MXPA06007703A - Use of idebenone for the preparation of a topically-applied depigmentation composition and corresponding composition - Google Patents

Abstract

The invention relates to the use of idebenone for the preparation of a topically-applied composition which is intended to inhibit melanogenesis, to reduce cutaneous coloration or to brighten same and/or produce cutaneous depigmentation. More specifically, the invention relates to a topically-applied composition comprising a cosmetic, pharmaceutical and/or dermatologically-effective amount of idebenone, derivatives thereof or mixtures of same, in which there is an effective amount of idebenone or the derivative thereof such as to produce cutaneous depigmentation.

Description

USE OF IDEBENONE TO PREPARE A DEPIGMENTING COMPOSITION OF TOPICAL USE AND CORRESPONDING COMPOSITION FIELD OF THE INVENTION The present invention relates to the use of idebenone in a composition intended to be applied to the skin, with the object of inhibiting melanogenesis. It also relates to a composition intended for topical application on the skin, comprising a cosmetically, pharmaceutically and / or dermatologically effective amount of idebenone, its derivatives or mixtures thereof. In particular, the present invention relates to a cosmetic preparation capable of conferring a beneficial effect on the processes of cutaneous hyperpigmentation. Preferably, the present invention relates to pharmaceutical or dermatological cosmetic preparations comprising idebenone and / or its derivatives, and which decrease the local increase in skin coloration caused by an increase in the production of melanins. Particularly, the present invention relates to a cosmetic or dermatological preparation usable in the treatment of cutaneous hyperpigmentation caused by hormonal stimuli and / or by physical, guímicas and / or biological insults. The invention also relates to a topical pharmaceutical composition comprising idebenone as a skin lightening ingredient.

BACKGROUND OF THE INVENTION Melanin is a dark pigment found in the skin, hair, eyes and in certain nerve cells, which is produced in cells called melanocytes. Melanocytes are cells of neuroectodermal origin originated in the neural crests of the embryo that, during the fetal stage, migrate towards the basal layer of the epidermis. Also, there are extracutaneous melanocytes scattered in other tissues. The epidermotropic melanocytes arrive in the fetal stage to the deepest layers of the epidermis, being located between the basal cells, at the rate of approximately 1 melanocyte per 10 basal cells, regardless of the race of the carrier. Once in their definitive position, these cells emit branched extensions called dendrites, in such a way that all the basal cells contact these extensions. The primary function of the melanocyte is to synthesize a dark pigment called melanin. This pigment accumulates in the cytoplasm of the melanocyte in ovoid structures similar to granules of secretion, called melanosomes, which after forming in the cell body, migrate through the melanocyte cytoskeleton to the dendrites. This process is controlled hormonally, there are hormones that promote the formation of melanin and others that inhibit it, as well as hormones that promote the mobilization of melanosomes to the periphery of the dendrites and others that concentrate them around the nucleus. This process turns out to be quite evident in inferior animals, although in humans it can also exist. The free ends of the melanocyte dendrites are introduced into the cytoplasm of the basal keratinocytes, literally injecting melanosomes into the cytoplasm of these cells. Thus, the entire epidermal basal layer and the hair follicle contain uniformly distributed melanin, on the one hand due to the presence of melanosomes in the melanocytes and on the other hand and to a large extent, due to the incorporation of melanosomes in the basal keratinocyte, known circumstantially as melanophore. What is striking about this process is that when the pigmented basal keratinocyte (melanophore) divides to give rise to different, more superficial spiny cells, the melanosomes are lost, and, on the other hand, the melanocyte dendrites do not inject melanosomes into differentiated spiny cells. . Those lost melanosomes can lodge in the intercellular space of the epidermis, and then be eliminated along with the ordinary desquamation of the skin. These melanosomes are completely degraded and no longer fulfill their pigmenting function.

The color of normal human skin is directly related to the size, configuration, type and color of melanosomes, and their distribution in melanocytes and keratinocytes. Melanin synthesis occurs exclusively in melanosomes and depends on the action of numerous genes. Each melanosome is a spherical or ovoid organoid, formed by a trilaminar lipoprotein cell membrane, an amorphous matrix with water, electrolytes and different solutes, in which active enzymes are diluted and an ultra tubulin protein structure that forms intra-membranous disposition tubules more or less parallel to each other. Until not long ago, it was considered that melanosomes were composed only of melanin and melanoprotein product of the interaction with tyrosinase. Recent studies have shown that melanosomes contain two different fractions, a lipid with lipids located outside the melanosome and another protein with structural proteins that are the central part of the melanosome. The lipid fraction is important in the functional regulation of the melanosome, while the matrix proteins control its structural differentiation.

The process for the formation of melanosomes and their melanization can be considered as a "cascade" of events channeled by internal regulatory controls that come into play as melanosomes are programmed to fulfill their functions. This process can be summarized as follows: i) Formation and organization of the melanosomal components: The structural and enzymatic proteins of the melanosomes are formed inside the vacuoles of the melanosome membrane. At an early stage, the membranes continue to incorporate specific proteins and lipids. Within the vacuoles formed in the smooth endoplasmic reticulum, proteins formed in the rough endoplasmic reticulum are placed, which are arranged in tubules, lamellae and filaments without a defined architectural organization. In addition, microvesicles formed in the Golgi apparatus are incorporated, containing enzymes or post-tyrosinase regulatory factors (such as dopachrome-tautomerase), which fuse with the limiting membrane. Tyrosinase is incorporated after glycosylation in the Golgi complex. With the passage of time, structural proteins continue to be incorporated into the melanosome, while the same occurs with tyrosinase. The structural proteins will be part of the membrane of the melanosome, and then they will go to the matrix. ii) Conversion into eumelanosomes and pheomelanosomes: The path that melanosomes will follow from here will depend on the levels of cysteine and / or compounds with sulfhydryl groups (e.g., glutathione) found inside the melanosome. If the levels are low, the stimulation of eumelanogenesis will occur with the formation of eumelanosomes. In this case, the lamellae will become the predominant component of the matrix and will be arranged in parallel. Tyrosinase will be transferred from the Golgi apparatus and fixed to the vesicles and lamellae already formed. In the absence of an inhibitory level of cysteine, tyrosinase will trigger the synthesis of melanin from the conversion of tyrosine to dopaquinone. Dopaquinone will be converted to eumelanin by auto-oxidation processes, in addition to those regulated by the dopachrome conversion factor. Apparently, indole-5,6-quinone is polymerized with several of its precursors to form melanin inside the melanosomes. On the other hand, if the levels of cysteine are high, the feomelanosome will form and the pheomelanin will be deposited on a conglomerate of microfilaments and vesicles not yet structured. Tyrosinase will convert tyrosine to dopaquinone, but it will diffuse into the matrix and combine with cysteine, forming cysteinyl-dopa, subsequently modified to form pheomelanin. Cysteinyl-dopa competes with dopaquinone, thus diverting your metabolism, without altering the tyrosinase activity. The post-tyrosinase activity is then inhibited by the presence of the 5,6-hydroxyindole metabolite that does not allow the synthesis of indole-5-6-quinone, which decreases the rate of melanogenesis, allowing the dopaquinone to accumulate in the matrix, preventing a normal synthesis of eumelanin. In other words, cysteine would act as a toxic substance for the melanosome, inhibiting certain enzymatic steps that block a normal conversion of intermediates into true melanin, also losing the possibility of melanin to be anchored to the structural proteins of the melanosome. iii) Transfer and degradation: The melanosomes are transferred from the site of their synthesis, in the pericary, to the ends of the dendrites by the action of the contractile movements of the melanocyte cytoskeleton, in a selective process for melanosomes. Once the melanosomes have been transferred to the interior of the keratinocytes, these latter cells phagocytose the free ends of the dendrites containing the melanosomes and then a phenomenon of membrane fusion occurs, releasing the melanosomes into the cytoplasm of the keratinocyte. Melanosomes are incorporated into the keratinocyte in secondary lysosomes. There, lysosomal enzymes will begin to degrade the melanosome and its components will be diluted in the cytoplasm, which can be reused when incorporated into a pool of metabolic substrates. One of the most important characteristics of this degradation is the passage of melanin from an oxidized state to a reduced state, decreasing the intensity of the color. In this way the melanosome cycle is completed, beginning with its synthesis in the melanocyte, transferring to the keratinocyte and finally degrading, in a continuous process, which ensures a uniform distribution of the pigment. Skin melanin pigmentation can be divided into several causative components: 1) Cutaneous melanin generated according to genetic programs in the absence of exposure to ultraviolet rays (constitutive skin color) and 2) reactions of immediate and delayed tanning induced by Direct exposure of the skin to uv radiation (optional skin color). The changes of the facultative color result from the consequence of a complex interaction between the sunlight, the hormones and the tanning capacity dependent on the individual genetic constitution. The constitutive coloration of the skin, hair and eyes is genetically determined by several genes, the latter being lacking in overt dominance. In addition, there is a high tendency to spontaneous mutation of these genes, so it is not uncommon to find individuals with more than one melanocytic population, becoming mosaics for this trait. Although the populations of melanocytes in the human skin present regional variations, all human beings, regardless of the color of their skin, possess approximately the same amount of epidermal melanocytes in a given anatomical area. Consequently, ethnic differences in skin color are mainly due to differences in the properties of melanosomes and not to the amount of melanocytes. In the interior of the melanocytes of the unexposed skin, the amount of melanosomes is greater in African-Americans, blacks in Africa and Australian aborigines (group 2) than in white Americans of European descent and Asians (group 1). Most of the melanosomes are found in stages of formation II and III, in individuals of group 1, while in those of group 2, a significant proportion of melanosomes are already melanized in their entirety (stage IV). Not only are melanosomes more numerous in group 2 ueratinocytes, but they are also larger. Other genetic and racial differences in the constitutive color are given by the amount of pheomelanin in relation to that of eumelanin. Pheomelanin adopts a lighter color, reddish, while eumelanin is black. The different constitutive tones of the skin will be given, then, by the concentration of melanin of one type or another, rather than by a quantitative problem. On the other hand, by means of experiments carried out in the 1960s, it was demonstrated that the injection of the polypeptide hormones melanotrofins alpha and beta (or melanocytic stimulants - MSH) induced an increase in pigmentation, secondary to an increase in melanogenesis in the of the epidermal melanocytes and the transport of the melanosomes derived from the melanocytes into the interior of the keratinocytes. This phenomenon is also observed when the adrenocortical-tropa pituitary hormone (ACTH) is administered, since it shares or has a great homology in its polypeptide sequence with MSH. Currently, it is accepted that the pituitary gland of the adult human being produces significant amounts of the hormones ACTH and beta-lipotrophin, which are able to exert melanotrophic activity. These hormones would not affect the lance pigmentation in normal humans. In fact, both these hormones and the sex hormones (androgens, estrogens and progesterone), would play a very limited role in maintaining the constitutive color of the skin of the adult human being. However, in the pituitary gland of the human fetus MSH occurs, which would have influences on the developing melanocytic system. On the other hand, the best example of the role that endogenous hormones would play in the darkening of the skin's constitutive color induced by ultraviolet radiation could be melasma. This is characterized by an increase in sectoral, irregular and usually symmetrical melanization, mainly in the areas of the cheeks, the forehead and sometimes the upper lip and neck. Melasma is frequent during normal pregnancy and usually usually disappears gradually after the end of it. Probably, progestogens and estrogens could prepare the ground for hyperpigmentation to occur, being the trigger and promoter of the expression of this phenomenon, exposure to sunlight. Thus, for example, a pigmentation similar to melasma can be observed in women who use oral contraceptives. In addition, experimental studies showed that the administration of hormones in conjunction with UV radiation induces a more intense hyperpigmentation of the skin than when any of these agents is used separately. In these studies it was also shown that in cells in culture, UV light determines an increase in the activity of MSH receptors, which suggests that normal skin tanning could be increased by melanotrophins. This fact would be supported by the lower tan coloration obtained by people suffering from hypopituitarism when exposed to UV radiation. Even in the absence of UV stimulation, the hormones produced during pregnancy and in certain hormonal disorders are capable of increasing human melanin pigmentation. For example, in Addison's disease (adrenal hypocorticism), the high production of ACTH not regulated by the absence of corticosteroids, promotes a generalized hyperpigmentation. Also, during pregnancy, pigmentation of unexposed areas increases, such as the labia majora, areola and nipple, and the abdominal midline.

The distribution of melanocytes is not uniform throughout the skin. In fact, there are individual variations and variations within different parts of the body of the same individual. For example, in humans of all races, there are more than 2,000 melanocytes per mm. Square on the skin of the head and forearms and usually about 1,000 on the rest of the body. Consequently, the racial differences of cutaneous pigmentation are not due to differences in the amount of melanocytes, but to differences in the synthesis of melanin and melanosomes. The reasons for these regional differences in the same individual are unknown, but constitutively they are from birth and even during fetal life. There is no clear correlation between the usual exposure to sunlight and functional melanocytes. However, although there is a greater amount of melanocytes in the exposed areas than in the unexposed areas of the forearm, an increase in the amount of functional melanocytes is also observed in the unexposed skin after UV irradiation, similar to the increase observed on the skin exposed to UV light. To be sure, it is not fully known if the increase in the number of functional melanocytes is due to the entry into mitosis of these cells or to a recruitment of quiescent cells that become functional. Obviously, the division of the melanocytes is important to amplify the production of functional melanocytes in the skin irradiated with UV light. The fact that the melanocytes also divide into non-irradiated skin indicates that a population turnover (although slow) is required, which could be related to the need to eliminate genetic lesions induced by intrinsic and extrinsic chemical and physical agents. During a person's life, there are apparent changes in skin color. For example, almost all black children are clearer at birth than a week later. Freckles, initially only apparent after exposure to the sun, become fixed in adolescence. The skin on the back of the hands acquires a mottled appearance in elderly subjects. These quantitative changes of the epidermal melanocyte population related to the age of the individual or the usual exposure to sunlight were studied extensively. In adult humans, there is a progressive and age-dependent decline in the amount of melanocytes, which is of a magnitude of 8 to 10% per decade of life. These values apply to the unexposed areas, since in the exposed areas, the reduction is much lower, probably due to the stimulating effect of UV light in the melanocytic population. In a study carried out correlating age with chronic exposure to the sun, it was determined that the numerical density of melanocytes in all subjects studied was approximately twice as high in exposed areas as in unexposed areas, but in both cases a decrease in the density in relation to age was detected. The melanocytes of the exposed areas were more active as far as melanin production is concerned, which explains the greater degree of pigmentation in the visible areas. Chronic exposure to the sun does not prevent a decline in the age-related amount of melanocytes, but it affects the production of melanin, and induces the activation or proliferation of the melanocytes. It is interesting to note that keratinocytes produce mitogenic substances for melanocytes, and that this production increases 6-fold if keratinocytes are exposed to UV light. In the healing process, the melanin producing unit is lost, so the skin of a scar is clearer than the surrounding tissue. With the passage of time, coloration can be recovered, depending on the age of the individual, sun exposure and other factors, such as hormonal factors. Paradoxically, there is a counterpart of hyperpigmentation of scars, which speaks clearly of the complex interaction of the different elements that intervene in the pigmentation process. In summary, we can say that the dynamics of the constitutive cutaneous pigmentation is dependent on genetic and ethnic factors, and on a correct interaction between keratinocytes and melanocytes, influenced by a basal hormonal state, also constitutive. On the other hand, the facultative coloration of the skin depends to a great extent on other external factors, such as sunlight. This acts by promoting the proliferation of melanocytes, the activation of the latter and the production of melanin, but for its action must occur certain phenomena of cellular and hormonal interaction. In turn, aging tends to decrease the normal homeostasis of the melanic unit of the skin, causing imbalances in the pigmentation process and maintenance thereof. The brown or black color observed in the pigmented cells is due to the presence of melanin. However, this is not the only pigment that produces these colors nor is melanin homogeneous in its chemical constitution, so it is difficult to define what the melanin pigment is. However, the melanin pigment of mammals has been divided into two main types of melanin: eumelanin and pheomelanin. The first, brown or black, is insoluble and nitrogenated and derived from tyrosine. The pheomelanin, in contrast, yellow or red, is soluble in alkalis, contains sulfur and also derives from tyrosine, but through an enzymatic shunt caused by the presence of sulfur amino acids such as cysteine. In the same individual both types of melanin coexist, although the one that predominates is eumelanin. The eumelanin of mammals is basically composed of units of indole-5,6-quinone. This is derived from tyrosine by the elimination of five oxygen atoms and the evolution of a molecule of carbon dioxide from the carboxylic group of tyrosine, transforming into dopaquinone. The indoles derive from the cyclization of the dopaquinone, and it is considered that the melanin mainly represents a poly-indole-quinone. The precise proportions of indole subunits in melanin are probably under enzymatic control, but depend on precise polymerization conditions. Eumelanin would be represented by a molecule with a rigid and rod-shaped chain, formed by indole-quinone units. The physical structure of the melanosomes would be represented by a copolymer in which the melanin and structural proteins of the melanosome run parallel to each other, but may join at the sites of the sugarcane groups. Then in the elliptical melanosome, the melanin would be arranged in the form of a double helix, polymerized with proteins. On the contrary, from a chemical point of view, pheomelanin is differentiated by the high amount of sulfur that is the result of the nucleophilic aggregate of the amino acid cysteine to the dopaquinone formed by the action of tyrosinase. The cysteine would interact primarily through a 1: 6 addition to the dopaquinone formed enzymatically, to yield the 5-S-cysteinyldopa compound. Similar intermediate compounds were also identified, depending on the sulfur source of pheomelanin. Unlike dopa, cysteinyl dopa is not a substrate for tyrosinase. Finally, it is likely that most of the melanin is of a mixed type, depending on the amount of synthesized eumelanin and pheomelanin intermediates. These compounds copolymerize to form a mixed melanin, which would explain the different optical tonalities obtained with the melanins. In mammals, tyrosinase is an enzyme that fulfills two functions: it converts tyrosine into dopa and then dopa into dopaquinone, which is then cyclized and oxidized again to give rise to the formation of eumelanin. In contrast, if dopaquinone binds to cysteine, pheomelanin will form. Tyrosinase exists in the form of three isomers, although it can be considered as a monoxigenase that contains copper and catalyzes the hydroxylation of monophenol and the oxidation of diphenol, that is, dopa (dihydroxyphenylalani), to form a quinone. The two enzymatic activities are generally referred to as "kinase activity" or "monophenone activity" and "catecholase activity" or "diphenolase". There are several factors that modify the product of tyrosinase, including the conversion factor of dopachrome, which accelerates the conversion of dopachrome into 5.6-dihydroxyindole, the indole blocking factor that inhibits the conversion of 5,6 dihydroxyquinol into melanochrome and the factor of indole conversion, which accelerates the conversion of 5,6-dihydroquinol into melanochrome. In particular, the indole blocking factor and the dopachrome conversion factor are intimately associated with the soluble isomeric forms of tyrosinase (types I and II, those with the lowest concentration within the melanosome), while the conversion factor of dopachrome is associated with the fixed tyrosinase isomer (type IV). These factors are auxiliary enzymatic systems, among which dopachrome-oxidoreductase (dopachrome-isomerase or dopachrome tautomerase). Its function is to form dopachrome tautomers to form carboxylic derivatives. Without these factors, melanin does not finish ripening to polymerize. In addition to the dopachrome tautomerase there are other enzymes (peroxidase, catalase and glutamine metabolic enzymes) and metal ions that act in the regulation of melanogenesis at the post-tyrosinase level. In synthesis, melanogenesis depends on a perfect functional interaction between the enzyme tyrosinase and its substrate tyrosine, to then give rise to dopa and subsequently dopaquinone. The latter is taken by post-tyrosinase enzymatic factors to produce its reconversion in indolic units that will end up polymerizing, to give rise to a co-polymer with structural proteins of the melanosome, producing eumelanin. The presence of cysteine in the melanosome matrix blocks the action of these post-tyrosinase factors, giving rise to other intermediate, soluble compounds with inability to polymerize. However, it is common to find a mixture of partially polymerized melanins, depending on the concentration of sulfur they contain. This explains the different tones found between the different melanins, since their varied structure will absorb certain wavelengths of the visible light spectrum, differently according to the type of melanin in play. This should not be confused with the color of the skin, since it only applies to the color of the pigment. In the conformation of the cutaneous color other factors intervene, such as the concentration of different types of melanin, the dispersion of these in the melanic unit, the types of melanosomes created and the diffraction that causes the epidermis that acts as a difultimating screen. They also intervene in the conformation of the skin color, the presence of other pigments in the skin, basically the hemoglobins, which in clear skins are properly visualized, but in dark skins, they are masked by the melanic pigment appositioned in the epidermis. Frequently, it occurs in a given individual that an area of the skin, in which the density of the melanin within the melanocytes is markedly increased, has a cutaneous color of the affected area darker than the color of the surrounding skin. These areas are known as areas of hyperpigmentation and can cause discomfort to the individual. Among the most frequent causes of hyperpigmentation are the exaggerated response of a skin sector to ultraviolet stimulation., hypersensitivity to ultraviolet light provided by exacerbating agents of the action of radiation (such as cosmetics with bergamot oil or agents known generically phototoxic), hormonal disturbances (such as alterations of thyroid hormones, sex steroids) , endogenous and exogenous and pregnancy) and secondary hyperpigmentation or consequent with an inflammatory lesion. In particular, post-inflammatory hyperpigmentation presents irregular spots, more pigmented than the surrounding skin, which occurs after an inflammation due to an injury to the skin from an insult such as acne, folliculitis, eczema, hair removal, scratching, etc. This post-inflammatory hyperpigmentation resolves slowly, but it can persist for months and even years, and is a frequent reason for medical consultation, requiring professional attention most of the time. To date, various topical skin compositions containing one or more ingredients capable of reducing the density of melanin in cutaneous melanocytes have been described. Such ingredients are generically referred to as depigmenting agents or bleaching agents. These agents are usually absorbed towards the lower layers of the skin, inhibiting melanin formation in melanocytes and specifically acting on determined stages of melanogenesis. The most frequent depigmenting agents are based on hydroquinone or derivatives thereof, such as benzyl-oxy-phenol and monobenzyl ether of hydroquinone (US Patent 3,060,097). This last compound has the disadvantage that it is not metabolized properly when it is absorbed by the skin, so it is associated with incidents of irreversible depigmentation that simulate a vitiligo (areas of skin depigmentation, often with a hyperpigmented border, which are extended gradually). Likewise, benzyl-oxy-phenol has the disadvantage that it is transported by the lymphatic system to other areas of the skin, far from the application site, where it can also exert a lightening effect. It has also been proposed as a skin depigmentation agent to the compound methoxyphenol, an ether of hydroquinone, which has been used in depigmenting pharmaceutical compositions, but has the drawback that, being relatively insoluble in aqueous media, it is difficult to be properly incorporated in cosmetic or dermatological formulations. Other compounds used to depigment the skin are 4-isopropyl catechol, a substituted derivative of hydroquinone (Application of South African Pat. No. 716,890) and hydroquinone fatty acid mono- and di-esters (European Patent Application No. 82301102.8). The direct use of hydroquinone in cosmetics has been proposed for the treatment of hyperpigmentation, since it is effective, soluble in water and rapidly metabolized and excreted. However, hydroquinone has the disadvantage that it is unstable in an alkaline medium and that it is oxidized to the quinone form, which imparts a brownish color to any pharmaceutical composition that contains it. To prevent this oxidation it is necessary to incorporate an antioxidant into the composition, such as ascorbic acid. In fact, it has been proposed, for example, the stabilization of the hydroquinone molecule by incorporating it into an anhydrous medium. Thus, US Pat. No. 4,466,955 describes a cosmetic preparation in which hydroquinone is dissolved in fatty esters and the resulting solution is incorporated into a nonaqueous cosmetic cream base in which hydroquinone is more stable and less prone to oxidation. This is because oxygen is less soluble in waxes than in water and therefore, the oxidation process occurs to a lesser extent. Furthermore, according to the revealed, this preparation favors the cutaneous absorption of hydroquinone. Hydroquinone is the generic name that receives compound 1, 4 benzenediol or p-dihydroxybenzene, which has a molecular weight of 110.0. Its mechanism of action is given by the inhibition of the enzymatic oxidation of tyrosine to 3, - ihydroxyphenyl-alanine (DOPA) and by the suppression of other melanocyte metabolic processes. The main disadvantage of hydroquinone is that it is also a skin irritant, which can cause paradoxical hyperpigmentation, called ochronosis. Likewise, the carcinogenic power of hydroquinone has been recently described, when at least 5 cases of cutaneous melanomas were described in a group of workers with daily contact with this substance. Idebenone, on the other hand, is a benzoquinone whose pharmacodynamic properties have been established within drugs with cytoprotective effects, as described for example in US Pat. No. 4,271,083. Idebenone is the generic name for the compound 6- (10-hydroxydecyl) -2,3-dimethoxy-5-methyl-1,4-benzoquinone (JP-B-62 3134 (1987), US Pat. No. 4,139,545) . Data obtained from in vitro trials suggest that the cytoprotective action of idebenone is achieved by facilitating the convergence of electrons in the mitochondrial respiratory cycle, inhibiting lipid peroxidation, reducing non-respiratory oxygen consumption and stimulating the formation of ATP. . Idebenone is considered a synthetic Coenzyme Q10 and is used, administered by mouth, to improve cognitive disorders, Alzheimer's disease, dementias and cerebral vascular disorders, and as a cardiac cytoprotector. Due to its antioxidant properties, it is administered orally, either alone, or in combination with other active substances, preferably also having anti-oxidant properties, such as vitamin E. Patent documents DE 3,049,039 , EP 0 788,793, US 4,436,753, US 5,059,627 and US 5,916,925 describe oral, parenteral or percutaneous preparations comprising idebenone or its derivatives, which can be used in the treatment of dementia, blood circulation disturbances or for the treatment of induction of neural growth factors. In particular, JP 1,279,818 discloses the use of idebenone and its derivatives in various preparations usable to give hair exogenous color (idebenone is a powder that has a strong orange color). To date, important toxic effects for idebenone have not been described (Arzneim, Forsch / drug res., 35 (II), 11, pp. 1704, 1985). Surprisingly, we have now found that a preparation for topical cutaneous use comprising idebenone can cause a significant decrease in pigment concentration in pigmented areas without producing significant side effects.

SUMMARY OF THE INVENTION The present invention relates to the use of idebenone in a composition intended to be applied to the skin, with the object of inhibiting melanogenesis. Also, the present invention relates to a composition intended for topical application on the skin, comprising a cosmetic, pharmaceutical and / or dermatologically effective amount of idebenone, its derivatives or mixtures thereof. In particular, the present invention relates to a cosmetic preparation capable of conferring a beneficial effect on the processes of cutaneous hyperpigmentation. Preferably, the present invention relates to cosmetic or dermatological preparations comprising idebenone and / or its derivatives, and which decrease the local increase in skin coloration caused by an increase in the production of melanins. The present invention also relates to the use of idebenone in a cosmetic composition intended to be applied to the skin in order to produce depigmentation of the skin at the site of application. In the present document, the term "depigmentation" should be understood as obtaining a discoloration in a pigmented area of the skin until achieving a coloration similar to that of the surrounding skin. In particular, the pigmented area may be due to some skin disorder and more particularly to skin disorders selected among psoriasis, rosacea, skin damaged by ultraviolet radiation, atopic dermatitis, post-drug hyperpigmentation, post-inflammatory hyperpigmentation, chloasma pregnancy and seborrheic dermatitis. Likewise, in the present document, the phrase "diminish skin coloration", should be understood as diminishing the tone of the skin until achieving a decrease in the colorimetric scale observable by the naked eye.

DETAILED DESCRIPTION OF THE INVENTION The composition intended for topical application on the skin of the invention can be, for example, in the form of a cream, gel, occlusive patch, emulsion or aerosol. Preferably, the composition of the invention is in the form of a cream (O / W). Also, according to the invention, the idebenone could be comprised in a controlled release topical composition, in particular, where the idebenone is liposomated or complexed. The formulation of this type of compositions is within the state of the art.

Preferably, the composition intended to be applied to the skin of the invention comprises idebenone or a derivative thereof in an amount comprised between 0.1% and 10% by weight. More preferably still, the idebenone or its derivative is in an amount comprised between 0.3% and 5% by weight. Examples of compounds derived from idebenone can be, among others, those disclosed in patent documents US 4,139,545, US 4,436,753, DE 3,049,039, EP 0,788,793, US 4,436,753, US 5,059,627 and US 5,916,925. The composition of the invention could be formulated by the person skilled in the art, using known cosmetically or pharmaceutically acceptable excipients. Preferably, the composition will comprise oily components and water-soluble components. Examples of oily components may be self-emulsifying wax, petrolatum, isopropyl myristate and cetyl alcohol. Examples of water-soluble components can be glycerin, methylparaben and propylparaben. Also, the composition of the invention could also contain skin beneficial agents such as humectants, moisturizers and vitamins, which are known and can be chosen by the person skilled in the art. If necessary, the composition of the invention may further comprise cosmetic and / or pharmaceutically acceptable antioxidants, filters and / or sun screens.

| The present invention also relates to a method for the treatment of unwanted skin pigmentation comprising placing in the pigmented site a composition comprising an effective desgregating dose of idebenone, allowing to act overnight and rinsing in the morning. . EXAMPLES Example No. 1 i) Formulations of aqueous cream (O / W) containing idebenone (IDB) Table I: ii) Procedure for preparing creams containing idebenone. The oily components (A) of the formulation (self-emulsifiable wax, Vaseline, Isopropyl myristate and Cetyl alcohol) are melted and heated to a temperature of 70 / 75aC. Separately, the water-soluble components (B) of the formulation (Glycerin, Methylparaben, and Propylparaben) are dissolved in the amount of water needed, as described above, and heated to 70 / 75aC. Then, checking that the temperature of the oily and water-soluble components is the same, the oil phase (A) is added to the aqueous phase (B) with vigorous and constant agitation. Cool in a water bath, and stir slowly until the temperature reaches 452C. Once the desired temperature is reached, the required amount of Idebenone, as described above, is dissolved in 0.5 ml of ethanol and added to the previous preparation with slow stirring until a homogeneous preparation is obtained. Allow to cool to desired consistency and properly packaged. In cases in which the concentration of Idebenone is greater than 3%, it is possible that it is necessary to increase the proportion of components of the oil phase to achieve solubilization of the active principle. If the concentration of Idebenone reguerida is much higher than 4%, the aqueous base cream can be replaced by an oily cream (W / O) Example No. 2 Effects of the application of a composition comprising idebenone applied on the skin of experimental animals. Creams containing 5% and 2.5% by weight of idebenone (IDV) were prepared in a neutral phase. Said creams and a cream of identical formulation but without idebenone were applied to nude adult mice of 3 months of age. The cream with IDB was applied on the right half of the body of the animals and the control cream on the left half according to the scheme that is detailed below. The animals were sacrificed after 1, 2, 3 or 4 hours after the application of the cream (p.a). Lot A: animal treated with IDB 5% (1 hour pa) Lot B: animal treated with IDB 2.5% (1 hour pa) Lot C: animal treated with IDB 5% (2 hours pa) Lot D: animal with IDB 2.5% (2 hours pa) Lot E: animal with IDB 5% (3 hours pa) Lot F: animal with IDB 2.5% (3 hours pa) Lot G: animal with IDB 5% (4 hours pa) Lot H: animal with IDB 2.5% (4 hours pa) The areas of treated and control skin were removed and divided into 3 sectors: one to dose idebenone by gas chromatography, another for determination of moisture retention and the third for inclusion in paraffin. Idebenone Dose by Gas Chromatography: The treated skin sections and controls were placed with the epidermis facing down on a cryostat plate and cuts were obtained parallel to the surface, 300 microns thick, in order to obtain a deep cut , a superficial cut and a medium cut. Each cut was identified, homogenized and resuspended in acetone. Each extract was analyzed by Gas Chromatography using a gaseous chromatograph model Hewlett Packard 5890, using a capillary column with methyl silicone as stationary phase (HP-IMS, 25m x 0.2 mm, 0.33μ of film thickness). The temperature program consisted of an initial temperature of 100 degrees Celsius for 3 minutes, then continue with a heating with temperature increases of 20 degrees Celsius per minute to reach 300 ° C. This last temperature was maintained for 5 minutes. A helium flow of 0.7ml / min was used. The chromatograph was fitted with a coupled quadrupole mass detector (model HP 5972) and electronic impact ionization at 70 eV was used, in SCAN mode, with a mass scan of 50 to 600 m / z. 2 μl of sample were injected in 1/25 split mode, with an injector temperature of 250 ° C and an interface temperature of 280 ° C. Moisture determination: Each section of treated and control skin was weighed on an analytical balance and then placed in an oven at 120aC for 30 minutes. Then the samples were cooled for 30 minutes at room temperature to be weighed again. The percentage of humidity was calculated according to the following formula: PREEVAPORATION WEIGHT - POST-EVAPORATION WEIGHT PREVIOUS WEIGHT In this way, the increase in water of the treated skin was calculated in relation to the control skin by dividing the percentage obtained in each treated area by the percentage obtained in the respective control. Morphological and morphometric studies: The thickness of the epidermis, the corneal layer, the papillary dermis and the reticular dermis were measured in at least 10 different points, the result being expressed as the average of the 10 measurements. Likewise, the diameters of the capillary vessels were measured in at least 10 points, expressing them by their average. The measurements were made using an image processing equipment Quantimet 500+ (Leica). Special colorations were made for components of the connective tissue and colorations of Giemsa, methylene blue, toluidine blue (to observe metachromasia and interstitial water distribution) and Schorr (the latter to observe keratin behavior). Immunohistochemical studies: in alternate sections of the material included in paraffin, overexpression of shock proteins was determined (heat shock proteins - HSPS) by enzymatic immunostaining techniques, using monoclonal antibodies directed against HSP27 (Dako Labs) and developed with an APAAP kit (Dako Labs). Morphology: The skins of the animals treated with cream with IDB at 5% and 2.5% did not show morphological alterations, being similar the microscopic images to the control skins. The special staining techniques did not show differences between the different samples examined, even in the different treatment times. There were also no changes in stains with Schorr stain for the observation of different qualities of keratins. Epidermal morphometry: The results are summarized in Table II. It can be seen that no significant differences were detected in the thickness of the epidermis or the stratum corneum between the treated skins and the control skins. No significant differences were detected between the two concentrations of IDB tested nor between the different application times of the creams. Therefore, it can be concluded then that idebenone applied topically does not substantially modify the epidermal thicknesses, thus showing local harmlessness. Table II: Thickness of total epidermis and corneal layer in mouse skin treated with creams containing 5 and 2.5% idebenone and its comparison with skin treated with a neutral cream without idebenone as control. The values are expressed in microns, as an average of ten measurements made (figures rounded to two decimals). In the case of the controls, the values are expressed as the average of the total measurements, that is, of two animals per point, since two controls were used, one for the cream containing TDB 5% and another one for the cream containing TDB 2, 5%.

Dermal morphometry: The thicknesses of the papillary dermis and the reticular dermis did not vary significantly among the different animals examined. Therefore, it can be concluded then that idebenone applied topically does not substantially modify the epidermal thicknesses, thus showing local harmlessness. Vascular diameters: The results are summarized in Table III. It can be seen that there are no significant differences between the vascular diameters of the microcirculation between the skins treated with IDB and the control skins, nor between the two concentrations of IDB tested or between the different application times of the creams. Therefore, it can be concluded that idebenone applied topically does not substantially modify the vascular diameters of the microcirculation, thus demonstrating the lack of local hemodynamic modifications. Table III: Diameters of dermal capillaries of skins treated with a cream containing IDB at 5%, a cream containing IDB at 2.5% and cream base (without IDB). The diameters are expressed in microns as an average of ten measurements made (figures rounded to two decimals). In the case of the controls, the values are expressed as the average of the total measurements, that is, of two animals per point, since two controls were used, one for the cream containing IDB 5% and another one for the cream containing IDB 2, 5%.

Overexpression of HSPs: No differences were detected in the expression of HSPs between the epidermis treated with the control cream (without IDB) and the epidermis treated with the cream containing IDB. There were also no differences between skins treated at different post-application times with creams containing IDB at 5% and 2%.,5%. Therefore, it can be concluded that the treatment with IDB in the concentrations studied does not produce increases in the expression of epidermal HSPs in the skin of mice, so it can be inferred that there is no epidermal injury that justifies the over-expression of this defense system cellular against aggression. Moisture determination: The weights of the treated and control skins, before and after the evaporative treatment, gave a similar percentage of humidity between the groups treated with different concentrations of IDB and the controls. There were also no significant differences between the different post-application times. The results are summarized in table IV.

Table IV: Percentages of moisture and water retention capacity in the treated skin with respect to the controls. The values are expressed in grams as the average of the determinations made at 1, 2 3 and 4 hours after the application of the creams.

Therefore, it can be concluded that treatment with IDB at the concentrations studied does not modify the amount of water in the tissues (the difference in water retention between skins treated with IDB and skins treated with cream without IDB is not statistically significant) . IDB skin penetration: After 2 hours of application, an IDB peak was obtained at a retention time of 17.6 minutes in the most superficial cut (this cut includes the entire epidermis and the upper portion of the dermis). ), both in the sample treated with IDB at 5% and with the sample treated with IDB at 2.5%. On the contrary, the samples corresponding to deep and middle sectors (reticular dermis and hypodermis) did not show this peak. On the other hand, 1 hour after the application, none of the samples showed this peak (neither those treated with IDB, nor the control samples). Therefore, it can be concluded that the IDB penetrates the skin and that it is retained after two hours of its application, in the most superficial sectors of the skin. Example No. 3 Effects of the application of compositions comprising different concentrations of idebenone on the skin of human beings. For these experiments skin samples were used from patients identified as Patients 1, 2 and 3, who underwent the following procedures: Patients 1 and 2: The mammary skin of two patients (both 74 and 71 years old) were used. years of age respectively) that would undergo a radical mastectomy and a simple mastectomy due to the presence of a mammary carcinoma and florid dysplasia. Approximately 45 minutes before admission to the operating room, the mammary surface was divided into three territories with a similar surface and approximately 120 mg of IDB containing 5% cream was added in the first, by means of a gentle circular massage, until the total absorption of the cream. The two remaining sectors were treated in a similar way, using in each of them cream containing approximately 120 mg of cream containing IDB 2.5% and cream control. Once in the operating room, and prior to the preparation of the operative field, the mammary surface was washed with ethanol 95a to remove any excess cream. Immediately after the operation (average surgical activity time: 45 minutes), approximately 4 cm2 of a skin area of each area was resected, identifying it correctly. Once the sector was resected, the subcutaneous adipose tissue was carefully removed, in such a way as to obtain only the epidermis and dermis. Patient 3: The mammary skin of a patient (female, 54 years of age) who would undergo a radical mastectomy due to the presence of a mammary carcinoma was used. Approximately 45 minutes before admission to the operating room, the mammary surface was divided into three territories with a similar surface and approximately 120 mg of IDB containing 5% cream was added in the first, by means of a gentle circular massage, until the total absorption of the cream. The two remaining sectors were treated in a similar way, using in each of them cream containing approximately 120 mg of cream containing IDB 0.5% and cream control. Once in the operating room, and prior to the preparation of the operative field, the mammary surface was washed with ethanol 95a to remove any excess cream. Immediately after the operation (average surgical activity time: 90 minutes), approximately 4 cm2 of a skin area of each area was resected, identifying it correctly. Once the sector was resected, the subcutaneous adipose tissue was carefully removed, in such a way as to obtain only the epidermis and dermis. The effect of the application of creams containing 0.5%, 2.5% and 5% idebenone on the morphology and morphometry of the different skin layers of the blood vessels was investigated on the skin samples of Patients 1, 2 and 3. of the dermal plexus and on the expression of HSPs, as a way to evaluate the epidermal response to an eventual deleterious effect of the creams. The leather sectors treated with creams containing IDB and with control cream were fixed in formaldehyde solution, were included in paraffin and stained with histological staining techniques by haematoxylin and eosin, Schorr, Giemsa, and toluidine blue. Morphometry: Measurements of epidermal thickness, corneal layer, papillary dermis, reticular dermis and capillary diameters of the dermal plexus were made on the histological sections.

Immunohistochemical study: Alternary cuts included in paraffin were dewaxed, and incubated with an antiserum of commercial origin directed against HSP27 (Dako Labs). The reaction was revealed using an APAAP kit (Dako). Macroscopic appearance: The areas of skin treated with IDB-containing creams, with control creams without IDB and without treatment did not show significant differences when they were observed with the naked eye. Therefore, it can be concluded that the treatment with IDB containing creams, in the different concentrations tested, did not produce irritation during the time they remained applied. Microscopy: no structural alterations were detected in the skins treated with the control creams or in the skins treated with creams containing different concentrations of IDB, even when special staining techniques were used. In particular, there was no interstitial fluid accumulation, vascular alterations or accumulation of inflammatory elements in the dermis. All the epidermal layers studied maintained their integrity and architecture. Morphometric analysis of epidermal thicknesses: The results obtained are briefly summarized in the following table.

Table V: Thickness values of the total epidermis and of the horny skin layer of mammary skin treated with creams containing TDB at different concentrations and control, for different time. The values obtained are expressed in microns, as a result of the average of 10 determinations made.

Therefore, it can be concluded then that the application on the skin of creams containing different concentrations of IDB does not significantly modify the epidermal thicknesses.

Morph ametry of the dermis: No significant differences were detected in the measurements of the thickness of the reticular dermis and papillary dermis between the different samples evaluated. Therefore, it can be concluded that the application of creams containing different concentrations of IDB does not produce immediate skin changes. Morphometry of dermal plexus vessels: No significant differences were detected in the measurements of vascular diameters between the different samples evaluated. The results obtained are summarized in the following table: Table VI: Vascular diameters of dermal plexus vessels of skins treated with creams containing different concentrations of IDB and control cream. The values obtained are expressed in microns, as a result of the average of 10 determinations made.

Table VI (continued) From the results obtained, it can be concluded that the application of creams containing different concentrations of IDB does not modify the vascular tone of the treated skin. Distribution and expression of HSP21: No differences were detected in the expression and distribution of HSP in the different samples treated with creams containing different concentrations of IDB and with control creams (without IDB) in any of the evaluated patients. From the results obtained, it can be concluded that the application of creams containing different concentrations of IDB does not modify the expression and distribution of HSP27, this protein being a parameter of the epidermal response to an eventual injury.

Example No. 4 Effects of the application of a composition comprising idebenone applied on the skin of humans: Determination of humidity The patient's mammary skin identified as 3 in the previous example was used. A base cream as used in Example 1 was fractionated into 3 aliquots, adding to the first a sufficient amount of idebenone (99.3% purity) to obtain a final concentration of IDB of 5%, to the second a sufficient amount of idebenone (99.3% purity) to obtain a final concentration of IDB 0.5% and the third aliquot was used (without IDB aggregate) as control. Moisture determination: Each section of treated and control skin was weighed on an analytical balance and then placed in an oven at 120aC for 30 minutes. Then the samples were cooled for 30 minutes at room temperature to be weighed again. The percentage of humidity was calculated according to the following formula: PREEVAPORATION WEIGHT - POST-EVAPORATION WEIGHT PREVIOUS WEIGHT In this way, the increase in water of the treated skin in relation to the control skin was calculated by dividing the percentage obtained in each treated area by the percentage obtained in the respective control. The results obtained are briefly summarized in the following table: Table VII Therefore, the IDB applied topically on the skin, at the concentrations studied, did not increase the amount of water contained in the skin. Example No. 5 Inhibition of melanogenesis by idebenone. In order to evaluate the ability of idebenone to inhibit melanogenesis, in vitro determinations were made following the method developed by Dooley et al. (Skin Pharmacol, 199; 7: 188-200), according to the procedure described continuation: Materials and methods: Cells: The study was conducted using a cell line derived from human melanoma, provided by ABAC (Asociación Banco Argentino de Células), with melanin synthesis capacity (SK-MEL-28, ATCC origin). The cells were grown in plastic culture flasks or in 24-well plastic plates, in a modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum (SBF) and kept at 37 ° C in a C02 to 5 atmosphere. %. Tested compounds: Idebenone, provided by Droguería Saporiti, Argentina, lot 02107, with 99.80% purity calculated on dry drug. Hydroquinone (1,4-benzenediol), provided by Droguería Saporiti, Argentina, lot 010715, with 99.85% purity, calculated on dry drug. Study of the compounds in vi tro: SK-MEL cells, raised with trypsin, were seeded in 24-well plastic plates (density of 1 x 105 cells per well) and incubated for 24 hours in modified Eagle's medium (DMEM) supplemented with serum. Fetal bovine (SBF) at 10% prior to treatment with the compound to be evaluated. After 24 hours, the medium was replaced by 990 μl of fresh medium. To the latter was added 10 μl of sterile vehicle (50% of propylene glycol, 30% of ethanol and 20% of distilled water) containing different concentrations of the compounds to be evaluated. The SK-el cells tolerated the vehicle well at 1% (final concentration: 0.5% propylene glycol and 0.3% ethanol). Decimal dilutions of each compound were prepared in the sterile vehicle to obtain final concentrations of the compound to be studied between 1,000 and 0.01 μg / ml. This procedure was repeated daily for three days. On the fourth day, the cells were not treated and on the fifth day, the remaining adherent cells were tested according to the methods described below. In this way, the cells were continuously exposed to the compounds under study during the 5 days that the culture lasted. All concentrations of the compounds were studied in triplicate, comparing the average of the 3 treated pits with the compounds with those treated with vehicle only. Determination of melanin content: the melanin content of the SK-el cells was determined after the removal of the culture medium and the washing of the cells with PBS. Next, the cells were lysed by the addition of 1 ml of IN NaOH to each well and repeated manual pipetting. The crude cell extract was analyzed using a spectrophotometer at 400 and 475 nm to determine the content of melanin and dopaquinone, respectively. The results were expressed as a percentage of cell cultures treated with vehicle.

Quantification of the cellular number with violet crystal: A staining with an aqueous solution of crystal violet was used in order to determine, by indirect methods, the number of cells adhering to the plastic surviving the treatment in vi tro. After the treatment period, the middle of the pits was decanted by inverting the plate and replaced by 0.5 ml of 0.1% violet crystal (in 10% ethanol) per pit. The plates were stained for 5 minutes at room temperature, on a rotating platform, with gentle shaking. Then, the excess dye was decanted by inversion and the whole plate was immersed 4 times in distilled water in a suitable container. After rinsing, the plates were inverted and allowed to drain on absorbent paper until complete removal of excess water. The violet crystal retained in the adherent cells was later extracted by the addition of 1 ml of ethanol (95%) per pit. Finally, the plates were placed on a rotary shaker for 30 minutes at room temperature. The optical densities of the alcohol samples were determined with the help of a spectrophotometer (wavelength = 590 nm) using plastic cuvettes with 95% ethanol as target. When the cell densities were very high (for example, when the optical densities were higher than 2.0), dilutions of each sample were prepared in 95% ethanol and thus were analyzed spectrophotometrically. To determine the fraction of cells surviving the treatment in a specific concentration of the agent in experimentation, the D0590 treated pits (average of three determinations) was divided by the D059o of the pits used with control vehicle (average of three determinations). The percentage of cellular survival (graduated as a percentage of the control vehicle) was obtained by multiplying said fraction by 100. Determination of melanin content: Table VIII shows the average values of D040o and D075 of three simultaneous determinations for idebenone dilutions and of hydroquinone. Table VIII Table VIII (continued) -5 0.034 0.0163 Control 0.033 0.0163 and, expressed as percentages: From the results obtained, it can be concluded that, in the model used, the compound idebenone inhibits the synthesis of melanin in a dose-dependent manner. Although at high concentrations the effect of idebenone could be considered similar to that of hydroquinone, after some dilution, the latter ceases to have an effect. In contrast, the idebenone compound continues to inhibit, even at higher dilutions. The production of dopaquinone is also affected in a similar way to melanin synthesis, indicating that the inhibition is complex, inhibition can occur at several sites of the metabolic pathway of melanin. Quantification of cell number with crystal violet: The following table summarizes the percentages of viable cells after treatment with different dilutions of idebenone and hydroquinone. Table IX Table LX (continued) From the results obtained, it can be concluded that high concentrations of idebenone can be toxic for the cells. Likewise, something similar happens with hydroquinone, although for the latter, the toxicity was greater. Since this toxicity could interfere with the reading of the optical densities of melanin and dopaquinone, similar experiments were developed using other dilutions, different incubation times and using only idebenone (since the effects of hydroquinone on this system and they are described in the bibliography). They are described in the following examples. Example No. 6 Inhibition of melanogenesis after 1 day of treatment with idebenone In order to establish whether idebenone inhibits melanogenesis in cells in culture, an experiment similar to that described in the previous example was designed, but in this case the cells were treated during 1 day only, while the results were evaluated on the third day. Likewise, the presence or absence of cytopathic effects on cell cultures was evaluated by using an inverted microscope, starting with a dilution -2 and reaching the dilution -6. Table X shows the optical densities 400 and 475 (for melanin and dopaquinone, respectively) of the different dilutions tested, and their respective percentages. Table X From these results it is inferred that idebenone begins to inhibit both the synthesis of melanin and that of its byproducts (for example dopaquinone) after 24 hours of treatment, in a dose-dependent manner. In this experiment, dilution -1 was not taken into account due to the cytopathic effects of the cultures. The remaining dilutions showed no cytopathic effect, so it can be considered that idebenone at the doses used is not cytotoxic. It is noteworthy that the -5 and -6 dilutions had a higher amount of melanin and dopaquinone than the controls. This could simply be due to an error in the method and, therefore, not be significant. However, without wanting to be tied to a particular theory, there would be the possibility that with the incubation time used and at these dilutions, the idebenone compound could exert a melanogenesis-stimulating effect, which is probably temporary. Example No. 7 Inhibition of melanogenesis after 2 days of treatment with idebenone In order to establish whether idebenone inhibits melanogenesis in cells in culture, an experiment similar to that described in the previous example was designed, but in this case the cells were treated for 2 days and on the fourth day the results were evaluated, day.

Likewise, the presence or absence of cytopathic effects on cell cultures was evaluated by using an inverted microscope, evaluating only dilutions -4, -5 and -6. Table XI shows the optical densities 400 and 475 (for melanin and dopaquinone, respectively) of the different dilutions tested, and their respective percentages. Table XI These results would indicate that there is a stimulation of the synthesis of melanin in the dilutions - 4 and -5, even though the dilution -6 shows an inhibition. This could be indicating that the stimulation, if any, would continue during the 2nd day of treatment, although the values found closely resemble the values of the controls, and the -6 dilution shows inhibition as expected. No cytopathic effect was observed.

Example No. 8 Inhibition of melanogenesis after 3 days of treatment with idebenone In order to establish whether idebenone inhibits melanogenesis in cells in culture, an experiment similar to that described in the previous example was designed, but in this case the cells were treated for 3 days and on the fifth day the results were evaluated, day. Also, by using an inverted microscope, the presence or absence of cytopathic effects on cell cultures was evaluated, evaluating only dilutions -4, -5 and -6. Table XII shows the optical densities 400 and 475 (for melanin and dopaquinone, respectively) of the different dilutions tested, and their respective percentages. I abl to XII These results would indicate that on the third day of treatment there is an inhibition of melanin synthesis in a dose-dependent manner. The amount of dopaquinone in the -6 dilution is similar to the control. No cytopathic effect was observed. Example No. 9 Inhibition of idebenone-mediated melanogenesis at high dilutions In order to establish the effect on melanogenesis in cells in culture, produced by low concentrations of idebenone, an experiment similar to that described in Example 6 was designed but using dilutions -2, -3, -4, -5, -6, -7 and -8. Table XIII shows the optical densities 400 and 475 (for melanin and dopaquinone, respectively) of the different dilutions tested, and their respective percentages. Table XIII Table XIII (continued The results indicate the compound idebenone, even when it is very diluted, retains its inhibitory capacity on melanogenesis. However, it was not possible to demonstrate a clear dose-response relationship. Example No. 10 Depigant capacity of a cream containing 2.5% idebenone, in a patient with chloasma of pregnancy. Female patient, of 43 years of age, of Peruvian nationality, with Inca ancestry and of skin type III, who claims to have had a pregnancy and a delivery 9 years ago and who during the second trimester of pregnancy presented a gravidarum stain ( chloasma of pregnancy), in the form of butterfly wings, on both malar regions of its face, a spot that persists to the present and that increases its pigmentation during the summer months by exposure to the sun, with well-defined edges and contrasting with the skin surrounding. Treatment: the patient was instructed to place a sufficient amount of 2.5% idebenone cream in the spot, according to Example 1, daily before going to bed, leaving the cream on overnight and rinsing the face with plenty of water and neutral soap the next morning. The application was made during 20 consecutive days. The patient was reviewed clinically at 7, 14 and 21 days after starting the treatment, comparing the pigmented area with the surrounding skin. Results: Gradually, a general decrease in the pigmentation of the hyperpigmented skin was observed, which became noticeable on day 21, although it did not reach a color similar to the skin without hyperpigmentation. The edges of the pigmented macule were attenuated, erased, ceasing to be marked and unmistakable, presenting a degradation from the central zone of the chloasma towards the surrounding skin. Conclusions: 2.5% idebenone cream is effective to attenuate the skin pigmentation of gravidarum chloasma, an entity characterized by a localized hyperpigmentation of probable hormonal etiology. Aungue the treatment was discontinued, the results indicate that the continuation of the treatment could lead to the complete disappearance of the hyperpigmentation. EXAMPLE 11 Depigmenting capacity of a cream containing 2.5% idebenone in a patient with post-inflammatory hyperpigmentation. Female patient, 40 years old, of Argentine nationality and white skin type II, who presents a significant photo-active damage and who claims to have had 3 pregnancies and three deliveries 9, 11 and 14 years ago and that after a process waxing of his bozo, presents in the traumatized area a residual hyperpigmentation of more than 3 years of evolution, which persists to the present, increasing its pigmentation during the summer months by exposure to the sun, well-defined, contrasting edges with the surrounding skin Treatment: the patient was instructed to place in the spot site a sufficient amount of 2.5% idebenone containing cream according to Example 1, daily before going to sleep, leaving the cream placed during the night and rinsing the face with plenty of water and neutral soap the next morning.The application was performed for 20 consecutive days.The patient was clinically reviewed at 7 , 14 and 21 days after starting the treatment, comparing the pigmented area with the surrounding skin. The patient was instructed not to expose herself directly to solar radiation during the entire treatment. Results: Seven days after the start of the treatment, there was a general decrease in the pigmentation of the hyperpigmented skin, which became noticeable on day 14, and by day 21, the hyperpigmented area modified its edges, decreasing the size of the macula, irregularly. The edges of the pigmented macula were attenuated, erasing in sectors. Conclusions: 2.5% idebenone-containing cream is effective in attenuating post-inflammatory skin pigmentation, an entity characterized by localized hyperpigmentation consistent with a dermal inflammatory process. Even if the treatment was discontinued, the results indicate that the continuation of the treatment could lead to the complete disappearance of the hyperpigmentation. EXAMPLE 12 Depigmenting capacity of a cream containing 5% idebenone, in a patient with post-drug hyperpigmentation Female patient, 46 years old, of Argentine nationality and of type III dark skin, who claims to have had 1 pregnancy and 1 childbirth 8 years ago and suffering from plaque psoriasis in both elbows. The patient states that after a treatment with psoralens she presented hyperpigged maculae in both elbows, on which plaques of psoriasis still develop, which remit and exacerbate, always leaving the hyperpigmented base more extensive than the area affected by psoriasis. The hyperpigmentation would be fixed for about 5 years. Treatment: the patient was instructed to place in the spot site a sufficient amount of 5% idebenone-containing cream according to Example 1, daily before going to sleep, leaving the cream on overnight and rinsing the application site with plenty of water and neutral soap the next morning. The application was made for 15 consecutive days. The patient was reviewed clinically 7 and 15 days after starting the treatment, comparing the pigmented area with the surrounding skin. The patient was instructed not to expose herself directly to solar radiation during the entire treatment. After having passed 6 months of the treatment, a new comparison of the pigmented area with the surrounding skin was made.

Results: Seven days after starting the treatment, a general decrease in the pigmentation of the hyperpigmented skin was observed, which became more noticeable by day 15, decreasing the size and color of the hyperpigmented areas and acquiring skin color. surrounding. Conclusions: the cream containing idebenone at 5% is effective to attenuate the post-drug cutaneous pigmentation. EXAMPLE 13 Stability Study in Rack of a Formulation containing Idebenone 0.3% The stability of two formulations elaborated on different dates, but of identical composition was studied. Both were formulated in the form of an aqueous cream (O / W) containing Idebenone 0.3%: The oldest formulation analyzed was packed in a white polystyrene jar and stored on a shelf for 600 days at room temperature. and sheltered from light. Table XIV: Quantitative formula of an aqueous cream (O / W) containing 0.3% idebenone. Amounts for 100 grams. COMPONENTS% IN WEIGHT Water 79.7 Table XIV (continued) The methodology used for the quantification of the active principle was UV-Vis spectrophotometry. A non-significant difference was obtained in the evaluation of the active principle, for the most recent creams (1 month since its preparation) and the oldest creams (20 months since its preparation). It is concluded that this cream can be considered stable for at least 600 days (20 months) EXAMPLE 14 Stability Study in a Formulation Rack containing Idebenone 3% The stability of two formulations elaborated on different dates, but of identical composition was studied. Both were formulated in the form of an aqueous cream (O / W) containing Idebenone 3%: The oldest formulation analyzed was packed in a white polystyrene jar and stored on a shelf for 600 days, at room temperature and at room temperature. shelter of light. Table XV: Quantitative formula of an aqueous cream (0 / W) containing 3% idebenone. Amounts for 100 grams.

The methodology used for the quantification of the active principle was UV-Vis spectrophotometry. A non-significant difference was obtained in the evaluation of the active ingredient, for the most recent creams (1 month since its preparation) and the oldest (20 months since its preparation). It is concluded that this cream can be considered stable for at least 600 days (20 months)

Claims (20)

1. NOVELTY OF THE INVENTION Having described the invention as above, property is claimed as contained in the following: CLAIMS l.Use of idebenone in a composition intended to be applied on the skin, characterized because it is used to inhibit melanogenesis.
2. 2. Use of the idebenone in a composition intended to be applied to the skin, according to claim 1, characterized in that it is used to reduce the coloration of the skin or to clarify it at the application site.
3. 3. Use of idebenone in a composition intended to be applied to the skin, according to claim 1, characterized in that it is used to produce depigmentation of the skin at the application site.
4. 4. Use of idebenone in a cosmetic, pharmaceutical and / or dermatological composition intended to be applied on the skin, according to claim 1 characterized by it is used to produce depigmentation of the skin in pigmented sites due to skin disorders .
5. 5. Use of idebenone according to claim 4 characterized in that the skin disorders are selected among psoriasis, rosacea, photodamaged skin, atopic dermatitis, post-drug hyperpigmentation, post-inflammatory hyperpigmentation, chloasma of pregnancy and seborrheic dermatitis.
6. 6. A cosmetic, pharmaceutical and / or dermatological composition intended to be applied to the skin characterized by the drug comprising idebenone or a derivative thereof and because the idebenone or its derivative is present in an amount effective to cause depigmentation of the skin.
7. 7. A composition intended to be applied to the skin according to claim 6 characterized by comprising idebenone or a derivative thereof and in that the idebenone or its derivative is in an amount comprised between 0.1% and 10% by weight.
8. 8. A composition intended to be applied to the skin according to claim 6, characterized in that it comprises idebenone or a derivative thereof and that the idebenone or its derivative is in an amount comprised between 0.3% and 5% by weight.
9. 9. A composition intended to be applied to the skin according to claim 6 or 7, characterized in that it is in the form of an occlusive patch.
10. 10. A composition intended to be applied to the skin according to claim 6 or 7, characterized in that it is in the form of a cream.
11. 11. A composition intended to be applied to the skin according to claim 6 or 7, characterized in that it is in the form of a gel.
12. 12. A composition intended to be applied to the skin according to claim 6 or 7, characterized in that it is in the form of an emulsion.
13. 13. A composition intended to be applied to the skin according to claim 6 or 7, characterized in that it is in the form of an aerosol.
14. 14. A composition intended to be applied to the skin according to claim 6 or 7 characterized in that the idebenone is liposome, complexed or in a controlled release system.
15. 15. A composition intended to be applied to the skin according to claim 6 or 7, characterized in that it also comprises oily components and water-soluble components.
16. 16. A composition intended to be applied to the skin according to claim 14, characterized in that it comprises self-emulsifying wax, petrolatum, isopropyl myristate and cetyl alcohol.
17. 17. A composition intended to be applied to the skin according to claim 14, characterized in that it comprises glycerin, methylparaben and propylparaben.
18. 18. A composition intended to be applied to the skin according to claim 14, characterized in that it also comprises skin beneficial agents, filters and / or sunscreens.
19. 19. A composition intended to be applied to the skin according to claim 14, characterized in that it also comprises cosmetic and / or pharmaceutically acceptable antioxidant agents.
20. 20. A method for the treatment of unwanted skin pigmentation characterized by comprising placing in the pigmented site a composition comprising an effective depigmenting dose of idebenone, allowing to act overnight and rinsing in the morning.