of melanin.

Indeed, without wishing to be bound by any theory of the invention, it seems that paracetamol acts not as a substrate for tyrosinase, but as an inhibitor of the hydroxylase and oxidase activities of tyrosinase.

Another subject of the present invention is the use of paracetamol in a depigmenting and / or whitening cosmetic composition for human skin, body hair or hair.

The present invention also relates to a depigmenting or whitening composition, characterized in that it contains, in a cosmetically and / or dermatologically acceptable medium, paracetamol. This composition is more particularly intended for topical use on the skin and / or its integuments (hair, hair and nails). The present invention also relates to a cosmetic and / or dermatological process for depigmentation and / or bleaching of human skin, hair or hair, consisting in applying to the skin, the hair or the hair a composition according to the invention.

The composition according to the invention is suitable for topical use and therefore contains a cosmetically or dermatologically acceptable medium, that is to say compatible with the skin, body hair or hair.

The paracetamol can in particular be present in an amount ranging from 0.01 to 10% and preferably from 0.3 to 3% of the total weight of the composition.

The composition of the invention can be in all dosage forms normally used for topical application, in particular in the form of an aqueous, hydroalcoholic or oily solution, of an oil-in-water or water-in-oil emulsion or multiple, of an aqueous or oily gel, of a liquid, pasty or solid anhydrous product, of an oil dispersion in an aqueous phase using spherules, these spherules possibly being polymeric nanoparticles such as nanospheres and nanocapsules or better lipid vesicles of ionic and / or nonionic type.

This composition can be more or less fluid and have the appearance of a white or colored cream, an ointment, a milk, a lotion, a serum, a paste, a foam. . It can optionally be applied to the skin or to the hair in the form of an aerosol. It can also be in solid form, and for example in the form of a stick. It can be used as a care product and / or as a makeup product. It can also be in the form of shampoos or conditioners. Finally, it can be in the form of a patch. In a known manner, the composition of the invention may also contain the adjuvants usual in the cosmetic and dermatological fields, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic active agents, preservatives, antioxidants, solvents, perfumes, fillers, filters, pigments, odor absorbers and coloring matter. The amounts of these various adjuvants are those conventionally used in the fields under consideration, and 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, into the lipid vesicles and / or into the nanoparticles.

When the composition of the invention is an emulsion, the proportion of the fatty phase can range from 5 to 80% by weight, and preferably from 5 to 50% by weight relative to the total weight of the composition. The oils, emulsifiers and coemulsifiers used in the composition in the form of an emulsion are chosen from those conventionally used in the field under consideration. The emulsifier and the coemulsifier are present in the composition in a proportion ranging from 0.3 to 30% by weight, and preferably from 0.5 to 20% by weight relative to the total weight of the composition.

As oils which can be used in the invention, mention may be made of mineral oils (petrolatum oil), oils of vegetable origin (avocado oil, soybean oil), oils of animal origin (lanolin), oils of synthesis (perhydrosqualene), silicone oils (cyclomethicone) and fluorinated oils (perfluoropolyethers). Fatty alcohols (cetyl alcohol), fatty acids, waxes (camauba wax, ozokerite) can also be used as fats.

As emulsifiers and coemulsifiers which can be used in the invention, mention may, for example, be made of fatty acid and polyethylene glycol esters such as PEG-20 stearate, and fatty acid and glycerin esters such as glyceryl stearate.

As hydrophilic gelling agents, mention may in particular be made of carboxyvinyl polymers (carbomers), acrylic copolymers such as acrylate / alkyl acrylate copolymers, polyacrylamides, polysaccharides, natural gums and clays, and, as lipophilic gelling agents, cite modified clays such as bentones, metal salts of fatty acids, hydrophobic silica and polyethylene.

As active agents, polyols (glycerin, propylene glycol), vitamins, keratolytic and / or desquamating agents (salicylic acid and its derivatives, alpha-hydroxy acids, ascorbic acid and its derivatives), anti-inflammatory agents, can be used, soothing agents and mixtures thereof. Paracetamol can also be combined with other depigmenting agents, such as kojic acid or hydroquinone and its derivatives, which makes it possible to use the latter in doses which are less toxic for the skin. In the event of incompatibility, these active agents and / or paracetamol can be incorporated into spherules, in particular ionic or nonionic vesicles and / or nanoparticles (nanocapsules and / or nanospheres), so as to isolate them from each other in the composition.

The composition is generally applied to the part (skin or mucous membranes) to be treated, then can optionally be held in position by an adhesive piece (patch). The adhesive piece can allow a partial or total occlusion of the composition on the part to be treated. One can for example use as an adhesive dressing, the product Tegaderm ^® sold by 3M Health Laboratories or like adhesive patch, the product Finn Chambers ^® sold by the company PROMEDICA. Tests:

- Tests have demonstrated the activity of paracetamol as a tyrosinase inhibitor by evaluating its inhibitory effects on the tyrosine hydroxylase activity and on the dopa-oxidase activity of the tyrosinase of fungi.

According to this test, the amount of dopachrome formed (intermediate product before the non-enzymatic oxidation reactions leading to the formation of melanin) is monitored by visible spectrometry at 475 nm as a function of time. These reactions are catalyzed in vitro by the fungus tyrosinase (5 μg at 3400 units / mg, sold by Sigma) in the presence of a part of 250 μM of L-tyrosiπe (FIG. 1) and on the other hand of 250 μM of L-dopa (Figure 2) with 100 μM of paracetamol.

The reaction medium used to carry out this test corresponds to 1 ml of a phosphate buffer solution (Dulbecco's PBS) at pH = 7.4. For the control, the amount of inhibitor was replaced by the same phosphate buffer at pH = 7.4. The zero of the curves was also calibrated using phosphate buffer.

The curves presented in FIGS. 1 and 2 were plotted by following, on the ordinate, the optical density obtained by the dopachrome formed as a function of the time indicated on the abscissa and expressed in seconds. Curves (a) (or represented by •) relate to the control and curves (b) (or represented by x) relate to paracetamol.

By comparing the two curves of the same figure, it is clearly seen that the presence of paracetamol causes a marked slowing down in the amount of dopachrome formed over time, which means that paracetamol has an effect of inhibiting tyrosinase. - In addition, the absorption spectrum between 190nm and 540nm was carried out to monitor a possible reaction of paracetamol with tyrosinase. Under the same conditions as above with concentrations of paracetamol which are here 1 mM and 100 μM and with an incubation time of 2 hours at 30 ° C., no change in the optical density is observed compared to the control. Which means that paracetamol is a very bad substrate for tyrosinase.

The invention will now be illustrated by means of the following examples. The concentrations are given as a percentage by weight.

Example 1: Treating cream

- Cetyl alcohol 1.05%

- PEG-20 stearate (Myrj 49 sold by the company ICI) 2%

- Cyclomethicone 6%

- Paracetamol 0.5%

- Carbomer 0.6%

- Glycerin 3%

- Triethanolamine 1%

- Preservatives 0.5%

- Demineralized water qs 100%

The cream obtained used in daily application, makes it possible to obtain a whitening of the skin.

Example 2: Treating gel

- Propylene glycol 10%

- Ethyl alcohol 40% - Glycerin 3%

- Paracetamol 0.5%

- Preservatives 0.15%

- Perfume 0.15% - Demineralized water qs 100%

The gel obtained can be used daily and is able to depigment the skin.

Example 3: Treatment Stick

- Camauba wax 5%

- Ozokerite 7% - Lanolin 6%

- Titanium dioxide (pigments) 20%

- Rice starch (load) 7%

- EDTA 0.1%

- Paracetamol 2% - Perhydrosqualene qs 100%

The stick obtained, used on pigmentation spots, makes it possible to attenuate them even to make them disappear.

Example 4: Depigmenting patch:

The self-adhesive patch contains 1% immobilized paracetamol. The patch is applied daily in the evening to an area to be depigmented, such as pigment spots.

Example 4 Demonstration of the topical depigmenting effect on the skin of a composition comprising paracetamol

Composition:

Paracetamol at 5% by weight by volume of a solution consisting of: water (22g), propylene glycol (23g) and alcohol (55g).

The treatment consists in applying to two forearm surfaces of 1 cm ² previously shaved 50 μl of the composition on the one hand (zone "paracetamol") and 50 μl of the vehicle (solution mentioned above without paracetamol) (zone " vehicle ") on the other hand, and this morning and evening for more than a month (from October 17 to November 23). This application is done using a pipette, wait 10 seconds of contact before massaging lightly until the surface dries.

On November 19, the skin surfaces previously treated, either by the composition or by the vehicle, are irradiated with UV-B radiation for 6 minutes (approximately 1 M.E.D.). Two surfaces of the untreated shaved skin are also irradiated adjacent to the two other zones which serve as a control (“control” zone).

The colorimetry (Minolta CR200® colorimeter) is followed for 4 days in these areas (day 0 corresponding to November 19). Three areas of colorimetry are taken into account. Thus, schematically, L, which is the luminance, corresponds to the clarity of the skin (the larger L, the lighter the skin), A corresponds to the redness of the skin (due in particular to the post theme -UV-B), B corresponds to the yellow color of the skin (the larger B, the more there is melanin pigmentation). FIG. 3 represents the difference in luminance of the “paracetamol” zone (c) on the one hand, of the “vehicle” zone (d) on the other hand with the corresponding “control” zone as a function of time (expressed in days : nov corresponds to november).

FIG. 4 represents the difference in redness of the "paracetamol" zone (c) on the one hand, of the "vehicle" zone (d) on the other hand with the corresponding "control" zone as a function of time (expressed in days ).

FIG. 5 represents the difference in yellow from the “paracetamol” zone (c) on the one hand, from the “vehicle” zone (d) on the other hand with the corresponding “control” zone as a function of time (expressed in days ).

We can see that, in these three areas of colorimetry, the "paracetamol" zone corresponds well to depigmented skin compared to the "vehicle" zone.

Claims

1. Use of paracetamol in and / or for the manufacture of a cosmetic and / or dermatological composition for depigmenting and / or bleaching human skin and / or removing pigment spots from the skin and / or depigmenting body hair and / or hair.

2. Use of paracetamol in and / or for the manufacture of a cosmetic and / or dermatological composition, as an inhibitor of tyrosinase and / or of the synthesis of melanin.

3. Use of paracetamol in a depigmenting and / or whitening cosmetic composition for human skin, body hair or hair.

4. A depigmenting or whitening composition, characterized in that it comprises, in a cosmetically and / or dermatologically acceptable medium, paracetamol.

5. Composition according to the preceding claim, characterized in that it is intended for topical use on the skin and / or its integuments.

6. Use and composition according to any one of the preceding claims, characterized in that the paracetamol is present in an amount ranging from 0.01 to 10% of the total weight of the composition.

7. Use and composition according to the preceding claim, characterized in that the paracetamol is present in an amount ranging from 0.3 to 3% of the total weight of the composition.

8. Use and composition according to any one of the preceding claims, characterized in that the composition also comprises at least one active agent chosen from keratolytic and / or desquamating, anti-inflammatory, soothing agents, other depigmenting agents and their mixtures.

9. Use and composition according to one of the preceding claims, characterized in that the paracetamol and / or the active ingredient is encapsulated in spherules.

10. Cosmetic process for depigmentation and / or bleaching of human skin, hair or hair, characterized in that it consists in applying to the skin, the hair or the hair a composition described according to one of the preceding claims 4 at 9.