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United States Patent (19) 11 Patent Number: 5,164,1859 9. Charpin et al. (45) Date of Patent: Nov. 17, 1992

54 PHARMACEUTICAL AND COSMETIC 56) References Cited DEPIGMENTATION COMPOSITIONS WITH A CAFFEIC ACID BASE U.S. PATENT DOCUMENTS 3,982,999 9/1976 Kharasch ...... 424/94.3

75) Inventors: Isabelle Charpin, St Maur Dess y w r 7 E. acquetI et al. ms:... SEElegin Men, 4,824,865 4/1989 Bowser et al...... 514/858 Christiane Montastier, Maisons 4,990,330 2/199i Oyama ...... 424/62 Laffitte; Francois Milecamps, Paris, FOREIGN PATENT DOCUMENTS all of France 1533371 7/1968 France . 26l3622 12/1978 F A. 73 Assignee: L'Oreal, Paris, France 239.060 10/1988 E. A. 2-55607 10/1990 Japan. 21 Appl. No.: 691,045 OTHER PUBLICATIONS 22 PCT Filed: Oct. 19, 1990 Patent Abstracts of Japan, vol. 11, No. 349 (C-456)(2796), Nov. 14, 1987. 86 PCT No.: PCT/FR90/00760 Patent Abstract of Japan, vol. 6, No. 44, (C-95)(922), S371 Date: Aug. 13, 1991 Mar. 19, 1982, S 102(e) Date: Aug. 31, 1991 Primary Examiner-Thurman K. Page Assistant Examiner-D. Colucci 87). PCT Pub. No.: WO91/05543 Attorney, Agent, or Firm-Cushman, Darby & Cushman PCT Pub. Date: May 2, 1991 57 ABSTRACT s A pharmaceutical or cosmetic depigmenting composi 30 Foreign Application Priority Data tion for application to the skin so as to improve the Oct. 20, 1989 FR France ...... 89 13774 aesthetic appearance of the skin or to treat pathological or accidental hyperpigmentation contains caffeic acid 5ll Int. Cl...... A61K 7/135 or an ester or amide thereof in an amount effective to 52 U.S. Cl...... 424/401; 424/62 depigment the skin. 58) Field of Search ...... 424/401, 62, 94.3; 514/852, 858 19 Claims, 5 Drawing Sheets NBION OF TE YROSNEATYROSNASE ACT WITY EFFECT OF CAFFEIC ACID O

O S O 15 20 2s 30 35 40 Tie in minutes corro 1) as so caffec acid (2) eases 25 Caffeic acid U.S. Patent Nov. 17, 1992 Sheet 1 of 5 5,164,185

FG.1

INHIBITION OF THE TYROSINE/TYROSINASE ACT WITY EFFECT OF CAFFEIC ACID 160

150 140 130

120 110

- 1OO K g 90 (2) O O SS BO g 3 (1) g 70 60

SO

40

30

20

10

O O S O 15 20 25 30 35 40

Time in minutes Control (1) r 50 Caffeic acid (2) e-elease 25 Caffeic acid U.S. Patent Nov. 17, 1992 Sheet 2 of 5 5,164,185 FG.2 : INHIBITION OF THE TYROSINE/TYROSINASE ACTIVITY 160 DERIVATIVE OF CAFFEIC ACID

150 140 130 120 (2) 110 - 100 90 o (1) 70 60 50 40 30 20 10 O 0 5 10 15 20 25 30 35 40 4.5 SO 55 60 Time in minutes Control (1) -x-x-x-x 50 C6 Caffeic acid amide C6 (2) -- 50 Ca Caffeic acid amide C8 U.S. Patent Nov. 17, 1992 Sheet 3 of 5 5,164,185

FIG.3 INHIBITION OF TYROSINE/TYROSINASE ACTIVITY COMBINATION OF CAFFEIC ACIC AND COPPER GLUCONATE 160 150 140 130 120

90 w (1)

(2)

15 20 25 30 35 40 Time in minutes CONTROL (1) K---- 50 CAFFEIC ACID (2)-3:25 COPPERCAFFEIC GLUCONATEACID + U.S. Patent Nov. 17, 1992 Sheet 4 of 5 5,164,185

FG. A. INHIBITION OF TYROSINE/TYROSINASE ACTIVITY COMBINATIONS BASED ON CAFFEIC ACID 100 95 90 85 80 75 70 65 60 55 4. (3) SO45 Ss. 1)2) 40 35 30 25 20 15,

00 0.5 10 1.5 20 TIME INDEX (TIME INDEX 1 FOR THE MAXIMAL CONCENTRATION OF THE CONTROL) CONTROL (1) +----- 25 CAFFEIC ACID + 25 COPPER GLULuATE (2) 25 CAFFEIC ACID + 25. HYDROQUINONE (3)------25 CAFFEIC ACID + 5. KOJIC ACID U.S. Patent Nov. 17, 1992 Sheet 5 of 5 5,164,185 FIG.5 INHIBITION OF TYROSINE/TYROSINASE ACITIWTY COMBINATION HAVING 3 AND 4 COMPONENTS CONTAINING CAFFEIC ACID

( )

O 5 10 15 20 25 30 35 40 Time in minutes CONTROL - 15 CAFFEICHYDROQUINONE ACID + 15, KOJIC ACID (2)------. 20. HYDROQUINONE + 10 CAFFEIC ACID + 10. KOJIC ACID + 10% COPPER GLUCONATE (3) ---- (16.5 CAFFEIC ACID + 16.5 KOJIC ACID + 17.5 COPPER GLUCONATE 5,164,185 2 ring, as well as certain leucodermas such as vitiligo, in PHARMACEUTICAL AND COSMETIC which, because pigmentation cannot be restored to the DEPIGMENTATION COMPOSITIONS WITH A injured skin, the areas of remaining normal skin are CAFFEIC ACID BASE depigmented so as to impart to the total skin area a homogeneous white color. The present invention relates to a pharmaceutical or Following various studies conducted on numerous cosmetic depigmenting composition which contains, as substances used either singly or in combination, it was an active ingredient, caffeic acid or one of its deriva found, surprisingly and unexpectedly, that caffeic acid tives. or its derivatives, and especially its esters and amides, It will be remembered that the mechanism which O produced an especially interesting depigmenting action, forms skin pigmentation, i.e., the formation of melanins, their efficacy being mainly the result of an inhibition of is especially complex and involves the triggering of the tyrosinasic activity leading to the limited formation of main steps diagrammed below: dopachrome and thus, of melanins. TYROSINE-DOPA-DOPAQUINONE 15 This new property of caffeic acid and its derivatives DOPACHROME-MELANINS had heretofore never been brought to light, despite the many studies conducted on this acid. tyrosinase being the main enzyme involved in this series Therefore, the present invention relates to a pharma of reactions. ceutical or cosmetic depigmenting composition used in The depigmenting agents currently used in cosmetol a topical application and containing, in a vehicle suit ogy are, more specifically, phenolic derivatives, and, 20 most notably, hydroquinone or a hydroquinone ether able for such an application, an effective quantity of such as hydroquinone monomethyl ether. caffeic acid or of one of its esters or amides. While these compounds have a certain level of effec Among the esters of caffeic acid, mention may be tiveness, they are not, unfortunately, free from side made especially of the compounds corresponding to the effects that make their use a sensitive, and even danger 25 formula: Ous, matter. Thus, hydroquinone, whose use is restricted, more (1) over, to a 2% concentration, is especially irritating and HO cytotoxic for melanocytes. Many authors have contem plated its total or partial replacement. 30 Thus, French Patent No. 87.08236 (2,616,325) pro HO posed a composition containing a combination of hy droquinone and kojic acid or of its derivatives, in partic R representing an alkyl radical of from 1 to 8 carbon ular its salts and esters. atoms, and preferably the methyl radical. International Application WO 85/0401 proposes, in 35 Among the caffeic acid amides, mention may be addition and for the same purpose, a depigmenting com made, in particular, of the compounds corresponding to position containing a combination of hydroquinone or its benzylic monoether and salicylic acid. the formula: Moreover, among the compositions producing a pro nounced depigmenting action, mention must also be (2) made of the Kligman trio, generally chosen as the com HO pound of reference, which is based on a combination of acidic Vitamin A, hydroquinone, and a steroid, either dexamethasone or hydrocortisone. The use of this com HO position has, however, been restricted to the extent that 45 it exhibits a high level of irritation caused by acidic R" representing an alkyl radical of from 1 to 8 carbon Vitamin A as well as undesirable effects caused by hy atoms, and preferably an alkyl of from 6 to 8 carbon pervitaminosis A. atoms. The amide having 6 carbon atoms is most espe It has now been well established that a substance cially preferred. produces a depigmenting action if it acts directly on the 50 In compositions according to the invention, the con vitality of the epidermal melanocytes where melano centration of caffeic acid or of one of its derivatives genesis normally takes place, and/or if it interferes with one of the stages of melanin biosynthesis, either by generally ranges between 0.1 and 8%, and preferably inhibiting one of the enzymes involved or by its inser between 1 and 3% by weight. tion as a structural analogue in the synthesis pathway, 55 The vehicle for the compositions according to the which can thus become blocked, thereby producing the invention may be, in particular, an aqueous or hydroal depigmenting effect. coholic solution, an oil-in-water or water-in-oil emul The use of harmless topical depigmenting substances sion, an emulsified gel, or a diphase system. exhibiting a high degree of efficacy is most especially The compositions according to the invention prefera sought in order to treat regional hyperpigmentation bly exist as lotions, creams, gels, masks, microspheres or caused by melanocytic hyperactivity, such as idiopathic nanospheres, or vesicular dispersions. In these latter, at melasmas occurring during pregnancy ('mask of preg least one of the active ingredients may be liposomes. nancy' or chloasma) or melasmas secondary to estro Moreover, it was discovered, surprisingly, that when gen-progesterone contraception, cases of localized hy caffeic acid or one of its derivatives was associated with perpigmentation caused by hyperactivity and benign 65 a substance chosen from among the following: hydro melanocytic proliferation, such as senile pigmentary quinone or one of its ethers, kojic acid (hydroxy-5 hy spots, termed actinic lentigos, accidental hyperpigmen droxymethyl-2H-4 pyranone-4), a water-soluble copper tation such as photosensitization and post-lesion scar salt, or a mixture of these substances, increased efficacy 5,164,185 3 4. of the depigmenting action was observed, and this ac tion could be attributed only to a synergistic effect. 'IN VITRO STUDY When the compositions according to the invention The efficacy of the various combination according to contain hydroquinone or a hydroquinone ether such as the invention have been studied in vitro by measuring hydroquinone monomethyl ether, the concentration out, using visible spectrophotometry (475 nm), the generally ranges between 0.2 and 6%, but preferably quantity of dopachrome formed during the chain of between 0.2 and 2% by weight, in order to prevent side tyrosine-oxidation reactions. These oxidation reactions effects. are catalyzed in vitro using fungus-derived tyrosinase in When the compositions contain kojic acid, the con the presence of a co-substrate (for example, a small O quantity of L-dopa) in order to trigger the hydroxyl centration generally ranges between 0.1 and 3% by ation reaction of L-tyrosine into L-dopa, this latter weight, and preferably between 0.5 and 2%. being then oxidized by catalysis into dopaquinone, then When the composition contain a water-soluble cop into dopachrome, an intermediate product formed be per salt, this latter exists in a molar Cu II concentration fore the non-enzymatic oxidation reactions leading to equivalent to that of caffeic acid or its derivatives. 15 melanin formation. These salts include, in particular, copper gluconate or Accordingly, the concentration of dopachrome sulfate, but preferably copper gluconate in a concentra formed over time is monitored in the presence of vari tion of between 0.2 and 20% by weight and preferably ous inhibitors of tyrosinasic activity. between 2.5 and 7.5%. The concentrations of inhibitors are expressed as According to one preferred embodiment, a keratoly 20 molar percents in relation to the concentration of tyro tic agent is included additionally in the composition in a sine present in the reactive medium. concentration, for example, of between 0.5 and 10% by The inhibitory effect may be expressed, in relation to weight, and preferably between 1 and 3%. the control curve (absence of inhibitor) by lowering of This keratolytic agent may include, in particular, urea the quantity of dopachrome formed and/or by a slow or a carboxylic hydroxyacid, such as glycolic, or prefer 25 ing of dopachrome-formation kinetics. ably salicylic, acid or its derivatives, and in particular, In the first case, this lowering signifies a reduction of n-octanoyl-5 salicylic acid. the maximum level of optical density reached (the case In accordance with the invention, the depigmenting of active products which tend to be limiters of formed composition may therefore be of the binary, ternary, dopachrome), and, in the second case, by a reduction of quaternary type. 30 the slope tangent to the origin (the case of active prod The combinations falling within the scope of the ucts which impede dopachrome formation). invention include most notably the following: BRIEF DESCRIPTION OF THE DRAWINGS caffeic acid--kojic acid-i-salicylic acid or one of its derivatives; The curves in FIGS. 1 to 5 illustrate the inhibitor caffeic acid-i-kojic acid-hydroquinone; 35 effect of the various substances and substance combina caffeic acid--kojic acid-copper gluconate; tion according to the invention. caffeic acid--kojic acid--hydroquinone-copper glu EXPERIMENTAL RECORD conate; Reagents caffeic acid--hydroquinone; caffeic acid-hydroquinone-copper gluconate; A-Phosphate buffer of 0.1M pH=6.5 caffeic acid-copper gluconate; B-Parent solution of L-tyrosine at 2,103M in A caffeic acid--kojic acid, the first four being especially Cs-Parent solution of L-dopa at 10-4M in A preferred. D-Parent solution of fungus-derived tyrosinase at The invention also relates to a procedure for the 45 2,400 units/ml in A preparation of the compositions described above, in E-Parent solution of the inhibitor at 10-2M in A (So which, using conventional methods, the ingredient or lutions C and D are to be prepared on the same day.) ingredients are mixed with the vehicle and any other Measurements ingredients that may be added. SO Reference cell: The present invention also relates to the use of caffeic 3 ml of A acid (or of one of its esters or amides), possibly in com Test cell: bination with the other above-mentioned ingredients, as m of B the active ingredient in the preparation of a cosmetic or O. m. of C pharmaceutical depigmenting composition. 85 ml of A-E The compositions according to the invention may of 55 Homogenize and equilibrate at 25 C. course contain other ingredients commonly used in Add 0.05 ml of D cosmetology or dermatological pharmacology, such as Mix rapidly and trigger absorption kinetics at 475 nm. moistening agents, preserving agents, coloring agents, There are provided, for purposes of illustration and perfumes, penetration agents such as diethylene glycol without limiting the scope of the invention, several monoethyl ether, etc. examples of the depigmenting compositions according These compositions are applied topically in humans, to the invention: in quantities corresponding to the normal application doses of the type of composition in question (gel, cream, EXAMPLE 1. lotion, etc.). For example, in the case of a cream, from 65 Depigmenting Cream 0.5 to 3 mg, and preferably from 1 to 2 mg of cream are used per cm of skin per application, at the rate of one or Caffeic acid 1.27% two applications daily. Kojic acid 12, 5,164,185 5 6 -continued -continued N-octanoyl-5-salicylic acid 2% Disodium salt of hydrated ethylene 0.1% Triethanolamine .3% diaminotetracetic acid (2 H2O) Jojoba oil 3% UWA-UWB filters 2% Mixture of ethyl-2 ketostearyl hexanoate 3% 5 Perfume 0.4% and isopropyl myristate Carboxyvinyl polymer 0.6% Hydrogenated isoparaffin 3% Diethylene glycol monoethyl ether 7.5% Stearic acid 2% Sterile dermineralized water 58.22% Ketostearyic alcohol .5% Polyethylene glycol stearate 3% Isopropyl myristate 3% Mixture of glyceryl monostearate and 3% Preserving agent 0.4% 10 polyethylene glycol stearate Buffer 0.71% Mixture of ketylstearylic alcohol 3% Disodium salt of hydrated ethylene 0.1% and oxyethylene-containing dianinotetracetic acid (2 H2O) ketylstearylic alcohol UVA-UVB filters 2% Perfume 0.4% Carboxyvinyl polymer 0.6% 5 Diethylene glycol monoethyl ether 7.5% EXAMPLE 3 Sterile demineralized water 58.22% Polyethylene glycol stearate 3% Depigmenting Cream Mixture of glyceryl monostearate and 3% polyethylene glycol stearate Mixture of ketylstearylic alcohol 3% . 20 Caffeic acid 1.27% and oxyethylene-containing Hydroquinone 2% ketylstearylic alcohol Triethanolamine 1.3% Jojoba oil 3% Mixture of ethyl-2 ketosteary) hexanoate 3% This cream was clinically tested on a group of 21 and isopropyl myristate Hydrogenated isoparaffin 3% subjects between 45 and 65 years old having age spots 25 Stearic acid 2% on their hands. sopropyl myristate 3% The treatment, which lasted two months, consisted in Ketylstearylic alcohol .5% a twice-daily application on one hand, the other hand Preserving agent 0.4% Buffer 0.71% serving as a control. 2 mg of cream per cm2 of skin was Disodium salt of hydrated ethylene 0.9% used for each application. 30 diaminotetracetic acid (2 H2O) At the end of the treatment, a quantitative evaluation UWA-UWB filters 2% was conducted using a CR 200 chromometer (Minolta) Perfume 0.4% Carboxyvinyl polymer 0.6% on the treated and untreated spots. Diethylene glycol monoethyl ether 7.5% The absolute color variation, which did not distin Steriie demineralized water 6.22% guish among any shades, between the time T=0 and 35 Polyethylene glycol stearate 3% T=2 months was computed as follows: Mixture of glyceryl monostearate and 3% polyethylene glycol stearate Mixture of ketylstearylic alcohol 2% and oxyethylene-containing AE-\al2 is a a ketylstearylic alcohol 40 L., a, and b being the coordinates which delimit the colorimetric space used (A signifies: change in). EXAMPLE 4 The results are as follows:- Depigmenting Lotion 45 Treated hand Untreated hand Caffeic acid 2.35% AE 2.3 2.8 % inhibition when 21.6 Hydroquinone 2% compared to the Copper gluconate 6% untreated hand Buffer 0.3% 50 Disodium salt of hydrated ethylene 4.9% diaminotetracetic acid (2 H2O) Ethylene diaminotetramethylene 0.1% The subjective efficacy of this cream is 60%. The phosphonic acid tolerance is 100%. Dimethylsulfoxide 42.8% EXAMPLE 2 Sterile demineralized water 42.35% Depigmenting Cream 55 EXAMPLE 5 Caffeic acid .27% Depigmenting Lotion Kojic acid 19% Hydroquinone 2% 60 Triethanolamine 1.3% Caffeic acid .6% Jojoba oil 3% Kojic acid .25% Mixture of ethyl-2 ketostearyl hexanoate 3% Hydroquinone 2% and isopropy myristate Copper gluconate 4% Hydrogenated isoparaffin 3% Ethylene diaminotetramethylene 0.9% Stearic acid 2% 65 phosphonic acid Ketostearylic alcohol 1.5% Buffer 0.3% Isopropyl myristate 3% Disodium salt of hydrated ethylene 3.3% Preserving agent 0.4% diaminotetracetic acid (2 H2O) Buffer 0.7% Dimethylsulfoxide 43.9% 5,164,185 7 8 The mixture is next homogenized at a temperature of -continued 70° C. using a VIRTIS-type ultradispersing machine. Sterile demineralized water 43.55% Next, 5 EXAMPLE 6 Kojic acid 1.0 g Depigmenting Lotion Denninetalized water 23.02 g are added. Caffeic acid 2.5% O After homogenization of the mixture using an ultra Kojic acid 2% Copper gluconate 6.5% dispersing machine at a temperature of 40 C., Buffer 0.3%. Disodium salt of hydrated ethylene 5.6% diaminotetracetic acid (2 H2O) Caffeic acid 1.27 g Ethylene diaminotetramethylene 0.1% 15 Diethylene glycol monoethyl ether 7.5g phosphonic acid Dimethylsulfoxide 41.6% are added, and then the mixture is homogenized once Sterile demineralized water 41.4% again at the same temperature. Thus, a dispersion of lipidic vesicles, having an aver EXAMPLE 7 20 age size of approximately 0.2 micron, is obtained. After bringing the temperature down to 25 C., the Depigmenting Lotion following are added:

Caffeic acid 8% 25 Vaseline oil 4g Buffer 0.15% Wolatile silicon oil 10 g. Ethylene diaminotetramethylene 0.2 phosphonic acid Dimethylsulfoxide 68.8% The mixture is homogenized using the ultradispersing Sterile demineralized water 22.95% machine, and finally, the following products are added: 30 EXAMPLE 8 Perfume 0.4g A vesicular dispersion is prepared according to the Carboxyvinyl polymer sold under the name 0.4g invention as a cream by implementing the following "CARBOPOL 940" by the Goodrich company procedure: 35 Triethanolamine 1.5g The following products are added to a beaker: Methyl parahydroxybenzoate 0.2g Demineralized water 10.41 g.

Non-ionic amphiphilic lipid corresponding to the formula: 3.75 g 40 A beige cream is thus obtained. RO-e-C3H3(OH)O-H EXAMPLE 9 in which: C3H5(OH)O- represents one or a mixture of In accordance with the invention, a vesicular disper the following structures: sion is prepared as a cream by proceeding as follows: 45 -ch-Ho- and/or -H-CHyo Non-ionic amphiphilic lipid corresponding to the formula: 3.75g CHOH CH2OH R being a hexadecyl radical and in having Ro-e-CH3(OH)O-i-H a mean statistic value of 3 50 in which: C3H5OH)O represents one or a mixture of Choiestero 3.75g the following structures: These two products are mixed by heating at a temper -CH-Ho- and/or -H-CHyo ature of 100 C. in a nitrogen atmosphere, then the CH2OH CH2OH temperature of the melted mixture is reduced to 90° C. 55 Then, R being a hexadecyl radical and n having a mean statistic value of 3 Cholesterol 3.75 g n-octanoyl-5-salicyclic acid 0.5g 60 These two products are mixed by heating at a temper is added to this mixture. ature of 100 C. in a nitrogen atmosphere, then the After homogenization of the mixture, the following temperature of the melted mixture is reduced to 90° C. products are added: Then, 65 Glycerine 3.0 g n-octanoyl-salicyclic acid 0.5g Deinineralized water 19.3g is added to this mixture. 5,164,185 After homogenization of the mixture, the following products are added: (1) HO Glycerine 3.0 g Demineralized water 14.5g HO wherein R represents C1-C8 alkyl. The mixture is then homogenized at a temperature of 4. The composition of claim 1 wherein the amide of 70 C. using a VIRTIS-type ultradispersing machine. O caffeic acid has the formula Next, (2) Hydroquinone 2g HO Sodium metabisulfite 0.17 g 15 Sodium sulfite 0.27g Citric acid 0.2g HO Demineralized water 26.12 g wherein R' represents C1-Cs alkyl. 20 5. The composition of claim 1 which also contains a are added. substance selected from hydroquinone, hydroquinone After homogenization of the mixture using an ultra ether, kojic acid, a water-soluble copper salt or a mix dispersing machine at a temperature of 40 C., ture thereof. 6. The composition of claim 1 which also contains 25 hydroquinone or hydroquinone ether in an amount Caffeic acid 1.27g ranging from 0.2 to 6 percent by weight based on the Diethylene glycol monoethyl ether 7.5g total weight of said composition. 7. The composition of claim 1 which also contains are added, and then the mixture is homogenized once kojic acid in an amount ranging from 0.1 to 3 percent by 30 weight based on the total weight of said composition. again at the same temperature. 8. The composition of claim 1 which also contains a Thus, a dispersion of lipidic vesicles, having an aver water-soluble copper salt in a molar concentration age size of approximately 0.2 micron, is obtained. equivalent to that of said caffeic acid or an ester or After bringing the temperature down to 25 C., the amide thereof. following are added: 35 9. The composition of claim 8 wherein said water-sol uble copper salt is copper gluconate. 10. The composition of claim 1 which also contains a Vaseline oil 14g keratolytic agent. Volatile silicon oil 10g. 11. The composition of claim 10 wherein said keratol 40 ytic agent is urea or a hydroxylated carboxylic acid. 12. The composition of claim 11 wherein said hydrox The mixture is homogenized using the ultradispersing ylated carboxylic acid is salicylic acid, a salicylic acid machine, and finally, the following products are added: derivative or glycolic acid. 13. The composition of claim 12 wherein said sali 45 cylic acid derivative is n-octanoyl-5-salicylic acid. 14. The composition of claim 10 wherein said keratol Perfume 0.4g ytic agent is present in an amount ranging from 0.5 to 10 Carboxyvinyl polymer sold under the name 0.4g percent by weight based on the total weight of said "CARBOPOL 940" by the Goodrich company composition. Triethanolanine 1.4g 50 15. The composition of claim 1 which contains a Methyl parahydroxybenzoate 0.2g combination of caffeic acid, kojic acid and n-octanoyl Dennineralized water 10.5l g. 5-salicylic acid. 16. The composition of claim 1 in the form of a lotion, A beige cream is thus obtained. a cream, a milk, a gel, a mask, microspheres, nanos 55 pheres or vesicular dispersions. I claim: 17. The composition of claim 1 which also contains at 1. A pharmaceutical or cosmetic depigmenting com least one of a moistening agent, a preservative, a color position for application to the skin comprising, in a ing agent, a perfume and a penetration agent. pharmaceutically or cosmetically acceptable vehicle for 18. A cosmetic treatment process for improving the application to the skin, caffeic acid or an ester or amide aesthetic appearance of the skin comprising applying to thereof in an amount effective to depigment said skin. the skin in an amount effective to improve the aesthetic appearance of the skin the composition of claim 1. 2. The composition of claim 1 wherein said caffeic 19. A pharmaceutical treatment process for the treat acid or an ester or amide thereof is present in an amount ment of pathological or accidental hyperpigmentation ranging from 0.1 to 8 percent by weight based on the 65 comprising applying to the skin in an amount effective total weight of said composition. to treat pathological or accidental hyperpigmentation 3. The composition of claim 1 wherein the ester of the composition of claim 1. caffeic acid has the formula k