US008778315B2

(12) United States Patent (10) Patent No.: US 8,778,315 B2 Mehta et al. (45) Date of Patent: Jul. 15, 2014

(54) MELANIN MODIFICATION COMPOSITIONS (56) References Cited AND METHODS OF USE U.S. PATENT DOCUMENTS (71) Applicant: Allergan, Inc., Irvine, CA (US) 3,598,122 A 8, 1971 Zaffaroni 3,598,123 A 8, 1971 Zaffaroni (72) Inventors: Rahul C. Mehta, San Marcos, CA (US); 3,710,795 A 1/1973 Higuchi et al. Elizabeth Tsin Ho Makino, Carlsbad, 3,731,683 A 5, 1973 Zaffaroni 3,742,951 A 7, 1973 Zaffaroni CA (US); Sujatha D. Sonti, San Marcos, 3,814,097 A 6, 1974 Ganderton et al. CA (US); John A. Garruto, Encinitas, 3,845,138 A 10/1974 Dunlop et al. CA (US) 3,921,636 A 11/1975 Zaffaroni 3,972.995 A 8, 1976 Tsuk et al. (73) Assignee: Allergan, Inc., Irvine, CA (US) 3,993,072 A 11/1976 Zaffaroni 3,993,073. A 11/1976 Zaffaroni 3.996,934 A 12/1976 Zaffaroni (*) Notice: Subject to any disclaimer, the term of this 4,126,695 A 11/1978 Razdan et al. patent is extended or adjusted under 35 4,147,770 A 4, 1979 Sichak U.S.C. 154(b) by 34 days. 4,202,877 A 5/1980 Sato et al. 4,290,974 A 9, 1981 Boillon et al. 4,391,603 A 7/1983 Rosenbaum et al. (21) Appl. No.: 13/777.552 4,654,167 A 3/1987 Degner et al. 4,668,712 A 5, 1987 Hino et al. (22) Filed: Feb. 26, 2013 4,714,609 A 12/1987 Carden 4,714,786 A 12/1987 Wuest et al. (65) Prior Publication Data 4,802,924 A 2f1989 Woznicki et al. 4,857,328 A 8, 1989 Trenzeluk US 2013/O177511 A1 Jul. 11, 2013 4,992.445 A 2f1991 Lawter et al. 4,997,850 A 3, 1991 Kimura et al. 5,001,139 A 3, 1991 Lawter et al. Related U.S. Application Data (Continued) (60) Division of application No. 13/532,289, filed on Jun. 25, 2012, which is a continuation of application No. FOREIGN PATENT DOCUMENTS 13/345,560, filed on Jan. 6, 2012, now Pat. No. DE 3214658 A1 11F1982 8,236,288. EP O022229 A1 1, 1981 (60) Provisional application No. 61/430.923, filed on Jan. (Continued) 7, 2011. OTHER PUBLICATIONS Arnold et al. “Evaluation of chemotherapeutic agents in different (51) Int. Cl. mechanistic classes using a rattracheal epithelial cell culture trans A6 IK 8/00 (2006.01) formation assay.” Cancer Res. 55:537, 1995. A6 IK 8/18 (2006.01) Batt DG et al. “2-substituted-1-naphtols as potent 5-lipoxygenase A61O 1704 (2006.01) inhibitors with topical antiinflammatory activity.” J Med Chem A6 IK 8/35 (2006.01) 33:360-70, 1990. A6 IK3I/07 (2006.01) Burton DE et al. “The mechanism of the antibacterial activity of A6 IK3 L/047 (2006.01) phenols and salicylaldehydes. III. Substituted benzaldehydes,” J A6 IK3I/445 (2006.01) ChemSoc. 2458-60, 1964. A6 IK 36/484 (2006.01) (Continued) A61O 19/02 (2006.01) A 6LX8/97 (2006.01) Primary Examiner — Mina Haghighatian A6 IK 8/33 (2006.01) Assistant Examiner — Luke Karpinski A 6LX3L/375 (2006.01) (74) Attorney, Agent, or Firm — Stephen Donovan A6 IK3I/22 (2006.01) (57) ABSTRACT A6 IK 8/67 (2006.01) A method for the modification of melanin distribution, and A6 IK 8/49 (2006.01) the composition thereof to modify melanin distribution are (52) U.S. Cl. disclosed. A method for the reduction of melanin distribution, CPC ...... A61K 8/33 (2013.01); A61 K 2800/92 and the composition thereof to reduce melanin distribution (2013.01); A61K 8/35 (2013.01); A61 K3I/07 are disclosed. A representative composition comprises (2013.01); A61 K3I/047 (2013.01); A61 K 4-ethoxybenzaldehyde and one or more additional active 31/445 (2013.01); A61K 36/484 (2013.01); agents as well as a pharmaceutically acceptable carrier or A61O 19/02 (2013.01); A61 K8/97 (2013.01); excipient. Carriers and excipients may beformulated for topi A6 IK3I/375 (2013.01); A61 K3I/122 cal administration. Compositions may also be formulated for (2013.01); A61K 8/671 (2013.01); A61 K transdermal administration. The compositions may be used 8/4926 (2013.01) for the prevention and treatment of pigmentation disorders, USPC ...... 424/59: 424/400 by way of non-limited example, post-inflammatory hyperpig (58) Field of Classification Search mentation and others. The compositions may be used for USPC ...... 424/59 lightening skin. See application file for complete search history. 7 Claims, 9 Drawing Sheets US 8,778,315 B2 Page 2

(56) References Cited WO 97-4728O 12/1997 WO 99-03446 1, 1999 U.S. PATENT DOCUMENTS WO 99-06388 2, 1999 WO 99-07336 2, 1999 5,023,252 A 6/1991 Hsieh WO 99-22703 5, 1999 5,100,654. A 3/1992 Pawelek et al. WO 00-38653 T 2000 5,217,709 A 6/1993 Lagrange et al. WO OO-74697 12/2000 5,508,310 A 4, 1996 Rhodes WO O1-341.06 A1 5.2001 5,601,838 A 2/1997 Hind WO O1-76626 10, 2001 5,614, 179 A 3/1997 Murphy et al. WO 02-083624 A1 10, 2002 5,626,852 A 5, 1997 Sufis WO O3-000214 A1 1, 2003 5,656,638 A 8/1997 Gaeta et al. WO 2004-103233 12, 2004 5,668,182 A 9/1997 Abraham et al. WO 2008-070368 6, 2008 5,733,53573; AR 3, 1998368 HollingsheadE. et al. OTHER PUBLICATIONS 5,760,085 A 6, 1998 Becket al. Chang et al. “Benzyloxybenzaldehyde analogues as novel adenyl 5,766,575 A 6/1998 Crotty et al. cyclase activators.” Bioorg Med Chem Lett 11:1871-1974, 2001. 5,968.484. A 10/1999 Habeck et al. Chen et al. “Effects of IHT64-3 on chemotactic migration of 6,046,232 A 42000 Kelleher et al. neutrophils induced by rhIL-8.” Chin J Pathophys 15:781, 1999. 6,086,903. A 7/2000 Trinh et al. English Abstract. 6,126,930 A 10, 2000 DuBois et al. 6,146,650 A 1 1/2000 Redlinger PCTUS2012/020550 International Search Report and Written Opin 6,204.229 B1 3/2001 Hasegawa ion dated May 14, 2012. 6.214.879 B1 4/2001 Abraham Clericietal. “In vitro immunomodulatory properties of Tucaresol in 6,248.763 B1 6, 2001 Scivoletto HIV infection. Clin Immunol 97:211, 2000. 6,258,852 B1 7/2001 Flitter et al. Farah et al. “Pharmacologically active prenylpropanoids from Senra 6,264,927 B1 7/2001 Monahan incana. Planta Medica 58:14-18, 1992. 6,284.234 B1 9, 2001 Niemiec et al. Felton et al. “New class of broad spectrum antibacterials' TGA 6,403,063 B1 6/2002 Sawyer Cosmetic J 2:16-19, 1970. 6,475,526 B1 1 1/2002 Smith Glenn "Anomalous biological effects of salicylates and 6,482,839 B1 1 1/2002 Thornfeldt prostaglandins.” Agents Actions 9:257, 1979. 6,673,844 B2 1/2004 Kumamoto et al. Inaoka et al. “Stud hai with ti bst from th 2003/010391.6 A1 6/2003 Imanaka et al. yonnair regrown promoting substances Iromine 2003/O1241.57 A1 7/2003 Engles et al. potent herbs, especially Polyporus umbellatus F.” Tennen Yuki 2003. O1571.54 A1 8, 2003 Fuller et al. Kagobutsu Toronkai Koen Yoshishu 36:32, 1994. English Abstract. 2004/025.4252 Al 12/2004 Engles et al. Jimenez Metal. "Competitive inhibition of mushroom tyrosinase by 2006/0257509 A1 1 1/2006 Zimmerman et al. 4-substitued benzaldehydes,” J Agri Food Chem 49:4060-4063, 2008.0004354 A1 1/2008 Engles et al. 2001. 2009, 0214628 A1 8/2009 De Rijk Kubo et al. “2-hydroxyl-4-methoxybenzaldehyde: a potent 2011/0217249 A1 9, 2011 Dreher tyrosinase inhibitor in African medicinal plants.” Planta Med 65:19, 1999. FOREIGN PATENT DOCUMENTS Magae et al. "Antitumor protective property of an isoprenoid antibi otic, ascofuranone.'J Antibiotics 35:1547, 1982. EP 0044970 B1 2, 1982 Nguyen et al. “Investigation on anti-acute inflammatory action of EP 0044976 2, 1982 beta-aminoketone, a dervative of vaniline.' Pharma J. 3:18, 2001. EP O193257 9, 1986 English translation. EP O332175 A2 9, 1989 Nomura M et al. “Studies on the use of cashew net shell oil. III. E. E. 1918 Synthesis of 6-Zi7-8, 1,14-pentadecatrienyl salicylic acid EP O914817 A1 5, 1999 derivatives and their inhibition properties towards tyrosinase or EP O9854.08 3, 2000 hyaluronidase.” Nippon Kagaku Kaishi 12:986-93, 1995. GB 1545954 4f1976 Oikawa et al. “Oxidative DNA damage and apoptosis induced by GB 2244645 A 12/1991 metabolites of butylated hydroxytoluene.” Biochem Pharmacol JP 55-045656 3, 1980 56:361-370, 1998. JP 55-045659 3, 1980 Opdyke DLJ "Monographs on fragrance raw materials JP 56-0 12310 2, 1981 p-ethoxybenzaldehyde.” Food Cosm Toxicol 18:681, 1980. JP 60-067424 4f1985 Reddy et al. “Studies on anti-inflammatory activity of spice prin JP 61-0257904 11, 1986 ciples and dietary n-3 polyunsaturated fatty acids on carrageenan JP 60-04892.9 2, 1994 induced inflammation in rats.” Ann Nutr Metab 38:349-58, 1994. E. E8 14.3 Whitehouse et al. "Alternatives to aspirin, derived from biological JP O7-242558 9, 1995 sources.” Agents Actions Suppl. 1:43-57, 1977. JP O7-258042 10, 1995 Remington: The Science and Practice of Pharmacy, 20th Ed., pp. JP O7-258074 10, 1995 836-844 and 917-918, 2000. JP O7-300412 11, 1995 Van Den Worm et al. “Effects of methoxylation of apocyanin and JP O1-106639 4/2001 analogs on the inhibition of reactive oxygen species production by WO 92-09276 6, 1992 stimulated human neutrophils.” Eur J Pharmacol 433:225-230, 2001. U.S. Patent Jul. 15, 2014 Sheet 1 of 9 US 8,778,315 B2

F.G. 1 Inhibition of Prostaglandin F2 Alpha Levels 350 cc.

Treatment U.S. Patent Jul. 15, 2014 Sheet 2 of 9 US 8,778,315 B2

FG. 2 Assessment of Protection Factors from Post-Inflammatory Hyperpigmentation Clinical Study

60 sc

Higher PF indicates better protection against UV-induced PH. Untreated PF = 0%.

1% 4EB Antioxidant Product

Treatment Comparison P-value (Pt) <0.0001 U.S. Patent Jul. 15, 2014 Sheet 3 of 9 US 8,778,315 B2

FIG 3 Assessment of the Reduction in Hyperpigmentation |||~~~~ |-~~~~ U.S. Patent Jul. 15, 2014 Sheet 4 of 9 US 8,778,315 B2

FG. 4 Assessment of Skin Brightness

P ention of Post-Inflammatory Hyperpigmentation

OOIS?oL^<†(Y)(N-O co |----

=--

U.S. Patent Jul. 15, 2014 Sheet 5 Of 9 US 8,778,315 B2

FIG.S Reduction in melanin

1OO : is 80 SS9 is- so S H C (c. O3 40 CD > 2O U.S. Patent Jul. 15, 2014 Sheet 6 of 9 US 8,778,315 B2

FIG. 6 Increase in Brightness of UV-induced Pigmentation

Untreated Hydroquinone 4%

Base + O.5% 4EB

O clic s : 1 MED 1.5 MED 2 MED 2.5 MED U.S. Patent Jul. 15, 2014 Sheet 7 Of 9 US 8,778,315 B2

FIG. 7 Significant Reduction in Hyperpigmentation

95 N -O-4% Hydroquinone 889 O5O 7 5 P<0.001 compared to baseline for everv time point U.S. Patent Jul. 15, 2014 Sheet 8 of 9 US 8,778,315 B2

FIG. 8 Comparable Distribution of Results in Individual Subjects

O4% Hydroquinone

Base + 0.5% 4EB U.S. Patent Jul. 15, 2014 Sheet 9 Of 9 US 8,778,315 B2

FIG. 9 Better Subject Preference with Base + 0.5% 4-EB than with 4% Hydroquinone

O4% HO Base + 0.5% 4EB

R Helps to fade brown spots on my skin miR Improves the evenness of my skin... O Lightens the darker patches on my... OR Increases the radiance and clarity of... R Improves my overall skin tone R

Decreases the appearance of... sea T Improved the overall condition of... GS Improves the overall appearance of... ru

Overall Improvement O "rese. 20 40 60 % Subjects 8O US 8,778,315 B2 1. 2 MELANN MODIFICATION COMPOSITIONS In one aspect, provided herein is a method is presented for AND METHODS OF USE modifying melanin distribution in an individual, the method comprising administering to the individual in need thereofan CROSS-REFERENCE effective amount of a composition comprising a Substituted benzaldehyde and a pharmaceutically or cosmetically accept This application is a divisional of U.S. patent application able carrier. In some embodiments, the substituted benzalde Ser. No. 13/532,289, filed Jun. 25, 2012, which is a continu hyde is 2-ethoxybenzaldehyde, 4-ethoxybenzaldehyde, 4-al ation of U.S. patent application Ser. No. 13/345,560, filed Jan. lyloxybenzaldehyde or 4-propoxybenzaldehyde. In a 6, 2012 (now U.S. Pat. No. 8.236,288); which claims the particular embodiment, the substituted benzaldehyde is 10 4-ethoxybenzaldehyde. In yet another embodiment, the sub benefit of U.S. Provisional Application No. 61/430,923, filed stituted benzaldehyde is 2-ethoxybenzaldehyde. Jan. 7, 2011, all of which are incorporated herein by reference In some embodiments, the pharmaceutically or cosmeti in their entirety. cally acceptable carrier is an oral or topical carrier. In other BACKGROUND OF THE INVENTION embodiments, the pharmaceutically or cosmetically accept 15 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 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 25 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 30 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 35 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, 40 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, 45 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, 50 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 55 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 60 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 65 embodiment, the amount of substituted benzaldehyde is mation is not treated. It was also identified 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 US 8,778,315 B2 3 4 about 1.0%, or from about 0.01% to about 2% Retinol. 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 2.0% to about 8.0%, from about 1% to about 10%, or from about 10.0% ethyllinoleate. about 0.5% to about 15.0% Niacinamide. In another embodi Compositions described herein may be used to lighten skin ment, the composition comprises from about 1.0% to about as well as to treat hyperpigmentation or a hypermelanosis 5.0%, from about 0.5% to about 8.0%, or from about 0.1% to disorder. In one embodiment, the hyperpigmentation is post about 15% Tetrahexyldecyl Ascorbate. In another embodi inflammatory hyperpigmentation. Hyperpigmentation and ment, the composition comprises from about 0.001% to about hypermelanosis disorders may result from an environmental 0.5%, from about 0.0005% to about 1.0% or from about stressor, physiological stressor, or mechanical stressor. 0.0001% to about 2% Licorice root extract. In another 10 Compositions described herein may reduce melanin distri embodiment, the composition comprises from about 0.1% to bution by about 10% to about 40% when applied to skin. about 3.0%, from about 0.05% to about 5.0%, or from about Compositions described herein may further comprise one 0.01% to about 10.0% Resorcinol. In another embodiment, or more additional active agents. An additional active agent the composition comprises from about 0.1% to about 3.0%, 15 may be, for example, an antioxidant, a Sunscreen, a Sunpro from about 0.05% to about 5.0%, or from about 0.01% to tectant, a Sunblock, a skin-lightening agent, an anti-inflam about 10.0% ethyl linoleate. matory agent, an anti-acne agent or mixtures thereof. Substituted benzaldehydes for use in the compositions In one embodiment, an antioxidant is selected from the include, for example, 2-ethoxybenzaldehyde, 4-ethoxyben group of vitamin E. Coenzyme Q10, idebenone, lycopene, Zaldehyde, 4-allyloxybenzaldehyde or 4-propoxybenzalde green tea polyphenols, Silybin, resveratrol, grape seed hyde. In one embodiment, the substituted benzaldehyde is extract, Oregon grape root (Mahonia aquifolium) extract, 4-ethoxybenzaldehyde, which may be present in the compo pomegranate extract, genistein, pycnogenol, curcumin, cur sition in an amount of about 0.5%. cuminoids, Tocopherol, Dunaliella Salina Extract or combi In another aspect, provided herein is a composition com nations thereof. prising from about 0.1% to about 0.5% 4-ethoxybenzalde 25 In one embodiment, a skin-lightening agent is selected hyde, about 0.01% to about 5.0% each of Retinol, Niacina from the group of hydroquinone, monobenzyl ether of hyd mide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra roquinone, azelaic acid, kojic acid, meduinol, retinoids, Soy (Licorice) Root Extract, Hexyl Resorcinol, ethyl linoleate, proteins, alpha-hydroxy acids, trichloroacetic acid, salicylic and a pharmaceutically or cosmetically acceptable carrier. In acid, hydroquinone-beta-D-glucopyranoside, paper mul one embodiment, the composition comprises from about 30 berry, glabridin, 4-isopropylcetichol, aleosin, N-acetyl-4-S- 0.1% to about 0.75%, from about 0.05% to about 1.0%, or cycteaminylphenol, N-propionyl-4-S-cysteaminylphenol, from about 0.01% to about 2%. Retinol. In another embodi N-acetyl glucosamine, tranexaminc acid, an alpha MSH ment, the composition comprises from about 2.0% to about antagonist (e.g. undecylenoyl phenylalanine), phytic acid or 8.0%, from about 1% to about 10%, or from about 0.5% to combinations thereof. about 15.0% Niacinamide. In another embodiment, the com 35 Pharmaceutically or cosmetically acceptable carriers for position comprises from about 1.0% to about 5.0%, from use in the present compositions are topical carriers. The topi about 0.5% to about 8.0%, or from about 0.1% to about 15% cal carrier may be a water-in-oil emulsion, cream, liquid, gel. Tetrahexyldecyl Ascorbate. In another embodiment, the com oil, paste, ointment, Suspension, foam, lotion, oil-in-water position comprises from about 0.001% to about 0.5%, from emulsion, water-in-oil-in-water emulsion, water-in-silicone about 0.0005% to about 1.0% or from about 0.0001% to about 40 emulsion, spray or serum carrier. 2% Licorice root extract. In another embodiment, the com The compositions described herein may also further com position comprises from about 0.1% to about 3.0%, from prise one or more of a solvent, film former, preservative, about 0.05% to about 5.0%, or from about 0.01% to about Viscosity increasing agent, fragrance, Surfactant, chelating 10.0% Resorcinol. In another embodiment, the composition agent, humectant, permeation enhancer, excipients, or a com comprises from about 0.1% to about 3.0%, from about 0.05% 45 bination thereof. to about 5.0%, or from about 0.01% to about 10.0% ethyl In one embodiment, a composition comprises from about linoleate. 0.1% to about 0.5% 4-ethoxybenzaldehyde, at least one addi In yet another aspect, provided herein is a composition tional active agent, and a pharmaceutically or cosmetically comprising about 0.5% 4-ethoxybenzaldehyde, about 0.01% acceptable carrier. In other embodiment, a composition com to about 5.0% each of Retinol, Niacinamide, Tetrahexyldecyl 50 prises from about 0.1% to about 0.5% 4-ethoxybenzalde Ascorbate, Glycyrrhiza Glabra (Licorice) Root Extract, hyde, at least two additional active agents, and a pharmaceu Hexyl Resorcinol, ethyllinoleate, and a pharmaceutically or tically or cosmetically acceptable carrier. In yet other cosmetically acceptable carrier. In one embodiment, the com embodiment, a composition comprises from about 0.1% to position comprises from about 0.1% to about 0.75%, from about 0.5% 4-ethoxybenzaldehyde, at least three additional about 0.05% to about 1.0%, or from about 0.01% to about 2% 55 active agents, and a pharmaceutically or cosmetically accept Retinol. In another embodiment, the composition comprises able carrier. In yet other embodiment, a composition com from about 2.0% to about 8.0%, from about 1% to about 10%, prises from about 0.1% to about 0.5% 4-ethoxybenzalde or from about 0.5% to about 15.0% Niacinamide. In another hyde, at least four additional active agents, and a embodiment, the composition comprises from about 1.0% to pharmaceutically or cosmetically acceptable carrier. In yet about 5.0%, from about 0.5% to about 8.0%, or from about 60 other embodiment, a composition comprises from about 0.1% to about 15% Tetrahexyldecyl Ascorbate. In another 0.1% to about 0.5% 4-ethoxybenzaldehyde, at least five addi embodiment, the composition comprises from about 0.001% tional active agents, and a pharmaceutically or cosmetically to about 0.5%, from about 0.0005% to about 1.0% or from acceptable carrier. In yet other embodiment, a composition about 0.0001% to about 2% Licorice root extract. In another comprises from about 0.1% to about 0.5% 4-ethoxybenzal embodiment, the composition comprises from about 0.1% to 65 dehyde, at least six additional active agents, and a pharma about 3.0%, from about 0.05% to about 5.0%, or from about ceutically or cosmetically acceptable carrier. In yet other 0.01% to about 10.0% Resorcinol. In another embodiment, embodiment, a composition comprises from about 0.1% to US 8,778,315 B2 5 6 about 0.5% 4-ethoxybenzaldehyde, at least seven additional hyde, 4-ethoxybenzaldehyde, 4-allyloxybenzaldehyde or active agents, and a pharmaceutically or cosmetically accept 4-propoxybenzaldehyde. In a particular embodiment, the able carrier. substituted benzaldehyde is 4-ethoxybenzaldehyde. In yet In one embodiment, a composition comprises about 0.5% another embodiment, the substituted benzaldehyde is 4-ethoxybenzaldehyde, at least one additional active agent, 2-ethoxybenzaldehyde. and a pharmaceutically or cosmetically acceptable carrier. In In some embodiments, the pharmaceutically or cosmeti other embodiment, a composition comprises about 0.5% cally acceptable carrier is an oral or topical carrier. In other 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% 10 4-ethoxybenzaldehyde, at least three additional active agents, gel, oil, paste, ointment, Suspension, foam, lotion, oil-in and a pharmaceutically or cosmetically acceptable carrier. In water emulsion, water-in-oil-in-water emulsion, water-in yet other embodiment, a composition comprises about 0.5% silicone emulsion, spray or serum carrier. In certain embodi 4-ethoxybenzaldehyde, at least four additional active agents, ments, the composition is topically administered to the skin of and a pharmaceutically or cosmetically acceptable carrier. In 15 the individual. In other embodiments, the composition is yet other embodiment, a composition comprises about 0.5% transdermally administered to the skin of the individual. 4-ethoxybenzaldehyde, at least five additional active agents, In some embodiments, the compositions further comprise and a pharmaceutically or cosmetically acceptable carrier. In at least one additional active agent. In particular embodi yet other embodiment, a composition comprises about 0.5% ments, an additional active agent may be, for example, an 4-ethoxybenzaldehyde, at least six additional active agents, antioxidant, a Sunscreen, a Sunprotectant, a Sunblock, a skin and a pharmaceutically or cosmetically acceptable carrier. In lightening agent, an anti-inflammatory agent, an anti-acne yet other embodiment, a composition comprises about 0.5% agent or mixtures thereof. In yet another embodiment, the 4-ethoxybenzaldehyde, at least seven additional active compositions comprise an antioxidant selected from the agents, and a pharmaceutically or cosmetically acceptable group of niacinamide, Vitamin E. Coenzyme Q10, idebenone, carrier. 25 lycopene, green tea polyphenols, Silybin, resveratrol, grape In one embodiment, a composition comprises from about seed extract, Oregon grape root (Mahonia aquifolium) 0.1% to about 0.5% 4-ethoxybenzaldehyde, at least one skin extract, pomegranate extract, genistein, pycnogenol, cur lightening agent, at least one skin conditioning agent, at least cumin, curcuminoids, or combinations thereof. In another one antioxidant, at least one occlusive, at least one emollient, embodiment, the compositions comprise a skin-lightening at least one preservative, at least one viscosity increasing 30 agent selected from the group of hydroquinone, monobenzyl agent, at least one fragrance, at least one skin conditioning ether of hydroquinone, azelaic acid, kojic acid, meduinol, agent, at least one surfactant, at least one chlating agent, at retinoids (e.g., tretinoin, adapalene), soy proteins, alpha-hy least one humectant, and a pharmaceutically or cosmetically droxyacids (e.g., glycolic acid), trichloroacetic acid, salicylic acceptable carrier. acid, hydroquinone-beta-D-glucopyranoside, paper mul On another embodiment, a composition comprises about 35 0.5% 4-ethoxybenzaldehyde, at least one skin lightening berry, glabridin, 4-isopropylcetichol, aleosin, N-acetyl-4-S- agent, at least one skin conditioning agent, at least one anti cycteaminylphenol, N-propionyl-4-S-cysteaminylphenol, oxidant, at least one occlusive, at least one emollient, at least N-acetyl glucosamine, tranexaminc acid, licorice extract one preservative, at least one viscosity increasing agent, at (e.g., Glycyrrhiza Glabra (licorice) root extract), an alpha least one fragrance, at least one skin conditioning agent, at 40 MSH antagonist (e.g. undecylenoyl phenylalanine), phytic least one surfactant, at least one chlating agent, at least one acid or combinations thereof. humectant, and a pharmaceutically or cosmetically accept In some embodiments, the substituted benzaldehyde com able carrier. position modifies melanin distribution by about 10%, by In some embodiments, the substituted benzaldehyde com about 15%, by about 20%, by about 25%, by about 30%, by position modifies melanin distribution by about 10%, by 45 about 35%, by about 40%, by about 45%, by about 50%, by about 15%, by about 20%, by about 25%, by about 30%, by about 55%, by about 60%, by about 65%, by about 70%, by about 35%, by about 40%, by about 45%, by about 50%, by about 75%, by about 80%, by about 85%, by about 90%, by about 55%, by about 60%, by about 65%, by about 70%, by about 95% or by about 100%. In other embodiments, the about 75%, by about 80%, by about 85%, by about 90%, by Substituted benzaldehyde composition reduces melanin dis about 95% or by about 100%. In another embodiment, the 50 tribution by about 10%, by about 15%, by about 20%, by Substituted benzaldehyde composition reduces melanin dis about 25%, by about 30%, by about 35%, by about 40%, by tribution by about 10%, by about 15%, by about 20%, by about 45%, by about 50%, by about 55%, by about 60%, by about 25%, by about 30%, by about 35%, by about 40%, by about 65%, by about 70%, by about 75%, by about 80%, by about 45%, by about 50%, by about 55%, by about 60%, by about 85%, by about 90%, by about 95% or by about 100%. about 65%, by about 70%, by about 75%, by about 80%, by 55 In another embodiment, the substituted benzaldehyde com about 85%, by about 90%, by about 95% or by about 100%. position reduces melanin distribution by about 5% to about In another embodiment, the substituted benzaldehyde com 50%. In yet another embodiment, the substituted benzalde position reduces melanin distribution by about 5% to about hyde composition reduces melanin distribution by about 10% 50%. In yet another embodiment, the substituted benzalde to about 40%. hyde composition reduces melanin distribution by about 10% 60 In a further aspect, provided herein is a method of treating to about 40%. a melanin disorder in an individual comprising contacting Another aspect relates to a method of modifying melanin keratinocytes with an effective amount of a composition com distribution in an individual, the method comprising contact prising a Substituted benzaldehyde and a pharmaceutically or ing keratinocytes with an effective amount of a composition cosmetically acceptable carrier. In some embodiments, the comprising a Substituted benzaldehyde and a pharmaceuti 65 substituted benzaldehyde is 2-ethoxybenzaldehyde, cally or cosmetically acceptable carrier. In some embodi 4-ethoxybenzaldehyde, 4-allyloxybenzaldehyde or 4-pro ments, the substituted benzaldehyde is 2-ethoxybenzalde poxybenzaldehyde. In a specific embodiment, the substituted US 8,778,315 B2 7 8 benzaldehyde is 4-ethoxybenzaldehyde. In yet another In some embodiments, the hyperpigmentation skin disor embodiment, the substituted benzaldehyde is 2-ethoxyben der results from an environmental stressor, physiological Zaldehyde. stressor, or mechanical stressor. In a particular embodiment, In some embodiments, the pharmaceutically or cosmeti the physiological stressor is a hormonal disorder. In yet cally acceptable carrier is an oral or topical carrier. In other 5 another embodiment, the environmental stressor is excessive embodiments, the pharmaceutically or cosmetically accept Sun exposure or chemical exposure. 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 embodiments, the pharmaceutically or cosmetically accept silicone emulsion, spray or serum carrier. In one embodiment, 10 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 15 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 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, Coenzyme Q10, idebenone, lycopene, green tea polyphenols, genistein, pycnogenol, curcumin, curcuminoids, or combina 25 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), 30 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, glucopyranoside, paper mulberry, glabridin, 4-isopropyl tranexaminc acid, licorice extract (e.g., Glycyrrhiza Glabra 35 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 cylenoyl phenylalanine), phytic acidor combinations thereof. about 15%, by about 20%, by about 25%, by about 30%, by 40 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 about 55%, by about 60%, by about 65%, by about 70%, by Substituted benzaldehyde composition reduces melanin dis 45 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 about 25%, by about 30%, by about 35%, by about 40%, by about 85%, by about 90%, by about 95% or by about 100%. 50 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% position reduces melanin distribution by about 5% to about to about 40%. 55 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 treating hyperpigmentation or a hypermelanosis disorder in comprising a Substituted benzaldehyde and a pharmaceuti 60 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 In one embodiment, the method further comprises admin stituted benzaldehyde is 4-ethoxybenzaldehyde. In yet 65 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) US 8,778,315 B2 10 Root Extract, Hexyl Resorcinol, ethyl linoleate. In another comprises from about 2.0% to about 8.0%, from about 1% to embodiment, the composition comprises from about 0.1% to about 10%, or from about 0.5% to about 15.0% Niacinamide. about 0.75%, from about 0.05% to about 1.0%, or from about In another embodiment, the composition comprises from 0.01% to about 2%. Retinol. In another embodiment, the about 1.0% to about 5.0%, from about 0.5% to about 8.0%, or composition comprises from about 2.0% to about 8.0%, from from about 0.1% to about 15% Tetrahexyldecyl Ascorbate. In about 1% to about 10%, or from about 0.5% to about 15.0% another embodiment, the composition comprises from about Niacinamide. In another embodiment, the composition com 0.001% to about 0.5%, from about 0.0005% to about 1.0% or prises from about 1.0% to about 5.0%, from about 0.5% to from about 0.0001% to about 2% Licorice root extract. In about 8.0%, or from about 0.1% to about 15% Tetrahexylde another embodiment, the composition comprises from about cyl Ascorbate. In another embodiment, the composition com 10 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% 15 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. 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, composition comprises from about 0.1% to about 0.75%, about 0.01% to about 5.0% each of Retinol, Niacinamide, 25 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, 30 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 from about 0.0001% to about 2% Licorice root extract. In another embodiment, the composition comprises from about 35 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 3.0%, from about 0.05% to about 5.0%, or from about 0.01% about 15% Tetrahexyldecyl Ascorbate. In another embodi 40 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 herein may be topical or transdermal administration to the about 3.0%, from about 0.05% to about 5.0%, or from about 45 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. paste, ointment, Suspension, foam, lotion, oil-in-water emul Substituted benzaldehydes for use in the compositions 50 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 chemical exposure), physiological stressor (e.g., a hormonal sition in an amount of about 0.5%. 55 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: Sunscreen, a Sunprotectant, a Sunblock, a skin-lightening from about 0.1% to about 0.5% 4-ethoxybenzaldehyde, about 60 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 Surfactant, chelating agent, humectant, permeation enhancer, ment, the composition comprises from about 0.1% to about 65 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, US 8,778,315 B2 11 12 resveratrol, grape seed extract, Oregon grape root (Mahonia about 3.0%, from about 0.05% to about 5.0%, or from about aquifolium) extract, pomegranate extract, genistein, pycno 0.01% to about 10.0% Resorcinol. In another embodiment, genol, curcumin, curcuminoids, or combinations thereof. the composition comprises from about 0.1% to about 3.0%, Exemplary skin-lightening agents include hydroquinone, from about 0.05% to about 5.0%, or from about 0.01% to monobenzyl ether of hydroquinone, azelaic acid, kojic acid, about 10.0% ethyllinoleate. meduinol, retinoids, soy proteins, alpha-hydroxy acids, In yet another aspect, provided herein is a method of light trichloroacetic acid, salicylic acid, hydroquinone-beta-D- ening skin in an individual, comprising administering to the glucopyranoside, paper mulberry, glabridin, 4-isopropyl individual in need thereof an effective amount of a composi cetichol, aleosin, N-acetyl-4-S-cycteaminylphenol, N-propio tion comprising: about 0.5% 4-ethoxybenzaldehyde, about nyl-4-S-cysteaminylphenol, N-acetyl glucosamine, 10 tranexaminc acid, an alpha MSH antagonist (e.g. undecyle 0.01% to about 5.0% each of Retinol, Niacinamide, Tetra noyl phenylalanine), phytic acid or combinations thereof. hexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice) Root In another aspect, provided herein is a method of lightening Extract, Hexyl Resorcinol, ethyllinoleate, and a pharmaceu skin in an individual, comprising administering to the indi tically or cosmetically acceptable carrier. In one embodiment, vidual in need thereof an effective amount of a composition 15 the amount of substituted benzaldehyde in the composition is comprising: from about 0.01% to about 2% substituted ben about 0.5%. In another embodiment, the composition com Zaldehyde, about 0.01% to about 5.0% each of Retinol, Niaci prises from about 0.1% to about 0.75%, from about 0.05% to namide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra about 1.0%, or from about 0.01% to about 2% Retinol. In (Licorice) Root Extract, Hexyl Resorcinol, ethyl linoleate, another embodiment, the composition comprises from about and a pharmaceutically or cosmetically acceptable carrier. In 2.0% to about 8.0%, from about 1% to about 10%, or from one embodiment, the amount of substituted benzaldehyde in about 0.5% to about 15.0% Niacinamide. In another embodi the composition is about 0.5%. In another embodiment, the ment, the composition comprises from about 1.0% to about composition comprises from about 0.1% to about 0.75%, 5.0%, from about 0.5% to about 8.0%, or from about 0.1% to from about 0.05% to about 1.0%, or from about 0.01% to about 15% Tetrahexyldecyl Ascorbate. In another embodi about 2% Retinol. In another embodiment, the composition 25 ment, the composition comprises from about 0.001% to about comprises from about 2.0% to about 8.0%, from about 1% to 0.5%, from about 0.0005% to about 1.0% or from about about 10%, or from about 0.5% to about 15.0% Niacinamide. 0.0001% to about 2% Licorice root extract. In another In another embodiment, the composition comprises from embodiment, the composition comprises from about 0.1% to about 1.0% to about 5.0%, from about 0.5% to about 8.0%, or about 3.0%, from about 0.05% to about 5.0%, or from about from about 0.1% to about 15% Tetrahexyldecyl Ascorbate. In 30 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%, 0.001% to about 0.5%, from about 0.0005% to about 1.0% or from about 0.05% to about 5.0%, or from about 0.01% to from about 0.0001% to about 2% Licorice root extract. In about 10.0% ethyllinoleate. another embodiment, the composition comprises from about Also provided is a method of lightening skin in an indi 0.1% to about 3.0%, from about 0.05% to about 5.0%, or from 35 vidual, comprising administering to the individual in need about 0.01% to about 10.0% Resorcinol. In another embodi thereof an effective amount of a composition comprising: ment, the composition comprises from about 0.1% to about from about 0.01% to about 2% substituted benzaldehyde and 3.0%, from about 0.05% to about 5.0%, or from about 0.01% a pharmaceutically or cosmetically acceptable carrier. to about 10.0% ethyl linoleate. In one embodiment, the method further comprises admin Substituted benzaldehydes for use in the compositions 40 istering to the individual in need thereof an effective amount include, for example, 2-ethoxybenzaldehyde, 4-ethoxyben of about 0.01% to about 5.0% each of Retinol, Niacinamide, Zaldehyde, 4-allyloxybenzaldehyde or 4-propoxybenzalde Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice) hyde. In one embodiment, the substituted benzaldehyde is Root Extract, Hexyl Resorcinol, ethyl linoleate. In another 4-ethoxybenzaldehyde, which may be present in the compo embodiment, the composition comprises from about 0.1% to sition in an amount of about 0.1% to about 0.5%. 45 about 0.75%, from about 0.05% to about 1.0%, or from about In another aspect, provided herein is a method of lightening 0.01% to about 2%. Retinol. In another embodiment, the skin in an individual, comprising administering to the indi composition comprises from about 2.0% to about 8.0%, from vidual in need thereof an effective amount of a composition about 1% to about 10%, or from about 0.5% to about 15.0% comprising: about 0.1% to about 0.5% 4-ethoxybenzalde Niacinamide. In another embodiment, the composition com hyde, about 0.01% to about 5.0% each of Retinol, Niacina 50 prises from about 1.0% to about 5.0%, from about 0.5% to mide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Lico about 8.0%, or from about 0.1% to about 15% Tetrahexylde rice) Root Extract, Hexyl Resorcinol, ethyl linoleate, and a cyl Ascorbate. In another embodiment, the composition com pharmaceutically or cosmetically acceptable carrier. In one prises from about 0.001% to about 0.5%, from about embodiment, the amount of substituted benzaldehyde in the 0.0005% to about 1.0% or from about 0.0001% to about 2% composition is about 0.5%. In another embodiment, the com 55 Licorice root extract. In another embodiment, the composi position comprises from about 0.1% to about 0.75%, from tion comprises from about 0.1% to about 3.0%, from about about 0.05% to about 1.0%, or from about 0.01% to about 2% 0.05% to about 5.0%, or from about 0.01% to about 10.0% Retinol. In another embodiment, the composition comprises Resorcinol. In another embodiment, the composition com from about 2.0% to about 8.0%, from about 1% to about 10%, prises from about 0.1% to about 3.0%, from about 0.05% to or from about 0.5% to about 15.0% Niacinamide. In another 60 about 5.0%, or from about 0.01% to about 10.0% ethyl embodiment, the composition comprises from about 1.0% to linoleate. about 5.0%, from about 0.5% to about 8.0%, or from about In some embodiments, the methods decrease the level of 0.1% to about 15% Tetrahexyldecyl Ascorbate. In another pigmentation by about 5%, by about 10%, by about 20%, by embodiment, the composition comprises from about 0.001% about 30% or by about 40%. to about 0.5%, from about 0.0005% to about 1.0% or from 65 The methods may be used to treat hyperpigmentation or a about 0.0001% to about 2% Licorice root extract. In another hypermelanosis disorder. In one embodiment, hyperpigmen embodiment, the composition comprises from about 0.1% to tation may result from an environmental stressor (e.g., exces US 8,778,315 B2 13 14 sive Sun exposure or chemical exposure), physiological stres prises from about 1.0% to about 5.0%, from about 0.5% to Sor (e.g., a hormonal disorder), or mechanical stressor. about 8.0%, or from about 0.1% to about 15% Tetrahexylde In some embodiments, the method reduces melanin distri cyl Ascorbate. In another embodiment, the composition com bution by about 10% to about 40%. prises from about 0.001% to about 0.5%, from about Application of the compositions in the methods described 0.0005% to about 1.0% or from about 0.0001% to about 2% herein may be topical or transdermal administration to the Licorice root extract. In another embodiment, the composi skin of the individual. tion comprises from about 0.1% to about 3.0%, from about In one embodiment, the pharmaceutically or cosmetically 0.05% to about 5.0%, or from about 0.01% to about 10.0% acceptable carrier is a topical carrier. Topical carriers include, Resorcinol. In another embodiment, the composition com for example, a water-in-oil emulsion, cream, liquid, gel, oil, 10 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 15 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 Root Extract, Hexyl Resorcinol, ethyl linoleate, and a phar former, preservative, Viscosity increasing agent, fragrance, maceutically or cosmetically acceptable carrier. In some Surfactant, chelating agent, humectant, permeation enhancer, embodiments, the cells being treated are located in skin of an excipient, or a combination thereof. individual. In another embodiment, the composition com Exemplary antioxidants include vitamin E. Coenzyme prises from about 0.1% to about 0.75%, from about 0.05% to Q10, idebenone, lycopene, green tea polyphenols, Silybin, 25 about 1.0%, or from about 0.01% to about 2% Retinol. In resveratrol, grape seed extract, Oregon grape root (Mahonia another embodiment, the composition comprises from about aquifolium) extract, pomegranate extract, genistein, pycno 2.0% to about 8.0%, from about 1% to about 10%, or from genol, curcumin, curcuminoids, Tocopherol, Dunaliella about 0.5% to about 15.0% Niacinamide. In another embodi Salina Extract or combinations thereof. ment, the composition comprises from about 1.0% to about Exemplary skin-lightening agents include hydroquinone, 30 5.0%, from about 0.5% to about 8.0%, or from about 0.1% to monobenzyl ether of hydroquinone, azelaic acid, kojic acid, about 15% Tetrahexyldecyl Ascorbate. In another embodi meduinol, retinoids, soy proteins, alpha-hydroxy acids, ment, the composition comprises from about 0.001% to about trichloroacetic acid, salicylic acid, hydroquinone-beta-D- 0.5%, from about 0.0005% to about 1.0% or from about glucopyranoside, paper mulberry, glabridin, 4-isopropyl 0.0001% to about 2% Licorice root extract. In another cetichol, aleosin, N-acetyl-4-S-cycteaminylphenol, N-propio 35 embodiment, the composition comprises from about 0.1% to nyl-4-S-cysteaminylphenol, N-acetyl glucosamine, about 3.0%, from about 0.05% to about 5.0%, or from about tranexaminc acid, an alpha MSH antagonist (e.g. undecyle 0.01% to about 10.0% Resorcinol. In another embodiment, noyl phenylalanine), phytic acid or combinations thereof. the composition comprises from about 0.1% to about 3.0%, Provided herein are methods of modifying melanin distri from about 0.05% to about 5.0%, or from about 0.01% to bution by modulating prostaglandin F2 alpha (PGF2 alpha) in 40 about 10.0% ethyllinoleate. a cell, comprising contacting said cell with a composition Provided is a method of modifying melanin distribution by comprising from about 0.01% to about 2% substituted ben modulating prostaglandin F2 alpha (PGF2 alpha) in skin cells Zaldehyde and a pharmaceutically or cosmetically acceptable in an individual, comprising administering to the individual carrier. in need thereof an effective amount of a composition com In one embodiment, the method further comprises admin 45 prising from about 0.01% to about 2% substituted benzalde istering to the individual in need thereof an effective amount hyde, about 0.01% to about 5.0% each of Retinol, Niacina of about 0.01% to about 5.0% each of Retinol, Niacinamide, mide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice) (Licorice) Root Extract, Hexyl Resorcinol, ethyl linoleate, Root Extract, Hexyl Resorcinol, ethyl linoleate. and a pharmaceutically or cosmetically acceptable carrier. In Provided is a method of modifying melanin distribution by 50 another embodiment, the composition comprises from about modulating prostaglandin F2 alpha (PGF2 alpha) in skin cells 0.1% to about 0.75%, from about 0.05% to about 1.0%, or in an individual, comprising administering to the individual from about 0.01% to about 2%. Retinol. In another embodi in need thereof an effective amount of a composition com ment, the composition comprises from about 2.0% to about prising from about 0.01% to about 2% substituted benzalde 8.0%, from about 1% to about 10%, or from about 0.5% to hyde and a pharmaceutically or cosmetically acceptable car 55 about 15.0% Niacinamide. In another embodiment, the com 1. position comprises from about 1.0% to about 5.0%, from In one embodiment, the method further comprises admin about 0.5% to about 8.0%, or from about 0.1% to about 15% istering to the individual in need thereof an effective amount Tetrahexyldecyl Ascorbate. In another embodiment, the com of about 0.01% to about 5.0% each of Retinol, Niacinamide, position comprises from about 0.001% to about 0.5%, from Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice) 60 about 0.0005% to about 1.0% or from about 0.0001% to about Root Extract, Hexyl Resorcinol, ethyl linoleate. In another 2% Licorice root extract. In another embodiment, the com embodiment, the composition comprises from about 0.1% to position comprises from about 0.1% to about 3.0%, from about 0.75%, from about 0.05% to about 1.0%, or from about about 0.05% to about 5.0%, or from about 0.01% to about 0.01% to about 2%. Retinol. In another embodiment, the 10.0% Resorcinol. In another embodiment, the composition composition comprises from about 2.0% to about 8.0%, from 65 comprises from about 0.1% to about 3.0%, from about 0.05% about 1% to about 10%, or from about 0.5% to about 15.0% to about 5.0%, or from about 0.01% to about 10.0% ethyl Niacinamide. In another embodiment, the composition com linoleate. US 8,778,315 B2 15 16 In one embodiment, the amount of substituted benzalde Also disclosed are methods of modifying melanin distri hyde is between about 0.1% to about 0.5%. In one embodi bution by modulating prostaglandin F2 alpha (PGF2alpha) in ment, the amount of substituted benzaldehyde in the compo skin cells in an individual, comprising administering to the sition is about 0.5%. individual in need thereof an effective amount of a composi Substituted benzaldehydes for use in the compositions tion comprising about 0.5% 4-ethoxybenzaldehyde, about include, for example, 2-ethoxybenzaldehyde, 4-ethoxyben 0.01% to about 5.0% each of Retinol, Niacinamide, Tetra Zaldehyde, 4-allyloxybenzaldehyde or 4-propoxybenzalde hexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice) Root hyde. In one embodiment, the substituted benzaldehyde is Extract, Hexyl Resorcinol, ethyllinoleate, and a pharmaceu 4-ethoxybenzaldehyde, which may be present in the compo tically or cosmetically acceptable carrier. In some embodi sition in an amount of about 0.1% to about 0.5%. In one 10 ments, the method reduces melanin distribution by about 10% 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 15 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 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 25 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 30 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 35 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. 40 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 45 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 50 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 55 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 60 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% 65 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 US 8,778,315 B2 17 18 maceutically or cosmetically acceptable carrier. In some stituted benzaldehyde is 4-ethoxybenzaldehyde. In yet embodiments, the substituted benzaldehyde is 2-ethoxyben another embodiment, the substituted benzaldehyde is Zaldehyde, 4-ethoxybenzaldehyde, 4-allyloxybenzaldehyde 2-ethoxybenzaldehyde. or 4-propoxybenzaldehyde. In a specific 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. 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 10 silicone emulsion, spray or serum carrier. In another embodi embodiments, the pharmaceutically or cosmetically accept ment, the composition is topically administered to the skin of 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 15 antioxidant, a Sunscreen, a Sunprotectant, a Sunblock, a skin ment, the composition is topically administered to the skin of 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 seed extract, Oregon grape root (Mahonia aquifolium) agent or mixtures thereof. In yet another embodiment, the extract, pomegranate extract, genistein, pycnogenol, cur compositions comprise an antioxidant selected from the cumin, curcuminoids, or combinations thereof. In another group of niacinamide, Vitamin E. Coenzyme Q10, idebenone, embodiment, the compositions comprise a skin-lightening lycopene, green tea polyphenols, Silybin, resveratrol, grape 25 agent selected from the group of hydroquinone, monobenzyl seed extract, Oregon grape root (Mahonia aquifolium) ether of hydroquinone, azelaic acid, kojic acid, meduinol, extract, pomegranate extract, genistein, pycnogenol, cur retinoids (e.g., tretinoin, adapalene), soy proteins, alpha-hy cumin, curcuminoids, or combinations thereof. In another droxyacids (e.g., glycolic acid), trichloroacetic acid, salicylic embodiment, the compositions comprise a skin-lightening acid, hydroquinone-beta-D-glucopyranoside, paper mul agent selected from the group of hydroquinone, monobenzyl 30 berry, glabridin, 4-isopropylcetichol, aleosin, N-acetyl-4-S- ether of hydroquinone, azelaic acid, kojic acid, meduinol, cycteaminylphenol, N-propionyl-4-S-cysteaminylphenol, retinoids (e.g., tretinoin, adapalene), soy proteins, alpha-hy N-acetyl glucosamine, tranexaminc acid, licorice extract droxyacids (e.g., glycolic acid), trichloroacetic acid, salicylic (e.g., Glycyrrhiza Glabra (licorice) root extract), an alpha acid, hydroquinone-beta-D-glucopyranoside, paper mul MSH antagonist (e.g. undecylenoyl phenylalanine), phytic berry, glabridin, 4-isopropylcetichol, aleosin, N-acetyl-4-S- 35 acid or combinations thereof. cycteaminylphenol, N-propionyl-4-S-cysteaminylphenol, In some embodiments, the substituted benzaldehyde com N-acetyl glucosamine, tranexaminc acid, licorice extract position modifies melanin distribution by about 10%, by (e.g., Glycyrrhiza Glabra (licorice) root extract), an alpha about 15%, by about 20%, by about 25%, by about 30%, by MSH antagonist (e.g. undecylenoyl phenylalanine), phytic about 35%, by about 40%, by about 45%, by about 50%, by acid or combinations thereof. 40 about 55%, by about 60%, by about 65%, by about 70%, by In some embodiments, the substituted benzaldehyde com about 75%, by about 80%, by about 85%, by about 90%, by position modifies melanin distribution by about 10%, by about 95% or by about 100%. In other embodiments, the about 15%, by about 20%, by about 25%, by about 30%, by Substituted benzaldehyde composition reduces melanin dis about 35%, by about 40%, by about 45%, by about 50%, by tribution by about 10%, by about 15%, by about 20%, by about 55%, by about 60%, by about 65%, by about 70%, by 45 about 25%, by about 30%, by about 35%, by about 40%, by about 75%, by about 80%, by about 85%, by about 90%, by about 45%, by about 50%, by about 55%, by about 60%, by about 95% or by about 100%. In other embodiments, the about 65%, by about 70%, by about 75%, by about 80%, by Substituted benzaldehyde composition reduces melanin dis about 85%, by about 90%, by about 95% or by about 100%. tribution by about 10%, by about 15%, by about 20%, by In another embodiment, the substituted benzaldehyde com about 25%, by about 30%, by about 35%, by about 40%, by 50 position reduces melanin distribution by about 5% to about about 45%, by about 50%, by about 55%, by about 60%, by 50%. In yet another embodiment, the substituted benzalde about 65%, by about 70%, by about 75%, by about 80%, by hyde composition reduces melanin distribution by about 10% about 85%, by about 90%, by about 95% or by about 100%. to about 40%. In another embodiment, the substituted benzaldehyde com In another aspect, provided herein is a method of treating a position reduces melanin distribution by about 5% to about 55 melanin disorder in an individual, the method comprising 50%. In yet another embodiment, the substituted benzalde contacting keratinocytes with an effective amount of a com hyde composition reduces melanin distribution by about 10% position comprising a Substituted benzaldehyde, at least one to about 40%. additional active agent and a pharmaceutically or cosmeti In a further aspect, provided herein is a method of modi cally acceptable carrier. In some embodiments, the Substi fying melanin distribution in an individual, the method com 60 tuted benzaldehyde is 2-ethoxybenzaldehyde, 4-ethoxyben prising contacting keratinocytes with an effective amount of a Zaldehyde, 4-allyloxybenzaldehyde O composition comprising a Substituted benzaldehyde, at least 4-propoxybenzaldehyde. In a specific embodiment, the Sub one additional active agent and a pharmaceutically or cos stituted benzaldehyde is 4-ethoxybenzaldehyde. In yet metically acceptable carrier. In some embodiments, the Sub another embodiment, the substituted benzaldehyde is stituted benzaldehyde is 2-ethoxybenzaldehyde, 4-ethoxy 65 2-ethoxybenzaldehyde. benzaldehyde, 4-allyloxybenzaldehyde O In some embodiments, the compositions further comprise 4-propoxybenzaldehyde. In a specific embodiment, the Sub a pharmaceutically or cosmetically acceptable carrier. In US 8,778,315 B2 19 20 another embodiment, the pharmaceutically or cosmetically ticular embodiment, the physiological stressor is a hormonal 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, 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 silicone emulsion, spray or serum carrier. In some embodi able topical carrier is a water-in-oil emulsion, cream, liquid, ments, the cell is present on skin of an individual. In another gel, oil, paste, ointment, Suspension, foam, lotion, oil-in embodiment, the composition is topically administered to the water emulsion, water-in-oil-in-water emulsion, water-in skin of the individual. In yet another embodiment, the com 10 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 In particular embodiments, the additional active agent is an lightening agent, an anti-inflammatory agent, an anti-acne 15 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 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 embodiment, the compositions comprise a skin-lightening ether of hydroquinone, azelaic acid, kojic acid, meduinol, 25 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- acid, hydroquinone-beta-D-glucopyranoside, paper mul cycteaminylphenol, N-propionyl-4-S-cysteaminylphenol, 30 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. MSH antagonist (e.g. undecylenoyl phenylalanine), phytic In some embodiments, the composition modifies melanin 35 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 about 8%, about 9%, about 10%, by about 15%, by about 50%, by about 55%, by about 60%, by about 65%, by about 40 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%, 100%. In other embodiments, the substituted benzaldehyde by about 35%, by about 40%, by about 45%, by about 50%, 45 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 about 75%, by about 80%, by about 85%, by about 90%, by tribution by about 5% to about 50%. In yet another embodi 50 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 melanin distribution by about 10% to about 40%. need thereof, the method comprising administering to the 55 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 benzaldehyde, at least one additional active agent and a phar Zaldehyde is 2-ethoxybenzaldehyde, 4-ethoxybenzaldehyde, 60 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. loxybenzaldehyde or 4-propoxybenzaldehyde. In a specific In some embodiments, the individual suffers from a hyper 65 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. US 8,778,315 B2 21 22 In some embodiments, the individual suffers from a hyper 4-ethoxybenzaldehyde. In yet another embodiment, the sub pigmentation disorder resulting from an environmental stres stituted benzaldehyde is 2-ethoxybenzaldehyde. Sor, physiological stressor or mechanical stressor. In a par In some embodiments, the compositions further comprise ticular embodiment, the physiological stressor is a hormonal a pharmaceutically or cosmetically acceptable carrier. In disorder. In yet another embodiment, the environmental stres another embodiment, the pharmaceutically or cosmetically sor is excessive Sun exposure or chemical exposure. acceptable carrier is an oral or topical carrier. In other In another embodiment, the pharmaceutically or cosmeti embodiments, the pharmaceutically or cosmetically accept cally 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 10 water emulsion, water-in-oil-in-water emulsion, water-in 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 15 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 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) 25 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, 30 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, 35 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 40 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 45 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%, 50 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 55 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 60 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 65 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. US 8,778,315 B2 23 24 In some embodiments, the compositions further comprise In another embodiment, the pharmaceutically or cosmeti a pharmaceutically or cosmetically acceptable carrier. In cally 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 5 gel, oil, paste, ointment, Suspension, foam, lotion, oil-in able topical carrier is a water-in-oil emulsion, cream, liquid, 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 ment, the composition is topically administered to the skin of water emulsion, water-in-oil-in-water emulsion, water-in the 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 10 In another embodiment, an amount of the substituted ben the individual. In yet another embodiment, the composition is Zaldehyde that is effective in reducing melanin levels in a transdermally administered to the skin of the individual. Subject is present in the composition. In some embodiments, In particular embodiments, the additional active agent is an the composition modifies melanin distribution by about 1%, antioxidant, a Sunscreen, a Sunprotectant, a Sunblock, a skin about 2%, about 3%, about 4%, about 5%, about 6%, about lightening agent, an anti-inflammatory agent, an anti-acne 15 7%, about 8%, about 9%, about 10%, by about 15%, by about agent or mixtures thereof. In yet another embodiment, the 20%, by about 25%, by about 30%, by about 35%, by about compositions comprise an antioxidant selected from the 40%, by about 45%, by about 50%, by about 55%, by about group of niacinamide, Vitamin E. Coenzyme Q10, idebenone, 60%, by about 65%, by about 70%, by about 75%, by about lycopene, green tea polyphenols, Silybin, resveratrol, grape 80%, by about 85%, by about 90%, by about 95% or by about seed extract, Oregon grape root (Mahonia aquifolium) 100%. In other embodiments, the composition reduces mela extract, pomegranate extract, genistein, pycnogenol, cur nin distribution by about 10%, by about 15%, by about 20%, cumin, curcuminoids, or combinations thereof. In another by about 25%, by about 30%, by about 35%, by about 40%, embodiment, the compositions comprise a skin-lightening by about 45%, by about 50%, by about 55%, by about 60%, agent selected from the group of hydroquinone, monobenzyl by about 65%, by about 70%, by about 75%, by about 80%, ether of hydroquinone, azelaic acid, kojic acid, meduinol, 25 by about 85%, by about 90%, by about 95% or by about retinoids (e.g., tretinoin, adapalene), soy proteins, alpha-hy 100%. In another embodiment, the substituted benzaldehyde droxyacids (e.g., glycolic acid), trichloroacetic acid, salicylic composition reduces melanin distribution by about 5% to acid, hydroquinone-beta-D-glucopyranoside, paper mul about 50%. In yet another embodiment, the substituted ben berry, glabridin, 4-isopropylcetichol, aleosin, N-acetyl-4-S- Zaldehyde composition reduces melanin distribution by about cycteaminylphenol, N-propionyl-4-S-cysteaminylphenol, 30 10% to about 40%. N-acetyl glucosamine, tranexaminc acid, licorice extract In particular embodiments, the additional active agent is an (e.g., Glycyrrhiza Glabra (licorice) root extract), an alpha antioxidant, a sunscreen, a Sunprotectant, a Sunblock, a skin MSH antagonist (e.g. undecylenoyl phenylalanine), orphytic lightening agent, an anti-inflammatory agent, an anti-acne acid combinations thereof. agent or mixtures thereof. In yet another embodiment, the In some embodiments, the composition modifies melanin 35 compositions comprise an antioxidant selected from the distribution by about 1%, about 2%, about 3%, about 4%, group of niacinamide, Vitamin E. Coenzyme Q10, idebenone, about 5%, about 6%, about 7%, about 8%, about 9%, about lycopene, green tea polyphenols, Silybin, resveratrol, grape 10%, by about 15%, by about 20%, by about 25%, by about seed extract, Oregon grape root (Mahonia aquifolium) 30%, by about 35%, by about 40%, by about 45%, by about extract, pomegranate extract, genistein, pycnogenol, cur 50%, by about 55%, by about 60%, by about 65%, by about 40 cumin, curcuminoids, or combinations thereof. In another 70%, by about 75%, by about 80%, by about 85%, by about embodiment, the compositions comprise a skin-lightening 90%, by about 95% or by about 100%. In other embodiments, agent selected from the group of hydroquinone, monobenzyl the composition reduces melanin distribution by about 10%, ether of hydroquinone, azelaic acid, kojic acid, meduinol, by about 15%, by about 20%, by about 25%, by about 30%, retinoids (e.g., tretinoin, adapalene), soy proteins, alpha-hy by about 35%, by about 40%, by about 45%, by about 50%, 45 droxyacids (e.g., glycolic acid), trichloroacetic acid, salicylic by about 55%, by about 60%, by about 65%, by about 70%, acid, hydroquinone-beta-D-glucopyranoside, paper mul by about 75%, by about 80%, by about 85%, by about 90%, berry, glabridin, 4-isopropylcetichol, aleosin, N-acetyl-4-S- by about 95% or by about 100%. In another embodiment, the cycteaminylphenol, N-propionyl-4-S-cysteaminylphenol, Substituted benzaldehyde composition reduces melanin dis N-acetyl glucosamine, tranexaminc acid, licorice extract tribution by about 5% to about 50%. In yet another embodi 50 (e.g., Glycyrrhiza Glabra (licorice) root extract), an alpha ment, the Substituted benzaldehyde composition reduces MSH antagonist (e.g. undecylenoyl phenylalanine), orphytic melanin distribution by about 10% to about 40%. acid combinations thereof. In a particular embodiment, the compositions disclosed Another aspect provided herein relates to the use of the herein modulate PGF2 alpha in a keratinocyte cell to modify composition to treat a hyperpigmentation disorder. In some melanin distribution. In some embodiments, the composi 55 embodiments, the hyperpigmentation disorder is due to post tions disclosed herein modulate PGF2. inflammatory hyperpigmentation disorder. In other embodi In a further aspect, provided herein are compositions com ments, the post-inflammatory hyperpigmentation disorder is prising a combination of a Substituted benzaldehyde, at least due to infections, allergic reactions, mechanical injuries, one additional active agent, and a pharmaceutically or cos reaction to medications, phototoxic eruptions, trauma, or metically acceptable carrier. In some embodiments, the Sub 60 reaction to ultrasound, radiofrequency, lasers, light-emitting stituted benzaldehyde is 2-ethoxybenzaldehyde, 4-ethoxy diodes, visible light therapy, microdermabrasion or chemical benzaldehyde, 4-allyloxybenzaldehyde O peel therapies. 4-propoxybenzaldehyde. In a specific embodiment, the Sub stituted benzaldehyde is 4-ethoxybenzaldehyde. In yet INCORPORATION BY REFERENCE another embodiment, the substituted benzaldehyde is 65 2-ethoxybenzaldehyde. In some embodiments, the substi All publications and patent applications mentioned in this tuted benzaldehyde is a skin lightening agent. specification are herein incorporated by reference to the same US 8,778,315 B2 25 26 extent as if each individual publication or patent application The disclosed compositions may modify melanin and/or was specifically and individually indicated to be incorporated melanocyte distribution and/or levels for the treatment of by reference. melanin or pigmentation disorders. The disclosed composi tions may modify melanin and/or melanocyte distribution BRIEF DESCRIPTION OF THE DRAWINGS and/or levels by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, by about 7%, about 7%, about 8%, about The novel features of the embodiments are set forth with 9%, by about 10%, by about 12%, by about 15%, by about particularity in the appended claims. A better understanding 20%, by about 25%, by about 30%, by about 35%, by about of the features and advantages of the present embodiments 35%, by about 40%, by about 45%, by about 50%, by about will be obtained by reference to the following detailed 10 55%, by about 60%, by about 70%, by about 80%, by about description that sets forth illustrative embodiments, in which 90%, by about 100%, by about 125% or by about 150%. The the principles of the invention are utilized, and the accompa disclosed compositions may decrease or increase melanin nying drawings of which: and/or melanocyte distribution and/or levels. For example, in FIG. 1 is a graph that depicts 4-ethoxybenzaldehyde the treatment of hyperpigmentation or hypermelanosis disor 15 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 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 25 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. 30 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 35 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 40 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), 45 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 50 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 55 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 60 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 65 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 US 8,778,315 B2 27 28 another embodiment, the composition comprises from about Compositions described herein may be used to lighten skin 2.0% to about 8.0%, from about 1% to about 10%, or from as well as to treat hyperpigmentation or a hypermelanosis about 0.5% to about 15.0% Niacinamide. In another embodi disorder. In one embodiment, the hyperpigmentation is post ment, the composition comprises from about 1.0% to about inflammatory hyperpigmentation. Hyperpigmentation and 5.0%, from about 0.5% to about 8.0%, or from about 0.1% to hypermelanosis disorders may result from an environmental about 15% Tetrahexyldecyl Ascorbate. In another embodi stressor, physiological stressor, or mechanical stressor. ment, the composition comprises from about 0.001% to about Compositions described herein may reduce melanin distri 0.5%, from about 0.0005% to about 1.0% or from about bution by about 10% to about 40% when applied to skin. 0.0001% to about 2% Licorice root extract. In another Compositions described herein may further comprise one embodiment, the composition comprises from about 0.1% to 10 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 matory agent, an anti-acne agent or mixtures thereof. about 10.0% ethyl linoleate. 15 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 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 comprising from In one embodiment, a skin-lightening agent is selected 0.1% to about 0.5% 4-ethoxybenzaldehyde, about 0.01% to from the group of hydroquinone, monobenzyl ether of hyd about 5.0% each of Retinol, Niacinamide, Tetrahexyldecyl roquinone, azelaic acid, kojic acid, meduinol, retinoids, Soy Ascorbate, Glycyrrhiza Glabra (Licorice) Root Extract, 25 proteins, alpha-hydroxy acids, trichloroacetic acid, salicylic Hexyl Resorcinol, ethyllinoleate, and a pharmaceutically or acid, hydroquinone-beta-D-glucopyranoside, paper mul cosmetically acceptable carrier. In another embodiment, the berry, glabridin, 4-isopropylcetichol, aleosin, N-acetyl-4-S- composition comprises from about 0.1% to about 0.75%, cycteaminylphenol, N-propionyl-4-S-cysteaminylphenol, from about 0.05% to about 1.0%, or from about 0.01% to N-acetyl glucosamine, tranexaminc acid, an alpha MSH about 2% Retinol. In another embodiment, the composition 30 antagonist (e.g. undecylenoyl phenylalanine), phytic acid or comprises from about 2.0% to about 8.0%, from about 1% to combinations thereof. about 10%, or from about 0.5% to about 15.0% Niacinamide. Pharmaceutically or cosmetically acceptable carriers for In another embodiment, the composition comprises from use in the present compositions are topical carriers. The topi about 1.0% to about 5.0%, from about 0.5% to about 8.0%, or cal carrier may be a water-in-oil emulsion, cream, liquid, gel. from about 0.1% to about 15% Tetrahexyldecyl Ascorbate. In 35 oil, paste, ointment, Suspension, foam, lotion, oil-in-water another embodiment, the composition comprises from about emulsion, water-in-oil-in-water emulsion, water-in-silicone 0.001% to about 0.5%, from about 0.0005% to about 1.0% or emulsion, spray or serum carrier. from about 0.0001% to about 2% Licorice root extract. In The compositions described herein may also further com another embodiment, the composition comprises from about prise one or more of a solvent, film former, preservative, 0.1% to about 3.0%, from about 0.05% to about 5.0%, or from 40 Viscosity increasing agent, fragrance, Surfactant, chelating about 0.01% to about 10.0% Resorcinol. In another embodi agent, humectant, permeation enhancer (skin penetrator), ment, the composition comprises from about 0.1% to about excipients, or a combination thereof. 3.0%, from about 0.05% to about 5.0%, or from about 0.01% In one embodiment, a composition comprises about 0.5% to about 10.0% ethyl linoleate. 4-ethoxybenzaldehyde, at least one additional active agent, In yet another aspect, provided herein is a comprising 45 and a pharmaceutically or cosmetically acceptable carrier. In about 0.5% 4-ethoxybenzaldehyde, about 0.01% to about other embodiment, a composition comprises about 0.5% 5.0% each of Retinol, Niacinamide, Tetrahexyldecyl Ascor 4-ethoxybenzaldehyde, at least two additional active agents, bate, Glycyrrhiza Glabra (Licorice) Root Extract, Hexyl and a pharmaceutically or cosmetically acceptable carrier. In Resorcinol, ethyl linoleate, and a pharmaceutically or cos yet other embodiment, a composition comprises about 0.5% metically acceptable carrier. In another embodiment, the 50 4-ethoxybenzaldehyde, at least three additional active agents, composition comprises from about 0.1% to about 0.75%, and a pharmaceutically or cosmetically acceptable carrier. In from about 0.05% to about 1.0%, or from about 0.01% to yet other embodiment, a composition comprises about 0.5% about 2% Retinol. In another embodiment, the composition 4-ethoxybenzaldehyde, at least four additional active agents, comprises from about 2.0% to about 8.0%, from about 1% to and a pharmaceutically or cosmetically acceptable carrier. In about 10%, or from about 0.5% to about 15.0% Niacinamide. 55 yet other embodiment, a composition comprises about 0.5% In another embodiment, the composition comprises from 4-ethoxybenzaldehyde, at least five additional active agents, about 1.0% to about 5.0%, from about 0.5% to about 8.0%, or and a pharmaceutically or cosmetically acceptable carrier. In from about 0.1% to about 15% Tetrahexyldecyl Ascorbate. In yet other embodiment, a composition comprises about 0.5% another embodiment, the composition comprises from about 4-ethoxybenzaldehyde, at least six additional active agents, 0.001% to about 0.5%, from about 0.0005% to about 1.0% or 60 and a pharmaceutically or cosmetically acceptable carrier. from about 0.0001% to about 2% Licorice root extract. In In another embodiment, a composition comprises from another embodiment, the composition comprises from about about 0.1% to about 0.5% 4-ethoxybenzaldehyde, at least one 0.1% to about 3.0%, from about 0.05% to about 5.0%, or from skin lightening agent, at least one skin conditioning agent, at about 0.01% to about 10.0% Resorcinol. In another embodi least one antioxidant, at least one occlusive, at least one ment, the composition comprises from about 0.1% to about 65 emollient, at least one preservative, at least one viscosity 3.0%, from about 0.05% to about 5.0%, or from about 0.01% increasing agent, at least one fragrance, at least one skin to about 10.0% ethyl linoleate. conditioning agent, at least one surfactant, at least one chelat US 8,778,315 B2 29 30 ing agent, at least one humectant, and a pharmaceutically or As used herein, the term “acyl refers to a radical formed cosmetically acceptable carrier. by removal of a hydroxyl group from an organic acid and has In another embodiment, a composition comprises about the general formula —C(O)—X where X is hydrogen, sub 0.5% 4-ethoxybenzaldehyde, at least one skin lightening stituted or unsubstituted alkyl, substituted or unsubstituted agent, at least one skin conditioning agent, at least one anti- 5 cycloalkyl, substituted or unsubstituted cycloheteroalkyl, oxidant, at least one occlusive, at least one emollient, at least substituted or unsubstituted aryl, substituted or unsubstituted one preservative, at least one viscosity increasing agent, at arylalkyl, substituted or unsubstituted heteroalkyl, substi least one fragrance, at least one skin conditioning agent, at tuted or unsubstituted heteroaryl, substituted or unsubstituted least one surfactant, at least one chelating agent, at least one heteroarylalkyl as defined herein. Representative examples humectant, and a pharmaceutically or cosmetically accept 10 include, but are not limited to, formyl, acetyl, cylcohexylcar able carrier. In another embodiment, the composition com bonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl prises from about 0.1% to about 0.75%, from about 0.05% to and the like. about 1.0%, or from about 0.01% to about 2% Retinol. In Acyloxy” refers to the group or radical —OC(O)R23 another embodiment, the composition comprises from about 15 where R23 is hydrogen, substituted or unsubstituted alkyl, 2.0% to about 8.0%, from about 1% to about 10%, or from substituted or unsubstituted aryl or substituted or unsubsti about 0.5% to about 15.0% Niacinamide. In another embodi tuted cycloalkyl. ment, the composition comprises from about 1.0% to about The term “alkyl as used herein refers to saturated or unsat 5.0%, from about 0.5% to about 8.0%, or from about 0.1% to urated, straight- or branched-chain hydrocarbon radicals about 15% Tetrahexyldecyl Ascorbate. In another embodi- 20 derived from a hydrocarbon moiety containing between one ment, the composition comprises from about 0.001% to about and twenty carbon atoms by removal of a single hydrogen 0.5%, from about 0.0005% to about 1.0% or from about atom. Alkyl groups as used herein may optionally include one 0.0001% to about 2% Licorice root extract. In another or more further substituent groups. This term is exemplified embodiment, the composition comprises from about 0.1% to by groups such as methyl, ethyl, n-propyl, isopropyl. n-butyl, about 3.0%, from about 0.05% to about 5.0%, or from about 25 iso-butyl, tert-butyl, n-hexyl, n-octyl, tert-octyl and the like, 0.01% to about 10.0% Resorcinol. In another embodiment, and may be substituted or unsubstituted. The term “lower the composition comprises from about 0.1% to about 3.0%, alkyl refers to alkyl groups having 1 to 6 carbon atoms. The from about 0.05% to about 5.0%, or from about 0.01% to term “alkyl also includes “cycloalkyls' as defined below. about 10.0% ethyl linoleate. Alkynyl refers to acetylenically or alkynically unsatur In some embodiments, the combination compositions dis- 30 ated hydrocarbyl groups particularly having 2 to 11 carbon closed herein may act additively or synergistically. In some atoms and more particularly 2 to 6 carbonatoms which can be embodiments, a “synergistic effect” may be seen where the straight-chained or branched and having at least 1 and par combination of the substituted benzaldehyde and additional ticularly from 1 to 2 sites of alkynyl unsaturation. Particular active agent(s) results in an activity that is more than the effect non-limiting examples of alkynyl groups include Substituted of the two individual agents alone. In other embodiments, a 35 or unsubstituted acetylenic, substituted or unsubstituted ethy “synergistic effect” may be seen where a combination of the nyl ( C=CH), substituted or unsubstituted propargyl Substituted benzaldehyde and additional active agent(s) (-CH2C=CH), and the like. results in a modulation in melanin distribution, but no effect is The term "aminoalkyl as used herein, refers to an amino seen when the agents are used individually. In yet other substituted alkyl radical. This term is meant to include alkyl embodiments, a “synergistic effect” may allow a decrease in 40 groups having an amino Substituent at any position and the amount of substituted benzaldehyde and/or additional wherein the alkyl group attaches the aminoalkyl group to the active agent(s) used, thereby decreasing the incidence of parent molecule. The alkyl and/or amino portions of the ami adverse side effects. Such as itching, pruritis, skin irritation or noalkyl group can be further substituted with substituent other adverse side effects. groups. As used in the specification and the appended claims, the 45 As used herein, the term “alkoxy' refers to a radical formed singular forms “a”, “an and “the include plural references between an alkyl group and an oxygen atom wherein the unless the context clearly dictates otherwise. Thus for oxygen atom is used to attach the alkoxy group to a parent example, reference to “the method’ includes one or more molecule. Alkoxy groups as used herein may optionally methods, and/or steps of the type described herein and/or include further Substituent groups. Particular alkoxy groups which will become apparent to those persons skilled in the art 50 include, by way of example, substituted or unsubstituted upon reading this disclosure. methoxy, substituted or unsubstituted ethoxy, substituted or The term “about' or “approximately’ means within an unsubstituted n-propoxy, Substituted or unsubstituted isopro acceptable error range for the particular value as determined poxy, substituted or unsubstituted n-butoxy, substituted or by one of ordinary skill in the art, which will dependin part on unsubstituted tert-butoxy, substituted or unsubstituted sec how the value is measured or determined, i.e., the limitations 55 butoxy, substituted or unsubstituted n-pentoxy, substituted or of the measurement system. For example, "about can mean unsubstituted n-hexoxy, substituted or unsubstituted 1,2-dim within 1 or more than 1 standard deviation, per the practice in ethylbutoxy, and the like. the art. Alternatively, “about can mean a range of up to 20%, As used herein, the term “alkenyl refers to a straight or preferably up to 10%, more preferably up to 5%, and more branched hydrocarbon chain radical containing up to twenty preferably still up to 1% of a given value. Alternatively, par- 60 four carbon atoms and having at least one carbon-carbon ticularly with respect to biological systems or processes, the double bond. Alkenyl groups as used herein may optionally term can mean within an order of magnitude, preferably include one or more further substituent groups. Particular within 5-fold, and more preferably within 2-fold, of a value. alkenyl groups include Substituted or unsubstituted ethenyl Where particular values are described in the application and (—CH=CH2), substituted or unsubstituted n-propenyl claims, unless otherwise stated the term “about’ meaning 65 (—CH2CH=CH2), substituted or unsubstituted isopropenyl within an acceptable error range for the particular value (—C(CH3)-CH2), substituted or unsubstituted vinyl and should be assumed. substituted vinyl, and the like. US 8,778,315 B2 31 32 As used herein, the term “aryl” refers to a mono- or poly stituted or unsubstituted cycloalkyl, or where the R37 groups cyclic carbocyclic ring system radicals having one or more are joined to form an alkylene group. aromatic rings. Aryl groups as used herein may optionally “Aminocarbonylamino” refers to the group —NR38C(O) include further Substituent groups. Typical aryl groups NR38R38 where each R38 is independently hydrogen, sub include, but are not limited to, groups derived from acean stituted or unsubstituted alkyl, substituted or unsubstituted thrylene, acenaphthylene, acephenanthrylene, anthracene, aryl or substituted or unsubstituted cycloalkyl, or where two aZulene, benzene, chrysene, coronene, fluoranthene, fluo R groups are joined to form an alkylene group. rene, hexacene, hexaphene, hexylene, as-indacene, S-in “Aminocarbonyloxy' refers to the group —OC(O) dacene, indane, indene, naphthalene, octacene, octaphene, NR39R39 where each R39 is independently hydrogen, sub octalene, ovalene, penta-2,4-diene, pentacene, pentalene, 10 stituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted cycloalkyl, or where the R pentaphene, perylene, phenalene, phenanthrene, picene, ple groups are joined to form an alkylene group. iadene, pyrene, pyranthrene, rubicene, triphenylene, trinaph Arylalkyloxy' refers to a substituted or unsubstituted thalene and the like, and may be substituted or unsubstituted. —O-arylalkyl radical where arylalkyl is as defined herein. Particularly, an aryl group comprises from 6 to 14 carbon 15 Arylamino” means a substituted or unsubstituted radical atOmS. —NHR40 where R40 represents an aryl group as defined Alkaryl” refers to an aryl group, as defined above, substi herein. tuted with one or more substituted or unsubstituted alkyl Aryloxycarbonyl refers to a substituted or unsubstituted groups, as defined above. radical —C(O)—O-aryl where aryl is as defined herein. Aralkyl or “arylalkyl refers to an alkyl group, as defined Arylsulfonyl refers to a r substituted or unsubstituted above, substituted with one or more substituted or unsubsti radical—S(O)2R41 where R41 is an aryl or heteroaryl group tuted aryl groups, as defined above. as defined herein. Aryloxy' refers to substituted or unsubstituted —O-aryl “AZido’ refers to the radical - N3. groups wherein “aryl' is as defined above. “Bicycloaryl refers to a monovalent aromatic hydrocar Alkylamino” refers to the group alkyl-NR28R29, wherein 25 bon group derived by the removal of one hydrogenatom from each of R28 and R29 are independently selected from hydro a single carbonatom of a parent bicycloaromatic ring system. gen and Substituted or unsubstituted alkyl. Typical bicycloaryl groups include, but are not limited to, Arylamino” refers to the group aryl-NR30R31, wherein groups derived from indane, indene, naphthalene, tetrahy each of R30 and R31 are independently selected from hydro dronaphthalene, and the like, and may be substituted or gen, Substituted or unsubstituted aryl and Substituted or 30 unsubstituted. Particularly, an aryl group comprises from 8 to unsubstituted heteroaryl. 11 carbon atoms. "Alkoxyamino” refers to a radical N(H)OR32 where “Bicycloheteroaryl” refers to a monovalent bicyclohet R32 represents a substituted or unsubstituted alkyl or substi eroaromatic group derived by the removal of one hydrogen tuted or unsubstituted cycloalkyl group as defined herein. atom from a single atom of a parent bicycloheteroaromatic Alkoxycarbonyl refers to a substituted or unsubstituted 35 ring system. Typical bicycloheteroaryl groups include, but radical —C(O)-alkoxy where alkoxy is as defined herein. are not limited to, groups derived from benzofuran, benzimi Alkylarylamino” refers to a substituted or unsubstituted dazole, benzindazole, benzdioxane, chromene, chromane, radical NR33R34 where R33 represents an alkyl or cinnoline, phthalazine, indole, indoline, indolizine, isoben cycloalkyl group and R34 is an aryl as defined herein. Zofuran, isochromene, isolindole, isoindoline, isoquinoline, Alkylsulfonyl refers to a substituted or unsubstituted 40 benzothiazole, benzoxazole, naphthyridine, benzoxadiazole, radical —S(O)2R35 where R35 is an alkyl or cycloalkyl pteridine, purine, benzopyran, benzpyrazine, pyridopyrimi group as defined herein. Representative examples include, dine, quinazoline, quinoline, quinolizine, quinoxaline, ben but are not limited to, methylsulfonyl, ethylsulfonyl, propyl Zomorphan, tetrahydroisoquinoline, tetrahydroquinoline, sulfonyl, butylsulfonyl and the like. and the like, and may be substituted or unsubstituted. Prefer Alkylsulfinyl refers to a substituted or unsubstituted radi 45 ably, the bicycloheteroaryl group is between 9-11 membered cal —S(O)R35 where R35 is an alkyl or cycloalkyl group as bicycloheteroaryl, with 5-10 membered heteroaryl being par defined herein. Representative examples include, but are not ticularly preferred. Particular bicycloheteroaryl groups are limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl, those derived from benzothiophene, benzofuran, benzothia butylsulfinyl and the like. Zole, indole, quinoline, isoquinoline, benzimidazole, benzox Alkylthio’ refers to a substituted or unsubstituted radical 50 azole and benzdioxane. —SR35 where R35 is an alkyl or cycloalkyl group as defined “Carbamoyl refers to the radical –C(O)N(R42)2 where herein that may be optionally substituted as defined herein. each R42 group is independently hydrogen, Substituted or Representative examples include, but are not limited to, unsubstituted alkyl, substituted or unsubstituted cycloalkyl or methylthio, ethylthio, propylthio, butylthio, and the like. substituted or unsubstituted aryl, as defined herein, which Amino refers to the radical NH2. 55 may be optionally substituted as defined herein. “Substituted amino” includes those groups recited in the “Carboxy” refers to the radical - C(O)OH. definition of “substituted herein, and particularly refers to “Carboxyamino” refers to the radical N(H)C(O)OH. the group —N(R36)2 where each R36 is independently “Cycloalkyl refers to cyclic hydrocarbyl groups having selected from the group consisting of hydrogen, alkyl, Sub from 3 to about 10 carbon atoms and having a single cyclic stituted alkyl, alkenyl, Substituted alkenyl, alkynyl, Substi 60 ring or multiple condensed rings, including fused and bridged tuted alkynyl, aryl, cycloalkyl, Substituted cycloalkyl, and ring systems, which optionally can be substituted with from 1 where both R groups are joined to form an alkylene group. to 3 alkyl groups. Such cycloalkyl groups include, by way of When both R groups are hydrogen, —N(R36)2 is an amino example, single ring structures such as cyclopropyl, cyclobu group. tyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methyl “Aminocarbonyl refers to the group –C(O)NR37R37 65 cyclopentyl, 2-methylcyclooctyl, and the like, and multiple where each R37 is independently hydrogen, substituted or ring structures Such as adamantanyl, and the like, and may be unsubstituted alkyl, substituted or unsubstituted aryland sub substituted or unsubstituted. US 8,778,315 B2 33 34 “Cycloalkoxy' refers to the group —OR43 where R43 is independently a halogen; each R46, R47, R48 and R49 are substituted or unsubstituted cycloalkyl. Such cycloalkoxy independently hydrogen, alkyl, Substituted alkyl, aryl, Substi groups include, by way of example, Substituted or unsubsti tuted alkyl, arylalkyl, substituted alkyl, cycloalkyl, substi tuted cyclopentoxy, Substituted or unsubstituted cyclohexoxy tuted alkyl, cycloheteroalkyl, substituted cycloheteroalkyl, and the like. heteroalkyl, substituted heteroalkyl, heteroaryl, substituted “Cycloalkenyl refers to cyclic hydrocarbyl groups having heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, from 3 to 10 carbon atoms and having a single cyclic ring or NR50R51, C(O)R50 or S(O)2R50 or optionally R50 multiple condensed rings, including fused and bridged ring and R51 together with the atom to which they are both systems and having at least one and particularly from 1 to 2 attached form a cycloheteroalkyl or substituted cyclohet sites of olefinic unsaturation. Such cycloalkenyl groups 10 eroalkyl ring; and R50 and R51 are independently hydrogen, include, by way of example, single ring structures such as alkyl, substituted alkyl, aryl, substituted alkyl, arylalkyl, sub 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 15 or substituted heteroarylalkyl. tuted cycloalkenyl having two of its ring carbon atoms in “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. “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 25 R2 Substituted heteroaryl group as defined herein. 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 30 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 OR the hydrocarbyl groups described above Such as alkyl, e.g. R heteroalkyl, cycloalkyl, e.g. cycloheteroalkyl, aryl, e.g. het OH eroaryl, cycloalkenyl, cycloheteroalkenyl, and the like having 35 from 1 to 5, and especially from 1 to 3 heteroatoms. “Heteroaryl” refers to a monovalent heteroaromatic group R 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 40 R OR6 from acridine, arsindole, carbazole, B-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, R indoline, indolizine, isobenzofuran, isochromene, isoindole, OR6 isoindoline, isoquinoline, isothiazole, isoxazole, naphthyri dine, oxadiazole, oxazole, perimidine, phenanthridine, 45 R3 Rs phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, R4 pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, qui noxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, wherein each R. R. R. Ra, and Rs is independently xanthene, and the like. Preferably, the heteroaryl group is 50 selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, acy between 5-15 membered heteroaryl, with 5-10 membered loxy, cycloalkyl, cycloheteroalkyl, alkoxy, alkoxyamino, heteroaryl being particularly preferred. Particular heteroaryl alkoxycarbonyl, cycloalkoxy, cycloalkenyl, cyano, cyanato, groups are those derived from thiophene, pyrrole, ben aryl, arylalkyl, alkylaryl, aryloxy, heteroaryl, heteroaryloxy, Zothiophene, benzofuran, indole, pyridine, quinoline, imida amino, aminoalkyl, alkylarylamino, alkylamino, aminocar Zole, oxazole and pyrazine. 55 bonylamino, aminocarbonyloxy, arylamino, azido, bicy “Substituted refers to a group in which one or more hydro 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 hydro not limited to, —X, —R46, —O— —O, —OR46, —SR46, gen; and each Re is independently alkyl. —S —S, NR46R47, =NR46, CX3, -CF3, CN, 60 "Pharmaceutically acceptable” means approved by a regu OCN, SCN, NO, NO2, —N2, N3, S(O)2O , 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. 65 “Cosmetically acceptable” means suitable for cosmetic 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 US 8,778,315 B2 35 36 side effects upon application of the composition or com “Prodrugs’ refers to compounds, including derivatives of pounds disclosed herein. Other applications include skin care disclosed compounds, which have cleavable groups and applications, including but not limited to lotions, cream, become by Solvolysis or under physiological conditions of cleansing creams or lotions, soaps and other cleansers, anti compounds which are pharmaceutically active in vivo. Such perspirant and/or deodorants, makeup products, such as face examples include, but are not limited to, choline ester deriva powders, foundations, rouge, eye shadow, mascara, eyeliner tives and the like, N-alkylmorpholine esters and the like. or lipstick, Sun protection products, such as Sunscreen or “Solvate” refers to forms of the compound that are associ other UV-protective cosmetics, lotions or creams, hairdress ated with a solvent, usually by a solvolysis reaction. Conven ing products, such as shampoo, rinses, or treatment setting tional solvents include water, ethanol, acetic acid and the like. 10 The compounds disclosed herein may be prepared e.g. in agents. The phrases “pharmaceutically acceptable' and "cos crystalline form and may be solvated or hydrated. Suitable metically acceptable' are not meant to imply mutual exclu Solvates include pharmaceutically acceptable Solvates, such 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 15 “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, pound, the disease and its severity, and the age, weight, etc., of and the like; or formed with organic acids such as acetic acid, the subject to be treated. propionic acid, hexanoic acid, cyclopentanepropionic acid, “Treating or “treatment of any disease or disorder refers, glycolic acid, pyruvic acid, lactic acid, malonic acid, Succinic 25 in one embodiment, to ameliorating the disease or disorder acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric (i.e., arresting or reducing the development of the disease or acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cin at least one of the clinical symptoms thereof). In another namic acid, mandelic acid, methanesulfonic acid, ethane embodiment “treating or “treatment” refers to ameliorating Sulfonic acid, 1.2-ethane-disulfonic acid, 2-hydroxyethane at least one physical parameter, which may not be discernible sulfonic acid, benzenesulfonic acid, 30 by the subject. In yet another embodiment, “treating or 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, “treatment” refers to modulating the disease or disorder, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicy either physically, (e.g., stabilization of a discernible symp clo2.2.2-oct-2-ene-1-carboxylic acid, glucoheptonic acid, tom), physiologically, (e.g., stabilization of a physical param 3-phenylpropionic acid, trimethylacetic acid, tertiary buty eter), or both. In yet another embodiment, “treating” or “treat lacetic acid, lauryl Sulfuric acid, gluconic acid, glutamic acid, 35 ment” refers to delaying the onset of the disease or disorder, hydroxynaphthoic acid, salicylic acid, Stearic acid, muconic or even preventing the same. In a still further embodiment, acid, and the like; or (2) salts formed when an acidic proton “treating or “treatment” refers to administration of the com present in the parent compound either is replaced by a metal pound or compositions disclosed herein for cosmetic pur ion, e.g., an alkali metal ion, an alkaline earth ion, or an poses. aluminum ion; or coordinates with an organic base Such as 40 Other derivatives of the disclosed compounds have activity ethanolamine, diethanolamine, triethanolamine, N-methyl in both their acid and acid derivative forms, but in the acid glucamine and the like. Salts further include, by way of sensitive form often offers advantages of solubility, tissue example only, sodium, potassium, calcium, magnesium, compatibility, or delayed release in the mammalian organism ammonium, tetraalkylammonium, and the like; and when the (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, compound contains a basic functionality, salts of non toxic 45 Elsevier, Amsterdam 1985). Prodrugs include acid deriva organic or inorganic acids, such as hydrochloride, hydrobro tives such as, for example, esters prepared by reaction of the mide, tartrate, mesylate, acetate, maleate, oxalate and the parent acid with a suitable alcohol, or amides prepared by like. In some embodiments, a “pharmaceutically acceptable reaction of the parent acid compound with a substituted or salt may also be used in conjunction with cosmeceutically unsubstituted amine, or acid anhydrides, or mixed anhy acceptable compositions. 50 drides. Simple aliphatic or aromatic esters, amides and anhy The term “pharmaceutically acceptable cation” refers to a drides derived from acidic groups pendant on the disclosed non toxic, acceptable cationic counter-ion of an acidic func compounds are preferred prodrugs. In some cases it is desir tional group. Such cations are exemplified by Sodium, potas able to prepare double ester type prodrugs such as (acyloxy) sium, calcium, magnesium, ammonium, tetraalkylammo alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Preferred nium cations, and the like. In some embodiments, a 55 are the C1 to C8 alkyl, C2-C8 alkenyl, aryl, C7-C12 substi “pharmaceutically acceptable cation' may also be used in tuted aryl, and C7-C12 arylalkyl esters of the disclosed com conjunction with cosmeceutically-acceptable compositions. pounds herein. “Pharmaceutically acceptable vehicle' refers to a diluent, As used herein, the term “isotopic variant” refers to a adjuvant, excipient or carrier with which a disclosed com compound that contains unnatural proportions of isotopes at pound is administered. In some embodiments, a “pharmaceu 60 one or more of the atoms that constitute Such compound. For tically acceptable vehicle' may also be used in conjunction example, an "isotopic variant' of a compound can contain one with cosmetically-acceptable compositions. or more non-radioactive isotopes, such as for example, deu “Preventing or “prevention” refers to a reduction in risk of terium (2H or D), carbon-13 (13C), nitrogen-15 (15N), or the acquiring a disease or disorder (i.e., causing at least one of the like. It will be understood that, in a compound where such clinical symptoms of the disease not to develop in a subject 65 isotopic Substitution is made, the following atoms, where that may be exposed to or predisposed to the disease but does present, may vary, so that for example, any hydrogen may be not yet experience or display symptoms of the disease). 2H/D, any carbon may be 13C, or any nitrogen may be 15N, US 8,778,315 B2 37 38 and that the presence and placement of Such atoms may be the striavascularis of the inner ear. Melanindisorders canthus determined within the skill of the art. Likewise, the disclosed affect a variety of physiological systems, including the skin, compounds may include the preparation of isotopic variants hair, eye, inner ear, as well as neurological structures in the with radioisotopes, in the instance for example, where the brain, where tissues with melanin include the medulla and resulting compounds may be used for drug and/or substrate 5 Zona reticularis of the adrenal gland, and pigment-bearing tissue distribution studies. The radioactive isotopes tritium, neurons within areas of the brainstem, such as the locus i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this coeruleus and the Substantia nigra. purpose in view of their ease of incorporation and ready Environmental and/or physiological stress can cause dis means of detection. Further, compounds may be prepared that orders in melanin production, as well as various genetic are Substituted with positron emitting isotopes, such as 11C, 10 abnormalities. With regards to hypopigmentation disorders, 18F 15O and 13N, and would be useful in Positron Emission there are approximately ten different types of oculocutaneous Topography (PET) studies for examining substrate receptor albinism, which is mostly an autosomal recessive disorder. Occupancy. Hypopigmentation occurs when pigment-producing cells All isotopic variants of the compounds provided herein, (melanocytes) are either destroyed or inactive. Other hypop radioactive or not, are intended to be encompassed within the 15 igmentation disorders include conditions due to skin damage Scope of the contemplated compounds. (e.g. burn or ablative laser resurfacing) or due to autoimmune It is also to be understood that compounds that have the disease where the immune system attacks melanocytes, as in same molecular formula but differ in the nature or sequence vitiligo. Vitiligo can also be caused by physical trauma or of bonding of their atoms or the arrangement of their atoms in certain diseases, such as Addison's disease or diabetes. space are termed "isomers'. Isomers that differ in the 20 Hyperpigmentation or hypermelanosis disorders result in arrangement of their atoms in space are termed “stereoiso an increase in melanin or melanocyte production and/or dis mers’. tribution. For example, post-inflammatory hyperpigmenta Stereoisomers that are not mirror images of one another are tion (“PIH) represents the sequelae of various cutaneous termed "diastereomers' and those that are non-Superimpos disorders, including infections, allergic reactions, mechani able mirror images of each other are termed “enantiomers. 25 cal injuries, reactions to medications, phototoxic eruptions, When a compound has an asymmetric center, for example, it trauma (e.g. burns), as well as reactions to devices, including is bonded to four different groups, a pair of enantiomers is electromagnetic devices such as ultrasound, radiofrequency, possible. An enantiomer can be characterized by the absolute lasers, light-emitting diodes and visible light therapy, as well configuration of its asymmetric center and is described by the as microdermabrasion reactions, shaving, chemical peels or R- and S-sequencing rules of Cahn and Prelog, or by the 30 other dermatological procedures. PIH occurs widely in the manner in which the molecule rotates the plane of polarized human population and can be the Source of significant psy light and designated as dextrorotatory or levorotatory (i.e., as chosocial distress for those affected with this disorder. PIH (+) or (-)-isomers respectively). A chiral compound can exist may occur as a pathophysiologic response to cutaneous as either individual enantiomer or as a mixture thereof. A inflammation. Melanocytes can be stimulated by the inflam mixture containing equal proportions of the enantiomers is 35 matory process to synthesize and secrete more melanin from called a “racemic mixture'. melanocytes, or the number of melanocytes can increase in “Tautomers' refer to compounds that are interchangeable the epidermis, leading to hyperpigmentation of the skin. PIH forms of a particular compound structure, and that vary in the can also occur when inflammation Succeeds in disrupting the displacement of hydrogen atoms and electrons. Thus, two basal cell layer, causing melanin pigment to be released and structures may be in equilibrium through the movement of it 40 Subsequently trapped by macrophages in the papillary der electrons and an atom (usually H). For example, enols and mis. PIH also occurs in instances where inflammation is 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 45 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- 50 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- 55 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. The compositions disclosed herein seek to treat melanin Melanin Disorders 60 disorders, including PIH and other hyperpigmentation disor ders by modifying melanin distribution and/or production. As discussed above, melanin in humans is the primary The compositions disclosed herein also seek to treatmela determinant of skin color. Melanin pigments (eumelanin, nin disorders in conjunction with treatments and/or proce pheomelanin and neuromelanin) are derivatives of the amino dures that may cause hypermelanosis or hyperpigmentation acid tyrosine, and production of melanin pigments is cataly- 65 disorders. Accordingly, the compositions disclosed herein sed by the enzyme tyrosinase. Melanin is also found in hair, may be used in conjunction with the treatment of skin disor the pigmented tissue underlying the iris of the eye, as well as ders or trauma as a result of a mechanical injury or therapy, US 8,778,315 B2 39 including but not limited to laser treatment, chemical peels, -continued intense pulsed light, dermabrasion or cryotherapy. O O

Compounds H Me H

Disclosed herein are compositions comprising Substituted OEt -> benzaldehydes, at least one or a blend of pharmaceutically or O O O cosmetically active agents, and a pharmaceutically or cos metically acceptable carrier. In some embodiments, the Sub 10 stituted benzaldehydes disclosed herein are used in combina H C H H tion with at least one additional therapeutic agent. OEt OAc

In some embodiments, the composition comprises a Sub OEt OMe stituted benzaldehyde of Formula I: O O 15

Formula I H H

FC NC

Non-limiting examples of substituted benzaldehydes include alkoxy-Substituted benzaldehydes (e.g., 4-ethoxy benzaldehyde, 2-ethoxybenzaldehyde, 2-acetoxy-3-meth 25 oxybenzaldehye, 4-allyloxybenzaldehyde, 4-propoxyben Zaldehyde, 4-butoxtbenzaldehyde, 2-fluoro-4- wherein each R. R. R. R. and Rs is independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, ary ethoxybenzaldehyde), amino-substituted benzaldehydes, loxy, cycloalkyl, cycloheteroalkyl, alkoxy, alkoxyamino, alkyl-substituted benzaldehydes, aryl-substituted benzalde alkoxycarbonyl, cycloalkoxy, cycloalkenyl, cyano, cyanato, 30 hydes, and sulfone-substituted benzaldehydes. In one aryl, arylalkyl, alkylaryl, aryloxy, heteroaryl, heteroaryloxy, embodiment, the substituted benzaldehyde is 4-ethoxyben amino, aminoalkyl, alkylarylamino, alkylamino, aminocar Zaldehyde, 2-ethoxybenzaldehyde, 4-allyloxybenzaldehyde bonylamino, aminocarbonyloxy, arylamino, azido, bicy and/or 4-propoxybenzaldehyde. In one particular embodi cloaryl, carbamoyl carboxy, carboxyamino, heteroary ment, the substituted benzaldehyde is 4-ethoxybenzalde lamino, alkylsulfonyl, alkylthio, and Sulfone; and wherein at 35 hyde. least one of R. R. R. R. or Rs is not hydrogen. In certain embodiments, the substituted benzaldehyde In specific embodiments, R3 is ethoxy. In other embodi compounds include their acetal and hemiacetal equivalents ments, R1, R2, R4, and R5 are hydrogen. (i.e., C(OR)(OH) and C(OR) replaces the formyl group or C(O)H of the benzaldehyde, wherein R is an alkyl group). Specific compounds of Formula I are shown below: 40 In some embodiments, the composition comprises the hemi acetal of Formula II: O O

Formula II O H O H 45 OR6 EtO MeO OH O F O

50 O H H MeOS EtO F O O wherein each R. R. R. R. and Rs is independently 55 selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, acy loxy, cycloalkyl, cycloheteroalkyl, alkoxy, alkoxyamino, H O H alkoxycarbonyl, cycloalkoxy, cycloalkenyl, cyano, cyanato, F F aryl, arylalkyl, alkylaryl, aryloxy, heteroaryl, heteroaryloxy, O O amino, aminoalkyl, alkylarylamino, alkylamino, aminocar 60 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 hydro 65 gen; and each Re is independently alkyl. OEt In other embodiments, the composition comprises the acetal of Formula III: US 8,778,315 B2 42 Other embodiments include phenols and phenolic acids Formula III (guaiacol, hydroquinone, Vanillin, gallic acids and their R OR6 esters, protocatechuic acid, quinic acid, Syringic acid, ellagic R2 acid, salicylic acid, nordihydroguaiaretic acid (NDGA), OR6 eugenol); curcumins, tocopherols (including tocopherols (al pha, beta, gamma, delta) and their derivatives, such as toco pheryl-acylate (e.g., -acetate, -laurate, myristate, -palmitate, R3 Rs -oleate, -linoleate, etc., or an y other suitable tocopheryl R4 lipoate), tocopheryl-POE-succinate; Dunaliella Salina 10 Extract; trolox and corresponding amide and thiocarboxam ide analogues; ascorbic acid and its salts, isoascorbate, alky wherein each R. R. R. R. and Rs is independently lascorbic acids, ascorbyl esters (e.g., 6-o-lauroyl, myristoyl, selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, acy palmitoyl-, oleoyl, or linoleoyl-L-ascorbic acid, etc.). Also loxy, cycloalkyl, cycloheteroalkyl, alkoxy, alkoxyamino, useful are oxidized compounds, such as sodium bisulphite, alkoxycarbonyl, cycloalkoxy, cycloalkenyl, cyano, cyanato, 15 Sodium metabisulphite, thiourea; chelating agents, such as aryl, arylalkyl, alkylaryl, aryloxy, heteroaryl, heteroaryloxy, EDTA (e.g., disodium EDTA), EGTA, desferral; transferrin, amino, aminoalkyl, alkylarylamino, alkylamino, aminocar lactoferrin, ferritin, cearuloplasmin, haptoglobion, hea bonylamino, aminocarbonyloxy, arylamino, azido, bicy mopexin, albumin, glucose, ubiquinol-10; enzymatic antioxi cloaryl, carbamoyl carboxy, carboxyamino, heteroary dants, such as Superoxide dismutase and metal complexes lamino, alkylsulfonyl, alkylthio, and Sulfone; with a similar activity, including catalase, glutathione peroxi wherein at least one of R. R. R. R. or Rs is not hydro dase, and less complex molecules, such as beta-carotene, gen; and each Re is independently alkyl. bilirubin, uric acid; flavonoids (flavones, flavonols, fla Vonones, flavanonals, chacones, anthocyanins), N-acetylcys Additional Active Agents tein, mesna, glutathione, thiohistidine derivatives, triazoles; 25 tannines, cinnamic acid, hydroxycinnamatic acids and their In one embodiment, the composition further comprises an 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 30 grape seed extract, pomegranate extract, Spice extracts (e.g., screens, Sunblocks, Sunprotectants, antibiotics, antivirals, 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 35 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 40 In other embodiments, the composition comprises at least stated above, wherein the like acting agent is a cosmetically 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 45 noyl phenylalanine), phytic acid, monobenzyl ether of phosphate or ascorbylglucosamine, or mixtures thereof. 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 50 din, 4-isopropylcetichol, aleosin, N-acetyl-4-S-cycteami aesthetic component. Such as fragrances, pigments, color 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 55 examples of botanical extracts are selected from the group example humectants and emollients, a skin Soothing agent, a 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, 60 rice extracts (e.g., glabridin, liquiritin, glabrene, isoliquiriti the retinoid is retinol, retinal, retinol esters, retinyl propi 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 65 cinnamic aid, cinnamic acid, Sophorcarpidine, aloe vera min E. Coenzyme Q10, idebenone, lycopene, green tea extract, alaria esculenta extract, alfalfa extract, algae extract, polyphenols, Silybin, resveratrol, genistein, and pycnogenol. althaea extract, angelica extract, apple extract, arnica US 8,778,315 B2 43 44 extract, ascorbyl palmitate, avocado oil, babassu palm tree screen”, “sunprotectant” or "sunblock” as used herein defines fruit, balm mint extract, bamboo extract, bergamot oil, betula ultraviolet ray-blocking compounds exhibiting absorption or extract, bilberry, birch leaf extract, bisabolol, blackcurrant blockage within the wavelength region between about 290 extract, black raspberry seed oil, bladderwrack extract, blue and 420 nm. Such agents may be classified into five groups green algae, blue malva extract, borage seed oil, boswellia based upon their chemical structure: para-amino benzoates; serrata, buddleja davidii extract, buckthorn, buckwheat seed salicylates; cinnamates; benzophenones; and miscellaneous extract, burdock root extract, burdock, butcher's broom, cal chemicals including menthyl anthralinate and digalloyl tri endula, calendula extract, Camelia oil, capsaicin, carrag oleate. Inorganic Sunscreens may also be used including tita eenan extract, carrot extract, cascara Sagrada, castor oil, cay nium dioxide, Zinc oxide, iron oxide and polymer particles enne, cedarwood, chamomile, chamomile extract, 10 Such as those of polyethylene and polyamides. Specific Suit chamomile oil, chaparral extract, chaste tree berry extract, able Sunscreen agents include, for example: p-aminobenzoic chia seed oil, chickpea seed extract, chlorella, chrysanthellis, acid, its salts and its derivatives (ethyl, isobutyl, glyceryl cinnamon bark, citrus extract, clover, clover blossom extract, esters, p-dimethylaminobenzoic acid); Anthranilates (i.e., clover extract, clover flower oil, cocoa extract, cocoa seed o-aminobenzoates; methyl, menthyl, phenyl, benzyl, phenyl butter, codonopsis, colleus forskohli, coriander, corn oil, cot 15 ethyl, linallyl, terpinyl, and cyclohexenyl esters); Salicylates tonseed oil, couch grass, crambe abyssinica seed extract, (amyl, phenyl, benzyl, menthyl, glyceryl, and dipropylene cranberry protein, Crithmum maritimum extract, cupuacu, glycol esters); Cinnamic acid derivatives (methyl and benzyl cypress oil, dandelion, dandelion extract, dong quai, esters, alpha-phenyl cinnamonitrile; butyl cinnamoyl pyru Dunaliella Salina extract, Echinacea angustifolia purpurea, vate); Dihydroxycinnamic acid derivatives (umbelliferone, echium plantagineum, elderberry, esculin, eucalyptus, methylumbelliferone, methylaceto-umbelliferone); Trihy evening primrose oil, fennel, ferula foetida root extract, flax droxycinnamic acid derivatives (esculetin, methylesculetin, seed oil, fucoidan extract, garcinia Cambogia, garlic, gera daphnetin, and the glucosides, esculin and daphnin); Hydro nium extract, geranium oil, ginger, ginger root extract, ginkgo carbons (diphenylbutadiene, stilbene); Dibenzalacetone and biloba, ginseng, ginseng extract, glucosamine, golden seal benzalacetophenone; Naphtholsulfonates (sodium salts of extract, gotu kola, grapefruit extract, grapeseed, grapeseed 25 2-naphthol-3,3-disulfonic and of 2-naphthol-6,8-disulfonic extract, grapeseed oil, green tea, green tea extract, guarana, acids); Dihydroxynaphthoic acid and its salts; o- and p-Hy guggul gum extract, gymnesa Sylvestre, hazel oil, hawthorn, droxybiphenyldisulfonates; Coumarin derivatives (7-hy holarrhena antidysenterica extract, honeysuckle extract, droxy, 7-methyl, 3-phenylyl); Diazoles (2-acetyl-3-bro hops extract, horse chestnut, horsetail extract, hybrid saf moindazole, phenyl benzoxazole, methyl naphthoxalole, flower oil, hydrolyzed soy protein, imperata cylindrical root 30 various arylbenzothiazoles); Quinine salts (bisulfate, sulfate, extract, ivy leaf extract, jasmine oil, jojoba oil, juniper oil, chloride, oleate, and tannate); quinoline derivatives (8-hy kelp, kiwi seed fruit oil, kukui nut oil, lactic acid, lactospore, droxyquinoline salts, 2-phenylduinoline); Hydroxy- or meth laminaria digitata, lavandin oil, lavender, lavender oil, lav oxy Substituted benzophenones; Uric and vilouric acids; Tan ender extract, L-carnitine, lecithin, lemon balm, lemon nic acid and its derivatives (e.g., hexaethylether): (Butyl extract, lemon fruit extract, lemon oil, lemon verbena botani 35 carbityl) (6-propyl piperonyl)ether; Hydroquinone; Ben cal plant essence, lemongrass extract, licorice extract (e.g., Zophenones (Oxybenzene, Sulisobenzone, Dioxybenzone, Glycyrrhiza Glabra (licorice) root extract), lime oil, linden Benzoresorcinol, 2,2,4,4'-Tetrahydroxybenzophenone, 2,2'- extract, lycium barbarum fruit extract, lysate extract, lysine, Dihydroxy-4,4'-dimethoxybenzophenone, Octabenzone; maca root, macadamia oil, magnesium ascorbyl phosphate, 4-Isopropyhldibenzoylmethane; Butylmethoxydibenzoyl Mahonium aquifolium (Oregon grape root) extract, maitake 40 methane; Etocrylene; and 4-isopropyl-di-benzoylmethane; extract, mallow extract, maracuja, marrubium vulgare titanium dioxide, iron oxide, Zinc oxide, and mixtures extract, marshmallow, manila oil, matricaria oil, mead thereof. Other cosmetically-acceptable Sunscreens and con owsweet. Melissa extract, menthol, milk thistle, moms alba centrations (percent by weight of the total cosmetic Sunscreen root extract, mulberry extract (e.g., mulberroside F, gallic composition) include diethanolamine methoxycinnamate acid, quercetin, linoleic acid, palmitic acid), nettle extract, 45 (10% or less), ethyl-bis(hydroxypropyl)aminobenzoate nettle root, nori sea lettuce, nutmeg oil, oat amino acids, oat (5% or less), glyceryl aminobenzoate (3% or less), 4-isopro extract, oat kernel meal, oligophycocorail (sea algae) extract, pyl dibenzoylmethane (5% or less), 4-methylbenzylidene olive oil, olive leaf extract, squalene (e.g., olive squalen), camphor (6% or less), terephthalylidenedicamphor sulfonic orange blossom, orange oil, orange fruit extract, orange peel acid (10% or less), and Sulisobenzone (also called benzophe extract, orchid extract, panax ginseng extract, pansy extract, 50 none-4, 10% or less). Yet other cosmetically-acceptable sun panthenol, papaya enzyme, passion fruit oil, patchouli oil, screens and concentrations (reported as a percentage by pea extract, pea protein, peach extract, peanut oil, pecan oil, weight of the total cosmetic Sunscreen composition, and pepper, peppermint, peppermint oil, perilla seed oil, pine leaf referring to the final percentage of the Sunscreen) include: oil, pineapple enzyme, plankton extract, plantain extract, aminobenzoic acid (also called para-aminobenzoic acid and polygonum fagopyrum seed extract, pomegranate extract, 55 PABA; 15% or less; a UVB absorbing organic sunscreen), pomegranate seed oil, portulaca extract, psyllium, pumpkin avobenzone (also called butyl methoxy dibenzoylmethane: seed oil, raspberry extract, red clover, red clover extract, red 3% or less, a UVAI absorbing organic Sunscreen), cinoxate marine algae extract, reishii, resveratrol, retinyl palmitate, (also called 2-ethoxyethyl p-methoxycinnamate; 3% or less, rice bran oil, rhodiola, rhubarb, rice protein, Rosa roxburghii a UVB absorbing organic Sunscreen), dioxybenzone (also fruit extract, rose geranium botanical plant essence, rosehip 60 called benzophenone-8; 3% or less, a UVB and UVA II extract, rosemary, scCharomyces boulardii, safflower oil, absorbing organic Sunscreen), homosalate (15% or less, a sage, sage extract, Sambucus Canadensis extract, Sandal UVB absorbing organic Sunscreen), menthyl anthranilate wood, turmeric (Curcuma longa root) extract, Bulbine frute (also called menthyl 2-aminobenzoate; 5% or less, a UVA II scens extract, Bulbine frutescens gel, and phytessence absorbing organic Sunscreen), octocrylene (also called 2-eth wakame (sea kelp). 65 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 (7.5% or less, a UVB absorbing organic sunscreen), octyl US 8,778,315 B2 45 46 salicylate (also called 2-ethylhexyl salicylate; 5% or less, a embodiment, the composition comprises from about 0.001% UVB absorbing organic Sunscreen), oxybenzone (also called to about 0.5%, from about 0.0005% to about 1.0% or from benzophenone-3; 6% or less, a UVB and UVA II absorbing about 0.0001% to about 2% Licorice root extract. In another organic Sunscreen), padimate 0 (also called octyl dimethyl embodiment, the composition comprises from about 0.1% to PABA; 8% or less, a UVB absorbing organic sunscreen), about 3.0%, from about 0.05% to about 5.0%, or from about phenylbenzimidazole sulfonic acid (water soluble; 4% or 0.01% to about 10.0% Resorcinol. In another embodiment, less, a UVB absorbing organic Sunscreen), Sulisobenzone the composition comprises from about 0.1% to about 3.0%, (also called benzophenone-4; 10% or less, a UVB and UVAII from about 0.05% to about 5.0%, or from about 0.01% to absorbing organic Sunscreen), titanium dioxide (25% or less, about 10.0% ethyllinoleate. an inorganic physical blocker of UVA and UVB), trolamine 10 salicylate (also called triethanolamine salicylate: 12% or less, Pharmaceutically or Cosmetically Suitable Carriers a UVB absorbing organic sunscreen), and zinc oxide (25% or and Compositions less, an inorganic physical blocker of UVA and UVB). In still other embodiments, the composition comprises at One aspect of the disclosed embodiments extends to a least one anti-acne agent. Suitable anti-acne agents may 15 formulation that comprises a combination of a Substituted include Salicylic acid; 5-octanoyl salicylic acid; resorcinol; benzaldehyde, additional active agents, and a carrier. In some retinoids such as retinoic acid and its derivatives; Sulfur embodiments, the active agent is selected from an antioxidant containing D and L amino acids other than cysteine; lipoic or a skin-lightening agent. In specific embodiments, the Sub acid; antibiotics and antimicrobials such as benzoyl peroxide, stituted benzaldehyde and active agents are administered in octopiroX, tetracycline, 2,4,4'-trichloro-2'-hydroxydiphenyl the form of a pharmaceutical or cosmetic composition. Such ether, 3,4,4-trichlorobanilide, azelaic acid, phenoxyethanol, compositions can be prepared by procedures well known in phenoxypropanol, phenoxisopropanol, ethyl acetate, clinda the pharmaceutical and cosmetic arts. The compositions dis mycin and melclocycline; flavonoids; and bile salts such as closed herein can contain a cosmetically or pharmacologi Scymnol Sulfate, deoxycholate and cholate. cally acceptable carrier. Such carriers are compatible with In yet still other embodiments, the composition comprises 25 skin, nails, mucous membranes, tissues and/or hair, and can at least one anti-inflammatory agent. Suitable anti-inflamma include any conventionally used cosmetic or pharmacologi tory agents include, but are not limited to, non-steroidal anti cal carrier. The compositions disclosed herein can be in any inflammatory drugs such as Salicylic acid, acetylsalicylic form Suitable for topical application, including aqueous, acid, methyl salicylate, aspirin, ibuprofen, naproxen, aqueous-alcoholic or oily solutions, lotion or serum disper diflunisal, Salsalate, olsalazine, SulfaSalazine, acetami 30 sions, aqueous, anhydrous or oily gels, emulsions obtained by nophen, indomethacin, Sulindac, etodolac, mefenamic acid, dispersion of a fatty phase in an aqueous phase (O/W or oil in meclofenamate sodium, tolmetin, ketorolac, dichlofenac, water) or, conversely, (W/O or water in oil), microemulsions ibuprofen, naproxen, naproxen Sodium, fenoprofen, ketopro or alternatively microcapsules, microparticles or lipid vesicle fen, flurbinprofen, oxaprozin, piroXicam, meloxicam, dispersions of ionic and/or nonionic type. These composi ampiroXicam, droxicam, pivoxicam, tenoxicam, nabume 35 tions can be prepared according to conventional methods. tome, phenylbutaZone, oxyphenbutaZone, antipyrine, ami Other than the agents disclosed, the amounts of the various nopyrine, apaZone and nimeSulide; leukotriene antagonists constituents of the compositions are those conventionally including, but not limited to, Zileuton, aurothioglucose, gold used in the art. These compositions in particular constitute Sodium thiomalate and auranofin, and other anti-inflamma protection, treatment or care creams, milks, lotions, gels or tory agents including, but not limited to, methotrexate, 40 foams for the face, for the hands, for the body and/or for the colchicine, allopurinol, probenecid, Sulfinpyrazone and ben mucous membranes, or for cleansing the skin. The composi Zbromarone. Additional anti-inflammatories useful in topical tions can also consist of solid preparations constituting soaps applications include corticosteroids, such as, but not limited or cleansing bars. to, flurandrenolide, clobetasol propionate, halobetasol propi In some embodiments, the compositions disclosed herein onate, fluticasone propionate, betamethasone dipropionate, 45 are administered in an effective amount to treat a melanin betamethasone benzoate, betamethasone Valerate, des disorder. Examples of routes of administration include, but Oximethasone, dexamethasone, diflorasone diacetate, are not limited to, oral, buccal, inhalation, intradermal, Sub mometasone furoate, amcinodine, halcinonide, fluocinonide, cutaneous, transmucosal, transdermal, or topical administra fluocinolone acetonide, desonide, triamcinolone acetonide, tion. Topical administration may also involve the use of trans hydrocortisone, hydrocortisone acetate, fluoromethalone, 50 dermal administration Such as transdermal patches or prednisone, methylprednisolone, and predinicarbate. iontophoresis devices. The construction and use of transder In yet still other embodiments, the composition comprises mal patches for the delivery of pharmaceutical agents is well at least one skin conditioning agents. Suitable skin condition known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992, ing agents include, but are not limited to, butylene glycol and 445, and 5,001,139. Such patches can be constructed for ethylhexylglycerin. 55 continuous, pulsatile, or on demand delivery of pharmaceu In one embodiment, the composition contains the follow tical agents. ing additional active ingredients: Retinol, Niacinamide, Tet Pharmaceutically or cosmetically appropriate vehicles for rahexyldecyl Ascorbate, Licorice root extract, Resorcinol, Such formulations include, for example, lower aliphatic alco and ethyllinoleate. In another embodiment, the composition hols, polyglycols (e.g., glycerol or polyethylene glycol), comprises from about 0.1% to about 0.75%, from about 60 esters of fatty acids, oils, fats, silicones, and the like. Such 0.05% to about 1.0%, or from about 0.01% to about 2% preparations can also include preservatives (e.g., p-hydroxy Retinol. In another embodiment, the composition comprises benzoic acid esters) and/or antioxidants (e.g., ascorbic acid from about 2.0% to about 8.0%, from about 1% to about 10%, and tocopherol). See also Dermatological Formulations: Per or from about 0.5% to about 15.0% Niacinamide. In another cutaneous absorption, Barry (Ed.), Marcel Dekker Incl. 1983. embodiment, the composition comprises from about 1.0% to 65 In other embodiments, the composition further comprises about 5.0%, from about 0.5% to about 8.0%, or from about at least one of water, a preservative, a Surfactant, an emulsi 0.1% to about 15% Tetrahexyldecyl Ascorbate. In another fier, a conditioner, an emollient, a wax, an oil, a polymer, a US 8,778,315 B2 47 48 thickener (viscosity increasing agent), a fixative, a colorant, a enhancers are used to increase absorption. Absorption humectant, a moisturizer, a stabilizer, a diluent, a solvent and enhancers or carriers include absorbable pharmaceutically a fragrance. acceptable solvents that assist passage through the skin. For In one embodiment, the composition further comprises at example, in one embodiment, transdermal devices are in the least one preservative. Suitable preservatives include, but are form of a bandage comprising a backing member, a reservoir not limited to, potassium Sorbate, acids, alcohols, glycols, containing the compound optionally with carriers, optionally parabens, quaternary-nitrogen containing compounds, a rate controlling barrier to deliver the compound to the skin isothiazolinones, aldehyde-releasing compounds and haloge of the host at a controlled and predetermined rate over a nated compounds. Illustrative alcohols include phenoxyetha prolonged period of time, and means to secure the device to nol, isopropyl alcohol, and benzyl alcohol; illustrative glycols 10 include propylene, butylene and pentylene glycols; illustra the skin. tive parabens include (also known as parahydroxybenzioc Transdermal formulations described herein may be admin acids) methyl, propyl and butyl parabens; illustrative quater istered using a variety of devices which have been described nary nitrogen containing compounds include benzalkonium in the art. For example, such devices include, but are not chloride, Quartenium 15; illustrative isothiazoles include 15 limited to, U.S. Pat. Nos. 3,598,122, 3,598,123, 3,710,795, methylisothiazoline, methychlorollisothiazoline; illustrative 3,731,683, 3,742,951, 3,814,097, 3,921,636, 3,972,995, aldehyde releasing agents include DMDM hydantion, imi 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,084, adolidinyl urea and diazolidinyl urea; illustrative antioxidants 4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299, include butylated hydroxytoluene, tocopherol and illustrative 4,292,303, 5,336,168, 5,665,378, 5,837,280, 5,869,090, halogenated compounds include triclosan and chlorohex 6,923,983, 6,929,801 and 6,946,144. idene digluconate. Examples of preservatives useful for the The transdermal dosage forms described herein may incor purpose of the present disclosure can be found in Steinberg, porate certain pharmaceutically acceptable excipients which D. “Frequency of Use of Preservatives 2007”. Cosmet. Toilet. are conventional in the art. Transdermal drug delivery sys 117, 41-44 (2002) and, “Preservative Encyclopedia Cosmet. tems are topically administered medicaments and may be in Toilet. 117, 80-96 (2002). In addition, enzyme preservative 25 the form of patches that deliver drugs for systemic effects at a systems such as those described in the article by Ciccognani predetermined and controlled rate. The components of trans D. Cosmetic Preservation Using Enzymes, in “Cosmetic and dermal devices include: (1) polymer matrix or matrices, (2) Drug Microbiology'. Orth DS ed., Francis & Taylor, Boca the drug, (3) permeation enhancers and (4) other excipients. Raton, Fla. (2006) can also be effective for use with the The polymer controls the release of the drug from the composition of the present disclosure. 30 device. Useful polymers for transdermal devices include, but In one embodiment, the composition further comprises at are not limited to Natural Polymers (e.g., Cellulose deriva least one occlusive. Suitable occlusives include, but are not tives, Zein, Gelatin, Shellac, Waxes, Proteins, Gums and their limited to, capryllic/capric triglycerides, and the like. derivatives, Natural rubber, Starch, etc.); Synthetic Elas In one embodiment, the composition further comprises at tomers (e.g., Polybutadieine, Hydrin rubber, Polysiloxane, least one emollient. Suitable emollients include, but are not 35 Silicone rubber, Nitrile, Acrylonitrile, Butyl rubber, Sty limited to, cetyl ethylhexanoate, mineral oils, lanolin, petro renebutadieine rubber, Neoprene, etc.); and Synthetic Poly latum, capric/caprylic triglyceraldehydes, cholesterol, sili mers (e.g., Polyvinyl alcohol, Polyvinyl chloride, Polyethyl cones such as dimeticone, cyclometicone, almond oil, jojoba ene, Polypropylene, Polyacrylate, Polyamide, Polyurea, oil, avocado oil, castor oil, sesame oil, Sunflower oil, coconut Polyvinylpyrrolidone, Polymethylmethacrylate, Epoxy, etc.) oil and grape seed oil, cocoa butter, olive oil aloe extracts, 40 Solvents increase penetration possibly by enclosing the fatty acids such as oleic and Stearic, fatty alcohols such as polar pathway and/or by fluidizing lipids. Examples include cetyl and hexadecyl. diisopropyl adipate, hydroxybenzoate water alcohols (e.g., methanol and ethanol); alkyl methyl esters, benzoic acid esters of C9-15-alcohols, isononyl iso Sulfoxides (e.g., dimethyl sulfoxide, alkyl homologs of nonanoate, ethers such as polyoxypropylene butyl ethers and methyl sulfoxide dimethyl acetamide and dimethyl forma polyoxypropylene cetyl ethers, and C12-15-alkylbenzoates, 45 mide); pyrrolidones (e.g., 2 pyrrolidone, N-methyl 2-purroli and mixtures thereof. done); laurocapram (AZone), miscellaneous solvents (e.g., In one embodiment, the composition further comprises at propylene glycol, glycerol, silicone fluids, isopropyl palmi least one film fomers. Suitable film fomers include, but are tate). not limited to, polyacrylate-13, Opadry IIR) or similar mate Surfactants may enhance polar pathway transport, espe rials, e.g., such as those described in U.S. Pat. No. 4,802.924, 50 cially of hydrophilic drugs. The ability of a surfactant to alter incorporated herein by reference, may be used as a film penetration is a function of the polar head group and the former. hydrocarbon chain length. Anionic Surfactants include, but In yet other embodiments, the compound of Formula (I) is are not limited to, Dioctyl sulphosuccinate, Sodium lauryl formulated for transdermal administration. Transdermal for sulphate, and Decodecylmethylsulphoxide. Nonionic surfac mulations may employ transdermal delivery devices and 55 tants include, but are not limited to, Pluronic F127, and Plu transdermal delivery patches and can be lipophilic emulsions ronic F68. Bile salts include, but are not limited to, Sodium or buffered, aqueous Solutions, dissolved and/or dispersed in ms taurocholate, Sodium deoxycholate, and Sodium tauro a polymer or an adhesive. In various embodiments, such glycocholate. Others include, for example, Propylene glycol patches are constructed for continuous, pulsatile, or on oleic acid and 1,4-butane diol-linoleic acid, urea, N,N-dim demand delivery of pharmaceutical agents. In additional 60 ethyl-m-toluamide, calcium thioglycolat, anticholinergic embodiments, the transdermal delivery of the compounds of agents, eucalyptol, di-O-methyl-3-cyclodextrin and Soyabean Formula (I) is accomplished by means of iontophoretic casein. patches and the like. In certain embodiments, transdermal The fastening of all transdermal devices to the skin has so patches provide controlled delivery of the compounds of For far been done by using a pressure sensitive adhesive which mula (I). The rate of absorption may be slowed by using 65 can be positioned on the face of the device or in the back of the rate-controlling membranes or by trapping the compound device and extending peripherally. Adhesive systems should within a polymer matrix or gel. Alternatively, absorption adhere to the skin aggressively, but be easily removed. They US 8,778,315 B2 49 50 should also not leave an unwashable residue on the skin, and art. For oral administration the pharmaceutical compositions they should not irritate or sensitize the skin. may take the form of for example, tablets or capsules pre The face adhesive system should also be physically and pared by conventional means with acceptable excipients or chemically compatible with the drug, excipients and enhanc carriers such as binding agents (e.g., pregelatinised maize ers of the device of which it is a part. Permeation of drug starch, polyvinylpyrrolidone or hydroxypropyl methylcellu should not be affected and the delivery of simple or blended lose); fillers (e.g., lactose, microcrystalline cellulose or cal permeation enhancers should not be affected. cium hydrogen phosphate); lubricants (e.g., magnesium Backing membranes are flexible and they provide a good Stearate, talc or silica); disintegrants (e.g., potato starch or bond to the drug reservoir, prevent drug from leaving the Sodium starch glycolae); or wetting agents (e.g., Sodium lau dosage form through the top, and accept printing. Backing 10 ryl sulphate). Tablets may be coated using methods well membranes are impermeable Substances that protect the known in the art. Liquid preparations for oral administration product during use on the skin (e.g., metallic plastic laminate, may take the form of, for example, Solutions, syrups or Sus plastic backing with absorbent pad and occlusive base plate pensions, or they may be presented as a dry product for (aluminum foil), adhesive foam pad (flexible polyurethane) constitution with water or other suitable vehicle before use. with occlusive base plate (aluminum foil disc), etc.). 15 Such liquid preparations may be prepared by conventional In addition, transdermal formulations can include addi means with acceptable excipients or carriers such as Suspend tional components such as, but not limited to, gelling agents, ing agents (e.g., Sorbitol syrup cellulose derivatives or hydro creams and ointment bases, and the like. In some embodi genated edible fats); emulsifying agents (e.g., lecithin or aca ments, the transdermal formulation further includes a woven cia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl or non-woven backing material to enhance absorption and alcohol or fractionated vegetable oils); and preservatives prevent the removal of the transdermal formulation from the (e.g., methyl or propyl-p-hydroxybenzoates or Sorbic acid). skin. In other embodiments, the transdermal formulations The preparations may also contain buffer salts, flavoring, described herein maintain a saturated or Supersaturated State coloring and Sweetening agents as appropriate. to promote diffusion into the skin Topical compositions disclosed herein may be in the form Compositions disclosed herein may be formulated in con 25 of a viscous liquid, Solution, Suspension, liposomal formula 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 30 gels, drops, Suppositories, sprays, liquids, powders, sham and standard therapeutic practice. As used herein, the term 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 35 So as to provide the composition in the desired form, e.g., as include water, saline, aqueous dextrose, Sugar Solutions, etha a liquid, lotion, cream, paste, gel, powder, or ointment, and nol, glycols and oils, including those of petroleum, animal, may be comprised of a material of either naturally occurring Vegetable, or synthetic origin, for example, peanut oil, Soy or synthetic origin. Examples of Suitable topical carriers for bean oil and mineral oil. In other embodiments, an agent or use herein include water, alcohols and other nontoxic organic combination of agents of the instant embodiments can be 40 Solvents, glycerin, mineral oil, silicone, petroleum jelly, lano formulated in an oleaginous hydrocarbon base, an anhydrous lin, fatty acids, vegetable oils, parabens, aloevera, waxes, and absorption base, a water-in-oil absorption base, an oil-in the like. water water-removable base and/or a water-soluble base. Ointments and creams can, for example, be formulated Examples of such carriers and excipients include, but are not with an aqueous or oily base with the addition of suitable limited to, humectants (e.g., urea), glycols (e.g., propylene 45 thickening and/or gelling agents. Lotions can be formulated glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), with an aqueous or oily base and will in general also contain Surfactants (e.g., polysorbate-80, isopropyl myristate and ing one or more emulsifying agents, stabilizing agents, dis Sodium lauryl Sulfate), pyrrolidones, glycerol monolaurate, persing agents, Suspending agents, thickening agents, or col Sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, oring agents. alkanols, water, calcium carbonate, calcium phosphate, Vari 50 Lubricants which can be used to form pharmaceutical com ous Sugars, starches, cellulose derivatives, gelatin, and poly positions and dosage forms include, but are not limited to, mers such as polyethylene glycols. calcium Stearate, magnesium Stearate, mineral oil, light min Compositions can also contain adjuvants common to the eral oil, glycerin, Sorbitol, mannitol, polyethylene glycol, cosmetic and dermatological fields, such as hydrophilic or other glycols, Stearic acid, sodium lauryl Sulfate, talc, hydro lipophilic gelling agents, hydrophilic or lipophilic active 55 genated vegetable oil (e.g., peanut oil, cottonseed oil, Sun agents, preserving agents, antioxidants, solvents, fragrances, flower oil, Sesame oil, olive oil, corn oil, and soybean oil), fillers, sunscreens, odor-absorbers and dyestuffs. The Zinc Stearate, ethyl oleate, ethyl laureate, agar, or mixtures amounts of these various adjuvants are those conventionally thereof. Additional lubricants include, for example, a syloid used in the fields considered and, for example, are from about silica gel, a coagulated aerosol of synthetic silica, or mixtures 0.01% to about 20% of the total weight of the composition. 60 thereof. A lubricant can optionally be added, in an amount of Depending on their nature, these adjuvants can be introduced less than about 1 weight percent of the pharmaceutical com into the fatty phase, into the aqueous phase and/or into the position. lipid vesicles. Thickeners (viscosity increasing agents) which can be used The compositions may be in the form of tablets, capsules, to form pharmaceutical compositions and dosage forms skin patches, inhalers, eye drops, nose drops, ear drops, Sup 65 include, but are not limited to, polyacrylate-13, poly positories, creams, ointments, injectables, hydrogels and into isobutene, Acetamide MEA; acrylamide/ethalkonium chlo any other appropriate formulation known to one of skill in the ride acrylate copolymer, acrylamide/ethyltrimonium chlo US 8,778,315 B2 51 52 ride acrylate/ethalkonium chloride acrylate copolymer; potato starch; hydrogenated tallow; hydrogenated tallowa acrylamides copolymer; acrylamide/sodium acrylate copoly mide DEA: hydrogenated tallow betaine; hydroxybutyl mer, acrylamide/sodium acryloyldimethyltaurate copoly methylcellulose; hydroxyethyl acrylate/sodium acryloyldim mer, acrylates/acetoacetoxyethyl methacrylate copolymer; ethyl taurate copolymer; hydroxyethylcellulose; hydroxy acrylates/beheneth-25 methacrylate copolymer; acrylates/ ethyl chitosan; hydroxyethyl ethylcellulose; hydroxyethyl C10-C30 alkyl acrylate crosspolymer; acrylates/ceteth-20 stearamide-MIPA: hydroxylauryl/hydroxymyristyl betaine; itaconate copolymer, acrylates/ceteth-20 methacrylate hydroxypropylcellulose; hydroxypropyl chitosan; hydrox copolymer, acrylates/laureth-25 methacrylate copolymer; ypropyl ethylene diamine carbomer, hydroxypropyl guar; acrylates/palmeth-25 acrylate copolymer, acrylates/palmeth hydroxypropyl methylcellulose; hydroxypropyl methylcellu 25 itaconate copolymer; acrylates/steareth-50 acrylate 10 lose Stearoxy ether; hydroxypropyl Starch; hydroxypropyl copolymer, acrylates/steareth-20 itaconate copolymer, acry starch phosphate; hydroxypropyl Xanthan gum; hydroxys lates/steareth-20 methacrylate copolymer, acrylates/Stearyl tearamide MEA: isobutylene/sodium maleate copolymer; methacrylate copolymer, acrylates/vinyl isodecanoate cross isostearamide DEA, isostearamide MEA: isostearamide polymer; acrylic acid/acrylonitrogens copolymer, adipic mIPA: isostearamidopropyl betaine; lactamide MEA: lanoli acid/methyl DEA crosspolymer; agar, agarose; alcaligenes 15 namide DEA.; lauramide DEA.; lauramide MEA: lauramide polysaccharides; algin; alginic acid; almondamide DEA. MIPA: lauramide/myristamide DEA: lauramidopropyl almondamidopropyl betaine; aluminum/magnesium hydrox betaine; lauramidopropyl hydroxysultaine; laurimino bispro ide Stearate; ammonium acrylates/acrylonitrogens copoly panediol; lauryl alcohol; lauryl betaine; lauryl hydroxysul mer, ammonium acrylates copolymer, ammonium acry taine; lauryl/myristylglycol hydroxypropyl ether, lauryl Sul loyldimethyltaurate/vinyl formamide copolymer; taine; lecithinamide DEA; linoleamide DEA; linoleamide 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; 25 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 30 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 35 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 40 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 45 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 50 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; cyanopsis 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/ 55 150 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 60 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 65 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 US 8,778,315 B2 53 54 tearamide; PPG-3 hydroxyethyl soyamide; PPG-14 laureth alcohols, ethoxydiglycol and dimethyl isosorbide. A skin 60 hexyl dicarbamate; PPG-14 laureth-60 isophoryl dicar penetration enhancer may be included at concentrations rang bamate; PPG-14 palmeth-60 hexyl dicarbamate; propylene ing from 5% to 95%, preferably 5% to 10% of the total glycol alginate; PVP/decene copolymer; PVP montmorillo composition. nite; pyrus Cydonia seed; pyrus malus (apple) fiber; rhizobian In a further embodiment of the combinations described gum; ricebranamide DEA; ricinoleamide DEA; ricinoleam above, a topical formulation is prepared that comprises a ide MEA: ricinoleamide MIPA: ricinoleamidopropyl betaine; composition for cosmetic or dermatological use, which com ricinoleic acid/adipic acid/AEEA copolymer; rosa multiflora position comprises a cosmetically and/or dermatologically flower wax; Sclerotium gum, Sesamide DEA, Sesamidopropyl effective amount of the combination stated above. betaine; sodium acrylate/acryloyldimethyl taurate copoly 10 In one embodiment, the compositions are in a form Suitable mer, sodium acrylates/acrolein copolymer, sodium acrylates/ for cosmetic application including, but not limited to, lotions, acrylonitrogens copolymer, sodium acrylates copolymer; ointments, creams, sprays, spritzes, aqueous or aqueous-al Sodium acrylates crosspolymer, Sodium acrylate/sodium coholic mixture gels, mousses, patches, pads, masks, moist acrylamidomethylpropane Sulfonate copolymer, sodium ened clothes, wipes, Solid Sticks, clear Sticks, lip Sticks, aero acrylates/vinyl isodecanoate crosspolymer, Sodium acrylate/ 15 Sol creams, anhydrous powders, talcs, tonics, oils, emulsions vinyl alcohol copolymer, Sodium carbomer, sodium car or bath salts. boxymethyl chitin; sodium carboxymethyl dextran; sodium In another embodiment, the composition also contains irri carboxymethyl beta-glucan, Sodium carboxymethyl starch; tation-mitigating additives to minimize or eliminate the pos Sodium carrageenan; Sodium cellulose Sulfate; sodium chlo sibility of skin irritation or skin damage resulting from the ride; sodium cyclodextrin Sulfate; sodium hydroxypropyl chemical compound to be administered, or other components 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 25 monensin), amphiphilic amines, animonium chloride, N-ace methacrylate; sodium polystyrene Sulfonate; sodium sili tylcysteine, capsaicin, and/or chloroquine. coaluminate; sodium starch octenylsuccinate; sodium Stear ate; sodium stearoxy PG-hydroxyethylcellulose sulfonate: Modulation of Melanin Production Sodium styrenefacrylates copolymer, Sodium sulfate; sodium tallowate; sodium tauride acrylates/acrylic acid/acrylonitro 30 In some embodiments, the compositions disclosed herein gens copolymer; sodium tocopheryl phosphate: Solanum modulate melanin product in a subject in need thereof. For tuberosum (potato) starch; soyamide DEA: soyamidopropyl example, the compositions disclosed herein may decrease betaine; starch/acrylates/acrylamide copolymer; starch melanin production to reduce pigmentation in a Subject in hydroxypropyltrimonium chloride; stearamide AMP; Steara need thereof. The compositions disclosed herein may also mide DEA; Stearamide DEA-distearate; stearamide DIBA 35 function to decrease the number of melanocytes present in the stearate; stearamide MEA: Stearamide MEA-stearate; steara epidermis, effectively decreasing melanin production and mide MIPA: stearamidopropyl betaine; steareth-60 cetyl reducing pigmentation in a subject in need thereof. A ether; steareth-100/PEG-136/HDI copolymer; stearyl alco decrease in melanin production may be desirable in the skin, hol; Stearyl betaine; sterculia urens gum, synthetic fluorphlo hair, pigmented pigmented tissue underlying the iris of the gopite; tallamide DEA: tallow alcohol; tallowamide DEA: 40 eye, or the stria vascularis of the inner ear. Administration or tallowamide MEA: tallowamidopropyl betaine; tallowami targeting of the compositions disclosed herein may act to dopropyl hydroxysultaine; tallowamine oxide; tallow locally effect melanin production and reduce pigmentation. betaine; tallow dihydroxyethyl betaine; tamarindus indica Hyperpigmentation or hypermelanosis disorders due to seed gum, tapioca starch; TEA-alginate; TEA-carbomer, environmental stressors, such as hormonal imbalance, can TEA-hydrochloride; trideceth-2 carboxamide MEA: tridecyl 45 also affect melanin or pigmentation levels in the skin. Hyper alcohol; triethylene glycol dibenzoate; trimethyl pentanol pigmentation or hypermelanosis disorders may also be due to hydroxyethyl ether, triticum vulgare (wheat) germ powder; physiological stressors or mechanical stressors. triticum vulgare (wheat) kernel flour; triticum vulgare Prostaglandin F2 alpha (PGF2 alpha) is a bioactive mol (wheat) starch; tromethamine acrylates/acrylonitrogens ecule in the prostanoid family of lipid mediators that regulate copolymer, tromethamine magnesium aluminum silicate; 50 numerous processes in the body, including inflammation. undecyl alcohol; undecylenamide DEA, undecylenamide While not wishing to be limited to a specific theory or mecha MEA, undecylenamidopropyl betaine; welan gum; wheat nism of action, it is believed that the compositions disclosed germamide DEA, wheat germanidopropyl betaine; Xanthan herein may act in two (2) ways to modulate melanin distribu gum, yeast beta-glucan; yeast polysaccharides and zea mays tion: 1) through the modulation of melanin production by (corn) starch. 55 melanocytes; and 2) by affecting melanin distribution by In some embodiments, one function of the carrier is to melanocytes. enhance skin penetration of the active ingredients. Perme 4-ethoxybenzaldehyde has been demonstrated to affect a ation enhancers are compounds which promote skin perme wide variety of inflammatory conditions, such as rheumatoid ability by altering the skin as a barrier to the flux of a desired arthritis, febrile conditions, edema, hyperalgesia, inflamma penetrant. These may be classified as solvents, Surfactants 60 tory bowel disease, and periodontal disease. However, and miscellaneous chemicals. Suitable carriers are well 4-ethoxybenzaldehyde has not previously been shown to be known to skilled practitioners, and include liposomes, etha useful in the treatment of hyperpigmentation, including post nol, dimethylsulfoxide (DMSO), petroleum jelly (petrola inflammatory hyperpigmentation, or to lighten skin. tum), mineral oil (liquid petrolatum), water, deimethylforma In one aspect, provided herein is a method of treating mide, dekaoxyethylene-oleylether, oleic acid, 2-pyrrolidone, 65 hyperpigmentation or a hypermelanosis disorder in an indi AZone(R) brand penetration enhancer (Upjohn), biologically vidual, comprising administering to the individual in need acceptable glycols, diglycols, polyglycols; alkyOXy C2-C8 thereof an effective amount of a composition comprising: US 8,778,315 B2 55 56 from about 0.01% to about 2% substituted benzaldehyde, about 2% Retinol. In another embodiment, the composition about 0.01% to about 5.0% each of Retinol, Niacinamide, comprises from about 2.0% to about 8.0%, from about 1% to Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice) about 10%, or from about 0.5% to about 15.0% Niacinamide. Root Extract, Hexyl Resorcinol, ethyl linoleate, and a phar In another embodiment, the composition comprises from maceutically or cosmetically acceptable carrier. In one about 1.0% to about 5.0%, from about 0.5% to about 8.0%, or embodiment, the amount of substituted benzaldehyde in the from about 0.1% to about 15% Tetrahexyldecyl Ascorbate. In composition is about 0.5%. In another embodiment, the com another embodiment, the composition comprises from about position comprises from about 0.1% to about 0.75%, from 0.001% to about 0.5%, from about 0.0005% to about 1.0% or about 0.05% to about 1.0%, or from about 0.01% to about 2% from about 0.0001% to about 2% Licorice root extract. In Retinol. In another embodiment, the composition comprises 10 another embodiment, the composition comprises from about from about 2.0% to about 8.0%, from about 1% to about 10%, 0.1% to about 3.0%, from about 0.05% to about 5.0%, or from or from about 0.5% to about 15.0% Niacinamide. In another about 0.01% to about 10.0% Resorcinol. In another embodi embodiment, the composition comprises from about 1.0% to ment, the composition comprises from about 0.1% to about about 5.0%, from about 0.5% to about 8.0%, or from about 3.0%, from about 0.05% to about 5.0%, or from about 0.01% 0.1% to about 15% Tetrahexyldecyl Ascorbate. In another 15 to about 10.0% ethyl linoleate. embodiment, the composition comprises from about 0.001% In some embodiments, the method reduces melanin distri to about 0.5%, from about 0.0005% to about 1.0% or from bution by about 10% to about 40%. about 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 herein may be topical or transdermal administeration 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. paste, ointment, Suspension, foam, lotion, oil-in-water emul Substituted benzaldehydes for use in the compositions 25 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 chemical exposure), physiological stressor (e.g., a hormonal sition in an amount of about 0.5%. 30 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: Sunscreen, a Sunprotectant, a Sunblock, a skin-lightening about 0.1% to about 0.5% 4-ethoxybenzaldehyde, about 35 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 Surfactant, chelating agent, humectant, permeation enhancer, ment, the composition comprises from about 0.1% to about 40 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. aquifolium) extract, pomegranate extract, genistein, pycno In another embodiment, the composition comprises from 45 genol, curcumin, curcuminoids, Tocopherol, Dunaliella about 1.0% to about 5.0%, from about 0.5% to about 8.0%, or Salina Extract or combinations thereof. from about 0.1% to about 15% Tetrahexyldecyl Ascorbate. In Exemplary skin-lightening agents include hydroquinone, another embodiment, the composition comprises from about monobenzyl ether of hydroquinone, azelaic acid, kojic acid, 0.001% to about 0.5%, from about 0.0005% to about 1.0% or meduinol, retinoids, soy proteins, alpha-hydroxy acids, from about 0.0001% to about 2% Licorice root extract. In 50 trichloroacetic acid, Salicylic acid, hydroquinone-beta-D- another embodiment, the composition comprises from about glucopyranoside, paper mulberry, glabridin, 4-isopropyl 0.1% to about 3.0%, from about 0.05% to about 5.0%, or from cetichol, aleosin, N-acetyl-4-S-cycteaminylphenol, N-propio about 0.01% to about 10.0% Resorcinol. In another embodi nyl-4-S-cysteaminylphenol, N-acetyl glucosamine, ment, the composition comprises from about 0.1% to about tranexaminc acid, an alpha MSH antagonist (e.g. undecyle 3.0%, from about 0.05% to about 5.0%, or from about 0.01% 55 noyl phenylalanine), phytic acid or combinations thereof. to about 10.0% ethyl linoleate. In another aspect, provided herein is a method of lightening In another aspect, provided herein is a method of treating skin in an individual, comprising administering to the indi hyperpigmentation or a hypermelanosis disorder in an indi vidual in need thereof an effective amount of a composition vidual, comprising administering to the individual in need comprising: from about 0.01% to about 2% substituted ben thereof an effective amount of a composition comprising: 60 Zaldehyde, about 0.01% to about 5.0% each of Retinol, Niaci about 0.5% 4-ethoxybenzaldehyde, about 0.01% to about namide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra 5.0% each of Retinol, Niacinamide, Tetrahexyldecyl Ascor (Licorice) Root Extract, Hexyl Resorcinol, ethyl linoleate, bate, Glycyrrhiza Glabra (Licorice) Root Extract, Hexyl and a pharmaceutically or cosmetically acceptable carrier. In Resorcinol, ethyl linoleate, and a pharmaceutically or cos one embodiment, the amount of substituted benzaldehyde in metically acceptable carrier. In another embodiment, the 65 the composition is about 0.5%. In another embodiment, the composition comprises from about 0.1% to about 0.75%, composition comprises from about 0.1% to about 0.75%, from about 0.05% to about 1.0%, or from about 0.01% to from about 0.05% to about 1.0%, or from about 0.01% to US 8,778,315 B2 57 58 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 5 0.01% to about 10.0% Resorcinol. from about 0.1% to about 15% Tetrahexyldecyl Ascorbate. In In another embodiment, the composition comprises from another embodiment, the composition comprises from about about 0.1% to about 3.0%, from about 0.05% to about 5.0%, 0.001% to about 0.5%, from about 0.0005% to about 1.0% or or from about 0.01% to about 10.0% ethyl linoleate. from about 0.0001% to about 2% Licorice root extract. In In some embodiments, the methods decrease the level of another embodiment, the composition comprises from about 10 pigmentation by about 5%, by about 10%, by about 20%, by 0.1% to about 3.0%, from about 0.05% to about 5.0%, or from about 30% or by about 40%. about 0.01% to about 10.0% Resorcinol. In another embodi The methods may be used to treat hyperpigmentation or a ment, the composition comprises from about 0.1% to about hypermelanosis disorder. In one embodiment, hyperpigmen 3.0%, from about 0.05% to about 5.0%, or from about 0.01% tation may result from an environmental stressor (e.g., exces to about 10.0% ethyl linoleate. 15 sive Sun exposure or chemical exposure), physiological stres Substituted benzaldehydes for use in the compositions Sor (e.g., a hormonal disorder), or mechanical stressor. include, for example, 2-ethoxybenzaldehyde, 4-ethoxyben In some embodiments, the method reduces melanin distri Zaldehyde, 4-allyloxybenzaldehyde or 4-propoxybenzalde bution by about 10% to about 40%. hyde. In one embodiment, the substituted benzaldehyde is Application of the compositions in the methods described 4-ethoxybenzaldehyde, which may be present in the compo herein may be topical or transdermal administeration to the sition in an amount of about 0.5%. skin of the individual. In another aspect, provided herein is a method of lightening In one embodiment, the pharmaceutically or cosmetically skin in an individual, comprising administering to the indi acceptable carrier is a topical carrier. Topical carriers include, vidual in need thereof an effective amount of a composition for example, a water-in-oil emulsion, cream, liquid, gel, oil, comprising: about 0.1% to about 0.5% 4-ethoxybenzalde 25 paste, ointment, Suspension, foam, lotion, oil-in-water emul hyde, about 0.01% to about 5.0% each of Retinol, Niacina Sion, water-in-oil-in-water emulsion, water-in-silicone emul mide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Lico Sion, spray or serum carrier. rice) Root Extract, Hexyl Resorcinol, ethyl linoleate, and a Compositions described herein for use in such methods pharmaceutically or cosmetically acceptable carrier. In one may further include one or more additional active agents. For embodiment, the amount of substituted benzaldehyde in the 30 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% 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%, 35 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% 40 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 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, 45 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. 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 50 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 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 55 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 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 60 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 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 65 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 US 8,778,315 B2 59 60 benzaldehyde, about 0.01% to about 5.0% each of Retinol, about 0.75%, from about 0.05% to about 1.0%, or from about Niacinamide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Gla 0.01% to about 2%. Retinol. In another embodiment, the bra (Licorice) Root Extract, Hexyl Resorcinol, ethyl composition comprises from about 2.0% to about 8.0%, from linoleate, and a pharmaceutically or cosmetically acceptable about 1% to about 10%, or from about 0.5% to about 15.0% carrier. In another embodiment, the composition comprises Niacinamide. In another embodiment, the composition com from about 0.1% to about 0.75%, from about 0.05% to about prises from about 1.0% to about 5.0%, from about 0.5% to 1.0%, or from about 0.01% to about 2% Retinol. In another about 8.0%, or from about 0.1% to about 15% Tetrahexylde embodiment, the composition comprises from about 2.0% to cyl Ascorbate. In another embodiment, the composition com about 8.0%, from about 1% to about 10%, or from about 0.5% prises from about 0.001% to about 0.5%, from about to about 15.0% Niacinamide. In another embodiment, the 10 0.0005% to about 1.0% or from about 0.0001% to about 2% composition comprises from about 1.0% to about 5.0%, from Licorice root extract. In another embodiment, the composi about 0.5% to about 8.0%, or from about 0.1% to about 15% tion comprises from about 0.1% to about 3.0%, from about Tetrahexyldecyl Ascorbate. In another embodiment, the com 0.05% to about 5.0%, or from about 0.01% to about 10.0% position comprises from about 0.001% to about 0.5%, from Resorcinol. In another embodiment, the composition com about 0.0005% to about 1.0% or from about 0.0001% to about 15 prises from about 0.1% to about 3.0%, from about 0.05% to 2% Licorice root extract. In another embodiment, the com about 5.0%, or from about 0.01% to about 10.0% ethyl position comprises from about 0.1% to about 3.0%, from linoleate. about 0.05% to about 5.0%, or from about 0.01% to about Also provided are methods of modifying melanin distribu 10.0% Resorcinol. In another embodiment, the composition tion by modulating prostaglandin F2 alpha (PGF2 alpha) in comprises from about 0.1% to about 3.0%, from about 0.05% skin cells in an individual, comprising administering to the to about 5.0%, or from about 0.01% to about 10.0% ethyl individual in need thereof an effective amount of a composi linoleate. tion comprising about 0.5% 4-ethoxybenzaldehyde, about In one embodiment, the amount of substituted benzalde 0.01% to about 5.0% each of Retinol, Niacinamide, Tetra hyde in the composition is about 0.5%. hexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice) Root Substituted benzaldehydes for use in the compositions 25 Extract, Hexyl Resorcinol, ethyllinoleate, and a pharmaceu include, for example, 2-ethoxybenzaldehyde, 4-ethoxyben tically or cosmetically acceptable carrier. In another embodi Zaldehyde, 4-allyloxybenzaldehyde or 4-propoxybenzalde 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%. 30 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 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, 35 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 40 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 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. 45 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 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 50 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 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 55 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. 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 60 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 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 65 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 resveratrol, grape seed extract, Oregon grape root (Mahonia US 8,778,315 B2 61 62 aquifolium) extract, pomegranate extract, genistein, pycno In another aspect, another patient population to be treated genol, curcumin, curcuminoids, Tocopherol, Dunaliella by the present methods is described below in Example 14. Salina Extract or combinations thereof. Representative patients include those with Fitzpatrick skin Exemplary skin-lightening agents include hydroquinone, type III and those who are in general good health as deter monobenzyl ether of hydroquinone, azelaic acid, kojic acid, mined by review of their health. meduinol, retinoids, soy proteins, alpha-hydroxy acids, In another aspect, an individual will not be eligible for trichloroacetic acid, salicylic acid, hydroquinone-beta-D- treatment if they meet any of the following exclusion criteria: glucopyranoside, paper mulberry, glabridin, 4-isopropyl Individuals with Fitzpatrick skin types I, II, IV, V and VI. cetichol, aleosin, N-acetyl-4-S-cycteaminylphenol, N-propio Individuals that have been instructed by a physician, pharma nyl-4-S-cysteaminylphenol, N-acetyl glucosamine, 10 cist, or health professional to avoid Sunlight because of a tranexaminc acid, an alpha MSH antagonist (e.g. undecyle medical condition and/or because of drug contraindications. noyl phenylalanine), or phytic acid combinations thereof. Individuals with known abnormal responses to Sunlight or In one aspect, one patient population to be treated by the UVR light sources. Individuals with a known allergy to any present methods is described below in Example 13. Repre ingredient in a personal care product. Individuals with known sentative patients include those with Fitzpatrick skin types 15 atopic skin diseases or neurodermatitis. Women known to be I-IV. Fitzpatrick skin classification is based on the skins pregnant, nursing, or planning to become pregnant within 6 unprotected response to the first 30 to 45 minutes of sun months. Individuals known to be treated for cancer or have a 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: 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 25 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 (e.g., perphenazine), psychotropic agents (e.g., chlorprom state or physical condition (e.g., psoriasis, moderate to severe azine), antihistamines (e.g., promethazine hydrochloride), rosacea, hirsutism, Scars, tattoos, etc.) which might increase oral hypoglycemic agents (e.g., tolubutamide, chlorpropam the health risk to the subject by treatment. Individuals to be 30 ide), and tetracycline antibiotics (e.g., dimethylchlorotetra treated include those who have not used systemic retinoids cycline, tetracycline). (e.g., Tazorac, Soriataine. Accutane, etc.) and/or any other systemic medication known to affect melasma at least 60 days Method of Administration prior to treatment and are not to use these products during treatment. Individuals to be treated are not to use topical 35 In some embodiments, any composition described herein is retinoids and/or all other topical medication (e.g., topical administered in the form of a cosmetic composition. In some steroids, products containing benzoyl peroxide, alpha- or embodiments, the cosmetic composition can be prepared beta-hydroxy acids, hydroquinone, and/or any other over the according to procedures well known in the cosmetic arts and counter (OTC) skin treatment medications) to the facial area comprise at least one active compound and two antioxidant known to affect melasma at least 14 days prior to treatment 40 agents. and are not to use these products during treatment. Patients In Some embodiments, the cosmetic composition is admin should be willing to avoid extended periods of sun exposure istered topically. In specific embodiments, the cosmetic com during treatment. Ifbrief (less than 20 minutes) periods of sun position is administered transdermally so that the active agent exposure cannot be avoided, then Subjects are asked to use an and antioxidant agents contact the skin. In a further or addi SPF 30 product and wear protective clothing prior to and 45 tional embodiment, the composition is administered transder during exposure. mally so as to deliver the compositions disclosed herein sys In another aspect, an individual will not be eligible for temically. treatment if they meet any of the following exclusion criteria: The compositions disclosed herein contain one or more Individuals with known allergies or sensitivities to skin light Substituted benzaldehyde and an optional at least one addi ening products, retinoids, hydroquinone, Sulfites, moisturiz 50 tional active agent. The amounts used are amounts effective ers, or other facial products. Individuals with active symp Such that when administered to a Subject for treating a dis toms of allergy, active psoriasis or eczema, Sunburn, ease, cosmetic or dermatological condition, is Sufficient to excessive scarring, tattoos, or other skin condition in the areas effect Such treatment for the disease, cosmetic or dermato to be treated. Individuals who are nursing, pregnant, or plan logical condition. Here, the amount will depend upon the ning to become pregnant during treatment. Individuals hav 55 endpoint desired, for example, the modification, for example ing uncontrolled disease Such as diabetes, hypertension, the increase or reduction of melanin and/or melanocyte pro hyper or hypo-thyroidism, active hepatitis, immune defi duction and/or distribution. The endpoint can be measured in ciency, or autoimmune disease as determined by the initial terms of the subjective interpretation of the subject being paperwork. Individuals who require electrolysis, waxing, or administered the disclosed compositions. For example, the use depilatories on the face during conduct of the study. 60 endpoint may be a study by which a subject is queried if the Individuals who have had a facial peel or a laser treatment of treatment regimen is “satisfactory” or “unsatisfactory'. Alter the face within 60 days prior to treatment. Individuals who natively, the endpoint may be measured quantitatively in have a pre-existing or dormant dermatologic condition (e.g., terms of the amount of melanin and/or melanocytes in a given psoriasis, atopic dermatitis, advanced skin cancer, rosacea, Subject or experimental procedure. The endpoint may be other inflammatory disorder, etc.). Individuals who are 65 measured by a trained medical professional, for example a receiving treatment for a skin disorder with another compo physician or nurse, or by a subject or other individual. The sition. endpoint may additionally be determined remotely, for US 8,778,315 B2 63 64 example, through comparisons of photographs or other and from about 2.5 to about 5 mg of substituted benzalde recordings by a trained medical professional or other indi hyde. In some embodiments, the compositions disclosed vidual. Furthermore, the degree of modification of melanin herein will contain from about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 production may be predetermined by a trained medical pro mg, 0.5, mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 2.0 mg. fessional, for example, by assigning a predetermined degree 3.0 mg, 4.0 mg, 5.0 mg, 7.0 mg, 10.0 mg, 15.0 mg, 20 mg, 25 of melanin and/or melanocyte presence as an endpoint value. mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 The “effective amount', however, will take into account mg, 90 mg or 100 mg of substituted benzaldehyde. In some any toxicity effects that may occur, for example, severe skin embodiments, the compositions disclosed herein will contain irritation with higher doses of the active agents disclosed from about 0.3 mg to about 0.75 mg of substituted benzalde herein. Suggested endpoints may first be measured in vitro or 10 hyde. in an animal model to determine the acceptable range of In some embodiment, the compositions disclosed herein active agents to be used in conjunction with the compositions comprises 4-ethoxybenzaldehyde in a concentration of about disclosed herein. One of ordinary skill in the art can then 0.01%, about 0.05%, about 0.08%, about 0.1%, about 0.15%, extrapolate doses that will avoid toxicity but maintain effi about 0.2%, about 0.5%, about 0.8%, about 1%, about 1.3%, cacy in treated Subjects, including humans. The “effective 15 about 1.5%, about 1.8%, about 2%, about 2.3%, about 2.5%, amount can vary depending on the compound, the disease about 2.8%, about 3%, about 3.5%, about 4%, about 5%, and its severity, and the age, weight, etc., of the Subject to be about 8%, about 10%, about 13%, about 15%, about 18%, treated. about 20%, about 22%, about 25%, about 30% or about 40%. 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 25 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%, 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 30 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 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 35 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%. 40 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 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 45 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. 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. 50 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. 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. 55 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. 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. 60 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. 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. 65 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, US 8,778,315 B2 65 66 7.5, 8.0, 8.5, 9.0, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, to about 10%, from about 1% to about 5%, from about 1% to 14.5, 15, 16, 17, 18, 19, 20, 25, 30, 3540, 45 or 50 mg/ml. about 2.5%, or from about 1% to about 2%. In other embodiments, the compositions disclosed herein The compositions disclosed herein may contain from about further includes an antioxidant in a concentration of about 0.01 mg to about 100 mg of skin-lightening agent or about 0.1 0.01%, about 0.05%, about 0.08%, about 0.1%, about 0.15%, mg to about 10 mg of skin-lightening agent. In some embodi about 0.2%, about 0.5%, about 0.8%, about 1%, about 1.3%, ments, the compositions disclosed herein may contain from about 1.5%, about 1.8%, about 2%, about 2.3%, about 2.5%, about 0.05 to about 5 mg of skin-lightening agent, or from about 2.8%, about 3%, about 3.5%, about 4%, about 5%, about 0.1 to about 3 mg of skin-lightening agent. In some about 8%, about 10%, about 13%, about 15%, about 18%, embodiments, the compositions disclosed herein may contain about 20%, about 23%, about 25%. In yet other embodi 10 from about 0.1 to about 50 mg, from about 0.1 to about 45 mg. ments, the compositions disclosed herein comprises a range from about 0.1 to about 40 mg, from about 0.1 to about 35 mg. of antioxidant from about 0.1% to about 25%, from about from about 0.1 to about 30 mg, from about 0.1 to about 25 mg. 0.5% to about 20%, from about 0.5% to about 10%, from from about 0.1 to about 20 mg, from about 0.1 to about 15 mg. about 0.5% to about 5%, from about 0.5% to about 3%, from from about 0.1 to about 10 mg. from about 0.1 to about 5 mg. about 0.75% to about 10%, from about 0.75% to about 7.5%, 15 from about 0.5 to about 50 mg, from about 0.5 to about 45 mg. from about 0.75% to about 5%, from about 1% to about 10%, from about 0.5 to about 40 mg, from about 0.5 to about 35 mg. from about 1% to about 5%, from about 1% to about 2.5%, or from about 0.5 to about 30 mg, from about 0.5 to about 25 mg. from about 1% to about 2%. from about 0.5 to about 20 mg, from about 0.5 to about 15 mg. 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 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. 25 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. 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. 30 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. 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. 35 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. 40 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. 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 45 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 of sunscreen agents from about 0.1% to about 25%, from mg, 7.0 mg, 10.0 mg, 15.0 mg, 20 mg, 25 mg, 30 mg, 35 mg. about 0.5% to about 20%, from about 0.5% to about 10%, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg 50 from about 0.5% to about 5%, from about 0.5% to about 3%, of antioxidant. In some embodiments, the compositions dis from about 0.75% to about 10%, from about 0.75% to about closed herein will contain from about 0.3 mg to about 0.75 mg 7.5%, from about 0.75% to about 5%, from about 1% to about of antioxidant. 10%, from about 1% to about 5%, from about 1% to about In other embodiments, the compositions disclosed herein 2.5%, or from about 1% to about 2%. further comprises a skin-lightening agent in a concentration 55 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%, 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%, 60 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 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 65 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 US 8,778,315 B2 67 68 to about 40 mg, from about 0.5 to about 35 mg, from about 0.5 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 to about 30 mg, from about 0.5 to about 25 mg, from about 0.5 mg, 5.0 mg, 7.0 mg, 10.0 mg, 15.0 mg, 20 mg, 25 mg, 30 mg. to about 20 mg, from about 0.5 to about 15 mg, from about 0.5 35 mg, 40 mg, 45 mg, 50 mg. 60 mg, 70 mg, 80 mg, 90 mg or to about 10 mg, from about 0.5 to about 5 mg, from about 1.0 100 mg of anti-acne agent. In some embodiments, the com to about 50 mg, from about 1.0 to about 45 mg, from about 1.0 positions disclosed herein will contain from about 0.3 mg to to about 40 mg, from about 1.0 to about 35 mg, from about 1.0 about 0.75 mg of anti-acne agent. to about 30 mg, from about 1.0 to about 25 mg, from about 1.0 In some embodiments, the compositions disclosed herein to about 20 mg, from about 1.0 to about 15 mg, from about 1.0 further comprises an anti-inflammatory agent in a concentra to about 10 mg, from about 1.0 to about 5 mg, from about 2.5 tion of about 0.01%, about 0.05%, about 0.08%, about 0.1%, to about 50 mg, from about 2.5 to about 45 mg, from about 2.5 10 about 0.15%, about 0.2%, about 0.5%, about 0.8%, about 1%, to about 40 mg, from about 2.5 to about 35 mg, from about 2.5 about 1.3%, about 1.5%, about 1.8%, about 2%, about 2.3%, to about 30 mg, from about 2.5 to about 25 mg, from about 2.5 about 2.5%, about 2.8%, about 3%, about 3.5%, about 4%, to about 20 mg, from about 2.5 to about 15 mg, from about 2.5 about 5%, about 8%, about 10%, about 13%, about 15%, to about 10 mg, and from about 2.5 to about 5 mg of sunscreen about 18%, about 20%, about 23%, about 25%. In yet other agent. In some embodiments, the compositions disclosed 15 embodiments, the compositions disclosed herein comprises a herein will contain from about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 range of anti-inflammatory agents from about 0.1% to about mg, 0.5, mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 2.0 mg. 25%, from about 0.5% to about 20%, from about 0.5% to 3.0 mg, 4.0 mg, 5.0 mg, 7.0 mg, 10.0 mg, 15.0 mg, 20 mg, 25 about 10%, from about 0.5% to about 5%, from about 0.5% to 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 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 25 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 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 30 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%, 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 35 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 40 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 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 45 to about 5 mg, from about 2.5 to about 50 mg, from about 2.5 mg, from about 0.1 to about 45 mg, from about 0.1 to about 40 to 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 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 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 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 55 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 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 60 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 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 65 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 US 8,778,315 B2 69 70 of emollients from about 0.1% to about 25%, from about from about 0.1 to about 15 mg, from about 0.1 to about 10 mg. 0.5% to about 20%, from about 0.5% to about 10%, from from about 0.1 to about 5 mg, from about 0.5 to about 50 mg. about 0.5% to about 5%, from about 0.5% to about 3%, from from about 0.5 to about 45 mg, from about 0.5 to about 40 mg. about 0.75% to about 10%, from about 0.75% to about 7.5%, from about 0.5 to about 35 mg, from about 0.5 to about 30 mg. from about 0.75% to about 5%, from about 1% to about 10%, from about 0.5 to about 25 mg, from about 0.5 to about 20 mg. from about 1% to about 5%, from about 1% to about 2.5%, or from about 0.5 to about 15 mg, from about 0.5 to about 10 mg. from about 1% to about 2%. from about 0.5 to about 5 mg, from about 1.0 to about 50 mg. The compositions disclosed herein may contain from about from about 1.0 to about 45 mg, from about 1.0 to about 40 mg. 0.01 mg to about 100 mg of emollient or about 0.1 mg to about from about 1.0 to about 35 mg, from about 1.0 to about 30 mg. 10 mg of emollient. In some embodiments, the compositions 10 from about 1.0 to about 25 mg, from about 1.0 to about 20 mg. disclosed herein may contain from about 0.05 to about 5 mg from about 1.0 to about 15 mg, from about 1.0 to about 10 mg. ofemollient, or from about 0.1 to about 3 mg of emollient. In from about 1.0 to about 5 mg, from about 2.5 to about 50 mg. Some embodiments, the compositions disclosed herein may from about 2.5 to about 45 mg, from about 2.5 to about 40 mg. contain from about 0.1 to about 50 mg, from about 0.1 to from about 2.5 to about 35 mg, from about 2.5 to about 30 mg. about 45 mg, from about 0.1 to about 40 mg, from about 0.1 15 from about 2.5 to about 25 mg, from about 2.5 to about 20 mg. to about 35 mg, from about 0.1 to about 30 mg, from about 0.1 from about 2.5 to about 15 mg, from about 2.5 to about 10 mg. to about 25 mg, from about 0.1 to about 20 mg, from about 0.1 and from about 2.5 to about 5 mg of film former. In some to about 15 mg, from about 0.1 to about 10 mg, from about 0.1 embodiments, the compositions disclosed herein will contain 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 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 25 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 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 30 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 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 35 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 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 40 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 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%, 45 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%, 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 50 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 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%, 55 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 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 60 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 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. 65 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 US 8,778,315 B2 71 72 about 2.5 to about 5 mg of occlusive. In some embodiments, 20%, by about 25%, by about 30%, by about 35%, by about the compositions disclosed herein will contain from about 0.1 40%, by about 45%, by about 45%, by about 50%, by about mg, 0.2 mg, 0.3 mg, 0.4 mg. 0.5, mg, 0.6 mg, 0.7 mg, 0.8 mg, 55%, by about 60%, by about 65%, by about 70%, by about 0.9 mg, 1.0 mg, 2.0 mg, 3.0 mg. 4.0 mg, 5.0 mg, 7.0 mg, 10.0 75%, by about 80% or more. mg, 15.0 mg, 20 mg, 25 mg, 30 mg. 35 mg, 40 mg, 45 mg, 50 In some embodiments, levels of PGF-2alpha are decreased mg, 60 mg, 70 mg, 80 mg. 90 mg or 100 mg of occlusive. In by about 1%, about 2%, about 3%, about 4%, about 5%, about Some embodiments, the compositions disclosed herein will 6%, by about 7%, about 7%, about 8%, about 9%, by about contain from about 0.3 mg to about 0.75 mg of occlusive. 10%, by about 12%, by about 15%, by about 17%, by about In some embodiments, the compositions disclosed herein 20%, by about 25%, by about 30%, by about 35%, by about are administered twice daily, three times a day, four times a 10 40%, by about 45%, by about 45%, by about 50%, by about day or more. In other embodiments, the compositions dis closed herein are administered once a day, once every other 55%, by about 60%, by about 65%, by about 70%, by about day, once every three days, once every four days, once every 75%, by about 80% or more. five days, once every six days, once a week, once every two EXAMPLES weeks, once a month, or less frequently. In some embodi 15 ments, the compositions administered may be temporarily reduced or temporarily Suspended for a certain length of time Example 1 (i.e., a “drug holiday'). The length of the drug holiday varies between 2 days and 1 year, including by way of example only, Inhibition of Prostaglandin F2 Alpha Levels 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 Human keratinocytes were harvested and exposed to with days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 UVB light to induce PGF2 alpha release. Following exposure days, 300 days, 320 days, 350 days, and 365 days. The dose to UVB irradiation, the cells were treated with a composition reduction during a drug holiday may be from 10%-100%, comprising 1% 4-ethoxybenzaldehyde, Indomethacin (posi including by way of example only 10%, 15%, 20%, 25%, 25 tive control) or left untreated (negative control). After 24 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, hours post-treatment, PGF2 alpha levels were measured by 80%, 85%, 90%, 95%, and 100%. ELISA analysis. The composition comprising 4-ethoxyben Zaldehyde provided dose-dependent inhibition of PGF2 alpha Dosing Effects in UVB-induced cells (FIG. 1). 30 In other embodiments, the compositions are administered Example 2 in an amount to achieve a desired cosmetic effect. In some embodiments, the level of pigmentation is decreased by about Skin Tone Clinical Study 5%, by about 10%, by about 12%, by about 15%, by about 17%, by about 20%, by about 25%, by about 30%, by about 35 Approximately 30 healthy subjects, aged 20-64 years with 35%, by about 40%, by about 45%, by about 45%, by about Fitzpatrick SkinTypes I-III, are enrolled in this single-center, 50%, by about 55%, by about 60%, by about 65%, by about double-blinded comparison study. Assignments of the test 70%, by about 75%, by about 80% or more. In some embodi product or vehicle to subjects are randomized 2:1 to avoid ments, the methods decrease the level of pigmentation by bias. A total of approximately 15 subjects receive the test about 5%, by about 10%, by about 20%, by about 30% or by 40 product and 15 subjects receive the vehicle. Subjects follow a about 40%. In some embodiments, the level of pigmentation twice-daily product application regiment for 4 weeks. No is increased by about 5%, by about 10%, by about 12%, by other moisturizers, lotions or products are allowed to be about 15%, by about 17%, by about 20%, by about 25%, by applied during the study. At the baseline visit, Subjects are about 30%, by about 35%, by about 40%, by about 45%, by graded by a dermatologist for uneven skin tone on their facial about 45%, by about 50%, by about 55%, by about 60%, by 45 skin. Standardized digital photographs of the test site (i.e., about 65%, by about 70%, by about 75%, by about 80% or face) are also taken. At the end of week 2, Subjects are graded O. by a dermatologist for uneven skin tone on their facial skin. In some embodiments, an even skintone or pigmentation is Standardized digital photographs of the test site (i.e., face) are desired, for example, in Subjects afflicted with uneven pig also taken. Twice-daily application of test product continues mentation, Such as vitiligo or uneven melanin distribution. In 50 for another 14 days. At the end of 4 weeks, subjects are graded Some embodiments, the level of pigmentation is uniformly by a dermatologist for uneven skin tone on their facial skin. increased or decreased in localized areas to achieve an even Standardized digital photographs of the test site (i.e., face) are skintone or pigmentation distribution. In some embodiments, also taken. the level of pigmentation in localized areas is decreased towards a more uniform distribution of melanin or melano 55 Example 3 cytes by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, by about 7%, about 7%, about 8%, about 9%, by Post-Inflammatory Hyperpigmentation Clinical about 10%, by about 12%, by about 15%, by about 17%, by Study about 20%, by about 25%, by about 30%, by about 35%, by about 40%, by about 45%, by about 45%, by about 50%, by 60 UV irradiation stimulates a variety of biochemical path about 55%, by about 60%, by about 65%, by about 70%, by ways in the skin, resulting in free radical formation as well as about 75%, by about 80% or more. In some embodiments, the the release of inflammatory mediators. The short-term clini level of pigmentation in localized areas is increased towards cal effects observed from these pathways, include cutaneous a more uniform distribution of melanin or melanocytes by inflammation and erythema, while long-term effects (for about 1%, about 2%, about 3%, about 4%, about 5%, about 65 example, in the absence of treatment of the inflammatory 6%, by about 7%, about 7%, about 8%, about 9%, by about response) result in photodamaged skin. UV irradiation may 10%, by about 12%, by about 15%, by about 17%, by about also cause the development of post-inflammatory hyperpig US 8,778,315 B2 73 74 mentation since it induces an inflammatory response in the methylparaben, propylparaben, sodium lauryl Sulfate, and skin that can proceed to hyperpigmentation. propylene glycol were dissolved in water. The resulting mix The 17 healthy female subjects, aged 26-63 years with ture is stirred until it congeals. Fitzpatrick Skin Types III-IV, were enrolled and completed this single-center, double-blinded comparison study. At base Example 6 line, test areas were marked onto the backs of the subjects: Untreated control, 1% w 4EB composition, antioxidant prod Topical Cream Formulation uct, and other test products. Assignments of the test products to test areas were randomized to avoid site bias. The minimal To a commercial mineral oil-water cold cream base (100 erythemal dose (MED) for each subject was also determined, gm) is added 0.75 grams of a compound of Formula I as a fine using a solar simulator with a spectral output comparable to 10 powder or liquid with continuous mixing and stirring to Sus that of natural solar radiation (UVB: 290-320 nm, UVA: pend the powder in the base and yield a cosmetic or pharma 320-400 nm). Thirty micro liters of each test product were ceutical composition. applied to the respective test sites by the study staff, once daily, for 4 days. On Day 5, test sites were irradiated with 1.0, Example 7 1.5, 2.0, and 2.5 MEDs. On Day 6, standardized digital pho 15 tographs were taken of the test sites and test product applica Topical Cream Formulation tion resumed for an additional eleven days. Standardized digital photographs were taken of the test sites on Day 20. The A cream composition containing 1% ethoxybenzaldehyde images were analyzed using a computer-aided colorimetry is formulated as follows. 1% ethoxybenzaldehyde (1% by algorithm, according to the CIE color standard, to determine weight), niacinamide (2% by weight), hydroquinone (2% by a (redness) on Day 6 and L* (brightness) on Day 20. weight) is dissolved in propylene glycol (15 mL). The solu Both the 1% 4EB product and the antioxidant product tion thus prepared is mixed with hydrophilic ointment, USP provided statistically significant protection from UV-induced grade (85gm) until a consistent cream is obtained. erythema and post-inflammatory hyperpigmentation when compared to untreated control (all P-0.01). The 1% w 4EB Example 8 composition provided significantly higher protection than the 25 antioxidant product from UV-induced post-inflammatory Topical Formulation hyperpigmentation (all P-0.0001, FIG. 2). The results from this clinical study Suggest that topical 1% 4EB provides sig A therapeutic composition contain 1% ethoxybenzalde nificant protection from UV-induced post-inflammatory hyde and additional active agents is formulated as follows. hyperpigmentation when compared to the antioxidant prod 30 Ethoxybenzaldehyde (1% by weight), niacinamide (2% by uct. The 1% w 4EB product provided a statistically significant weight), and kojic acid (2% by weight) are dissolved in a reduction in hyperpigmentation (FIG. 3) and increase in skin mixture of ethanol (70 mL), water (10 mL) and propylene brightness (FIG. 4) when compared to the untreated control glycol until a clear Solution is obtained. sample and the other test products (all P-0.0001). Results from this clinical study suggest that topical 1% 35 Example 9 4EB may provide significant short-term and long-term pro tection from UV-induced post-inflammatory hyperpigmenta Tablet Formulation tion. The results depicted in FIG. 3 from the clinical study Suggest that topical 1% 4EB provides a statistically signifi A compound of Formula I is mixed with dry gelatin binder cant reduction in hyperpigmentation when compared to the 40 untreated control sample and the other test products (all and starch diluent in a 0.1:1:1 weight ratio. A lubricating P<0.0001). Additionally, as seen in FIG. 4, the 1% 4EB amount of magnesium Stearate is added and the mixture is product provided a statistically significant increase in skin formed into 210 mg tablets containing 10 mg of the active brightness when compared to the other test products (all substituted benzaldehyde. P<0.0001). 45 Example 10 Example 4 Capsule Formulation Topical Formulation A compound of Formula I is admixed as a dry powder with A mixture (Part A) of deionized water (69.30% by weight), 50 a starch diluent in an approximate 0.1:2 weight ratio. The glycerin-USP (3.00%), Glycereth-7 (2.50%), polyacryla mixture is filled into 210 mg capsules (10 mg of active com mide (2.25%), and ethoxydiglycol (2.20%) was heated to 80° pound per capsule). C. A separate mixture (Part B) of glyceryl Stearate (5.00%), jojoba oil (3.00%), isocetyl stearate (3.25%), squalane Example 11 (4.10%), cetyl ricinoleate (3.40%), 4-ethoxybenzaldehyde 55 (1.00%), and phenoxyethanol (1.00%) was heated to 80°C. Transdermal Formulation Part B was added to Part A with continuous mixing and stirring. The combined mixture was cooled to 30° C. with A compound of Formula I is admixed with a polymer continuous mixing to yield a cosmetic or pharmaceutical matrix, a permeation enhancer and one or more other excipi composition. 60 ents. The formulation is place on a backing membrane. Example 5 Example 12 Topical Formulation Exemplary Topical Formulation 65 Stearyl alcohol and a white petrolatum is melted at about An amount of 0.1-0.5% 4EB is admixed with 0.1-0.75% 75° C. and then a mixture of a compound of the invention, Retinol, 2.0-8.0% Niacinamide, 1.0-5.0% Tetrahexyldecyl US 8,778,315 B2 75 Ascorbate, 0.001-0.5% Licorice root extract, 0.1-3.0% -continued Resorcinol, and 0.1-3.0% ethyl linoleate and one or more other excipients. Product Description Code. Formula Number Test Productii.3 Base -- 0.5% 4EB Example 13 5 Test ProductiiA. Hydroquinone 4% Half-Face Study to Assess the Efficacy and Tolerance of Four Topical Products in the Treatment The base composition contains Retinol, Niacinamide, Tet of Facial Hyperpigmentation rahexyldecyl Ascorbate, Licorice root extract, Resorcinol, 10 and ethyl linoleate and a pharmaceutically/cosmetically 1.0 Background acceptable carrier. Hyperpigmentation is an increase in pigmentation or color 5.3 Method of Treatment Assignment of the skin that is abnormally dark. Hyperpigmentation Subjects are numbered sequentially in the order in which occurs when an excess amount of melanin is produced. they qualify for entry into the study. 15 Prior to the start of the study, the biostatistics department Causes of hyperpigmentation include Sun exposure, certain will generate a randomization list to establish treatment medications, hormonal changes, PIH (post inflammatory assignment. Subjects are assigned to use 2 of the 4 test mate hyperpigmentation) or a congenital pigmentation disorder. rials according to a half-face design. One of the test materials Hyperpigmentation results in uneven skin color (tone) and a is applied to the left side of the face and another test material photoaged appearance. Dyspigmentation is identified as an o is applied to the right side of the face, as determined by the abnormality in the formation or distribution of pigment, espe randomization design. Randomization is based on a balanced cially in the skin. incomplete block design with n=30 (approximately) for each 2.0 Purpose treatment product. This controlled clinical usage study will be conducted to All subjects are distributed a cleanser, moisturizer and evaluate and compare the tolerance and efficacy of four topi- 25 Sunscreen product to use throughout the study. cal products designed to treat facial hyperpigmentation when 5.4 Instructions for Use used by females with moderate to severe dyspigmentation on Sun exposure is to be avoided as much as possible. If Sun the face. exposure cannot be avoided, sunscreen SPF30 is to be re Evaluations of efficacy will be made using clinical grading, applied to the facial skin prior to Sun exposure. Chroma Meter measurements, digital photography, and self- 30 It is important that the LEFT designated products are only assessment questionnaires. Tolerance will be evaluated by applied on the LEFT side of your face, and the RIGHT des clinical grading of objective irritation, Subject assessment of ignated products are only applied on the RIGHT side of the Subjective sensations, and monitoring of adverse events and face. reactions. In the morning and evening, the face is washed with the 3.0 Assessments 35 Facial Cleanser and gently patted dry. The topical treatments will produce statistically significant Left Facial Side: improvements in clinical grading scores for efficacy param Using your LEFT hand, apply a thin amount of Test Prod eters and have statistically non-significant changes objective uct labeled LEFT onto your LEFT facial side only. Wait for irritation assessments after 12 weeks of use compared to product to absorb before applying moisturizer. baseline. 40 Using your LEFT hand, apply the provided Ultra Sheer 4.0 Study Endpoints Moisturizer onto your LEFT facial side. 4.1 Primary Endpoints Mornings only: using your LEFT hand, apply the provided Efficacy grading is conducted at baseline, week 4 week 8, All-Physical Sunscreen SPF30 to the LEFT side of face and and week 12. Efficacy grades is evaluated for statistical sig throughout the day as needed. nificance in: (1) changes from baseline (weeks 4, 8 and 12); 4s Right Facial Side: and (2) comparisons to the other test products (weeks 4, 8 and Using your RIGHT hand, apply a thin amount of Base 12). Product labeled RIGHT onto your RIGHT facial side only. Chroma Meter measurements are conducted at baseline, Wait for product to absorb before applying moisturizer. week 4, week 8, and week 12. Chroma Meter measurements Using your RIGHT hand, apply the provided Ultra Sheer are evaluated for statistical significance in: (1) changes from 50 Moisturizer onto your RIGHT facial side. baseline (weeks 4, 8 and 12) and (2) comparisons to the other Mornings only: using your RIGHT hand, apply the pro test products (weeks 4, 8 and 12). PL 4.2 Secondary End vided All-Physical Sunscreen SPF30 to the RIGHT side of points face and throughout the day as needed. Self-assessment questionnaires are conducted at baseline, Avoid contact with eyes. If contact occurs, rinse thor week 4, week 8, and week 12. 55 oughly with water. If irritation or rash occurs, discontinue use 5.0 Test Material Information and contact your doctor. 5.1 Study Identification Procedures 5.6 Treatment Blinding Each study product(s) is assigned a unique test material The following procedures will be followed in order to identification number (TMIN) in order to provide proper maintain the double-blinded nature of this study and ensure identification in records and reports. 60 appropriate evaluator blinding: 5.2 Study Product Description(s) The study products will be dispensed by someone other than the investigator or other evaluator(s). Additionally, the person in charge of study product dispensation and the Subject Product Description Code. Formula Number will be instructed not to discuss the study products with the Test Productii1 Base + 0.5% 4EB + 0.1% Osthol 65 Investigator or other evaluator(s). Test Productii.2 Base + 0.1% 4EB + 0.1% Osthol The randomization list will be secured in a locked cabinet and/or computer file with restricted access to a data commit US 8,778,315 B2 77 78 tee consisting of selected representatives from clinical Ser procedures. Subjects are ineligible to participate in this study vices, quality assurance and the statistical department. without a signed informed consent. Subjects will not be made aware of treatment assignment. 6.3 Subject Identification Any study product that has a label indicating its identity Subjects are assigned a three-digit number which, when used in conjunction with the clinical study number, uniquely will be covered and labeled as Test product #1, Test product identifies every subject on the study. This number remains #2, Test product #3 and Test product #4. with the subject throughout the study and should be used in all 6.0 Subject references to the individual in this study. No number is reas 6.1 Number of Subjects signed once the study begins. Sixty Subjects meeting the eligibility requirements are 10 6.4 Eligibility Criteria expected to complete participation in the clinical trial. Each Individuals are admitted to study at the discretion of the subject will use 2 of the 4 test materials, so that each test Investigator or designated, and based on medical history and material will be used by approximately 30 subjects. findings of the pre-study interview and examination. Indi 6.2 Informed Consent Agreement viduals are screened for the eligibility criteria listed below An IRB approved informed consent agreement, consistent is prior to study enrollment. with the requirements in 21 CFR S50.25, is given to each Inclusion Criteria: a subject is eligible to participate if they subject before the start of this study according to standard meet all of the following inclusion criteria:

Females, between the ages of 30 and 65 years 2 Fitzpatrickskin 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 pigmente 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 physica 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 o 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 to 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. US 8,778,315 B2 79 80 -continued

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. 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 upus 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 In ividuals who have had a facial peel or a laser treatment of the face within 60 days prior o 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 acility or a doctors office during this study.

Individuals are admitted to study at the discretion of the 8.2 Visit 1: Baseline Investigator or his/her designate based on medical history and Candidate Subjects are screened for qualifying criteria. findings of the pre-study interview and examination. Subjects that pass the screening are assigned a screening number and graded for the remaining efficacy evaluations and 7.0 Study Design tolerance (safety) evaluations as outlined in Sections 9.1 and 7.1 Description 25 92. This controlled clinical usage study is conducted to evalu ate and compare the efficacy and tolerance (safety) of the 4 Candidate subjects will complete an Eligibility and Health test materials in improving the clinical signs of facial skin Questionnaire, a Confidentiality Agreement and a HIPAA hyperpigmentation. The study is conducted over the course of form. Those who pass eligibility requirements are enrolled 12 weeksandwill consist of 4 visits, at baseline, week 4, week 30 into the study and assigned a Subject number. 8, and week 12. Those who qualify will be enrolled in the study and Women with clinically determined dyspigmentation of the assigned a subject number. facial skin are recruited for this study. Subjects will use 2 of the 4 test materials according to a half-face design, as Subjects will have Chroma Meter measurements and digi assigned by a randomization schedule. Test material evalua 35 tal photography procedures performed as described in Sec tions are conducted using clinical grading, bioinstrumenta tions 9.3 and 9.4. Subjects will complete a self-assessment tion (Chroma Meter measurements), digital photography, and questionnaire as described in Section 9.5. self-assessment questionnaires. Subjects are distributed pre-weighed units of 2 of the test 7.2. Outline of Procedures materials, according to a randomization design. One of the

Visit 1 Visit 2 Visit 3 Visit 4 Procedures: Baseline Week 4 Week 8 Week 12 Qualification screening (facial exam) and eligibility paperwork X Clinical evaluations on the right and left sides of the face by X X X X Expert Grader: Efficacy Parameters: overall hyperpigmentation, investigator's global assessment, global improvement Tolerance Parameters: objective and subjective irritation (erythema, Scaling, burning stinging, itching, tightness, tingling) Chroma Meter measurements on the right and left sides of the X X X X face of a hyperpigmented area Full-face Right and Left face digital images (cross polarized X X X X and standard lighting) using VISIACR Subject Self-assessment Questionnaire completed by X X X X Subjects regarding various skin condition parameters for the right and left sides of the face

8.0 Conduct of Study test materials is applied to the right side of the face and the 8.1 Pre-Study Procedures other test material is applied to the left side of the face. Test 60 Candidate subjects are screened with the eligibility material units are clearly labeled as “Left' and “Right'. Sub requirements by telephone prior to Visit 1. jects are also distributed a cleanser, moisturizer and Sunscreen Candidate subjects are instructed to wash their faces and to use throughout the study. remove all makeup at least 20 minutes prior to arrival at the Usage instructions are discussed with Subjects and written clinic of the baseline visit. 65 usage instructions are provided. Subjects are also provided Candidate Subjects are assigned an appointment time for with a calendar of study visits and a daily diary to record test visiting the clinic. material application times and comments. US 8,778,315 B2 81 8.3 Visit 2: Week 4 and Visit 3: Week 8 -continued A clinician records concomitant medications and asks Sub jects if they have experienced any changes in their health 4 Moderately Improved since the last visit. 5 Markedly Improved Daily diaries are collected and reviewed for compliance. Subjects that are non-compliant are counseled that if they 9.2 Tolerability Evaluations continue to be non-compliant they will be dropped from the At baseline, week 4 week 8, and week 12, the following study. New diaries are distributed as needed. tolerance/safety parameters are scored on the right and left Subjects participate in the following procedures: efficacy sides of each subject’s face: evaluations as described in Section 9.1; tolerability evalua 10 tions described in Section 9.2: Chroma Meter measurements as described in Section 9.3; and digital photography as Objective parameters (clinically graded) erythema, Scaling described in Section 9.4. Subjects will complete a self-assess Subjective parameters (assessed by Subjects) burning? stinging, itching, ment questionnaire as described in section 9.5. tightness, tingling 8.4 Visit 4: Week 12 15 A clinician records concomitant medications and asks Sub Results of the tolerance assessments will be recorded using jects if they have experienced any changes in their health the following scale (with half-point scores used as necessary): since the last visit. Daily diaries will be collected and reviewed for compli aCC. O None Subjects participate in the following procedures: efficacy 1 Mild 2 Moderate evaluations as described in Section 9.1; tolerability evalua 3 Severe tions described in Section 9.2: Chroma Meter measurements as described in Section 9.3; and digital photography as described in Section 9.4. Subjects will complete a self-assess 25 9.3 Chroma Meter Measurements ment questionnaire and a final product evaluation question The Minolta Chroma Meter CR-400, in conjunction with a naire as described in section 9.5. computer, is used to instrumentally assess skin color. The 9.0 Assessments following values are recorded: 9.1 Efficacy Evaluations 30 At baseline, week 4 week 8, and week 12, an expert clini L* Values describe the relative brightness on a gray scale from cal grader evaluates Subjects on the right and left sides of the black to white; scores increase as the skin tone becomes brighter face for the following efficacy parameters using the indicated a: Values describe the color hue ranging from red to green; scores grading scales (half-points may be used for all scales below to increase with vascularization or blood flow b* Values describe the color hue ranging from blue to yellow: better describe a condition): scores increase with the amount of melanin in the skin 35 Overall Hyperpigmentation O None Chroma Meter measurements are performed at baseline, 1 to 3 Mild week 4, week 8, and week 12. A single measurement is taken 4 to 6 Moderate on the right and left sides of each subject’s face on a hyper 7 to 9 Severe 40 pigmented area selected by the expert grader. The location is recorded on a facial diagram to ensure consistency in mea Subjects will be required to have a score of 4 to 9 for overall Surement location at each visit. hyperpigmentation on both sides of the face to qualify for 9.4 Digital Photography study participation. Digital photography using a Nikon camera (Canfield Investigator's Global Assessment-Hyperpigmentation: 45 VISIA-CR Camera System) is performed at baseline, week 4, week 8, and week 12, to document visible changes in facial hyperpigmentation. For each Subject, a full-face image is Score Rating Description taken of the right and left sides of the face (2 images per Subject) with standard and cross-polarized lighting/filter con Clear No brown spots or areas of discoloration 1 Almost Overall there are a few brown spots with increased 50 ditions. The focus revolves around the brown channel images clear pigmentation; they are very small in size and (derived from the cross-polarized images) and the standard only very slightly darker than Surrounding skin lighting photos. 2 Mild Several brown spots with increased pigmentation; they are Small in size and slightly darker Photos taken at weeks 4, 8 and 12 are compared to the than Surrounding skin baseline photo to ensure consistent focus, lighting, placement 3 Moderate Many brown spots with increased pigmentation: 55 and color. At each photography visit, color standards are they are medium in size and much darker photographed prior to beginning each day's photography. than Surrounding skin 4 Sewere Many large brown spots with increased pigmentation; 9.5 Self-Assessment Questionnaires they are large in size and markedly darker At baseline, week 4 week 8, and week 12, subjects will than Surrounding skin complete a self-assessment questionnaire regarding various 60 skin condition parameters on the right and left sides of the face. Investigator's Global Improvement Assessment: 10.0 Adverse Events 10.1 Definition of an Adverse Event 1 Worse An adverse event (AE) is any untoward medical occurrence 2 No Improvement 65 in a clinical investigation where a subject is administered a 3 Mildly Improved pharmaceutical product/biologic (at any dose), OTC, cos metic product or medical device and which does not neces US 8,778,315 B2 83 84 sarily require a causal relationship with a test article. An AE When an adverse event persists at the end of the study, the can therefore be any unfavorable and unintended sign (in investigator conducts a follow-up of the subject until the event cluding an abnormal laboratory finding, for example), Symp is satisfactorily resolved. tom or disease temporally associated with the use of a medici All adverse events are recorded by the Investigator onto the nal product whether or not considered related to the medicinal 5 product. Adverse events will be recorded on the appropriate Adverse Event page of the source documents describing the case report forms and Source documents. adverse event, onset and stop date, severity, opinion of cau 10.2 Assessment of Severity and Relationship sality, the course of action taken, if any, as well as any perti The investigator or his medical staff will evaluate all nent data necessary to allow a complete evaluation of the adverse events as to their severity and relation to the test 10 adverse event. For serious adverse events, an additional report article. The severity of adverse events will be graded as fol (SAE Report Form) is completed. lows: 10.5 Procedures for Reporting Serious Adverse Events Any serious adverse event that occurs during the study whether related to the treatment or not, expected or not, is Mild: Awareness of a sign or symptom but easily tolerated reported. Moderate: Discomfort sufficient to cause interference with usual activity 15 or to affect clinical status 10.6 Unanticipated Adverse Events Sewere: Incapacitating with inability to do usual activity or to Unanticipated adverse effect is defined as any serious significantly affect clinical status adverse effect on health or safety, any life-threatening prob lem or death caused by, or associated with, the test article if Assessment of Causality: the Investigator and/or trained 20 that effect, problem, or death was not previously identified in staff member will also assess the relationship of any adverse nature, severity, or degree of incidence in the application; or event to the use of the study article, based upon available any other unanticipated serious problem associated with the information, using the following guidelines: test article that relates to the rights, safety, or welfare of Subjects. 25 10.7 Anticipated Reactions O Unlikely No temporal association, or the cause of the event has The test material when applied to the face may produce been identified, or the test article cannot be implicated 1 Possible Temporal association, but other etiologies are likely mild to moderate, transient erythema, dryness, burning, sting to be the cause; however, involvement of the test article ing and/or itching. The responses discussed above will not be cannot be excluded treated as adverse reactions. These conditions may or may not 2 Probable Temporal association, other etiologies are possible, 30 but 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 35 11.0 Biostatistics and Data Management occurring at any dose that results in any of the following 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 40 procedures. Clinical grading scores and Chroma Meter mea life-threatening, or require hospitalization may be considered 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- 45 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 50 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 55 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?”). 60 electronic format. The 3 major aspects of EDC are a graphical Directed questioning and examination will be performed user interface for data entry, a validation component to check when appropriate. All reported adverse events are docu for user data and a reporting tool for analysis of the collected mented on the appropriate forms without omitting any data. Statistical analyses are performed using SAS Software requested and known information. Every time a concomitant version 9 series (SAS Statistical Institute). therapy is reported during the study, an Adverse Event Form 65 The self-assessment questionnaires are completed by Sub will be completed if appropriate and the reason for the treat jects electronically using HIPAA compliant Zoomerang ment noted. online survey software. US 8,778,315 B2 85 86 Data review and analyses is performed by an independent Prior to the start of the study, the biostatistics department data committee. The data committee will consist of selected generates a randomization based on a site rotational basis to representatives from clinical services, quality assurance and avoid skin site bias. The irradiated, untreated site is to be the statistical department. included in the randomization assignment. 12.0 Results UV Radiation FIGS. 7, 8 and 9 provide the results from this study. Over all, 4% hydriguinone and Base+0.5% 4EB both significantly UV radiation is supplied by an artificial source, which has reduced hyperpigmentation compared to baseline for every a spectral output in the ultraviolet range comparable to that of time point (See FIG. 7). the natural solar spectrum (UVB: 290-320 nm and UVA: FIG. 8 illustrates the overall level of hyperpigmentation as 10 320-400 nm). The artificial light source used complies with a change from baseline. Sites treated with 4% hydriduinone the Source spectral specifications as described in published and Base--0.5% 4EB demonstrated comparable distribution testing guidelines. UV irradiation is performed with a single of results in individuals. port solar simulator (Model 16S, Solar UV Simulator, Solar FIG. 9 provides the results of the patient self-assessment Light Co., Philadelphia) with a 150 watt xenon arc lamp. questionnaires. Better subject preference was observed with 15 UVB+UVA radiation is obtained by using a combination of treatment with Base--0.5% 4EB than with 4% Hydroquinone. the UG-1 1/1 mm and WG-320 filters (Schott Glass Technolo gies) that are placed in the radiation path of the Solar simula Example 14 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 light. Exposures are performed by varying the time of expo The following example examines acute exposure to ultra 25 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) 30 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 warm-up. The topical formulations being tested will protect human skin from the harmful effects of ultraviolet (UV) radiation 35 compared to an untreated site as measured by changes in 5.4 Product Application colorimetry (“L* and b values, or degree of tanning accord Thirty (30) microliters (ul) of each test material is applied ing to the International Commission on Illumilation (CIE) to designated sites using an open application technique with color standard). rubbing. 4.0 Endpoints 40 Primary Endpoint: Significant changes in L* values com One irradiated, untreated site does not receive product pared to the untreated area application. Secondary Endpoint: Significant changes in b values 6.0 Subject Enrollment compared to untreated area, Number of Subjects 5.0 Test Material Information 45 5.1 Study Identification Procedures Fifteen (15) subjects meeting the eligibility requirements Each study product(s) is assigned a unique test material are expected to complete participation in the clinical trial. identification number (TMIN) in order to provide proper Informed Consent Agreement identification in records and reports. An informed consent agreement, consistent with the 5.2 Study Product Description(s) 50 requirements in 21 CFR S50.25, is given to each subject before the start of this study according to standard proce Product Description dures. Test Product #1 Base Subject Identification Test Product #2 Base - 1% 4EB 55 Subjects are assigned a three-digit number which, when Test Product #3 Base -- 0.5% 4EB used in conjunction with the clinical study number, uniquely Test Product #4 Base - 1% 4EB -- 0.2% DSE extract Test Product #5 Base + 1% 4EB + 0.1% Osthol identifies every subject on the study. This number remains Test Product #6 4% hydroquinone with the subject throughout the study and is used in all refer ences to the individual in this study. No number is reassigned 60 once the study begins. The base composition contains Retinol, Niacinamide, Tet rahexyldecyl Ascorbate, Licorice root extract, Resorcinol, Eligibility Criteria and ethyl linoleate and a pharmaceutically/cosmetically Individuals are admitted to study at the discretion of an acceptable carrier. Investigator or designated, and based on medical history and 5.3 Method of Treatment Assignment 65 findings of the pre-study interview and examination. Indi Subjects are numbered sequentially in the order in which viduals are screened for the eligibility criteria listed below they qualify for entry into the study. prior to study enrollment. US 8,778,315 B2 87 88 -continued Inclusion Criteria Exclusion Criteria Age: 18 years or older 2 Gender: Male or female hydrochloride), oral hypoglycemic agents (e.g., tolubutamide, 3 Fitzpatrick skin type III 5 chlorpropamide), and tetracycline antibiotics (e.g., The Fitzpatrick skin classification is based on the unprotected dimethylchloroteteacycline, tetracycline). response of the skin 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: p 9. Individuals are admitted to the study at the discretion of the I. Always burns easily; never tans 10 Investigators based on medical history and findings of the II. Always burns easily; tans minimally pre-study interview and examination. Each subject is III. Burns moderately; tans gradually expected to complete the full course of the study. IV. Burns minimally: always tans well 7.0 Study Design V. Rarely pils d Description VI. Never burns; deeply pigmente is This open application clinical study is conducted to evalu 4 eligibilityGeneral good questionnaire health as determined by review of the health and ate the effectiveness of six (6) test materials to suppress the 5 Willingness to cooperate and participate by following study elect skin p1gmentation s rece1V1ng varying requirements for the duration of the study and to report any oses of UV uS1ng 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 18, 21, 24, 27 3-26 Off Days 8, 12, 16, Days 8-13, Visit 1 Visit 2 Days 3-7, 14, 19, 22, 25, 29, 15-20, 22-27, Visit 27 Day 1 Day 2 21, 28 and 35 32, 36 29-34 Day 36 Paperwork and X Screening MED X Determination Grade MED X 1.0, 1.5, 2.0 and 2.5 X MED Exposure Test Material X Application Chromameter X* X Photography X* X Photography and Chromameter is done prior to test material application,

8.0 Conduct of Study Exclusion Criteria 45 8.1 Visit 1: Baseline: Day 1 1 Individuals with Fitzpatrick skin types I, II, IV, V and VI. Individuals are given an informed consent (IC) document 2 In R tha hy been SNS 8. py, Rail or to read. They have all of their study related questions and/orhealth professionalbecause of drug to avoid contraindications sunlight because (see ofexclusion a medical #10). condition answered by the Investigator or his/her designated staff and if 3 Individuals with known abnormal responses to sunlight or UVR they agree, they S1gn two copies of the IC. ight sources. 50 Subjects complete a health and eligibility questionnaire, a 4 careIndividuals product. with a known allergy to any ingredient in a personal confidentialityfidentiali agreement-photographich hi release1 form,f andd a 5 Individuals with known atopic skin diseases or neurodermatitis. HIPAA release form. 6 Women known to be pregnant, nursing, or planning to become The Investigator or his/her designated staff examine the 7 Individualspregnant within known 6 months. to be treated for cancer or have a history of 55 backaC (test S1te area) fOr eVenneSS OTSK1ntOnefski (F 1tzpatrick ick skiskin C8CC. type III only) and to ensure the lack of uneven Suntan, Sun 8 Individuals with observable Sunburn, Suntan, Scars, uneven burn, Scars, birthmarks, moles, vitiligo, keloids, skin abnor E. R s conditions on the test malities, or any other dermal markings. areas that might influence the test results. - 9 Any disease or condition that the examining Investigator deems Eligible individuals are enrolled into the study and inappropriate for participation (e.g., uncontrolled high blood assigned a Sub ect number. pressure, individuals with dermal hyperSensitivity requiring 60 Subjects receive 5-7 irradiation exposures expressed as treatments with medications in exclusion #10, etc.). 10 Individuals taking medication(s) which in the opinion of the J/sq cm (adjusted to the erythema action spectrum) on adja nvestigator, would interfere with the Subject's participation on cent unprotected skin sites on the lower back. Each exposure he study. Such medications include (but are not limited to) antihypertensive agents (hydrochorothiazide, furosemide, represents a 25% increase in energy over the previous expo meticrane), ataractics (e.g., periphenazine), psychotropic agents 65 SUC. (e.g., chlorpromazine), antihistamines (e.g., promethazine Seven (7) 3.0 cmx5.0 cm areas are marked on the lower back. US 8,778,315 B2 89 90 8.2 Visit 2: Day 2 10.0 Adverse Events 1. Test sites from Visit 1 are examined using either a tung 10.1 Definition of an Adverse Event sten or warm white fluorescent light that provides 450 to 550 An adverse event (AE) is any untoward medical occurrence lux of illumination. in a clinical investigation where a subject is administered a 2. Sites are scored for erythema using the scale outlined in 5 pharmaceutical product/biologic (at any dose), OTC, cos section 9.1 for MED Determination. metic product or medical device and which does not neces 3. Using the determined MED value, UVR exposures are sarily require a causal relationship with a test article. An AE calculated. The amount of UVR delivered to each subjects can therefore be any unfavorable and unintended sign (in test sites depends on this value. cluding an abnormal laboratory finding, for example), Symp 4. Each area is exposed to UVR in doses of 1.0x, 1.5x and 10 tom or disease temporally associated with the use of a medici 2.0x and 2.5x the previously determined MED. nal product whether or not considered related to the medicinal 5. Subjects have a rest period of 5 days while tanning product. develops at the irradiated sites. Subjects resume study proce 10.2 Assessment of Severity and Relationship dures on Day 8. 15 The investigator or his/her medical staff evaluates all 8.3 Visits 3, 7, 10, 13, 15, 18, 21 & 24: Days 8, 12, 16, 19, adverse events as to their severity and relation to the test 22, 25, 29 & 32 article. The severity of adverse events is graded as follows: 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 Moderate Discomfort sufficient to cause interference with usual activity in section 9.2 or to affect clinical status Test Materials are applied as outlined in Section 5.4. A 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 & 25 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 article, based upon available information, using the following seventh site will serve as an irradiated untreated control. guidelines: 8.5 Visit 27: Day 36 Digital photography are conducted as outlined in section 30 9.3 and chromameter measurements are conducted as out O Unlikely No temporal association, or the cause of the event has been identified, or the test article cannot be lined in section 9.2 implicated 9.0 Assessments 1 Possible Temporal association, but other etiologies are likely to be the cause; however, involvement of the test article 9.1 MED Determination Scoring 35 cannot be excluded 2 Probable Temporal association, other etiologies 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 present 40 10.3 Definition of a Serious Adverse Event (SAE) A serious adverse event is any experience or reaction The site receiving the lowest dose of combined UV that occurring at any dose that results in any of the following produced mild redness reaching the borders of the site will outcomes: death; is life threatening; inpatient hospitalization receive a score of +, and will be recorded as the MED (US) for or prolongation of hospitalization; a persistent or significant that subject. 45 disability/incapacity; or a congenital anomaly/birth defect. Each subject's MED may be different, but will likely be Important medical events that may not result in death, be approximately 70 m.J/cm2. The intensity of UVR delivered to life-threatening, or require hospitalization may be considered each subject's test sites depends on this value. a serious adverse event when, based upon appropriate medi 9.2 Chromameter Measurements cal judgment, they may jeopardize the patient or subject and 50 The Minolta Chroma Meter CR-400, in conjunction with a may require medical or Surgical intervention to prevent one of computer, is used to assess skin color. L* values describe the the outcomes listed in this definition. The term “life-threat relative brightness on a gray Scale from black to white, and ening” refers to an event in which the subject was at risk of scores increase as the skin tone becomes brighter/lighter. b death at the time of event; it does not refer to an event that values describe the color hue ranging from blue to yellow and 55 hypothetically might have caused death if it was more severe. scores increase with the amount of melanin in the skin. One Hospitalization solely for the purpose of diagnostic tests, measurement is taken at each of the six treated sites and the even if related to an adverse event, elective hospitalization for untreated irradiated control site. an intervention which was already planned before the inclu 9.3 Imaging Procedures sion of the Subject in the study, and admission to a day-care Digital photography is performed on the six treated sites 60 facility may not themselves constitute Sufficient grounds to be and the untreated irradiated control site using a Nikon D300 considered as a serious adverse event. Hospitalization is camera and Micro Nikkor lens. Test and control sites are defined as being admitted to a hospital as an in-patient for clearly labeled for each individual, and color standards are greater than 24 hours. visible in each Subject's photograph. Images are saved as raw 10.4 Procedures for Reporting Adverse Events data (NEF files) and also as JPEG files, arranged by subject. 65 At each visit, the Subject is questioned about adverse events Photographs are analyzed for colorimetry using Image Pro using an open question (e.g., "Have you noticed any change in Analysis software. your health since the last visit?). US 8,778,315 B2 91 92 Directed questioning and examination is performed when assessment of product efficacy. The UV exposure will create appropriate. All reported adverse events are documented on Sunburn and possible discomfort. Hypo- or hyperpigmenta the appropriate forms without omitting any requested and tion may occur at the skin sites, and the skin may show known information. irritation where test material or vehicle is applied. These Every time a concomitant therapy is reported during the 5 conditions may or may not resolve over t1me. Symptoms that study, an Adverse Event Form is completed if appropriate and epersistent andate G SeVer nature, ad that inst the reason for the treatment noted. e evation (e.g., edema, papules, Vesicles, spreading) will be When an adverse event persists at the end of the study, considered adverse events (AEs). follow-up of the subject is conducted until the event is satis 11.0 Biostatistics and Data Management factorily resolved. 10 Digital photographs will be taken of the entire treatment 10.5 Unanticipated Ad Event and control areas under standardized conditions. Images will U is unan pal s fined be analyzed via a computer-aided colorimetry algorithm to nanticipated adverse effect 1s de ned as any serious determine L values and b values. The L values of the adverse effect on health or safety, any life-threatening prob- treated areas and untreated areas from the images and Chro lem or death caused by, or associated with the test article if 15 mameter measurements will be compared to provide a 'Skin that effect, problem, or death was not previously identified in Lightening Factor.” nature, severity, or degree of incidence in the application; or The “L*and b colorimeter values are expected to be dif any other unanticipated serious problem associated with the ferent between the test material-treated and untreated, irradi test article that relates to the rights, safety, or Welfare of ated area. Since each patient will serve as his own control, Subjects. 20 p-values will be determined by the two-tailed Student t-test. 10.6 Anticipated Reactions The test material when applied to the skin may produce Appendix 2 mild irritation Such as erythema, tanning, Scaling/dryness, burning and/or stinging at the test site or Surrounding the test Exemplary Study Calendar

SUNDAY MONDAY TUESDAY WEDNESDAY THURSDAY FRIDAY SATURDAY

17 8 19 2O 21 22 23 V1 D1 V2D2 D3 D4 D5 D6 O:OO-12:OO 10:00-1:OO OFF OFF OFF OFF 4:30-6:00 4:00-6:00 Paperwork Irradiation MED 24 25 26 27 28 29 30 D7 V3.D8 V4.D9 V5, D10 V6.D11 V7 D12 V8,D13 OFF 1:00-1:00 11:30-12:30 11:30-12:30 11:30-12:30 1:00-1:OO 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 Product App Product App Product App Photos Chromameter Chromameter Product App Product App 1 2 3 4 5 6 7 D14 V9, D15 W10, D16 W11 D17 11:30-12:30 V12 D18 11:30-12:30 V13 D19 W14;D2O OFF 1:30-12:30 1:00-1:OO 5:00-6:00 5:00-6:00 1:00-1:OO 10:OO-12:OO 5:00-6:00 4:30-6:00 Product Product App 4:30-6:00 Product App Product App Photos App Photos Chromameter Chromameter Product App Product App 8 9 O 1 2 3 14 D21 V15/D22 W16AD23 W17 D24 V18. D25 W19 D26 V2OD27 OFF :OO-1:00 1:30-12:30 1:30-12:30 1:00-1:OO 1:30-12:30 10:00-12:00 4:30-6:00 5:00-6:00 5:00-6:00 4:30-6:00 5:00-6:00 Product App Photos Product App Product App Photos Product App Chromameter Chromameter Product App Product App 15 6 7 8 9 2O 21 D28 OFF W21 D29 W22 D30 V23 D31 V24, D32 V25, D33 W26.D34 :OO-1:00 1:30-12:30 1:30-12:30 1:00-1:OO 4:30-6:00 11:30-12:30 10:00-12:00 4:30-6:00 5:00-6:00 5:00-6:00 Photos 5:00-6:00 Product App Photos Product App Product App Chromameter Product App Chromameter Product App Product App 22 23 24 25 26 27 28 D35 V27, D36 OFF :OO-1:00 4:30-6:00 Photos Chromameter

sites. The responses discussed above will not be treated as 12.0 Results adverse reactions. If sites begin to show mild levels of 65 An increase in brightness of UV-induced pigmentation was erythema, then product applications may be skipped as observed in patient sites treated with Base+0.5% 4EB com needed in order to avoid redness, which would interfere in the pared to 4% hydroquinone (See FIG. 6). US 8,778,315 B2 93 94 Example 15 What is claimed: 1. A method of treating hyperpigmentation or a hypermel MelanoDerm Model anosis disorder in an individual, comprising administering to the individual in need thereof an effective amount of a com position comprising: from about 0.01% to about 2% substi The following example provides a validated model for tuted benzaldehyde, selected from the group consisting of melanin production using human skin equivalent. 2-ethoxybenzaldehyde, 4-ethoxybenzaldehyde, 4-allyloxy Melanogenesis study: The melanoderm tissues (MEL benzaldehyde and 4-propoxybenzaldehyde, and a pharma 300B) were obtained from Mattek Corporation and cultured ceutically or cosmetically acceptable carrier. for 14 days at specified conditions. The tissues were treated 2. The method of claim 1, further comprising administer with 15ul of formulations or with 25ul of positive (1% Kojic 10 ing to the individual in need thereof an effective amount of acid solution) and negative (DI water) controls every other from about 0.01% to about 5.0% of an additional agent, day during this period. Tissues were taken out in between this wherein the additional agent is selected from the group con period at specific days and fixed for histological imaging, sisting of retinol, niacinamide, tetrahexyldecyl ascorbate, light microscopy or for melanin quantification. glycyrrhiza glabra (licorice) root extract, hexyl resorcinol, 15 ethyl linoleate, or mixtures thereof. As seen in FIG. 6, Base+1% 4EB was more effective than 3. The method claim 1, wherein the amount of substituted Kojic Acid in reducing the melanin content of the skin equiva benzaldehyde in the composition is about 0.5%. lent. 4. The method of claim 1, wherein the method reduces While preferred embodiments have been shown and melanin distribution by about 10% to about 40%. described herein, it will be obvious to those skilled in the art 5. The method of claim 1, wherein the composition is that such embodiments are provided by way of example only. topically or transdermally administered to the skin of the Numerous variations, changes, and Substitutions will now individual. occur to those skilled in the art without departing from the 6. The method of claim 1, wherein the composition further embodiments. It should be understood that various alterna comprises one or more additional active agents. tives to the embodiments described herein may be employed 25 7. The method of claim 6, wherein the additional active in practicing the embodiments. It is intended that the follow agent is an antioxidant, a Sunscreen, a Sunprotectant, a Sun ing claims define the scope of the embodiments and that block, a skin-lightening agent, an anti-inflammatory agent, an methods and structures within the scope of these claims and anti-acne agent or mixtures thereof. their equivalents be covered thereby. k k k k k