WO2013030794A2

WO2013030794A2 - Use of substituted pyridines as skin depigmenting compounds

Info

Publication number: WO2013030794A2
Application number: PCT/IB2012/054488
Authority: WO
Inventors: Behrooz Kasraee
Original assignee: Behrooz Kasraee
Priority date: 2011-08-31
Filing date: 2012-08-31
Publication date: 2013-03-07
Also published as: WO2013030794A3

Abstract

The present invention relates to skin and/or hair depigmentation compositions comprising a pyridine derivative and dermatologically acceptable carriers. The skin and/or hair depigmentation compositions can also comprise cysteamine hydrochloride. The present invention also relates to the cosmetic and pharmaceutical use thereof for reducing skin and/or hair pigmentation.

Description

USE OF SUBSTITUTED PYRIDINES AS SKIN DEPIGMENTING COMPOUNDS

FIELD OF THE INVENTION

The present invention relates to skin and/or hair depigmentation compositions comprising a pyridine derivative and dermatologically acceptable carriers. The skin and/or hair

depigmentation compositions can also comprise cysteamine hydrochloride. The present invention also relates to the cosmetic and pharmaceutical use thereof for reducing skin and/or hair pigmentation.

BACKGROUND OF THE INVENTION Human skin and hair colours are quite variable around the world. Cutaneous 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 and within the hair follicles. 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 defence against sun-induced damage, such as sunburn, photoaging and photocarcinogenesis.

Hyperpigmentation, hypopigmentation, and other 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 might occur following any inflammatory state of the skin such as chemical burns or 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 and/or hair colour.

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 for skin and hair depigmentation, 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 colour and odour 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 hydrogen peroxide 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 nicotinamide.

Nicotinamide is a 3 -substituted pyridine which exerts its skin depigmenting effect through the inhibition of melanosomal transfer from melanocytes to keratinocytes. Despite good tolerability on human skin, nicotinamide has a poor skin depigmenting efficacy and does not exhibit any hair lightening effect.

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

The 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

The present invention provides a skin and/or hair depigmentation composition comprising (i) a depigmentation effective amount of a pyridine derivative of formula I or formula II

Formula I

or pharmaceutically acceptable salts thereof

wherein in Formula I

X is S or O

Ri_, R_2, are independently H, -SH, or Ci-Cig saturated or unsaturated, linear, branched cyclic hydrocarbon groups

R and R₃ are independently H, -OH, -SH, or Ci-Cig saturated or unsaturated, linear, branched or cyclic hydrocarbon groups

Y is -SH, Ci-Cig saturated or unsaturated, linear, branched or cyclic hydrocarbon group, or NHR₄ represented by the Formula A: H

/

N

\

Formula A

R4 is H, -OH, -SH, C1-C1₈ saturated or unsaturated, linear, branched or cyclic hydrocarbon group, or the moiety:

Formula II

or pharmaceutically acceptable salts thereof

wherein in Formula II:

X is S or O

Ris H, -SH, or Ci-Cig saturated or unsaturated, linear, branched or cyclic hydrocarbon groups

Ri_, R₂ and R₃ are independently H, -OH, -SH, or Ci-Cig saturated or unsaturated, linear, branched or cyclic hydrocarbon groups

Y is H, SH, Ci-Cig saturated or unsaturated, linear, branched or cyclic hydrocarbon group, or NHR₄ represented by the Formula A:

H

/

N

\

R4

Formula A R4 is H, -OH, -SH, C1-C1₈ saturated or unsaturated, linear, branched or cyclic hydrocarbon group, or the moiety:

and

(ii) dermatologically acceptable carriers.

The present invention further provides a skin and/or hair depigmentation composition comprising

(i) a depigmentation effective amount of a pyridine derivative of formula I or formula II

Formula I

Formula II

or pharmaceutically acceptable salts thereof

wherein:

X is S or O

R, Ri_; R₂, and R₃ are independently H, -OH, -SH, or Ci-Cig saturated or unsaturated, linear, branched or cyclic hydrocarbon groups, Y is H, OH, SH, C1-C1₈ saturated or unsaturated, linear, branched or cyclic

hydrocarbon group, or NHR₄ represented by the Formula A:

H

/

N

\

R4

Formula A

(ii) cysteamine hydrochloride, and

(iii) dermatologically acceptable carriers.

The present invention further relates to use of the skin and/or hair depigmentation

compositions of the invention for reducing pigmentation of normal skin and/or hair.

The present invention also relates to a skin depigmentation compositions of the invention for use in a method for reducing skin pigmentation disorders.

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. 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. In the case of conflict, the present specification, including definitions, will control.

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 terms "subject" are 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 (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 lightening, bleaching, whitening and brightening used interchangeably herein) is the lightening of the skin and/or hair, or loss of pigment. The skin depigmentation agents or compositions are also referred as "skin lightener", "skin whitener", "skin even-toner" and "skin brightener". The hair depigmentation agents or compositions are referred to as "hair lightener", "hair whitener" and "hair brightener".

Whatever terminology is employed, the general premise is that they all relate to a reduction in the melanization or rate of melanization of the skin and/or hair, 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 and/or hair 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 compositions of the present invention onto the surface of the skin and/or a portion thereof such as hair. 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 melanization or rate of melanization of the skin and/or hair, 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 colour.

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 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 (Dermatology. 2002; 205:329-39).

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 (H₂0₂) as a by-product. Intracellular H₂0₂, generated after UV irradiation or in response to cytokines, such as tumour necrosis factor- (TNF- ) or transforming growth factor-/? (TGF- ?), can induce a transient reduction of tyrosinase and other melanogenic protein activities, through the down-regulation of the MITF transcription factor. However, it provides the peroxidase-H₂0₂ system with hydrogen peroxide and thus induces the peroxidase dependent steps in melanogenesis process such as the polymerization of indolic eumelanin monomers DHI and DHICA. The inhibition of peroxidase, reducing the polymerization rate of eumelanin monomers, results in

depigmentation.

The Applicant has surprisingly found that the topical application of pyridine derivatives, such as picolinamide or isonicotinic acid hydrazide produces skin and/or hair depigmentation when applied to human skin and/or other mammals such as black guinea pig skin.

The present invention thus provides a skin and/or hair depigmentation composition comprising (i) a depigmentation effective amount of a pyridine derivative of formula I or formula II

Formula I

or pharmaceutically acceptable salts thereof

wherein in Formula I

X is S or O

R and R₃ are independently H, -OH, -SH, or Ci-Cig saturated or unsaturated, linear, branched or cyclic hydrocarbon groups Y is -SH, C1-C1₈ saturated or unsaturated, linear, branched or cyclic hydrocarbon group, or NHR₄ represented by the Formula A:

H

/

N

\

R4

Formula A

Formula II

or pharmaceutically acceptable salts thereof

wherein in Formula II:

X is S or O

Y is H, SH, Ci-Cig saturated or unsaturated, linear, branched or cyclic hydrocarbon group, or NHR₄ represented by the Formula A: H

/

N

\

R4

Formula A

and

(ii) dermatologically acceptable carriers. Preferably said pyridine derivative is selected from the group comprising picolinamide, isonicotinic acid hydrazide, N-benzyl-3-(N'-(pyridine-4 carbonyl)hydrazino)propanamide, 2- ethylpyridine-4-carbothioamide, N'-isopropylisonicotinohydrazide. More preferably said pyridine derivative is selected from the group comprising picolinamide, N-benzyl-3-(N'- (pyridine-4 carbonyl)hydrazino)propanamide, isonicotinic acid hydrazide.

According to an embodiment, the skin and/or hair depigmentation compositions of the present invention further comprises at least one skin and/or hair benefit agent selected from the group comprising alpha-hydroxy acids, beta-hydroxy acids, polyhydroxy acids, nicotinamide, kojic acid, arbutin, deoxyarbutin, depigmenting oligopeptides, soybean extract, licorice extract, phyllanthus emblica extract, Bellis perennis extract, glabridin, polyphenol antioxidants, thiolic antioxidants, cysteamine hydrochloride, hydroquinone, methimazole, t-butyl hydroquinone, Vitamin E derivatives, Vitamin B derivatives, dioic acids, retinoids, corticosteroids, 4- substituted resorcinol derivatives, and mixtures thereof. The skin and/or hair depigmentation compositions of the present invention further comprises cysteamine hydrochloride. According to another embodiment, the skin and/or hair depigmentation composition of the present invention comprises

(i) a depigmentation effective amount of a pyridine derivative selected from the group comprising picolinamide, isonicotinic acid hydrazide, N-benzyl-3-(N'-(pyridine-4

carbonyl)hydrazino)propanamide, 2-ethylpyridine-4-carbothioamide, N'- isopropylisonicotinohydrazide,

(ii) cysteamine hydrochloride, and

(iii) dermatologically acceptable carriers.

The skin and/or hair depigmentation compositions of the present invention can comprise one pyridine derivative of the present invention or a mixture of two or more pyridine derivatives of the present invention.

According to a further embodiment, the present invention provides a skin and/or hair depigmentation composition comprising

Formula II

or pharmaceutically acceptable salts thereof wherein:

X is S or O

R, Ri_; R_2, and R₃ are independently H, -OH, -SH, or Ci-Cig saturated or unsaturated, linear, branched or cyclic hydrocarbon groups,

Y is H, OH, SH, Ci-Cig saturated or unsaturated, linear, branched or cyclic

hydrocarbon group, or NHR₄ represented by the Formula A:

H

/

N

\

R4

Formula A

R₄ is H, -OH, -SH, Ci-Cig saturated or unsaturated, linear, branched or cyclic hydrocarbon group, or the moiety:

(ii) cysteamine hydrochloride, and

(iii) dermatologically acceptable carriers.

Preferably a pyridine derivative is selected from the group comprising isonicotinamide, picolinamide, isonicotinic acid hydrazide, N-benzyl-3-(N'-(pyridine-4

carbonyl)hydrazino)propanamide, 2-ethylpyridine-4-carbothioamide, N'- isopropylisonicotinohydrazide.

The skin and/or hair depigmentation compositions can further comprise at least one skin and/or hair benefit agent selected from the group comprising alpha-hydroxy acids, beta-hydroxy acids, polyhydroxy acids, nicotinamide, kojic acid, arbutin, deoxyarbutin, depigmenting

oligopeptides, soybean extract, licorice extract, phyllanthus emblica extract, Bellis perennis extract, glabridin, polyphenol antioxidants, thiolic antioxidants, cysteamine hydrochloride, hydroquinone, methimazole, t-butyl hydroquinone, Vitamin C derivatives, Vitamin E derivatives, Vitamin B derivatives, dioic acids, retinoids, corticosteroids, 4-substituted resorcinol derivatives, and mixtures thereof. As used herein, the term "at least one" means "one or more" and also encompasses the terms "at least two", "at least three", "at least four", etc.

In addition to pyridine derivatives of the Formula (I) and the Formula (II), the pyridine derivatives of the present invention include pharmaceutically acceptable salts thereof.

The term "pharmaceutically acceptable salts" as used herein refers to salts that retain the desired biological activity of the pyridine derivatives of the present invention, and include pharmaceutically acceptable acid addition salts and base addition salts. Suitable

pharmaceutically acceptable acid addition salts of the pyridine derivatives of Formula (I) and Formula (II) may be prepared from an inorganic acid or from an organic acid, or can be prepared in situ during the final isolation and purification of the pyridine derivatives of the invention. Examples of such inorganic acids are hydrochloric, sulfuric, and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic, arylsulfonic. Suitable pharmaceutically acceptable base addition salts of the pyridine derivatives of Formula (I) and Formula (II) include metallic salts made from lithium, sodium, potassium, magnesium, calcium, aluminium, and zinc, and organic salts made from organic bases such as choline, diethanolamine, morpholine. Other examples of organic salts are:

ammonium salts, quaternary salts such as tetramethylammonium salt; amino acid addition salts such as salts with glycine and arcjinine. Additional information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds, agents and salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulae. The term"Ci-Ci₈ saturated or unsaturated, linear or branched hydrocarbon groups" as used herein refers to saturated or unsaturated, linear (straight) or branched chain hydrocarbon radicals derived from a hydrocarbon moiety containing between one and eighteen carbon atoms, such as, but limited to methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl , n- hexyl, n- heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-docecyl.

"Cyclic hydrocarbon group" refers to a saturated or partially saturated, monocyclic or fused or spiro polycyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. It includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems such as decalin, and polycyclic systems such as adamantane. The group may be a terminal group or a bridging group.

Isonicotinamide

Picolinamide

Isonicotinic acid hydrazide

N'-isopropylisonicotinohydrazide

2-ethylpyridine-4-carbothioamide

NH ,

N-benzyl-3 -(N'-(pyridine-4

carbonyl)hydrazino)propanamide

According to an embodiment of the present invention, the Applicant has shown, for the first time, that the topical application of a pyridine derivative of the present invention, preferably isonicotinamide or picolinamide, onto the human skin produces skin depigmentation and that isonicotinamide and picolinamide are each significantly more effective than nicotinamide in producing skin depigmentation in human while being very well tolerated by human skin.

In a further embodiment of the present invention, the Applicant has also shown that the repeated topical application of the pyridine derivative "isonicotinic acid hydrazide" (also known as Isoniazid) produces skin and hair depigmentation in black guinea pigs without producing any signs of skin irritation or inflammation.

In addition, in another embodiment of the present invention, the Applicant has shown that a combination of a pyridine derivative of the present invention with cysteamine hydrochloride has a particular advantage for skin and/or hair depigmentation. Indeed a combination of a pyridine derivative of the present invention with cysteamine hydrochloride demonstrates a synergistic skin and/or hair depigmenting effect, rather than an additive depigmenting effect. Preferably picolinamide, isonicotinic acid hydrazide or isonicotinamide are combined with cysteamine hydrochloride.

The skin depigmentation compositions of the present invention may contain a concentration of pyridine derivative, preferably selected from the group comprising isonicotinamide, picolinamide, and isonicotinic acid hydrazide, of about 0.001-30%, preferably 0.01-10.0%, most preferably 0.1-5.0% by weight of the composition.

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 preferred form of the skin depigmentation compositions of the present invention is an oil in water hydrophil cream (vanishing cream) containing stearic acid, petrolatum, cetyl alcohol, paraffin, sorbitol, glycerin, triethanolamine, pottasium sorbate, sodium benzoate, butylated hydroxytoluene and distilled water together with 5% (w/w) isonicotinamide or picolinamide.

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

The skin depigmentation compositions of the invention contain 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 colouring 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, easily be chosen by a person skilled in the art.

A moisturizing substance may be incorporated into 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 C₉-i5-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 incorporated into 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. 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- monobutylether, 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.

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 0.001 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. The skin and/or hair 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; C₉-n or C12-15 fatty alcohols; azone; alkyl pyrrolidones; diethoxy glycol (Transcutol); lecithin; etc. Surfactants can also be used as penetration enhancers.

The skin and/or hair depigmentation compositions of the present invention may also include a skin and/or hair benefit agent selected from the group comprising alpha-hydroxy acids, beta- hydroxy acids, polyhydroxy acids, nicotinamide, kojic acid, arbutin, deoxyarbutin,

depigmenting oligopeptides, soybean extract, licorice extract, phyllanthus emblica extract, Bellis perennis extract, glabridin, polyphenol antioxidants, thiolic antioxidants, cysteamine hydrochloride, hydroquinone, methimazole, t-butyl hydroquinone, Vitamin C derivatives, Vitamin E derivatives, Vitamin B derivatives, dioic acids, retinoids, corticosteroids, 4- substituted resorcinol derivatives, and mixtures thereof. The skin and/or hair depigmentation compositions of the present invention may also include liposomes (unilamellar and/or multilamellar liposomes of any size) in order to facilitate the delivery of any component(s) of the depigmenting composition to its site of action. The optimal type and size of liposome(s) and the nature of the medium in which the liposomes are dispersed, can be easily chosen by a person skilled in the art.

The present invention further provides the use of the skin and/or hair depigmentation compositions of the invention for reducing pigmentation of normal skin and/or normal hair. Said skin and hair is preferably at least one of facial skin and/or facial hair, skin and/or hair on the neck, skin and/or hair on the arms, skin and/or hair on the hands, skin and/or hair on the legs and skin and/or hair on the scalp. The terms "normal skin" and "normal hair" are referred to healthy skin and healthy hair having no pigmentation disorders. The present invention also provides skin depigmentation compositions of the invention for use in a method for reducing skin pigmentation disorders.

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 hyperpigmentation, 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 -melanocyte stimulating hormone ( -MSH) release, are triggering factors for these disorders.

Preferably pigmentation disorders are selected from the group comprising hyperpigmentation, melasma, postinflammatory hyperpigmentation, lentigo, freckles, drug induced

hyperpigmentation, light induced hyperpigmentation and chemical induced hyperpigmentation.

The present invention also provides a method for reducing pigmentation of normal skin and/or normal hair, comprising topically applying to the skin and/or hair depigmentation compositions of the invention to the skin and/or hair. 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, comprising topically applying to the skin depigmentation compositions of the invention to the skin and/or hair. The present invention further provides a method for reducing skin pigmentation disorders, comprising topically applying to the skin depigmentation compositions of the invention to the skin.

Additionally, skin and/or hair depigmentation compositions of the present invention can be useful in preventing pigmentation of normal skin and/or hair and in preventing pigmentation disorders. The term "preventing" as used herein, means that the normal (healthy) pigmentation or disease related pigmentation would 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 of the skin and/or hair, preferably human skin and/or hair, is induced.

In the method according to the invention the skin and/or hair depigmentation compositions are applied to the skin and/or hair, preferably human skin and/or hair. The amount of the skin and/or hair depigmentation composition that is to be applied to the skin and/or hair depends upon the form of the skin/hair depigmentation composition and its mode of application. For example, a spray formulation may be applied so as to provide a light, even coat on the skin and/or hair. Similarly, lotions, creams, gels, shampoos and the like are typically applied in an amount to provide a light coating to the treatment 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 surface, including hairy or non- hairy skin, is to be treated, is about 20 to 60 ml for the entire body, i.e., for the exposed skin of an "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 surface, including hairy or non-hairy skin surface. On the face, a typical application rate is 1.2 to 1.7 ml. At such levels of application, the amount of skin and/or hair 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 and/or hair.

The compositions may be applied once 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, or to alter the dark normal colour of the scalp or body hair to a lighter colour by applying appropriate skin and/or hair depigmentation compositions to the scalp, face and neck areas. However, the skin and/or hair 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.

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, 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 6.9.

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

Three different topical preparations were made: The first preparation contained 5% (w/w) isonicotinamide, the second 5% (w/w) picolinamide and the third 5% (w/w)

nicotinamide in a hydrophil cream vehicle. The three preparations were applied to three separate areas, each with a surface area of 9 cm², on the external aspect of the arm of 6 healthy individuals with phototype IV. The hydrophil cream alone was applied on a separate area of the external aspect of the arm of the same subjects and served as negative control. Applications were performed daily for 8 consecutive weeks. The skin lightening effect of the products was evaluated at the end of the study by a clinician blinded to the treatment identifications and through using a chromameter.

Isonicotinamide and picolinamide containing formulations were significantly more effective than nicotinamide in producing skin depigmentation. These two formulations were very well tolerated by the subjects and induced no signs of skin irritation or inflammation.

Example 2

Isonicotinic acid hydrazide was made into a 5% cream through dissolving the agent in a hydrophil cream vehicle. The cream was then applied on one of the ears of each of the 6 black guinea pigs enrolled in the study. The hydrophil cream alone, serving as the negative control, was applied simultaneously on the contralateral ears of the animals. Applications were performed once daily for two consecutive weeks. The skin depigmenting effect of the two creams was evaluated by histologic examination of the skin (Fontana-Masson) as well as the spectrophotometric quantification of extracted melanin in punch biopsies taken from the drug treated vs. control vehicle-treated ears.

Isonicotinic acid hydrazide produced visually recognizable skin depigmentation in all treated areas while the areas treated by the hydrophil cream alone produced no changes in pigmentation. Histologic examinations confirmed the significant decrease of epidermal melanin in the areas treated with isonicotinic acid hydrazide. Melanin quantification confirmed more than 70% decrease in the amount of epidermal melanin compared to the control area treated with the hydrophil cream alone.

Example 3

Two separate areas each with a surface area of 4 cm² were shaved on the flank of each of the six black guinea pigs. A hydrophil cream containing 5% isonicotinic acid hydrazide was daily applied on one of the areas and the hydrophil cream alone was applied on the other area. The regrowing hair was shaved every other days. After two weeks of daily treatment, the applications were stopped and the areas were no more shaved, allowing the hair to regrow. The re-growed hair in the areas treated with isonicotinic acid hydrazide showed a significant lightening and was blond instead of black. The hair re-growed in the control areas treated with the hydrophil cream alone was black and did not show any colour change. The histologic examinations of Fontana-Masson stained specimens confirmed the reduction of melanin content in the areas treated with isonicotinic acid hydrazide in comparison with the control areas.

Example 4

Seven healthy male individuals with phototype IV participated the study. 5 identical, uniformly pigmented, 2x2 cm quadrants were chosen on the external aspect of the left arm of each individual. Once daily application of the products (see the product list below) were done during 21 consecutive days on each specific quadrant in each individual. 500mg of each cream was applied daily onto the associated area. Application of the creams was done daily by an independant medical assistant. The individuals were not exposed to sun-light or any artificial source of UV light during the study and did not use any other topical products during this period.

The coulour of skin (melanin and erythema) was measured just before the first application and once again 24 hours after the last application. Prior to colour measurements, the skin was washed by soap and water, gently dried by a tissue and then hydrated by a moisturizing cream. The excess of the moisturizing cream was gently removed by a tissue.

Colour measurements were done by Dermacatch skin colorimeter (Colorix company,

Switzerland). Skin colour measurement in each area was repeated 10 consecutive times for statistical means and the mean values were considered for each area.

List of the topical products applied :

- The vehicle alone (vanishing cream) as the placebo. This vanishing cream was used in all the below mentioned products as the vehicle.

- The cream containing 5% (w/w) Nicotinamide

- The cream containing 5% (w/w) Picolinamide

- The cream containing 5% (w/w) Cysteamine hydrochloride

- The cream containing 5% (w/w) Picolinamide + 5% (w/w) Cysteamine hydrochloride Nicotinamide, Picolinamide and Cysteamine hydrochloride were obtained from Sigma company (Switzerland). The vanishing cream vehicle was commercially obtained form Scientis Pharma company (Geneva, Switzerland). Table 1 : summary of the results of colour measurements before and after the treatment.

Before After

Melanin Erythema Melanin Erythema

Placebo 672±35 422±16 681±24 429±11

Nicotinamide 5% 670±32 418±16 653±26 413±14

Picolinamide 5% 677±28 415±18 604±11 411±11

Cysteamine HC1 5% 668±22 415±19 641±14 419±23

Picolinamide 5% + 678±28 423±17 522±21 419±13

Cysteamine HC1 5%

Each Melanin or Erythema value represents the mean value of all the areas treated by the same product (7 areas per product). All products, except for the placebo, were effective in reducing the melanin index of the skin. Picolinamide, however, was significantly more effective than nicotinamide in reducing the melanin index (p<0.05).

The combination of Picolinamide with Cysteamine hydrochloride was significantly more effective than each of the molecules alone (p<0.05). The above mentioned results indicate that Picolinamide and Cysteamine HC1 show a « synergistic » skin depigmenting effect, rather than an additive depigmenting effect, when combined together.

The erythema index was not significantly affected by any of the treatments. All treatments were well tolerated by the patients and none oft he produced any signs of inflammation or irritation. Example 5

The study was done in the Jahrom University Medical School (Iran) upon the authorisation of the university ethical commitee.

Six uniformly pigmented, black male guinea pigs were treated for 10 consecutive days with a 10% isonicotinic acid hydrazide cream on the dorsal aspect of one of their ears and with the vehicle alone on the contraletral ears. Skin colour measurement was done by Dermacatch skin colorimeter (Colorix company, Switzerland) just before starting the treatments and once again 24 hours after the last application. The skin was washed and gently dried before colour measurements. Colour measurement was done 10 times on each area and the mean value was considered for statistical analyses. At the end of the study, biopsy speciemens were taken under general anesthesia by the IM injection of ketamine and xylasine and were processed for histologic examinations (H&E and Fontana-Masson stainings).

Table 2 : Summary of the results obtained through skin colorimetry.

Each Melanin or Erythema value represents the mean value of all the areas treated by the same product (6 areas per product).

In contrast to the vehicle alone, isonicotinic acid hydrazide significantly reduced the melanin index of the black guinea pig skin (p<0.05). The erythema index remained unchanged by both treatments. The histologic examinations confirmed the significant reduction of epidermal melanin in the isonicotinic acid hydrazide-treated skin compared to the vehicle alone. The product did not induce any signs of irritation or inflammation and was well tolerated by all animals.

Claims

1. A skin and/or hair depigmentation composition comprising

Formula I

or pharmaceutically acceptable salts thereof

wherein in Formula I

X is S or O

Y is -SH, Ci-Cig saturated or unsaturated, linear, branched or cyclic hydrocarbon group, or NHR₄ represented by the Formula A:

H

/

N

\

R4

Formula A

R4 is H, -OH, -SH, Ci-Cig saturated or unsaturated, linear, branched or cyclic hydrocarbon group, or the moiety:

Formula II

or pharmaceutically acceptable salts thereof

wherein in Formula II:

X is S or O

H

/

N

\

R4

Formula A

and

(ii) dermatologically acceptable carriers.

2. The skin and/or hair depigmentation composition of claim 1 , wherein said pyridine derivative is selected from the group comprising picolinamide, isonicotinic acid hydrazide, N- benzyl-3 -(N'-(pyridine-4 carbonyl)hydrazino)propanamide, 2-ethylpyridine-4-carbothioamide, N'-isopropylisonicotinohydrazide.

3. The skin and/or hair depigmentation composition of claim 1 , wherein said pyridine derivative is selected from the group comprising picolinamide, N-benzyl-3-(N'-(pyridine-4 carbonyl)hydrazino)propanamide, isonicotinic acid hydrazide.

4. The skin and/or hair depigmentation composition of claims 1 to 3, wherein said composition further comprises at least one skin and/or hair benefit agent selected from the group comprising alpha-hydroxy acids, beta-hydroxy acids, polyhydroxy acids, nicotinamide, kojic acid, arbutin, deoxyarbutin, depigmenting oligopeptides, soybean extract, licorice extract, phyllanthus emblica extract, Bellis perennis extract, glabridin, polyphenol antioxidants, thiolic antioxidants, cysteamine hydrochloride, hydroquinone, methimazole, t-butyl hydroquinone, Vitamin E derivatives, Vitamin B derivatives, dioic acids, retinoids, corticosteroids, 4- substituted resorcinol derivatives, and mixtures thereof.

5. The skin and/or hair depigmentation composition of claims 1 to 4, wherein said composition further comprises cysteamine hydrochloride.

6. The skin and/or hair depigmentation composition of claims 1 to 5 comprising

(ii) cysteamine hydrochloride, and

(iii) dermatologically acceptable carriers.

7. A skin and/or hair depigmentation composition comprising

Formula II

or pharmaceutically acceptable salts thereof

wherein:

X is S or O

Y is H, OH, SH, Ci-Cig saturated or unsaturated, linear, branched or cyclic hydrocarbon group, or NHR₄ represented by the Formula A:

H

/

N

\

R4

Formula A

(ii) cysteamine hydrochloride, and

(iii) dermatologically acceptable carriers.

8. The skin and/or hair depigmentation composition of claim 7, wherein said a pyridine derivative is selected from the group comprising isonicotinamide, picolinamide, isonicotinic acid hydrazide, N-benzyl-3-(N'-(pyridine-4 carbonyl)hydrazino)propanamide, 2-ethylpyridine- 4-carbothioamide, N'-isopropylisonicotinohydrazide.

9. The skin and/or hair depigmentation composition of claim 7, wherein said composition further comprises at least one skin and/or hair benefit agent selected from the group comprising alpha-hydroxy acids, beta-hydroxy acids, polyhydroxy acids, nicotinamide, kojic acid, arbutin, deoxyarbutin, depigmenting oligopeptides, soybean extract, licorice extract, phyllanthus emblica extract, Bellis perennis extract, glabridin, polyphenol antioxidants, thiolic antioxidants, cysteamine hydrochloride, hydroquinone, methimazole, t-butyl hydroquinone, Vitamin C derivatives, Vitamin E derivatives, Vitamin B derivatives, dioic acids, retinoids, corticosteroids, 4-substituted resorcinol derivatives, and mixtures thereof.

10. The skin and/or hair depigmentation composition of claims 1 to 9, wherein said depigmentation 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, or a skin or hair conditioning agent.

11. Use of the skin and/or hair depigmentation composition of claims 1 to 10 for reducing pigmentation of normal skin and/or normal hair of a subject.

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

13. The skin and/or hair depigmentation composition for use in a method for reducing skin pigmentation disorders of claim 12, wherein said pigmentation disorders are selected from the group comprising hyperpigmentation, melasma, postinflammatory hyperpigmentation, lentigo, freckles, drug induced hyperpigmentation, light induced hyperpigmentation and chemical induced hyperpigmentation.

14. A method for reducing pigmentation of normal skin and/or hair, comprising topically applying the skin and/or hair depigmentation composition of claims 1 to 10 to the skin and/or hair of a subject in need thereof.

15. A method for reducing skin pigmentation disorders, comprising topically applying the skin and/or hair depigmentation composition of claims 1 to 10 to the skin of a subject in need thereof.

16. The method of claim 15, wherein said pigmentation disorders are selected from the group comprising hyperpigmentation, melasma, postinflammatory hyperpigmentation, lentigo, freckles, drug induced hyperpigmentation, light induced hyperpigmentation and chemical induced hyperpigmentation.