WO2012020070A2 - Enhancement of the skin depigmentation - Google Patents

Abstract

The invention relates to a skin depigmentation composition comprising (i) a methimazole derivative, (ii) at least one compound selected from the group consisting of primary antioxidants and secondary antioxidants, and/or (iii) dermatologically acceptable carriers. The present invention further relates to the cosmetic and pharmaceutical use thereof for reducing skin pigmentation.

Description

ENHANCEMENT OF THE SKIN DEPIGMENTATION

RELATED APPLICATIONS

This application claims priority to USSN 61/372,126, filed August 10, 2010, which herein incorporated by reference in its entirety.

FIELD OF THE INVENTION

The invention relates to a skin depigmentation composition comprising (i) a methimazole derivative, (ii) at least one compound selected from the group consisting of primary antioxidants, secondary antioxidants, and metal chelators, and (iii) dermatologically acceptable carriers. The present invention further relates to the cosmetic and pharmaceutical use thereof for reducing skin pigmentation.

BACKGROUND OF THE INVENTION

Human skin color is quite variable around the world. Skin coloration in humans arises from a complex series of cellular processes that are carried out within the melanocytes located in the lower part of the epidermis. These processes result in the synthesis and transfer of a pigment, melanin, which, besides being responsible for skin color and tone, is the key physiological defense against sun-induced damage, such as sunburn, photoaging and photocarcinogenesis.

Hyperpigmentation, hypopigmentation, and other skin pigmentation disorders are quite common and can arise from a number of causes including excessive sun exposure, medications and the like. Common pigmentation disorders include melasma (dark patches experienced during or after pregnancy) and liver spots (which often develop with age), and may arise as a side effect of birth control pills, and/or as a persistent result of acne, burns, bites and other skin injuries. Similarly, freckles, chloasma and pigmentary deposits after sun exposure tend to occur or increase or become difficult to disappear with increasing age, thus being one of the more disconcerting and/or common problems of skin care for persons of middle to advanced age. Post inflammatory hyper-pigmentation is also found to occur following laser therapy.

In an effort to simply obtain brighter/lighter skin or address the pigmentation disorders, various compositions have been formulated. The use of such compositions is not limited for use in treating pigmentation disorders but is also used in some cultures/markets merely for the purpose of changing or modifying ones natural healthy skin color.

A large number of agents and methods for skin depigmentation have been developed and put on the market. Such methods include the oral administration of large doses of Vitamin C, the parenteral administration of glutathione, the topical administration of peroxide bleaching agents such as hydrogen peroxide, zinc peroxide, sodium peroxide and the like, and the topical application of Vitamin C and/or cysteine. Vitamin C, however, has stability issues, especially in water based formulations, resulting in color and odor changes. Thiol compounds such as glutathione and cysteine have slow and/or generally poor depigmentation

performance properties. The most commonly employed depigmentation agent has been hydroquinone and its derivatives. However, these compounds, while effective, have serious, detrimental side effects. Even at concentrations below 2%, hydroquinone is both irritating and cytotoxic to the melanocytes. Similar problems have been experienced with kojic acid depigmentation agents as well. Another known depigmentation agent is tretinoin, an effective treatment for both wrinkles and skin pigmentation but is also known to cause skin irritation that can lead to skin darkening.

A wide-range of polyphenols present in plant extracts have also been used for skin depigmentation purposes. Such natural polyphenols are for example anthraquinones, arylbenzofurans, chalcones, coumarins, and flavonoids. One class of polyphenols compounds that has received a lot of attention is that based on substituted resorcinols and their derivatives. However, despite their relatively good skin lightening capabilities, they tend to suffer from stability issues, which also oftentimes coincide with loss of skin lightening efficacy, rendering them generally unsuitable for topical applications.

Another agent, which demonstrated interesting depigmentation effects, is the peroxidase inhibitor methimazole (1 -methyl-2-mercapto imidazole; MMI) (J. Invest.

Dermatol., 2002;118:205-207; J. Invest. Dermatol., 2004: 122:1338-1341; Dermatology, 2005;211(4):360-2). Methimazole, an antithyroid agent belonging to the thionamide group, exerts inhibitory action towards both mushroom tyrosinase and peroxidase and, in brown guinea-pigs, induces mild to moderate inhibi tion of melanization, with morphologic changes of melanocytes. Unlike most above-mentioned depigmentation agents, such as hydroquinone and kojic acid, methimazole is a noncytotoxic, nonmutagenic compound. However methimazole has a weak to moderate depigmentation effect in-vivo despite its potent peroxidase inhibitory action.

Consequently there is still a need for a skin depigmentation composition that provides effective skin depigmentation capabilities and does not cause significant inflammation, irritation, or photosensitivity of the skin following application.

An ideal skin depigmentation composition should have a potent, rapid and selective depigmentation effect on melanocytes, carry no short- or long-term side-effects and lead to a permanent removal of undesired pigment, acting at one or more steps of the pigmentation process.

SUMMARY OF THE INVENTION Provided herein are skin depigmentation compositions containing i) a methimazole derivative of formula I

formula I

wherein Y is selected from the group consisting of Ή, C C20 alkyl, C1-C20 substituted alkyl; -N02, and the phenyl moiety

and wherein no more than one Y group in said methimazole derivative may be the phenyl moiety;

Rl is selected from the group Consisting of H, C1-C10 alkyl and CI -CIO substituted alkyl;

R2 is selected from the group consisting of null, H, -OH, C1-C4 alkyl, and C1-C4 substituted alkyl;

R3 is selected from the group consisting of H, -OH, C1-C4 alkyl, and CI -C4 substituted alkyl;

R4 is selected from the group consisting of H, C1-C4 alkyl, and C1-C4 substituted alkyl;

X is selected from =S, =0 and -SH; or a pharmaceutically acceptable salts thereof; ii) at least one compound selected from the group consisting of primary antioxidants and secondary antioxidants, and iii) one or more dermatologically acceptable carriers.

The combination of a methimazole derivative with one or more primary antioxidants and/or one or more secondary antioxidants enhances the skin depigmentation effect of the methimazole derivative in a synergistic manner. Also provided are methods for preventing or reducing pigmentation of normal skin. The present invention further provides methods for preventing and reducing skin pigmentation disorders in patients suffering therefrom.

The methimazole derivative of the present invention can include, but is not limited to, l-methyl-2-mercaptoimidazole. Preferably, the methimazole derivative of the present invention is l-methyl-2-mercaptoimidazole or methimazole. Any of the skin depigmentation compositions of the present invention may contain a concentration (e.g. , "a depigmentation effective amount") of methimazole or a methimazole derivative of about 0.001 -30%, preferably 0.01-10.0%, most preferably 0.1-5.0% by weight of the composition.

Suitable primary antioxidants of the present invention include, but are not limited to, butylated hydroxy toluene (BUT), butylated hydroxyanisole, tertiary-butylhydroqiunone, melatonin, glutathione and its derivatives, nicotinamide, the vitamin B group and their derivatives vitamin E and its derivatives, retinoic acid and its derivatives, polyphenols, carotenoids, licopene, hindered amines, phosphites, and/or mixtures thereof. In one preferred embodiment, the one or more primary antioxidants of the present invention is BHT.

Preferably, the primary antioxidant is not vitamin C, or ascorbic acid. The amount of the one or more primary antioxidants in the skin depigmentation composition of the present invention may range from about 0.0001 to 20% based on the weight of the total composition, preferably from about 0.01 to 10.0%.

Additionally or alternatively, the composition may contain one or more secondary antioxidants. For example, the one or more secondary antioxidants of the present invention can include, but are not limited to, thiodipropionic acid derivatives, thioesters, metal thiolates, Dioctadecyl disulphide and 1 ,3-dihydro-4(or 5)-methyl-2H-benzimidazole-2-thione or mixtures thereof. In a preferred embodiment, the one or more secondary antioxidants of the present invention is dileuryl thio dipropionate (DLTDP). The amount of the one or more secondary antioxidants in the skin depigmentation composition of the present invention may range from about 0.0001 to 20.0% based on the weight of the total composition, preferably from about 0.05 to 10.0%.

Preferably, the compositions and methods disclosed herein are used on mammalian skin (e.g. , human skin).

In one preferred embodiment, the skin depigmentation composition of present invention comprises l -methyl-2-mercaptoimidazole, BHT, and one or more dermatologically acceptable carriers.

Examples of suitable dermatologically acceptable carriers include, but are not limited to, preservatives, antioxidants, bactericides, perfumes, substances for preventing foaming, dyestuffs, pigments which have a coloring effect, thickeners, propellants, surfactant substances, emulsifiers, softening, moisturizing and/or moisture-retaining substances, distilled water, fats, oils, waxes or other conventional constituents of a cosmetic or dermatological compositions, such as alcohols, polyols, polymers, foam stabilizers, electrolytes, organic solvents or silicone derivatives. The necessary amounts of the dermatologically acceptable carriers can, based on the desired product, routinely be ehosen by a person skilled in the art, without undue experimentation.

In some embodiments, the skin depigmentation compositions of the present invention may further comprise the usual alcohols, especially lower alcohols, for example, ethanol and/ or isopropanol, low diols or polyols and their ethers. In some embodiments, the skin depigmentation compositions of the present invention may further comprise one or more thickeners, and/or one or more neutralizing agents, and/or one or more filter substances that absorb UV radiation, and/or one or more skin penetrants.

The skin depigmentation compositions of the invention may be cosmetic, dermatologic, or pharmaceutical compositions, and may exist in a wide variety of forms, such as emulsions, suspensions, solutions and the like. In certain embodiments, the compositions of the invention are in the form of lotions, creams, gels, solutions, sprays, cleansers, powders, ointments, waxes, lipsticks, soaps, shampoos, hydroalcoholic solutions, suspensions, scrubs, saturated pads, skin or hair conditioning agents, and other types of cosmetic compositions. In further embodiments, the compositions of the invention may be, for example anhydrous preparations, oil-free preparations, emulsions or microemulsions of the type water-in-oil (W/O) or of the type oil-in-water (O/W), multiple emulsions, for example of the type water-in-oil-in-water (W/O/W), solid sticks, or even aerosols.

The compositions of the invention can be prepared by any method(s) known in the art for cosmetic and/or dermatological compositions.

In one preferred embodiment, the form of the present skin depigmentation composition is: an oil in water hydrophilic cream (vanishing cream) containing stearic acid, petrolatum, cetyl alcohol, lanolin, paraffin, sorbitol, glycerin, metyl paraben and propyl paraben, triethanolamine and water (76.5% w/w) together with 5% methimazole and 0.04% butylated hydroxytoluene.

The skin depigmentation composition of the present invention can be used to prevent and treat skin pigmentation disorders, including, but not limited to, hyperpigmentation, melasma, postinflammatory hyperpigmentation, lentigo, freckles, drug induced

hyperpigmentation, light induced hyperpigmentation and/or chemical-induced

hyperpigmentation. Those skilled in the art will recognize that any of the methods and compositions for use of the invention can be used to treat any skin diseases and disorders where individuals suffering from the disease or disorder have abnormally high or elevated levels of pigmentation in skin as compared to normal skin.

The skin depigmentation composition of the present invention can be further used in cosmetic methods for preventing or reducing pigmentation of normal skin. In such cosmetic methods for preventing or reducing pigmentation of normal skin, an effective amount of any of the skin depigmentation compositions of the invention are topically applied to the skin of a patient. Determination of the effective amount of the skin depigmentation composi tions of the invention is within the routine skill of those in the art.

The skin is preferably at least one of facial skin, skin on the neck, skin on the arms, skin on the hands and skin on the legs. As used herein, the term "normal skin" is referred to healthy skin having no pigmentation disorders.

Any of the compositions described herein can be used for treatment of skin

pigmentation disorders or in cosmetic methods for preventing or reducing pigmentation of mammal skin. Likewise, any of the compositions described herein can be used in the manufacture of the medicament for treating skin pigmentation disorders or for preventing or reducing pigmentation of mammal skin.

In any of the methods according to the invention, the skin depigmentation compositions are applied to the skin, preferably human skin. Preferably, the compounds and compositions described herein are applied topically to a mammal's skin (i.e., human skin). The amount of the skin depigmentation composition that is to be applied to the skin depends upon the form of the skin depigmentation composition and its mode of application. The compositions may be applied one or more times per day depending on the activities the particular subject is engaged in.

Also provided are skin depigmentation compositions containing 0.001-30% (e.g., 5%) by weight 1 -methyl-2-mercapto imidazole (methimazole)

0.0001-20% (e.g., 0.04%) by weight butylated hydroxytoluene (BHT), and one or more dermatologically acceptable carriers. Likewise, the invention also provides skin

depigmentation compositions containing 0.001-30% (e.g., 5%) by weight l-methyl-2- mercapto imidazole (methimazole)

0.0001 -20% (e.g., 0.5%) by weight dileuryl thio dipropionate (DLTDP), and one or more dermatologically acceptable carriers.

Those skilled in the art will recognize that either of these skin depigmentation compositions can be used in the manufacture of a medicament for preventing or treating a skin depigmentation disorder selected from the group consisting of hyperpigmentation, melasma, postinflammatory hyperpigmentation, lentigo, freckles, drug induced

hyperpigmentation, light induced hyperpigmentation and chemical induced

hyperpigmentation. Similarly, either of these compositions can also be used in the manufacture of a medicament for preventing or reducing pigmentation of normal skin.

Moreover, the invention also provides methods of preventing, treating or reducing a skin pigmentation disorder selected from the group consisting of hyperpigmentation, melasma, postinflammatory hyperpigmentation, lentigo, freckles, drug induced

hyperpigmentation, light induced hyperpigmentation and chemical induced

hyperpigmentation by administering a therapeutically effective amount of such skin depigmentation compositions to a patient suffering from said skin pigmentation disorder. Similarly, the invention also provides cosmetic methods of preventing or reducing pigmentation of normal skin by administering an effective amount of these skin

depigmentation compositions to a patient or subject.

The invention further provides skin depigmentation compositions containing 0.001- 30% (e.g., 5%) by weight l-methyl-2-mercapto imidazole (methimazole)

0.0001-20% {e.g. , 0.04%) by weight butylatcd hydroxytoluene (BH ), and one or more dermatologically acceptable earners for use in treating-a skin depigmentation disorder selected from the group consisting of hypcrpigmentation, melasma, postinflammatory hyperpigmentation, lentigo, freckles, drug induced hyperpigmentation, light induced hyperpigmentation and chemical induced hyperpigmentation, Also provided are skin depigmentation compositions containing l-methyl-2-mercapto imidazole (metliimazple)

0.001-30% (e.g., 0.04%) by weight butylated hydroxytoluene (BHT), and one or more dermatologically acceptable carriers foT use in preventing or reducing pigmentation of normal skin.

Similarly, the invention also encompasses skin depigmentation compositions containing 0.001-30% (e.g., 5%) by weight l-methyl-2-mercapto imidazole (methimazole)

0.0001-20% (e.g., 0.5%) by weight dileuryl thio dipropionate (DLTDP), and one or more dermatologically acceptable carriers for use in treating a skin depigmentation disorder selected from the group consisting of hyperpigmentation, melasma, postin flammatory hyperpigmentation, lentigo, freckles, drug induced hyperpigmentation, light induced hyperpigmentation and chemical induced hyperpigmentation In addition, the invention also provides skin depigmentation compositions containing 0.001-30% (e.g., 5%) by weight 1- methyl-2-mercapto imidazole (methimazole)

0.0001-20% (e.g. , 0.5%) by weight dileuryl thio dipropionate (DLTDP), and one or more dermatologically acceptable carriers for use in preventing or reducing pigmentation of normal skin.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows before and after photos of a patient who was treated with a 4% hydroquinone cream on the left side of the patient's face, and a combination of methimazole (5%) and BHT (0.04%) on the right side of the patient's face.

Figure 2 shows before and after photos of the left side of a second patient's face, which was treated with a combination of methimazole (5%) and BHT (0.04%).

Figure 3 shows before and after photos of the right side of the second patient's face, which was treated with a 4% hydroquinone cream. DETAILED DESCRIPTION OF THE INVENTION

Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The publications and applications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. In the case of conflict, the present specification, including definitions, will control.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in art to which the subject matter herein belongs. As used herein, the following definitions are supplied in order to facilitate the understanding of the present invention. The term "comprise" is generally used in the sense of include, that is to say permitting the presence of one or more features or components.

As used in the specification and claims, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise.

As used herein, the term "subject" is well-recognized in the art, and, are used herein to refer to a mammal, and most preferably a human. In some embodiments, the subject is a subject in need of treatment or a subject with a skin pigmentation disease or disorder, such as hyperpigmentation. However, in other embodiments, the subject can be a normal subject who has a normal healthy skin and who needs to lighten (i.e., whiten) his skin. The term does not denote a particular age or sex. Thus, adult and newborn subjects, whether male or female, are intended to be covered.

As used herein, the term "depigmentation" or the terms lightening, bleaching, whitening and brightening are used interchangeably herein to refer to the lightening of the skin, or loss of pigment. The skin depigmentation agents or compositions are also referred as "skin lightener", "skin whitener", "skin even-toner" and "skin brightener". Whatever terminology is employed, the general premise is that they all relate to a reduction in the formation and/or rate of formation of melanin, which results in loss of pigment. As used herein, the term "dermatologically acceptable" means that the compositions or components thereof so described are suitable for use in contact with skin of a mammal, preferably of human, without undue toxicity, incompatibility, instability, irritability, allergic response, and the like.

As used herein, the term "topical" or "topically" refers to the application of the composition of the present invention onto the surface of the skin or a portion thereof.

As used herein, the term "pharmaceutically acceptable salt(s)," includes, but is not limited to, salts of acidic or basic groups that may be present in the compounds of the invention, such as methimazole derivatives.

As used herein, the term "depigmentation effective amount" means an amount of a compound or composition sufficient to significantly induce a positive benefit, preferably a reduction in the formation or rate of formation of melanin, but low enough to avoid serious side effects.

As used herein, the term "post-inflammatory hyperpigmentation" refers to the changes in melanin content as a response to an inflammatory event (e.g., acne, scratch, laser therapy, insect sting or bite, sunburn, etc.), especially in individuals of darker skin tone or color.

Melanin synthesis or melanogenesis in mammalian skin occurs in epidermal melanocytes. The so formed melanin is accumulated/deposited in melanosomes, vesicles found within the melanocyte cells, which are subsequently transferred from the melanocytes and taken up and internalized by the keratinocytes, which then carry them to the surface of the skin. Usually, skin coloration is primarily regulated by the amount and type of melanin synthesized by the epidermal melanocyte. This synthesis process starts through the hydroxylation of the amino acid tyrosine to DOPA which is further oxidized to dopaquinone. Both of these steps are accomplished by the enzyme tyrosinase. Dopaquinone is then spontaneously converted to dopachrome which further gives rise to the two indolic melanin monomers dihydroxyindole and dihydroxyindole-2-carboxylic acid. These monomers are in turn metabolized by the peroxidase-H₂0₂ system to produce eumelanin (brown-black melanin). Pheomelanin (yellow-red melanin) would be formed if dopaquinone encounters cellular thiols such as glutathione or cysteine. The peroxidase- H₂0₂ system plays an important role in the metabolisation of pheomelanin intermediates to form pheomelanin pigments (See Dermatology. 2002; 205:329-39, which is herein incorporated by reference in its entirety). Typically, depigmentation can be achieved by regulating (i) the transcription and activity of tyrosinase, tyrosinase related protein-1 (TRP-1), tyrosinase related protein-2 (TRP- 2), and/or peroxidase; (ii) the uptake and distribution of melanosomes in recipient keratinocytes and (iii) melanin and melanosome degradation and turnover of "pigmented" keratinocytes. The involvement of peroxidase in the polymerization of melanogenic intermediates has been suggested by the high efficiency of peroxidase in the oxidation of 5,6- dihydroxyindole (DHI) with the generation of hydrogen peroxide (I ½0₂) as a by-product, intracellular H₂0₂, generated after UV irradiation or in response to cytokines, such as tumour necrosis factor- (TNF-a) or transforming growth factor-/? (TGF-/7), can induce a transient reduction of tyrosinase and other melanogenic protein activities, through the down-regulation of the MITF transcription factor. The inhibition of peroxidase results in depigmentation, reducing the polymerization rate of eumelanin.

However, one of the important non-enzymatic mechanisms capable of forming melanin is the Fenton reaction. In such reactions H₂0₂ is converted by metal ions (Fe, Cu, etc.) to hydroxy 1 radicals. These hydroxyl radicals, if not neutralized, can efficiently hydroxylate tyrosine and continue the reaction up to the formation of melanin. Although the inhibition of peroxidase reduces the enzymatic synthesis of melanins, it would probably provide the Fenton reactions with more H₂0₂ (non-metabolized by peroxidase) and might, thus, provide the non-enzymatic reactions with more H₂0₂ resulting in increased melanin synthesis by such routes.

The Applicant has surprisingly found that the depigmentation effect of a methimazole derivative, such as 1 methyl-2-mercaptoimidazole (methimazole) is increased when non- enzymatic Fenton reactions are inhibited in addition to peroxidase inhibition. As

demonstrated herein, this combination of a methimazole derivative and an antioxidant surprisingly displays a synergistic depigmentation effect.

Methimazole derivatives of the present invention are represented by the formula I

formula 1

wherein Y is selected from the group consisting of H, C₁-C₂₀ alkyl, C₁-C₂₀ substituted alkyl, - N0₂, and the phenyl moiety

and wherei no. more than one Y group in said methimazole derivative may be the phenyl moiety; Rl is selected from the group consisting of H, Ci-Ci₀ alkyl and Ci-Cio substituted alkyl;

R2 is selected from the group consisting of null, H, -OH, C1-C4 alkyl, and C1-C4 substituted alkyl;

R3 is selected from the group consisting of H, -OH, C1-C4 alkyl, and C1-C4 substituted alkyl; R4 is selected from the group consisting oi^'H, C|-C₄ alkyl, and C1-C4 substituted alkyl;

X is selected from =S, =0 and -SH; or pharmaceutically acceptable salts thereof.

Preferably methimazole derivative is 1 methyl-2-mercaptoimidazole (methimazole) and 1-decyl, 2-mercaptomethylimidazole, or pharmaceutically acceptable salts thereof. Most preferably, the methimazole derivative is 1 methyl-2-mercaptoimidazole (methimazole).

Thus the enliancement of the depigmentation effect of a methimazole derivative can be obtained when said methimazole derivative is combined with at least one compound selected from primary antioxidants, secondary antioxidants, and/or metal chelators.

Primary antioxidants are electron donors and can neutralize the hydroxyl radicals. In order to inhibit the Fenton reactions, it is possible to neutralize the hydroxyl radicals formed during the Fenton reaction. Neutralization of hydroxyl radicals would suppress tyrosine hydroxylation mediated by Fenton reactions. Preferably, the primary antioxidants selected for use in the methods and compositions described herein can be selected from the group consisting of, but are not limited to, butylated hydroxytoluene (BHT), butylated

hydroxyanisole, tertiary-butylhydroquinone, melatonin, glutathione and its derivatives, nicotinamide, the vitamin B group and their derivatives vitamin E and its derivatives, retinoic acid and its derivatives, polyphenols, carotenoids, licopene, hindered amines, phosphites, and mixtures thereof. Preferably, the primary antioxidants of the invention are not vitamin C or ascorbic acid.

Preferred phenolic antioxidants are selected from the group consisting of, but are not limited to,

1 ,3 ,5-tris(3 ,5-di-tert-butyl-4-hydroxybenzy 1) isocynaurate,

l,3,5-tris[[4-tert-bulyl-3-hydroxy-2,6-xyty one 2-( 1 , 1 -dimethylethyI)-6-[[3 -(1,1 -dimethy lethy l)-2-hydroxy-5-methylpheny l]methy l]-4- methylphenyl acrylate,

2,2^,,6,6'-tetra-tert-butyl-4,4^,-methylenediphenol,

2,2'-ethylidenebis[4,6-di-tert-butylphenol],

2,2'-methylenebis[6-(l-methylcyclohexyl)-p-cresol],

2',3-bis[[3-[3,5-di-tert-butyl-4-hydroxyphenyl]propionyrj]propionohydrazide,

2,4-Bis [(octylthio)rnethyl]-o-cresol,

2.4- di -tert-butylphenol,

2,5-di-tert-butylhydroquinone,

2.5- di-tert-pentylhydroquinone,

2.6- di-tert-butyl-4-nony lphenol,

2,6-di-tert-butyl-p-cresol,

2,6-di-tert-butylphenol, 2,6-di-tert-butyl-a-dimethylamino-p-cresol,

3,3^3^, 5,5 5'-hexa-tert-butyl-α,α^,,α^,'-(raesitylene-2,4,6-triyl)tΓi- -cresol,

4,4',4"-(l-methylpropanyl-3-ylidene)tris[6-tert-butyl-m-cresolj_>

4-sec-butyl-2,6-di-tert-butylphenol,

Phenol, 4,4'-(l -methyl ethylidene)bis-, reaction products with isobutylene and styrene,

Diethyl [[3,5-bis(l,l-dimethylethyl)-4-hydroxyphenyl]methyl]phosphonate,

4-(2-methylprop-2-enyl)phenol,

6,6'-di-tert-butyl-2,2'-methylenedi-p-cresol,

6,6'-di-tert-butyl-2,2'-thiodi-p-cresol,

6,6'-di-tert-butyl-4,4'-butylidenedi-m-cresol,

6,6'-di-tert-butyl-4,4^,-diethyl-2₅2'-methylenediphenol,

6,6^,-di-tcrt-butyl-4,4'-thiodi-m-crcsol,

6-tert-butyl-2,4-xylenol,

2 -tert-butylhy droquinone,

Calcium diethyl bis[[[3,5-bis(l,l-dimethylethyl 4-hydroxyphenyl]methyl]phosphonate],

Ethylene bis[3,3-bis(3-tert-butyl-4-hydroxyphenyl)butyiate],

Ethylenebis(oxyethylene)bis[3-(5-tert-butyl-4-hydroxy-m-tolyl)propionate],

Hexamethylene bis [3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionate],

Hydroquinone monomethyl ether,

Isotridecyl-3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionate,

N,N'-hexane-l,6-diylbis[3-(3,5-di-tert-butyl-4-hydroxyphenylpropionamide],

N,N'-propane-l,3-diylbis[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionamide],

Octadecyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate,

Pentaerythritol tctrakis (3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate),

Phenol, 4-methyl-, reaction products with dicyclopentadiene and isobutylene,

Phenol, styrenated,

Thiodiethylene bis [3 -(3 , 5 -di-tert-buty 1-4-hydroxy phenyl)propionate], and

Tris( 1 -phenylethyl)phenol.

Preferred amine antioxidants are selected from the group consisting of, but are not limited to, 1,4-Benzenediamine, Ν,Ν'-mixed phenyl and tolyl derivatives,

4'-anilinotoluene-4-sulphonanilide,

4-( 1 -methyl- 1 -phenylethyl>N- 4-( 1 -methyl- 1 -phenylethyl)phenyl]aniline,

Benzenamine, 2-ethyl-N-(2-ethylphenyl , (tripropenyl) derivatives,

Benzenamine, N-{4-[(l,3-Dimethylbutyl)imino]-2,5-cyclohexadiene-l-ylidine},

Benzenamine, N-phenyl-, reaction products with 2,4,4-trimethylpentene,

Bis(4-octylphenyl)amine,

Diphenylamine,

Diphenylamine and acetone low-temperature reaction products,

Ethoxyquine,

N- 1 -naphthylaniline,

N-l,3-dimethylbutyl-N'-phenyl-p-phenylenediamine,

N-isopropyl-N'-phenyl-p-phenylenediamine,

N,N'-bis(l,4-dimethylpentyl)-p-phenylenediamine,

N,N'-di-2-naphthyl-p-phenylenediamine,

N,N'-di-sec-butyl-p-phenylenediamine,

Ν,Ν'-diphenyl-p-phenylenediamine, and

Polymerized 1 ,2-dihydro-2,2,4-trimethylquinoline.

Preferred phosphite antioxidants are selected from the group consisting of, but are not limited to,

2,4,6-Tri-t-butylphenyl 2 butyl-2-ethy 1-1, 3 -propanediol Phosphat,

3,9-bis(2,4-di-tert-butylphenoxy 2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane, Bis (2,4-dicumylphenyl) pentaerythritol diphosphate,

Bis(2,4-di-tert-butyl-6-methylphenyl)ethyl phosphate,

Isodecyl diphenyl phosphite,

Isooctyl diphenyl phosphite,

Ο,Ο'-dioctadecylpentaerythritol bis(phosphite),

Phosphor trichloride, reaction products with Ι,Γ-biphenyl and 2,4-bis (1,1 -dimethyl) phenol, Tetrakis(2,4-di-tert-burylphenyl) [ 1 , l-biphenyl]-4,4'-diylbisphosphonite, Tributyl phosphite,

Tridodecyl phosphite,

Triisodecyl phosphite,

Triphenyl phosphite,

Tris(2,4-ditert-butylphenyl) phosphite,

Tris(nonylphenyl) phosphite, and

Tris[4,4^,-thiobis[3-methyl-6-tert-butylphenol]]phosphite.

Secondary antioxidants are the antioxidants that remove H₂0₂, which is essential for the peroxidase-H₂0₂ system to be functional. In addition to the inhibition of peroxidase by methimazole derivatives, the simultaneous removal of H₂0 would further suppress this enzymatic system. H₂0₂ removal would not only inhibit the enzymatic system but also would inhibit the Fenton reactions. Suitable secondary antioxidants can include any H₂0₂ decomposer. Preferably the secondary antioxidants are selected from the group consisting of, but are not limited to, thiodipropionic acid derivatives, thioesters, metal thiolates, dioctadecyl disulphide and l,3-dihydro-4(or 5)-methyl-2H-benzimidazole-2-thione and/or mixtures thereof. Most preferably, thiodipropionic acid derivatives are selected from the group consisting of dileuryl thiodipropionate (DLTDP), dimethyl thiodipropionate, ebselen.

Most preferably, thioesters and metal thiolates are selected from the group consisting of, but are not limited to:

2,2-bis[[3-(dodecylthio)-l-oxopropoxy]methyl]propane-l ,3-diyI bis[3-

(dodecylthio)propionate],

Di(tridecyl) 3,3'-thiodipropionate,

Didodecyl 3 ,3 '-thiodipropionate,

Dioctadecyl 3 ,3'-thiodipropionate,

Ditetradecyl 3,3'-thiobispropionate,

Poly (1,4-cyclohexylenedimethylene 3, 3 '-thiodipropionate terminated with 1-octadecanol l,3-dihydro-4(or 5)-methyl-2H-benzimidazole-2-thione, zinc salt,

Bis(diisobutyldithiocarbamato)nickel,

Nickel bis(dibutyldithiocarbamate), Zinc bis(dibutyldithiocarbamate),

Zinc di(bcnzimidazol-2-yl) disulphide,

4.4.4.3 Other Sulphuric Compounds,

Dioctadecyl disulphide, and

l,3-dihydro-4(or 5)-methyl-2H-benzimidazole-2-thione.

Those skilled in the art will also recognize that the Fenton reactions are mediated by metal ions and can be inhibited if the metals are removed from the reaction by metal chelators. Therefore, the compositions and methods of the invention can additionally or alternatively include one or more metal chelators. Preferably the metal chelators are selected from the group consisting of, but are not limited to, ethylenediamine tetraacetic acid (EDTA) and derivatives and salts thereof, dihydroxyethyl glycine, histidine, citric acid or salts thereof, glucuronic acid or salts thereof, Lecithin, trientine, desferrioxamine, inositol hexaphosphate (IP6), tartaric acid, thiolic metal chelators, and/or mixtures thereof.

Preferred thiolic metal chelators are selected from the group consisting of, but are not limited to, dithiotreitol, diethyl dithiocarbamate, thioctic acid and salts thereof, 2,3 dimercapto-l-propanol (BAL), 2,3 dimcrcapto-l-propanesulphonate and derivatives thereof, N(2-mercaptopropyl)glaycin, 2,3-dimercaptosuccinic acid and derivatives thereof, and D- penicillamine. In the present invention, the Applicants have shown, for the first time, that the combination of a methimazole derivative with one or more primary antioxidants, preferably butylated hydroxytoluene (BUT) and/or one or more secondary antioxidants, preferably dileuryl thio dipropionate (DLTDP) increases the skin depigmentation effect of the methimazole derivative in a synergistic manner. The combination of a methimazole derivative with metal chelators (with or without presence of one or more primary or secondary antioxidants) could also result in the increase of the depigmentation effect of the methimazole derivative.

While any combination of a methimazole derivative and one or more primary and/or secondary antioxidants can be used in the skin depigmentation compositions of the invention, in one preferred embodiment, the skin depigmentation composition contains 0.001-30% by weight of methimazole in combination with 0.0001 to 20% by weight of the primary antioxidant butylated hydroxytoluene (BHT). Such skin depigmentation composition can also contain (additionally or alternatively) between 0.0001 to 20% by weight of the secondary antioxidant dileuryl thio dipropionate (DLTDP). As demonstrated in the Examples, this combination of methimazole and BHT (and/or DLTDP) surprisingly and unexpectedly increases the skin depigmentation effect of methimazole in a synergistic manner.

The combination of a methimazole derivative with one or more primary and/or secondary antioxidants increases the depigmentation activity observed with the methimazole derivative alone. This increase is of a synergic nature, as neither the BHT nor the DLTDP alone exerted any significant skin depigmentation effect. Thus, the combination of methimazole and BHT and/or DLTDP can be used in the treatment of skin depigmentation diseases or disorders in subjects suffering therefrom and/or for decreasing the pigmentation (i.e. , lighten or whiten) of normal human skin. The increase of the depigmentation effect is not due to a simple stabilizing effect of the antioxidants on methimazole molecule, although some of the primary and/or secondary antioxidants (with or without metal chelators), can and probably must be used to stabilize methimazole in topical preparations, such as creams, ointments, gels, etc., which results in an acceptable shelf life. HPLC analyses on methimazole cream show that at ambient temperature (i.e. 25°C) methimazole is stable at least for a few days in the cream formulation (instability (i.e. , degradation) of methimazole occurred in stress conditions at higher temperatures, such as 45°C or in longer durations more than a few days in the ambient temperature ). On the other hand all formulations used in the study were freshly prepared everyday just prior to applications. Any of the skin depigmentation compositions of the present invention may contain a concentration of methimazole or a methimazole derivative of about 0.001 -30%, preferably 0.01 -10.0%, most preferably 0.1-5.0% by weight of the composition.

The amount of a primary antioxidant in the skin depigmentation composition of the present invention may range from about 0.0001 to 20% based on the weight of the total composition, preferably from about 0.01 to 10.0%.

The amount of a secondary antioxidant in the skin depigmentation composition of the present invention may range from about 0.0001 to 20.0% based on the weight of the total composition, preferably from about 0.05 to 10.0%.

The amount of a metal chelator in the skin depigmentation composition of the invention may range from about 0.0001 to 20% based on the weight of the total composition, preferably from about 0.05 to 10.0%.

Any of the skin depigmentation compositions of the invention may be cosmetic, dermatologic, or pharmaceutical compositions, and may exist in a wide variety of forms, such as emulsions, suspensions, solutions and the like. In certain embodiments, the compositions of the invention are in the form of lotions, creams, gels, solutions, sprays, cleansers, powders, ointments, waxes, lipsticks, soaps, shampoos, hydroalcoholic solutions, suspensions, scrubs, saturated pads, skin or hair conditioning agents, and other types of cosmetic compositions. In further embodiments, the compositions of the invention may be, for example anhydrous preparations, oil-free preparations, emulsions or microemulsions of the type water-in-oil (W/O) or of the type oil-in-water (O/W), multiple emulsions, for example of the type water- in-oil-in- water (W/O/W), solid sticks, or even aerosols.

One preferred form of the compositions of the invention is: an oil in water hydrophilic cream (e.g., vanishing cream) containing stearic acid, petrolatum, cetyl alcohol, lanolin, paraffin, sorbitol, glycerin, metyl paraben and propyl paraben, triethanolamine and water (76.5% w/w) together with 5% methimazole and 0.04% butylated hydroxytoluene.

For administration, the cosmetic and dermatological compositions of the invention may be topically applied to the skin (to body surface) in adequate depigmentation effective amount in the manner conventional for cosmetics and which has a topical effect, i.e. a local effect rather than systemic effects.

Any of the skin depigmentation compositions of the invention may also contain one or more dermatologically acceptable carriers , as are used conventionally in such compositions, for example preservatives, antioxidants, bactericides, perfumes, substances for preventing foaming, dyestuffs, pigments which have a coloring effect, thickeners, propellants, surfactant substances, emulsifiers, softening, moisturizing and/or moisture-retaining substances, distilled water, fats, oils, waxes or other conventional constituents of a cosmetic or dermatological compositions, such as alcohols, polyols, polymers, foam stabilizers, electrolytes, organic solvents or silicone derivatives. The necessary amounts of any such dermatologically acceptable carriers can, based on the desired product, routinely be chosen by a person skil led in the art, without undue experimentation. A moisturizing substance may be incorporated into any of the skin depigmentation compositions of the present invention to maintain hydration or rehydrate the skin.

Moisturizers that prevent water from evaporating from the skin by providing a protective coating are called emollients. Additionally an emollient provides a softening or soothing effect on the skin surface and is generally considered safe for topical use. Preferred emollients include mineral oils, lanolin, petrolatum, capric/caprylic triglyceraldehydes, cholesterol, silicones such as dimeticone, cyclometicone, almond oil, jojoba oil, avocado oil, castor oil, sesame oil, sunflower oil, coconut oil and grape seed oil, cocoa butter, olive oil aloe extracts, fatty acids such as oleic and stearic, fatty alcohols such as cetyl and hexadecyl (ENJAY), diisopropyl adipate, hydroxybenzoate esters, benzoic acid esters of Cg-is-alcohols, isononyl iso-nonanoate, ethers such as polyoxypropylene butyl ethers and polyoxypropylene cetyl ethers, and C12- 15- alkyl benzoates, and mixtures thereof. Moisturizing substances that bind water, thereby retaining it on the skin surface are called humectants. Suitable humectants can be incoiporated into any of the skin depigmentation compositions of the present invention such as glycerin, polypropylene glycol, polyethylene glycol, lactic acid, pyrrolidone carboxylic acid, urea, phospholipids, collagen, elastin, ceramides, lecithin sorbitol, PEG-4, and mixtures thereof.

Any of the skin depigmentation compositions of the present invention can also contain the usual alcohols, especially lower alcohols, preferably ethanol and/ or isopropanol, low diols or polyols and their ethers, preferably propyleneglycol, glycerin, ethyleneglycol, ethyleneglycol monoethyl- or monobutylether, propyleneglycol monomethyl- or - monoethyl- or-rnonobutylether, diethyleneglycol monomethyl-or monoethylether and analogue products, polymers, foam stabilizers; electrolytes and especially one or more thickeners.

Thickeners that may be used in the skin depigmentation compositions of the present invention to assist in making the consistency of a product suitable include carbomer, siliciumdioxide, magnesium and/ or aluminium silicates, beeswax, stearic acid, stearyl alcohol polysaccharides and their derivatives such as xanthan gum, hydroxypropyl cellulose, polyacrylamides, acrylate crosspolymers preferably a carbomer, such as carbopole^® of type 980, 981, 1382, 2984, 5984 alone or mixtures thereof. Suitable neutralizing agents which may be included in the skin depigmentation compositions of the present invention to neutralize components such as e.g., an emulsifier or a foam builder/stabilizer include but are not limited to alkali hydroxides such as a sodium and potassium hydroxide; organic bases such as diethanolamine (DEA), triethanolamine (TEA), aminomethyl propanol, and mixtures thereof; amino acids such as arginine and lysine and any combination of any foregoing.

Any of the skin depigmentation compositions of the present invention may also contain filter substances that absorb UV radiation, or sunscreens, wherein the total quantity of filter substances is, for example 0.1 to 30 %, preferably 0.5 to 10 %, based on the total weight of the preparation. The compositions may also serve as sunscreen agents for the skin. Such UV filter substances include, for example, the following: avenobenzene, cinoxate, dioxybenzone, homosalate, menthyl anthranilate, octocrylene, octyl methoxycinnamate, octyl salicylate, oxybenzone, padimate O, phenylbenzimidazole sulfonic acid, sulisobenzone, titanium dioxide, trolamine salicylate, and zinc oxide.

Any of the skin depigmentation compositions of the present invention may also include one or more skin penetrants. These are additives that, when applied to the skin, have a direct effect on the permeability of the skin barrier: increasing the speed with which and/or the amount by which certain other compounds are able to penetrate into the skin layers.

Exemplary organic penetration enhancers include dimethyl sulfoxide; isopropyl myristate; decyl, undecyl or dodecyl alcohol; propylene glycol; polyethylene glycol; Q.n or C12-15 fatty alcohols; azone; alkyl pyrrolidones; diethoxy glycol (Transcutol); lecithin; etc. Surfactants can also be used as penetration enhancers.

The present invention further provides skin depigmentation compositions for use in a method for preventing or reducing pigmentation of normal skin. Preferably, the skin is at least one of facial skin, skin on the neck, skin on the arms, skin on the hands and skin on the legs. As used herein, the term "normal skin" referrs to healthy skin having no pigmentation disorders.

The present invention also provides skin depigmentation compositions for use in a method for preventing and reducing skin pigmentation disorders. Also provided are compositions for use in preventing, treating and/or reducing skin pigmentation disorders.

Those skilled in the art will recognize that increased production and accumulation of melanins characterize a large number of skin pigmentation disorders, which include acquired hyperpigmentation, such as melasma (dark patches experienced during or after pregnancy), postinflammatory melanoderma, solar lentigo, etc. epidermal and dermal hyperpigmentation can be dependent on either increased numbers of melanocytes or activity of melanogenic enzymes. Ultraviolet light, chronic inflammation, and rubbing of the skin as well as abnormal a-melanocyte stimulating hormone ( -MSH) release, are triggering factors for these skin pigmentation disorders. Preferably pigmentation disorders to be treated using any of the compositions described herein are selected from the group consisting of hyperpigmentation, melasma, postinflammatory hyperpigmentation, lentigo, freckles, drug induced hyperpigmentation, light induced hyperpigmentation and chemical induced hyperpigmentation.

The present invention also provides a method for preventing or reducing pigmentation of normal skin, comprising topically applying the skin depigmentation composition of the invention to the skin. Also provided are compositions for use in preventing or reducing pigmentation of norm al skin . The present invention also provides a method for reducing pigmentation of normal skin, in patients with generalized vitiligo in order to reduce the contrast between the diseased and the normal skin.

The present invention further provides a method for preventing and reducing skin pigmentation disorders, comprising topically applying the skin depigmentation composition of the invention to the skin.

The term "preventing" as used herein, means that the normal (healthy) pigmentation or disease related pigmentation does not occur on the skin, preferably human skin. The term "reducing" as used herein, means that a significant reduction in the formation or rate of formation of pigmentation on the skin, preferably human skin, is induced.

In the method according to the invention any of the skin depigmentation compositions are applied to the skin, preferably human skin. The amount of the skin depigmentation composition that is to be applied to the skin depends upon the form of the skin

depigmentation composition as well as its mode of application. For example, a spray formulation may be applied so as to provide a light, even coat on the skin. Similarly, lotions, creams, gels and the like are typically applied in an amount to provide a light coating to the treated skin area: consistent with the application of topical pharmaceutical ointments, creams, lotions, and the like. Generally the rate of application, especially where all or substantially all of the skin is to be treated, is about 20 to 60 ml for the entire body, i.e., for the exposed skin of a "average individual" wearing a swimsuit and standing 1.65 m tall, weighing 68 kg, and having a 0.81 m waist. This translates to an application rate of about 2 mg/cm² of skin. On the face, a typical application rate is 1.2 to 1.7 ml. At such levels of application, the amount of skin depigmentation solution applied lies in the range of from about 0.1 to about 10 mg/cm², preferably from about 1 to about 3 mg/cm², of skin. The compositions may be applied one or more times per day depending on the activities the particular subject is engaged in. For example, a subject engaging in normal workday activities may wish to apply the compositions twice a day, once in the morning, and once in the evening, in conjunction with normal grooming. On the other hand, if the subject plans outdoor activities such as sunbathing and athletics, the compositions may be applied prior to, and during, such activities, much like a sunscreen composition is applied periodically during the day. The compositions may be used for hyperpigmentation on the face and neck, by applying appropriate skin depigmentation compositions to the face and neck areas.

However, the skin depigmentation compositions of the present invention may also be applied to the entire body, particularly areas which are not covered by clothing, such as the arms, neck, and lower legs.

Any of the skin depigmentation compositions of the present invention can be prepared by any method known in the art for cosmetic and/or dermatological compositions. Generally, the method comprises the simple mixing or blending of the components; though, especially where insoluble or immiscible components are employed higher agitation or homogenization may be necessary to prepare an appropriate composition, e.g., an emulsion or suspension, etc. Additionally, during the preparation, it may be desirable to add known pH adjusters to in order to maintain a proper pH of the composition for topical application, especially if basic ingredients are to be employed. Generally, the pH should be on the neutral to slightly acidic side, perhaps as low as pH 4. Preferably, though, the pH will be in the range of from about 5 to about 6.5.

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications without departing from the spirit or essential characteristics thereof. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features. The present disclosure is therefore to be considered as in all aspects illustrated and not restrictive, the scope of the invention being indicated by the appended Claims, and all changes which come within the meaning and range of equivalency are intended to be embraced therein.

The foregoing description will be more fully understood with reference to the following Examples. Such Examples, are, however, exemplary of methods of practising the present invention and are not intended to limit the scope of the invention.

EXAMPLES

Example 1

Materials and Methods

The study was performed upon the acceptance of the ethical committee of Jahrom University of Medical Sciences, Jahrom, Iran. Ears of 2 months old female brown guinea pigs were treated once daily for six consecutive weeks with the following formulations (6 ears per treatment condition):

1) Methimazole 5%

2) Butylated hydoxytoluene (BHT) 0.04%

3) Dileuryl thio dipropionate (DLTDP) 0.5%

4) Ascorbic acid 1%

5) Methimazole 5% + BHT 0.04%

6) Methimazole 5% + DLTDP 0.5%

7) Methimazole 5% + ascorbic acid 1%

8) The vehicle alone (negative control, consisting of a vanishing cream containing stearic acid, 75% (w/w) distilled water, 1% ethanol, cetyl alcohol, Sensoft, paraffin and lanolin).

Formulations were freshly prepared, using the same vehicle, prior to each application. Applications were performed using 2mg/cm² per application of each formulation on the test areas by a research worker blinded to the treatment identifications. At the end of 6 weeks, guinea pigs underwent general anesthesia through the IM injection of Ketamine (30 mg/kg) and Xylazine (5 mg/kg) and 6 mm punch biopsies were taken of each application site. The epidermis was split from the dermis by the incubation of the biopsied specimens during lh in IN NaBr at 37°C. The split epidermis was weighed, and then incubated in proteinase-K overnight to extract epidermal melanin. After overnight incubation the samples were sonicated and centrifuged, the extracted melanin was dissolved in DMSO by sonication and the light absorption was spectrophotometrically determined at 375nm. Melanin quantity was determined using a concentration-absorption curve. The amount of melanin per mg of epidermis was determined. Results

Table 1 summarizes the results of the melanin quantifications. The treatment with methimazole 5% induced a 25% reduction in the amount of epidermal melanin compared to the vehicle alone (p<0.05). However, the treatment with BUT alone, DLTDP alone or ascorbic acid alone induced no significant reduction in the epidermal melanin content. The combination of methimazole (5%) with BHT (0.04%), however, reduced the melanin content by 50% compared to control (significantly different from methimazole alone, p<0.05). The combination of methimazole (5%) with DLTDP (0.5%) was more effective than the methimazole alone and reduced the melanin content by more than 45% (significantly different from methimazole alone, p<0.05). The combination of methimazole (5%) with ascorbic acid (1%) was less effective than methimazole (5%). This combination was also significantly less effective than the combinations containing "methimazole and BHT" or "methimazole and DLTDP ".

Table 1

Example 2: Clinical study comparing the combination of methimazole and BHT with hydroquinone in melasma patients

Hydroquinone is the gold standard treatment for melasma and is used in 2-4% concentrations. Hydroquinone creams have been used for many years for the treatment of hyperpigmentary disorders. However, recent toxicologic studies have raised serious questions of concern about the continued use of hydroquinone in skin depigmenting products. In a clinical study, 50 female melasma patients were treated with a 4% hydroquinone cream on half of their face and with a cream containing methimazole (5%) and BHT (0.04%) on the opposite side of their face. The study was randomized, and the patients were blinded to the treatment identifications. The applications were done once daily for 6 consecutive weeks. Before-after photos were then evaluated by two clinicians blinded to the treatment identifications. Results of this study revealed that the combination of methimazole and BHT formulation was as effective as hydroquinone 4% for the treatment of melasma (See Figures 1-3).

Moreover, five cases (10% of total patients) showed signs of contact dermatitis/irritation on the side treated by hydroquinone while the combination of methimazole and BUT formula was very well tolerated in all cases.

OTHER EMBODIMENTS

While the invention has been described in conjunction with the detailed description thereof^ the foregoing description is intended to illustrate and not limit the scope of the invention, which is defihed by the scope of the appended clainm Other aspects, advantages* and modifications are within the scope of the foUowin claims.

Claims

1. A skin depigmentation composition comprising

(i) a depigmentation effective amount of a methimazole derivative of formula I

formula I

wherei Y is selected from the group consisting of H, Ct-Cjo alkyl, C|-C¾) substituted alkyl, NC , and the phenyl moiety

and wherein no more than one Y group in said methimazole derivative may be the phenyl moiety;

Rl is selected from the group consisting of H, CI -CIO alkyl and

alkyl R2 is selected from the group consisting of null, H, -OH, C1-C4 alkyl, and C1-C4 substituted alkyl; R3 is selected from the group consisting of H, -OH, C 1-C4 alkyl, and C1-C4 substituted alkyl;

R4 is selected from the group consisting of H, Ci-C₄ alkyl, and C1 -C4 substituted alkyl;

X is selected from =S, =0 and -SH; or a pharmaceutically acceptable salts thereof. (ii) at least one compound selected from the group consisting of primary antioxidants and secondary antioxidants, and

(iii) one or more dermatologically acceptable carriers.

2. The skin depigmentation composition of claim 1 , wherein said methimazole derivative is 1 -methyl-2-mercaptoimidazole.

3. The skin depigmentation composition of claim 1 or 2, wherein said methimazole derivative is about 0.001-30% by weight of the composition

4. The skin depigmentation composition of claims 1 to 3, wherein said primary antioxidant is selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole, tertiary-butylhydroquinone, melatonin, glutathione and its derivatives, nicotinamide, the vitamin B group and their derivatives vitamin E and its derivatives, Retinoic acid and its derivatives, polyphenols, carotenoids, licopene, hindered amines, phosphites and/or mixtures thereof.

5. The skin depigmentation composition of claims 1-4, wherein said primary antioxidant is about 0.0001 to 20% by weight of the composition.

6. The skin depigmentation composition of claims 1 to 5, wherein said secondary antioxidant is selected from the group consisting of thiodipropionic acid derivatives, thioesters, metal thiolates, Dioctadecyl disulphide and l,3-dihydro-4(or 5)-methyl-2H- benzimidazole-2-thione and/or mixtures thereof.

7. The skin depigmentation composition of claims 1-6, wherein said secondary antioxidant is about 0.0001 to 20% by weight of the composition.

8. The skin depigmentation composition of claims 1 to 7, wherein said skin is a mammal skin.

9. The skin depigmentation composition of claim 8, wherein said mammal skin is human skin.

10. The skin depigmentation composition of claims 1 to 9, wherein said composition is in the form of a lotion, a cream, a gel, a solution, a spray, a cleanser, a powder, an ointment, a wax, a lipstick, a soap, a shampoo, a hydroalcoholic solution, a suspension, a scrub, a saturated pad, and a skin or hair conditioning agent.

1 1. A skin depigmentation composition of claims 1 to- 10 for use in a cosmetic method for preventing or reducing pigmentation of normal skin.

12. A skin depigmentation composition of claims 1 to 10 for use in a method for preventing and reducing skin pigmentation disorders.

13. The skin depigmentation composition for use in a method for preventing and reducing skin pigmentation disorders of claim 12, wherein said pigmentation disorders are selected from the group consisting of hyperpigmentation, melasma, postinflammatory

hyperpigmentation, lentigo, freckles, drug induced hyperpigmentation, light induced hyperpigmentation and chemical induced hyperpigmentation.

14. A cosmetic method for preventing or reducing pigmentation of normal skin, comprising topically applying the skin depigmentation composition of claims 1 to 10 to the skin of a patient.

15. A method for preventing and reducing skin pigmentation disorders, comprising topically applying the skin depigmentation composition of claims 1 to 10 to the skin of a patient suffering from said disorder.

16. The method of claim 15, wherein the skin pigmentation disorder is selected from the group consisting of hyperpigmentation, melasma, postinflammatory hyperpigmentation, lentigo, freckles, drug induced hyperpigmentation, light induced hyperpigmentation and chemical induced hyperpigmentation.

17. A skin depigmentation composition comprising 5% by weightl -methyl-2-mercapto imidazole (methimazole)

0.04% by weight butylated hydroxytoluene (BHT), and one or more dermatologically acceptable carriers.

18. A skin depigmentation composition comprising 5% by weight 1 -methyl-2-mercapto imidazole (methimazole)

H₃C

0.5% by weight dileuryl thio dipropionate (DLTDP), and one or more dermatologically acceptable carriers.

19. A method of preventing, treating or reducing a skin pigmentation disorder selected from the group consisting of hyperpigmentation, melasma, postinflammatory

hyperpigmentation, lentigo, freckles, drug induced hyperpigmentation, light induced hyperpigmentation and chemical induced hyperpigmentation comprising administering a therapeutically effective amount of the composition of claim 17 or claim 18 to a patient suffering from said skin pigmentation disorder.

20. A cosmetic method of preventing or reducing pigmentation of normal skin comprising administering an effective amount of the composition of claim 17 or claim 18 to a subject.

21. A skin depigmentation composition comprising 5% by weight 1 -methyl-2-mercapto imidazole (methimazole)

0.04% by weight butylated hydroxytoluene (BHT), and one or more dermatologically acceptable carriers for use in treating a skin depigmentation disorder selected from the group consisting of hyperpigmentation, melasma, postinflammatory hyperpigmentation, lentigo, freckles, drug induced hyperpigmentation, light induced hyperpigmentation and chemical induced hyperpigmentation.

22. A skin depigmentation composition comprising 5% by weight l-methyl-2-mercapto imidazole (methimazole)

0.04% by weight butylated hydroxytoluene (BHT), and one or more dermatologically acceptable carriers for use in preventing or reducing pigmentation of normal skin.

23. A skin depigmentation composition comprising 5% by weight 1 -methyl-2-mercapto imidazole (methimazole)

0.5% by weight dileuryl thio dipropionate (DLTDP), and one or more dermatologically acceptable carriers for use in treating a skin depigmentation disorder selected from the group consisting of hyperpigmentation, melasma, postinflammatory hyperpigmentation, lentigo, freckles, drug induced hyperpigmentation, light induced hyperpigmentation and chemical induced hyperpigmentation.

24. A skin depigmentation composition comprising 5% by weight -methyl-2-mercapto imidazole (methimazole)

0.5% by weight dileuryl thio dipropionate (DLTDP), and one or more dermatologically acceptable carriers for use in preventing or reducing pigmentation of normal skin.

25. Use of the skin depigmentation composition of claim 17 or 18 in the manufacture of a medicament for preventing or treating a skin depigmentation disorder selected from the group consisting of hyperpigmentation, melasma, postinflammatory hyperpigmentation, lentigo, freckles, drug induced hyperpigmentation, light induced hyperpigmentation and chemical induced hyperpigmentation.

26. Use of the skin depigmentation composition of claim 17 or 18 in the manufacture of a medicament for preventing or reducing pigmentation of normal skin.