WO2019021287A1 - Treatment of skin ailment - Google Patents

Abstract

Compounds for use in the treatment of uneven skin pigmentation and/or for use in lightening skin are described herein, as well as methods utilizing same. The compounds may be a non-steroidal anti-inflammatory drug (NSAID), urea, or a combination thereof.

Description

TREATMENT OF SKIN AILMENT

FIELD AND BACKGROUND OF THE INVENTION

The present invention, in some embodiments thereof, relates to a cosmetic treatment, and more particularly, but not exclusively, to a treatment of spots on skin. Melanin synthesis occurs in melanocytes, and is initiated by oxidation of tyrosine to dopaquinone by tyrosinase. Further oxidation reactions result in 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2- carboxylic acid (DHICA), which undergoes polymerization to form the common black or brown forms of melanin [Chang, Materials 2012, 5: 1661-1685]. Each melanocyte in the epidermis transfers melanin via dendrites to approximately 30-40 surrounding keratinocytes [Bastonini et si., Ann Dermatol 2016, 28:279-289].

A lentigo (plural "lentigines") is a small pigmented spot on the skin. A typical lentigo is a benign hyperplasia of melanocytes which is linear in spread, that is, the hyperplasia of melanocytes is restricted to the cell layer directly above the basement membrane of the epidermis where melanocytes normally reside. Accordingly, other skin lesions that proliferate linearly within the basal cell layer are described as "lentiginous".

In contrast to lentigines, moles (melanocytic nevi) contain multi-layer melanocytes; and freckles have a normal number of melanocytes but an increased amount of melanin.

Solar lentigines, also known as "age spots" or "liver spots", are skin blemishes associated with aging and exposure to ultraviolet light from the sun. They range in color from light brown to red or black, and become particularly common among people aged 40 and older, as the skin becomes less able to regenerate following sun exposure. Solar lentigines are associated with increased levels in the skin of growth factors that regulate melanocyte activity keratinocytes [Bastonini et al., Ann Dermatol 2016, 28:279-289].

Techniques for removing solar lentigines, as well as other forms of hyperpigmentation, include electrosurgery, laser treatment, cryotherapy, and the use of topical depigmentation agents, such as hydroquinone (and related compounds such as arbutin and deoxyarbutin), retinoic acid, cysteamine, azelaic acid, kojic acid, niacinamide, antioxidants (such as ascorbic acid, vitamin B and vitamin E), or a-hydroxyacids (e.g., glycolic acid or lactic acid) [Chang, Materials 2012, 5: 1661-1685; Gillbro & Olsson, Int J Cosmetic Sci 2011, 33:210-221].

A variety of mechanisms of depigmentation agents have been proposed [Gillbro & Olsson, Int J Cosmetic Sci 2011, 33:210-221], although the mechanism in many cases remains unclear. Hydroquinone (and the related compounds arbutin and deoxyarbutin), kojic acid and azelaic acid are described as inhibiting melanin synthesis by inhibiting tyrosinase. Tyrosinase has an active site in which copper ions are bound by histidine residues. Kojic acid may inhibit tyrosinase by chelating the copper ions, whereas hydroquinone is reported to bind to the histidine residues. Depigmentation may be effected by skin exfoliation (e.g., by retinoic acid, linoleic acid, ascorbic acid, or a-hydroxyacids) which removes the uppermost layer of melanin- containing skin cells. Some compounds, such as niacinamide, have been reported to inhibit melanin transfer from melanocytes to surrounding keratinocytes. Antioxidants are hypothesized to inhibit the induction of melanin synthesis by ultraviolet light and/or to impede polymerization of melanin intermediates.

Kim et al. [Exp Dermatol 2012, 21:420-425] has reported that siRNA-mediated knockdown of COX-2 in melanocytes suppresses melanogenesis, and suggested that COX-2 inhibitors might be of use in whitening cosmetics for hyperpigmentation disorders such as melasma, postinflammatory hyperpigmentation and solar lentigo.

Urea-containing creams are applied to skin to treat skin dryness, hyperkeratosis and/or itching, e.g., such as may occur in psoriasis, dermatitis, ichthyosis, eczema, keratosis, keratoderma, corns and/or calluses.

Additional background art includes Davis & Callender [ Clin Aesthet Dermatol 2010, 3:20-31]; and Shilakari Asthana et al. [J Drug Deliv 2016, 2016:9324567].

SUMMARY OF THE INVENTION

According to an aspect of some embodiments of the invention, there is provided a compound for use in the treatment of uneven skin pigmentation, wherein the compound is a nonsteroidal anti-inflammatory drug (NSAID).

According to an aspect of some embodiments of the invention, there is provided a compound for use in lightening skin, wherein the compound is a non-steroidal anti-inflammatory drug (NSAID).

According to an aspect of some embodiments of the invention, there is provided a compound for use in the treatment of uneven skin pigmentation, wherein the compound is urea.

According to an aspect of some embodiments of the invention, there is provided a compound for use in lightening skin, wherein the compound is urea.

According to an aspect of some embodiments of the invention, there is provided a combination of a non-steroidal anti-inflammatory drug (NSAID) and urea, for use in the treatment of uneven skin pigmentation. According to an aspect of some embodiments of the invention, there is provided a combination of a non-steroidal anti-inflammatory drug (NSAID) and urea, for use in lightening skin.

According some embodiments of any of the embodiments of the invention described herein, the uneven skin pigmentation is associated with at least one lentigo and/or nevus.

According some embodiments of any of the embodiments of the invention described herein, lightening skin comprises lightening at least one lentigo and/or nevus.

According some embodiments of any of the embodiments of the invention described herein relating to at least one lentigo, the at least one lentigo comprises a solar lentigo.

According some embodiments of any of the embodiments of the invention described herein, the treatment is effected by systemic administration of the compound.

According some embodiments of the invention, the treatment is effected by systemic administration of the NSAID and/or the urea.

According some embodiments of any of the embodiments of the invention described herein, the treatment is effected by topical administration of the compound.

According some embodiments of the invention, the treatment is effected by topical administration of the NSAID and/or the urea.

According some embodiments of any of the embodiments of the invention described herein, the treatment is effected by topical administration of the compound to a region of skin to be lightened.

According some embodiments of any of the embodiments of the invention described herein, the treatment is effected by transdermal administration of the compound.

According some embodiments of any of the embodiments of the invention described herein, the treatment is effected by topical administration of the compound to a region of skin characterized by uneven pigmentation.

According some embodiments of any of the embodiments of the invention described herein, the compound forms a part of a composition comprising urea at a concentration in a range of from 5 to 50 weight percents, and a dermatologically acceptable carrier.

According some embodiments of any of the embodiments of the invention described herein, the treatment is effected by topical administration of a composition comprising urea at a concentration in a range of from 5 to 50 weight percents, and a dermatologically acceptable carrier. According some embodiments of any of the embodiments of the invention described herein, the treatment is effected by administering a composition comprising the NSAID and the urea.

According some embodiments of any of the embodiments of the invention described herein, the treatment is effected by co-administering a first composition comprising the NSAID and a second composition comprising the urea.

According some embodiments of any of the embodiments of the invention described herein relating to a composition, the composition comprises dimethicone.

According some embodiments of any of the embodiments of the invention described herein relating to an NSAID, the NSAID comprises an indole moiety.

According some embodiments of the invention, the NSAID is selected from the group consisting of etodolac, indomethacin, and pravadoline.

According some embodiments of the invention, the compound is etodolac.

Unless otherwise defined, all technical and/or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and/or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

The present invention, in some embodiments thereof, relates to a cosmetic treatment, and more particularly, but not exclusively, to a treatment of spots on skin.

Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details set forth in the following description or exemplified by the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways.

The present inventor has uncovered that excessive and/or uneven pigmentation can surprisingly be treated by administration of an NSAID and/or urea.

According to an aspect of some embodiments of the invention, there is provided a compound or a combination of compounds (according to any of the respective embodiments described herein) for use in the treatment of uneven skin pigmentation. According to an aspect of some embodiments of the invention, there is provided a use of a compound or a combination of compounds (according to any of the respective embodiments described herein) in the manufacture of a cosmetic and/or medicament for the treatment of uneven skin pigmentation.

According to an aspect of some embodiments of the invention, there is provided a method of treating uneven skin pigmentation, the method comprising administering to a subject in need thereof an effective amount of a compound or a combination of compounds (according to any of the respective embodiments described herein).

In some embodiments of any of the respective embodiments described herein, the uneven skin pigmentation is associated with at least one lentigo and/or nevus. In some such embodiments, the at least one lentigo comprises at least one solar lentigo.

Herein and in the art, the term "lentigo" (plural "lentigines") refers to a small pigmented spot on the skin, which is associated with hyperplasia of melanocytes. The melanocytes in a lentigo are typically linear in spread, being restricted to the cell layer directly above the basement membrane of the epidermis where melanocytes normally reside.

Herein and in the art, the term "solar lentigo" refers to a lentigo associated with aging and exposure to ultraviolet radiation from the sun. Distribution of solar lentigines is typically correlated with exposure to sun, occurring more frequently on hands, arms, face, shoulders and forehead (and scalp, in bald subjects). Solar lentigines occur most frequently in subjects aged 40 or older.

Herein, the term "nevus" (plural "nevi") refers to a visible, hyperpigmented region of on the skin (other than a lentigo), which is characterized by increased melanin concentrations. In some embodiments of any of the embodiments described herein relating to a nevus, the nevus is associated with a benign neoplasia or hyperplasia, e.g., wherein the melanocytes are in a multi- layer form (rather than the linear spread of a lentigo).

According to an aspect of some embodiments of the invention, there is provided a compound or a combination of compounds (according to any of the respective embodiments described herein) for use in lightening skin.

According to an aspect of some embodiments of the invention, there is provided a use of a compound or a combination of compounds (according to any of the respective embodiments described herein) in the manufacture of a cosmetic and/or medicament for lightening skin.

According to an aspect of some embodiments of the invention, there is provided a method of lightening skin, the method comprising administering to a subject in need thereof an effective amount of a compound or a combination of compounds (according to any of the respective embodiments described herein).

In some embodiments of any of the respective embodiments described herein, lightening skin comprises lightening at least one lentigo and/or nevus (as these terms are defined herein) on the skin. In some such embodiments, the at least one lentigo comprises at least one solar lentigo.

In some embodiments of any of the embodiments described herein, according to any of the aspects described herein, the compound is a non-steroidal anti-inflammatory drug (NSAID) or urea. In some such embodiments, the combination of compounds (according to any of the respective embodiments described herein) is a combination of an NSAID and urea.

Herein, the term "urea" encompasses the compound having the formula H₂N-C(=0)- NH₂, as well as derivatives thereof.

Such urea derivative can include, for example, substituted urea, which can be generally described, for example, by the general formula:

R¹R²N-C(=0)-NR³R⁴ wherein each of R¹, R², R³ and R⁴ is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl and aryl, or, alternatively, one of R¹ and R² and one of R³ and R⁴ are linked therebetween to thereby form a heteroalicyclic ring.

However, other derivatives of urea such as, for example, ureaform, urazole, thiourea or dimeric forms of urea (including substituted or non-substituted urea according to any of the respective embodiments described herein) are also within the scope of the present invention.

The urea is optionally in a form of a urea-containing cream.

Herein and in the art, a "urea-containing cream" refers to a topical product that contains urea as an identified active ingredient, for example, for treating skin dryness and/or itching. It is to be appreciated that "urea-containing cream" is a term of the art, and is not intended to exclude types of composition and/or carrier which are which are not "creams". Rather, any product containing urea as an identified active ingredient, and formulated in a manner suitable for topical administration of the urea therein, is encompassed by this term; including creams, gels, pastes, ointments, foams, lotions, soaps, and the like (e.g., according to any of the respective embodiments described herein).

Suitable examples of commercially available urea-containing creams include, without limitation, Flexitol®, Decubal™, Carmol® (e.g., Carmol® 20, Carmol® 40) and Keralac™ topical creams. The urea-containing cream may optionally comprise at least 5 weight percents, and optionally from 5 to 50 weight percents (e.g., about 10, about 20 or about 40 weight percents) urea, and a dermatologically acceptable carrier (as defined herein).

A cream according to any of the respective embodiments described herein may optionally comprise dimethicone.

Herein, the term "dimethicone" refers to polydimethylsiloxane, that is, a polymer comprising a plurality of -0-S(CH₃)2- residues; for example, having the formula (CH₃)₃-[0- S(CH₃)₂-]nCH₃, wherein n is an integer of at least 2 (e.g., from 2 to 10,000 or from 2 to 1,000). The polymer may be linear, cyclic and/or branched, and is optionally a linear polymer.

Dimethicone may optionally be a volatile liquid, a non-volatile liquid, or a viscous semisolid. The viscosity (and volatility) of the dimethicone depend, e.g., on the molecular weight of the dimethicone. Dimethicone is commonly characterized in the art according to its viscosity, for example, in units of 5 cSt (centistokes).

In some of any of the respective embodiments described herein, the dimethicone is characterized by a viscosity of at least 5 cSt, for example, in a range of from 5 to 1,000,000 cSt. In some embodiments, the dimethicone is characterized by a viscosity of from 5 to 10,000 cSt. In some embodiments, the dimethicone is characterized by a viscosity of from 5 to 1,000 cSt.

Without being bound by any particular theory, it is believed that dimethicone with a viscosity of at least 5 cSt is sufficiently non-volatile to facilitate interaction with the skin. It is further believed that dimethicone with a viscosity of no more than 10,000 cSt (e.g., no more than 1,000 cSt) is relatively easily spreadable on the skin.

In some of any of the respective embodiments described herein, a concentration of dimethicone in the cream is at least 1 weight percent, optionally at least 2 weight percents, optionally at least 5 weight percents, optionally at least 10 weight percents, optionally at least 20 weight percents, and optionally at least 50 weight percents.

Herein, the terms "NSAID" and "non-steroidal anti-inflammatory drug" (which are used herein interchangeably) refer to a class of non-steroidal agents which inhibit cyclooxygenase- 1 (COX-1) and/or cyclooxygenase-2 (COX-2), resulting in inhibition of inflammatory responses.

Examples of NSAIDS which may be utilized according to any of the embodiments described herein include, without limitation, aspirin, diflunisal, salsalate, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaproxin, loxoprofen, indomethacin, pravadoline, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone, piroxicam, lysine clonixinate, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, nimesulide, licofelone, and coxibs (e.g., celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib and firocoxib), as well as derivatives thereof (e.g., wherein the compounds is substituted by one or more of a substituent described herein). In some embodiments, the NSAID is a COX-1 inhibitor (e.g., an NSAID which is not a coxib).

In some embodiments of any of the embodiments described herein, the NSAID comprises an indole moiety (e.g., the NSAID is a substituted indole). Examples of NSAIDs comprising an indole moiety include, without limitation, etodolac, indomethacin, and pravadoline. In exemplary embodiments, the NSAID is etodolac.

The NSAID is optionally in a form of a composition for oral, rectal, intravenous and/or topical administration.

Herein throughout, the phrase "topical administration" refers to administration to a body surface, and encompasses both administration of agents which remain in a region of said body surface (e.g., local administration) and administration of agents which spread throughout the body (e.g., transdermal administration).

Suitable examples of commercially available etodolac formulations (e.g., for oral administration of etodolac) include, without limitation, Etopan™, Lodine™ and Eccoxolac™ pharmaceutical compositions.

Without being bound by any particular theory, it is believed that NSAIDs comprising an indole moiety are structurally similar to melanin and/or precursors thereof (e.g., dihydroxyindole and/or 5,6-dihydroxyindole-2-carboxylic acid), which may facilitate modulation of melanin levels in skin by interacting with proteins involved in melanin production.

For any of the embodiments described herein, and any combination thereof, the compound(s) (e.g., an NSAID and/or urea according to any of the respective embodiments described herein) may be in a form of a salt, for example, a pharmaceutically acceptable salt.

As used herein, the phrase "pharmaceutically acceptable salt" refers to a charged species of the parent compound and its counter-ion, which is typically used to modify the solubility characteristics of the parent compound and/or to reduce any significant irritation to an organism by the parent compound, while not abrogating the biological activity and properties of the administered compound. A pharmaceutically acceptable salt of a compound as described herein can alternatively be formed during the synthesis of the compound, e.g., in the course of isolating the compound from a reaction mixture or re-crystallizing the compound.

In the context of some of the present embodiments, a pharmaceutically acceptable salt of the compounds described herein may optionally be an acid addition salt and/or a base addition salt. An acid addition salt comprises at least one basic (e.g., amine and/or guanidinyl) group of the compound which is in a positively charged form (e.g., wherein the basic group is protonated), in combination with at least one counter-ion, derived from the selected acid, that forms a pharmaceutically acceptable salt. The acid addition salts of the compounds described herein may therefore be complexes formed between one or more basic groups of the compound and one or more equivalents of an acid.

A base addition salt comprises at least one acidic (e.g., carboxylic acid) group of the compound which is in a negatively charged form (e.g., wherein the acidic group is deprotonated), in combination with at least one counter-ion, derived from the selected base, that forms a pharmaceutically acceptable salt. The base addition salts of the compounds described herein may therefore be complexes formed between one or more acidic groups of the compound and one or more equivalents of a base.

Depending on the stoichiometric proportions between the charged group(s) in the compound and the counter-ion in the salt, the acid additions salts and/or base addition salts can be either mono-addition salts or poly-addition salts.

The phrase "mono-addition salt", as used herein, refers to a salt in which the stoichiometric ratio between the counter- ion and charged form of the compound is 1: 1, such that the addition salt includes one molar equivalent of the counter-ion per one molar equivalent of the compound.

The phrase "poly- addition salt", as used herein, refers to a salt in which the stoichiometric ratio between the counter-ion and the charged form of the compound is greater than 1: 1 and is, for example, 2: 1, 3: 1, 4: 1 and so on, such that the addition salt includes two or more molar equivalents of the counter-ion per one molar equivalent of the compound.

An example, without limitation, of a pharmaceutically acceptable salt would be an ammonium cation or guanidinium cation and an acid addition salt thereof, and/or a carboxylate anion and a base addition salt thereof.

The base addition salts may include a cation counter-ion such as sodium, potassium, ammonium, calcium, magnesium and the like, that forms a pharmaceutically acceptable salt.

The acid addition salts may include a variety of organic and inorganic acids, such as, but not limited to, hydrochloric acid which affords a hydrochloric acid addition salt, hydrobromic acid which affords a hydrobromic acid addition salt, acetic acid which affords an acetic acid addition salt, ascorbic acid which affords an ascorbic acid addition salt, benzenesulfonic acid which affords a besylate addition salt, camphorsulfonic acid which affords a camphorsulfonic acid addition salt, citric acid which affords a citric acid addition salt, maleic acid which affords a maleic acid addition salt, malic acid which affords a malic acid addition salt, methanesulfonic acid which affords a methanesulfonic acid (mesylate) addition salt, naphthalenesulfonic acid which affords a naphthalenesulfonic acid addition salt, oxalic acid which affords an oxalic acid addition salt, phosphoric acid which affords a phosphoric acid addition salt, toluenesulfonic acid which affords a p-toluenesulfonic acid addition salt, succinic acid which affords a succinic acid addition salt, sulfuric acid which affords a sulfuric acid addition salt, tartaric acid which affords a tartaric acid addition salt and trifluoroacetic acid which affords a trifluoro acetic acid addition salt. Each of these acid addition salts can be either a mono-addition salt or a poly-addition salt, as these terms are defined herein.

The present embodiments further encompass any enantiomers, diastereomers, prodrugs, solvates and/or hydrates of the compounds (e.g., NSAID or urea) described herein.

As used herein, the term "enantiomer" refers to a stereoisomer of a compound that is superposable with respect to its counterpart only by a complete inversion/reflection (mirror image) of each other. Enantiomers are said to have "handedness" since they refer to each other like the right and left hand. Enantiomers have identical chemical and physical properties except when present in an environment which by itself has handedness, such as all living systems. In the context of the present embodiments, a compound may exhibit one or more chiral centers, each of which exhibiting an R- or an S-configuration and any combination, and compounds according to some embodiments of the present invention, can have any their chiral centers exhibit an R- or an S-configuration.

The term "diastereomers", as used herein, refers to stereoisomers that are not enantiomers to one another. Diastereomerism occurs when two or more stereoisomers of a compound have different configurations at one or more, but not all of the equivalent (related) stereocenters and are not mirror images of each other. When two diastereomers differ from each other at only one stereocenter they are epimers. Each stereo-center (chiral center) gives rise to two different configurations and thus to two different stereoisomers. In the context of the present invention, embodiments of the present invention encompass compounds with multiple chiral centers that occur in any combination of stereo-configuration, namely any diastereomer.

The term "prodrug" refers to an agent, which is converted into the active compound (the active parent drug) in vivo. Prodrugs are typically useful for facilitating the administration of the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. A prodrug may also have improved solubility as compared with the parent drug in pharmaceutical compositions. Prodrugs are also often used to achieve a sustained release of the active compound in vivo. An example, without limitation, of a prodrug would be a compound of the present invention, having one or more carboxylic acid moieties, which is administered as an ester (the "prodrug"). Such a prodrug is hydrolyzed in vivo, to thereby provide the free compound (the parent drug). The selected ester may affect both the solubility characteristics and the hydrolysis rate of the prodrug.

The term "solvate" refers to a complex of variable stoichiometry (e.g., di-, tri-, tetra-, penta-, hexa-, and so on), which is formed by a solute (the compound of the present invention) and a solvent, whereby the solvent does not interfere with the biological activity of the solute. Suitable solvents include, for example, ethanol, acetic acid and the like.

The term "hydrate" refers to a solvate, as defined hereinabove, where the solvent is water.

The compounds according to any of the embodiments presented herein can be utilized (individually or in combination) either per se, or, preferably, as a part of a pharmaceutical composition. In any of the embodiments described herein relating to a combination of compounds, the individual compounds of the combination may optionally be co-formulated in the same pharmaceutical composition, or formulated in different pharmaceutical compositions which are utilized in combination (e.g., co-administered to a subject, according to any of the respective embodiments described herein).

As used herein a "pharmaceutical composition" refers to a preparation of one or more of the compounds described herein, with other chemical components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism. The phrase "pharmaceutical composition" encompasses cosmeceutical compositions.

As used herein, the phrase "cosmeceutical composition" refers to a composition for topical administration as a cosmetic, which comprises a biologically active ingredient (e.g., a compound according to any of the respective embodiments described herein).

Herein, the phrases "physiologically acceptable carrier" and "pharmaceutically acceptable carrier" which may be interchangeably used refer to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound, for an indicated route of administration. For example, in embodiments wherein a compound is administered onto skin and/or hair (e.g., according to any of the respective embodiments described herein), the abovementioned phrases encompass a dermatologically acceptable carrier. An adjuvant is also included under these phrases. The phrase "dermatologically acceptable carrier", as used herein, refers to a carrier that does not cause significant irritation to an organism, and does not abrogate the activity and properties of the administered compound upon application of the compound onto skin and/or hair.

Herein, the terms "pharmaceutical" and "pharmaceutically" refer to any compound and/or composition intended for beneficially altering a condition and/or behavior of at least a portion of the body (e.g., skin), including cosmetically altering, e.g., the skin. It is to be appreciated that such a definition may be broader than the use of such terms by regulatory agencies, which may exclude, for example, cosmetic effects from the scope of the terms.

In some embodiments of any of the embodiments described herein, the pharmaceutical composition is a cosmetic composition which alters the skin (as opposed, for example, to cosmetic compositions, e.g., make-up, which merely mask the skin).

Herein the term "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

Examples of suitable solid or gel phase carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycols.

Techniques for formulation and administration of drugs may be found in "Remington's

Pharmaceutical Sciences" Mack Publishing Co., Easton, PA, latest edition, which is incorporated herein by reference.

Pharmaceutical compositions described herein according to various embodiments of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.

Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the abovementioned compounds into preparations which, can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.

According to some embodiments of any of the embodiments described herein, the pharmaceutical composition is formulated for topical administration, e.g., by selecting a dermatologically acceptable carrier and optionally other ingredients suitable for topical application. Thus, the pharmaceutical compositions can be, for example, in a form of a cream, an ointment, a paste, a gel, a lotion, and a soap. Ointments are semisolid preparations, typically based on vegetable oil (e.g., shea butter and/or cocoa butter), dimethicone, petrolatum or petroleum derivatives. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and nonsensitizing.

Lotions are preparations that may to be applied to the skin without friction. Lotions are typically liquid or semiliquid preparations with a water or alcohol base, for example, an emulsion of the oil-in-water type. Lotions are typically preferred for treating large areas, due to the ease of applying a more fluid composition.

Creams are viscous liquids or semisolid emulsions, either oil-in-water or water-in-oil. Cream bases typically contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also called the "lipophilic" phase, optionally comprises dimethicone, petrolatum and/or a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase optionally contains a humectant. The emulsifier in a cream formulation is optionally a nonionic, anionic, cationic or amphoteric surfactant.

Pastes are semisolid dosage forms which, depending on the nature of the base, may be a fatty paste or a paste made from a single-phase aqueous gel. The base in a fatty paste is generally petrolatum, hydrophilic petrolatum and the like. The pastes made from single-phase aqueous gels generally incorporate carboxymethylcellulose or the like as a base.

Gel formulations are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but also, preferably, contains a non-aqueous solvent and, optionally, an oil. Preferred organic macromolecules, i.e., gelling agents, are crosslinked acrylic acid polymers such as the family of carbomer polymers, e.g., carboxypolyalkylenes that may be obtained commercially under the trademark Carbopol®. Other types of preferred polymers in this context are hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers and polyvinyl alcohol; cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methyl cellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin. In order to prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing or stirring, or combinations thereof.

A pharmaceutical composition formulated for topical (e.g., intradermal and/or transdermal) administration may optionally be present in a patch, a swab, a pledget, and/or a pad. Dermal patches and the like may comprise some or all of the following components: a pharmaceutical composition (e.g., as described herein), a liner for protecting the patch during storage, which is optionally removed prior to use, an adhesive for adhering different components together and/or adhering the patch to the skin, a backing which protects the patch from the outer environment, and/or a membrane which controls release of a drug into the skin.

According to optional embodiments, the pharmaceutical composition is in a form of a water-in-oil emulsion. The water-in-oil emulsion may be, for example, in the form of a cream.

As used herein and in the art, a "water-in-oil emulsion" is an emulsion characterized by an aqueous phase which is dispersed within a lipophilic phase.

Herein, the term "emulsion" refers to a composition comprising liquids in two or more distinct phases (e.g., a hydrophilic phase and a lipophilic phase). Non-liquid substances (e.g., dispersed solids and/or gas bubbles) may optionally also be present.

In some embodiments of any of the embodiments described herein, the composition comprises at least one suitable solvent, for example, a solvent suitable for a lipophilic phase of an emulsion (according to any of the respective embodiments described herein). The one or more solvent may optionally be combined with one or more additional ingredients, such as surfactants, solubilizing agents and/or sustained release agents (e.g., according to any of the respective embodiments described herein).

Topical administration according to any of the respective embodiments described herein may optionally comprise local administration, for example, effected by topically administering the compound and/or composition (according to any of the respective embodiments described herein) directly onto a region of skin to be treated and/or lightened (e.g., a region of skin characterized by uneven pigmentation).

Alternatively, topical administration according to any of the respective embodiments described herein may optionally comprise transdermal administration, wherein the topically administered compound crosses the skin so as to reach other parts of the body (e.g., by entering the blood stream). For example, transdermal administration may optionally be effected by applying the compound and/or composition (according to any of the respective embodiments described herein) onto a region of skin other than the region of skin to be treated and/or lightened.

In some embodiments of any of the respective embodiments described herein, systemic administration comprises topical (e.g., transdermal) administration. In some embodiments, systemic administration of urea comprises topical (e.g., transdermal) administration. In some of any of the embodiments relating to a combination of urea and NSAID, the treatment is effected by co-administration of the NSAID and the urea.

Co-administration according to any of the respective embodiments described herein is optionally effected by concomitantly effecting administration of the NSAID (according to any of the respective embodiments described herein) and administration of the urea (according to any of the respective embodiments described herein).

As used herein, the terms "concomitant" and "concomitantly" refer to an event (e.g., administration of an NSAID) being performed as closely in time as is practically possible to another event (e.g., administration of urea). In some embodiments, "concomitant" and "concomitantly" refer to events separated by no more than 1 hour. In some embodiments, "concomitant" and "concomitantly" refer to events separated by no more than 45 minutes. In some embodiments, "concomitant" and "concomitantly" refer to events separated by no more than 30 minutes. In some embodiments, "concomitant" and "concomitantly" refer to events separated by no more than 20 minutes. In some embodiments, "concomitant" and "concomitantly" refer to events separated by no more than 10 minutes.

Alternatively or additionally, co-administration according to any of the respective embodiments described herein is optionally effected by administering one compound prior to administration of another compound. In some embodiments, administration of the NSAID (according to any of the respective embodiments described herein) is effected prior to administration of urea (according to any of the respective embodiments described herein). In some embodiments, administration of urea (according to any of the respective embodiments described herein) is effected prior to administration of the NSAID (according to any of the respective embodiments described herein).

In some of any one of the embodiments described herein, co-administration is such that the NSAID is administered during a time period ranging from 24 hours prior to administration of urea to 24 hours subsequent to administration of urea. In some embodiments, co-administration is such that the NSAID is administered during a time period ranging from 12 hours prior to administration of urea to 12 hours subsequent to administration of urea. In some embodiments, co-administration is such that the NSAID is administered during a time period ranging from 6 hours prior to administration of urea to 6 hours subsequent to administration of urea.

In some embodiments, co-administration is such that the NSAID is administered during a time period ranging from 3 hours prior to administration of urea to 3 hours subsequent to administration of urea. In some embodiments, co-administration is such that the NSAID is administered during a time period ranging from 2 hours prior to administration of urea to 2 hours subsequent to administration of urea.

In some of any of the embodiments relating to a combination of urea and NSAID, the combination is in a form of a composition comprising both the NSAID and the urea, e.g., wherein co-administration (according to any of the respective embodiments described herein) is effected by administering a composition comprising both the NSAID and the urea. Such a composition may optionally be in accordance with any of the respective embodiments described herein with respect to a composition comprising an NSAID and/or a composition comprising urea.

In some embodiments, a composition comprising both the NSAID and the urea is formulated for systemic administration of the NSAID and/or the urea (e.g., according to any of the respective embodiments described herein).

In some embodiments, a composition comprising both the NSAID and the urea is formulated for topical administration of the NSAID and the urea (e.g., according to any of the respective embodiments described herein), for example, for effecting local administration of the NSAID and/or urea (e.g., according to any of the respective embodiments described herein), and/or for effecting systemic (e.g., transdermal) administration of the NSAID and/or urea (e.g., according to any of the respective embodiments described herein).

In some of any of the embodiments relating to a combination of urea and NSAID, the combination is in a form of a plurality of compositions, e.g., wherein the treatment (according to any of the respective embodiments described herein) is effected by co-administering a first composition comprising said NSAID (according to any of the embodiments described herein relating to a composition comprising an NSAID) and a second composition comprising said urea (according to any of the embodiments described herein relating to a composition comprising urea). The first composition is optionally administered prior to, concomitantly with, and/or subsequent to administration of the second composition (according to any of the respective embodiments described herein).

In some of any of the embodiments relating to a combination of urea and NSAID, the combination is in a form of an NSAID (according to any of the respective embodiments described herein) packaged in a packaging material and identified for use (e.g., in or on the packaging material) in combination with urea (e.g., by co-administration), according to any of the embodiments described herein. In some such embodiments, the NSAID is formulated as a first composition according to any of the respective embodiments described herein. In some of any of the embodiments relating to a combination of urea and NSAID, the combination is in a form of urea (according to any of the respective embodiments described herein) packaged in a packaging material and identified for use (e.g., in or on the packaging material) in combination with an NSAID (e.g., by co-administration), according to any of the embodiments described herein. In some such embodiments, the urea is formulated as a second composition according to any of the respective embodiments described herein.

In some of any of the embodiments relating to a combination of urea and NSAID, the combination is in a form of a kit comprising the NSAID and the urea, for example, wherein the NSAID and urea are packaged separately within the kit. The kit optionally comprises a first composition comprising an NSAID and a second composition comprising urea (according to any of the respective embodiments described herein).

In some of any of the respective embodiments described herein, the kit further comprises instructions regarding co-administration of the NSAID and urea (e.g., co-administration according to any of the respective embodiments described herein).

In some of any of the embodiments relating to a combination of urea and NSAID, urea is topically (e.g., transdermally) administered, and the NSAID is topically administered (optionally co-formulated with the urea) and/or administered via a different route (e.g., as part of a separate pharmaceutical composition), according to any of the embodiments described herein.

In exemplary embodiments relating to a combination of urea and NSAID, the urea is topically (e.g., transdermally) administered, and the NSAID is orally administered.

It is to be appreciated that topical administration of a combination of compounds may optionally effect systemic (e.g., transdermal) administration of a compound (e.g., urea), but only local administration of another compound (e.g., NSAID). In such embodiments, topical administration of a composition comprising such compounds is optionally effected directly onto a region of skin to be treated and/or lightened (e.g., a region of skin characterized by uneven pigmentation). Alternatively or additionally, the compounds may be topically administered at different regions (e.g., in separate compositions), for example, wherein local administration of a compound (e.g., NSAID) is effected by topical administration onto a region of skin to be treated and/or lightened, and systemic administration of a compound (e.g., urea) is effected by topical administration onto another skin region.

Additionally or alternatively, compounds of embodiments of the invention may be formulated for routes of administration other than topical administration.

Suitable routes of administration may, for example, include oral, rectal, transmucosal, especially transnasal, intestinal or parenteral delivery, including intramuscular, subcutaneous and intramedullary injections as well as intrathecal, intravenous, intraperitoneal, intranasal, or intraocular injections.

In some embodiments of any of the respective embodiments described herein, administration comprises systemic administration (e.g., oral, rectal, transmucosal, and/or parenteral administration). In some such embodiments, systemic administration comprises oral administration. In some embodiments, the orally administered compound is an NSAID (according to any of the embodiments described herein); optionally in combination with urea, which may be orally administered (optionally co-formulated with the NSAID) and/or administered via a different route (e.g., as part of a separate pharmaceutical composition) - e.g., via topical administration - according to any of the embodiments described herein.

Alternately, one may administer the pharmaceutical composition in a local rather than systemic manner, for example, via topical administration (according to any of the respective embodiments described herein) or injection (e.g., subcutaneous injection) of the pharmaceutical composition directly into a tissue region of a patient, e.g., a region of skin to be treated and/or lightened (according to any of the respective embodiments described herein).

For oral administration, the compounds of embodiments of the invention can be formulated readily by combining the compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient.

Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose; and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active doses. Pharmaceutical compositions, which can be used orally, include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for the chosen route of administration.

For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

The compounds of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.

The compounds described herein may be formulated for parenteral administration, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multidose containers with optionally, an added preservative. The compositions may be suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

Pharmaceutical compositions for parenteral administration include aqueous solutions of the compounds of the present invention prepared in water-soluble form. Additionally, suspensions of the compounds may be prepared as appropriate oily injection suspensions and emulsions (e.g., water-in-oil, oil-in-water or water-in-oil in oil emulsions). Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

Alternatively, the compounds of the present invention may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

For injection, the compounds of embodiments of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer with or without organic solvents such as propylene glycol, polyethylene glycol. For transmucosal administration, penetrants are used in the formulation. Such penetrants are generally known in the art.

For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation (which typically includes powdered, liquefied and/or gaseous carriers) from a pressurized pack or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compounds of the present invention and a suitable powder base such as, but not limited to, lactose or starch.

Pharmaceutical compositions suitable for use in context of embodiments of the present invention include compositions wherein the active ingredients are contained in a therapeutically effective amount for achieving the intended purpose.

Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.

Toxicity of the compounds described herein may be known to the skilled person; and can, if necessary, be determined by standard pharmaceutical procedures in experimental animals, e.g., by determining the LD50 (lethal dose causing death in 50% of the tested animals) for a subject compound. The data obtained from these animal studies can be used in formulating a range of dosage for use in human.

The dosage may vary depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl et al., 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p.l).

For example, urea (a relatively non-toxic compound) may optionally be formulated at a concentration of from 5 to 50 weight percents (e.g., about 10 weight percents), for example, in a composition for topical administration (according to any of the respective embodiments described herein).

NSAIDs may optionally be utilized in concentrations and/or amounts used in the art for treating pain and/or inflammation, or lower concentrations and/or amounts (e.g., as low as 80 %, 50 %, 20%, or 10 % of a minimal concentration and/or amount used for treating pain and/or inflammation). Dosage amount and interval may be adjusted individually to provide plasma levels of the active compound which are sufficient to maintain the desired effects, termed the minimal effective concentration (MEC). The MEC will vary for each preparation, but can be estimated from, e.g., the concentration necessary in plasma to achieve, over a given period of time, a desired effect in the skin of human subjects. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. HPLC assays or bioassays can be used to determine plasma concentrations.

Dosage intervals can also be determined using the MEC value. Preparations should be administered using a regimen, which maintains plasma levels above the MEC for 10-90 % of the time, preferable between 30-90 % and most preferably 50-90 %.

The amount of a composition to be administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.

The amount of the compound to be administered can depend on the pharmacokinetics of the compound, for example, a half-life of the administered compound and/or a product of hydrolysis of the administered compound in plasma, and/or a rate of absorption of an administered compound (e.g., when administered orally and/or topically).

Compositions of the present invention may, if desired, be presented in a pack or dispenser device, such as an FDA (the U.S. Food and Drug Administration) approved kit, which may contain one or more unit dosage forms containing the active ingredient. The pack, dispenser device and/or kit may optionally comprise a plurality of compositions, for example, a first composition comprising an NSAID (according to any of the respective embodiments described herein) and a second composition comprising urea (according to any of the respective embodiments described herein). The pack may, for example, comprise metal or plastic foil, such as, but not limited to a blister pack or a pressurized container (for inhalation). The pack or dispenser device may be accompanied by instructions for administration of a composition or plurality of compositions (according to any of the respective embodiments described herein). The pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions for human or veterinary administration. Such notice, for example, may be of labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of skin (e.g., according to any of the embodiments described herein).

Thus, according to some embodiments of the present invention, the pharmaceutical compositions described herein are packaged in a packaging material and identified in print, in or on the packaging material, for use in the lightening skin and/or treating uneven skin pigmentation (e.g., according to any of the respective embodiments described herein) in a subject in need thereof.

Without being bound by any particular theory, it is believed that at least some skin conditions described herein are associated with copper ions, and that an ability to bind to copper ions (e.g., by chelation) contributes to the activity of at least some of the compounds described herein.

It is expected that during the life of a patent maturing from this application many relevant NSAIDs will be developed and the scope of the term "NSAID" is intended to include all such new technologies a priori.

As used herein throughout, the term "alkyl" refers to any saturated aliphatic hydrocarbon including straight chain and branched chain groups. Preferably, the alkyl group has 1 to 20 carbon atoms.

Whenever a numerical range; e.g., "1-20", is stated herein, it implies that the group, in this case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms. More preferably, the alkyl is a medium size alkyl having 1 to 10 carbon atoms. Most preferably, unless otherwise indicated, the alkyl is a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be substituted or non-substituted.

When substituted, the substituent group can be, for example, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azide, phosphonyl, phosphinyl, oxo, carbonyl, thiocarbonyl, a urea group, a thiourea group, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C- amido, N-amido, C-carboxy, O-carboxy, sulfonamido, guanyl, guanidinyl, hydrazine, hydrazide, thiohydrazide, and amino, as these terms are defined herein.

Herein, the term "alkenyl" describes an unsaturated aliphatic hydrocarbon comprise at least one carbon-carbon double bond, including straight chain and branched chain groups. Preferably, the alkenyl group has 2 to 20 carbon atoms. More preferably, the alkenyl is a medium size alkenyl having 2 to 10 carbon atoms. Most preferably, unless otherwise indicated, the alkenyl is a lower alkenyl having 2 to 4 carbon atoms. The alkenyl group may be substituted or non-substituted. Substituted alkenyl may have one or more substituents, whereby each substituent group can independently be, for example, alkynyl, cycloalkyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azide, phosphonyl, phosphinyl, oxo, carbonyl, thiocarbonyl, a urea group, a thiourea group, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C- carboxy, O-carboxy, sulfonamido, guanyl, guanidinyl, hydrazine, hydrazide, thiohydrazide, and amino.

Herein, the term "alkynyl" describes an unsaturated aliphatic hydrocarbon comprise at least one carbon-carbon triple bond, including straight chain and branched chain groups. Preferably, the alkynyl group has 2 to 20 carbon atoms. More preferably, the alkynyl is a medium size alkynyl having 2 to 10 carbon atoms. Most preferably, unless otherwise indicated, the alkynyl is a lower alkynyl having 2 to 4 carbon atoms. The alkynyl group may be substituted or non-substituted.

Substituted alkynyl may have one or more substituents, whereby each substituent group can independently be, for example, cycloalkyl, alkenyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azide, phosphonyl, phosphinyl, oxo, carbonyl, thiocarbonyl, a urea group, a thiourea group, O- carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O- carboxy, sulfonamido, guanyl, guanidinyl, hydrazine, hydrazide, thiohydrazide, and amino.

A "cycloalkyl" group refers to a saturated on unsaturated all-carbon monocyclic or fused ring (i.e., rings which share an adjacent pair of carbon atoms) group wherein one of more of the rings does not have a completely conjugated pi-electron system. Examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, cycloheptane, cycloheptatriene, and adamantane. A cycloalkyl group may be substituted or non-substituted. When substituted, the substituent group can be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azide, phosphonyl, phosphinyl, oxo, carbonyl, thiocarbonyl, a urea group, a thiourea group, O- carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O- carboxy, sulfonamido, guanyl, guanidinyl, hydrazine, hydrazide, thiohydrazide, and amino, as these terms are defined herein. When a cycloalkyl group is unsaturated, it may comprise at least one carbon-carbon double bond and/or at least one carbon-carbon triple bond.

An "aryl" group refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. The aryl group may be substituted or non-substituted. When substituted, the substituent group can be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azide, phosphonyl, phosphinyl, oxo, carbonyl, thiocarbonyl, a urea group, a thiourea group, O- carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O- carboxy, sulfonamido, guanyl, guanidinyl, hydrazine, hydrazide, thiohydrazide, and amino, as these terms are defined herein.

A "heteroaryl" group refers to a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms, such as, for example, nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system. Examples, without limitation, of heteroaryl groups include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline and purine. The heteroaryl group may be substituted or non-substituted. When substituted, the substituent group can be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azide, phosphonyl, phosphinyl, oxo, carbonyl, thiocarbonyl, a urea group, a thiourea group, O- carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O- carboxy, sulfonamido, guanyl, guanidinyl, hydrazine, hydrazide, thiohydrazide, and amino, as these terms are defined herein.

A "heteroalicyclic" group refers to a monocyclic or fused ring group having in the ring(s) one or more atoms such as nitrogen, oxygen and sulfur. The rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system. The heteroalicyclic may be substituted or non-substituted. When substituted, the substituted group can be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azide, phosphonyl, phosphinyl, oxo, carbonyl, thiocarbonyl, a urea group, a thiourea group, O- carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O- carboxy, sulfonamido, guanyl, guanidinyl, hydrazine, hydrazide, thiohydrazide, and amino, as these terms are defined herein. Representative examples are piperidine, piperazine, tetrahydrofuran, tetrahydropyran, morpholine and the like.

Herein, the terms "amine" and "amino" each refer to either a -NR'R" group or a - N⁺R'R"R' " group, wherein R', R" and R' " are each hydrogen or a substituted or non- substituted alkyl, alkenyl, alkynyl, cycloalkyl, heteroalicyclic (linked to amine nitrogen via a ring carbon thereof), aryl, or heteroaryl (linked to amine nitrogen via a ring carbon thereof), as defined herein. Optionally, R', R" and R' " are hydrogen or alkyl comprising 1 to 4 carbon atoms. Optionally, R' and R" (and R" ', if present) are hydrogen. When substituted, the carbon atom of an R', R" or R" ' hydrocarbon moiety which is bound to the nitrogen atom of the amine is preferably not substituted by oxo, such that R', R" and R' " are not (for example) carbonyl, C- carboxy or amide, as these groups are defined herein, unless indicated otherwise.

An "azide" group refers to a -N=N⁺=N^" group.

An "alkoxy" group refers to both an -O-alkyl and an -O-cycloalkyl group, as defined herein.

An "aryloxy" group refers to both an -O-aryl and an -O-heteroaryl group, as defined herein.

A "hydroxy" group refers to a -OH group.

A "thiohydroxy" or "thiol" group refers to a -SH group.

A "thioalkoxy" group refers to both an -S-alkyl group, and an -S-cycloalkyl group, as defined herein.

A "thioaryloxy" group refers to both an -S-aryl and an -S-heteroaryl group, as defined herein.

A "carbonyl" group refers to a -C(=0)-R' group, where R' is defined as hereinabove.

A "thiocarbonyl" group refers to a -C(=S)-R' group, where R' is as defined herein.

A "carboxyl", "carboxylic" or "carboxylate" refers to both "C-carboxy" and O-carboxy".

A "C-carboxy" group refers to a -C(=0)-0-R' groups, where R' is as defined herein.

An "O-carboxy" group refers to an R'C(=0)-0- group, where R' is as defined herein.

A "carboxylic acid" refers to a -C(=0)OH group, including the deprotonated ionic form and salts thereof.

An "oxo" group refers to a =0 group.

A "thiocarboxy" or "thiocarboxylate" group refers to both -C(=S)-0-R' and -0-C(=S)R' groups.

A "halo" group refers to fluorine, chlorine, bromine or iodine.

A "sulfinyl" group refers to an -S(=0)-R' group, where R' is as defined herein.

A "sulfonyl" group refers to an -S(=0)₂-R' group, where R' is as defined herein.

A "sulfonate" group refers to an -S(=0)₂-0-R' group, where R' is as defined herein. A "sulfate" group refers to an -0-S(=0)₂-0-R' group, where R' is as defined as herein. A "sulfonamide" or "sulfonamido" group encompasses both S-sulfonamido and N- sulfonamido groups, as defined herein. An "S-sulfonamido" group refers to a -S(=0)2-NR'R" group, with each of R' and R" as defined herein.

An "N-sulfonamido" group refers to an R'S(=0)2-NR" group, where each of R' and R" is as defined herein.

An "O-carbamyl" group refers to an -OC(=0)-NR'R" group, where each of R' and R" is as defined herein.

An "N-carbamyl" group refers to an R'OC(=0)-NR"- group, where each of R' and R" is as defined herein.

A "carbamyl" or "carbamate" group encompasses O-carbamyl and N-carbamyl groups. An "O-thiocarbamyl" group refers to an -OC(=S)-NR'R" group, where each of R' and

R" is as defined herein.

An "N-thiocarbamyl" group refers to an R'OC(=S)NR"- group, where each of R' and R" is as defined herein.

A "thiocarbamyl" or "thiocarbamate" group encompasses O-thiocarbamyl and N- thiocarbamyl groups.

A "C-amido" group refers to a -C(=0)-NR'R" group, where each of R' and R" is as defined herein.

An "N-amido" group refers to an R'C(=0)-NR"- group, where each of R' and R" is as defined herein.

A "urea group" refers to an -N(R')-C(=0)-NR"R"' group, where each of R', R" and

R" is as defined herein.

A "thiourea group" refers to a -N(R')-C(=S)-NR"R" ' group, where each of R', R" and R" is as defined herein.

A "nitro" group refers to an -NO2 group.

A "cyano" group refers to a -C≡N group.

The term "phosphonyl" or "phosphonate" describes a -P(=0)(OR')(OR") group, with R' and R' ' as defined hereinabove.

The term "phosphate" describes an -0-P(=0)(OR')(OR") group, with each of R' and R" as defined hereinabove.

The term "phosphinyl" describes a -PR'R" group, with each of R' and R" as defined hereinabove.

The term "hydrazine" describes a -NR'-NR"R"' group, with R', R", and R'" as defined herein. As used herein, the term "hydrazide" describes a -C(=0)-NR'-NR"R"' group, where R', R" and R'" are as defined herein.

As used herein, the term "thiohydrazide" describes a -C(=S)-NR'-NR"R"' group, where R', R" and R'" are as defined herein.

A "guanidinyl" group refers to an -RaNC(=NRd)-NRbRc group, where each of Ra, Rb,

Rc and Rd can be as defined herein for R' and R' ' .

A "guanyl" or "guanine" group refers to an RaRbNC(=NRd)- group, where Ra, Rb and Rd are as defined herein.

As used herein the term "about" refers to ± 20 %.

The terms "comprises", "comprising", "includes", "including", "having" and their conjugates mean "including but not limited to".

The term "consisting of means "including and limited to".

The term "consisting essentially of means that the composition, method or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.

As used herein, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

Throughout this application, various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases "ranging/ranges between" a first indicate number and a second indicate number and "ranging/ranges from" a first indicate number "to" a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween. As used herein the term "method" refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.

As used herein, the terms "treating" and "treatment" includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition.

When reference is made to particular sequence listings, such reference is to be understood to also encompass sequences that substantially correspond to its complementary sequence as including minor sequence variations, resulting from, e.g., sequencing errors, cloning errors, or other alterations resulting in base substitution, base deletion or base addition, provided that the frequency of such variations is less than 1 in 50 nucleotides, alternatively, less than 1 in 100 nucleotides, alternatively, less than 1 in 200 nucleotides, alternatively, less than 1 in 500 nucleotides, alternatively, less than 1 in 1000 nucleotides, alternatively, less than 1 in 5,000 nucleotides, alternatively, less than 1 in 10,000 nucleotides.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples.

EXAMPLES

Reference is now made to the following examples, which together with the above descriptions illustrate some embodiments of the invention in a non-limiting fashion.

EXAMPLE 1

An adult male subject was orally administered etodolac (Etopan™, Taro Israel) at a dose of 400 mg, twice per day (for treatment of rheumatic pain). In addition, a urea-containing cream (Flexitol®; 10 % urea, with dimethicone and aloe vera) was administered topically on the hands of the subject. Following treatment, facial solar lentigines (diagnosed a few months earlier) were observed to fade to a considerable degree.

EXAMPLE 2

Etodolac is administered topically onto a hyperpigmented region of skin, such as lentigines and/or nevi (optionally solar lentigines), at a concentration in a range of from 0.01 to 50 weight percents. The etodolac is optionally dissolved in a commercially available skin cream formulation. Topical administration is optionally repeated - e.g., daily or weekly - until clearance of the hyperpigmentation is observed to a desired degree.

EXAMPLE 3

A urea-containing cream is administered topically onto skin of a subject afflicted by a hyperpigmentation, optionally on a hyperpigmented region of skin, such as lentigines and/or nevi (optionally solar lentigines), at a concentration in a range of from 5 to 50 weight percents (e.g., Flexitol® 10 % urea cream). Etodolac is optionally co-administered topically, at a concentration in a range of from 0.01 to 50 weight percents, the etodolac optionally being dissolved in the urea- containing cream. Topical administration is optionally repeated - e.g., daily or weekly - until clearance of the hyperpigmentation is observed to a desired degree.

Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting.

Claims

WHAT IS CLAIMED IS:

1. A compound for use in the treatment of uneven skin pigmentation, wherein the compound is a non-steroidal anti-inflammatory drug (NSAID).

2. The compound for use according to claim 1, wherein said NSAID comprises an indole moiety.

3. The compound for use according to claim 2, wherein said NSAID is selected from the group consisting of etodolac, indomethacin, and pravadoline.

4. The compound for use according to claim 1, wherein the compound is etodolac.

5. The compound for use according to any of claims 1 to 4, wherein said uneven skin pigmentation is associated with at least one lentigo and/or nevus.

6. The compound for use according to claim 5, wherein said at least one lentigo comprises a solar lentigo.

7. The compound for use according to any of claims 1 to 6, wherein said treatment is effected by systemic administration of the compound.

8. The compound for use according to any of claims 1 to 6, wherein said treatment is effected by topical administration of the compound.

9. A compound for use in lightening skin, wherein the compound is a non-steroidal anti-inflammatory drug (NSAID).

10. The compound for use according to claim 9, wherein said NSAID comprises an indole moiety.

11. The compound for use according to claim 10, wherein said NSAID is selected from the group consisting of etodolac, indomethacin, and pravadoline.

12. The compound for use according to claim 9, wherein the compound is etodolac.

13. The compound for use according to any of claims 9 to 12, wherein said lightening skin comprises lightening at least one lentigo and/or nevus.

14. The compound for use according to claim 13, wherein said at least one lentigo comprises a solar lentigo.

15. The compound for use according to any of claims 9 to 14, wherein said treatment is effected by systemic administration of the compound.

16. The compound for use according to any of claims 9 to 14, wherein said treatment is effected by topical administration of the compound.

17. A compound for use in the treatment of uneven skin pigmentation, wherein the compound is urea.

18. The compound for use according to claim 17, wherein said uneven skin pigmentation is associated with at least one lentigo and/or nevus.

19. The compound for use according to claim 18, wherein said at least one lentigo comprises a solar lentigo.

20. The compound for use according to any of claims 17 to 19, wherein said treatment is effected by systemic administration of the compound.

21. The compound for use according to claim 20, wherein said treatment is effected by transdermal administration of the compound.

22. The compound for use according to any of claims 17 to 19, wherein said treatment is effected by topical administration of the compound to a region of skin characterized by uneven pigmentation.

23. The compound for use according to claim 21 or 22, wherein the compound forms a part of a composition comprising urea at a concentration in a range of from 5 to 50 weight percents, and a dermatologically acceptable carrier.

24. A compound for use in lightening skin, wherein the compound is urea.

25. The compound for use according to claim 24, wherein said lightening skin comprises lightening at least one lentigo and/or nevus.

26. The compound for use according to claim 25, wherein said at least one lentigo comprises a solar lentigo.

27. The compound for use according to any of claims 24 to 26, wherein said treatment is effected by systemic administration of the compound.

28. The compound for use according to claim 27, wherein said treatment is effected by transdermal administration of the compound.

29. The compound for use according to any of claims 24 to 26, wherein said treatment is effected by topical administration of the compound to a region of skin to be lightened.

30. The compound for use according to claim 28 or 29, wherein the compound forms a part of a composition comprising urea at a concentration in a range of from 5 to 50 weight percents, and a dermatologically acceptable carrier.

31. A combination of a non-steroidal anti-inflammatory drug (NSAID) and urea, for use in the treatment of uneven skin pigmentation.

32. The combination for use according to claim 31, wherein said NSAID comprises an indole moiety.

33. The combination for use according to claim 31, wherein said NSAID is etodolac.

34. The combination for use according to any of claims 31 to 33, wherein said uneven skin pigmentation is associated with at least one lentigo and/or nevus.

35. The combination for use according to claim 34, wherein said at least one lentigo comprises a solar lentigo.

36. The combination for use according to any of claims 31 to 35, wherein said treatment is effected by systemic administration of said NSAID and/or said urea.

37. The combination for use according to any of claims 31 to 35, wherein said treatment is effected by topical administration of said NSAID and/or said urea.

38. The combination for use according to claim 37, wherein said treatment is effected by topical administration of a composition comprising urea at a concentration in a range of from 5 to 50 weight percents, and a dermatologically acceptable carrier.

39. The combination for use according to any of claims 31 to 38, wherein said treatment is effected by administering a composition comprising said NSAID and said urea.

40. The combination for use according to any of claims 31 to 38, wherein said treatment is effected by co-administering a first composition comprising said NSAID and a second composition comprising said urea.

41. A combination of a non-steroidal anti-inflammatory drug (NSAID) and urea, for use in lightening skin.

42. The combination for use according to claim 41, wherein said NSAID comprises an indole moiety.

43. The combination for use according to claim 41, wherein said NSAID is etodolac.

44. The combination for use according to any of claims 41 to 43, wherein said lightening skin comprises lightening at least one lentigo and/or nevus.

45. The combination for use according to any of claims 41 to 44, wherein said treatment is effected by systemic administration of said NSAID and/or said urea.

46. The combination for use according to any of claims 41 to 44, wherein said treatment is effected by topical administration of said NSAID and/or said urea.

47. The combination for use according to claim 46, wherein said treatment is effected by topical administration of a composition comprising urea at a concentration in a range of from 5 to 50 weight percents, and a dermatologically acceptable carrier.

48. The combination for use according to any of claims 41 to 47, wherein said treatment is effected by administering a composition comprising said NSAID and said urea.

49. The combination for use according to any of claims 41 to 47, wherein said treatment is effected by co-administering a first composition comprising said NSAID and a second composition comprising said urea.

50. The combination for use according to any one of claims 23, 30 and 38, or the combination for use according to claim 47, wherein said composition comprises dimethicone.