Method and composition for skin lightening

BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention concerns a method and compositions for lightening the color of skin.
2. The Related Art
Ever since the first freckle or hyperpigmented spot appeared on the human face, there has been demand for treatment. Historically treatments have involved preparations of mercury, plant extracts and even lemon juice. Bleaching of skin with ammoniated mercury and other salts of this metal are reported to be quite effective. Of course there are significant safety issues involved with mercurials.
Zinc peroxide has been utilized in anhydrous ointments as a bleaching agent. Monobenzyl ether of hydroquinone was marketed for its skin lightening effect but questions of safety were here also raised.
Ascorbic acid preparations, either pure or made from some natural material, such as lemon juice, were suggested as useful. While seemingly entirely safe, they do not seem to be very effective.
U.S. Pat. No. 4,096,240 (Mathur) refers to niacin as effective in skin lightening. This material is postulated to operate by retarding melanin dispersion or distribution into the epidermis. Since unpleasant skin flushing occurs with niacin, the patent suggests use of niacinamide as a substitute. Compositions based upon niacinamide are effective, but only to a limited extent.
Accordingly, it is an object of the present invention to provide a skin lightening composition and actives to accomplish this function which are more efficient than materials heretofore known and are safe to use.
Another object of the present invention is to provide a skin lightening composition and actives to accomplish this function which are particularly effective against agespots, freckles and hyperpigmentation.
These and other objects of the present invention will become more readily apparent from consideration of the following summary and detailed description.
SUMMARY OF THE INVENTION
A method for lightening the color of skin is provided which includes applying to the skin a compound having structure (I): ##STR2## wherein R is selected from the group consisting of C.sub.1 -C.sub.30 alkyl, cycloalkyl and aryl radicals.
A composition for skin lightening is also provided which includes:
(i) an effective amount to achieve skin lightening of an active having structure (I);
(ii) from 0.1 to 30% by weight of a sunscreen agent; and
(iii) a pharmaceutically acceptable carrier to deliver the active l) and the sunscreen agent.
DETAILED DESCRIPTION
Now it has been discovered that acetaminophen and its analogs are active agents in lightening skin. These actives are effective against hyperpigmentation, agespots and freckles. They have the general structure (I): ##STR3## wherein R is selected from the group consisting of C.sub.1 -C.sub.30 alkyl, cycloalkyl and aryl radicals.
Most preferred is where R is methyl and the hydroxy radical is in a para position. This material is generically known as acetaminophen having structure (II). ##STR4##
Amounts of the active (I) may range from 0.1 to 20%, preferably from 0.5 to 10%, optimally from 1 to 5% by weight.
Use of (I) may be according to a regime that applies compositions containing the active repeatedly to the same area of the skin. For instance, application can be done daily for periods from several days to several weeks, before skin lightening becomes evident.
In a further aspect of the invention, the action of the skin lightening active (I) is ensured against reversal of melanisation through the presence of an ultraviolet absorbing sunscreen. By the term "sunscreen" is meant any material whether organic or inorganic which can shield the skin from ultraviolet radiation within the range of 290 to 400 nm.
When the sunscreen is an organic material, it will usually contain at least one chromophoric agent absorbing within the ultraviolet range somewhere from 290 to 400 nm. Chromophoric organic sunscreen agents may be divided into the following categories (with specific examples) including: p-Aminobenzoic acid, its salts and its derivatives (ethyl, isobutyl, glyceryl esters; p-dimethylaminobenzoic acid); Anthranilates (o-aminobenzoates; methyl, phenyl, benzyl, phenylethyl, linalyl, terpinyl, and cyclohexenyl esters); Salicylates (octyl, amyl, phenyl, benzyl, menthyl, glyceryl, and dipropyleneglycol esters); Cinnamic acid derivatives (menthyl and benzyl esters, .alpha.-phenyl cinnamonitrile; butyl cinnamoyl pyruvate); Dihydroxycinnamic acid derivatives (umbelliferone, methylumbelliferone, methylaceto-umbelliferone); Trihydroxycinnamic acid derivatives (esculetin, methylesculetin, daphnetin, and the glucosides, esculin and daphnin); Hydrocarbons (diphenylbutadiene, stilbene); Dibenzalacetone and benzalacetophenone; Naptholsulfonates (sodium salts of 2-naphthol-3,6-disulfonic and of 2-naphthol-6,8-disulfonic acids); Dihydroxy-napthoic acid and its salts; o- and p-Hydroxybiphenyldisulfonates; Coumarin derivatives (7-hydroxy, 7-methyl, 3-phenyl); Diazoles (2-acetyl-3-bromoindazole, phenyl benzoxazole, methyl naphthoxazole, various aryl benzothiazoles); Quinine salts (bisulfate, sulfate, chloride oleate and tannate); Quinoline derivatves (8-hydroxyquinoline salts, 2-phenylquinoline); Hydroxy-or methoxy-substituted benzophenones; Uric and vilouric acids; Tannic acid and its derivatives (e.g. hexaethylether); (Butyl carbityl) (6-propyl piperonyl) ether; Hydroquinone; Benzophenones (Oxybenzone, Sulisobenzone, Dioxybenzone, Benzoresorcinol, 2,2',4,4'-Tetrahydroxybenzophenone, 2,2'-Dihydroxy-4,4'-dimethoxybenzophenone, Octabenzone; 4-isopropyldibenzoylmethane, Butylmethoxydibenzoylmethane; Etocrylene; and 4-isopropyl-dibenzoylmethane).
Particularly useful are: 2-ethylhexyl p-methoxycinnamate,4,4'-t-butyl methoxydibenzoylmethane, 2-hydroxy-4-methoxybenzophenone, octyldimethyl p-aminobenzoic acid, digalloyltrioleate, 2,2-dihydroxy-4-methoxybenzophenone, ethyl-4-�bis(hydroxypropyl)!aminobenzoate, 2-ethylhexyl-2-cyano-3,3-diphenylacrylate, 2-ethylhexylsalicylate, glyceryl p-aminobenzoate, 3,3,5-trimethylcyclohexylsalicylate, methylanthranilate, p-dimethylaminobenzoic acid or aminobenzoate, 2-ethylhexyl p-dimethylaminobenzoate, 2-phenylbenzimidazole-5-sulfonic acid, 2-(p-dimethylaminophenyl)-5-sulfoniobenzoxazoic acid and mixtures thereof.
Suitable commercially available organic sunscreen agents are those identified under the following table.
TABLE I______________________________________CTFA NAME TRADE NAME SUPPLIER______________________________________Benzophenone-3 UVINUL M-40 BASF Chemical Co.Benzophenone-4 UVINUL MS-40 BASF Chemical Co.Benzophenone-8 SPECTRA-SORB UV-24 American CyanamidDEA-Methoxycinnamate BERNEL HYDRO Bernel ChemicalEthyl dihydroxypropyl- AMERSCREEN P Amerchol Corp.PABAGlyceryl PABA NIPA G.M.P.A. Nipa Labs.Homosalate KENESTER HMS Humko ChemicalMenthyl anthranilate SUNAROME UVA Felton WorldwideOctocrylene UVINUL N-539 BASF Chemical Co.Octyl dimethyl PABA AMERSCOL Amerchol Corp.Octyl methoxycinnamate PARSOL MCX Bernel ChemicalOctyl salicylate SUNAROME WMO Felton WorldwidePABA PABA National Starch2-Phenylbenzimidazole- EUSOLEX 6300 EM industries5-sulphonic acidTEA salicylate SYBARINE W Felton Worldwide2-(4-Methylbenzlidene)- EUSOLEX 6300 EM IndustriescamphorBenzophenone-1 UVINUL 400 BASF Chemical Co.Benzophenone-2 UVINUL D-50 BASF Chemical Co.Benzophenone-6 UVINUL D-49 BASF Chemical Co.Benzophenone-12 UVINUL 408 BASF Chemical Co.4-Isopropyl dibenzoyl EUSOLEX 8020 EM IndustriesmethaneButyl Methoxy dibenzoyl PARSOL 1789 Givaudan Corp.methaneEtocrylene UVINUL N-35 BASF Chemical Co.______________________________________
Inorganic sunscreen actives may also be employed such as microfine titanium dioxide, zinc oxide, polyethylene, polyamides (e.g. nylon) and various other polymers. Amounts of the sunscreen agents (whether organic or inorganic) will generally range from 0.1 to 30%, preferably from 2 to 20%, optimally from 4 to 10% by weight.
Compositions of the present invention will utilize a pharmaceutically acceptable carrier. The carrier may either be aqueous, anhydrous or an emulsion. Preferably the compositions are aqueous, especially water and oil emulsions of the W/O or O/W variety. Water when present will be in amounts which may range from 5 to 95%, preferably from 20 to 70%, optimally between 35 and 60% by weight.
Besides water, relatively volatile solvents may also serve as carriers within compositions of the present invention. Most preferred are monohydric C.sub.1 -C.sub.3 alkanols. These include ethyl alcohol, methyl alcohol and isopropyl alcohol. The amount of monohydric alkanol may range from 1 to 70%, preferably from 10 to 50%, optimally between 15 to 40% by weight.
Emollient materials may also serve as pharmaceutically acceptable carriers. These may be in the form of silicone oils and synthetic esters. Amounts of the emollients may range anywhere from 0.1 to 30%, preferably between 1 and 20% by weight.
Silicone oils may be divided into the volatile and non-volatile variety. The term "volatile" as used herein refers to those materials which have a measurable vapor pressure at ambient temperature. Volatile silicone oils are preferably chosen from cyclic or linear polydimethylsiloxanes containing from 3 to 9, preferably from 4 to 5, silicon atoms.
Linear volatile silicone materials generally have viscosities less than about 5 centistokes at 25.degree. C. while cyclic materials typically have viscosities of less than about 10 centistokes.
Nonvolatile silicone oils useful as an emollient material include polyalkyl siloxanes, polyalkylaryl siloxanes and polyether siloxane copolymers. The essentially non-volatile polyalkyl siloxanes useful herein include, for example, polydimethyl siloxanes with viscosities of from about 5 to about 100,000 centistokes at 25.degree. C. Among the preferred non-volatile emollients useful in the present compositions are the polydimethyl siloxanes having viscosities from about 10 to about 400 centistokes at 25.degree. C.
Among the ester emollients are:
(1) Alkenyl or alkyl esters of fatty acids having 10 to 20 carbon atoms. Examples thereof include isoarachidyl neopentanoate, isononyl isonanonoate, oleyl myristate, oleyl stearate, and oleyl oleate.
(2) Ether-esters such as fatty acid esters of ethoxylated fatty alcohols.
(3) Polyhydric alcohol esters. Ethylene glycol mono and di-fatty acid esters, diethylene 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 monooleate, polypropylene glycol 2000 monostearate, ethoxylated propylene glycol monostearate, glyceryl mono- and di-fatty acid esters, polyglycerol poly-fatty esters, ethoxylated glyceryl monostearate, 1,3-butylene glycol monostearate, 1,3-butylene glycol distearate, polyoxyethylene polyol fatty acid ester, sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty acid esters are satisfactory polyhydric alcohol esters.
(4) Wax esters such as beeswax, spermaceti, myristyl myristate, stearyl stearate and arachidyl behenate.
(5) Sterols esters, of which cholesterol fatty acid esters are examples thereof.
Fatty acids having from 10 to 30 carbon atoms may also be included as pharmaceutically acceptable carriers for compositions of this invention. Illustrative of this category are pelargonic, lauric, myristic, palmitic, stearic, isostearic, hydroxystearic, oleic, linoleic, ricinoleic, arachidic, behenic and erucic acids.
Humectants of the polyhydric alcohol-type may also be employed as pharmaceutically acceptable carriers in compositions of this invention. The humectant aids in increasing the effectiveness of emollients, reduces scaling, stimulates removal of built-up scale and improves skin feel. Typical polyhydric alcohols include glycerol, polyalkylene glycols and more preferably alkylene polyols and their derivatives, including propylene glycol, dipropylene glycol, polypropylene glycol, polyethylene glycol and derivatives thereof, sorbitol, hydroxypropyl sorbitol, hexylene glycol, 1,3-butylene glycol, 1,2,6-hexanetriol, ethoxylated glycerol, propoxylated glycerol and mixtures thereof. For best results the humectant is preferably propylene glycol. The amount of humectant may range anywhere from 0.5 to 30%, preferably between 1 and 15% by weight of the composition.
Thickeners may also be utilized as part of the pharmaceutically acceptable carrier of compositions according to the present invention. Typical thickeners include crosslinked acrylates (e.g. Carbopol 9827), hydrophobically-modified acrylates (e.g. Carbopol 13827), cellulosic derivatives and natural gums. Among useful cellulosic derivatives are sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose and hydroxymethyl cellulose. Natural gums suitable for the present invention include guar, xanthan, sclerotium, carrageenan, pectin and combinations of these gums. Amounts of the thickener may range from 0.0001 to 5%, usually from 0.001 to 1%, optimally from 0.01 to 0.5% by weight.
Collectively the water, solvents, silicones, esters, fatty acids, humectants and/or thickeners will constitute the pharmaceutically acceptable carrier in amounts from 1 to 99.9%, preferably from 80 to 99% by weight.
Cosmetic compositions of the present invention may be in any form. These forms may include emulsified systems such as lotions and creams, microemulsions, roll-on formulations, mousses, ointments (hydrophilic and hydrophobic), aerosol and non-aerosol sprays and pad-applied formulations.
Surfactants may also be present in compositions of the present invention. Total concentration of the surfactant will range from 0.1 to 40%, preferably from 1 to 20%, optimally from 1 to 5% by weight of the composition. The surfactant may be selected from the group consisting of anionic, nonionic, cationic and amphoteric actives. Particularly preferred nonionic surfactants are those with a C.sub.10 -C.sub.20 fatty alcohol or acid hydrophobe condensed with from 2 to 100 moles of ethylene oxide or propylene oxide per mole of hydrophobe; C.sub.2 -C.sub.10 alkyl phenols condensed with from 2 to 20 moles of alkylene oxide; mono- and di- fatty acid esters of ethylene glycol; fatty acid monoglyceride; sorbitan, mono- and di- C.sub.8 -C.sub.20 fatty acids; block copolymers (ethylene oxide/propylene oxide); and polyoxyethylene sorbitan as well as combinations thereof. Alkyl polyglycosides and saccharide fatty amides (e.g. methyl gluconamides) are also suitable nonionic surfactants.
Preferred anionic surfactants include soap, alkyl ether sulfate and sulfonates, alkyl sulfates and sulfonates, alkylbenzene sulfonates, alkyl and dialkyl sulfosuccinates, C.sub.8 -C.sub.20 acyl isethionates, acyl glutamates, C.sub.8 -C.sub.20 alkyl ether phosphates and combinations thereof.
Preservatives can desirably be incorporated into the compositions of this invention to protect against the growth of potentially harmful microorganisms. Suitable traditional preservatives for compositions of this invention are alkyl esters of para-hydroxybenzoic acid. Other preservatives which have more recently come into use include hydantoin derivatives, propionate salts, and a variety of quaternary ammonium compounds. Cosmetic chemists are familiar with appropriate preservatives and routinely choose them to satisfy the preservative challenge test and to provide product stability. Particularly preferred preservatives are phenoxyethanol, methyl paraben, propyl paraben, imidazolidinyl urea, sodium dehydroacetate and benzyl alcohol. The preservatives should be selected having regard for the use of the composition and possible incompatibilities between the preservatives and other ingredients in the emulsion. Preservatives are preferably employed in amounts ranging from 0.01% to 2% by weight of the composition.
Keratolytic agents such as C.sub.2 -C.sub.25 .alpha.-hydroxy carboxylic and .beta.-hydroxycarboxylic acids may also be incorporated into compositions of this invention. Illustrative materials are glycolic, lactic, salicylic, .alpha.-hydroxyoctanoic acids and salts thereof. The salts may be selected from alkalimetal, ammonium and C.sub.1 -C.sub.20 alkyl or alkanolammonium counterions. Levels of these keratolytic agents may range from 0.001 to 10%, preferably between 0.2 and 8%, optimally between 1 and 4% by weight.
Minor adjunct ingredients may also be present in the compositions. Among these may be the water-insoluble vitamins such as Vitamin A Palmitate, Vitamin E Acetate and DL-panthenol.
Colorants, fragrances, opacifiers and abrasives may also be included in compositions of the present invention. Each of these substances may range from about 0.05 to about 5%, preferably between 0.1 and 3% by weight.

The following Examples will more fully illustrate embodiments of this invention. All parts, percentages and proportions referred to herein and in the appended claims are by weight unless otherwise indicated.
EXAMPLE 1
A series of tests were performed to evaluate the efficacy of acetaminophen to promote lightening of skin. Melanin synthesis effects by acetaminophen were evaluated in the B16 Melanoma Cell Test.
Test Method
Pigment producing cells derived from a mammalian melanoma are grown in culture by standard methods. Preferred cell lines are B16 or S-91 cells, but other lines or primary mouse or human melanocytes can be used.
Melanoma cells are grown in cell culture medium such as RPMI 1640 (GIBCO) supplemented with fetal calf serum and glutamine to approximately 1/3 confluence. The active is dissolved in culture medium, the pH adjusted as required and sterile filtered. The solution is then added to the cells.
The cells are cultured for a further period of 4 days and the amount of melanin produced assayed by measuring the absorbance at 540 nm of the melanin released into the medium.
Cell viability in the presence of the inhibitor is tested using neutral red (3-amino-7-dimethylamino-2-methyl phenazine hydrochloride), a water soluble vital dye which passes through the intact plasma membrane and becomes concentrated by lysosomes of viable cells. For any culture, the amount of dye taken up is proportional of the number of viable cells and agents that damage cell and lysosomal membranes to inhibit dye incorporation.
The cells are incubated in 50 .mu.g/ml neutral red solution for 3 hours at 37.degree. C. in 5% CO.sub.2 in air. The solution is aspirated, the cells washed once in saline and to them added a solvent (50% H.sub.2 O, 49% ethanol, 1% active acid) to solubilize the dye. The amount of neutral red dye is quantified by measuring absorbance at 540 nm.
Results
Results of the test are listed in Table I below. Lower values indicate improved success at inhibiting melanin (color) formation. The tabulated data demonstrates acetaminophen as having quite a significant effect on inhibiting melanin formation.
TABLE I______________________________________Melanin synthesis in B16 Melanoma Cells Melanin Synthesis* Viability** 100 uM 100 uMExperiment Control Acetaminophen Control Acetaminophen______________________________________1 0.206 0.126 1.649 2.1562 0.260 0.135 2.036 2.2773 0.243 0.126 1.854 2.2154 0.295 0.125 1.988 2.134Mean 0.235 0.128 2.048 2.196 (100%) (42.2%)*** (100%) (107%)SD 0.028 0.005 0.124 0.064______________________________________ *Measured as absarbance of culture medium at 540 nm **Neutral red dye uptake by cells, values are absorbance at 540 nm ***Significant compared to control, ttest, p < 0.000
EXAMPLE 2
A microemulsion formulation according to the present invention is outlined under Table II.
TABLE II______________________________________INGREDIENT WEIGHT (%)______________________________________PPG-5-Ceteth-20 4.00PEG-40 Hydrogenated Castor Oil 1.75Polyglyceryl-10 Decaoleate 10.50PEG-8 Caprylic/capric Glycerides 10.50SD Alcohol 40 12.00Isodecyl Neopentanoate 16.00Gyceryl Trioctanoate 8.00DC Silicone Fluid 3447 8.50Propylparaben 0.15Isostearic Acid 2.50Acetamino#hen 3.75Hydroxycaprilic Acid 0.10Tocopheryl Acetate 0.25Phenoxyethanol 0.30Deionized Water Q.S______________________________________
EXAMPLE 3
A skin lotion (water in oil type) formulation according to the present invention is outlined under Table III.
TABLE III______________________________________INGREDIENT WEIGHT (%)______________________________________Cetyl Dimethicone 2.50DC Silicone Fluid 3447 4.00DC Silicone Fluid 2007 (20 CST) 1.25Squalane 1.75Octyl Octanoate 2.00Zinc Myristate 1.25Dimethicone Copolyol 2.50Butylene Glycol 4.50Glycerin 1.50Sodium Hyaluronate 1.00Acetaminophen 6.00Salacos HS7 2.50Isostearic Acid 2.50Isononyl Isononanoate 3.75Hydroxycaprilic Acid 0.10Methylparaben 0.20Propylparaben 0.10Tocopheryl Acetate 0.55Phenoxyethanol 0.20Deionized Water Q.S______________________________________
EXAMPLE 4
A skin cream (oil in water type) with sunscreen formulation according to the present invention is outlined under Table IV.
TABLE IV______________________________________INGREDIENT WEIGHT (%)______________________________________Hydroxyethylcellulose 0.50Magnesium Aluminum Silicate 0.75Cocoa Butter 1.25Squalene 1.05Isostearyl Isononanoate 2.25DC Silicone Fluid 2007 (50 CST) 1.25DC Silicone Fluid 2007 (100 CST) 0.50Butylene Glycol 3.00Parsol MCX7 3.00Parsol 17897 3.00Glycerin 2.50Sodium Hyaluronate 0.50Acetaminophen 5.00Glycereth-7 Hydroxystearate 1.50Stearic Acid 3.50Cetyl/Stearyl Alcohol 2.55Sodium PCA 2.10Glyceryl Hydroxystearate 1.25Tocopheral 0.35Methylparaben 0.20Propylparaben 0.10Glydant .RTM. 0.30Steareth-20 1.20Disodium EDTA 0.05Triethanolamine 1.50Deionized Water Q.S______________________________________
EXAMPLE 5
An anhydrous system with an inorganic (titanium dioxide) sunscreen formulation according to the present invention is outlined under Table V.
TABLE V______________________________________INGREDIENT WEIGHT (%)______________________________________Zinc Oxide 8.00Sepigel 3057 1.50SD Alcohol 40 (200.degree.) 20.00Squalene 1.05Octyl Isononanoate 2.25DC Silicone Fluid 2007 (10 CST) 5.25Isononyl Isononanoate 30.00Butylene Glycol 1.00Tocopheryl Linoleate 0.50Propylparaben 0.10Tocopheryl Acetate 0.10Acetaminophen 2.75Dimethiconol 2.50DC Silicone Fluid 3447 QS______________________________________
EXAMPLE 6
A skin lotion (oil in water type) formulation according to the present invention is outlined under Table VI.
TABLE VI______________________________________INGREDIENT WEIGHT (%)______________________________________Xanthan Gum 0.20Magnesium Aluminum Silicate 0.75Shea Butter Glycerides 1.25Squalene 2.25Coco Caprylate/Caprate 3.25DC Silicone Fluid 2007 (50 CST) 0.75DC Silicone Fluid 2007 (50 CST) 0.50Butylene Glycol 3.00Glycerin 2.00Sodium Hyaluronate 0.35Acetaminophen 3.50Cetyl Alcohol 1.00DEA-Cetyl Phosphate 2.15Saccharide Isomerate 1.00Sodium PCA 2.10Sucrose Laurate 0.50Ceteth-2 0.50Methylparaben 0.20Propylparaben 0.10Germall 117 0.30Steareth-20 1.20Tocopheryl Acetate 0.20Disodium EDTA 0.05Lactic Acid 0.10Deionized Water Q.S______________________________________
EXAMPLE 7
A protective skin lotion with sunscreen formulation according to the present invention is outlined under Table VII.
TABLE VII______________________________________INGREDIENT WEIGHT (%)______________________________________Xanthan Gum 0.15Sepigel 5017 1.50Shea Butter 1.50Squalene 2.00Coco Caprylate/Caprate 2.25Propylene Glycol Dicaprylate/Dicaprate 3.55DC Silicone Fluid 2007 (20 CST) 0.50DC Silicone Fluid 2007 (350 CST) 1.00Butylene Glycol 3.00Glycerin 1.00Sodium Hyaluronate 0.35Acetaminophen 3.00Cetyl Alcohol 1.00DEA-Cetyl Phosphate 1.25Parsol MCX7 6.00Benzophenone-3 3.00Ceteth-2 0.50Ceteareth-20 1.20Methylparaben 0.30Propylparaben 0.15Glydant .RTM. 0.20Aloe Vera Gel 2.00Tacopheryl Acetate 0.30Disodium EDTA 0.05Deionized Water Q.S______________________________________
The foregoing description and Examples illustrate selected embodiments of the present invention. In light thereof, various modifications will be suggested to one skilled in the art, all of which are within the spirit and purview of this invention.

Number	Name	Date	Kind
4096240	Mathur	Jun 1978
5635469	Fowler et al.	Jun 1997

Method and composition for skin lightening

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