WO2000069407A1

WO2000069407A1 - Methods for upregulating and/or modulating kgf production and increasing receptivity of keratinocytes to kgf

Info

Publication number: WO2000069407A1
Application number: PCT/US2000/013646
Authority: WO
Inventors: John Erich Oblong; Brent William Mason
Original assignee: The Procter & Gamble Company
Priority date: 1999-05-18
Filing date: 2000-05-18
Publication date: 2000-11-23
Also published as: AU5026700A

Abstract

The present invention relates to various methods for upregulating and/or modulating the production of keratinocyte growth factor wherein the methods each comprise the step of topically applying to the keratinous tissue of a host in need of such treatment a safe and effective amount of a composition comprising: a) a safe and effective amount of a compound effective for upregulating and/or modulating the production of keratinocyte growth factor; and b) a dermatologically acceptable carrier for the compound. The present invention further relates to methods for increasing the receptivity of keratinocytes to KGF wherein the methods involve the same step as outlined above. Preferably, the compound is a xanthine compound selected from the group consisting of aminophylline, caffeine, theobromine, theophylline, and combinations thereof.

Description

METHODS FOR L PREGl LATIN G AND/OR MODULATING

KGF PRODUCTION AND INCREASING

RECEPTIVITY OF KERATINOCYTES TO KGF

CROSS REFERENCE TO RELATED APPLICATION This application claims the benefit of U.S. Provisional Application No. 60/134,687, filed May 18, 1999

TECHNICAL FIELD The present invention relates to methods for upregulating and/or modulating the production of keratinocyte growth factor (KGF) and increasing the receptivity of keratmocytes to KGF The methods involve topical application to the keratinous tissue of a host of a composition containing a compound effective for upregulating and/or modulating the production of keratinocyte growth factor (KGF) and increasing the receptivity of keratmocytes to KGF. Preferably, the compound of interest is a xanthine compound selected from the group consisting of aminophylline, caffeine, theobromine, theophylline, and combinations thereof.

BACKGROUND OF THE INVENTION

Keratinocyte growth factor (KGF) is a protein component that is involved in regulating the biology of epidermal skm cells, namely keratmocytes. This growth factor is a member of the fibroblast growth factor family (FGF) and was originally referred to as FGF7. "KGF" includes isoforms of KGF, KGFI and KGFII which have been identified. Each of these hereafter will be referred to as keratinocyte growth factor.

Research has shown that the only cell that is impacted by KGF is keratmocytes. Without being limited by theory, it is believed that the ability of KGF to only impact keratmocytes is dπven by the presence of a select receptor protein present in keratmocytes that only recognizes KGF. Thus, this singular recognition allows for the selective action of KGF. This selective action serves as an important distinction of KGF from other members of the FGF family, which are capable of modulating the biology of vaπous cell types, based again by the presence of their respective receptors. Currently, each of the principle functions of KGF m mammalian organisms are not known. Research efforts, however, have found that KGF plays an important role in wound healing, which suggests a cπtical role in the reepithelia zation process. Researchers have also speculated that KGF may play a role in regulating the normal epidermal turnover that occurs m human sk . A need therefore exists for a manner of upregulating and/or modulating the levels of KGF that are present m keratinous tissue like skm, especially m the instances of injuries or slowly generating skm cells.

Applicants have found that compositions containing certain compounds tend to upregulate and/or modulate the production of KGF when topically applied to a keratinous tissue of a host in need of such treatment. In addition, Applicants have discovered that such compositions are also suitable for use to increase the receptivity of keratmocytes to KGF thus further aiding in the generation of new skin cells. Preferably, the compositions contain certain xanthine compounds.

SUMMARY OF THE INVENTION The present invention relates to a method for upregulating and/or modulating the production of keratinocyte growth factor wherein the method comprises the step of topically applying to the keratinous tissue of a host in need of such treatment a safe and effective amount of a composition comprising- a) a safe and effective amount of a compound effective for upregulating and/or modulating the production of keratinocyte growth factor; and b) a dermatologically acceptable carrier for the compound.

Furthermore, this invention relates to a method for increasing the receptivity of keratmocytes to KGF wherein the method comprises the step of topically applying to the keratinous tissue of a host in need of such treatment a safe and effective amount of a composition comprising: a) a safe and effective amount of a compound effective for increasing the receptivity of keratmocytes to KGF; and b) a dermatologically acceptable carrier for the compound.

In preferred embodiments, suitable compounds effective for the methods of the present invention include, but are not limited to, xanthine compounds selected from the group consisting of ammophylline, caffeine, theobromine, theophylline, and combinations thereof.

DETAILED DESCRIPTION OF THE INVENTION All percentages and ratios used herein are by weight of the total composition and all measurements made are at 25 C, unless otherwise designated

The compositions of the present invention can comprise, consist essentially of, or consist of, the essential as well as optional ingredients and components described herein. As used herein, "consisting essentially of means that the composition or component may include additional ingredients, but only if the additional ingredients do not materially alter the basic and novel characteristics of the claimed compositions or methods.

All publications cited herein are hereby incoφorated by reference m their entirety. The term "keratinous tissue", as used herein, refers to keratin-contammg layers disposed as the outermost protective covering of mammals which includes, but is not limited to, skm, hair, nails (e.g., toenails, fingernails, hooves, cuticles, etc.).

The term "topical application", as used herein, means to apply or spread the compositions of the present invention onto the surface of keratinous tissue including skm, hair , nails.

The term "safe and effective amount" as used herein means an amount of a compound or composition sufficient to significantly induce a positive benefit, preferably a positive keratinous tissue appearance or feel benefit, including independently the benefits disclosed herein, but low enough to avoid serious side effects, i.e., to provide a reasonable benefit to risk ratio, within the scope of sound judgment of the skilled artisan.

The compositions of the present invention are useful for upregulating and/or modulating the production of KGF as well as increasing the receptivity of the keratmocytes to KGF via topical application Without being limited by theory, it is believed that control of KGF production, particularly upregulation, plays an important role in the heightened regeneration of cells, particularly skin cells. Increasing the receptivity of keratmocytes to KGF also increases the regeneration rate of cells.

The compositions of the present invention, including the essential and optional components thereof, are described in detail hereinafter. Effective Compound The topical compositions of the present invention comprise a safe and effective amount of a compound effective for upregulating and/or modulating the production of KGF and increasing the receptivity of the keratmocytes to KGF. Suitable compounds include xanthine compounds, e.g., caffeine, theophylline, etc., and Coleus forkohln extract derivatives, e.g., forsko n. Preferably, the compound is a xanthine compound selected from the group consisting of aminophylline, caffeine, theobromine, theophylline, and combinations thereof. More preferably, the xanthine compound is selected from the group consisting of theobromine, theophylline, and combinations thereof.

Aminophylline (also referred to as 3,7-Dιhydro-l,3-dιmethyl-lH-puπne-2,6-dιone compound with 1,2-ethanedιamιne (2: 1)), caffeine (also referred to as 3.7-Dιhydro-l,3,7- tπrnethyl-lH-purme-2,6-dιone), theophylline (also referred to as 3,7-Dιhydro-l,3-dιmethyl-lH- puπne-2,6-dιone or 1,3-dιmethylxanthιne), and theobromine (also referred to as 3,7-Dιhydro-3,7- dιmethyl-lH-puπne-2,6-dιone) are commercially available from Sigma Chemical Company (St. Louis, MO); Aldπch Chemical Company (Milwaukee, WI), and Fluka Chemika-USA (Ronkonkonma, NY). In the compositions of the present invention, the xanthine compound preferably comprises from about 0.01% to about 50%, by weight of the composition, more preferably from about 0.1% to about 20%, even more preferably from about 1% to about 10%, even still more preferably from about 2% to about 8%, and most preferably from about 4% to about 6%. Without intending to be limited by theory, it is believed that the xanthine compounds increase the turnover rate of the epidermis, which in turn leads to an ultimate improvement in the texture appearance of keratinous tissue, especially skm It is believed that the mechanism of action for such xanthine compounds involves an increase in cellular cyclic adenosine monophosphate (cAMP) levels that leads to induction of secondary signaling pathways such as increases in intracellular calcium and mositol phosphate formation. Ultimately, this leads to alterations in gene expression patterns that impact the homeostasis of cells. Dermatologically Acceptable Carrier

The topical compositions of the present invention also comprise a dermatologically acceptable carrier for the compound, preferably the xanthine compound. The phrase "dermatologically acceptable carrier", as used herein, means that the carrier is suitable for topical application to mammalian keratinous tissue, has good aesthetic properties, is compatible with the actives of the present invention and any other components, and will not cause any untoward safety or toxicity concerns A safe and effective amount of carrier is from about 50% to about 99.99%, preferably from about 80% to about 99.9%, more preferably from about 90% to about 98%, and most preferably from about 90% to about 95% of the composition.

The carrier can be in a wide variety of forms. For example, emulsion earners, including, but not limited to, oil-m-water, water-in-oil, water- -oil-in-water, and oil-m-water-in-sihcone emulsions, are useful herein.

Preferred carriers comprise an emulsion such as oil-m-water emulsions or water-in-oil emulsions, e.g., silicone-in-water and water-in-silicone. As will be understood by the skilled artisan, a given component will distribute primarily into either the water or oil phase, depending on the water solubihty/dispersibihty of the component in the composition The xanthine compounds distribute primarily into the water phase

Emulsions according to the present invention generally contain a solution as descπbed above and a lipid or oil. Lipids and oils may be derived from animals, plants, or petroleum and may be natural or synthetic (l e., man-made). Preferred emulsions also contain a humectant, such as glycerin Emulsions will preferably further contain from about 1% to about 10%, more preferably from about 2% to about 5%, of an emulsifier, based on the weight of the earner. Emulsifiers may be nonio c, amonic or cationic. Suitable emulsifiers are disclosed in, for example, U.S Patent No. 3,755,560, issued August 28, 1973. Dickert et al ; U.S. Patent No. 4,421,769, issued December 20, 1983, Dixon et al ; and McCutcheon's Detergents and Emulsifiers, North American Edition, pages 317-324 (1986)

The emulsion may also contain an anti-foammg agent to minimize foaming upon application to the skm Anti-foammg agents include high molecular weight sihcones and other materials well known in the art for such use.

Preferred water-in-silicone and oil-m-water emulsions are described in greater detail below a) Water-in-silicone emulsion Water-m-silicone emulsions contain a continuous silicone phase and a dispersed aqueous phase.

(0 Continuous silicone phase Preferred water-m-silicone emulsions of the present invention comprise from about 1% to about 60%, preferably from about 5% to about 40%, more preferably from about 10% to about 20%), by weight of a continuous silicone phase. The continuous silicone phase exists as an external phase that contains or surrounds the discontinuous aqueous phase described hereinafter.

The continuous silicone phase contains a polyorganosiloxane oil A preferred water-in- sihcone emulsion system is formulated to provide an oxidatively stable vehicle for the optional retmoid. The continuous silicone phase of these preferred emulsions comprises between about 50%) and about 99.9% by weight of organopolysiloxane oil and less than about 50% by weight of a non-sihcone oil. In an especially preferred embodiment, the continuous silicone phase comprises at least about 50%, preferably from about 60% to about 99.9%, more preferably from about 70% to about 99.9%, and even more preferably from about 80%o to about 99.9%, polyorganosiloxane oil by weight of the continuous silicone phase, and up to about 50% non- silicone oils, preferably less about 40%, more preferably less than about 30%>, even more preferably less than about 10%, and most preferably less than about 2%, by weight of the continuous silicone phase. These preferred emulsion systems provide more oxidative stability to the retmoid over extended periods of time than comparable water-in-oil emulsions containing lower concentrations of the polyorganosiloxane oil. Concentrations of non-sihcone oils in the continuous silicone phase are minimized or avoided altogether so as to further enhance oxidative stability of the selected retmoid in the compositions. Water- ln-sihcone emulsions of this type are described in copendmg U.S. Patent Application Serial No. 08/570,275, filed December 11, 1995, in the names of Joseph Michael Zukowski, Brent William Mason, Larry Richard Robinson and Greg George Hillebrand. The organopolysiloxane oil for use in the composition may be volatile, non-volatile, or a mixture of volatile and non-volatile sihcones The term "nonvolatile" as used m this context refers to those sihcones that are liquid under ambient conditions and ha\ e a flash point (under one atmospheric of pressure) of or greater than about 100°C The term "volatile" as used in this context refers to all other silicone oils Suitable organopolysiloxanes can be selected from a wide variety of sihcones spanning a broad range of volatilities and viscosities Examples of suitable organopolysiloxane oils include polyalkylsiloxanes, cyclic polyalkylsiloxanes, and polyalkylarylsiloxanes

Polyalkylsiloxanes useful in the composition herein include polyalkylsiloxanes with viscosities of from about 0 5 to about 1,000,000 centistokes at 25°C Such polyalkylsiloxanes can be represented by the general chemical formula R3SιO[R2SιO]_xSιR3 wherein R is an alkyl group having from one to about 30 carbon atoms (preferably R is methyl or ethyl, more preferably methyl, also mixed alkyl groups can be used m the same molecule), and x is an integer from 0 to about 10,000, chosen to achieve the desired molecular weight which can range to over about 10.000,000 Commercially available polyalkylsiloxanes include the polydimethylsiloxanes, which are also known as dimethicones, examples of which include the Vicasil® series sold by General Electric Company and the Dow Corning® 200 series sold by

Dow Corning Corporation Specific examples of suitable polydimethylsiloxanes include Dow

Corning® 200 fluid having a viscosity of 0.65 centistokes and a boiling point of 100°C, Dow

Corning® 225 fluid having a viscosity of 10 centistokes and a boiling point greater than 200°C, and Dow Corning® 200 fluids having viscosities of 50, 350, and 12,500 centistokes, respectively, and boiling points greater than 200°C Suitable dimethicones include those represented by the chemical formula (CH3)₃SιO[(CH3)₂SιO]_x[CH3RSιO]_ySι(CH3)3 wherein R is straight or branched chain alkyl having from two to about 30 carbon atoms and x and y are each integers of 1 or greater selected to achieve the desired molecular weight which can range to over about 10,000,000 Examples of these alkyl-substituted dimethicones include cetyl dimethicone and lauryl dimethicone

Cyclic polyalkylsiloxanes suitable for use m the composition include those represented by the chemical formula [SιR2-0]_n wherein R is an alkyl group (preferably R is methyl or ethyl, more preferably methyl) and n is an integer from about 3 to about 8, more preferably n is an integer from about 3 to about 7, and most preferably n is an integer from about 4 to about 6 When R is methyl, these materials are typically referred to as cyclomethicones Commercially available cyclomethicones include Dow Corning® 244 fluid having a viscosity of 2.5 centistokes, and a boiling point of 172°C, which primarily contains the cyclomethicone tetramer (i.e. n=4), Dow Corning® 344 fluid having a viscosity of 2 5 centistokes and a boiling point of 178°C, which primarily contains the cyclomethicone pentamer (i.e. n=5), Dow Corning® 245 fluid having a viscosity of 4.2 centistokes and a boiling point of 205°C, which pnmanly contains a mixture of the cyclomethicone tetramer and pentamer (i.e n=4 and 5), and Dow Coming® 345 fluid having a viscosity of 4 5 centistokes and a boiling point of 217°, which primarily contains a mixture of the cyclomethicone tetramer, pentamer, and hexamer (I e n=4, 5, and 6)

Also useful are materials such as tπmethylsiloxysihcate, which is a polymeric matenal corresponding to the general chemical formula [(CH2)3SιOι/2]_x[Sιθ2]y, wherein x is an integer from about 1 to about 500 and y is an integer from about 1 to about 500 A commercially available tπmethylsiloxysilicate is sold as a mixture with dimethicone as Dow Corning® 593 fluid

Dimethiconols are also suitable for use in the composition These compounds can be represented by the chemical formulas R SιO[R₂SιO]_xSιR2θH and HOR₂SιO[R SιO]_xSιR2θH wherein R is an alkyl group (preferably R is methyl or ethyl, more preferably methyl) and x is an integer from 0 to about 500, chosen to achieve the desired molecular weight Commercially available dimethiconols are typically sold as mixtures with dimethicone or cyclomethicone (e g Dow Corning® 1401 , 1402, and 1403 fluids)

Poly alky land siloxanes are also suitable for use the composition Polymethylphenyl siloxanes having viscosities from about 15 to about 65 centistokes at 25°C are especially useful

Preferred for use herein are organopolysiloxanes selected from the group consisting of polyalkylsiloxanes, alkyl substituted dimethicones, cyclomethicones, tπmethylsiloxysilicates, dimethiconols, polyalkylaryl siloxanes, and mixtures thereof More preferred for use herein are polyalkylsiloxanes and cyclomethicones Preferred among the polyalkylsiloxanes are dimethicones

As stated above, the continuous silicone phase may contain one or more non-sihcone oils Concentrations of non-sihcone oils m the continuous silicone phase are preferably minimized or avoided altogether so as to further enhance oxidative stability of the selected retmoid m the compositions Suitable non-sihcone oils have a melting point of about 25°C or less under about one atmosphere of pressure Examples of non-sihcone oils suitable for use in the continuous silicone phase are those well known in the chemical arts in topical personal care products in the form of water-in-oil emulsions, e g , mineral oil, vegetable oils, synthetic oils, semisynthetic oils, etc

(n) Dispersed aqueous phase The topical compositions of the present invention comprise from about 30% to about 90%, more preferably from about 50% to about 85%, and most preferably from about 70% to about 80%) of a dispersed aqueous phase In emulsion technology, the term "dispersed phase" is a term well-known to one skilled in the art which means that the phase exists as small particles or droplets that are suspended in and surrounded by a continuous phase The dispersed phase is also known as the internal or discontinuous phase The dispersed aqueous phase is a dispersion of small aqueous particles or droplets suspended m and surrounded by the continuous silicone phase described hereinbefore

The aqueous phase can be water, or a combination of water and one or more water soluble or dispersible ingredients Nonhmiting examples of such optional ingredients include thickeners, acids, bases, salts, chelants, gums, water-soluble or dispersible alcohols and polyols, buffers, preservatives, sunscreening agents, colorings, and the like

The topical compositions of the present invention will typically comprise from about 25% to about 90%, preferably from about 40% to about 80%, more preferably from about 60% to about 80%), water in the dispersed aqueous phase by weight of the composition (in) Emulsifier for dispersing the aqueous phase

The water-m-silicone emulsions of the present invention preferably comprise an emulsifier. In a preferred embodiment, the composition contains from about 0 1% to about 10% emulsifier, more preferably from about 0 5% to about 7 5%, most preferably from about 1% to about 5%, emulsifier by weight of the composition The emulsifier helps disperse and suspend the aqueous phase within the continuous silicone phase

A wide variety of emulsifying agents can be employed herein to form the preferred water- m-sihcone emulsion. Known or conventional emulsifying agents can be used in the composition, provided that the selected emulsifying agent is chemically and physically compatible with essential components of the composition, and provides the desired dispersion characteristics Suitable emulsifiers include silicone emulsifiers, non-silicon-contaimng emulsifiers, and mixtures thereof, known by those skilled in the art for use in topical personal care products. Preferably these emulsifiers have an HLB value of or less than about 14, more preferably from about 2 to about 14, and most preferably from about 4 to about 14. Emulsifiers having an HLB value outside of these ranges can be used in combination with other emulsifiers to achieve an effective weighted average HLB for the combination that falls withm these ranges.

Silicone emulsifiers are preferred A wide variety of silicone emulsifiers are useful herein These silicone emulsifiers are typically organically modified organopolysiloxanes, also known to those skilled in the art as silicone surfactants Useful silicone emulsifiers include dimethicone copolyols These materials are polydimethyl siloxanes that have been modified to include polyether side chains such as polyethylene oxide chains, polypropylene oxide chains, mixtures of these chains, and polyether chains containing moieties derived from both ethyiene oxide and propylene oxide. Other examples include alkyl-modified dimethicone copolyols, I e , compounds which contain C2-C30 pendant side chains Still other useful dimethicone copolyols include matenals having various cationic, aniomc, amphoteπc, and zwitteπonic pendant moieties. The dimethicone copolyol emulsifiers useful herein can be described by the following general structure: CH, CH, CH, CH, CH, I ^" I I I CH,— Si— O- -Si— -O -Si— -O -Si— -o -Si— CH₃

I I

CH, CH, R R2 CH₃

wherein R is C1-C30 straight, branched, or cyclic alkyl and R^ is selected from the group consisting of

~(CH₂)n--O--(CH₂CHR3θ)_m--H. and

-(CH₂)_n-0-(CH₂CHR³0)_m-(CH2CHR⁴0)₀-H, wherein n is an integer from 3 to about 10, R³ and R⁴ are selected from the group consisting of H and C1-C6 straight or branched chain alkyl such that R³ and R⁴ are not simultaneously the same; and m, o, x, and y are selected such that the molecule has an overall molecular weight from about 200 to about 10,000,000, with m, o, x, and y being independently selected from integers of zero or greater such that m and o are not both simultaneously zero, and z being independently selected from integers of 1 or greater. It is recognized that positional isomers of these copolyols can be achieved The chemical representations depicted above for the R^ moieties containing the R³ and R⁴ groups are not meant to be limiting but are shown as such for convenience.

Also useful herein, although not strictly classified as dimethicone copolyols, are silicone surfactants as depicted m the structures in the previous paragraph wherein R^ is: -(CH₂)_n-0-R5, wherein R^ is a cationic, anionic, amphoteπc, or zwitteπonic moiety Nonhmiting examples of dimethicone copolyols and other silicone surfactants useful as emulsifiers herein include polydimethylsiloxane polyether copolymers with pendant polyethylene oxide sidechains, polydimethylsiloxane polyether copolymers with pendant polypropylene oxide sidechains, polydimethylsiloxane polyether copolymers with pendant mixed polyethylene oxide and polypropylene oxide sidechains, polydimethylsiloxane polyether copolymers with pendant mixed poly(ethylene)(propylene)oxιde sidechains, polydimethylsiloxane polyether copolymers with pendant organobetame sidechains, polydimethylsiloxane polyether copolymers with pendant carboxylate sidechains, polydimethylsiloxane polyether copolymers with pendant quaternary ammonium sidechains; and also further modifications of the preceding copolymers containing pendant C2-C30 straight, branched, or cyclic alkyl moieties. Examples of commercially available dimethicone copolyols useful herein sold by Dow Corning Corporation are Dow Corning® 190, 193, Q2-5220, 2501 Wax, 2-5324 fluid, and 3225C (this later material being sold as a mixture with cyclomethicone). Cetyl dimethicone copolyol is commercially available as a mixture with polyglyceryl-4 isostearate (and) hexyl laurate and is sold under the tradename ABIL® WE-09 (available from Goldschmidt). Cetyl dimethicone copolyol is also commercially available as a mixture with hexyl laurate (and) polyglyceryl-3 oleate (and) cetyl dimethicone and is sold under the tradename ABIL® WS-08 (also available from Goldschmidt) Other nonlimiting examples of dimethicone copolyols also include lauryl dimethicone copolyol, dimethicone copolyol acetate, diemethicone copolyol adipate, dimethicone copolyolamine, dimethicone copolyol behenate, dimethicone copolyol butyl ether, dimethicone copolyol hydroxy stearate, dimethicone copolyol isostearate, dimethicone copolyol laurate, dimethicone copolyol methyl ether, dimethicone copolyol phosphate, and dimethicone copolyol stearate. See International Cosmetic Ingredient Dictionary. Fifth Edition, 1993.

Dimethicone copolyol emulsifiers useful herein are described, for example, in U.S. Patent No. 4,960,764, to Figueroa, Jr. et al., issued October 2, 1990: European Patent No. EP 330,369, to SanoGueira, published August 30, 1989; G.H. Dahms, et al., "New Formulation Possibilities Offered by Silicone Copolyols," Cosmetics & Toiletries, vol. 1 10, pp. 91-100, March 1995; M.E. Carlotti et al., "Optimization of W/O-S Emulsions And Study Of The Quantitative Relationships Between Ester Structure And Emulsion Properties," J. Dispersion Science And Technology. 13(3), 315-336 (1992); P. Hameyer, "Comparative Technological Investigations of Organic and Organosihcone Emulsifiers m Cosmetic Water-m-Oil Emulsion Preparations," HAPPI 28(4), pp. 88-128 (1991); J. Smid-Korbar et al., "Efficiency and usability of silicone surfactants in emulsions," Provisional Communication, International Journal of Cosmetic Science, 12, 135-139 (1990); and D.G. Krzysik et al., "A New Silicone Emulsifier For Water-in-Oil Systems," Drug and Cosmetic Industry, vol. 146(4) pp. 28-81 (April 1990).

Among the non-sihcone-contaming emulsifiers useful herein are various non-ionic and anionic emulsifying agents such as sugar esters and polyesters, alkoxylated sugar esters and polyesters, C1-C30 fatty acid esters of C1-C30 fatty alcohols, alkoxylated derivatives of C1-C30 fatty acid esters of C1-C30 fatty alcohols, alkoxylated ethers of C1-C30 fatty alcohols, polyglyceryl esters of C1-C30 fatty acids, C1-C30 esters of polyols, C1-C30 ethers of polyols, alkyl phosphates, polyoxyalkylene fatty ether phosphates, fatty acid amides, acyl lactylates, soaps, and mixtures thereof Other suitable emulsifiers are described, for example, m McCutcheon's, Detergents and Emulsifiers. North American Edition (1986), published by Allured Publishing Corporation; U.S. Patent No. 5,01 1,681 to Ciotti et al., issued April 30, 1991; U.S. Patent No 4,421,769 to Dixon et al., issued December 20, 1983; and U.S. Patent No. 3,755,560 to Dickert et al, issued August 28, 1973. Nonlimiting examples of these non-silicon-contammg emulsifiers include: polyethylene glycol 20 sorbitan monolaurate (Polysorbate 20), polyethylene glycol 5 soya sterol, Steareth-20, Ceteareth-20, PPG-2 methyl glucose ether distearate, Ceteth-10, Polysorbate 80. cetyl phosphate, potassium cetyl phosphate, diethanolamme cetyl phosphate, Polysorbate 60. glyceryl stearate, PEG- 100 stearate, polyoxyethylene 20 sorbitan tπoleate (Polysorbate 85), sorbitan monolaurate, polyoxyethylene 4 lauryl ether sodium stearate, polyglyceryl-4 isostearate, hexyl laurate. steareth-20, ceteareth-20, PPG-2 methyl glucose ether distearate, ceteth- 10, diethanolamme cetyl phosphate, glyceryl stearate, PEG- 100 stearate, and mixtures thereof. b Oil-in-Water Emulsions

Other preferred topical carriers include oil-m-water emulsions, ha\ ιng a continuous aqueous phase and a hydrophobic, water-insoluble phase ("oil phase") dispersed therein. Examples of suitable carriers comprising oil-in-water emulsions are described m U.S. Pat. No. 5,073,371 , to Turner, D.J. et al., issued Dec. 17, 1991 , and U.S. Pat. No. 5.073,372, to Turner, D.J. et al , issued Dec. 17, 1991. An especially preferred oil-m-water emulsion, containing a structuring agent, hydrophihc surfactant and water, is described in detail hereinafter. d) Structuring Agent A preferred oil-in-water emulsion comprises a structuring agent to assist in the formation of a liquid crystalline gel network structure. Without being limited by theory, it is believed that the structuring agent assists in providing rheological characteristics to the composition that contribute to the stability of the composition. The structuring agent may also function as an emulsifier or surfactant. Preferred compositions of this invention comprise from about 0.5% to about 20%), more preferably from about 1% to about 10%, most preferably from about 1% to about 5%, by weight of the composition, of a structuring agent.

The preferred structuring agents of the present invention are selected from the group consisting of steaπc acid, palmitic acid, stearyl alcohol, cetyl alcohol, behenyl alcohol, steaπc acid, palmitic acid, the polyethylene glycol ether of stearyl alcohol having an average of about 1 to about 21 ethyiene oxide units, the polyethylene glycol ether of cetyl alcohol having an average of about 1 to about 5 ethyiene oxide units, and mixtures thereof. More preferred structuring agents of the present invention are selected from the group consisting of stearyl alcohol, cetyl alcohol, behenyl alcohol, the polyethylene glycol ether of stearyl alcohol having an average of about 2 ethyiene oxide units (steareth-2), the polyethylene glycol ether of stearyl alcohol having an average of about 21 ethyiene oxide units (steareth-21), the polyethylene glycol ether of cetyl alcohol having an average of about 2 ethyiene oxide units, and mixtures thereof. Even more preferred structuring agents are selected from the group consisting of steanc acid, palmitic acid, stearyl alcohol, cetyl alcohol, behenyl alcohol, steareth-2, steareth-21 , and mixtures thereof. (ii) Hydrophihc surfactant The preferred oil-m-water emulsions comprise from about 0.05% to about 10%, preferably from about 1 % to about 6%, and more preferably from about 1% to about 3% of at least one hydrophihc surfactant which can disperse the hydrophobic materials the water phase

(percentages by weight of the topical earner). The surfactant, at a minimum, must be hydrophihc enough to disperse in water.

Suitable surfactants include any of a wide variety of knowτi cationic, anionic, zwitteπonic, and amphoteric surfactants. See, McCutcheon's. Detergents and Emulsifiers. North Amencan

Edition (1986), published by Allured Publishing Corporation; U.S. Patent No. 5,011 ,681 ; U.S.

Patent No. 4,421,769; and U.S. Patent No. 3,755,560.

The exact surfactant chosen will depend upon the pH of the composition and the other components present. Preferred are cationic surfactants, especially dialkyl quaternary ammonium compounds, examples of which are described in U.S. Patent No. 5,151 ,209; U.S. Patent No. 5,151,210; U.S.

Patent No. 5,120,532; U.S. Patent No. 4,387,090; U.S. Patent No. 3,155,591; U.S. Patent No.

3,929,678; U.S. Patent No. 3.959,461 ; McCutcheon's. Detergents & Emulsifiers, (North

American edition 1979) M.C. Publishing Co.; and Schwartz, et al., Surface Active Agents, Their Chemistry and Technology. New York: Interscience Publishers, 1949; which descriptions are incorporated herein by reference. The cationic surfactants useful herein include cationic ammonium salts such as those having the formula:

wherein Ri , is an alkyl group having from about 12 to about 30 carbon atoms, or an aromatic, aryl or alkaryl group having from about 12 to about 30 carbon atoms; R2, R3, and R4 are independently selected from hydrogen, an alkyl group having from about 1 to about 22 carbon atoms, or aromatic, aryl or alkaryl groups having from about 12 to about 22 carbon atoms; and X is any compatible anion, preferably selected from the group consisting of chloride, bromide, iodide, acetate, phosphate, nitrate, sulfate, methyl sulfate, ethyl sulfate, tosylate, lactate, citrate, glycolate, and mixtures thereof. Additionally, the alkyl groups of R_j , R2, R3, and R4 can also contain ester and/or ether linkages, or hydroxy or amino group substituents (e.g., the alkyl groups can contain polyethylene glycol and polypropylene glycol moieties).

More preferably, R_j is an alkyl group having from about 12 to about 22 carbon atoms; R2 is selected from H or an alkyl group having from about 1 to about 22 carbon atoms: R3 and R4 are independently selected from H or an alkyl group having from about 1 to about 3 carbon atoms; and X is as descnbed previously.

Most preferably, R_j is an alkyl group having from about 12 to about 22 carbon atoms; R2,

R3, and R4 are selected from H or an alkyl group having from about 1 to about 3 carbon atoms; and X is as descnbed previously. Alternatively, other useful cationic emulsifiers include ammo-amides, wherein the above structure Rj is alternatively R5C0NH-(CH2)_n, wherein R5 is an alkyl group having from about 12 to about 22 carbon atoms, and n is an integer from about 2 to about 6, more preferably from about 2 to about 4, and most preferably from about 2 to about 3 Nonlimiting examples of these cationic emulsifiers include stearamidopropyl PG-dimomum chloride phosphate, behenamidopropyl PG dimomum chloride, stearamidopropyl ethyldimonium ethosulfate, stearamidopropyl dimethyl (myπstyl acetate) ammonium chloride, stearamidopropyl dimethyl cetearyl ammonium tosylate, stearamidopropyl dimethyl ammonium chloride, stearamidopropyl dimethyl ammonium lactate, and mixtures thereof Especially preferred is behenamidopropyl PG dimomum chloride.

Nonlimiting examples of quaternary ammonium salt cationic surfactants include those selected from the group consisting of cetyl ammonium chloride, cetyl ammonium bromide, lauryl ammonium chloride, lauryl ammonium bromide, stearyl ammonium chlonde, stearyl ammonium bromide, cetyl dimethyl ammonium chloride, cetyl dimethyl ammonium bromide, lauryl dimethyl ammonium chloride, lauryl dimethyl ammonium bromide, stearyl dimethyl ammonium chloride, stearyl dimethyl ammonium bromide, cetyl tπmethyl ammonium chloride, cetyl tπmethyl ammonium bromide, lauryl tπmethyl ammonium chloride, lauryl tπmethyl ammonium bromide, stearyl tπmethyl ammonium chloride, stearyl tπmethyl ammonium bromide, lauryl dimethyl ammonium chloride, stearyl dimethyl cetyl ditallow dimethyl ammonium chlonde, dicetyl ammonium chloride, dicetyl ammonium bromide, dilauryl ammonium chloride, dilauryl ammonium bromide, distearyl ammonium chloride, distearyl ammonium bromide, dicetyl methyl ammonium chloride, dicetyl methyl ammonium bromide, dilauryl methyl ammonium chloride, dilauryl methyl ammonium bromide, distearyl methyl ammonium chloride, distearyl methyl ammonium bromide, and mixtures thereof. Additional quaternary ammonium salts include those wherein the C12 to C30 alkyl carbon chain is derived from a tallow fatty acid or from a coconut fatty acid. The term "tallow" refers to an alkyl group derived from tallow fatty acids (usually hydrogenated tallow fatty acids), which generally have mixtures of alkyl chains in the C\ to

Ci g range The term "coconut" refers to an alkyl group derived from a coconut fatty acid, which generally have mixtures of alkyl chains m the C12 to C14 range. Examples of quaternary ammonium salts derived from these tallow and coconut sources include ditallow dimethyl ammonium chloride, ditallow dimethyl ammonium methyl sulfate, dι(hydrogenated tallow) dimethyl ammonium chloride, dι(hydrogenated tallow) dimethyl ammonium acetate, ditallow dipropyl ammonium phosphate, ditallow dimethyl ammonium nitrate, dι(coconutalkyl)dιmethyl ammonium chloride, dι(coconutalkyl)dιmethyl ammonium bromide, tallow ammonium chloride, coconut ammonium chloride, stearamidopropyl PG-dimomum chloride phosphate, stearamidopropyl ethyldimonium ethosulfate, stearamidopropyl dimethyl (mynstyl acetate) ammonium chloride, stearamidopropyl dimethyl cetearyl ammonium tosylate, stearamidopropyl dimethyl ammonium chloride, stearamidopropyl dimethyl ammonium lactate, and mixtures thereof. An example of a quaternary ammonium compound having an alkyl group with an ester linkage is ditallowyl oxyethyl dimethyl ammonium chloride. More preferred cationic surfactants are those selected from the group consisting of behenamidopropyl PG dimomum chloride, dilauryl dimethyl ammonium chloride, distearyl dimethyl ammonium chloride, dimyristyl dimethyl ammonium chloride, dipalmityl dimethyl ammonium chloride, distearyl dimethyl ammonium chloride, stearamidopropyl PG-dimonium chloride phosphate, stearamidopropyl ethyldiammonium ethosulfate, stearamidopropyl dimethyl (myπstyl acetate) ammonium chloride, stearamidopropyl dimethyl cetearyl ammonium tosylate, stearamidopropyl dimethyl ammonium chloride, stearamidopropyl dimethyl ammonium lactate, and mixtures thereof.

Most preferred cationic surfactants are those selected from the group consisting of behenamidopropyl PG dimomum chloride, dilauryl dimethyl ammonium chloride, distearyl dimethyl ammonium chloride, dimyristyl dimethyl ammonium chloride, dipalmityl dimethyl ammonium chloride, and mixtures thereof.

A preferred combination of cationic surfactant and structuring agent is behenamidopropyl

PG dimonium chloride and/or behenyl alcohol, wherein the ratio is preferably optimized to maintained to enhance physical and chemical stability, especially when such a combination contains ionic and/or highly polar solvents. This combination is especially useful for delivery of sunscreenmg agents such as zinc oxide and octyl methoxycmnamate.

A wide variety of anionic surfactants are also useful herein. See, e.g., U.S. Patent No.

3,929,678, to Laughlm et al., issued December 30, 1975, which is incorporated herein by reference m its entirety. Nonlimiting examples of anionic surfactants include the alkoyl isethionates, and the alkyl and alkyl ether sulfates. The alkoyl isethionates typically have the formula RCO-OCF CF SO-M wherein R is alkyl or alkenyl of from about 10 to about 30 carbon atoms, and M is a water-soluble cation such as ammonium, sodium, potassium and tπethanolamme. Nonlimiting examples of these isethionates include those alkoyl isethionates selected from the group consisting of ammonium cocoyl isethionate, sodium cocoyl lsethionate, sodium lauroyl isethionate, sodium stearoyl isethionate, and mixtures thereof.

The alkyl and alkyl ether sulfates typically have the respective formulae ROSO^M and

RO(C-H .O) SO.-M, wherein R is alkyl or alkenyl of from about 10 to about 30 carbon atoms, x is from about 1 to about 10, and M is a water-soluble cation such as ammonium, sodium, potassium and tπethanolamine Another suitable class of anionic surfactants are the water-soluble salts of the organic, sulfuπc acid reaction products of the general formula: R- -SO₃-M wherein R₁ is chosen from the group consisting of a straight or branched chain, saturated aliphatic hydrocarbon radical having from about 8 to about 24, preferably about 10 to about 16, carbon atoms; and M is a cation. Still other anionic synthetic surfactants include the class designated as succmamates, olefin sulfonates having about 12 to about 24 carbon atoms, and β- alkyloxy alkane sulfonates. Examples of these materials are sodium lauryl sulfate and ammonium lauryl sulfate. Other anionic materials useful herein are soaps (i.e. alkali metal salts, e.g., sodium or potassium salts) of fatty acids, typically having from about 8 to about 24 carbon atoms, preferably from about 10 to about 20 carbon atoms. The fatty acids used m making the soaps can be obtained from natural sources such as, for instance, plant or animal-derived glyceπdes (e.g., palm oil, coconut oil, soybean oil, castor oil, tallow, lard, etc.) The fatty acids can also be synthetically prepared. Soaps are described in more detail m U.S. Patent No. 4,557,853, cited above.

Amphoteπc and zwitteπonic surfactants are also useful herein. Examples of amphoteπc and zwitteπonic surfactants which can be used in the compositions of the present invention are those which are broadly described as derivatives of aliphatic secondary and tertiary amines in which the aliphatic radical can be straight or branched chain and wherein one of the aliphatic substituents contains from about 8 to about 22 carbon atoms (preferably Cg - Cj §) and one contains an anionic water solubihzing group, e.g., carboxy, sulfonate, sulfate, phosphate, or phosphonate. Examples are alkyl immo acetates, and lmmodialkanoates and ammoalkanoates of the formulas RN[CH₂)_mC0₂M]₂ and R H(CH₂)_mC0₂M wherein m is from 1 to 4, R is a Cg-C22 alkyl or alkenyl, and M is H, alkali metal, alkaline earth metal ammonium, or alkanolammomum. Also included are lmidazolinium and ammonium derivatives. Specific examples of suitable amphoteπc surfactants include sodium 3-dodecyl-amιnopropιonate, sodium 3-dodecylamιnopropane sulfonate, N-alkyltauπnes such as the one prepared by reacting dodecylamme with sodium isethionate according to the teaching of U.S. Patent No. 2,658,07; N-higher alkyl aspartic acids such as those produced according to the teaching of U.S. Patent No. 2,438,091 ; and the products sold under the trade name "Miranol" and described U.S. Patent No. 2,528,378. Other examples of useful amphoteπcs include phosphates, such as coamidopropyl PG-dimomum chloride phosphate (commercially available as Monaquat PTC, from Mona Corp.).

Also useful herein as amphoteπc or zwitteπonic surfactants are the betaines. Examples of betaines include the higher alkyl betaines, such as coco dimethyl carboxymethyl betaine, lauryl dimethyl carboxymethyl betaine, lauryl dimethyl alphacarboxyethyl betaine, cetyl dimethyl carboxymethyl betaine, cetyl dimethyl betaine (available as Lonzaine 16SP from Lonza Corp.), lauryl bιs-(2-hydroxyethyl) carboxymethyl betaine, stearyl bιs-(2-hydroxypropyl) carboxymethyl betaine, oleyl dimethyl gamma-carboxypropyl betaine, lauryl bιs-(2-hydroxypropyl)alpha-carboxyethyl betaine, coco dimethyl sulfopropyl betame, stearyl dimethyl sulfopropyl betaine, lauryl dimethyl sulfoethyl betaine, lauryl bιs-(2-hydroxyethyl) sulfopropyl betaine, and amidobetaines and amidosulfobetaines (wherein the RCONH(CH-)-. radical is attached to the nitrogen atom of the betaine), oleyl betame (available as amphoteπc Velvetex OLB-50 from Henkel), and cocamidopropyl betaine (available as Velvetex BK-35 and BA-35 from Henkel). Other useful amphoteπc and zwitteπonic surfactants include the sultames and hydroxysul tames such as cocamidopropyl hydroxysultame (available as Miratame CBS from Rhone-Poulenc), and the alkanoyl sarcosmates corresponding to the formula RC0N(CH₃)CH₂CH₂C0₂M wherein R is alkyl or alkenyl of about 10 to about 20 carbon atoms, and M is a water-soluble cation such as ammonium, sodium, potassium and trialkanolamme (e.g., triethanolamme), a preferred example of which is sodium lauroyl sarcosmate.

(in) Water The preferred oil-in-water emulsion comprises from about 25% to about 98%), preferably from about 65 % to about 95%, more preferably from about 70% to about 90%> water by weight of the topical carrier.

The hydrophobic phase is dispersed m the continuous aqueous phase. The hydrophobic phase may contain water insoluble or partially soluble materials such as are known in the art, including but not limited to the sihcones described herein reference to silicone-in-water emulsions, and other oils and lipids such as described above in reference to emulsions. The topical compositions of the subject invention, including but not limited to lotions and creams, may comprise a dermatologically acceptable emollient Such compositions preferably contain from about 2% to about 50% of the emollient. As used herein, "emollient" refers to a material useful for the prevention or relief of dryness, as well as for the protection of the skm. A wide variety of suitable emollients are known and may be used herein. Sagann, Cosmetics. Science and Technology. 2nd Edition, Vol 1, pp 32-43 (1972), contains numerous examples of materials suitable as an emollient. A preferred emollient is glycerin. Glycerin is preferably used in an amount of from or about 0.001 to or about 20%. more preferably from or about 0.01 to or about 10%, most preferably from or about 0 1 to or about 5%, e.g., 3%. Lotions and creams according to the present invention generally comprise a solution carrier system and one or more emollients Lotions typically comprise from about 1% to about 20%), preferably from about 5% to about 10%, of emollient, from about 50%o to about 90%, preferably from about 60% to about 80%, water, and the xanthine compound in the above described amounts. A cream typically comprises from about 5% to about 50%, preferably from about 10%) to about 20%, of emollient; from about 45% to about 85%, preferably from about 50% to about 75%o, water; and the xanthine compound in the above described amounts.

Ointments of the present invention may comprise a simple carrier base of animal or vegetable oils or semi-solid hydrocarbons (oleaginous), absoφtion ointment bases which absorb water to form emulsions; or water soluble carriers, e.g., a water soluble solution carrier. Ointments may further comprise a thickening agent, such as described in Sagarin, Cosmetics. Science and Technology, 2nd Edition, Vol. 1, pp. 72-73 (1972), and/or an emollient For example, an ointment may comprise from about 2% to about 10%ι of an emollient; from about 0.1% to about 2% of a thickening agent; and the xanthine compound in the above described amount. Compositions of this invention useful for cleansing ("cleansers") are formulated with a suitable carrier, e.g., as described above, and preferably contain, in addition to the xanthine compound in the above described amounts, from about 1% to about 90%, more preferably from about 5% to about 10%, of a dermatologically acceptable surfactant The surfactant is suitably selected from anionic, nomonic, zwitteπonic, amphoteπc and ampholytic surfactants, as well as mixtures of these surfactants Such surfactants are well known to those skilled in the detergency art. Nonlimiting examples of possible surfactants include ιsoceteth-20, sodium methyl cocoyl taurate, sodium methyl oleoyl taurate, and sodium lauryl sulfate. See U S Patent No. 4,800,197, to Kowcz et al., issued January 24, 1989, for exemplary surfactants useful herein. Examples of a broad variety of additional surfactants useful herein are described in McCutcheon's Detergents and Emulsifiers. North American Edition (1986), published by Allured Publishing Coφoration. The cleansing compositions can optionally contain, at their art-established levels, other materials which are conventionally used in cleansing compositions.

The physical form of the cleansing compositions is not critical The compositions can be, for example, formulated as toilet bars, liquids, shampoos, bath gels, hair conditioners, hair tonics, pastes, or mousses. Toilet bars are most preferred since this is the form of cleansing agent most commonly used to wash the sk R se-off cleansing compositions, such as shampoos, require a delivery system adequate to deposit sufficient levels of actives on the skm and scalp. A preferred delivery system involves the use of insoluble complexes For a more complete disclosure of such delivery systems, see U.S. Patent No. 4,835,148, Barford et al . issued May 30, 1989. As used herein, the term "foundation" refers to a liquid, semi-liquid, semi-solid, or solid skm cosmetic which includes, but is not limited to lotions, creams, gels, pastes, cakes, and the like. Typically the foundation is used over a large area of the skm, such as over the face, to provide a particular look. Foundations are typically used to provide an adherent base for color cosmetics such as rouge, blusher, powder and the like, and tend to hide skin imperfections and impart a smooth, even appearance to the skm Foundations of the present invention include a dermatologically acceptable carrier for the xanthine compound and may include conventional ingredients such as oils, colorants, pigments, emollients, fragrances, waxes, stabilizers, and the like Exemplary carriers and such other ingredients which are suitable for use herein are described, for example, in copendmg patent application Serial No 08/430,961 , filed on April 28, 1995 m the names of Marcia L. Canter, Bram D. Barford, and Brian D. Hofrichter, and U.K. Patent Application GB 2274585-A, published on Jan. 23, 1993.

EM

The compositions of the present invention preferably exhibit a pH of from about 4 to about 10. More preferably, the pH is from about 4.5 to 9.5, even more preferably from about 5 to 9, and most preferably from about 7 to 9. In even more preferred embodiments, the pH is from about 4 to about 6 or from about 8 to 10, more preferably from about 5 to about 6 or from about 8 to about 9. Without being limited by theory, it is believed that such a defined pH aids m penetration of the xanthine compound of the present compositions into the skin, hair, or nails of a mammal. This penetration occurs due to charge distribution on the xanthme molecule, thereby making it more amenable to penetration. Additionally, it is possible that higher pH levels allow for alterations m the permeation pathways through the skin (e.g., lipid distribution and protein interactions in stratum corneum), thereby allowing for greater penetration of the xanthme molecules. Optional Components The compositions of the present invention may contain a variety of other ingredients such as are conventionally used in a given product type provided that they do not unacceptably alter the benefits of the invention.

In a preferred embodiment, where the composition is to be in contact with human skin, the optional components should be suitable for application to skin, that is, when incoφorated into the composition they are suitable for use in contact with human skin without undue toxicity, incompatibility, instability, allergic response, and the like within the scope of sound medical judgment. The CTFA Cosmetic Ingredient Handbook, Second Edition (1992) descπbes a wide variety of nonlimiting cosmetic and pharmaceutical ingredients commonly used m the skin care industry, which are suitable for use in the compositions of the present invention. Examples of these ingredient classes include: abrasives, absorbents, aesthetic components such as fragrances, pigments, colorings/colorants, essential oils, skin sensates, astringents, etc. (e.g., clove oil, menthol, camphor, eucalyptus oil, eugenol. menthyl lactate, witch hazel distillate), anti-acne agents, anti-cakmg agents, antifoammg agents, antimicrobial agents (e.g., lodopropyl butylcarbamate), antioxidants, binders, biological additives, buffering agents, bulking agents, chelating agents, chemical additives, colorants, cosmetic astringents, cosmetic biocides, denaturants, drug astringents, external analgesics, film formers or materials, e g., polymers, for aiding the film-forming properties and substantivity of the composition (e.g , copolymer of eicosene and vinyl pyrrohdone), opacifying agents, pH adjusters, propellants. reducing agents sequestrants, skin bleaching and lightening agents (e.g., hydroqumone, kojic acid, ascorbic acid magnesium ascorbyl phosphate, ascorbyl glucosamme), skm-conditioning agents (e.g. humectants, including miscellaneous and occlusive), skin soothing and/or healing agents (e.g. panthenol and derivatives (e.g., ethyl panthenol), aloe vera, pantothe c acid and its derivatives allantom, bisabolol, and dipotassium glycyrrhizmate), skm treating agents, thickeners, and vitamins and derivatives thereof. In any embodiment of the present invention, however, the actives useful herein can be categorized by the benefit they provide or by their postulated mode of action. However, it is to be understood that the actives useful herein can in some instances provide more than one benefit or operate via more than one mode of action. Therefore, classifications herein are made for the sake of convenience and are not intended to limit the active to that particular application or applications listed.

Desquamation Actives

A safe and effective amount of a desquamation active may be added to the compositions of the present invention, more preferably from about 0.1 % to about 10%), even more preferably from about 0.2% to about 5%, also preferably from about 0.5%) to about 4%, by weight of the composition. Desquamation actives enhance the skm appearance benefits of the present invention. For example, the desquamation actives tend to improve the texture of the skin (e.g., smoothness). One desquamation system that is suitable for use herein comprises sulfhydryl compounds and zwitteπonic surfactants and is described in copendmg application Serial No. 08/480,632, filed on June 7, 1995 m the name of Donald L. Bissett, corresponding to PCT Application No. U.S 95/08136, filed 6/29/95 Another desquamation system that is suitable for use herein comprises salicylic acid and zwitteπonic surfactants and is described in copendmg patent application Serial No. 08/554,944, filed on November 13, 1995 as a continuation of Senal No. 08/209,401, filed on March 9, 1994 in the name of Bissett, corresponding to PCT Application No. 94/12745, filed 1 1/4/94, published 5/18/95. Zwitteπonic surfactants such as described in these applications are also useful as desquamatory agents herein, with cetyl betaine being particularly preferred Anti-Acne Actives

The compositions of the present invention may comprise a safe and effective amount of one or more anti-acne actives Examples of useful anti-acne actives include resorcinol, sulfur, salicylic acid, erythromycin, zinc, etc Further examples of suitable anti-acne actives are described m further detail in U S Patent No. 5,607,980, issued to McAtee et al, on March 4,

1997.

Anti -Wrinkle Actives/ Anti-Atrophy Actives The compositions of the present invention may further comprise a safe and effective amount of one or more anti-wrinkle actives or anti-atrophy actives. Exemplary anti-wπnkle/anti- atrophy actives suitable for use in the compositions of the present invention include sulfur- contain g D and L ammo acids and their derivatives and salts, particularly the N-acetyl derivatives, a preferred example of which is N-acetyl-L-cysteine; thiols, e.g. ethane thiol; hydroxy acids, phytic acid, lipoic acid; lysophosphatidic acid, skm peel agents (e.g., phenol and the like), vitamin B₃ compounds and retinoids which enhance the skin appearance benefits of the present invention. a) Vitamin B- Compounds

The compositions of the present invention may comprise a safe and effective amount of a vitamin B3 compound Vitamin B₃ compounds are particularly useful for regulating skin condition as described m co-pending U. S. Application Serial No. 08/834,010, filed April 11 , 1997 (corresponding to international publication WO 97/39733 Al , published October 30, 1997). When vitamin B₃ compounds are present in the compositions of the instant invention, the compositions preferably comprise from about 0.01% to about 50%, more preferably from about 0.1% to about 10%), even more preferably from about 0.5%> to about 10%>, and still more preferably from about 1% to about 5%, most preferably from about 2% to about 5%, by weight of the composition, of the vitamin B3 compound.

As used herein, "vitamin B3 compound" means a compound having the formula:

wherein R is - CONH2 ( ^e-_> acmamide), - COOH (i.e , mcotmic acid) or - CH2OH (i.e., nicotmyl alcohol); derivatives thereof; and salts of any of the foregoing

Exemplary derivatives of the foregoing vitamin B3 compounds include mcotmic acid esters, including non-vasodilatmg esters of mcotmic acid (e g , tocpheryl nicotmate), nicotmyl ammo acids, nicotmyl alcohol esters of carboxylic acids, mcotmic acid N-oxide and macmamide N-oxide.

Examples of suitable vitamin B3 compounds are well known in the art and are commercially available from a number of sources, e.g., the Sigma Chemical Company (St. Louis, MO); ICN Biomedicals, Inc (Irvm, CA) and Aldπch Chemical Company (Milwaukee, WI) Preferably, the vitamin B₃ compound is macmamide

The vitamin compounds may be included as the substantially pure material, or as an extract obtained by suitable physical and/or chemical isolation from natural (e.g., plant) sources, b) Retinoids The compositions of the present invention may also comprise a retmoid unless otherwise specified. As used herein, "retmoid" includes all natural and/or synthetic analogs of Vitamin A or retinol-hke compounds which possess the biological activity of Vitamin A in the skm as well as the geometric isomers and stereoisomers of these compounds The retmoid is preferably retmol, retmol esters (e.g., C2 - C22 alkyl esters of retmol, including retinyl palmitate, retinyl acetate, retmyl propionate), retinal, and/or retinoic acid (including all-trans retinoic acid and/or 13-cιs-retιnoιc acid), more preferably retinoids other than retinoic acid These compounds are well known in the art and are commercially available from a number of sources, e.g., Sigma Chemical Company (St. Louis, MO), and Boerhmger Mannheim (Indianapolis, IN). Other retinoids which are useful herein are described in U.S. Patent Nos. 4,677,120, issued Jun. 30, 1987 to Pansh et al; 4,885,31 1 , issued Dec. 5, 1989 to Parish et al.; 5,049,584, issued Sep. 17, 1991 to Purcell et al.; 5,124,356, issued Jun. 23, 1992 to Purcell et al.; and Reissue 34,075, issued Sep. 22, 1992 to Purcell et al.. Other suitable retinoids are tocopheryl-retinoate [tocopherol ester of retinoic acid (trans- or cis-), adapalene {6-[3-(l-adamantyl)-4-methoxyphenyl]-2-naphthoιc acid}, and tazarotene (ethyl 6-[2-(4,4-dιmethylthιochroman-6-yl)-ethynyl]nιcotιnate) Preferred retinoids are retmol, retinyl palmitate. retmyl acetate, retinyl proprionate, retinal and combinations thereof. The retmoid may be included as the substantially pure material, or as an extract obtained by suitable physical and/or chemical isolation from natural (e.g., plant) sources. The retinoid is preferably substantially pure, more preferably essentially pure.

The compositions of this invention may contain a safe and effective amount of the retinoid, such that the resultant composition is safe and effective for regulating keratinous tissue condition, preferably for regulating visible and/or tactile discontinuities in skin texture. The compositions preferably contain from or about 0.005% to or about 2%, more preferably 0.01% to or about 2%, retinoid. Retinol is most preferably used in an amount of from or about 0.01% to or about 0.15%; retinol esters are most preferably used in an amount of from or about 0.01% to or about 2% (e.g., about 1%); retinoic acids are most preferably used in an amount of from or about 0.01%) to or about 0.25%; tocopheryl-retinoate, adapalene, and tazarotene are most preferably used in an amount of from or about 0.01% to or about 2%.

Where the compositions of the present invention contain both a retinoid and a Vitamin B3 compound, the retinoid is preferably used in the above amounts, and the vitamin B3 compound is preferably used in an amount of from or about 0.1%) to or about 10%>, more preferably from or about 2% to or about 5%. Anti-Oxidants/Radical Scavengers

The compositions of the present invention may include a safe and effective amount of an anti-oxidant/radical scavenger. The anti-oxidant/radical scavenger is especially useful for providing protection against UV radiation that can cause increased scaling or texture changes in the stratum comeum and against other environmental agents that can cause skin damage.

A safe and effective amount of an anti-oxidant/radical scavenger may be added to the compositions of the subject invention, preferably from about 0.1% to about 10%>, more preferably from about 1% to about 5%, of the composition. Anti-oxidants/radical scavengers such as ascorbic acid (vitamin C) and its salts, ascorbyl esters of fatty acids, ascorbic acid derivatives (e.g., magnesium ascorbyl phosphate), tocopherol (vitamin E), tocopherol sorbate, tocopherol acetate, other esters of tocopherol, butylated hydroxy benzoic acids and their salts, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid

(commercially available under the tradename Trolox^-), gallic acid and its alkyl esters, especially propyl gallate, uric acid and its salts and alkyl esters, sorbic acid and its salts, amines (e.g., N,N- diethylhydroxylamine, amino-guanidine), sulfhydryl compounds (e.g., glutathione), dihydroxy fumaric acid and its salts, lycine pidolate, arginine pilolate, nordihydroguaiaretic acid, bioflavonoids, lysine, methionine, proline, superoxide dismutase, silymarin, tea extracts, grape skin/seed extracts, melanin, and rosemary extracts may be used. Preferred anti-oxidants/radical scavengers are selected from tocopherol sorbate and other esters of tocopherol, more preferably tocopherol sorbate. For example, the use of tocopherol sorbate m topical compositions and applicable to the present invention is described in U.S Patent No. 4,847,071, issued on July 11, 1989 to Donald L. Bissett, Rodney D. Bush and Ranjit Chatterjee. Chelators

The compositions of the present invention may also comprise a safe and effective amount of a chelator or chelating agent. As used herein, "chelator" or "chelating agent" means an active agent capable of removing a metal ion from a system by forming a complex so that the metal ion cannot readily participate in or catalyze chemical reactions. The inclusion of a chelating agent is especially useful for providing protection against UV radiation that can contribute to excessive scaling or skm texture changes and against other environmental agents that can cause skm damage.

A safe and effective amount of a chelating agent may be added to the compositions of the subject invention, preferably from about 0.1% to about 10%, more preferably from about 1% to about 5%, of the composition. Exemplary chelators that are useful herein are disclosed m U.S. Patent No. 5,487,884, issued 1/30/96 to Bissett et al.; International Publication No. 91/16035, Bush et al., published 10/31/95; and International Publication No. 91/16034, Bush et al., published 10/31/95. Preferred chelators useful in compositions of the subject invention are fuπldioxime and derivatives thereof. Flavonoids

The compositions of the present invention may optionally comprise a flavonoid compound Flavonoids are broadly disclosed in U.S. Patents Nos. 5,686,082 and 5.686,367. Flavonoids suitable for use in the present invention are flavanones selected from the group consisting of unsubstituted flavanones, mono-substituted flavanones, and mixtures thereof; chalcones selected from the group consisting of unsubstituted chalcones, mono-substituted chalcones, di -substituted chalcones, tπ-substituted chalcones, and mixtures thereof; fiavones selected from the group consisting of unsubstituted fiavones, mono-substituted fiavones, di- substituted fiavones, and mixtures thereof; one or more isoflavones; coumarms selected from the group consisting of unsubstituted coumanns, mono-substituted coumanns, di-substituted coumaπns, and mixtures thereof; chromones selected from the group consisting of unsubstituted chromones, mono-substituted chromones, di-substituted chromones, and mixtures thereof; one or more dicoumarols; one or more chromanones; one or more chromanols; isomers (e.g., cis/trans isomers) thereof; and mixtures thereof. By the term "substituted" as used herein means flavonoids wherein one or more hydrogen atom of the flavonoid has been independently replaced with hydroxyl, C1-C8 alkyl, C1-C4 alkoxyl. O-glycoside. and the like or a mixture of these substituents.

Examples of suitable flavonoids include, but are not limited to, unsubstituted flavanone, mono-hydroxy flavanones (e.g., 2'-hydroxy flavanone, 6-hydroxy flavanone, 7-hydroxy flavanone, etc.), mono-alkoxy flavanones (e.g., 5-methoxy flavanone, 6-methoxy flavanone, 7- methoxy flavanone, 4'-methoxy flavanone, etc.), unsubstituted chalcone (especially unsubstituted trans-chalcone), mono-hydroxy chalcones (e.g., 2'-hydroxy chalcone, 4'-hydroxy chalcone, etc.), di-hydroxy chalcones (e.g., 2',4-dιhydroxy chalcone, 2'.4'-dιhydroxy chalcone, 2,2'-dιhydroxy chalcone, 2',3-dιhydroxy chalcone, 2',5'-dιhydroxy chalcone, etc.), and tn-hydroxy chalcones (e.g., 2',3',4'-tnhydroxy chalcone, 4,2',4'-tπhydroxy chalcone, 2,2',4'-tnhydroxy chalcone, etc.), unsubstituted flavone, 7,2'-dιhydroxy flavone, 3',4'-dιhydroxy naphthoflavone, 4'-hydroxy flavone, 5,6-benzoflavone, and 7,8-benzoflavone, unsubstituted lsoflavone, daidzem (7,4'- dihydroxy lsoflavone), 5,7-dιhydroxy-4'-methoxy isoflavone, soy isoflavones (a mixture extracted from soy), unsubstituted coumaπn, 4-hydroxy coumarm, 7-hydroxy coumaπn, 6- hydroxy-4-methyl coumarm, unsubstituted chromone, 3-formyl chromone, 3-formyl-6-ιsopropyl chromone, unsubstituted dicoumarol, unsubstituted chromanone, unsubstituted chromanol, and mixtures thereof.

Preferred for use herein are coumanns, unsubstituted flavanone, methoxy flavanones, unsubstituted chalcone, 2',4-dιhydroxy chalcone, and mixtures thereof. Most preferred are unsubstituted flavanone, unsubstituted chalcone (especially the trans isomer), and mixtures thereof.

They can be synthetic materials or obtained as extracts from natural sources (e.g., plants). The naturally sourced material can also further be deπvatized (e.g., an ester or ether derivative prepared following extraction from a natural source). Flavonoid compounds useful herein are commercially available from a number of sources, e.g., Indofine Chemical Company, Inc. (Somerville, New Jersey), Steraloids, Inc. (Wilton, New Hampshire), and Aldπch Chemical Company, Inc. (Milwaukee, Wisconsin).

Mixtures of the above flavonoid compounds may also be used.

The herein described flavonoid compounds are preferably present m the instant invention at concentrations of from about 0.01% to about 20%, more preferably from about 0.1% to about 10% , and most preferably from about 0.5% to about 5%>.

Anti -Inflammatory Agents

A safe and effective amount of an anti-mflammatory agent may be added to the compositions of the present invention, preferably from about 0.1% to about 10%o, more preferably from about 0 5% to about 5%, of the composition The anti-mflammatory agent enhances the skin appearance benefits of the present invention, e g , such agents contπbute to a more uniform and acceptable skin tone or color The exact amount of anti-mflammatory agent to be used in the compositions will depend on the particular anti-mflammatory agent utilized since such agents vary widely in potency

Steroidal anti-inflammatory agents, including but not limited to, corticosteroids such as hydrocortisone, hydroxyltπamcmolone, alpha-methyl dexamethasone, dexamethasone- phosphate, beclomethasone dipropionates, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichloπsone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocmo de, flucortme butylesters, fluocortolone, fluprednidene (fluprednyhdene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylpredmsolone, tπamcmolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone, fludrocortisone, diflurosone diacetate, fluradrenolone acetonide, medrysone, amcinafel, amcmafide, betamethasone and the balance of its esters, chloroprednisone, chloφredmsone acetate, clocortelone, clescmolone, dichloπsone, difluφrednate, flucloronide, flunisolide, fluoromethalone, fluperolone, flupredmsolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone, paramethasone, predmsolone, predmsone, beclomethasone dipropionate, tπamcmolone, and mixtures thereof may be used. The preferred steroidal anti-mflammatory for use is hydrocortisone.

A second class of anti-mflammatory agents that is useful in the compositions includes the nonsteroidal anti-mflammatory agents The variety of compounds encompassed by this group are well-known to those skilled in the art For detailed disclosure of the chemical structure, synthesis, side effects, etc. of non-steroidal anti-inflammatory agents, one may refer to standard texts, including Anti-inflammatory and Anti-Rheumatic Drugs, K D. Ramsford, Vol. I-III, CRC Press, Boca Raton, (1985), and Anti-mflammatory Agents. Chemistry and Pharmacology. 1, R. A. Scherrer, et al, Academic Press, New York (1974)

Specific non-steroidal anti-inflammatory agents useful m the composition invention include, but are not limited to

1) the oxicams, such as piroxicam, lsoxicam, tenoxicam, sudoxicam, and CP-14,304,

2) the sahcylates, such as aspirin, disalcid, benorylate, tπhsate, safapryn, solpπn, diflunisal, and fendosal; 3) the acetic acid derivatives, such as diclofenac, fenclofenac, mdomethacm. suhndac, tolmetin, isoxepac, furofenac, tiopinac, zidometacm, acematacm. fentiazac, zomepirac, clmdanac, oxepmac, felbmac, and ketorolac;

4) the fenamates, such as mefenamic, meclofenamic, flufenamic. mflumic, and tolfenamic acids;

5) the propionic acid derivatives, such as ibuprofen, naproxen. benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, mdopropfen, piφrofen, caφrofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, almmoprofen, and tiaprofemc; and 6) the pyrazoles, such as phenylbutazone, oxyphenbutazone, feprazone, azapropazone, and tπmethazone.

Mixtures of these non-steroidal anti-mflammatory agents may also be employed, as well as the dermatologically acceptable salts and esters of these agents. For example, etofenamate, a flufenamic acid derivative, is particularly useful for topical application. Of the nonsteroidal anti- inflammatory agents, ibuprofen, naproxen, flufenamic acid, etofenamate, aspiπn, mefenamic acid, meclofenamic acid, piroxicam and felbmac are preferred; ibuprofen, naproxen, ketoprofen, etofenamate, aspirin and flufenamic acid are most preferred.

Finally, so-called "natural" anti-mflammatory agents are useful in methods of the present invention Such agents may suitably be obtained as an extract by suitable physical and/or chemical isolation from natural sources (e.g., plants, fungi, by-products of microorganisms). For example, candehlla wax, alpha bisabolol, aloe vera, Manjistha (extracted from plants m the genus Rubia. particularly Rubia Cordifolia). and Guggal (extracted from plants in the genus Commiphora. particularly Commiphora Mukul), kola extract, chamomile, and sea whip extract, may be used. Additional anti-inflammatory agents useful herein include compounds of the Liconce

(the plant genus/species Glvcyrrhiza glabra) family, including glycyrrhetic acid, glycyrrhizic acid, and derivatives thereof (e.g., salts and esters) Suitable salts of the foregoing compounds include metal and ammonium salts. Suitable esters include C₂ - C24 saturated or unsaturated esters of the acids, preferably C_jr_j - C24, more preferably Ci g - C24. Specific examples of the foregoing include oil soluble licorice extract, the glycyrrhizic and glycyrrhetic acids themselves, monoammonium glycyrrhizmate, monopotassium glycyrrhizmate, dipotassium glycyrrhizinate, 1-beta-glycyrrhetιc acid, stearyl glycyrrhetinate, and 3-stearyloxy-glycyrrhetιmc acid, and disodium 3-succmyloxy-beta-glycyrrhetιnate. Stearyl glycyrrhetinate is preferred. Topical Anesthetics

The compositions of the present invention may also compπse a safe and effective amount of a topical anesthetic. Examples of topical anesthetic drugs include benzocame. lidocame, bupivacaine, chloφrocaine, dibucame, etidocame, mepivacame, tetracame, dyclonme, hexyl- came, procaine, cocaine, ketamme, pramoxme, phenol, and pharmaceutically acceptable salts thereof.

Tanning Actives

The compositions of the present invention may comprise a tanning active. When present, it is preferable that the compositions compπse from about 0.1% to about 20%, more preferably from about 2% to about 7%, and most preferably from about 3% to about 6%, by weight of the composition, of dihydroxyacetone as an artificial tanning active.

Dihydroxyacetone, which is also known as DHA or 1.3-dιhydroxy-2-propanone, is a white to off-white, crystalline powder. This material can be represented by the chemical formula C3H6O3 and the following chemical structure.

O

HOH₂C— C — CH₂OH

The compound can exist as a mixture of monomers and dimers, with the dimers predominating m the solid crystalline state. Upon heating or melting, the dimers break down to yield the monomers. This conversion of the dimeπc form to the monomeπc form also occurs in aqueous solution. Dihydroxyacetone is also known to be more stable at acidic pH values. See The Merck Index. Tenth Edition, entry 3167, p. 463 (1983), and "Dihydroxyacetone for Cosmetics", E. Merck Technical Bulletin, 03-304 110, 319 897, 180 588. Skm Lightening Agents

The compositions of the present invention may compπse a skm lightening agent. When used, the compositions preferably comprise from about 0.1% to about 10%, more preferably from about 0.2%) to about 5%, also preferably from about 0.5%) to about 2%, by weight of the composition, of a skin lightening agent. Suitable skin lightening agents include those known m the art, including kojic acid, arbutm, ascorbic acid and derivatives thereof, e.g., magnesium ascorbyl phosphate or sodium ascorbyl phosphate. Skm lightening agents suitable for use herein also include those described in copendmg patent application Serial No. 08/479,935, filed on June 7, 1995 in the name of Hillebrand, corresponding to PCT Application No. U.S. 95/07432, filed 6/12/95; and copendmg patent application Serial No. 08/390,152, filed on February 24, 1995 in the names of Kalla L Kvalnes, Mitchell A DeLong, Barton J Bradbuiy , Curtis B Motley, and John D Carter, corresponding to PCT Application No U S 95/02809, filed 3/1/95, published 9/8/95

Antimicrobial and Antifungal Actives The compositions of the present invention may compπse an antimicrobial or antifungal active Such actives are capable of destroying microbes, preventing the development of microbes or preventing the pathogenic action of microbes A safe and effective amount of an antimicrobial or antifungal active may be added to the present compositions, preferably, from about 0 001% to about 10%), more preferably from about 0 01% to about 5%. and most preferably from about 0 05% to about 2%

Examples of antimicrobial and antifungal actives include β-lactam drugs, qumolone drugs, ciprofloxacm, norfloxacm, tetracyclme, erythromyc , amikacin, 2,4,4'-tπchloro-2'- hydroxy diphenyl ether, 3,4,4'-tπchlorobamlιde, phenoxyethanol, phenoxy propanol, phenoxyisopropanol, doxycyclme, capreomycm, chlorhexidme, chlortetracycline, oxytetracycline, clindamycm, ethambutol, hexamidine isethionate, metronidazole, pentamidme, gentamicm, kanamycin, lmeomycin, methacychne, methenamme, mmocyclme, neomycin, netilmicm, paromomycm, streptomycin, tobramycm, miconazole, tetracyclme hydrochlonde, erythromycm, zinc erythromycm, erythromycm estolate, erythromycm stearate, amikacin sulfate, doxycyclme hydrochlonde, capreomycm sulfate, chlorhexidme gluconate, chlorhexidme hydrochlonde, chlortetracycline hydrochlonde, oxytetracycline hydrochlonde, clmdamycin hydrochlonde, ethambutol hydrochlonde, metronidazole hydrochlonde, pentamidme hydrochlonde, gentamicm sulfate, kanamycin sulfate, lmeomycm hydrochlonde, methacychne hydrochloπde, methenamme hippurate, methenamme mandelate, mmocyclme hydrochlonde, neomycin sulfate, netilmicm sulfate, paromomycm sulfate, streptomycin sulfate, tobramycm sulfate, miconazole hydrochlonde, amanfadme hydrochlonde, amanfadine sulfate, octopirox, parachlorometa xylenol, nystatm, tolnaftate, zinc pyπthione and clotπmazole

Preferred examples of actives useful herein include those selected from the group consisting of salicylic acid, benzoyl peroxide, 3 -hydroxy benzoic acid, glycohc acid, lactic acid, 4-hydroxy benzoic acid, acetyl salicylic acid, 2-hydroxybutanoιc acid. 2-hydroxypentanoιc acid, 2-hydroxyhexanoιc acid, cis-retinoic acid, trans-retmoic acid, retmol, phytic acid, N-acetyl-L- cysteine, lipoic acid, azelaic acid, arachidomc acid, benzoylperoxide. tetracyclme, ibuprofen, naproxen, hydrocortisone, acetominophen, resorcmol, phenoxyethanol, phenoxypropanol, phenoxyisopropanol, 2,4,4'-tπchloro-2'-hydroxy diphenyl ether, 3,4,4'-tnchlorocarbanιlιde, octopirox, docaine hydrochloπde, clotπmazole, miconazole, neocycin sulfate, and mixtures thereof.

Sunscreen Actives

Exposure to ultraviolet light can result in excessive scaling and texture changes of the stratum corneum. Therefore, the compositions of the subject invention may optionally contain a sunscreen active. As used herein, "sunscreen active" includes both sunscreen agents and physical sunblocks. Suitable sunscreen actives may be organic or inorganic

A wide variety of conventional sunscreen actives are suitable for use herein. Sagarin, et al., at Chapter VIII, pages 189 et seq , of Cosmetics Science and Technology (1972). discloses numerous suitable actives Specific suitable sunscreen actives include, for example: p- am obenzoic acid, its salts and its derivatives (ethyl, isobutyl, glyceryl esters; p- dimethylarmnobenzoic acid); anthramlates (I e., o-ammo-benzoates, methyl, menthyl, phenyl, benzyl, phenylethyl, lmalyl, teφmyl, and cyclohexenyl esters), sahcylates (amyl, phenyl, octyl, benzyl, menthyl, glyceryl, and di-pro-pyleneglycol esters); cmnamic acid derivatives (menthyl and benzyl esters, a-phenyl cmnamonitπle; butyl cinnamoyl pyruvate), dihydroxycmnamic acid derivatives (umbelhferone, methylumbelliferone, methylaceto-umbelliferone); tπhydroxy- cmnamic acid derivatives (esculetm, methylesculetin, daphnetm, and the glucosides, escuhn and daphnm); hydrocarbons (diphenylbutadiene, stilbene); dibenzalacetone and benzalacetophenone; naphtholsulfonates (sodium salts of 2-naphthol-3,6-dιsulfonιc and of 2-naphthol-6,8-dιsulfonιc acids); di-hydroxynaphthoic acid and its salts; o- and p-hydroxybiphenyldisulfonates; coumaπn derivatives (7-hydroxy, 7-methyl, 3-phenyl); diazoles (2-acetyl-3-bromoιndazole, phenyl benzoxazole, methyl naphthoxazole, various aryl benzothiazoles), quinine salts (bisulfate, sulfate, chloride, oleate, and tannate); qumolme derivatives (8-hydroxyquιnohne salts, 2- phenylquinohne); hydroxy- or methoxy-substituted benzophenones, uric and violuπc acids; tannic acid and its derivatives (e.g., hexaethylether); (butyl carbotol) (6-propyl piperonyl) ether; hydroquinone; benzophenones (oxybenzene, suhsobenzone, dioxybenzone, benzoresorcmol, 2,2',4,4'-tetrahydroxybenzophenone, 2,2'-dιhydroxy-4,4'-dιmethoxybenzophenone, octabenzone; 4-ιsopropyldιbenzoylmethane; butylmethoxydibenzoy .methane; etocrylene; octocrylene; [3-(4'- methylbenzyhdene bornan-2-one) and 4-ιsopropyl-dι-benzoylmethane. Of these, 2-ethylhexyl-p-methoxycmnamate (commercially available as PARSOL

MCX), 4,4'-t-butyl methoxydibenzoyl-methane (commercially available as PARSOL 1789), 2- hydroxy-4-methoxybenzophenone, octyldimethyl-p-aminobenzoic acid, digalloyltπoleate, 2,2- dιhydroxy-4-methoxybenzophenone, ethyl-4-(bιs(hydroxy-propyl))amιnobenzoate, 2-ethylhexyl- 2-cyano-3,3-dιphenylacrylate, 2-ethylhexyl-salιcylate, glyceryl-p-ammobenzoate, 3,3,5-tn- methylcyclohexylsahcylate. methylanthranilate, p-dimethyl-aminobenzoic acid or aminobenzoate, 2-ethylhexyl-p-dιmethyl-amιno-benzoate. 2-phenylbenzιmιdazole-5-sulfonιc acid, 2-(p-dιmethylammophenyl)-5-sulfonιcbenzoxazoιc acid, octocrylene and mixtures of these compounds, are preferred. More preferred organic sunscreen actives useful m the compositions useful in the subject invention are 2-ethylhexyl-p-methoxycιnnamate, butylmethoxydibenzoyl-methane, 2-hydroxy-4- methoxybenzo-phenone, 2-phenylbenzιmιdazole-5-sulfonιc acid, octyldimethyl-p-ammobenzoic acid, octocrylene and mixtures thereof

Also particularly useful in the compositions are sunscreen actives such as those disclosed in U.S. Patent No. 4,937,370 issued to Sabatelli on June 26, 1990, and U.S. Patent No. 4,999,186 issued to Sabatelli & Spirnak on March 12, 1991. The sunscreemng agents disclosed therein have, m a single molecule, two distinct chromophore moieties that exhibit different ultra-violet radiation absoφtion spectra One of the chromophore moieties absorbs predominantly m the UVB radiation range and the other absorbs strongly in the UVA radiation range. Preferred members of this class of sunscreemng agents are 4-N,N-(2-ethylhexyl)methyl- ammobenzoic acid ester of 2,4-dιhydroxybenzophenone; N,N-dι-(2-ethylhexyl)-4-amιnobenzoιc acid ester with 4-hydroxydιbenzoylmethane, 4-N,N-(2-ethylhexyl)methyl-ammobenzoιc acid ester with 4-hydroxydιbenzoylmethane; 4-N,N-(2-ethylhexyl)methyl-ammobenzoιc acid ester of 2-hydroxy-4-(2-hydroxyethoxy)benzophenone, 4-N,N-(2-ethylhexyl)-methylamιnobenzoιc acid ester of 4-(2-hydroxyethoxy)dιbenzoylmethane; N,N-dι-(2-ethylhexyl)-4-amιnobenzoιc acid ester of 2-hydroxy-4-(2-hydroxyethoxy)benzophenone; and N,N-dι-(2-ethylhexyl)-4- ammobenzoic acid ester of 4-(2-hydroxyethoxy)dιbenzoylmethane and mixtures thereof

Especially preferred sunscreen actives include 4,4'-butylmethoxydιbenzoylmethane, 2- ethylhexyl-p-methoxycmnamate, phenyl benzimidazole sulfo c acid, and octocrylene. A safe and effective amount of the sunscreen active is used, typically from about 1% to about 20%, more typically from about 2% to about 10% by weight of the composition. Exact amounts will vary depending upon the sunscreen chosen and the desired Sun Protection Factor (SPF).

Conditioning Agents The compositions of the present invention may comprise a conditioning agent selected from the group consisting of humectants, moisturizers, or skm conditioners. A vanety of these matenals can be employed and each can be present at a level of from about 0.01% to about 20%, more preferably from about 0.1%> to about 10%), and most preferably from about 0.5%> to about 7% by weight of the composition. These materials include, but are not limited to, guanidme; glycohc acid and glycolate salts (e.g. ammonium and quaternary alkyl ammonium); salicylic acid; lactic acid and lactate salts (e.g., ammonium and quaternary alkyl ammonium); aloe vera in any of its variety of forms (e.g., aloe vera gel); polyhydroxy alcohols such as sorbitol, glycerol, hexanetπol, butanetπol. propylene glycol. butylene glycol, hexylene glycol and the like; polyethylene glycols; sugars (e.g., mehbiose) and starches; sugar and starch derivatives (e.g., alkoxylated glucose and fucose); hyaluromc acid; lactamide monoethanolamme; acetamide monoethanolam e; and mixtures thereof. Also useful herein are the propoxylated glycerols described m U. S. Patent No. 4,976,953. to Orr et al, issued December 1 1, 1990.

Also useful are various C,-C₃₀ monoesters and polyesters of sugars and related materials. These esters are derived from a sugar or polyol moiety and one or more carboxylic acid moieties. Such ester materials are further described in, U. S. Patent No. 2,831,854, U. S. Patent No. 4,005,196, to Jandacek, issued January 25, 1977; U. S. Patent No. 4,005,195, to Jandacek, issued January 25, 1977, U. S. Patent No. 5,306,516, to Letton et al, issued April 26, 1994; U. S. Patent No. 5,306,515, to Letton et al, issued April 26, 1994; U. S. Patent No. 5,305,514, to Letton et al, issued April 26, 1994; U. S. Patent No. 4,797,300, to Jandacek et al, issued January 10, 1989; U. S. Patent No. 3,963,699, to Rizzi et al, issued June 15, 1976; U. S. Patent No. 4,518,772, to Volpenhem, issued May 21 , 1985; and U. S. Patent No. 4,517,360, to Volpenhem, issued May 21, 1985.

Thickening Agent (including thickeners and gelling agents) The compositions of the present invention can comprise one or more thickening agents, preferably from about 0.1 %> to about 5%, more preferably from about 0.1 %> to about 3%, and most preferably from about 0.25% to about 2%, by weight of the composition.

Nonlimiting classes of thickening agents include those selected from the group consisting of: a) Carboxylic Acid Polymers

These polymers are crosshnked compounds containing one or more monomers derived from acrylic acid, substituted acrylic acids, and salts and esters of these acrylic acids and the substituted acrylic acids, wherein the crosshnkmg agent contains two or more carbon-carbon double bonds and is derived from a polyhydπc alcohol. Polymers useful m the present invention are more fully described in U. S. Patent No. 5,087,445, to Haffey et al, issued February 1 1, 1992; U. S. Patent No. 4,509,949, to Huang et al, issued April 5, 1985; U. S. Patent No. 2,798,053, to Brown, issued July 2, 1957: and in CTFA International Cosmetic Ingredient Dicttonaiy, Fourth Edition, 1991 , pp. 12 and 80. Examples of commercially available carboxylic acid polymers useful herein include the carbomers, which are homopolymers of acrylic acid crosslmked with allyl ethers of sucrose or pentaerytntol. The carbomers are available as the Carbopol® 900 series from B.F. Goodπch

(e.g., Carbopol® 954). In addition, other suitable carboxylic acid polymeric agents include copolymers of C J Q-30 alkyl acrylates with one or more monomers of acrylic acid, methacrylic acid, or one of their short chain (i.e.. C_j.4 alcohol) esters, wherein the crosslmking agent is an allyl ether of sucrose or pentaerytntol. These copolymers are known as acrylates/C,_{0 3}n alkyl acrylate crosspolymers and are commercially available as Carbopol® 1342, Carbopol® 1382, Pemulen TR-1, and Pemulen TR-2, from B.F. Goodπch. In other words, examples of carboxylic acid polymer thickeners useful herein are those selected from the group consisting of carbomers, acrylates/C₁₀-C₃₀ alkyl acrylate crosspolymers, and mixtures thereof. b) Crosslmked Polyacrylate Polymers

The compositions of the present invention can optional comprise crosslmked polyacrylate polymers useful as thickeners or gelling agents including both cationic and nomonic polymers, with the cationics being generally preferred. Examples of useful crosslmked nomonic polyacrylate polymers and crosslmked cationic polyacrylate polymers are those described m U. S. Patent No. 5,100,660, to Hawe et al, issued March 31, 1992, U. S Patent No. 4,849,484, to Heard, issued July 18, 1989; U. S. Patent No. 4,835,206, to Farrar et al, issued May 30, 1989; U.S. Patent No. 4,628,078 to Glover et al issued December 9, 1986; U.S. Patent No. 4,599,379 to Flesher et al issued July 8, 1986; and EP 228,868, to Farrar et al, published July 15, 1987. c) Polyacrylamide Polymers

The compositions of the present invention can optionally comprise polyacrylamide polymers, especially nomonic polyacrylamide polymers including substituted branched or unbranched polymers. Most preferred among these polyacrylamide polymers is the nomonic polymer given the CTFA designation polyacrylamide and isoparaffin and laureth-7, available under the Tradename Sepigel 305 from Seppic Coφoration (Fairfield, NJ).

Other polyacrylamide polymers useful herein include multi-block copolymers of acrylamides and substituted acrylamides with acrylic acids and substituted acrylic acids Commercially available examples of these multi-block copolymers include Hypan SR150H, SS500V, SS500W, SSSA100H, from Lipo Chemicals, Inc., (Patterson, NJ). d) Polysaccharides

A wide variety of polysaccharides are useful herein. "Polysaccharides" refer to gelling agents that contain a backbone of repeating sugar (i.e., carbohydrate) units Nonlimiting examples of polysacchaπde gelling agents include those selected from the group consisting of cellulose, carboxymethyl hydroxyethylcellulose, cellulose acetate propionate carboxylate, hydroxyethylcellulose, hydroxyethyl ethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, methyl hydroxyethylcellulose, microcrystallme cellulose, sodium cellulose sulfate, and mixtures thereof Also useful herein are the alkyl substituted celluloses In these polymers, the hydroxy groups of the cellulose polymer is hydroxyalkylated (preferably hydroxyethylated or hydroxypropylated) to form a hydroxyalkylated cellulose which is then further modified with a C_]0-C₃₀ straight chain or branched chain alkyl group through an ether linkage Typically these polymers are ethers of C_l0-C₃₀ straight or branched chain alcohols with hydroxyalkylcelluloses Examples of alkyl groups useful herein include those selected from the group consisting of stearyl, isostearyl, lauryl, myπstyl, cetyl, isocetyl, cocoyl (1 e alkyl groups derived from the alcohols of coconut oil), palmityl, oleyl, lmoleyl, lmolenyl, πcmoleyl, behenyl, and mixtures thereof Preferred among the alkyl hydroxyalkyl cellulose ethers is the material given the CTFA designation cetyl hydroxyethylcellulose, which is the ether of cetyl alcohol and hydroxyethylcellulose This material is sold under the tradename Natrosol® CS Plus from Aqualon Coφoration (Wilmington, DE)

Other useful polysaccharides include scleroglucans comprising a linear chain of (1-3) linked glucose units with a (1-6) linked glucose every three units, a commercially available example of which is Clearogel™ CS1 1 from Michel Mercier Products Inc (Mountainside, NJ) e) Gums

Other thickening and gelling agents useful herein include materials that are pnmanly derived from natural sources Nonlimiting examples of these gelling agent gums include materials selected from the group consisting of acacia, agar, algm, algimc acid, ammonium algmate, amylopectm, calcium alginate, calcium carrageenan, carnitine, carrageenan, dextnn, gelatin, gellan gum, guar gum, guar hydroxypropyltnmonium chloride, hectorite, hyaluroinic acid, hydrated silica, hydroxypropyl chitosan, hydroxypropyl guar, karaya gum, kelp, locust bean gum, natto gum, potassium algmate, potassium carrageenan, propylene glycol alginate, sclerotium gum, sodium carboyxmethyl dextran, sodium carrageenan, tragacanth gum, xanthan gum, and mixtures thereof Preferred compositions of the present invention include a thickening agent selected from the group consisting of carboxylic acid polymers, crosslmked polyacrylate polymers, polyacrylamide polymers, and mixtures thereof, more preferably selected from the group consisting of carboxylic acid polymers, polyacrylamide polymers, and mixtures thereof While a variety of optional components may be included in the compositions of the presently claimed methods, the compositions are preferably free of retinoids. especially when such compositions are intended for regulating visible and/or tactile discontinuities in mammalian skm texture Furthermore, the compositions are preferably free of procame when such compositions are utilized for prevention and relief of itch. As used herein, "free of means that the compound or component may not be detected m the compositions. Composition Preparation

The compositions of the present invention are generally prepared by conventional methods such as are known m the art of making topical compositions. Such methods typically involve mixing of the ingredients in one or more steps to a relatively uniform state, with or without heating, cooling, application of vacuum, and the like

Methods for Upregulating and/or Modulating the Production of KGF and Related Methods The compositions of the present invention are useful for upregulating the production of keratinocyte growth factor as well as increasing the receptivity of keratmocytes to keratinocyte growth factor. These methods compπse the step of topically applying to the skm of a host a safe and effective amount of a composition comprising: a) a safe and effective amount of a xanthine compound selected from the group consisting of aminophylline, caffeine, theobromine, theophylline, and combinations thereof; and b) a dermatologically acceptable earner for the xanthine compound. The amount of the composition that is applied, the frequency of application and the peπod of use will vary widely depending upon the level of the xanthine compound and/or other components of a given composition and the level of upregulation or increased receptivity of the keratmocytes that is desired.

In a preferred embodiment, the composition is chronically applied to the skm. By "chronic topical application" is meant continued topical application of the composition over an extended period during the subject's lifetime, preferably for a period of at least about one week, more preferably for a period of at least about one month, even more preferably for at least about three months, even more preferably for at least about six months, and more preferably still for at least about one year. While benefits are obtainable after various maximum periods of use (e.g., five, ten or twenty years), it is preferred that chronic application continue throughout the subject's lifetime. Typically applications would be on the order of about once per day over such extended periods, however application rates can vary from about once per week up to about three times per day or more.

A wide range of quantities of the compositions of the present invention can be employed to provide a skm appearance and/or feel benefit. Quantities of the present compositions that are typically applied per application are, in mg

to about 10 mg/cm-. A particularly useful application amount is about 1 mg/cπr to about 2 mg/cm^.

Upregulating and or modulating the production of KGF and increasing the receptivity of the keratmocytes to KGF is preferably practiced by applying a composition in the form of a skm lotion, cream, gel, foam, emulsion, spray, conditioner, tonic, cosmetic, lipstick, foundation, nail polish, after-shave, or the like which is intended to be left on the skin or other keratm structure for some esthetic, prophylactic, therapeutic or other benefit (i.e., a "leave-on" composition). After applying the composition to the skin, it is preferably left on the skin for a period of at least about 15 minutes, more preferably at least about 30 minutes, even more preferably at least about 1 hour, most preferably for at least several hours, e.g., up to about 12 hours Any part of the external portion of the face, hair, and/or nails can be treated, e.g., face, lips, under-eye area, eyelids, scalp, neck, torso, arms, hands, legs, fingernails, toenails. scalp hair, eyelashes, eyebrows, etc. Another approach to ensure a continuous exposure of the skm to at least a minimum level of the composition is to apply the composition by use of a patch applied, e.g., to the face. The patch can be occlusive, semi-occlusive or non-occlusive. The compositions of the present invention can be contained within the patch or be applied to the skm prior to application of the patch. The patch can also include additional actives such as chemical initiators for exothermic reactions such as those described m PCT application WO 9701313 to Burkett et al. The patch is preferably left on the skm for a period of at least about 5 minutes, more preferably at least about 15 minutes, more preferably still at least about 30 minutes, even more preferably at least about 1 hour, most preferably at night as a form of night therapy.

The compositions of the present invention may be presented to a user or potential user (hereinafter "users") of the composition m association with information which informs such users that use of the composition will provide one or more benefits, including, but not limited to, upregulating and/or modulating the production of KGF, increasing the receptivity of the keratmocytes to KGF, and the like. Such information may also include instructions for use to obtain such benefits, e.g., including the method steps described above. By "in association with information" it is meant that the information is either directly printed on the container for the composition itself (including direct printing on the container per se or indirectly via a label or the like affixed to the container), or presented in a different manner including, but not limited to, a brochure, print advertisement, electronic advertisement and/or other advertisement, so as to communicate the information to a consumer of the composition Such information may accordingly comprise words, pictures, and the like.

Examples The following examples further describe and demonstrate embodiments withm the scope of the present invention. The examples are given solely for the puφose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention.

Example 1 A skm cream is prepared by conventional methods from the following components.

Blend the A phase components with a suitable mixer (e.g., Tekmar model RW20DZM), and heat with mixing to melt the components. Separately, blend the B phase components except for theophylline with a suitable mixer and heat while stirring to a temperature of 70-75°C. At temperature add theophylline. Separately, blend the C phase components and heat while stirring to a temperature of 70-75° C. At temperature, add phase C to phase B and mill for 5 minutes (e.g., using a Tekmar T50 Mill). Then add phase D and mix for 5 minutes. Allow to cool to 50°C and then add phase A.

Apply the composition to the facial skm of a subject in need of treatment at the rate of 2 mg

skin once or twice daily for a period of at least 3-6 months.

Example 2 An emulsion is prepared by conventional methods from the following components:

Form Phase A (water phase) in a suitable vessel charged with the water as follows: gradually add the remaining components with stirring and heat to 55°C.

Form Phase B (oil phase) in a separate suitable vessel by adding and stirring together the components of Phase B. Begin heating and stirπng to 50°C.

Add Phase A to Phase B slowly with stirring and mill for 15 minutes.

skin once or twice daily for a period of at least 3-6 months. Example 3 A skm cream is prepared by conventional methods from the following components.

Blend the A phase components with a suitable mixer (e.g , Tekmar model RW20DZM), and heat with mixing to melt the components. Separately, blend the B phase components except for theobromine with a suitable mixer and heat while stirring to a temperature of 70-75°C. At temperature add theobromine. Separately, blend the C phase components and heat while stirring to a temperature of 70-75° C. At temperature, add phase C to phase B and mill for 5 minutes (e.g., using a Tekmar T50 Mill). Then add phase D and mix for 5 minutes. Allow to cool to 50°C and then add phase A.

skm once or twice daily for a period of at least 3-6 months.

While particular embodiments of the subject invention have been described, it will be obvious to those skilled m the art that various changes and modifications to the subject invention can be made without departing from the spirit and scope of the invention. It is intended to cover, in the appended claims, all such modifications that are withm the scope of the subject invention.

Claims

What is claimed is

1 A method of upregulating and or modulating the production of keratinocyte growth factor characterized in that said method compπses the step of topically applying to a keratinous tissue of a host a safe and effective amount of a composition compπsmg a) a safe and effecti e amount of a compound effective for upregulating and'or modulating the production of keratmocyte growth factor, and b) a dermatologically acceptable earner for the compound

2 A method of upregulating and or modulating the production of keratinocyte growth factor characterized in that said method comprises the step of topically applymg to a keratinous tissue of a host a safe and effective amount of a composition compπsmg a) a safe and effectiv e amount of a xanthme compound selected from the group consistmg of aminophyllme, caffeme. theobromine. theophylline. and combmations thereof, and b) a dermatologically acceptable carrier for the xanthme compound

3 A method of mcreasmg the receptivity of keratmocytes to keratmocyte growth factor characterized m that said method comprises the step of topically applymg to a keratinous tissue of a host a safe and effective amount of a composition compnsmg a) a safe and effective amount of a compound effective for increasing the receptivity of keratmocytes to keratmocyte growth factor, and b) a dermatologically acceptable carrier for the compound

A method of mcreasmg the receptivity of keratmocytes to keratinocyte growth factor characterized in that said method comprises the step of topically applymg to a keratinous tissue of a host a safe and effective amount of a composition comprising a) a safe and effective amount of a xanthine compound selected from the group consistmg of aminophylline, caffeme, theobromine. theophylline, and combinations thereof, and b) a dermatologically acceptable carrier for the xanthme compound

The method of any one of the preceding claims wherem the composition comprises from about 0 01% to about 50%. by weight of the composition, of the xanthine compound

The method of anv one of the preceding claims wherein the composition exhibits a pH of from about 4 to about 10

The method of

one of the preceding claims wherein said composition addmonalh compπses a safe and effective amount of a skm care activ e selected from the group consisting of desquamatorv activ es anti-acne actives, vitamin B, compounds, retinoids, anti-oxidants, radical scavengers, chelators, anti- mflammatory agents, topical anesthetics, tanning actives, skm lightening agents, anti-cellulite agents, flavonoids, antimicrobial actives, antifungal actives, sunscreen actives, conditionmg agents, and combinations thereof

The method of any one of the precedmg claims wherein said composition additionally compπses a safe and effective amount of a skm care active selected from the group consisting of desquamatory actives, anti-acne actives, vitamin B- compounds, retinoids, anti-oxidants, radical scavengers, chelators, anti- mflammatory agents, topical anesthetics, tanning actives, skm lightening agents, anti-cellulite agents, flavonoids, antimicrobial actives, antifungal actives, sunscreen actives, conditionmg agents, and combinations thereof