WO2008035152A1

WO2008035152A1 - Cosmetic method to remove the dark undereye marks

Info

Publication number: WO2008035152A1
Application number: PCT/IB2007/001986
Authority: WO
Inventors: Carlo Ghisalberti
Original assignee: Individual
Current assignee: Individual
Priority date: 2006-09-18
Filing date: 2007-07-13
Publication date: 2008-03-27
Anticipated expiration: 2009-03-18
Also published as: ITMI20061770A1

Abstract

The invention refers to a cosmetic method to treat dark undereye circles comprising the screening of specific and safe iron chelating agent(s), the preparation of a cosmetic composition, and its application onto the discoloured undereye area.

Description

COSMETIC METHOD TO REMOVE THE DARK UNDEREYE MARKS

FIELD OF THE INVENTION

Cosmetic method to treat the dark undereye marks. BACKGROUND OF THE INVENTION The dark undereye circles - alias "shadows under the eyes", alias "cernes" (French), or "occhiaie" (Italian) - are a familiar problem for many women and also men.

The purplish-dark colour are related with the tiny microcapillaries and with a poor and/or defective circulation, being triggered by factors such as stress, lack of sleep, and so on. A common thought is that the thin skin of lower eyelids makes the veins underneath and the darker shadows of bone to show through. Actually, skin gets thinner with age due to break down of the "scaffolding" formed by collagen fibres and the weakening of elastic fibres which keep the skin taut.

But this view covers only part of the phenomenon, hi fact, only covering makeups and a variety of purported "eye-care" cosmetic products claiming esthetic advantages on the shadows under the eyes are available on the marketplace.

However, all fail to get the key point, i.e. to provide an effective (and endurable) cosmetic treatment of the discolouration under the eyes.

Surprisingly, none has so far focused the attention on the fact dark under-eye circles begin in the capillaries, the tiny blood vessels that web the delicate skin around the eyes. The periocular capillaries are so small that red blood cells sometimes have to line up to get through and, frequently, red blood cells extravasate into the surrounding skin. While there are physiological mechanism to remove the hemoglobin extravasate, its fragmentation, oxididation and fixation into the skin protein as hemosiderin which results in permanent dark blue-to-black stains.

Some experiment directed to the use of iron chelation have made use of ginkgo biloba extract and deferoxamine to minimize the oxidative stress in in vitro models (Celikόz B et all., Eur J Plast Surg, 1997, 20, 4, 197-201).

While desferoxamine is a known, potent chelator with broad clinical use in iron chelation, it is an example of cosmetic inadequancy due to its poor skin penetration. SUMMARY

We have found out that dark undereye circles are mainly driven by leaky capillaries, wherein stress while environmental factors just enhance the microvessel fragility therey causing hemosiderin extravasation on the periocular skin, hence with cumulative (visible) effects.

The invention refers to a cosmetic method to remove the undereyes hemosiderinic depots, which comprise the screening of one or more "Selective Undereye Hemosiderin Remover(s)" ("SUHR"), the preparation of a cosmetic composition, and its application onto the periocular area. A SUHR selection is mandatory since there are several agents potentiually capable of depleting iron hemosiderin, still an improper choice will lead to unefficacy and/or to burdens in the delicate periocular site.

The criteria to make a chelating agent elegible for SUHR include high affinity and specificity for Fe³⁺, good skin bioavailability and/or disposition kinetic of the formed complex, and safe use, i.e. non-sensitization and non-irritanting properties.

These and other embodiments of the present invention will become apparent in conjunction with the figures, description and claims that follow. DETAILED DESCRIPTION OF THE INVENTION

The invention is directed to a cosmetic method to treat dark undereye marks. The efficient method to remove the undereyes hemosiderinic depots on a subject with dark undereye circles comprises: a) identification of safe and effective agent(s) based on selectivity, affinity, and local bioailability along with and safety for the use on the periocular area; herewith named "Selective Undereye Hemosiderin Remover(s)" ("SUHR"); b) preparation of a cosmetic composition comprising SUHR; and c) local application of said compositions to a subject with dark undereye circles. Noteworthy, the method and the relevant compositions of the present invention actually differ from existing and/or prototype cosmetic compositions which may occasionally contain chelating agents, but can be either ineffective for the purpose, or uncompatible for the use in dark under-eye circles for safety and/or efficacy reasons. 1 Step (a)

As steted before, the screening of SUHR is fundamental in order to design a cosmetic composition which is fully effective for the cosmetic target, while also being safe in the periocular application. The selection of SUHR suitable for the purpose is therefore based on the matching of critical parameters for efficacy and safety (tolerability) which would be otherwise encountered.

A cosmetic method must include validation steps without the use of animal model and, possibly, limit as much as possible the number and the extent of (unnecessary hazardous) tests on human volunteers. Therefore, step (a) is primary construed with in vitro assays, which are shown herewith after.

1.1 Affinity

The binding capacity of a candidate SUHR with Fe³⁺, i.e. to form a chelate complex with the infiltrated hemosiderinic iron, is an essential requisite for efficacy. Therefore, the parameter #1 for SUHR is the absolute affinity for Fe³⁺, expressed as pFe^{3+ =} -log[Fe³⁺], to be misured in vitro as explained in the Example 1.1.

By analogy with pH, pFe³⁺ is defined as pFe³⁺ = -log[Fe³⁺] where [Fe³⁺] is the molar concentration of hexaaquoiron^(III). It is clear that the higher the affinity of a ligand for iron^(III), the lower the value of [Fe³⁺] in solution, that is the larger the pFe³⁺ value. To compare SHUR candidates, the conditions must be defined, and the adopted values are: [Fe³⁺]_totai 5 x 10^'6 M, and [SUHR]_totai = 5 x 10^"5 M at pH 7.4.

The summarized criterium is: pFe³⁺ > 16, preferably > 20.

1.2 Specificity

The specificity for Fe³⁺ with respect to other polyvalent essential cation, typically Zn²⁺ or Cu^{+ 2+} is a further requirement to achieve both efficacy and safety as claimed by the method according to the invention. hi fact, a selective deplection of the Fe is necessary, since competition with e.g. Zinc and Zn-dependent enzymes will otherwise cause the typical side-effects of the zinc depletion, tipically dermatitis. The selectivity is represented by the ratio among the absolute affinity of the candidate SUHR for Fe3+ Therefore, parameter #2 is expressed as Rlog_PF_e ³⁺/_Pzn²⁺ = -log[Fe³⁺]/ -log[Zn²⁺], to be misured in vitro as explained in the Example 1.2.

The summarized criterium is: Rlogβ(F_e3+/zn2+) > 2, preferably > 4. 1.3 Bioavailability Another condition is the skin bioavailability, for the efficacy of SUHR is also related to the contact with the hemosiderinic iron as well as to the capacity to exctreted it from the skin layer after the complex is formed.

Therefore, the parameter #3 is a composed factor which express the local bioavailability, wich has been herewith defined as "modified Veber rule". The criteria are: RB. < 10 and PSA2 < a 140 A or H-bound_to, < 12; and logD «10 - 0.1, preferably =5 — 1, whose single parameters are specified in the Example 1.3. 1.4-5 Irritant and sensitizing behaviour

The requirement of a SUHR and the composition comprising thereof is their suitability for the use in contact with periocular skin and, occasionally, to the eyes without undue toxicity, incompatibility, instability, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio.

The summarized criteria are: cyctotoxicity expressed as AOI % = [OD_SUHR / ODnegative _control] x 100 > 40%, preferably > 60%; and sensitization expressed as MSC < 1 mg/ml, preferably < 100 microg/ml. Notewhorty, the afore mentioned criteria must be matched either by an individual r substances or, collectively, or by a mix of iron chelating agents. 2 Step Qo)

Once the SUHR have been dewtermined as described in Step (a), then the SUHR can be formulated in cosmetic composition to be applied in the periocular area, said composition may be produced by know technics. 2.1 Delivery systems

The concentration of SUHR on the cosmetic composition according to the invention depends on their class, as specified in the Example session.

The composition of the invention may be in any cosmetical/galenical form normally used for periocular application, especially in the form of aqueous, hydroalcoholic or oily solution, aqueous or oily gel, liquid, paste or solid anhydrous product, dispersion of oil in aqueous phase in the presence of spherules, nanoparticles (nanospheres, nanocapsules or ionic and/or nonionic type lipid vesicles), direct (O/W), inverse (W/O) or multiple (0/W/O and W/O/W) emulsion. The composition used according to the invention is preferably in the form of an aqueous gel or an OAV emulsion.

For example, this composition may be more or less fluid and have the appearance of a white or coloured cream, a milk, a lotion, a serum, a paste or a foam. It may possibly be applied in the form of an aerosol, or in solid form, and for example in stick or compact product form. It may be used as a skin care and/or make-up product, for example as a foundation.

The aqueous phase may contain mostly water and may also comprise a mixture of water and a water-miscible organic solvent, i.e. having a miscibility in water greater than 50% w/w at 25°C. The aqueous phase may typically be present in an amount greater than or equal to 10%, preferably 30%, even more preferably 50%, or even 70% w/w relative to the total weight of the composition. hi a known manner, the composition of the invention may also contain adjuvants common in the cosmetic field, such as hydrophilic or lipophilic gelling agents an active agents, preservatives, antioxidants, solvents, fragrances, fillers, sunscreens, pigments, odour absorbers and dyes. The quantities of these various adjuvants are those conventionally used in the field under consideration, and, for example, are from

0.01 to 20% by total weight of the composition. These adjuvants, depending on their nature, may be introduced into the fatty phase, into the aqueous phase, into the lipid vesicles and/or into the nanoparticles.

When the composition of the invention is in an emulsion, the proportion of the fatty phase may range from 5 to 80% w/w, and preferably from 5 to 50% w/w. The fatty substances, the emulsifiers used in the emulsion composition are chosen from those conventionally used in the field under consideration. The emulsifϊer are preferably present, in the composition, in a proportion ranging from 0.3 to 30% w/w, and preferably from 0.5 to 20% w/w of the composition. As fatty substances that can be used in the invention, mention may be made of oils and especially mineral oils (liquid petroleum, isoparaffines), oils of plant origin (avocado oil, soybean oil), oils of animal origin (lanolin), synthetic oils (perhydrosqualene), silicone oils (cyclomethicone) and fluorinated oils (perfluoropolyethers). It is also possible to use, as fatty substances, fatty alcohols (cetylic alcohol), fatty acids, waxes and gums and, in particular, silicone gums.

As emulsifiers that can be used in the invention, mention may be made of, for example, fatty acid esters and polyethylene glycol esters such as PEG-50 stearate, and fatty acid esters and polyol esters such as glyceryl stearate and sorbitan tristearate. As hydrophilic gelling agents, mention may be made of, in particular, carboxyvinyl polymers (carbomers), acrylic copolymers such as acrylate/alkylacrylates copolymers, polyacrylamides, polysaccharides, natural gums and clays, and, as lipophilic gelling agents, bentones, metal salts of fatty acids, hydrophobic silica and polyethylenes. 2.2 Additional active ingredients The compositions according to the invention may comprise as additional active agents at least one compound chosen from: desquamating and/or hydrating agents; depigmenting agents; agents for stimulating the proliferation of fibroblasts; keratinocytes and/or differentiation stimulators; matrix metalloproterases (MMP) inhibitors; skin macromolecule promoters; muscle relaxants; anti-radicals and antiglycating agents; vasoprotective compounds; and mixtures thereof. Examples of such active agents are: retinol and its derivatives such as retinyl palmitate; ascorbic acid and its derivatives such as magnesium ascorbyl phosphate and ascorbyl glucoside; tocopherol and its derivatives such as tocopheryl acetate; nicotinic acid and its precursors such as nicotinamide; ubiquinone; glutathion and its precursors such as L-2-oxothiazolidine-4-carboxylic acid; plant extracts and especially olive leaf extracts, and also the plant proteins and their hydrolysates such as rice or soybean protein hydrolysates; algal extracts and in particular laminaria extracts; bacterial extracts; sapogenins such as diosgenin and Dioscorea extracts, in particular wild yam extracts; α-hydroxy acids; β-hydroxy acids e.g salicylic acid and 5-n-octanoylsalicylic acid; oligopeptides and pseudodipeptides and their acylderivatives, lycopene; manganese and magnesium salts; and mixtures thereof. Furthermore, it is also possible to combine with the SUHR selected according to the invention other compounds, especially plant proteins, plant polysaccharides.

Examples of such compounds may be chosen from: phosphodiesterase inhibitors such as caffeine and theobromine; monomethylsilanetriol mannuronate; tea, coffee, guarana, mate, or cola extracts; Ginkgo biloba extracts; horse chestnut extracts; Dioscorea extracts containing diosgenin; algal extracts and in particular Laminaria digitata extracts; and mixtures thereof. 3 Step (c) The composition according to the invention is applied as external formulations either by the subject itself or by a praticioner, cosmetologist, or esthetician.

Said compositions may comprise a percutaneous penetration enhancer that augments delivery of active ingredient to the dermal layers. Various compounds for enhancing the permeability of skin are known in the art and are described in the pertinent texts and literature. Compounds enhancing the skin permeability include: sulfoxides such as dimethyl sulfoxide (DMSO) and decylmethylsulfoxide (ClOMSO); ethers such as diethylene glycol monoethyl ether (Transcutol™) and diethylene glycol monomethyl ether; surfactants such as sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer (231, 182, 184), Tween (20, 40, 60, 80), and lecithin; 1 -substituted azacycloheptan-2- ones, particularly Azone™; alcohols such as ethanol, propanol, octanol, benzyl alcohol, and the like; fatty acids such as lauric acid, oleic acid and valeric acid; fatty acid esters such as isopropyl myristate, isopropyl palmitate, and ethyl oleate; polyols and esters thereof such as propylene glycol, ethylene glycol, glycerol, butanediol, and polyethylene glycol monolaurate; amides and other nitrogenous compounds such as urea, dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone, 1- methyl-2-pyrrolidone, ethanolamine, diethanolamine and triethanolamine; terpenes; alkanones; and organic acids, particularly salicylic acid and salicylates, citric acid, and succinic acid. The book Percutaneous Penetration Enhancers (Smith et al., editors, CRC Press, 1995) provides an excellent overview of the field and further background information on percutaneous enhancers. The application can be carried out by device tools with increase skin porosity and/or hydration, such as occlusion devices, hydrocolloid patches and other intradermal delivery systems, lipophilic penetrants including liposomes, microemulsions and lipospheres, electroporation, ultrasound, iontophoresis, and the like methods. More particularly, for such an intradermal route several tool can be applied, including local injection, e.g. syringe or dermojet, in the latter modes of application of SUHR will conveniently suspended in a sterilized liquid composition.

For best results in the cosmetic treatment, the method of application of the composition according to the invention should be at least once per day, even preferably repeated several times per day, such as in the range of 2 to 8 times per day, preferably 2-3 times per day, and continued for several days, preferably at least 3 to 5 weeks.

Additional objects, advantages, and novel features of the present invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting.

EXAMPLES

Example 1 - Screening method Parameter #1

The affinity constant for the iron^(IU)-SUHR interaction is determined by a spectrophotometric competition study as described in Plant Physiology, 2000, 124, 1149-57; and Inorg. Chem. 1988, 27, 4140-9.

The iron^(III) complexes of the ligand [Fe¹¹¹ SUHR]₂ is prepared in a 10:1 ligand:iron molar ratio (total iron concentration 4.4 x 10^"5 M) in 0.1 m MOPS-KOH buffer, pH

7.4. This solution is then titrated against maltol resulting in the dissociation of iron^^m^-SUHR complex and the formation of the orange iron(H[)-maltol complex.

The resulting spectrophotometric data is inserted into the COMPTl program to evaluate the affinity constants of the complex. pFe³⁺ plots are calculated from pKa and KFe^m values using the program SPECIAZl with metal and SUHR concentration, ATF_e(_Hi₎ values of complexes, K for iron^(III)-OH interactions, and pKa values as data entry. Parameter #2

Rlogβ(Fe₃+/zn2+) ⁼ the ratio of cumulated stability constant of the complexes [SUHR- Fe³⁺] and [SUHR-Zn²⁺], which are indipendently calculated as described in Biological Trace Element Research, 1989, 21, 295. Parameter #3

The modified Veber rule (Veber DF et all.; J. Med. Chem. 2002, 45, 2615-23) is allow the provisional calculation of skin bioavailability by the following parameters:

RB = Rotatable bonds is calculated by sum of apparent values, or with the program "Marvin View - Topology Analysis " (ChemAxon Ltd., Budapest, Hungary). PSA = Polar surface area as calculated by the atom-based method (Ertl, Rohde & Selzer J. Med. Chem. 2000, 43, 3714-3717; or Clark J Pharm Sci 1999, 88: 815-821) or with the program "Marvin View - Polar Surface Area (PSA) Plugin" (ChemAxon).

H-boundtot is the total H-acceptor and donor bounds, calculated "by hand", or with "Marvin View - Hydrogen Bond Donor-Acceptor (HBDA) Plugin" (ChemAxon). logD = Distribution coefficient, determind in octanol/MOPS (pH 7.4), or with the programs "ACD/logD Suite" (ACD Inc., Toronto, Canada) or ChemDBsoft Lite. Parameter #4

The irritation potential is misured by the viability of the candidate SUHR on human corneal epithelial (HCE) model (SkinEthic Laboratories, Nice, France) as described in Toxicology in Vitro, 2006, 20, 1 - 17.

In brief, a candidate SUHR is applied directly onto the surface of the epithelial culture for exposure periods (10, 20, 30 and 60 minutes) and the induced cytotoxicity is monitored as a decreased MTT metabolism relative to the negative (vehicle) control cultures. The percentage viability (AOI %) is then calculated for each culture to identify the most relevant exposure time. Parameter #5

The sensitization potential is performed as described in Toxicol hi Vitro, 2001, 15, 4-5, 327-31 and in Contact Dermatitis 46, suppl. 4, 117.

Langerhans cells and immature dendritic cells are the model systems for screening of skin sensitizers are used to test the sensitizing potential of the candidate SUHR. The test is carried out on a primary cell line of dendritic cells derived from human monocytes of healthy volunteers peripheral blood . Cells are kept in RPMI 1640, FCS (10%), GM-CSF (50 ng/ml) e IL-4 (1000 IU/ml) added. After the incubation with the tested substance and the controls, cells are collected, checked under the microscope for their vitality by staining with Trypan Blue dye and counting in a cell counter chamber, washed in PBS and then marked with a fluoresceinated anti-B7.1 or B7.2 antibody. After washing, to eliminate the excess antibody, the MFI (Mean Fluorescence Intensity) linked to the cells was evaluated by means of a flux cytofluorimeter (FACS, Fluorescence Activated Cell Sorter, Becton Dickinson, Mountain View, CA). This value is proportional to the expression of costimulatory molecules. The MFI of untreated cells and treate cells with a monoclonal isotype- matched antibody is used as an internal control (basal fluorescence).

The minimum sensitization concentration (MSC) as the concentration which ellicit at least a 10% increase of CD80 and CD86 of dendritic cell expression. Example 2 - Classification

Based on the calculation method of Example 1, the following rating has been established.

Class "A" are ideal SUHR in terms of affinity, specificity, bioavailability, and (periocular) skin safety. The compound belonging to this class can be applied in the composition of invention in amount from about 10% to about 0.5% w/w, preferably from about 5% to about 1% w/w.

Class "A" includes: 3-hydroxy-2-methyl-4-pyrone (maltol); 3-hydroxy-2-ethyl-4- pyrone (ethyl maltol); l-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(lH)-pyridone (octopirox); 6-cyclohexyl-l-hydroxy-4-methyl-2(lH)-pyridinone (ciclopirox); 6-[[p- chlorophenoxy)phenoxy]methyl]-lhydroxy-4-methyl-2(lH)-pyridone (rilopirox); 1 ,2-dimethyl-3-hydroxypyrid-4-one (deferiprone); 1 -methyl-2-ethyl-3-hydroxypyrid- 4-one; l,2-diethyl-3-hydroxypyrid-4-one; 2,6-pyridinedicarboxylic acid (dipicolinic acid); and salts thereof, particularly the ethanolamine ("olamine") salts.

Class "B" are second choice SUHR due to limitations mainly referred to the safety, for their low specificity along with irritation/sensitization behaviour. The compound belonging to this class can be applied in the composition of invention in amount from about 1% to about 0.05% w/w, preferably from about 0.5% to about 0.1% w/w.

Class "B" includes: gallic acid; gallic acid esters (e.g. propyl gallate, lauryl gallate), salicyl hydroxamic acid, decyl hydroxamic acid; 5-hydroxy-2-(hydroxymethyl)-4H- pyran-4-one (kojic acid); gentisic acid, methyl gentisate, mimosine, and the like.

Class "C" are low efficacy SUHR from a limited activity, particularly low specificity and local bioavailability, instead with a good profile in terms of safety. The compound belonging to this class can be applied in the composition of invention in association to Class "A" compounds in various cosmetically acceptable amounts. Class "C" includes: tartaric acid; citric acid; minotrimethylene phosphonic acid; β- alanine diacetic acid, EDTA; ethylenediamine-N,N-bis-(2-hydroxyphenylacetic acid) dimethyl ester; cyclohexanediaminetetracetic acid; oxalic acid and its esters; edetic acid; etidronic acid; HEDTA; aminotrimethylene phosphonate; pentetic acid; phyytic acid; nitrilotriacetic acid; and salt and derivatives thereof. Class "D" are less recommended SUHR for they do not match one or more parameters of activity or safety. The compound belonging to this class can be applied in the composition of invention in association to Class "A" and, optionally, "B" and/or "C" compounds in amount below 1% w/w, preferably below 0.1%.

Class "D" representative compounds include: 6-hydroxy-2-phenyl-3(2H)- pyridazinone; 2,3-dihydroxybenzoic acid; 4,5-dihydroxy-l,3-benzene-disulfonic acid; 2,3-dihydroxypyridine; 2,4,5-trihydroxypyrimidine; 2,3-dihydroxynaphthalene; and 4-(2-amino- 1 -hydroxyethyl)- 1 ,2-benzenediol; N-benzoyl-N-phenylhydroxylamine; 2,2'-dipyridylamine; 1,10-phenanthroline; 2,3-bis(2-pyridyl)pyrazine; 2,3-bis(2- pyridyl)-5,6-dihydropyrazine; 1,1 '-carbonyldiimidazole; 2,4-bis(5,6-diphenyl- 1,2,4- triazine-3-yl)pyridine; 2,4,6-tri(2-pyridyl)-l,3,5triazine; 4,4'-dimethyl-2,2'-dipyridyl; 2,2 '-biquino line; 2,2'-bipyrazine; 3-(2-pyridyl)-5,6-diphenyl-l,2,4-triazine; 3-(4- phenyl-2-pyridyl)-5-phenyl-l,2,4-triazine or -5,6-di-phenyl-l,2,4-triazine; 2,4,5- trihydroxypyrimidine; phenyl 2-pyridyl ketoxime; 3-amino-5,6-dimethyl-l,2,4- triazine; 6-hydroxy-2-phenyl-3(2H)-pyridazinone; 2,4-pteridinediol; 2,2'-dipyridyl; 2,3-dihydroxypyridine; 5,7-dichloro-8-hydroxyquinoline; di-2-pyridylketone; 1,1'- carbonyldiimidazole; di-2-pyridyl glyoxal; 2-furildioxime; phenyl 2-pyridylketoxime; 1,2-cyclohexanedionedioxime; 2-furildioxime; phenyl 2-pyridylketoxime. Composition Example #1 - Gel

100 g of gel contain: (g) Gomma xanthan 0.7

Lactic acid 8.0

Ethylmaltol 3.5

2,6-Dipicolinic acid 0.5

NaOH q.b. to pH 5.5 Water q.b. to 100 g

This gel can be used as such or applied directly or by assisted method such as electroporation, ultrasound, or iontophoresis. Composition Example #2 - Emulsion

100 g of emulsion contain: (g) Glycerin 2.0

Propylenglycol 10

Octopirox olamine 0.5

Deferiprone 1.0

Ascorbic acid 5.0 Retinol 0.3

Lactic acid 5.0

Ciclomethicone (cyclopentadimethylsiloxane) 20

Abil WO9 (mix of PEO and PPO-cetyldimethylsiloxane, 3.0 4-polyglycerol isoglyceryl isostearate and hexyl laurate) Parfumes, preservatives, colorants q.b.

Water q.b. to 100 g

Composition Example #4 - Lotion

100 g of hydroalcoholic solution contain: (g)

Ethyl alcohol 96% 50 PEG (8-mol) (poliethylenglycol 8 POE) 30 Ethoxydiglycol 5.0

Tartaric acid 2.0

Maltol 2.5

Retinol 0.3

Ammonium hydrate q.b. to pH 5.2

Parfumes, preservatives, colorants q.b.

Water q.b. to 100 g

Incremental Composition Example #1

By high-speed mixing, e.g. by Minipimer™, a commercial eye formulation can be additivated with a SUHR. Said formulation is "Lierac Diopticerne Cr Occhiaie", originally comprising the following ingredients: Water (aqua), Elaeis Guineensis, Butcherbroom Extract, Carbomer, Triethanolamine, Arnica montana, Tocopheryl Acetate, Phenoxyethanol, Parabens. Incremental Composition Example #2 A SUHR blend is added to "Rilastil Young Eye Contour Gel", originally comprising the following ingredients: Water, Glycerin, Glyceril Polyacrilate, Panthenol, Aloe Barbadensis, Sodium Hyaluronate, Prunus Africana, Saccharomyces Lysate, PEG-40, Hydrogenated Castor Oil, Arginine, Propylene Glycol, Phenoxyethanol, Imidazolidinyl Urea, Parabens, Disodium EDTA. Incremental Composition Example #3

With similar procedure of the previous example, a SUHR blend is added to "Lierac Dioptigel", originally comprising the following ingredients: Water, Alchemilla Vulgaris, Hedera Helix, Chamomilla Recutita, Equisetum Arvense, Carbomer, Tromethamine, Phenoxyethanol, Parabens. Example 3 - Case study

The Composition Example #1 has been supplied to a female subject of 36 years of age and instructed to apply it the lower perioculare area regularly at least once a day for three weeks. During the treatment the regularization and the progressive disappearance of dark undereyes marks has been noticed. No intolerance phenomena were noticed.

Claims

1. Cosmetic method to remove the dark undereyes marks comprising the application of an effective and safe iron chelator onto the area.

2. Method according to Claim 1 comprising: a) identification of "Selective Undereye Hemosiderin Remover(s)" ("SUHR"); b) preparation of a periocular composition comprising SUHR; and c) application of said composition to a subject with dark undereye circles.

3. Method according to Claims 1 or 2, characterized in that said step (a) is carried out exclusively by in vitro assays.

4. Method according to any one of Claims 1 to 3, characterized in that said composition is a solution, a gel, a liquid product, a paste, a stick, or an emulsion.

5. Method according to Claim 2, characterized in that said step (c) of application is carried out by the subject itself.

6. Method according to Claim 2, characterized in that said step (c) of application is carried out by a praticioner, a cosmetologist, a dermatologist or an esthetician on a the subject with dark undereyes marks

7. Method according to Claim 5 or 6, characterized in that the application is carried out by means of occlusion devices, hydrocolloid patches, or by systems comprising lipophilic penetrants including liposomes, microemulsions, nanospheres, nanocapsules or ionic and/or nonionic type lipid vesicles.

8. Method according to any one of Claims 1 to 7, characterized in that the said composition is assisted with electroporation, ultrasound, or iontophoresis.

9. Method according to any one of Claims 1 to 8, characterized in that the said SUHR is selected from the group consisting of maltol; ethyl maltol; octopirox; ciclopirox; rilopirox; deferiprone; dipicolinic acid; and salts thereof.

10. Cosmetic composition suitable to carry out the method according to any one of Claims 1 to 9, manufactured as a white or coloured cream, a milk, a lotion, a serum, a paste, a foam, a stick, or compact product form such as a foundation.