WO2014151891A1

WO2014151891A1 - Topical products

Info

Publication number: WO2014151891A1
Application number: PCT/US2014/026624
Authority: WO
Inventors: Darlene WALLEY
Original assignee: Walley Darlene
Priority date: 2013-03-14
Filing date: 2014-03-13
Publication date: 2014-09-25

Abstract

Topical products comprising a plurality of Nrf2-activating agents are disclosed. The topical products are effective for reducing oxidative stress and improving conditions associated with oxidative stress in a hard surface such as skin, hair or nail of a subject. The NRF2 activating agents act on target genes located in the Antioxidant Response Element, upregulating the expression of said target genes and thereby enable anti-inflammatory and antioxidant effect.

Description

TOPICAL PRODUCTS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 61/782,284, filed March 14, 2013, the entire contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] Oxidative stress is a condition characterized by elevated levels of free radicals and reactive oxygen species. Exposure to ultraviolet irradiation, gamma irradiation, and certain toxins and chemicals can cause oxidative stress in hard surfaces of humans and animals, for example, in the skin, hair, nails, and teeth. Oxidative stress in these tissues is associated with a variety of disorders and conditions, including inflammation, aging, and carcinogenesis.

Accordingly, a need exists for topical products that reduce oxidative stress and thereby improve the health and appearance of hard surfaces of humans and animals.

[0003] Nuclear factor erythroid-2 -related factor 2 (Nrf2; also known as nuclear factor

(erythorid-derived 2)-like 2, or NFE2L2) is a transcription factor that plays a central role in the Nrf2 antioxidant response pathway. Nrf2 regulates the expression of several antioxidant enzymes, including genes located in the Antioxidant Response Element. Under normal conditions, Nrf2 is kept in the cytoplasm by a cluster of proteins that degrade it quickly. Under oxidative stress, Nrf2 is not degraded, but instead travels to the nucleus where it binds to DNA and initiates transcription and/or translation of antioxidative and cytoprotective genes, including NAD(P)H quinone oxidoreductase 1, glutamine-cysteine ligase, heme oxygenase- 1, glutathione S-transferase, UDP-glucuronosyltransferase, and multidrug resistance-associated proteins, which enable cells to survive in the face of stress from free radicals and other oxidizing agents. Nrf2 also down-regulates other genes that promote inflammation and fibrosis. SUMMARY OF THE INVENTION

[0004] Disclosed here are methods comprising topically administering to a hard surface of a subject a composition comprising an effective amount of a plurality of Nrf2-activating agents and optionally one or more inactive ingredients. In some embodiments, said hard surface is selected from one or more of the group consisting of skin, hair, nails, and teeth. In some embodiments, said plurality of Nrf2-activating agents initiates the expression of target genes in cells in said surface. In certain embodiments, said target genes are located in the Antioxidant Response Element. In some specific embodiments, said target genes are selected from one or more of the group consisting of NAD(P)H quinone oxidoreductase 1, glutamine-cysteine ligase, heme oxygenase- 1, glutathione S-transferase, UDP-glucuronosyltransferase, and multidrug resistance-associated proteins. In some embodiments, said cells are skin cells located in the epidermis. In certain specific embodiments, said skin cells are selected from one or more of the group consisting of keratinocytes, melanocytes, Langerhans cells, and Merkel cells. In some embodiments, said plurality of Nrf2-activating agents are selected from the group consisting of Bacopa extract, milk thistle extract, Ashwagandha extract, green tea extract, turmeric extract, Gotu kola powder, Aloe vera powder, Gingko biloba leaf extract, N- Acetyl Cysteine, piperine, resveratrol, pterostilbene, sulforaphane, ginger, cinnamon, wasabi, carnosic acid, lipoic acid, licorice, and lycopene.

[0005] Disclosed herein are methods of improving a dermatological condition comprising topically administering to a hard surface of a subject a composition comprising an effective amount of a plurality of Nrf2-activating agents and optionally one or more inactive ingredients. In some embodiments, said hard surface is selected from one or more of the group consisting of skin, hair, and nails. In some embodiments, said plurality of Nrf2-activating agents initiates the expression of target genes in cells in said surface. In certain embodiments, wherein said target genes are located in the Antioxidant Response Element. In some specific embodiments, said target genes are selected from one or more of the group consisting of NAD(P)H quinone oxidoreductase 1, glutamine-cysteine ligase, heme oxygenase- 1, glutathione S-transferase, UDP- glucuronosyltransferase, and multidrug resistance-associated proteins. In some embodiments, said cells are skin cells located in the epidermis. In certain specific embodiments, said skin cells are selected from one or more of the group consisting of keratinocytes, melanocytes, Langerhans cells, and Merkel cells. In some embodiments, said plurality of Nrf2-activating agents are selected from the group consisting of Bacopa extract, milk thistle extract, Ashwagandha extract, green tea extract, turmeric extract, Gotu kola powder, Aloe vera powder, Gingko biloba leaf extract, N-Acetyl Cysteine, piperine, resveratrol, pterostilbene, sulforaphane, ginger, cinnamon, wasabi, carnosic acid, lipoic acid, licorice, and lycopene. In certain embodiments, said dermato logical condition is associated with oxidative stress. In a specific embodiment, said dermatological condition is aging of the skin. In some embodiments, said dermatological condition results from breakdown of ATP, exposure to sunlight, exposure to smoke, exposure to pollutants, unhealthy diet, lack of exercise, over-exercise, stress, illness, or combinations thereof.

[0006] Disclosed herein are methods comprising reducing oxidative stress in a hard surface of a subject by topically administering to said hard surface a composition comprising an effective amount of a plurality of Nrf2-activating agents and optionally one or more inactive ingredients. In some embodiments, said hard surface is selected from one or more of the group consisting of skin, hair, nails, and teeth. In some embodiments, said plurality of Nrf2-activating agents initiates the expression of target genes in cells in said surface. In certain embodiments, said target genes are located in the Antioxidant Response Element. In some specific embodiments, said target genes are selected from one or more of the group consisting of NAD(P)H quinone oxidoreductase 1, glutamine-cysteine ligase, heme oxygenase- 1, glutathione S -transferase, UDP- glucuronosyltransferase, and multidrug resistance-associated proteins. In some embodiments, said cells are skin cells located in the epidermis. In certain embodiments, said skin cells are selected from one or more of the group consisting of keratinocytes, melanocytes, Langerhans cells, and Merkel cells. In some embodiments, said plurality of Nrf2-activating agents are selected from the group consisting of Bacopa extract, milk thistle extract, Ashwagandha extract, green tea extract, turmeric extract, Gotu kola powder, Aloe vera powder, Gingko biloba leaf extract, N-Acetyl Cysteine, piperine, resveratrol, pterostilbene, sulforaphane, ginger, cinnamon, wasabi, carnosic acid, lipoic acid, licorice, and lycopene.

[0007] Disclosed herein are topical formulations comprising an effective amount of a plurality of Nrf2-activating agents and optionally one or more inactive ingredients. In some embodiments, said plurality of Nrf2-activating agents are selected from the group consisting of Bacopa extract, milk thistle extract, Ashwagandha extract, green tea extract, turmeric extract, Gotu kola powder, Aloe vera powder, Gingko biloba leaf extract, N- Acetyl Cysteine, piperine, resveratrol, pterostilbene, sulforaphane, ginger, cinnamon, wasabi, carnosic acid, lipoic acid, licorice, and lycopene.

[0008] Disclosed herein are methods of activating Nrf2 in keratinocytes comprising topically administering to a hard surface of a subject a composition comprising an effective amount of a plurality of Nrf2-activating agents and optionally one or more inactive ingredients. In some embodiments, said hard surface is selected from one or more of the group consisting of skin, hair, nails, and teeth. In some embodiments, said plurality of Nrf2-activating agents initiates the expression of target genes in cells in said surface. In certain embodiments, said target genes are located in the Antioxidant Response Element. In some specific embodiments, said target genes are selected from one or more of the group consisting of NAD(P)H quinone oxidoreductase 1, glutamine-cysteine ligase, heme oxygenase- 1, glutathione S-transferase, UDP- glucuronosyltransferase, and multidrug resistance-associated proteins. In some embodiments, said plurality of Nrf2-activating agents are selected from the group consisting of Bacopa extract, milk thistle extract, Ashwagandha extract, green tea extract, turmeric extract, Gotu kola powder, Aloe vera powder, Gingko biloba leaf extract, N-Acetyl Cysteine, piperine, resveratrol, pterostilbene, sulforaphane, ginger, cinnamon, wasabi, carnosic acid, lipoic acid, licorice, and lycopene.

DETAILED DESCRIPTION OF THE INVENTION

[0009] Disclosed herein are topical products for reducing oxidative stress hard surfaces of humans and animals. In some embodiments, the topical products disclosed herein improve conditions associated with oxidative stress, including but not limited to aging.

[0010] The topical products disclosed herein may be used in subjects. As used herein, a "subject" is a living organism, and includes vertebrates, particularly mammals, and more particularly humans.

[0011] The topical products disclosed herein comprise an effective amount of a plurality of Nrf2-activating agents. As used herein, a "Nrf2-activating agent" is a chemical compound, biological molecule, composition, formulation, and/or extract that activates Nrf2, which initiates transcription and/or translation of target genes through the Nrf2 antioxidant response pathway. In some embodiments, the target genes may include antioxidative and/or cytoprotective genes. In some embodiments, the target genes are located in the Antioxidant Response Element. In certain specific embodiments, the target genes are selected from one or more of the group consisting of NAD(P)H quinone oxidoreductase 1, glutamine-cysteine ligase, heme oxygenase- 1, glutathione S- transferase, UDP-glucuronosyltransferase, multidrug resistance-associated proteins.

[0012] In some embodiments, administration of topical products comprising a plurality of Nrf2- activating agents activates Nrf2 in a hard surface of a subject. As used herein, a "hard surface" is an external surface of a subject to which the topical products are applied, and includes one or more of the group consisting of skin, hair, nails, and teeth. In some embodiments, administration of topical products comprising a plurality of Nrf2-activating agents activates Nrf2 in skin cells in the epidermis. In some embodiments, the skin cells in the epidermis are selected from the group consisting of one or more of keratinocytes, melanocytes, Langerhans cells, and Merkel cells. In a specific embodiment, administration of topical products comprising a plurality of Nrf2-activating agents activates Nrf2 in keratinocytes.

[0013] As used herein, the term "effective amount" is an amount of a plurality of Nrf2- activating agents that initiates the expression of target genes in cells whose transcription is regulated by Nrf2 when topically administered to a hard surface of a subject, and thereby provides a therapeutic, prophylactic, or cosmetic effect. For example, an "effective amount" of a plurality of Nrf2-activating agents may be an amount that is effective to treat, inhibit, reduce, and/or prevent oxidative stress in a subject when topically administered on a hard surface of a subject. In some embodiments, an "effective amount" of a plurality of Nrf2-activating agents may be an amount that is effective to treat, inhibit, and/or prevent a disorder or condition that is associated with oxidative stress in a hard surface of a subject, including the skin, hair, nails, and teeth, of a subject when topically administered on a hard surface of the subject. Such disorders or conditions may include dermatological conditions such as aging.

[0014] An "effective amount" may also be an amount of a plurality of Nrf2-activating agents that initiates the expression of target genes in cells whose transcription is regulated by Nrf2 when topically administered to a hard surface of a subject, and thereby provides a desired cosmetic effect. For example, an "effective amount" may be an amount that provides a visible

improvement or visible change in the skin of a subject during, immediately after, or following topical administration of a composition disclosed herein in a method disclosed herein on a hard surface of a subject.

[0015] As used herein, the term "about," when located before a dosage amount or dosage range of a specific ingredient, refers to an amount or range closely above and/or closely below the stated amount or range that does not manifestly alter the therapeutic effect of the specific ingredient from the stated amount or range and is meant to encompass at least all equivalents of that amount. In some specific embodiments, the term "about," when located before a dosage amount or dosage range of a specific ingredient, refers to an amount or range that is ± 10% of the stated amount or range. Numerical quantities given herein are approximate unless stated otherwise, meaning that the term "about" can be inferred when not expressly stated.

[0016] In some specific embodiments, an effective amount of a plurality of Nrf-2 activating agents is from about 25 mg to about 1,000 mg, or from about 50 mg to about 750 mg, or from about 75 mg to about 650 mg, or from about 100 mg to about 500 mg, or from about 100 mg to about 200 mg, or from about 125 mg to about 175 mg. In certain specific embodiments, an effective amount of a Nrf-2 activating agent is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 750 mg, or about 1,000 mg. In a specific embodiment, an effective amount of a plurality of Nrf-2 activating agents is at least about 150 mg.

[0017] In certain embodiments, Nrf2-activating agents may comprise plant extracts or powders. In some embodiments, the plant extracts or powders are solubilized in an appropriate solvent. Suitable Nrf2-activating agents for use in topical products disclosed herein include Bacopa extract, milk thistle extract, Ashwagandha powder, green tea extract, turmeric extract, Gotu kola powder, Aloe vera powder, Gingko biloba leaf extract, N-Acetyl Cysteine, piperine, resveratrol, pterostilbene, sulfurophane, ginger, cinnamon, wasabi, carnosic acid, lipoic acid, licorice, lycopene, and combinations thereof.

[0018] Bacopa monniera

[0019] Bacopa monniera (common names: water hyssop and Brahmi) is a creeping perennial that thrives in warmer temperate climates. The genus Bacopa includes over 100 species of aquatic herbs distributed throughout the warmer regions of the world. The plant is a profusely branched herb, rooting at the nodes and forming dense mats. In one embodiment, the topical products disclosed herein may comprise a B. monniera extract. Such an extract may comprise a standardized extract (such as Bacopin®) prepared from the leaves of the B. monniera plant (Sabinsa Corporation, Piscataway, N.J., USA). In some embodiments, the extract may be standardized for a minimum of about 20% bacosides A & B. In other embodiments, the extracts of the B. monniera plant may be standardized for greater minimum levels of bacosides A & B (e.g., about 30%, 40%, 50%, 60%, 70%, 80%, 90% and more, etc.) and may be used in the topical products disclosed herein and can be prepared by extraction techniques known in the art. An extract of B. monniera is commercially available, e.g., from Viable Herbal Solutions (Morris ville, Pa., USA).

[0020] In some embodiments, the topical products disclosed herein may comprise from about 1 mg to about 1,000 mg B. monniera extract, or from about 10 mg to about 500 mg B. monniera

-Ί- extract, or from about 20 mg to about 100 mg B. monniera extract. In a specific embodiment, the topical products disclosed herein may comprise at least about 33.33 mg B. monniera extract. In another specific embodiment, the topical products disclosed herein may comprise about 33.33 mg B. monniera extract. In specific embodiments, the B. monniera extract may comprise Bacopin®.

[0021] In a specific embodiment, topical products disclosed herein may comprise a B. monniera extract standardized for at least about 20% bacosides A & B. In another specific embodiment, the topical products disclosed herein may comprise a B. monniera extract standardized for at least about 30%) bacosides A & B. In another specific embodiment, topical products disclosed herein may comprise a B. monniera extract standardized for at least about 40% bacosides A & B. In another specific embodiment, topical products disclosed herein may comprise a B. monniera extract standardized for at least about 50% bacosides A & B. In another specific embodiment, topical products disclosed herein may comprise a B. monniera extract standardized for about 50%> bacosides A & B.

[0022] Milk Thistle

[0023] Milk thistle (botanical name; Silybum marianum; other common names: Marian, Silybum, Silymarin) is a fine, tall plant, about the size of the Cotton Thistle, with cut into root- leaves, waved and spiny at the margin, of a deep, glossy green, with milk white veins, and is found not uncommonly in hedgebanks and on waste ground. Useful parts of the plant include, e.g., the whole herb, root, leaves, seeds, and hull. Milk thistle seeds contain a bioflavonoid complex known as silymarin. Silymarin is an extract of the seeds of the milk thistle plant. In some embodiments, a standardized extract may be about 80% silymarin (the active ingredient). Silymarin is made up of three parts: silibinin, silidianin, and silicristin. Milk thistle (80% silymarin) extract is commercially available, e.g., from Stayleaner.com (Las Vegas, Nev., USA).

[0024] In some embodiments, the topical products disclosed herein may comprise from about 15 mg to about 2,000 mg milk thistle extract (70%-80% silymarin), or from about 25 mg to about 500 mg milk thistle extract (70%-80% silymarin), or from about 40 mg to about 150 mg milk thistle extract (70%>-80%> silymarin). In a specific embodiment the topical products disclosed herein may comprise at least about 50 mg milk thistle extract (70%-80% silymarin). In a specific embodiment the topical products disclosed herein may comprise about 50 mg milk thistle extract (70%-80% silymarin).

[0025] In some embodiments, the topical products disclosed herein may comprise from about 15 mg to about 2,000 mg milk thistle extract, or from about 25 mg to about 500 mg milk thistle extract, or from about 40 mg to about 150 mg milk thistle extract. In a specific embodiment the topical products disclosed herein may comprise at least about 50 mg milk thistle extract. In a specific embodiment the topical products disclosed herein may comprise about 50 mg milk thistle extract.

[0026] Ashwagandha

[0027] Ashwagandha (botanical names: Withania somnifera and Physalis flexuosa; other common names: winter cherry, Ashgandh, Achuvagandi, Amikkira-gadday, Amkulang-kalang, Amukkira-kilzhangu, Amukran-kizhangu, Asagandha, Asana, Asgandh, Asundha, Asvagandhi, Fatarfoda, Hirimaddina-gadday, Hirre-gadday, Penneroo-gadda, Pevette, Sogade-beru, Indian ginseng) is an erect branched shrub native to India, Pakistan and Sri Lanka. Ashwaganda powder is commercially available, e.g., from iHerb Inc. (Monrovia, Calif, USA).

[0028] In some embodiments, the topical products disclosed herein may comprise from about 1 mg to about 1,000 mg Ashwagandha root extract, or from about 10 mg to about 500 mg

Ashwagandha root extract, or from about 20 mg to about 100 mg Ashwagandha root extract. In a specific embodiment, the topical products disclosed herein may comprise at least about 33.33 mg Ashwagandha root extract. In a specific embodiment, the topical products disclosed herein may comprise about 33.33 mg Ashwagandha root extract.

[0029] In some embodiments, the topical products disclosed herein may comprise from about 1 mg to about 1,000 mg Ashwagandha powder, or from about 10 mg to about 500 mg Ashwagandha powder, or from about 20 mg to about 100 mg Ashwagandha powder. In a specific embodiment, the topical products disclosed herein may comprise at least about 33.33 mg Ashwagandha powder. In a specific embodiment, the topical products disclosed herein may comprise about 33.33 mg Ashwagandha powder. [0030] Turmeric

[0031] Turmeric extract 95% is prepared from the root or rhizome of the Curcuma longa plant (common names: Curcuma, Turmeric, Ukon, Goeratji, Kakoenji, Koenjet, Kondin, Kunir, Kunyit, Oendre, Rame, Renet, Temu kuning, Temu kunyit, Tius. Curcumin). C. longa is a perennial plant native to India. A compound called curcumin is an extract of the root. In some embodiments, turmeric extract may be standardized to 95% curcumin contains turmeric (with 95% curcumin). Turmeric extract 95% is commercially available, e.g., from EZ-FITNESS (Northborough, Mass., USA).

[0032] In some embodiments, the topical products disclosed herein may comprise from about 1 mg to about 1,000 mg Turmeric extract, or from about 10 mg to about 300 mg Turmeric extract, or from about 12.5 mg to about 100 mg Turmeric extract. In a specific embodiment, the topical products disclosed herein may comprise, at least about 16.67 mg Turmeric extract. In a specific embodiment, the topical products disclosed herein may comprise about 16.67 mg Turmeric extract.

[0033] In some embodiments, the topical products disclosed herein may comprise from about 1 mg to about 1,000 mg Turmeric extract (95% curcumin), or from about 10 mg to about 300 mg Turmeric extract (95% curcumin), or from about 12.5 mg to about 100 mg Turmeric extract (95% curcumin). In a specific embodiment, the topical products disclosed herein may comprise, at least about 16.67 mg Turmeric extract (95% curcumin). In another specific embodiment, the topical products disclosed herein may comprise about 16.67 mg Turmeric extract (95%> curcumin).

[0034] Gotu kola

[0035] Gotu kola (botanical names: Hydrocotyle asiatica, Centella asiatica; other common names: Centella, March Pennywort, Indian Pennywort, Hydrocotyle, Brahmi (Sanskrit), Luei Gong Gen (Chinese)) is a slender, creeping perennial plant that grows commonly in swampy areas of India, Sri Lanka, Madagascar, South Africa and the tropics. Gotu kola is distinct from the kola nut. Gotu kola powder may be prepared from the leaves and aerial parts of the plant and used for medicinal purposes. Gotu kola powder is commercially available, e.g., may @Internatural (Twin Lakes, Wis., USA).

[0036] In some embodiments, the topical products disclosed herein may comprise from about 10 mg to about 4,000 mg Gotu kola powder, or from about 25 mg to about 2,000 mg Gotu kola powder, or from about 50 mg to about 1,000 mg Gotu kola powder. In a specific embodiment, the topical products disclosed herein may comprise at least about 200 mg Gotu kola powder. In a specific embodiment, the topical products disclosed herein may comprise about 200 mg Gotu kola powder.

[0037] Aloe vera

[0038] Aloe vera (common names: medicinal aloe, burn plant, Barbados aloe, unguentine cactus) is a perennial plant. The strong, fibrous root produces a rosette of fleshy basal leaves as in the agave but considerably smaller that grows wild in East and South Africa and also cultivated in the West Indies and other tropical areas. Aloe vera powder is commercially available, e.g., from Red Lion International Trading & Brokerage Co. (Fullerton, Calif, USA).

[0039] In some embodiments, the topical products disclosed herein may comprise from about 10 mg to about 4,000 mg Aloe vera powder, or from about 25 mg to about 2,000 mg Aloe vera powder, or from about 50 mg to about 1,000 mg Aloe vera powder. In a specific embodiment, the topical products disclosed herein may comprise at least about 200 mg Aloe vera powder. In a specific embodiment, the topical products disclosed herein may comprise about 200 mg Aloe vera powder.

[0040] Green Tea

[0041] In some embodiments, the topical products disclosed herein may comprise green tea extracts. In some embodiments, the green tea extract may be standardized for polyphenols. For example, green tea extract, 98% polyphenols containing 45% polyphenols such as polyphenol (-)- epigallocatechin gallate (EGCG) may be prepared from the leaf of the tea herb Camellia sinensis. Green tea extracts are commercially available, e.g., from Hunan Kinglong Bio-Resource Co., Ltd., (Xingsha, Changsha, Hunan, P. R. China). [0042] In some embodiments, the topical products disclosed herein may comprise from about 1 mg to about 1,000 mg green tea extract, or from about 10 mg to about 300 mg green tea extract, or from about 12.5 mg to about 100 mg green tea extract. In a specific embodiment, the topical products disclosed herein may comprise at least about 16.67 mg green tea extract. In another specific embodiment, the topical products disclosed herein may comprise about 16.67 mg green tea extract.

[0043] In some embodiments, the topical products disclosed herein may comprise from about 1 mg to about 1,000 mg green tea extract (98% polyphenols, 45% EGCG), or from about 10 mg to about 300 mg green tea extract (98% polyphenols, 45% EGCG), or from about 12.5 mg to about 100 mg green tea extract (98% polyphenols, 45% EGCG). In a specific embodiment, the topical products disclosed herein may comprise at least about 16.67 mg green tea extract (98%

polyphenols, 45% EGCG). In a specific embodiment, the topical products disclosed herein may comprise about 16.67 mg green tea extract (98% polyphenols, 45% EGCG).

[0044] Gingko biloba

[0045] Ginkgo biloba (common name: Maidenhair tree) is a dioecious tree. Ginko biloba extract is commercially available, e.g., from iHerb Inc. (Monrovia, Calif, USA).

[0046] In some embodiments, the topical products disclosed herein may comprise from about 5 mg to about 2,000 mg G. biloba leaf extract, or from about 10 mg to about 1,000 mg G. biloba leaf extract, or from about 50 mg to about 500 mg G. biloba leaf extract. In a specific

embodiment, the topical products disclosed herein may comprise at least about 200 mg G. biloba leaf extract. In a specific embodiment, the topical products disclosed herein may comprise about 200 mg G. biloba leaf extract.

[0047] N-Acetyl Cysteine

[0048] N-Acetyl Cysteine (NAC) is an acetylated form of the amino acid cysteine. N-Acetyl Cystein is commercially available, e.g., from Doctor's Trust Vitamins (Orlando, Fla., USA). [0049] In some embodiments, the topical products disclosed herein may comprise from about 50 mg to about 5,000 mg N-Acetyl Cysteine, or from about 100 mg to about 4,000 mg N-Acetyl Cysteine, or from about 250 mg to about 2,000 mg N-Acetyl cysteine. In a specific embodiment, the topical products disclosed herein may comprise at least about 500 mg N-Acetyl Cysteine. In a specific embodiment, the topical products disclosed herein may comprise about 500 mg N-Acetyl Cysteine.

[0050] Piperine

[0051] Piperine is an alkaloid that can be isolated from black pepper, white pepper, and long pepper. Chavicine is an isomer of piperine. Piperine is commercially available as an extract of black pepper (BioPerine®) or as the isolated compound, e.g., from Sigma-Aldrich® (St. Louis, MO).

[0052] Resveratrol

[0053] Resveratrol is a stilbenoid and phytoalexin that is produced naturally by several plants, including grapes. Resveratrol is commercially available in various extracts or as the isolated compound, e.g., from Sigma-Aldrich® (St. Louis, MO).

[0054] Pterostilbene

[0055] Pterostilbene is a stilbenoid and phytoalexin that is produced naturally by blueberries and grapes. Pterostilbene is commercially available in various extracts or as the isolated compound, e.g., from Sigma-Aldrich® (St. Louis, MO).

[0056] Sulforaphane

[0057] Sulforaphane is an isothiocyanate-containing molecule that is found in cruciferous vegetables such as broccoli, Brussels sprouts, and cabbages. Sulforaphane is commercially available in various extracts or as the isolated compound, e.g., from Sigma-Aldrich® (St. Louis, MO). [0058] Ginger

[0059] Ginger is the rhizome of the plant Zingiber officinale. Various formulations and extracts of ginger are commercially available, e.g., from Nature's Answer® (Hauppauge, NY).

[0060] Cinnamon

[0061] Cinnamon, sometimes referred to specifically as "true cinnamon" or "cassia," is a spice obtained from the inner bark of trees from the genus Cinnamomum, including Cinnamomum verum. Various formulations and extracts of cinnamon are commercially available, e.g., from Herb Pharm (Williams, Oregon).

[0062] Wasabi

[0063] Wasabi is a member of the Brassicaceae family of plants. Wasabi is available in powder and paste forms, e.g. from Eden® (Clinton, MI).

[0064] Carnosic Acid

[0065] Carnosic acid is a benzenediol abietane diterpene found in rosmarius officinalis and Salvia officinalis. Carnosic acid is commercially available in various plant extracts or as the isolated compound, e.g., from Sigma-Aldrich® (St. Louis, MO).

[0066] Lipoic Acid

[0067] Lipoic acid (also known as a-lipoic acid) is found in many natural food sources, but is more prevalent in kidney, heart, liver, spinach, broccoli, and yeast extract. The amount of lipoic acid present is food sources is typically quite low, but the compound can be synthesized by methods known in the art. Purified lipoic acid is commercially available, e.g., from Sigma- Aldrich® (St. Louis, MO).

[0068] Licorice

[0069] Licorice is the root of Glycyrrhiza glabra. Various extracts of licorice are commercially available, e.g., from Nature's Answer® (Hauppauge, NY). [0070] Lycopene

[0071] Lycopene is a bright red carotenoid (carotene) pigment and phytochemical found in various red fruits and vegetables, including tomatoes, red carrots, red bell peppers, watermelons, gac, and papayas. Lycopene is available in various plant extracts, e.g., from Sigma-Aldrich® (St. Louis, MO).

[0072] The term "topical product," as used herein, is the vehicle in which the plurality of Nrf2- activating agents is topically administered to a subject. Topical products disclosed herein may be administered in any suitable dosage forms. Suitable dosage forms include, for example, creams, gels, liniments, balms, lotions, ointments, solutions, suspensions, emulsions, transdermal patches, liposomes, anhydrous bases, and the like. The dosage forms may be administered as frequently as needed until the desired cosmetic effect is achieved, for example, once daily, twice daily, thrice daily, etc.

[0073] In some embodiments, the topical products disclosed herein may include biologically or pharmacologically active agents useful for reducing oxidative stress other than those specifically disclosed herein. For example, in certain specific embodiments, topical products disclosed herein may include additional Nrf2-activating ingredients other than those specifically disclosed herein. In some embodiments, topical products disclosed herein may include agents useful for conditions associated with oxidative stress. For example, in certain specific embodiments, topical products disclosed herein include agents that improve skin conditions, inflammation, and aging.

[0074] In some embodiments, the topical products disclosed herein may include inactive agents, i.e., agents that do not possess biological or pharmacological activity in the methods disclosed herein, consistent with the definition of inactive ingredients in 21 C.F.R. § 210.3(b)(8). In certain embodiments, said inactive ingredients include, but are not limited to, emollients and moisturizing agents, e.g, humectants and occlusive agents, sun screens, skin lightening agents, vitamins, trace metals, antimicrobial agents, fragrances, preservatives, anti-inflammatory agents, dyes, and coloring agents. [0075] In some embodiments, any combination of Nrf2-activating agents, inactive ingredients, dosages, administration routes, and/or dosage forms may be excluded. For example, in certain embodiments, any Nrf2-activating agents may be expressly excluded from the topical products disclosed herein.

[0076] The present disclosure will be further illustrated by the following non-limiting

Examples. These Examples are understood to be exemplary only, and they are not to be construed as limiting the scope of the invention as defined by the appended embodiments.

EXAMPLES

Example 1 - A representative topical product

[0078] Inactive Ingredients: Glycereth-26, Hispagel 200, Disodium EDTA, Carbopol 940, lecinol S-10, Cosmowax J, Finsolv TN, Dimethicone, Isostearyl Alcohol, Cetyl Alcohol, Silica, Triethanolamine, Tocopherol Acetate, and Water. [0079] Example 2 - Clinical trial conducted with representative topical product

[0080] General Design

[0081] The following study is conducted to determine whether a topical product comprising a plurality of Nrf2-activating agents provides long-term visual and measurable anti-aging benefits on the human face by reducing oxidative stress in the skin.

[0082] Materials and Methods

[0083] Fifty subjects apply the composition of Example 1 twice a day, morning and evening, to the face. The subjects are monitored for skin condition at: the beginning of the study, before treatment and at four weeks after using the product. The skin is evaluated for face and neck moisture, elasticity, wrinkle depth, and a survey administered. Moisture is measured with a Comeometer and elasticity / firmness is measured with a Cutometer. Surface fine lines are measured by image analysis with images analyzed by ImagePro software.

[0084] Results

[0085] Continued improvement is seen for the skin condition parameters by 4 weeks of the study for the test group.

Claims

1. A method comprising: topically administering to a hard surface of a subject a

composition comprising an effective amount of a plurality of Nrf2-activating agents and optionally one or more inactive ingredients.

2. The method of claim 1, wherein said hard surface is selected from one or more of the group consisting of skin, hair, nails, and teeth.

3. The method of claim 1, wherein said plurality of Nrf2-activating agents initiates the expression of target genes in cells in said surface.

4. The method of claim 3, wherein said target genes are located in the Antioxidant Response Element.

5. The method of claim 3, wherein said target genes are selected from one or more of the group consisting of NAD(P)H quinone oxidoreductase 1, glutamine-cysteine ligase, heme oxygenase- 1, glutathione S-transferase, UDP-glucuronosyltransferase, and multidrug resistance- associated proteins.

6. The method of claim 3, wherein said cells are skin cells located in the epidermis.

7. The method of claim 6, wherein said skin cells are selected from one or more of the group consisting of keratinocytes, melanocytes, Langerhans cells, and Merkel cells.

8. The method of claim 1, wherein said plurality of Nrf2-activating agents are selected from the group consisting of Bacopa extract, milk thistle extract, Ashwagandha extract, green tea extract, turmeric extract, Gotu kola powder, Aloe vera powder, Gingko biloba leaf extract, N- Acetyl Cysteine, piperine, resveratrol, pterostilbene, sulforaphane, ginger, cinnamon, wasabi, carnosic acid, lipoic acid, licorice, and lycopene.

9. A method of improving a dermato logical condition comprising: topically administering to a hard surface of a subject a composition comprising an effective amount of a plurality of Nrf2- activating agents and optionally one or more inactive ingredients.

10. The method of claim 9, wherein said hard surface is selected from one or more of the group consisting of skin, hair, and nails.

11. The method of claim 9, wherein said plurality of Nrf2-activating agents initiates the expression of target genes in cells in said surface.

12. The method of claim 11 , wherein said target genes are located in the Antioxidant Response Element.

13. The method of claim 11 , wherein said target genes are selected from one or more of the group consisting of NAD(P)H quinone oxidoreductase 1, glutamine-cysteine ligase, heme oxygenase- 1, glutathione S-transferase, UDP-glucuronosyltransferase, and multidrug resistance- associated proteins.

14. The method of claim 11, wherein said cells are skin cells located in the epidermis.

15. The method of claim 14, wherein said skin cells are selected from one or more of the group consisting of keratinocytes, melanocytes, Langerhans cells, and Merkel cells.

16. The method of claim 9, wherein said plurality of Nrf2-activating agents are selected from the group consisting of Bacopa extract, milk thistle extract, Ashwagandha extract, green tea extract, turmeric extract, Gotu kola powder, Aloe vera powder, Gingko biloba leaf extract, N- Acetyl Cysteine, piperine, resveratrol, pterostilbene, sulforaphane, ginger, cinnamon, wasabi, carnosic acid, lipoic acid, licorice, and lycopene.

17. The method of claim 9, wherein said dermatological condition is associated with oxidative stress.

18. The method of claim 9, wherein said dermatological condition is aging of the skin.

19. The method of claim 9, wherein said dermatological condition results from breakdown of ATP, exposure to sunlight, exposure to smoke, exposure to pollutants, unhealthy diet, lack of exercise, over-exercise, stress, illness, or combinations thereof.

20. A method comprising: reducing oxidative stress in a hard surface of a subject by topically administering to said hard surface a composition comprising an effective amount of a plurality of Nrf2-activating agents and optionally one or more inactive ingredients.

21. The method of claim 20, wherein said hard surface is selected from one or more of the group consisting of skin, hair, nails, and teeth.

22. The method of claim 20, wherein said plurality of Nrf2-activating agents initiates the expression of target genes in cells in said surface.

23. The method of claim 22, wherein said target genes are located in the Antioxidant Response Element.

24. The method of claim 22, wherein said target genes are selected from one or more of the group consisting of NAD(P)H quinone oxidoreductase 1, glutamine-cysteine ligase, heme oxygenase- 1, glutathione S-transferase, UDP-glucuronosyltransferase, and multidrug resistance- associated proteins.

25. The method of claim 22, wherein said cells are skin cells located in the epidermis.

26. The method of claim 25, wherein said skin cells are selected from one or more of the group consisting of keratinocytes, melanocytes, Langerhans cells, and Merkel cells.

27. The method of claim 20, wherein said plurality of Nrf2-activating agents are selected from the group consisting of Bacopa extract, milk thistle extract, Ashwagandha extract, green tea extract, turmeric extract, Gotu kola powder, Aloe vera powder, Gingko biloba leaf extract, N- Acetyl Cysteine, piperine, resveratrol, pterostilbene, sulforaphane, ginger, cinnamon, wasabi, carnosic acid, lipoic acid, licorice, and lycopene.

28. A topical formulation comprising an effective amount of a plurality of Nrf2-activating agents and optionally one or more inactive ingredients.

29. The topical formulation of claim 28, wherein said plurality of Nrf2-activating agents are selected from the group consisting of Bacopa extract, milk thistle extract, Ashwagandha extract, green tea extract, turmeric extract, Gotu kola powder, Aloe vera powder, Gingko biloba leaf extract, N-Acetyl Cysteine, piperine, resveratrol, pterostilbene, sulforaphane, ginger, cinnamon, wasabi, carnosic acid, lipoic acid, licorice, and lycopene.

30. A method of activating Nrf2 in keratinocytes comprising topically administering to a hard surface of a subject a composition comprising an effective amount of a plurality of Nrf2- activating agents and optionally one or more inactive ingredients.

31. The method of claim 30, wherein said hard surface is selected from one or more of the group consisting of skin, hair, nails, and teeth.

32. The method of claim 30, wherein said plurality of Nrf2-activating agents initiates the expression of target genes in cells in said surface.

33. The method of claim 32, wherein said target genes are located in the Antioxidant Response Element.

34. The method of claim 32, wherein said target genes are selected from one or more of the group consisting of NAD(P)H quinone oxidoreductase 1, glutamine-cysteine ligase, heme oxygenase- 1, glutathione S-transferase, UDP-glucuronosyltransferase, and multidrug resistance- associated proteins.

35. The method of claim 30, wherein said plurality of Nrf2-activating agents are selected from the group consisting of Bacopa extract, milk thistle extract, Ashwagandha extract, green tea extract, turmeric extract, Gotu kola powder, Aloe vera powder, Gingko biloba leaf extract, N- Acetyl Cysteine, piperine, resveratrol, pterostilbene, sulforaphane, ginger, cinnamon, wasabi, carnosic acid, lipoic acid, licorice, and lycopene.