MC200053A1 - Use of L-arginine derivatives as photoprotective agents and optimizing the melanin response in cosmetic compositions - Google Patents

Description

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10 PATENT OF INVENTION

TITLE OF THE INVENTION:

USE OF L-ARGININE DERIVATIVES AS PHOTOPROTECTIVE AGENTS AND MELANIC RESPONSE OPTIMIZERS IN COSMETIC COMPOSITIONS

DEPOSITOR:

EXSYMOL S.A.M.

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The present invention relates to the cosmetic use of L-arginine derivatives as photoprotective agents and 35 optimizing the melanic response, particularly in a composition aimed at protecting the skin against the harmful effects of the sun.

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Solar radiation induces an overproduction of photoprotective pigments, melanins, by melanocytes in the skin. Numerous strategies have been described aimed at modifying the activity of these cells, and in particular the function of a key enzyme in melanogenesis, tyrosinase.

However, the mechanisms involved in this skin pigmentation process are gradually becoming clearer, and it is now known that exposure of the skin to ultraviolet (UV) radiation induces the production of multiple endogenous factors that modulate melanocyte activity. The discovery of these agents, produced by both melanocytes and keratinocytes, has notably led to the definition of a functional entity located in the deep layers of the epidermis, the "melano-epidermal" unit (T.D. Fitzpatrick, Biology of the melanin pigmentary system (1979), T.D. Fitzpatrick Ed, McGraw Hill Book Co, N.Y., pp.131-163) where cellular cooperation between keratinocytes and melanocytes takes place.

20 It is now established that nitric oxide (NO) is one of these endogenous agents capable of activating melanogenesis, via its action on the "melano-epidermal" unit. Studies have thus demonstrated that in response to UV stimulation, on the one hand, melanocytes react by producing endogenous NO which 25 induces an overexpression of tyrosinase (M. Sasaki, Pigment Cell Res., vol.13 (2000), pp.248-252), on the other hand, keratinocytes also produce NO which also activates the synthesis of melanin pigments via this cell communication effect between melanocytes and adjacent keratinocytes (C. 30 Roméro-Graillet, J. Clin. Invest., vol.99 (1997), pp.635-642).

Therefore, there is a need to act on this "melano-epidermal" unit, in particular on cellular cooperation within this unit, and therefore to act on the production of NO.

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However, NO has long been considered incompatible with cosmetic use due to its multiple biological effects (important player in the inflammatory response, vasodilator, neurotransmitter) and

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including destructive (cytotoxic, in vivo generator of free radicals and toxic by-products such as peroxynitrous anion, inducer of apoptosis).

However, more recent work has highlighted the protective properties of NO with an antioxidant effect on skin exposed to UV-B (S.C. Lee, British J. of Dermatology, vol. 142 (2000), pp.653-659), and above all a role as an essential biological messenger in many useful physiological processes.

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This duality of NO effects is largely explained by the coexistence in tissues, particularly skin tissues, of two different forms of the enzyme specialized in NO production, NO synthase (NOS). We distinguish between the inducible isoform of NO synthase (iNOS), present in tissues only under certain conditions, and the constitutive isoform (cNOS), always present in tissues. These two isoforms have different biological roles.

20 The problem posed is therefore to strengthen the protection of the skin against the harmful effects of the sun by acting on the NO-dependent mechanism of its melanin response, while taking into account the physiological situation described above, namely the duality of the effects of NO, and the fact that the induction 25 of undesirable side effects is unacceptable for a cosmetic product.

The new approach proposed in this patent is therefore based on the use of active ingredients that optimize the melanin response following UV stimulation, by promoting NO production in the epidermis, without inducing abnormal NO production by skin cells. Similarly, another important feature of the invention is to avoid potential undesirable side effects that could result from abnormal NO production by these skin cells in the absence of UV stimulation.

From the perspective of providing NO-synthase with "raw material", arginine in its L form (L-ARG) appears as a tvv/

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solution to audit problem, since it is the natural substrate of said NO-synthase, and is considered the natural precursor of NO.

5 It is important to emphasize that this precursor role is quite distinct from that of activator or inducer, for example, of the degree of enzyme expression and that, in no case can an intake of arginine induce an overproduction of NO.

10. However, the low bioavailability of arginine deposited on the skin surface constitutes a major obstacle to its use for the claimed purposes, given that the "melano-epidermal" unit is located in the deeper layers of the epidermis. Indeed, its poor skin penetration, a consequence of its highly polar structure, and its metabolism by the upper layers of the skin preclude its use by the "melano-epidermal" unit.

The object of the present invention is therefore to propose the use of arginine derivatives capable of reforming a NO-synthase substrate in vivo, and possessing a bioavailability compatible with stimulation of the melano-epidermal unit. Another characteristic of the use of these derivatives according to the invention is to reduce the metabolism of L-arginine by the superficial layers of the epidermis.

By providing exogenous L-arginine in the form of arginine derivatives according to the invention, it is possible to optimize the functioning of NO-dependent cutaneous mechanisms in response to skin exposure to solar radiation. Indeed, UV radiation causes the appearance of the inducible form of NO synthase (iNOS) in both keratinocytes and melanocytes, which produces only a physiologically insufficient amount of NO from the arginine naturally present in the skin. Therefore, an exogenous supply of arginine becomes necessary for the proper functioning of the "melano-epidermal" unit, since, in mammals, virtually all cells use arginine of extracellular origin.

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(S.M. Morris Jr., Annu. Rev. Nutr., vol. 12 (1992), pp. 81-101). This same problem has also been raised for other situations such as the healing process (J.-H. Chyun, J. of Nutrition, vol. 114 (1984), pp. 1697-1704) or certain pathological situations (M.A. Creager, J. Clin. Invest., vol. 90 (1992), pp. 1248-1253).

Furthermore, it is known that the so-called "constitutive" isoforms of NO synthase do not respond to an exogenous supply of arginine. They require pre-activation by other agents such as calcium and calmodulin. Consequently, once again, a bioavailable exogenous supply according to the invention cannot induce, in the absence of UV stimulation, an undesirable production of NO in the skin.

Furthermore, it is also important to note that melanocytes and keratinocytes express iNOS in response to UV radiation. The physiological conditions favorable to the use of the derivatives 20 according to the invention are therefore met, since these derivatives can then act on the two components of the "melano-epidermal" unit and can effectively promote its activity.

25 Another advantage of using arginine derivatives, which are the subject of the invention, is related to their photoprotective capacity, particularly due to their antioxidant properties. It is well known that solar radiation is a major cause of oxidative stress in the skin, particularly affecting melanocytes, which are especially vulnerable. Protecting them with the arginine derivatives according to the invention amounts to acting on the melanin response and, in particular, promoting melanin production. Furthermore, the protective capacity of these derivatives is complemented by the known effects (chelating behavior towards metal ions, ability to form in situ photoprotective agents such as nitrosothiols) of the by-products of their biotransformation, particularly L-arginine.

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To date, and to our knowledge, no use of arginine or arginine derivatives has been claimed as an actor in skin pigmentation, and in particular in the process of hyperpigmentation induced by the sun.

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On the contrary, the Japanese patent application published under No. JP 3 178 912 A2 advocates the use of arginine and some of its derivatives as a bleaching agent.

10. The association of an arginine derivative, N(O-monomethyl-L-arginine acetate), with sunscreens to enhance protection against the negative effects of solar radiation has been reported (G.M. Halliday, Redox Rep., vol. 4(6) (1999), pp. 316-318). This derivative does not fall within the scope of the invention and, moreover, differs from the objects of the invention in its principle of action, insofar as it is an inhibitor of NO-synthase and does not regenerate L-arginine upon contact with the skin.

20 Furthermore, PCT patent US98 05346 describes agents capable of activating endogenous NO production and stimulating melanogenesis. These are terpene diols which, according to various studies published by the authors (D.A. Brown, J. Invest. Dermatol., vol. 110 (1998), pp. 428-437 and D.A. Brown, 25 Pigment Cell Res., vol. 12 (1999), pp. 36-47), can induce melanin synthesis in the absence of sunlight. In a "self-tanning" approach, the effects of the sun are reproduced by the use of these active ingredients, but this is not the effect claimed in the present invention.

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Beiersdorf offers topical application of arginine to produce a nitrosothiol-type photoprotective agent in situ (G. Sauermann, Proc. of the 19th IFSCC Congress (1996), R089). This application does not address a photo-induced pigmentation process, and in particular, does not involve optimizing the melanin response.

Lipophilic derivatives of arginine are described (T. Cavaletti "Lipoaminoacids are powerful scavengers of free radicals" Proc.

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of the 16th IFSCC Congress, vol.2 (1990), pp.354-363) and proposed as an anti-radical agent, but they cannot reform the starting amino acid in situ.

5 To our knowledge, no prior art antioxidant derivative possessing these properties has been used to act on the UV-induced melanin response. Certainly, prodrug derivatives based on arginine can still be found since they are capable of reforming arginine in vivo, but in a context where 10 1*arginine is not the active principle (H. Tsunematsu "Synthesis and enzymatic hydrolysis of aspirin-basic aminoacid ethyl esters" Int. J. Pharmaceutics, vol. 68 (1991), pp.77-86).

Finally, the mode of action of the derivatives that are the subject of the invention must be clearly distinguished from that of a family of compounds known as "NO donors" (e.g., S-nitroso-N-acetylpenicillamine, 1-propamine, 3-(2-hydroxy-2-nitroso-l-

propylhydrazine) whose effect on melanogenesis has been described (A. A. Oureshi, J. Invest. Dermatol., vol. 108, IV (1997), 20 pp. 627). These agents produce NO without using biological systems such as NO synthases, cofactors, etc. This principle of action is quite different from that of the invention and is incompatible with use in cosmetics.

25 The family of arginine derivatives, which are the subject of the present invention, has already been described in part in a European patent application filed by the applicant and published under No. EP 1 060 7 39 Al. This application describes a topical slimming cosmetic composition based on arginine derivatives.

Recent experiments carried out by the applicant have shown that these same derivatives could be used as agents capable of optimizing the melanin response and thus protecting the skin against the harmful effects of the sun, also via their intrinsic protective properties.

Although the different isoforms of NO-synthase exhibit strong specificity towards arginine, it has been demonstrated (C.

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Moali et al., Biochemistry, 37(29) (1998), pp.10453) that they could still accept other substrates, and in particular an analogous compound of L-arginine, homo-L-arginine.

5. Therefore, the present invention relates to the cosmetic use of a family of derivatives of arginine or an analogue of L-arginine, or any of their salts, as photoprotective agents and optimizing the melanic response, said derivatives corresponding to the following general formula (I) 10:

.Ri

HN

H9N NH .X .Ro

" " (CH2) ^ ^ "

Y

° (I)

in which:

15 Ri represents an acyl radical, acyloxy, or an "-amino acid" linked by a peptide bond, which may or may not be substituted on its free α-amine function.

R2 represents a hydroxyl, amino, alkylamine or alkoxy radical, or an α-amino acid linked by a peptide bond 20 which may or may not be substituted on its free cx-carboxylic function,

and n is equal to 3 or 4.

All these derivatives have improved bioavailability with a lipophilic character that promotes their skin penetration, and structural characteristics that oppose their metabolization by enzymes that can use arginine (NO-synthases, arginases).

This is most simply achieved by esterification of the 30 « -carboxylic function and/or amidation of the examine function, transformations which, on the one hand, make these functions non-ionizable at physiological pH and which reinforce the lipophilic character, and, on the other hand, make the derivatives obtained insensitive to the action of NO-synthases and arginases.

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It is also useful that the Ri and R2 radicals are biodegradable substituents, which can be hydrolyzed under physiological pH conditions or in the presence of skin enzymes to reform arginine, or its analogue, in vivo.

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Since inducible NO-synthase is sensitive to the configuration of its substrate, it is essential that, in all compounds according to the invention, the configuration of the asymmetric carbon of arginine (or stereochemistry) is identical to that of arginine usable by NO-synthase (L form).

According to one embodiment of the invention, the compound of general formula (I) is such that Ri and/or R2 results from the condensation on arginine of an α-amino acid of configuration

15 L, chosen from the following amino acids: L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-citrulline, L-cysteine, L-glutamic acid, L-glutamine, glycine, L-histidine, L-hydroxyproline, L-isoleucine, L-leucine, L-lysine, L-methionine, L-norleucine, L-ornithine, L-phenylalanine, L-20 proline, L-pyroglutamic acid, sarcosine, L-serine, L-threonine, L-tryptophan, L-valine.

Another particularly advantageous embodiment of the invention consists of substituting the α-carboxylic 25 and/or α-amine functions of arginine or its analogue, with radicals which are themselves hydrophobic and which will contribute to strengthening the lipophilic character of the precursor molecule, and thus further promote the penetration of the active ingredient into the epidermis.

This is achieved when the α-amine function is substituted by a weakly polar radical, such as the acetyl group, or a more hydrophobic substituent such as a propionyl or tert-butyloxycarbonyl (Boc) radical. This is also achieved when the α-carboxylic function is esterified by an ethyl radical.

or by an even more hydrophobic substituent such as the radical 35 isopropyl, n-butyl, n-octyl, or by pivalloyloxymethyl, a substituent which has the particularity of being stable at the external pH of the skin (pH 5 approximately) and hydrolyzed at pH close to neutrality, which is the pH of the deeper layers of the skin.

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When Ri and/or R2 result from the condensation of a μ-amino acid onto arginine or its analogue, the preferred amino acids will therefore be chosen from among the most hydrophobic, that is to say, those which will be most likely to enhance the lipophilic character of the precursor molecule, and thus further promote its penetration into the epidermis. They are chosen from among the α-

the following amino acids: alanine, leucine, isoleucine, phenylalanine, tryptophan or valine.

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To obtain the most lipophilic derivative possible, when the R2 radical is an α-amino acid, it is preferable to substitute its free α-carboxylic group to make it non-ionizable at physiological pH. Similarly, when the Ri radical is an α-amino acid, it is also preferable to substitute its free α-amine group to make it non-ionizable at physiological pH.

Preferably, these functions are replaced by the groupings mentioned above.

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When Ri and/or R2 represent an α-amino acid possessing an asymmetric carbon, a particular embodiment of the invention consists of this type of substituent having a stereochemistry that is less favorable to biodegradability by cutaneous proteases. This makes it possible to modulate the sensitivity of the derivatives to cutaneous enzymatic systems capable of bioactivating the derivative (proteases, esterases, acylases that generate L-arginine in situ). This particular approach can thus optimize the bioavailability of the derivative, notably by allowing manipulation of the time it takes for L-arginine to become available. Since the L configuration is the most sensitive to proteases, this will be obtained when Ri and/or R2 is an α-amino acid of D configuration, chosen from the following α-amino acids: D-alanine, D-arginine, D-asparagine, D-35 aspartic acid, D-citrulline, D-cysteine, D-glutamic acid, D-glutamine, D-histidine, D-hydroxyproline, D-isoleucine, D-leucine, D-lysine, D-methionine, D-norleucine, D-ornithine, D-phenylalanine, D-proline, D-pyroglutamic acid, D-serine, D-threonine, D-tryptophan, D-valine.

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In general, the resistance of derivatives to the enzymatic systems of the upper layers of the epidermis will be enhanced when the Ri substituent and/or the R2 substituent carries a sterically bulky radical.

Thus, when Ri is an acyloxy radical and/or R2 is an alkoxy radical, this will be achieved when the alkyl chain attached to these radicals is an isopropyl, isobutyl, secbutyl, or tert-butyl group. Similarly, when Ri and/or R2 is an amino acid, this will be achieved when the amino acid possesses a bulky side chain. This is achieved when the amino acid is chosen from valine, leucine, or isoleucine.

According to another embodiment that increases the resistance of compound (I) to cutaneous enzymatic systems, the α-amino acids used to form the Ri and/or R2 radicals are chosen from amino acids that are substrates of specific enzymes. These derivatives will therefore encounter fewer enzymes capable of biotransforming them as they pass through the upper layers of the skin. Such amino acids may include citrulline, homoserine, norleucine, norvaline, ornithine, penicillamine, or sarcosine.

According to this embodiment, a particularly interesting derivative is the natural dipeptide L-citrullinyl-L-arginine 25 (Ri = citrulline and R2 = OH) produced by a red alga (Chondrus crispus)

Finally, a particularly interesting embodiment of the invention consists of producing derivatives with the highest possible photoprotective potential. According to this particular embodiment of the invention, a biodegradable substituent Ri or R2 is condensed onto L-arginine, or its analog, specifically designed to enhance the antioxidant power of the derivative. This is achieved when Ri is an acyloxy group (tert-butyloxycarbonyl or benzyloxycarbonyl radical), or when the substituents bear a thiol or thioether function (R1/R2 = cysteine or methionine), an imidazole ring (R1/R2 = histidine), or a phenol (R1/R2 = tyrosine).

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A particularly important aspect of the invention is the derivative in which arginine, or its analog, is condensed to the amino acid L-tyrosine. This amino acid possesses, in addition to the characteristics already mentioned (hydrophobic, antioxidant), the property of being the substrate of tyrosinase, a key enzyme in melanin biosynthesis. This particular embodiment of the invention therefore has the unique ability to promote UV-induced skin pigmentation by acting on two enzymatic activities necessary for the melanin response: the activity of NO synthase and the activity of tyrosinase, by providing these enzymes with their respective substrates.

The compounds of general formula (I) can be prepared 15 according to methods known to a person skilled in the art.

The following examples give a non-exhaustive list of derivatives according to the invention, and illustrate in a non-exhaustive way the possible uses of said derivatives.

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Examples of structure:

N-acetyl-L-arginine ethyl ester

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(NAc-L-ARG-OEt)

H O

30

ÎR/

13

N-acetyl-L-tyrosyl-L-arginine ethyl ester

(NAc-L-TYR-L-ARG-OEt)

HO.

H O

N

HN xr o=(

o

HN' HN^^NH.

N-acetyl-L-arginyl-(D or L)-isoleucine ethyl ester

(NAc-L-ARG-(D,L)-ILE-OEt)

H O

o

H O

HN'

HAS

HN NHo

10 N-acetyl-(D or L)-histidyl-L-arginine ethyl ester

(NAc-(D,L)-HIS-L-ARG-OEt)

HN

/^N

HN

o= o

H O N.

O'

HN' HN^^NHo in/

N-acetyl-(D or L)methionyl-L-arginine ethyl ester

(NAc-(D,L)-MET-L-ARG-OEt)

sch3

H O

N

HN V "O'

O— o

HN' HN^^NHo

N-acetyl-L-citrullinyl-L-arginine ethyl ester

(NAc-L-CIT-L-ARG-OEt)

HoN.

Y

NH

S

H O HN "O'

^ I

HN'

X

HN NH-

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N-Acetyl-(D or L)-phenylalanyl-L-arginine octyl ester

(NAc-(D,L)-PheALA-L-ARG-Ooctyl)

N-Boc-L-citrullinyl-L-arginine ethyl ester

(NBoc-L-CIT-L-ARG-OEt)

NH

K

H O

N

HN >r v O'

0=^ o ô

HN' HN^^NH^

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Examples of activities:

Test 1: demonstration of the protective power of arginine derivatives (measurement of the trapping of the hydroxyl radical OH * ).

The test, performed according to the method described by B. Halliwell et al. (Analytical Biochem., vol. 165 (1987), pp. 215-219), demonstrates the protection of deoxyribose by the tested substance (S) against the effects of OH*. The protective capacity is deduced from the comparison of the reaction kinetics, expressed by a rate constant of S on OH* (scavenging of OH*).

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Results :

substance S

trap velocity constant (M-1.S-1)

L-arginine

1.5 (±0.2)xl09

NAc-L-ARG-OEt

5.2 (±0.2)xl09

NAc-L-ARG-L-ILE-OEt

6.1 (±0.4)xl09

NAc-L-HIS-L-ARG-OEt

9.0 (±0.2)xl09

L-histidine

2.5 (±0.2)xl09

NAc-(D,L)-MET-L-ARG-OEt

0.7 (±0.2)xl010

NAc-L-TYR-L-ARG-OEt

8.1 (+0.3)xl09

The rate constants correspond to the average value (± D.S.) calculated from 3 independent experiments.

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Test 2: Demonstration of the effect of arginine derivatives on the "melano-epidermal" unit and the melanin response

We have developed an experimental model reproducing

10 the "melano-epidermal" unit, which allows us to highlight the effects of an exogenous supply of arginine derivatives on the melanic response following UV radiation (direct effect on melanocytes and indirect effect via "cell communication" between keratinocytes and melanocytes).

15 This is an in vitro co-culture model of melanocytes (a) and keratinocytes (b), as shown in the drawing board, having a particular culture medium (CM), a lower chamber (c) and an upper chamber (d).

20 The porous bottom of the upper chamber allows the passage, from one compartment to another, of endogenous factors secreted by the cells (NO) and of substance (S).

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Results :

Substance S

co-culture + MdC

co-culture + MdC

co-culture + MdC

added to the

"ARG = 84mg/L"a

"ARG = 84mg/L"a

"ARG-free" co-culture without UVB irradiation

irradiated by UVB

0

22.0

40.6

26.4

(without addition)

(±0.5)

(±5)

(±3.3)

NAc-ARG-OEt

24.4

38.4

43.8

(0.48 mM)

(±1.2)

(±4.5)

(±5.1)

NAC-ARG-OEt

20.9

42.6

37.5

(0.24 mM)

(±2.3)

(±3.2)

(±2.2)

NAC-ARG-OEt

23.1

39.5

30.7

(0.12 mM)

(±0.8)

(±3.4)

(±3.1)

NAc-HIS-ARG-OEt

18.8

40.7

42.5

(0.48 mM)

(±0.8)

(±4)

(±4.9)

NAC-HIS-ARG-OEt

22.5

36.2

41.0

(0.24 mM)

(±1.0)

(±2.5)

(±1.5)

NAC-HIS-ARG-OEt

22.7

41.6

38.8

(0.12 mM)

(±0.8)

(±2.5)

(±2.3)

a: The culture medium contains supra-physiological concentrations of arginine (standard MdC)

b: the culture medium reproduces an insufficient physiological concentration of arginine

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Claims (10)

DEMANDS 1. Use of at least one L-arginine derivative or an L-arginine analogue, or any of their salts, as a photoprotective agent and melanin response optimizer in a cosmetic composition, said derivative being represented by the following general formula (I): H,N NH ^ - Y - 10 NH ° (I) in which: Rl represents an acyl radical, acyloxy radical, or an α-amino acid linked by a peptide bond, which may or may not be substituted on its free α-amine function. 15 R2 represents a hydroxyl, amino, alkylamine or alkoxy radical, or an α-amino acid linked by a peptide bond, which may or may not be substituted on its free α-carboxylic function. and n is equal to 3 or 4. 20 2. Use according to claim 1, characterized in that said derivative of formula (I) is such that Ri and/or R2 results from the condensation on arginine of an α-amino acid of configuration L, substituted or not on its α-amine or α-25 carboxylic function, selected from the following amino acids: L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-citrulline, L-cysteine, L-glutamic acid, L-glutamine, glycine, L-histidine, L-hydroxyproline, L-isoleucine, L-leucine, L-lysine, L-methionine, L-norleucine, L-ornithine, L-phenylalanine, L-30 proline, L-pyroglutamic acid, sarcosine, L-serine, L-threonine, L-tryptophan, L-valine. Trx/ 19 3. Use according to claim 2, characterized in that said derivative of formula (I) is such that Ri and/or R2 is alanine, leucine, isoleucine, phenylalanine, tryptophan or valine. 5 4. Use according to claim 1, characterized in that said derivative of formula (I) is such that Ri and/or R2 represents an α-amino acid of configuration D, substituted or not on its α-amine or α-carboxylic function, selected from the amino acids The following 10: D-alanine, D-arginine, D-asparagine, D-aspartic acid, D-citrulline, D-cysteine, D-glutamic acid, D-glutamine, D-histidine, D-hydroxyproline, D-isoleucine, D-leucine, D-lysine, D-methionine, D-norleucine, D-ornithine, D-phenylalanine, D-proline, D-pyroglutamic acid, D-serine, D- 15 threonine, D-tryptophan, D-valine. 5. Use according to claim 1, characterized in that said derivative of formula (I) is such that Ri is an acetyl, propionyl, or tert-butyloxycarbonyl radical, and R2 is a 20 radical ethyl, isopropyl, n-butyl, n-octyl or pivalloyloxymethyl. 6. Use according to claim 1, characterized in that said derivative of formula (I) is such that Ri and/or R2 represents 25 an amino acid substituted or not on its a-amine or a-carboxylic function, chosen from the following amino acids: citrulline, homoserine, norleucine, norvaline, ornithine, penicillamine, sarcosine. 30 7. Use according to claim 1, characterized in that said derivative of formula (I) is such that Ri is citrulline and R2 is the hydroxyl radical. 8. Use according to claim 1, characterized in that 35 said derivative of formula (I) is such that Ri is the tert-butyloxycarbonyl or benzyloxycarbonyl radical, and Ri and/or R2 represents a thiol or thioether function, or an imidazole nucleus. 9. Use according to claim 1, characterized in that said derivative of formula (I) is such that Ri and/or R2 represents L-tyrosine substituted or not at its α-amine or <x- carboxylic. 10. Use according to any one of claims 1 to 9, said composition being intended to protect the skin against solar radiation and in particular ultraviolet radiation.