WO2020075158A2

WO2020075158A2 - Gallium compounds for skin lightening

Info

Publication number: WO2020075158A2
Application number: PCT/IL2019/051073
Authority: WO
Inventors: Sharon Moalem; Joseph MOALEM
Original assignee: Sharon Moalem; Moalem Joseph
Priority date: 2018-10-09
Filing date: 2019-10-02
Publication date: 2020-04-16
Also published as: WO2020075158A3

Abstract

The present invention provides cosmetic or pharmaceutical compositions for skin lightening. Particularly, the present invention provides cosmetic or pharmaceutical compositions comprising gallium-containing compounds for use in reducing pigmentation in human skin, including pigmentary spots.

Description

GALLIUM COMPOUNDS FOR SKIN LIGHTENING

FIELD OF THE INVENTION

The present invention relates to cosmetic or pharmaceutical compositions for skin lightening. Particularly, the present invention relates to cosmetic or pharmaceutical compositions comprising gallium-containing compounds for use in reducing pigmentation in human skin, including pigmentary spots.

BACKGROUND OF THE INVENTION

Skin color is primarily determined by the amount and type of melanin pigments. Lower amounts of melanin result in the appearance of lighter skin color while higher amounts result in the appearance of darker skin color. Melanin synthesis (also termed melanogenesis) occurs in melanocytes within specialized organelles called melanosomes. This process is controlled by at least three enzymes: tyrosinase, tyrosinase -related-protein 1 (TRP1), and tyrosinase-related-protein 2 (TRP2), the former has a key role in melanin synthesis by catalyzing the rate limiting steps of hydroxylation of tyrosine to L-DOPA and of oxidation of L-DOPA into dopaquinone.

Melanocytes are connected to neighboring keratinocytes via dendrites. One melanocyte contacts up to 30-40 keratinocytes to transfer melanin. The process involves synthesis, packaging, transfer, and uptake of melanin by keratinocytes which is ultimately responsible for skin color. Regardless of their skin color, ail individuals have about the same number of melanocytes within their skin.

Melanin provides UV photo-protection and scavenges free radicals. An excessive production of melanin in the skin can lead to hyperpigmentation, also called hypermelanosis, and is associated with medical skin disorders such as melasma, post- inflammatory hyperpigmentation (PIH) and lentigosenilis (LS).

The need to modify tire content of melanin in the skin or to lighten pigmented spots is highly desired by many individuals. Efforts to develop effective compositions have focused on agents that inhibit the activity of tyrosinase. As tyrosinase consists of two copper atoms in its active site, compounds which can bind copper have been used to inhibit tyrosinase activity. For example, hydroquinone, kojic acid, azae!ic acid, and _{n , n /nc}. _nTO

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2 arbutin have been used for the treatment of byperpigmentation conditions by virtue of

their inhibition of tyrosinase activity. However, many of these agents exhibit major

drawbacks due to their potential and undesired side effects. For example, due to its

potential carcinogenic activity, products containing up to 2% hydroquinone are currently

approved only as prescribed medications for topical treatment of hyperpigmentation.

Kojic acid has been banned for quasi-drug usage in Japan due to its possible mutagenic

properties.

Other skin whitening compositions have been described. Yet, many of these skin

whitening compositions contain harsh chemicals such as peroxides, acids, formaldehyde,

or thxolated materials, which can damage the skin and can cause serious side effects, e.g.,

skin irritation and redness, allergic contact dermatitis, and even systemic toxicity.

Retinoids and corticosteroids have been suggested for topical use as

hypopigmenting agents, hut these agents also fall short due to undesirable long- term side

effects and potential health risks posed to users.

Gallium

Gallium is a metallic element that has been used for many years as a tool in the

field of nuclear medicine for diagnosing hard to detect microbial infections in

humans. This metallic element has also been shown to be efficacious in the treatment of

hypercalcemia in patients with cancer. In addition, gallium has been demonstrated to

have anti-microbial activity, probably due to its ability to compete with ferric iron (i.e.,

Fe³⁺); it is taken up by the rapidly proliferating microbial cells, but as it is not functional

in DNA synthesis, the microbial cells do not divide and ultimately die by apoptosis.

WO 1993/011095 discloses sunscreen metal complexes having enhanced ultraviolet

A (UVA) absorption. The complexes comprise a sunscreen moiety complexed to a metal

cation, alternatively an ammonium or substituted ammonium cation, in which the

sunscreen moiety further comprises a dibenzoylmethane UVA-absorbing chromophore, a

UVB-absorbing chromophore, and a linking group connecting the two chromophores.

Among the preferred metal cations, aluminium, titanium, copper, iron and zinc are listed,

the aluminium being the most preferred.

U.S. Pat. No. 5,456,904 discloses photoprotection compositions comprising

chelating agents and methods of use thereof for preventing the deleterious effects of the

sun with minimal interference to the tanning response. _{onl Q/n}, _{l n7q}

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3

U.S. Pat. No. 5,556,645 discloses methods of enhancing skin, connective and

support tissue repair and augmentation by administering to a subject with a wound, tear

or break, or deficiency of matrix components in skin, connective and support tissues, a

pharmaceutically acceptable gallium-containing compound in an amount sufficient to

increase the selective synthesis of matrix components so as to enhance repair or augment

the strength and appearance of the skin, connective and support tissues.

U.S. Pat. No. 5,747,482 discloses methods for inhibiting mammalian skin cell

proliferation, particularly human keratinocyte proliferation, by topical administration of

neutral gallium complexes. Among the conditions associated with hyper-proliferation of

keratinocytes, psoriasis, atopic dermatitis, and contact dermatitis are listed.

U.S. Pat. No. 6,071 ,543 discloses compositions and methods for preventing and

reversing the signs and symptoms of chronologic aging and photo aging. According to

U.S. 6,071,543, the compositions include one or more pyridine-thiols and tautomers with

various attached metallic moieties. Various metal oxides and metal sulfides are also

disclosed as useful in these methods.

U.S. Pat. No. 8,168,214 discloses methods for treating pain comprising

administering gallium compositions to the skin and mucous membranes.

U.S. Pat. No. 8,652,509 discloses pharmaceutical compositions and methods for

topical wound treatment by topical treatment with gallium salts, preferably gallium

nitrate.

U.S. Pat. No. 8,975,294 discloses methods using desferrioxiamine (DFO)-metal

complexes, specifically Zinc-DFO and gallium-DFO complexes, for preventing, treating,

ameliorating or inhibiting an immune-related disorder, specifically a skin -related

inflammatory disorder such as psoriasis, dermatitis, acne, vitiligo and wounds.

U.S. Pat. No. 8,895,077 discloses methods for preventing or treating infectious

diseases caused by extracellular microorganisms, such as bacteria and fungi, by

systemically administering to a patient a compound containing gallium.

U.S. Application Publication No. 2017/0181941 discloses tunable sunscreen

compositions which include nanoparticles having quantum confined absorption at

specific wavelengths, the nanoparticles selected from the group consisting of zinc oxide

nanoparticles, titanium oxide nanoparticles, and gallium nitride-based nanoparticles. _{onl Q/n}, _{l n7q}

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4

There is an unmet need for improved methods and compositions for reducing

pigmentation of hvperpigrnented skin areas, which methods provide improved efficacy

and are essentially devoid of side effects. SUMMARY OF THE INVENTION

The present invention provides methods for reducing melanin content or reducing

pigmentation in mammalian skin comprising applying topically to an area of the

mammalian skin a cosmetic or pharmaceutical composition comprising a gallium- containing compound and a cosmetically or pharmaceutically acceptable carrier, thereby

reducing pigmentation in said area of skin and achieving lightening of the area of skin

so as to obtain an even skin tone. The present invention, therefore, provides methods for

lightening skin including pigmentary spots.

The present invention is based in part on the unexpected finding that topical

application of a pharmaceutical composition comprising a gallium-containing

compound, such as gallium maltolate, twice daily onto the face of a 24- year old female

subject resulted in an overall appearance of skin lightening within 10 days of use. No

skin irritation or side effects were reported.

The present invention further discloses that topical appheation of a

pharmaceutical composition comprising a gallium-containing compound, such as

gallium maltolate, onto a benign skin macule, e.g., a benign birthmark, twice daily for

seven days reduced significantly the pigmentation of that birthmark. Topical appheation

of said pharmaceutical composition once daily for sixty days almost completely

abolished the birthmark, yielding the appearance of essentially even skin tone. No skin

irritation or toxicity has been noted.

Thus, the methods of the present invention are highly efficacious for skin

lightening, do not cause noticeable skin irritation, are essentially devoid of toxic

effects, can be applied by the user with ease, and achieve the lightening result within

days, e.g., a week up to two months, with good patient comphance. The methods of the

present invention are therefore advantageous over known skin lightening methods.

According to one aspect, the present invention provides a method of reducing skin

melanin content comprising applying topically to an area of skin of a subject a cosmetic

or pharmaceutical composition comprising an effective amount of a gallium-containing _{onl Q/n}, _{l n7q}

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5 compound and a cosmetically or pharmaceutically acceptable carrier, thereby reducing

melanin content in the area of skin and skin lightening, wherein the gallium-containing

compound is essentially devoid of side effects, and wherein said gallium-containing

compound is other than gallium oxide, gallium sulfide, gallium nitrate, gallium nitride,

gallium associated with a pyridine-thiol, gallium complexed to dibenzoylmethane

chromophore, or gallium complexed to violuric acid or to a derivative thereof.

Examples of side-effects include skin irritation, skin redness, allergic contact dermatitis,

systemic toxicity, and teratogenicity.

According to some embodiments, the gallium-containing compound is selected

from the group consisting of gallium complexes of 3-hydroxy-4-pyrones, gallium

pyridinones, gallium porphyrins, gallium tartrate, gallium succinate, gallium gluconate,

gallium palmitate, gallium citrate, gallium chloride, gallium 8-quinolinolate, gallium

pyridoxal isonicotinoyl hydrazine, and gallium transferrin. Each possibility represents a

separate embodiment of the present invention. According to a certain embodiment, the

gallium complex of 3 -hydroxy-4 -pyrone is gallium maltolate.

According to further embodiments, the subject is a human subject. According to

still further embodiments, the subject is a companion animal.

According to some embodiments, the skin of the human subject to be lightened by

the method of the present invention is classified as Fitzpatrick phototype I, Fitzpatrick

phototype II, Fitzpatrick phototype III, Fitzpatrick phototype IV, Fitzpatrick phototype

V, or Fitzpatrick phototype VI. According to additional embodiments, the skin of the

human subject to be lightened by the method of the present invention is classified as

Fitzpatrick phototype I or more. Each possibility represents a separate embodiment of

the present invention.

According to additional embodiments, the area of skin of the human subject to be

lightened is selected from the group consisting of facial skin, chest skin, neck skin, arm

skin, leg skin, back skin, shoulder skin, skin of the torso, buttocks skin, skin of the back

of the hand, and skin of the feet. Each possibility represents a separate embodiment of

the present invention.

According to further embodiments, the area of the skin to be lightened is a

pigmentary spot. According to additional embodiments, the pigmentary spot is selected

from the group consisting of birthmarks including, but not limited to, cafe au lait spots;

melasma; post inflammatory pigmentary spots; pigmentary spots after injury; and _{onl Q/n}, _{l n7q}

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6 pigmentary spots after burns. According to certain embodiments, the pigmentary spot is

a birthmark or melasma. According to still further embodiments, the pigmentary spot is

caused by LTV radiation and includes, but is not limited to, solar lentigo and freckles.

According to additional embodiments, the pigmentary spot is a macule, papule, or a

nodule. Each possibility represents a separate embodiment of the present invention.

According to exemplary embodiments, the method is useful for reducing melanin

content in an area of human skin wherein the skin color is classified as Fitzpatrick

phototype I or above, and wherein the gallium-containing compound is a gallium

complex of 3-hydroxy-4-pyrone. According to a certain embodiment, the gallium

complex of 3-hydroxy-4-pyrone is gallium maltolate.

According to another exemplary embodiment, the method is useful for reducing

melanin content in a pigmentary spot of a human subject, wherein the pigmentary spot is

selected from the group consisting of a birthmark and melasma, and wherein the

gallium-containing compound is a gallium complex of 3 -hydroxy-4 -pyrone. According

to a certain embodiment, the gallium complex of 3-hydroxy-4-pyrone is gallium

maltolate.

According to some embodiments, the cosmetic or pharmaceutical composition to

be used according to the methods of the present invention is formulated in a form

selected from the group consisting of a liquid, a lotion, a suspension, a cream, an

ointment, a paste, a gel, an aerosol, a foam, a mask, and a powder. Each possibility

represents a separate embodiment of the present invention.

According to additional embodiments, the cosmetic or pharmaceutical

composition further comprises one or more excipients selected from the group

consisting of emollients, thickening agents, emulsifiers, humectants, and preservatives.

According to some embodiments, the cosmetic or pharmaceutical composition

comprises an oil, at least one thickening agent, and water. According to additional

embodiments, the oil is selected from the group consisting of a mineral oil and a

vegetable oil, and the thickening agent comprises one or more waxes. According to

exemplary embodiments, the composition comprises mineral oil, mineral wax, lanolin

alcohol, petrolatum, water, and optionally a vegetable oil.

According to further embodiments, the gallium-containing compound within the

cosmetic or pharmaceutical composition is present in an amount ranging from about

0.00001 % to about 50 % by weight of the composition, alternatively in an amount _{onl Q/n}, _{l n7q}

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7 ranging from about 0.001 % to about 10 % by weight of the composition, or in an

amount ranging from about 0.1 % to about 1 % by weight of the composition. Each

possibility represents a separate embodiment of the present invention.

According to additional embodiments, water is present in the composition in an

amount ranging from about 5 % to about 80 % by weight of the composition,

alternatively in an amount ranging from about 10 % to about 50 % by weight of the

composition. Each possibility represents a separate embodiment of the present

invention.

According to certain embodiments, the composition comprises gallium maltolate

in an amount of about 0.1 % to about 1 % by weight of the composition, mineral oil,

mineral wax, lanolin alcohol, petrolatum, and water in an amount ranging from about 10

% to about 50 % by weight of the composition, optionally further comprising a

vegetable oil.

According to exemplary embodiments, the cosmetic or pharmaceutical

composition is formulated as a cream.

According to some embodiments, the composition is applied once or twice daily

for seven days up to two months or so long as skin melanin content is reduced or skin

lightening is achieved or desired. According to further embodiments, the composition is

applied once or twice daily for seven days up to one month or up to two months.

According to a certain embodiment, the composition is applied once or twice daily for

seven days. Each possibility represents a separate embodiment of the present invention.

According to additional embodiments, the cosmetic or pharmaceutical

composition further comprises a known skin lightening agent.

According to further embodiments, the method further comprises a step of

applying to the area of skin an additional cosmetic or pharmaceutical composition

comprising a known skin lightening agent.

According to another aspect, the present invention provides a method of

protecting skin from UV radiation comprising applying topically to an area of skin of a

human subject a cosmetic or pharmaceutical composition comprising a gallium- containing compound in an amount effective to prevent skin tanning, the cosmetic or

pharmaceutical composition further comprising a cosmetically or pharmaceutically

acceptable carrier, wherein the gallium-containing compound is essentially devoid of

side effects, and wherein said gallium-containing compound is other than gallium oxide, _{onl Q/n}, _{l n7q}

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gallium sulfide, gallium nitrate, gallium nitride, gallium associated with a pyridine-thiol,

gallium complexed to dibenzoylmethane chromophore, or gallium complexed to

violuric acid or to a derivative thereof. Examples of side effect include skin irritation,

skin redness, allergic contact dermatitis, systemic toxicity, and teratogenicity.

According to some embodiments, the gallium-containing compound to be used in

the method of protecting skin from radiation is selected from the group consisting of

gallium complexes of 3-hydroxy-4-pyrones, gallium pyridinones, gallium porphyrins,

gallium tartrate, gallium succinate, gallium gluconate, gallium palmitate, gallium citrate,

gallium chloride, gallium 8-quinolinolate, gallium pyridoxal isonicotinoyl hydrazine,

and gallium transferrin. Each possibility represents a separate embodiment of the

present invention. According to a certain embodiment, the gallium complex of 3- hydroxy-4-pyrone is gallium maltolate.

According to some embodiments, the cosmetic or pharmaceutical composition

further comprises a known sunscreen agent.

According to additional embodiments, the method further comprises a step of

comprising a known sunscreen agent.

According to a further aspect, the present invention provides a cosmetic or

pharmaceutical composition for use in reducing melanin content in an area of skin of a

subject, the cosmetic or pharmaceutical composition comprises a gallium-containing

compound and a cosmetically or pharmaceutically acceptable carrier, wherein the

gallium-containing compound is essentially devoid of side effects, and wherein said

gallium-containing compound is other than gallium oxide, gallium sulfide, gallium

nitrate, gallium nitride, gallium associated with a pyridine-thiol, gallium complexed to

dibenzoylmethane chromophore, or gallium complexed to violuric acid or to a derivative

thereof, according to the principles of the present invention.

According to yet further aspect, the present invention provides a cosmetic or

pharmaceutical composition for use in protecting skin of a subject from UV radiation,

the cosmetic or pharmaceutical composition comprises a gallium-containing compound

and a cosmetically or pharmaceutically acceptable carrier, wherein the gallium- containing compound is essentially devoid of side effects, and wherein said gallium- containing compound is other than gallium oxide, gallium sulfide, gallium nitrate,

gallium nitride, gallium associated with a pyridine-thiol, gallium complexed to _{onl Q/n}, _{l n7q}

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9 dibenzoylmethane chromophore, or gallium complexed to violuric acid or to a derivative

thereof, according to the principles of the present invention.

These and other embodiments of the present invention will be better understood in

relation to the figures, description, examples, and claims that follow.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides methods for reducing melanin content or reducing

pigmentation in an area of skin of a subject comprising applying topically to the area of

skin a cosmetic or dermatological composition comprising a gallium-containing

compound and a cosmetically or dermatologically acceptable carrier, wherein the

cosmetic or dermatological composition is formulated for topical application.

Chevion et al. (U.S. Pat. No. 8,975,294) discloses desferrioxamine (DFO)-metal

complexes, specifically Zinc (Zn)-DFO and gallium (Ga)-DFO complexes, for use in

treating skin-related inflammatory disorders such as psoriasis and vitiligo, the latter is a

chronic disorder that causes complete depigmentation of patches of skin due to the loss

of melanocyte cells within the skin.

Thornfeldt (U.S. Pat. No. 6,071 ,543) discloses pyridine-thiols attached to various

metal ions, metal oxides, and metal sulfides for treating signs of aging, e.g., wrinkling,

irregular pigmentation, and in elasticity. The metal ions disclosed in U.S. Pat. No.

6,071 ,543 are titanium, tin, strontium, selenium, scandium, germanium, gallium,

cadmium, chromium, and arsenic, among others. While the preferred compounds in

U.S. Pat. No. 6,071 ,543 are zinc pyrithione, silver pyrithione, selenium pyrithione, and

copper pyrithione, only zinc-pyrithione has been evaluated, and zinc-pyrithione

combined with salicylic acid has been described to cause moderate diminution of

wrinkling and irregular pigmentation after sixteen weeks of treatment. It should be

noted, however, that gallium oxide and gallium sulfide are known to be toxic for skin

and are not suitable for use in human skin preparations. In addition, other gallium

compounds, i.e., gallium nitrate and gallium nitride, are toxic for skin as well. It should

be, therefore, understood that the gallium containing compounds useful for practicing

the methods of the present invention are non-irritant and non-toxic and are thus safe for

human use. The present invention excludes the use of gallium containing compounds

which are not safe for use in humans or in companion animals. _{onl Q/n}, _{l n7q}

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10

The inventors of the present invention show the surprising results that a gallium- containing compound, such as gallium maltolate is highly effective in lightening skin,

particularly pigmentary spots, whether the pigmentary spots are a macule present from

birth such as a birthmark or melasma. The present invention shows that the lightening

effect is pronounced seven days after the beginning of treatment, without any side

effects such as pruritis, skin irritation or any discomfort throughout the treatment period.

The gallium-containing compounds, such as gallium maltolate, are shown herein to act

as highly efficient skin lightening agents. Without being bound to any mechanism of

action, the skin lightening activity of the gallium-containing compounds is found to be

reversible and is probably associated with a reduction in melanin production by

melanocytes. Such activity is distinct from the anti-inflammatory activity of previously

known metallic compounds. The methods of the present invention are therefore useful

in reducing melanin content or lightening human skin classified as Fitzpatrick phototype

I or above, so as to lighten the skin color according to Fitzpatrick scale by at least one

score or grade, thereby achieving essentially even or uniform skin color. As such

lightening effect is achieved within a couple of days, the compositions useful in

practicing the methods of the present invention are highly efficient as compared to

known skin lightening agents which require months for achieving that effect. Gal burn -containing compounds and compositions

The cosmetic or pharmaceutical compositions to be used in the methods of the

present invention comprise a gallium-containing compound and a cosmetically or

pharmaceutically acceptable carrier.

The term "gallium-containing compound" denotes a cosmetically or

pharmaceutically/dermatologically acceptable compound capable of providing cosmetic

or therapeutic levels of elemental gallium. The active ingredient in gallium-containing

compounds is the elemental gallium itself and not any accompanying compound.

Therefore, any compound which provides adequate level of elemental gallium in the

treated skin area can be used according to the present invention, which compound is

essentially devoid of side effects such as skin irritation, allergic contact dermatitis,

systemic toxicity, and/or teratogenicity. _{onl Q/n}, _{l n7q}

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11

The term "cosmetic" composition denotes a product, typically non-prescription

product, which is utilized in the cosmetic industry which produces measurable structural

changes in the skin.

The term "pharmaceutically acceptable" means approved by a regulatory agency

of the Federal or a state government or listed in the U. S. Pharmacopeia or other

generally recognized pharmacopeia for use in humans and in animals.

The term "dermatologically acceptable" means that the compound or

compositions is suitable for use in contact with human skin tissue without undue

allergic response, toxicity, incompatibility, instability, and the like.

The term "carrier" refers to a diluent or vehicle with which the active agent, i.e.,

the gallium-containing compound is administered. Such cosmetic or pharmaceutical

carriers can be liquids, such as water and oils, including those of petroleum, animal,

vegetable or synthetic origin, such as peanut oil, soybean oil, sesame oil, mineral oil,

and the like, polyethylene glycols, glycerin, propylene glycol or other synthetic

solvents.

The term “essentially devoid of side effects” refers to a gallium-containing

compound which causes noticeable skin irritation and/or allergic contact dermatitis in

no more than 5 %, preferably no more than 2 %, of the subjects treated with the

gallium-containing compound once or twice a day for seven days. The term“essentially

devoid of side effects” also refers to a gallium-containing compound which causes

systemic toxicity or teratogenicity in no more than 1 % of the subjects treated with the

gallium-containing compound once or twice a day for seven days. According to

preferred embodiments, the gallium-containing compound is devoid of side effects, i.e.,

the gallium-containing compound may cause noticeable skin irritation and/or allergic

contact dermatitis in no more than 1 % of the subjects treated with said gallium- containing compound once or twice a day for seven days, and preferably does not cause

noticeable or detectable side effects in any subject treated with the gallium-containing

compound once or twice a day for seven days. It is to be noted that the subjects being

treated have normal and healthy skin.

The term“systemic toxicity” refers to severe adverse effects a compound can have

on the body, such as seizures, induction of coma, neurological damage and cardiovascular

impairment, which includes, but is not limited to, low blood pressure (hypotension), _{onl Q/n}, _{l n7q}

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12 ischemia, cardiac arrhythmia, cardiotoxicity, cardiovascular collapse, cardiac arrest, heart

failure and asystole.

The term“about” as used herein denotes ± 10 % of the value indicated.

Gallium-containing compounds which can be used for practicing the methods of

the present invention include, but are not limited to, gallium complexes of 3-hydroxy-4- pyrones including gallium maltolate, gallium pyridinones, gallium tartrate, gallium

succinate, gallium gluconate, gallium palmitate, gallium 8-quinolinolate, gallium

porphyrins including gallium (III) protoporphyrin IX, gallium pyridoxal isonicotinoyl

hydrazone, gallium citrate, gallium chloride, gallium complexes of kenpaullone and its

derivatives, gallium transferrin, and any other cosmetically or pharmaceutically

acceptable gallium inorganic salts, organic salts, inorganic compounds, chelates,

coordination compounds, complexes, and organometallic compounds so long as the

gallium-containing compound is essentially devoid of side effects. Gallium maltolate,

having the formula tris(3-hydroxy-2-methyl-4H-pyran-4-onato)gallium, is a preferred

gallium-containing compound of the invention. It is to be noted that the gallium- containing complex to be used in the present invention is not a multi-metal complex; the

gallium-containing complex of the present invention consists of gallium as the metallic

moiety. It should be also noted that the present invention does not encompass any

gallium-containing compound which is known to be useful in reducing skin melanin

content and/or in preventing skin tanning and/or in protecting skin from UV radiation.

The cosmetic or pharmaceutical compositions of the present invention comprise a

gallium-containing compound as an active agent and a cosmetically or

pharmaceutically/dermatologically acceptable carrier, which compositions are

formulated for topical application on an affected skin.

The pharmaceutical or cosmetic compositions of the present invention can be

formulated as a topical formulation as known in the art. Examples of topical

formulations include, but are not limited to, a liquid, a lotion, a suspension, a cream, an

ointment, a paste, a gel, an aerosol, a foam, a mask, and a powder. Particularly preferred

formulations are odorless ointments, lotions, creams, and gels.

Ointments are semisolid preparations which are divided into oleaginous

ointments, emulsifiable ointments, emulsion ointments, and water-soluble ointments on

the basis of their base carrier. Oleaginous ointment bases include, but are not limited to,

vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from _{onl Q/n}, _{l n7q}

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13 petroleum. Emulsifiable ointment bases contain little or no water and include, but not

limited to, hydroxystearin sulfate, anhydrous lanolin, and hydrophilic petrolatum.

Emulsion ointment bases are either water-in-oil emulsions or oil-in-water emulsions,

and include, for example, cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid.

Water-soluble ointment bases are typically prepared from polyethylene glycols of

varying molecular weight. A particularly preferred ointment base for use in conjunction

with the present invention contains a hydrophilic petrolatum which may be obtained

under the trademark Eucerin^® (Beiersdorf, Inc., Norwalk, Conn., U.S.A.).

Lotions are typically liquid or semiliquid preparations in which solid particles,

including the active agent, are present in a water or alcohol base carrier. Lotions can be

formulated with an oily base carrier or may comprise an oil-in-water emulsion. It is

generally necessary that the insoluble matter in a lotion be finely dispersed throughout.

Lotions will typically contain suspending agents to produce better dispersions as well as

compounds useful for localizing and holding the active agent in contact with the skin,

such as methylcellulose, sodium carboxymethylcellulose, or the like.

Creams are viscous liquids or semisolid emulsions, either oil-in-water or water- in-oil emulsions. Cream bases typically contain an oil phase, an emulsifier, and an

aqueous phase. The oil phase generally comprises mineral oil and/or petrolatum such as

a petroleum jelly, and optionally a fatty alcohol such as cetyl or stearyl alcohol; the

aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and

generally contains a humectant. The emulsifier in a cream formulation is generally a

nonionic, anionic, cationic, or amphoteric surfactant.

Gels 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, contain an alcohol and, optionally, an oil.

The compositions of the invention can be formulated as a sustained release

formulation using liposomes.

The composition of the invention can also be applied via a transdermal patch,

wherein the composition is contained within a laminated structure that serves as a drug

delivery device to be affixed to the skin. In such a structure, the composition of the

invention is contained in a layer, or "reservoir," underlying an upper backing layer. The

laminated structure may contain a single reservoir, or it may contain multiple reservoirs

as known in the art. _{onl Q/n}, _{l n7q}

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14

The composition can also be applied using a mask such as a facial mask which

comprises a mask substrate. The substrate is preferably a water-insoluble substrate

which can have a size and shape such that it covers the face of a human user.

Topical formulations can be prepared by combining the gallium-containing

compounds with conventional pharmaceutical and/or cosmetic carriers and excipients

commonly used in topical formulations. Ointment and creams can, for example, be

formulated with an aqueous or oily base carrier with the addition of suitable thickening

and/or gelling agents. Such base carriers can include water and/or an oil such as mineral

oil or a vegetable oil such as almond oil, peanut oil or castor oil. Thickening agents

which can be used according to the nature of the base include waxes (e.g., mineral wax,

lanolin, petrolatum, beeswax), aluminum stearate, cetostearyl alcohol, propylene glycol,

polyethylene glycols, animal and/or vegetable fats, and the like. Powders can be formed

with the aid of any suitable powder base, e.g., talc, lactose, starch, and the like.

Solutions or suspensions can be formulated with an aqueous base or non-aqueous base,

and can also include one or more dispersing agents, suspending agents, solubilizing

agents, and the like.

The ointments, pastes, creams and gels can also contain excipients, such as

silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and

sprays can also contain excipients such as lactose, talc, silicic acid, aluminum

hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.

Solutions of the gallium-containing compound can be converted into aerosols or sprays

by any of the known means routinely used for making aerosol inhalant pharmaceuticals.

In general, such methods comprise pressurizing or providing a means of pressurizing a

container of the solution, usually with an inert carrier gas, and passing the pressurized

gas through a small orifice. Sprays can additionally contain customary propellants, such

as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane

and propane.

The cosmetic or dermatological/pharmaceutical compositions of the present

invention can further comprise additional excipients including, but not limited to,

emollients (e.g., hydrocarbon oils, ester oils, or dimethicone oils), thickening agents

(e.g., waxes, cellulose derivatives, starch, tragacanth), skin permeation enhancers (e.g.,

dimethylsulfoxide, dimethyl formamide), emulsifiers (e.g., surfactants such as isopropyl

myristate, sodium lauryl sulfate), humectants (e.g., urea, glycols such as propylene _{onl Q/n}, _{l n7q}

ru i / IL201 9/051 073

15 glycol, fatty acids), antioxidants (e.g., BHT, ascorbic acid, sodium ascorbate, ascorbyl

palmitate, beta-carotene), preservatives (e.g., methyl hydroxybenzoate, propyl

hydroxybenzoate, benzalkonium chloride, phenoxyethanol), opacifiers, colorants,

fragrances, flavoring agents, and the like.

According to some embodiments, the cosmetic or dermatological/pharmaceutical

composition of the present invention comprises a gallium-containing compound, an oil,

at least one thickening agent, and water, wherein the gallium containing compound is a

gallium complex of 3-hydroxy-4-pyrone, preferably gallium maltolate.

According to additional embodiments, the composition comprises a gallium- containing compound, mineral oil, mineral wax, lanolin alcohol, petrolatum, water, and

optionally further comprising a vegetable oil, wherein the gallium containing compound

is a gallium complex of 3-hydroxy-4-pyrone, preferably gallium maltolate.

The amount of the gallium-containing compound in the compositions of the

present invention is generally of about 0.00000001 % to about 50 % by weight of the

composition, alternatively is of about 0.00001 % to about 15 % by weight of the

composition, further alternatively of about 0.001 % to about 5 %, and yet further

alternatively is of about 0.1 % to about 1 % by weight of the composition. Any

percentage in between is encompassed.

According to further embodiments, gallium maltolate is present in the composition

in an amount ranging from about 0.001 % to about 10 % by weight of the composition,

or in an amount ranging from about 0.1 % to about 1 % by weight of the composition.

According to additional embodiments, water is present in the composition in an

amount ranging from about 7 % to about 50 % by weight of the composition, or in an

amount ranging from about 10 % to about 40 % by weight of the composition.

The compositions of the invention can also comprise one or more other active

agents, including, without limitation, anti-acne agents and/or sebum secretion reducing

agents such as niacinamide, retinoids, and/or vitamin C derivatives such as sodium

ascorbyl phosphate.

Other active agents that can be added to the compositions are other known skin

lightening agents, including tyrosinase inhibitors and/or melanosome transfer inhibitors.

Special mention may be made of hydroquinone and the monobenzyl ether thereof,

hydroquinone-beta-D-glucopyranoside, retinoids (e.g., retinoic acid), tretinoin, azelaic

acid, Kojic acid (5-hydroxy-4-pyran-4-one-2-methyl), Mequinol (4-hydroxyanisole), _{onl Q/n}, _{l n7q}

ru i / IL201 9/051 073

16 hydroxytetronic acid, tetronic acid, an a-hydroxy acid, a fatty acid ester of ascorbic

acid, and the like.

A useful effective amount of each of the known skin lightening agents is from

about 0.001 % to about 10% by weight, or from about 0.005% to about 5% by weight, or

from about 0.01 % to about 2.5% by weight, or from about 0.05% to about 1.5% by

weight, or from about 0.1 to about 1 % by weight, based on the total weight of the

composition.

The composition can also comprise active ingredients having anti-aging benefits.

Exemplary anti-aging components include, but are not limited to, botanicals (e.g., Butea

frondosa extract); phytol; retinoids (e.g., 9-cis retinoic acid, l3-cis retinoic acid, all- trans retinoic acid and derivatives thereof, phytanic acid, retinol (Vitamin A) and esters

thereof, such as retinol palmitate, retinol acetate and retinol propionate, and salts thereof

and others); hydroxy acids (including alpha-hydroxy acids and beta-hydroxy acids),

sahcylic acid and alkyl salicylates; exfoliating agents (e.g., glycolic acid, 3,6,9- trioxaundecanedioic acid, etc.), estrogen synthetase stimulating compounds (e.g.,

caffeine and derivatives); compounds capable of inhibiting 5 alpha-reductase activity

(e.g., hnolenic acid, linoleic acid, finasteride, and mixtures thereof); and barrier function

enhancing agents (e.g., ceramides, glycerides, cholesterol and its esters, alpha-hydroxy

and omega-hydroxy fatty acids and esters thereof, etc.), to name a few.

Methods of use

The present invention provides methods for reducing melanin content or reducing

pigmentation in an area of skin of a mammalian subject comprising applying topically

onto the area of skin a cosmetic or pharmaceutical composition comprising an amount

of a gallium-containing compound effective to reduce melanin content in said area of

skin and a cosmetically or pharmaceutically acceptable carrier, thereby lightening the

area of skin.

The terms“pigmentary spot” or“hyperpigmented area” are interchangeable and

refer to a skin region having larger content of melanin pigments as compared to an

adjacent skin region. The pigmentary spot is brownish or darker and is distinguishable

from its adjacent region having a brighter or even skin tone. _{onl Q/n}, _{l n7q}

ru i / IL201 9/051 073

17

The term“effective amount” of an active agent is meant a sufficient amount of a

compound to provide the desired effect with essentially no detectable side effects such

as systemic toxicity and/or skin irritation.

Pigmentary spots or hyperpigmented areas which can be treated by the

compositions of the present invention include, but are not limited to, macules, papules,

or nodules. Pigmentary spots or hyperpigmented areas can appear in newborns as

birthmarks. Additionally or alternatively, pigmentary spots or hyperpigmented areas can

be hormonal dependent melasma.

The term“melasma” refers to a pigmentary spot or a hyperpigmented area which

causes cosmetic disfigurement, most commonly occurring on the skin of the face. About

half the cases of melasma are thought to be associated with changes in the level of

hormones that occurs in pregnancy or through the use of hormonal contraception.

Although the exact cause of melasma is not currently known, hormonal factors are

thought to play a key role in the development of melasma, as it rarely occurs before

puberty. Melasma has also been associated with the intake of certain types of drugs,

such as particular anti-epileptic medications. Thyroid dysfunction has also been

associated with the development of melasma in predisposed individuals. Exposure to

UV radiation can also worsen the appearance of melasma. Melasma can therefore

appear in any time point during the life course of a woman or man, even in the absence

of exposure to sun or UV radiation.

Additionally or alternatively, pigmentary spots, such as post inflammatory

byperpigmeniation, pigmentary spots after injury or burns, and pigmented acne marks

can also be treated with the gallium-containing compounds of the present invention.

Reducing skin melanin content or lightening skin can be measured by observing

changes in Fitzpatrick scale value of an area of skin of a subject. The Fitzpatrick Scale

(also known as Fitzpatrick skin typing test or Fitzpatrick phototyping scale) is a

numerical classification schema for the color of skin, and remains a recognized tool for

dermatologists for determining the color of skin. The Fitzpatrick scale measures several

components, including genetic disposition, reaction to sun exposure, and tanning habits,

and classifies skin into six types: Type I (scores 0-7) refers to white, very fair skin,

typical albino skin, that always burns, never tans; Type II (scores 8-16) refers to white,

fair skin, that usually burns, or tans with difficulty; Type III (scores 17-24) refers to

beige, which is very common, and which sometimes suffers mild burn, gradually tans to _{onl Q/n}, _{l n7q}

ru i / IL201 9/051 073

18 a light brown; Type IV (scores 25-30) refers to beige skin with a brown tint, and which

rarely burns, tans with ease to a moderate brown; Type V (scores over 30) refers to dark

brown skin which very rarely burns, tans very easily; Type VI refers to black skin that

never burns, tans very easily, and is deeply pigmented. The methods of the present

invention which reduce skin melanin content enable lightening the skin color or skin

tone of a treated area of skin by at least one score within a Fitzpatrick phototype grade

or by at least one skin type grade on the Fitzpatrick scale, for example, from Fitzpatrick

phototype II to Fitzpatrick phototype I, or from Fitzpatrick phototype III to Fitzpatrick

phototype II or I, etc., so as to achieve essentially even or uniform skin color.

Measurement tools to determine the color of a hyperpigmented area are known in

the art and include, for example, chromameter to obtain color data, derma spectrometer

to obtain color data, and multispectral camera to capture multispectral images.

In the treatment of skin lightening, it will be recognized by those skilled in the art

that the optimal dosages of the gallium compositions of the invention will be

determined by the nature and extent of the condition being treated, the form of the

composition, and the particular individual undergoing treatment, and that such dosages

can be determined by conventional techniques. It will also be appreciated by one skilled

in the art that the optimal dosing regimen, i.e., the number of doses of a gallium

composition of the invention, can be ascertained using conventional course of treatment

determination tests. Generally, a dosing regimen will involve topical application of the

selected formulation at least once daily, and preferably one to four times daily, to an

area of skin to be treated until the skin area has been lightened by at least one skin type

on the Fitzpatrick phototyping scale or until the pigmented spot has disappeared. In

some cases, a single dose will suffice, while in other cases dosing may continue for

days, weeks, or up to a few months, until the desired skin lightening has been

achieved. Flowever, if the skin lightening effect is desired for a long period of time, e.g.,

for years, the composition can be applied continuously as required.

Typical topical doses of the gallium composition, expressed as the amount of

contained elemental gallium per square centimeter of skin area are, for example, from

about 0.000001 to about 1 mg, alternatively from about 0.0001 to about 0.1 mg, or from

about 0.0005 to about 0.005 mg; such doses are typically administered, for example,

one to four times per day or once per week. When administered continuously, as by the

use of a patch, typical daily doses of the gallium composition, expressed as the amount _{onl Q/n}, _{l n7q}

ru i / IL201 9/051 073

19 of contained elemental gallium per square centimeter of skin surface area are, for

example, from about 0.000005 to about 5 mg, alternatively from about 0.0005 to about

0.5 mg, or from about 0.001 to about 0.05 mg.

The present invention further provides combination treatment protocols wherein

the methods of the present invention further comprise an additional step of applying one

or more known skin lightening agents.

The present invention further provides a method of preventing or reducing skin

tanning and/or protecting skin from UV radiation comprising applying topically onto a

skin area of a human subject the cosmetic or pharmaceutical compositions detailed

herein above so as to prevent or reduce skin tanning and/or protect skin from UV

radiation.

Such protection from UV radiation by the compositions comprising a gallium- containing compound includes protection from damage resulting from acute UV

exposure, e.g. erythema. It also includes protection from damage resulting from chronic

UV exposure, e.g. photoaging.

The cosmetic or pharmaceutical compositions are preferably applied in

conjunction with UV exposure, i.e., prior to, during, or after UV exposure. More

specifically, the compositions are preferably apphed from several hours, preferably up

to 4 hours, prior to UV exposure, to up to 72 hours after UV exposure, or anytime in

between.

For protection against acute damage from UV radiation, topical apphcation of the

cosmetic or pharmaceutical compositions of the present invention prior to exposure of

the skin to UV radiation is preferred.

For protection against chronic damage from UV radiation, topical apphcation of

the cosmetic or pharmaceutical compositions of the present invention is preferably done

on a continuous basis. The compositions are preferably topically apphed to the skin

daily, preferably prior to substantial exposure of the skin to UV radiation. Such

apphcation preferably occurs from at least about once a day to about 5 times daily, more

preferably about 2 times daily, but for particularly effective compositions preferably

once daily.

According to some embodiments, the cosmetic or pharmaceutical composition

can further comprise a sunscreen agent selected from the group consisting of organic

sunscreen agents and inorganic sunscreen agents. _{onl Q/n}, _{l n7q}

ru i / IL201 9/051 073

20

Organic sunscreen agents include, but are not limited to, homosalate, octocrylene,

octyl-p-methoxycinnamate, phenyl benzimidazole sulfonic acid, 2-hydroxy-4- methoxybenzophenone (Benzophenone-3), 2-ethylhexyl-salicylate, butyl

methoxydibenzoylmethane, ethylhexyl methoxycinnamate, phenylbenzimidazole

sulfonic acid, terephthalylidene dicamphor sulfonic acid, benzophenone-3,

benzophenone-4, benzophenone-5,4 methylbenzylidene camphor, benzimidazilate,

anisotriazine, ethylhexyl triazone, diethylhexyl butamido triazone, methylene bis- benzotriazolyl tetramethylbutylphenol, drometrizole trisiloxane, and mixtures thereof

Inorganic sunscreen agents include, but are not limited to, the following metallic

oxides: titanium dioxide, zinc oxide, zirconium oxide, iron oxide, and mixtures thereof

When included in the present compositions, the sunscreens are included in

amounts of from about 0.1% to about 20%, or from about 0.5% to about 10%, more

preferably from about 1 % to about 5%, by weight of the composition. Exact amounts

will vary depending upon the sunscreen or sunscreens chosen and the desired Sun

Protection Factor (SPF).

According to additional embodiments, the method for protecting skin from

radiation can further comprise a step of applying to said area of skin an additional

known chemical sunscreen agent or a physical sunscreen product.

According to the invention, when a combination treatment protocol is applied, the

composition comprising a gallium-containing compound can be applied to the area of

skin prior to, concomitantly with, or following the application of a composition

comprising a known skin lightening agent or a sunscreen agent. Each possibility

represents a separate embodiment of the present invention.

The present invention further provides a cosmetic or dermatological composition

for topical application to human skin for reducing melanin content in an area of the skin,

the composition comprises a gallium-containing compound and, optionally, a known

skin lightening agent. The gallium-containing compound is essentially devoid of side

effects, preferably the gallium-containing compound is devoid of side effects, as

detailed herein above. According to certain embodiments, the gallium-containing

compound is other than gallium oxide, gallium sulfide, gallium nitrate or gallium nitride

known to cause skin irritation and to be toxic or other than gallium associated with

pyridine-thiol or gallium complexed to dibenzoylmethane chromophore. _{onl Q/n}, _{l n7q}

ru i / IL201 9/051 073

21

The present invention further provides a cosmetic, dermatological or a sunscreen

composition for topical application to human skin, the composition comprises a

gallium-containing compound and, optionally, an agent known to prevent skin tanning.

The gallium-containing compound is essentially devoid of side effects, preferably the

gallium-containing compound is devoid of side effects as detailed herein above.

According to certain embodiments, the gallium-containing compound is other than

gallium oxide, gallium sulfide, gallium nitrate or gallium nitride known to cause skin

irritation and to be toxic and is other than gallium associated with pyridine-thiol,

gallium complexed to dibenzoylmethane chromophore, or gallium complexed to

violuric acid or to derivatives thereof as disclosed in U.S. Pat. No. 5,456,904 (the

content of which is incorporated as if fully set forth herein).

The following examples are presented to provide a more complete understanding

of the invention. The specific techniques, conditions, materials, proportions and

reported data set forth to illustrate the principles of the invention are exemplary and

should not be construed as limiting the scope of the invention.

EXAMPLE 1 The following gallium maltolate formulation for topical application to the skin

was prepared at room temperature with the following ingredients: 85 wt % of Eucerin^®

(Beiersdorf, Inc., Norwalk, Conn., U.S. A.); 10 wt % of water (sterile, deionized): 4.75

wt % of almond oil; and 0.25 wt % of gallium maltolate.

The formulation was prepared as follows: 5 grams of gallium maltolate powder

were added to 200 gr of sterile deionized water and mixed for 120 min, with occasional

stirring. This solution/suspension was then slowly added to 1700 gr of Eucerin^®, over a

period of 5 min, with continuous stirring. Then 95 gr of almond oil was added and the

mixture was stirred for an additional 45 minutes, until a homogeneous white cream was

produced, which was then transferred into containers for topical use. _{onl Q/n}, _{l n7q}

ru i / IL201 9/051 073

22

EXAMPLE 2

The following gallium maltolate formulation for topical application to the skin

was prepared at room temperature with the following ingredients: 49.5 wt % of

Eucerin^® (Beiersdorf, Inc., Norwalk, Conn., U.S.A.); 50 wt % of water (sterile,

deionized); and 0.5 wt % of gallium maltolate.

The formulation was prepared as follows: 4 grams of gallium maltolate powder

were added to 400 gr of sterile deionized water and mixed for 120 min, with occasional

stirring. This solution was then slowly added to 396 g of Eucerin^® over a period of 25

minutes, with continuous stirring. Stirring then continued for an additional 60 minutes,

until a homogeneous white cream was produced, which was then transferred into

containers for topical use.

EXAMPLE 3

A 24 year old female applied the formulation described herein above in Example

2 to her face as follows: after washing her face, the female subject applied a small

amount of the formulation topically to her face, and she kept applying the formulation

multiple times until all her face areas were sufficiently covered. This treatment was

performed twice a day, upon waking and before retiring to bed in the evening. This

process was repeated for 60 days. The subject noticed an overall appearance of skin

lightening within 10 days of use. No skin irritation or side effects were reported.

EXAMPLE 4

A 54 year old male with a birthmark on his nose was treated with the

formulation described herein above in Example 1 as follows: The subject washed his

nose with a mild soap. The composition was then applied topically twice a day with a

finger and spread evenly on the birthmark. The treatment was then repeated for 60 days.

The subject began to see noticeable improvement and skin lightening within 7 days of

use. No skin irritation or side effects were reported. _{onl Q/n}, _{l n7q}

ru i / IL201 9/051 073

23

EXAMPLE 5

A 34 year old female with melasma on her face was treated after giving birth

with the formulation described herein above in Example 1 as follows: The subject

washed her face with a mild soap. The composition was then applied topically twice a

day with a finger and spread evenly on the birthmark. The treatment was then repeated

for 60 days. The subject began to see noticeable improvement and skin lightening

within 7 days of use. No skin irritation or side effects were reported.

EXAMPLE 6

A 64 year old female with solar lentigines on the dorsum of both hands was

treated with the formulation described herein above in Example 2 as follows: The

subject washed her hands with a mild soap. The composition was then applied topically,

twice a day with a finger and spread evenly on the solar lentigines. This was then

repeated for 60 days. The subject began to see noticeable improvement and skin

lightening within 7 days of use. No skin irritation or side effects were reported.

It will be appreciated by persons skilled in the art that the present invention is not limited

by what has been particularly shown and described herein above. Rather the scope of the

invention is defined by the claims that follow.

Claims

onl Q/n, l n7q ru i / IL201 9/051 07324 CLAIMS

1. A method of reducing skin melanin content comprising applying topically to an

area of skin of a subject a cosmetic or pharmaceutical composition comprising

an effective amount of a gallium-containing compound and a cosmetically or

pharmaceutically acceptable carrier, thereby reducing melanin content in said

area of skin, wherein the gallium-containing compound is essentially devoid of

side effects, and wherein said gallium-containing compound is other than

gallium oxide, gallium sulfide, gallium nitrate, gallium nitride, gallium

associated with a pyridine-thiol, gallium complexed to dibezoylmethane

chromophore, or gallium complexed to violuric acid or to a derivative thereof.

2. The method according to claim 1 , wherein the gallium-containing compound is

selected from the group consisting of gallium complexes of 3-hydroxy-4- pyrones, gallium pyridinones, gallium porphyrins, gallium tartrate, gallium

succinate, gallium gluconate, gallium palmitate, gallium citrate, gallium chloride,

gallium 8-quinolinolate, gallium pyridoxal isonicotinoyl hydrazine, and gallium

transferrin.

3. The method according to claim 2, wherein the gallium complex of 3-hydroxy-4- pyrone is gallium maltolate.

4. The method according to claim 1 , wherein the subject is a human subject.

5. The method according to claim 4, wherein the skin of the human subject is

classified as Fitzpatrick phototype I, Fitzpatrick phototype II, Fitzpatrick

phototype III, Fitzpatrick phototype IV, Fitzpatrick phototype V, or Fitzpatrick

phototype VI.

6. The method according to claim 1 , wherein the area of skin is selected from the

group consisting of facial skin, chest skin, neck skin, arm skin, leg skin, back

skin, shoulder skin, skin of the torso, buttocks skin, skin of the back of the hand,

and skin of the feet.

7. The method according to claim 1 , wherein the area of skin is a pigmentary spot. _{onl Q/n}, _{l n7q}

ru i / IL201 9/051 073

25

8. The method according to claim 7, wherein the pigmentary spot is selected from

the group consisting of birthmarks, melasma, post inflammatory

hyperpigmentation spots pigmentary spots after injury, and pigmentary spots

after burns.

9. The method according to claim 8, wherein the pigmentary spot is a birthmark.

10. The method according to claim 8, wherein the pigmentary spot is melasma.

11. The method according to claim 7, wherein the pigmentary spot is selected from

the group consisting of a macule, papule, and a nodule.

12. The method according to claim 1, wherein the skin of the human subject is

classified as Fitzpatrick phototype I or above, and wherein the gallium- containing compound is a gallium complex of 3-hydroxy-4-pyrone.

13. The method according to claim 12, wherein the gallium complex of 3-hydroxy- 4-pyrone is gallium maltolate.

14. The method according to claim 1 , wherein the area of skin is a pigmentary spot

selected from the group consisting of a birthmark and melasma, and wherein the

gallium-containing compound is a gallium complex of 3-hydroxy-4-pyrone.

15. The method according to claim 14, wherein the gallium complex of 3-hydroxy- 4-pyrone is gallium maltolate.

16. The method according to claim 1 , wherein the cosmetic or pharmaceutical

composition is formulated in a form selected from the group consisting of a

liquid, a lotion, a suspension, a cream, an ointment, a paste, a gel, an aerosol, a

foam, a mask, and a powder.

17. The method according to claim 1 , wherein the cosmetic or pharmaceutical

composition further comprising one or more excipients selected from the group

consisting of emollients, thickening agents, emulsifiers, humectants, and

preservatives.

18. The method according to claim 17, wherein the composition comprises an oil, at

least one thickening agent, and water. _{onl Q/n}, _{l n7q}

ru i / IL201 9/051 073

26

19. The method according to claim 18, wherein the oil is selected from the group

consisting of a mineral oil and a vegetable oil, and wherein the thickening agent

comprises one or more waxes.

20. The method according to claim 19, wherein the composition comprises mineral

oil, mineral wax, lanolin alcohol, petrolatum, water, and optionally a vegetable

oil.

21. The method according to claim 1 , wherein the gallium-containing compound is

present in the composition in an amount of about 0.00001 % to about 50 % by

weight of the composition.

22. The method according to claim 21 , wherein the gallium-containing compound is

present in the composition in an amount of about 0.1 % to about 1 % by weight

of the composition.

23. The method according to claim 18, wherein water is present in the composition

in an amount ranging from about 5 % to about 80 % by weight of the

composition.

24. The method according to claim 19, wherein the composition comprises gallium

maltolate in an amount of about 0.1 % to about 1 % by weight of the

composition, mineral oil, mineral wax, lanolin alcohol, petrolatum, and water in

an amount ranging from about 10 % to about 50 % by weight of the composition,

optionally further comprising a vegetable oil.

25. The method according to claim 24, wherein the cosmetic or pharmaceutical

composition is formulated as a cream.

26. The method according to claim 1 , wherein applying the composition is

performed once or twice daily for seven days up to two months or so long as skin

melanin content is reduced or skin lightening is achieved.

27. The method according to claim 1 , wherein the cosmetic or pharmaceutical

composition further comprising a known skin lightening agent.

28. The method according to claim 1 , further comprising a step of applying to the

area of skin an additional cosmetic or pharmaceutical composition comprising a

known skin lightening agent. _{onl Q/n}, _{l n7q}

ru i / IL201 9/051 073

27

29. A method of protecting skin from UV radiation comprising applying topically to

an area of skin of a human subject a cosmetic or pharmaceutical composition

comprising an effective amount of a gallium-containing compound and a

cosmetically or pharmaceutically acceptable carrier, wherein the gallium- containing compound is essentially devoid of side effects, and wherein said

gallium-containing compound is other than gallium oxide, gallium sulfide,

gallium nitrate, gallium nitride, gallium associated with a pyridine-thiol, gallium

complexed to dibezoylmethane chromophore, or gallium complexed to violuric

acid or to a derivative thereof.

30. The method according to claim 29, wherein the gallium-containing compound is

succinate, gallium gluconate, gallium palmitate, gallium citrate, gallium

chloride,, gallium 8-quinolinolate, gallium pyridoxal isonicotinoyl hydrazine,

and gallium transferrin.

31. The method according to claim 30, wherein the gallium complex of 3-hydroxy- 4-pyrone is gallium maltolate.

32. The method according to claim 29, wherein the cosmetic or pharmaceutical

composition further comprising a known sunscreen agent.

33. The method according to claim 29, further comprising a step of applying to the

area of skin an additional cosmetic or pharmaceutical composition comprising a

known sunscreen agent.

34. A cosmetic or pharmaceutical composition comprising a gallium-containing

compound and a cosmetically or pharmaceutically acceptable carrier for use in

reducing skin melanin content in an area of skin of a subject, wherein the

gallium-containing compound is essentially devoid of side effects, and wherein

said gallium-containing compound is other than gallium oxide, gallium sulfide,

complexed to dibezoylmethane chromophore, or gallium complexed to violuric

acid or to a derivative thereof. _{onl Q/n}, _{l n7q}

ru i / IL201 9/051 073

28

35. The cosmetic or pharmaceutical composition for use according to claim 34,

wherein the gallium-containing compound is selected from the group consisting

of gallium complexes of 3-hydroxy-4-pyrones, gallium pyridinones, gallium

porphyrins, gallium tartrate, gallium succinate, gallium gluconate, gallium

palmitate, gallium citrate, gallium chloride, gallium 8-quinolinolate, gallium

pyridoxal isonicotinoyl hydrazine, and gallium transferrin.

36. The cosmetic or pharmaceutical composition for use according to claim 35,

wherein the gallium complex of 3-hydroxy-4-pyrone is gallium maltolate.

37. The cosmetic or pharmaceutical composition for use according to any one of

claims 34 to 36, wherein the subject is a human subject.

38. The cosmetic or pharmaceutical composition for use according to claim 37,

wherein the skin of the human subject is classified as Fitzpatrick phototype I,

Fitzpatrick phototype II, Fitzpatrick phototype III, Fitzpatrick phototype IV,

Fitzpatrick phototype V, or Fitzpatrick phototype VI.

39. The cosmetic or pharmaceutical composition for use according to any one of

claims 34 to 38, wherein the area of skin is selected from the group consisting of

facial skin, chest skin, neck skin, arm skin, leg skin, back skin, shoulder skin,

skin of the torso, buttocks skin, skin of the back of the hand, and skin of the feet.

40. The cosmetic or pharmaceutical composition for use according to any one of

claims 34 to 39, wherein the area of skin is a pigmentary spot.

41. The cosmetic or pharmaceutical composition for use according to claim 40,

wherein the pigmentary spot is selected from the group consisting of birthmarks,

melasma, post inflammatory hyperpigmentation spots, pigmentary spots after

injury, and pigmentary spots after burns.

42. The cosmetic or pharmaceutical composition for use according to any one of

claims 40 and 41, wherein the pigmentary spot is selected from the group

consisting of a macule, papule, and a nodule.

43. The cosmetic or pharmaceutical composition for use according to any one of

claims 34 to 42, wherein the skin of the human subject is classified as Fitzpatrick

phototype I or above, and wherein the gallium-containing compound is a gallium

complex of 3-hydroxy-4-pyrone. _{onl Q/n}, _{l n7q}

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29

44. The cosmetic or pharmaceutical composition for use according to claim 43,

wherein the gallium complex of 3-hydroxy-4-pyrone is gallium maltolate.

45. The cosmetic or pharmaceutical composition for use according to any one of

claims 34 to 42, wherein the area of skin is a pigmentary spot selected from the

group consisting of a birthmark and melasma, and wherein the gallium- containing compound is a gallium complex of 3-hydroxy-4-pyrone.

46. The cosmetic or pharmaceutical composition for use according to claim 45,

wherein the gallium complex of 3-hydroxy-4-pyrone is gallium maltolate.

47. The cosmetic or pharmaceutical composition for use according to any one of

claims 34 to 46, being formulated in a form selected from the group consisting of

a liquid, a lotion, a suspension, a cream, an ointment, a paste, a gel, an aerosol, a

foam, a mask, and a powder.

48. The cosmetic or pharmaceutical composition for use according to any one of

claims 34 to 47, further comprising one or more excipients selected from the

group consisting of emollients, thickening agents, emulsifiers, humectants, and

preservatives.

49. The cosmetic or pharmaceutical composition for use according to any one of

claims 34 to 48, comprising an oil, at least one thickening agent, and water.

50. The cosmetic or pharmaceutical composition for use according to claim 49,

wherein the oil is selected from the group consisting of a mineral oil and a

vegetable oil, and wherein the thickening agent comprises one or more waxes.

51. The cosmetic or pharmaceutical composition for use according to any one of

claims 49 and 50, comprising mineral oil, mineral wax, lanolin alcohol,

petrolatum, water, and optionally a vegetable oil.

52. The cosmetic or pharmaceutical composition for use according to any one of

claims 34 to 51, wherein the gallium-containing compound is present in an

amount of about 0.00001 % to about 50 % by weight of the composition.

53. The cosmetic or pharmaceutical composition for use according to claim 52,

wherein the gallium-containing compound is present in an amount of about

0.001 % to about 10 % by weight of the composition. _{onl Q/n}, _{l n7q}

ru i / IL201 9/051 073

30

54. The cosmetic or pharmaceutical composition for use according to claim 53,

wherein the gallium-containing compound is present in an amount of about 0.1

% to about 1 % by weight of the composition.

55. The cosmetic or pharmaceutical composition for use according to any one of

claims of 49 to 54, wherein water is present in an amount ranging from about 5

% to about 80 % by weight of the composition.

56. The cosmetic or pharmaceutical composition for use according to claim 55,

wherein water is present in an amount ranging from about 10 % to about 50 %

by weight of the composition.

57. The cosmetic or pharmaceutical composition for use according to any one of

claims 51 to 56, comprising gallium maltolate in an amount of about 0.1 % to

about 1 % by weight of the composition, mineral oil, mineral wax, lanolin

alcohol, petrolatum, and water in an amount ranging from about 10 % to about

50 % by weight of the composition, optionally further comprising a vegetable

oil.

58. The cosmetic or pharmaceutical composition for use according to any one of

claims 51 to 57, being formulated as a cream.

59. The cosmetic or pharmaceutical composition for use according to any one of

claims 34 to 58, adapted to be applied onto the area of skin of the subject once or

twice daily for seven days up to two months or so long as skin melanin content is

reduced or skin lightening is achieved.

60. The cosmetic or pharmaceutical composition for use according to claim 59,

adapted to be applied once or twice daily for seven days up to two months.

61. The cosmetic or pharmaceutical composition for use according to any one of

claims 34 to 60, further comprising a known skin lightening agent.

62. A cosmetic or pharmaceutical composition comprising a gallium-containing

compound and a cosmetically or pharmaceutically acceptable carrier for use in

protecting skin from UV radiation, wherein the gallium-containing compound is

essentially devoid of side effects, and wherein said gallium-containing

compound is other than gallium oxide, gallium sulfide, gallium nitrate, gallium

nitride, gallium associated with a pyridine-thiol, gallium complexed to _{onl Q/n}, _{l n7q}

ru i / IL201 9/051 073

31 dibezoylmethane chromophore, or gallium complexed to violuric acid or to a

derivative thereof.

63. The cosmetic or pharmaceutical composition for use according to claim 62,

wherein the gallium-containing compound is selected from the group consisting

of gallium complexes of 3-hydroxy-4-pyrones, gallium pyridinones, gallium

porphyrins, gallium tartrate, gallium succinate, gallium gluconate, gallium

palmitate, gallium citrate, gallium chloride,, gallium 8-quinolinolate, gallium

pyridoxal isonicotinoyl hydrazine, and gallium transferrin.

64. The cosmetic or pharmaceutical composition according to claim 63, wherein the

gallium complex of 3-hydroxy-4-pyrone is gallium maltolate.

65. The cosmetic or pharmaceutical composition according to any one of claims 62

to 64, further comprising a known sunscreen agent.