Composition for protecting cells from oxidation and mitochondrial stress

Abstract

The present invention describes a composition comprising an effective amount of nicotinamide; quercetin; a rutin derivative; zinc or a salt thereof; ascorbic acid; parsley, or apigenin derivatives; and alpha-lipoic acid. The composition is used for enhancing the tolerance of cells to DNA damage, oxidative stress and mitochondrial dysfunction, or improving the DNA repair capacity.

Description

Technical Field

[0001] The present invention relates to novel compositions generally for oral or topical administration to mitigate the effects of aging.

[0002] In particular, the present invention relates to compositions and methods for enhancing the tolerance of cells to DNA damage, oxidative stress, mitochondrial dysfunction, or improving DNA repair capacity. Background Art

[0003] The decline in DNA protection and repair capacity is an important cause of genomic instability, which in turn may lead to a variety of diseases such as cancer, the risk of which increases exponentially with age.

[0004] Protecting DNA and other important cellular machinery from damage and repairing it when damage occurs is essential for high-functioning cells. This cellular protection and repair is normally associated with youth and health. Furthermore, with aging, these protective and repair functions decline in body cells and are responsible for much of the decline in cellular and tissue function. Summary of the invention

[0005] We have now discovered novel compositions comprising certain active ingredients that are particularly useful for enhancing the tolerance of cells to DNA damage, oxidative stress, mitochondrial dysfunction or for improving DNA repair capacity.

[0006] Therefore, according to a first aspect of the present invention, a composition is provided, which comprises an effective amount of a combination of two or more components selected from acacetin, ACT1 peptide, α-lipoic acid, alprostadil, anisomycin, apigenin, ascorbic acid, astragalus, berberine, β-lapachone, β-hydroxy-β-methylbutyrate, bacopa monnieri, catechins, catechols, chamomile, chrysin, coumestrol, curcumin, dinitrophenol, dinoprost, ellagic acid, (-)- Epigallocatechin gallate, green tea extract, fisetin, genistein, ginsenoside RE, glabridin, 18-α-glycyrrhetinic acid, 18-β-glycyrrhetinic acid, glycyrrhizin, hydroquinone, isoquercetin (EMIQ), kaempferol, black bean anthocyanin (kuromanin), leucine, lithium, luteolin, luteolin, luteolin, melatonin, menadione, 1-methylnicotinamide (MNA), methyl salicylate, myricetin, nicotinamide adenine dinucleotide (nadide), niacin (vitamin B 3), nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), nicotinic acid adenine dinucleotide (NaAD), nicotinic acid mononucleotide (NaMN), parsley (petroselinium crispum), phenylephrine, pokeweed mitogen, 15-Δ prostaglandin J2, puromycin, quercetin, quinolinic acid, retinoic acid, trichostatin A, troxerutin, rutin, tryptophan, vitamin D3, withaferin A, wortmannin and zinc (including salts thereof); and derivatives thereof; and any combination thereof.

[0007] The amount of active ingredient in the composition according to this aspect of the invention may vary depending on the nature of the active ingredient, the mode of administration, etc. Exemplary amounts of active ingredients that may be present in the composition are from about 1 mg to about 1000 mg; or from about 50 mg to about 900 mg; or from about 100 mg to about 800 mg; or from about 150 mg to about 700 mg; or from about 200 mg to about 600 mg; or from about 250 mg to about 500 mg.

[0008] The hope is to increase the tolerance of cells, especially skin cells, to DNA damage by enhancing the cells' DNA protection and repair capabilities, and by increasing their ability to withstand oxidative stress and mitochondrial stress and dysfunction.

[0009] According to this aspect of the invention, there is provided a composition for enhancing the tolerance of cells to DNA damage, oxidative stress, mitochondrial dysfunction or improving the DNA repair capacity.

[0010] In another aspect of the present invention, the composition is used to enhance the tolerance of cells to DNA damage, such as enhancing the tolerance of skin cells to DNA damage.

[0011] In another aspect of the present invention, the composition is used to enhance the tolerance of cells to oxidative stress, such as enhancing the tolerance of skin cells to oxidative stress.

[0012] In another aspect of the invention, the composition is used to enhance the tolerance of cells to mitochondrial dysfunction, such as enhancing the tolerance of cells to mitochondrial dysfunction.

[0013] In another aspect of the present invention, the composition is used to enhance the DNA repair ability of cells, such as enhancing the DNA repair ability of skin cells.

[0014] In one aspect of the present invention, the composition is used to enhance the tolerance of cells to DNA damage, oxidative stress, mitochondrial dysfunction, and improve DNA repair capacity.

[0015] Therefore, according to this aspect of the invention, there is provided a composition comprising an effective amount of one or more components selected from the group consisting of acacetin, ACT1 peptide, α-lipoic acid, alprostadil, anisomycin, apigenin, ascorbic acid, astragalus, berberine, β-lapachone, β-hydroxy-β-methylbutyrate, Bacopa monnieri, catechins, catechols, chamomile, chrysin, coumestrol, curcumin, dinitrophenol, dinoprost, ellagic acid, (-)-epiped. Epigallocatechin gallate, green tea extract, fisetin, genistein, ginsenoside RE, glabridin, 18-α-glycyrrhetinic acid, 18-β-glycyrrhetinic acid, glycyrrhizin, hydroquinone, isoquercetin (EMIQ), kaempferol, black bean anthocyanins, leucine, lithium, luteolin, luteolin, luteolin, melatonin, menadione, 1-methylnicotinamide (MNA), methyl salicylate, myricetin, nicotinamide adenine dinucleotide, niacin (vitamin B 3 ), nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), nicotinic acid adenine dinucleotide (NaAD), nicotinic acid mononucleotide (NaMN), parsley, phenylephrine, pokeweed mitogen, 15-Δ prostaglandin J2, puromycin, quercetin, quinolinic acid, retinoic acid, trichostatin A, troxerutin, rutin, tryptophan, vitamin D3, withaferin A, wortmannin and zinc (including salts thereof); and their derivatives; and any combination thereof; the composition is used to enhance the tolerance of cells to DNA damage, oxidative stress, mitochondrial dysfunction, or to improve DNA repair capacity.

[0016] Therefore, according to another aspect of the present invention, a composition is provided, which comprises an effective amount of one or more components selected from acacetin, ACT1 peptide, α-lipoic acid, alprostadil, anisomycin, apigenin, ascorbic acid, astragalus, berberine, β-lapachone, β-hydroxy-β-methylbutyrate, Bacopa monnieri, catechin, catechol, chamomile, chrysin, coumestrol, curcumin, dinitrophenol, dinoprost, ellagic acid, (-)- Epigallocatechin gallate, green tea extract, fisetin, genistein, ginsenoside RE, glabridin, 18-α-glycyrrhetinic acid, 18-β-glycyrrhetinic acid, glycyrrhizin, hydroquinone, isoquercetin (EMIQ), kaempferol, black bean anthocyanins, leucine, lithium, luteolin, luteolin, luteolin, melatonin, menadione, 1-methylnicotinamide (MNA), methyl salicylate, myricetin, nicotinamide adenine dinucleotide, niacin (vitamin B 3), nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), nicotinic acid adenine dinucleotide (NaAD), nicotinic acid mononucleotide (NaMN), parsley, phenylephrine, pokeweed mitogen, 15-Δ prostaglandin J2, puromycin, quercetin, quinolinic acid, retinoic acid, trichostatin A, troxerutin, rutin, tryptophan, vitamin D3, withaferin A, wortmannin and zinc (including salts thereof); and their derivatives; and any combination thereof; the composition is used to enhance the DNA repair ability of cells.

[0017] According to this aspect of the invention, there is provided a composition as described herein for enhancing the tolerance of cells to DNA damage, oxidative stress, mitochondrial dysfunction or improving DNA repair capacity.

[0018] The amount of active ingredient in the composition according to this aspect of the invention may vary depending on the nature of the active ingredient, the mode of administration, etc. Exemplary amounts of active ingredients that may be present in the composition are from about 1 mg to about 1000 mg per day; or from about 50 mg to about 900 mg; or from about 100 mg to about 800 mg; or from about 150 mg to about 700 mg; or from about 200 mg to about 600 mg; or from about 250 mg to about 500 mg.

[0019] According to another aspect of the present invention, a composition as described herein is provided for enhancing the tolerance of cells, such as skin cells, to DNA damage, oxidative stress, mitochondrial dysfunction or improving DNA repair capacity, comprising topically applying an effective amount of the composition to the skin of an individual.

[0020] According to another aspect of the present invention, there is provided a composition as described herein for reducing, alleviating or improving the effects of aging by enhancing the tolerance of cells, such as skin cells, to DNA damage, oxidative stress, mitochondrial dysfunction, or improving DNA repair capacity.

[0021] According to this aspect of the invention there is provided a composition as described herein for use in reducing, alleviating or ameliorating the effects of aging as described herein.

[0022] The effects of aging can include age-related skin conditions, sun-related skin conditions, pollution-related skin conditions, oxidative stress-related skin conditions, and skin conditions associated with lifestyle choices such as diet, alcohol, and / or smoking. In addition, the compositions of the present invention may be advantageous in alleviating, relieving, or improving skin conditions associated with inflammatory skin diseases and skin conditions associated with autoimmune disease skin diseases. The compositions of the present invention may be advantageous in alleviating, relieving, or improving other age-related conditions such as, but not limited to, increased frailty, loss of elasticity, loss of muscle strength, loss of muscle endurance, fatigue, loss of cognitive acuity, memory loss, and the like. More specifically, the compositions of the present invention may be advantageous in alleviating, relieving, or improving other age-related conditions such as, but not limited to, atherosclerosis and cardiovascular disease, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes, hypertension, and Alzheimer's disease; the incidence of these conditions increases with age.

[0023] Age-related skin conditions that may be alleviated, relieved or improved should include, but should not be limited to, one or more of sagging, wrinkles, skin elasticity, skin aging, skin moisture, trauma, acne, skin darkening, skin lightening, pigmentation, age spots, loss of radiance, puffiness, uneven skin tone, redness, rosacea, loss of barrier function, loss of skin elasticity, laxity, stretch marks, cellulite and dryness.

[0024] Sun-related skin conditions that may be alleviated, relieved or improved include, but should not be limited to, one or more of actinic keratosis, freckles, lentigo or age spots, moles, photosensitivity, polymorphic light eruption, seborrheic keratosis, skin cancers (such as melanoma, squamous cell carcinoma, basal cell carcinoma), solar elastosis or wrinkles, and sunburn.

[0025] Skin conditions associated with inflammatory skin diseases that may be alleviated, relieved or improved include, but should not be limited to, one or more of acne, seborrheic eczema, atopic dermatitis, contact dermatitis, discoid eczema, eczematous drug eruption, erythema multiforme, erythroderma, gravitational / varicose eczema, hand eczema, chronic lichenoid keratosis, lichen luster, lichen planus, lichen simplex, lichen striatum, mycosis fungoides, pityriasis lichenoides, psoriasis, seborrheic dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis and vasculitis.

[0026] Skin conditions associated with autoimmune disease skin disorders that may be alleviated, relieved or improved include, but should not be limited to, one or more of alopecia areata, bullous pemphigoid, dermatomyositis, dystrophic epidermolysis bullosa, eosinophilic fasciitis, pemphigus vulgaris, psoriasis, pyoderma gangrenosum, scleroderma, systemic lupus erythematosus and vitiligo.

[0027] According to another aspect of the present invention, there is provided a composition as described herein for reducing, alleviating or ameliorating the effects of autoimmune diseases by improving the tolerance of cells such as skin cells to DNA damage and / or enhancing the DNA repair capacity of skin cells.

[0028] Such autoimmune diseases and related immune diseases should include but should not be limited to systemic lupus erythematosus (SLE), rheumatoid arthritis, non-glomerular nephropathy, psoriasis, chronic active hepatitis, ulcerative colitis, Crohn's disease, Behcet's disease, chronic glomerulonephritis, chronic thrombocytopenic purpura and autoimmune hemolytic anemia.

[0029] The compositions of the present invention may be administered topically, orally or parenterally; or may comprise controlled-release, sustained-release or extended-release preparations containing appropriately reduced amounts of the desired active ingredients in the form of powders, granules, sterile parenteral solutions or suspensions, oral solutions or suspensions, oil-in-water emulsions, and implants and microencapsulated delivery systems.

[0030] Parenteral administration

[0031] Thus, according to one aspect of the present invention, there is provided a composition as described herein for parenteral administration.

[0032] When the composition of the present invention is administered parenterally, it may be in the form of intramuscular, intravenous, subcutaneous, intraperitoneal, topical or transdermal injection.

[0033] Topical application

[0034] Preferably, the composition of the present invention can be applied topically or transdermally. Therefore, according to this aspect of the present invention, a composition for topical application as described herein is provided. According to another aspect of the present invention, a composition for transdermal application as described herein is provided.

[0035] Suitable formulations for topical or transdermal administration comprise an effective amount of a composition of the invention comprising an active ingredient as defined herein with one or more carriers. Carriers include absorbable pharmaceutically acceptable solvents to assist penetration into the skin of the host.

[0036] Suitable formulations for topical application, e.g., to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels, sprayable formulations, transdermal patches or bandages, e.g., for delivery by aerosols, etc. Such topical delivery systems will be particularly suitable for skin applications, for preventive use in sunscreens, lotions, sprays, etc. Therefore, they are particularly suitable for topical formulations well known in the art, including cosmetic formulations. Such formulations may contain solubilizers, stabilizers, tonicity enhancers, buffers, and preservatives.

[0037] Transdermal devices can be in the form of a bandage comprising a backing member, a reservoir containing a composition of the present invention, optionally with a carrier, optionally a rate controlling barrier for delivering the composition of the present invention to the skin of the host at a controlled and predetermined rate over an extended period of time, and means for securing the device to the skin.

[0038] The composition of the present invention may also include a cosmetically acceptable carrier. The amount of the carrier may be in the range of 1% to 99.9%, preferably 70% to 95%, optimally 80% to 90%. Available carriers include water, emollients, fatty acids, fatty alcohols, thickeners, and combinations thereof. The carrier may be aqueous, anhydrous, or an emulsion. Preferably, the composition is aqueous, especially a water-in-oil or water-in-oil type water and oil emulsion, or a composite emulsion of a water-in-oil-in-water or oil-in-water-in-oil type. When present, the amount of water may be in the range of 5% to 95% by weight, preferably about 20% to about 70% by weight, optimally 35% to 60% by weight.

[0039] Emollient materials can be used as cosmetically acceptable carriers. These emollient materials can be in the form of silicone oils, natural or synthetic esters, hydrocarbons, alcohols and fatty acids. The amount of the emollient can be any value in the range of 0.1% to 95% by weight of the composition, preferably between 1% and 50% by weight.

[0040] Silicone oils can be divided into volatile and non-volatile categories. As used herein, the term "volatile" refers to those materials having a measurable vapor pressure at ambient temperature. Volatile silicone oils are preferably selected from cyclic (cyclomethicone) or linear polydimethylsiloxanes containing 3 to 9, preferably 5 to 6 silicon atoms. Non-volatile silicone oils that can be used as emollient materials include polyalkyl siloxanes, polyalkylaryl siloxanes and polyether siloxane copolymers. Substantially non-volatile polyalkyl siloxanes useful herein include, for example, having a viscosity of 5×10-6 to 0.1 m at 25°C. 2 / s polydimethylsiloxane. Preferred non-volatile emollients that can be used in the composition of the present invention include those having a viscosity of 1×10<-5> to about 4×10<-4> m at 25°C. <2> Another class of nonvolatile silicones are emulsifying and non-emulsifying silicone elastomers. Representatives of this class are dimethicone / vinyl dimethicone crosspolymers available under the trade names Dow Corning 9040, General Electric SFE 839, and Shin-Etsu KSG-18. Silicone waxes such as Silwax WS-L (dimethicone copolyol laurate) may also be useful.

[0041] Esters include:

[0042] a) Alkyl esters of saturated fatty acids having 10 to 24 carbon atoms. Examples thereof include behenyl neopentanoate, isononyl isononanoate, isopropyl myristate and octyl stearate.

[0043] b) Ether esters, such as fatty acid esters of ethoxylated saturated fatty alcohols.

[0044] c) Polyol esters. Ethylene glycol mono- and di-fatty acid esters, ethylene glycol mono- and di-fatty acid esters, polyethylene glycol (200-6000) mono- and di-fatty acid esters, propylene glycol mono- and di-fatty acid esters, polypropylene glycol 2000 monostearate, ethoxylated propylene glycol monostearate, glycerol mono- and di-fatty acid esters, polyglycerol poly-fatty acid esters, ethoxylated glycerol monostearate, 1,3-butylene glycol monostearate, 1,3-butylene glycol distearate, polyoxyethylene polyol fatty acid esters, sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty acid esters are satisfactory polyol esters. Particularly useful are pentaerythritol, trimethylolpropane, and neopentyl glycol esters of C1-C30 alcohols.

[0045] d) Wax esters, such as beeswax, spermaceti and triphein.

[0046] e) Sugar esters of fatty acids, such as sucrose polybehenate and sucrose polycottonseedate.

[0047] Natural ester emollients are mainly based on monoglycerides, diglycerides and triglycerides. Representative glycerides include sunflower seed oil, cottonseed oil, borage oil, borage seed oil, evening primrose oil, castor oil and hydrogenated castor oil, rice bran oil, soybean oil, olive oil, safflower oil, shea butter, jojoba oil and combinations thereof. Animal-derived emollients are represented by lanolin oil and lanolin derivatives. The amount of natural esters can be in the range of 0.1% to 20% by weight of the composition.

[0048] Hydrocarbons which are suitable cosmetically acceptable carriers include petrolatum, mineral oil, C11-C13 isoparaffins, polybutenes, especially isohexadecane which is commercially available from Presperse Inc. under the trade name Permethyl 101A.

[0049] Fatty acids having 10 to 30 carbon atoms may also be suitable as cosmetically acceptable carriers. Examples of this class include pelargonic acid, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid, hydroxystearic acid and behenic acid, and mixtures thereof.

[0050] Fatty alcohols having 10 to 30 carbon atoms are another useful class of cosmetically acceptable carriers. Examples of this class are stearyl alcohol, lauryl alcohol, myristyl alcohol, oleyl alcohol and cetyl alcohol, and mixtures thereof.

[0051] Thickeners or rheology modifiers may be used as part of the cosmetically acceptable carrier of the compositions according to the present invention. Typical thickeners include cross-linked acrylates (e.g. ), hydrophobically modified acrylates (e.g. ), polyacrylamide (e.g. ), acryloyl methyl propane sulfonic acid / salt polymers and copolymers (e.g. and ), cellulose derivatives and natural gums. Useful cellulose derivatives include sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose and hydroxymethyl cellulose. Natural gums suitable for use in the present invention include guar gum, xanthan gum, sclerotium gum, carrageenan, pectin and combinations of these gums. Inorganic substances can also be used as thickeners, particularly clays such as bentonite and hectorite, fumed silica, talc, calcium carbonate and silicates such as magnesium aluminum silicate. The amount of thickener may range from 0.0001% to 10%, typically 0.001% to 1%, or 0.01% to 0.5%.

[0052] Emollients particularly useful in products intended for application to the face to improve sensory properties are selected from polypropylene glycol-14 butyl ether (also known as Tegosoft PBE), or PPG15 stearyl ether (such as Tegosoft E), other oils such as esters, especially isopropyl myristate, isopropyl palmitate, other oils may include castor oil and its derivatives.

[0053] Polyol type humectants can be used as cosmetically acceptable carriers. Typical polyols include glycerol, polyalkylene glycols and more preferably alkylene polyols and derivatives thereof, including propylene glycol, dipropylene glycol, polypropylene glycol, polyethylene glycol and derivatives thereof, sorbitol, hydroxypropyl sorbitol, hexylene glycol, 1,3-butylene glycol, isoprene glycol, 1,2,6-hexanetriol, ethoxylated glycerol, propoxylated glycerol and mixtures thereof. The amount of the humectant can be any value in the range of 0.5% to 50% by weight of the composition, preferably between 1% and 15% by weight.

[0054] Skin moisturizers such as hyaluronic acid and / or its precursor N-acetylglucosamine may be included. N-acetylglucosamine may be found in shark cartilage or shiitake mushrooms and is commercially available from Maypro Industries, Inc., New York. Other moisturizers include hydroxypropyl tri(C1-C3 alkyl)ammonium salts. These salts can be obtained by a variety of synthetic methods, most particularly by hydrolysis of chlorohydroxypropyl tri(C1-C3 alkyl)ammonium salts. The specific substance is 1,2-dihydroxypropyl trimethylammonium chloride, in which the C1-C3 alkyl is a methyl group. The amount of the salt may be in the range of 0.2% to 30% by weight of the topical composition, preferably 0.5% to 20% by weight, and optimally 1% to 12% by weight, including all ranges contained therein.

[0055] Typically, the C1-C3 alkyl component on the quaternary ammonium group will be methyl, ethyl, n-propyl, isopropyl or hydroxyethyl, and mixtures thereof. Particularly preferred is the trimethylammonium group designated by the INCI nomenclature as the "trimethylammonium" group. Any anion may be used in the quaternary ammonium salt. The anion may be organic or inorganic, provided that the material is cosmetically acceptable. Typical inorganic anions are halides, sulfate, phosphate, nitrate and borate. Most preferred are halides, especially chloride. Organic anionic counterions include methylsulfate, toluoylsulfate, acetate, citrate, tartrate, lactate, gluconate and benzenesulfonate.

[0056] Other humectants that can be used in combination with the above ammonium salts include substituted ureas such as hydroxymethyl urea, hydroxyethyl urea, hydroxypropyl urea; bis-(hydroxymethyl) urea; bis(hydroxyethyl) urea; bis(hydroxypropyl) urea; N,N'-dimethylol urea; N,N'-dihydroxyethyl urea; N,N'-dihydroxypropyl urea; N,N,N'-trihydroxyethyl urea; tetra(hydroxymethyl) urea; tetra(hydroxyethyl) urea; tetra(hydroxypropyl) urea; N-methyl-N'-hydroxyethyl urea; N-ethyl-N'-hydroxyethyl urea; N-hydroxypropyl-N'-hydroxyethyl urea and N,N'-dimethyl-N-hydroxyethyl urea. Where the term hydroxypropyl occurs, this meaning is common to 3-hydroxy-n-propyl, 2-hydroxy-n-propyl, 3-hydroxy-isopropyl or 2-hydroxy-isopropyl groups. Most preferred is hydroxyethyl urea. The latter is available as a 50% aqueous liquid. The amount of substituted urea useful in the topical compositions of the present invention ranges from 0.01% to 20%, or from 0.5% to 15%, or from 2% to 10%.

[0057] When ammonium salts and substituted ureas are used, in the most particularly preferred embodiments, at least 0.01% to 25%, or 0.2% to 20%, or 1% to 15% of a humectant, such as glycerol, is used. Other humectants useful herein include petrolatum and / or various aquaporin-manipulating actives and / or oat kernel flour.

[0058] In one embodiment, the pH of the topical composition is between 3.5 and 8.5. In some embodiments, the pH of the topical composition is between pH 3.5 and pH 8. In some embodiments, the pH of the topical composition is between pH 5 and pH 7.8. In some embodiments, the pH of the topical composition is between 5 and 7.5.

[0059] In some embodiments, the topical compositions of the present invention include sunscreens. These are typically a combination of organic and inorganic sunscreens. It is particularly desirable to include both UV-A and UV-B radiation sunscreens.

[0060] The UV-B sunscreen may be selected from cinnamic acid, salicylic acid, diphenyl acrylic acid or their derivatives. The UV-B sunscreen may contain one or more of octyl salicylate, 3,3,5-trimethylcyclohexyl 2-hydroxybenzoate, ethylhexyl salicylate, 2-ethylhexyl 2-cyano-3,3-diphenyl-2-acrylate or 2-ethylhexyl 4-methoxycinnamate (also known as octyl methoxycinnamate or "OMC"). Such UV-B sunscreens are generally commercially available, such as Octisalate TM (Ethyl Salicylate), Homosalate TM (2-Hydroxybenzoic acid 3,3,5-trimethylcyclohexyl ester), NeoHeliopan TM (A range of organic UV filters, including OMC (Neo Heliopan AV TM ) and ethylhexyl salicylate (Neo Heliopan OS TM ))、Octocrylene TM and Milestab3039 TM (2-ethylhexyl 2-cyano-3,3-diphenyl-2-propenoate) or Parsol MCX™ (2-ethylhexyl 4-methoxycinnamate). The amount of UV-B sunscreen in the topical composition may be 0.1 wt % to 20 wt %, or 0.2 wt % to 10 wt %, or 0.5 wt % to 7 wt %, or 2 wt % to 6 wt %.

[0061] The topical composition may also include a water-soluble UV-B sunscreen. The water-soluble UV-B sunscreen may also include phenylbenzimidazole sulfonic acid (also known as ensolazole), 4-aminobenzoic acid (also known as p-aminobenzoic acid or "PABA"), or both.

[0062] The topical composition of any of the above embodiments may further comprise 0.1% to 10% by weight of a UV-A sunscreen. The UV-A sunscreen may comprise 4-tert-butyl-4'-methoxydibenzoylmethane ("avobenzone"), 2-methyldibenzoylmethane, 4-methyl-dibenzoyl-ethane, 4-isopropyldibenzoyl-methane, 4-tert-butyldibenzoylmethane, 2,4-dimethyldibenzoylmethane, 2,5-dimethyldibenzoylmethane, 4,4'-diisopropyldibenzoylmethane, One or more of 2-methyl-5-isopropyl-4'-methoxy-dibenzoylmethane, 2-methyl-5-tert-butyl-4'-methoxy-dibenzoylmethane, 2,4-dimethyl-4'-methoxy-dibenzoylmethane, 2,6-dimethyl-4-tert-butyl-4'methoxy-dibenzoylmethane, diethylaminohydroxybenzoyl hexyl benzoate, ecamsul or methyl anthranilate. The amount of UV-A sunscreen in the topical composition may be 0.5 wt % to 7 wt %, or 1 wt % to 5 wt %.

[0063] Other suitable sunscreens for use in the topical composition include those commercially available from BASF: Uvinul T-150 (ethylhexyl triazone; UV-B sunscreen), Uvinul A Plus (diethylamino hydroxybenzoyl hexyl benzoate; UV-A sunscreen), Tinosorb S (bis-ethylhexyloxyphenol methoxyphenyl triazine; UV-A and UV-B sunscreen), Tinosorb M (methylene bisbenzotriazolyl tetramethylbutylphenol; UV-A and UV-B sunscreen). Bisdisulizone disodium may also be included in the topical composition.

[0064] A specific combination of a UV-A sunscreen and a UV-B sunscreen is avobenzone and 2-ethylhexyl 4-methoxycinnamate.

[0065] In some embodiments, the sunscreen is an inorganic sunscreen. Examples of inorganic sunscreens suitable for use in the skin care compositions of the present invention include, but are not limited to, ultrafine titanium dioxide, zinc oxide, polyethylene, and various other polymers. By the term "ultrafine" is meant particles having an average particle size in the range of 10 nm to 200 nm, or 20 nm to 100 nm. When present in a skin care formulation according to some embodiments of the present invention, the amount of sunscreen may be in the range of 0.1% to 30%, or 2% to 20%, or 4% to 10%.

[0066] In addition to the niacinamide included herein, the compositions of the present invention may also include skin lightening compounds to obtain optimal skin lightening performance at optimal cost. Exemplary substances are placental extracts, lactic acid, resorcinol (4-substituted, 2,5-disubstituted, 4,5-disubstituted and 4,6-disubstituted, especially 4-hexyl, 4-methyl, 4-butyl, 4-isopropyl, phenethyl resorcinol), arbutin, kojic acid, ferulic acid, hydroquinone, resorcinol derivatives (including disubstituted resorcinols) and combinations thereof. In one embodiment, such skin lightening compounds are tyrosinase inhibitors, most preferably compounds selected from the group consisting of kojic acid, hydroquinone and 4-substituted resorcinols. In addition, dicarboxylic acids represented by the formula HOOC-(CxHy)-COOH, wherein x=4 to 20 and y=6 to 40, such as azelaic acid, sebacic acid, oxalic acid, succinic acid, fumaric acid, octadecenedioic acid (e.g. Arlatone DC) or their salts or mixtures thereof, most preferably fumaric acid or its salts, especially the disodium salt. It has been found that the combination of 12HSA and fumaric acid or its salts is particularly preferred, especially for skin lightening preparations. The amount of these agents may range from 0.1% to 10% by weight, preferably from 0.5% to 2% by weight of the composition. Preferably, the skin lightening co-active agent according to the present invention is 4-alkylresorcinol and / or 12-hydroxystearic acid.

[0067] Another preferred ingredient of the compositions of the present invention is a retinoid. As used herein, "retinoid" includes all natural and / or synthetic analogs of vitamin A or retinoid compounds that have the biological activity of vitamin A in the skin, as well as geometric isomers and stereoisomers of these compounds. The retinoid is preferably retinol, a retinol ester (e.g., a C2-C22 alkyl ester of retinol, including retinyl palmitate, retinyl acetate, retinyl propionate), retinal and / or retinoic acid (including all-trans retinoic acid and / or 13-cis-retinoic acid), more preferably a retinoid other than retinoic acid. These compounds are well known in the art and can be commercially obtained from many sources, such as Sigma Chemical Company (St. Louis, Mo.) and Boerhinger Mannheim (Indianapolis, Ind.). Other retinoids useful herein are described in U.S. Pat. No. 4,677,120, U.S. Pat. No. 4,885,311, U.S. Pat. No. 5,049,584, U.S. Pat. No. 5,124,356. Other suitable retinoids are tocopheryl retinoate (tocopheryl ester of retinoic acid (trans or cis), adapalene {6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid} and tazarotene (6-[2-(4,4-dimethylthiochroman-6-yl)-ethynyl]nicotinate ethyl ester). Preferred retinoid vitamins are retinol, retinyl palmitate, retinyl acetate, retinyl propionate, retinal and combinations thereof. Retinoids are preferably substantially pure, more preferably essentially pure. The compositions of the present invention may include a safe and effective amount of retinoids such that the resulting composition is useful for regulating keratinous tissue condition, optimizing Preferably, the composition is safe and effective for regulating visible and / or tactile discontinuities of the skin, more preferably for regulating symptoms of skin aging, and even more preferably for regulating visible and / or tactile discontinuities of skin texture associated with skin aging. The composition preferably comprises 0.005% to 2%, or 0.01% to 2% of retinoids. Retinol is preferably used in an amount of 0.01% to 0.15%; retinol esters are preferably used in an amount of 0.01% to 2% (e.g., 1%); retinoic acid is preferably used in an amount of 0.01% to 0.25%; tocopheryl retinoate, adapalene and tazarotene are preferably used in an amount of 0.01% to 2%.

[0068] Various herbal extracts may optionally be included in the compositions of the present invention. Exemplary herbal extracts are pomegranate, Betula Alba, green tea, chamomile, licorice, and combinations of extracts thereof. The extracts may be water-soluble or water-insoluble materials carried in hydrophilic or hydrophobic solvents, respectively. Water and ethanol are preferred extraction solvents.

[0069] The topical composition may also include from about 0.1% to about 8% by weight of a film-forming polymer. Such film-forming polymers include, but are not limited to, polyalkyleneoxy-terminated polyamides (e.g., INCI names: polyamide-3, polyamide-4), polyether polyamides (e.g., INCI name: polyamide-6), mixed acid-terminated polyamides (e.g., INCI name: polyamide-7), and ester-terminated poly(esteramides) (e.g., INCI name: polyamide-8). Such film-forming polymers may be synthetic or commercially available, such as Sylvaclear® from Arizona Chemical Company, LLC. TM OleoCraft series products and Croda International PLC TM Series of products. Film-forming polymers also include, but are not limited to, INCI-named polyester-5 (e.g., Eastman AQ TM 38S polymer), PPG-17 / IPDI / DMPA copolymer (e.g., Avalure TM UR 450 polymer), acrylate copolymers (e.g., Avalure TM AC 120 polymer) and polysaccharides such as Xilogel (tamarind gum), locust bean gum, tara gum, beta-glucan, pullulan, carboxymethylcellulose, hydroxypropylcellulose, sodium alginate, potato starch, carrageenan. The film-forming polymer may comprise a combination of any two or more of the polymers listed above. The amount of film-forming polymer in the topical composition may be from 0.1 wt % to 8 wt %.

[0070] Preservatives may be ideally incorporated into the compositions of the present invention to prevent the growth of potentially harmful microorganisms. Conventional preservatives suitable for use in the compositions of the present invention are alkyl esters of parahydroxybenzoic acid. Other preservatives that have recently come into use include hydantoin derivatives, propionates, and various quaternary ammonium compounds. Cosmetic chemists are familiar with appropriate preservatives and routinely select them to meet preservative challenge tests and provide product stability. Particular preservatives are iodopropynyl butylcarbamate, phenoxyethanol, caprylyl glycol, C1-6 parabens (especially methylparaben and / or propylparaben), imidazolidinyl urea, sodium dehydroacetate, and benzyl alcohol. The selection of preservatives should take into account the use of the composition and possible incompatibility between the preservative and other ingredients in the emulsion. Preservatives may be used in an amount ranging from 0.01% to 2%. A particular combination is octylene and caprylyl glycol, as caprylyl glycol has been disclosed to enhance UVA and UVB protection.

[0071] Antifungal agents suitable for inclusion in topical compositions are well known to those skilled in the art. Examples include, but are not limited to, climbazole, ketoconazole, fluconazole, clotrimazole, miconazole, econazole, ethiconazole, terbinafine, salts (e.g., hydrochlorides) of any one or more of these, zinc pyrithione, selenium disulfide, and combinations of two or more thereof.

[0072] In some embodiments, topical compositions of the present invention include vitamins. Exemplary vitamins are vitamin A (retinol), vitamin B2, vitamin B3 (niacin), vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, and biotin. Derivatives of vitamins may also be used. For example, vitamin C derivatives include ascorbyl tetraisopalmitate, magnesium ascorbyl phosphate, and ascorbyl glycoside. Derivatives of vitamin E include tocopheryl acetate, tocopheryl palmitate, and tocopheryl linoleate. DL-panthenol and its derivatives may also be used. In some embodiments, the vitamin B3 derivative is nicotinamide riboside. In some embodiments, the vitamin B6 derivative is pyridoxine palmitate. Flavonoids may also be available, particularly glucosyl hesperidin, rutin, and soy isoflavones (including genistein, daidzein, equol, and their glucosyl derivatives) and mixtures thereof. When present, the total amount of vitamins or flavonoids may range from 0.0001% to 10%, or 0.001% to 10%, or 0.01% to 10%, or 0.1% to 10%, or 1% to 10%, or 0.01% to 1%, or 0.1% to 0.5%.

[0073] In some embodiments, the topical compositions of the present invention comprise enzymes such as oxidases, proteases, lipases, and combinations thereof. In some embodiments, the topical compositions of the present invention comprise superoxide dismutase commercially available from Brooks Company, USA as Biocell SOho aD.

[0074] In some embodiments, the topical compositions of the present invention comprise a desquamation promoting agent. In some embodiments, the topical compositions of the present invention comprise a desquamation promoting agent at a concentration of 0.01% to 15%, or 0.05% to 15%, or 0.1% to 15%, or 0.5% to 15%.

[0075] Exemplary desquamation promoters include monocarboxylic acids. The monocarboxylic acids may be substituted or unsubstituted, and the carbon chain length is a maximum of 16. In some embodiments, the carboxylic acid is an alpha-hydroxycarboxylic acid, a beta-hydroxycarboxylic acid, or a polyhydroxycarboxylic acid. The term "acid" is meant to include not only free acids, but also salts thereof and C1-C30 alkyl esters or aryl esters, and lactones generated by removing water to form a cyclic or linear lactone structure. Representative acids include glycolic acid, lactic acid, malic acid, and tartaric acid. In some embodiments, the salt is ammonium lactate. In some embodiments, the beta-hydroxycarboxylic acid is salicylic acid. In some embodiments, phenolic acids include ferulic acid, salicylic acid, kojic acid, and salts thereof.

[0076] In some embodiments, at least one additional component can be present at 0.000001% to 10% by weight, or 0.00001% to 10% by weight, or 0.0001% to 10% by weight, or 0.001% to 10% by weight, or 0.01% to 10% by weight, or 0.1% to 10% by weight, or 0.0001% to 1% by weight of the composition. Colorants, sunscreens, or abrasives may also be included in the composition of the present invention. Colorants, sunscreens, or abrasives can be included at a concentration of 0.05% to 5% by weight, or between 0.1% and 3% by weight of the composition.

[0077] In some embodiments, the personal care products of the present invention may also include peptides, such as the pentapeptide derivative Matrixyl 1-hydroxy- ... TM As another example, in some embodiments, the personal care products of the present invention may further comprise carnosine.

[0078] The compositions of the present invention may include a variety of other optional components. The CTFA Cosmetic Ingredient Handbook (Second Edition, 1992) describes various non-limiting cosmetic and pharmaceutical ingredients commonly used in the topical cosmetic skin care industry that are suitable for use in the compositions of the present invention, and the entire content of the document is incorporated herein by reference. Examples include: antioxidants, binders, biological additives, buffers, colorants, thickeners, polymers, astringents, fragrances, humectants, sunscreens, conditioners, exfoliants, pH adjusters, preservatives, natural extracts, essential oils, skin sensates, skin soothing agents, and skin healing agents.

[0079] The topical composition of the present invention is preferably non-solid. The composition of the present invention is preferably a leave-on composition. The composition of the present invention is preferably a leave-on composition to be applied to remain on the skin. These leave-on compositions are distinguished from compositions that are applied to the skin and then removed by washing, rinsing, wiping, etc. after or during product application. Surfactants commonly used in rinse-off compositions have physicochemical properties that enable them to produce foam / soap bubbles that are easy to rinse off when used; they can be composed of a mixture of anionic, cationic, amphoteric and nonionic. On the other hand, the surfactants used in leave-on compositions do not need to have such properties. On the contrary, since leave-on compositions are not intended to be rinsed off, they need to be non-irritating, so it is necessary to minimize the total content of surfactants and the total content of anionic surfactants in the leave-on composition. The total content of surfactants in the composition of the present invention is preferably 1% to no more than 10%, more preferably less than 8%, most preferably at most 5%, and optimally at most 3%.

[0080] In some embodiments, anionic surfactants are present in the leave-on skin care composition in an amount of from 0.01% to up to 5% by weight of the composition, or from 0.01% to 4% by weight of the composition, or from 0.01% to 3% by weight of the composition, or from 0.01% to 2% by weight of the composition, or are substantially absent (less than 1%, or less than 0.1%, or less than 0.01%). In some embodiments, the total amount of surfactants in the skin care composition does not exceed 10%, or is less than 8%, or is at most 5%.

[0081] In some embodiments, the surfactant is selected from the group consisting of anionic, nonionic, cationic, and amphoteric actives.

[0082] In some embodiments, nonionic surfactants are those having the following: C10-C20 fatty alcohols or acid hydrophobes, condensed with 2 to 100 moles of ethylene oxide or propylene oxide per mole of hydrophobe; C2-C10 alkylphenols condensed with 2 to 20 moles of alkylene oxide; mono- and di-fatty acid esters of ethylene glycol; fatty acid monoglycerides; sorbitan mono- and di-C8-C20 fatty acids; and polyoxyethylene sorbitan, and combinations thereof. In some embodiments, nonionic surfactants are selected from the group consisting of alkyl polyglycosides, sugar fatty acid amides (e.g., methyl glucamide) and trialkylamine oxides.

[0083] According to some embodiments of the present invention, amphoteric surfactants suitable for use in the skin care composition include cocamidopropyl betaine, C12-C20 trialkyl betaine, sodium lauroamphoacetate, and sodium lauroyl diamphoacetate.

[0084] According to some embodiments of the present invention, anionic surfactants suitable for use in the skin care composition include soaps, alkyl ether sulfates and sulfonates, alkyl sulfates and sulfonates, alkyl benzene sulfonates, alkyl sulfosuccinates and dialkyl sulfosuccinates, C8-C20 acyl isethionates, C8-C20 alkyl ether phosphates, C8-C20 sarcosinates, C8-C20 acyl lactylates, sulfoacetates, and combinations thereof.

[0085] The composition of the present invention is generally in the form of an oil-in-water or water-in-oil emulsion. In some embodiments, the topical composition is a vanishing cream and an ointment or lotion based on an oil-in-water emulsion. The vanishing cream base is a base comprising 5% to 40% fatty acids and 0.1% to 20% soap. In this emulsion, the fatty acid is preferably essentially a mixture of stearic acid and palmitic acid, and the soap is preferably a potassium salt of a fatty acid mixture, but other counterions and mixtures thereof may also be used. The fatty acid in the vanishing cream base is generally prepared using hysteric acid, which is essentially (usually about 90% to 95%) a mixture of stearic acid and palmitic acid. In a total palmitic acid-stearic acid mixture, a typical hysteric acid comprises about 52% to 55% palmitic acid and 45% to 48% stearic acid. Therefore, it is within the scope of the present invention to include hysteric acid and its soap to prepare a vanishing cream base. It is particularly preferred that the composition comprises more than 7%, preferably more than 10%, more preferably more than 12% fatty acid.A typical vanishing cream base consists of a crystalline network and is sensitive to the addition of various ingredients.

[0086] In one embodiment, the topical composition is formulated as a water-in-oil emulsion in which the cystine is substantially dissolved in the aqueous phase. In one embodiment, the topical composition is formulated as a water-in-oil emulsion with cystine in aqueous droplets, wherein at least 90% of the droplets have a diameter in the range of 100 nm to 20 microns, or in the alternative 200 nm to 20 microns or to 10 microns.

[0087] In some embodiments, the topical composition is formulated as a facial mask. In some embodiments, the topical composition is formulated as a facial mask according to the formulation described in U.S. Patent No. 5,139,771. In some embodiments, the topical composition is formulated as a facial mask according to the formulation described in U.S. Patent No. 4,933,177. In some embodiments, the topical composition is formulated as a facial mask according to the formulation described in U.S. Patent No. 6,001,367.

[0088] Oral administration

[0089] Thus, according to one aspect of the present invention, there is provided a composition for oral administration as described herein.

[0090] When the composition of the present invention is administered orally, it may be in the form of a tablet or a capsule.

[0091] The composition of the present invention can be prepared in solid form, including capsules, tablets, pills, granules, powders, block foods or confectionery; or in liquid form, including solutions, suspensions or emulsions, or in the form of syrups, sweet syrups, elixirs, liquid beverages (such as yogurt beverages) or foods (such as yogurt).

[0092] The composition may be subjected to conventional operations, such as sterilization, and / or may contain conventional inert diluents, lubricants or buffers, and adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers and the like.

[0093] Typically, when the composition is in the form of a tablet or capsule, such as a gelatin capsule, the composition may contain one or more active ingredients;

[0094] as well as

[0095] a) diluents, such as lactose, glucose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0096] b) lubricants, for example silicon dioxide, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; (also used for tablets);

[0097] c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone (if necessary);

[0098] d) disintegrants, for example starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or

[0099] e) absorbents, colorants, flavorings and sweeteners.

[0100] Tablets may be film coated or enteric coated according to methods known in the art.

[0101] Suitable compositions for oral administration include an effective amount of the active ingredients described herein in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, bar foods, confectioneries, solutions, emulsions, hard or soft capsules, syrups, syrups, elixirs, liquid beverages or foods.

[0102] Compositions intended for oral use may be prepared according to any method known in the art for making effective compositions; and such compositions may contain one or more additional agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives to provide aesthetically pleasing and palatable preparations.

[0103] Tablets contain a composition comprising the active ingredients described herein mixed with non-toxic, orally acceptable excipients suitable for making tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used.

[0104] Preparations for oral use can be in the form of hard gelatin capsules, in which the composition containing the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin; or in the form of soft gelatin capsules, in which the composition containing the active ingredient is mixed with water or an oil medium (such as peanut oil, liquid paraffin or olive oil).

[0105] Soft capsules can be prepared using techniques well known in the art. For example, soft capsules are typically prepared using a rotary die encapsulation process. The active agent preparation is gravity fed into an encapsulation machine. In one embodiment, the preparation comprises a pharmaceutical excipient such as olive oil, gelatin, glycerin, purified water, yellow beeswax, sunflower lecithin, silicon dioxide, titanium dioxide, FD&C blue 1 and FD&C red 4, microcrystalline cellulose, hypromellose, vegetable magnesium stearate and / or silicon dioxide.

[0106] The capsule shell may comprise one or more plasticizers such as glycerol, sorbitol, sorbitan, maltitol, glycerol, polyethylene glycol, polyols having 3 to 6 carbon atoms, citric acid, citric acid esters, triethyl citrate, and combinations thereof. In one embodiment, the plasticizer is glycerol.

[0107] In addition to plasticizers, the capsule shell may contain other suitable shell additives such as opacifiers, colorants, wetting agents, preservatives, flavoring agents and buffer salts and acids.

[0108] When the encapsulated active agent is light sensitive, an opacifier is used to make the capsule shell opaque. Suitable opacifiers include, but are not limited to, titanium dioxide, zinc oxide, calcium carbonate, and combinations thereof. In one embodiment, the opacifier is titanium dioxide.

[0109] Colorants can be used for marketing and product identification and / or differentiation purposes. Suitable colorants include synthetic and natural dyes and combinations thereof.

[0110] Wetting agent can be used to suppress the water activity of soft gel. Suitable wetting agent includes glycerine and sorbitol, which are usually components of plasticizer composition. Because the water activity of dry and properly stored soft capsule is low, the greatest microbial risk comes from mold and yeast. For this reason, preservative can be incorporated into the capsule shell. Suitable preservative includes alkyl esters of p-hydroxybenzoic acid such as methylparaben, ethylparaben, propylparaben, butylparaben and heptylparaben (collectively referred to as "parabens") or their combination.

[0111] According to another aspect of the present invention, a method for improving cell tolerance to DNA damage is provided, the method comprising administering an effective amount of a composition comprising an effective amount of one or more components selected from the group consisting of acacetin, ACT1 peptide, α-lipoic acid, alprostadil, anisomycin, apigenin, ascorbic acid, astragalus, berberine, β-lapachone, β-hydroxy-β-methylbutyrate, Bacopa monnieri, catechins, catechols, chamomile, chrysin, coumestrol, curcumin, dinitrophenol, dimethoate, and dapoxetine. Noprostil, ellagic acid, (-)-epigallocatechin gallate, green tea extract, fisetin, genistein, ginsenoside RE, glabridin, 18-α-glycyrrhetinic acid, 18-β-glycyrrhetinic acid, glycyrrhizin, hydroquinone, isoquercetin (EMIQ), kaempferol, black bean anthocyanins, leucine, lithium, luteolin, luteolin, luteolin, melatonin, menadione, 1-methylnicotinamide (MNA), methyl salicylate, myricetin, nicotinamide adenine dinucleotide, niacin (vitamin B 3 ), nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), nicotinic acid adenine dinucleotide (NaAD), nicotinic acid mononucleotide (NaMN), parsley, phenylephrine, pokeweed mitogen, 15-Δ prostaglandin J2, puromycin, quercetin, quinolinic acid, retinoic acid, trichostatin A, troxerutin, rutin, tryptophan, vitamin D3, withaferin A, wortmannin and zinc (including salts thereof); and derivatives thereof; and any combination thereof.

[0112] According to another aspect of the present invention, a method for improving the DNA repair ability of cells is provided, the method comprising administering an effective amount of a composition comprising an effective amount of one or more components selected from acacetin, ACT1 peptide, α-lipoic acid, alprostadil, anisomycin, apigenin, ascorbic acid, astragalus, berberine, β-lapachone, β-hydroxy-β-methylbutyrate, Bacopa monnieri, catechin, catechol, chamomile, chrysin, coumestrol, curcumin, dinitrophenol, dinoflagellate, dapoxetine ... Prostaglandins, ellagic acid, (-)-epigallocatechin gallate, green tea extract, fisetin, genistein, ginsenoside RE, glabridin, 18-α-glycyrrhetinic acid, 18-β-glycyrrhetinic acid, glycyrrhizin, hydroquinone, isoquercetin (EMIQ), kaempferol, black bean anthocyanins, leucine, lithium, luteolin, luteolin, luteolin, melatonin, menadione, 1-methylnicotinamide (MNA), methyl salicylate, myricetin, nicotinamide adenine dinucleotide, niacin (vitamin B 3 ), nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), nicotinic acid adenine dinucleotide (NaAD), nicotinic acid mononucleotide (NaMN), parsley, phenylephrine, pokeweed mitogen, 15-Δ prostaglandin J2, puromycin, quercetin, quinolinic acid, retinoic acid, trichostatin A, troxerutin, rutin, tryptophan, vitamin D3, withaferin A, wortmannin and zinc (including salts thereof); and derivatives thereof; and any combination thereof.

[0113] According to this aspect of the invention, there is provided a method of enhancing the tolerance of cells to DNA damage, oxidative stress, mitochondrial dysfunction or improving DNA repair capacity as described herein.

[0114] The amount of active ingredient administered in the method according to this aspect of the invention may vary depending on the nature of the active ingredient, the mode of administration, etc. Exemplary amounts of active ingredients that may be administered in the method are from about 1 mg to about 1000 mg; or from about 50 mg to about 900 mg; or from about 100 mg to about 800 mg; or from about 150 mg to about 700 mg; or from about 200 mg to about 600 mg; or from about 250 mg to about 500 mg. The foregoing dosages may be administered once a day, twice a day, or up to three or four times a day.

[0115] According to another aspect of the present invention, there is provided a method as described herein, the method comprising reducing, alleviating or ameliorating the effects of aging in a host.

[0116] According to this aspect of the invention, there is provided a method for alleviating, alleviating or ameliorating the effects of aging in a host by improving the tolerance of cells to DNA damage and / or enhancing the DNA repair capacity of cells.

[0117] The method according to this aspect of the invention may include alleviating, relieving or improving skin conditions associated with age, skin conditions associated with sun exposure, skin conditions associated with pollution exposure, skin conditions associated with oxidative stress, and skin conditions associated with lifestyle choices such as diet, alcohol and / or smoking. In addition, the method of the invention may be advantageous in alleviating, relieving or improving skin conditions associated with inflammatory skin diseases and skin conditions associated with autoimmune disease skin diseases by improving the tolerance of cells to DNA damage and / or enhancing the DNA repair capacity of cells.

[0118] Specifically, according to this aspect of the invention, there is provided a method for improving the tolerance of skin cells to DNA damage and / or enhancing the DNA repair capacity of skin cells, the method comprising topically applying an effective amount of the composition described herein to the skin.

[0119] The selection of a specific effective dose can be determined by a person skilled in the art based on consideration of several factors known to those skilled in the art (e.g., via clinical trials), such as the skin disease to be alleviated, relieved or improved; the nature and severity of the skin disease to be treated, the weight of the host; etc. The exact dose employed to alleviate, relieve or improve the skin disease may also depend on the route of administration. The effective dose can be inferred from a dose-response curve derived from an in vitro or animal model test system.

[0120] However, in general, satisfactory results are obtained with the compositions of the invention at a daily dosage of from about 0.1 mg / kg body weight to about 500 mg / kg body weight, or from about 1 mg / kg to about 400 mg / kg, or from about 1 mg / kg to about 300 mg / kg, or from about 1 mg / kg to about 200 mg / kg, or from about 1 mg / kg to about 100 mg / kg, or from about 10 mg / kg to about 50 mg / kg, for example, in divided doses up to three or four times a day (e.g., twice a day) or in sustained release form.

[0121] It is generally feasible to administer a daily dose of the composition of the invention at multiple hours of the day. The amount of the active composition administered may depend on factors such as the solubility of the active composition, the formulation used, the subject's condition (such as body weight) and / or the route of administration. BRIEF DESCRIPTION OF THE DRAWINGS

[0122] The present invention will now be described by way of example only and with reference to the accompanying drawings, in which:

[0123] Figure 1 Enhancement of SIRT1 expression in human PBMCs from blood samples in a clinical trial over 16 days of exposure to the combined conditions is shown.

[0124] Figure 2 HDF results showing protection against oxidative stress; and

[0125] FIG. 3( a ) and FIG. 3( b ) show the HDF results for protection against mitochondrial stress. DETAILED DESCRIPTION

[0126] DNA damage is measured using the "alkaline DNA unwinding fluorescence analysis (FADU)" method [Birnboim HC, Jevcak JJ. Cancer Res (Cancer Research) (1981) 41: 1889-1892]. This is a sensitive method for quantifying DNA chain breaks, which is based on partial denaturation ("unwinding") of double-stranded DNA under controlled alkaline conditions. In short, after DNA damage is caused by irradiation, cell lysis is performed. Then controlled unwinding of DNA is performed under controlled pH and temperature conditions. The DNA chain breaks are sites that are easy to unwind, so more DNA damage will lead to more DNA unwinding. In order to terminate the unwinding, a neutralizing solution is added. In order to quantify the amount of double-stranded DNA retained after alkaline incubation, a fluorescent probe is added that specifically binds to double-stranded DNA. Low fluorescence intensity indicates that a large number of DNA chain breaks are present during lysis. DNA repair is measured by allowing the cells to recover after irradiation (1 hour) and then measuring the fluorescence intensity.

[0127] Human skin fibroblasts were treated with a composition comprising a combination of nicotinamide, quercetin, zinc citrate, ascorbic acid, apigenin and alpha-lipoic acid for 24 hours prior to FADU analysis, and then DNA damage and repair levels were measured and compared to values ​​for untreated (control) cells. The results are as follows:

[0128]

[0129] For each condition, values ​​are the mean of at least 3 replicates (and coefficient of variation expressed in %).

[0130] The results are expressed in % and are shown as:

[0131] DNA damage (%) = fluorescence signal intensity lost after 5Gy irradiation

[0132] DNA repair (%) = % of damage recovered after 1 h repair at 37°C

[0133] The results showed that there was no loss in fluorescence intensity in cells treated with our composition compared to a 28% loss in control cells, indicating that our composition can protect cells from DNA damage.

[0134] Example 1

[0135] SIRT1 expression

[0136] The changes in SIRT1 expression of PBMC (peripheral blood mononuclear cells) of clinical participants were analyzed using Western blot analysis. SIRT1 expression increased significantly within 16 days of exposure to our composition. The increase in SIRT1 expression indicates that our composition activates beneficial downstream pathways associated with enhanced DNA repair.

[0137] See also Figure 1 .

[0138] Clinical Outcomes: Proteomics

[0139] Mass spectrometry was used to determine how the levels of proteins associated with aging change as a function of composition.

[0140] Mitochondrial proteins detected in increased abundance in the volunteers' samples included:

[0141] Fumarate Hydratase: Catalyzes the hydration of fumarate to L-malate in the tricarboxylic acid (TCA) cycle to facilitate the transition step in energy production in the form of NADH.

[0142] Aspartate aminotransferase: catalyzes the transamination reaction of L-tryptophan metabolite L-kynurenine to form kynurenic acid (KA) as part of the de novo pathway for NAD synthesis

[0143] VDAC2: a mitochondrial membrane channel

[0144] Complex IV subunits: Specifically, COX5A has been shown to decrease in the skin with age, resulting in reduced mitochondrial function

[0145] Complex V subunits: have also been found to decrease with age, leading to mitochondrial dysfunction.

[0146] Proteasome proteins detected in increased abundance in the volunteer samples included:

[0147] 19S and 20S proteasome subunits: These subunits complex together to form the 26S proteasome, which degrades damaged and unfolded proteins that are known to accumulate with age.

[0148] The proteasome is also important in mitochondrial biogenesis. This is because many mitochondrial proteins are synthesized in the cytoplasm and then need to be transported across the mitochondrial membrane (unfolded). The proteasome ensures that all damaged proteins are cleared during this process. The 20S subunit is specifically involved in the degradation of mitochondrial unfolded precursor proteins prior to mitochondrial import, suggesting that our composition increases mitochondrial biogenesis.

[0149] Telomere-associated proteins detected in increased abundance in the volunteers' samples included:

[0150] RIF1: The telomere-associated protein RIF-1 has been shown to be involved in the maintenance of telomere length and the coordinated repair of telomeric DNA damage.

[0151] We tested combined interventions in human dermal fibroblasts (HDFs) against multiple cellular stressors.

[0152] Example 2

[0153] HDF Results: Protection against Oxidative Stress

[0154] Pretreatment with NAM or combination

[0155] Subsequent exposure to oxidative stress (tbh7ox)

[0156] Measuring cell viability to assess protection against oxidative stress

[0157] Our combination provides better protection than niacinamide

[0158] This combination is required to produce this enhanced protective effect, as predicted by systems pharmacology

[0159] The composition is alpha lipoic acid, apigenin, ascorbic acid, zinc citrate, niacinamide and quercetin.

[0160] The results are shown in Figure 2 middle.

[0161] Example 3

[0162] HDF results: protection against mitochondrial stress

[0163] Example 3 (a)

[0164] Pre-treatment with NAM or our combination

[0165] Subsequent exposure to mitochondrial stress (rotenone – complex I inhibitor)

[0166] Measuring cell viability to assess protection against mitochondrial dysfunction Our composition provided better protection than nicotinamide The composition is alpha lipoic acid, apigenin, ascorbic acid, zinc citrate and nicotinamide The results are shown in Figure 3(a).

[0167] Example 3(b)

[0168] Pre-treatment with NAM or our combination

[0169] Subsequent exposure to mitochondrial stress (NaN 3 – Complex IV inhibitors)

[0170] Measuring cell viability to assess protection against mitochondrial dysfunction Our composition provided better protection than nicotinamide The composition is alpha lipoic acid, apigenin, ascorbic acid, zinc citrate and nicotinamide The results are shown in Figure 3(b).

Claims

1. A composition comprising an effective amount of nicotinamide; quercetin; a rutin derivative; zinc or a salt thereof; ascorbic acid; parsley, or an apigenin derivative; and alpha-lipoic acid.

2. The composition of claim 1, wherein the active ingredient is present in the composition in an amount of about 1 mg to about 1000 mg.

3. The composition according to any one of claims 1 or 2, wherein the composition comprises an acceptable excipient.

4. A composition comprising an effective amount of nicotinamide; quercetin; a rutin derivative; zinc or a salt thereof; ascorbic acid; parsley, or an apigenin derivative; and alpha-lipoic acid; The composition is used for enhancing the tolerance of cells to DNA damage, oxidative stress, mitochondrial dysfunction, or improving DNA repair ability. The composition according to claim 4 , which is used to enhance the tolerance of cells to DNA damage. The composition according to claim 4 , which is used for enhancing the tolerance of cells to oxidative stress.

7. The composition according to claim 4, which is used to enhance the tolerance of cells to mitochondrial dysfunction. The composition according to claim 4 , which is used to improve the DNA repair ability of cells.

9. The composition according to claim 4, wherein the composition is used to enhance the tolerance of cells to DNA damage, oxidative stress, mitochondrial dysfunction, and improve DNA repair capacity.

10. The composition according to any one of claims 4 to 9, wherein the active ingredient is present in the composition in an amount of from about 1 mg to about 1000 mg.

11. A composition according to any one of claims 4 to 10, wherein the composition comprises an acceptable excipient.

12. The composition according to claim 4, which is used to enhance the tolerance of cells to DNA damage, oxidative stress, mitochondrial dysfunction or improve DNA repair ability, comprising topically applying an effective amount of the composition to the skin of an individual.

13. The composition according to claim 12, which is used to reduce, alleviate or improve the effects of aging by enhancing the tolerance of cells to DNA damage, oxidative stress, mitochondrial dysfunction or improving DNA repair capacity.

14. The composition according to claim 12, which is used to reduce, alleviate or improve the effects of aging.

15. The composition of claim 14, wherein the effects of aging include age-related skin conditions, sun-related skin conditions, pollution-exposure-related skin conditions, oxidative stress-related skin conditions, and lifestyle-choice-related skin conditions such as diet, alcohol, and / or smoking.

16. The composition of claim 15, wherein the effects of aging include skin conditions associated with inflammatory skin diseases and skin conditions associated with autoimmune disease skin diseases.

17. The composition of claim 14, wherein the effects of aging include increased frailty, loss of elasticity, loss of muscle strength, loss of muscle endurance, fatigue, loss of cognitive acuity, memory loss, etc.

18. The composition of claim 14, wherein the effects of aging include atherosclerosis and cardiovascular disease, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes, hypertension, and Alzheimer's disease.

19. The composition of claim 14, wherein the effect of aging is an age-related skin condition.

20. The composition of claim 19, wherein the age-related skin condition comprises one or more of sagging, wrinkles, skin elasticity, skin aging, skin moisture, trauma, acne, skin darkening, skin lightening, pigmentation, age spots, loss of radiance, puffiness, uneven skin tone, redness, rosacea, loss of barrier function, loss of skin elasticity, sagging, stretch marks, cellulite, and dryness.

21. The composition of claim 15, wherein the skin condition is caused by sun exposure.

22. The composition of claim 15, wherein the skin condition comprises one or more of actinic keratosis, freckles, lentigo or age spots, moles, photosensitivity, polymorphous light eruption, seborrheic keratosis, skin cancer (such as melanoma, squamous cell carcinoma, basal cell carcinoma), solar elastosis or wrinkles, and sun damage.

23. The composition of claim 16, wherein the skin condition is caused by inflammation.

24. The composition of claim 23, wherein the skin condition comprises one or more of acne, xerosis, atopic dermatitis, contact dermatitis, discoid eczema, eczematous drug eruption, erythema multiforme, erythroderma, gravitational / varicose eczema, hand eczema, chronic lichenoid keratosis, lichen luster, lichen planus, lichen simplex, lichen striatum, mycosis fungoides, pityriasis lichenoides, psoriasis, seborrheic dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and vasculitis.

25. The composition of claim 16, wherein the skin condition is caused by an autoimmune disease.

26. The composition of claim 25, wherein the skin condition comprises one or more of alopecia areata, bullous pemphigoid, dermatomyositis, dystrophic epidermolysis bullosa, eosinophilic fasciitis, pemphigus vulgaris, psoriasis, pyoderma gangrenosum, scleroderma, systemic lupus erythematosus, and vitiligo.

27. The composition according to claim 4, which is used to alleviate, relieve or improve an autoimmune disease.

28. The composition of claim 27, wherein the autoimmune disease is selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, non-glomerular nephropathy, psoriasis, chronic active hepatitis, ulcerative colitis, Crohn's disease, Behcet's disease, chronic glomerulonephritis, chronic thrombocytopenic purpura, and autoimmune hemolytic anemia; and combinations thereof.

29. The composition according to any one of the preceding claims, wherein the composition comprises an effective amount of one or more of glabridin, 18-α-glycyrrhetinic acid, 18-β-glycyrrhetinic acid and glycyrrhizin.

30. The composition according to claim 1, wherein the amount of active ingredients present in the composition includes 150 mg to 700 mg niacinamide; 150 mg to 700 mg quercetin, or a rutin derivative; zinc, or a salt thereof; ascorbic acid; 1 mg to 1,000 mg parsley, or an apigenin derivative; and 150 mg to 700 mg alpha-lipoic acid.

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