USOO823.6288B2

(12) United States Patent (10) Patent No.: US 8.236,288 B2 Mehta et al. (45) Date of Patent: Aug. 7, 2012

(54) MELANIN MODIFICATION COMPOSITIONS 5,217,709 A 6/1993 Lagrange et al. AND METHODS OF USE 5,508,310 A 4/1996 Rhodes 5,601,838 A 2, 1997 Hind 5,614, 179 A 3/1997 Murphy et al. (75) Inventors: Rahul C. Mehta, San Marcos, CA (US); 5,626,852 A 5, 1997 Sufis Elizabeth Tsin Ho Makino, Carlsbad, 5,656,638 A 8, 1997 Gaeta et al. 5,668,182 A 9, 1997 Abraham et al. CA (US); Sujatha D. Sonti, San Marcos, 5,733,535 A 3/1998 Hollingshead et al. CA (US); John A. Garruto, Encinitas, 5,747,537 A 5/1998 Gordon et al. CA (US) 5,760,085 A 6/1998 Becket al. 5,766,575 A 6/1998 Crotty et al. (73) Assignee: Skinnedica, Inc., Carlsbad, CA (US) 5,968.484 A 10, 1999 Habeck et al. 6,046,232 A 4/2000 Kelleher et al. 6,086,903. A 7/2000 Trinh et al. (*) Notice: Subject to any disclaimer, the term of this 6,126,930 A 10/2000 DuBois et al. patent is extended or adjusted under 35 6,146,650 A 1 1/2000 Redlinger U.S.C. 154(b) by 0 days. 6,204.229 B1 3/2001 Hasegawa 6,214,879 B1 4/2001 Abraham 6,248,763 B1 6/2001 Scivoletto (21) Appl. No.: 13/345,560 6,258,852 B1 7/2001 Flitter et al. 6,264,927 B1 7/2001 Monahan (22) Filed: Jan. 6, 2012 6,403,063 B1 6/2002 Sawyer 6,475,526 B1 1 1/2002 Smith (65) Prior Publication Data 6,482,839 B1 * 1 1/2002 Thornfeldt ...... 514,345 6,673,844 B2 1/2004 Kumamoto et al. US 2012/O177586 A1 Jul. 12, 2012 2003/010391.6 A1* 6/2003 Imanaka et al...... 424.62 2003/O1241.57 A1 7/2003 Engles et al. 2003. O1571.54 A1 8, 2003 Fuller et al. Related U.S. Application Data 2004/0254252 Al 12/2004 Engles et al. (60) Provisional application No. 61/430.923, filed on Jan. 2006/0257509 A1* 11/2006 Zimmerman et al...... 424.737 2008/0004354 A1* 1/2008 Engles et al...... 514,699 7, 2011. 2009, 0214628 A1 8/2009 De Rijk 2011/0217249 A1* 9, 2011 Dreher ...... 424,59 (51) Int. Cl. A6 IK 8/00 (2006.01) FOREIGN PATENT DOCUMENTS A6 IK 8/18 (2006.01) DE 3214658 A1 11F1982 A6 IK 8/02 (2006.01) (Continued) A61O 1704 (2006.01) (52) U.S. Cl...... 424/59: 424/401 OTHER PUBLICATIONS (58) Field of Classification Search ...... 424/59, 424/401 Arnold et al. “Evaluation of chemopreventive agents in different See application file for complete search history. mechanistic classes using a rattracheal epithelial cell culture trans formation assay” Cancer Res. 55:537 (1995). (56) References Cited (Continued) U.S. PATENT DOCUMENTS 3,598,122 A 8, 1971 Zaffaroni Primary Examiner — Mina Haghighatian 3,598,123 A 8, 1971 Zaffaroni Assistant Examiner — Luke Karpinski 3,710,795 A 1/1973 Higuchi et al. 3,731,683 A 5, 1973 Zaffaroni (74) Attorney, Agent, or Firm — Wilson, Sonsini, 3,742,951 A 7, 1973 Zaffaroni Goodrich & Rosati 3,814,097 A 6, 1974 Ganderton et al. 3,845,138 A 10/1974 Dunlop et al. 3,921,636 A 11/1975 Zaffaroni (57) ABSTRACT 3,972.995 A 8, 1976 Tsuk et al. 3,993,072 A 11, 1976 Zaffaroni A method for the modification of melanin distribution, and 3,993,073. A 11, 1976 Zaffaroni the composition thereof to modify melanin distribution are 3.996,934 A 12/1976 Zaffaroni disclosed. A method for the reduction of melanin distribution, 4,126,695 A 11, 1978 Razdan et al. and the composition thereof to reduce melanin distribution 4,147,770 A 4, 1979 Sichak are disclosed. A representative composition comprises 4,202,877 A 5, 1980 Sato et al. 4,290,974 A 9, 1981 Boillon et al. 4-ethoxybenzaldehyde and one or more additional active 4,391,603 A 7, 1983 Rosenbaum et al. agents as well as a pharmaceutically acceptable carrier or 4,654,167 A 3/1987 Degner et al. excipient. Carriers and excipients may beformulated for topi 4,668,712 A 5, 1987 Hino et al. cal administration. Compositions may also be formulated for 4,714,609 A 12/1987 Carden 4,714,786 A 12/1987 Wuest et al. transdermal administration. The compositions may be used 4,802,924 A 2f1989 Woznicki et al. for the prevention and treatment of pigmentation disorders, 4,857,328 A 8, 1989 Trenzeluk by way of non-limited example, post-inflammatory hyperpig 4,992.445 A 2f1991 Lawter et al. mentation and others. The compositions may be used for 4,997,850 A 3, 1991 Kimura et al. lightening skin. 5,001,139 A 3, 1991 Lawter et al. 5,023,252 A 6, 1991 HSeih 5,100,654 A 3, 1992 Pawelek et al. 9 Claims, 9 Drawing Sheets US 8,236.288 B2 Page 2

FOREIGN PATENT DOCUMENTS Ciccognani D. Cosmetic Preservation Using Enzymes, in "Cosmetic EP O022229 A1 1, 1981 and Drug Microbiology”. Orth DS ed., Francis & Taylor, Boca Raton, EP 0044970 B1 2, 1982 FL (2006). EP 0044976 2, 1982 Clericietal. “In vitro immunomodulatory properties of Tucaresol in EP O193257 9, 1986 HIV infection” Clin. Immunology 97:211 (2000). EP O332175 A2 9, 1989 Farah et al., “Pharmacologically Active Prenylpropanoids from EP O395441 10, 1990 Senra Incana'. Plainta Medica, (1992), vol. 58, No. 1, pp. 14-18. EP O635208 1, 1995 Felton et al., “New Class of Broad Spectrum Antibacterials'. TGA EP O914817 A1 5, 1999 Cosmetic J., (1970), vol. 2, No. 1, pp. 16-19. EP O9854.08 3, 2000 Glenn "Anomalous biological effects of salicylates and GB 1545954 4f1976 prostaglandins' Agents Actions 9:257 (1979). GB 2244645 A 12/1991 Inaoka et al. “Study on hair regrowth promoting Substances from the JP 52-044375 11, 1977 potent herbs, especially Polyporus umbellatus F.” Tennen Yuki JP 55-045656 3, 1980 Kagobutsu Toronkai Koen Yoshishu 36:32 (1994) (with English JP 55-045659 3, 1980 abstract). JP 56-0 12310 2, 1981 Jimenez et al., Competitive inhibition of mushroom tyrosinase by JP 60-067424 4f1985 4-substituted benzakdehydes, Journal of Agricultural and Food JP 61-0257904 11, 1986 Chemistry, (2001), vol. 49, No. 8, pp. 4060-4063. JP 60-04892.9 2, 1994 Kubo et al. “2-hydroxy-4-methoxybenzaldehyde: A potent JP O6-329.516 11, 1994 tyrosinase inhibitor in african medicinal plants' Planta Med. 65:19 JP 63-029516 11, 1994 (1999). JP O7-002640 1, 1995 Magae et al. "Antitumor protective property of an isoprenoid antibi JP O7-242558 9, 1995 otic, ascofuranone” Journal of Antibiotics 35:1547 (1982). JP T2-042558 9, 1995 Nguyen et al., “Investigation on anti-acute inflammatory action of JP O7-258042 10, 1995 beta-aminoketone, a derivative of vaniline.' Pharmaceutical Journal JP O7-258074 10, 1995 (Vietnamese) 3:18 (2001) (with complete English translation). JP O7-300412 11, 1995 JP 73-000412 11, 1995 Nomura et al., Studies on the utilization of cashew nut shell oil. III. JP O1-106639 4/2001 Systhesis of 6-(Z.ii7)-8, 11, 14-pentadecatrienyl salicylic acid WO WO92-09276 6, 1992 derivatives and their inhibition properties toward tyrosinase or WO WO 97-4728O 12/1997 hyauronidase, Nippon Kagaku Kaishi, (1995), pp.986-993, vol. 12. WO WO99-03446 1, 1999 Oikawa et al., “Oxidative DNA Damage and Apoptosis Induced by WO WO99-06388 2, 1999 Metabolites of Butylated Hydroxtolune, Biochemical Pharmacol WO WO99-07336 2, 1999 ogy”. Elsevier, (1998), vol. 56, pp. 361-370. WO WO99-22703 5, 1999 Opdyke, D. L. J., “Monographs on fragrance raw materials WO WOOO-38653 T 2000 p-Ethoxybenaldehyde' Food and Cosmetic Toxicology, (1980), vol. WO WOOO-74697 12/2000 18, No. 6, p. 681. WO WOO1-28507 A1 4/2001 Reddy et al. “Studies on anti-inflammatory activity of spice prin WO WOO1-3410.6 A1 5, 2001 ciples and dietary n-3 polyunsaturated fatty acids on carrageenan WO WOO1-76626 10, 2001 WO WO O2-083624 A1 10, 2002 induced inflammation in rats' Ann. Nutr. Metab. 38:34958 (1994). WO WO 03-000214 A1 1, 2003 Remington: The Science and Practice of Pharmacy, 20" Edition, ed. WO WO-2004-103233 12, 2004 By Alfonso R. Gennaro (2000) published by Lippincott Williams and Wilkins, pp. 747-748,849,856. WO WO-2008-070368 6, 2008 Remington: The Science and Practice of Pharmacy.20" Edition, OTHER PUBLICATIONS (2000) Published by the Philadelphia College of Pharmacy and Sci ence, Edited by Alfonso R. Gennaro et al., pp. 836-844 and 917-918. Batt et al., “2-Substituted-1-naphtols as potent 5-lipoxygenase Remington's Pharmaceutical Sciences, 18' Ed., Part 8, “Pharmaceu inhibitors with topical anti-inflammatory activity”, Journal of tical Preparations and their Manufacture', (1990), pp. 1435-1693, Mack Publishing Company, Easton, PA. Medicinal Chemistry, (1990), vol. 33, No. 1, pp. 360-370. Van Den Worm et al., “Effects of Methoxylation of Apocyanin and Burton et al., The mechanism of the antibacterial action of phenols Analogs on the Inhibition of Reactive Oxygen Species Production by and salicylaldehydes. III. Substituted Benzaldehydes, J. Chem. Soc., Stimulated Human Neutrophils'. Eur, J. Pharmacol., (2001), vol. (1964) pp. 2458-2460. 433, No. 2-3, pp. 225-230. Chang et al., “Benzyloxybenzaldehyde Analogues as Novel Adenyl Whitehouse et al "Alternatives to aspirin, derived from biological Cyclase Activators'. Bioorg. Med. Chem. Letters, (2001), vol. 11, sources' Agents Actions Suppl. 1:43-57 (1977). No. 15, pp. 1871-1974. PCT/US2012/020550 International Search Report and Writ. Op. Chen et al. “Effects of IHT64-3 on chemotactic migration of dated May 14, 2012. neutrophils induced by rhIL-8” Chinese Journal Pathophysiology 15:781 (1999) (with English abstract). * cited by examiner U.S. Patent Aug. 7, 2012 Sheet 1 of 9 US 8,236.288 B2

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isgroves the eyes: app: 388 of. i x83 is 3x8:8: US 8,236,288 B2 1. 2 MELANN MODIFICATION COMPOSITIONS able carrier. In some embodiments, the substituted benzalde AND METHODS OF USE hyde is 2-ethoxybenzaldehyde, 4-ethoxybenzaldehyde, 4-al lyloxybenzaldehyde or 4-propoxybenzaldehyde. In a CROSS-REFERENCE particular embodiment, the substituted benzaldehyde is 4-ethoxybenzaldehyde. In yet another embodiment, the sub This application claims the benefit of U.S. Provisional stituted benzaldehyde is 2-ethoxybenzaldehyde. Application No. 61/430,923, filed Jan. 7, 2011, which appli In some embodiments, the pharmaceutically or cosmeti cation is incorporated herein by reference in its entirety. cally acceptable carrier is an oral or topical carrier. In other embodiments, the pharmaceutically or cosmetically accept BACKGROUND OF THE INVENTION 10 able topical carrier is a water-in-oil emulsion, cream, liquid, gel, oil, paste, ointment, Suspension, foam, lotion, oil-in Melanin in humans is the primary determinant of skin water emulsion, water-in-oil-in-water emulsion, water-in color. Melanin in skin is produced by melanocytes in the silicone emulsion, spray or serum carrier. In certain embodi epidermis in response to environmental triggers, such as ments, the composition is topically administered to the skin of increased Sun exposure, or other physical or chemical pertur 15 the individual. In other embodiments, the composition is bation. Melanin is also found in hair, the pigmented tissue transdermally administered to the skin of the individual. underlying the iris of the eye, as well as the stria vascularis of In some embodiments, the compositions further comprise the inner ear. at least one additional active agent. In some embodiments, the Environmental and/or physiological stress can cause dis compositions further comprise at least two additional active orders in melanin production. For example, post-inflamma agents. In some embodiments, the compositions further com tory hyperpigmentation (“PIH) represents the sequelae of prise at least three additional active agents. An additional various cutaneous disorders, including infections, allergic active agent may be, for example, an antioxidant, a Sunscreen, reactions, mechanical injuries, reactions to medications, pho a Sunprotectant, a Sunblock, a skin-lightening agent, an anti totoxic eruptions, trauma (e.g., burns), inflammatory diseases inflammatory agent, an anti-acne agent or mixtures thereof. (e.g., lichen planus, lupus erythematosus and atopic derma 25 In other embodiments, the compositions further comprise one titis), as well as reactions to devices, including electromag or more of a solvent, film former, preservative, viscosity netic devices such as ultrasound, radiofrequency, lasers, increasing agent, fragrance, Surfactant, chelating agent, light-emitting diodes and visible light therapy, as well as humectant, or a combination thereof. In yet another embodi microdermabrasion reactions. PIH occurs widely in the ment, a composition comprises an antioxidant selected from human population and can be the Source of significant psy 30 the group of niacinamide, Vitamin E. Coenzyme Q10, ide chosocial distress for those affected with this disorder. PIHis benone, lycopene, green tea polyphenols, Silybin, resveratrol, a pathophysiologic response to cutaneous inflammation. grape seed extract, Oregon grape root (Mahonia aquifolium) Melanocytes can be stimulated by the inflammatory process extract, pomegranate extract, genistein, pycnogenol, cur to synthesize and secrete more melanin from melanocytes, or cumin, curcuminoids, or combinations thereof. In yet another the number of melanocytes can increase in the epidermis, 35 embodiment, a composition comprises niacinamide, butylene leading to hyperpigmentation of the skin. PIH can also occur glycol, tetrahexyldecyl ascorbate, caprylic/capric triglycer when inflammation disrupts the basal cell layer, causing ides, polyacrylate-13, cetyl ethylhexanoate, phenoxyethanol, melanin pigment to be released and Subsequently trapped by hexylresorcinol, ethyllinoleate, polyisobutene, 4-ethoxyben macrophages in the papillary dermis. Hyperpigmentation or Zaldehyde, squalene, tocopherol, potassium Sorbate, retinol, hypermelanosis disorders due to environmental stressors, 40 polysorbate 20, ethylhexylglycerine, phytic acid, disodium Such as hormonal imbalance, can also affect melanin or pig EDTA, dunaliella salina extract and water. mentation levels in the skin. In another embodiment, the compositions comprise a skin lightening agent selected from the group of hydroquinone, SUMMARY OF THE INVENTION monobenzyl ether of hydroquinone, azelaic acid, kojic acid, 45 meduinol, retinoids (e.g., tretinoin, adapalene), soy proteins, Provided herein are pharmaceutical and cosmetic compo alpha-hydroxy acids (e.g., glycolic acid), trichloroacetic acid, sitions and methods of treating disorders relating to pigmen salicylic acid, hydroquinone-beta-D-glucopyranoside, paper tation or melanin levels. Provided herein are pharmaceutical mulberry, glabridin, 4-isopropylcetichol, aleosin, N-acetyl-4- and cosmetic compositions and methods of lightening skin. In S-cycteaminylphenol, N-propionyl-4-S-cysteaminylphenol, Some embodiments, the composition comprises a Substituted 50 N-acetyl glucosamine, tranexaminc acid, licorice extract benzaldehyde such as, for example 4-ethoxybenzaldehye. In (e.g., Glycyrrhiza Glabra (licorice) root extract), an alpha other embodiments, the composition comprises a Substituted MSH antagonist (e.g., undecylenoyl phenylalanine), phytic benzaldehyde and at least one additional active agent. Certain acid or combinations thereof. embodiments disclosed herein provide a method for modu In one aspect, provided herein is a composition comprising lating PGF2-alpha levels. Other embodiments provide a 55 from about 0.01% to about 2% substituted benzaldehyde, method for the treatment of pigmentation disorders compris about 0.01% to about 5.0% each of Retinol, Niacinamide, ing administration of the composition to an individual. The Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice) inventors of the present application identified for the first time Root Extract, Hexyl Resorcinol, ethyl linoleate, and a phar that the compositions described herein may be use to treat maceutically or cosmetically acceptable carrier. In one post-inflammatory hyperpigmentation (PIH), where inflam 60 embodiment, the amount of substituted benzaldehyde is mation is not treated. It was also indentified for the first time about 0.5%. In another embodiment, the composition com that the compositions described herein lighten skin. prises from about 0.1% to about 0.75%, from about 0.05% to In one aspect, provided herein is a method is presented for about 1.0%, or from about 0.01% to about 2% Retinol. In modifying melanin distribution in an individual, the method another embodiment, the composition comprises from about comprising administering to the individual in need thereofan 65 2.0% to about 8.0%, from about 1% to about 10%, or from effective amount of a composition comprising a Substituted about 0.5% to about 15.0% Niacinamide. In another embodi benzaldehyde and a pharmaceutically or cosmetically accept ment, the composition comprises from about 1.0% to about US 8,236,288 B2 3 4 5.0%, from about 0.5% to about 8.0%, or from about 0.1% to inflammatory hyperpigmentation. Hyperpigmentation and about 15% Tetrahexyldecyl Ascorbate. In another embodi hypermelanosis disorders may result from an environmental ment, the composition comprises from about 0.001% to about stressor, physiological stressor, or mechanical stressor. 0.5%, from about 0.0005% to about 1.0% or from about Compositions described herein may reduce melanin distri 0.0001% to about 2% Licorice root extract. In another bution by about 10% to about 40% when applied to skin. embodiment, the composition comprises from about 0.1% to Compositions described herein may further comprise one about 3.0%, from about 0.05% to about 5.0%, or from about or more additional active agents. An additional active agent 0.01% to about 10.0% Resorcinol. In another embodiment, may be, for example, an antioxidant, a Sunscreen, a Sunpro the composition comprises from about 0.1% to about 3.0%, tectant, a Sunblock, a skin-lightening agent, an anti-inflam from about 0.05% to about 5.0%, or from about 0.01% to 10 matory agent, an anti-acne agent or mixtures thereof. about 10.0% ethyl linoleate. In one embodiment, an antioxidant is selected from the Substituted benzaldehydes for use in the compositions group of vitamin E. Coenzyme Q10, idebenone, lycopene, include, for example, 2-ethoxybenzaldehyde, 4-ethoxyben green tea polyphenols, Silybin, resveratrol, grape seed Zaldehyde, 4-allyloxybenzaldehyde or 4-propoxybenzalde extract, Oregon grape root (Mahonia aquifolium) extract, hyde. In one embodiment, the substituted benzaldehyde is 15 pomegranate extract, genistein, pycnogenol, curcumin, cur 4-ethoxybenzaldehyde, which may be present in the compo cuminoids, Tocopherol, Dunaliella Salina Extract or combi sition in an amount of about 0.5%. nations thereof. In another aspect, provided herein is a composition com In one embodiment, a skin-lightening agent is selected prising from about 0.1% to about 0.5% 4-ethoxybenzalde from the group of hydroquinone, monobenzyl ether of hyd hyde, about 0.01% to about 5.0% each of Retinol, Niacina roquinone, azelaic acid, kojic acid, meduinol, retinoids, Soy mide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra proteins, alpha-hydroxy acids, trichloroacetic acid, salicylic (Licorice) Root Extract, Hexyl Resorcinol, ethyl linoleate, acid, hydroquinone-beta-D-glucopyranoside, paper mul and a pharmaceutically or cosmetically acceptable carrier. In berry, glabridin, 4-isopropylcetichol, aleosin, N-acetyl-4-S- one embodiment, the composition comprises from about cycteaminylphenol, N-propionyl-4-S-cysteaminylphenol, 0.1% to about 0.75%, from about 0.05% to about 1.0%, or 25 N-acetyl glucosamine, tranexaminc acid, an alpha MSH from about 0.01% to about 2%. Retinol. In another embodi antagonist (e.g. undecylenoyl phenylalanine), phytic acid or ment, the composition comprises from about 2.0% to about combinations thereof. 8.0%, from about 1% to about 10%, or from about 0.5% to Pharmaceutically or cosmetically acceptable carriers for about 15.0% Niacinamide. In another embodiment, the com use in the present compositions are topical carriers. The topi position comprises from about 1.0% to about 5.0%, from 30 cal carrier may be a water-in-oil emulsion, cream, liquid, gel. about 0.5% to about 8.0%, or from about 0.1% to about 15% oil, paste, ointment, Suspension, foam, lotion, oil-in-water Tetrahexyldecyl Ascorbate. In another embodiment, the com emulsion, water-in-oil-in-water emulsion, water-in-silicone position comprises from about 0.001% to about 0.5%, from emulsion, spray or serum carrier. about 0.0005% to about 1.0% or from about 0.0001% to about The compositions described herein may also further com 2% Licorice root extract. In another embodiment, the com 35 prise one or more of a solvent, film former, preservative, position comprises from about 0.1% to about 3.0%, from Viscosity increasing agent, fragrance, Surfactant, chelating about 0.05% to about 5.0%, or from about 0.01% to about agent, humectant, permeation enhancer, excipients, or a com 10.0% Resorcinol. In another embodiment, the composition bination thereof. comprises from about 0.1% to about 3.0%, from about 0.05% In one embodiment, a composition comprises from about to about 5.0%, or from about 0.01% to about 10.0% ethyl 40 0.1% to about 0.5% 4-ethoxybenzaldehyde, at least one addi linoleate. tional active agent, and a pharmaceutically or cosmetically In yet another aspect, provided herein is a composition acceptable carrier. In other embodiment, a composition com comprising about 0.5% 4-ethoxybenzaldehyde, about 0.01% prises from about 0.1% to about 0.5% 4-ethoxybenzalde to about 5.0% each of Retinol, Niacinamide, Tetrahexyldecyl hyde, at least two additional active agents, and a pharmaceu Ascorbate, Glycyrrhiza Glabra (Licorice) Root Extract, 45 tically or cosmetically acceptable carrier. In yet other Hexyl Resorcinol, ethyllinoleate, and a pharmaceutically or embodiment, a composition comprises from about 0.1% to cosmetically acceptable carrier. In one embodiment, the com about 0.5% 4-ethoxybenzaldehyde, at least three additional position comprises from about 0.1% to about 0.75%, from active agents, and a pharmaceutically or cosmetically accept about 0.05% to about 1.0%, or from about 0.01% to about 2% able carrier. In yet other embodiment, a composition com Retinol. In another embodiment, the composition comprises 50 prises from about 0.1% to about 0.5% 4-ethoxybenzalde from about 2.0% to about 8.0%, from about 1% to about 10%, hyde, at least four additional active agents, and a or from about 0.5% to about 15.0% Niacinamide. In another pharmaceutically or cosmetically acceptable carrier. In yet embodiment, the composition comprises from about 1.0% to other embodiment, a composition comprises from about about 5.0%, from about 0.5% to about 8.0%, or from about 0.1% to about 0.5% 4-ethoxybenzaldehyde, at least five addi 0.1% to about 15% Tetrahexyldecyl Ascorbate. In another 55 tional active agents, and a pharmaceutically or cosmetically embodiment, the composition comprises from about 0.001% acceptable carrier. In yet other embodiment, a composition to about 0.5%, from about 0.0005% to about 1.0% or from comprises from about 0.1% to about 0.5% 4-ethoxybenzal about 0.0001% to about 2% Licorice root extract. In another dehyde, at least six additional active agents, and a pharma embodiment, the composition comprises from about 0.1% to ceutically or cosmetically acceptable carrier. In yet other about 3.0%, from about 0.05% to about 5.0%, or from about 60 embodiment, a composition comprises from about 0.1% to 0.01% to about 10.0% Resorcinol. In another embodiment, about 0.5% 4-ethoxybenzaldehyde, at least seven additional the composition comprises from about 0.1% to about 3.0%, active agents, and a pharmaceutically or cosmetically accept from about 0.05% to about 5.0%, or from about 0.01% to able carrier. about 10.0% ethyl linoleate. In one embodiment, a composition comprises about 0.5% Compositions described herein may be used to lighten skin 65 4-ethoxybenzaldehyde, at least one additional active agent, as well as to treat hyperpigmentation or a hypermelanosis and a pharmaceutically or cosmetically acceptable carrier. In disorder. In one embodiment, the hyperpigmentation is post other embodiment, a composition comprises about 0.5% US 8,236,288 B2 5 6 4-ethoxybenzaldehyde, at least two additional active agents, embodiments, the pharmaceutically or cosmetically accept and a pharmaceutically or cosmetically acceptable carrier. In able topical carrier is a water-in-oil emulsion, cream, liquid, yet other embodiment, a composition comprises about 0.5% gel, oil, paste, ointment, Suspension, foam, lotion, oil-in 4-ethoxybenzaldehyde, at least three additional active agents, water emulsion, water-in-oil-in-water emulsion, water-in and a pharmaceutically or cosmetically acceptable carrier. In silicone emulsion, spray or serum carrier. In certain embodi yet other embodiment, a composition comprises about 0.5% ments, the composition is topically administered to the skin of 4-ethoxybenzaldehyde, at least four additional active agents, the individual. In other embodiments, the composition is and a pharmaceutically or cosmetically acceptable carrier. In transdermally administered to the skin of the individual. yet other embodiment, a composition comprises about 0.5% In some embodiments, the compositions further comprise 4-ethoxybenzaldehyde, at least five additional active agents, 10 at least one additional active agent. In particular embodi and a pharmaceutically or cosmetically acceptable carrier. In ments, an additional active agent may be, for example, an yet other embodiment, a composition comprises about 0.5% antioxidant, a Sunscreen, a Sunprotectant, a Sunblock, a skin 4-ethoxybenzaldehyde, at least six additional active agents, lightening agent, an anti-inflammatory agent, an anti-acne and a pharmaceutically or cosmetically acceptable carrier. In agent or mixtures thereof. In yet another embodiment, the yet other embodiment, a composition comprises about 0.5% 15 compositions comprise an antioxidant selected from the 4-ethoxybenzaldehyde, at least seven additional active group of niacinamide, Vitamin E. Coenzyme Q10, idebenone, agents, and a pharmaceutically or cosmetically acceptable lycopene, green tea polyphenols, Silybin, resveratrol, grape carrier. seed extract, Oregon grape root (Mahonia aquifolium) In one embodiment, a composition comprises from about extract, pomegranate extract, genistein, pycnogenol, cur 0.1% to about 0.5% 4-ethoxybenzaldehyde, at least one skin cumin, curcuminoids, or combinations thereof. In another lightening agent, at least one skin conditioning agent, at least embodiment, the compositions comprise a skin-lightening one antioxidant, at least one occlusive, at least one emollient, agent selected from the group of hydroquinone, monobenzyl at least one preservative, at least one viscosity increasing ether of hydroquinone, azelaic acid, kojic acid, meduinol, agent, at least one fragrance, at least one skin conditioning retinoids (e.g., tretinoin, adapalene), soy proteins, alpha-hy agent, at least one Surfactant, at least one chlating agent, at 25 droxyacids (e.g., glycolic acid), trichloroacetic acid, salicylic least one humectant, and a pharmaceutically or cosmetically acid, hydroquinone-beta-D-glucopyranoside, paper mul acceptable carrier. berry, glabridin, 4-isopropylcetichol, aleosin, N-acetyl-4-S- On another embodiment, a composition comprises about cycteaminylphenol, N-propionyl-4-S-cysteaminylphenol, 0.5% 4-ethoxybenzaldehyde, at least one skin lightening N-acetyl glucosamine, tranexaminc acid, licorice extract agent, at least one skin conditioning agent, at least one anti 30 (e.g., Glycyrrhiza Glabra (licorice) root extract), an alpha oxidant, at least one occlusive, at least one emollient, at least MSH antagonist (e.g. undecylenoyl phenylalanine), phytic one preservative, at least one viscosity increasing agent, at acid or combinations thereof. least one fragrance, at least one skin conditioning agent, at In some embodiments, the substituted benzaldehyde com least one surfactant, at least one chlating agent, at least one position modifies melanin distribution by about 10%, by humectant, and a pharmaceutically or cosmetically accept 35 about 15%, by about 20%, by about 25%, by about 30%, by able carrier. about 35%, by about 40%, by about 45%, by about 50%, by In some embodiments, the substituted benzaldehyde com about 55%, by about 60%, by about 65%, by about 70%, by position modifies melanin distribution by about 10%, by about 75%, by about 80%, by about 85%, by about 90%, by about 15%, by about 20%, by about 25%, by about 30%, by about 95% or by about 100%. In other embodiments, the about 35%, by about 40%, by about 45%, by about 50%, by 40 Substituted benzaldehyde composition reduces melanin dis about 55%, by about 60%, by about 65%, by about 70%, by tribution by about 10%, by about 15%, by about 20%, by about 75%, by about 80%, by about 85%, by about 90%, by about 25%, by about 30%, by about 35%, by about 40%, by about 95% or by about 100%. In another embodiment, the about 45%, by about 50%, by about 55%, by about 60%, by Substituted benzaldehyde composition reduces melanin dis about 65%, by about 70%, by about 75%, by about 80%, by tribution by about 10%, by about 15%, by about 20%, by 45 about 85%, by about 90%, by about 95% or by about 100%. about 25%, by about 30%, by about 35%, by about 40%, by In another embodiment, the substituted benzaldehyde com about 45%, by about 50%, by about 55%, by about 60%, by position reduces melanin distribution by about 5% to about about 65%, by about 70%, by about 75%, by about 80%, by 50%. In yet another embodiment, the substituted benzalde about 85%, by about 90%, by about 95% or by about 100%. hyde composition reduces melanin distribution by about 10% In another embodiment, the substituted benzaldehyde com 50 to about 40%. position reduces melanin distribution by about 5% to about In a further aspect, provided herein is a method of treating 50%. In yet another embodiment, the substituted benzalde a melanin disorder in an individual comprising contacting hyde composition reduces melanin distribution by about 10% keratinocytes with an effective amount of a composition com to about 40%. prising a Substituted benzaldehyde and a pharmaceutically or Another aspect relates to a method of modifying melanin 55 cosmetically acceptable carrier. In some embodiments, the distribution in an individual, the method comprising contact substituted benzaldehyde is 2-ethoxybenzaldehyde, ing keratinocytes with an effective amount of a composition 4-ethoxybenzaldehyde, 4-allyloxybenzaldehyde or 4-pro comprising a Substituted benzaldehyde and a pharmaceuti poxybenzaldehyde. In a specific embodiment, the substituted cally or cosmetically acceptable carrier. In some embodi benzaldehyde is 4-ethoxybenzaldehyde. In yet another ments, the substituted benzaldehyde is 2-ethoxybenzalde 60 embodiment, the substituted benzaldehyde is 2-ethoxyben hyde, 4-ethoxybenzaldehyde, 4-allyloxybenzaldehyde or Zaldehyde. 4-propoxybenzaldehyde. In a particular embodiment, the In some embodiments, the pharmaceutically or cosmeti substituted benzaldehyde is 4-ethoxybenzaldehyde. In yet cally acceptable carrier is an oral or topical carrier. In other another embodiment, the substituted benzaldehyde is embodiments, the pharmaceutically or cosmetically accept 2-ethoxybenzaldehyde. 65 able topical carrier is a water-in-oil emulsion, cream, liquid, In some embodiments, the pharmaceutically or cosmeti gel, oil, paste, ointment, Suspension, foam, lotion, oil-in cally acceptable carrier is an oral or topical carrier. In other water emulsion, water-in-oil-in-water emulsion, water-in US 8,236,288 B2 7 8 silicone emulsion, spray or serum carrier. In one embodiment, able topical carrier is a water-in-oil emulsion, cream, liquid, the cell is present in an individual. In another embodiment, gel, oil, paste, ointment, Suspension, foam, lotion, oil-in the composition is topically administered to the skin of the water emulsion, water-in-oil-in-water emulsion, water-in individual. In yet another embodiment, the composition is silicone emulsion, spray or serum carrier. In another embodi transdermally administered to the skin of the individual. ment, the composition is topically administered to the skin of In some embodiments, the compositions further comprise the individual. In yet another embodiment, the composition is an additional active agent. In particular embodiments, the transdermally administered to the skin of the individual. additional active agent is an antioxidant, a Sunscreen, a Sun In some embodiments, the compositions further comprise protectant, a Sunblock, a skin-lightening agent, an anti-in an additional active agent. In particular embodiments, the flammatory agent, an anti-acne agent or mixtures thereof. In 10 additional active agent is an antioxidant, a Sunscreen, a Sun yet another embodiment, the compositions comprise an anti protectant, a Sunblock, a skin-lightening agent, an anti-in oxidant selected from the group of niacinamide, vitamin E, flammatory agent, an anti-acne agent or mixtures thereof. In Coenzyme Q10, idebenone, lycopene, green tea polyphenols, yet another embodiment, the compositions comprise an anti Silybin, resveratrol, grape seed extract, Oregon grape root oxidant selected from the group of niacinamide, Vitamin E, (Mahonia aquifolium) extract, pomegranate extract, 15 Coenzyme Q10, idebenone, lycopene, green tea polyphenols, genistein, pycnogenol, curcumin, curcuminoids, or combina Silybin, resveratrol, grape seed extract, Oregon grape root tions thereof. In another embodiment, the compositions com (Mahonia aquifolium) extract, pomegranate extract, prise a skin-lightening agent selected from the group of hyd genistein, pycnogenol, curcumin, curcuminoids, or combina roquinone, monobenzyl ether of hydroquinone, azelaic acid, tions thereof. In another embodiment, the compositions com kojic acid, meduinol, retinoids (e.g., tretinoin, adapalene), prise a skin-lightening agent selected from the group of hyd soy proteins, alpha-hydroxy acids (e.g., glycolic acid), roquinone, monobenzyl ether of hydroquinone, azelaic acid, trichloroacetic acid, salicylic acid, hydroquinone-beta-D- kojic acid, meduinol, retinoids (e.g., tretinoin, adapalene), glucopyranoside, paper mulberry, glabridin, 4-isopropyl soy proteins, alpha-hydroxy acids (e.g., glycolic acid), cetichol, aleosin, N-acetyl-4-S-cycteaminylphenol, N-propio trichloroacetic acid, Salicylic acid, hydroquinone-beta-D- nyl-4-S-cysteaminylphenol, N-acetyl glucosamine, 25 glucopyranoside, paper mulberry, glabridin, 4-isopropyl tranexaminc acid, licorice extract (e.g., Glycyrrhiza Glabra cetichol, aleosin, N-acetyl-4-S-cycteaminylphenol, N-propio (licorice) root extract), an alpha MSH antagonist (e.g. unde nyl-4-S-cysteaminylphenol, N-acetyl glucosamine, cylenoyl phenylalanine), phytic acidor combinations thereof. tranexaminc acid, licorice extract (e.g., Glycyrrhiza Glabra In a particular embodiment, the substituted benzaldehyde (licorice) root extract), an alpha MSH antagonist (e.g. unde composition modifies melanin distribution by about 10%, by 30 cylenoyl phenylalanine), phytic acidor combinations thereof. about 15%, by about 20%, by about 25%, by about 30%, by In a particular embodiment, the substituted benzaldehyde about 35%, by about 40%, by about 45%, by about 50%, by composition modifies melanin distribution by about 10%, by about 55%, by about 60%, by about 65%, by about 70%, by about 15%, by about 20%, by about 25%, by about 30%, by about 75%, by about 80%, by about 85%, by about 90%, by about 35%, by about 40%, by about 45%, by about 50%, by about 95% or by about 100%. In another embodiment, the 35 about 55%, by about 60%, by about 65%, by about 70%, by Substituted benzaldehyde composition reduces melanin dis about 75%, by about 80%, by about 85%, by about 90%, by tribution by about 10%, by about 15%, by about 20%, by about 95% or by about 100%. In another embodiment, the about 25%, by about 30%, by about 35%, by about 40%, by Substituted benzaldehyde composition reduces melanin dis about 45%, by about 50%, by about 55%, by about 60%, by tribution by about 10%, by about 15%, by about 20%, by about 65%, by about 70%, by about 75%, by about 80%, by 40 about 25%, by about 30%, by about 35%, by about 40%, by about 85%, by about 90%, by about 95% or by about 100%. about 45%, by about 50%, by about 55%, by about 60%, by In another embodiment, the substituted benzaldehyde com about 65%, by about 70%, by about 75%, by about 80%, by position reduces melanin distribution by about 5% to about about 85%, by about 90%, by about 95% or by about 100%. 50%. In yet another embodiment, the substituted benzalde In another embodiment, the substituted benzaldehyde com hyde composition reduces melanin distribution by about 10% 45 position reduces melanin distribution by about 5% to about to about 40%. 50%. In yet another embodiment, the substituted benzalde In some embodiments, provided herein is a method of hyde composition reduces melanin distribution by about 10% treating a hyperpigmentation skin disorder in an individual in to about 40%. need thereof, the method comprising administering to the In some embodiments, provided herein are methods of skin of the individual an effective amount of a composition 50 treating hyperpigmentation or a hypermelanosis disorder in comprising a Substituted benzaldehyde and a pharmaceuti an individual, comprising administering to the individual in cally or cosmetically acceptable carrier. In some embodi need thereof an effective amount of a composition compris ments, the substituted benzaldehyde is 2-ethoxybenzalde ing: from about 0.01% to about 2% substituted benzaldehyde hyde, 4-ethoxybenzaldehyde, 4-allyloxybenzaldehyde or and a pharmaceutically or cosmetically acceptable carrier. 4-propoxybenzaldehyde. In a specific embodiment, the Sub 55 In one embodiment, the method further comprises admin stituted benzaldehyde is 4-ethoxybenzaldehyde. In yet istering to the individual in need thereof an effective amount another embodiment, the substituted benzaldehyde is of about 0.01% to about 5.0% each of Retinol, Niacinamide, 2-ethoxybenzaldehyde. Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice) In some embodiments, the hyperpigmentation skin disor Root Extract, Hexyl Resorcinol, ethyl linoleate. In another der results from an environmental stressor, physiological 60 embodiment, the composition comprises from about 0.1% to stressor, or mechanical stressor. In a particular embodiment, about 0.75%, from about 0.05% to about 1.0%, or from about the physiological stressor is a hormonal disorder. In yet 0.01% to about 2%. Retinol. In another embodiment, the another embodiment, the environmental stressor is excessive composition comprises from about 2.0% to about 8.0%, from Sun exposure or chemical exposure. about 1% to about 10%, or from about 0.5% to about 15.0% In some embodiments, the pharmaceutically or cosmeti 65 Niacinamide. In another embodiment, the composition com cally acceptable carrier is an oral or topical carrier. In other prises from about 1.0% to about 5.0%, from about 0.5% to embodiments, the pharmaceutically or cosmetically accept about 8.0%, or from about 0.1% to about 15% Tetrahexylde US 8,236,288 B2 10 cyl Ascorbate. In another embodiment, the composition com 0.1% to about 3.0%, from about 0.05% to about 5.0%, or from prises from about 0.001% to about 0.5%, from about about 0.01% to about 10.0% Resorcinol. In another embodi 0.0005% to about 1.0% or from about 0.0001% to about 2% ment, the composition comprises from about 0.1% to about Licorice root extract. In another embodiment, the composi 3.0%, from about 0.05% to about 5.0%, or from about 0.01% tion comprises from about 0.1% to about 3.0%, from about to about 10.0% ethyl linoleate. 0.05% to about 5.0%, or from about 0.01% to about 10.0% In another aspect, provided herein is a method of treating Resorcinol. In another embodiment, the composition com hyperpigmentation or a hypermelanosis disorder in an indi prises from about 0.1% to about 3.0%, from about 0.05% to vidual, comprising administering to the individual in need about 5.0%, or from about 0.01% to about 10.0% ethyl thereof an effective amount of a composition comprising: linoleate. 10 about 0.5% 4-ethoxybenzaldehyde, about 0.01% to about In another aspect, provided herein is a method of treating 5.0% each of Retinol, Niacinamide, Tetrahexyldecyl Ascor hyperpigmentation or a hypermelanosis disorder in an indi bate, Glycyrrhiza Glabra (Licorice) Root Extract, Hexyl vidual, comprising administering to the individual in need Resorcinol, ethyl linoleate, and a pharmaceutically or cos thereof an effective amount of a composition comprising: metically acceptable carrier. In another embodiment, the from about 0.01% to about 2% substituted benzaldehyde, 15 composition comprises from about 0.1% to about 0.75%, about 0.01% to about 5.0% each of Retinol, Niacinamide, from about 0.05% to about 1.0%, or from about 0.01% to Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice) about 2% Retinol. In another embodiment, the composition Root Extract, Hexyl Resorcinol, ethyl linoleate, and a phar comprises from about 2.0% to about 8.0%, from about 1% to maceutically or cosmetically acceptable carrier. In one about 10%, or from about 0.5% to about 15.0% Niacinamide. embodiment, the amount of substituted benzaldehyde is In another embodiment, the composition comprises from between about 0.1% to about 0.5%. In another embodiment, about 1.0% to about 5.0%, from about 0.5% to about 8.0%, or the amount of substituted benzaldehyde in the composition is from about 0.1% to about 15% Tetrahexyldecyl Ascorbate. In about 0.5%. In another embodiment, the composition com another embodiment, the composition comprises from about prises from about 0.1% to about 0.75%, from about 0.05% to 0.001% to about 0.5%, from about 0.0005% to about 1.0% or about 1.0%, or from about 0.01% to about 2% Retinol. In 25 from about 0.0001% to about 2% Licorice root extract. In another embodiment, the composition comprises from about another embodiment, the composition comprises from about 2.0% to about 8.0%, from about 1% to about 10%, or from 0.1% to about 3.0%, from about 0.05% to about 5.0%, or from about 0.5% to about 15.0% Niacinamide. In another embodi about 0.01% to about 10.0% Resorcinol. In another embodi ment, the composition comprises from about 1.0% to about ment, the composition comprises from about 0.1% to about 5.0%, from about 0.5% to about 8.0%, or from about 0.1% to 30 3.0%, from about 0.05% to about 5.0%, or from about 0.01% about 15% Tetrahexyldecyl Ascorbate. In another embodi to about 10.0% ethyl linoleate. ment, the composition comprises from about 0.001% to about In some embodiments, the method reduces melanin distri 0.5%, from about 0.0005% to about 1.0% or from about bution by about 10% to about 40%. 0.0001% to about 2% Licorice root extract. In another Application of the compositions in the methods described embodiment, the composition comprises from about 0.1% to 35 herein may be topical or transdermal administration to the about 3.0%, from about 0.05% to about 5.0%, or from about skin of the individual. 0.01% to about 10.0% Resorcinol. In another embodiment, In one embodiment, the pharmaceutically or cosmetically the composition comprises from about 0.1% to about 3.0%, acceptable carrier is a topical carrier. Topical carriers include, from about 0.05% to about 5.0%, or from about 0.01% to for example, a water-in-oil emulsion, cream, liquid, gel, oil, about 10.0% ethyl linoleate. 40 paste, ointment, Suspension, foam, lotion, oil-in-water emul Substituted benzaldehydes for use in the compositions Sion, water-in-oil-in-water emulsion, water-in-silicone emul include, for example, 2-ethoxybenzaldehyde, 4-ethoxyben Sion, spray or serum carrier. Zaldehyde, 4-allyloxybenzaldehyde or 4-propoxybenzalde In one embodiment, hyperpigmentation may result from an hyde. In one embodiment, the substituted benzaldehyde is environmental stressor (e.g., excessive Sun exposure or 4-ethoxybenzaldehyde, which may be present in the compo 45 chemical exposure), physiological stressor (e.g., a hormonal sition in an amount of about 0.5%. disorder), or mechanical stressor. In another aspect, provided herein is a method of treating Compositions described herein for use in such methods hyperpigmentation or a hypermelanosis disorder in an indi may further include one or more additional active agents. For vidual, comprising administering to the individual in need example, an additional active agent may be an antioxidant, a thereof an effective amount of a composition comprising: 50 Sunscreen, a Sunprotectant, a Sunblock, a skin-lightening from about 0.1% to about 0.5% 4-ethoxybenzaldehyde, about agent, an anti-inflammatory agent, an anti-acne agent or mix 0.01% to about 5.0% each of Retinol, Niacinamide, Tetra tures thereof. Compositions described herein for use in such hexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice) Root methods may further include one or more of a solvent, film Extract, Hexyl Resorcinol, ethyllinoleate, and a pharmaceu former, preservative, Viscosity increasing agent, fragrance, tically or cosmetically acceptable carrier. In another embodi 55 Surfactant, chelating agent, humectant, permeation enhancer, ment, the composition comprises from about 0.1% to about excipients, or a combination thereof. 0.75%, from about 0.05% to about 1.0%, or from about 0.01% Exemplary antioxidants include vitamin E. Coenzyme to about 2% Retinol. In another embodiment, the composition Q10, idebenone, lycopene, green tea polyphenols, Silybin, comprises from about 2.0% to about 8.0%, from about 1% to resveratrol, grape seed extract, Oregon grape root (Mahonia about 10%, or from about 0.5% to about 15.0% Niacinamide. 60 aquifolium) extract, pomegranate extract, genistein, pycno In another embodiment, the composition comprises from genol, curcumin, curcuminoids, or combinations thereof. about 1.0% to about 5.0%, from about 0.5% to about 8.0%, or Exemplary skin-lightening agents include hydroquinone, from about 0.1% to about 15% Tetrahexyldecyl Ascorbate. In monobenzyl ether of hydroquinone, azelaic acid, kojic acid, another embodiment, the composition comprises from about meduinol, retinoids, soy proteins, alpha-hydroxy acids, 0.001% to about 0.5%, from about 0.0005% to about 1.0% or 65 trichloroacetic acid, Salicylic acid, hydroquinone-beta-D- from about 0.0001% to about 2% Licorice root extract. In glucopyranoside, paper mulberry, glabridin, 4-isopropyl another embodiment, the composition comprises from about cetichol, aleosin, N-acetyl-4-S-cycteaminylphenol, N-propio US 8,236,288 B2 11 12 nyl-4-S-cysteaminylphenol, N-acetyl glucosamine, 0.01% to about 5.0% each of Retinol, Niacinamide, Tetra tranexaminc acid, an alpha MSH antagonist (e.g. undecyle hexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice) Root noyl phenylalanine), phytic acid or combinations thereof. Extract, Hexyl Resorcinol, ethyllinoleate, and a pharmaceu In another aspect, provided herein is a method of lightening tically or cosmetically acceptable carrier. In one embodiment, skin in an individual, comprising administering to the indi the amount of substituted benzaldehyde in the composition is vidual in need thereof an effective amount of a composition about 0.5%. In another embodiment, the composition com comprising: from about 0.01% to about 2% substituted ben prises from about 0.1% to about 0.75%, from about 0.05% to Zaldehyde, about 0.01% to about 5.0% each of Retinol, Niaci about 1.0%, or from about 0.01% to about 2% Retinol. In namide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra another embodiment, the composition comprises from about (Licorice) Root Extract, Hexyl Resorcinol, ethyl linoleate, 10 2.0% to about 8.0%, from about 1% to about 10%, or from and a pharmaceutically or cosmetically acceptable carrier. In about 0.5% to about 15.0% Niacinamide. In another embodi one embodiment, the amount of substituted benzaldehyde in ment, the composition comprises from about 1.0% to about the composition is about 0.5%. In another embodiment, the 5.0%, from about 0.5% to about 8.0%, or from about 0.1% to composition comprises from about 0.1% to about 0.75%, about 15% Tetrahexyldecyl Ascorbate. In another embodi from about 0.05% to about 1.0%, or from about 0.01% to 15 ment, the composition comprises from about 0.001% to about about 2% Retinol. In another embodiment, the composition 0.5%, from about 0.0005% to about 1.0% or from about comprises from about 2.0% to about 8.0%, from about 1% to 0.0001% to about 2% Licorice root extract. In another about 10%, or from about 0.5% to about 15.0% Niacinamide. embodiment, the composition comprises from about 0.1% to In another embodiment, the composition comprises from about 3.0%, from about 0.05% to about 5.0%, or from about about 1.0% to about 5.0%, from about 0.5% to about 8.0%, or 0.01% to about 10.0% Resorcinol. In another embodiment, from about 0.1% to about 15% Tetrahexyldecyl Ascorbate. In the composition comprises from about 0.1% to about 3.0%, another embodiment, the composition comprises from about from about 0.05% to about 5.0%, or from about 0.01% to 0.001% to about 0.5%, from about 0.0005% to about 1.0% or about 10.0% ethyllinoleate. from about 0.0001% to about 2% Licorice root extract. In Also provided is a method of lightening skin in an indi another embodiment, the composition comprises from about 25 vidual, comprising administering to the individual in need 0.1% to about 3.0%, from about 0.05% to about 5.0%, or from thereof an effective amount of a composition comprising: about 0.01% to about 10.0% Resorcinol. In another embodi from about 0.01% to about 2% substituted benzaldehyde and ment, the composition comprises from about 0.1% to about a pharmaceutically or cosmetically acceptable carrier. 3.0%, from about 0.05% to about 5.0%, or from about 0.01% In one embodiment, the method further comprises admin to about 10.0% ethyl linoleate. 30 istering to the individual in need thereof an effective amount Substituted benzaldehydes for use in the compositions of about 0.01% to about 5.0% each of Retinol, Niacinamide, include, for example, 2-ethoxybenzaldehyde, 4-ethoxyben Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice) Zaldehyde, 4-allyloxybenzaldehyde or 4-propoxybenzalde Root Extract, Hexyl Resorcinol, ethyl linoleate. In another hyde. In one embodiment, the substituted benzaldehyde is embodiment, the composition comprises from about 0.1% to 4-ethoxybenzaldehyde, which may be present in the compo 35 about 0.75%, from about 0.05% to about 1.0%, or from about sition in an amount of about 0.1% to about 0.5%. 0.01% to about 2%. Retinol. In another embodiment, the In another aspect, provided herein is a method of lightening composition comprises from about 2.0% to about 8.0%, from skin in an individual, comprising administering to the indi about 1% to about 10%, or from about 0.5% to about 15.0% vidual in need thereof an effective amount of a composition Niacinamide. In another embodiment, the composition com comprising: about 0.1% to about 0.5% 4-ethoxybenzalde 40 prises from about 1.0% to about 5.0%, from about 0.5% to hyde, about 0.01% to about 5.0% each of Retinol, Niacina about 8.0%, or from about 0.1% to about 15% Tetrahexylde mide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Lico cyl Ascorbate. In another embodiment, the composition com rice) Root Extract, Hexyl Resorcinol, ethyl linoleate, and a prises from about 0.001% to about 0.5%, from about pharmaceutically or cosmetically acceptable carrier. In one 0.0005% to about 1.0% or from about 0.0001% to about 2% embodiment, the amount of substituted benzaldehyde in the 45 Licorice root extract. In another embodiment, the composi composition is about 0.5%. In another embodiment, the com tion comprises from about 0.1% to about 3.0%, from about position comprises from about 0.1% to about 0.75%, from 0.05% to about 5.0%, or from about 0.01% to about 10.0% about 0.05% to about 1.0%, or from about 0.01% to about 2% Resorcinol. In another embodiment, the composition com Retinol. In another embodiment, the composition comprises prises from about 0.1% to about 3.0%, from about 0.05% to from about 2.0% to about 8.0%, from about 1% to about 10%, 50 about 5.0%, or from about 0.01% to about 10.0% ethyl or from about 0.5% to about 15.0% Niacinamide. In another linoleate. embodiment, the composition comprises from about 1.0% to In some embodiments, the methods decrease the level of about 5.0%, from about 0.5% to about 8.0%, or from about pigmentation by about 5%, by about 10%, by about 20%, by 0.1% to about 15% Tetrahexyldecyl Ascorbate. In another about 30% or by about 40%. embodiment, the composition comprises from about 0.001% 55 The methods may be used to treat hyperpigmentation or a to about 0.5%, from about 0.0005% to about 1.0% or from hypermelanosis disorder. In one embodiment, hyperpigmen about 0.0001% to about 2% Licorice root extract. In another tation may result from an environmental stressor (e.g., exces embodiment, the composition comprises from about 0.1% to sive Sun exposure or chemical exposure), physiological stres about 3.0%, from about 0.05% to about 5.0%, or from about Sor (e.g., a hormonal disorder), or mechanical stressor. 0.01% to about 10.0% Resorcinol. In another embodiment, 60 In some embodiments, the method reduces melanin distri the composition comprises from about 0.1% to about 3.0%, bution by about 10% to about 40%. from about 0.05% to about 5.0%, or from about 0.01% to Application of the compositions in the methods described about 10.0% ethyl linoleate. herein may be topical or transdermal administration to the In yet another aspect, provided herein is a method of light skin of the individual. ening skin in an individual, comprising administering to the 65 In one embodiment, the pharmaceutically or cosmetically individual in need thereof an effective amount of a composi acceptable carrier is a topical carrier. Topical carriers include, tion comprising: about 0.5% 4-ethoxybenzaldehyde, about for example, a water-in-oil emulsion, cream, liquid, gel, oil, US 8,236,288 B2 13 14 paste, ointment, Suspension, foam, lotion, oil-in-water emul prises from about 0.1% to about 3.0%, from about 0.05% to Sion, water-in-oil-in-water emulsion, water-in-silicone emul about 5.0%, or from about 0.01% to about 10.0% ethyl Sion, spray or serum carrier. linoleate. Compositions described herein for use in such methods Provided is a method of modifying melanin distribution by may further include one or more additional active agents. For 5 modulating prostaglandin F2 alpha (PGF2 alpha) in a cell, example, an additional active agent may be an antioxidant, a comprising contacting said cell with a composition compris Sunscreen, a Sunprotectant, a Sunblock, a skin-lightening ing from about 0.01% to about 2% substituted benzaldehyde, agent, an anti-inflammatory agent, an anti-acne agent or mix about 0.01% to about 5.0% each of Retinol, Niacinamide, tures thereof. Compositions described herein for use in such Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice) methods may further include one or more of a solvent, film 10 Root Extract, Hexyl Resorcinol, ethyl linoleate, and a phar former, preservative, Viscosity increasing agent, fragrance, maceutically or cosmetically acceptable carrier. In some embodiments, the cells being treated are located in skin of an Surfactant, chelating agent, humectant, permeation enhancer, individual. In another embodiment, the composition com excipient, or a combination thereof. prises from about 0.1% to about 0.75%, from about 0.05% to Exemplary antioxidants include vitamin E. Coenzyme 15 about 1.0%, or from about 0.01% to about 2% Retinol. In Q10, idebenone, lycopene, green tea polyphenols, Silybin, another embodiment, the composition comprises from about resveratrol, grape seed extract, Oregon grape root (Mahonia 2.0% to about 8.0%, from about 1% to about 10%, or from aquifolium) extract, pomegranate extract, genistein, pycno about 0.5% to about 15.0% Niacinamide. In another embodi genol, curcumin, curcuminoids, Tocopherol, Dunaliella ment, the composition comprises from about 1.0% to about Salina Extract or combinations thereof. 5.0%, from about 0.5% to about 8.0%, or from about 0.1% to Exemplary skin-lightening agents include hydroquinone, about 15% Tetrahexyldecyl Ascorbate. In another embodi monobenzyl ether of hydroquinone, azelaic acid, kojic acid, ment, the composition comprises from about 0.001% to about meduinol, retinoids, soy proteins, alpha-hydroxy acids, 0.5%, from about 0.0005% to about 1.0% or from about trichloroacetic acid, salicylic acid, hydroquinone-beta-D- 0.0001% to about 2% Licorice root extract. In another glucopyranoside, paper mulberry, glabridin, 4-isopropyl 25 embodiment, the composition comprises from about 0.1% to cetichol, aleosin, N-acetyl-4-S-cycteaminylphenol, N-propio about 3.0%, from about 0.05% to about 5.0%, or from about nyl-4-S-cysteaminylphenol, N-acetyl glucosamine, 0.01% to about 10.0% Resorcinol. In another embodiment, tranexaminc acid, an alpha MSH antagonist (e.g. undecyle the composition comprises from about 0.1% to about 3.0%, noyl phenylalanine), phytic acid or combinations thereof. from about 0.05% to about 5.0%, or from about 0.01% to Provided herein are methods of modifying melanin distri 30 about 10.0% ethyllinoleate. bution by modulating prostaglandin F2 alpha (PGF2 alpha) in Provided is a method of modifying melanin distribution by a cell, comprising contacting said cell with a composition modulating prostaglandin F2 alpha (PGF2 alpha) in skin cells comprising from about 0.01% to about 2% substituted ben in an individual, comprising administering to the individual Zaldehyde and a pharmaceutically or cosmetically acceptable in need thereof an effective amount of a composition com carrier. 35 prising from about 0.01% to about 2% substituted benzalde In one embodiment, the method further comprises admin hyde, about 0.01% to about 5.0% each of Retinol, Niacina istering to the individual in need thereof an effective amount mide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra of about 0.01% to about 5.0% each of Retinol, Niacinamide, (Licorice) Root Extract, Hexyl Resorcinol, ethyl linoleate, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice) and a pharmaceutically or cosmetically acceptable carrier. In Root Extract, Hexyl Resorcinol, ethyl linoleate. 40 another embodiment, the composition comprises from about Provided is a method of modifying melanin distribution by 0.1% to about 0.75%, from about 0.05% to about 1.0%, or modulating prostaglandin F2 alpha (PGF2 alpha) in skin cells from about 0.01% to about 2%. Retinol. In another embodi in an individual, comprising administering to the individual ment, the composition comprises from about 2.0% to about in need thereof an effective amount of a composition com 8.0%, from about 1% to about 10%, or from about 0.5% to prising from about 0.01% to about 2% substituted benzalde 45 about 15.0% Niacinamide. In another embodiment, the com hyde and a pharmaceutically or cosmetically acceptable car position comprises from about 1.0% to about 5.0%, from 1. about 0.5% to about 8.0%, or from about 0.1% to about 15% In one embodiment, the method further comprises admin Tetrahexyldecyl Ascorbate. In another embodiment, the com istering to the individual in need thereof an effective amount position comprises from about 0.001% to about 0.5%, from of about 0.01% to about 5.0% each of Retinol, Niacinamide, 50 about 0.0005% to about 1.0% or from about 0.0001% to about Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice) 2% Licorice root extract. In another embodiment, the com Root Extract, Hexyl Resorcinol, ethyl linoleate. In another position comprises from about 0.1% to about 3.0%, from embodiment, the composition comprises from about 0.1% to about 0.05% to about 5.0%, or from about 0.01% to about about 0.75%, from about 0.05% to about 1.0%, or from about 10.0% Resorcinol. In another embodiment, the composition 0.01% to about 2%. Retinol. In another embodiment, the 55 comprises from about 0.1% to about 3.0%, from about 0.05% composition comprises from about 2.0% to about 8.0%, from to about 5.0%, or from about 0.01% to about 10.0% ethyl about 1% to about 10%, or from about 0.5% to about 15.0% linoleate. Niacinamide. In another embodiment, the composition com In one embodiment, the amount of substituted benzalde prises from about 1.0% to about 5.0%, from about 0.5% to hyde is between about 0.1% to about 0.5%. In one embodi about 8.0%, or from about 0.1% to about 15% Tetrahexylde 60 ment, the amount of substituted benzaldehyde in the compo cyl Ascorbate. In another embodiment, the composition com sition is about 0.5%. prises from about 0.001% to about 0.5%, from about Substituted benzaldehydes for use in the compositions 0.0005% to about 1.0% or from about 0.0001% to about 2% include, for example, 2-ethoxybenzaldehyde, 4-ethoxyben Licorice root extract. In another embodiment, the composi Zaldehyde, 4-allyloxybenzaldehyde or 4-propoxybenzalde tion comprises from about 0.1% to about 3.0%, from about 65 hyde. In one embodiment, the substituted benzaldehyde is 0.05% to about 5.0%, or from about 0.01% to about 10.0% 4-ethoxybenzaldehyde, which may be present in the compo Resorcinol. In another embodiment, the composition com sition in an amount of about 0.1% to about 0.5%. In one US 8,236,288 B2 15 16 embodiment, the substituted benzaldehyde is 4-ethoxyben to about 40%. In another embodiment, the composition com Zaldehyde, which may be present in the composition in an prises from about 0.1% to about 0.75%, from about 0.05% to amount of about 0.5%. about 1.0%, or from about 0.01% to about 2% Retinol. In Also provided are methods of modifying melanin distribu another embodiment, the composition comprises from about tion by modulating prostaglandin F2 alpha (PGF2 alpha) in a 2.0% to about 8.0%, from about 1% to about 10%, or from cell, comprising contacting said cell with a composition com about 0.5% to about 15.0% Niacinamide. In another embodi prising about 0.1% to about 0.5% 4-ethoxybenzaldehyde, ment, the composition comprises from about 1.0% to about about 0.01% to about 5.0% each of Retinol, Niacinamide, 5.0%, from about 0.5% to about 8.0%, or from about 0.1% to Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice) about 15% Tetrahexyldecyl Ascorbate. In another embodi Root Extract, Hexyl Resorcinol, ethyl linoleate, and a phar 10 ment, the composition comprises from about 0.001% to about maceutically or cosmetically acceptable carrier. In some 0.5%, from about 0.0005% to about 1.0% or from about embodiments, the cells being treated are located in skin of an 0.0001% to about 2% Licorice root extract. In another individual. In another embodiment, the composition com embodiment, the composition comprises from about 0.1% to prises from about 0.1% to about 0.75%, from about 0.05% to about 3.0%, from about 0.05% to about 5.0%, or from about about 1.0%, or from about 0.01% to about 2% Retinol. In 15 0.01% to about 10.0% Resorcinol. In another embodiment, another embodiment, the composition comprises from about the composition comprises from about 0.1% to about 3.0%, 2.0% to about 8.0%, from about 1% to about 10%, or from from about 0.05% to about 5.0%, or from about 0.01% to about 0.5% to about 15.0% Niacinamide. In another embodi about 10.0% ethyllinoleate. ment, the composition comprises from about 1.0% to about Application of the compositions in the methods described 5.0%, from about 0.5% to about 8.0%, or from about 0.1% to herein may be topical or transdermal administration to the about 15% Tetrahexyldecyl Ascorbate. In another embodi skin of the individual. ment, the composition comprises from about 0.001% to about In one embodiment, the pharmaceutically or cosmetically 0.5%, from about 0.0005% to about 1.0% or from about acceptable carrier is a topical carrier. Topical carriers include, 0.0001% to about 2% Licorice root extract. In another for example, a water-in-oil emulsion, cream, liquid, gel, oil, embodiment, the composition comprises from about 0.1% to 25 paste, ointment, Suspension, foam, lotion, oil-in-water emul about 3.0%, from about 0.05% to about 5.0%, or from about Sion, water-in-oil-in-water emulsion, water-in-silicone emul 0.01% to about 10.0% Resorcinol. In another embodiment, Sion, spray or serum carrier. the composition comprises from about 0.1% to about 3.0%, Compositions described herein for use in such methods from about 0.05% to about 5.0%, or from about 0.01% to may further include one or more additional active agents. For about 10.0% ethyl linoleate. 30 example, an additional active agent may be an antioxidant, a Provided herein is a method of modifying melanin distri Sunscreen, a Sunprotectant, a Sunblock, a skin-lightening bution by modulating prostaglandin F2 alpha (PGF2 alpha) in agent, an anti-inflammatory agent, an anti-acne agent or mix a cell, comprising contacting said cell with a composition tures thereof. Compositions described herein for use in such comprising about 0.5% 4-ethoxybenzaldehyde, about 0.01% methods may further include one or more of a solvent, film to about 5.0% each of Retinol, Niacinamide, Tetrahexyldecyl 35 former, preservative, Viscosity increasing agent, fragrance, Ascorbate, Glycyrrhiza Glabra (Licorice) Root Extract, Surfactant, chelating agent, humectant, permeation enhancer, Hexyl Resorcinol, ethyllinoleate, and a pharmaceutically or excipient, or a combination thereof. cosmetically acceptable carrier. In some embodiments, the Exemplary antioxidants include vitamin E. Coenzyme cells being treated are located in skin of an individual. In Q10, idebenone, lycopene, green tea polyphenols, Silybin, another embodiment, the composition comprises from about 40 resveratrol, grape seed extract, Oregon grape root (Mahonia 0.1% to about 0.75%, from about 0.05% to about 1.0%, or aquifolium) extract, pomegranate extract, genistein, pycno from about 0.01% to about 2%. Retinol. In another embodi genol, curcumin, curcuminoids, Tocopherol, Dunaliella ment, the composition comprises from about 2.0% to about Salina Extract or combinations thereof. 8.0%, from about 1% to about 10%, or from about 0.5% to Exemplary skin-lightening agents include hydroquinone, about 15.0% Niacinamide. In another embodiment, the com 45 monobenzyl ether of hydroquinone, azelaic acid, kojic acid, position comprises from about 1.0% to about 5.0%, from meduinol, retinoids, soy proteins, alpha-hydroxy acids, about 0.5% to about 8.0%, or from about 0.1% to about 15% trichloroacetic acid, Salicylic acid, hydroquinone-beta-D- Tetrahexyldecyl Ascorbate. In another embodiment, the com glucopyranoside, paper mulberry, glabridin, 4-isopropyl position comprises from about 0.001% to about 0.5%, from cetichol, aleosin, N-acetyl-4-S-cycteaminylphenol, N-propio about 0.0005% to about 1.0% or from about 0.0001% to about 50 nyl-4-S-cysteaminylphenol, N-acetyl glucosamine, 2% Licorice root extract. In another embodiment, the com tranexaminc acid, an alpha MSH antagonist (e.g. undecyle position comprises from about 0.1% to about 3.0%, from noyl phenylalanine), phytic acid or combinations thereof. about 0.05% to about 5.0%, or from about 0.01% to about In some embodiments, provided herein is a method of 10.0% Resorcinol. In another embodiment, the composition modifying melanin distribution in an individual, the method comprises from about 0.1% to about 3.0%, from about 0.05% 55 comprising administering to the individual in need thereofan to about 5.0%, or from about 0.01% to about 10.0% ethyl effective amount of a composition comprising a Substituted linoleate. benzaldehyde, at least one additional active agent and a phar Also disclosed are methods of modifying melanin distri maceutically or cosmetically acceptable carrier. In some bution by modulating prostaglandin F2 alpha (PGF2 alpha) in embodiments, the substituted benzaldehyde is 2-ethoxyben skin cells in an individual, comprising administering to the 60 Zaldehyde, 4-ethoxybenzaldehyde, 4-allyloxybenzaldehyde individual in need thereof an effective amount of a composi or 4-propoxybenzaldehyde. In a specific embodiment, the tion comprising about 0.5% 4-ethoxybenzaldehyde, about substituted benzaldehyde is 4-ethoxybenzaldehyde. In yet 0.01% to about 5.0% each of Retinol, Niacinamide, Tetra another embodiment, the substituted benzaldehyde is hexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice) Root 2-ethoxybenzaldehyde. Extract, Hexyl Resorcinol, ethyllinoleate, and a pharmaceu 65 In some embodiments, the pharmaceutically or cosmeti tically or cosmetically acceptable carrier. In some embodi cally acceptable carrier is an oral or topical carrier. In other ments, the method reduces melanin distribution by about 10% embodiments, the pharmaceutically or cosmetically accept US 8,236,288 B2 17 18 able topical carrier is a water-in-oil emulsion, cream, liquid, the individual. In yet another embodiment, the composition is gel, oil, paste, ointment, Suspension, foam, lotion, oil-in transdermally administered to the skin of the individual. water emulsion, water-in-oil-in-water emulsion, water-in In particular embodiments, the additional active agent is an silicone emulsion, spray or serum carrier. In another embodi antioxidant, a Sunscreen, a Sunprotectant, a Sunblock, a skin ment, the composition is topically administered to the skin of 5 lightening agent, an anti-inflammatory agent, an anti-acne the individual. In yet another embodiment, the composition is agent or mixtures thereof. In yet another embodiment, the transdermally administered to the skin of the individual. compositions comprise an antioxidant selected from the In particular embodiments, the additional active agent is an group of niacinamide, Vitamin E. Coenzyme Q10, idebenone, antioxidant, a Sunscreen, a Sunprotectant, a Sunblock, a skin lycopene, green tea polyphenols, Silybin, resveratrol, grape lightening agent, an anti-inflammatory agent, an anti-acne 10 agent or mixtures thereof. In yet another embodiment, the seed extract, Oregon grape root (Mahonia aquifolium) compositions comprise an antioxidant selected from the extract, pomegranate extract, genistein, pycnogenol, cur group of niacinamide, Vitamin E. Coenzyme Q10, idebenone, cumin, curcuminoids, or combinations thereof. In another lycopene, green tea polyphenols, Silybin, resveratrol, grape embodiment, the compositions comprise a skin-lightening seed extract, Oregon grape root (Mahonia aquifolium) 15 agent selected from the group of hydroquinone, monobenzyl extract, pomegranate extract, genistein, pycnogenol, cur ether of hydroquinone, azelaic acid, kojic acid, meduinol, cumin, curcuminoids, or combinations thereof. In another retinoids (e.g., tretinoin, adapalene), soy proteins, alpha-hy embodiment, the compositions comprise a skin-lightening droxyacids (e.g., glycolic acid), trichloroacetic acid, salicylic agent selected from the group of hydroquinone, monobenzyl acid, hydroquinone-beta-D-glucopyranoside, paper mul ether of hydroquinone, azelaic acid, kojic acid, meduinol, berry, glabridin, 4-isopropylcetichol, aleosin, N-acetyl-4-S- retinoids (e.g., tretinoin, adapalene), soy proteins, alpha-hy cycteaminylphenol, N-propionyl-4-S-cysteaminylphenol, droxyacids (e.g., glycolic acid), trichloroacetic acid, salicylic N-acetyl glucosamine, tranexaminc acid, licorice extract acid, hydroquinone-beta-D-glucopyranoside, paper mul (e.g., Glycyrrhiza Glabra (licorice) root extract), an alpha berry, glabridin, 4-isopropylcetichol, aleosin, N-acetyl-4-S- MSH antagonist (e.g. undecylenoyl phenylalanine), phytic cycteaminylphenol, N-propionyl-4-S-cysteaminylphenol, 25 acid or combinations thereof. N-acetyl glucosamine, tranexaminc acid, licorice extract In some embodiments, the substituted benzaldehyde com (e.g., Glycyrrhiza Glabra (licorice) root extract), an alpha position modifies melanin distribution by about 10%, by MSH antagonist (e.g. undecylenoyl phenylalanine), phytic about 15%, by about 20%, by about 25%, by about 30%, by acid or combinations thereof. about 35%, by about 40%, by about 45%, by about 50%, by In some embodiments, the substituted benzaldehyde com 30 position modifies melanin distribution by about 10%, by about 55%, by about 60%, by about 65%, by about 70%, by about 15%, by about 20%, by about 25%, by about 30%, by about 75%, by about 80%, by about 85%, by about 90%, by about 35%, by about 40%, by about 45%, by about 50%, by about 95% or by about 100%. In other embodiments, the about 55%, by about 60%, by about 65%, by about 70%, by Substituted benzaldehyde composition reduces melanin dis about 75%, by about 80%, by about 85%, by about 90%, by 35 tribution by about 10%, by about 15%, by about 20%, by about 95% or by about 100%. In other embodiments, the about 25%, by about 30%, by about 35%, by about 40%, by Substituted benzaldehyde composition reduces melanin dis about 45%, by about 50%, by about 55%, by about 60%, by tribution by about 10%, by about 15%, by about 20%, by about 65%, by about 70%, by about 75%, by about 80%, by about 25%, by about 30%, by about 35%, by about 40%, by about 85%, by about 90%, by about 95% or by about 100%. about 45%, by about 50%, by about 55%, by about 60%, by 40 In another embodiment, the substituted benzaldehyde com about 65%, by about 70%, by about 75%, by about 80%, by position reduces melanin distribution by about 5% to about about 85%, by about 90%, by about 95% or by about 100%. 50%. In yet another embodiment, the substituted benzalde In another embodiment, the substituted benzaldehyde com hyde composition reduces melanin distribution by about 10% position reduces melanin distribution by about 5% to about to about 40%. 50%. In yet another embodiment, the substituted benzalde 45 In another aspect, provided herein is a method of treating a hyde composition reduces melanin distribution by about 10% melanin disorder in an individual, the method comprising to about 40%. contacting keratinocytes with an effective amount of a com In a further aspect, provided herein is a method of modi position comprising a Substituted benzaldehyde, at least one fying melanin distribution in an individual, the method com additional active agent and a pharmaceutically or cosmeti prising contacting keratinocytes with an effective amount of a 50 cally acceptable carrier. In some embodiments, the Substi composition comprising a Substituted benzaldehyde, at least tuted benzaldehyde is 2-ethoxybenzaldehyde, 4-ethoxyben one additional active agent and a pharmaceutically or cos Zaldehyde, 4-allyloxybenzaldehyde O metically acceptable carrier. In some embodiments, the Sub 4-propoxybenzaldehyde. In a specific embodiment, the Sub stituted benzaldehyde is 2-ethoxybenzaldehyde, 4-ethoxy stituted benzaldehyde is 4-ethoxybenzaldehyde. In yet benzaldehyde, 4-allyloxybenzaldehyde O 55 another embodiment, the substituted benzaldehyde is 4-propoxybenzaldehyde. In a specific embodiment, the Sub 2-ethoxybenzaldehyde. stituted benzaldehyde is 4-ethoxybenzaldehyde. In yet In some embodiments, the compositions further comprise another embodiment, the substituted benzaldehyde is a pharmaceutically or cosmetically acceptable carrier. In 2-ethoxybenzaldehyde. another embodiment, the pharmaceutically or cosmetically In some embodiments, the pharmaceutically or cosmeti 60 acceptable carrier is an oral or topical carrier. In other cally acceptable carrier is an oral or topical carrier. In other embodiments, the pharmaceutically or cosmetically accept embodiments, the pharmaceutically or cosmetically accept able topical carrier is a water-in-oil emulsion, cream, liquid, able topical carrier is a water-in-oil emulsion, cream, liquid, gel, oil, paste, ointment, Suspension, foam, lotion, oil-in gel, oil, paste, ointment, Suspension, foam, lotion, oil-in water emulsion, water-in-oil-in-water emulsion, water-in water emulsion, water-in-oil-in-water emulsion, water-in 65 silicone emulsion, spray or serum carrier. In some embodi silicone emulsion, spray or serum carrier. In another embodi ments, the cell is present on skin of an individual. In another ment, the composition is topically administered to the skin of embodiment, the composition is topically administered to the US 8,236,288 B2 19 20 skin of the individual. In yet another embodiment, the com silicone emulsion, spray or serum carrier. In another embodi position is transdermally administered to the skin of the indi ment, the composition is topically administered to the skin of vidual. the individual. In yet another embodiment, the composition is In particular embodiments, the additional active agent is an transdermally administered to the skin of the individual. antioxidant, a Sunscreen, a Sunprotectant, a Sunblock, a skin- 5 In particular embodiments, the additional active agent is an lightening agent, an anti-inflammatory agent, an anti-acne antioxidant, a Sunscreen, a Sunprotectant, a Sunblock, a skin agent or mixtures thereof. In yet another embodiment, the lightening agent, an anti-inflammatory agent, an anti-acne compositions comprise an antioxidant selected from the agent or mixtures thereof. In yet another embodiment, the group of niacinamide, Vitamin E. Coenzyme Q10, idebenone, compositions comprise an antioxidant selected from the lycopene, green tea polyphenols, Silybin, resveratrol, grape 10 group of niacinamide, Vitamin E. Coenzyme Q10, idebenone, seed extract, Oregon grape root (Mahonia aquifolium) lycopene, green tea polyphenols, Silybin, resveratrol, grape extract, pomegranate extract, genistein, pycnogenol, cur seed extract, Oregon grape root (Mahonia aquifolium) cumin, curcuminoids, or combinations thereof. In another extract, pomegranate extract, genistein, pycnogenol, cur embodiment, the compositions comprise a skin-lightening cumin, curcuminoids, or combinations thereof. In another agent selected from the group of hydroquinone, monobenzyl 15 embodiment, the compositions comprise a skin-lightening ether of hydroquinone, azelaic acid, kojic acid, meduinol, agent selected from the group of hydroquinone, monobenzyl retinoids (e.g., tretinoin, adapalene), soy proteins, alpha-hy ether of hydroquinone, azelaic acid, kojic acid, meduinol, droxyacids (e.g., glycolic acid), trichloroacetic acid, salicylic retinoids (e.g., tretinoin, adapalene), soy proteins, alpha-hy acid, hydroquinone-beta-D-glucopyranoside, paper mul droxyacids (e.g., glycolic acid), trichloroacetic acid, salicylic berry, glabridin, 4-isopropylcetichol, aleosin, N-acetyl-4-S- 20 acid, hydroquinone-beta-D-glucopyranoside, paper mul cycteaminylphenol, N-propionyl-4-S-cysteaminylphenol, berry, glabridin, 4-isopropylcetichol, aleosin, N-acetyl-4-S- N-acetyl glucosamine, tranexaminc acid, licorice extract cycteaminylphenol, N-propionyl-4-S-cysteaminylphenol, (e.g., Glycyrrhiza Glabra (licorice) root extract), an alpha N-acetyl glucosamine, tranexaminc acid, licorice extract MSH antagonist (e.g. undecylenoyl phenylalanine), phytic (e.g., Glycyrrhiza Glabra (licorice) root extract), an alpha acid or combinations thereof. 25 MSH antagonist (e.g. undecylenoyl phenylalanine), phytic In some embodiments, the composition modifies melanin acid or combinations thereof. distribution by about 1%, about 2%, about 3%, about 4%, In some embodiments, the substituted benzaldehyde com about 5%, about 6%, about 7%, about 8%, about 9%, about position modifies melanin distribution by about 1%, about 10%, by about 15%, by about 20%, by about 25%, by about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, 30%, by about 35%, by about 40%, by about 45%, by about 30 about 8%, about 9%, about 10%, by about 15%, by about 50%, by about 55%, by about 60%, by about 65%, by about 20%, by about 25%, by about 30%, by about 35%, by about 70%, by about 75%, by about 80%, by about 85%, by about 40%, by about 45%, by about 50%, by about 55%, by about 90%, by about 95% or by about 100%. In other embodiments, 60%, by about 65%, by about 70%, by about 75%, by about the composition reduces melanin distribution by about 10%, 80%, by about 85%, by about 90%, by about 95% or by about by about 15%, by about 20%, by about 25%, by about 30%, 35 100%. In other embodiments, the substituted benzaldehyde by about 35%, by about 40%, by about 45%, by about 50%, composition reduces melanin distribution by about 10%, by by about 55%, by about 60%, by about 65%, by about 70%, about 15%, by about 20%, by about 25%, by about 30%, by by about 75%, by about 80%, by about 85%, by about 90%, about 35%, by about 40%, by about 45%, by about 50%, by by about 95% or by about 100%. In another embodiment, the about 55%, by about 60%, by about 65%, by about 70%, by Substituted benzaldehyde composition reduces melanin dis- 40 about 75%, by about 80%, by about 85%, by about 90%, by tribution by about 5% to about 50%. In yet another embodi about 95% or by about 100%. In another embodiment, the ment, the Substituted benzaldehyde composition reduces Substituted benzaldehyde composition reduces melanin dis melanin distribution by about 10% to about 40%. tribution by about 5% to about 50%. In yet another embodi In some embodiments, provided herein is a method of ment, the Substituted benzaldehyde composition reduces treating a hyperpigmentation skin disorder in an individual in 45 melanin distribution by about 10% to about 40%. need thereof, the method comprising administering to the In a further aspect, provided herein is a method of modu skin of the individual an effective amount of a composition lating the skin pigmentation of an individual, the method comprising a substituted benzaldehyde, at least one addi comprising administering to the skin of the individual an tional active agent and a pharmaceutically or cosmetically effective amount of a composition comprising a Substituted acceptable carrier. In some embodiments, the substituted ben- 50 benzaldehyde, at least one additional active agent and a phar Zaldehyde is 2-ethoxybenzaldehyde, 4-ethoxybenzaldehyde, maceutically or cosmetically acceptable carrier, wherein the 4-allyloxybenzaldehyde or 4-propoxybenzaldehyde. In a substituted benzaldehyde modulates PGF2-alpha in said indi specific embodiment, the substituted benzaldehyde is vidual. In some embodiments, the substituted benzaldehyde 4-ethoxybenzaldehyde. In yet another embodiment, the sub is 2-ethoxybenzaldehyde, 4-ethoxybenzaldehyde, 4-ally stituted benzaldehyde is 2-ethoxybenzaldehyde. 55 loxybenzaldehyde or 4-propoxybenzaldehyde. In a specific In some embodiments, the individual suffers from a hyper embodiment, the substituted benzaldehyde is 4-ethoxyben pigmentation disorder resulting from an environmental stres Zaldehyde. In yet another embodiment, the substituted ben Sor, physiological stressor or mechanical stressor. In a par Zaldehyde is 2-ethoxybenzaldehyde. ticular embodiment, the physiological stressor is a hormonal In some embodiments, the individual suffers from a hyper disorder. In yet another embodiment, the environmental stres- 60 pigmentation disorder resulting from an environmental stres sor is excessive Sun exposure or chemical exposure. Sor, physiological stressor or mechanical stressor. In a par In another embodiment, the pharmaceutically or cosmeti ticular embodiment, the physiological stressor is a hormonal cally acceptable carrier is an oral or topical carrier. In other disorder. In yet another embodiment, the environmental stres embodiments, the pharmaceutically or cosmetically accept sor is excessive Sun exposure or chemical exposure. able topical carrier is a water-in-oil emulsion, cream, liquid, 65 In another embodiment, the pharmaceutically or cosmeti gel, oil, paste, ointment, Suspension, foam, lotion, oil-in cally acceptable carrier is an oral or topical carrier. In other water emulsion, water-in-oil-in-water emulsion, water-in embodiments, the pharmaceutically or cosmetically accept US 8,236,288 B2 21 22 able topical carrier is a water-in-oil emulsion, cream, liquid, silicone emulsion, spray or serum carrier. In certain embodi gel, oil, paste, ointment, Suspension, foam, lotion, oil-in ments, the composition is topically administered to the skin of water emulsion, water-in-oil-in-water emulsion, water-in the individual. In other embodiments, the composition is silicone emulsion, spray or serum carrier. In another embodi transdermally administered to the skin of the individual. ment, the composition is topically administered to the skin of In some embodiments, the compositions further comprise the individual. In yet another embodiment, the composition is an additional active agent. In particular embodiments, the transdermally administered to the skin of the individual. additional active agent is an antioxidant, a Sunscreen, a Sun In particular embodiments, the additional active agent is an protectant, a Sunblock, a skin-lightening agent, an anti-in antioxidant, a Sunscreen, a Sunprotectant, a Sunblock, a skin flammatory agent, an anti-acne agent or mixtures thereof. In lightening agent, an anti-inflammatory agent, an anti-acne 10 yet another embodiment, the compositions comprise an anti agent or mixtures thereof. In yet another embodiment, the oxidant selected from the group of niacinamide, Vitamin E, compositions comprise an antioxidant selected from the Coenzyme Q10, idebenone, lycopene, green tea polyphenols, group of niacinamide, Vitamin E. Coenzyme Q10, idebenone, Silybin, resveratrol, grape seed extract, Oregon grape root lycopene, green tea polyphenols, Silybin, resveratrol, grape (Mahonia aquifolium) extract, pomegranate extract, seed extract, Oregon grape root (Mahonia aquifolium) 15 genistein, pycnogenol, curcumin, curcuminoids, or combina extract, pomegranate extract, genistein, pycnogenol, cur tions thereof. In another embodiment, the compositions com cumin, curcuminoids, or combinations thereof. In another prise a skin-lightening agent selected from the group of hyd embodiment, the compositions comprise a skin-lightening roquinone, monobenzyl ether of hydroquinone, azelaic acid, agent selected from the group of hydroquinone, monobenzyl kojic acid, meduinol, retinoids (e.g., tretinoin, adapalene), ether of hydroquinone, azelaic acid, kojic acid, meduinol, soy proteins, alpha-hydroxy acids (e.g., glycolic acid), retinoids (e.g., tretinoin, adapalene), soy proteins, alpha-hy trichloroacetic acid, Salicylic acid, hydroquinone-beta-D- droxyacids (e.g., glycolic acid), trichloroacetic acid, salicylic glucopyranoside, paper mulberry, glabridin, 4-isopropyl acid, hydroquinone-beta-D-glucopyranoside, paper mul cetichol, aleosin, N-acetyl-4-S-cycteaminylphenol, N-propio berry, glabridin, 4-isopropylcetichol, aleosin, N-acetyl-4-S- nyl-4-S-cysteaminylphenol, N-acetyl glucosamine, cycteaminylphenol, N-propionyl-4-S-cysteaminylphenol, 25 tranexaminc acid, licorice extract (e.g., Glycyrrhiza Glabra N-acetyl glucosamine, tranexaminc acid, licorice extract (licorice) root extract), an alpha MSH antagonist (e.g. unde (e.g., Glycyrrhiza Glabra (licorice) root extract), an alpha cylenoyl phenylalanine), orphytic acid combinations thereof. MSH antagonist (e.g. undecylenoyl phenylalanine), orphytic In some embodiments, the substituted benzaldehyde com acid combinations thereof. position modifies melanin distribution by about 1%, about In some embodiments, the composition modifies melanin 30 2%, about 3%, about 4%, about 5%, about 6%, about 7%, distribution by about 1%, about 2%, about 3%, about 4%, about 8%, about 9%, about 10%, by about 15%, by about about 5%, about 6%, about 7%, about 8%, about 9%, about 20%, by about 25%, by about 30%, by about 35%, by about 10%, by about 15%, by about 20%, by about 25%, by about 40%, by about 45%, by about 50%, by about 55%, by about 30%, by about 35%, by about 40%, by about 45%, by about 60%, by about 65%, by about 70%, by about 75%, by about 50%, by about 55%, by about 60%, by about 65%, by about 35 80%, by about 85%, by about 90%, by about 95% or by about 70%, by about 75%, by about 80%, by about 85%, by about 100%. In another embodiment, the substituted benzaldehyde 90%, by about 95% or by about 100%. In other embodiments, composition reduces melanin distribution by about 10%, by the composition reduces melanin distribution by about 10%, about 15%, by about 20%, by about 25%, by about 30%, by by about 15%, by about 20%, by about 25%, by about 30%, about 35%, by about 40%, by about 45%, by about 50%, by by about 35%, by about 40%, by about 45%, by about 50%, 40 about 55%, by about 60%, by about 65%, by about 70%, by by about 55%, by about 60%, by about 65%, by about 70%, about 75%, by about 80%, by about 85%, by about 90%, by by about 75%, by about 80%, by about 85%, by about 90%, about 95% or by about 100%. In another embodiment, the by about 95% or by about 100%. In another embodiment, the Substituted benzaldehyde composition reduces melanin dis Substituted benzaldehyde composition reduces melanin dis tribution by about 5% to about 50%. In yet another embodi tribution by about 5% to about 50%. In yet another embodi 45 ment, the Substituted benzaldehyde composition reduces ment, the Substituted benzaldehyde composition reduces melanin distribution by about 10% to about 40%. melanin distribution by about 10% to about 40%. In a further aspect, provided herein is a method of modi Another aspect provided herein relates to a method of fying melanin distribution by modulating prostaglandin F2 modifying melanin distribution by modulating prostaglandin alpha (PGF2 alpha) in a cell, the method comprising contact F2 alpha (PGF2 alpha) in a cell, the method comprising 50 ing said cell with a composition comprising a Substituted contacting said cell with a composition comprising a Substi benzaldehyde and at least one additional active agent. In some tuted benzaldehyde. In a particular embodiment, the compo embodiments, the substituted benzaldehyde is 2-ethoxyben sition modulates PGF2 alpha in a keratinocyte cell to modify Zaldehyde, 4-ethoxybenzaldehyde, 4-allyloxybenzaldehyde melanin distribution. In some embodiments, the substituted or 4-propoxybenzaldehyde. In a specific embodiment, the benzaldehyde is 2-ethoxybenzaldehyde, 4-ethoxybenzalde 55 substituted benzaldehyde is 4-ethoxybenzaldehyde. In yet hyde, 4-allyloxybenzaldehyde or 4-propoxybenzaldehyde. In another embodiment, the substituted benzaldehyde is a specific embodiment, the substituted benzaldehyde is 2-ethoxybenzaldehyde. 4-ethoxybenzaldehyde. In yet another embodiment, the sub In some embodiments, the compositions further comprise stituted benzaldehyde is 2-ethoxybenzaldehyde. a pharmaceutically or cosmetically acceptable carrier. In In some embodiments, the compositions further comprise 60 another embodiment, the pharmaceutically or cosmetically a pharmaceutically or cosmetically acceptable carrier. In acceptable carrier is an oral or topical carrier. In other another embodiment, the pharmaceutically or cosmetically embodiments, the pharmaceutically or cosmetically accept acceptable carrier is an oral or topical carrier. In other able topical carrier is a water-in-oil emulsion, cream, liquid, embodiments, the pharmaceutically or cosmetically accept gel, oil, paste, ointment, Suspension, foam, lotion, oil-in able topical carrier is a water-in-oil emulsion, cream, liquid, 65 water emulsion, water-in-oil-in-water emulsion, water-in gel, oil, paste, ointment, Suspension, foam, lotion, oil-in silicone emulsion, spray or serum carrier. In another embodi water emulsion, water-in-oil-in-water emulsion, water-in ment, the composition is topically administered to the skin of US 8,236,288 B2 23 24 the individual. In yet another embodiment, the composition is In another embodiment, an amount of the substituted ben transdermally administered to the skin of the individual. Zaldehyde that is effective in reducing melanin levels in a In particular embodiments, the additional active agent is an Subject is present in the composition. In some embodiments, antioxidant, a Sunscreen, a Sunprotectant, a Sunblock, a skin the composition modifies melanin distribution by about 1%, lightening agent, an anti-inflammatory agent, an anti-acne 5 about 2%, about 3%, about 4%, about 5%, about 6%, about agent or mixtures thereof. In yet another embodiment, the 7%, about 8%, about 9%, about 10%, by about 15%, by about compositions comprise an antioxidant selected from the 20%, by about 25%, by about 30%, by about 35%, by about group of niacinamide, Vitamin E. Coenzyme Q10, idebenone, 40%, by about 45%, by about 50%, by about 55%, by about lycopene, green tea polyphenols, Silybin, resveratrol, grape 60%, by about 65%, by about 70%, by about 75%, by about seed extract, Oregon grape root (Mahonia aquifolium) 10 80%, by about 85%, by about 90%, by about 95% or by about extract, pomegranate extract, genistein, pycnogenol, cur 100%. In other embodiments, the composition reduces mela cumin, curcuminoids, or combinations thereof. In another nin distribution by about 10%, by about 15%, by about 20%, embodiment, the compositions comprise a skin-lightening by about 25%, by about 30%, by about 35%, by about 40%, agent selected from the group of hydroquinone, monobenzyl by about 45%, by about 50%, by about 55%, by about 60%, ether of hydroquinone, azelaic acid, kojic acid, meduinol, 15 by about 65%, by about 70%, by about 75%, by about 80%, retinoids (e.g., tretinoin, adapalene), soy proteins, alpha-hy by about 85%, by about 90%, by about 95% or by about droxyacids (e.g., glycolic acid), trichloroacetic acid, salicylic 100%. In another embodiment, the substituted benzaldehyde acid, hydroquinone-beta-D-glucopyranoside, paper mul composition reduces melanin distribution by about 5% to berry, glabridin, 4-isopropylcetichol, aleosin, N-acetyl-4-S- about 50%. In yet another embodiment, the substituted ben cycteaminylphenol, N-propionyl-4-S-cysteaminylphenol, Zaldehyde composition reduces melanin distribution by about N-acetyl glucosamine, tranexaminc acid, licorice extract 10% to about 40%. (e.g., Glycyrrhiza Glabra (licorice) root extract), an alpha In particular embodiments, the additional active agent is an MSH antagonist (e.g. undecylenoyl phenylalanine), orphytic antioxidant, a Sunscreen, a Sunprotectant, a Sunblock, a skin acid combinations thereof. lightening agent, an anti-inflammatory agent, an anti-acne In some embodiments, the composition modifies melanin 25 agent or mixtures thereof. In yet another embodiment, the distribution by about 1%, about 2%, about 3%, about 4%, compositions comprise an antioxidant selected from the about 5%, about 6%, about 7%, about 8%, about 9%, about group of niacinamide, Vitamin E. Coenzyme Q10, idebenone, 10%, by about 15%, by about 20%, by about 25%, by about lycopene, green tea polyphenols, Silybin, resveratrol, grape 30%, by about 35%, by about 40%, by about 45%, by about seed extract, Oregon grape root (Mahonia aquifolium) 50%, by about 55%, by about 60%, by about 65%, by about 30 extract, pomegranate extract, genistein, pycnogenol, cur 70%, by about 75%, by about 80%, by about 85%, by about cumin, curcuminoids, or combinations thereof. In another 90%, by about 95% or by about 100%. In other embodiments, embodiment, the compositions comprise a skin-lightening the composition reduces melanin distribution by about 10%, agent selected from the group of hydroquinone, monobenzyl by about 15%, by about 20%, by about 25%, by about 30%, ether of hydroquinone, azelaic acid, kojic acid, meduinol, by about 35%, by about 40%, by about 45%, by about 50%, 35 retinoids (e.g., tretinoin, adapalene), soy proteins, alpha-hy by about 55%, by about 60%, by about 65%, by about 70%, droxyacids (e.g., glycolic acid), trichloroacetic acid, salicylic by about 75%, by about 80%, by about 85%, by about 90%, acid, hydroquinone-beta-D-glucopyranoside, paper mul by about 95% or by about 100%. In another embodiment, the berry, glabridin, 4-isopropylcetichol, aleosin, N-acetyl-4-S- Substituted benzaldehyde composition reduces melanin dis cycteaminylphenol, N-propionyl-4-S-cysteaminylphenol, tribution by about 5% to about 50%. In yet another embodi 40 N-acetyl glucosamine, tranexaminc acid, licorice extract ment, the Substituted benzaldehyde composition reduces (e.g., Glycyrrhiza Glabra (licorice) root extract), an alpha melanin distribution by about 10% to about 40%. MSH antagonist (e.g. undecylenoyl phenylalanine), orphytic In a particular embodiment, the compositions disclosed acid combinations thereof. herein modulate PGF2 alpha in a keratinocyte cell to modify Another aspect provided herein relates to the use of the melanin distribution. In some embodiments, the composi 45 composition to treat a hyperpigmentation disorder. In some tions disclosed herein modulate PGF2. embodiments, the hyperpigmentation disorder is due to post In a further aspect, provided herein are compositions com inflammatory hyperpigmentation disorder. In other embodi prising a combination of a Substituted benzaldehyde, at least ments, the post-inflammatory hyperpigmentation disorder is one additional active agent, and a pharmaceutically or cos due to infections, allergic reactions, mechanical injuries, metically acceptable carrier. In some embodiments, the Sub 50 reaction to medications, phototoxic eruptions, trauma, or stituted benzaldehyde is 2-ethoxybenzaldehyde, 4-ethoxy reaction to ultrasound, radiofrequency, lasers, light-emitting benzaldehyde, 4-allyloxybenzaldehyde O diodes, visible light therapy, microdermabrasion or chemical 4-propoxybenzaldehyde. In a specific embodiment, the Sub peel therapies. stituted benzaldehyde is 4-ethoxybenzaldehyde. In yet another embodiment, the substituted benzaldehyde is 55 INCORPORATION BY REFERENCE 2-ethoxybenzaldehyde. In some embodiments, the substi tuted benzaldehyde is a skin lightening agent. All publications and patent applications mentioned in this In another embodiment, the pharmaceutically or cosmeti specification are herein incorporated by reference to the same cally acceptable carrier is an oral or topical carrier. In other extent as if each individual publication or patent application embodiments, the pharmaceutically or cosmetically accept 60 was specifically and individually indicated to be incorporated able topical carrier is a water-in-oil emulsion, cream, liquid, by reference. gel, oil, paste, ointment, Suspension, foam, lotion, oil-in water emulsion, water-in-oil-in-water emulsion, water-in BRIEF DESCRIPTION OF THE DRAWINGS silicone emulsion, spray or serum carrier. In another embodi ment, the composition is topically administered to the skin of 65 The novel features of the embodiments are set forth with the individual. In yet another embodiment, the composition is particularity in the appended claims. A better understanding transdermally administered to the skin of the individual. of the features and advantages of the present embodiments US 8,236,288 B2 25 26 will be obtained by reference to the following detailed 90%, by about 100%, by about 125% or by about 150%. The description that sets forth illustrative embodiments, in which disclosed compositions may decrease or increase melanin the principles of the invention are utilized, and the accompa and/or melanocyte distribution and/or levels. For example, in nying drawings of which: the treatment of hyperpigmentation or hypermelanosis disor FIG. 1 is a graph that depicts 4-ethoxybenzaldehyde ders, the disclosed compositions may decrease melanin and/ (“4EB') dose-dependent inhibition of PGF2 alpha in UVB or melanocyte distribution and/or levels by about 1%, about induced keratinocytes. Keratinocytes treated with 2%, about 3%, about 4%, about 5%, about 6%, by about 7%, indomethacin are used as a positive control. about 7%, about 8%, about 9%, by about 10%, by about 12%, FIG. 2 is a graph depicting the protection factors assessed by about 15%, by about 20%, by about 25%, by about 30%, from the post-inflammatory hyperpigmentation clinical 10 by about 35%, by about 35%, by about 40%, by about 45%, study. by about 50%, by about 55%, by about 60%, by about 70%, FIG. 3 is a graph depicting the reduction in hyperpigmen by about 80%, by about 90% or by about 100%. In another tation assessed from the post-inflammatory hyperpigmenta embodiment, melanin distribution may be decreased by about tion clinical study. 5% to about 50%. In yet another embodiment, melanin dis FIG. 4 is a graph depicting the increase in skin brightness 15 tribution may be decreased by about 10% to about 40%. The (L) assessed from the post-inflammatory hyperpigmenta disclosed compositions may optionally modify or treat other tion clinical study. cosmetic ortherapeutic disorders, including dry skin, eczema FIG.5 is a graph depicting the reduction of melanin content or other cosmetic or dermatological disorders. The formula in human skin equivalent treated with a negative control, tions disclosed herein may comprise a form for topical positive control (1% Kojic acid) or Base+1% 4EB. administration, including a lotion, emulsion, cream, gel, oint FIG. 6 is a graph depicting the increase in brightness of ment, foam, liquid, paste or other topically administrable UV-induced pigmentation where human skin is left untreated, form. Alternatively, the formulations disclosed herein may or is treated with 4% hydroquinone or Base--0.5% 4EB. comprise a form Suitable for transdermal administration, FIG. 7 is a graph depicting the decrease in hyperpigmen including a transdermal patch, transdermal lotion, transder tation compared to baseline after treatment with 4% hydro 25 mal cream, transdermal gel, transdermal ointment, transder quinone or Base+0.5% 4EB. mal foam, transdermal liquid, transdermal paste or other FIG. 8 is a graph depicting the distribution of results in transdermally-administrable form. individual subjects after treatment with 4% hydroquinone or In some embodiments, an additional active agent(s) may be Base--0.5% 4EB. used in combination with the substituted benzaldehyde com FIG. 9 is a graph depicting the results from the patient 30 positions disclosed. For example, other skin lightening agents self-assessment questionnaire after treatment with 4% hyd may be used in combination with the substituted benzalde roquinone or Base+0.5% 4EB. hydes, including hydroquinone, retinoids, corticosteroids, glycolic acid, other fruit acids, azelaic acid, vitamin C, lico DETAILED DESCRIPTION OF THE INVENTION rice extract (e.g., Glycyrrhiza Glabra (licorice) root extract), 35 an alpha MSH antagonist (e.g. undecylenoyl phenylalanine), The present disclosure relates to compositions comprising phytic acid or mixtures thereof. In addition, skin or dermato substituted benzaldehydes and optionally at least one addi logical agents may also be used in combination with the tional active agent, and methods for using the compositions. substituted benzaldehyde compositions disclosed herein, The compositions disclosed may be used for the treatment of including antioxidants, Sunscreen and Sunprotectants, emol skin disorders, including the treatment of melanin or pigmen 40 lients, barrier treatments, topical steroids, antibiotics, antimi tation disorders, including but not limited to hyperpigmenta crobials, acne medications, antiperspirants, deodorants, per tion or hypermelanosis disorders that affect melanin or pig fuming agents and other skin or dermatological agents or mentation levels in the skin. Such disorders may be due to mixtures thereof. Alternatively, pre, simultaneous or Subse environmental stressors, such as excessive Sun, or physiologi quent dermatological treatments may also take place in com cal stressors, such as hormonal imbalance. Such disorders 45 bination with the compositions disclosed herein, including include melasma, chloasma, post-inflammatory hyperpig laser treatment, chemical peels, intense pulsed light, derm mentation, acanthosis nigricans, pigmented purpura, urti abrasion or cryotherapy. caria, pityriasis, Solar lentigines, vitiligo, birthmarks, port In one aspect, provided herein is a composition comprising wine stains, dark spots, age spots, freckles or Sun spots. Other from about 0.01% to about 2% substituted benzaldehyde, examples of uses of the disclosed compositions include hyper 50 about 0.01% to about 5.0% each of Retinol, Niacinamide, or hypopigmentation due to scarring, or exposure to environ Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice) mental antigens or allergens, including phytodermatitis or Root Extract, Hexyl Resorcinol, ethyl linoleate, and a phar phytophotodermatitis. In addition, the disclosed composi maceutically or cosmetically acceptable carrier. In one tions may be used in conjunction with and/or for the treatment embodiment, the amount of substituted benzaldehyde is of skin disorders or trauma as a result of a mechanical injury 55 about 0.5%. In another embodiment, the composition com ortherapy, including but not limited to laser treatment, chemi prises from about 0.1% to about 0.75%, from about 0.05% to cal peels, intense pulsed light, dermabrasion or cryotherapy. about 1.0%, or from about 0.01% to about 2% Retinol. In The disclosed compositions may modify melanin and/or another embodiment, the composition comprises from about melanocyte distribution and/or levels for the treatment of 2.0% to about 8.0%, from about 1% to about 10%, or from melanin or pigmentation disorders. The disclosed composi 60 about 0.5% to about 15.0% Niacinamide. In another embodi tions may modify melanin and/or melanocyte distribution ment, the composition comprises from about 1.0% to about and/or levels by about 1%, about 2%, about 3%, about 4%, 5.0%, from about 0.5% to about 8.0%, or from about 0.1% to about 5%, about 6%, by about 7%, about 7%, about 8%, about about 15% Tetrahexyldecyl Ascorbate. In another embodi 9%, by about 10%, by about 12%, by about 15%, by about ment, the composition comprises from about 0.001% to about 20%, by about 25%, by about 30%, by about 35%, by about 65 0.5%, from about 0.0005% to about 1.0% or from about 35%, by about 40%, by about 45%, by about 50%, by about 0.0001% to about 2% Licorice root extract. In another 55%, by about 60%, by about 70%, by about 80%, by about embodiment, the composition comprises from about 0.1% to US 8,236,288 B2 27 28 about 3.0%, from about 0.05% to about 5.0%, or from about may be, for example, an antioxidant, a Sunscreen, a Sunpro 0.01% to about 10.0% Resorcinol. In another embodiment, tectant, a Sunblock, a skin-lightening agent, an anti-inflam the composition comprises from about 0.1% to about 3.0%, matory agent, an anti-acne agent or mixtures thereof. from about 0.05% to about 5.0%, or from about 0.01% to In one embodiment, an antioxidant is selected from the about 10.0% ethyl linoleate. group of vitamin E. Coenzyme Q10, idebenone, lycopene, Substituted benzaldehydes for use in the compositions green tea polyphenols, Silybin, resveratrol, grape seed include, for example, 2-ethoxybenzaldehyde, 4-ethoxyben extract, Oregon grape root (Mahonia aquifolium) extract, Zaldehyde, 4-allyloxybenzaldehyde or 4-propoxybenzalde pomegranate extract, genistein, pycnogenol, curcumin, cur hyde. In one embodiment, the substituted benzaldehyde is cuminoids, Tocopherol, Dunaliella Salina Extract or combi 4-ethoxybenzaldehyde, which may be present in the compo 10 nations thereof. sition in an amount of about 0.5%. In one embodiment, a skin-lightening agent is selected In another aspect, provided herein is a comprising from from the group of hydroquinone, monobenzyl ether of hyd 0.1% to about 0.5% 4-ethoxybenzaldehyde, about 0.01% to roquinone, azelaic acid, kojic acid, meduinol, retinoids, Soy about 5.0% each of Retinol, Niacinamide, Tetrahexyldecyl proteins, alpha-hydroxy acids, trichloroacetic acid, salicylic Ascorbate, Glycyrrhiza Glabra (Licorice) Root Extract, 15 acid, hydroquinone-beta-D-glucopyranoside, paper mul Hexyl Resorcinol, ethyllinoleate, and a pharmaceutically or berry, glabridin, 4-isopropylcetichol, aleosin, N-acetyl-4-S- cosmetically acceptable carrier. In another embodiment, the cycteaminylphenol, N-propionyl-4-S-cysteaminylphenol, composition comprises from about 0.1% to about 0.75%, N-acetyl glucosamine, tranexaminc acid, an alpha MSH from about 0.05% to about 1.0%, or from about 0.01% to antagonist (e.g. undecylenoyl phenylalanine), phytic acid or about 2% Retinol. In another embodiment, the composition combinations thereof. comprises from about 2.0% to about 8.0%, from about 1% to Pharmaceutically or cosmetically acceptable carriers for about 10%, or from about 0.5% to about 15.0% Niacinamide. use in the present compositions are topical carriers. The topi In another embodiment, the composition comprises from cal carrier may be a water-in-oil emulsion, cream, liquid, gel. about 1.0% to about 5.0%, from about 0.5% to about 8.0%, or oil, paste, ointment, Suspension, foam, lotion, oil-in-water from about 0.1% to about 15% Tetrahexyldecyl Ascorbate. In 25 emulsion, water-in-oil-in-water emulsion, water-in-silicone another embodiment, the composition comprises from about emulsion, spray or serum carrier. 0.001% to about 0.5%, from about 0.0005% to about 1.0% or The compositions described herein may also further com from about 0.0001% to about 2% Licorice root extract. In prise one or more of a solvent, film former, preservative, another embodiment, the composition comprises from about Viscosity increasing agent, fragrance, Surfactant, chelating 0.1% to about 3.0%, from about 0.05% to about 5.0%, or from 30 agent, humectant, permeation enhancer (skin penetrator), about 0.01% to about 10.0% Resorcinol. In another embodi excipients, or a combination thereof. ment, the composition comprises from about 0.1% to about In one embodiment, a composition comprises about 0.5% 3.0%, from about 0.05% to about 5.0%, or from about 0.01% 4-ethoxybenzaldehyde, at least one additional active agent, to about 10.0% ethyl linoleate. and a pharmaceutically or cosmetically acceptable carrier. In In yet another aspect, provided herein is a comprising 35 other embodiment, a composition comprises about 0.5% about 0.5% 4-ethoxybenzaldehyde, about 0.01% to about 4-ethoxybenzaldehyde, at least two additional active agents, 5.0% each of Retinol, Niacinamide, Tetrahexyldecyl Ascor and a pharmaceutically or cosmetically acceptable carrier. In bate, Glycyrrhiza Glabra (Licorice) Root Extract, Hexyl yet other embodiment, a composition comprises about 0.5% Resorcinol, ethyl linoleate, and a pharmaceutically or cos 4-ethoxybenzaldehyde, at least three additional active agents, metically acceptable carrier. In another embodiment, the 40 and a pharmaceutically or cosmetically acceptable carrier. In composition comprises from about 0.1% to about 0.75%, yet other embodiment, a composition comprises about 0.5% from about 0.05% to about 1.0%, or from about 0.01% to 4-ethoxybenzaldehyde, at least four additional active agents, about 2% Retinol. In another embodiment, the composition and a pharmaceutically or cosmetically acceptable carrier. In comprises from about 2.0% to about 8.0%, from about 1% to yet other embodiment, a composition comprises about 0.5% about 10%, or from about 0.5% to about 15.0% Niacinamide. 45 4-ethoxybenzaldehyde, at least five additional active agents, In another embodiment, the composition comprises from and a pharmaceutically or cosmetically acceptable carrier. In about 1.0% to about 5.0%, from about 0.5% to about 8.0%, or yet other embodiment, a composition comprises about 0.5% from about 0.1% to about 15% Tetrahexyldecyl Ascorbate. In 4-ethoxybenzaldehyde, at least six additional active agents, another embodiment, the composition comprises from about and a pharmaceutically or cosmetically acceptable carrier. 0.001% to about 0.5%, from about 0.0005% to about 1.0% or 50 In another embodiment, a composition comprises from from about 0.0001% to about 2% Licorice root extract. In about 0.1% to about 0.5% 4-ethoxybenzaldehyde, at least one another embodiment, the composition comprises from about skin lightening agent, at least one skin conditioning agent, at 0.1% to about 3.0%, from about 0.05% to about 5.0%, or from least one antioxidant, at least one occlusive, at least one about 0.01% to about 10.0% Resorcinol. In another embodi emollient, at least one preservative, at least one viscosity ment, the composition comprises from about 0.1% to about 55 increasing agent, at least one fragrance, at least one skin 3.0%, from about 0.05% to about 5.0%, or from about 0.01% conditioning agent, at least one surfactant, at least one chelat to about 10.0% ethyl linoleate. ing agent, at least one humectant, and a pharmaceutically or Compositions described herein may be used to lighten skin cosmetically acceptable carrier. as well as to treat hyperpigmentation or a hypermelanosis In another embodiment, a composition comprises about disorder. In one embodiment, the hyperpigmentation is post 60 0.5% 4-ethoxybenzaldehyde, at least one skin lightening inflammatory hyperpigmentation. Hyperpigmentation and agent, at least one skin conditioning agent, at least one anti hypermelanosis disorders may result from an environmental oxidant, at least one occlusive, at least one emollient, at least stressor, physiological stressor, or mechanical stressor. one preservative, at least one viscosity increasing agent, at Compositions described herein may reduce melanin distri least one fragrance, at least one skin conditioning agent, at bution by about 10% to about 40% when applied to skin. 65 least one surfactant, at least one chelating agent, at least one Compositions described herein may further comprise one humectant, and a pharmaceutically or cosmetically accept or more additional active agents. An additional active agent able carrier. In another embodiment, the composition com US 8,236,288 B2 29 30 prises from about 0.1% to about 0.75%, from about 0.05% to Acyloxy” refers to the group or radical —OC(O)R23 about 1.0%, or from about 0.01% to about 2% Retinol. In where R23 is hydrogen, substituted or unsubstituted alkyl, another embodiment, the composition comprises from about substituted or unsubstituted aryl or substituted or unsubsti 2.0% to about 8.0%, from about 1% to about 10%, or from tuted cycloalkyl. about 0.5% to about 15.0% Niacinamide. In another embodi The term “alkyl as used herein refers to saturated or unsat ment, the composition comprises from about 1.0% to about urated, straight- or branched-chain hydrocarbon radicals 5.0%, from about 0.5% to about 8.0%, or from about 0.1% to derived from a hydrocarbon moiety containing between one about 15% Tetrahexyldecyl Ascorbate. In another embodi and twenty carbon atoms by removal of a single hydrogen ment, the composition comprises from about 0.001% to about atom. Alkyl groups as used herein may optionally include one 0.5%, from about 0.0005% to about 1.0% or from about 10 or more further substituent groups. This term is exemplified 0.0001% to about 2% Licorice root extract. In another by groups such as methyl, ethyl, n-propyl, isopropyl. n-butyl, embodiment, the composition comprises from about 0.1% to iso-butyl, tert-butyl, n-hexyl, n-octyl, tert-octyl and the like, about 3.0%, from about 0.05% to about 5.0%, or from about and may be substituted or unsubstituted. The term “lower 0.01% to about 10.0% Resorcinol. In another embodiment, alkyl refers to alkyl groups having 1 to 6 carbon atoms. The the composition comprises from about 0.1% to about 3.0%, 15 term “alkyl also includes “cycloalkyls' as defined below. from about 0.05% to about 5.0%, or from about 0.01% to Alkynyl refers to acetylenically or alkynically unsatur about 10.0% ethyl linoleate. ated hydrocarbyl groups particularly having 2 to 11 carbon In some embodiments, the combination compositions dis atoms and more particularly 2 to 6 carbonatoms which can be closed herein may act additively or synergistically. In some straight-chained or branched and having at least 1 and par embodiments, a “synergistic effect” may be seen where the ticularly from 1 to 2 sites of alkynyl unsaturation. Particular combination of the substituted benzaldehyde and additional non-limiting examples of alkynyl groups include Substituted active agent(s) results in an activity that is more than the effect or unsubstituted acetylenic, substituted or unsubstituted ethy of the two individual agents alone. In other embodiments, a nyl ( C=CH), substituted or unsubstituted propargyl “synergistic effect” may be seen where a combination of the (-CH2C=CH), and the like. Substituted benzaldehyde and additional active agent(s) 25 The term "aminoalkyl as used herein, refers to an amino results in a modulation in melanin distribution, but no effect is substituted alkyl radical. This term is meant to include alkyl seen when the agents are used individually. In yet other groups having an amino Substituent at any position and embodiments, a “synergistic effect” may allow a decrease in wherein the alkyl group attaches the aminoalkyl group to the the amount of substituted benzaldehyde and/or additional parent molecule. The alkyl and/or amino portions of the ami active agent(s) used, thereby decreasing the incidence of 30 noalkyl group can be further substituted with substituent adverse side effects. Such as itching, pruritis, skin irritation or groups. other adverse side effects. As used herein, the term “alkoxy” refers to a radical formed As used in the specification and the appended claims, the between an alkyl group and an oxygen atom wherein the singular forms “a”, “an and “the include plural references oxygen atom is used to attach the alkoxy group to a parent unless the context clearly dictates otherwise. Thus for 35 molecule. Alkoxy groups as used herein may optionally example, reference to “the method’ includes one or more include further Substituent groups. Particular alkoxy groups methods, and/or steps of the type described herein and/or include, by way of example, substituted or unsubstituted which will become apparent to those persons skilled in the art methoxy, substituted or unsubstituted ethoxy, substituted or upon reading this disclosure. unsubstituted n-propoxy, Substituted or unsubstituted isopro The term “about' or “approximately’ means within an 40 poxy, substituted or unsubstituted n-butoxy, substituted or acceptable error range for the particular value as determined unsubstituted tert-butoxy, substituted or unsubstituted sec by one of ordinary skill in the art, which will dependin part on butoxy, substituted or unsubstituted n-pentoxy, substituted or how the value is measured or determined, i.e., the limitations unsubstituted n-hexoxy, substituted or unsubstituted 1,2-dim of the measurement system. For example, "about can mean ethylbutoxy, and the like. within 1 or more than 1 standard deviation, per the practice in 45 As used herein, the term “alkenyl refers to a straight or the art. Alternatively, “about can mean a range of up to 20%, branched hydrocarbon chain radical containing up to twenty preferably up to 10%, more preferably up to 5%, and more four carbon atoms and having at least one carbon-carbon preferably still up to 1% of a given value. Alternatively, par double bond. Alkenyl groups as used herein may optionally ticularly with respect to biological systems or processes, the include one or more further substituent groups. Particular term can mean within an order of magnitude, preferably 50 alkenyl groups include Substituted or unsubstituted ethenyl within 5-fold, and more preferably within 2-fold, of a value. (—CH=CH2), substituted or unsubstituted n-propenyl Where particular values are described in the application and (—CH2CH=CH2), substituted or unsubstituted isopropenyl claims, unless otherwise stated the term “about’ meaning (—C(CH3)-CH2), substituted or unsubstituted vinyl and within an acceptable error range for the particular value substituted vinyl, and the like. should be assumed. 55 As used herein, the term “aryl” refers to a mono- or poly As used herein, the term “acyl refers to a radical formed cyclic carbocyclic ring system radicals having one or more by removal of a hydroxyl group from an organic acid and has aromatic rings. Aryl groups as used herein may optionally the general formula —C(O)—X where X is hydrogen, sub include further Substituent groups. Typical aryl groups stituted or unsubstituted alkyl, substituted or unsubstituted include, but are not limited to, groups derived from acean cycloalkyl, substituted or unsubstituted cycloheteroalkyl, 60 thrylene, acenaphthylene, acephenanthrylene, anthracene, substituted or unsubstituted aryl, substituted or unsubstituted aZulene, benzene, chrysene, coronene, fluoranthene, fluo arylalkyl, substituted or unsubstituted heteroalkyl, substi rene, hexacene, hexaphene, hexylene, as-indacene, S-in tuted or unsubstituted heteroaryl, substituted or unsubstituted dacene, indane, indene, naphthalene, octacene, octaphene, heteroarylalkyl as defined herein. Representative examples octalene, ovalene, penta-2,4-diene, pentacene, pentalene, include, but are not limited to, formyl, acetyl, cylcohexylcar 65 pentaphene, perylene, phenalene, phenanthrene, picene, ple bonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl iadene, pyrene, pyranthrene, rubicene, triphenylene, trinaph and the like. thalene and the like, and may be substituted or unsubstituted. US 8,236,288 B2 31 32 Particularly, an aryl group comprises from 6 to 14 carbon Arylalkyloxy' refers to a substituted or unsubstituted atOmS. —O-arylalkyl radical where arylalkyl is as defined herein. Alkaryl” refers to an aryl group, as defined above, substi Arylamino” means a substituted or unsubstituted radical tuted with one or more substituted or unsubstituted alkyl —NHR40 where R40 represents an aryl group as defined groups, as defined above. herein. Aralkyl or “arylalkyl refers to an alkyl group, as defined Aryloxycarbonyl refers to a substituted or unsubstituted above, substituted with one or more substituted or unsubsti radical —C(O)—O-aryl where aryl is as defined herein. tuted aryl groups, as defined above. Arylsulfonyl refers to a r substituted or unsubstituted Aryloxy' refers to substituted or unsubstituted —O-aryl adical —S(O)2R41 where R41 is an aryl or heteroaryl group groups wherein “aryl' is as defined above. 10 as defined herein. Alkylamino” refers to the group alkyl-NR28R29, wherein “AZido’ refers to the radical - N3. each of R28 and R29 are independently selected from hydro “Bicycloaryl refers to a monovalent aromatic hydrocar gen and Substituted or unsubstituted alkyl. bon group derived by the removal of one hydrogenatom from Arylamino” refers to the group aryl-NR30R31, wherein 15 a single carbonatom of a parent bicycloaromatic ring system. each of R30 and R31 are independently selected from hydro Typical bicycloaryl groups include, but are not limited to, gen, Substituted or unsubstituted aryl and Substituted or groups derived from indane, indene, naphthalene, tetrahy unsubstituted heteroaryl. dronaphthalene, and the like, and may be substituted or Alkoxyamino” refers to a radical —N(H)OR32 where unsubstituted. Particularly, an aryl group comprises from 8 to R32 represents a substituted or unsubstituted alkyl or substi 11 carbon atoms. tuted or unsubstituted cycloalkyl group as defined herein. “Bicycloheteroaryl refers to a monovalent bicyclohet Alkoxycarbonyl refers to a substituted or unsubstituted eroaromatic group derived by the removal of one hydrogen radical —C(O)-alkoxy where alkoxy is as defined herein. atom from a single atom of a parent bicycloheteroaromatic Alkylarylamino” refers to a substituted or unsubstituted ring system. Typical bicycloheteroaryl groups include, but radical NR33R34 where R33 represents an alkyl or 25 are not limited to, groups derived from benzofuran, benzimi cycloalkyl group and R34 is an aryl as defined herein. dazole, benzindazole, benzdioxane, chromene, chromane, Alkylsulfonyl refers to a substituted or unsubstituted cinnoline, phthalazine, indole, indoline, indolizine, isoben radical —S(O)2R35 where R35 is an alkyl or cycloalkyl Zofuran, isochromene, isolindole, isoindoline, isoquinoline, group as defined herein. Representative examples include, benzothiazole, benzoxazole, naphthyridine, benzoxadiazole, 30 pteridine, purine, benzopyran, benzpyrazine, pyridopyrimi but are not limited to, methylsulfonyl, ethylsulfonyl, propyl dine, quinazoline, quinoline, quinolizine, quinoxaline, ben sulfonyl, butylsulfonyl and the like. Zomorphan, tetrahydroisoquinoline, tetrahydroquinoline, Alkylsulfinyl refers to a substituted or unsubstituted radi and the like, and may be substituted or unsubstituted. Prefer cal —S(O)R35 where R35 is an alkyl or cycloalkyl group as ably, the bicycloheteroaryl group is between 9-11 membered defined herein. Representative examples include, but are not 35 bicycloheteroaryl, with 5-10 membered heteroaryl being par limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl, ticularly preferred. Particular bicycloheteroaryl groups are butylsulfinyl and the like. those derived from benzothiophene, benzofuran, benzothia Alkylthio’ refers to a substituted or unsubstituted radical Zole, indole, quinoline, isoquinoline, benzimidazole, benzox —SR35 where R35 is an alkyl or cycloalkyl group as defined azole and benzdioxane. herein that may be optionally substituted as defined herein. 40 “Carbamoyl refers to the radical –C(O)N(R42)2 where Representative examples include, but are not limited to, each R42 group is independently hydrogen, Substituted or methylthio, ethylthio, propylthio, butylthio, and the like. unsubstituted alkyl, substituted or unsubstituted cycloalkyl or Amino refers to the radical NH2. substituted or unsubstituted aryl, as defined herein, which “Substituted amino” includes those groups recited in the may be optionally substituted as defined herein. definition of “substituted herein, and particularly refers to 45 “Carboxy” refers to the radical - C(O)OH. the group —N(R36)2 where each R36 is independently “Carboxyamino” refers to the radical N(H)C(O)OH. selected from the group consisting of hydrogen, alkyl, Sub “Cycloalkyl refers to cyclic hydrocarbyl groups having stituted alkyl, alkenyl, Substituted alkenyl, alkynyl, Substi from 3 to about 10 carbon atoms and having a single cyclic tuted alkynyl, aryl, cycloalkyl, Substituted cycloalkyl, and ring or multiple condensed rings, including fused and bridged where both R groups are joined to form an alkylene group. 50 ring systems, which optionally can be substituted with from 1 When both R groups are hydrogen, —N(R36)2 is an amino to 3 alkyl groups. Such cycloalkyl groups include, by way of group. example, single ring structures such as cyclopropyl, cyclobu “Aminocarbonyl refers to the group –C(O)NR37R37 tyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methyl where each R37 is independently hydrogen, substituted or cyclopentyl, 2-methylcyclooctyl, and the like, and multiple unsubstituted alkyl, substituted or unsubstituted aryland sub 55 ring structures Such as adamantanyl, and the like, and may be stituted or unsubstituted cycloalkyl, or where the R37 groups substituted or unsubstituted. are joined to form an alkylene group. “Cycloalkoxy' refers to the group —OR43 where R43 is Aminocarbonylamino” refers to the group —NR38C(O) substituted or unsubstituted cycloalkyl. Such cycloalkoxy NR38R38 where each R38 is independently hydrogen, sub groups include, by way of example, Substituted or unsubsti stituted or unsubstituted alkyl, substituted or unsubstituted 60 tuted cyclopentoxy, Substituted or unsubstituted cyclohexoxy aryl or substituted or unsubstituted cycloalkyl, or where two and the like. R groups are joined to form an alkylene group. “Cycloalkenyl refers to cyclic hydrocarbyl groups having Aminocarbonyloxy' refers to the group —OC(O) from 3 to 10 carbon atoms and having a single cyclic ring or NR39R39 where each R39 is independently hydrogen, sub multiple condensed rings, including fused and bridged ring stituted or unsubstituted alkyl, substituted or unsubstituted 65 systems and having at least one and particularly from 1 to 2 aryl or substituted or unsubstituted cycloalkyl, or where the R sites of olefinic unsaturation. Such cycloalkenyl groups groups are joined to form an alkylene group. include, by way of example, single ring structures such as US 8,236,288 B2 33 34 substituted or unsubstituted cyclohexenyl, substituted or stituted alkyl, cycloalkyl, substituted alkyl, cycloheteroalkyl, unsubstituted cyclopentenyl, substituted or unsubstituted substituted cycloheteroalkyl, heteroalkyl, substituted het cyclopropenyl, and the like. eroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl “Fused Cycloalkenyl refers to a substituted or unsubsti or substituted heteroarylalkyl. tuted cycloalkenyl having two of its ring carbon atoms in 5 “Benzaldehyde' refers to an aryl group substituted with a common with a second aliphatic or aromatic ring and having formyl group or radical (i.e. —C(O)H). Examples of repre its olefinic unsaturation located to impart aromaticity to the sentative substituted benzaldehydes (Formula I) and the cycloalkenyl ring. hemiacetal (Formula II) and acetal (Formula III) equivalents “Cyanato” refers to the radical OCN. include the following: “Cyano” refers to the radical —CN. 10 “Dialkylamino” means a radical —NR44R45 where R44 and R45 independently represent an alkyl, substituted alkyl, Formula I aryl, Substituted aryl, cycloalkyl, Substituted cycloalkyl, R O cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, or R2 Substituted heteroaryl group as defined herein. 15 H The terms “halo' and “halogen' as used herein refer to an atom selected from fluorine, chlorine, bromine, and iodine. “Hetero” when used to describe a compound or a group R3 Rs present on a compound means that one or more carbonatoms R4 in the compound or group have been replaced by a nitrogen, Formula II oxygen, or Sulfur heteroatom. Hetero may be applied to any of R OR6 the hydrocarbyl groups described above Such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. cycloheteroalkyl, aryl, e.g. het R eroaryl, cycloalkenyl, cycloheteroalkenyl, and the like having OH from 1 to 5, and especially from 1 to 3 heteroatoms. 25 “Heteroaryl” refers to a monovalent heteroaromatic group R3 Rs derived by the removal of one hydrogen atom from a single R4 atom of a parent heteroaromatic ring system. Typical het Formula III eroaryl groups include, but are not limited to, groups derived R OR6 from acridine, arsindole, carbazole, B-carboline, chromane, 30 chromene, cinnoline, furan, imidazole, indazole, indole, R indoline, indolizine, isobenzofuran, isochromene, isoindole, OR6 isoindoline, isoquinoline, isothiazole, isoxazole, naphthyri dine, oxadiazole, oxazole, perimidine, phenanthridine, R3 Rs phenanthroline, phenazine, phthalazine, pteridine, purine, 35 pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, R4 pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, qui noxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, wherein each R. R. R. R. and Rs is independently selected xanthene, and the like. Preferably, the heteroaryl group is from hydrogen, halogen, alkyl, alkenyl, alkynyl, acyloxy, between 5-15 membered heteroaryl, with 5-10 membered 40 cycloalkyl, cycloheteroalkyl, alkoxy, alkoxyamino, alkoxy heteroaryl being particularly preferred. Particular heteroaryl carbonyl, cycloalkoxy, cycloalkenyl, cyano, cyanato, aryl, groups are those derived from thiophene, pyrrole, ben arylalkyl, alkylaryl, aryloxy, heteroaryl, heteroaryloxy, Zothiophene, benzofuran, indole, pyridine, quinoline, imida amino, aminoalkyl, alkylarylamino, alkylamino, aminocar Zole, oxazole and pyrazine. bonylamino, aminocarbonyloxy, arylamino, azido, bicy “Substituted refers to a group in which one or more hydro 45 cloaryl, carbamoyl carboxy, carboxyamino, heteroary gen atoms are each independently replaced with the same or lamino, alkylsulfonyl, alkylthio, and Sulfone; different substituent(s). Typical substituents include, but are wherein at least one of R. R. R. R. or Rs is not hydrogen; not limited to, —X, —R46, —O— —O, —OR46, —SR46, and each R is independently alkyl. —S —S, NR46R47, =NR46, CX3, -CF3, CN, "Pharmaceutically acceptable” means approved by a regu OCN, SCN, NO, NO2, —N2, N3, S(O)2O , 50 latory agency of the Federal or a state government or listed in —S(O)2OH, -S(O)2R46, OS(O2)O, OS(O)2R46, the U.S. Pharmacopoeia or other generally recognized phar macopoeia for use in animals, and more particularly in humans. “Cosmetically acceptable” means suitable for cosmetic 55 applications, including topical application of the composi NR46R47 and –C(NR48)NR46R47, where each X is tions disclosed herein in the absence of significant adverse independently a halogen; each R46, R47, R48 and R49 are side effects upon application of the composition or com independently hydrogen, alkyl, Substituted alkyl, aryl, Substi pounds disclosed herein. Other applications include skin care tuted alkyl, arylalkyl, substituted alkyl, cycloalkyl, substi applications, including but not limited to lotions, cream, tuted alkyl, cycloheteroalkyl, substituted cycloheteroalkyl, 60 cleansing creams or lotions, soaps and other cleansers, anti heteroalkyl, substituted heteroalkyl, heteroaryl, substituted perspirant and/or deodorants, makeup products. Such as face heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, powders, foundations, rouge, eye shadow, mascara, eyeliner NR50R51, C(O)R50 or S(O)2R50 or optionally R50 or lipstick, Sun protection products, such as Sunscreen or and R51 together with the atom to which they are both other UV-protective cosmetics, lotions or creams, hairdress attached form a cycloheteroalkyl or substituted cyclohet 65 ing products, such as shampoo, rinses, or treatment setting eroalkyl ring; and R50 and R51 are independently hydrogen, agents. The phrases “pharmaceutically acceptable' and "cos alkyl, substituted alkyl, aryl, substituted alkyl, arylalkyl, sub metically acceptable' are not meant to imply mutual exclu US 8,236,288 B2 35 36 siveness in all applications. In some embodiments, a compo as hydrates, and further include both stoichiometric solvates sition may be both “pharmaceutically acceptable' and and non-stoichiometric Solvates. "cosmetically acceptable dependent upon the need and “Subject' includes humans. The terms “human, patient’ course of action of the compositions disclosed herein. and “subject' are used interchangeably herein. “Pharmaceutically acceptable salt” refers to a salt of a “Effective amount’ means the amount of a compound that, compound disclosed herein that is pharmaceutically accept when administered to a subject for treating a disease, cos able and that possesses the desired pharmacological activity metic or dermatological condition, is sufficient to effect Such of the parent compound. Such salts include: (1) acid addition treatment for the disease, cosmetic or dermatological condi salts, formed with inorganic acids such as hydrochloric acid, tion. The “effective amount can vary depending on the com hydrobromic acid, Sulfuric acid, nitric acid, phosphoric acid, 10 and the like; or formed with organic acids such as acetic acid, pound, the disease and its severity, and the age, weight, etc., of propionic acid, hexanoic acid, cyclopentanepropionic acid, the subject to be treated. glycolic acid, pyruvic acid, lactic acid, malonic acid, Succinic “Treating or “treatment of any disease or disorder refers, acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric in one embodiment, to ameliorating the disease or disorder acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cin 15 (i.e., arresting or reducing the development of the disease or namic acid, mandelic acid, methanesulfonic acid, ethane at least one of the clinical symptoms thereof). In another Sulfonic acid, 1.2-ethane-disulfonic acid, 2-hydroxyethane embodiment “treating or “treatment” refers to ameliorating sulfonic acid, benzenesulfonic acid, at least one physical parameter, which may not be discernible 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, by the subject. In yet another embodiment, “treating or 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicy “treatment” refers to modulating the disease or disorder, clo2.2.2-oct-2-ene-1-carboxylic acid, glucoheptonic acid, either physically, (e.g., stabilization of a discernible symp 3-phenylpropionic acid, trimethylacetic acid, tertiary buty tom), physiologically, (e.g., stabilization of a physical param lacetic acid, lauryl Sulfuric acid, gluconic acid, glutamic acid, eter), or both. In yet another embodiment, “treating” or “treat hydroxynaphthoic acid, salicylic acid, Stearic acid, muconic ment” refers to delaying the onset of the disease or disorder, acid, and the like; or (2) salts formed when an acidic proton 25 or even preventing the same. In a still further embodiment, present in the parent compound either is replaced by a metal “treating or “treatment” refers to administration of the com ion, e.g., an alkali metal ion, an alkaline earth ion, or an pound or compositions disclosed herein for cosmetic pur aluminum ion; or coordinates with an organic base Such as poses. ethanolamine, diethanolamine, triethanolamine, N-methyl Other derivatives of the disclosed compounds have activity glucamine and the like. Salts further include, by way of 30 example only, sodium, potassium, calcium, magnesium, in both their acid and acid derivative forms, but in the acid ammonium, tetraalkylammonium, and the like; and when the sensitive form often offers advantages of solubility, tissue compound contains a basic functionality, salts of non toxic compatibility, or delayed release in the mammalian organism organic or inorganic acids, such as hydrochloride, hydrobro (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, mide, tartrate, mesylate, acetate, maleate, oxalate and the 35 Elsevier, Amsterdam 1985). Prodrugs include acid deriva like. In some embodiments, a “pharmaceutically acceptable tives such as, for example, esters prepared by reaction of the salt may also be used in conjunction with cosmeceutically parent acid with a suitable alcohol, or amides prepared by acceptable compositions. reaction of the parent acid compound with a substituted or The term “pharmaceutically acceptable cation” refers to a unsubstituted amine, or acid anhydrides, or mixed anhy non toxic, acceptable cationic counter-ion of an acidic func 40 drides. Simple aliphatic or aromatic esters, amides and anhy tional group. Such cations are exemplified by Sodium, potas drides derived from acidic groups pendant on the disclosed sium, calcium, magnesium, ammonium, tetraalkylammo compounds are preferred prodrugs. In some cases it is desir nium cations, and the like. In some embodiments, a able to prepare double ester type prodrugs such as (acyloxy) “pharmaceutically acceptable cation' may also be used in alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Preferred conjunction with cosmeceutically-acceptable compositions. 45 are the C1 to C8 alkyl, C2-C8 alkenyl, aryl, C7-C12 substi “Pharmaceutically acceptable vehicle' refers to a diluent, tuted aryl, and C7-C12 arylalkyl esters of the disclosed com adjuvant, excipient or carrier with which a disclosed com pounds herein. pound is administered. In some embodiments, a “pharmaceu As used herein, the term “isotopic variant” refers to a tically acceptable vehicle' may also be used in conjunction compound that contains unnatural proportions of isotopes at with cosmetically-acceptable compositions. 50 one or more of the atoms that constitute Such compound. For “Preventing or “prevention” refers to a reduction in risk of example, an "isotopic variant' of a compound can contain one acquiring a disease or disorder (i.e., causing at least one of the or more non-radioactive isotopes, such as for example, deu clinical symptoms of the disease not to develop in a subject terium (2H or D), carbon-13 (13C), nitrogen-15 (15N), or the that may be exposed to or predisposed to the disease but does like. It will be understood that, in a compound where such not yet experience or display symptoms of the disease). 55 isotopic Substitution is made, the following atoms, where “Prodrugs’ refers to compounds, including derivatives of present, may vary, so that for example, any hydrogen may be disclosed compounds, which have cleavable groups and 2H/D, any carbon may be 13C, or any nitrogen may be 15N, become by Solvolysis or under physiological conditions of and that the presence and placement of Such atoms may be compounds which are pharmaceutically active in vivo. Such determined within the skill of the art. Likewise, the disclosed examples include, but are not limited to, choline ester deriva 60 compounds may include the preparation of isotopic variants tives and the like, N-alkylmorpholine esters and the like. with radioisotopes, in the instance for example, where the “Solvate” refers to forms of the compound that are associ resulting compounds may be used for drug and/or substrate ated with a solvent, usually by a Solvolysis reaction. Conven tissue distribution studies. The radioactive isotopes tritium, tional Solvents include water, ethanol, acetic acid and the like. i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this The compounds disclosed herein may be prepared e.g. in 65 purpose in view of their ease of incorporation and ready crystalline form and may be solvated or hydrated. Suitable means of detection. Further, compounds may be prepared that Solvates include pharmaceutically acceptable Solvates, such are Substituted with positron emitting isotopes, such as 11C, US 8,236,288 B2 37 38 18F 15O and 13N, and would be useful in Positron Emission Hypopigmentation occurs when pigment-producing cells Topography (PET) studies for examining substrate receptor (melanocytes) are either destroyed or inactive. Other hypop Occupancy. igmentation disorders include conditions due to skin damage All isotopic variants of the compounds provided herein, (e.g. burn or ablative laser resurfacing) or due to autoimmune radioactive or not, are intended to be encompassed within the disease where the immune system attacks melanocytes, as in Scope of the contemplated compounds. vitiligo. Vitiligo can also be caused by physical trauma or It is also to be understood that compounds that have the certain diseases, such as Addison's disease or diabetes. same molecular formula but differ in the nature or sequence Hyperpigmentation or hypermelanosis disorders result in of bonding of their atoms or the arrangement of their atoms in an increase in melanin or melanocyte production and/or dis space are termed "isomers'. Isomers that differ in the 10 tribution. For example, post-inflammatory hyperpigmenta arrangement of their atoms in space are termed “stereoiso mers’. tion (“PIH) represents the sequelae of various cutaneous Stereoisomers that are not mirror images of one another are disorders, including infections, allergic reactions, mechani termed "diastereomers' and those that are non-Superimpos cal injuries, reactions to medications, phototoxic eruptions, able mirror images of each other are termed “enantiomers’. 15 trauma (e.g. burns), as well as reactions to devices, including When a compound has an asymmetric center, for example, it electromagnetic devices such as ultrasound, radio frequency, is bonded to four different groups, a pair of enantiomers is lasers, light-emitting diodes and visible light therapy, as well possible. An enantiomer can be characterized by the absolute as microdermabrasion reactions, shaving, chemical peels or configuration of its asymmetric center and is described by the other dermatological procedures. PIH occurs widely in the R- and S-sequencing rules of Cahn and Prelog, or by the human population and can be the Source of significant psy manner in which the molecule rotates the plane of polarized chosocial distress for those affected with this disorder. PIH light and designated as dextrorotatory or levorotatory (i.e., as may occur as a pathophysiologic response to cutaneous (+) or (-)-isomers respectively). A chiral compound can exist inflammation. Melanocytes can be stimulated by the inflam as either individual enantiomer or as a mixture thereof. A matory process to synthesize and secrete more melanin from mixture containing equal proportions of the enantiomers is 25 melanocytes, or the number of melanocytes can increase in called a “racemic mixture'. the epidermis, leading to hyperpigmentation of the skin. PIH “Tautomers' refer to compounds that are interchangeable can also occur when inflammation Succeeds in disrupting the forms of a particular compound structure, and that vary in the basal cell layer, causing melanin pigment to be released and displacement of hydrogen atoms and electrons. Thus, two Subsequently trapped by macrophages in the papillary der structures may be in equilibrium through the movement of it 30 mis. PIH also occurs in instances where inflammation is electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted untreated. One example of PIH as a result of inflammation is by treatment with either acid or base. Another example of acne scarring. Hyperpigmentation or hypermelanosis disor tautomerism is the aci- and nitro-forms of phenylni ders due to environmental stressors, such as hormonal imbal tromethane, that are likewise formed by treatment with acid 35 ance, can also affect melanin or pigmentation levels in the or base. skin. Other hyperpigmentation disorders include café au lait Tautomeric forms may be relevant to the attainment of the macules, melasma, choasma, age spots, drug-induced hyper optimal chemical reactivity and biological activity of a com pigmentation, Addison's disease, epheides (freckles), sebor pound of interest. rheic keratosis, acanthosis nigricans, Solar lentigines (Sun The disclosed compounds may possess one or more asym 40 spots), photoxic/photoallergic reaction, hemochromatosis metric centers; such compounds can therefore be produced as and diabetic dermopathy. individual (R)- or (S)-stereoisomers or as mixtures thereof. Current treatment of hyperpigmentation disorders include Unless indicated otherwise, the description or naming of a topical lightening agents, laser/intense pulsed light, cryo particular compound in the specification and claims is therapy and chemical peels. However, for many individuals, intended to include both individual enantiomers and mix 45 cosmetic camouflaging of hyper or hypopigmentation cuta tures, racemic or otherwise, thereof. The methods for the neous manifestations is the only viable alternative. Effective determination of stereochemistry and the separation of stere treatment of hypo and hyperpigmentation disorders, there oisomers are well-known in the art. fore, is needed. Melanin Disorders The compositions disclosed herein seek to treat melanin As discussed above, melanin in humans is the primary 50 disorders, including PIH and other hyperpigmentation disor determinant of skin color. Melanin pigments (eumelanin, ders by modifying melanin distribution and/or production. pheomelanin and neuromelanin) are derivatives of the amino The compositions disclosed herein also seek to treatmela acid tyrosine, and production of melanin pigments is cataly nin disorders in conjunction with treatments and/or proce sed by the enzyme tyrosinase. Melanin is also found in hair, dures that may cause hypermelanosis or hyperpigmentation the pigmented tissue underlying the iris of the eye, as well as 55 the striavascularis of the inner ear. Melanin disorders canthus disorders. Accordingly, the compositions disclosed herein affect a variety of physiological systems, including the skin, may be used in conjunction with the treatment of skin disor hair, eye, inner ear, as well as neurological structures in the ders or trauma as a result of a mechanical injury or therapy, brain, where tissues with melanin include the medulla and including but not limited to laser treatment, chemical peels, Zona reticularis of the adrenal gland, and pigment-bearing 60 intense pulsed light, dermabrasion or cryotherapy. neurons within areas of the brainstem, such as the locus Compounds coeruleus and the Substantia nigra. Disclosed herein are compositions comprising Substituted Environmental and/or physiological stress can cause dis benzaldehydes, at least one or a blend of pharmaceutically or orders in melanin production, as well as various genetic cosmetically active agents, and a pharmaceutically or cos abnormalities. With regards to hypopigmentation disorders, 65 metically acceptable carrier. In some embodiments, the Sub there are approximately ten different types of oculocutaneous stituted benzaldehydes disclosed herein are used in combina albinism, which is mostly an autosomal recessive disorder. tion with at least one additional therapeutic agent. US 8,236,288 B2 39 40 In some embodiments, the composition comprises a Sub -continued stituted benzaldehyde of Formula I: O O

Formula I 5

FC NC

Non-limiting examples of substituted benzaldehydes 10 include alkoxy-Substituted benzaldehydes (e.g., 4-ethoxy benzaldehyde, 2-ethoxybenzaldehyde, 2-acetoxy-3-meth oxybenzaldehye, 4-allyloxybenzaldehyde, 4-propoxyben Zaldehyde, 4-butoxtbenzaldehyde, 2-fluoro-4- wherein each R. R. R. R. and Rs is independently selected ethoxybenzaldehyde), amino-substituted benzaldehydes, from hydrogen, halogen, alkyl, alkenyl, alkynyl, acyloxy, 15 alkyl-substituted benzaldehydes, aryl-substituted benzalde cycloalkyl, cycloheteroalkyl, alkoxy, alkoxyamino, alkoxy hydes, and sulfone-substituted benzaldehydes. In one carbonyl, cycloalkoxy, cycloalkenyl, cyano, cyanato, aryl, embodiment, the substituted benzaldehyde is 4-ethoxyben arylalkyl, alkylaryl, aryloxy, heteroaryl, heteroaryloxy, Zaldehyde, 2-ethoxybenzaldehyde, 4-allyloxybenzaldehyde amino, aminoalkyl, alkylarylamino, alkylamino, aminocar and/or 4-propoxybenzaldehyde. In one particular embodi bonylamino, aminocarbonyloxy, arylamino, azido, bicy ment, the substituted benzaldehyde is 4-ethoxybenzalde cloaryl, carbamoyl carboxy, carboxyamino, heteroary hyde. lamino, alkylsulfonyl, alkylthio, and Sulfone; and wherein at In certain embodiments, the substituted benzaldehyde least one of R. R. R. R. or Rs is not hydrogen. compounds include their acetal and hemiacetal equivalents In specific embodiments, R3 is ethoxy. In other embodi 25 (i.e., —C(OR)(OH) and —C(OR), replaces the formyl ments, R1, R2, R4, and R5 are hydrogen. group or —C(O)H of the benzaldehyde, wherein R is an alkyl Specific compounds of Formula I are shown below: group). In some embodiments, the composition comprises the hemiacetal of Formula II:

O O 30 Formula II OR6

? H O H OH EtO MeO 35 O F O O H H MeOS Et O 40 wherein each R. R. R. R. and Rs is independently selected F O from hydrogen, halogen, alkyl, alkenyl, alkynyl, acyloxy, cycloalkyl, cycloheteroalkyl, alkoxy, alkoxyamino, alkoxy carbonyl, cycloalkoxy, cycloalkenyl, cyano, cyanato, aryl, arylalkyl, alkylaryl, aryloxy, heteroaryl, heteroaryloxy, 45 amino, aminoalkyl, alkylarylamino, alkylamino, aminocar bonylamino, aminocarbonyloxy, arylamino, azido, bicy cloaryl, carbamoyl carboxy, carboxyamino, heteroary lamino, alkylsulfonyl, alkylthio, and Sulfone; wherein at least one of R. R. R. R. or Rs is not hydrogen; 50 and each R is independently alkyl. In other embodiments, the composition comprises the acetal of Formula III:

55 Formula III OR6

OR6 60

65 wherein each R. R. R. R. and Rs is independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, acyloxy, cycloalkyl, cycloheteroalkyl, alkoxy, alkoxyamino, alkoxy US 8,236,288 B2 41 42 carbonyl, cycloalkoxy, cycloalkenyl, cyano, cyanato, aryl, lactoferrin, ferritin, cearuloplasmin, haptoglobion, hea arylalkyl, alkylaryl, aryloxy, heteroaryl, heteroaryloxy, mopexin, albumin, glucose, ubiquinol-10; enzymatic antioxi amino, aminoalkyl, alkylarylamino, alkylamino, aminocar dants, such as Superoxide dismutase and metal complexes bonylamino, aminocarbonyloxy, arylamino, azido, bicy with a similar activity, including catalase, glutathione peroxi cloaryl, carbamoyl carboxy, carboxyamino, heteroary dase, and less complex molecules, such as beta-carotene, lamino, alkylsulfonyl, alkylthio, and Sulfone; bilirubin, uric acid; flavonoids (flavones, flavonols, fla wherein at least one of R. R. R. R. or Rs is not hydrogen; Vonones, flavanonals, chacones, anthocyanins), N-acetylcys and each R is independently alkyl. tein, mesna, glutathione, thiohistidine derivatives, triazoles; Additional Active Agents tannines, cinnamic acid, hydroxycinnamatic acids and their In one embodiment, the composition further comprises an 10 esters (coumaric acids and esters, caffeic acid and their esters, active ingredient. Suitable active ingredients include, but are ferulic acid, (iso-)chlorogenic acid, sinapic acid). Also not limited to botanicals, nutraceuticals, cosmeceuticals, included are extracts, including but not limited to plant therapeutics, pharmaceuticals, antimicrobials, steroidal hor extracts or cell extracts containing antioxidants, including mones, antidandruff agents, anti-acne components, Sun grape seed extract, pomegranate extract, Spice extracts (e.g., screens, Sunblocks, Sunprotectants, antibiotics, antivirals, 15 from clove, cinnamon, Sage, rosemary, mace, oregano, all antifungals, steroids, analgesics, antitumor drugs, investiga spice, nutmeg); oat flour extracts, such as avenanthramide 1 tional drugs, skin conditioning agents, or any compounds and 2; thioethers, dithioethers, sulphoxides, tetralkylthiuram which would result in a complimentary or synergistic com disulphides and extracts from other plant derived material. bination with the factors in the metabolized conditioned Also included is carnosic acid, carnosol, carsolic acid; ros media or metabolized cell extract. marinic acid, rosmaridiphenol, gentisic acid, ferulic acid; In a further embodiment, also included are topical formu phytic acid, steroid derivatives (e.g., U74006F); tryptophan lations that comprise a composition for cosmetic or derma metabolites (e.g., 3-hydroxykynurenine, 3-hydroxyanthra tological use, which composition comprises a cosmetically nilic acid), and organochalcogenides. and/or dermatologically effective amount of the combination In other embodiments, the composition comprises at least stated above, wherein the like acting agent is a cosmetically 25 one additional skin lightening agent. Non-limiting examples active agent. More particularly, the like-acting agent is a skin of skin-lightening agents are selected from the group of hyd lightening or skin bleaching compound. In some embodi roquinone, licorice extract (e.g., Glycyrrhiza Glabra (lico ments, the skin lightening or skin bleaching compound is rice) root extract), an alpha MSH antagonist (e.g. undecyle hydroquinone, kojic acid, ascorbic acid, magnesium ascorbyl noyl phenylalanine), phytic acid, monobenzyl ether of phosphate or ascorbylglucosamine, or mixtures thereof. 30 hydroquinone, azelaic acid, kojic acid, meduinol, retinoids In another embodiment of the combination described (e.g., tretinoin, adapalene), soy proteins, alpha-hydroxy acids above, the additional pharmaceutical or cosmetic agent is a (e.g., glycolic acid), trichloroacetic acid, salicylic acid, hyd skin care active agent. In some embodiments, the skin care roquinone-beta-D-glucopyranoside, paper mulberry, glabri active agent is an abrasive, an absorbent, an astringent, an din, 4-isopropylcetichol, aleosin, N-acetyl-4-S-cycteami aesthetic component. Such as fragrances, pigments, color 35 nylphenol, N-propionyl-4-S-cysteaminylphenol, N-acetyl ings/colorants, essential oils, skin sensates, astringents and glucosamine, and tranexaminc acid. other aesthetic components, an antioxidant, a free-radical In other embodiments, the composition comprises at least Scavenging agent, a reducing agent, a sequestrant, a skin one botanical ingredient and/or extract. Non-limiting bleaching or lightening agent, a skin conditioning agent, for examples of botanical extracts are selected from the group example humectants and emollients, a skin Soothing agent, a 40 arbutin, alpha-arbutin, deoxyarbutin, aloesin, flavonoids, skin healing agent, such as pathenol and derivatives, aloe isoflavones (e.g., 6.7,4'-trihydroxyisoflavone, glycitein, daid Vera, pantothenic acid, allantoin, bisbolol, dipotassium gly Zein, genistein), flavonones (e.g., hesperidin, eriodictyol, and cyrrhizinate, skin treating agents, vitamins and derivatives, naringenin), flavonols, p-coumaric acid, gentisic acid, lico Such as a retinoid, or mixtures thereof. In some embodiments, rice extracts (e.g., glabridin, liquiritin, glabrene, isoliquiriti the retinoid is retinol, retinal, retinol esters, retinyl propi 45 genin licuraside, isoliduiritin, licochalcone A), niacinamide, onate, retinoic acid, retinyl palmitate, or mixtures thereof. yeast derivatives, polyphenols, (e.g., proanthocyanidins, pro In other embodiments, the composition comprises one or cyanidins, ellagic acid), ammonium glycyrrhizinate, icariin, more antioxidant(s). Non-limiting examples of antioxidants piceid, salidroside, epigallocatechin-3-gallate, glycyrrhiza are selected from the group consisting of niacinamide, Vita cinnamic aid, cinnamic acid, Sophorcarpidine, aloe Vera min E. Coenzyme Q10, idebenone, lycopene, green tea 50 extract, alaria esculenta extract, alfalfa extract, algae extract, polyphenols, Silybin, resveratrol, genistein, and pycnogenol. althaea extract, angelica extract, apple extract, arnica extract, Other embodiments include phenols and phenolic acids ascorbyl palmitate, avocado oil, babassu palm tree fruit, balm (guaiacol, hydroquinone, Vanillin, gallic acids and their mint extract, bamboo extract, bergamot oil, betula extract, esters, protocatechuic acid, quinic acid, Syringic acid, ellagic bilberry, birch leaf extract, bisabolol, blackcurrant extract, acid, salicylic acid, nordihydroguaiaretic acid (NDGA), 55 black raspberry seed oil, bladderwrack extract, blue-green eugenol); curcumins, tocopherols (including tocopherols (al algae, blue malva extract, borage seed oil, boswellia Serrata, pha, beta, gamma, delta) and their derivatives, such as toco buddleja davidii extract, buckthorn, buckwheat seed extract, pheryl-acylate (e.g., -acetate, -laurate, myristate, -palmitate, burdock root extract, burdock, butcher's broom, calendula, -oleate, -linoleate, etc., or any other suitable tocopheryl calendula extract, camelia oil, capsaicin, carrageenan lipoate), tocopheryl-POE-succinate; Dunaliella Salina 60 extract, carrot extract, cascara Sagrada, castor oil, cayenne, Extract; trolox and corresponding amide and thiocarboxam cedarwood, chamomile, chamomile extract, chamomile oil, ide analogues; ascorbic acid and its salts, isoascorbate, alky chaparral extract, chaste tree berry extract, chia seed oil, lascorbic acids, ascorbyl esters (e.g., 6-o-lauroyl, myristoyl, chickpea seed extract, chlorella, chrysanthellis, cinnamon palmitoyl-, oleoyl, or linoleoyl-L-ascorbic acid, etc.). Also bark, citrus extract, clover, clover blossom extract, clover useful are oxidized compounds. Such as sodium bisulphite, 65 extract, clover flower oil, cocoa extract, cocoa seed butter, Sodium metabisulphite, thiourea; chelating agents, such as codonopsis, coleus forskohli, coriander, corn oil, cottonseed EDTA (e.g., disodium EDTA), EGTA, desferral; transferrin, oil, couch grass, crambe abyssinica seed extract, cranberry US 8,236,288 B2 43 44 protein, crithmum maritimum extract, cupuacu, cypress oil, esters, alpha-phenyl cinnamonitrile; butyl cinnamoyl pyru dandelion, dandelion extract, dong quai, Dunaliella Salina vate); Dihydroxycinnamic acid derivatives (umbelliferone, extract, Echinacea angustifolia purpurea, echium plan methylumbelliferone, methylaceto-umbelliferone); Trihy tagineum, elderberry, esculin, eucalyptus, evening primrose droxycinnamic acid derivatives (esculetin, methylesculetin, oil, fennel, ferula foetida root extract, flaxseed oil, fucoidan daphnetin, and the glucosides, esculin and daphnin); Hydro extract, garcinia cambogia, garlic, geranium extract, gera carbons (diphenylbutadiene, stilbene); Dibenzalacetone and nium oil, ginger, ginger root extract, ginkgo biloba, ginseng, benzalacetophenone; Naphtholsulfonates (sodium salts of ginseng extract, glucosamine, golden Seal extract, gotu kola, 2-naphthol-3,3-disulfonic and of 2-naphthol-6,8-disulfonic grapefruit extract, grapeseed, grapeseed extract, grapeseed acids); Dihydroxynaphthoic acid and its salts; o- and p-Hy oil, green tea, green tea extract, guarana, guggul gum extract, 10 droxybiphenyldisulfonates; Coumarin derivatives (7-hy gymnesa Sylvestre, hazel oil, hawthorn, holarrhena antidyS droxy, 7-methyl, 3-phenylyl); Diazoles (2-acetyl-3-bro enterica extract, honeysuckle extract, hops extract, horse moindazole, phenyl benzoxazole, methyl naphthoxalole, chestnut, horsetail extract, hybrid safflower oil, hydrolyzed various arylbenzothiazoles); Quinine salts (bisulfate, sulfate, soy protein, imperata cylindrical root extract, ivy leaf extract, chloride, oleate, and tannate); quinoline derivatives (8-hy jasmine oil, jojoba oil, juniper oil, kelp, kiwi seed fruit oil, 15 droxyquinoline salts, 2-phenylduinoline); Hydroxy- or meth kukui nut oil, lactic acid, lactospore, laminaria digitata, lavan oxy Substituted benzophenones; Uric and vilouric acids; din oil, lavender, lavender oil, lavender extract, L-carnitine, Tannnic acid and its derivatives (e.g., hexaethylether): (Butyl lecithin, lemon balm, lemon extract, lemon fruit extract, carbityl) (6-propyl piperonyl)ether; Hydroquinone; Ben lemon oil, lemon verbena botanical plant essence, lemon Zophenones (Oxybenzene, Sulisobenzone, Dioxybenzone, grass extract, licorice extract (e.g., Glycyrrhiza Glabra (lico Benzoresorcinol, 2,2,4,4'-Tetrahydroxybenzophenone, 2,2'- rice) root extract), lime oil, linden extract, lycium barbarum Dihydroxy-4,4'-dimethoxybenzophenone, Octabenzone; fruit extract, lysate extract, lysine, maca root, macadamia oil, 4-Isopropyhldibenzoylmethane; Butylmethoxydibenzoyl magnesium ascorbyl phosphate, Mahonium aquifolium (Or methane; Etocrylene; and 4-isopropyl-di-benzoylmethane; egon grape root) extract, maitake extract, mallow extract, titanium dioxide, iron oxide, Zinc oxide, and mixtures maracuja, marrubium Vulgare extract, marshmallow, manila 25 thereof. Other cosmetically-acceptable Sunscreens and con oil, matricaria oil, meadowsweet. Melissa extract, menthol, centrations (percent by weight of the total cosmetic Sunscreen milk thistle, moms alba root extract, mulberry extract (e.g., composition) include diethanolamine methoxycinnamate mulberroside F, gallic acid, quercetin, linoleic acid, palmitic (10% or less), ethyl-bis(hydroxypropyl)aminobenzoate acid), nettle extract, nettle root, nori sea lettuce, nutmeg oil, (5% or less), glyceryl aminobenzoate (3% or less), 4-isopro oat amino acids, oat extract, oat kernel meal, oligophycoco 30 pyl dibenzoylmethane (5% or less), 4-methylbenzylidene rail (sea algae) extract, olive oil, olive leaf extract, squalene camphor (6% or less), terephthalylidenedicamphor sulfonic (e.g., olive squalen), orange blossom, orange oil, orange fruit acid (10% or less), and Sulisobenzone (also called benzophe extract, orange peel extract, orchid extract, panax ginseng none-4, 10% or less). Yet other cosmetically-acceptable sun extract, pansy extract, panthenol, papaya enzyme, passion screens and concentrations (reported as a percentage by fruit oil, patchouli oil, pea extract, pea protein, peach extract, 35 weight of the total cosmetic Sunscreen composition, and peanut oil, pecan oil, pepper, peppermint, peppermint oil, referring to the final percentage of the Sunscreen) include: perilla seed oil, pine leaf oil, pineapple enzyme, plankton aminobenzoic acid (also called para-aminobenzoic acid and extract, plantain extract, polygonum fagopyrum seed extract, PABA; 15% or less; a UVB absorbing organic sunscreen), pomegranate extract, pomegranate seed oil, portulaca extract, avobenzone (also called butyl methoxy dibenzoylmethane: psyllium, pumpkin seed oil, raspberry extract, red clover, red 40 3% or less, a UVAI absorbing organic Sunscreen), cinoxate clover extract, red marine algae extract, reishii, resveratrol, (also called 2-ethoxyethyl p-methoxycinnamate; 3% or less, retinyl palmitate, rice bran oil, rhodiola, rhubarb, rice protein, a UVB absorbing organic Sunscreen), dioxybenzone (also Rosa roxburghii fruit extract, rose geranium botanical plant called benzophenone-8; 3% or less, a UVB and UVA II essence, rosehip extract, rosemary, Scoharomyces boulardii, absorbing organic Sunscreen), homosalate (15% or less, a safflower oil, sage, Sage extract, Sambucus Canadensis 45 UVB absorbing organic Sunscreen), menthyl anthranilate extract, sandalwood, turmeric (Curcuma longa root) extract, (also called menthyl 2-aminobenzoate; 5% or less, a UVA II Bulbine frutescens extract, Bulbine frutescens gel, and phy absorbing organic Sunscreen), octocrylene (also called 2-eth tessence wakame (sea kelp). ylhexyl-2-cyano-3,3 diphenylacrylate: 10% or less, a UVB In yet other embodiments, the composition comprises at absorbing organic Sunscreen), octyl methoxycinnamate least one Sunscreen, Sunprotectant or Sunblock agent. “Sun 50 (7.5% or less, a UVB absorbing organic sunscreen), octyl screen”, “sunprotectant” or "sunblock” as used herein defines salicylate (also called 2-ethylhexyl salicylate; 5% or less, a ultraviolet ray-blocking compounds exhibiting absorption or UVB absorbing organic Sunscreen), oxybenzone (also called blockage within the wavelength region between about 290 benzophenone-3; 6% or less, a UVB and UVA II absorbing and 420 nm. Such agents may be classified into five groups organic Sunscreen), padimate O (also called octyl dimethyl based upon their chemical structure: para-amino benzoates; 55 PABA; 8% or less, a UVB absorbing organic sunscreen), salicylates; cinnamates; benzophenones; and miscellaneous phenylbenzimidazole sulfonic acid (water soluble; 4% or chemicals including menthyl anthralinate and digalloyl tri less, a UVB absorbing organic Sunscreen), Sulisobenzone oleate. Inorganic Sunscreens may also be used including tita (also called benzophenone-4; 10% or less, a UVB and UVAII nium dioxide, Zinc oxide, iron oxide and polymer particles absorbing organic Sunscreen), titanium dioxide (25% or less, Such as those of polyethylene and polyamides. Specific Suit 60 an inorganic physical blocker of UVA and UVB), trolamine able Sunscreen agents include, for example: p-aminobenzoic salicylate (also called triethanolamine Salicylate: 12% or less, acid, its salts and its derivatives (ethyl, isobutyl, glyceryl a UVB absorbing organic sunscreen), and zinc oxide (25% or esters, p-dimethylaminobenzoic acid); Anthranilates (i.e., less, an inorganic physical blocker of UVA and UVB). o-aminobenzoates; methyl, menthyl, phenyl, benzyl, phenyl In still other embodiments, the composition comprises at ethyl, linallyl, terpinyl, and cyclohexenyl esters); Salicylates 65 least one anti-acne agent. Suitable anti-acne agents may (amyl, phenyl, benzyl, menthyl, glyceryl, and dipropylene include Salicylic acid; 5-octanoyl salicylic acid; resorcinol; glycol esters); Cinnamic acid derivatives (methyl and benzyl retinoids such as retinoic acid and its derivatives; Sulfur US 8,236,288 B2 45 46 containing D and L amino acids other than cysteine; lipoic the form of a pharmaceutical or cosmetic composition. Such acid; antibiotics and antimicrobials such as benzoyl peroxide, compositions can be prepared by procedures well known in octopiroX, tetracycline, 2,4,4'-trichloro-2'-hydroxydiphenyl the pharmaceutical and cosmetic arts. The compositions dis ether, 3,4,4-trichlorobanilide, azelaic acid, phenoxyethanol, closed herein can contain a cosmetically or pharmacologi phenoxypropanol, phenoxisopropanol, ethyl acetate, clinda cally acceptable carrier. Such carriers are compatible with mycin and melclocycline; flavonoids; and bile salts such as skin, nails, mucous membranes, tissues and/or hair, and can Scymnol Sulfate, deoxycholate and cholate. include any conventionally used cosmetic or pharmacologi In yet still other embodiments, the composition comprises cal carrier. The compositions disclosed herein can be in any at least one anti-inflammatory agent. Suitable anti-inflamma form Suitable for topical application, including aqueous, tory agents include, but are not limited to, non-steroidal anti 10 aqueous-alcoholic or oily solutions, lotion or serum disper inflammatory drugs such as Salicylic acid, acetylsalicylic sions, aqueous, anhydrous or oily gels, emulsions obtained by acid, methyl salicylate, aspirin, ibuprofen, naproxen, dispersion of a fatty phase in an aqueous phase (O/W or oil in diflunisal, Salsalate, olsalazine, SulfaSalazine, acetami water) or, conversely, (W/O or water in oil), microemulsions nophen, indomethacin, Sulindac, etodolac, mefenamic acid, or alternatively microcapsules, microparticles or lipid vesicle meclofenamate Sodium, tolmetin, ketorolac, dichlofenac, 15 dispersions of ionic and/or nonionic type. These composi ibuprofen, naproxen, naproxen Sodium, fenoprofen, ketopro tions can be prepared according to conventional methods. fen, flurbinprofen, oxaprozin, piroXicam, meloxicam, Other than the agents disclosed, the amounts of the various ampiroXicam, droxicam, pivoxicam, tenoxicam, nabume constituents of the compositions are those conventionally tome, phenylbutaZone, oxyphenbutaZone, antipyrine, ami used in the art. These compositions in particular constitute nopyrine, apaZone and nimeSulide; leukotriene antagonists protection, treatment or care creams, milks, lotions, gels or including, but not limited to, Zileuton, aurothioglucose, gold foams for the face, for the hands, for the body and/or for the Sodium thiomalate and auranofin, and other anti-inflamma mucous membranes, or for cleansing the skin. The composi tory agents including, but not limited to, methotrexate, tions can also consist of solid preparations constituting soaps colchicine, allopurinol, probenecid, Sulfinpyrazone and ben or cleansing bars. Zbromarone. Additional anti-inflammatories useful in topical 25 In some embodiments, the compositions disclosed herein applications include corticosteroids, such as, but not limited are administered in an effective amount to treat a melanin to, flurandrenolide, clobetasol propionate, halobetasol propi disorder. Examples of routes of administration include, but onate, fluticasone propionate, betamethasone dipropionate, are not limited to, oral, buccal, inhalation, intradermal, Sub betamethasone benzoate, betamethasone Valerate, des cutaneous, transmucosal, transdermal, or topical administra Oximethasone, dexamethasone, diflorasone diacetate, 30 tion. Topical administration may also involve the use of trans mometasone furoate, amcinodine, halcinonide, fluocinonide, dermal administration Such as transdermal patches or fluocinolone acetonide, desonide, triamcinolone acetonide, iontophoresis devices. The construction and use of transder hydrocortisone, hydrocortisone acetate, fluoromethalone, mal patches for the delivery of pharmaceutical agents is well prednisone, methylprednisolone, and predinicarbate. known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992, In yet still other embodiments, the composition comprises 35 445, and 5,001,139. Such patches can be constructed for at least one skin conditioning agents. Suitable skin condition continuous, pulsatile, or on demand delivery of pharmaceu ing agents include, but are not limited to, butylene glycol and tical agents. ethylhexylglycerin. Pharmaceutically or cosmetically appropriate vehicles for In one embodiment, the composition contains the follow Such formulations include, for example, lower aliphatic alco ing additional active ingredients: Retinol, Niacinamide, Tet 40 hols, polyglycols (e.g., glycerol or polyethylene glycol), rahexyldecyl Ascorbate, Licorice root extract, Resorcinol, esters of fatty acids, oils, fats, silicones, and the like. Such and ethyllinoleate. In another embodiment, the composition preparations can also include preservatives (e.g., p-hydroxy comprises from about 0.1% to about 0.75%, from about benzoic acid esters) and/or antioxidants (e.g., ascorbic acid 0.05% to about 1.0%, or from about 0.01% to about 2% and tocopherol). See also Dermatological Formulations Per Retinol. In another embodiment, the composition comprises 45 cutaneous absorption, Barry (Ed.), Marcel Dekker Incl. 1983. from about 2.0% to about 8.0%, from about 1% to about 10%, In other embodiments, the composition further comprises or from about 0.5% to about 15.0% Niacinamide. In another at least one of water, a preservative, a Surfactant, an emulsi embodiment, the composition comprises from about 1.0% to fier, a conditioner, an emollient, a wax, an oil, a polymer, a about 5.0%, from about 0.5% to about 8.0%, or from about thickener (viscosity increasing agent), a fixative, a colorant, a 0.1% to about 15% Tetrahexyldecyl Ascorbate. In another 50 humectant, a moisturizer, a stabilizer, a diluent, a solvent and embodiment, the composition comprises from about 0.001% a fragrance. to about 0.5%, from about 0.0005% to about 1.0% or from In one embodiment, the composition further comprises at about 0.0001% to about 2% Licorice root extract. In another least one preservative. Suitable preservatives include, but are embodiment, the composition comprises from about 0.1% to not limited to, potassium Sorbate, acids, alcohols, glycols, about 3.0%, from about 0.05% to about 5.0%, or from about 55 parabens, quaternary-nitrogen containing compounds, 0.01% to about 10.0% Resorcinol. In another embodiment, isothiazolinones, aldehyde-releasing compounds and haloge the composition comprises from about 0.1% to about 3.0%, nated compounds. Illustrative alcohols include phenoxyetha from about 0.05% to about 5.0%, or from about 0.01% to nol, isopropyl alcohol, and benzyl alcohol, illustrative glycols about 10.0% ethyl linoleate. include propylene, butylene and pentylene glycols; illustra Pharmaceutically or Cosmetically Suitable Carriers and 60 tive parabens include (also known as parahydroxybenzioc Compositions acids) methyl, propyl and butyl parabens; illustrative quater One aspect of the disclosed embodiments extends to a nary nitrogen containing compounds include benzalkonium formulation that comprises a combination of a Substituted chloride, Quartenium 15; illustrative isothiazoles include benzaldehyde, additional active agents, and a carrier. In some methylisothiazoline, methychlorollisothiazoline; illustrative embodiments, the active agent is selected from an antioxidant 65 aldehyde releasing agents include DMDM hydantion, imi or a skin-lightening agent. In specific embodiments, the Sub adolidinyl urea and diazolidinyl urea; illustrative antioxidants stituted benzaldehyde and active agents are administered in includebutylated hydroxytoluene, tocopherol and illustrative US 8,236,288 B2 47 48 halogenated compounds include triclosan and chlorohex The transdermal dosage forms described herein may incor idene digluconate. Examples of preservatives useful for the porate certain pharmaceutically acceptable excipients which purpose of the present disclosure can be found in Steinberg, are conventional in the art. Transdermal drug delivery sys D. “Frequency of Use of Preservatives 2007”. Cosmet. Toilet. tems are topically administered medicaments and may be in 117, 41-44 (2002) and, “Preservative Encyclopedia Cosmet. 5 the form of patches that deliver drugs for systemic effects at a Toilet. 117, 80-96 (2002). In addition, enzyme preservative predetermined and controlled rate. The components of trans systems such as those described in the article by Ciccognani dermal devices include: (1) polymer matrix or matrices, (2) D. Cosmetic Preservation Using Enzymes, in “Cosmetic and the drug, (3) permeation enhancers and (4) other excipients. Drug Microbiology'. Orth DS ed., Francis & Taylor, Boca The polymer controls the release of the drug from the Raton, Fla. (2006) can also be effective for use with the 10 device. Useful polymers for transdermal devices include, but composition of the present disclosure. are not limited to Natural Polymers (e.g., Cellulose deriva In one embodiment, the composition further comprises at tives, Zein, Gelatin, Shellac, Waxes, Proteins, Gums and their least one occlusive. Suitable occlusives include, but are not derivatives, Natural rubber, Starch, etc.); Synthetic Elas limited to, capryllic/capric triglycerides, and the like. tomers (e.g., Polybutadieine, Hydrin rubber, Polysiloxane, In one embodiment, the composition further comprises at 15 Silicone rubber, Nitrile, Acrylonitrile, Butyl rubber, Sty least one emollient. Suitable emollients include, but are not renebutadieine rubber, Neoprene, etc.); and Synthetic Poly limited to, cetyl ethylhexanoate, mineral oils, lanolin, petro mers (e.g., Polyvinyl alcohol, Polyvinyl chloride, Polyethyl latum, capric/caprylic triglyceraldehydes, cholesterol, sili ene, Polypropylene, Polyacrylate, Polyamide, Polyurea, cones such as dimeticone, cyclometicone, almond oil, jojoba Polyvinylpyrrolidone, Polymethylmethacrylate, Epoxy, etc.) oil, avocado oil, castor oil, sesame oil, Sunflower oil, coconut 20 Solvents increase penetration possibly by enclosing the oil and grape seed oil, cocoa butter, olive oil aloe extracts, polar pathway and/or by fluidizing lipids. Examples include fatty acids such as oleic and Stearic, fatty alcohols such as water alcohols (e.g., methanol and ethanol); alkyl methyl cetyl and hexadecyl. diisopropyl adipate, hydroxybenzoate Sulfoxides (e.g., dimethyl sulfoxide, alkyl homologs of esters, benzoic acid esters of C9-15-alcohols, isononyl iso methyl sulfoxide dimethyl acetamide and dimethyl forma nonanoate, ethers such as polyoxypropylene butyl ethers and 25 mide); pyrrolidones (e.g., 2 pyrrolidone, N-methyl 2-purroli polyoxypropylene cetyl ethers, and C12-15-alkylbenzoates, done); laurocapram (AZone), miscellaneous solvents (e.g., and mixtures thereof. propylene glycol, glycerol, silicone fluids, isopropyl palmi In one embodiment, the composition further comprises at tate). least one film fomers. Suitable film fomers include, but are Surfactants may enhance polar pathway transport, espe not limited to, polyacrylate-13, Opadry IIR) or similar mate- 30 cially of hydrophilic drugs. The ability of a surfactant to alter rials, e.g., such as those described in U.S. Pat. No. 4,802.924, penetration is a function of the polar head group and the incorporated herein by reference, may be used as a film hydrocarbon chain length. Anionic surfactants include, but former. are not limited to, Dioctyl sulphosuccinate, Sodium lauryl In yet other embodiments, the compound of Formula (I) is sulphate, and Decodecylmethylsulphoxide. Nonionic surfac formulated for transdermal administration. Transdermal for 35 tants include, but are not limited to, Pluronic F127, and Plu mulations may employ transdermal delivery devices and ronic F68. Bile salts include, but are not limited to, Sodium transdermal delivery patches and can be lipophilic emulsions ms taurocholate, Sodium deoxycholate, and Sodium tauro or buffered, aqueous Solutions, dissolved and/or dispersed in glycocholate. Others include, for example, Propylene glycol a polymer or an adhesive. In various embodiments, such oleic acid and 1,4-butane diol-linoleic acid, urea, N,N-dim patches are constructed for continuous, pulsatile, or on 40 ethyl-m-toluamide, calcium thioglycolat, anticholinergic demand delivery of pharmaceutical agents. In additional agents, eucalyptol, di-O-methyl-3-cyclodextrin and Soyabean embodiments, the transdermal delivery of the compounds of casein. Formula (I) is accomplished by means of iontophoretic The fastening of all transdermal devices to the skin has so patches and the like. In certain embodiments, transdermal far been done by using a pressure sensitive adhesive which patches provide controlled delivery of the compounds of For- 45 can be positioned on the face of the device or in the back of the mula (I). The rate of absorption may be slowed by using device and extending peripherally. Adhesive systems should rate-controlling membranes or by trapping the compound adhere to the skin aggressively, but be easily removed. They within a polymer matrix or gel. Alternatively, absorption should also not leave an unwashable residue on the skin, and enhancers are used to increase absorption. Absorption they should not irritate or sensitize the skin. enhancers or carriers include absorbable pharmaceutically 50 The face adhesive system should also be physically and acceptable solvents that assist passage through the skin. For chemically compatible with the drug, excipients and enhanc example, in one embodiment, transdermal devices are in the ers of the device of which it is a part. Permeation of drug form of a bandage comprising a backing member, a reservoir should not be affected and the delivery of simple or blended containing the compound optionally with carriers, optionally permeation enhancers should not be affected. a rate controlling barrier to deliver the compound to the skin 55 Backing membranes are flexible and they provide a good of the host at a controlled and predetermined rate over a bond to the drug reservoir, prevent drug from leaving the prolonged period of time, and means to secure the device to dosage form through the top, and accept printing. Backing the skin. membranes are impermeable Substances that protect the Transdermal formulations described herein may be admin product during use on the skin (e.g., metallic plastic laminate, istered using a variety of devices which have been described 60 plastic backing with absorbent pad and occlusive base plate in the art. For example, Such devices include, but are not (aluminum foil), adhesive foam pad (flexible polyurethane) limited to, U.S. Pat. Nos. 3,598,122, 3,598,123, 3,710,795, with occlusive base plate (aluminum foil disc), etc.). 3,731,683, 3,742,951, 3,814,097, 3,921,636, 3,972,995, In addition, transdermal formulations can include addi 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,084, tional components such as, but not limited to, gelling agents, 4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299, 65 creams and ointment bases, and the like. In some embodi 4,292,303, 5,336,168, 5,665,378, 5,837,280, 5,869,090, ments, the transdermal formulation further includes a woven 6,923,983, 6,929,801 and 6,946,144. or non-woven backing material to enhance absorption and US 8,236,288 B2 49 50 prevent the removal of the transdermal formulation from the The preparations may also contain buffer salts, flavoring, skin. In other embodiments, the transdermal formulations coloring and Sweetening agents as appropriate. described herein maintain a saturated or Supersaturated State Topical compositions disclosed herein may be in the form to promote diffusion into the skin of a viscous liquid, Solution, Suspension, liposomal formula Compositions disclosed herein may be formulated in con ventional manner using one or more pharmaceutically or tions, gel, jelly, cream, lotion, ointment, Suppository, foam, cosmetically acceptable carriers comprising excipients and aerosol spray aqueous or oily Suspensions or solutions, emul auxiliaries which facilitate processing of the substituted ben sions, or emulsion ointments. Topical formulation for appli Zaldehydes and optional combination agents. Proper formu cation to skin may include ointments, lotions, pastes, creams, lation is dependent upon the route of administration chosen gels, drops, Suppositories, sprays, liquids, powders, sham and standard therapeutic practice. As used herein, the term 10 poos, and transdermal patches. In one embodiment, a topical “pharmaceutically or cosmetically acceptable carrier” means composition is provided which includes a topical carrier. For an inert, non toxic Solid or liquid filler, diluent or encapsulat example, thickeners, diluents, emulsifiers, dispersing aids or ing material, not reacting adversely with the active compound binders may be used as needed. The topical carrier is selected or with the subject. Suitable carriers are well known, and So as to provide the composition in the desired form, e.g., as include water, saline, aqueous dextrose, Sugar Solutions, etha 15 nol, glycols and oils, including those of petroleum, animal, a liquid, lotion, cream, paste, gel, powder, or ointment, and Vegetable, or synthetic origin, for example, peanut oil, Soy may be comprised of a material of either naturally occurring bean oil and mineral oil. In other embodiments, an agent or or synthetic origin. Examples of Suitable topical carriers for combination of agents of the instant embodiments can be use herein include water, alcohols and other nontoxic organic formulated in an oleaginous hydrocarbon base, an anhydrous Solvents, glycerin, mineral oil, silicone, petroleum jelly, lano absorption base, a water-in-oil absorption base, an oil-in lin, fatty acids, vegetable oils, parabens, aloe Vera, waxes, and water water-removable base and/or a water-soluble base. the like. Examples of such carriers and excipients include, but are not Ointments and creams can, for example, be formulated limited to, humectants (e.g., urea), glycols (e.g., propylene with an aqueous or oily base with the addition of suitable glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), 25 thickening and/or gelling agents. Lotions can be formulated Surfactants (e.g., polysorbate-80, isopropyl myristate and with an aqueous or oily base and will in general also contain Sodium lauryl Sulfate), pyrrolidones, glycerol monolaurate, ing one or more emulsifying agents, stabilizing agents, dis Sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, persing agents, Suspending agents, thickening agents, or col alkanols, water, calcium carbonate, calcium phosphate, Vari oring agents. ous Sugars, starches, cellulose derivatives, gelatin, and poly 30 Lubricants which can be used to form pharmaceutical com mers such as polyethylene glycols. positions and dosage forms include, but are not limited to, Compositions can also contain adjuvants common to the calcium Stearate, magnesium Stearate, mineral oil, light min cosmetic and dermatological fields, such as hydrophilic or eral oil, glycerin, Sorbitol, mannitol, polyethylene glycol, lipophilic gelling agents, hydrophilic or lipophilic active other glycols, Stearic acid, sodium lauryl Sulfate, talc, hydro agents, preserving agents, antioxidants, solvents, fragrances, 35 genated vegetable oil (e.g., peanut oil, cottonseed oil, Sun fillers, sunscreens, odor-absorbers and dyestuffs. The flower oil, Sesame oil, olive oil, corn oil, and soybean oil), amounts of these various adjuvants are those conventionally Zinc Stearate, ethyl oleate, ethyl laureate, agar, or mixtures used in the fields considered and, for example, are from about thereof. Additional lubricants include, for example, a syloid 0.01% to about 20% of the total weight of the composition. silica gel, a coagulated aerosol of synthetic silica, or mixtures Depending on their nature, these adjuvants can be introduced 40 thereof. A lubricant can optionally be added, in an amount of into the fatty phase, into the aqueous phase and/or into the less than about 1 weight percent of the pharmaceutical com lipid vesicles. position. The compositions may be in the form of tablets, capsules, Thickeners (viscosity increasing agents) which can be used skin patches, inhalers, eye drops, nose drops, ear drops, Sup to form pharmaceutical compositions and dosage forms positories, creams, ointments, injectables, hydrogels and into 45 include, but are not limited to, polyacrylate-13, poly any other appropriate formulation known to one of skill in the isobutene, Acetamide MEA; acrylamide/ethalkonium chlo art. For oral administration the pharmaceutical compositions ride acrylate copolymer, acrylamide/ethyltrimonium chlo may take the form of for example, tablets or capsules pre ride acrylate/ethalkonium chloride acrylate copolymer; pared by conventional means with acceptable excipients or acrylamides copolymer; acrylamide/sodium acrylate copoly carriers such as binding agents (e.g., pregelatinised maize 50 mer, acrylamide/sodium acryloyldimethyltaurate copoly starch, polyvinylpyrrolidone or hydroxypropyl methylcellu mer, acrylates/acetoacetoxyethyl methacrylate copolymer; lose); fillers (e.g., lactose, microcrystalline cellulose or cal acrylates/beheneth-25 methacrylate copolymer; acrylates/ cium hydrogen phosphate); lubricants (e.g., magnesium C10-C30 alkyl acrylate crosspolymer; acrylates/ceteth-20 Stearate, talc or silica); disintegrants (e.g., potato starch or itaconate copolymer, acrylates/ceteth-20 methacrylate Sodium starch glycolae); or wetting agents (e.g., Sodium lau 55 copolymer, acrylates/laureth-25 methacrylate copolymer; ryl sulphate). Tablets may be coated using methods well acrylates/palmeth-25 acrylate copolymer, acrylates/palmeth known in the art. Liquid preparations for oral administration 25 itaconate copolymer; acrylates/steareth-50 acrylate may take the form of for example, Solutions, syrups or Sus copolymer, acrylates/steareth-20 itaconate copolymer, acry pensions, or they may be presented as a dry product for lates/steareth-20 methacrylate copolymer, acrylates/Stearyl constitution with water or other suitable vehicle before use. 60 methacrylate copolymer, acrylates/vinyl isodecanoate cross Such liquid preparations may be prepared by conventional polymer; acrylic acid/acrylonitrogens copolymer; adipic means with acceptable excipients or carriers such as Suspend acid/methyl DEA crosspolymer; agar, agarose; alcaligenes ing agents (e.g., Sorbitol syrup cellulose derivatives or hydro polysaccharides; algin; alginic acid; almondamide DEA. genated edible fats); emulsifying agents (e.g., lecithin or aca almondamidopropyl betaine; aluminum/magnesium hydrox cia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl 65 ide Stearate; ammonium acrylates/acrylonitrogens copoly alcohol or fractionated vegetable oils); and preservatives mer, ammonium acrylates copolymer, ammonium acry (e.g., methyl or propyl-p-hydroxybenzoates or Sorbic acid). loyldimethyltaurate/vinyl formamide copolymer; US 8,236,288 B2 51 52 ammonium acryloyldimethyltaurate/VP copolymer; ammo MEA: linoleamide MIPA: lithium magnesium silicate; nium alginate; ammonium chloride; ammonium polyacry lithium magnesium Sodium silicate; macrocystis pyrifera loyldimethyl taurate; ammonium sulfate; amylopectin; apri (kelp); magnesium alginate; magnesium/aluminum/hydrox cotamide DEA, apricotamidopropyl betaine, arachidyl ide/carbonate; magnesium aluminum silicate; magnesium alcohol; arachidylglycol, arachis hypogaea (peanut) flour; silicate; magnesium trisilicate; methoxy PEG-22/dodecyl ascorbyl methylsilanol pectinate; astragalus gummifer gum, glycol copolymer; methylcellulose; methyl ethylcellulose; attapulgite; avena sativa (oat) kernel flour, avocadamide methyl hydroxyethylcellulose; microcrystalline cellulose; DEA: avocadamidopropyl betaine; azelamide MEA: babas milkamidopropyl betaine; minkamide DEA, minkamidopro suamide DEA; babassuamide MEA: babassuamidopropyl pyl betaine; MIPA-myristate; montmorillonite; Moroccan betaine; behenamide DEA; behenamide MEA: behenami 10 lava clay; myristamide DEA. myristamide MEA: myrista dopropyl betaine; behenyl betaine; bentonite; butoxy chito mide MIPA: myristamidopropyl betaine; myristamidopropyl San: caesalpinia spinosa gum, calcium alginate, calcium car hydroxysultaine; myristyl alcohol; myristyl betaine; natto boxymethyl cellulose; calcium carrageenan; calcium gum; nonoxynyl hydroxyethylcellulose; oatamide MEA: chloride; calcium potassium carbomer, calcium starch octe oatamidopropyl betaine; octacosanylglycol isostearate; octa nylsuccinate; C20-40 alkyl Stearate; canolamidopropyl 15 decene/MA copolymer, oleamide DEA, oleamide MEA: betaine; capramide DEA, capryl/capramidopropyl betaine; oleamide MIPA: oleamidopropyl betaine; oleamidopropyl carbomer; carboxybutyl chitosan; carboxymethyl cellulose hydroxysultaine; oleyl betaine; olivamide DEA. olivami acetate butyrate; carboxymethyl chitin: carboxymethyl chi dopropyl betaine; oliveamide MEA: palmamide DEA; pal tosan; carboxymethyl dextran; carboxymethylhydroxyethyl mamide MEA: palmamide MIPA: palmamidopropyl betaine; cellulose; carboxymethylhydroxypropyl guar, carnitine; cel palmitamide DEA; palmitamide MEA: palmitamidopropyl lulose acetate propionate carboxylate; cellulose gum, betaine; palm kernel alcohol; palm kernelamide DEA. palm ceratonia siliqua gum, cetearyl alcohol, cetyl alcohol, cetyl kernelamide MEA: palm kernelamide MIPA: palm kernela babassuate; cetyl betaine; cetylglycol, cetyl hydroxyethyl midopropyl betaine; peanutamide MEA: peanutamide MIPA: cellulose; chimyl alcohol; cholesterol/HDI/pullulan copoly pectin: PEG-800; PEG-crosspolymer; PEG-150/decyl alco mer, cholesteryl hexyl dicarbamate pullulan; citrus auran 25 hol/SMDI copolymer; PEG-175 diisostearate; PEG-190 dis tium dulcis (orange) peel extract; cocamide DEA, cocamide tearate; PEG-15 glyceryl tristearate; PEG-140 glyceryl MEA: cocamide MIPA: cocamidoethyl betaine; cocami tristearate; PEG-240/HDI copolymer bis-decyltetradeceth dopropyl betaine; cocamidopropyl hydroxysultaine; coco 20 ether; PEG-100/IPDI copolymer; PEG-180/laureth-50/ betaine; coco-hydroxysultaine; coconut alcohol; cocofolea TMMG copolymer; PEG-10/lauryl dimethicone crosspoly midopropyl betaine, coco-Sultaine; cocoyl sarcosinamide 30 mer; PEG-15/lauryl dimethicone crosspolymer; PEG-2M; DEA; cornamide? cocamide DEA; cornamide DEA; croscar PEG-5M; PEG-7M; PEG-9M; PEG-14M; PEG-20M; PEG mellose; crosslinked bacillus/glucose/sodium glutamate fer 23M; PEG-25M; PEG-45M; PEG-65M; PEG-90M; PEG ment; cyamopsis tetragonoloba (guar) gum, decyl alcohol; 115M; PEG-160M; PEG-18OM; PEG-120 methyl glucose decyl betaine; dehydroxanthan gum, dextrin; dibenzylidene trioleate; PEG-180/octoxynol-40/TMMG copolymer; PEG sorbitol; diethanolaminooleamide DEA; diglycol/CHDM/ 35 150 pentaerythrity1 tetrastearate; PEG-4 rapeseedamide: isophthalates/SIP copolymer; dihydroabietyl behenate; dihy PEG-150/stearyl alcohol/SMDI copolymer; phaseolus angu drogenated tallow benzylmonium hectorite; dihydroxyalu laris seed powder, polianthes tuberosa extract; polyacrylate minum amino acetate; dimethicone/PEG-10 crosspolymer; 3; polyacrylic acid; polycyclopentadiene; polyether-1; poly dimethicone/PEG-15 crosspolymer; dimethicone propyl PG ethylenefisopropyl maleate/MA copolyol; polyglyceryl-3 betaine; dimethylacrylamide/acrylic acid/polystyrene ethyl 40 disiloxane dimethicone; polyglyceryl-3 polydimethylsiloxy methacrylate copolymer, dimethylacrylamide/sodium acry ethyl dimethicone; polymethacrylic acid; polyduaternium loyldimethyltaurate crosspolymer; disteareth-100 IPDI; 52; polyvinyl alcohol; potassium alginate; potassium alumi DMAPA acrylates/acrylic acid/acrylonitrogens copolymer; num polyacrylate; potassium carbomer, potassium erucamidopropyl hydroxysultaine; ethylene/sodium acrylate carrageenan, potassium chloride; potassium palmate; potas copolymer; gelatin; gellan gum; glyceryl alginate; glycine 45 sium polyacrylate; potassium sulfate; potato starch modified; Soja (Soybean) flour, guar hydroxypropyltrimonium chloride; PPG-2 cocamide; PPG-1 hydroxyethyl caprylamide; PPG-2 hectorite; hyaluronic acid; hydrated silica; hydrogenated hydroxyethyl cocamide; PPG-2 hydroxyethyl cocofisos potato starch; hydrogenated tallow; hydrogenated tallowa tearamide; PPG-3 hydroxyethyl soyamide; PPG-14 laureth mide DEA: hydrogenated tallow betaine; hydroxybutyl 60 hexyl dicarbamate; PPG-14 laureth-60 isophoryl dicar methylcellulose; hydroxyethyl acrylate/sodium acryloyldim 50 bamate; PPG-14 palmeth-60 hexyl dicarbamate; propylene ethyl taurate copolymer; hydroxyethylcellulose; hydroxy glycol alginate; PVP/decene copolymer; PVP montmorillo ethyl chitosan; hydroxyethyl ethylcellulose; hydroxyethyl nite; pyrus Cydonia seed; pyrus malus (apple) fiber, rhizobian stearamide-MIPA: hydroxylauryl/hydroxymyristyl betaine; gum; ricebranamide DEA; ricinoleamide DEA; ricinoleam hydroxypropylcellulose; hydroxypropyl chitosan; hydrox ide MEA: ricinoleamide MIPA: ricinoleamidopropyl betaine; ypropyl ethylene diamine carbomer, hydroxypropyl guar; 55 ricinoleic acid/adipic acid/AEEA copolymer; rosa multiflora hydroxypropyl methylcellulose; hydroxypropyl methylcellu flower wax, Sclerotium gum, Sesamide DEA, Sesamidopropyl lose Stearoxy ether; hydroxypropyl Starch; hydroxypropyl betaine; sodium acrylate/acryloyldimethyl taurate copoly starch phosphate; hydroxypropyl Xanthan gum; hydroxyS mer, Sodium acrylates/acrolein copolymer, sodium acrylates/ tearamide MEA: isobutylene/sodium maleate copolymer; acrylonitrogens copolymer, Sodium acrylates copolymer; isostearamide DEA, isostearamide MEA: isostearamide 60 Sodium acrylates crosspolymer, Sodium acrylate/sodium mIPA: isostearamidopropyl betaine; lactamide MEA: lanoli acrylamidomethylpropane Sulfonate copolymer, sodium namide DEA.; lauramide DEA.; lauramide MEA: lauramide acrylates/vinyl isodecanoate crosspolymer, Sodium acrylate/ MIPA: lauramide/myristamide DEA: lauramidopropyl vinyl alcohol copolymer, Sodium carbomer, Sodium car betaine; lauramidopropyl hydroxysultaine; laurimino bispro boxymethyl chitin; sodium carboxymethyl dextran; sodium panediol; lauryl alcohol; lauryl betaine; lauryl hydroxysul 65 carboxymethyl beta-glucan: Sodium carboxymethyl starch; taine; lauryl/myristylglycol hydroxypropyl ether, lauryl Sul Sodium carrageenan; Sodium cellulose Sulfate; sodium chlo taine; lecithinamide DEA; linoleamide DEA; linoleamide ride; sodium cyclodextrin Sulfate; sodium hydroxypropyl US 8,236,288 B2 53 54 starch phosphate; sodium isooctylene/MA copolymer; of the composition. Suitable irritation-mitigating additives Sodium magnesium fluorosilicate; sodium oleate; sodium include for example: tocopherols, monoamine oxidase palmitate, Sodium palm kernelate; sodium polyacrylate; inhibitors (e.g., 2-phenyl-1-ethanol), glycerin, Salicylates, Sodium polyacrylate starch; sodium polyacryloyldimethyl ascorbates (e.g., tetrahexyldecylascorbate), ionophores (e.g., taurate; sodium polygamma-glutamate; sodium poly monensin), amphiphilic amines, animonium chloride, N-ace methacrylate; sodium polystyrene Sulfonate; sodium sili tylcysteine, capsaicin, and/or chloroquine. coaluminate; sodium starch octenylsuccinate; sodium Stear Modulation of Melanin Production ate; sodium stearoxy PG-hydroxyethylcellulose sulfonate: In some embodiments, the compositions disclosed herein Sodium styrenefacrylates copolymer, Sodium sulfate; sodium modulate melanin product in a subject in need thereof. For tallowate; sodium tauride acrylates/acrylic acid/acrylonitro 10 gens copolymer; sodium tocopheryl phosphate: Solanum example, the compositions disclosed herein may decrease tuberosum (potato) starch; soyamide DEA, Soyamidopropyl melanin production to reduce pigmentation in a Subject in betaine; starch/acrylates/acrylamide copolymer; starch need thereof. The compositions disclosed herein may also hydroxypropyltrimonium chloride; stearamide AMP; Steara function to decrease the number of melanocytes present in the mide DEA; Stearamide DEA-distearate; stearamide DIBA 15 epidermis, effectively decreasing melanin production and stearate; stearamide MEA: Stearamide MEA-stearate; steara reducing pigmentation in a subject in need thereof. A mide MIPA: stearamidopropyl betaine; steareth-60 cetyl decrease in melanin production may be desirable in the skin, ether; steareth-100/PEG-136/HDI copolymer; stearyl alco hair, pigmented pigmented tissue underlying the iris of the hol; Stearyl betaine; Sterculia urens gum, synthetic fluorphlo eye, or the stria vascularis of the inner ear. Administration or gopite; tallamide DEA: tallow alcohol; tallowamide DEA: targeting of the compositions disclosed herein may act to tallowamide MEA: tallowamidopropyl betaine; tallowami locally effect melanin production and reduce pigmentation. dopropyl hydroxysultaine; tallowamine oxide; tallow Hyperpigmentation or hypermelanosis disorders due to betaine; tallow dihydroxyethyl betaine; tamarindus indica environmental stressors, such as hormonal imbalance, can seed gum, tapioca starch; TEA-alginate; TEA-carbomer, also affect melanin or pigmentation levels in the skin. Hyper TEA-hydrochloride; trideceth-2 carboxamide MEA: tridecyl 25 pigmentation or hypermelanosis disorders may also be due to alcohol; triethylene glycol dibenzoate; trimethyl pentanol physiological stressors or mechanical stressors. hydroxyethyl ether, triticum vulgare (wheat) germ powder; Prostaglandin F2 alpha (PGF2 alpha) is a bioactive mol triticum vulgare (wheat) kernel flour; triticum vulgare ecule in the prostanoid family of lipid mediators that regulate (wheat) starch; tromethamine acrylates/acrylonitrogens numerous processes in the body, including inflammation. copolymer, tromethamine magnesium aluminum silicate; 30 While not wishing to be limited to a specific theory or mecha undecyl alcohol; undecylenamide DEA, undecylenamide nism of action, it is believed that the compositions disclosed MEA: undecylenamidopropyl betaine; welan gum; wheat herein may act in two (2) ways to modulate melanin distribu germamide DEA, wheat germanidopropyl betaine; Xanthan tion: 1) through the modulation of melanin production by gum, yeast beta-glucan; yeast polysaccharides and zea mays melanocytes; and 2) by affecting melanin distribution by (corn) starch. 35 melanocytes. In some embodiments, one function of the carrier is to 4-ethoxybenzaldehyde has been demonstrated to affect a enhance skin penetration of the active ingredients. Perme wide variety of inflammatory conditions, such as rheumatoid ation enhancers are compounds which promote skin perme arthritis, febrile conditions, edema, hyperalgesia, inflamma ability by altering the skin as a barrier to the flux of a desired tory bowel disease, and periodontal disease. However, penetrant. These may be classified as solvents, Surfactants 40 4-ethoxybenzaldehyde has not previously been shown to be and miscellaneous chemicals. Suitable carriers are well useful in the treatment of hyperpigmentation, including post known to skilled practitioners, and include liposomes, etha inflammatory hyperpigmentation, or to lighten skin. nol, dimethylsulfoxide (DMSO), petroleum jelly (petrola In one aspect, provided herein is a method of treating tum), mineral oil (liquid petrolatum), water, deimethylforma hyperpigmentation or a hypermelanosis disorder in an indi mide, dekaoxyethylene-oleylether, oleic acid, 2-pyrrolidone, 45 vidual, comprising administering to the individual in need AZone(R) brand penetration enhancer (Upjohn), biologically thereof an effective amount of a composition comprising: acceptable glycols, diglycols, polyglycols; alkyOXy C2-C8 from about 0.01% to about 2% substituted benzaldehyde, alcohols, ethoxydiglycol and dimethyl isosorbide. A skin about 0.01% to about 5.0% each of Retinol, Niacinamide, penetration enhancer may be included at concentrations rang Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice) ing from 5% to 95%, preferably 5% to 10% of the total 50 Root Extract, Hexyl Resorcinol, ethyl linoleate, and a phar composition. maceutically or cosmetically acceptable carrier. In one In a further embodiment of the combinations described embodiment, the amount of substituted benzaldehyde in the above, a topical formulation is prepared that comprises a composition is about 0.5%. In another embodiment, the com composition for cosmetic or dermatological use, which com position comprises from about 0.1% to about 0.75%, from position comprises a cosmetically and/or dermatologically 55 about 0.05% to about 1.0%, or from about 0.01% to about 2% effective amount of the combination stated above. Retinol. In another embodiment, the composition comprises In one embodiment, the compositions are in a form Suitable from about 2.0% to about 8.0%, from about 1% to about 10%, for cosmetic application including, but not limited to, lotions, or from about 0.5% to about 15.0% Niacinamide. In another ointments, creams, sprays, spritzes, aqueous or aqueous-al embodiment, the composition comprises from about 1.0% to coholic mixture gels, mousses, patches, pads, masks, moist 60 about 5.0%, from about 0.5% to about 8.0%, or from about ened clothes, wipes, Solid sticks, clear Sticks, lip Sticks, aero 0.1% to about 15% Tetrahexyldecyl Ascorbate. In another Sol creams, anhydrous powders, talcs, tonics, oils, emulsions embodiment, the composition comprises from about 0.001% or bath salts. to about 0.5%, from about 0.0005% to about 1.0% or from In another embodiment, the composition also contains irri about 0.0001% to about 2% Licorice root extract. In another tation-mitigating additives to minimize or eliminate the pos 65 embodiment, the composition comprises from about 0.1% to sibility of skin irritation or skin damage resulting from the about 3.0%, from about 0.05% to about 5.0%, or from about chemical compound to be administered, or other components 0.01% to about 10.0% Resorcinol. In another embodiment, US 8,236,288 B2 55 56 the composition comprises from about 0.1% to about 3.0%, In one embodiment, the pharmaceutically or cosmetically from about 0.05% to about 5.0%, or from about 0.01% to acceptable carrier is a topical carrier. Topical carriers include, about 10.0% ethyl linoleate. for example, a water-in-oil emulsion, cream, liquid, gel, oil, Substituted benzaldehydes for use in the compositions paste, ointment, Suspension, foam, lotion, oil-in-water emul include, for example, 2-ethoxybenzaldehyde, 4-ethoxyben Sion, water-in-oil-in-water emulsion, water-in-silicone emul Zaldehyde, 4-allyloxybenzaldehyde or 4-propoxybenzalde Sion, spray or serum carrier. hyde. In one embodiment, the substituted benzaldehyde is In one embodiment, hyperpigmentation may result from an 4-ethoxybenzaldehyde, which may be present in the compo environmental stressor (e.g., excessive Sun exposure or sition in an amount of about 0.5%. chemical exposure), physiological stressor (e.g., a hormonal In another aspect, provided herein is a method of treating 10 disorder), or mechanical stressor. hyperpigmentation or a hypermelanosis disorder in an indi Compositions described herein for use in such methods vidual, comprising administering to the individual in need may further include one or more additional active agents. For thereof an effective amount of a composition comprising: example, an additional active agent may be an antioxidant, a about 0.1% to about 0.5% 4-ethoxybenzaldehyde, about 15 Sunscreen, a Sunprotectant, a Sunblock, a skin-lightening 0.01% to about 5.0% each of Retinol, Niacinamide, Tetra agent, an anti-inflammatory agent, an anti-acne agent or mix hexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice) Root tures thereof. Compositions described herein for use in such Extract, Hexyl Resorcinol, ethyllinoleate, and a pharmaceu methods may further include one or more of a solvent, film tically or cosmetically acceptable carrier. In another embodi former, preservative, Viscosity increasing agent, fragrance, ment, the composition comprises from about 0.1% to about Surfactant, chelating agent, humectant, permeation enhancer, 0.75%, from about 0.05% to about 1.0%, or from about 0.01% excipients, or a combination thereof. to about 2% Retinol. In another embodiment, the composition Exemplary antioxidants include vitamin E. Coenzyme comprises from about 2.0% to about 8.0%, from about 1% to Q10, idebenone, lycopene, green tea polyphenols, Silybin, about 10%, or from about 0.5% to about 15.0% Niacinamide. resveratrol, grape seed extract, Oregon grape root (Mahonia In another embodiment, the composition comprises from 25 aquifolium) extract, pomegranate extract, genistein, pycno about 1.0% to about 5.0%, from about 0.5% to about 8.0%, or genol, curcumin, curcuminoids, Tocopherol, Dunaliella from about 0.1% to about 15% Tetrahexyldecyl Ascorbate. In Salina Extract or combinations thereof. another embodiment, the composition comprises from about Exemplary skin-lightening agents include hydroquinone, 0.001% to about 0.5%, from about 0.0005% to about 1.0% or monobenzyl ether of hydroquinone, azelaic acid, kojic acid, from about 0.0001% to about 2% Licorice root extract. In 30 meduinol, retinoids, soy proteins, alpha-hydroxy acids, another embodiment, the composition comprises from about trichloroacetic acid, Salicylic acid, hydroquinone-beta-D- 0.1% to about 3.0%, from about 0.05% to about 5.0%, or from glucopyranoside, paper mulberry, glabridin, 4-isopropyl about 0.01% to about 10.0% Resorcinol. In another embodi cetichol, aleosin, N-acetyl-4-S-cycteaminylphenol, N-propio ment, the composition comprises from about 0.1% to about nyl-4-S-cysteaminylphenol, N-acetyl glucosamine, 3.0%, from about 0.05% to about 5.0%, or from about 0.01% 35 tranexaminc acid, an alpha MSH antagonist (e.g. undecyle to about 10.0% ethyl linoleate. noyl phenylalanine), phytic acid or combinations thereof. In another aspect, provided herein is a method of treating In another aspect, provided herein is a method of lightening hyperpigmentation or a hypermelanosis disorder in an indi skin in an individual, comprising administering to the indi vidual, comprising administering to the individual in need vidual in need thereof an effective amount of a composition thereof an effective amount of a composition comprising: 40 comprising: from about 0.01% to about 2% substituted ben about 0.5% 4-ethoxybenzaldehyde, about 0.01% to about Zaldehyde, about 0.01% to about 5.0% each of Retinol, Niaci 5.0% each of Retinol, Niacinamide, Tetrahexyldecyl Ascor namide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra bate, Glycyrrhiza Glabra (Licorice) Root Extract, Hexyl (Licorice) Root Extract, Hexyl Resorcinol, ethyl linoleate, Resorcinol, ethyl linoleate, and a pharmaceutically or cos and a pharmaceutically or cosmetically acceptable carrier. In metically acceptable carrier. In another embodiment, the 45 one embodiment, the amount of substituted benzaldehyde in composition comprises from about 0.1% to about 0.75%, the composition is about 0.5%. In another embodiment, the from about 0.05% to about 1.0%, or from about 0.01% to composition comprises from about 0.1% to about 0.75%, about 2% Retinol. In another embodiment, the composition from about 0.05% to about 1.0%, or from about 0.01% to comprises from about 2.0% to about 8.0%, from about 1% to about 2% Retinol. In another embodiment, the composition about 10%, or from about 0.5% to about 15.0% Niacinamide. 50 comprises from about 2.0% to about 8.0%, from about 1% to In another embodiment, the composition comprises from about 10%, or from about 0.5% to about 15.0% Niacinamide. about 1.0% to about 5.0%, from about 0.5% to about 8.0%, or In another embodiment, the composition comprises from from about 0.1% to about 15% Tetrahexyldecyl Ascorbate. In about 1.0% to about 5.0%, from about 0.5% to about 8.0%, or another embodiment, the composition comprises from about from about 0.1% to about 15% Tetrahexyldecyl Ascorbate. In 0.001% to about 0.5%, from about 0.0005% to about 1.0% or 55 another embodiment, the composition comprises from about from about 0.0001% to about 2% Licorice root extract. In 0.001% to about 0.5%, from about 0.0005% to about 1.0% or another embodiment, the composition comprises from about from about 0.0001% to about 2% Licorice root extract. In 0.1% to about 3.0%, from about 0.05% to about 5.0%, or from another embodiment, the composition comprises from about about 0.01% to about 10.0% Resorcinol. In another embodi 0.1% to about 3.0%, from about 0.05% to about 5.0%, or from ment, the composition comprises from about 0.1% to about 60 about 0.01% to about 10.0% Resorcinol. In another embodi 3.0%, from about 0.05% to about 5.0%, or from about 0.01% ment, the composition comprises from about 0.1% to about to about 10.0% ethyl linoleate. 3.0%, from about 0.05% to about 5.0%, or from about 0.01% In some embodiments, the method reduces melanin distri to about 10.0% ethyl linoleate. bution by about 10% to about 40%. Substituted benzaldehydes for use in the compositions Application of the compositions in the methods described 65 include, for example, 2-ethoxybenzaldehyde, 4-ethoxyben herein may be topical or transdermal administeration to the Zaldehyde, 4-allyloxybenzaldehyde or 4-propoxybenzalde skin of the individual. hyde. In one embodiment, the substituted benzaldehyde is US 8,236,288 B2 57 58 4-ethoxybenzaldehyde, which may be present in the compo Application of the compositions in the methods described sition in an amount of about 0.5%. herein may be topical or transdermal administeration to the In another aspect, provided herein is a method of lightening skin of the individual. skin in an individual, comprising administering to the indi In one embodiment, the pharmaceutically or cosmetically vidual in need thereof an effective amount of a composition 5 acceptable carrier is a topical carrier. Topical carriers include, comprising: about 0.1% to about 0.5% 4-ethoxybenzalde for example, a water-in-oil emulsion, cream, liquid, gel, oil, hyde, about 0.01% to about 5.0% each of Retinol, Niacina paste, ointment, Suspension, foam, lotion, oil-in-water emul mide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Lico Sion, water-in-oil-in-water emulsion, water-in-silicone emul rice) Root Extract, Hexyl Resorcinol, ethyl linoleate, and a Sion, spray or serum carrier. pharmaceutically or cosmetically acceptable carrier. In one 10 Compositions described herein for use in such methods may further include one or more additional active agents. For embodiment, the amount of substituted benzaldehyde in the example, an additional active agent may be an antioxidant, a composition is about 0.5%. In another embodiment, the com Sunscreen, a Sunprotectant, a Sunblock, a skin-lightening position comprises from about 0.1% to about 0.75%, from agent, an anti-inflammatory agent, an anti-acne agent or mix about 0.05% to about 1.0%, or from about 0.01% to about 2% 15 tures thereof. Compositions described herein for use in such Retinol. In another embodiment, the composition comprises methods may further include one or more of a solvent, film from about 2.0% to about 8.0%, from about 1% to about 10%, former, preservative, Viscosity increasing agent, fragrance, or from about 0.5% to about 15.0% Niacinamide. In another Surfactant, chelating agent, humectant, permeation enhancer, embodiment, the composition comprises from about 1.0% to excipients, or a combination thereof. about 5.0%, from about 0.5% to about 8.0%, or from about Exemplary antioxidants include vitamin E. Coenzyme 0.1% to about 15% Tetrahexyldecyl Ascorbate. In another Q10, idebenone, lycopene, green tea polyphenols, Silybin, embodiment, the composition comprises from about 0.001% resveratrol, grape seed extract, Oregon grape root (Mahonia to about 0.5%, from about 0.0005% to about 1.0% or from aquifolium) extract, pomegranate extract, genistein, pycno about 0.0001% to about 2% Licorice root extract. In another genol, curcumin, curcuminoids, tetrahexyldecyl Tocopherol, embodiment, the composition comprises from about 0.1% to 25 Dunaliella Salina Extract or combinations thereof. about 3.0%, from about 0.05% to about 5.0%, or from about Exemplary skin-lightening agents include hydroquinone, 0.01% to about 10.0% Resorcinol. In another embodiment, monobenzyl ether of hydroquinone, azelaic acid, kojic acid, the composition comprises from about 0.1% to about 3.0%, meduinol, retinoids, soy proteins, alpha-hydroxy acids, from about 0.05% to about 5.0%, or from about 0.01% to trichloroacetic acid, Salicylic acid, hydroquinone-beta-D- about 10.0% ethyl linoleate. 30 glucopyranoside, paper mulberry, glabridin, 4-isopropyl In another aspect, provided herein is a method of lightening cetichol, aleosin, N-acetyl-4-S-cycteaminylphenol, N-propio skin in an individual, comprising administering to the indi nyl-4-S-cysteaminylphenol, N-acetyl glucosamine, vidual in need thereof an effective amount of a composition tranexaminc acid, an alpha MSH antagonist (e.g. undecyle comprising: about 0.5% 4-ethoxybenzaldehyde, about 0.01% noyl phenylalanine), phytic acid or combinations thereof. to about 5.0% each of Retinol, Niacinamide, Tetrahexyldecyl 35 Provided are methods of modifying melanin distribution Ascorbate, Glycyrrhiza Glabra (Licorice) Root Extract, by modulating prostaglandin F2 alpha (PGF2 alpha) in a cell, Hexyl Resorcinol, ethyllinoleate, and a pharmaceutically or comprising contacting said cell with a composition compris cosmetically acceptable carrier. In one embodiment, the ing from about 0.01% to about 2% substituted benzaldehyde, amount of substituted benzaldehyde in the composition is about 0.01% to about 5.0% each of Retinol, Niacinamide, about 0.5%. In another embodiment, the composition com 40 Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice) prises from about 0.1% to about 0.75%, from about 0.05% to Root Extract, Hexyl Resorcinol, ethyl linoleate, and a phar about 1.0%, or from about 0.01% to about 2% Retinol. In maceutically or cosmetically acceptable carrier. In some another embodiment, the composition comprises from about embodiments, the cells being treated are located in skin of an 2.0% to about 8.0%, from about 1% to about 10%, or from individual. about 0.5% to about 15.0% Niacinamide. In another embodi 45 Also disclosed are methods of modifying melanin distri ment, the composition comprises from about 1.0% to about bution by modulating prostaglandin F2 alpha (PGF2alpha) in 5.0%, from about 0.5% to about 8.0%, or from about 0.1% to skin cells in an individual, comprising administering to the about 15% Tetrahexyldecyl Ascorbate. In another embodi individual in need thereof an effective amount of a composi ment, the composition comprises from about 0.001% to about tion comprising from about 0.01% to about 2% substituted 0.5%, from about 0.0005% to about 1.0% or from about 50 benzaldehyde, about 0.01% to about 5.0% each of Retinol, 0.0001% to about 2% Licorice root extract. In another Niacinamide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Gla embodiment, the composition comprises from about 0.1% to bra (Licorice) Root Extract, Hexyl Resorcinol, ethyl about 3.0%, from about 0.05% to about 5.0%, or from about linoleate, and a pharmaceutically or cosmetically acceptable 0.01% to about 10.0% Resorcinol. In another embodiment, carrier. In another embodiment, the composition comprises the composition comprises from about 0.1% to about 3.0%, 55 from about 0.1% to about 0.75%, from about 0.05% to about from about 0.05% to about 5.0%, or from about 0.01% to 1.0%, or from about 0.01% to about 2% Retinol. In another about 10.0% ethyl linoleate. embodiment, the composition comprises from about 2.0% to In some embodiments, the methods decrease the level of about 8.0%, from about 1% to about 10%, or from about 0.5% pigmentation by about 5%, by about 10%, by about 20%, by to about 15.0% Niacinamide. In another embodiment, the about 30% or by about 40%. 60 composition comprises from about 1.0% to about 5.0%, from The methods may be used to treat hyperpigmentation or a about 0.5% to about 8.0%, or from about 0.1% to about 15% hypermelanosis disorder. In one embodiment, hyperpigmen Tetrahexyldecyl Ascorbate. In another embodiment, the com tation may result from an environmental stressor (e.g., exces position comprises from about 0.001% to about 0.5%, from sive Sun exposure or chemical exposure), physiological stres about 0.0005% to about 1.0% or from about 0.0001% to about Sor (e.g., a hormonal disorder), or mechanical stressor. 65 2% Licorice root extract. In another embodiment, the com In some embodiments, the method reduces melanin distri position comprises from about 0.1% to about 3.0%, from bution by about 10% to about 40%. about 0.05% to about 5.0%, or from about 0.01% to about US 8,236,288 B2 59 60 10.0% Resorcinol. In another embodiment, the composition Also provided are methods of modifying melanin distribu comprises from about 0.1% to about 3.0%, from about 0.05% tion by modulating prostaglandin F2 alpha (PGF2 alpha) in to about 5.0%, or from about 0.01% to about 10.0% ethyl skin cells in an individual, comprising administering to the linoleate. individual in need thereof an effective amount of a composi In one embodiment, the amount of substituted benzalde tion comprising about 0.5% 4-ethoxybenzaldehyde, about hyde in the composition is about 0.5%. 0.01% to about 5.0% each of Retinol, Niacinamide, Tetra Substituted benzaldehydes for use in the compositions hexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice) Root include, for example, 2-ethoxybenzaldehyde, 4-ethoxyben Extract, Hexyl Resorcinol, ethyllinoleate, and a pharmaceu Zaldehyde, 4-allyloxybenzaldehyde or 4-propoxybenzalde tically or cosmetically acceptable carrier. In another embodi 10 ment, the composition comprises from about 0.1% to about hyde. In one embodiment, the substituted benzaldehyde is 0.75%, from about 0.05% to about 1.0%, or from about 0.01% 4-ethoxybenzaldehyde, which may be present in the compo to about 2% Retinol. In another embodiment, the composition sition in an amount of about 0.5%. comprises from about 2.0% to about 8.0%, from about 1% to In some embodiments, provided are methods of modifying about 10%, or from about 0.5% to about 15.0% Niacinamide. melanin distribution by modulating prostaglandin F2 alpha 15 In another embodiment, the composition comprises from (PGF2 alpha) in a cell, comprising contacting said cell with a about 1.0% to about 5.0%, from about 0.5% to about 8.0%, or composition comprising about 0.1 to about 0.5% 4-ethoxy from about 0.1% to about 15% Tetrahexyldecyl Ascorbate. In benzaldehyde, about 0.01% to about 5.0% each of Retinol, another embodiment, the composition comprises from about Niacinamide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Gla 0.001% to about 0.5%, from about 0.0005% to about 1.0% or bra (Licorice) Root Extract, Hexyl Resorcinol, ethyl from about 0.0001% to about 2% Licorice root extract. In linoleate, and a pharmaceutically or cosmetically acceptable another embodiment, the composition comprises from about carrier. In some embodiments, the cells being treated are 0.1% to about 3.0%, from about 0.05% to about 5.0%, or from located in skin of an individual. In another embodiment, the about 0.01% to about 10.0% Resorcinol. In another embodi composition comprises from about 0.1% to about 0.75%, ment, the composition comprises from about 0.1% to about from about 0.05% to about 1.0%, or from about 0.01% to 25 3.0%, from about 0.05% to about 5.0%, or from about 0.01% about 2% Retinol. In another embodiment, the composition to about 10.0% ethyl linoleate. In some embodiments, the comprises from about 2.0% to about 8.0%, from about 1% to method reduces melanin distribution by about 10% to about about 10%, or from about 0.5% to about 15.0% Niacinamide. 40%. In another embodiment, the composition comprises from Application of the compositions in the methods described about 1.0% to about 5.0%, from about 0.5% to about 8.0%, or 30 herein may be topical or transdermal administeration to the from about 0.1% to about 15% Tetrahexyldecyl Ascorbate. In skin of the individual. another embodiment, the composition comprises from about In one embodiment, the pharmaceutically or cosmetically 0.001% to about 0.5%, from about 0.0005% to about 1.0% or acceptable carrier is a topical carrier. Topical carriers include, from about 0.0001% to about 2% Licorice root extract. In for example, a water-in-oil emulsion, cream, liquid, gel, oil, another embodiment, the composition comprises from about 35 paste, ointment, Suspension, foam, lotion, oil-in-water emul 0.1% to about 3.0%, from about 0.05% to about 5.0%, or from Sion, water-in-oil-in-water emulsion, water-in-silicone emul about 0.01% to about 10.0% Resorcinol. In another embodi Sion, spray or serum carrier. ment, the composition comprises from about 0.1% to about Compositions described herein for use in such methods 3.0%, from about 0.05% to about 5.0%, or from about 0.01% may further include one or more additional active agents. For to about 10.0% ethyl linoleate. 40 example, an additional active agent may be an antioxidant, a Provided are methods of modifying melanin distribution Sunscreen, a Sunprotectant, a Sunblock, a skin-lightening by modulating prostaglandin F2 alpha (PGF2 alpha) in a cell, agent, an anti-inflammatory agent, an anti-acne agent or mix comprising contacting said cell with a composition compris tures thereof. Compositions described herein for use in such ing about 0.5% 4-ethoxybenzaldehyde, about 0.01% to about methods may further include one or more of a solvent, film 5.0% each of Retinol, Niacinamide, Tetrahexyldecyl Ascor 45 former, preservative, Viscosity increasing agent, fragrance, bate, Glycyrrhiza Glabra (Licorice) Root Extract, Hexyl Surfactant, chelating agent, humectant, permeation enhancer, Resorcinol, ethyl linoleate, and a pharmaceutically or cos excipients, or a combination thereof. metically acceptable carrier. In some embodiments, the cells Exemplary antioxidants include vitamin E. Coenzyme being treated are located in skin of an individual. In another Q10, idebenone, lycopene, green tea polyphenols, Silybin, embodiment, the composition comprises from about 0.1% to 50 resveratrol, grape seed extract, Oregon grape root (Mahonia about 0.75%, from about 0.05% to about 1.0%, or from about aquifolium) extract, pomegranate extract, genistein, pycno 0.01% to about 2%. Retinol. In another embodiment, the genol, curcumin, curcuminoids, Tocopherol, Dunaliella composition comprises from about 2.0% to about 8.0%, from Salina Extract or combinations thereof. about 1% to about 10%, or from about 0.5% to about 15.0% Exemplary skin-lightening agents include hydroquinone, Niacinamide. In another embodiment, the composition com 55 monobenzyl ether of hydroquinone, azelaic acid, kojic acid, prises from about 1.0% to about 5.0%, from about 0.5% to meduinol, retinoids, soy proteins, alpha-hydroxy acids, about 8.0%, or from about 0.1% to about 15% Tetrahexylde trichloroacetic acid, Salicylic acid, hydroquinone-beta-D- cyl Ascorbate. In another embodiment, the composition com glucopyranoside, paper mulberry, glabridin, 4-isopropyl prises from about 0.001% to about 0.5%, from about cetichol, aleosin, N-acetyl-4-S-cycteaminylphenol, N-propio 0.0005% to about 1.0% or from about 0.0001% to about 2% 60 nyl-4-S-cysteaminylphenol, N-acetyl glucosamine, Licorice root extract. In another embodiment, the composi tranexaminc acid, an alpha MSH antagonist (e.g. undecyle tion comprises from about 0.1% to about 3.0%, from about noyl phenylalanine), or phytic acid combinations thereof. 0.05% to about 5.0%, or from about 0.01% to about 10.0% In one aspect, one patient population to be treated by the Resorcinol. In another embodiment, the composition com present methods is described below in Example 13. Repre prises from about 0.1% to about 3.0%, from about 0.05% to 65 sentative patients include those with Fitzpatrick skin types about 5.0%, or from about 0.01% to about 10.0% ethyl I-IV. Fitzpatrick skin classification is based on the skins linoleate. unprotected response to the first 30 to 45 minutes of sun US 8,236,288 B2 61 62 exposure after a winter season without Sun exposure. The history of cancer. Individuals with observable sunburn, sun categories of skin types are as follows: (I): Always burns tan, Scars, uneven tone/pigmentation, nevi or other dermal easily; never tans; (II): Always burns easily; tans minimally; conditions on the areas to be treated that might influence the (III): Burns moderately; tans gradually; (IV): Burns mini results. Individuals with uncontrolled high blood pressure, mally: always tans well; (V): Rarely burns; tans profusely: 5 individuals with dermal hypersensitivity requiring treatments and (VI): Never burns; deeply pigmented. Patients also may with medications. Individuals taking medication(s) which exhibit the presence of clinically determined moderate to would interfere with the subject’s treatment. Such medica severe dyspigmentation on the face as determined by a score tions include, but are not limited to, antihypertensive agents of 4-9 from the Overall Hyperpigmentation scale. Individuals (hydrochorothiazide, furosemide, meticrane), ataractics to be treated are in good general health and free of any disease 10 (e.g., perphenazine), psychotropic agents (e.g., chlorprom state or physical condition (e.g., psoriasis, moderate to severe rosacea, hirsutism, Scars, tattoos, etc.) which might increase azine), antihistamines (e.g., promethazine hydrochloride), the health risk to the subject by treatment. Individuals to be oral hypoglycemic agents (e.g., tolubutamide, chlorpropam treated include those who have not used systemic retinoids ide), and tetracycline antibiotics (e.g., dimethylchlorotetra (e.g., TaZorac, Soriataine. Accutane, etc.) and/or any other 15 cycline, tetracycline). systemic medication known to affect melasma at least 60 days Method of Administration prior to treatment and are not to use these products during In some embodiments, any composition described herein is treatment. Individuals to be treated are not to use topical administered in the form of a cosmetic composition. In some retinoids and/or all other topical medication (e.g., topical embodiments, the cosmetic composition can be prepared steroids, products containing benzoyl peroxide, alpha- or 20 according to procedures well known in the cosmetic arts and beta-hydroxy acids, hydroquinone, and/or any other over the comprise at least one active compound and two antioxidant counter (OTC) skin treatment medications) to the facial area agents. known to affect melasma at least 14 days prior to treatment In Some embodiments, the cosmetic composition is admin and are not to use these products during treatment. Patients istered topically. In specific embodiments, the cosmetic com should be willing to avoid extended periods of sun exposure 25 position is administered transdermally so that the active agent during treatment. Ifbrief (less than 20 minutes) periods of sun and antioxidant agents contact the skin. In a further or addi exposure cannot be avoided, then Subjects are asked to use an tional embodiment, the composition is administered transder SPF 30 product and wear protective clothing prior to and mally so as to deliver the compositions disclosed herein sys during exposure. temically. In another aspect, an individual will not be eligible for 30 The compositions disclosed herein contain one or more treatment if they meet any of the following exclusion criteria: Substituted benzaldehyde and an optional at least one addi Individuals with known allergies or sensitivities to skin light tional active agent. The amounts used are amounts effective ening products, retinoids, hydroquinone, Sulfites, moisturiz Such that when administered to a Subject for treating a dis ers, or other facial products. Individuals with active symp ease, cosmetic or dermatological condition, is Sufficient to toms of allergy, active psoriasis or eczema, Sunburn, 35 effect Such treatment for the disease, cosmetic or dermato excessive scarring, tattoos, or other skin condition in the areas logical condition. Here, the amount will depend upon the to be treated. Individuals who are nursing, pregnant, or plan endpoint desired, for example, the modification, for example ning to become pregnant during treatment. Individuals hav the increase or reduction of melanin and/or melanocyte pro ing uncontrolled disease Such as diabetes, hypertension, duction and/or distribution. The endpoint can be measured in hyper or hypo-thyroidism, active hepatitis, immune defi- 40 terms of the subjective interpretation of the subject being ciency, or autoimmune disease as determined by the initial administered the disclosed compositions. For example, the paperwork. Individuals who require electrolysis, waxing, or endpoint may be a study by which a subject is queried if the use depilatories on the face during conduct of the study. treatment regimen is “satisfactory” or “unsatisfactory'. Alter Individuals who have had a facial peel or a laser treatment of natively, the endpoint may be measured quantitatively in the face within 60 days prior to treatment. Individuals who 45 terms of the amount of melanin and/or melanocytes in a given have a pre-existing or dormant dermatologic condition (e.g., Subject or experimental procedure. The endpoint may be psoriasis, atopic dermatitis, advanced skin cancer, rosacea, measured by a trained medical professional, for example a other inflammatory disorder, etc.). Individuals who are physician or nurse, or by a subject or other individual. The receiving treatment for a skin disorder with another compo endpoint may additionally be determined remotely, for sition. 50 example, through comparisons of photographs or other In another aspect, another patient population to be treated recordings by a trained medical professional or other indi by the present methods is described below in Example 14. vidual. Furthermore, the degree of modification of melanin Representative patients include those with Fitzpatrick skin production may be predetermined by a trained medical pro type III and those who are in general good health as deter fessional, for example, by assigning a predetermined degree mined by review of their health. 55 of melanin and/or melanocyte presence as an endpoint value. In another aspect, an individual will not be eligible for The “effective amount', however, will take into account treatment if they meet any of the following exclusion criteria: any toxicity effects that may occur, for example, severe skin Individuals with Fitzpatrick skin types I, II, IV, V and VI. irritation with higher doses of the active agents disclosed Individuals that have been instructed by a physician, pharma herein. Suggested endpoints may first be measured in vitro or cist, or health professional to avoid Sunlight because of a 60 in an animal model to determine the acceptable range of medical condition and/or because of drug contraindications. active agents to be used in conjunction with the compositions Individuals with known abnormal responses to Sunlight or disclosed herein. One of ordinary skill in the art can then UVR light sources. Individuals with a known allergy to any extrapolate doses that will avoid toxicity but maintain effi ingredient in a personal care product. Individuals with known cacy in treated Subjects, including humans. The “effective atopic skin diseases or neurodermatitis. Women known to be 65 amount can vary depending on the compound, the disease pregnant, nursing, or planning to become pregnant within 6 and its severity, and the age, weight, etc., of the Subject to be months. Individuals known to be treated for cancer or have a treated. US 8,236,288 B2 63 64 In certain embodiments, the compositions disclosed herein Preferably, the compositions disclosed herein comprises a comprises a Substituted benzaldehyde in a concentration of 4-ethoxybenzaldehyde in a concentration from about 0.01% about 0.01%, about 0.05%, about 0.08%, about 0.1%, about to about 50%, from about 0.1% to about 30%, from about 0.15%, about 0.2%, about 0.5%, about 0.8%, about 1%, about 0.1% to about 20%, from about 0.5% to about 20%, from 1.3%, about 1.5%, about 1.8%, about 2%, about 2.3%, about about 0.5% to about 10%, from about 0.5% to about 5%, from 2.5%, about 2.8%, about 3%, about 3.5%, about 4%, about about 0.5% to about 3%, from about 0.5% to about 2.0%, 5%, about 8%, about 10%, about 13%, about 15%, about from about 0.5% to about 1.5%, from about 0.75% to about 18%, about 20%, about 22% or about 25%. Preferably, the 10%, from about 0.75% to about 7.5%, from about 0.75% to compositions disclosed herein comprises a Substituted ben about 5%, from about 1% to about 10%, from about 1% to Zaldehyde in a concentration from about 0.01% to about 50%, 10 about 5%, from about 1% to about 2.5%, from about 1% to from about 0.1% to about 30%, from about 0.1% to about about 2%, from about 0.1% to about 2%, from about 0.01% to 20%, from about 0.5% to about 20%, from about 0.5% to about 2%, from about 0.01% to about 2%, from about 0.01% about 10%, from about 0.5% to about 5%, from about 0.5% to to about 2%, from about 0.1% to about 1%, from about 0.1% about 3%, from about 0.5% to about 2.0%, from about 0.5% to about 0.5%, or from about 0.5% to about 2%. to about 1.5%, from about 0.75% to about 10%, from about 15 The compositions disclosed herein may also have a con 0.75% to about 7.5%, from about 0.75% to about 5%, from centration of 4-ethoxybenzaldehyde of from about 0.01 about 1% to about 10%, from about 1% to about 5%, from mg/ml to about 50 mg/ml, preferably from about 0.1 mg/ml to about 1% to about 2.5%, from about 1% to about 2%, from about 10 mg/ml. In some embodiments, the compositions about 0.1% to about 2%, from about 0.01% to about 2%, from disclosed herein may have a concentration of 4-ethoxyben about 0.01% to about 2%, from about 0.01% to about 2%, Zadehyde of from about 0.1 mg/ml to about 5 mg/ml, or from from about 0.1% to about 1%, from about 0.1% to about about 0.3 mg/ml to about 3 mg/ml. In some embodiments, the 0.5%, or from about 0.5% to about 2%. compositions will have a concentration of 4-ethoxybenzalde The compositions disclosed herein may contain from about hyde of from about 0.1 to about 50 mg/ml, from about 0.1 to 0.01 mg to about 100 mg of substituted benzaldehyde or about 45 mg/ml, from about 0.1 to about 40 mg/ml, from about 0.1 mg to about 10 mg of substituted benzaldehyde. In 25 about 0.1 to about 35 mg/ml, from about 0.1 to about 30 Some embodiments, the compositions disclosed herein may mg/ml, from about 0.1 to about 25 mg/ml, from about 0.1 to contain from about 0.05 to about 5 mg of substituted benzal about 20 mg/ml, from about 0.1 to about 15 mg/ml, from dehyde, or from about 0.1 to about 3 mg of substituted ben about 0.1 to about 10 mg/ml, from about 0.1 to about 5 mg/ml, Zaldehyde. In some embodiments, the compositions dis 0.5 to about 50 mg/ml, from about 0.5 to about 45 mg/ml, closed herein may contain from about 0.1 to about 50 mg. 30 from about 0.5 to about 40 mg/ml, from about 0.5 to about 35 from about 0.1 to about 45 mg, from about 0.1 to about 40 mg. mg/ml, from about 0.5 to about 30 mg/ml, from about 0.5 to from about 0.1 to about 35 mg, from about 0.1 to about 30 mg, about 25 mg/ml, from about 0.5 to about 20 mg/ml, from from about 0.1 to about 25 mg, from about 0.1 to about 20 mg. about 0.5 to about 15 mg/ml, from about 0.5 to about 10 from about 0.1 to about 15 mg, from about 0.1 to about 10 mg. mg/ml, from about 0.5 to about 5 mg/ml, 1.0 to about 50 from about 0.1 to about 5 mg, from about 0.5 to about 50 mg. 35 mg/ml, from about 1.0 to about 45 mg/ml, from about 1.0 to from about 0.5 to about 45 mg, from about 0.5 to about 40 mg. about 40 mg/ml, from about 1.0 to about 35 mg/ml, from from about 0.5 to about 35 mg, from about 0.5 to about 30 mg. about 1.0 to about 30 mg/ml, from about 1.0 to about 25 from about 0.5 to about 25 mg, from about 0.5 to about 20 mg. mg/ml, from about 1.0 to about 20 mg/ml, from about 1.0 to from about 0.5 to about 15 mg, from about 0.5 to about 10 mg. about 15 mg/ml, from about 1.0 to about 10 mg/ml, from from about 0.5 to about 5 mg, from about 1.0 to about 50 mg. 40 about 1.0 to about 5 mg/ml, 2.5 to about 50 mg/ml, from about from about 1.0 to about 45 mg, from about 1.0 to about 40 mg. 2.5 to about 45 mg/ml, from about 2.5 to about 40 mg/ml, from about 1.0 to about 35 mg, from about 1.0 to about 30 mg. from about 2.5 to about 35 mg/ml, from about 2.5 to about 30 from about 1.0 to about 25 mg, from about 1.0 to about 20 mg. mg/ml, from about 2.5 to about 25 mg/ml, from about 2.5 to from about 1.0 to about 15 mg, from about 1.0 to about 10 mg. about 20 mg/ml, from about 2.5 to about 15 mg/ml, from from about 1.0 to about 5 mg, from about 2.5 to about 50 mg. 45 about 2.5 to about 10 mg/ml, from about 2.5 to about 5 mg/ml from about 2.5 to about 45 mg, from about 2.5 to about 40 mg. of 4-ethoxybenzaldehyde. In some embodiments, the com from about 2.5 to about 35 mg, from about 2.5 to about 30 mg. positions disclosed herein will have a concentration of from about 2.5 to about 25 mg, from about 2.5 to about 20 mg. 4-ethoxybenzaldehyde of 0.1, 0.2,0.3, 0.4,0.5,0.6, 0.7, 0.8, from about 2.5 to about 15 mg, from about 2.5 to about 10 mg. 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, and from about 2.5 to about 5 mg of substituted benzalde 50 7.5, 8.0, 8.5, 9.0, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, hyde. In some embodiments, the compositions disclosed 14.5, 15, 16, 17, 18, 19, 20, 25, 30, 3540, 45 or 50 mg/ml. herein will contain from about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 In other embodiments, the compositions disclosed herein mg, 0.5, mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 2.0 mg. further includes an antioxidant in a concentration of about 3.0 mg, 4.0 mg, 5.0 mg, 7.0 mg, 10.0 mg, 15.0 mg, 20 mg, 25 0.01%, about 0.05%, about 0.08%, about 0.1%, about 0.15%, mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 55 about 0.2%, about 0.5%, about 0.8%, about 1%, about 1.3%, mg, 90 mg or 100 mg of substituted benzaldehyde. In some about 1.5%, about 1.8%, about 2%, about 2.3%, about 2.5%, embodiments, the compositions disclosed herein will contain about 2.8%, about 3%, about 3.5%, about 4%, about 5%, from about 0.3 mg to about 0.75 mg of substituted benzalde about 8%, about 10%, about 13%, about 15%, about 18%, hyde. about 20%, about 23%, about 25%. In yet other embodi In some embodiment, the compositions disclosed herein 60 ments, the compositions disclosed herein comprises a range comprises 4-ethoxybenzaldehyde in a concentration of about of antioxidant from about 0.1% to about 25%, from about 0.01%, about 0.05%, about 0.08%, about 0.1%, about 0.15%, 0.5% to about 20%, from about 0.5% to about 10%, from about 0.2%, about 0.5%, about 0.8%, about 1%, about 1.3%, about 0.5% to about 5%, from about 0.5% to about 3%, from about 1.5%, about 1.8%, about 2%, about 2.3%, about 2.5%, about 0.75% to about 10%, from about 0.75% to about 7.5%, about 2.8%, about 3%, about 3.5%, about 4%, about 5%, 65 from about 0.75% to about 5%, from about 1% to about 10%, about 8%, about 10%, about 13%, about 15%, about 18%, from about 1% to about 5%, from about 1% to about 2.5%, or about 20%, about 22%, about 25%, about 30% or about 40%. from about 1% to about 2%. US 8,236,288 B2 65 66 The compositions disclosed herein may contain from about from about 0.5 to about 10 mg. from about 0.5 to about 5 mg. 0.01 mg to about 100 mg of antioxidant or about 0.1 mg to from about 1.0 to about 50 mg, from about 1.0 to about 45 mg. about 10 mg of antioxidant. In some embodiments, the com from about 1.0 to about 40 mg, from about 1.0 to about 35 mg. positions disclosed herein may contain from about 0.05 to from about 1.0 to about 30 mg, from about 1.0 to about 25 mg. about 5 mg of antioxidant, or from about 0.1 to about 3 mg of 5 from about 1.0 to about 20 mg, from about 1.0 to about 15 mg. antioxidant. In some embodiments, the compositions dis from about 1.0 to about 10 mg. from about 1.0 to about 5 mg. closed herein may contain from about 0.1 to about 50 mg. from about 2.5 to about 50 mg, from about 2.5 to about 45 mg. from about 0.1 to about 45 mg, from about 0.1 to about 40 mg. from about 2.5 to about 40 mg, from about 2.5 to about 35 mg. from about 0.1 to about 35 mg, from about 0.1 to about 30 mg. from about 2.5 to about 30 mg, from about 2.5 to about 25 mg. from about 0.1 to about 25 mg, from about 0.1 to about 20 mg. 10 from about 2.5 to about 20 mg, from about 2.5 to about 15 mg. from about 0.1 to about 15 mg, from about 0.1 to about 10 mg. from about 2.5 to about 10 mg, and from about 2.5 to about 5 from about 0.1 to about 5 mg, from about 0.5 to about 50 mg. mg of skin-lightening agent. In some embodiments, the com from about 0.5 to about 45 mg, from about 0.5 to about 40 mg. positions disclosed herein will contain from about 0.1 mg, 0.2 from about 0.5 to about 35 mg, from about 0.5 to about 30 mg. mg, 0.3 mg, 0.4 mg. 0.5, mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, from about 0.5 to about 25 mg, from about 0.5 to about 20 mg. 15 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 7.0 mg, 10.0 mg, 15.0 from about 0.5 to about 15 mg, from about 0.5 to about 10 mg. mg, 20 mg, 25 mg, 30 mg, 35 mg. 40 mg, 45 mg, 50 mg, 60 from about 0.5 to about 5 mg, from about 1.0 to about 50 mg. mg, 70 mg, 80 mg, 90 mg or 100 mg of skin-lightening agent. from about 1.0 to about 45 mg, from about 1.0 to about 40 mg. In some embodiments, the compositions disclosed herein will from about 1.0 to about 35 mg, from about 1.0 to about 30 mg. contain from about 0.3 mg to about 0.75 mg of skin-lighten from about 1.0 to about 25 mg, from about 1.0 to about 20 mg. ing agent. from about 1.0 to about 15 mg, from about 1.0 to about 10 mg. In some embodiments, the compositions disclosed herein from about 1.0 to about 5 mg, from about 2.5 to about 50 mg. further comprises a Sunscreen agent in a concentration of from about 2.5 to about 45 mg, from about 2.5 to about 40 mg. about 0.01%, about 0.05%, about 0.08%, about 0.1%, about from about 2.5 to about 35 mg, from about 2.5 to about 30 mg. 0.15%, about 0.2%, about 0.5%, about 0.8%, about 1%, about from about 2.5 to about 25 mg, from about 2.5 to about 20 mg. 25 1.3%, about 1.5%, about 1.8%, about 2%, about 2.3%, about from about 2.5 to about 15 mg, from about 2.5 to about 10 mg. 2.5%, about 2.8%, about 3%, about 3.5%, about 4%, about and from about 2.5 to about 5 mg of antioxidant. In some 5%, about 8%, about 10%, about 13%, about 15%, about embodiments, the compositions disclosed herein will contain 18%, about 20%, about 23%, about 25%. In yet other embodi from about 0.1 mg, 0.2 mg, 0.3 mg 0.4 mg. 0.5, mg, 0.6 mg, ments, the compositions disclosed herein comprises a range 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 30 ofsuncreenagents from about 0.1% to about 25%, from about mg, 7.0 mg, 10.0 mg, 15.0 mg, 20 mg, 25 mg, 30 mg, 35 mg. 0.5% to about 20%, from about 0.5% to about 10%, from 40 mg, 45 mg, 50 mg. 60 mg, 70 mg, 80 mg, 90 mg or 100 mg about 0.5% to about 5%, from about 0.5% to about 3%, from of antioxidant. In some embodiments, the compositions dis about 0.75% to about 10%, from about 0.75% to about 7.5%, closed herein will contain from about 0.3 mg to about 0.75 mg from about 0.75% to about 5%, from about 1% to about 10%, of antioxidant. 35 from about 1% to about 5%, from about 1% to about 2.5%, or In other embodiments, the compositions disclosed herein from about 1% to about 2%. further comprises a skin-lightening agent in a concentration The compositions disclosed herein may contain from about of about 0.01%, about 0.05%, about 0.08%, about 0.1%, 0.01 mg to about 100 mg of a Sunscreen agent or about 0.1 mg about 0.15%, about 0.2%, about 0.5%, about 0.8%, about 1%, to about 10 mg of a Sunscreen agent. In some embodiments, about 1.3%, about 1.5%, about 1.8%, about 2%, about 2.3%, 40 the compositions disclosed herein may contain from about about 2.5%, about 2.8%, about 3%, about 3.5%, about 4%, 0.05 to about 5 mg of sunscreen agent, or from about 0.1 to about 5%, about 8%, about 10%, about 13%, about 15%, about 3 mg of Sunscreen agent. In some embodiments, the about 18%, about 20%, about 23%, about 25%. In yet other compositions disclosed herein may contain from about 0.1 to embodiments, the compositions disclosed herein comprises a about 50 mg, from about 0.1 to about 45 mg, from about 0.1 range of skin-lightening agents from about 0.1% to about 45 to about 40 mg, from about 0.1 to about 35 mg, from about 0.1 25%, from about 0.5% to about 20%, from about 0.5% to to about 30 mg, from about 0.1 to about 25 mg, from about 0.1 about 10%, from about 0.5% to about 5%, from about 0.5% to to about 20 mg, from about 0.1 to about 15 mg, from about 0.1 about 3%, from about 0.75% to about 10%, from about 0.75% to about 10 mg, from about 0.1 to about 5 mg, from about 0.5 to about 7.5%, from about 0.75% to about 5%, from about 1% to about 50 mg, from about 0.5 to about 45 mg, from about 0.5 to about 10%, from about 1% to about 5%, from about 1% to 50 to about 40 mg, from about 0.5 to about 35 mg, from about 0.5 about 2.5%, or from about 1% to about 2%. to about 30 mg, from about 0.5 to about 25 mg, from about 0.5 The compositions disclosed herein may contain from about to about 20 mg, from about 0.5 to about 15 mg, from about 0.5 0.01 mg to about 100 mg of skin-lightening agent or about 0.1 to about 10 mg, from about 0.5 to about 5 mg, from about 1.0 mg to about 10 mg of skin-lightening agent. In some embodi to about 50 mg, from about 1.0 to about 45 mg, from about 1.0 ments, the compositions disclosed herein may contain from 55 to about 40 mg, from about 1.0 to about 35 mg, from about 1.0 about 0.05 to about 5 mg of skin-lightening agent, or from to about 30 mg, from about 1.0 to about 25 mg, from about 1.0 about 0.1 to about 3 mg of skin-lightening agent. In some to about 20 mg, from about 1.0 to about 15 mg, from about 1.0 embodiments, the compositions disclosed herein may contain to about 10 mg, from about 1.0 to about 5 mg, from about 2.5 from about 0.1 to about 50 mg, from about 0.1 to about 45 mg. to about 50 mg, from about 2.5 to about 45 mg, from about 2.5 from about 0.1 to about 40 mg, from about 0.1 to about 35 mg. 60 to about 40 mg, from about 2.5 to about 35 mg, from about 2.5 from about 0.1 to about 30 mg, from about 0.1 to about 25 mg. to about 30 mg, from about 2.5 to about 25 mg, from about 2.5 from about 0.1 to about 20 mg, from about 0.1 to about 15 mg. to about 20 mg, from about 2.5 to about 15 mg, from about 2.5 from about 0.1 to about 10 mg. from about 0.1 to about 5 mg. to about 10 mg, and from about 2.5 to about 5 mg of sunscreen from about 0.5 to about 50 mg, from about 0.5 to about 45 mg. agent. In some embodiments, the compositions disclosed from about 0.5 to about 40 mg, from about 0.5 to about 35 mg. 65 herein will contain from about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 from about 0.5 to about 30 mg, from about 0.5 to about 25 mg. mg, 0.5, mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 2.0 mg. from about 0.5 to about 20 mg, from about 0.5 to about 15 mg. 3.0 mg, 4.0 mg, 5.0 mg, 7.0 mg, 10.0 mg, 15.0 mg, 20 mg, 25 US 8,236,288 B2 67 68 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 about 3%, from about 0.75% to about 10%, from about 0.75% mg, 90 mg or 100 mg of Sunscreen agent. In some embodi to about 7.5%, from about 0.75% to about 5%, from about 1% ments, the compositions disclosed herein will contain from to about 10%, from about 1% to about 5%, from about 1% to about 0.3 mg to about 0.75 mg of Sunscreen agent. about 2.5%, or from about 1% to about 2%. In some embodiments, the compositions disclosed herein 5 The compositions disclosed herein may contain from about further comprises an anti-acne agent in a concentration of 0.01 mg to about 100 mg of anti-inflammatory agent or about about 0.01%, about 0.05%, about 0.08%, about 0.1%, about 0.1 mg to about 10 mg of anti-inflammatory agent. In some 0.15%, about 0.2%, about 0.5%, about 0.8%, about 1%, about embodiments, the compositions disclosed herein may contain 1.3%, about 1.5%, about 1.8%, about 2%, about 2.3%, about from about 0.05 to about 5 mg of anti-inflammatory agent, or 2.5%, about 2.8%, about 3%, about 3.5%, about 4%, about 10 from about 0.1 to about 3 mg of anti-inflammatory agent. In 5%, about 8%, about 10%, about 13%, about 15%, about Some embodiments, the compositions disclosed herein may 18%, about 20%, about 23%, about 25%. In yet other embodi contain from about 0.1 to about 50 mg, from about 0.1 to ments, the compositions disclosed herein comprises a range about 45 mg, from about 0.1 to about 40 mg, from about 0.1 of an anti-acne agent from about 0.1% to about 25%, from to about 35 mg, from about 0.1 to about 30 mg, from about 0.1 about 0.5% to about 20%, from about 0.5% to about 10%, 15 to about 25 mg, from about 0.1 to about 20 mg, from about 0.1 from about 0.5% to about 5%, from about 0.5% to about 3%, to about 15 mg, from about 0.1 to about 10 mg, from about 0.1 from about 0.75% to about 10%, from about 0.75% to about to about 5 mg, from about 0.5 to about 50 mg, from about 0.5 7.5%, from about 0.75% to about 5%, from about 1% to about to about 45 mg, from about 0.5 to about 40 mg, from about 0.5 10%, from about 1% to about 5%, from about 1% to about to about 35 mg, from about 0.5 to about 30 mg, from about 0.5 2.5%, or from about 1% to about 2%. to about 25 mg, from about 0.5 to about 20 mg, from about 0.5 The compositions disclosed herein may contain from about to about 15 mg, from about 0.5 to about 10 mg, from about 0.5 0.01 mg to about 100 mg of anti-acne agent or about 0.1 mg to about 5 mg, from about 1.0 to about 50 mg, from about 1.0 to about 10 mg of anti-acne agent. In some embodiments, the to about 45 mg, from about 1.0 to about 40 mg, from about 1.0 compositions disclosed herein may contain from about 0.05 to about 35 mg, from about 1.0 to about 30 mg, from about 1.0 to about 5 mg of anti-acne agent, or from about 0.1 to about 3 25 to about 25 mg, from about 1.0 to about 20 mg, from about 1.0 mg of anti-acne agent. In some embodiments, the composi to about 15 mg, from about 1.0 to about 10 mg, from about 1.0 tions disclosed herein may contain from about 0.1 to about 50 to about mg, from about 2.5 to about 50 mg, from about 2.5 to mg, from about 0.1 to about 45 mg, from about 0.1 to about 40 about 45 mg, from about 2.5 to about 40 mg, from about 2.5 mg, from about 0.1 to about 35 mg, from about 0.1 to about 30 to about 35 mg, from about 2.5 to about 30 mg, from about 2.5 mg, from about 0.1 to about 25 mg, from about 0.1 to about 20 30 to about 25 mg, from about 2.5 to about 20 mg, from about 2.5 mg, from about 0.1 to about 15 mg, from about 0.1 to about 10 to about 15 mg, from about 2.5 to about 10 mg, and from mg, from about 0.1 to about 5 mg, from about 0.5 to about 50 about 2.5 to about 5 mg of anti-inflammatory agent. In some mg, from about 0.5 to about 45 mg, from about 0.5 to about 40 embodiments, the compositions disclosed herein will contain mg, from about 0.5 to about 35 mg, from about 0.5 to about 30 from about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg. 0.5, mg, 0.6 mg, mg, from about 0.5 to about 25 mg, from about 0.5 to about 20 35 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 2.0 mg, 3.0 mg. 4.0 mg, 5.0 mg, from about 0.5 to about 15 mg, from about 0.5 to about 10 mg, 7.0 mg, 10.0 mg, 15.0 mg, 20 mg, 25 mg, 30 mg, 35 mg. mg, from about 0.5 to about 5 mg, from about 1.0 to about 50 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg mg, from about 1.0 to about 45 mg, from about 1.0 to about 40 of anti-inflammatory agent. In some embodiments, the com mg, from about 1.0 to about 35 mg, from about 1.0 to about 30 positions disclosed herein will contain from about 0.3 mg to mg, from about 1.0 to about 25 mg, from about 1.0 to about 20 40 about 0.75 mg of anti-inflammatory agent. mg, from about 1.0 to about 15 mg, from about 1.0 to about 10 In some embodiments, the compositions disclosed herein mg, from about 1.0 to about 5 mg, from about 2.5 to about 50 further comprises an emollient in a concentration of about mg, from about 2.5 to about 45 mg, from about 2.5 to about 40 0.01%, about 0.05%, about 0.08%, about 0.1%, about 0.15%, mg, from about 2.5 to about 35 mg, from about 2.5 to about 30 about 0.2%, about 0.5%, about 0.8%, about 1%, about 1.3%, mg, from about 2.5 to about 25 mg, from about 2.5 to about 20 45 about 1.5%, about 1.8%, about 2%, about 2.3%, about 2.5%, mg, from about 2.5 to about 15 mg, from about 2.5 to about 10 about 2.8%, about 3%, about 3.5%, about 4%, about 5%, mg, and from about 2.5 to about 5 mg of anti-acne agent. In about 8%, about 10%, about 13%, about 15%, about 18%, Some embodiments, the compositions disclosed herein will about 20%, about 23%, about 25%. In yet other embodi contain from about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg. 0.5, mg, ments, the compositions disclosed herein comprises a range 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 50 of emollients from about 0.1% to about 25%, from about mg, 5.0 mg, 7.0 mg, 10.0 mg, 15.0 mg, 20 mg, 25 mg, 30 mg. 0.5% to about 20%, from about 0.5% to about 10%, from 35 mg, 40 mg. 45 mg, 50 mg. 60 mg, 70 mg, 80 mg, 90 mg or about 0.5% to about 5%, from about 0.5% to about 3%, from 100 mg of anti-acne agent. In some embodiments, the com about 0.75% to about 10%, from about 0.75% to about 7.5%, positions disclosed herein will contain from about 0.3 mg to from about 0.75% to about 5%, from about 1% to about 10%, about 0.75 mg of anti-acne agent. 55 from about 1% to about 5%, from about 1% to about 2.5%, or In some embodiments, the compositions disclosed herein from about 1% to about 2%. further comprises an anti-inflammatory agent in a concentra The compositions disclosed herein may contain from about tion of about 0.01%, about 0.05%, about 0.08%, about 0.1%, 0.01 mg to about 100 mg of emollient or about 0.1 mg to about about 0.15%, about 0.2%, about 0.5%, about 0.8%, about 1%, 10 mg of emollient. In some embodiments, the compositions about 1.3%, about 1.5%, about 1.8%, about 2%, about 2.3%, 60 disclosed herein may contain from about 0.05 to about 5 mg about 2.5%, about 2.8%, about 3%, about 3.5%, about 4%, ofemollient, or from about 0.1 to about 3 mg of emollient. In about 5%, about 8%, about 10%, about 13%, about 15%, Some embodiments, the compositions disclosed herein may about 18%, about 20%, about 23%, about 25%. In yet other contain from about 0.1 to about 50 mg, from about 0.1 to embodiments, the compositions disclosed herein comprises a about 45 mg, from about 0.1 to about 40 mg, from about 0.1 range of anti-inflammatory agents from about 0.1% to about 65 to about 35 mg, from about 0.1 to about 30 mg, from about 0.1 25%, from about 0.5% to about 20%, from about 0.5% to to about 25 mg, from about 0.1 to about 20 mg, from about 0.1 about 10%, from about 0.5% to about 5%, from about 0.5% to to about 15 mg, from about 0.1 to about 10 mg, from about 0.1 US 8,236,288 B2 69 70 to about 5 mg, from about 0.5 to about 50 mg, from about 0.5 from about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg. 0.5, mg, 0.6 mg, to about 45 mg, from about 0.5 to about 40 mg, from about 0.5 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 2.0 mg, 3.0 mg. 4.0 mg, 5.0 to about 35 mg, from about 0.5 to about 30 mg, from about 0.5 mg, 7.0 mg, 10.0 mg, 15.0 mg, 20 mg, 25 mg, 30 mg, 35 mg. to about 25 mg, from about 0.5 to about 20 mg, from about 0.5 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg to about 15 mg, from about 0.5 to about 10 mg, from about 0.5 5 of film former. In some embodiments, the compositions dis to about 5 mg, from about 1.0 to about 50 mg, from about 1.0 closed herein will contain from about 0.3 mg to about 0.75 mg to about 45 mg, from about 1.0 to about 40 mg, from about 1.0 of film former. to about 35 mg, from about 1.0 to about 30 mg, from about 1.0 In some embodiments, the compositions disclosed herein to about 25 mg, from about 1.0 to about 20 mg, from about 1.0 further comprises an occlusive in a concentration of about to about 15 mg, from about 1.0 to about 10 mg, from about 1.0 10 0.01%, about 0.05%, about 0.08%, about 0.1%, about 0.15%, to about 5 mg, from about 2.5 to about 50 mg, from about 2.5 about 0.2%, about 0.5%, about 0.8%, about 1%, about 1.3%, to about 45 mg, from about 2.5 to about 40 mg, from about 2.5 about 1.5%, about 1.8%, about 2%, about 2.3%, about 2.5%, to about 35 mg, from about 2.5 to about 30 mg, from about 2.5 about 2.8%, about 3%, about 3.5%, about 4%, about 5%, to about 25 mg, from about 2.5 to about 20 mg, from about 2.5 about 8%, about 10%, about 13%, about 15%, about 18%, to about 15 mg, from about 2.5 to about 10 mg, and from 15 about 20%, about 23%, about 25%. In yet other embodi about 2.5 to about 5 mg of emollient. In some embodiments, ments, the compositions disclosed herein comprises a range the compositions disclosed herein will contain from about 0.1 of occlusives from about 0.1% to about 25%, from about mg, 0.2 mg, 0.3 mg, 0.4 mg. 0.5, mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.5% to about 20%, from about 0.5% to about 10%, from 0.9 mg, 1.0 mg, 2.0 mg, 3.0 mg. 4.0 mg, 5.0 mg, 7.0 mg, 10.0 about 0.5% to about 5%, from about 0.5% to about 3%, from mg, 15.0 mg, 20 mg, 25 mg, 30 mg. 35 mg, 40 mg, 45 mg, 50 20 about 0.75% to about 10%, from about 0.75% to about 7.5%, mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg of emollient. In from about 0.75% to about 5%, from about 1% to about 10%, Some embodiments, the compositions disclosed herein will from about 1% to about 5%, from about 1% to about 2.5%, or contain from about 0.3 mg to about 0.75 mg of emollient. from about 1% to about 2%. In some embodiments, the compositions disclosed herein The compositions disclosed herein may contain from about further comprises a film former in a concentration of about 25 0.01 mg to about 100 mg of occlusive or about 0.1 mg to about 0.01%, about 0.05%, about 0.08%, about 0.1%, about 0.15%, 10 mg of film former. In some embodiments, the composi about 0.2%, about 0.5%, about 0.8%, about 1%, about 1.3%, tions disclosed herein may contain from about 0.05 to about 5 about 1.5%, about 1.8%, about 2%, about 2.3%, about 2.5%, mg of occlusive, or from about 0.1 to about 3 mg of occlusive. about 2.8%, about 3%, about 3.5%, about 4%, about 5%, In some embodiments, the compositions disclosed herein about 8%, about 10%, about 13%, about 15%, about 18%, 30 may contain from about 0.1 to about 50 mg, from about 0.1 to about 20%, about 23%, about 25%. In yet other embodi about 45 mg, from about 0.1 to about 40 mg, from about 0.1 ments, the compositions disclosed herein comprises a range to about 35 mg, from about 0.1 to about 30 mg, from about 0.1 of film formers from about 0.1% to about 25%, from about to about 25 mg, from about 0.1 to about 20 mg, from about 0.1 0.5% to about 20%, from about 0.5% to about 10%, from to about 15 mg, from about 0.1 to about 10 mg, from about 0.1 about 0.5% to about 5%, from about 0.5% to about 3%, from 35 to about 5 mg, from about 0.5 to about 50 mg, from about 0.5 about 0.75% to about 10%, from about 0.75% to about 7.5%, to about 45 mg, from about 0.5 to about 40 mg, from about 0.5 from about 0.75% to about 5%, from about 1% to about 10%, to about 35 mg, from about 0.5 to about 30 mg, from about 0.5 from about 1% to about 5%, from about 1% to about 2.5%, or to about 25 mg, from about 0.5 to about 20 mg, from about 0.5 from about 1% to about 2%. to about 15 mg, from about 0.5 to about 10 mg, from about 0.5 The compositions disclosed herein may contain from about 40 to about 5 mg, from about 1.0 to about 50 mg, from about 1.0 0.01 mg to about 100 mg of film former or about 0.1 mg to to about 45 mg, from about 1.0 to about 40 mg, from about 1.0 about 10 mg of film former. In some embodiments, the com to about 35 mg, from about 1.0 to about 30 mg, from about 1.0 positions disclosed herein may contain from about 0.05 to to about 25 mg, from about 1.0 to about 20 mg, from about 1.0 about 5 mg of emollient, or from about 0.1 to about 3 mg of to about 15 mg, from about 1.0 to about 10 mg, from about 1.0 film former. In some embodiments, the compositions dis- 45 to about 5 mg, from about 2.5 to about 50 mg, from about 2.5 closed herein may contain from about 0.1 to about 50 mg. to about 45 mg, from about 2.5 to about 40 mg, from about 2.5 from about 0.1 to about 45 mg, from about 0.1 to about 40 mg. to about 35 mg, from about 2.5 to about 30 mg, from about 2.5 from about 0.1 to about 35 mg, from about 0.1 to about 30 mg. to about 25 mg, from about 2.5 to about 20 mg, from about 2.5 from about 0.1 to about 25 mg, from about 0.1 to about 20 mg. to about 15 mg, from about 2.5 to about 10 mg, and from from about 0.1 to about 15 mg, from about 0.1 to about 10 mg, 50 about 2.5 to about 5 mg of occlusive. In some embodiments, from about 0.1 to about 5 mg, from about 0.5 to about 50 mg. the compositions disclosed herein will contain from about 0.1 from about 0.5 to about 45 mg, from about 0.5 to about 40 mg. mg, 0.2 mg, 0.3 mg, 0.4 mg. 0.5, mg, 0.6 mg, 0.7 mg, 0.8 mg, from about 0.5 to about 35 mg, from about 0.5 to about 30 mg. 0.9 mg, 1.0 mg, 2.0 mg, 3.0 mg. 4.0 mg, 5.0 mg, 7.0 mg, 10.0 from about 0.5 to about 25 mg, from about 0.5 to about 20 mg. mg, 15.0 mg, 20 mg, 25 mg, 30 mg. 35 mg, 40 mg, 45 mg, 50 from about 0.5 to about 15 mg, from about 0.5 to about 10 mg, 55 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg of occlusive. In from about 0.5 to about 5 mg, from about 1.0 to about 50 mg. Some embodiments, the compositions disclosed herein will from about 1.0 to about 45 mg, from about 1.0 to about 40 mg. contain from about 0.3 mg to about 0.75 mg of occlusive. from about 1.0 to about 35 mg, from about 1.0 to about 30 mg. In some embodiments, the compositions disclosed herein from about 1.0 to about 25 mg, from about 1.0 to about 20 mg. are administered twice daily, three times a day, four times a from about 1.0 to about 15 mg, from about 1.0 to about 10 mg, 60 day or more. In other embodiments, the compositions dis from about 1.0 to about 5 mg, from about 2.5 to about 50 mg. closed herein are administered once a day, once every other from about 2.5 to about 45 mg, from about 2.5 to about 40 mg. day, once every three days, once every four days, once every from about 2.5 to about 35 mg, from about 2.5 to about 30 mg. five days, once every six days, once a week, once every two from about 2.5 to about 25 mg, from about 2.5 to about 20 mg. weeks, once a month, or less frequently. In some embodi from about 2.5 to about 15 mg, from about 2.5 to about 10 mg. 65 ments, the compositions administered may be temporarily and from about 2.5 to about 5 mg of film former. In some reduced or temporarily Suspended for a certain length of time embodiments, the compositions disclosed herein will contain (i.e., a “drug holiday'). The length of the drug holiday varies US 8,236,288 B2 71 72 between 2 days and 1 year, including by way of example only, to UVB irradiation, the cells were treated with a composition 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, comprising 1% 4-ethoxybenzaldehyde, Indomethacin (posi 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 tive control) or left untreated (negative control). After 24 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 hours post-treatment, PGF2 alpha levels were measured by days, 300 days, 320 days, 350 days, and 365 days. The dose ELISA analysis. The composition comprising 4-ethoxyben reduction during a drug holiday may be from 10%-100%, including by way of example only 10%, 15%, 20%, 25%, Zaldehyde provided dose-dependent inhibition of PGF2 alpha 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, in UVB-induced cells (FIG. 1). 80%, 85%, 90%, 95%, and 100%. Dosing Effects Example 2 In other embodiments, the compositions are administered 10 in an amount to achieve a desired cosmetic effect. In some Skin Tone Clinical Study embodiments, the level of pigmentation is decreased by about 5%, by about 10%, by about 12%, by about 15%, by about Approximately 30 healthy subjects, aged 20-64 years with 17%, by about 20%, by about 25%, by about 30%, by about Fitzpatrick SkinTypes I-III, are enrolled in this single-center, 35%, by about 40%, by about 45%, by about 45%, by about 15 double-blinded comparison study. Assignments of the test 50%, by about 55%, by about 60%, by about 65%, by about product or vehicle to subjects are randomized 2:1 to avoid 70%, by about 75%, by about 80% or more. In some embodi bias. A total of approximately 15 subjects receive the test ments, the methods decrease the level of pigmentation by product and 15 subjects receive the vehicle. Subjects follow a about 5%, by about 10%, by about 20%, by about 30% or by twice-daily product application regiment for 4 weeks. No about 40%. In some embodiments, the level of pigmentation other moisturizers, lotions or products are allowed to be is increased by about 5%, by about 10%, by about 12%, by applied during the study. At the baseline visit, Subjects are about 15%, by about 17%, by about 20%, by about 25%, by graded by a dermatologist for uneven skin tone on their facial about 30%, by about 35%, by about 40%, by about 45%, by skin. Standardized digital photographs of the test site (i.e., about 45%, by about 50%, by about 55%, by about 60%, by face) are also taken. At the end of week 2, Subjects are graded about 65%, by about 70%, by about 75%, by about 80% or 25 by a dermatologist for uneven skin tone on their facial skin. O. Standardized digital photographs of the test site (i.e., face) are In some embodiments, an even skintone or pigmentation is also taken. Twice-daily application of test product continues desired, for example, in Subjects afflicted with uneven pig for another 14 days. At the end of 4 weeks, subjects are graded mentation, Such as vitiligo or uneven melanin distribution. In by a dermatologist for uneven skin tone on their facial skin. Some embodiments, the level of pigmentation is uniformly 30 Standardized digital photographs of the test site (i.e., face) are increased or decreased in localized areas to achieve an even also taken. skintone or pigmentation distribution. In some embodiments, the level of pigmentation in localized areas is decreased Example 3 towards a more uniform distribution of melanin or melano cytes by about 1%, about 2%, about 3%, about 4%, about 5%, 35 Post-Inflammatory Hyperpigmentation Clinical about 6%, by about 7%, about 7%, about 8%, about 9%, by Study about 10%, by about 12%, by about 15%, by about 17%, by about 20%, by about 25%, by about 30%, by about 35%, by UV irradiation stimulates a variety of biochemical path about 40%, by about 45%, by about 45%, by about 50%, by ways in the skin, resulting in free radical formation as well as about 55%, by about 60%, by about 65%, by about 70%, by 40 the release of inflammatory mediators. The short-term clini about 75%, by about 80% or more. In some embodiments, the cal effects observed from these pathways, include cutaneous level of pigmentation in localized areas is increased towards inflammation and erythema, while long-term effects (for a more uniform distribution of melanin or melanocytes by example, in the absence of treatment of the inflammatory about 1%, about 2%, about 3%, about 4%, about 5%, about response) result in photodamaged skin. UV irradiation may 6%, by about 7%, about 7%, about 8%, about 9%, by about 45 also cause the development of post-inflammatory hyperpig 10%, by about 12%, by about 15%, by about 17%, by about mentation since it induces an inflammatory response in the 20%, by about 25%, by about 30%, by about 35%, by about skin that can proceed to hyperpigmentation. 40%, by about 45%, by about 45%, by about 50%, by about The 17 healthy female subjects, aged 26-63 years with 55%, by about 60%, by about 65%, by about 70%, by about Fitzpatrick Skin Types III-IV, were enrolled and completed 75%, by about 80% or more. 50 this single-center, double-blinded comparison study. At base In some embodiments, levels of PGF-2alpha are decreased line, test areas were marked onto the backs of the subjects: by about 1%, about 2%, about 3%, about 4%, about 5%, about Untreated control, 1% w 4EB composition, antioxidant prod 6%, by about 7%, about 7%, about 8%, about 9%, by about uct, and other test products. Assignments of the test products 10%, by about 12%, by about 15%, by about 17%, by about to test areas were randomized to avoid site bias. The minimal 20%, by about 25%, by about 30%, by about 35%, by about 55 erythemal dose (MED) for each subject was also determined, 40%, by about 45%, by about 45%, by about 50%, by about using a solar simulator with a spectral output comparable to 55%, by about 60%, by about 65%, by about 70%, by about that of natural solar radiation (UVB: 290-320 nm, UVA: 75%, by about 80% or more. 320-400 nm). Thirty micro liters of each test product were applied to the respective test sites by the study staff, once EXAMPLES 60 daily, for 4 days. On Day 5, test sites were irradiated with 1.0, 1.5, 2.0, and 2.5 MEDs. On Day 6, standardized digital pho Example 1 tographs were taken of the test sites and test product applica tion resumed for an additional eleven days. Standardized Inhibition of Prostaglandin F2 Alpha Levels digital photographs were taken of the test sites on Day 20. The 65 images were analyzed using a computer-aided colorimetry Human keratinocytes were harvested and exposed to with algorithm, according to the CIE color standard, to determine UVB light to induce PGF2 alpha release. Following exposure a (redness) on Day 6 and L* (brightness) on Day 20. US 8,236,288 B2 73 74 Both the 1% 4EB product and the antioxidant product weight), niacinamide (2% by weight), hydroquinone (2% by provided statistically significant protection from UV-induced weight) is dissolved in propylene glycol (15 mL). The solu erythema and post-inflammatory hyperpigmentation when tion thus prepared is mixed with hydrophilic ointment, USP compared to untreated control (all P-0.01). The 1% w 4EB composition provided significantly higher protection than the grade (85gm) until a consistent cream is obtained. antioxidant product from UV-induced post-inflammatory Example 8 hyperpigmentation (all P-0.0001, FIG. 2). The results from this clinical study Suggest that topical 1% 4EB provides sig nificant protection from UV-induced post-inflammatory Topical Formulation hyperpigmentation when compared to the antioxidant prod uct. The 1% w 4EB product provided a statistically significant 10 A therapeutic composition contain 1% ethoxybenzalde reduction in hyperpigmentation (FIG. 3) and increase in skin hyde and additional active agents is formulated as follows. brightness (FIG. 4) when compared to the untreated control Ethoxybenzaldehyde (1% by weight), niacinamide (2% by sample and the other test products (all P-0.0001). weight), and kojic acid (2% by weight) are dissolved in a Results from this clinical study suggest that topical 1% mixture of ethanol (70 mL), water (10 mL) and propylene 4EB may provide significant short-term and long-term pro 15 glycol until a clear Solution is obtained. tection from UV-induced post-inflammatory hyperpigmenta tion. The results depicted in FIG. 3 from the clinical study Example 9 Suggest that topical 1% 4EB provides a statistically signifi cant reduction in hyperpigmentation when compared to the Tablet Formulation untreated control sample and the other test products (all P<0.0001). Additionally, as seen in FIG. 4, the 1% 4EB A compound of Formula I is mixed with dry gelatin binder product provided a statistically significant increase in skin and starch diluent in a 0.1:1:1 weight ratio. A lubricating brightness when compared to the other test products (all amount of magnesium Stearate is added and the mixture is P<0.0001). 25 formed into 210 mg tablets containing 10 mg of the active Example 4 substituted benzaldehyde. Topical Formulation Example 10 A mixture (Part A) of deionized water (69.30% by weight), 30 Capsule Formulation glycerin USP (3.00%), Glycereth-7 (2.50%), polyacryla mide (2.25%), and ethoxydiglycol (2.20%) was heated to 80° A compound of Formula I is admixed as a dry powder with C. A separate mixture (Part B) of glyceryl Stearate (5.00%), a starch diluent in an approximate 0.1:2 weight ratio. The jojoba oil (3.00%), isocetyl stearate (3.25%), squalane mixture is filled into 210 mg capsules (10 mg of active com (4.10%), cetyl ricinoleate (3.40%), 4-ethoxybenzaldehyde 35 pound per capsule). (1.00%), and phenoxyethanol (1.00%) was heated to 80°C. Part B was added to Part A with continuous mixing and Example 11 stirring. The combined mixture was cooled to 30° C. with continuous mixing to yield a cosmetic or pharmaceutical Transdermal Formulation composition. 40 A compound of Formula I is admixed with a polymer Example 5 matrix, a permeation enhancer and one or more other excipi ents. The formulation is place on a backing membrane. Topical Formulation 45 Example 12 Stearyl alcohol and a white petrolatum is melted at about 75° C. and then a mixture of a compound of the invention, Exemplary Topical Formulation methylparaben, propylparaben, sodium lauryl Sulfate, and propylene glycol were dissolved in water. The resulting mix An amount of 0.1-0.5% 4EB is admixed with 0.1-0.75% ture is stirred until it congeals. 50 Retinol, 2.0-8.0% Niacinamide, 1.0-5.0% Tetrahexyldecyl Ascorbate, 0.001-0.5% Licorice root extract, 0.1-3.0% Example 6 Resorcinol, and 0.1-3.0% ethyl linoleate and one or more other excipients. Topical Cream Formulation 55 Example 13 To a commercial mineral oil-water cold cream base (100 gm) is added 0.75 grams of a compound of Formula I as a fine Half-Face Study to Assess the Efficacy and powder or liquid with continuous mixing and stirring to Sus Tolerance of Four Topical Products in the Treatment pend the powder in the base and yield a cosmetic or pharma of Facial Hyperpigmentation ceutical composition. 60 1.0 Background Example 7 Hyperpigmentation is an increase in pigmentation or color of the skin that is abnormally dark. Hyperpigmentation Topical Cream Formulation occurs when an excess amount of melanin is produced. 65 Causes of hyperpigmentation include Sun exposure, certain A cream composition containing 1% ethoxybenzaldehyde medications, hormonal changes, PIH (post inflammatory is formulated as follows. 1% ethoxybenzaldehyde (1% by hyperpigmentation) or a congenital pigmentation disorder. US 8,236,288 B2 75 76 Hyperpigmentation results in uneven skin color (tone) and a randomization design. Randomization is based on a balanced photoaged appearance. Dyspigmentation is identified as an incomplete block design with n=30 (approximately) for each abnormality in the formation or distribution of pigment, espe treatment product. cially in the skin. All subjects are distributed a cleanser, moisturizer and 2.0 Purpose Sunscreen product to use throughout the study. This controlled clinical usage study will be conducted to 5.4 Instructions for Use evaluate and compare the tolerance and efficacy of four topi Sun exposure is to be avoided as much as possible. If Sun cal products designed to treat facial hyperpigmentation when exposure cannot be avoided, sunscreen SPF30 is to be re used by females with moderate to severe dyspigmentation on applied to the facial skin prior to Sun exposure. the face. 10 It is important that the LEFT designated products are only Evaluations of efficacy will be made using clinical grading, applied on the LEFT side of your face, and the RIGHT des Chroma Meter measurements, digital photography, and self ignated products are only applied on the RIGHT side of the assessment questionnaires. Tolerance will be evaluated by face. clinical grading of objective irritation, Subject assessment of 15 In the morning and evening, the face is washed with the Subjective sensations, and monitoring of adverse events and Facial Cleanser and gently patted dry. reactions. Left Facial Side: 3.0 Assessments Using your LEFT hand, apply a thin amount of Test Prod The topical treatments will produce statistically significant uct labeled LEFT onto your LEFT facial side only. Wait for improvements in clinical grading scores for efficacy param product to absorb before applying moisturizer. eters and have statistically non-significant changes objective Using your LEFT hand, apply the provided Ultra Sheer irritation assessments after 12 weeks of use compared to Moisturizer onto your LEFT facial side. baseline. Mornings only: using your LEFT hand, apply the provided 4.0 Study Endpoints All-Physical Sunscreen SPF30 to the LEFT side of face and 4.1 Primary Endpoints: 25 throughout the day as needed. Efficacy grading is conducted at baseline, week 4 week 8, Right Facial Side: and week 12. Efficacy grades is evaluated for statistical sig Using your RIGHT hand, apply a thin amount of Base nificance in: (1) changes from baseline (weeks 4, 8 and 12); Product labeled RIGHT onto your RIGHT facial side only. and (2) comparisons to the other test products (weeks 4, 8 and Wait for product to absorb before applying moisturizer. 12). 30 Using your RIGHT hand, apply the provided Ultra Sheer Chroma Meter measurements are conducted at baseline, Moisturizer onto your RIGHT facial side. week 4, week 8, and week 12. Chroma Meter measurements Mornings only: using your RIGHT hand, apply the pro are evaluated for statistical significance in: (1) changes from vided All-Physical Sunscreen SPF30 to the RIGHT side of baseline (weeks 4, 8 and 12) and (2) comparisons to the other 35 face and throughout the day as needed. test products (weeks 4, 8 and 12). Avoid contact with eyes. If contact occurs, rinse thor 4.2 Secondary Endpoints: oughly with water. If irritation or rash occurs, discontinue use Self-assessment questionnaires are conducted at baseline, and contact your doctor. week 4, week 8, and week 12. 5.6 Treatment Blinding 5.0 Test Material Information 40 The following procedures will be followed in order to 5.1 Study Identification Procedures maintain the double-blinded nature of this study and ensure Each study product(s) is assigned a unique test material appropriate evaluator blinding: identification number (TMIN) in order to provide proper The study products will be dispensed by someone other identification in records and reports. than the investigator or other evaluator(s). Additionally, the 5.2 Study Product Description(s) 45 person in charge of study product dispensation and the Subject will be instructed not to discuss the study products with the Investigator or other evaluator(s). The randomization list will be secured in a locked cabinet Product Description Code. Formula Number and/or computer file with restricted access to a data commit Test Productii1 Base + 0.5% 4EB + 0.1% Osthol 50 tee consisting of selected representatives from clinical Ser Test Productii.2 Base + 0.1% 4EB + 0.1% Osthol vices, quality assurance and the statistical department. Test Productii.3 Base -- 0.5% 4EB Subjects will not be made aware of treatment assignment. Test ProductiiA. Hydroquinone 4% Any study product that has a label indicating its identity will be covered and labeled as Test product #1, Test product The base composition contains Retinol, Niacinamide, Tet 55 #2, Test product #3 and Test product #4. rahexyldecyl Ascorbate, Licorice root extract, Resorcinol, 6.0 Subject and ethyl linoleate and a pharmaceutically/cosmetically 6.1 Number of Subjects acceptable carrier. Sixty Subjects meeting the eligibility requirements are 5.3 Method of Treatment Assignment expected to complete participation in the clinical trial. Each Subjects are numbered sequentially in the order in which 60 subject will use 2 of the 4 test materials, so that each test they qualify for entry into the study. material will be used by approximately 30 subjects. Prior to the start of the study, the biostatistics department 6.2 Informed Consent Agreement will generate a randomization list to establish treatment An IRB approved informed consent agreement, consistent assignment. Subjects are assigned to use 2 of the 4 test mate with the requirements in 21 CFR S50.25, is given to each rials according to a half-face design. One of the test materials 65 subject before the start of this study according to standard is applied to the left side of the face and another test material procedures. Subjects are ineligible to participate in this study is applied to the right side of the face, as determined by the without a signed informed consent. US 8,236,288 B2 77 78 6.3 Subject Identification 6.4 Eligibility Criteria Individuals are admitted to study at the discretion of the Subjects are assigned a three-digit number which, when Investigator or designated, and based on medical history and used in conjunction with the clinical study number, uniquely findings of the pre-study interview and examination. Indi identifies every subject on the study. This number remains s viduals are screened for the eligibility criteria listed below with the subject throughout the study and should be used in all prior to study enrollment. references to the individual in this study. No number is reas- Inclusion Criteria: a subject is eligible to participate if they signed once the study begins. meet all of the following inclusion criteria:

Females, between the ages of 30 and 65 years 2 Fitzpatrick skin type I-IV The Fitzpatrick skin classification is based on the skin's unprotected response to the first 30 to 45 minutes of Sun exposure after a winter season without Sun exposure. The categories of skin types are as follows: I. Always burns easily; never tans II. Always burns easily; tans minimally III. Burns moderately; tans gradually IV. Burns minimally: always tans well V. Rarely burns; tans profusely VI. Never burns; deeply pigmented Presence of clinically determined moderate to severe dyspigmentation on the face as determined by a score of 4-9 from the Overall Hyperpigmentation scale. Willing and able to provide informed consent and to cooperate and participate by following study requirements for the duration of the study and to report any adverse event symptoms immediately Good general health and free of any disease state or physical condition (e.g., psoriasis, moderate to severe rosacea, hirsutism, Scars, tattoos, etc.) which might impair evaluations of the test sites or increase the health risk to the subject by study participation. Willingness to cleanse the face and remove all makeup at least 20 minutes prior to each scheduled clinic visit. No other topical products should be applied to the face until the study visit has been completed. individuals who have not used systemic retinoids (e.g., Tazorac, Soriataine, Accutane, etc.) and/or any other systemic medication known to affect melasma at least 60 days prior to the study entry and will not use these products throughout the duration of the study individuals who have not used topical retinoids and/or all other topical medication (e.g., opical steroids, products containing benzoyl peroxide, alpha- or beta-hydroxy acids, hydroquinone, and/or any other OTC skin treatment medications) to the facial area known o affect melasma at least 14 days prior to study entry and will not use these products hroughout the duration of the study. Willingness to not use any other skin lightening products for the duration of the study. Subjects may continue to use regular cosmetic products (as long as they meet inclusion criteria #7 and #8), but may not begin the use of any new facial products other than the provided materials for the duration of the study. Regular use is defined as products used for a minimum of one month prior to enrollment without any incidence of irritation. 10 fSubjects are taking hormone replacement or hormones for birth control, then they must be willing not to stop or change this medication for the duration of the study. individuals who are not taking hormones at the start of the study must be willing not to start their use during the course of the study. 11 Women of childbearing potential must be willing to use a medically proven method of birth control for the duration of the study. 12 Willingness to avoid extended periods of sun exposure for the duration of the study (including tanning beds), especially from 10 AM to 2 PM. If brief (less than 20 minutes) periods of Sun exposure cannot be avoided, then subjects are asked to use an SPF 30 product and wear protective clothing prior to and during exposure. Any extended Sun exposure must be recorded on the diary. 13 Willingness to have facial exams and digital photos performed on the face.

Exclusion Criteria: a subject will not be eligible to partici pate if they meet any of the following exclusion criteria:

1 Individuals with known allergies or sensitivities to skin lightening products, retinoids, hydroquinone, Sulfites, moisturizers, or other facial products. 2 Individuals with active symptoms of allergy, active psoriasis or eczema, Sunburn, excessive scarring, tattoos, or other skin condition in the test areas that would interfere with the assessments of this study. 3 Individuals who are nursing, pregnant, or planning to become pregnant during the study. 4 Uncontrolled disease Such as diabetes, hypertension, hyper or hypo-thyroidism, active hepatitis, immune deficiency, or autoimmune disease as determined by the initial paperwork. US 8,236,288 B2 79 80 -continued 5 Individuals who have a pre-existing or dormant dermatologic condition (e.g., psoriasis, atopic dermatitis, advanced skin cancer, rosacea, acne Vulgaris, atopic dermatitis, discoid lupus erythematosus, fixed drug eruption, general drug eruption, idiopathic eruptive macular pigmentation, impetigo, vitiligo, insect bites, irritant and allergic contact and photocontact dermatitis, lichen planus, lichen simplex chronicus, morphea, pityrasis rosea, polymorphous light eruption, psoriasis, etc.) 6 Individuals who require electrolysis, waxing, or use depilatories on the face during conduct of the study. 7 Individuals who have had a facial peel or a laser treatment of the face within 60 days prior to the start of the study. 8 Subjects who participated on another facial usage study within the last 30 days, or who are currently participating on another usage study. 9 Subjects currently on or planning to participate on any type of research study at another facility or a doctors office during this study.

15 Individuals are admitted to study at the discretion of the Candidate Subjects are assigned an appointment time for Investigator or his/her designate based on medical history and visiting the clinic. findings of the pre-study interview and examination. 8.2 Visit 1: Baseline 7.0 Study Design Candidate Subjects are screened for qualifying criteria. 7.1 Description Subjects that pass the screening are assigned a screening This controlled clinical usage study is conducted to evalu number and graded for the remaining efficacy evaluations and ate and compare the efficacy and tolerance (safety) of the 4 tolerance (safety) evaluations as outlined in Sections 9.1 and test materials in improving the clinical signs of facial skin 92. hyperpigmentation. The study is conducted over the course of 25 Candidate subjects will complete an Eligibility and Health 12 weeksandwill consist of 4 visits, at baseline, week 4, week Questionnaire, a Confidentiality Agreement and a HIPAA 8, and week 12. form. Those who pass eligibility requirements are enrolled Women with clinically determined dyspigmentation of the into the study and assigned a Subject number. facial skin are recruited for this study. Subjects will use 2 of Those who qualify will be enrolled in the study and the 4 test materials according to a half-face design, as 30 assigned a subject number. assigned by a randomization schedule. Test material evalua Subjects will have Chroma Meter measurements and digi tions are conducted using clinical grading, bioinstrumenta tal photography procedures performed as described in Sec tion (Chroma Meter measurements), digital photography, and tions 9.3 and 9.4. Subjects will complete a self-assessment self-assessment questionnaires. questionnaire as described in Section 9.5. 7.2. Outline of Procedures 35 Subjects are distributed pre-weighed units of 2 of the test materials, according to a randomization design. One of the test materials is applied to the right side of the face and the other test material is applied to the left side of the face. Test Visit 1 Visit 2 Visit 3 Visit 4 Base Week Week Week material units are clearly labeled as “Left' and “Right'. Sub 40 jects are also distributed a cleanser, moisturizer and Sunscreen Procedures: line 4 8 12 to use throughout the study. Qualification screening (facial exam) X and eligibility paperwork Usage instructions are discussed with Subjects and written Clinical evaluations on the right and usage instructions are provided. Subjects are also provided left sides of the face by Expert Grader: with a calendar of study visits and a daily diary to record test 45 material application times and comments. Efficacy Parameters: overall X X 8.3 Visit 2: Week 4 and Visit 3: Week 8 hyperpigmentation, investigators global assessment, global improvement A clinician records concomitant medications and asks Sub Tolerance Parameters: objective and jects if they have experienced any changes in their health Subjective irritation (erythema, since the last visit. Scaling, burning stinging, itching, 50 tightness, tingling) Daily diaries are collected and reviewed for compliance. Chroma Meter measurements on the X X Subjects that are non-compliant are counseled that if they right and left sides of the face of a continue to be non-compliant they will be dropped from the hyperpigmented area study. New diaries are distributed as needed. Full-face Right and Left face digital X X Subjects participate in the following procedures: efficacy images (cross polarized and standard lighting) using VISIACR 55 evaluations as described in Section 9.1; tolerability evalua Subject Self-assessment Questionnaire X X tions described in Section 9.2: Chroma Meter measurements completed by Subjects regarding as described in Section 9.3; and digital photography as various skin condition parameters for described in Section 9.4. Subjects will complete a self-assess the right and left sides of the face ment questionnaire as described in section 9.5. 60 8.4 Visit 4: Week 12 8.0 Conduct of Study A clinician records concomitant medications and asks Sub 8.1 Pre-Study Procedures jects if they have experienced any changes in their health Candidate subjects are screened with the eligibility since the last visit. requirements by telephone prior to Visit 1. Daily diaries will be collected and reviewed for compli Candidate Subjects are instructed to wash their faces and 65 ance. remove all makeup at least 20 minutes prior to arrival at the Subjects participate in the following procedures: efficacy clinic of the baseline visit. evaluations as described in Section 9.1; tolerability evalua US 8,236,288 B2 81 82 tions described in Section 9.2: Chroma Meter measurements as described in Section 9.3; and digital photography as O None described in Section 9.4. Subjects will complete a self-assess 1 Mild ment questionnaire and a final product evaluation question 2 Moderate naire as described in section 9.5. 5 3 Severe 9.0 Assessments 9.1 Efficacy Evaluations 9.3 Chroma Meter Measurements At baseline, week 4 week 8, and week 12, an expert clini The Minolta Chroma Meter CR-400, in conjunction with a cal grader evaluates Subjects on the right and left sides of the 10 computer, is used to instrumentally assess skin color. The face for the following efficacy parameters using the indicated following values are recorded: grading scales (half-points may be used for all scales below to better describe a condition): 15 L* Values describe the relative brightness on a gray scale from black to white; scores increase as the skin tone becomes brighter a Values describe the color hue ranging from red to green; scores Overall Hyperpigmentation increase with vascularization or blood flow b* Values describe the color hue ranging from blue to yellow; scores None increase with the amount of melanin in the skin 1 to 3 Mild 4 to 6 Moderate 7 to 9 Severe Chroma Meter measurements are performed at baseline, week 4, week 8, and week 12. A single measurement is taken Subjects will be required to have a score of 4 to 9 for overall on the right and left sides of each subject’s face on a hyper hyperpigmentation on both sides of the face to qualify for 25 pigmented area selected by the expert grader. The location is study participation. recorded on a facial diagram to ensure consistency in mea Investigator's Global Assessment—Hyperpigmentation: Surement location at each visit. 9.4 Digital Photography

30 Digital photography using a Nikon camera (Canfield Score Rating Description VISIA-CR Camera System) is performed at baseline, week 4, week 8, and week 12, to document visible changes in facial O Clear No brown spots or areas of discoloration 1 Almost clear Overall there are a few brown spots with increased hyperpigmentation. For each Subject, a full-face image is pigmentation; they are very small in size and taken of the right and left sides of the face (2 images per only very slightly darker than Surrounding skin Subject) with standard and cross-polarized lighting/filter con Mild Several brown spots with increased pigmentation; 35 they are Small in size and slightly darker ditions. The focus revolves around the brown channel images than Surrounding skin (derived from the cross-polarized images) and the standard 3 Moderate Many brown spots with increased pigmentation; lighting photos. they are medium in size and much darker than Surrounding skin Photos taken at weeks 4, 8 and 12 are compared to the Severe Many large brown spots with increased pigmenta 40 baseline photo to ensure consistent focus, lighting, placement tion; they are large in size and markedly and color. At each photography visit, color standards are darker than Surrounding skin photographed prior to beginning each day's photography. 9.5 Self-Assessment Questionnaires Investigator's Global Improvement Assessment: At baseline, week 4 week 8, and week 12, subjects will 45 complete a self-assessment questionnaire regarding various skin condition parameters on the right and left sides of the face. Worse No Improvement 10.0 Adverse Events Mildly Improved Moderately Improved 50 10.1 Definition of an Adverse Event Markedly Improved An adverse event (AE) is any untoward medical occurrence in a clinical investigation where a subject is administered a pharmaceutical product/biologic (at any dose), OTC, cos 9.2 Tolerability Evaluations metic product or medical device and which does not neces At baseline, week 4 week 8, and week 12, the following 55 sarily require a causal relationship with a test article. An AE tolerance/safety parameters are scored on the right and left can therefore be any unfavorable and unintended sign (in sides of each subject’s face: cluding an abnormal laboratory finding, for example), Symp tom or disease temporally associated with the use of a medici 60 nal product whether or not considered related to the medicinal Objective parameters (clinically erythema, Scaling product. Adverse events will be recorded on the appropriate graded) case report forms and source documents. Subjective parameters (assessed by burning? stinging, itching, Subjects) tightness, tingling 10.2 Assessment of Severity and Relationship The investigator or his medical staff will evaluate all 65 adverse events as to their severity and relation to the test Results of the tolerance assessments will be recorded using article. The severity of adverse events will be graded as fol the following scale (with half-point scores used as necessary): lows: US 8,236,288 B2 83 84 10.5 Procedures for Reporting Serious Adverse Events Any serious adverse event that occurs during the study Mild: Awareness of a sign or symptom but easily tolerated Moderate: Discomfort sufficient to cause interference with usual whether related to the treatment or not, expected or not, is activity or to affect clinical status reported. Severe: Incapacitating with inability to do usual activity or to 10.6 Unanticipated Adverse Events significantly affect clinical status Unanticipated adverse effect is defined as any serious adverse effect on health or safety, any life-threatening prob Assessment of Causality: the Investigator and/or trained lem or death caused by, or associated with, the test article if staff member will also assess the relationship of any adverse that effect, problem, or death was not previously identified in event to the use of the study article, based upon available 10 nature, severity, or degree of incidence in the application; or information, using the following guidelines: any other unanticipated serious problem associated with the test article that relates to the rights, safety, or welfare of Subjects. O Unlikely No temporal association, or the cause of the eventhas 15 10.7 Anticipated Reactions been identified, or the test article cannot be implicated The test material when applied to the face may produce 1 Possible Temporal association, but other etiologies are likely to be mild to moderate, transient erythema, dryness, burning, sting the cause; however, involvement of the test article cannot be excluded ing and/or itching. The responses discussed above will not be 2 Probable Temporal association, other etiologies are possible, but treated as adverse reactions. These conditions may or may not not likely resolve overtime. Symptoms that are persistent and moderate 3 Definite Clear-cut temporal association to severe in nature, or that involve elevation (e.g., edema, papules, Vesicles, spreading) are considered adverse events 10.3 Definition of a Serious Adverse Event (SAE) (AEs). A serious adverse event is any experience or reaction 11.0 Biostatistics and Data Management occurring at any dose that results in any of the following 25 Statistical Analysis outcomes: death, is life threatening, inpatient hospitalization The per protocol (PP) population is the primary population or prolongation of hospitalization, a persistent or significant for efficacy and tolerance testing. The PP population includes disability/incapacity, or a congenital anomaly/birth defect. all subjects who were randomized and completed all study Important medical events that may not result in death, be procedures. Clinical grading scores and Chroma Meter mea life-threatening, or require hospitalization may be considered 30 Surement values at week 4 week 8, and week 12 are compared a serious adverse event when, based upon appropriate medi to baseline scores/values using a paired t-test. The average cal judgment, they may jeopardize the patient or subject and percent change from baseline is calculated for all parameters may require medical or Surgical intervention to prevent one of at each post-baseline time point. Comparisons among the the outcomes listed in this definition. The term “life-threat 35 three test materials are performed using analysis of variance ening refers to an event in which the subject was at risk of (ANOVA) with paired comparisons using Fisher's Least Sig death at the time of event; it does not refer to an event that nificant Difference (LSD). All differences are considered to hypothetically might have caused death if it was more severe. be statistically significant at the p-0.05 level. Hospitalization solely for the purpose of diagnostic tests, Subject Self-assessment questionnaires regarding skin even if related to an adverse event, elective hospitalization for 40 condition parameters completed by Subjects at all visits are an intervention which was already planned before the inclu analyzed using descriptive statistics presenting the percent sion of the Subject in the study, and admission to a day-care ages for each question. facility may not themselves constitute sufficient grounds to be Data Management considered as a serious adverse event. Hospitalization is Clinical grading and Chroma Meter measurements are per defined as being admitted to a hospital as an in-patient for 45 formed using electronic data capture system (EDC) which greater than 24 hours. documents the identity of the evaluator as well as the time and 10.4 Procedures for Reporting Adverse Events date of all entries, or all corrected entries. At each visit, the Subjects are questioned about adverse The electronic data capture system (EDC) is a computer events using an open question (e.g., "Have you noticed any ized system designed for the collection of clinical data in change in your health since the last visit?”). 50 electronic format. The 3 major aspects of EDC are a graphical Directed questioning and examination will be performed when appropriate. All reported adverse events are docu user interface for data entry, a validation component to check mented on the appropriate forms without omitting any for user data and a reporting tool for analysis of the collected requested and known information. Every time a concomitant data. Statistical analyses are performed using SAS Software therapy is reported during the study, an Adverse Event Form 55 version 9 series (SAS Statistical Institute). will be completed if appropriate and the reason for the treat The self-assessment questionnaires are completed by Sub ment noted. jects electronically using HIPAA compliant Zoomerang When an adverse event persists at the end of the study, the online survey software. investigator conducts a follow-up of the subject until the event Data review and analyses is performed by an independent is satisfactorily resolved. 60 data committee. The data committee will consist of selected All adverse events are recorded by the Investigator onto the representatives from clinical services, quality assurance and Adverse Event page of the Source documents describing the the statistical department. adverse event, onset and stop date, severity, opinion of cau 12.0 Results sality, the course of action taken, if any, as well as any perti FIGS. 7, 8 and 9 provide the results from this study. Over nent data necessary to allow a complete evaluation of the 65 all, 4% hydriguinone and Base+0.5% 4EB both significantly adverse event. For serious adverse events, an additional report reduced hyperpigmentation compared to baseline for every (SAE Report Form) is completed. time point (See FIG. 7). US 8,236,288 B2 85 86 FIG. 8 illustrates the overall level of hyperpigmentation as the natural solar spectrum (UVB: 290-320 nm and UVA: a change from baseline. Sites treated with 4% hydriduinone 320-400 nm). The artificial light source used complies with and Base--0.5% 4EB demonstrated comparable distribution the Source spectral specifications as described in published of results in individuals. testing guidelines. UV irradiation is performed with a single FIG. 9 provides the results of the patient self-assessment port solar simulator (Model 16S, Solar UV Simulator, Solar questionnaires. Better subject preference was observed with Light Co., Philadelphia) with a 150 watt xenon arc lamp. treatment with Base--0.5% 4EB than with 4% Hydroquinone. UVB+UVA radiation is obtained by using a combination of the UG-1 1/1 mm and WG-320 filters (Schott Glass Technolo Example 14 gies) that are placed in the radiation path of the Solar simula 10 tOr. An Open Application Trial Evaluating the Efficacy An adjustable patient stop is used to keep the distance from of Six Topical Whitening Formulations to UVR Solar simulator to the radiated Surface constant. At a distance Induced Tanning of approximately 6.5 cm from the lamp housing, the radiated surface is exposed to a 1.0 cm diameter spot of UVA/UVB 1.0 Background 15 light. Exposures are performed by varying the time of expo The following example examines acute exposure to ultra Sure (in seconds) while keeping the energy level constant. violet radiation (UVR) stimulates melanogensis resulting in Opening and closing of the light shutter is performed manu skin darkening, or hyperpigmentation. ally. The radiation output of the Xenon bulb is measured using 2.0 Purpose the 3D-600 meter (Solar Light Co.). If a different radiometer This study evaluates the effectiveness of six (6) test mate is used for determination of radiation output, then a descrip rials to reduce UV-induced tanning (hyper pigmentation) tion of the model and accessories is included in the report. The after receiving varying doses of UVR using a post-exposure Xenon arc lamp is ignited and left on for at least 10 minutes regimen. prior to use in the study. Measurements are taken after lamp 3.0 Assessment 25 warm-up. The topical formulations being tested will protect human 5.4 Product Application skin from the harmful effects of ultraviolet (UV) radiation Thirty (30) microliters (ul) of each test material is applied compared to an untreated site as measured by changes in to designated sites using an open application technique with colorimetry (“L* and b values, or degree of tanning accord rubbing. ing to the International Commission on Illumination (CIE) 30 One irradiated, untreated site does not receive product color standard). application. 4.0 Endpoints 6.0 Subject Enrollment Primary Endpoint: Significant changes in L* values com Number of Subjects pared to the untreated area Fifteen (15) subjects meeting the eligibility requirements Secondary Endpoint: Significant changes in b values 35 are expected to complete participation in the clinical trial. compared to untreated area, Informed Consent Agreement 5.0 Test Material Information An informed consent agreement, consistent with the 5.1 Study Identification Procedures requirements in 21 CFR S50.25, is given to each subject Each study product(s) is assigned a unique test material before the start of this study according to standard proce identification number (TMIN) in order to provide proper 40 dures. identification in records and reports. Subject Identification 5.2 Study Product Description(s) Subjects are assigned a three-digit number which, when used in conjunction with the clinical study number, uniquely identifies every subject on the study. This number remains 45 with the subject throughout the study and is used in all refer Product Description ences to the individual in this study. No number is reassigned Test Product #1 Base once the study begins. Test Product #2 Base - 1% 4EB Eligibility Criteria Test Product #3 Base -- 0.5% 4EB Test Product #4 Base - 1% 4EB - O.2% DSE Individuals are admitted to study at the discretion of an extract 50 Investigator or designated, and based on medical history and Test Product #5 Base + 1% 4EB + 0.1% Osthol findings of the pre-study interview and examination. Indi Test Product #6 4% hydroquinone viduals are screened for the eligibility criteria listed below prior to study enrollment. The base composition contains Retinol, Niacinamide, Tet rahexyldecyl Ascorbate, Licorice root extract, Resorcinol, 55 and ethyl linoleate and a pharmaceutically/cosmetically acceptable carrier. Inclusion Criteria 5.3 Method of Treatment Assignment 1 Age: 18 years or older 2 Gender: Male or female Subjects are numbered sequentially in the order in which 3 Fitzpatrick skin type III they qualify for entry into the study. 60 The Fitzpatrick skin classification is based on the unprotected Prior to the start of the study, the biostatistics department response of the skin to the first 30 to 45 minutes of sun exposure generates a randomization based on a site rotational basis to after a winter season without Sun exposure. The categories of skin types are as follows: avoid skin site bias. The irradiated, untreated site is to be I. Always burns easily; never tans included in the randomization assignment. II. Always burns easily; tans minimally UV Radiation 65 III. Burns moderately; tans gradually UV radiation is supplied by an artificial source, which has IV. Burns minimally: always tans well a spectral output in the ultraviolet range comparable to that of US 8,236,288 B2 87 88 -continued Individuals are admitted to the study at the discretion of the Investigators based on medical history and findings of the Inclusion Criteria pre-study interview and examination. Each subject is expected to complete the full course of the study. V. Rarely burns; tans profusely 7.0 Study Design VI. Never burns; deeply pigmented Description General good health as determined by review of the health This open application clinical study is conducted to evalu and eligibility questionnaire. ate the effectiveness of six (6) test materials to suppress the Willingness to cooperate and participate by following study 10 development of skin pigmentation after receiving varying requirements for the duration of the study and to report any doses of UVR using a pre-exposure/post-exposure regimen. adverse symptoms immediately. Procedures are conducted as outlined in the table of proce dures. Outline of Procedures

Visits 3, 7, 10, 13, 15, Visits Visit 1 Visit 2 Off 18, 21, 24, 27 3-26 Day Day Days 3-7, 14, Days 8, 12, 16, 19, Days 8-13, 15-20, Visit 27 2 21, 28 and 35 22, 25, 29, 32,36 22–27, 29-34 Day 36 Paperwork and X Screening MED X Determination Grade MED 1.0, 1.5, 2.0 and 2.5 MED Exposure Test Material Application Chromameter Photography Photography and Chromameter is done prior to test material application.

8.0 Conduct of Study 35 8.1 Visit 1: Baseline: Day 1 Exclusion Criteria Individuals are given an informed consent (IC) document to read. They have all of their study related questions (ndividuals with Fitzpatrick skin types I, II, IV, V and VI. answered by the Investigator or his/her designated staff and if individuals that have been instructed by a physician, pharma they agree, they sign two copies of the IC. cist, or health professional to avoid Sunlight because of a 40 Subjects complete a health and eligibility questionnaire, a medical condition and/or because of drug contraindications confidentiality agreement-photographic release form, and a (see exclusion #10). HIPAA release form. individuals with known abnormal responses to Sunlight or The Investigator or his/her designated staff examine the UVR ligh SOUCES. individuals with a known allergy to any ingredient in a back (test site area) for evenness of skintone (Fitzpatrick skin personal care product. 45 type III only) and to ensure the lack of uneven Suntan, Sun individuals with known atopic skin diseases or neuro burn, Scars, birthmarks, moles, vitiligo, keloids, skin abnor dermatitis. malities, or any other dermal markings. Women known to be pregnant, nursing, or planning to Eligible individuals are enrolled into the study and become pregnant within 6 months. assigned a subject number. (ndividuals known to be treated for cancer or have a history 50 Subjects receive 5-7 irradiation exposures expressed as of cancer. J/sq cm (adjusted to the erythema action spectrum) on adja individuals with observable Sunburn, Suntan, Scars, uneven one pigmentation, nevi or other dermal conditions on the test cent unprotected skin sites on the lower back. Each exposure areas that might influence the test results. represents a 25% increase in energy over the previous expo Any disease or condition that the examining Investigator SUC. deems inappropriate for participation (e.g., uncontrolled high 55 Seven (7) 3.0 cmx5.0 cm areas are marked on the lower blood pressure, individuals with dermal hypersensitivity back. requiring treatments with medications in exclusion #10, etc.). 8.2 Visit 2: Day 2 10 individuals taking medication(s) which in the opinion of the 1. Test sites from Visit 1 are examined using either a tung nvestigator, would interfere with the Subject's participation sten or warm white fluorescent light that provides 450 to 550 on the study. Such medications include (but are not limited 60 lux of illumination. o) antihypertensive agents (hydrochorothiazide, furosemide, meticrane), ataractics (e.g., periphenazine), 2. Sites are scored for erythema using the scale outlined in psychotropic agents (e.g., chlorpromazine), antihistamines section 9.1 for MED Determination. (e.g., promethazine hydrochloride), oral hypoglycemic agents 3. Using the determined MED value, UVR exposures are (e.g., tolubutamide, chlorpropamide), and tetracycline calculated. The amount of UVR delivered to each subjects antibiotics (e.g., dimethylchloroteteacycline, tetracycline). 65 test sites depends on this value. 4. Each area is exposed to UVR in doses of 1.0x, 1.5x and 2.0x and 2.5x the previously determined MED. US 8,236,288 B2 89 90 5. Subjects have a rest period of 5 days while tanning 10.2 Assessment of Severity and Relationship develops at the irradiated sites. Subjects resume study proce The investigator or his/her medical staff evaluates all dures on Day 8. adverse events as to their severity and relation to the test 8.3 Visits 3, 7, 10, 13, 15, 18, 21 & 24: Days 8, 12, 16, 19, article. The severity of adverse events is graded as follows: 22, 25, 29 & 32 5 Digital photography will be conducted as outlined in sec tion 9.3 Chromameter measurements will be conducted as outlined Mild Awareness of a sign or symptom but easily tolerated in section 9.2 Moderate Discomfort sufficient to cause interference with usual activity or to affect clinical status Test Materials are applied as outlined in Section 5.4. A 10 Severe Incapacitating with inability to do usual activity or to seventh site serves as an irradiated untreated control. significantly affect clinical status 8.4 Visits 4-6, 8, 9, 11, 12, 14, 16, 17, 19, 20, 22, 23, 25 & 26: Days 9-11, 13, 15, 17, 18, 20, 23, 24, 26, 27, 30, 31, 33 & The Investigator and/or trained Staff member also assesses 34 the relationship of any adverse event to the use of the study Test Materials will be applied as outlined in Section 5.4. A 15 seventh site will serve as an irradiated untreated control. article, based upon available information, using the following 8.5 Visit 27: Day 36 guidelines: Digital photography are conducted as outlined in section 9.3 and chromameter measurements are conducted as out lined in section 9.2 O Unlikely No temporal association, or the cause of the eventhas 9.0 Assessments been identified, or the test article cannot be implicated 9.1 MED Determination Scoring 1 Possible Temporal association, but other etiologies are likely to be the cause; however, involvement of the test article cannot be excluded 2 Probable Temporal association, other etiologies 25 are possible, but not likely no visible erythema 3 Definite Clear-cut temporal association questionable response; unclear -- erythema, extending to the borders ---- erythema, with or without edema 10.3 Definition of a Serious Adverse Event (SAE) present A serious adverse event is any experience or reaction 30 occurring at any dose that results in any of the following The site receiving the lowest dose of combined UV that outcomes: death; is life threatening; inpatient hospitalization produced mild redness reaching the borders of the site will or prolongation of hospitalization; a persistent or significant receive a score of +, and will be recorded as the MED (US) for disability/incapacity; or a congenital anomaly/birth defect. that subject. Important medical events that may not result in death, be Each subject's MED may be different, but will likely be 35 life-threatening, or require hospitalization may be considered approximately 70 m.J/cm2. The intensity of UVR delivered to a serious adverse event when, based upon appropriate medi each subject's test sites depends on this value. cal judgment, they may jeopardize the patient or subject and 9.2 Chromameter Measurements may require medical or Surgical intervention to prevent one of The Minolta Chroma Meter CR-400, in conjunction with a the outcomes listed in this definition. The term “life-threat computer, is used to assess skin color. L* values describe the 40 ening” refers to an event in which the subject was at risk of relative brightness on a gray Scale from black to white, and death at the time of event; it does not refer to an event that scores increase as the skin tone becomes brighter/lighter. b hypothetically might have caused death if it was more severe. values describe the color hue ranging from blue to yellow and Hospitalization solely for the purpose of diagnostic tests, scores increase with the amount of melanin in the skin. One even if related to an adverse event, elective hospitalization for measurement is taken at each of the six treated sites and the 45 an intervention which was already planned before the inclu untreated irradiated control site. sion of the Subject in the study, and admission to a day-care 9.3 Imaging Procedures facility may not themselves constitute Sufficient grounds to be Digital photography is performed on the six treated sites considered as a serious adverse event. Hospitalization is and the untreated irradiated control site using a Nikon D300 defined as being admitted to a hospital as an in-patient for camera and Micro Nikkor lens. Test and control sites are 50 greater than 24 hours. clearly labeled for each individual, and color standards are 10.4 Procedures for Reporting Adverse Events visible in each Subject's photograph. Images are saved as raw At each visit, the Subject is questioned about adverse events data (NEF files) and also as JPEG files, arranged by subject. using an open question (e.g., "Have you noticed any change in Photographs are analyzed for colorimetry using Image Pro your health since the last visit?). Analysis software. 55 Directed questioning and examination is performed when 10.0 Adverse Events appropriate. All reported adverse events are documented on 10.1 Definition of an Adverse Event the appropriate forms without omitting any requested and Anadverse event (AE) is any untoward medical occurrence known information. in a clinical investigation where a subject is administered a Every time a concomitant therapy is reported during the pharmaceutical product/biologic (at any dose), OTC, cos 60 study, an Adverse Event Form is completed if appropriate and metic product or medical device and which does not neces the reason for the treatment noted. sarily require a causal relationship with a test article. An AE When an adverse event persists at the end of the study, can therefore be any unfavorable and unintended sign (in follow-up of the subject is conducted until the event is satis cluding an abnormal laboratory finding, for example), Symp factorily resolved. tom or disease temporally associated with the use of a medici 65 10.5 Unanticipated Adverse Events nal product whether or not considered related to the medicinal Unanticipated adverse effect is defined as any serious product. adverse effect on health or safety, any life-threatening prob US 8,236,288 B2 91 92 lem or death caused by, or associated with, the test article if The “L*and b' colorimeter values are expected to be dif that effect, problem, or death was not previously identified in ferent between the test material-treated and untreated, irradi nature, severity, or degree of incidence in the application; or ated area. Since each patient will serve as his own control, any other unanticipated serious problem associated with the p-values will be determined by the two-tailed Student t-test. test article that relates to the rights, safety, or welfare of 5 Subjects. 10.6 Anticipated Reactions APPENDIX 2 The test material when applied to the skin may produce mild irritation Such as erythema, tanning, Scaling/dryness, Exemplary Study Calendar

SUNDAY MONDAY TUESDAY WEDNESDAY THURSDAY FRIDAY SATURDAY

17 8 9 20 D3 OFF 21 D 4 OFF 22 D 5 OFF 23 D6 OFF W1. D 1 V2D 2 O:OO-12:00 O:OO-1:00 4:30-6:00 4:00-6:00 Paperwork rradiation MED 24D 7 OFF 25 26 27 28 29 30 V3.D 8 V4,D 9 VSD 10 V6 D 11 V7D 12 V8,D 13 1:OO-1:00 1:30-12:30 1:30-12:30 1:30-12:30 1:OO-1:00 10:OO-12:OO 4:30-6:00 5:00-6:00 5:00-6:00 5:00-6:00 4:30-6:00 Product App Photos Chromameter Product App Product App Product App Photos Chromameter Product App Product App 1D 14 OFF 2 3 4 5 6 7 V9,D 15 V1 OiD 16 V11. D 17 V12AD 18 W13.D. 19 W14;D 20 1:30-12:30 1:OO-1:00 1:30-12:30 1:30-12:30 1:OO-1:00 10:OO-12:OO 5:00-6:00 4:30-6:00 5:00-6:00 5:00-6:00 4:30-6:00 Product App Product App Photos Chromameter Product App Product App Photos Chromameter Product App Product App 8D 21 OFF 9 O 1 2 3 14 V15/D 22 W16AD 23 W17AD 24 V18.D 25 W19,D 26 V2O.D 27 1:OO-1:00 1:30-12:30 1:30-12:30 1:00-1:00 1:30-12:30 10:OO-12:OO 4:30-6:00 5:00-6:00 5:00-6:00 4:30-6:00 5:00-6:00 Product App Photos Chromameter Product App Product App Photos Chromameter Product App Product App Product App 15D 28 OFF 6 7 8 9 2O 21 V21AD 29 W22AD 30 V23.D 31 V24;D32 V25. D 33 W26.D 34 1:OO-1:00 1:30-12:30 1:30-12:30 1:00-1:00 1:30-12:30 10:OO-12:OO 4:30-6:00 5:00-6:00 5:00-6:00 4:30-6:00 5:00-6:00 Product App Photos Chromameter Product App Product App Photos Chromameter Product App Product App Product App 22 D35 OFF 23 24 25 26 27 28 V27, D36 1:OO-1:00 4:30-6:00 Photos Chromameter burning and/or stinging at the test site or Surrounding the test 12.0 Results sites. The responses discussed above will not be treated as 45 An increase in brightness of UV-induced pigmentation was adverse reactions. If sites begin to show mild levels of observed in patient sites treated with Base+0.5% 4EB com erythema, then product applications may be skipped as pared to 4% hydroquinone (See FIG. 6). needed in order to avoid redness, which would interfere in the Example 15 assessment of product efficacy. The UV exposure will create Sunburn and possible discomfort. Hypo- or hyperpigmenta 50 MelanoDerm Model tion may occur at the skin sites, and the skin may show irritation where test material or vehicle is applied. These The following example provides a validated model for conditions may or may not resolve over time. Symptoms that melanin production using human skin equivalent. are persistent and moderate to severe in nature, or that involve Melanogenesis study: The melanoderm tissues (MEL elevation (e.g., edema, papules, vesicles, spreading) will be 55 300B) were obtained from Mattek Corporation and cultured for 14 days at specified conditions. The tissues were treated considered adverse events (AEs). with 15ul of formulations or with 25ul of positive (1% Kojic acid solution) and negative (DI water) controls every other 11.0 Biostatistics and Data Management day during this period. Tissues were taken out in between this Digital photographs will be taken of the entire treatment 60 period at specific days and fixed for histological imaging, and control areas under standardized conditions. Images will light microscopy or for melanin quantification. be analyzed via a computer-aided colorimetry algorithm to As seen in FIG. 6, Base+1% 4EB was more effective than determine L values and b values. The L values of the Kojic Acid in reducing the melanin content of the skin equiva lent. treated areas and untreated areas from the images and Chro 65 While preferred embodiments have been shown and mameter measurements will be compared to provide a “Skin described herein, it will be obvious to those skilled in the art Lightening Factor.” that such embodiments are provided by way of example only. US 8,236,288 B2 93 94 Numerous variations, changes, and Substitutions will now 5. The method of claim 1, wherein the pharmaceutically or occur to those skilled in the art without departing from the cosmetically acceptable topical carrier is a water-in-oil emul embodiments. It should be understood that various alterna Sion, cream, liquid, gel, oil, paste, ointment, Suspension, tives to the embodiments described herein may be employed foam, lotion, oil-in-water emulsion, water-in-oil-in-water emulsion, water-in-silicone emulsion, spray or serum carrier. in practicing the embodiments. It is intended that the follow 6. The method of claim 1, wherein the composition further ing claims define the scope of the embodiments and that comprises one or more additional active agents. methods and structures within the scope of these claims and 7. The method of claim 6, wherein the additional active their equivalents be covered thereby. agent is an antioxidant, a Sunscreen, a Sunprotectant, a Sun block, a skin-lightening agent, an anti-inflammatory agent, an What is claimed: 10 anti-acne agent or mixtures thereof. 8. The method of claim 7, wherein the antioxidant is 1. A method of lightening skin in an individual in need selected from the group of vitamin E. Coenzyme Q10, ide thereof, comprising administering to the individual in need benone, lycopene, green tea polyphenols, Silybin, resveratrol, thereof an effective amount of a composition comprising: a grape seed extract, Oregon grape root (Mahonia aquifolium) skin-lightening effective amount of a substituted benzalde 15 extract, pomegranate extract, genistein, pycnogenol, cur hyde of from about 0.1% to about 0.5% 4-ethoxybenzalde cumin, curcuminoids, tocopherol, dunaliella salina extract or hyde, from about 0.01% to about 5.0% each of retinol, niaci combinations thereof. namide, tetrahexyldecyl ascorbate, glycyrrhiza glabra 9. The method of claim 7, wherein the skin-lightening (licorice) root extract, hexyl resorcinol, and ethyl linoleate, agent is selected from the group of hydroquinone, monoben and a pharmaceutically or cosmetically acceptable carrier. Zyl ether of hydroquinone, azelaic acid, kojic acid, meduinol, 2. The method of claim 1, wherein the substituted benzal retinoids, soy proteins, alpha-hydroxy acids, trichloroacetic dehyde composition reduces melanin distribution from about acid, salicylic acid, hydroquinone-beta-D-glucopyranoside, 10% to about 40%. paper mulberry, glabridin, 4-isopropylcetichol, aleosin, 3. The method of claim 1, wherein the composition is N-acetyl-4-S-cycteaminylphenol, N-propionyl-4-S-cys topically or transdermally administered to the skin of the 25 teaminylphenol, N-acetyl glucosamine, tranexaminc acid, individual. undecylenoyl phenylalanine, an alpha melanocyte stimulat 4. The method of claim 1, wherein the pharmaceutically or ing hormone antagonist, phytic acid, or combinations thereof. cosmetically acceptable carrier is a topical carrier. k k k k k