FR2783714A1 - Skin depigmenting composition contains hydroquinone and an alkali metal metabisulfite - Google Patents

Abstract

A composition comprises hydroquinone and an alkali metal metabisulfite useful in cosmetics and dermatology.

Description

[The present invention relates to a new cosmetic composition or

  dermatological, and more particularly a composition comprising in combination hydroquinone and a metabisulfite, usable by topical application for depigmentation of the skin. The pigmentation of the skin results from the synthesis of melanin in the melanocytes of the dermis, according to a complex mechanism during which a cuproprotein enzyme, tyrosinase (or monophenol mono-oxygenase), catalyzes the O10 transformation of tyrosine into dihydroxyphenylalanine (dopa), which is then transformed into dopaquinone, then into dopachrome, to lead to melanin. We can therefore obtain a depigmentation effect on the skin by using a compound which degrades melanin, or an inhibitor of melanin biosynthesis, or a tyrosinase inhibitor which blocks or

  inhibits the mechanism described above.

  We tried to develop substances or

  depigmenting compositions to combat dysregulation

  pigmentation, or against hyperpigmentation, of the skin often observed in humans, and generally linked to

  aging or overexposure to the sun. The hyper-

  Skin pigmentation can also result from hormonal or contraceptive treatment with estrogen-progestins. These disturbances or hyperpigmentation result in the appearance of brown spots resulting from too high a concentration of melanin in the keratinocytes of the epidermis. The number and intensity of these brown spots

  may vary with subject's age and condition.

  Hydroquinone, or 1,4-benzenediol, and certain derivatives, and in particular hydroquinone ethers, have been proposed as bases for depigmenting compositions which can be used topically, by direct application to the skin. Hydroquinone is known to act by inhibiting tyrosinase and preventing the attachment of its natural substrate, tyrosine. Thus, US-A-4,692,261 describes a depigmenting composition containing hydroquinone, an anionic detergent and a

  stabilizing. Patent EP-A-060.092 describes an ester of hydro-

  quinone and fatty acid. US-A-5,310,730 describes a hydroquinone glucoside having a depigmentation effect

skin.

  There are also known associations based on hydro-

  quinone, for example a combination of hydroquinone and acid

  salicylic as in patent FR-A-2,754,253.

  However, the use of hydroquinone, although it provides some effectiveness, has drawbacks

  linked to its high toxicity leading to side effects.

  Thus, prolonged contact of a composition containing hydroquinone with the skin can cause dermatoses or keratoses. This is why the use of hydroquinone is strictly regulated, and its concentration is limited in

Europe at 2%.

  Other depigmenting substances have been proposed to replace hydroquinone, and for example melatonin derivatives as in patent FR-A-2,751,535, derivatives of salicylic acid as in patent FR-A-2,732,594 or extracts of plants of the genus Mitracarpus as in

FR-A-2,751,874.

  Certain sulfites are used in food compositions and in cosmetic compositions because of their antioxidant property making it possible to use them as

  preservative. So sodium sulfite and meta-

  sodium bisulfite are salts which are very soluble in water but poorly soluble in alcohols, the properties of which are very similar. Patent application WO-A-98.19665 describes a lightening cosmetic composition conditioned for topical application to the skin, containing a sulfite or a

  metabisulfite, avoiding any use of hydroquinone.

  The work carried out by the applicant has made it possible to unexpectedly show that a significant depigmenting effect can be obtained by combining hydroquinone and an alkali metal metabisulfite, even at low doses, much lower than the doses at which the toxic effects appear.

recalled above.

  It then becomes possible to produce a significant effect

  lo inhibition of tyrosinase resulting in depigmen-

  skin without causing the side effects well

  known related to the use of hydroquinone.

  The present invention therefore relates to a combination of hydroquinone and an alkali metal bisulfite having depigmenting properties, usable in cosmetology

and / or in dermatology.

  The subject of the invention is also a new cosmetic and / or dermatological composition which can be administered topically, comprising a combination of hydroquinone and alkali metal metabisulfite, and one or more excipients.

  or pharmaceutically acceptable carriers.

  In accordance with classic terminology, the adminis-

  topical tration means any method of

  applying the composition directly to the skin.

  According to a preferred embodiment of the invention, the alkali metal metabisulfite is chosen from sodium metabisulfite and potassium metabisulfite.

  In accordance with another advantageous form of realization

  tion, the composition according to the present invention comprises

  another alpha hydroxy acid, in combination with meta-

  alkali metal bisulfite and hydroquinone. This alpha-

  hydroxy acid is preferably chosen from acids

  glycolic, citric, lactic, malic, tartaric, ascor-

  bique, mandélique, and their salts and esters.

  Studies and experiments have shown that

  tyrosinase inhibitory activity exerted by hydro-

  quinone is potentiated in combination with the alkali metal metabisulfite while it is not if the metabisulfite is replaced by the sulfite. The inhibitory activity of several compounds and combinations of compounds

  has been tested as shown below.

  The evaluation of the activity of tyrosinase was made using the technique described by T. Hamada et al., "Intracellular localization of tyrosinase inhibitor in amelanotic and melanotic malignant melanoma", British Journal

of Dermatology, 86, 385-394 (1972).

  In a medium buffered to pH 6.8, containing fungus tyrosinase (Sigma) and the substrate (tyrosine),

  increasing amounts of test substances are introduced.

  The inhibitory concentrations 50 (IC50 or concentration inhibiting 50% of the activity of tyrosinase) are measured for hydroquinone (6.g), sodium metabisulfite (7 Mg), sodium sulfite (30.g). For comparison, the IC50 of ascorbic acid could not be determined, no activity being demonstrated because ascorbic acid is strongly

  degraded during the incubation of the reaction medium.

  The percentage inhibition of each product or product combination was then determined, and the results are shown in the table below. The combinations of sodium metabisulfite and hydroquinone, on the one hand, sodium sulfite and hydroquinone, on the other hand, have been

  compared to their components used in isolation.

  Product Inhibition percentage Hydroquinone 4 # g 30 Sodium metabisulfite 3gg 15 Sodium sulfite 15gg 20 Hydroquinone (4 # g) + 90 sodium metabisulfite (3 # g) Hydroquinone (4yg) + sodium sulfite 40 (15jg)

  The results indicated above demonstrate that the activity

  of hydroquinone is significantly doubled when

  that it is combined with metabisulfite, while no potentiation is observed with sulfite. The composition according to the invention generally comprises between 0.1 and 2% by weight of metabisulfite and between 0.1 and 2% by weight of hydroquinone, relative to the total weight of the composition. According to a preferred embodiment, the metabisulfite content is between 0.3 and 1 k in

  by weight, and the hydroquinone content between 1 and 2% by weight.

  The hydroquinone / metal metabisulfite weight ratio

  alkaline is between 1: 2 and 20: 1, and preferably

between 1: 1 and 7: 1.

  The composition according to the invention may contain other substances known to exert a beneficial activity

  complementary, and as indicated above, it is all parti-

  Particularly advantageous to incorporate alpha-hydroxy acids into the composition which facilitate the exfoliation of the pigment-laden cells on the surface of the epidermis and promote the action of hydroquinone. We can also incorporate vitamins such as vitamin C or vitamin A, or

tocopherol.

  The composition may also contain various substances and excipients chosen as a function of their known properties and of the dosage form envisaged. Thus, preservatives, emulsifiers, thickeners, gelling agents, antioxidants, hydrating agents, surfactants, perfumes and various additives intended to improve the physical properties of the composition can be incorporated into the composition. It is also advantageously possible to incorporate filters or sunscreens chosen according to the degree of

protection sought.

  For example, the emulsifiers can be chosen from those commonly used in the art such as a Polysorbate (for example Tween 60 or Tween 80), a sorbitan ester such as sorbitan stearate or laurate, or derivatives of stearic acid such as PEG 100 stearate, or propylene glycol stearate, or alternatively

sugar ester.

  The usual preservatives of the technique of dermatological or cosmetic compositions can be used in

  the invention, for example benzoic acid and a p-

  alkyl hydroxybenzoate such as methyl and propyl p-hydroxy benzoates (Methylparaben and Propylparaben), or

imidazolidinyl urea.

  The hydrating agent can be, for example, a polyol, sorbitol, glyceryl polyacrylates and polymethacrylates,

  glycerol or glycerol derivatives.

  The gelling agents can be chosen, for example, from

  polyacrylamides, cellulose derivatives such as hydroxy-

  propyl cellulose, or natural gums.

  The constituents of the fatty phase can be chosen from petrolatum oil, stearic acid and some of its esters such as octyl stearate, palmitic acid, glyceryl palmitate, octyl palmitate, a triglyceride capric and caprylic acids, or even

  silicone, for example dimethicone and cyclomethicone.

  Hydrophilic or lipophilic ultraviolet filters and sunscreens can advantageously be incorporated into

  the composition of the invention, and for example one can incorporate

  pore titanium or zinc oxides.

  The pH of the composition is preferably between 4.5 and 5.5, and can be adjusted, depending on the compositions, by adding an acid such as citric acid or a base

such as sodium hydroxide.

  The solvent is chosen according to the components used lo and the form of administration envisaged. He can be

  consisting of water, and preferably demineralized water

  produced, as well as a specific solvent such as propylene glycol, an alcohol, in particular ethanol, or an ether of

diethylene glycol.

  The composition in accordance with the present invention may be presented in the forms conventionally used for topical application, that is to say in the form of gel, lotion, emulsion (in particular cream or milk), mask, stick or ointment, containing, in addition hydroquinone and metabisulfite,

  usual compatible and pharmaceutical excipients and carriers

  ceutically acceptable. These forms of topical administration are prepared by known techniques, and for example, in the case of a cream, by dispersion of a fatty phase in an aqueous phase to obtain an oil-in-water emulsion, or vice versa to prepare a water in oil emulsion. The compositions in accordance with the present invention can be advantageously used in cosmetology and in dermatology as depigmenting compositions intended for the treatment and elimination of brown spots linked to pigmentation disorders, resulting for example from aging, from excessive exposure to radiation. natural or artificial ultraviolet, or a natural disturbance linked to pregnancy. They can be applied directly to the skin, one or more times a day, for a variable period depending on the severity of the condition. For example, in the case of the treatment of brown spots in a subject 50 to 60 years old with spots of medium intensity, a composition can be applied twice a day for an uninterrupted period of 7 to 8 weeks. The first results can be seen with the naked eye after 3 to 5

weeks approx.

  lo They can also be used regularly to prevent the appearance of dark spots in subjects predisposed to this condition, or to obtain a lightening effect on the skin of a subject seeking an effect.

aesthetic.

  It can be observed that the composition according to the present

  invention provides a depigmenting effect resulting from the inhibition

  tyrosinase, not a scaling effect. When a substance peels the skin, this results in the elimination of superficial brown spots on the epidermis, but it is generally accompanied by inflammation, which can have the effect of stimulating the synthesis of melanin, which is contrary to the desired effect. The composition in accordance with the

  The present invention avoids this drawback.

  The following examples illustrate the invention in more detail without limiting its scope. In all the examples of compositions which follow, the parts are expressed in

weight, unless otherwise noted.

Example 1

  According to the usual techniques, a depigmenting lotion is prepared having the following composition: Sodium metabisulfite 1.0 g Hydroquinone 2.0 g Propylene glycol 30.0 g Ethyl alcohol 15.0 g Methyl paraben 0.1 g Propyl paraben 0.05g Citric acid qs pH 5.0 EDTA 0.4 g Perfume 0.2 g Demineralized water q.s.p. 100.0 g

Example 2

  An aqueous depigmenting gel based on sodium bisulfite and hydroquinone is prepared by conventional techniques, and its composition is as follows: Sodium metabisulfite 1.7 g Hydroquinone 2.0 g Gelling agent (polyacrylamide) 3.3 g Propylene glycol 20.0 g Dimethicone copolyol 1.0 g Phenoxyethanol (and) Methylparaben (and) Butyparaben (and) Ethylparaben (and) Propylparaben 0.3 g Citric acid qs pH 5.0 EDTA 0.4 g Perfume 0.3 g Demineralized water q.s.p. 100.0 g

Example 3

  A depigmenting emulsion (O / W) having the composition indicated below is prepared: Sodium metabisulfite 0.5 g Hydroquinone 2.0 g Triglycerides of capric and caprylic acids 4.0 g Octyl palmitate 6.0 g Glyceryl stearate (and) PEG-100 stearate 1.0 g Polyglyceryl methyl glucose distearate 3.0 g Glyceryl stearate 2.5 g Dimethicone 1.0 g Glycolic acid 6.0 g Butylene glycol 4.0 g Glycerin 5.0 g Polyacrylamide 1.5 g Sodium hydroxide qs pH 4.6 Preservatives 0.5 g l0 Sunscreen 2.0 g Perfume 0.15 g Demineralized water q.s. 100.0 g

Example 4

  A depigmenting cream (W / O emulsion) having the composition indicated below is prepared in the usual manner: Potassium metabisulfite 1.0 g Hydroquinone 2.0 g Triglycerides of capric and caprylic acids 7.5 g Isohexadecane 5.0 g Dimethicone 2.0 g Propylene glycol 10.0 g Glycerin 5.0 g PEG-30 dipolyhydroxystearate 2.0 g Citric acid 0.6 g EDTA 0.4 g Magnesium sulfate 0.5 g Preservatives 0.5 g Fragrance 0, 2 g Demineralized water qs 100.0 g

Example 5

  A water in silicone emulsion having the compound is prepared

  following sition: Sodium metabisulfite 0.7 g Hydroquinone 1.5 g Cyclomethicone 10.0 g Phenyl trimethicone 5.0 g Dimethicone 2.0 g Cetyl dimethicone 1.0 g Cyclomethicone (and) dimethicone copolyol 10.0 g Sodium chloride 2.0 g EDTA 0.4 g Lactic acid 5.0 g Glycerin 6.0 g Preservatives 0.6 g Fragrance 0.2 g Demineralized water qs 100.0 g

Example 6

  A depigmenting cream is prepared having the composition indicated below: Sodium metabisulfite 0.7 g Hydroquinone 2.0 g Triglycerides of capric and caprylic acids 10.0 g Glyceryl stearate (and) PEG-100 stearate 1.0 g Polyglyceryl distearate methyl glucose 3.0 g Stearyl alcohol 2.0 g Glycerol stearate 2.5 g Dimethicone 1.0 g Glycerin 5.0 g Ammonium lactate 12.0 g Citric acid qs pH 5.0 Sunscreen 2.0 g Gelling agent (polyacrylamide) 2.0 g Preservatives 0.9 g Perfume 0.1 g Demineralized water q.s. 100.0 g

Claims (10)

  1. Combination of hydroquinone and alkali metal metabisulfite having depigmenting properties,   usable in cosmetology and / or dermatology.   2. Combination according to claim 1, characterized in that the alkali metal metabisulfite is chosen from   sodium metabisulfite and potassium metabisulfite.   3. Combination according to any one of the claims.   previous cations, characterized in that the hydroquinone / metabisulfite alkali metal weight ratio is lo between 1: 2 and 20: 1.   4. Cosmetic and / or dermatological composition allowed   topically nistrable, comprising a combination of hydroquinone and the following alkali metal metabisulfite   any one of claims 1 to 3 and one or more   pharmaceutically acceptable excipients or carriers.   5. Composition according to claim 4, characterized in that the alkali metal metabisulfite is chosen from   sodium metabisulfite and potassium metabisulfite.   6. Composition according to claim 4, characterized in that the hydroquinone / metabisulfite weight ratio of   alkali metal is between 1: 2 and 20: 1.   7. Composition according to any one of the claims   cations 4 to 6, characterized in that it contains between 0.1 and 2% by weight of metabisulfite, relative to the total weight of composition.   8. Composition according to any one of the claims   cations 4 to 6, characterized in that it contains between 0.1 and 2% by weight of hydroquinone, relative to the total weight of the composition.   9. Composition according to any one of the claims   cations 4 to 8, characterized in that it also contains a alpha hydroxy acid.   10. Composition according to claim 9, characterized in that the alphahydroxy acid is chosen from glycolic, citric, lactic, malic, tartaric, ascorbic, mandelic acids, as well as their salts and esters.