PERFUME COMPOSITIONS

The present invention is directed to methods of providing a skin lightening effect by employing certain odiferous fragrance ingredient compounds, fragrance compositions comprising said compounds to provide said effect, and personal care products formed by admixing said compounds or compositions. For the purposes of this invention a fragrance composition is defined as a mixture of fragrance ingredients, if desired mixed with or dissolved in a suitable solvent or solvents and/or mixed with a solid substrate. In this specification, the terms perfume and fragrance are used synonymously. Perfume or fragrance ingredients are well known to those skilled in the art, and include those mentioned, for example, in S. Arctander, Perfume and Flavor Chemicals (Montclair, N.J., 1969), in S. Arctander, Perfume and Flavor Materials of Natural Origin (Elizabeth, NJ. , 1960) and in "Flavor and Fragrance Materials - 1991", Allured Publishing Co. Wheaton, III. USA. Perfume ingredients may include natural products such as extracts, essential oils, absolutes, resinoids, resins, concretes etc., and also synthetic basic substances such as hydrocarbons, alcohols, aldehydes, ketones, ethers, acids, esters, acetals, ketals, nitriles, etc., including saturated and unsaturated compounds, aliphatic, alicyclic and heterocyclic compounds.

Products that have skin lightening, also called skin whitening, effect are available on the market for consumers who wish to prevent or reverse skin tanning, age spots and/or hyperpigmentation for aesthetic reasons. Skin tanning is caused by the accumulation of melanin in the skin. If melanin accumulates in isolated spots, age spots and hyperpigmentation result.

Melanin is formed from tyrosine in a reaction catalysed by the enzyme Tyrosinase. Known skin lightening compounds, for example, Kojic Acid and Arbutin, reduce the catalytic activity of the tyrosinase thereby slowing or stopping the production of melanin. Arbutin is a hydroquinone derivative extracted from the leaves of the bearberry, cranberry and blueberry shrubs, as well as most types of pear.

Other common ingredients of skin lightening personal care products are anti-oxidants such as ascorbic acid and its derivatives such as palmitoyl ascorbic acid, glucosides of ascorbic acid and particularly ascorbic acid-2-phosphate; and the natural polyphenol^ compounds Emblicanin A and Emblicanin B.

Another potential mechanism of action for achieving reduction of melanin formation, and therefore a skin lightening effect, is the suppression of tyrosinase formation at the transcription or translation level. Such an effect is achieved with octadecenedioic acid.

The use of certain perfume ingredients to reduce melanin formation in melanocyte cultures is known, for example, the use of eugenol, certain trimethyl cyclohexane derivatives and the use of sandalwood oil are all know to impart a skin lightening effect.

Certain fragrance ingredients are known as inhibitors of melanin formation, for example, Beta-ionone, tetrahydroionone and both forms of dihydro-beta-ionone, the fragrant macrocyclic ketones described in EP1264594 A2 and the fragrant terpene alcohols and their esters as disclosed in US 5466718.

In the case of personal care products (in particular those applied to the human skin in the form of a cream, lotion, gel or spray), the skin lightening agents should have a sufficient skin lightening activity, in particular when used at a concentration of maximally 0.05-3%, in the personal care product.

While several skin lightening agents are known, there remains a need for additional or alternative compounds, particularly those having one or more of the following desirable characteristics: a high skin lightening efficiency at low concentration, substantivity on skin, a low volatility and good stability.

With the relatively few fragrant skin lightening compounds known to date, it is difficult for perfumers to achieve perfume compositions with sufficient activity and an acceptable odour. This is made even more difficult for skin lightening ingredients that need to be integrated into a perfume composition in a high concentration to have a skin lightening effect in the product. The odour is crucial for consumer acceptance of a product. Using only one fragrant skin lightening compound (or a skin lightening compound comprising a mixture of compounds with one skin lightening perfume ingredient being dominant), an overpowering fragrance note may result. This is particularly true for such compounds or ingredients that require a high concentration for skin lightening activity. The availability of a larger variety of skin lightening compounds would provide the perfumer with more possibilities to create a

hedonically desirable fragrance accord whilst maintaining a high performance skin lightening effect.

The use of such compounds in perfumes in general is known. This includes, for example, perfumes comprising lso E Super and Galaxolide (WO 96/12467). Products according to WO 96/12467 include such perfumes and optionally for skin bleaching, bleaching agents such as hydrochinone, ascorbic acid, kojic acid and/or sodium bisulphite. However, these perfumes do not contain the identified skin lighteners in a high concentration nor in combinations according to the invention. If only one skin lightening compound is used in sufficiently high concentration, it will be difficult to formulate a perfume composition that is both hedonically acceptable and effective as a skin lightener.

WO 06/102777 teaches the utility of fragrance ingredients and compositions that go some way to addressing a number of the abovementioned problems. However, the range of ingredients disclosed therein is limited in general to those with woody, musky or floral or fruity hedonic descriptors, thereby limiting the creative scope of the perfumer. In addition, the tyrosinase inhibition assay results of materials disclosed in the present invention are superior to those described in the aforementioned application.

The identified skin lightening perfume compounds can be incorporated into personal care products to lighten human skin. Because of their pleasant fragrance characteristics and their high skin lightening efficiency even at low concentrations, they are readily integrated into perfume compositions for skin lightening personal care products.

Skin lightening compounds for use in compositions and methods according to the invention can be used to form stable skin lightening perfume compositions and skin lightening personal care products.

Further, skin lightening fragrance compounds for use in compositions and methods according to the invention can be combined with other known skin lightening compounds, in particular one or more compounds selected from the group consisting of arbutin and octadecenedioic acid (CAS 70445-23-7, commercially available as Arlatone dioic DCA™ from Seppic, Netherlands) and have an enhancing effect. Therefore, they can be used to reduce the concentration of the odourless or low odour skin lightener used in combination whilst maintaining or enhancing the effect at a given concentration.

In a first aspect, the invention is directed to the use of skin lightening fragrance compounds as described herein for the cosmetic lightening of skin and, in particular, to a cosmetic method employing one or more skin lightening compounds for the lightening of human skin. In a preferred embodiment, the method involves applying at least three skin lightening perfume compounds, preferably at least 4, 5 or 6 skin lightening perfume compounds, to the skin to achieve a lightening effect thereof. The skin lightening compounds may be applied in the form of a skin lightening personal care product.

Skin lightening perfume ingredients for use in compositions and methods according to the invention are chosen from the group consisting of:

4-(methyloxy)benzaldehyde, benzoin, 2-ethyl-3-hydroxy-4H-pyran-4-one and 4-[4- (methyloxy)phenyl]butan-2-one, 4-[4-(methyloxy)phenyl]butan-2-one, 2-(4- methylphenyl)ethanal, 1 -(2-((1 -(ethyloxy)ethyl)oxy)ethyl)benzene, 1 -(2,2- di(methyloxy)ethyl)benzene, Ethyl Lactate, (2E)-3-phenylprop-2-enal, Paramethoxyacetophenone, 2,6,6,8-tetramethyltricyclo[5.3.1.0 1 ,5]undecan-8-ol, 2- (methyloxy)-4-[(1 E)-prop-1 -enyljphenol, 1 -naphthalen-1 -ylethanone, 3-(1 ,3- benzodioxol-5-yl)-2-methylpropanal, Phenyl Ethyl Salicylate, Benzyl Acetate, 4- formyl-2-(methyloxy)phenyl 2-methylpropanoate, 1.θ-Dioxacycloheptadecan-Z-one, 2H-2-chromenone, methyl 2-((-2-methylpentylidene)amino)-1 -benzenecarboxylate, (4-(methyloxy)phenyl)methyl ethanoate, Rose Oil, 1 ,3-benzodioxole-5-carbaldehyde, 4-(4-hydroxy-4-methylpentyl)cyclohex-3-enecarbaldehyde, 2-methyl-4-phenylbutan- 2-ol, 1 ,3-benzodioxol-5-ylmethyl acetate, methyl 2-{[(E)-(2,4-dimethylcyclohex-3-en- 1-ylidene)methyl]amino}benzoate and 3-(4-(1 ,1-dimethylethyl)phenyl)propanal.

Preferred skin lightening perfume ingredients for use in compositions and methods according to the invention are chosen from the group consisting of:

Phenyl Ethyl Salicylate, 4-formyl-2-(methyloxy)phenyl 2-methylpropanoate, 4-[4- (methyloxy)phenyl]butan-2-one, 3-(4-(1 ,1-dimethylethyl)phenyl)propanal, (4- (methyloxy)phenyl)methyl ethanoate, 1 ,3-benzodioxol-5-ylmethyl acetate, 1- naphthalen-1 -ylethanone and 1.θ-Dioxacycloheptadecan-Z-one.

In another aspect, the invention is directed towards skin lightening perfume compositions, said skin lightening perfume composition comprising

(a) At least 25% (w/w) of at least three skin lightening fragrance compounds selected from those described hereinabove and;

(b) Up to 70% (w/w) of optional ingredients selected from one or more of additional perfume ingredients including additives, excipients, and solvents used in perfumes.

(c) Also comprising at least 5% (w/w) selected from 2-[2-(4-methyl-3-cyclohexen-1-yl)- propyl]-cyclopentanone, 6- isopropyl-octahydro-naphthalen-2-one, 4,7,7-trimethyl-2- (3-methyl-but-2-enyl)-bicyclo[4.1.0]heptan-3-one, 1 -(5,6,7,8-tetrahydro-3,5,5, 6,8,8- hexamethyl-2-naphthal-enyl)-ethanone, 1 ,1 ,2,3,3,8-hexamethyl-2,3,5,7,8- hexahydro-6-oxa-cyclopenta[b]naphthalene, 6,7-epoxy-1 ,1 ,2,4,4, 7-hexamethyl- octahydro-naphthalene, 1 ,1 ,2,3,3-pentamethyl-1 ,2,3,5,6,7-hexahydro-inden-4-one, 1-(2,3,8,8-tetramethyl-1 ,2,3,4,5,6,7,8-octahydro-naphthalen-2-yl)-ethanone, 2,2,3 ^l ,7\7'-pentamethylspiro(1 ,3-dioxan-5l2 ^l -norcarane), methyl-n-3,7-dimethyl-7- hydroxyoctylidene anthranilate, 2-[3-(4-tert-butyl-phenyl)-2-methyl-propenylamino]- benzoic acid methyl ester, 2-[(2,4-dimethyl-cyclohex-3-enylmethylene)-amino]- benzoic acid methyl ester, 2-methyl-4-(2,6,6-trimethyl-cyclohex-2-enyl)- butyraldehyde, 3-(3-isopropyl-phenyl)-butyraldehyde, 3-(4-isobutyl-phenyl)-2-methyl- propionaldehyde, [1-methyl-2-(1 ,2,2-trimethyl-bicyclo[3.1.0]hex-3-ylmethyl)- cyclopropyl]-methanol, 2-ethyl-4-(2,2,3-trimethyl-cyclopent-3-en-1- yl)-but-2-en-1-ol, 3-(5,5,6-trimethylbicyclo[2.2.1]hept-2-yl) cyclohexanol, the product of the sandela- process comprising 3-(5,5,6-trimethylbicyclo[2.2.1]hept-2-yl) cyclohexanol, 3-methyl- 5-(2,2,3-trimethyl-cyclopent-3-enyl)-pentan-2-ol, 3-methyl-5-(2,2,3-trimethyl-3- cyclopenten-1 -yl)-4-penten-2-ol, (e)-oxacycloheptadec-i 0-en-2-one, 3- methylcyclotetradec-5-en-1-on, 4-methylcyclotetradec-6-en-1-on, and oxacyclohexadec-12-en-2-one.

In another aspect, the invention is directed to a method of preparing a skin lightening personal care product wherein at least three skin lightening compounds, as defined hereinabove, are admixed.

In another aspect, the invention is directed to skin lightening personal care products comprising skin lightening compounds or perfume compositions as defined herein.

In another aspect, the invention is directed to the cosmetic use of at least three skin lightening perfume compound as described hereinabove as skin lightening actives in skin lightening personal care products.

In another aspect, the invention is directed to a method of cosmetic lightening of the skin by applying at least three skin lightening perfume compound as defined hereinabove to pigmented or hyperpigmented skin in a sufficient amount to cause lightening of the so- treated skin.

The skin lightening personal care product is formed by admixing at least three skin lightening perfume compounds, preferably at least 4, 5 or 6 skin lightening perfume compounds, as defined hereinabove, with a personal care formulation in a sufficient concentration to provide a skin lightening effect. A skin lightening personal care product may be formulated by first preparing a skin lightening perfume composition and then combining this perfume composition with the rest of the formulation. Such a perfume composition is made up of skin lightening products as described hereinabove and other optional ingredients such as other perfume ingredients, excipients and solvents used in perfumes.

The concentration of a skin lightening perfume compound suitable for use in a personal care product depends on the particular compound. Because of skin penetration and dilution in the underlying tissue, the concentration needed in a personal care product is generally somewhat higher than the active concentration in an enzymic assay.

A preferred sufficient concentration is 0.05% to 3%, preferably between 0.1% and 2% and more preferably between 0.5% and 1.5% of the total skin lightening personal care composition. Effective concentrations of skin lightening perfume compounds also depend on the type of personal care product and, in particular, the method of application to and duration of contact with the skin, as will be apparent to the skilled person. For rinse-off products, i.e. products applied for the skin for a short time (e.g. a few seconds up to a few minutes) such as soaps, shower gels etc., a higher concentration and/or a more active material should be used. Typical concentrations in these products should be, for example, between 0.5% and 3% and more preferably between 1% and 2% of the total composition. For personal care products such as creams, lotions, gels and similar that stay of the skin for a longer period, lower concentrations and/or less active ingredients may be used. Typical concentrations in these products should be, for example, between 0.05% and 1.5%, preferably between 0.1% and 1.2% and more preferably between 0.25 and 1%.

Skin lightening personal care products according to the invention are formed by admixing skin lightening compounds and skin lightening fragrance compositions with ingredients for personal care products as known in the art. Such products may be formed, for example, as described in Kosmetik, W. Umbach (ed.) Georg Thieme Verlag, Stuttgart; 1995. In particular, the products include personal care products for application to the human skin such as creams, lotions, gels, talcum powders, sprays, sunscreen and after-sun preparations in any suitable form; wash formulations for the human skin including hand wash formulations, soap bars, aqueous soap formulations, synthetic detergents and shower gels. These products may contain excipients including, for example, surfactants, emulsifiers, soap acids, solvents, colorants, preservatives, anti-oxidants, antifoaming agents, antimicrobial agents, anti-redeposition agents, enzymes, vegetal or mineral oils, fats, fluorescent materials, fungicides, hydrotropes, moisturisers, perfume carriers, perfume, proteins, silicones, solubilisers, sugar derivatives, sun screens, vitamins, plant extracts and waxes. Excipients generally used in such products may be found in the "International Cosmetic Ingredient Dictionary," Cosmetic, Toiletry & Fragrance Association, Inc. Washington, 1995.

Perfume compositions according to the present invention comprise at least three skin lightening perfume ingredient as described hereinabove, preferably 4, 5 or 6 skin lightening perfume ingredients in a concentration (w/w) of between 0.5% and 10% of the total skin lightening personal care product, preferably between 0.5% and 5% and more preferably between 1 % and 3%.

The abovementioned formulation rules of the invention are based upon extensive enzyme inhibition studies. Materials of the invention are described in greater detail in the following section.

MATERIALS OF THE INVENTION

The forthcoming list includes, where appropriate, trade names and suppliers of the materials of the invention, as well as common or trivial names used in the perfume industry. Descriptions of these materials may be found in standard perfume industry texts such as Perfume & Flavor Chemicals (Aroma Chemicals) by Steffen Arctander (Newark, NJ. USA, 1969); Common Fragrance & Flavor Materials, VCH, Weinheim, Germany 1990, by Bauer, Garbe and Surburg, ISBN 3-527-27961 , and Allured's Flavor & Fragrance Materials 2005, ISBN-1-932633-09-X:

4-(methyloxy)benzaldehyde {Anisic Aldehyde), Benzoin, 2-ethyl-3-hydroxy-4H- pyran-4-one (Ethyl Maltol), 4-[4-(methyloxy)phenyl]butan-2-one, (Raspberry Ketone), 2-(4-methylphenyl)ethanal (Syringa Aldehyde), 1-(2-((1- (ethyloxy)ethyl)oxy)ethyl)benzene (e.g. Efetaal™ (G)), 1-(2,2- di(methyloxy)ethyl)benzene (Phenyl Acetaldehyde Dimethyl Acetal), Ethyl Lactate, (2E)-3-phenylprop-2-enal (Cinnamic Aldehyde), Paramethoxyacetophenone, 2,6,6,8-tetramethyltricyclo[5.3.1.0 1 ,5]undecan-8-ol (e.g. Cedrenol) 2-(methyloxy)-4- [(1E)-prop-1-enyl]phenol (Iso Eugenol), 1-naphthalen-1-ylethanone (Methyl Naphthyl Ketone), 3-(1 ,3-benzodioxol-5-yl)-2-methylpropanal (e.g. Helional™ (IFF)), Phenyl Ethyl Salicylate, Benzyl Acetate, 4-formyl-2-(methyloxy)phenyl 2-methylpropanoate (e.g. Iso Butavan™ (G)) 1.θ-Dioxacycloheptadecan^-one (e.g. Cervolide™ (G)), 2H- 2-chromenone (Coumarin) methyl 2-((-2-methylpentylidene)amino)-1- benzenecarboxylate (e.g. Mevantraal™ (G)), (4-(methyloxy)phenyl)methyl ethanoate (Anisyl Acetate), 1 ,3-benzodioxole-5-carbaldehyde (Heliotropin), 4-(4-hydroxy-4- methylpentyl)cyclohex-3-enecarbaldehyde (e.g. Lyral™ (IFF)) 2-methyl-4- phenylbutan-2-ol (Dimethyl Phenyl Ethyl Carbinol), 1 ,3-benzodioxol-5-ylmethyl acetate (Heliotropyl Acetate), Rose Oil, methyl 2-{[(E)-(2,4-dimethylcyclohex-3-en-1- ylidene)methyl]amino}benzoate (e.g. Ligantraal™ (G)) and 3-(4-(1 ,1- dimethylethyl)phenyl)propanal (e.g. Bourgeonal (G)).

IFF: Supplied by or trademark of International Flavors & Fragrances

G: Supplied by or trademark of Givaudan

The following examples illustrate the invention, but the invention is not in any way limited thereto.

EXAMPLE 1 : TYROSINASE INHIBITION TEST

0.08Og of each perfumery ingredient was weighed and made up to 5g with 50 mM modified potassium phosphate buffer. The ingredient stock solution was vortexed and 188μl of each stock was added to wells in columns 1 and 7 of a 96 well microtitre plate (300μl well volumes). Each row (A to F) was allocated to one ingredient. To all other wells 94μl modified potassium phosphate buffer was added. The contents of all wells in column 1 were mixed by sucking samples up and down in pipette tips before 94μl was transferred to column 2. The same pipette tips were used to transfer 94μl of each well in column 7 in to the appropriate well in column 8. Using fresh tips the process was repeated by transferring 94μl from column 2 into column 3 (and 8 into 9). The process was continued until all wells in

columns 6 and 12 contained 188μl. After mixing 94μl was discarded from wells in columns 6 and 12 to waste.

The wells in row G were filled with 94μl Kojic Acid solution at 121 μM as a positive control. The wells in row H were filled with 94μl buffer as a negative control. To every well 90μl distilled water and 100μl tyrosine solution was added. The optical density at 490 nm of the plate was read and the results stored for use as a blank. To start the reaction 16μl of 5,000 units/ml solution of tyrosinase was added to every well. The reaction was carried out at room temperature (22 ⁰ C). Final optical density at 490 nm was measured after 30 minutes. The blank readings were subtracted from the final OD readings to eliminate the colorimetric interference of the fragrance ingredients. Six fragrance ingredients were tested on each plate in duplicate and at six concentrations. Each experiment was repeated using fresh fragrance ingredient stocks to give an independent replicate. In total, 4 sets of data were collected for each fragrance ingredient. In a 300μl reaction mix the final concentrations were: o 18mM modified potassium phosphate buffer o 0.3mM tyrosine solution o Fragrance Ingredient Concentration range = 156.25 to 5000ppm o 80 units tyrosinase

For example, among the most active tyrosinase inhibiting ingredients, cinnamic aldehyde had a tyrosinase inhibition score of 93% at a concentration of 5000ppm, compared with a standardised sample of kojic acid with a value of 58%. By the same method, ingredients disclosed in WO 06/102777 such as ambrettolide has a score of 9%. Table 1 has further details:

Table 1 Results of Tyrosinase Inhibition Assay

EXAMPLE 2: HIGHLY ACTIVE PERFUME COMPOSITIONS