US009364424B2

(12) United States Patent (10) Patent No.: US 9,364,424 B2 Caetano et al. (45) Date of Patent: *Jun. 14, 2016

(54) TOPICAL COSMETIC SKIN LIGHTENING (56) References Cited COMPOSITIONS AND METHODS OF USE THEREOF U.S. PATENT DOCUMENTS 5,609,875 A 3, 1997 Hadas (71) Applicant: Stiefel Laboratories, Inc., New Castle, 6,090,369 A 7/2000 Stewart DE (US) 2001 OO16213 A1 8/2001 Singh-Verma 2003. O198612 A1 10/2003 Chaudhuri et al. 2004/0028642 A1 2/2004 Hansenne et al. (72) Inventors: Joao Paulo Caetano, Sao Paulo (BR): 2004/0175439 A1 9/2004 Cyr Monica Alves Mariani De Oliveira, Sao 2005, 0163731 A1* 7, 2005 PeliSSon ...... A61K 8,347 Pauloa (BR) 424,59 2006, OO18867 A1 1/2006 Kawasaki et al. 2006/0280704 A1 12/2006 John (73) Assignee: Stiefel Laboratories, Inc., Wilmington, 2007/0020203 A1* 1/2007 Chaudhuri ...... A61K 8,675 New Castle, DE (US) 424,59 2007/O122492 A1 5, 2007 Behr (*) Notice: Subject to any disclaimer, the term of this 2008, OOSO459 A1 2/2008 Elie et al. patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. FOREIGN PATENT DOCUMENTS This patent is Subject to a terminal dis FR WO2005/063.191 * 7, 2005 ...... A61K 7.48 claimer. JP 01-311011 A 12/1989 JP 06-271442 A 9, 1994 JP 09-077638 A 3, 1997 (21) Appl. No.: 14/950,395 JP 2003-063925. A 3, 2003 JP 2003-081749 A 3, 2003 (22) Filed: Nov. 24, 2015 JP 2004-352697 A 12, 2004 JP 2005-139070 A 6, 2005 (65) Prior Publication Data WO WO 2003/0593.13 A1 T 2003 WO WO 2005/025532 A1 3, 2005 US 2016/OO743 15 A1 Mar. 17, 2016 WO WO 2005/063.191 A1 7/2005 WO WO 2005/067885 A1 7/2005 WO WO 2006/053912 5, 2006 Related U.S. Application Data WO WO 2007/107268 A1 9, 2007 (63) Continuation-in-part of application No. 12/743,353, OTHER PUBLICATIONS filed as application No. PCT/US2008/012952 on Nov. Halder, et al. Skin Therapy Letter, 9(6): 1 (2004). 19, 2008, now Pat. No. 9,241,893, which is a Masato Suzuki (Editorial Supervisor), Functional Cosmetics III, continuation-in-part of application No. CMC Limited, Jan. 1, 2000, pp. 27-35 (in Japanese). Masato Suzuki (Editorial Supervisor), Functional Cosmetics III, PCT/US2007/024109, filed on Nov. 19, 2007. CMC Limited, Jan. 1, 2000 (English translation). (51) Int. Cl. A 6LX8/97 (2006.01) * cited by examiner A61O 1704 (2006.01) Primary Examiner — Sean Basquill A61O 19/08 (2006.01) (74) Attorney, Agent, or Firm — Dara L. Dinner; Theodore A61O 19/02 (2006.01) R. Furman A6 IK 8/35 (2006.01) A6 IK S/37 (2006.01) (57) ABSTRACT A6 IK 8/49 (2006.01) Topical cosmetic compositions are provided that can com (52) U.S. Cl. prise a Phyllanthus extract, a Bellis extract, and a licorice CPC. A61K 8/97 (2013.01); A61K 8/35 (2013.01); (Glycyrrhiza) extract. These compositions are used for topi A61K 8/355 (2013.01); A61 K8/37 (2013.01); cal cosmetic applications, particularly to lighten skin. Meth A61K 8/496 (2013.01); A61O 1704 (2013.01); ods for lightening skin are also provided and can comprise A61O 19/02 (2013.01); A61O 19/08 (2013.01) topically administering a therapeutically effective amount of (58) Field of Classification Search a topical cosmetic composition comprising a Phyllanthus CPC ...... A61K 8/97: A61K 8/35; A61K 8/355; extract, a Bellis extract, and a licorice extract, to skin of a A61K 8/37; A61K 8/496; A61Q 17/04; subject in need thereof. A61Q 19/08: A61Q 19/02 See application file for complete search history. 17 Claims, 5 Drawing Sheets U.S. Patent Jun. 14, 2016 Sheet 1 of 5 US 9,364,424 B2

Hydroquinone

F.G. U.S. Patent Jun. 14, 2016 Sheet 2 of 5 US 9,364,424 B2

New Formation

: New Fontatio:

FG, 2 U.S. Patent Jun. 14, 2016 Sheet 3 of 5 US 9,364,424 B2

F.G. 3 U.S. Patent Jun. 14, 2016 Sheet 4 of 5 US 9,364,424 B2

3.Hydroquinone & New Formula Control

F.G. 4 U.S. Patent Jun. 14, 2016 Sheet 5 of 5 US 9,364,424 B2

. 5a & b. Photogrgraph ic Register ; Hydroqui O at T0 (day 0) and T2 (day 21)

Fig. 5 c & d. Photographic Register New Formulation at T0 and T21

ig. 5 e & f. Photograph C egister Control at T0 and T2

FG. 5 US 9,364,424 B2 1. 2 TOPCAL COSMETC SKN LIGHTENING present in Phyllanthus extract, Bellis extract, or licorice COMPOSITIONS AND METHODS OF USE extract. In a further embodiment, the cosmetic composition THEREOF does not comprise oligopeptide-4 (pro-collagen oligopep tide) or oligopeptide-5 (pro-elastin oligopeptide). In another FIELD OF THE INVENTION embodiment, the cosmetic composition does not comprise at least one oligopeptide having a suitable molecular weight So The presently described subject matter relates to topical that it is able to act as carrier of Phyllanthus Embilica extract cosmetic or dermatological compositions comprising plant and penetrate skin to maximize the efficacy. extracts. These compositions are used for topical cosmetic In an embodiment, the present Subject matter relates to a applications, particularly to treat undesired skin pigmenta 10 topical cosmetic composition, comprising, consisting essen tion. tially of, or consisting of a Phyllanthus embilica extract; a Bellis perennis extract; and a licorice extract. BACKGROUND OF THE INVENTION In another embodiment, the present Subject matter relates to a topical cosmetic composition, comprising, consisting Topical cosmetic skin lightening compositions that are safe 15 essentially of, or consisting of a skin-lightening active com and effective are particularly desirable for treating undesir ponent comprising, consisting essentially of or consisting of able skin pigmentation, including for example, regional a Phyllanthus extract, a Bellis extract, and a licorice extract; at hyperpigmentation caused by melanocytic hyperactivity Such least one Sunscreen; and a cosmetically acceptable carrier. as idiopathic melasma occurring during pregnancy (mask of In another embodiment, the present Subject matter relates pregnancy or chloasma) or secondary to estrogen-progester to a topical cosmetic composition, comprising, consisting one contraception; local hyperpigmentation caused by benign essentially of, or consisting of a skin-lightening active com melanocytic hyperactivity and proliferation Such as lentigo ponent comprising, consisting essentially of or consisting of senilis, known as liver spots; accidental hyperpigmentation a Phyllanthus embilica extract, a Bellis perennis extract, and Such as post-lesional photosensitization and scarring, skin a licorice extract; at least one Sunscreen; and a cosmetically ageing (for example lentigines seniles); and certain forms of 25 acceptable carrier. leukoderma Such as vitiligo where, if the injured skin cannot In an embodiment, the present Subject matter relates to a be repigmented, the residual Zones of normal skin are light topical cosmetic composition, comprising, consisting essen ened or depigmented to impart a homogeneous color to the tially of, or consisting of a skin-lightening active component entire skin. comprising, consisting essentially of, or consisting of a Phyl Several active ingredients and preparations that lighten 30 lanthus extract, a Bellis extract, and a licorice extract; and a skin, i.e., counteract skin pigmentation, are currently known. non-skin lightening component comprising at least one Sun These products that are currently used contain hydroquinone, SCC. but such products have recently been deemed unacceptable In an embodiment, the present Subject matter relates to a for toxicological reasons. In fact, RDC 215 forbids the use of topical cosmetic composition, comprising, consisting essen hydroquinone in cosmetic products after December, 2007. 35 tially of, or consisting of a skin-lightening active component U.S. Published Patent Application No. 2008/0050459 comprising, consisting essentially of, or consisting of a Phyl describes a cosmetic composition comprising an extract of lanthus embilica extract, a Bellis perennis extract, and a lico Phyllanthus Embilica, an extract of Bellis Perrenis, an extract rice extract; and a non-skin lightening component comprising of Glycyrrhiza Glabra, and requiring at least one oligopep at least one Sunscreen. tide to achieve its cosmetic effect for the combined cosmetic 40 In another embodiment, the present Subject matter relates treatment of fine lines and wrinkles, and/or skin brightening. to a method of lightening skin pigmentation in a Subject, Suitable oligopeptides are described as those having a Suit comprising topically administering to skin of a subject in able molecular weight so that they are able to act as carriers of need thereof, a therapeutically effective amount of a topical Phyllanthus Embilica extract and penetrate skin to maximize cosmetic composition in accordance with the presently the efficacy. The only oligopeptides described in the publica 45 described subject matter. tion for achieving the cosmetic composition are oligopep In yet another embodiment, the present Subject matter tide-4 (pro-collagen oligopeptide) and oligopeptide-5 (pro relates to a method of treating a skin disorder or condition in elastin oligopeptide). a Subject, comprising topically administering to skin of a There remains a need in the art for improved topical cos subject in need thereofatherapeutically effective amount of a metic compositions containing agents that safely and effec 50 topical cosmetic composition in accordance with the pres tively lighten skin. ently described subject matter. SUMMARY OF THE INVENTION BRIEF DESCRIPTION OF THE FIGURES

The present Subject matter relates generally to topical cos 55 FIG. 1 illustrates progressive lightening over time that metic compositions useful for treating various skin disorders becomes statistically significant after 21 days for Site B or conditions associated with undesired skin pigmentation. treated with 2% hydroquinone. Further, the present subject matter relates to topical cosmetic FIG. 2 illustrates progressive lightening over time that compositions useful for cosmetic lightening of skin areas becomes statistically significant after 14 days for Site E whose pigmentation is adequate for the individual skin type. 60 treated with the present topical cosmetic composition. In an embodiment, the present Subject matter relates to a FIG. 3 illustrates progressive lightening (natural degrada topical cosmetic composition, comprising, consisting essen tion of the synthesized melanin), without any significance tially of, or consisting of a Phyllanthus extract; a Bellis over the experimental times for the control location (Site F) extract; and a licorice extract. In one embodiment, the cos which was not treated. metic composition does not comprise at least one oligopep 65 FIG. 4 illustrates the comparison between the averages of tide. In another embodiment, the cosmetic composition does the colorimetric values in treatments 1 (Site B) and 2 (Site E) not comprise at least one oligopeptide that is not normally and the control (Site F) over the evaluation times. US 9,364,424 B2 3 4 FIG. 5 illustrates photographs of clinical data Supporting which are neither biologically nor otherwise undesirable. A the colorimetric results in treatments 1 (Site B) and 2 (Site E) salt, ester, or Solvate can beformed with, for example, organic and the control (Site F) comparing evaluation times T0 and or inorganic acids. Water or oil-soluble or dispersible prod T21. ucts are thereby obtained. As used herein, a “penetration enhancer refers to a com DETAILED DESCRIPTION pound, Substance or composition that reversibly reduces the barrier resistance of the horny layer of the skin, allowing an Definitions active agent to reach the living tissues at a greater rate. As used herein, a “pH adjuster” or “pH modifier” refers to As used herein, the terms 'administering”, “administra 10 a specific pH adjusting agent added to a composition to con tion', and like terms refer to any method which, in sound vey a certain designated pH to the composition. medical or cosmetic practice, delivers the composition to a As used herein, "oligopeptide' refers to a peptide having a Subject in Such a manner as to provide a positive effect on a suitable molecular weight so that it is able to act as a carrier of dermatological disorder, condition, or appearance. The com Phyllanthus Embilica extract and penetrate skin. Oligopep positions can be administered Such that they cover the entire 15 tides that might act as carriers of Phyllanthus Embilica extract area to be treated. and penetrate skin include oligopeptide-4 (pro-collagen oli As used herein “aqueous solvent refers to a solvent such gopeptide) and oligopeptide-5 (pro-elastin oligopeptide). As as water or containing water. Other dissolved components used herein, "oligopeptide' does not refer to any peptide that may be present in Small amounts, such as, for example, salts, is normally present in Phyllanthus extract, Bellis extract, or buffers, and other components understood by one of ordinary licorice extract. It is noted that in an embodiment of the skill in the art to be optionally present in an aqueous solution. present Subject matter, the cosmetic composition does not Anhydrous formulation” refers to any formulation of the comprise at least one oligopeptide that is not normally present present topical cosmetic composition that does not contain in Phyllanthus extract, Bellis extract, or licorice extract. Water. As used herein, "serum” refers to a hydrophilic liquid “Cosmetically acceptable” refers to a non-toxic, inert, and/ 25 formulation. A serum may optionally be free from one or or physiologically compatible composition. more of an emollient, a wax and a silicone. As used herein, the phrases an “effective amount’ or a As used herein, “skin lightening agent” refers to any com “therapeutically effective amount of an active agentoringre pound, Substance, or composition which upon topical appli dient, which are synonymous herein, refer to an amount of the cation to skin lightens or depigments the skin. Such skin active agent sufficient enough to have a positive effect on the 30 lightening agents can include, but are not limited to, pigmen area of application. Accordingly, these amounts are sufficient tation inhibitors, tyrosinase inhibitors, and melanocyte mel to modify the skin disorder, condition, or appearance to be anogenesis inhibitors. treated but low enough to avoid serious side effects, within the As used herein, “subject' or “individual' or “animal' or Scope of Sound medical or dermatological advice. “patient’ or “mammal.” refers to any subject, particularly a As used herein, "epithelium’ or “epithelial refers to the 35 mammalian Subject, for whom diagnosis, prognosis, or layer of cells forming the epidermis of the skin and the surface therapy is desired, for example, a human. layer of mucous and serous membranes. Epithelial cells have As used herein, “synergistic skin lightening system” or the general functions of protection, absorption, and secretion. “synergistic skin lightening component” refers to a skin light Epithelial cells are often in close proximity to blood vessels, ening active component comprising, consisting essentially although generally lacking in a direct blood Supply. 40 of, or consisting of a Phyllanthus embilica extract, a Bellis As used herein, “extract” refers to one or more components perennis extract, and a licorice extract, that exhibits synergis isolated from a plant source in a fluid or powder form. The tic skin lightening efficacy as compared to the skin lightening plant source can comprise or consist of the entire plant or one efficacy of each individual skin lightening active agent. In this or more parts of the plant, for example, the plant fruit, flower, regard, the combination of these ingredients provides a root, leaves, stems, and/or bark. A fluid or liquid extract can 45 greater than additive skin lightening effect. be dried, for example, spray dried or desiccated, to form a As used herein, a “treatment' or “treating of a skin dis powder. The extract can be a mixture of one or more compo ease, disorder, or condition encompasses alleviation of at nents from a plant in a fluid and/or powder form. least one symptom thereof, a reduction in the severity thereof, By “non-skin lightening is meant any compound, Sub or the delay, prevention, or inhibition of the progression stance or composition; or agent, or component comprising, 50 thereof. Treatment need not mean that the disease, disorder, or consisting essentially of, or consisting of one or more agents, condition is totally cured. A useful composition herein needs Substances, compounds and compositions, which upon topi only to reduce the severity of a skin disease, disorder, or cal application to skin does not depigment or lighten the skin. condition, reduce the severity of symptoms associated there Such agents can include, for example, one or more active with, provide improvement to a patient’s quality of life, or agents, for example, a Sunscreen, an anti-acne agent, an anti 55 delay, prevent, or inhibit the onset of a skin disease, disorder, microbial agent, an anti-wrinkle agent, an anti-atrophy agent, or condition. an anti-inflammatory agent, and an optical brightener, and/or It is noted that, as used in this specification and the one or more cosmetically acceptable excipients, for example, appended claims, the singular forms “a” “an and “the a thickener, a chelating agent, a moisturizer, an emollient, a include plural references unless the context clearly dictates humectant, a gelling agent, a pH adjuster, a surfactant, a 60 otherwise. stabilizer, a vitamin, a penetration enhancer, a perfume, a Unless defined otherwise all technical and scientific terms coloring agent, and a solvent; and/or combinations thereof, as used herein have the same meaning as commonly understood described herein. to one of ordinary skill in the art to which the presently As used herein, “pharmaceutically acceptable free bases, described Subject matter pertains. salts, esters, or Solvates' refers to free bases, salts, esters, or 65 Where a range of values is provided, for example, concen Solvates of Subject compound(s) which possesses the same tration ranges, percentage ranges, or ratio ranges, it is under pharmacological activity as the Subject compound(s) and stood that each intervening value, to the tenth of the unit of the US 9,364,424 B2 5 6 lower limit, unless the context clearly dictates otherwise, incorporated herein by reference in its entirety. Phyllanthus between the upper and lower limit of that range and any other embilica extract typically contains low-molecular weighttan stated or intervening value in that stated range, is encom nins, namely Emblicanin A and Emblicanin B, along with passed within the described subject matter. The upper and Pedunculagin and Punigluconin, Rutin and Gallo-elagitan lower limits of these Smaller ranges may independently be noids. included in the Smaller ranges, and Such embodiments are “Bellis extract’ means an extract obtained from a member also encompassed within the described Subject matter, Sub of the Bellis genus, including for example, the extract ject to any specifically excluded limit in the stated range. obtained from the flowers of a member of the Bellis genus, for Where the stated range includes one or both of the limits, example, from Bellis perennis flowers and/or from Bellis ranges excluding either or both of those included limits are 10 also included in the described subject matter. rotundifolia L. flowers. The Bellis extract can comprise or Throughout the application, descriptions of various consist of one or more bioactive molecules including embodiments use “comprising language; however, it will be saponins (triterpene glycosides), polyphenols (phenolic understood by one of skill in the art, that in some specific acid), flavonoid glycosides, polysaccharides and inulin. instances, an embodiment can alternatively be described 15 “Bellis perennis extract’ means the extract obtained from using the language "consisting essentially of or “consisting Bellis perennis flowers that can comprise or consist of one or Of more bioactive molecules including Saponins (triterpene gly For purposes of better understanding the present teachings cosides), polyphenols (phenolic acid), flavonoid glycosides, and in no way limiting the scope of the teachings, unless polysaccharides and inulin. Suitable Bellis perennis extracts otherwise indicated, all numbers expressing quantities, per can include BELIDES(R) available from CLR Chemisches centages or proportions, and other numerical values used in Laboratorium, Berlin, Germany. Bellis perennis is also com the specification and claims, are to be understood as being monly known as Bellis alpina Hegetschw. Bellis hortensis modified in all instances by the term “about.” Accordingly, Mill. Bellis hybrida Ten. Bellis integrifolia DC., and Bellis unless indicated to the contrary, the numerical parameters set scaposa Gilib. forth in the following specification and attached claims are 25 “Licorice extract’ means an extract obtained from a mem approximations that may vary depending upon the desired ber of the Glycyrrhiza genus, for example obtained from the properties sought to be obtained. At the very least, each root of a member of the Glycyrrhiza genus. The genus “Gly numerical parameter should at least be construed in light of cyrrhiza is a member of the family “Fabaceae.” Suitable the number of reported significant digits and by applying Glycyrrhiza extracts can include the oil soluble licorice ordinary rounding techniques. 30 Topical Cosmetic Compositions extract available from Bioland, Korea. Other suitable Glycyr The present subject matter relates to a topical cosmetic rhiza extracts can be obtained from one or more of the fol composition, comprising, consisting essentially of, or con lowing members of the Glycyrrhiza genus including Glycyr sisting of a Phyllanthus extract; a Bellis extract; and a licorice rhiza echinata L. (Chinese licorice), Glycyrrhiza glabra L. eXtract. 35 (cultivated licorice), Glycyrrhiza lepidota L., Glycyrrhiza Primary Skin Lightening Active Agents glutinosa, polypodium Glycyrrhiza, Glycyrrhiza brachy In accordance with the presently described subject matter, carpa Boiss., Glycyrrhiza germanica Tourn. Glycyrrhiza the present topical cosmetic compositions can comprise or glandulifera Waldst. et Kit., Glycyrrhiza hirsuta L., Glycyr consist of a Phyllanthus extract, i.e., Phyllanthus embilica rhiza laevis Pall. Glycyrrhiza officinalis Lepech., Glycyr extract; a Bellis extract, i.e., a Bellis perennis extract; and a 40 rhiza pallida Boiss., Glycyrrhiza siliquosa Tourn. Glycyr licorice extract. rhiza violacea Boiss., Glycyrrhiza viscosa Turcz. ex Ledeb., “Phyllanthus extract” means an extract obtained from the Glycyrrhiza vulgaris Gueldenst. ex Ledeb, Liquiritia offici fruit of a member of the Phyllanthus genus, including for nalis Moench, and Liquiritia officinarum Medik. example, of Phyllanthus embilica, Phyllanthus niruri L., In an embodiment, the present topical cosmetic composi Phyllanthus elegans Wall, Phyllanthus iniruri, Phyllanthus 45 tion can comprise, consist essentially of, or consist of a skin reticulatus, Phyllanthus urinaria L., Phyllanthus reticulatus lightening active component that can comprise or consist of a Poir, Phyllanthus conami Sw, Phyllanthus lathyroides H. B. Phyllanthus extract, a Bellis extract, and a licorice extract. K., Phyllanthus casticum Soy-Will, and Phyllanthus mada In an embodiment, the present topical cosmetic composi gascariensis. Phyllanthus extract is a safe and effective natu tion can comprise, consist essentially of, or consist of a skin ral antioxidant. 50 lightening active component that can comprise or consist of a “Phyllanthus embilica extract’ means a standardized Phyllanthus embilica extract, a Bellis perennis extract, and a extract of Phyllanthus embilica, including for example, licorice extract. EMBLICAR (Merck KGaA, Darmstadt, Germany and EM In an embodiment, the present Subject matter relates to a industries, Inc., USA, an affiliate of Merck KGaA). Phyllan topical cosmetic composition wherein the total skin lighten thus embilica is also commonly known as "Emblica officina 55 ing active component is present in the topical cosmetic com lis Gaertn’ and is a member of the family “Euphorbiaceae.” position in an amount of from about 0.5% to about 43% by Phyllanthus embilica is a very rich source of vitamin C, weight, from about 1% to about 30% by weight, from about having an ascorbic acid content in the range from 1000 to 1.5% to about 23% by weight, from about 1.5% to about 15% 1800 mg per 100 grams of fruit. Phyllanthus embilica extract by weight, from about 3% to about 10% by weight, from is a safe and effective natural antioxidant that has no pro 60 about 6% to about 8% by weight, or about 7.05% by weight, oxidation activity and can exhibit dual functionality, i.e., che based on the total weight of the composition. lation and antioxidant. Unlike most antioxidants that go from In another embodiment, the present Subject matter relates an active to an inactive form, Phyllanthus embilica extract can to a topical cosmetic composition wherein the Phyllanthus exhibit a cascading effect that provides long-lasting and extract, for example, the Phyllanthus embilica extract, is stable antioxidant activity. Phyllanthus embilica extract can 65 present in the topical cosmetic composition in an amount of be produced by extracting premium quality fruits using a from about 0.1% to about 8% by weight, from about 0.25% to water-based process as described in U.S. Pat. No. 6,124,268, about 4% by weight, from about 0.5% to about 3% by weight, US 9,364,424 B2 7 8 from about 0.5% to about 2% by weight, from about 1% to for example a Phyllanthus embilica extract; a Bellis extract, about 2% by weight, or about 2% by weight, based on the total for example, a Bellis perennis extract; and licorice extract. weight of the composition. The topical cosmetic composition and/or the cosmetically In a further embodiment, the present subject matter relates acceptable carrier and/or one or more cosmetically accept to a topical cosmetic composition wherein the Bellis extract, able excipients, can be free from any plant derived skin light for example, the Bellis perennis extract, is present in the ening agents other than a Phyllanthus extract, for example a topical cosmetic composition in an amount of from about Phyllanthus embilica extract; a Bellis extract, for example, a 0.5% to about 30% by weight, from about 1% to about 20% Bellis perennis extract; and licorice extract. The topical cos by weight, from about 2% to about 10% by weight, from metic composition and/or the cosmetically acceptable carrier about 3% to about 7% by weight, from about 4% to about 6% 10 and/or one or more cosmetically acceptable excipients can be by weight, or about 5.0% by weight, based on the total weight free from any non-plant derived skin lightening agents. of the composition. In an embodiment, the present Subject matter relates to a In yet another embodiment, the present Subject matter topical cosmetic composition, wherein the composition and/ relates to a topical cosmetic composition wherein the licorice or a skin lightening active component and/or a non-skin light extract is present in the topical cosmetic composition in an 15 ening component, does not comprise hydroquinone or a amount of from about 0.005% to about 5% by weight, from derivative thereof, and/or does not comprise a polyorganosi about 0.01% to about 2% by weight, from about 0.01% to loxane-containing epsilon-polylysine compound, and/or about 1% by weight, from about 0.02% to about 0.08% by does not comprise a flavan. weight, from about 0.03% to about 0.07% by weight, or about Synergistic Skin Lightening Component 0.05% by weight, based on the total weight of the composi In another embodiment, the present Subject matter relates tion. to atopical cosmetic composition that can comprise or consist In another embodiment, the present Subject matter relates ofa Synergistic skin lightening active component comprising, to a topical cosmetic composition wherein the Phyllanthus consisting essentially of, or consisting of a Phyllanthus extract, for example, the Phyllanthus embilica extract, is extract, for example a Phyllanthus embilica extract; a Bellis present in the topical cosmetic composition in an amount of 25 extract, for example, a Bellis perennis extract; and licorice from about 0.50 wt % to about 2 wt %; the Bellis extract, for extract, wherein the synergistic skin lightening active com example, the Bellis perennis extract, is present in the topical ponent exhibits synergistic skin lightening efficacy as com cosmetic composition in an amount of from about 1 wt % to pared to the skin lightening efficacy of each individual skin about 20 wt %; and the licorice extract is present in the topical lightening active agent. cosmetic composition in an amount of from about 0.01 wt % 30 In an embodiment, the present Subject matter relates to a to about 1 wt %. synergistic skin lightening component for use in a topical In yet another embodiment, the present subject matter cosmetic composition comprising, consisting essentially of relates to a topical cosmetic composition, wherein the Phyl or consisting of a Phyllanthus extract, for example a Phyllan lanthus embilica extract is present in the topical cosmetic thus embilica extract; a Bellis extract, for example, a Bellis composition in an amount of about 2 wt %; the Bellisperennis 35 perennis extract; and licorice extract. extract is present in an amount of about 5 wt %; and the In another embodiment, the present Subject matter relates licorice extract is present in the topical cosmetic composition to a synergistic skin lightening component for use in a topical in an amount of about 0.05 wt %. cosmetic composition comprising, consisting essentially of In an embodiment, the present Subject matter relates to a or consisting of a Phyllanthus extract, for example a Phyllan topical cosmetic composition, comprising, consisting essen 40 thus embilica extract; a Bellis extract, for example, a Bellis tially of, or consisting of a skin-lightening active component perennis extract; and licorice extract, wherein the synergistic comprising, consisting essentially of, or consisting of a Phyl skin lightening component demonstrates enhanced skin light lanthus extract, for example, a Phyllanthus embilica extract; ening efficacy. The synergistic skin lightening component can a Bellis extract, for example, a Bellis perennis extract; and a be free from hydroquinone. licorice extract; at least one Sunscreen; and a cosmetically 45 In an embodiment, the topical cosmetic composition in acceptable carrier. The cosmetically acceptable carrier can accordance with the presently described subject matter, can comprise or consist of one or more cosmetically acceptable comprise or consist of a skin lightening active component that excipients. exhibits synergistic skin lightening efficacy. In another embodiment, the present Subject matter relates In a further embodiment, the topical cosmetic composition to a topical cosmetic composition, comprising, consisting 50 in accordance with the presently described subject matter, can essentially of, or consisting of a skin-lightening active com comprise or consist of a skin lightening active component that ponent comprising, consisting essentially of, or consisting of exhibits synergistic skin lightening efficacy, wherein the topi a Phyllanthus extract, for example, a Phyllanthus embilica cal cosmetic composition is free from hydroquinone. extract; a Bellis extract, for example, a Bellisperennis extract; In an embodiment, the topical cosmetic composition or the and a licorice extract; and a non-skin lightening component. 55 synergistic skin lightening system, in accordance with the The non-skin lightening component can comprise or consist presently described Subject matter, can comprise or consist of of one or more of an active agent, for example, a Sunscreen; a a skin lightening active component that exhibits synergistic cosmetically acceptable carrier, and/or a cosmetically accept skin lightening efficacy, wherein the topical cosmetic com able excipient, as described herein. position is free from hydroquinone and/or a flavan and/or a In a further embodiment, the present subject matter relates 60 polyorganosiloxane-containing epsilon-polylysine com to a topical cosmetic composition in accordance with the pound. Subject matter described herein that can comprise one or more Cosmetically Acceptable Carrier non-skin lightening active agents. Any non-toxic, inert, and effective topical cosmetically In yet another embodiment, the topical cosmetic composi acceptable carrier may be used to formulate the compositions tion and/or the cosmetically acceptable carrier and/or one or 65 described herein. Well-known carriers used to formulate more cosmetically acceptable excipients, can be free from other topical therapeutic compositions for administration to any skin lightening agents other than a Phyllanthus extract, humans are useful in these compositions. Examples of these US 9,364,424 B2 9 10 components that are well known to those of skill in the art are acid, octyldimethyl-p-aminobenzoicacid, octocrylene, 4-N. described in The Merck Index, Thirteenth Edition, Budavariet N-(2-ethylhexyl)methyl-aminobenzoic acid ester of 2,4-di al., Eds. Merck & Co., Inc., Rahway, N.J. (2001); the CTFA hydroxybenzophenone, N,N-di-(2-ethylhexyl)-4-aminoben (Cosmetic, Toiletry, and Fragrance Association) Interna Zoic acid ester with 4-hydroxydibenzoylmethane, 4-N,N-(2- tional Cosmetic Ingredient Dictionary and Handbook, Tenth ethylhexyl)-methylaminobenzoic acid ester of 4-(2- Edition (2004); and the “Inactive Ingredient Guide', U.S. hydroxyethoxy)dibenzoylmethane, N,N-di-(2-ethylhexyl)- Food and Drug Administration (FDA) Center for Drug Evalu 4-aminobenzoic acid ester of 2-hydroxy-4-(2- ation and Research (CDER) Office of Management, January hydroxyethoxy)benzophenone, N,N-di-(2-ethylhexyl)-4- 1996, the contents of which are hereby incorporated by ref aminobenzoic acid ester of 4-(2-hydroxyethoxy) erence in their entirety. Examples of such useful cosmetically 10 dibenzoylmethane, pharmaceutically or cosmetically acceptable excipients, carriers and diluents include distilled acceptable salts thereof, and mixtures thereof. water, physiological saline, Ringer's Solution, dextrose solu In an embodiment, the present topical cosmetic composi tion, Hank's solution, and DMSO, which are among those tions can comprise a Sunscreen comprising or consisting of suitable for use herein. one or more of methylene bis-benzotriazolyl tetramethylbu These additional other inactive components, as well as 15 tylphenol, diethylamino hydroxybenzoyl hexyl benzoate, effective formulations and administration procedures, are coated Zinc oxide, ethylhexyl methoxycinnamate, isoamyl well known in the art and are described in standard textbooks, methoxycinnamate, homosalate ethylhexyl salicilate, octoc Such as Goodman and Gillman's. The Pharmacological rylene, polysilicone-15, butyl methoxydibenzoylmethane, Bases of Therapeutics, 8th Ed., Gilman et al. Eds. Pergamon menthyl anthranilate, and ethylhexyl dimethyl PABA. Press (1990) and Remington's Pharmaceutical Sciences, In an additional embodiment, the present topical cosmetic 17th Ed., Mack Publishing Co., Easton, Pa. (1990), both of compositions can comprise a Sunscreen comprising one or which are incorporated by reference herein in their entirety. more of methylene bis-benzotriazolyl tetramethylbutylphe Sunscreens nol (TINOSORB M available from CIBA), diethylamino In another embodiment, the present Subject matter relates hydroxybenzoylhexylbenzoate, and coated Zinc oxide, in an to a topical cosmetic composition that can comprise at least 25 amount of from about 1% to about 20% by weight, from about one Sunscreen. The at least one Sunscreen can be present in an 2% to about 10% by weight, or of about 5% by weight, based amount of from about 0.5% to about 30% by weight based on on the total weight of the composition. For example, the the total weight of the topical cosmetic composition, from present topical cosmetic compositions can comprise a Sun about 1% by weight to about 20% by weight, or from about screen comprising methylene bis-benzotriazolyl tetrameth 1% by weight to about 10% by weight based on the total 30 ylphenol in an amount of from about 1% to about 20% by weight of the composition. weight, from about 2% to about 10% by weight, or of about Suitable sunscreens can include broad-spectrum Sun 5% by weight, based on the total weight of the composition screens that protect against both UVA and UVB radiation, or Inafurther embodiment, the present topical cosmetic com Sunscreen agents that protect against UVA or UVB radiation. positions can comprise a Sunscreen comprising or consisting Non-limiting examples of suitable Sunscreens include Sun 35 of one or more of ethylhexyl methoxycinnamate (available screen agents that can comprise or consist of one or more of from BASF), isoamyl methoxycinnamate, homosalate ethyl 2-ethylhexyl p-methoxycinnamate, 2-ethylhexyl N,N-dim hexyl salicilate, octocrylene, polysilicone-15, butyl meth ethyl-p-aminobenzoate, p-aminobenzoic acid, 2-phenylben oxydibenzoylmethane, menthyl anthranilate, and ethylhexyl Zimidazole-5-Sulfonic acid, octocrylene, oxybenzone, homo dimethyl PABA, in an amount of from about 1% to about menthyl salicylate, octyl salicylate, 4,4'-methoxy-t- 40 10%, from about 5% to about 9%, or of about 7.5% by weight, butyldibenzoylmethane, 4-isopropy dibenzoylmethane, based on the total weight of the composition. 3-benzylidene camphor, 3-(4-methylbenzylidene) camphor, In an embodiment, the present topical cosmetic composi titanium dioxide, Zinc oxide, silica, iron oxide, 4-N,N-(2- tions can comprise one or more Sunscreens in an amount of ethylhexyl)methylaminobenzoic acid ester of 2,4-dihydroxy from about 0.5% by weight to about 30% by weight, from benzophenone, 4-N,N-(2-ethylhexyl)-methylaminobenzoic 45 about 1% by weight to about 20% by weight, or from about acid ester with 4-hydroxydibenzoylmethane, 4-N,N-(2-eth 1% by weight to about 10% by weight based on the total ylhexyl)-methylaminobenzoic acid ester of 2-hydroxy-4-(2- weight of the composition. hydroxyethoxy)benzophenone, 4-N,N-(2-ethylhexyl)-me In an embodiment, the at least one Sunscreen can comprise thylaminobenzoic acid ester of 4-(2-hydroxyethoxy) or consist of a first Sunscreen selected from the group con dibenzoylmethane, dihydroxycinnamic acid, trihydroxy 50 sisting of methylene bis-benzotriazolyl tetramethylphenol, cinnamic acid, diphenylbutadiene, Stilbene, dibenZalacetone, diethylamino hydroxybenzoyl hexyl benzoate, and coated benzalacetophenone, naphtholsulfonates, 2-naphthol-3,6- Zinc oxide; and a second Sunscreen selected from the group disulfonic, 2-naphthol-6,8-disulfonic acids, di-hydroxynaph consisting of ethylhexyl methoxycinnamate, isoamyl meth thoic acid, o- and p-hydroxybiphenyldisulfonates, coumarin, oxycinnamate, homosalate ethyl hexyl salicilate, octoc diazoles, 2-acetyl-3-bromoindazole, phenyl benzoxazole, 55 rylene, polysilicone-15, butyl methoxydibenzoylmethane, methyl naphthoxazole, various arylbenzothiazoles, quinine menthyl anthranilate, and ethylhexyl dimethyl PABA. The salts, quinoline derivatives, 8-hydroxyquinoline, 2-phe first Sunscreen can be present in an amount of from about 1% nylduinoline, hydroxy- and methoxy-Substituted benzophe to about 20% by weight, and the second sunscreen can be nones, uric, violuric acids, tannic acid, benzophenones, oxy present in an amount of from about 1% to about 10% by benzene, Sulisobenzone, dioxybenzone, benzoresorcinol, 60 weight, based on the total weight of the topical cosmetic 2,2',4,4-tetrahydroxybenzophenone, 2,2'-dihydroxy-4,4'- composition. The first Sunscreen can comprise or consist of dimethoxybenzophenone, octabenzone, 4-isopropyldiben methylene bis-benzotriazolyl tetramethylbutylphenol, and Zoylmethane, butylmethoxydibenzoylmethane, etocrylene, the second Sunscreen can comprise or consist of ethylhexyl octocrylene, 3-(4-methylbenzylidene boman-2-one), tereph methoxycinnamate. thalylidenedicamphor Sulfonic acid, 4-isopropyl-di-benzoyl 65 In an embodiment, the present Subject matter relates to a methane, butylmethoxydibenzoyl-methane, 2-hydroxy-4- topical cosmetic composition that has an SPF of greater than methoxybenzo-phenone, 2-phenylbenzimidazole-5-Sulfonic about 10, has an SPF of greater than about 15, an SPF of at US 9,364,424 B2 11 12 least about 15, an SPF of about 15, an SPF of from about 10 0.05% by weight, based on the total weight of the composi to about 45, an SPF of from about 15 to about 45, oran SPF tion. The present topical cosmetic composition can comprise of from about 15 to about 25. an antioxidant that can comprise or consist of butylated Aqueous Solvent hydroxytoluene and sodium metabisSulfite, for example, in a The present topical cosmetic compositions can addition combined amount of from about 0.01% to about 0.6% by ally comprise an aqueous solvent. In an embodiment, the weight, from about 0.2% to about 0.5% by weight, or about present compositions comprise an aqueous solvent, for 0.35% by weight, based on the total weight of the composi example, water, in an amount of from about 5% to about 95% tion. by weight, from about 10% to about 90% by weight, from The one or more antioxidants can be present in the topical about 25% to about 80% by weight, from about 55% to about 10 cosmetic composition, for example, in an amount of from 75% by weight, from about 60% to about 70% by weight, or about 0.01% to about 0.6% by weight, from about 0.1% to about 63% by weight, based on the total weight of the com about 0.5% by weight, or from about 0.2% to about 0.5% by position. weight, based on the total weight of the composition. Cosmetically Acceptable Excipients Chelating Agents In yet another embodiment, the present Subject matter 15 The present topical cosmetic compositions may optionally relates to a topical cosmetic composition that can comprise further comprise one or more chelating agents. Suitable water and at least one cosmetically acceptable excipient. Suit chelating agents that can optionally be included in these com able cosmetically acceptable excipients include those com positions can comprise or consist of one or more of citric acid, monly known to one of ordinary skill in the art as useful in isopropyl (mono) citrate, Stearyl citrate, lecithin citrate, glu topical compositions. conic acid, tartaric acid, oxalic acid, phosphoric acid, sodium In an embodiment, the at least one cosmetically acceptable tetrapyrophosphate, potassium monophosphate, sodium hex excipient can comprise or consist of one or more members ametaphosphate, calcium hexametaphosphate, Sorbitol, gly selected from the group consisting of an antioxidant, a chelat cine (aminoacetic acid), methylglucamine, triethanolamine ing agent, a pH adjuster, an emollient, a thickening agent, (trolamine), EDTA, DEG (dihydroxyethylglycine), DPTA gelling agent, free radical scavenger, a preservative, an emul 25 (diethylene triamine pentaacetic acid), NTA (Nitrilotriacetic sifier, a humectant, a moisturizer, a Suspending agent, a Sur Acid), HEDTA (N-(hydroxyethyl)-ethylenetriaminetriacetic factant, a stabilizer, a vitamin, a penetration enhancer, a per acid), aminocarboxylates, dimercaperol (BAL), larixinic acid fume or fragrance, a coloring agent, fluid alkyl alcohols, (Maltol), unidentate ligands (fluoride and cyanide ions), polysiloxanes, modified polysiloxanes, and combinations diphenylthiocarbazone. 0-phenanthroline, barium dipheny thereof. 30 lamine Sulfonate, sodium glucoheptonate, 8-hydroxyquino Antioxidants line, olefin complexes (such as dicyclopentadienyl iron), por The topical cosmetic compositions may optionally further phyrins, phosponates, pharmaceutically or cosmetically comprise one or more anti-oxidants. Suitable anti-oxidants acceptable salts thereof, derivatives thereof, and mixtures that can optionally be included in these compositions can thereof. comprise or consist of one or more of ascorbic acid, ascorbyl 35 The present topical cosmetic composition can include one esters of fatty acids, magnesium ascorbyl phosphate, sodium or more chelating agents present in an amount of from about ascorbyl phosphate, ascorbyl Sorbate, tocopherol, tocopherol 0.05% to about 1% by weight, from about 0.1% to about 0.5% Sorbate, tocopherol acetate, butylated hydroxybenzoic acid, by weight, or about 0.2% by weight, based on the total weight thioglycolates, persulfate salts, 6-hydroxy-2,5,7,8-tetrameth of the composition. ylchroman-2-carboxylic acid, lipoic acid, gallic acid, propyl 40 In an embodiment, the present topical cosmetic composi gallate, uric acid, Sorbic acid, lipoic acid, amines, N,N-dieth tion can include a chelating agent that can comprise or consist ylhydroxylamine, N-acetyl-L-cysteine, amino-guanidine, of one or more of disodium edetate, EDTA, disodium EDTA, Sulfhydryl compounds, glutathione, dihydroxy fumaric acid, trisodium EDTA, and tetrasodium EDTA, for example, in an lysine pidolate, arginine pilolate, nordihydroguaiaretic acid, amount of from about 0.2% to about 0.4% by weight, based bioflavonoids, curcumin, lysine, 1-methionine, proline, 45 on the total weight of the composition. Superoxide dismutase, silymarin, tea extracts, grape skin/ pH Adjusters seed extracts, melanin, rosemary extracts, derivatives thereof, The present topical cosmetic compositions may optionally and combinations thereof. further comprise one or more pH adjusters. Suitable neutral In an embodiment, the present topical cosmetic composi izing pH adjusters that can optionally be included in these tion can include a Suitable antioxidant that can comprise or 50 compositions can comprise or consist of one or more of consist of one or more of butylated hydroxytoluene, sodium inorganic hydroxides, inorganic oxides, inorganic salts of metabissulfite, butylated hydroxyl anisol, ascorbic acid and weak acids, derivatives thereof, and mixtures thereof. derivatives thereof, a sulfite and derivatives thereof, an ester, Suitable inorganic hydroxides useful in this regard can and tocopherol acetate, for example, in an amount of from comprise or consist of one or more of ammonium hydroxide, about 0.01% to about 0.5% by weight, offrom about 0.01% to 55 alkali metal hydroxide, alkaline earth metal hydroxides, about 0.2% by weight, from about 0.02% to about 0.1% by derivatives thereof, and mixtures thereof. weight, from about 0.03% to about 0.07% by weight, or about Suitable inorganic hydroxides useful in this regard can 0.05% by weight, based on the total weight of the composi comprise or consist of one or more of ammonium hydroxide, tion. The present topical cosmetic composition can comprise monovalent alkali metal hydroxides such as Sodium hydrox Sodium metabisSulfite, for example, in an amount of from 60 ide and potassium hydroxide, divalent alkali earth metal about 0.1% to about 0.5% by weight, from about 0.2% to hydroxides Such as calcium hydroxide and magnesium about 0.4% by weight, or about 0.3% by weight, based on the hydroxide, derivatives thereof, and mixtures thereof. total weight of the composition. In addition, the present topi Suitable inorganic oxides useful in this regard can com cal cosmetic composition can comprise butylated hydroxy prise or consist of one or more of magnesium oxide, calcium toluene, for example, in an amount of from about 0.01% to 65 oxide, derivatives thereof, and mixtures thereof. about 0.2% by weight, from about 0.02% to about 0.1% by Suitable inorganic salts of weak acids useful in this regard weight, from about 0.03% to about 0.07% by weight, or about can comprise or consist of one or more of ammonium phos US 9,364,424 B2 13 14 phate (dibasic), alkali metal salts of weak acids such as polysorbate 60, a carbomer derivative, an acrylate, an acry Sodium acetate, sodium borate, sodium metaborate, sodium lamide, Xanthan gum, carrageenan gum, aluminium silicate, carbonate, sodium bicarbonate, Sodium phosphate (tribasic), magnesium silicate, and a cellulose derivate, for example, Sodium phosphate (dibasic), potassium carbonate, potassium present in an amount of from about 1% to about 10% by bicarbonate, potassium citrate, potassium acetate, potassium weight, from about 2% to about 8% by weight, from about 3% phosphate (dibasic), potassium phosphate (tribasic), alkaline to about 7% by weight, or about 5% by weight, based on the earth metal salts of weak acids such as magnesium phosphate total weight of the composition. and calcium phosphate, derivatives thereof, and mixtures A Suitable thickening agent can comprise or consist of thereof. hydroxyethyl acrylate, sodium acryloyldimethyltaurate In an embodiment, the present topical cosmetic composi 10 copolymer, squalane, and polysorbate 60, for example, in an tion can include a pH adjuster that can comprise or consist of amount of from about 1% to about 10% by weight, or about one or more of triethanolamine, aminomethylpropanol, and 5% by weight, based on the total weight of the composition, sodium hydroxide. The pH adjuster can be present in the which is available as SIMUGEL NSR) from SEPPIC, Fair composition, for example, in an amount of from about 0.1% field, N.J. This thickening agent can be used in the presently to about 1% by weight, from about 0.2% to about 0.9% by 15 described topical cosmetic composition in combination with weight, or about 0.6% by weight, based on the total weight of a further thickening agent, for example, cetyl alcohol, in an the composition. The present topical cosmetic composition amount of from about 0.5% to about 2% by weight, or about can comprise a pH in the range of from about 2.5 to about 8, 2% by weight, based on the total weight of the composition. or from about 3 to about 7. The one or more thickening agents can be present in the Emollients topical cosmetic composition in an amount of from about The present topical cosmetic compositions may further 0.25% to about 15% by weight, from about 1% to about 12% comprise an emollient. Suitable non-limiting examples of by weight, from about 4% to about 10% by weight, from emollients useful in the present compositions include one or about 5% to about 9% by weight or about 7% by weight, more of myristyl lactate, isopropyl palmitate, light liquid based on the total weight of the composition. paraffin, cetearyl alcohol, lanolin, lanolin derivatives, mineral 25 Free Radical Scavengers oil, petrolatum, cetyl esters wax, cholesterol, glycerol, glyc The described topical cosmetic compositions may option erol monostearate, isopropyl myristate, a glycol, lecithin, and ally further comprise an effective amount of a free radical mixtures thereof. Scavenger. By “effective amount' is meant an amount Suffi In an embodiment, a Suitable emollient can comprise or cient to provide protection when the composition is properly consist of one or more of glycerin; a glycol, for example, 30 applied, but not so much as to cause any side effects or propylene glycol, butyleneglycol, and pentyleneglycol, adverse skin reactions; generally from about 0.1% to about cyclopentasiloxane dimethicone crosspolymer (DC9040 20%, or from about 1% to about 5%, of the composition. available from Dow Corning); cyclopentasiloxane PEG/ Examples of Such free radical scavengers include but are not PPG-18/18 dimethicone (DC5225C available from Dow limited to, ascorbic acid (Vitamin C) and its salts and deriva Corning); and a silicon derivate. The emollient may be 35 tives (e.g., magnesium ascorbyl phosphate, Sodium ascorbyl present in an amount of from about 1% to about 20% by phosphate, Ascorbyl palmitate, etc.), tocopherol (Vitamin E), weight, from about 2% to about 10% by weight, from about tocopherol esters (e.g., tocopheryl acetate, tocopheryl Succi 3% to about 8% by weight, or about 4% by weight. nate, tocopheryl Sorbate), butylated hydroxy benzoic acids Thickening/Gelling Agents and their salts, 6-hydroxy-2,5,7,8-tetramethylchroman-2- The present topical cosmetic composition may optionally 40 carboxylic acid (commercially available under the tradename further comprise one or more thickening agents. Suitable TROLOX R(R), gallic acid and its alkyl esters (propyl gal thickening agents that can optionally be included in these late), uric acid and its salts and alkyl esters, Sorbic acid and its compositions can comprise or consist of, but are not limited salts, the ascorbyl esters of fatty acids, amines (e.g., N.N- to, one or more of a cellulosic polymer, such as gum arabic, diethylhydroxylamine, aminoguanidine), Sulfhydryl com gum tragacanth, locust bean gum, guar gum, Xanthan gum, 45 pounds (e.g., glutathione), and dihydroxyfumaric acid and its cellulose gum, methylcellulose, hydroxyethylcellulose, salts. Additionally, catechins and polyphenols (e.g., those hydroxypropylcellulose, and hydroxypropylmethylcellu found in green tea extract) and flavonoids (e.g., isoflavones lose; sodium carbomer, carbomer, a polyacrylic polymer, an Such as genistein, and daidxein which are found in Soy aqueous gelling agent. Such as neutral, anionic, and cationic extracts, flavones, chalcones, flavanones, coumarins, etc.) polymers; polymers, such as carboxy vinyl polymers, such as 50 can be used. carboxypolymethylene; an acrylate copolymer, a polysor Preservatives bate; a fatty alcohol, for example, cetyl alcohol and Stearyl The described topical cosmetic compositions may option alcohol; glyceryl Stearate; an alkyl derivate; and mixtures ally further comprise one or more preservatives. Suitable thereof. Suitable acrylate copolymers can comprise or consist preservatives that can optionally be included in these compo of, but are not limited to, one or more of hydroxyethyl acrylate 55 sitions can comprise or consist of, but are not limited to, one and sodium acryloyldimethyltaurate copolymer. or more of propylene glycol, glycerol, butylene glycol, pen In an embodiment, a Suitable thickening agent can com tylene glycol, hexylene glycol, Sorbitol, benzyl alcohol, prise or consist of one or more of a fatty alcohol, for example, derivatives thereof, and mixtures thereof. cetyl alcohol and Stearyl alcohol; glyceryl Stearate; an alkyl In an embodiment, a suitable preservative can comprise or derivate; and combinations thereof; for example, presentinan 60 consist of one or more of phenoxyethanol, methylisothiazoli amount of from about 0.25% to about 4% by weight, from none, phenoxyethanol, a paraben, imidazolynidyl urea, and about 0.5% to about 3% by weight, from about 1% to about combinations thereof. Additionally, the preservative can be 2% by weight, or about 2% by weight, based on the total present in an amount of from about 0.05% to about 1.5% by weight of the composition. weight, from about 0.1% to about 1% by weight, from about In an embodiment, a Suitable thickening agent can com 65 0.1% to about 0.6% by weight, or of about 0.6% by weight, prise or consist of one or more of hydroxyethyl acrylate, based on the total weight of the composition. In a further Sodium acryloyldimethyltaurate copolymer, squalane, embodiment, a suitable preservative can comprise or consist US 9,364,424 B2 15 16 of phenoxyethanol and methylisothiazolinone, for example, gum, kaolin, magnesium aluminum silicate, maltitol, triglyc NEOLONE PE(R) which is a formaldehyde-free broad-spec erides, methylcellulose, polyoxyethylene fatty acid esters, trum bactericide based on methylisothiazolinone and phe polyvinylpyrrolidone, propylene glycol alginate, sodium noxyethanol Rohm & Haas, Philadelphia, Pa. alginate, Sorbitan fatty acid esters, tragacanth, and mixtures Emulsifiers 5 thereof. The topical cosmetic compositions may optionally further Surfactants comprise one or more emulsifiers. Suitable emulsifiers that The topical cosmetic compositions may optionally further can optionally be included in these compositions can com comprise one or more surfactants. Suitable Surfactants that prise or consist of any of a wide variety of nonionic, cationic, can optionally be included in these compositions can com anionic, Zwitterionic and amphoteric emulsifiers. 10 prise or consist of one or more of Zwitterionic, amphoteric, Suitable non-limiting examples of emulsifiers useful in this anionic, cationic, and nonionic Surfactants, and mixtures regard can include emulsifiers that can comprise or consist of thereof. Suitable Zwitterionic, amphoteric, anionic, cationic, one or more of glycol esters, fatty acids, fatty alcohols, fatty and nonionic Surfactants include those disclosed in McCutch acid glycol esters, fatty esters, fatty ethers, esters of glycerin, eons, Detergents and Emulsifiers, North American edition esters of propylene glycol, fatty acid esters of polyethylene 15 (1986), published by Allured Publishing Corporation, and glycol, fatty acid esters of polypropylene glycol, esters of McCutcheons, Functional Materials, North American Edi sorbitol, esters of sorbitan anhydrides, carboxylic acid tion (1992), both of which are hereby incorporated by refer copolymers, esters and ethers of glucose, ethoxylated ethers, ence herein in their entirety. ethoxylated alcohols, alkyl phosphates, polyoxyethylene Non-limiting examples of surfactants useful in the present fatty ether phosphates, fatty acid amides, acyl lactylates, compositions include nonionic Surfactants, anionic Surfac Soaps, polyethylene glycol 20 Sorbitan monolaurate (polysor tants, amphoteric Surfactants, cationic Surfactants, and mix bate 20), polyethylene glycol 5 soya sterol, steareth-2, ste tures thereof. areth-20, steareth-21, ceteareth-20, PPG-2 methyl glucose Non-limiting examples of amphoteric Surfactants useful in ether distearate, ceteth-10, polysorbate 80, cetyl phosphate, the present compositions are those selected from the group potassium cetyl phosphate, diethanolamine cetyl phosphate, 25 consisting of alkyl betaines, alkylamidobetaines, aminopro polysorbate 60, glyceryl Stearate, PEG-100 stearate, deriva pionates, iminodipropionates, aminoglycinates, imidazo tives thereof, and mixtures thereof. linium betaines, sulfobetaines, and mixtures thereof. In an embodiment, the present topical cosmetic composi Specific, non-limiting examples of amphoteric Surfactants tion can include an emulsifier that can comprise or consist of useful in the present compositions are those selected from the one or more of a Calcohol and a Coalkyglucoside, for 30 group consisting of sodium 3-dodecyl-aminopropionate, example, MONTANOV L(R) which is a combination of fatty Sodium 3-dodecylaminopropane Sulfonate, Sodium lauroam alcohols and alkylglucosides available fro SEPPIC, Fairfield, phoacetate, coco dimethyl carboxymethyl betaine, cocoami N.J. Suitable emulsifiers can include one or more of potas dopropyl betaine, cocobetaine, lauryl amidopropyl betaine, sium cetyl phosphate, an alkyl phosphate, PEG 100-glyceryl oleyl betaine, lauryl dimethyl carboxymethyl betaine, lauryl stearate and blends thereof, an ethoxylated fatty alcohol in 35 dimethyl alphacarboxyethyl betaine, cetyl dimethyl car combination with one or more fatty alcohols and/or glyceryl boxymethyl betaine, lauryl bis-(2-hydroxyethyl) carboxym Stearates, and an alkyl Sulphate. ethyl betaine, stearyl bis-(2-hydroxypropyl) carboxymethyl In an embodiment, the present topical cosmetic skin-light betaine, oleyl dimethyl gamma-carboxypropyl betaine, lauryl ening compositions can comprise of from about 0.5% to bis-(2-hydroxypropyl)alpha-carboxyethyl betaine, oleami about 10% by weight of an emulsifier, from about 1% to about 40 dopropyl betaine, coco dimethyl sulfopropyl betaine, Stearyl 5% by weight, from about 1.5% to about 3.5% by weight, or dimethyl sulfopropyl betaine, lauryl dimethyl sulfoethyl about 2% by weight emulsifier, based on the total weight of betaine, lauryl bis-(2-hydroxyethyl) sulfopropyl betaine, and the composition. mixtures thereof. Humectants Similarly, non-limiting examples of anionic Surfactants The present topical cosmetic compositions may further 45 useful in the present compositions are those selected from the comprise a humectant. Suitable non-limiting examples of group consisting of alkyl Sulfates, alkyl ethoxylated Sulfates, humectants useful in the present compositions include glyc beta-alkyloxy alkane Sulfonates, alkyl ether sulfates, alkyl erin, butylene glycol, propylene glycol, Sorbitol, and triace glyceryl ether Sulfonates, alkyl ether carboxylates, acyl tin. isethionates, acyl sarcosinates, acyl taurines, succinates, Moisturizers 50 alkali metal, ammonium, or alkanolammonium salts thereof, The topical cosmetic compositions may optionally further and mixtures thereof. comprise one or more moisturizers. Suitable moisturizers can Specific, non-limiting examples of anionic Surfactants use comprise or consist of, but are not limited to, one or more of ful in the present compositions are those selected from the glycerin, pentylene glycol, butylene glycol, polyethylene group consisting of ammonium lauryl Sulfate, Sodium lauryl glycol, Sodium pyrrolidone carboxylate, alpha-hydroxy 55 Sulfate, ammonium laureth Sulfate, Sodium laureth Sulfate, acids, beta-hydroxy acids, polyhydric alcohols, ethoxylated alkyl glyceryl ether sulfonate, triethylamine lauryl sulfate, and propoxylated polyols, polyols, polysaccharides, pan triethylamine laureth sulfate, triethanolamine lauryl sulfate, thenol, hexylene glycol, propylene glycol, dipropylene gly triethanolamine laureth Sulfate, monoethanolamine lauryl col, Sorbitol, derivatives thereof, and mixtures thereof. Sulfate, monoethanolamine laureth Sulfate, diethanolamine Suspending Agents 60 lauryl sulfate, diethanolamine laureth sulfate, lauric The present topical cosmetic compositions may further monoglyceride Sodium sulfate, potassium lauryl Sulfate, comprise a Suspending agent. Non-limiting examples of Suit potassium laureth Sulfate, Sodium lauryl sarcosinate, sodium able Suspending agents useful in the present compositions lauroyl sarcosinate, lauryl sarcosine, cocoyl sarcosine, include one or more of alginic acid, bentonite, carbomer, ammonium cocoyl Sulfate, ammonium lauroyl Sulfate, carboxymethylcellulose and salts thereof, hydroxyethylcel 65 Sodium cocoyl sulfate, sodium lauroyl sulfate, potassium lulose, hydroxypropylcellulose, microcrystalline cellulose, cocoyl Sulfate, potassium lauryl Sulfate, triethanolamine lau colloidal silicon dioxide, dextrin, gelatin, guar gum, Xanthan ryl Sulfate, triethanolamine lauryl Sulfate, monoethanolamine US 9,364,424 B2 17 18 cocoyl Sulfate, monoethanolamine lauryl Sulfate, sodium function as an antioxidant, either alone or in combination tridecyl benzene sulfonate, sodium dodecyl benzene sul with other antioxidants, in the present topical cosmetic com fonate, Sodium and ammonium salts of coconut alkyl trieth position. ylene glycol ether sulfate; tallow alkyl triethylene glycol Penetration Enhancers ether sulfate, tallow alkylhexaoxyethylene sulfate, disodium The present topical cosmetic compositions may optionally N-octadecylsulfoSuccinnate, disodium lauryl SulfoSuccinate, further comprise one or more penetration enhancers. Non diammonium lauryl Sulfo Succinate, tetrasodium N-(1,2-di limiting examples of Suitable penetration enhancers can carboxyethyl)-N-octadecylsulfosuccinnate, diamyl ester of include penetration enhancers that comprise or consist of one or more of a hydrophilic solvent, for example, DMSO, DMF, Sodium SulfoSuccinic acid, dihexyl ester of sodium sulfo Suc DMA, glycerol, polyethylene glycol, pyrrolidone derivatives, cinic acid, dioctyl esters of sodium SulfoSuccinic acid, docu 10 N-Decyl-methylsulfoxide (Brij 36T), lower alcohols, fatty sate Sodium, and mixtures thereof. acids, and/or esters; a lipophilic enhancer, for example, dede Specific, non-limiting examples of cationic Surfactants cylazacycloheptane-2-one (aZone), ethyl acetate, ethylpropi useful in the present compositions include those selected onate, liquid paraffin, lamonin, lard, hexadecyl alcohol, oleyl from the group consisting of behenyl trimethyl ammonium alcohol, hydro ethyl lactamide, Solketal, glycofural, tetrahy chloride, bis(acyloxyethyl) hydroxyethyl methyl ammonium 15 dro-furfuryl alcohol, oleic acid, isopropyl myristate, lauryl methosulfate, cetrimonium bromide, cetrimonium chloride, alcohol, miglyol-oil, linoleic acid, lauric acid, dodecyl-L- cetyl trimethyl ammonium chloride, cocamido propylamine pyroglutomate, and methyl laurate; a Surfactant, for example oxide, distearyl dimethyl ammonium chloride, ditallowdimo an anionic Surfactant, including for example, Sodium lauryl nium chloride, guar hydroxypropyltrimonium chloride, lau Sulfate, Sodium dioctyl-SulfoSuccinate, Sorbitan monopalmi ralkonium chloride, lauryl dimethylamine oxide, lauryl dim tate, poloxamers, polyoxy-8-stearate, polyxyethelene-o- ethylbenzyl ammonium chloride, lauryl polyoxyethylene oleyl-ether, long chain alkylsulfoxide, lauryl ether, Brij 36T. dimethylamine oxide, lauryl trimethyl ammonium chloride, cetyl trimethyl ammonium bromide, and sodium oleate; a lautrimonium chloride, methyl-1-oleyl amide ethyl-2-oleyl Sunscreen, including for example, octyl methoxycinnamate, imidazolinium methyl sulfate, picolin benzyl ammonium oxybenzone, homosalate, octyl salicylate, padimate-o, and chloride, polyduaternium, Stearalkonium chloride, Stearyl 25 Sulisobenzone; a polymer, urea or a derivative thereof lipo dimethylbenzyl ammonium chloride, stearyl trimethyl Somes; and/or combinations thereof. ammonium chloride, trimethylglycine, and mixtures thereof. Fragrances Specific, non-limiting examples of nonionic Surfactants The present topical cosmetic compositions may optionally useful in the present compositions include those selected further comprise a fragrance. Suitable non-limiting examples from the group consisting of polyoxyethylene fatty acid 30 of fragrances can include essential oils and blends, for esters, Sorbitan esters, cetyl octanoate, cocamide DEA, coca example, Perfume FAV22000 (BOUQUETR) available from mide MEA, cocamido propyl dimethylamine oxide, coconut Firmenich), and any perfume. fatty acid diethanol amide, coconut fatty acid monoethanol Coloring Agents amide, diglyceryl diisostearate, diglyceryl monoisoStearate, The present topical cosmetic compositions may optionally diglyceryl monolaurate, diglyceryl monooleate, ethylene 35 further comprise a coloring agent, including but not limited glycol distearate, ethylene glycol monostearate, ethoxylated to, one or more of a dye, a colorant, a pigment, a nanopigment, castor oil, glyceryl monoisoStearate, glyceryl monolaurate, and/or combinations thereof. glyceryl monomyristate, glyceryl monooleate, glyceryl Pigments can be present in the composition in an amount monostearate, glyceryl tricaprylate/caprate, glyceryl triisos ranging from 0.01 to 25 wt.% of the final composition, for tearate, glyceryl trioleate, glycol distearate, glycol 40 example, from 3 to 10 wt.%. They can be white or colored, monostearate, isooctyl Stearate, lauramide DEA, lauric acid inorganic or organic. Non-limiting examples include the tita diethanol amide, lauric acid monoethanol amide, lauric/ nium, Zirconium or cerium oxides, as well as the Zinc, iron or myristic acid diethanol amide, lauryl dimethyl amine oxide, chromium oxides, ferric blue, chromium hydroxide, carbon lauryl/myristyl amide DEA, lauryl/myristyl dimethyl amine black, ultramarines (polysulphides of aluminosilicates), oxide, methylgluceth, methylglucose sesquistearate, oleam 45 manganese pyrophosphate and certain metal powders such as ide DEA, PEG-distearate, polyoxyethylene butyl ether, poly those of silver or of aluminium. Further non-limiting oxyethylene cetyl ether, polyoxyethylene laurylamine, poly examples include the D&C pigments and the lakes commonly oxyethylene lauryl ester, polyoxyethylene lauryl ether, employed for imparting a make-up effect to the lips and to the polyoxyethylene nonylphenyl ether, polyoxyethylene octyl skin, which include Salts of calcium, of barium, of alu ether, polyoxyethylene octylphenyl ether, polyoxyethylene 50 minium, of strontium or of Zirconium. oleylamine, polyoxyethyelen oleyl cetyl ether, polyoxyeth Among the fat-soluble or water-soluble dyes that can be ylene oleyl ester, polyoxyethylene oleyl ether, polyoxyethyl present in the composition, alone or as a mixture, in an ene Stearylamine, polyoxyethylene Stearyl ester, polyoxyeth amount ranging from 0.001 to 15 wt.%, for example from ylene Stearyl ether, polyoxyethylene tallow amine, 0.01 to 5 wt.% or from 0.1 to 2 wt.%, relative to the total polyoxyethylene tridecyl ether, propylene glycol monostear 55 weight of the composition. Non-limiting examples include ate, Sorbitan monolaurate, Sorbitan monooleate, Sorbitan the disodium salt of ponceau, the disodium salt of alizarin monopalmitate, Sorbitan monostearate, Sorbitan sesqui green, quinoline yellow, amaranth trisodium salt, tartrazine oleate, sorbitan trioleate, Stearamide DEA, stearic acid disodium salt, rhodamine monosodium salt, fuchsin diso diethanol amide, Stearic acid monoethanol amide, laureth-4. dium salt, Xanthophyll, methylene blue, carmine, halo-acid, and mixtures thereof. 60 aZO and anthraquinone dyes, copper or iron Sulphate, Sudan Vitamins brown, Sudan red and annatto, as well as beetroot juice and The present topical cosmetic compositions may optionally carotene, and/or combinations thereof. further comprise one or more vitamins or derivatives thereof. In an embodiment, the present topical cosmetic compositions Other Embodiments in accordance with the subject matter described herein can 65 comprise vitamin C and/or vitamin E. For example, vitamin C In an embodiment, the described topical cosmetic compo and/or vitamin E can be present in an amount effective to sitions can optionally further comprise at least one cosmeti US 9,364,424 B2 19 20 cally acceptable excipient that can comprise or consist of at described skin-lightening active agents. Such agents can least one of an antioxidant that can comprise or consist of one include, for example, additional skin lightening active agents or more members selected from the group consisting ofbuty including plant derived and non-plant derived skin lightening lated hydroxytoluene, sodium metabissulfite, butylated agents, including for example, pigmentation inhibitors, tyro hydroxyl anisol, ascorbic acid and derivatives thereof, a sinase inhibitors, and/or melanocyte melanogenesis inhibi sulfite and derivatives thereof, an ester, tocoferyl acetate, and tors; and/or non-skin lightening active agents, including for combinations thereof a chelating agent that can comprise or example, optical brightening agents, Sunscreen agents, anti consist of one or more members selected from the group inflammatory agents, anti-microbial agents, anti-fungal consisting of disodium edetate. EDTA, disodium EDTA, tri agents, anti-wrinkle agents, anti-atrophy agents, anti-acne sodium EDTA, tetrasodium EDTA, and combinations 10 agents, free-radical scavengers, keratolytic agents, vitamins, thereof an emollient that can comprise or consist of one or anti-elastase and/or anti-collagenase agents, peptides, fatty more members selected from the group consisting of a glycol, acid derivatives, steroids, trace elements, extracts of algae a silicon-containing emollient, and combinations thereof a and/or of planktons, enzymes and/or coenzymes, flavonoids thickening agent that can comprise or consist of one or more and/or ceramides, a-hydroxy acids, and combinations members selected from the group consisting of an acrylate 15 thereof. copolymer, an acrylate, an acrylamide, a polysorbate, a fatty Additional Skin Lightening Active Agents alcohol, a gum, a silicate, a carbomer derivative, a cellulose The topical cosmetic compositions may optionally further derivative, and combinations thereof a preservative that can contain one or more additional skin lightening agents. Suit comprise or consist of one or more members selected from the able additional skin lightening agents can comprise or consist group consisting of phenoxyethanol, methylisothiazolinone, of but are not limited to, one or more of gingko extract, carob phenoxyethanol, a paraben, imidazolynidyl urea, and combi extract, rose fruit extract, geranium herb extract, Perilla nations thereof a pH adjuster that can comprise or consist of extract, cinnamon extract, Sweet marjoram extract, Arnica one or more members selected from the group consisting of extract, Concha Blanca extract, cola ed Caballo, Piri-Piri, triethanolamine, aminomethylpropanol, Sodium hydroxide, Pinon Negro, Pinon Blanco, extracts of clove, alfalfa, and combinations thereof, and an emulsifier that can com 25 Baliospermum montanum, Melia azadirachta, Convolvulus prise or consist of one or more members selected from the arvensis, Gaiyo, Sansonin, Syuroyo, Seimkko, Soukyo, group consisting of a Ca22 alcohol, a C12-20 alkylglucoside, Taiso, Hakusempi, Woodfordia fructosa, Lagerstroemia spe and combinations thereof. ciosa, passiflorine, tepeZcohite, amoule, Hobiyu, Bafalo uri, In a further embodiment, the present subject matter relates Achote, Guayule, Adhatoda, Cymbopogon nardus, Desmo to a topical cosmetic composition wherein the emollient can 30 dium gangeticum, Murraya koenigii, Smilax zeylanica, Gas comprise or consist of one or more members selected from the trodia elata, Karukeija, Biota Orientalis, Kichiascoporia, group consisting of propylene glycol, glycerin, butylenegly Arecatachu, Phyllostachys nigra leaves, Atractylodes col, pentyleneglycol, cyclopentasiloxane dimethicone cross japonica, KoidZumi, Tila, Camotede azafran, Jamaica, Poleo polymer, cyclopentasiloxane PEG/PPG-18/18 dimethicone, verde, Navo negro, Cyperus, Kanzo, Broussonetia, Karojitsu, and combinations thereof, and/or the thickening agent can 35 Trichosanthis radix, Dioscorea phizoma, and Aquilliaria. comprise or consist of one or more members selected from the Yet other skin lightening agents can comprise or consist of group consisting of hydroxyethyl acrylate, sodium acry but are not limited to, one or more of teprenone, dihydroxy loyldimethyltaurate copolymer, squalane, polysorbate 60, a isoquinoline, indomethacin, 3-hydroxymanule, Vitamin K carbomer derivative, Xanthan gum, carrageenan gum, alu (such as vitamin K1-K7, its homologues, salts, and deriva minium silicate, magnesium silicate, a cellulose derivate, 40 tives), thiazolidinone derivatives, and kynurenine and its cetyl alcohol, Stearyl alcohol, cetyl and Stearyl alcohol, glyc derivatives and salts, retinol and its derivatives (e.g., Tretin eryl Stearate, and combinations thereof. oin, retinoic acid), resorcinol and its derivatives (e.g., 4-alkyl Topical Formulations resorcinols, etc.), reservatol, placenta extracts, ellagic acid, In an embodiment, the present topical cosmetic composi linoleic acid and a-lipoic acid, and aminophenols e.g., such as tions are formulated in a serum, a gel cream, a lotion, a cream, 45 those described in U.S. Pat. No. 6,203.781 (formula I). an ointment, a gel, an aerosol, a foam, a foamable liquid, a Amounts of additional skin lightening agents generally range Solution (solubilized system), a paste, a Suspension, a disper from about 0.01% to about 20%, based on total weight of the Sion, an emulsion, a skin cleanser, a milk, a mask, a solid composition. A Suitable additional skin lightening agent is Stick, a bar (Such as a Soapbar), an encapsulated formulation, a-lipoic acid. a microencapsulated formulation, microspheres or nano 50 The cosmetic composition according to the present Subject spheres or vesicular dispersions, or other cosmetically matter may optionally comprise a pigmentation inhibitor. acceptable topical dosage form. In the case of vesicular dis Specific examples of the pigmentation inhibitor include, but persions, the lipids of which the vesicles are made can be of are not limited to, p-aminobenzoic acid derivatives, salicylic the ionic or nonionic type, or a mixture thereof. The formu acid derivatives, benzenesulfonamide derivatives, imidazole lation can comprise one or more of an aqueous formulation 55 derivatives, naphthalene derivatives, hydroxyanthranilic acid and/or an anhydrous formulation. or salts thereof and their derivatives, anthranilic acid deriva In another embodiment, the present topical cosmetic com tives, coumarin derivatives, amino acid derivatives (e.g., position in accordance with the Subject matter described 2-amino-3-1-carboxyl-2-(1H-imidazol-4-yl)ethylami herein can comprise or consist of an anhydrous formulation, nobutanoic acid, 2-amino-3-1-carboxyl-2-(1H-imidazol-) an aqueous formulation, or an emulsion. 60 ethylaminobutanoic acid hydrochloride, 2-amino-3-1-car In yet another embodiment, the present topical cosmetic boxyl-2- (1H-imidazol-)ethylaminobutanoic acid sodium compositions in accordance with the Subject matter described salt, and 2-amino-3-(1-carboxyl-2-(1H-imidazol-)ethylami herein are formulated in a serum or a gel cream. nobutanoic acid potassium salt), benzotriazole derivatives, Optional Additional Active Agents tetrazole derivatives, imidazoline derivatives, pyrimidine The presently described topical cosmetic compositions can 65 derivatives, dioxane derivatives, camphor derivatives, furan optionally further comprise one or more cosmetic active derivatives, pyrone derivatives, nucleic acid derivatives, agents or dermatological active agents in addition to the allantoin derivatives, nicotinic acid derivatives, ascorbic acid US 9,364,424 B2 21 22 or salts thereof and their derivatives (e.g., magnesium-L- DL-gamma-tocopheryl glucoside, DL-gamma-tocopheryl ascorbic acid phosphate, ascorbyl palmitate, ascorbyl maltoside, DL-delta-tocopheryl glucoside, DL-delta-toco dipalmitate, ascorbic acid hydroxyproline phosphate ester, pherylmaltoside, D-alpha-tocopheryl glucoside, D-alpha-to 5-O-alpha-D-glucopyranosyl-L-ascorbic acid, L-ascorbic copherylmaltoside, D-beta-tocopheryl glucoside, D-beta acid phosphate ester Sodium salt, L-ascorbic acid phosphate tocopherylmaltoside, D-gamma-tocopheryl glucoside, ester potassium salt, L-ascorbic acid phosphate ester magne D-gamma-tocopherylmaltoside, D-delta-tocopheryl gluco sium salt, L-ascorbic acid phosphate ester calcium salt, side, D-delta-tocopherylmaltoside, L-alpha-tocopheryl glu L-ascorbic acid phosphate ester aluminum salt, L-ascorbic coside, L-alpha-tocopherylmaltoside, L-beta-tocopherylglu acid Sulfate ester Sodium salt, L-ascorbic acid Sulfate ester coside, L-beta-tocopherylmaltoside, L-gamma-tocopheryl potassium salt, L-ascorbic acid sulfate ester magnesium salt, 10 glucoside, L-gamma-tocopherylmaltoside, L-delta-toco L-ascorbic acid sulfate ester calcium salt, L-ascorbic acid pherylglucoside, L-delta-tocopherylmaltoside, 1-(Sulfoethy Sulfate ester aluminum salt, L-ascorbic acid sodium salt, lamino)-3-(alpha-tocopheryl-6-yloxy)propan-2-ol. 1-(car L-ascorbic acid potassium salt, L-ascorbic acid magnesium boxypropylamino)-3-(alpha-tocopheryl-6-yloxy)propan-2- salt, L-ascorbic acid calcium salt, L-ascorbic acid aluminum ol hydrochloride, S-3-(alpha-tocopheryl-6-yloxy)-2- salt, 6-o-alpha-D-galactopyranosyl-L-ascorbic acid, 2-o- 15 hydroxypropylcysteine, S-3-(alpha-tocopheryl-6-yloxy)- beta-D-galactopyranosyl-L-ascorbic acid, L-ascorbic acid 2-hydroxypropyl-gamma-glutamyl cysteinyl glycine, N-3- phosphate ester magnesium salt, L-ascorbic acid phosphate (alpha-tocopheryl-6-yloxy)-2-hydroxypropylaspartic acid, ester sodium salt, L-ascorbic acid sulfate ester sodium salt, and N-3-(alpha-tocopheryl-6-yloxy)-2-hydroxypropyl 6-O-acylascorbic acid phosphate ester sodium salt, 6-O-acy glutamic acid), tocotrienol or salts thereof and their deriva lascorbic acid phosphate ester ammonium salt, 6-O-acy tives (e.g., alpha-tocotrienol, beta-tocotrienol, gamma-tocot lascorbic acid phosphate ester isopropanolamine salt, 3-o- rienol, delta-tocotrienol, tocotrienol acetate, tocotrienol isopropyl-L-ascorbic acid, 6-O-alkylascorbic acid phosphate nicotinate, tocotrienol Succinate, tocotrienol linoleate, and ester potassium salt, 6-O-alkylascorbic acid phosphate ester tocotrienol orotate), kojic acid or derivatives thereof (e.g., calcium salt, 6-O-alkylascorbic acid phosphate ester barium 2-methoxymethyl-hydroxy-4H-pyran-, 2-ethoxymethyl-5- salt, 6-O-alkylascorbic acid phosphate ester ammonium salt, 25 hydroxy-4H-pyran-, 2-benzoyloxymethyl-5-hydroxy-4H 6-O-alkylascorbic acid phosphate ester monoethanolamine pyran-, 2-cinnamoyloxymethyl-5-hydroxy-4H-pyran-, salt, 6-O-alkylascorbic acid phosphate ester diethanolamine 2-phenoxymethyl-5-hydroxy-4H- pyran-, kojic acid glyco salt, 6-O-alkylascorbic acid phosphate ester triethanolamine side, geranyl acetone, kojic acid monobutylate, kojic acid salt, 6-O-alkylascorbic acid phosphate ester monoisopro monocaprate, kojic acid monopalmitate, kojic acid panolamine salt, 6-O-alkylascorbic acid phosphate ester 30 monostearate, kojic acid monocinnamate, kojic acid diisopropanolamine salt, 6-O-alkylascorbic acid phosphate monobenzoate, kojic acid dibutyrate, kojic acid dipalmitate, ester triisopropanolamine salt, 3-o-glycosy-L-ascorbic acid, kojic acid distearate, and kojic acid dioleate), oxybenzone, 6-O-beta-D-galactopyranosyl-L-ascorbic acid, ascorbic acid benzophenone, guaiaZulene, shikonin, baicalin or salts cholesterol phosphate ester, L-ascorbyl palmitate, L-ascorbyl thereof and their derivatives, baicalein or salts thereof and isopalmitate, L-ascorbyl dipalmitate, L-ascorbyl diisopalmi 35 their derivatives, berberine or salts thereof and their deriva tate, L-ascorbyl Stearate, L-ascorbyl isostearate, L-ascorbyl tives, chrysin or salts thereof and their derivatives, apigenin or distearate, L-ascorbyl diisoStearate, L-ascorbyl myristate, salts thereof and their derivatives, luteolin or salts thereofand L-ascorbyl isomyristate, L-ascorbyl dimyristate, L-ascorbyl their derivatives, acacetin or salts thereof and their deriva diisomyristate, L-ascorbyl 2-ethylhexanoate, L-ascorbyl tives, diosmetin or salts thereof and their derivatives, di-2-ethylhexanoate, oleic acid-L-ascorbic acid, 2-o-alpha 40 kaempferol or salts thereof and their derivatives, triforine or D-glucosyl-L-ascorbic acid, 2-o-alpha-D-maltosyl-L-ascor salts thereof and their derivatives, astragalin or salts thereof bic acid, 2-O-alpha-D-maltotriosyl-L-ascorbic acid, 3-o-al and their derivatives, quercetin or salts thereof and their pha-D-glucosyl-L-ascorbic acid, 2-o-alpha-D-maltosyl-L- derivatives, quercitrin or salts thereof and their derivatives, ascorbic acid, 2-O-alpha-D-maltotriosyl-L-ascorbic acid, isoquercitrin or salts thereof and their derivatives, rutin or L-ascorbic acid tetraisopalmitate ester, L-ascorbic acid tetra 45 salts thereof and their derivatives, morin or salts thereof and laurate ester, L-ascorbic acid tetra-2-ethylhexanoate ester, their derivatives, myricetin or salts thereof and their deriva L-ascorbic acid tetraoleate ester, 5.6-isopropylidene-L- tives, myricitrin or salts thereof and their derivatives, datis ascorbic acid, L-ascorbic acid retinol ester, L-ascorbic acid cetin or salts thereof and their derivatives, quercetagetin or DL-tocopherol phosphate ester, L-3-O-ethylascorbic acid, salts thereof and their derivatives, isorhamnetin or salts L-ascorbic acid tristearate, L-ascorbic acid tripalmitate, 50 thereof and their derivatives, pinocembrin or salts thereofand L-ascorbic acid trioleate, ascorbic acid triphosphate ester, their derivatives, naringenin or salts thereof and their deriva 2-O-ascorbyl cinnamate, 2-O-ascorbyl ferulate, 2-O-ascorbyl tives, hesperetin or salts thereof and their derivatives, eriod caffeate, 2-o-ascorbyl Sinapate, 2-o-6-palmitoylascorbyl ictyol or salts thereof and their derivatives, pinobanksin or 4'-acetoxy ferulate, DL-alpha-tocopherol-2-L-ascorbic acid salts thereof and their derivatives, aromadendrin or salts phosphate diester, ascorbic acid inositol-binding derivatives, 55 thereof and their derivatives, engeletin or salts thereof and ascorbic acid phosphorus amide derivatives, ascorbic acid their derivatives, taxifolin or salts thereof and their deriva arbutin binding compounds, ascorbyl-phosphoryl-choles tives, astilbin or salts thereof and their derivatives, ampelop terol, chromanylascorbic acid derivatives, and ascorbic acid/ sin or salts thereof and their derivatives, spiraeoside, sialic acid derivatives), tocopherol or salts thereof and their kaempferol-7-neohesperidoside, glutathione or salts thereof derivatives (e.g., alpha-tocopherol, beta-tocopherol, gamma 60 and their derivatives, isoflavone glycosides (e.g., 6-o-apio tocopherol, delta-tocopherol, epsilon-tocopherol, alpha-to Sylpuerarin-4'-O-glucoside, 6-O-glucosylpuerarin, 3'-hy copheryl retinoate, aminomethylated tocopherol, hydroxym droxypuerarin-4'-O-glucoside, and 6-o-apiosyl-3'-hydroxy ethylated tocopherol, tocopheryl phosphate ester, tocopherol puerarin), gamma-pyrone glycosides (e.g., maltol-3-O-(6'-o- acetate, tocopherol nicotinate, tocopherol Succinate, toco apiosyl)-glucoside, and maltol-3-O-(6'-o-apiosyl)- pherol linoleate, tocopherol orotate, DL-alpha-tocopheryl 65 glucoside), isononyl ferulate, elagic acid or salts thereof and glucoside, DL-alpha-tocopherylmaltoside, DL-beta-toco their derivatives (e.g., 5,4-dimethylellagic acid, 3,3'-dimeth pheryl glucoside, DL-beta-tocopherylmaltoside, ylellagic acid, 3,3',4-trimethylellagic acid, 3.3',4,4-tetram US 9,364,424 B2 23 24 ethyl-5-methoxyellagic acid, 3-ethyl-4-methyl-5-hydroxyel acid phosphate ester ammonium salt, 6-O-alkylascorbic acid lagic acid, and amritoside), lucinol, onjisaponin, phosphate ester monoethanolamine salt, 6-O-alkylascorbic Ophiopogonis Saponin, ruscogenin, sericoside, asiaticoside, acid phosphate ester diethanolamine salt, 6-O-alkylascorbic hederin, Senegin, benzoic acid anilides (e.g., 4-hydroxy-N- acid phosphate ester triethanolamine salt, 6-O-alkylascorbic (2-hydroxyphenyl)benzoic acid amide, 4-hydroxy-N-(3-hy 5 acid phosphate ester monoisopropanolamine salt, 6-O-alky droxyphenyl)benzamide, 4-hydroxy-N-(4-hydroxyphenyl) lascorbic acid phosphate ester diisopropanolamine salt, 6-o- benzamide, 3,5-di-t-butyl-4-hydroxy-N-(4-hydroxyphenyl) alkylascorbic acid phosphate ester triisopropanolamine salt, benzamide, 3,5-di-t-butyl-4-hydroxy-N-(3-hydroxyphenyl) 3-O-glycosy-L-ascorbic acid, 6-O-beta-D-galactopyranosyl benzamide, and 3,5-di-t-butyl-4-hydroxy-N-(2- L-ascorbic acid, ascorbic acid cholesterol phosphate ester, hydroxyphenyl)benzamide), diphenylpyraline, 10 L-ascorbyl palmitate, L-ascorbyl isopalmitate, L-ascorbyl ciproheptadine, triprolidine, dimethindene, oZagrel, dipalmitate, L-ascorbyl diisopalmitate, L-ascorbyl Stearate, isothipendyl, iproheptine, homochlorcyclizine, alimemazine, L-ascorbyl isostearate, L-ascorbyl distearate, L-ascorbyl di bucillamine, okitosamide, Vidarabine, Xanthotoxol, phe SoStearate, L-ascorbyl myristate, L-ascorbyl isomyristate, nylmercuric hexachlorophene, mercuric oxide, mercurous L-ascorbyl dimyristate, L-ascorbyl diisomyristate, L-ascor chloride, aqueous hydrogen peroxide, Zinc peroxide, pla 15 byl 2-ethylhexanoate, L-ascorbyl di-2-ethylhexanoate, oleic centa extracts (e.g., those derived from bovine placenta, acid-L-ascorbic acid, 2-o-alpha-D-glucosyl-L-ascorbic acid, Swine placenta, equine placenta, and ovine placenta), 2-O-alpha-D-maltosyl-L-ascorbic acid, 2-o-alpha-D-maltot almond (BIAN TAO) extract, Foeniculum vulgare leaf riosyl-L-ascorbic acid, 3-o-alpha-D-glucosyl-L-ascorbic extract, Atractylodes ovata extract, Atractylodes japonica acid, 2-o-alpha-D-maltosyl-L-ascorbic acid, 2-o-alpha-D- extract, konfuyou extract, Uncaria extract, Uncaria gambir maltotriosyl-L-ascorbic acid, L-ascorbic acid tetraisopalmi extract, kakoujyuyou extract, Glycyrrhizae radix extract, tate ester, L-ascorbic acid tetralaurate ester, L-ascorbic acid Gardenia jasminoides (ZHI ZI) extract, kuranigean extract, tetra-2-ethylhexanoate ester, L-ascorbic acid tetraoleate Sophora flavescens extract, Scutellaria baicalensis (HUANG ester, 5.6-isopropylidene-L-ascorbic acid, L-ascorbic acid QIN) extract, Triticum aestivum L. (wheat) extract, Oryza retinolester, L-ascorbic acid-DL-tocopherol phosphate ester, sativa L. (rice) extract, Coriaria extract, Woodfordia fruti 25 L-3-O-ethylascorbic acid, L-ascorbic acid tristearate, cosa Sidowayah extract, Sanukyu extract, Sanbitoro extract, L-ascorbic acid tripalmitate, L-ascorbic acid trioleate, ascor Cassia Mimosoides L. extract, Bletilla striata (BAIJI) bic acid triphosphate ester, 2-O-ascorbyl cinnamate, 2-o- extract, Ligusticum chuanxiong (CHUAN XIONG) extract, ascorbyl ferulate, 2-O-ascorbyl caffeate, 2-o-ascorbyl Sinap Cassia acutifolia extract, Inula britannica extract, Lythrum ate, 2-O-6-palmitoylascorbyl-4'-acetoxy ferulate, anceps extract, Surigatin extract, Angelica decursiva (QIAN 30 DL-alpha-tocopherol-2-L-ascorbic acid phosphate diester, HU) extract, Coix lachryma-jobi L. (YIYI REN) extract, ascorbic acid inositol-binding derivatives, ascorbic acid Vitex rotundifolia L. extract, Vitex trifolia (MANJING ZI) phosphorus amide derivatives, ascorbic acid-arbutin binding extract, Hamamelis virginiana extract, palm extract, Pari compounds, ascorbyl-phosphoryl-cholesterol, chromanyl etaria extract, Carthamus tinctorius (HONG HUA) extract, ascorbic acid derivatives, and ascorbic acid/sialic acid deriva Morus alba L. (SANG BAI PI) extract, Sophora flavescens 35 tives), kojic acid or salts thereof and their derivatives (e.g., (KUSHEN) extract, Iris germanica L. extract, Iris florentina 2-methoxymethyl-hydroxy-4H-pyran-, 2-ethoxymethyl-5- L. extract, Artemisia mongolia extract, Alnus firma fruit hydroxy-4H-pyran-, 2-benzoyloxymethyl-5-hydroxy-4H extract, Hong Kong extract, Sanguisorba officinalis (DIYU) pyran-, 2-cinnamoyloxymethyl-5-hydroxy-4H-pyran-, extract, Daphniphyllum macropodum extract, Polygonum 2-phenoxymethyl-5-hydroxy-4H-pyran-, kojic acid glyco multiflorum extract, and Fatsia japonica extract. 40 side, geranyl acetone, kojic acid monobutylate, kojic acid The cosmetic composition according to the present Subject monocaprate, kojic acid monopalmitate, kojic acid matter may contain a tyrosinase inhibitor. Specific examples monostearate, kojic acid monocinnamate, kojic acid of the tyrosinase inhibitor include ascorbic acid or salts monobenzoate, kojic acid dibutyrate, kojic acid dipalmitate, thereof and their derivatives (e.g., magnesium-L-ascorbic kojic acid distearate, and kojic acid dioleate), tocopherol or acid phosphate, ascorbyl palmitate, ascorbyl dipalmitate, 45 salts thereof and their derivatives (e.g., alpha-tocopherol, ascorbic acid hydroxyproline phosphate ester, 5-O-alpha-D- beta-tocopherol, gamma-tocopherol, delta-tocopherol, epsi glucopyranosyl-L-ascorbic acid, L-ascorbic acid phosphate lon-tocopherol, alpha-tocopheryl retinoate, aminomethy ester sodium salt, L-ascorbic acid phosphate ester potassium lated tocopherol, hydroxymethylated tocopherol, tocopheryl salt, L-ascorbic acid phosphate ester magnesium salt, phosphate ester, tocopherol acetate, tocopherol nicotinate, L-ascorbic acid phosphate ester calcium salt, L-ascorbic acid 50 tocopherol Succinate, tocopherol linoleate, tocopherol oro phosphate ester aluminum salt, L-ascorbic acid sulfate ester tate, DL-alpha-tocopheryl glucoside, DL-alpha-tocopheryl Sodium salt, L-ascorbic acid Sulfate ester potassium salt, maltoside, DL-beta-tocopheryl glucoside, DL-beta-toco L-ascorbic acid Sulfate ester magnesium salt, L-ascorbic acid pherylmaltoside, DL-gamma-tocopheryl glucoside, Sulfate ester calcium salt, L-ascorbic acid Sulfate ester alumi DL-gamma-tocopherylmaltoside, DL-delta-tocopheryl glu num salt, L-ascorbic acid sodium salt, L-ascorbic acid potas 55 coside, DL-delta-tocopherylmaltoside, D-alpha-tocopheryl sium salt, L-ascorbic acid magnesium salt, L-ascorbic acid glucoside, D-alpha-tocopherylmaltoside, D-beta-tocopheryl calcium salt, L-ascorbic acid aluminum salt, 6-o-alpha-D- glucoside, D-beta-tocopherylmaltoside, D-gamma-toco galactopyranosyl-L-ascorbic acid, 2-o-beta-D-galactopyra pheryl glucoside, D-gamma-tocopherylmaltoside, D-delta nosyl-L-ascorbic acid, L-ascorbic acid phosphate ester mag tocopherylglucoside, D-delta-tocopherylmaltoside, L-alpha nesium salt, L-ascorbic acid phosphate ester Sodium salt, 60 tocopheryl glucoside, L-alpha-tocopherylmaltoside, L-beta L-ascorbic acid sulfate ester Sodium salt, 6-O-acylascorbic tocopheryl glucoside, L-beta-tocopherylmaltoside, acid phosphate ester sodium salt, 6-O-acylascorbic acid phos L-gamma-tocopherylglucoside, L-gamma-tocopherylmalto phate ester ammonium salt, 6-O-acylascorbic acid phosphate side, L-delta-tocopherylglucoside, L-delta-tocopherylmalto ester isopropanolamine salt, 3-O-isopropyl-L-ascorbic acid, side, L-(sulfoethylamino)-3-(alpha-tocopheryl-6-yloxy)pro 6-O-alkylascorbic acid phosphate ester potassium salt, 6-o- 65 pan-2-ol. 1-(carboxypropylamino)-3-(alpha-tocopheryl-6- alkylascorbic acid phosphate ester calcium salt, 6-O-alky yloxy)propan-2-ol hydrochloride, S-3-(alpha-tocopheryl-6- lascorbic acid phosphate esterbarium salt, 6-O-alkylascorbic yloxy)-2-hydroxypropylcysteine, S-3-(alpha-tocopheryl US 9,364,424 B2 25 26 6-yloxy)-2-hydroxypropyl-gamma-glutamyl cysteinyl sis Lam. seed) extract, HSU SUITZU (Euphorbia lathyris glycine, N-3-(alpha-tocopheryl-6-yloxy)-2-hydroxypropyl seed) extract, SHE GAN (Belancanda chinensis rhizome) aspartic acid, and N-3-(alpha-tocopheryl-6-yloxy)-2-hy extract, MA HUANG (Ephedra sinica stem and leaf Ephe droxypropylglutamic acid), tocotrienol or salts thereof and drae Herba) extract, CHUAN XIONG (Cnidium officinale their derivatives (e.g., alpha-tocotrienol, beta-tocotrienol, rhizome: Cnidii Rhizoma) extract, DU HUO (Aralia cordata gamma-tocotrienol, delta-tocotrienol, tocotrienol acetate, root and rhizome) extract, CHAI HU (Bupleurum falcatum tocotrienol nicotinate, tocotrienol Succinate, tocotrienol root; Bupleuri Radix) extract, FANG. FENG (Saposhnikovia linoleate, and tocotrienol orotate), N-acetyl tyrosine or salts divaricata root; Saposhnikoviae Radix) extract, BEI SHA thereof and their derivatives, glutathione or salts thereof and SHEN (Glehnia littoralis root; Glehniae Radix cum Rhi their derivatives, ellagic acid or salts thereof and their deriva 10 Zoma) extract, HUANG QIN (Scutellaria baicalensis root; tives (e.g., 3,4-dimethylellagic acid, 3,3'-dimethylellagic Scutellariae Radix) extract, MUDAN PI (Paeonia suffruti acid, 3.3',4-trimethylellagic acid, 3,3',4,4-tetramethyl-5- cosa root; Moutan Cortex) extract, SHAO YAO (Paeonia methoxyellagic acid, 3-ethyl-4-methyl-5-hydroxyellagic lactifolia root: Paeoniae Radix) extract, Geranium thunbergii acid, and amritoside), isonitrile antibiotics Such as isonitrinA, extract, GE GEN (Pueraria lobata root; Puerariae Radix) isonitrin B, isonitrin C, isonitrin D, isonitrinic acid E. isoni 15 extract, WUBEI ZI (Galla Rhois) extract, Aloe arborescens trinic acid F, derumadein, and toricobilidein, orsellinic acid extract, SHENG MA (Cimicifuga simplex root; Cimicifugae derivatives (e.g., Orsellinic acid, orSellinic acid ethyl ester Rhizoma) extract, HONG HUA (Carthamus tinctorius orcinol, p-geranyl orSellinic acid, p-geranyl orsellinic acid flower; Carthami Flos) extract, green tea extract, red tea ethyl ester geranyl orcinol, p-farnesyl orsellinic acid, p-far extract, and Acacia catechu extract. nesyl orsellinic acid ethyl ester farnesyl orcinol, p-dodecanyl The cosmetic composition according to the present Subject orsellinic acid, p-dodecanyl orsellinic acid ethyl ester dode matter may contain a melanocyte melanogenesis inhibitor. canyl orcinol, p-tetradecanyl orSellinic acid, p-tetradecanyl Specific examples of the melanocyte melanogenesis inhibitor orsellinic acid ethyl ester tetradecanyl orcinol, p-hexadecanyl include lobeline or lobeline derivatives, liquiritin derivatives orsellinic acid, p-hexadecanylorsellinic acid ethyl ester hexa (e.g., liquiritin-alpha-glucoside, and liquiritin-alpha-malto decanyl orcinol, p-undecanyl orsellinic acid, p-undecanyl 25 side), phenylchroman derivatives, chromone derivatives orsellinic acid ethyl ester undecanyl orcinol, p-tridecanyl (e.g., 2-butylchromone, 2-pentylchromone, 2-heptyl orsellinic acid, p-tridecanyl orsellinic acid ethyl ester unde chromone, 2-nonylchromone, 2-hexadecylchromone, 2-(1- canyl orcinol, p-pentadecanylorsellinic acid, p-pentadecanyl ethylpentyl)chromone, 2-butyl-7-methoxychromone, 2-pen orsellinic acid ethyl ester pentadecanyl orcinol, ethylhexyl tyl-7-methoxychromone, 2-heptyl-7-methoxychromone, orsellinic acid, p-ethylhexylorsellinic acid ethyl ester ethyl 30 2-nonyl-7-methoxychromone, 2-pentadecyl-7-methoxy hexyl orcinol, p-cyclohexylmethyl orsellinic acid, p-cyclo chromone, 2-(1-ethylpentyl)-7-methoxychromone, 7-hy hexylmethyl orsellinic acid ethyl ester cyclohexylmethyl droxy-2-methylchromone, 7-hydroxy-2-butylchromone, orcinol, p-hydroxyethylhexyl orsellinic acid methyl ester, 7-hydroxy-2-pentylchromone, 7-hydroxy-2-heptyl and p-hydroxyethylhexyl orsellinic acidhydroxyethylhexyl chromone, 7-hydroxy-2-nonylchromone, 7-hydroxy-2-pen orcinol), umbellic acid, brefeldin, oxydesberatrol, resorcinol 35 tadecylchromone, and 7-hydroxy-2-(1-ethylpentyl) derivatives (4-cyclohexyl resorcinol), 3-hydroxyketone com chromone), azelaic acid derivatives (e.g., azelaic acid pounds (e.g., 1.5-bis(p-hydroxyphenyl)-2-hydroxypentan-4- monoalkyl ester, and azelaic acid dialkyl ester), phosphati one, 1.5-bis(op-dihydroxyphenyl)-2-hydroxypentan-4-one, dylglucosamine, lysophosphatidylglucosamine, 3-beta-D- and 1.5-bis(p-hydroxyphenyl-m-methoxyphenyl)-2-hy glucopyranosyl manool, 3-beta-D-maltopyranosyl manool, droxypentan-4-one), 1,3-diketone compounds (e.g., 1.5-bis 40 substituted amino acid derivatives (e.g., DL-N-formyl-3-(1- (p-hydroxyphenyl)-2,4-pentanedione, 1.5-bis(op-dihydrox naphthyl)alanine, DL-N-acetyl-3-(1-naphthyl)alanine, yphenyl)-2,4-pentanedione, and 1.5-bis(p-hydroxyphenyl DL-N-propionyl-3-(1-naphthyl)alanine, DL-N-butyryl-3-(1- m-methoxyphenyl)-2,4-pentanedione), naphthyl)alanine, DL-N-isobutyryl-3-(1-naphthyl)alanine, bishydroxybenzylamides, gamma-aminobutyric acid or DL-N-Valeryl-3-(1-naphthyl)alanine, DL-N-isovaleryl-3-(1- derivatives thereof (e.g., N-methyl-gamma-aminobutyric 45 naphthyl)alanine, DL-N-(2-methylvaleryl)-3-(1-naphthyl) acid, N-dimethyl-gamma-aminobutyric acid, and gamma alanine, DL-N-(3-methylvaleryl)-3-(1-naphthyl)alanine, aminobutyric acid oleyl ester), hydrogen peroxide, Zinc per DL-N-(4-methylvaleryl)-3-(1-naphthyl)alanine, DL-N-t-bu oxide, placenta extracts, lucinol, silk extract, acacia extract, tylacetyl-3-(1-naphthyl)alanine, DL-N-pivaloyl-3-(1-naph acelora extract, Abutilon theophrasti (Semen Abutili) extract, thyl)alanine, DL-N-caproyl-3-(1-naphthyl)alanine, DL-N- Betula pendula extract, quercus (MOSHI ZI; chestnut gall 50 (2-ethylhexanoyl)-3-(1-naphthyl)alanine, DL-N-(2- wasp) extract, chestnut extract, Plectranthus kameba extract, methylhexanoyl)-3-(1-naphthyl)alanine, DL-N-heptanoyl Isodon trichocarpus extract, Plectranthus japonicus (dried) 3-(1-naphthyl)alanine, DL-N-octanoyl-3-(1-naphthyl) extract, Oenanthe stolonifera extract, Fagopyrum esculentum alanine, DL-N-(2-propylpentanoyl)-3-(1-naphthyl)alanine, extract, Durvillea extract, Capsella bursa-pastoris extract, DL-N-nonanoyl-3-(1-naphthyl)alanine, DL-N-decanoyl-3- Eupatorium japonicum (dried) extract, Matricaria chamo 55 (1-naphthyl)alanine, DL-N-undecanoyl-3-(1-naphthyl)ala milla L. extract, Morus alba extract, Gardenia jasminoides nine, DL-N-dodecanoyl-3-(1-naphthyl)alanine, DL-N-tride extract, Angelica acutiloba extract, Sanguisorba officinalis canoyl-3-(1-naphthyl)alanine, DL-N-tetradecanoyl-3-(1- extract, Sophora flavescens extract, Artemisia indica extract, naphthyl)alanine, DL-N-pentadecanoyl-3-(1-naphthyl) Lonicera japonica extract, Phellodendron amurense extract, alanine, DL-N-hexadecanoyl-3-(1-naphthyl)alanine, DL-N- Houttuynia Cordata extract, Poria Cocos extract, Coix lach 60 heptadecanoyl-3-(1-naphthyl)alanine, DL-N-octadecanoyl ryma jobi L. extract, Lamium album var. barbatum extract, 3-(1-naphthyl)alanine, DL-N-nonadecanoyl-DL-3-(1- Humulus lupulus extract, Crataegus cuneata extract, euca naphthyl)alanine, DL-N-icosanoyl-3-(1-naphthyl)alanine, lyptus extract, Achillea millefolium extract, althaea extract, DL-N-acroyl-3-(1-naphthyl)alanine, DL-N-crotonyloyl-3- GUI PI (Cinnamomum cassia bark; Cinnamomi Cortex) (1-naphthyl)alanine, DL-N-methacryloyl-3-(1-naphthyl)ala extract, MAN JING ZI (Vitex rotundifolia fruit) extract, 65 nine, DL-N-vinylacetyl-3-(1-naphthyl)alanine, DL-N-cyclo Hamamelis virginiana extract, Morus bombycis extract, propanoyl-3-(1-naphthyl)alanine, DL-N-(2-pentenoyl)-3-(1- Platycodon grandiflorum extract, TUSIZI (Cuscuta chinen naphthyl)alanine, DL-N-(4-pentenoyl)-3-(1-naphthyl)

US 9,364,424 B2 31 32 mezereum extract, Cassia obtusifolia extract, JUEMING ZI Sargassum kjellmanianum extract, Sargassum siliquastrum (Cassia obtusifolia seed; Cassiae Semen) extract, HUANG extract, Sargassum serratifolium extract, Sargassum QI (Astragalus mongholicus root; Astragali Radix) extract, giganteifolium extract, Grateloupia filicina extract, Halyme Astragalus membranaceus extract, Trichosanthes bracteata nia agardhi extract, kuronurakusa extract, Halymenia (Trichosanthes root) extract, Xanthium strumarium acuminata extract, Carpopeltis affinis extract, Graciliaria (CHANG ER ZI) extract, Gastrodia elata (TIAN MA) gigas extract, Ceratodictyon spongiosum extract, Lomentaria extract, Pyracantha fortuneana extract, Polygonum Sachalin catenata extract, himefishitsunagi extract, Lomentaria Oka ense extract, WUYAO (Lindera Strychnifolia root; Linderae murae extract, Laurencia intermedia extract, Laurencia Radix) extract, pumpkin extract, Tipha latifolia (PU undulata extract, Laurencia pinnata extract, Laurencia HUANG) extract, Euphorbia kansui (GAN SUI) extract, 10 brongniartii extract, Odonthalia corymbifera extract, Tila Agrimonia pilosa var. japonica (XIAN HE CAO) extract, extract, Camotede azafran extract, Jamaica extract, Poleo Lindera umbellata extract, Saxifraga fisca var kikubuki verde extract, Navo negro extract, Schisandra chinensis extract, sisal (Agave sisalana) extract, Clematis chinensis extract, Schisandra nigra extract, and Kadsura japonica extract, Clematis chinensis extract, Clematis chinensis (WEI eXtract. LING XIAN) extract, Prunus lannesiana var. speciosa 15 Optical Brighteners extract, Prunus Sargentii extract, Prunus incisa extract, Pru The topical cosmetic compositions may optionally further nus nipponica Matsumura extract, Prunus subhirtella extract, comprise one or more optical brighteners. Optical brighteners Prunus lannesiana extract, Aster tataricus (ZIWAN) extract, are described in Fluorescent Whitening Agent, Encyclopedia Trachycarpus fortunei extract, Iris florentina L. extract, of Chemical Technology, Kirk-Othmer, Vol. 11, pp. 227-241, Clematisterniflora (DALIAO) extract, Magnolia salicifolia 4th edition, 1994, Wiley, which is hereby incorporated by (XINYI HUA) extract, Saxifraga fortunei var. incisolobata reference herein in its entirety. Optical brighteners can be extract, Oenothera tetraptera extract, TU SI ZI (Cuscuta defined more particularly as compounds which absorb in the chinensis Lam. Seed) extract, Cuscuta australis extract, Cus UVA range between 300 and 390 nm and re-emit essentially cuta japonica extract, Artemisia absinthium L. extract, Achil between 400 and 525 nm. Suitable optical brighteners can lea alpina extract, Dictamnus dasycarpus (BAI XIAN PI) 25 comprise or consist of, but are not limited to, one or more of extract, Anethum graveolens extract, Fallopia japonica var. stilbene derivatives (e.g., Sodium 4,4'-bis(4,6-dianilino-1.3, hachidvoensis extract, Tribulus terrestris extract, Pyrrosia 5-triazin-2-yl)aminostilbene-2,2'-disulphonate), coumarin lingua (SHI WEI) extract, Tipha angustifolia L. (XIANG derivatives, oxazole and benzoxazole derivatives (e.g., 2.5- PU) extract, Angelica dahurica extract, Buddleja Americana thiophenediylbis(5-tert-butyl-1,3-benzoxazole)) and imida L. extract, Brickellia cabanillesy extract, Artemisia fukudo 30 Zole-derivatives. Amounts of optical brighteners generally extract, Convolvulus arvensis extract, sandalwood extract, range from about 0.1% to about 5.0%, based on total weight Ganoderma lucidum (LING ZHI) extract, Leonurus japoni of the composition. A suitable optical brightener is oxazole. cus (YI MU CAO) extract, Salix gilgiana extract, Salix Anti-Inflammatory Agents chaenomeloides extract, Salix gracilistyla extract, Salix inte The topical cosmetic compositions may optionally further gra extract, Salix kinuyanagi extract, Salix koriyanagi 35 comprise one or more anti-inflammatory agents. Suitable extract, Salix matsudana cv. Tortuosa extract, Salix Reinii anti-inflammatory agents useful in this regard can comprise extract, Salix Sieboldiana extract, Toisusu urbaniana extract, or consist of, but are not limited to, one or more of propionic Salix Schwernii extract, Salix vulpina extract, Populus maxi acid derivatives, acetic acid derivatives, fenamic acid deriva mowiczii extract, Myrica rubra (YANG MEI PI) extract, tives, biphenylcarboxylic acid derivatives, oxicams, acetyl Agave americana extract, Agave americana var. marginata 40 salicylic acid, ibuprofen, naproxen, benoxaprofen, flurbipro extract, Agave americana Marginata extract, Edgeworthia fen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, chrysantha extract, Enteromorpha (green layer) extract, carprofen, oxaprozin, pranoprofen, microprofen, tioxapro Enteromorpha linza extract, Enteromorpha prolifera extract, fen, Suprofen, alminoprofen, tiaprofenic acid, fluprofen, Enteromorpha compressa extract, Enteromorpha intestinalis bucloxic acid, apaZone, bromfenac, celecoxib, diclofenac, extract, hosoeda aomori extract, Laminaria (sea tangle) 45 difenpiramide, diflunisal, etodolac, flufenamic acid, extract, Laminaria japonica extract, Laminaria Ochotensis indomethacin, ketorolac, meclofenamate, mefenamic acid, extract, Laminaria religiosa extract, Laminaria angustata meloxicam, nabumetone, phenylbutaZone, piroxicam, buti extract, Undaria pinnatifida extract, Undaria undaroides bufen, rofecoxib, Salicylic acid, Sulindac, tolmetin, ketorolac extract, Undaria peterseniana extract, Hizikia fusiformis tromethamine, antihistaminic agents, diphenhydramine, extract, Fucus evanescens extract, Padina arborescens 50 chlorpheniramine, diphenhydramine hydrochloride, chlor extract, Padina australis extract, kirebanoumiuchiwa extract, pheniramine maleate, corticosteroids, alclometasone, dex akabaumiuchiwa extract, Padina crassa extract, Padina amethasone, flumethasone, hydrocortisone, hydrocortisone japonica extract, Padina minor extract, etsukiumiuchiwa 21-monoesters, hydrocortisone-21-acetate, hydrocortisone extract, Eucheuma serra extract, Eucheuma amakusaense 21-butyrate, hydrocortisone-21-propionate, hydrocortisone extract, Eucheuma extract, byakushinkirinsai extract, Chon 55 21-valerate, hydrocortisone-17,21-diesters, hydrocortisone drus ocellatus extract, Chondrus verrucosus extract, Chon 17,21-diacetate, hydrocortisone-17-acetate-21-butyrate, drus nipponicus extract, Chondrus pinnulatus extract, Chon hydrocortisone-17,21-dibutyrate, prednisolone, methylpred dracanthus tenellus extract, Chondracanthus teedii extract, nisolone, betamethasone benzoate, betamethasone dipropri Chondracanthus intermedius extract, Dictyopteris latiuscula onate, clobetasol propionate, diflorasone diacetate, fluocino extract, uraboshiyahazu extract, Padina arborescens extract, 60 nide, fluticasone propionate, mometasone furoate, Sphaerotrichia divaricata extract, Cymathaere extract, triamcinolone acetonide, topical corticosteroids, hydroxyltri Cymathaere japonica extract, Sargassum hemiphyllum amcinolone, alpha-methyl dexamethasone, dexamethasone extract, nagashimamoku extract, Sargassum filicinum phosphate, clobetasol Valerate, desonide, desoxymethasone, extract, Sargassum sagamianum extract, Sargassum nigrifo desoxycorticosterone acetate, dexamethasone, dichlorisone, lium extract, Sargassumpiluliferum extract, tatsukuri extract, 65 diflorasone diacetate, diflucortolone Valerate, fluadrenolone, Sargassum patens extract, Sargassum thunbergii extract, Sar fluclorolone acetonide, fludrocortisone, flumethasone piv gassum ringgoldianum extract, Sargassum confilsum extract, alate, fluosinolone acetonide, fluocinonide, flucortine buty US 9,364,424 B2 33 34 lesters, fluocortolone, fluprednidene (fluprednylidene) miconazole, miconazole nitrate, naftifine, naftifine hydro acetate, flurandrenolone, halcinonide, hydrocortisone chloride, nystatin, oxiconazole, oxiconazole nitrate, salicylic acetate, hydrocortisone butyrate, methylprednisolone, triam acid, selenium, selenium sulfide, Sulconazole, Sulconazole cinolone acetonide, cortisone, cortodoxone, flucetonide, nitrate, terbinafine, terbinafine hydrochloride, terconazole, medrysone, amcinafel, amcinafide, betamethasone, chloro tioconazole, undecylenic acid, acitretin, alclometasone prednisone, chlorprednisone acetate, clocortelone, clescino dipropionate, anthralin, azathioprine, calcipotriene, cal lone, dichlorisone, diflurprednate, flucloronide, flunisolide, citriol, colchicine, cyclosporine, methoXSalen, retinoids, fluoromethalone, fluperolone, fluprednisolone, hydrocorti 3-hydroxybenzoic acid, glycolic acid, lactic acid, 4-hydroxy Sone Valerate, hydrocortisone cyclopentylpropionate, hydro benzoic acid, acetyl salicylic acid, 2-hydroxybutanoic acid, cortamate, meprednisone, paramethasone, prednisone, 10 2-hydroxypentanoic acid, 2-hydroxyhexanoic acid, azelaic beclomethasone dipropionate, triamcinolone, isoxicam, acid, arachidonic acid, benzethonium chloride, benzalko tenoxicam, Sudoxicam, CP-14.304, Salicylates, disalcid, nium chloride, boric acid, 8-quinolinol benzoate, secondary benorylate, trilisate, Safapryn, Solprin, fendosal, fenclofenac, amyltricresols, cetylpyridinium chloride, chlorothymol, and indomethacin, Sulindac, tolmetin, isoxepac, furofenac, tiopi 8-hydroxyquinoline Sulfate, pharmaceutically or cosmeti nac, Zidometacin, acematacin, fentiazac, Zomepirac, clin 15 cally acceptable salts thereof, and mixtures thereof. danac, oxepinac, felbinac, ketorolac, fenamates, mefenamic, Anti-Wrinkle and Anti-Atrophy Agents meclofenamic, flufenamic, niflumic, tolfenamic acid, pyra The topical cosmetic compositions may optionally further Zoles, phenylbutaZone, oxyphenbutaZone, feprazone, aza comprise one or more anti-wrinkle and/or anti-atrophy propaZone, trimethaZone, candelilla wax, bisabolol, alpha agents. Suitable non-limiting examples of anti-wrinkle and/ bisabolol, aloe Vera, plant sterols, phytosterol, Manjistha, or anti-atrophy agents useful in this regard can include anti Guggal, kola extract, chamomile, red clover extract, Piper wrinkle and/or anti-atrophy agents that can comprise or con methysticum extract, Bacopa monieri extract, Sea whip sist of one or more of cis and trans retinoic acid, retinol, extract, and mixtures thereof. retinolesters, salicylic acid, Sulfur-containing D and Lamino Anti-Microbial Agents acids, N-acetyl derivatives Sulfur-containing D and L amino Non-limiting examples of suitable anti-microbial and anti 25 acids, N-acetyl-L-cystein, thiols, ethane thiol, alpha-hydroxy fungal agents useful in this regard include, but are not limited acids, glycolic acid, lactic acid, phytic acid, lipoic acid, lyso to, beta-lactam drugs, quinolone drugs, ciprofloxacin, nor phosphatidic acid, skin peel agents, phenol, pharmaceutically floxacin, tetracycline, erythromycin, amikacin, 2.4,4'- or cosmetically acceptable salts thereof, and mixtures trichloro-2'-hydroxy diphenyl ether, 3,4,4-trichlorobanilide, thereof. phenoxyethanol, phenoxy propanol, phenoxyisopropanol, 30 Anti-Acne Agents doxycycline, capreomycin, chlorhexidine, chlortetracycline, The topical cosmetic compositions may optionally further oxytetracycline, clindamycin, ethambutol, hexamidine comprise one or more anti-acne agents. Suitable non-limiting isethionate, metronidazole, pentamidine, gentamicin, kana examples of anti-acne agents useful in this regard can include mycin, lineomycin, methacycline, methenamine, minocy anti-acne agents that can comprise or consist of one or more cline, neomycin, netilmicin, paromomycin, Streptomycin, 35 of keratolytics, salicylic acid (o-hydroxybenzoic acid), 5-oc tobramycin, miconazole, tetracycline hydrochloride, Zinc tanoyl salicylic acid, resorcinol, retinoids, cis and trans ret erythromycin, erythromycin estolate, erythromycin steaer inoic acid, Sulfur-containing D and L amino acids, N-acetyl ate, amikacin Sulfate, doxycycline hydrochloride, capreomy Sulfur-containing D and Lamino acids, N-acetyl-L-cysteine, cin Sulfate, chlorhexidine gluconate, chlorhexidine hydro lipoic acid, sebostats, flavonoids, bile salts, Scymnol Sulfate, chloride, chlortetracycline hydrochloride, oxytetracycline 40 deoxycholate, cholate, adapalene, azelaic acid, benzoyl per hydrochloride, clindamycin hydrochloride, ethambutol oxide, clindamycin, clindamycin phosphate, doxycycline, hydrochloride, metronidazole hydrochloride, pentamidine erythromycin, norgestimate, organic peroxides, isotretinoin, hydrochloride, gentamicin Sulfate, kanamycin Sulfate, line tretinoin, Sulfacetamide Sodium, tazarotene, pharmaceuti omycin hydrochloride, methacycline hydrochloride, meth cally or cosmetically acceptable salts thereof, and mixtures enamine hippurate, methenamine mendelate, minocycline 45 thereof. hydrochloride, neomycin Sulfate, netilmicin Sulfate, paromo Methods of Treatment mycin Sulfate, Streptomycin Sulfate, tobramycin Sulfate, In an embodiment, the present Subject matter relates to a miconazole hydrochloride, amanfadine hydrochloride, method of lightening skin pigmentation in a Subject, compris amanfadine Sulfate, octopirox, parachlorometa Xyleneol. ing topically administering to skin of a Subject in need nystatin, tolnaftate, clotrimazole, benzoyl peroxide, azelaic 50 thereof, a therapeutically effective amount of the topical cos acid, ethyl acetate, meclocycline, lincomycinics, tetracyclin metic composition in accordance with the Subject matter ics, Sulfur-based antibiotics, Sulfonamides, mupirocin, described herein. magainin I, magainin II, lincomycin, (6,8-dideoxy-6-(1- In another embodiment, the present Subject matter relates methyl-4-propyl-2-pyrrolidinyl)-carbonylamino-1-thio-L- to a method of treating a skin disorder or condition in a threo-alpha-D-galacto-octopyranoside), 7-chloro-6,7,8- 55 Subject, comprising topically administering to skin of a Sub trideoxy-6-(1-methyl-4-propyl-2-pyrrolidinyl)carbonyl ject in need thereof, a therapeutically effective amount of the amino-1-thio-L-threo-alpha-D-galacto-octopyranoside, (4- topical cosmetic composition in accordance with the Subject (dimethylamino)-1,4,4-alpha,5.5-alpha, 6,11,12-alpha matter described herein. The skin disorder or condition can be octahydro-3,6,12,12-alpha-pentahydroxy-6-methyl-1,11 a disorder or condition associated with undesirable skin pig dioxo-2-naphthacene-carboxamide), chlortetracycline, 60 mentation. demeclocycline, rollitetracycline, Sulfacetamide, Sulfabenza In another embodiment, the present Subject matter relates mide, Sulfadiazine, Sulfadoxine, Sulfamerazine, SulfamethaZ to a method of lightening skin pigmentation in a Subject or ine, Sulfamethizole, Sulfamethoxazole, Sulfacetamide treating a skin disorder or condition in a Subject, comprising Sodium, amphotericin B, benzoic acid, butenafine, butenafine topically administering for at least once per day for at least HCl, butoconazole, butoconazole nitrate, caprylic acid, 65 three days, for at least five days, for at least seven days, for at chloroxylenol, ciclopirox, clotrimazole, econazole, econa least ten days, or for at least fourteen days, to skin of a subject Zole nitrate, fluconazole, itraconazole, ketoconazole, in need thereof, a therapeutically effective amount of the US 9,364,424 B2 35 36 topical cosmetic composition in accordance with the Subject oil phase, adding the oil phase to the aqueous phase, for matter described herein. In this regard, after three days, five example with mixing and/or homogenization (with high days, seven days, ten days, or fourteen days, respectively, of shear), to an emulsion. After the emulsion is produced, one or administration of the present topical compositions the skin is more of the following components can be optionally added visibly altered. thereto, for example, in the following order, to produce the In an embodiment, the present Subject matter relates to a final emulsion or cream: one or more skin lightening actives; method of lightening skin pigmentation in a subject or treat one or more pH adjusters; one or more emollients; one or ing a skin disorder or condition in a subject, comprising more skin lightening actives; one or more Sunscreen actives; topically administering for at least once per day for at least one or more thickening agents; one or more antioxidants; and three weeks to skin of a subject in need thereof, a therapeu 10 one or more fragrances. Prior to forming the emulsion, the tically effective amount of the topical cosmetic composition aqueous phase and the oil phase can be separately heated to a in accordance with the subject matter described herein, temperature of from about 70° C. to about 99° C.; from about wherein after three weeks the skin is visibly lightened. 75° C. to about 95°C.; from about 80° C. to about 90° C.; or The present topical cosmetic compositions are effective in about 85°C. After heating the oil phase can be slowly added treating a variety of skin disorders or conditions characterized 15 to the aqueous phase, for example, with mixing and high by undesirable skin pigmentation. Non-limiting examples of shear homogenization. The resultant emulsion can then be Such disorders and/or conditions can include regional hyper cooled while maintaining mixing and high shear homogeni pigmentation caused by melanocytic hyperactivity Such as zation, for example, to a temperature of from about 47°C. to idiopathic melasma occurring during pregnancy (mask of about 27°C.; from about 42°C. to about 30° C.; from about pregnancy or chloasma) or secondary to estrogen-progester 39°C. to about 35°C.; or about 37°C. Thereafter, one or more one contraception; local hyperpigmentation caused by benign of the above-described optional components can then be melanocytic hyperactivity and proliferation Such as lentigo added to the cooled emulsion, for example, with mixing and/ senilis, known as liver spots; accidental hyperpigmentation or high shear homogenization. The produced emulsion or Such as post-lesional photosensitization and scarring; freck cream can have a pH of from about 4.5 to 6.5 and/or a les; malpigmentation; and certain forms of leukoderma Such 25 viscosity of from about 5,000 cF to about 15,000 cF and/or a as vitiligo where, if the injured skin cannot be repigmented, density of from about 1.01 to about 1.06. the residual Zones of normal skin are lightened or depig Further contemplated as within the scope of the present mented to imparta homogeneous color to the entire skin. Skin Subject matter are topical cosmetic compositions produced can be treated according to the presently described methods according to the above-described processes. If produced for purely cosmetic lightening of areas, for example, large 30 according to these processes, these compositions exhibit areas, of skin whose pigmentation, although undesired, is chemical and physical stability Suitable for topical adminis adequate for the individual skin type. In an embodiment, the tration. skin disorder or condition to be treated according to the The topical cosmetic compositions produced according to present methods is undesired skin pigmentation. The admin these processes can be placed in a Suitable containment vessel istration of the present topical cosmetic composition to areas 35 comprising a product contact Surface composed of a material of the skin that contain undesired pigmentation, lightens selected from the group consisting of glass, plastic, Steel, those areas. Accordingly, the present methods lighten areas of stainless steel, aluminum, Teflon, polymeric structure, the skin to which the present topical cosmetic compositions ceramic structure, alloys, and mixtures thereof. These con are administered. tainment vessels are used to facilitate manufacturing, han Suitable skin areas for treatment and/or lightening in 40 dling, processing, packaging, storage, and administration of accordance with the subject matter described herein can said topical cosmetic composition. Suitable containment ves include thin skin areas including for example areas of skin on sels in this regard can be selected from the group consisting of the face, neck, and/or hands. The present compositions and plastic tubes, bottles, metal tubes, and any combination methods as described herein are suitable for use in both men thereof. and women, and are Suitable for use on all skin types includ 45 Routes of Administration/Dosage ing dry skin types, normal skin types, and greasy skin types. To be effective, the route of administration for topical In a further embodiment, the present subject matter relates cosmetic compositions used in the present methods must to a method of treating a skin disorder or condition in a readily affect the target skin areas. Effective results in most Subject, or to a method of lightening skin pigmentation in a cases are achieved by topical application of a thin layer over Subject, wherein topically administering to skin comprises 50 the affected area, or the area where one seeks to achieve the administering at least once per day or at least twice per day for desired effect. Effective results can be achieved with appli a period of at least two weeks, at least 3 weeks, or at least 4 cation rates from one application every two or three days to weeks, wherein skin pigmentation is lightened. Administer four or more applications per day. ing at least once per day can comprise administering once in Appropriate dosage levels for the active agents contem the morning or in the evening. Administering at least twice 55 plated in the present topical cosmetic compositions and meth per day can comprise administering once in the morning and ods are well known to those of ordinary skill in the art and are once in the evening. selected to maximize the treatment of the above skin condi Methods of Production tions. Dosage levels on the order of about 0.001 mg to about Various formulations of the present topical cosmetic com 5,000 mg per kilogram body weight of the skin lightening positions in accordance with the presently described subject 60 active components are known to be useful in the treatment of matter can be readily produced by the skilled artisan accord the diseases, disorders, and conditions contemplated herein. ing to known methods of producing Such formulations Typically, this effective amount of the skin lightening active including for example, a cream, a gel, a serum, a lotion, or components will generally comprise from about 0.001 mg to other formulation described herein, without undue experi about 100 mg per kilogram of patient body weight per day. mentation. 65 Moreover, it will be understood that this dosage of ingredients A process for producing a cream or emulsion formulation can be administered in a single or multiple dosage units to can comprise separately producing an aqueous phase and an provide the desired therapeutic effect. US 9,364,424 B2 37 38 If desired, other therapeutic agents can be employed in about 10gm to about 60 gm, between about 20gm and about conjunction with those provided in the above-described com 50gm, or about 30 gm, or about 40gm. positions. The amount of active ingredients that may be com Single dosage kits and packages containing once per day bined with the carrier materials to produce a single dosage amount of composition may be prepared. Single dose, unit form will vary depending upon the host treated, the nature of 5 dose, and once-daily disposable containers of the present the disease, disorder, or condition, and the nature of the active compositions are contemplated as within the scope of the ingredients. present Subject matter. The present compositions may be given in a single dose or The present topical cosmetic compositions in accordance multiple doses daily. In an embodiment, the present topical with the subject matter described herein may be formulated cosmetic compositions are given from one to four times daily. 10 for storage in a Substantially non-reactive laminated package Starting with a low dose once or twice daily and slowly to enhance stability of the package. This method of storage working up to higher doses if needed is a strategy. The amount provides enhanced package stability in comparison with of active ingredients that may be combined with the carrier other, paper-based packages. materials to produce a single dosage form will vary depend The amount of composition per single packet may range be 15 from about 0.1 ml to about 20.0 ml, between about 0.5 and ing upon the host treated, the nature of the disease, disorder, about 5.0 ml, or between about 1 and about 3 ml. or condition, and the nature of the active ingredients. In an In particular, the ability to formulate compositions capable embodiment, the topical cosmetic compositions may be topi of long term storage, without pre-mixing or compounding cally applied once or multiple times per day. In an embodi requirements prior to application is also contemplated. Spe ment, the present topical cosmetic compositions are topically cifically, the present compositions remain unexpectedly applied from one to four times daily. For example, starting stable in storage for periods including between about 3 with once daily and progressing to more frequent applica months and about 3 years, about 3 months and about 2.5 tions, if needed, is one strategy. years, between about 3 months and about 2 years, between In an embodiment, the present topical cosmetic composi about 3 months and about 20 months, and alternately any time tions are topically applied from one to four times daily, for 25 period between about 6 months and about 18 months. example, in the morning, at noon, in the afternoon, and/or in In an embodiment, the presently described topical cos the evening. metic formulation in accordance with the Subject matter In an embodiment, the topical cosmetic compositions as described herein remains stable for at least three years at a described herein can be administered once or multiple times temperature of less than 30°C. In an embodiment, the pres per day for a period of time of at least one week, for a period 30 ently described topical cosmetic formulation remains stable of at least two weeks, for a period of at least four weeks, or for for at least two years at a temperature of less than or equal to a period of at least eight weeks. The topical cosmetic com 30° C. In an embodiment, the presently described topical positions can be administered once or multiple times per day cosmetic formulation remains stable for at least two years at for a period of time of up to one year, of up to six months, of a temperature of less than or equal to 25°C. up to three months, or of up to two months. 35 It is understood, however, that a specific dose level for any EXAMPLES particular patient will vary depending upon a variety of fac tors, including the activity of the specific active agent; the age, The following examples are illustrative of the present topi body weight, general health, sex and diet of the patient; the cal cosmetic compositions and are not intended to be limita time of administration; the rate of excretion; possible drug 40 tions thereon. Any polymer molecular weights are mean aver combinations; the severity of the particular condition being age molecular weights. All percentages are based on the treated; and the form of administration. One of ordinary skill percent by weight of the final delivery system or formulation in the art would appreciate the variability of such factors and prepared unless otherwise indicated and all totals equal 100% would be able to establish specific dose levels using no more by weight. than routine experimentation. 45 Pharmacokinetic parameters such as bioavailability, Example 1 absorption rate constant, apparent Volume of distribution, unbound fraction, total clearance, fraction excreted The following example illustrates the clarifying efficacy of unchanged, first-pass metabolism, elimination rate constant, the present topical cosmetic composition as compared to a half-life, and mean residence time are well known in the art. 50 2% hydroquinone composition, determined through colorim The optimal cosmetic formulations can be determined by etry instrumental methodology. one skilled in the art depending upon considerations such as In a monocentric, double-blind, comparative clinical trial the particular ingredients and the desired dosage. See, for over a period of six (6) weeks, the clarifying efficacy of each example, Remington's Pharmaceutical Sciences, 18th ed. of two topical products was evaluated in the previously pig (1990, Mack Publishing Co., Easton, Pa. 18042), pp. 1435 55 mented skin of 10 (ten) volunteers. Dermatological evalua 1712, and “Harry's Cosmeticology’, 8th ed. (2000, Chemical tions were performed at the beginning and the end of the study Publishing Co., Inc., New York, N.Y. 10016), the disclosure Skin color was measured by colorimetry, together with the of each of which is hereby incorporated by reference herein in photographic documentation, at T0, T07, T14, and T21. UVB its entirety. Such formulations may influence the physical pigmentation was induced in the previously pigmented skin state, stability, rate of in vivo release, and rate of in vivo 60 of the Volunteers through the use of a light emitting source, clearance. i.e., the solar simulator with Xenon arc light 601/300 W. In an embodiment, the present topical cosmetic composi produced by Solar Light CO. tion in accordance with the subject matter described herein A Minolta Chroma Meter CR400 through a standard color may be a gel cream packaged in, for example, a tube, or a system CIE (The Commission Internacional de l’Eclairage) serum packaged in, for example, a non-aerosol non-foaming 65 was used to determine the skin coloration. The color is pump container or bottle, wherein the amount of the compo expressed by a system of three-dimensional coordinates sition contained in the container can be in the range of from where the L* axis corresponds to skin luminosity, thea axis US 9,364,424 B2 39 40 corresponds to green and red colors, and the b axis corre 3. In a suitable vessel, place the Propylene Glycol. Add and sponds to blue and yellow colors. disperse the Licorice Extract. Mix until uniform. The solar simulator with Xenon arc light 601/300 W. pro 4. In a suitable vessel disperse the Phyllanthus Embilica fruit duced by Solar Light CO, was used as the light source. This extract in a small quantity of Purified Water. Mix until uni equipment provides continuous light emission in the UVB form. and UVA spectrum, ranging between 290 and 400 nm. The 5. In a suitable vessel disperse the Triethanolamine in a small device includes a set of lenses and filters that absorb or dis quantity of Purified Water. Mix until uniform. perse irradiation lower than 320 nm or higher than 400 nm. 6. In a suitable vessel disperse the Sodium Metabisulfite in a The irradiation occurs through a set of 6 branches of optic small quantity of Purified Water. Mix until uniform. fiber called “ports, programmed to apply pre-established 10 7. To the main manufacturing vessel, add the remaining Puri individual doses of irradiation. Irradiation monitoring was fied Water While mixing, add and disperse the Sodium EDTA. performed using a Dose Controlling System (DCS), which Heat the contents to about 85°C. includes a UVB irradiation detector and an electronic moni 8. To a suitable vessel, add the cetyl alcohol, C-14-22 alcohols tor. In this study, only three “ports” were used for each appli and C-12-20 alkylglycoside, cetyl alcohol, Ethylhexyl meth cation site of the tested compositions. 15 oxycinnamate, and Butylated Hydroxytoluene. Heat to about Evaluated Samples 85° C. and mix until uniform. 1. Hydroquinone 2% (positive control): 9. Add the mixture of Step 8 to the mixture of Step 7 with agitation. Mix until uniform. 10. While mixing, cool batch to about 37° C. Component Function 9% WW 11. Add while mixing add the mixture of Step 4 and then add Citric acid pH adjuster O.08 the mixture of Step 5. Mix until uniform. Purified water vehicle 67.08 12. Add while mixing Phenoxyethanol and Methylisothiaz Benzophenone-3 Sunscreen active 1.5 Octyl methoxycinnamate Sunscreen active 6 olinone. Hydroquinone lightening agent 2 13. While mixing add the mixture of Step 2, then the mixture Lanette emulsifier 13 25 from Step 3. Mix until uniform. Sodium metablissulfite antioxidant O.14 14. Add the Belis Perennis flower extract and mix until uni Isopropyl palmitate emollient 5 Propylene glycol emollient 5 form. Methylparaben preservative O.15 15. While mixing add the mixture from Step 1 and mix until Propylparaben preservative O.OS uniform. 30 16. Add the Hydroxyethyl acrylate, sodium acryloyldimeth 100.0% yltaurate copolymer, squalene and polysorbate 60. Mix until uniform. 2. The present topical cosmetic composition comprising: 17. While mixing add the mixture from Step 6. Mix until uniform. 35 18. While mixing add the Perfume. Mix until uniform. Component Function 9% WW 19. This formulation has a pH ranging from 4.5-6.5; a viscos Purified water carrier 62.2SO ity ranging from 5,000 to 15,000 cp; and a density ranging Cetyl alcohol thickening agent 2.2 from 1.01 to 1.06. Butylated hydroxytoluene antioxidant O.OSO Alternative topical cosmetic composition comprising: (C14-22 alcohols and C12-20 emulsifier 5 40 alkylglucoside) Cyclopentasiloxane PEG/PPG-18/18 emollient 1 dimethicone Function Component 9% WW Cyclopentasiloxane dimethicone emollient 1 O1. 1 Portion Purified Water Vehicle 46.470 crosspolymer 02. 2' Portion Purified Water Vehicle S.OOO Sodium EDTA chelating agent O.2 45 03. 3 Portion Purified Water Vehicle S.OOO Bellis perennis flower extract antioxidant active 5 04.4" Portion Purified Water Vehicle S.OOO Phyllanthus embilica fruit extract antioxidant active 2 O5.5 Portion Purified Water Vehicle 2.OOO Licorice extract antioxidant active O.OSO Phenoxyethanol and methylisothiazolinone preservative O6 06. Cetyl Alcohol Thickener 2.OOO Perfume fragrance O.3 07. Butylhydroxytoluene Antioxidant O.OSO Hydroxyethyl acrylate, thickening agent 5 08. Disodium EDTA Chelating O.200 50 Agent Sodium acryloyldimethyltaurate copolymer, 09. Sodium Metabisulfite Antioxidant O.300 Squalane, and Polysorbate 60 0. Ethylhexyl methoxycinnamate Solar Filter 7.500 Sodium metablissulfite antioxidant O.3 Methylene bis-benzotriazolyl Sunscreen active 5 1. Propylene Glycol Solubilizer 2.OOO tetramethylphenol 2. Triethanolamine 99W Regulation 0.550 Ethylhexyl Methoxycinnamate Sunscreen active 7.5 of pH 55 3. Methylene Bis-Benzotriazolyl Solar Filter S.OOO Propylene glycol emollient 2 Tetramethylbutylphenol (and) Decyl Glucoside Triethanolamine pH adjuster 0.55 (and) Xanthan Gum (and) Propylene glycol (and) Water (Ciba) 100.0% 4. Cyclopentasiloxane/PEG/PPG-18/18 Emollient 2.OOO Dimethicone (Dow Corning) 5. Dimethicone Crosspolymer (and) Emollient 2.OOO Formulation: 60 Cyclomethicone (Dow Corning) Method of Manufacturing 6. Hydroxyethyl Acrylate (and) Sodium Thickener S.OOO 1. In a suitable vessel disperse the Methylene bis-benzotria Acryloyldimethyl Taurate Copolymer (and) Zolyl tetramethylphenol in a small quantity of Purified Water. Squalane (and) Polysorbate 60 (Chemyunion) Mix until uniform. 7. Phenoxyethanol (and) Methylisothiazolinone Preservative 0.570 (Rohm & Haas) 2. In a suitable vessel, blend until uniform the Cyclopentasi 65 8. C14/C22 Alcohol (and) C12/C20 Alkyl Emulsifier 2.OOO loxane PEG/PPG-18/18 dimethicone and Cyclopentasilox glucoside (Chemyunion) ane dimethicone crosspolymer. US 9,364,424 B2 41 42 -continued 15. Add Simugel NSR (Hydroxyethyl Acrylate (and) Acry loyldimethyl Copolymer (and) Sodium Taurate (and) Function Component % WW Squalane (and) Polysorbate 60) to the main reactor under

20. Extract of Bellis Perennis (Chemisches Active S.OOO 5 the materia 1s in the tank. gitate and homogenize well for Laboratorium Dr. Kurt Richter GmBh) at least 15 minutes. 21. Emblica (Merck KGaA) Active 2.OOO 16. Add Fragrance FAV 22000(R) and homogenize. 22. Fragrance FAV 22000 (FAV105) Perfume O.300 17. Add Premix F, agitate and homogenize well for at least 15 100% minutes. " 18. Collect a sample from the top and from the bottom, Alternative Method of Manufacture of Alternative Com- measure the pH (range between 5.0 to 6.5). No variation in position the results of the pH between the samples should be greater This alternative method achieved a change in formulation than 0.3 arbitrary pH units, which shows homogeneity. If pH from a pH ranging from 4.0 to 6.5 to a pH ranging from 5.0 15 necessary, continue agitating until the aforementioned to 6.5. Extract of licorice, extract of bellis perennis and t s emblica were generally kept under yellow light and/or pro- Screening o Vo unteers tected from exposure to white light. In one embodiment, the 1. Population Sampling: entire process, including packaging, preferably takes place Ten (10) volunteers, of both sexes, of ages between 18 and under yellow light. In another embodiment, the resulting 20 60 years old, were screened for the performance of the study. formulation is stored without exposure to white light and air. The subjects participating had the first four letters of the name Premixes and the first letter of the family name, an individual identifi 1. Premix A: In an additional suitable container add Tinosorb cation number (generated by electronic system) and a proto M(R) (Methylene Bis-Benzotriazolyl Tetramethylbutylphe- col number nol (and) Decyl Glucoside (and) Xanthan Gum (and) Pro- 25 2. Inclusion Criteria: pylene glycol (and) Water and Purified Water 2" Portion. Age level: 18 to 60 years old; Agitate until totally dispersed. Reserve. Phototypes II and III, according to Fitzpatrick's classifica 2. Premix B: In an additional suitable container add tion; DC9040R (Dimethicone Crosspolymer (and)Cyclomethi- so Whole skin at test site; CO and DC5 225 CR (Cyclopentasiloxane?PEG/PPG-18/ Agreement to follow the assay procedures and to come to 18 Dimethicone). Agitate until totally dispersed. Reserve. the clinic at the days and times determined for the evalu 3. Premix C: In an additional suitable container add Propy- ations; les y and Licorice Extract. Agitate until totally dis- Signature of the informed consent form. SOTWCC. S.V. 35 4. Premix D: In an additional suitable container add Emblica 3. Exclusion Criteria and Purified Water 3' Portion Agitate until totally dis- Pregnancy or breastfeeding: persed. Reserve. Use of anti-inflammatory or immunosuppressant drugs; 5. Premix E: In an additional suitable container add Trietha- Personal precedents of atopy; play and Purified Water 4" Portion. Agitate until 40 Use of topical or systemic photosensitizing medication; totally diluted. Reserve. Hist fphototoxi hotoallergi tions: 6. Premix F: In an additional suitable container add Sodium s ory of pno otoxic or p o o a ergic reac 1OnS, Metabisulfite and Purified Water 5" Portion. Agitate until History of sensitization or irritation to topic production; totally dissolved. Reserve. Photo-induced pathologies, such as Sun hives, lupus Preparation of Oily Phase 45 erythematosus, polyform rash at light, recurring herpes 7. In a suitable container, prepare the Oily Phase adding Cetyl simplex; Alcohol, Montanov L(R) (C14/C22 Alcohol C12/C20Alkyl Presence of active inflammatory dermatoses at test site: Glycoside), Ethylhexyl methoxycinnamate and Butylhy- Presence of nevus lesions at the test site; droxytoluene. Heat during agitation to 75° C.2°C. Active skin pathologies; Preparation of Aqueous Phase 50 rsr 8. Add Purified Water 1' Portion and Disodium EDTA to the History of sensitization or irritation to topic production; principal reactor. Heat to 75°C.2°C. during agitation and Frequent exposure to Sun or tanning beds; homogenization. In use of new innovative drugs within the last 6 months; Emulsion Methodology 9. When both phases reach 75°2 C. pour oily phase over 55 1. Methodological Procedures: the aqueous phase, during intense agitation and homogeni- After the initial d he mini h Zation. Check to see if the emulsion formed is homogenous ter the initial procedures, the minimum erythematose after 15 minutes of homogenization. If necessary, agitate dose necessary to induce pigmentation in each Volunteer, was and homogenize for longer time s determined as described below. 10. Cool to 37° C.2° C. 60 a. Calculation of the Minimum Erythematose Dose: 11. Add Premix D and agitate until completely homogenized. Each volunteer was subjected to a pre-test to evaluate the 12. Add Premix E, agitate and homogenize well for at least 15 minimum erythematose dose (MED). A series of six expo minutes. Sures were applied to the unprotected skin of each Volunteer, 13. Add Premix A under intense agitation. each one of them being 12% higher than the previous one, in 14. Add Neolone PER (Phenoxyethanol (and) Methylisothia 65 geometric progression. The median dose was previously Zolinone), Premix B, Premix C, and Belides(R (Extract of determined according to Fitzpatrick Phototype, shown in Bellis Perennis). Agitate and homogenize until Smooth. Table I below: US 9,364,424 B2 43 44 TABLE I d. Product Application: After the irradiation, the volunteers were dismissed and Color Sensitivity Reaction MED instructed to return after 72 hours for photographic documen I White - Pale Very Sensitive Always burns, never tans 0.85 tation and colorimetric evaluation of the sites. Subjects were Light eyes and hair tested in triplicate with each of Site B, E, and F corresponding II White Very Sensitive Always burns, never tans 1 to three distinct irradiation areas to provide a total of three test III Darker Sensitive Burns moderately, tans 1.3 Sites and nine designation areas per Subject. After evaluation, white moderately IV Light brown Little Sensitive Burns minimally, 1.75 2 mg of each test material was applied to a designated irra always tans 10 diation area of a test Site on each Subject once daily according V Brown Little Sensitive Burns rarely, always tans 2.3 VI Black Non-Sensitive Never burns, always 4.6 to the sequence below: pigments Site B: Hydroquinone 2%; Site E: The present topical cosmetic composition; Site F: Negative Control: Site with no product application. After irradiation, the volunteers were dismissed and 15 In order to optimize the products permeation and avoid instructed to return after 24 hours. Exposure data was product migration, handling or UV exposure, the product recorded for each volunteer. application sites were occluded with filter paper, Supported b. Reading: by a semi-permeable adhesive tape. The volunteer returned to After irradiation, each volunteer was released and the clinic for application, readings and evaluations according instructed to return within 24 hours, whereby the exposure to Table II below. TABLE II

Fri Mon Wed Fri Mon Wed Fri Mon Wed Fri Mon T-3 TO TO2 TO4 TO7 T09 T11 T14 T16 T18 T21

Derma X X ological Evaluation Color imetric evaluation Photo graphic docu mentation Reading X X of irradiated site Products application X irradiation site was read with the Volunteer in a vertical position at a e. Colorimetric Evaluation: predetermined distance and illumination which was kept con The colorimetric evaluation was performed using a stant for each volunteer. The MED was then determined for 45 CHROMAMETER. All measurements were performed three each volunteer. times, the L*a*b* parameters average were recorded for each The individual Minimum Erythematose Dose (iMED) is Volunteer. The L* parameter was separately statistically ana defined as the minimum ultraviolet (UV) radiation dose nec lyzed, as its value decreases. essary to produce clear and well-defined contour erythema at f. Statistics: the exposure site, which was used as a reference during the 50 To check if there is a statistically significant difference test Stage. between the treated and control sites and between the experi Accordingly, Sub-sites not presenting erythema were a mental timepoints, the parameter L* was compared. This required criterion for the test evaluation. If this does not comparison was made throught-student tests for paired data. occur, new applications must be performed to determine the Results MED. 55 The treatments were evaluated clinically and colorimetri c. Induction of Pigmentation: cally on day T7, T14 and T21. Site B which contained the After iMED determination, each test site, located on the positive control (Hydroquinone 2%) had the colorimetric back, between the pelvic and scapular waist, laterally to the average for each experimental time as shown in FIG. 1. FIG. medial line of the spine, was marked with the volunteer in a 60 1 illustrates progressive lightening over time that becomes horizontal position and using a marker. Three sites indicated for the application of the products were delimited, i.e., Site B. statistically significant after 21 days. Table III below shows Site E, and Site F. Each site was 35 cm (07x05 cm). At each the results of the comparison test between the L* of TO of the delimited sites, irradiation equivalent to 1.5 times the averages and the other experimental times for area 1 (Site B). minimum erythematose dose, previously calculated for each 65 Talbe IV shows the raw data for the individual results for the Volunteer, was applied. This application was repeated twice area 1 (Site B) for each volunteerinterm of L*, a, and b* for whereby each site was irradiated a total of three times. each of T0, T07, T14, and T21. US 9,364,424 B2 45 46 TABLE III TABLE III-continued

EVALUATED EVALUATED DIFFERENCE P-VALUE CONCLUSION: DIFFERENCE P-VALUE CONCLUSION:

TO and T7 O.3626 Does not reject TO and T21 O.O182 Rejects the the hypothesis.** hypothesis. TO and T14 O.1049 Does not reject the hypothesis *Level of Significance: 5% **Hypothesis: there are no differences between the treated area and control area.

TABLE IV Individual results of the hydroquinone treatment area TO TO7 T14 T21

Wol a: b* a: b* L* a: b: L* a: b:

59.9 7.53 15.73 7.42 15.69 62.O3 5.93 15.68 63.76 4.85 14.48 56.0 14.38 10.40 8.98 11.06 60.53 8.28 12.11 58.87 9.17 13.64 60.1 6.66 16.34 6.39 15.55 61.74 4.86 15.25 618 4.71 17.09 65.74 7.13 15.32 7.63 1416 64.97 7.93 14.44 65.32 6.47 15.01 S4.45 1242 17.88 9.90 19.02 53.77 9.90 19.02 54:39 10.55 18.22 61.36 8.21 12.76 7.53 13.82 62.44 7.OO 14.40 62.79 8.74 13.08 59.06 10.74 16.83 8.24 16.84 59.68 8.19 19.00 61.74 8.18 16...SS 59.16 11.14 15.70 9.8O 16.17 60.95 8.91 15.96 60.96 11.34 16.72 57.67 10.24 13.93 6.99 16.36 S8.58 6.76 17.54 61.44 6.63 16.14 1 59.92 12.78 13.45 9.01 15.86 62.OO 8.OO 15.53 62.91 9.74 15.37

FIG. 2 illustrates the results obtained for Site E, i.e., the application location of the evaluated present topical cosmetic 30 composition. FIG. 2 illustrates that there is progressive light ening over time that becomes statistically significant after 14 days. Table V below illustrates the results of the comparison test between the L* of TO averages and the other experimental 35 times for area 2 (Site E). Table VI shows the raw data for the individual results for area 2 (Site E) for each volunteerinterm of L*, a, and b* for each of TO, T07, T14, and T21.

TABLEV 40 EVALUATED DIFFERENCE P-VALUE CONCLUSION: TO and TO7 O.2228 Does not reject the hypothesis.** TO and T14 O.0022 Rejects the 45 hypothesis. TO and T21 O.OO20 Rejects the hypothesis. *Level of Significance: 5% **Hypothesis: there are no differences between the treated area and control area.

TABLE VI

Individual results of the present topical cosmetic composition

TO TO7 T14 T21

Wol a: b* a: b* L* a: b: L* a: b:

58.82 10.34 14.33 61.SS 6.50 14.68 62.66 7.49 13.97 64.68 4.01 15.29 55.96 15.97 11.69 57.50 8.82 10.81 59.20 9.68 12.34 6017 8.06 12.S1 61.33 7.02 16...SS 61.99 6.41 15.87 61.23 5.78 15.16 62.9 7 6.OO 16.77 63.82 8.53 14.95 62.64 9.37 14.60 62.69 9.03 15.8S 62.01 9.48 15:40 54.76 10.98 18.08 55.08 9.53 1829 55.08 9.53 18.29 SS.22 9.90 18.66 60.8 9 7.76 14.O1 60.64 8.61 1483 61.81 6.78 15.30 62.32 8.39 13.50 60.34 9.17 16.28 60.69 7.98 16.54 60.27 7.03 18.OS 60.67 9.09 17.34 US 9,364,424 B2 47 48 TABLE VI-continued Individual results of the present topical cosmetic composition

TO TO7 T14 T21

Wol L* a: b* L* a: b: L* a: b: L* a: b:

8 S8.6S 11.75 15.60 58.64 11.23 15.51 60.90 8.60 16.34 62.28 1O.S2 14.14 9 57.75 10.59 15.10 59.00 7.54 16.11 61.44 5.36 16...SO 63.43 6.39 14.44 1O 59.72 10.61 15.83 60.66 8.59 15.77 61.41 7.27 13.70 62.17 9.39 16.58

FIG.3 illustrates, for the control location Site F, i.e., where TABLE IX-continued there was no treatment for the irradiation, progressive light ening (natural degradation of the synthesized melanin), with EVALUATED out any significance over the experimental times. Table VII 15 DIFFERENCE P-VALUE CONCLUSION: below shows the results of the comparilson test between the New formulation and O.O2 Rejects the L* of TO averages and the other experimental times for the Control hypothesis. Hydroquinone and Control O.10 Does not reject the control area (Site F). Table VIII shows the raw data for the hypothesis.**tks individual results for the control area (Site F) for each volun teer in term of L*, a, and b* for each of T0, T07, T14, and *Level of Significance: 5% T21. **Hypothesis: there are no differences between the areas. Discussion TABLE VII In an experimental model with UV radiation induced pig EVALUATED 25 mentation (melanogenesis) and having no preexisting pig DIFFERENCE P-VALUE CONCLUSION: mentary dysfunction, clinical pigmentation will be reduced TO and TO7 O.2220 Does not reject spontaneously over time, on the treated areas. All locations, the hypothesis.** including the untreated control, exhibited a significant reduc TO and T14 O.2386 Does not reject tion in pigmentation up to T21 as evaluated using a colorim the hypothesis. 30 eter. TO and T21 O.2O39 Does not reject Therefore, this experiment was carried out to compara the hypothesis. tively evaluate which treatments would cause the quickest *Level of Significance: 5% and most significant depigmentation. Because all of the treat **Hypothesis; there are no differences between the treated area and control area. ments were applied simultaneously to each Volunteer, the variable of melanization capacity was significantly reduced. TABLE VIII

Individual results of the control area

TO TO7 T14 T21

Wol L* a: b* L* a: b: L* a: b: L* a: b:

1 59.14 9.94 18.73 58.38 6.89 17.12 60.71 5.48 15.25 61.01 4.32 16.09 2 57.38 13.43 11.23 57.72 9.40 12.29 58.80 8.28 13.08 57.63 6.68 14.60 3 60.69 7.01 17.36 60.76 5.08 16.74 59. OS 4.85 16.93 60.54 3.89 16.60 4 67.55 S.62 16.95 65.16 6.98 15.57 64.54 6.83 16.21 64.12 6.52 16.70 5 53.18 11.24 1846 54.10 8.04 19.13 54.10 8.04 19.13 S422 8.53 1996 6 62.73 8.22 13.81 62.86 6.29 13.85 62.34 5.87 15.20 63.19 7.10 13.15 7 57.51 10.47 1863 59.11 7.91 17.33 59.67 5.92 19.21 60.97 7.70 18.03 8 S8.68 11.31 15.10 59.69 9.20 17.29 61.96 7.41 16.20 59.31 12.23 17.90 9 S9.68 8.49 15.60 59.91 7.05 17.01 62.OS 5.53 15.59 63.37 7.12 11.30 10 S9.33 12.14 1427 59.60 7.99 16.56 60.29 7.13 16.40 60.15 9.OO 17.06

FIG. 4 illustrates the comparison between the averages of Accordingly, depigmentation would occur at the same speed the colorimetric values in treatments 1 and 2 and the control on all of the tested locations, in each volunteer. over the evaluation times. Table IX illustrates that only the 55 Starting from this premise, the lightening effect was clini present topical cosmetic formulation exhibited Statistically cally observed overtime for each location, which has already significant reduction in pigmentation as compared to the allowed for a visual evaluation and a comparative analysis. spontaneous reduction in pigmentation observed in the con trol group. To improve the accuracy of these observations and to allow 60 for objective, consistent, and reproducible evaluation, the colorimeter was used as a complementary instrumental evalu TABLE IX ation, enabling the detection of differences which the human EVALUATED eye cannot detect. DIFFERENCE P-VALUE CONCLUSION: According to the colorimetry, the L* parameter provided New formulation and O.13 Does not reject the 65 by the colorimetric measurement is the index directly related Hydroquinone hypothesis.** to the skin's luminosity. The higher the value of L* the lighter the evaluated region. US 9,364,424 B2 49 50 Clinically and colorimetrically evaluating the treatments the progressive depigmentation was expected, as it deals with Component Function 9% WW an experimental melanization phenomenon. The irradiated Purified water carrier 63.43 but untreated control locations, presented a significant colo Butylated hydroxytoluene antioxidant O.OS rimetric improvement of L* as from T21, with the hydro Disodium edietate chelating agent O.2O Propylene glycol emollient 2.OO quinone; nevertheless, the lightening levels, when compared Phyllanthus embilica fruit extract antioxidant active 2.OO to the hydroquinone on T07 and T14, were statistically lower. Hydroxyethyl acrylate, thickening agent S.OO Sodium acryloyldimethyltaurate copolymer, Still considering the data over time, the results differ in the Squalane, and Polysorbate 60 following manner: Hydroquinone: significantly improves as 10 Methylene bis-benzotriazolyl Sunscreen active S.OO from T21; The present topical cosmetic composition: signifi tetramethylphenol Bellis perennis extract antioxidant active S.OO cantly improves as from T14, with statistically significant Cyclopentasiloxane dimethicone emollient 2.OO higher lightening levels when compared to the control. crosspolymer Accordingly, the present topical cosmetic composition pro Cyclopentasiloxane PEG/PPG-18/18 emollient 2.OO vided a faster and more significant lightening effect (provides dimethicone 15 Phenoxyethanol and methylisothiazolinone preservative O.6O a higher lightening index) as compared to hydroquinone. Triethanolamine pH adjuster 0.57 FIG. 5 shows photographs of clinical data Supporting the Perfume perfume O.30 colorimetric results, where the greater average lightening Cetyl alcohol thickening agent 2.OO C14-22 alcohols and C12-20 alkylglucoside emulsifier 2.OO effect was obtained on the location with the new formula. The Ethylhexyl methoxycinnamate Sunscreen active 7.50 hydroquinone treatment and the new formulation were simi Sodium metablissulfite antioxidant O.30 lar at the end of the study, although the new formulation is Licorice extract antioxidant active O.OS faster and provides a higher lightening index. 100.0% Example 2 25 The composition was prepared as in Example 1. The following example illustrates the preparation of a Example 4 cream in accordance with the presently described subject matter: The following example illustrates a generally applicable 30 method for administering a composition in accordance with the presently described subject matter: Component Function % WW A topical cosmetic composition is administered topically Purified water carrier 62.2SO to the skin of a subject being treated by conventional means. Cetyl alcohol thickening agent 2 Xanthan gum thickening agent .2 35 This is preferably done through the use of a serum or cream Butylated hydroxytoluene antioxidant OSO gel formulation. A topical preparation may thus be applied to C14-22 alcohols and C12-20 alkylglucoside emulsifier 2 the desired skin surface area with, for example, the use of the Potassium cetylphosphate emulsifier 1 fingertips. Glyceryl Stearate and PEG-100 stearate emulsifier 2 Cyclomethicone emollient 2 For topical administration of the cosmetic composition, the Disodium edietate chelating agent .2 40 subject should be told to first clean the affected area gently Bellis perennis flower extract antioxidant active 5 and to pat it dry. The topical cosmetic composition may then Phyllanthus Embilica Fruit Extract antioxidant active 2 Licorice extract antioxidant active OSO be applied directly to the affected skin area or dispensed into Phenoxyethanol and methylisothiazolinone preservative .6 the palm of the hand or suitable vessel from which material Perfume FAV22000-Essential Oils Blend fragrance 3 Hydroxyethyl acrylate, thickening agent 5 may be taken and manually applied to the skin area to be Sodium acryloyldimethyltaurate copolymer, 45 treated. Squalane, and Polysorbate 60 Sodium metablissulfite antioxidant 3 Example 5 Methylene bis-benzotriazolyl Sunscreen active 5 tetramethylphenol Ethylhexyl Methoxycinnamate Sunscreen active 7.5 A subject is suffering from undesired skin pigmentation. A Propylene Glycol emollient 2 50 topical cosmetic composition as described herein is topically Triethanolamine pH adjuster 55 administered to undesirably pigmented areas of the skin of 100.0% the subject. It would be expected that the undesirably pig mented areas of the skin of the subject would be lightened. The composition is prepared as in Example 1. More spe 55 Example 6 cifically, after Premix E is added to the emulsion, Neolone PE (Phenoxiethanol and Methylisothiazolinone) and cyclom A subject is Suffering from vitiligo. A topical cosmetic ethicone are added under high shearing homogenization and composition as described herein is topically administered to mixing for about 15 minutes. The thickening agents including the residual areas of normal skin of the subject. It would be Xanthan gum are added in the oil phase. 60 expected that the residual areas of normal skin of the subject would be lightened to impart a homogeneous color to the Example 3 entire skin. Example 7 The following example illustrates the preparation of a 65 cream in accordance with the presently described subject A subject is Suffering from age spots. A topical cosmetic matter: composition as described herein is topically administered to US 9,364,424 B2 51 52 the affected skin areas of the subject. It would be expected ing agent, a pH adjuster, an emollient, a thickening agent, a that the age spots would be lightened. gelling agent, a free radical scavenger, a preservative, an All publications cited in the specification are indicative of emulsifier, a humectant, a moisturizer, a suspending agent, a the level of skill of those skilled in the art to which the Surfactant, a stabilizer, a vitamin, a penetration enhancer, a presently described subject matter pertains. All of these pub perfume or fragrance, a coloring agent, a fluid alkyl alcohol, lications are hereby incorporated by reference herein to the a polysiloxane, a modified polysiloxane and combinations same extent as if each individual publication were specifically thereof. and individually indicated as being incorporated by refer 6. The topical cosmetic composition according to claim 2, CCC. wherein the non-skin lightening agent, non-plant derived The present subject matter being thus described, it will be 10 agent is a Sunscreen. apparent that the same may be modified or varied in many 7. The topical cosmetic composition according to claim 6, ways. Such modifications and variations are not to be wherein the Sunscreen is present in an amount of from about regarded as a departure from the spirit and scope of the 0.5 wt % to 30 wt %, based on the total weight of the topical present Subject matter, and all such modifications and varia cosmetic composition. tions are intended to be included within the scope of the 15 8. The topical cosmetic composition according to claim 7. following claims. wherein the sunscreen comprises: We claim: a first sunscreen selected from the group consisting of 1. A topical cosmetic composition, comprising: methylene bis-benzotriazolyl tetramethylbutylphenol, a) a skin lightening component consisting of diethylamino hydroxybenzoyl hexyl benzoate, coated a Phyllanthus extract; Zinc oxide, ethylhexyl methoxycinnamate, isoamyl a Bellis extract; and methoxycinnamate, homosalate, ethylhexyl salicylate, a licorice extract; octocrylene, polysilicone-15, butyl methoxydibenzoyl b) at least one non-skin lightening agent, non-plant methane, methyl anthranilate, and ethylhexyl dimethyl derived, selected from PABA and combinations thereof. i) an anti-acne agent, 25 9. The topical cosmetic composition according to claim 8. ii) an anti-microbial agent, wherein the composition comprises a second sunscreen iii) an anti-fungal agent, Selected from the group consisting of ethylhexyl methoxy iv) an anti-wrinkle agent, cinnamate, isoamyl methoxycinnamate, homosalate, ethyl V) an anti-atrophy agent, hexyl salicylate, octocrylene, polysilicone-15, butyl meth Vi) an anti-inflammatory agent, 30 oxydibenzoylmethane, menthyl anthranilate, ethylhexyl vii) a keratolytic agent, dimethyl PABA, and combinations thereof. viii) a peptide, 10. The topical cosmetic composition according to claim9, ix) a fatty acid derivative, wherein the first sunscreen is present in an amount of from X) a sunscreen, about 1 wt.% to 20 wt %, and the second sunscreen is present xi) an optical brightener, and combinations thereof; and 35 in an amount of from about 1 wt % to about 10 wt %, based on c) at least one cosmetically acceptable carrier or excipient, the total weight of the topical cosmetic composition. wherein the compositionis provided in a topical delivery 11. The topical cosmetic composition according to claim 9. System selected from the group consisting of a serum, a wherein the first sunscreen is methylene bis-benzotriazolyl lotion, a cream, an ointment, a gel, an aerosol, a foam, a tetramethylphenol, and the second sunscreen is ethylhexyl foamable liquid, an emulsion, a skin cleaner, a milk, a 40 methoxycinnamate. mask, and a solid stick. 12. The composition according to claim 9, wherein the 2. The topical cosmetic composition of claim 1, wherein sunscreen in the composition provides for an SPF of greater the Phyllanthus extract comprises a Phyllanthus embilica than about 10. extract, the Bellis extract comprises a Bellis perennis extract 13. The topical cosmetic composition according to claim 1, and the licorice extract comprises a licorice root extract. 45 wherein the carrier is water. 3. The topical cosmetic composition of claim 2, wherein 14. The topical cosmetic composition according to claim the Phyllanthus embilica extract is present in an amount of 13, wherein the water is present in an amount of from about 3 from about 0.25 wt % to about 4 wt %; the Bellis perennis wt % to about 95 wt %, based on the total weight of the extract is present in an amount of from about 1 wt % to about composition. 20 wt %; and the licorice extract is present in an amount of 50 15. The topical composition according to claim 1 which is from about 0.01 wt % to about 1 wt %, based on the total a cream, a gel, a serum, or a lotion. weight of the composition. 16. The topical composition according to claim 5 wherein 4. The topical cosmetic composition according to claim 2, the composition comprises as an excipientathickening agent, wherein the at least one cosmetically acceptable carrier is an antioxidant, a surfactant, a chelating agent, an emollient, a Selected from the group consisting of distilled water, saline, 55 preservative and a pH adjuster. Ringer's solution, dextrose solution, Hanks solution and 17. A method of lightening skin pigmentation in a subject, DMSO. comprising topically administering to skin of a subject in 5. The topical cosmetic composition according to claim 2, need thereof, a therapeutically effective amount of the topical wherein the at least one cosmetically acceptable excipient is cosmetic composition of claim 1. Selected from the group consisting of an antioxidant, a chelat ck ck -: ck ck