WO2021249760A1

WO2021249760A1 - A cosmetic composition comprising 6-methyl-picolinamide

Info

Publication number: WO2021249760A1
Application number: PCT/EP2021/063837
Authority: WO
Inventors: Rezwan Shariff; Anita DAMODARAN
Original assignee: Unilever Ip Holdings B.V.; Unilever Global Ip Limited; Conopco, Inc., D/B/A Unilever
Priority date: 2020-06-10
Filing date: 2021-05-25
Publication date: 2021-12-16

Abstract

The present invention relates to a cosmetic composition. Particularly, the present invention relates to a cosmetic composition comprising 6-methyl picolinamide that provides even tone to skin.

Description

A COSMETIC COMPOSITION COMPRISING 6-METHYL-PICOLINAMIDE

Field of the invention

The present invention relates to a cosmetic composition. Particularly, the present invention relates to a cosmetic composition that provides even tone to skin together with skin brightening.

Background of the invention

People often try to take care of themselves and of their body surfaces e.g. skin, scalp including hairs, axilla and oral cavity, with a desire of enjoying a healthy lifestyle. Some of the benefits people tend to have desire for include, healthy and infection-free skin, even skin tone, adequate moisturization, skin lightening and brightening and protection from ultraviolet rays contained in sunlight. Skin is the outermost protective covering of living beings; and is the largest organ in the body. It acts as a barrier and protects the body from external factors e.g. dust, dirt, pollution and ultraviolet radiation contained in sunlight. Skin also helps prevent entry of harmful or potentially harmful microbes e.g. bacteria, fungi and viruses, from entering the body thereby preventing infection and/or other ill effects that may be caused.

However, being the outermost covering, skin is always exposed to one or more factors mentioned earlier. As a result, skin is susceptible to developing one or more conditions e.g. dryness, wrinkles, loose/saggy skin, age spots, blotchy skin, melasma, freckle and increased pigmentation, which may lead to less preferred uneven skin tone.

One of the ways to reduce occurrence of such conditions is to avoid exposure to factors causing such conditions. However, in many instances, avoiding exposure to factors e.g. sunlight, is difficult, and at times, unavoidable. For reasons like these, consumers tend to rely on cosmetic compositions comprising one or more actives that deliver benefits e.g. moisturizing, anti-aging and skin brightening, when applied on a surface of the human body e.g. skin.

A few cosmetic compositions comprising such actives are known in the prior art. WO 2017/215863 A1 (Unilever) discloses a cosmetic composition comprising: (i) at least one pyridine compound of Formula I or II disclosed therein (ii) an alkyl substituted resorcinol; and, (iii) a dermatologically acceptable base. Also disclosed is use of a pyridine compound of Formula I or II disclosed therein in the preparation of a cosmetic composition which provides enhanced TDD of an alkyl substituted resorcinol. WO 2017/215863 A1 discloses a combination of picolinamide and 4-hexyl resorcinol.

WO2013/030794 A2 (Kasraee Behrooz) discloses a skin depigmentation composition containing picolinamide or isonicotinamide and said composition further comprises 4- substituted resorcinol.

In the field of cosmetics, people typically give more attention towards facial care; and often look forward to cosmetic compositions comprising new actives, that would deliver benefits e.g. skin lightening / brightening for which they tend to look forward to new technologies e.g. a new active or combination of actives, that provides superior benefit e.g. superior brightening along with an even skin tone.

Need therefore exists to provide a cosmetic composition comprising new actives that provide benefits e.g. even skin tone.

It has been surprisingly found that 6-methyl picolinamide (6-MP) provides superior even skin tone and brightening as compared to that provided by known skin lightening actives e.g. kojic acid. Further, it has also been found that 6-MP when combined with a known skin lightening active e.g. 4-hexyl resorcinol (4-HR), provides synergistic reduction in melanin content that gives the consumer a more even skin tone that also appears bright and glowing.

Summary of the invention In a first aspect the present invention relates to a cosmetic composition comprising from 0.001 to 10 wt% 6-methyl picolinamide. In a second aspect the present invention relates to a method for providing even tone to skin wherein the method comprises:

(i) applying the composition of the first aspect to the skin; and

(ii) optionally, rinsing it. In a third aspect the present invention relates to the use of the composition of the first aspect for providing even tone to skin.

In a fourth aspect the present invention relates to the use of 6-methyl picolinamide for providing even tone to skin.

Detailed description of the invention

Definitions

Preferably, "Skin" as used herein is meant to include skin on the face and body (e.g., neck, chest, back, arms, underarms, hands, legs, buttocks and scalp). The composition as per the present invention is preferably but especially useful for application to skin areas with the highest incidence of hyperpigmentation such as-face and underarms, most preferably the composition is a skin cosmetic composition, e.g., creams, deodorants and anti-perspirants. "Even toned skin" as used herein, preferably means the evening out the spots

(hyperpigmentation) on the skin, like age spots and freckles while providing it with a bright and glowing appearance. It also indicates lightening of the colour of the skin to some degree. Any feature of one aspect of the present invention may be utilized in any other aspect of the invention. The word “comprising” is intended to mean “including” but not necessarily “consisting of” or “composed of.” In other words, the listed steps or options need not be exhaustive. Except in the operating and comparative examples, or where otherwise explicitly indicated, all numbers in this description indicating amounts of material or conditions of reaction, physical properties of materials and/or use are to be understood as modified by the word “about”. Numerical ranges expressed in the format "from x to y" are understood to include x and y. When for a specific feature multiple preferred ranges are described in the format "x to y", it is understood that all ranges combining the different endpoints are also contemplated. Unless specified otherwise, amounts as used herein are expressed in percentage by weight based on total weight of the composition and is abbreviated as “wt%”. The use of any and all examples or exemplary language e.g. “such as” provided herein is intended merely to better illuminate the invention and does not in any way limit the scope of the invention otherwise claimed.

In a first aspect a cosmetic composition according to the present invention (the composition) relates to a cosmetic composition comprising from 0.001 to 10 wt% 6-MP. 6-MP

The composition comprises 6-MP, also known as 2-pyridinecarboxamide, 6-methyl- (CAS number: 63668-37-1); that has the following structure:

The composition comprises from 0.001 to 10 wt%, preferably from 0.01 to 9 wt%, more preferably from 0.1 to 7 wt%, even more preferably from 0.1 to 5 wt%, further more preferably from 0.1 to 3 wt%, still more preferably from 0.1 to 2 wt%, yet more preferably from 0.1 to 1 wt% 6-MP.

Preferably, 6-MP is not encapsulated.

It has been found that 6-MP provides the desired even skin tone. Moreover, it has been found that such effect obtained is superior than that obtained using a known agent e.g. kojic acid. Additional skin lightening agent

Preferably, the composition further comprises one or more additional skin lightening agents. Examples of the additional skin lightening agents include niacinamide, picolinamide, 4-alkyl substituted resorcinol, vitamin B6, vitamin C, vitamin A, glutathione precursors, galardin, adapalene, aloe extract, ammonium lactate, arbutin, azelaic acid, butyl hydroxy anisole, butyl hydroxy toluene, citrate esters, deoxyarbutin, 1,3-diphenyl propane derivatives, 2,5-dihydroxybenzoic acid and its derivatives, 2-(4- acetoxyphenyl)-1,3-dithiane, 2-(4-hydroxyphenyl)-1,3-dithiane, ellagic acid, gluco pyranosyl-1 -ascorbate, gluconic acid, glycolic acid, green tea extract, 4-Hydroxy-5- methyl-3[2H]-furanone, 4-hydroxyanisole and its derivatives, 4-hydroxybenzoic acid derivatives, hydroxycaprylic acid, inositol ascorbate, lactic acid, lemon extract, linoleic acid, magnesium ascorbyl phosphate, 5-octanoyl salicylic acid, salicylic acid, 3,4,5- trihydroxybenzyl derivatives, acetylglucosamine, pitera extract, symwhite, calcium pantothenate (Melano-block), seppiwhite, soybean extract (bowman birk inhibitor), 12- hydroxystearic acid and mixtures thereof. When used in the composition, 12- hydroxystearic acid is used as a skin lightening agent and not as a fatty acid.

Preferably, the additional skin lightening agent is selected from the group consisting of niacinamide, picolinamide, isonicotinamide, 12-hydroxystearic acid, 4-alkyl substituted resorcinol and mixtures thereof. More preferably, the additional skin lightening agent selected is 4-alkyl substituted resorcinol selected from the group consisting of 4-ethyl resorcinol (4-ER), 4-isopropyl resorcinol (4-IPR), 4-butyl resorcinol (4-BR), 4-pentyl resorcinol(4-PR), 4-phenylethyl resorcinol (4-PER), 4-HR and mixtures thereof. Even more preferably, the additional skin lightening agent is selected from the group consisting of 4-ER, 4-HR and mixtures thereof. Further more preferably, the additional skin lighting agent selected is 4-HR.

It will be understood that the composition may comprise a combination of 6-MP along with one or more additional skin lightening agents described above. For example, the composition may preferably comprise 6-MP along with niacinamide, 6-MP along with 4- HR and 6-MP along with 4-HR and niacinamide. Likewise, it will also be understood that the composition may preferably comprise 6-MP along with niacinamide and 4-HR. Preferably, the composition comprises from 0.001 to 10 wt%, more preferably from 0.01 to 8 wt%, even more preferably from 0.1 to 7 wt%, further more preferably from 0.1 to 5 wt%, still more preferably from 0.1 to 3 wt%, yet more preferably from 0.1 to 1 wt% and still further more preferably from 0.25 to 0.5 wt% of an additional skin lightening agent.

Preferably, none of the additional skin lightening agents e.g. 4-alkyl substituted resorcinol, are encapsulated. For example, at least 20%, more preferably at least 30% and even more preferably at least 40%, further more preferably at least 50%, still more preferably at least 70%, even more preferably at least 90% and most preferably 100% of 4-alkyl substituted resorcinol is not encapsulated.

Preferably, the composition comprises: a. 0.001 to 10 wt% 6-methyl picolinamide; and b. 0.001 to 5 wt% 4-alkyl substituted resorcinol.

More preferably, the composition comprises: a. 0.001 to 10 wt% 6-methyl picolinamide; and b. 0.001 to 5 wt% 4-hexyl resorcinol.

UVA organic sunscreen

Preferably, the composition comprises UVA organic sunscreen that absorbs UVA radiations and prevent them from reaching a surface e.g. skin of a user. Examples of sunscreens that may be used as UVA organic sunscreen in the composition are dibenzoylmethane compound, bisdisulizole disodium (commercially available as Neo Heliopan® AP), diethylamino hydroxy benzoyl hexyl benzoate (commercially available as Uvinul® A Plus), Ecamsule (commercially available as Mexoryl SX) and Methyl anthranilate.

Preferably, sunscreen that may be used as UVA organic sunscreen is selected from a dibenzoylmethane compound. Examples of sunscreen of dibenzoymethane compound that may be used as UVA organic sunscreen in the composition include BMDM (commercially available as Parsol® 1789 or Avobenzone), 2-methyldibenzoylmethane, 4-isopropyldibenzoyl- methane, 4-tert-butyldibenzoylmethane, 2,4-dimethyldibenzoylmethane, 2,5- dimethyldibenzoylmethane, 4,4'-diisopropyl-dibenzoylmethane, 2-methyl-5-isopropyl-4'- methoxydibenzoylmethane, 2-methyl-5-tert-butyl-4'-methoxy-dibenzoyl methane, 2,4- dimethyl-4'-methoxy dibenzoylmethane or 2,6-dimethyl-4-tert-butyl-4'-methoxy- dibenzoylmethane. Most preferably, dibenzoylmethane compound that may be used as UVA organic sunscreen is BMDM.

Preferably, the composition comprises from 0.01 to 10 wt%, more preferably from 0.1 to 8 wt%, even more preferably from 1 to 6 wt%, further more preferably 1 to 5 wt%, still more preferably from 1 to 3 wt%, yet more preferably from 1 to 2.5 wt% of one or more UVA organic sunscreens.

UVB sunscreen

Preferably, the composition further comprises UV-B organic sunscreen. Preferably, the composition further comprises UVB organic sunscreens that absorbs UVB radiations and prevent them from reaching a surface e.g. skin of a user.

Examples of UVB organic sunscreens that may be used in the composition include compounds from the class of cinnamic acid, salicylic acid, diphenyl acrylic acid and derivatives thereof. Examples of such compounds include 2-ethylhexyl salicylate (commercially available as OctisalateTM), 3,3,5-Trimethylcyclohexyl 2- hydroxybenzoate (commercially available as HomosalateTM), Ethylhexyl Methoxycinnamate (commercially available as NeoHelipan® AV), 2-ethylhexyl 2-cyano- 3,3-diphenylacrylate (OCR; commercially available as OctocryleneTM), 2-Hydroxy-4- methoxybenzophenone (commercially available as OxybenzoneTM), 2-ethyl-hexyl-4- methoxy cinnamate (MCX; commercially available as Parsol MCXTM) and mixtures thereof. Preferably, UVB organic sunscreens that may be used in the composition are selected from OCR, MCX and mixtures thereof.

When incorporated in the composition, UVB organic sunscreens may preferably be incorporated from 0.1 to 10 wt%, more preferably from 0.5 to 7 wt%, even more preferably from 1 to 5 wt%, further more preferably from 1 to 3.5 wt%, yet more preferably from 1 to 3 wt%, still more preferably 1 to 2.5 wt% in the composition.

Preferably, the composition comprises from 0.01 to 10 wt%, more preferably from 0.1 to 8 wt%, even more preferably from 1 to 6 wt%, further more preferably 1 to 5 wt%, still more preferably from 1 to 3 wt%, yet more preferably from 1 to 2.5 wt% of one or more UV-B organic sunscreens.

Preferably, the composition further comprises inorganic sunblocks. Examples of inorganic sunblock that may be used in the composition include zinc oxide (ZnO), iron oxide, silica, such as fumed silica and titanium dioxide ( PO2). Preferably, inorganic sunblock that may be used in the composition are selected from TiC>2_,ZnO and mixtures thereof.

When incorporated the composition, inorganic sunblock may preferably be incorporated from 0.1 to 10 wt%, more preferably from 0.5 to 7 wt%, even more preferably from 1 to 5 wt%, further more preferably from 1 to 3.5 wt%, yet more preferably from 1 to 3 wt%, still more preferably 1 to 2.5 wt%, in the composition.

Nonionic surfactant

Preferably, the composition further comprises a nonionic surfactant. More preferably the nonionic surfactant is selected from those having HLB value in the range 9 to 20, preferably 10 to 19, more preferably 12 to 18, even more preferably 13 to 17 and yet more preferably 15 to 17.

HLB is calculated using the Griffin method wherein HLB = 20 x Mh / M wherein Mh is the molecular mass of the hydrophilic portion of the molecule and M is the molecular mass of the whole molecule, giving a result on an arbitrary scale of 0 to 20. Typical values for various surfactants are given below:

A value <10 : Lipid soluble (water insoluble)

A value >10 : Water soluble A value from 4 to 8 indicates an anti-foaming agent

A value from 7 to 11 indicates a W/O (water in oil) emulsifier A value from 12 to 16 indicates oil in water emulsifier A value from 11 to 14 indicates a wetting agent A value from 12 to 15 is typical of detergents A value of 16 to 20 indicates a solubiliser or a hydrotrope.

Preferably, the nonionic surfactant having HLB value in the range 9 to 20 is selected from fatty alcohol ethoxylates, alkyl phenol ethoxylates, polyoxyethylene sorbitan alkyl esters and mixtures thereof. Preferably, the nonionic surfactants are ones with at least 9 alkylene oxide groups preferably at least 9 ethylene oxide groups.

Examples of fatty alcohol ethoxylates that may be used as nonionic surfactants in the composition include polyoxyethylene lauryl ether (HLB= 16.9; commercially available as Brij^® 35), polyoxyethylene (20) cetyl ether (HLB=16; commercially available as Brij^® 58), polyethylene glycol octadecyl ether (HLB= 18.8; commercially available as Brij^®

700) and Laureth - 9 (C12E09; HLB=14.3; commercially available as Brij^® L9).

Examples of alkyl phenol ethoxylates that may be used as nonionic surfactant in the composition include octylphenol ethoxylate (HLB=15.5; commercially available as Triton™ X165), octylphenol ethoxylate (HLB=17.6; commercially available as Triton™ X405) and octylphenol ethoxylate (HLB=18.4; commercially available as Triton™

X705).

Examples of polyoxyethylene sorbitan alkyl esters that may be used as the nonionic surfactant in the composition include polyoxyethylenesorbitan monolaurate (HLB=13.3; commercially available as Tween^® 21), polyoxyethylenesorbitan monolaurate (HLB=16.7; commercially available as Tween^® 20), Polyoxyethylenesorbitan monopalmitate (HLB=15.6; commercially available as Tween^® 40) and polyoxyethylene sorbitan monostearate (HLB= 14.9; commercially available as Tween^® 60).

Even more preferably, the nonionic surfactant having HLB value in the range 9 to 20 that may be present in the composition is fatty alcohol ethoxylate with saturated carbon chain having HLB higher than 15.5.

Preferably, the composition comprises 0.5 to 5 wt%, more preferably 1 to 4 wt%, even more preferably from 2 to 3 wt% nonionic surfactant having HLB in the range 9 to 20.

Fatty acid

Preferably, the composition comprises fatty acid. Fatty acids when present in a composition along with a soap provides the so-called vanishing cream effect, i.e. a composition, when applied on to the human skin, vanishes on the skin leaving behind no significant streaks of the composition.

Preferably, the composition comprises fatty acids having 10 to 30, more preferably 12 to 25, even more preferably 14 to 20, further more preferably 16 to 18 carbon atoms. Examples of fatty acids that may be used in the composition include pelargonic, lauric, myristic, palmitic, stearic, isostearic, oleic, linoleic, arachidic, behenic, erucic acid and mixtures thereof.

Preferably, the fatty acid that may be used is stearic acid or palmitic acid or a mixture thereof. The fatty acid in the present invention is preferably hystric acid which is substantially (generally about 90 to 95%) a mixture of stearic acid and palmitic acid in a ratio of between 55:45 to 45:55.

Preferably, the composition comprises from 3 to 25 wt%, more preferably from 4 to 22 wt%, even more preferably from 6 to 20 wt%, further more preferably from 8 to 19 wt% and still more preferably from 10 to 18 wt% and yet more preferably from 12 to 16 wt% fatty acid. Soap

Preferably, the composition comprises soap. Soap, when present in combination with fatty acid in the composition, provides the vanishing effect described above. Preferably, soap of the invention is generally prepared by in-situ neutralization of fatty acid that may be present in the composition. Thus, it is preferred that the soap has a carbon chain length that corresponds to the chain length of fatty acid in the composition. The soap is formed from the fatty acid through use of alkali metal hydroxides e.g. sodium hydroxide or potassium hydroxide. Of the two, potassium hydroxide is more preferred. Thus, the soap is preferably a potassium soap (potassium salt of fatty acid).

Preferably, the composition comprises from 0.1 to 10 wt%, more preferably from 1 to 8 wt%, even more preferably from 2 to 7 wt%, further more preferably from 3 to 6 wt% soap.

Water

Preferably, the composition comprises water in amount from 5 to 99.9 wt%, more preferably from 10 to 95 wt%, even more preferably from 15 to 90 wt%, further more preferably from 20 to 80 wt%, still more preferably 25 to 75 wt% and yet more preferably 30 to 70 wt%.

Polymer

Preferably, the composition further comprises a polymer. The polymer acts as thickener in the composition and improves sensorial properties of the composition.

The polymer is preferably selected from the following classes: acrylate / R-methacrylate copolymer e.g. acrylates/ steareth-20 methacrylate copolymer (commercially available as Aculyn™ 22) and acrylates/ beheneth-25 methacrylate copolymer (commercially available as Aculyn™ 28), acrylate / R-methacrylate crosspolymer e.g. acrylates/steareth-20 methacrylate crosspolymer (commercially available as Aculyn™ 88), acrylates copolymer (commercially available as Aculyn™ 33), acrylate/R-alkyl acrylate crosspolymer e.g. acrylates/C 10-C30 alkyl acrylate crosspolymer (commercially available as Pemulen™ TR-2), copolymer of ammonium acryloyldimethyltaurate with vinyl pyrrolidone (commercially available as Aristoflex^® AVC), - copolymer of sodium acryloyldimethyltaurate with vinyl pyrrolidone

(commercially available as Aristoflex^® AVS); and crosspolymer of acryloyldimethyltaurate with R-alkyl acrylate and methyacrylate e.g. Ammonium acryloyldimethyltaurate/ beheneth-25 methacrylate crosspolymer (commercially available as Aristoflex^® HMB and Aristoflex^® BLV).

Preferably, the composition comprises 0.1 to 5 wt%, more preferably 0.5 to 4.5 wt%, even more preferably 1 to 4 wt%, further more preferably from 1.5 to 3.5 wt%, still more preferably from 2 to 3 wt% polymer. Emollients

Preferably, the composition further comprises emollients. Examples of emollients that may be used in the composition include stearyl alcohol, glyceryl monoricinoleate, mink oil, cetyl alcohol, isopropyl isostearate, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, eicosanyl alcohol, behenyl alcohol, cetyl palmitate, silicone oils such as dimethylpolysiloxane, din-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, cocoa butter, corn oil, cotton seed oil, olive oil, palm kernel oil, rape seed oil, safflower seed oil, evening primrose oil, soybean oil, sunflower seed oil, avocado oil, sesame seed oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum jelly, mineral oil, butyl myristate, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate and mixtures thereof.

Solvents Preferably, the composition further comprises solvents. Examples of solvents that may be used in the composition include ethyl alcohol, isopropanol, acetone, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether and mixtures thereof. Powders

Preferably, the composition further comprises powders. Examples of powders that may be used in the composition include chalk, talc, fullers earth, kaolin, starch, gums, colloidal silica sodium polyacrylate, tetra alkyl and/or trialkyl aryl ammonium smectites, chemically modified magnesium aluminium silicate, organically modified montmorillonite clay, hydrated aluminium silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate and mixtures thereof. Preservatives

Preferably, the composition further comprises preservatives to protect against the growth of potentially harmful microorganisms. Examples of ingredients that may be used as preservatives in the composition include alkyl esters of para-hydroxybenzoic acid, hydantoin derivatives, propionate salts, and a variety of quaternary ammonium compounds. More preferably, ingredients that may be used as preservative in the composition are sodium benzoate, iodopropynyl butyl carbamate, methylisothiazolinone, iodopropynylbutylcarbamate, phenoxyethanol, methyl paraben, propyl paraben, imidazolidinyl urea, sodium dehydroacetate, ethylhexylglycerin, benzyl alcohol, alkane diols and mixtures thereof. The alkane diols that are suitable for use as preservative are C6-C12 alkanes that are vicinally substituted with hydroxy groups. Illustrative examples include 1,2-octane diol (caprylyl glycol), 2,3-octane diol, 1,2-nonane diol, 1,2-decane diol, 1,2-hexane diol, 3,4-octane diol, mixtures thereof or the like where caprylyl glycol is typically the most preferred.

When present in the composition, preservatives are added preferably in an amount 0.001 to 5 wt%, more preferably 0.01 to 3 wt% and most preferably 0.02 to 2 wt%.

Optional ingredients

Preferably, the composition further comprises a range of other optional ingredients that include antioxidants, binders, buffering agents, colorants, astringents, fragrance, opacifying agents, conditioners, exfoliating agents, pH adjusters, skin sensates, skin soothing agents, and skin healing agents.

Product form The composition is preferably formulated in the form of a powder, flake, lotion, cream, gel or mousse. More preferably, the composition is formulated in the form of cream or lotion and most preferably in the form of cream. The composition can be a leave-on or wash-off type of composition. The composition is preferably a leave-on type of composition. The packaging for the composition of this invention can be a patch, bottle, tube, roll-ball applicator, propellant driven aerosol device, squeeze container or lidded jar. The composition can be packaged in a suitable container to suit its viscosity and intended use by the consumer. For example, a lotion or fluid cream can be packaged in a bottle or a roll-ball applicator or a propellant-driven aerosol device or a container fitted with a pump suitable for finger operation. When the composition is a cream, it can simply be stored in a non-deformable bottle or squeeze container, such as a tube or a lidded jar. When the composition is a solid or semi-solid stick, it may be packaged in a suitable container for manually or mechanically pushing out or extruding the composition.

Preferably the composition is non-therapeutic.

Method of using the composition

In a second aspect, the present invention relates to a method for providing even tone to skin wherein the method comprises:

(i) applying the composition of the first aspect to the skin; and

(ii) optionally, rinsing it.

The method is intended primarily for using the cosmetic composition for topical application to human skin to lighten the skin, to reduce the degree of pigmentation in the skin, or to even the skin tone. Preferably the method is non-therapeutic.

For example, an appropriate quantity, for example from 1 to 5 ml_, may be applied to exposed areas of the skin, from a suitable container or applicator and, if necessary, it is then spread over and/or rubbed into the skin using the hand or fingers or a suitable device. After applying it, optionally, the composition may be removed by rinsing it preferably with water. If the step of rinsing is carried out, it is preferably carried out after 30 minutes, more preferably after 20 minutes, even more preferably after 10 minutes and further more preferably after 5 minutes from when it was applied on to the skin in the first step.

In a third aspect, the present invention relates to the use of the composition of the first aspect for providing even tone to skin. When the composition of the first aspect was applied to the skin, more even skin tone was obtained. Preferably, the use Is non- therapeutic.

In a fourth aspect, the present invention also relates to use of 6-MP for providing even skin tone. It has been found that when 6-MP was applied on to the skin, more even skin tone was obtained. Preferably, the use is non-therapeutic.

Preferably, non-therapeutic; as referred to in the first, the second, the third and the fourth aspect, means a cosmetic improvement in skin appearance in healthy subjects, rather than treating any underlying medical disease or disorder. Examples

Materials

6-MP (DH-85523, ASW Med Chem),

Reconstructed human pigmented epidermis (RHPE; Episkin, France, age - 10 days, 0.5 cm², Phototype VI), Human epidermal melanocytes, neonatal, darkly pigmented donor, (HEMn-DP; C-202- 5C, Invitrogen),

Melanocyte growth medium (Medium 254; M-254-500, Invitrogen),

Human melanocyte growth supplement (HMGS; S-002-5, Invitrogen),

Human keratinocyte growth supplement (HKGS; S-001-5, Invitrogen), Keratinocyte growth medium (EpiLife® Medium) with 60 mM Calcium (MEPI 500 CA, Invitrogen),

HaCaT cell line was provided by Professor N. E. Fusenig (German Cancer Research Center, Heidelberg, Germany), Dulbecco's Modified Eagle Medium (DMEM; AL219A-500ML, HIMEDIA), Fetal Bovine Serum (FBS; 16000044-500 ML, Invitrogen),

Trypsin EDTA (R-00100, Invitrogen),

T Neutralizer - (R-00200, Invitrogen), Neutral Red (RM 122, HIMEDIA), p-Formladehyde (15,812-7, Sigma Aldrich),

Sodium chloride (27605, Fischer Scientific),

Potassium chloride (61753305001730, Merck),

Disodium Hydrogen Phohphate (40158, S.D. Fine Chemical Ltd.), Potassium Dihydrogen Phosphate (20203, S.D. Fine Chemical Ltd.), 4-HR (209465-2, Merck),

Saponin (47036-50G-F, Sigma); and Dimethyl sulfoxide (DMSO; D2650, Sigma).

Protocol

3D skin epiderm model to identify the desired technologies Day 0

1. Episkin RHPE inserts were removed from the transport plate and placed in to a new 24 well plate containing 500 pL of maintenance media (provided by supplier). Inserts were placed gently to avoid any air bubble between an insert and the media.

2. Plate was Incubated at 37°C under 5% CO2 for 2 h. After 2 h, 50 pL of the spent media was collected from each well and stored at -80°C for Lactate dehydrogenase (LDH) release measurements (Note: This spent media served as spontaneous LDH release).

3. The plates were incubated at 37°C under 5% CO2 for 12 h.

Day 1

4. Episkin RHPE inserts were removed from the plate, the spent media was collected and stored in -80°C.

5. Inserts were transferred to a fresh 24 well plate containing 450 pL of growth media and incubated at 37°C under 5% CO2.

6. Meanwhile nylon mesh was prepared for active application, placed gently on top of the RHPE inserts. 7. Actives were added gently on top of the nylon mesh and were incubated further under the same conditions (Note: Inserts free of actives serve as untreated control).

Day 3 8. Episkin RHPE inserts were removed from the plate, spent media was collected and stored in -80°C.

9. Re-dose the Episkin RHPE with test actives as outlined in steps 5 to 8 was carried out.

Day 6 10. The steps as on Day3 were repeated.

Day 9

11. One of the Episkin RHPE were treated with 10 pl_ of neat lysis reagent (10X) supplied in the LDH kit, for 6 to 8 h. After the treatment, the spent media was collected and stored in -80°C. Ultrapure water wash was given to remove the formulation sticking to the Episkin RHPE tissue. The Episkin RHPE inserts were progressed for further analysis.

12. All tissues were photographed for macroscopic darkening and processed further for L* measurements and melanin assay. LDH Cytotoxicity Assay:

The measurement of cytotoxicity was carried out according to the manufacture’s protocol. (Pierce LDH Cytotoxicity Assay Kit # Cat no. 88953).

Briefly,

1. 50 pL of each Episkin RHPE insert spent medium collected at all steps as mentioned above, was transferred to a 96-well flat bottom plate in duplicates.

2. 50 pL of reaction mixture was added to each well and were mixed by gentle tapping.

3. The plate was incubated at room temperature for 30 minutes (covered with aluminium foil to protect from light). 4. 50 pL stop solution was added to each well and mixed by gentle tapping (Note: bubbles if any, present in wells, were busted with a syringe needle and/or centrifugation before reading). 5. Absorbance was measured at 490nm (ref wavelength 680nm); and the percentage cytotoxicity was calculated by using the equation below:

Compound-treated LDH Activity -Spontaneous LDH activity

% Cytotoxicity = X 100 Maximum LDH activity - Spontaneuous LDH activity

Luminance (*L) Measurement:

An instrumental measurement of lightness (L*) was carried out on an intact RHPE post treatment, using a CM26000d. The chromameter works on the principle of reflection and absorption of specific wavelengths of light in the L*a*b* colour space, in this colour space L* indicates lightness and a* and b* are chromaticity co-ordinates, a* is the red to green direction and b* is the yellow to blue direction. In this study the main parameter of interest was pigmentation reduction therefore the lightness, (L*) score were recorded. All readings were taken from the underside of the cultures and in triplicate to account for any variations in the readings. The mean and standard deviations for each triplicate were calculated for each treatment and compared against the scores for the untreated controls.

Steps:

1) L* measurements were done using Minolta Spectrophotometer (model CM26000d) connected to software SpectraMagic NX.

2) Instrument based on physical measurement of reflected light, at specific wavelengths (400-700 nm at 10 nm steps) which correspond to the spectrum of visible light.

3) Colorimetric values were expressed in terms of L* (luminance) which gave the relative brightness on a scale from 0 (black) to 100 (white).

4) Episkin RHPE inserts were at first air dried completely and proceeded for L* measurement.

5) Episkin RHPE inserts were placed at the centre 0.5 cm port of spectrophotometer and collected L* measurements for 3 three times. Melanin Content Estimation:

After the 8-day incubation period, the Episkin RHPE cultures were removed from the incubation plates and melanin content was estimated as described below.

1. Episkin RHPE tissues were carefully removed from the insert and placed in 1.5 ml_ tubes tissues.

2. 150 pl_ of Solvable™ (Tissue and Gel Solubilizer 0.5 M — Packard BioScience Co. Catalogue No. 6NE9100) was added to each tube while ensuring tissue is completely submerged.

3. The tubes with inserts were incubated at 60°C for 12 to 16 h with gentle shaking.

4. After complete dissolution, tubes were kept in room temperature for 30 min.

5. Tubes were centrifuged at 1000 rpm for 10 minutes.

6. 100 mI_ of the supernatant was collected in a 384 well plate and spectrophotometric OD readings were collected at 490nm using a Tecan plate reader.

Examples A-C, 1: % reduction in melanin obtained using 6-MP Table 1

(Note: Reduction in melanin content translates to proportionate brightening and even tone of the skin)

Examples D,E, 2-4: Synergistic reduction in melanin content obtained using 6-MP and 4-HR in the composition Table 2

(Note: Reduction in melanin content translates to proportionate lightening of the skin)

Examples F, 5: Melanin synthesis obtained from 6-methyl picolinamide as compared to picolinamide:

Comparison of the efficacy of 6-methyl picolinamide as per the invention with a compound known for this efficacy viz. picolinamide was carried out using the melanin synthesis/ content assay which is described below:

Melanin synthesis/content assay: The principle behind this assay is to quantify the amount of change in melanin in melanocytes over a period of 72 hours to mimic process of melanin synthesis in skin, a first key step in regulating skin colour. In this assay primary melanocytes isolated from various donors (ethnic, phototype) were cultured as monolayers. They were then treated with different regulators expected to alter the production of melanin. After 72 hours, cells were lysed and change in melanin was measured by standard spectrophotometric method. We evaluated this method with known melanin production inhibitors and showed the specificity and robustness of this method.

Method:

Human primary melanocytes were grown in melanocytes growth medium (MGM) with human melanocyte growth supplement. 500 pL/well (5X10⁴ cells/well) of this solution was plated in a 24 wells plate and incubated in an incubator (Thermo Scientific, Model 3111) at 37°C with 5% CO2 atmosphere. After 24 hours of incubation, cell cultures were treated with the lead actives either dissolved in water or DMSO. The cells were again incubated for 72 hours in an incubator (Thermo Scientific, Model 3111; conditions: 5% CO2, at 37°C). After incubation, spent media is drained and fresh solution of 0.15 ml of 1N NaOH (in 10% DMSO) per well was added. Cells were lysed by resuspension and incubation (60 °C/1 hr.). Then, 0.12 ml of this lysate was transferred to a fresh 396-well plate and OD405nm (optical density at 405 nm) in a TECAN M1000 plate reader was measured to give an estimate of relative melanin content.

Calculation for melanin content:

The spectrophotometric OD at 405nm for untreated cells (No active) is considered as 100% melanin content, With respect to this, treatment (active) percentage is calculated.

Th experiment was carried out with various concentrations of picolinamide and 6-methyl picolinamide and the results are summarised in the Table - 3 below:

The data in the table above indicates that 6-methyl picolinamide is vastly superior to picolinamide in melanin content assay, a key indicator of the benefit to be obtained by the present invention.

Claims

Claims:

1. A cosmetic composition comprising from 0.001 to 10 wt% 6-methyl picolinamide.

2. The composition as claimed in claim 1 wherein the composition further comprises from 0.001 to 10 wt% of an additional skin lightening agent selected from the group consisting of niacinamide, picolinamide, isonicotinamide, 12-hydroxystearic acid, 4-alkyl substituted resorcinol and mixtures thereof.

3. The composition as claimed in claims 1 or 2 wherein the additional skin lightening agent selected is 4-alkyl substituted resorcinol selected from the group consisting of 4-ethyl resorcinol, 4-isopropyl resorcinol, 4-butyl resorcinol, 4-pentyl resorcinol, 4-phenylethyl resorcinol and 4-hexyl resorcinol.

4. The composition as claimed in any one of claims 1 to 3 wherein the additional skin lightening agent is selected from the group consisting of 4-ethyl resorcinol and 4-hexyl resorcinol.

5. The composition as claimed in any one of claims 1 to 4 wherein the additional skin lighting agent selected is 4-hexyl resorcinol.

6. The composition as claimed in any one of claims 1 to 5 wherein the composition further comprises from 0.01 to 10 wt% UVA organic sunscreen.

7. The composition as claimed in any one of claims 1 to 6 wherein the UVA organic sunscreen is selected from a dibenzoylmethane compound.

8. The composition as claimed in any one of claims 1 to 7 wherein the UVA organic sunscreen is 4-tert-butyl-4'-methoxydibenzoylmethane.

9. The composition as claimed in any one of claims 1 to 8 wherein the composition further comprises from 0.01 to 10 wt% UVB organic sunscreen.

10. The composition as claimed in any one of claims 1 to 9 wherein the composition further comprises from 0.1 to 10 wt% nonionic surfactant.

11. The composition as claimed in any one of claims 1 to 10 wherein the composition further comprises from 3 to 22 wt% fatty acid.

12. The composition as claimed in any one of claims 1 to 11 wherein the composition further comprises from 0.1 to 10 wt% soap.

13. A method for providing even tone to skin wherein the method comprises:

(i) applying the composition as claimed in any one of claims 1 to 12 to the skin; and

(ii) optionally, rinsing it.

14. Use of the composition as claimed in any one of claims 1 to 12 for providing even tone to skin.

15. Use of 6-methyl picolinamide for providing even tone to skin.