WO2001066105A1 - Method and composition for lightening the skin - Google Patents
Method and composition for lightening the skin Download PDFInfo
- Publication number
- WO2001066105A1 WO2001066105A1 PCT/US2001/007182 US0107182W WO0166105A1 WO 2001066105 A1 WO2001066105 A1 WO 2001066105A1 US 0107182 W US0107182 W US 0107182W WO 0166105 A1 WO0166105 A1 WO 0166105A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acid
- composition
- hydroxy
- derivatives
- present
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 10
- 150000001261 hydroxy acids Chemical class 0.000 claims abstract description 22
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- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 150000001277 beta hydroxy acids Chemical class 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229940073669 ceteareth 20 Drugs 0.000 description 1
- 229940081733 cetearyl alcohol Drugs 0.000 description 1
- 229940056318 ceteth-20 Drugs 0.000 description 1
- 229940082500 cetostearyl alcohol Drugs 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- ZAKOWWREFLAJOT-UHFFFAOYSA-N d-alpha-Tocopheryl acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-UHFFFAOYSA-N 0.000 description 1
- 239000007854 depigmenting agent Substances 0.000 description 1
- 229940008099 dimethicone Drugs 0.000 description 1
- 239000004205 dimethyl polysiloxane Substances 0.000 description 1
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 229940117360 ethyl pyruvate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- PMMXXYHTOMKOAZ-UHFFFAOYSA-N hexadecyl 7-methyloctanoate Chemical compound CCCCCCCCCCCCCCCCOC(=O)CCCCCC(C)C PMMXXYHTOMKOAZ-UHFFFAOYSA-N 0.000 description 1
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- XYQREBYZFVVGCJ-UHFFFAOYSA-N icosan-10-ol Chemical compound CCCCCCCCCCC(O)CCCCCCCCC XYQREBYZFVVGCJ-UHFFFAOYSA-N 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 206010024217 lentigo Diseases 0.000 description 1
- CWKLZLBVOJRSOM-UHFFFAOYSA-N methyl pyruvate Chemical compound COC(=O)C(C)=O CWKLZLBVOJRSOM-UHFFFAOYSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 230000000803 paradoxical effect Effects 0.000 description 1
- 231100000760 phototoxic Toxicity 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 229920002523 polyethylene Glycol 1000 Polymers 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- WUBJISGMPZWFKY-UHFFFAOYSA-N propan-2-yl 2-oxopropanoate Chemical compound CC(C)OC(=O)C(C)=O WUBJISGMPZWFKY-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/36—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/36—Carboxylic acids; Salts or anhydrides thereof
- A61K8/362—Polycarboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/36—Carboxylic acids; Salts or anhydrides thereof
- A61K8/365—Hydroxycarboxylic acids; Ketocarboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/36—Carboxylic acids; Salts or anhydrides thereof
- A61K8/368—Carboxylic acids; Salts or anhydrides thereof with carboxyl groups directly bound to carbon atoms of aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
- A61K8/4953—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom containing pyrimidine ring derivatives, e.g. minoxidil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
- A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/67—Vitamins
- A61K8/676—Ascorbic acid, i.e. vitamin C
Definitions
- This invention relates to a method and composition for lightening skin color.
- Melanin is a pigment found in the skin which plays a key role in protecting the body from ultraviolet radiation. Melanin is produced in the form of granules called melanosomes within a type of cell called a melanocyte. Melanosomes are transferred to a layer of keratin-producing cells near the outer surface of the skin known as keratinocytes. The greater the number of melanosomes transferred to keratmocytes, the darker the skin appears. Occasionally alterations occur in this process whereby excessive darkening of the skin is observed.
- hyperpigmentation can be associated with freckles, senile lentigo, lentigines, pregnancy, melasma, chloasma, post- inflammatory hyperpigmentation, sunburn, phototoxic reactions, and other conditions. While not usually life-threatening, hyperpigmentation is viewed as cosmetically undesirable and psychologically debilitating.
- the only treatment approved for lightening the skin in the United States is topical application of 1,4 benzenediol, also known as hydroquinone, which acts by reducing the number of melanosomes produced by melanocytes. Hydroquinone is sold in concentrations up to 2% without prescription, and in concentrations of 3-4% by prescription.
- Hydroquinone preparations can cause side effects ranging from skin redness, burning and sensitization to paradoxical effects such as skin darkening.
- There is a need for new treatments for hyperpigmentation which are at least as effective as hydroquinone but are hydroquinone-free.
- a method for lightening the skin comprises applying to hyperpigmented areas of the skin a composition which includes: (1) Kojic acid and/or derivatives thereof, (2) an anti-oxidant and (3) a hydroxy acid and/or derivatives thereof.
- a composition for lightening the skin is also provided which includes: (1) Kojic acid and/or derivatives thereof, (2) an anti-oxidant and (3) a hydroxy acid and/or derivatives thereof.
- Kojic acid is a well known and commercially-available compound. Dermally-available derivatives of Kojic acid may also be used, such as Kojic dipalmitate. A dermally-available derivative of Kojic acid is a compound that makes Kojic acid or a biologically active form of Kojic acid available in the skin.
- Kojic acid and/or derivatives thereof may be employed in the composition in the range of about 1 to 25% w/w, and preferably between 2 and 10% w/w.
- Anti-oxidants for use in the invention may include ascorbic acid (vitamin C) and/or derivatives thereof, especially Magnesium ascorbal phosphate; tocopherol (vitamin E), Tocopherol acetate, other esters thereof; butylated hydroxy benzoic acids and their salts; 6-hydroxy-2,5,7,8 tetramethylchroman-2- carboxylic acid (commercially available under the trademark TROLOX); gallic acid and its alkyl esters, especially propyl gallate; uric acid and its salts and alkyl esters; sorbic acid and its salts, the ascorbyl esters of fatty acids; amines, such as N,N-diethylhydroxylamine and amino-guanidine; sulfhydryl compounds, such as glutathione and N-acetyl cysteine; and dihydroxy fumaric acid and its salts.
- ascorbic acid vitamin C
- vitamin E tocopherol
- acetate other esters thereof
- anti-oxidants may be used alone or in combination.
- the anti-oxidant component may be employed in the composition in a concentration sufficient to exhibit anti- oxidant activity in vivo; for example, in the case of ascorbic acid or magnesium ascorbyl phosphate, concentration range of about 1 to 25% should be employed, preferably between 5 and 10% w/w.
- Hydroxy acids for use in the invention encompass the general class of organic compounds containing at least one hydroxy group and at least one carboxyl group, wherein at least one hydroxyl group is located on the alpha- or beta-carbon atom.
- the hydroxy acid will have a single hydroxyl group (other than that associated with a carboxyl moiety), on the alpha-carbon atom, and may contain one, two or three carboxyl groups.
- these compounds will have a basic structure of lower aliphatic compounds having from two to six carbon atoms.
- the derivatives of these hydroxy acids most typically will involve derivatives related to carboxyl functionality, i.e., wherein the hydroxy or hydroxyl portion of the carboxyl moiety is substituted by metallic ions (to form salts), alkoxy groupings (to form esters), ammonium ions (to form ammonium salts), as well as other substitution reactions and products leading to formation of corresponding lactones, anhydrides or amides.
- the derivatives may also include reactions involving the alpha-hydroxyl group, most notably ketone formation, to form corresponding alpha-keto carboxyl acids.
- hydroxy acids and derivative compounds useful in the present invention are glycolic acid, glucuronic acid, galacturonic acid, gluconic acid, glucoheptonic acid, -hydroxybutyric acid, -hydroxyisobutyric acid, - hydroxyisocaproic acid, -hydroxyisovaleric acid, lactic acid, malic acid, muric acid, citric acid, saccharic acid, tartaric acid, tartronic acid, isocitric acid, dihydroxymaleic acid, dihydroxytartaric acid and dihydroxyfumaric acid.
- keto acids and keto esters such as pyruvic acid, methyl pyruvate, ethyl pyruvate, isopropyl pyruvate, benzoylformic acid, methyl benzoylformate and ethyl benzoylformate.
- keto acids and keto esters such as pyruvic acid, methyl pyruvate, ethyl pyruvate, isopropyl pyruvate, benzoylformic acid, methyl benzoylformate and ethyl benzoylformate.
- keto acids and keto esters such as pyruvic acid, methyl pyruvate, ethyl pyruvate, isopropyl pyruvate, benzoylformic acid, methyl benzoylformate and ethyl benzoylformate.
- beta hydroxyacid for use in the invention is salicylic acid.
- the hydroxy acids and related compounds may be employed as free acids or esters, lactones, amides, anhydrides, inorganic metal salts, ammonium salts or salts created by reacting a hydroxy acid with an amino acid. Because of the natural presence of water-soluble acids in human skin, certain salts of these acids may convert, at least partially, to free acid form upon application.
- the hydroxyacid and/or derivatives thereof should be employed at a concentration of between about 1 and 25% w/w, and preferably between 2.0 and 10%.
- the three components, together with appropriate carriers or vehicles, can be compounded into dermatologically useful cream, lotion, solution or gel preparations as follows:
- the cream is prepared by combining the oil-phase ingredients in a mixing container and heating them to 70 degrees C.
- the water phase ingredients except for the Lactic acid and Magnesium ascorbyl phosphate, are combined and heated to the same temperature.
- the two phases are then combined and cooled with constant mixing.
- At approximately 50 degrees the Lactic acid and ascorbate are dissolved.
- it may be advantageously packaged as a dry powder in a separate container which would accompany ajar of the cream. At time of dispensing or first use, the powder would be incorporated into the cream with a stirring rod where it would dissolve in the water phase.
- the lotion is prepared by combining the oil-phase ingredients in a mixing container and heating them to 75 degrees C.
- the water phase ingredients except for the Lactic acid and Magnesium ascorbyl phosphate, are combined and heated to the same temperature.
- the two phases arc then combined and cooled with constant mixing.
- the Lactic acid and ascorbate are dissolved.
- it may be advantageously packaged as a dry powder in a separate container which would accompany a bottle of the lotion. At time of dispensing or first use, the powder would be added to the lotion and shaken where it would dissolve in the water phase.
- the solution is prepared by combining the alcohol, laureth-4 and squalane and adding the resulting solution slowly with mixing to the aqueous solution of the other ingredients at room temperature.
- they may be advantageously packaged as a dry blended powder in a separate container which would accompany the bottle of the solution. At time of dispensing or first use, the powder would be added to the solution and shaken where it would dissolve in the hydro-alcoholic solvent carrier.
- the gel is prepared by combining the alcohol, Salicylic acid, laureth-4 and squalane and adding the resulting solution slowly with mixing to the aqueous solution of the other ingredients at room temperature.
- the kojic acid, N-Acetyl cysteine and ascorbate may be advantageously packaged as a dry blended powder in a separate container which would accompany the bottle of the solution.
- the powder would be added to the gel and stirred or shaken where it would dissolve in the hydro-alcohol solvent carrier.
- the Melanoderm assay is an in vitro model of the human epidermis consisting of well differentiated, cultured human keratinocytes and melanocytyes. This model can be used to evaluate the efficacy, stability and cytotoxicity of skin lightening agents.
- L-DOPA L- Dihydroxyphenylalanine
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- Epidemiology (AREA)
- Birds (AREA)
- Emergency Medicine (AREA)
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- Pharmacology & Pharmacy (AREA)
- Dermatology (AREA)
- Cosmetics (AREA)
Abstract
A method for lightening the skin is provided which comprises applying to hyperpigmented areas of the skin a composition which includes: (1) Kojic acid and/or derivatives thereof, (2) an anti-oxidant and (3) a hydroxy acid and/or derivatives thereof. A composition for lightening the skin is also provided which includes: (1) Kojic acid and/or derivatives thereof, (2) an anti-oxidant and (3) a hydroxy acid and/or derivatives thereof.
Description
METHOD AND COMPOSITION FOR LIGHTENING THE SKIN
Field of the Invention
This invention relates to a method and composition for lightening skin color.
Background of the Invention
Melanin is a pigment found in the skin which plays a key role in protecting the body from ultraviolet radiation. Melanin is produced in the form of granules called melanosomes within a type of cell called a melanocyte. Melanosomes are transferred to a layer of keratin-producing cells near the outer surface of the skin known as keratinocytes. The greater the number of melanosomes transferred to keratmocytes, the darker the skin appears. Occasionally alterations occur in this process whereby excessive darkening of the skin is observed. Such so-called "hyperpigmentation" can be associated with freckles, senile lentigo, lentigines, pregnancy, melasma, chloasma, post- inflammatory hyperpigmentation, sunburn, phototoxic reactions, and other conditions. While not usually life-threatening, hyperpigmentation is viewed as cosmetically undesirable and psychologically debilitating. The only treatment approved for lightening the skin in the United States is topical application of 1,4 benzenediol, also known as hydroquinone, which acts by reducing the number of melanosomes produced by melanocytes. Hydroquinone is sold in concentrations up to 2% without prescription, and in concentrations of 3-4% by prescription. Although fairly effective, Hydroquinone preparations can cause side effects ranging from skin redness, burning and sensitization to paradoxical effects such as skin darkening. There is a need for new treatments for hyperpigmentation which are at least as effective as hydroquinone but are hydroquinone-free.
Summary of the Invention
A method for lightening the skin is provided which comprises applying to
hyperpigmented areas of the skin a composition which includes: (1) Kojic acid and/or derivatives thereof, (2) an anti-oxidant and (3) a hydroxy acid and/or derivatives thereof. A composition for lightening the skin is also provided which includes: (1) Kojic acid and/or derivatives thereof, (2) an anti-oxidant and (3) a hydroxy acid and/or derivatives thereof.
Detailed Description of the Invention
Kojic acid is a well known and commercially-available compound. Dermally-available derivatives of Kojic acid may also be used, such as Kojic dipalmitate. A dermally-available derivative of Kojic acid is a compound that makes Kojic acid or a biologically active form of Kojic acid available in the skin.
Kojic acid and/or derivatives thereof may be employed in the composition in the range of about 1 to 25% w/w, and preferably between 2 and 10% w/w.
Anti-oxidants for use in the invention may include ascorbic acid (vitamin C) and/or derivatives thereof, especially Magnesium ascorbal phosphate; tocopherol (vitamin E), Tocopherol acetate, other esters thereof; butylated hydroxy benzoic acids and their salts; 6-hydroxy-2,5,7,8 tetramethylchroman-2- carboxylic acid (commercially available under the trademark TROLOX); gallic acid and its alkyl esters, especially propyl gallate; uric acid and its salts and alkyl esters; sorbic acid and its salts, the ascorbyl esters of fatty acids; amines, such as N,N-diethylhydroxylamine and amino-guanidine; sulfhydryl compounds, such as glutathione and N-acetyl cysteine; and dihydroxy fumaric acid and its salts. Such anti-oxidants may be used alone or in combination. The anti-oxidant component may be employed in the composition in a concentration sufficient to exhibit anti- oxidant activity in vivo; for example, in the case of ascorbic acid or magnesium ascorbyl phosphate, concentration range of about 1 to 25% should be employed, preferably between 5 and 10% w/w.
Hydroxy acids for use in the invention encompass the general class of organic compounds containing at least one hydroxy group and at least one carboxyl group, wherein at least one hydroxyl group is located on the alpha- or
beta-carbon atom. Typically, the hydroxy acid will have a single hydroxyl group (other than that associated with a carboxyl moiety), on the alpha-carbon atom, and may contain one, two or three carboxyl groups. Most typically, these compounds will have a basic structure of lower aliphatic compounds having from two to six carbon atoms.
The derivatives of these hydroxy acids most typically will involve derivatives related to carboxyl functionality, i.e., wherein the hydroxy or hydroxyl portion of the carboxyl moiety is substituted by metallic ions (to form salts), alkoxy groupings (to form esters), ammonium ions (to form ammonium salts), as well as other substitution reactions and products leading to formation of corresponding lactones, anhydrides or amides. However, the derivatives may also include reactions involving the alpha-hydroxyl group, most notably ketone formation, to form corresponding alpha-keto carboxyl acids.
Among the hydroxy acids and derivative compounds useful in the present invention are glycolic acid, glucuronic acid, galacturonic acid, gluconic acid, glucoheptonic acid, -hydroxybutyric acid, -hydroxyisobutyric acid, - hydroxyisocaproic acid, -hydroxyisovaleric acid, lactic acid, malic acid, muric acid, citric acid, saccharic acid, tartaric acid, tartronic acid, isocitric acid, dihydroxymaleic acid, dihydroxytartaric acid and dihydroxyfumaric acid. Derivatives involving keto groups include keto acids and keto esters such as pyruvic acid, methyl pyruvate, ethyl pyruvate, isopropyl pyruvate, benzoylformic acid, methyl benzoylformate and ethyl benzoylformate. An example of a suitable beta hydroxyacid for use in the invention is salicylic acid.
The hydroxy acids and related compounds may be employed as free acids or esters, lactones, amides, anhydrides, inorganic metal salts, ammonium salts or salts created by reacting a hydroxy acid with an amino acid. Because of the natural presence of water-soluble acids in human skin, certain salts of these acids may convert, at least partially, to free acid form upon application. The hydroxyacid and/or derivatives thereof should be employed at a concentration of between about 1 and 25% w/w, and preferably between 2.0 and 10%.
The three components, together with appropriate carriers or vehicles, can be compounded into dermatologically useful cream, lotion, solution or gel preparations as follows:
Example 1 Cream
Ingredient %
Cetearyl alcohol (and) Ceteareth-20 4.0
Mineral Oil 9.0
Glyceryl stearate (and) PEG 100 Stearate 3.0 Vitamin E Acetate 2.5
Kojic Dipalmitate 4.2
Cetostearyl alcohol 1.5
Glycerin 2.0
Disodium EDTA 0.1 Lactic acid 7.5
Magnesium ascorbyl phosphate 9.5
Sodium or Ammonium hydroxide Q.S.
Preservative Q.S.
Deionized water Q.S.
The cream is prepared by combining the oil-phase ingredients in a mixing container and heating them to 70 degrees C. The water phase ingredients, except for the Lactic acid and Magnesium ascorbyl phosphate, are combined and heated to the same temperature. The two phases are then combined and cooled with constant mixing. At approximately 50 degrees the Lactic acid and ascorbate are dissolved. Preferably, due to the sensitivity of the ascorbate to elevated temperatures and oxidation in aqueous solvents, it may be advantageously packaged as a dry powder in a separate container which would accompany ajar of the cream. At time of dispensing or first use, the powder would be incorporated into the cream with a stirring rod where it would dissolve in the water phase.
Example 2 Lotion
Ingredient %
Glyceryl stearate (and) PEG 100 stearate 1.5 Glyceryl stearate and ceteth-20 1.5
Cetyl alcohol 1.0
Octyl 2 dodecanol 3.0
Caprylic/capric triglyceride 8.0
Cetearyl isononanoate 4.0 Dimethicone, 100 cst 0.5
Kojic dipalmitate 3.0
Glycerin 2.0
Disodium EDTA 0.1
Xanthan gum 0.3 Magnesium aluminum silicate 1.0
Lactic acid 8.0
Magnesium ascorbyl phosphate 10.0
Sodium or Ammonium hydroxide Q.S.
Preservative Q.S. Deionized water Q.S.
The lotion is prepared by combining the oil-phase ingredients in a mixing container and heating them to 75 degrees C. The water phase ingredients, except for the Lactic acid and Magnesium ascorbyl phosphate, are combined and heated to the same temperature. The two phases arc then combined and cooled with constant mixing. At approximately 45 degrees the Lactic acid and ascorbate are dissolved. Preferably, due to the sensitivity of the ascorbate to elevated temperatures and oxidation in aqueous solvents, it may be advantageously packaged as a dry powder in a separate container which would accompany a bottle of the lotion. At time of dispensing or first use, the powder would be added to the lotion and shaken where it would dissolve in the water phase.
Example 3 Solution
Ingredient %
Deionized water Q.S. Vitamin E PEG 1000 Succinate 0.3
Propylene glycol 5.0
Gly colic acid 5.0
Ascorbic acid 7.0
Kojic acid 3.0 Ethanol 16.0
Laureth-4 1.0
Squalane 0.2
Sodium or Ammonium hydroxide Q.S.
Preservative Q.S.
The solution is prepared by combining the alcohol, laureth-4 and squalane and adding the resulting solution slowly with mixing to the aqueous solution of the other ingredients at room temperature. Preferably, due to the sensitivity of the kojic acid and ascorbate to oxidation in aqueous solvents, they may be advantageously packaged as a dry blended powder in a separate container which would accompany the bottle of the solution. At time of dispensing or first use, the powder would be added to the solution and shaken where it would dissolve in the hydro-alcoholic solvent carrier.
Example 4 Gel
Ingredient %
Deionized water Q.S.
Hydroxy ethyl cellulose 0.3
Propylene glycol 5.0
Glycolic acid 2.0 N-Acetyl cysteine 1.0
Magnesium ascorbyl phosphate 5.0
Kojic acid 2.0
Ethanol 20.0
Salicylic acid 1.0
Laureth-4 1.0 Squalane 0.2
Sodium or Ammonium hydroxide Q.S.
Preservative Q.S.
The gel is prepared by combining the alcohol, Salicylic acid, laureth-4 and squalane and adding the resulting solution slowly with mixing to the aqueous solution of the other ingredients at room temperature. Preferably, due to the sensitivity of the kojic acid, N-Acetyl cysteine and ascorbate to oxidation in aqueous solvents, they may be advantageously packaged as a dry blended powder in a separate container which would accompany the bottle of the solution. At time of dispensing or first use, the powder would be added to the gel and stirred or shaken where it would dissolve in the hydro-alcohol solvent carrier.
Example 5
The Melanoderm assay is an in vitro model of the human epidermis consisting of well differentiated, cultured human keratinocytes and melanocytyes. This model can be used to evaluate the efficacy, stability and cytotoxicity of skin lightening agents.
After application of a skin lightening test preparation and L- Dihydroxyphenylalanine (L-DOPA) the Melanoderm is incubated. The resultant changes in the formation of melanin are compared with a positive L-DOPA control without any of the test preparation. Any reduction in melanin formation of the test preparation-treated Melanoderm compared with the control predicts skin lightening activity of the test preparation.
The following table summarizes reduction of melanin formation for test creams formulated as in Example 1 containing Kojic dipalmitate, Lactic acid and Magnesium ascorbyl phosphate individually and in combination, along with a commercially-available 4% Hydroquinone cream:
TABLE 1
Test Preparation % Melanin Reduction
Kojic dipalmitate only 45%
Lactic acid only 40%
Magnesium ascorbyl phosphate only 33%
Kojic dipalmitate + Lactic acid 52%
Kojic dipalmitate + Magnesium ascorbyl phosphate only 48%
Lactic acid + Magnesium ascorbyl phosphate only 45%
Kojic dipalmitate + Lactic acid +
Magnesium ascorbyl phosphate 65%
Hydroquinone, 4% Cream 59%
The results suggest the combination of Kojic derivative, hydroxy acid and ascorbate anti-oxidant produce an unexpectedly greater skin lightening effect than each agent used individually or in paired combination. Furthermore, the combination was at least as effective as a commercially-available Hydroquinone
Cream.
Claims
1. A composition for lightening the skin which comprises: (1) Kojic acid and/or derivatives thereof, (2) an anti-oxidant and (3) a hydroxy acid and/or derivatives thereof.
2. The composition of claim 1, wherein the Kojic acid and/or derivative thereof is present in the range of about 1 to 25% w/w, preferably 2 to 10% w/w.
3. The composition of claim 1, wherein the anti-oxidant is selected from the group consisting of ascorbic acid and/or derivatives thereof, especially Magnesium ascorbal phosphate; tocopherol, Tocopherol acetate, other esters thereof; butylated hydroxy benzoic acids and their salts; 6-hydroxy-2,5,7,8 tetramethylchroman-2-carboxylic acid; gallic acid and its alkyl esters, especially propyl gallate; uric acid and its salts and alkyl esters; sorbic acid and its salts; the ascorbyl esters of fatty acids; amines, such as N,N-diethylhydroxylamine and amino-guanidine; sulfhydryl compounds, such as glutathione and N-acetyl cysteine and dihydroxy fumaric acid and its salts.
4. The composition of claim 1, wherein the anti-oxidant is present in the range of about 1 to 25% w/w, preferably 5 to 10% w/w.
5. The composition of claim 1, wherein the hydroxy acid is selected from the group consisting of organic compounds containing at least one hydroxy group and at least one carboxyl group, wherein at least one hydroxyl group is located on the alpha- or beta-carbon atom.
6. The composition of claim 1, wherein hydroxy acid derivative has the hydroxyl portion of the carboxyl moiety substituted by metallic ions, alkoxy groupings, ammonium ions, as well as other substitution reactions and products leading to formation of corresponding lactones, anhydrides or amides, or reactions involving the alpha-hydroxyl group, especially ketone formation, to form corresponding alpha-keto carboxyl acids.
7. The composition of claim 1, wherein the hydroxy acid and/or derivatives thereof is selected from the group consisting of glycolic acid, glucuronic acid, galacturonic acid, gluconic acid, glucoheptonic acid, hydroxybutyric acid, -hydroxyisobutyric acid, -hydroxyisocaproic acid, - hydroxyisovaleric acid, lactic acid, malic acid, muric acid, citric acid, saccharic acid, tartaric acid, tartronic acid, isocitric acid, dihydroxymaleic acid, dihydroxytartaric acid, dihydroxyfumaric acid, keto acids and keto esters such as pyruvic acid, methyl pymvate, ethyl pymvate, isopropyl pymvate, benzoylformic acid, methyl benzoylformate and ethyl benzoylformate, and salicylic acid.
8. The composition of claim 1, wherein the hydroxy acid and/or derivatives thereof are present as free acids or esters, lactones, amides, anhydrides, inorganic metal salts, ammonium salts or salts created by reacting a hydroxy acid with an amino acid.
9. The composition of claim 1, wherein the hydroxy acid and/or derivatives thereof is present in the range of about 1 and 25% w/w, preferably 2.0 and 10%.
10. The composition of claim 1, wherein the Kojic acid and/or derivative thereof is present in the range of about 1 to 25% w/w, preferably 2 to 10% w/w, the anti-oxidant is present in the range of about 1 to 25% w/w, preferably 5 to 10% w/w; and the hydroxy acid and/or derivatives thereof is present in the range of about 1 and 25% w/w, preferably 2.0 and 10%.
11. A method for lightening the skin which comprises applying to hyperpigmented areas of the skin a composition of cream, lotion, solution, or gel which includes Kojic acid and/or derivative thereof present in the range of about 1 to 25%o w/w, preferably 2 to 10% w/w.
12. The method of claim 11 wherein the composition comprises an anti- oxidant and a hydroxy acid and/or derivatives thereof.
13. The method of claim 12, wherein the anti-oxidant is present in the range of about 1 to 25% w/w, preferably 5 to 10% w/w; and the hydroxy acid and/or derivatives thereof is present in the range of about 1 and 25%> w/w, preferably 2.0 and 10%).
14. The method of claim 11, wherein the Kojic acid and/or derivatives thereof is Kojic dipalmitate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2001245474A AU2001245474A1 (en) | 2000-03-07 | 2001-03-07 | Method and composition for lightening the skin |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US18752000P | 2000-03-07 | 2000-03-07 | |
| US60/187,520 | 2000-03-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2001066105A1 true WO2001066105A1 (en) | 2001-09-13 |
Family
ID=22689316
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2001/007182 WO2001066105A1 (en) | 2000-03-07 | 2001-03-07 | Method and composition for lightening the skin |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU2001245474A1 (en) |
| WO (1) | WO2001066105A1 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002026206A1 (en) * | 2000-09-29 | 2002-04-04 | Beiersdorf Ag | Cosmetic or dermatological formulations containing aminoguanidine |
| DE102010051689A1 (en) | 2010-11-17 | 2012-05-24 | Merck Patent Gmbh | Dihydroxyfumaric acid derivatives and their use for skin lightening |
| US20130156710A1 (en) * | 2010-05-25 | 2013-06-20 | Symrise Ag | Cyclohexyl carbamate compounds as skin and/or hair lightening actives |
| GB2497985A (en) * | 2011-12-28 | 2013-07-03 | Pangaea Lab Ltd | Stable kojic acid composition to lighten the skin |
| CN110785395A (en) * | 2017-06-26 | 2020-02-11 | 巴斯夫欧洲公司 | Alkoxylation of hydroxy acids |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999036053A1 (en) * | 1998-01-16 | 1999-07-22 | Color Access, Inc. | Stabilized whitening compositions and method of preparing same |
-
2001
- 2001-03-07 AU AU2001245474A patent/AU2001245474A1/en not_active Abandoned
- 2001-03-07 WO PCT/US2001/007182 patent/WO2001066105A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999036053A1 (en) * | 1998-01-16 | 1999-07-22 | Color Access, Inc. | Stabilized whitening compositions and method of preparing same |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002026206A1 (en) * | 2000-09-29 | 2002-04-04 | Beiersdorf Ag | Cosmetic or dermatological formulations containing aminoguanidine |
| US20130156710A1 (en) * | 2010-05-25 | 2013-06-20 | Symrise Ag | Cyclohexyl carbamate compounds as skin and/or hair lightening actives |
| US9072676B2 (en) * | 2010-05-25 | 2015-07-07 | Symrise Ag | Cyclohexyl carbamate compounds as skin and/or hair lightening actives |
| DE102010051689A1 (en) | 2010-11-17 | 2012-05-24 | Merck Patent Gmbh | Dihydroxyfumaric acid derivatives and their use for skin lightening |
| WO2012065680A2 (en) | 2010-11-17 | 2012-05-24 | Merck Patent Gmbh | Dihydroxyfumaric acid derivatives, and use thereof for bleaching skin |
| WO2012065680A3 (en) * | 2010-11-17 | 2013-06-27 | Merck Patent Gmbh | Dihydroxyfumaric acid derivatives, and use thereof for bleaching skin |
| CN103269677A (en) * | 2010-11-17 | 2013-08-28 | 默克专利股份有限公司 | Dihydroxyfumaric acid derivatives, and use thereof for bleaching skin |
| JP2013542964A (en) * | 2010-11-17 | 2013-11-28 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング | Dihydroxyfumaric acid derivatives and their use for skin whitening |
| GB2497985A (en) * | 2011-12-28 | 2013-07-03 | Pangaea Lab Ltd | Stable kojic acid composition to lighten the skin |
| GB2497985B (en) * | 2011-12-28 | 2014-03-12 | Pangaea Lab Ltd | A composition to stabilise kojic acid |
| AU2012268879B2 (en) * | 2011-12-28 | 2015-08-06 | Medik8 Limited | A Composition to Stabilise Kojic Acid |
| CN110785395A (en) * | 2017-06-26 | 2020-02-11 | 巴斯夫欧洲公司 | Alkoxylation of hydroxy acids |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2001245474A1 (en) | 2001-09-17 |
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