WO2000069409A1 - Methods for upregulating and/or modulating kgf production and increasing receptivity of keratinocytes to kgf - Google Patents

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 forskolin; and b) a dermatologically acceptable carrier for the forskolin. 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.

Description

METHODS FOR UPREGULATING 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 60/134,688, 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 keratirrocytes to KGF The methods involve topical application of a forskolin-containing composition to the keratinous tissue of a host

BACKGROUND OF THE INVENTION Keratinocyte growth factor (KGF) is a protein component that is involved in regulating the biology of epidermal skin cells, namely keratinocytes This growth factor is a member of the fibroblast growth factor family (FGF) and was originally referred to as FGF7 "KGF" includes lsoforms 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 keratinocytes Without being limited by theory, it is believed that the ability of KGF to only impact keratinocytes is driven by the presence of a select receptor protein present in keratinocytes 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 in mammalian organisms are not known Research efforts, however, have found that KGF plays an important role in wound healing, which suggests a critical role in the reepithe alization process Researchers have also speculated that KGF may play a role in regulating the normal epidermal turnover that occurs in human skm A need therefore exists for a manner of upregulating and or modulating the levels of KGF that are present in keratinous tissue like skin, especially in the instances of injuries or slowly generating skin cells Applicant has found that compositions containing forskolin tend to upregulate and/or modulate the production of KGF when topically applied to the keratinous tissue of a host in need of such treatment In addition, Applicant has discovered that such compositions are also suitable for use to increase the receptivity of keratinocytes to KGF thus further aiding in the generation of new skm cells

SUMMARY OF THE INVENTION The present .m ention relates to a method for upregulating and or modulating the production of keratinocyte grow th factor wherein the method comprises the step of topically applying to a keratinous tissue of a host in need of such treatment a safe and effectiv e amount of a composition comprising a) a safe and effectiv e amount of forskolin, and b) a dermatologically acceptable carrier for the forskolin

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

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 nov el characteristics of the claimed compositions or methods

All publications cited herein are hereby incorporated by reference in 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, l e , to provide a reasonable benefit to risk ratio, withm 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 keratinocytes 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 skm cells Increasing the receptivity of keratinocytes 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 Forskolin The topical compositions of the present invention comprise a safe and effective amount of forskolin Forskolin is the extract of Coleus forskohln and is also known as colforsin and [3R (3 alpha ,4a beta ,5 beta ,6 beta 6a alpha 10 alpha ,10a beta ,10b alpha

loxy)-3- ethenyldodecahydro-6, 10,10b-trιhydro\y-3 ,4a,7,7, 1 Oa-pentamethyl- 1 H-naphtho [2 1 -bjpyran- 1 -one

Forskolin is commercially available under the tradenames forskolin from Sigma Chemical Company (St Louis, MO), ICN Biomedicals, Inc (Irvm, CA) and Aldπch Chemical Company (Milwaukee, WI) Fluka Chermka-USA (Ronkonkonma, NY),

In the compositions of the present invention, forskolin 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%, ev en 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 belie ed that forskolin increases 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 forskolin involves an increase in cellular cyclic adenosme monophosphate (cAMP) levels which leads to induction of secondary signaling pathways such as increases in mtracellular calcium and mositol phosphate formation Ultimately, this leads to alterations in gene expression patterns that impact the homeostasis of cells Dermatologicalh Acceptable Carrier

The topical compositions of the present invention also comprise a dermatologically acceptable carrier for the forskolin The phrase "dermatologically acceptable carrier", as used herein, means that the carrier is suitable for topical application to the skm of a host, 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%o to about 95% of the composition

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

Preferred carriers comprise an emulsion such as oil-in-water emulsions or water-in-oil emulsions, e g , si cone-in-water and water-in-silicone As will be understood by the skilled artisan, a given component will distribute primarily mto either the water or oil phase, depending on the water solubility/dispersibility of the component in the composition The forskolin distributes primarily into the water phase Oil-m-water and water-m-silicone emulsions are especially preferred

Emulsions according to the present invention generally contain an aqueous solution as described above and a pid or oil Lipids and oils may be derived from animals, plants, or petroleum and may be natural or synthetic (I 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 carrier Emulsifiers may be noniomc, anionic 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-foaming agents include high molecular weight sihcones and other mateπals well known m the art for such use

Preferred water-in-si cone and oil-m-water emulsions are described m greater detail below a} Water-in-silicone emulsion

Water-m-sihcone emulsions contain a continuous silicone phase and a dispersed aqueous phase d) Continuous silicone phase Preferred water- ln-si cone emulsions of the present invention comprise from about 1 % to about

60%, preferably from about 5%> to about 40%>, more preferably from about 10%o to about 20%, by w eight of a continuous silicone phase The continuous silicone phase exists as an external phase that contams or surrounds the discontinuous aqueous phase described hereinafter

The continuous silicone phase contains a polyorganosiloxane oil A preferred water-m-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 preferablv from about 80%) to about 99 9%o, polyorganosiloxane oil by weight of the continuous silicone phase, and up to about 50%) non-sihcone 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 w eight of the continuous silicone phase These preferred emulsion systems provide more oxidative stability to the retmoid over extended periods of time than comparable water-m-oil emulsions containing low er 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 m the compositions Water-m-sihcone emulsions of this type are described in copending U S Patent Application

Serial No 08/570,275, filed December 11, 1995, in the names of Joseph Michael Zukowski, Brent λ\ llliam

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 in this context refers to those sihcones that are liquid under ambient conditions and have 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 mclude 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]_χSιR₃ wherein R is an alky 1 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 in the same molecule), and x is an integer from 0 to about 10,000 chosen to achieve the desired molecular w eight which can range to o er 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 havmg a viscosity of 10 centistokes and a boiling point greater than 200°C, and Dow Corning® 200 fluids havmg 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]_χ[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 [S1R2-O]-- 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 contams the cyclomethicone tetramer (1 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 (1 e n=5), Dow Corning®

245 fluid having a viscosity of 4 2 centistokes and a boiling point of 205°C, which primarily contains a mixture of the cyclomethicone tetramer and pentamer (1 e n=4 and 5), and Dow Corning® 345 fluid having a viscosity of 4 5 centistokes and a boiling point of 217°, which primarily contams a mixture of the cyclomethicone tetramer, pentamer, and hexamer (1 e n=4, 5, and 6)

Also useful are materials such as trimethylsiloxysilicate, which is a polymeric mateπal corresponding to the general chemical formula [(CH2)3SιO_j 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 trimethylsiloxysilicate 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 R₃SιO[R2SιO]_χSιR₂OH and HOR₂SιO[R₂SιO]_xSιR₂OH 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 av ailable dimethiconols are typically sold as mixtures with dimethicone or cyclomethicone (e g Dow Corning® 1401, 1402. and 1403 fluids)

Polyalkylaryl siloxanes are also suitable for use in the composition Polymethylphenyl siloxanes having viscosities from about 15 to about 65 centistokes at 25°C are especially useful Preferred for use herein are organopoly siloxanes selected from the group consisting of polyalkylsiloxanes, alkyl substituted dimethicones, cyclomethicones, trimethylsiloxysihcates, dimethiconols, polyalkylaryl siloxanes, and mixtures thereof More preferred for use herein are polyalkylsiloxanes and cyclomethicones Preferred among the polyalkylsiloxanes aie dimethicones

As stated above, the continuous silicone phase may contain one or more non-sihcone oils Concentrations of non-sihcone oils in the continuous silicone phase aie preferably minimized or avoided altogether so as to further enhance oxidative stability of the optional retmoid in 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 m topical personal care products in the form of water-in-oil emulsions, e g , mineral oil, vegetable oils, synthetic oils, semisynthetic oils, etc

(π^") 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 suπounded 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 in 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 Nonlimiting 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-in-sihcone emulsions of the present invention preferably comprise an emulsifier In a preferred embodiment, the composition contams 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 contmuous silicone phase A wide variety of emulsifying agents can be employed herein to form the preferred water-in- si cone 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-sihcon-contammg emulsifiers, and mixtures thereof, known by those skilled m 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 havmg 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 m the art as silicone surfactants Useful silicone emulsifiers include dimethicone copolyols These materials are polydimethyl siloxanes which have been modified to include polyether side chams such as polyethylene oxide chains, polypropylene oxide chams, mixtures of these chains, and polyether chams containing moieties derived from both ethylene oxide and propylene oxide Other examples mclude alkyl-modified dimethicone copolyols, l e , compounds which contain C2-C30 pendant side chams Still other useful dimethicone copolyols include materials havmg various catiomc, anionic, amphoteπc, and zwitteπomc pendant moieties

The dimethicone copolyol emulsifiers useful herein can be described by the following general structure

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

-(CH2)_n-0-(CH2CHR³0)_m-H, and

-(CH₂)_n-0-(CH2CHR³0)_m-(CH₂CHR⁴0)₀-H, wherein n is an integer from 3 to about 10, R-> and R⁴ are selected from the group consisting of H and Cl-

C6 straight or branched chain alkyl such that R-⁵ 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 R2 moieties containing the R-⁵ 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 catiomc, anionic, amphoteπc, or zwitteπonic moiety Nonlimiting examples of dimethicone copolyols and other silicone surfactants useful as emulsifiers herein include polydimethylsiloxane polyether copolymers with pendant polyethylene oxide sidechams, polydimethylsiloxane polyether copolymers with pendant polypropylene oxide sidechams, polydimethylsiloxane polyether copolymers with pendant mixed polyethylene oxide and polypropylene oxide sidechams, polydimethylsiloxane polyether copolymers with pendant mixed poly(ethylene)(propylene)oxιde sidechams, polydimethylsiloxane polyether copolymers with pendant organobetame sidechams, polydimethylsiloxane polyether copolymers with pendant carboxylate sidechams, polydimethylsiloxane polyether copolymers with pendant quaternary ammonium sidechams, 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 av ailable 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, diemefhicone copolyol adipate, dimethicone copolyolamme, 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 110, 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-contaimng emulsifiers useful herein are various non-iomc 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 deriv ativ es 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, Cl- 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, in McCutcheon's, Detergents and Emulsifiers. North American Edition (1986), published by Allured Publishing Corporation, U S Patent No 5,011,681 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-sihcon-containmg 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, diethanolamine cetyl phosphate, Polysorbate 60, glyceryl stearate, PEG- 100 stearate, polyoxyethylene 20 sorbitan trioleate (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, diethanolamine cetyl phosphate, glyceryl stearate, PEG- 100 stearate, and mixtures thereof b) Oil-in-Water Emulsions

Other preferred topical carriers include oil-in-water emulsions, having 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-in-water emulsion, containing a structuring agent, hydrophihc surfactant and water, is described in detail hereinafter d) Structuring Agent

A preferred oil-m-water emulsion comprises a structuring agent to assist m 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 which 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 ethylene oxide units, the polyethylene glycol ether of cetyl alcohol having an average of about 1 to about 5 ethylene 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 ethylene oxide units (steareth-2), the polyethylene gly col ether of stearyl alcohol havmg an average of about 21 ethylene oxide units (steareth-21), the polyethylene glycol ether of cetyl alcohol having an average of about 2 ethylene oxide units, and mixtures thereof Even more preferred structuring agents are selected from the group consisting of steaπc acid, palmitic acid, stearyl alcohol, cetyl alcohol, behenyl alcohol, steareth-2, steareth-21, and mixtures thereof (π) Hydrophilic surfactant The preferred oil-in- 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 hydrophilic surfactant which can disperse the hydrophobic materials in the water phase (percentages by w eight of the topical carrier) The surfactant, at a minimum, must be hydrophilic enough to disperse in water

Suitable surfactants include any of a wide variety of known canonic, anionic, zwitteπonic, and amphoteπc surfactants See McCutcheon's. Detergents and Emulsifiers. North American Edition (1986), published by Allured Publishing Corporation, U S Patent No 5,01 1,681 , 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 catiomc surfactants, especially dialkyl quaternary ammonium compounds, examples of which are described m U S Patent Nos 5,151,209, 5,151,210, 5,120,532, 4,387,090, 3,155,591 , 3,929,678, 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 catiomc surfactants useful herein include catiomc ammonium salts such as those having the formula

wherein R_j , 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 R 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 amon, 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 ammo 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 described 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 described previously

Alternatively, other useful catiomc emulsifiers include ammo-amides, wherein in the above structure R1 is alternatively R5CONH-(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 catiomc emulsifiers include stearamidopropyl PG-dimomum chloride phosphate, behenamidopropyl PG dimomum chloride, stearamidopropyl ethyldimomum ethosulfate, stearamidopropyl dimethyl (myπstyl acetate) ammonium chloride, stearamidopropyl dimethyl cetearyl ammonium tosylate, stearamidopropy l dimethyl ammonium chloride, stearamidopropyl dimethyl ammonium lactate. and mixtures thereof Especially preferred is behenamidopropyl PG dimomum chloride Nonlimiting examples of quaternary ammonium salt catiomc surfactants include those selected from the group consisting of cetyl ammonium chloride, cetyl ammonium bromide, lauryl ammonium chloπde, lauryl ammonium bromide, stearyl ammonium chloride, 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 trimethyl ammonium chloride, cetyl trimethyl ammonium bromide, lauryl trimethyl ammonium chloride, lauryl trimethyl ammonium bromide, stearyl trimethyl ammonium chloride, stearyl trimethyl ammonium bromide, lauryl dimethyl ammonium chloride, stearyl dimethyl cetyl ditallow dimethyl ammonium chloride, dicetyl ammonium chloride, dicetyl ammonium bromide, dilauryl ammonium chloπde, dilauryl ammonium bromide, distearyl ammonium chloπde, distearyl ammonium bromide, dicetyl methyl ammonium chloride, dicetyl methyl ammonium bromide, dilauryl methyl ammonium chloride, dilauryl methyl ammonium bromide, distearyl methyl ammonium chloπde, 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 chams in the C_jg to C_j g range The term "coconut" refers to an alkyl group derived from a coconut fatty acid, which generally have mixtures of alkyl chains in the C12 to C14 range Examples of quaternary ammonium salts derived from these tallow and coconut sources mclude 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 chloπde, coconut ammonium chloride, stearamidopropyl PG-dimomum chloride phosphate, stearamidopropyl ethyldimomum ethosulfate, stearamidopropyl dimethyl (myπstyl 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 hav mg an alkyl group with an ester linkage is ditallowyl oxyethyl dimethyl ammonium chloπde More preferred catiomc surfactants are those selected from the group consistmg of behenamidopropyl PG dimomum chloride, dilauryl dimethyl ammonium chloride, distearyl dimethyl ammonium chloride, dimyπstyl dimethyl ammonium chloride, dipalmityl dimethyl ammonium chloπde, distearyl dimethyl ammonium chloride, stearamidopropyl PG-dimomum chloride phosphate, stearamidopropyl ethyldiammomum ethosulfate, stearamidopropyl dimethyl (myπstyl acetate) ammonium chloπde, stearamidopropyl dimethyl cetearyl ammonium tosylate, stearamidopropyl dimethyl ammonium chloride, stearamidopropyl dimethyl ammonium lactate, and mixtures thereof

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

A preferred combination of catiomc surfactant and structuring agent is behenamidopropyl PG dimomum chloπde and/or behenyl alcohol, wherein the ratio is preferably optimized to maintamed 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 zmc oxide and octyl methoxycinnamate

A wide variety of anionic surfactants are also useful herein See, e g , U S Patent No 3,929,678, to Laugh n et al , issued December 30, 1975 Nonlimiting examples of anionic surfactants mclude the alkoyl lsethionates, and the alkyl and alkyl ether sulfates The alkoyl lsethionates typically hav e the formula RCO-OCH CH 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 triethanolamine Nonlimiting examples of these lsethionates include those alkoyl lsethionates selected from the group consisting of ammonium cocoyl lsethionate, sodium cocoyl lsethionate, sodium lauroyl lsethionate, sodium stearoyl lsethionate, 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. -S0₃-M wherem R 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 succinamates. 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 (l 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 in 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 in U S Patent No 4,557,853, cited above Amphoteπc and zwitteπonic surfactants are also useful herein Examples of amphoteπc and zwitteriomc 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 - C_j g) and one contams an anionic water solubihzing group, e g , carboxy, sulfonate, sulfate, phosphate, or phosphonate Examples are alkyl imino acetates, and iminodialkanoa.es and aminoalkanoates of the formulas RNIYCH-,) CO-M], and RNH(CH„) CO„M

2 m 2 2 2 m 2 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 alkanolammonium Also included are lmidazo mum and ammonium derivatives Specific examples of suitable amphoteπc surfactants include sodium 3-dodecyl-ammopropιonate, sodium 3-dodecylammopropane sulfonate, N-alkyltauπnes such as the one prepared by reacting dodecylamine with sodium lsethionate according to the teaching of U S Patent No 2,658,072, 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 in U S Patent No 2,528,378 Other examples of useful amphoteπcs include phosphates, such as coamidopropyl PG-dimonmm chloride phosphate (commercially available as Monaquat PTC, from Mona Corp )

Also useful herein as amphoteπc or zwitteπonic surfactants are the betames Examples of betaines mclude the higher alkyl betames, such as coco dimethyl carboxymethyl betaine, lauryl dimethyl carboxymethyl betaine, lauryl dimethyl alphacarboxyethyl betaine, cetyl dimethyl carboxymethyl betaine, cetyl dimethyl betaine (available as Lonzame 16SP from Lonza Corp ), lauryl bιs-(2-hydroxyethyl) carboxymethyl betame, stearyl bιs-(2-hydroxypropyl) carboxymethyl betaine, oleyl dimethyl gamma-carboxypropyl betaine, lauryl bιs-(2-hydroxypropyl)alpha-carboxyethyl betaine, coco dimethyl sulfopropyl betaine, stearyl dimethyl sulfopropyl betaine, lauryl dimethyl sulfoethyl betame, lauryl bιs-(2-hydroxyethyl) sulfopropyl betaine, and amidobetaines and amidosulfobetames (wherein the RCONH(CH ) radical is attached to the nitrogen atom of the betaine), oleyl betaine (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 zwitteπomc surfactants include the sultames and hydroxysultaines such as cocamidopropyl hydroxysultame (available as Mirataine CBS from Rhone-Poulenc), and the alkanoyl sarcosinates corresponding to the formula RCON(CH,)CH CH CO,M 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 tπalkanolamme (e g triethanolamine), a preferred example of which is sodium lauroyl sarcosinate

(in) Water The preferred oil- -water emulsion comprises from about 25% to about 98%, preferably from about 65%o to about 95%, more preferably from about 70% to about 90% water bv 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 in reference to sihcone-m-water emulsions, and other oils and pids such as described above in reference to emulsions The topical compositions of the subject inv ention, 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 Sagarin, 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%>, of water, and the forskolin m 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%, water, and the forskolin in the abov e described amounts

Ointments of the present invention may comprise a simple carrier base of animal or vegetable oils or semi-sohd hydrocarbons (oleaginous), absorption 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), incorporated herein by reference, and/or an emollient For example, an ointment may comprise from about 2% to about 10% of an emollient, from about 0 1 % to about 2%> of a thickening agent, and the forskolin in the abov e 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 forskolin in the above descπbed 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, noniomc, 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 m McCutcheon's Detergents and Emulsifiers. North American Edition (1986), published by Allured Publishing Corporation The cleansing compositions can optionally contain, at their art-established levels, other materials which are conventionally used cleansing compositions

The physical form of such 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 skm Rmse-off cleansing compositions, such as shampoos, require a deliv ery system adequate to deposit sufficient levels of actives on the skin 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 skin 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 forskolin 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 copending patent application Serial No 08/430,961, filed on April 28, 1995 in the names of Marcia L Canter, Brain D Barford, and Brian D Hofπchter, and U K Patent Application GB 2274585-A, published on Jan 23, 1993 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 skm. the optional components should be suitable for application to skm, that is, when incorporated into the composition they are suitable for use in contact with human skm 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) describes a wide variety of nonlimiting cosmetic and pharmaceutical ingredients commonly used in the skm care industry, which are suitable for use in the compositions of the present inv ention Examples of these ingredient classes include abrasiv es, absorbents, aesthetic components such as fragrances, pigments, colormgs/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-cak g agents, antifoammg agents, antimicrobial agents (e g . lodopropyl butylcarbamate), antioxidants, binders, biological additives, buffering agents, bulking agents, chelatmg agents, chemical additiv es, 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- conditionmg agents (e g , humectants, including miscellaneous and occlusiv e), skin soothing and/or healing agents (e g , panthenol and derivatives (e g , ethyl panthenol), aloe vera. pantothemc acid and its derivatives, allantom, bisabolol, and dipotassmm glycyrrhizmate), skm treating agents, thickeners, and vitamins and derivatives thereof In any embodiment of the present invention, however, the activ es 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 skm (e g , smoothness) One desquamation system that is suitable for use herein comprises sulfhydryl compounds and zwitteriomc surfactants and is described in copending 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 herem comprises salicylic acid and zwitteriomc surfactants and is described in copending patent application Serial No 08/554,944, filed on November 13, 1995 as a continuation of Serial 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 Zwitteriomc 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 in ention 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 in further detail in U S Patent No 5,607,980, issued to McAtee et al , on March 4, 1997 Anti-Wrinkle Activ es/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 activ es suitable for use in the compositions of the present invention include sulfur-contammg D and L ammo acids and their derivatives and salts, particularly the N-acetyl deriv atives, a preferred example of which is N-acetyl- L-cysteine, thiols, e g ethane thiol, hydroxy acids, phytic acid, poic acid, lysophosphatidic acid, skin peel agents (e g , phenol and the like), vitamin B, compounds and retinoids which enhance the skin appearance benefits of the present invention a) Vitamin B, Compounds The compositions of the present inv ention may comprise a safe and effective amount of a vitamin

B3 compound Vitamin B₃ compounds are particularly useful for regulating skin condition as described in co-pending U S Application Serial No Oδ'834,010, filed April 11, 1997 (coπesponding to international publication WO 97/39733 Al, published October 30, 1997) When vitamin B, compounds are present 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 (1 e , macinamide), - COOH (1 e , mcotmic acid) or - CH2OH (1 e , nicotmyl alcohol), derivatives thereof, and salts of any of the foregoing

Exemplary derivatives of the foregoing vitamin B3 compounds include nicotimc acid esters, including non-vasodilating esters of mcotmic acid (e g , tocpheryl mcotinate), nicotmyl ammo acids, nicotmyl alcohol esters of carboxyhc acids, mcotmic acid N-oxide and macinamide 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 (Irvin, CA) and Aldπch Chemical Company (Milwaukee, WI)

Preferably, the vitamin B, compound is macinamide,

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-like compounds which possess the biological activity of Vitamin A in the skin as well as the geometric isomers and stereoisomers of these compounds The retmoid is preferably retinol. retinol esters (e g , C2 - C22 alkyl esters of retinol, including retmyl palmitate, retinyl acetate, retmyl propionate), retinal, and or retinoic acid (including all-trans retinoic acid andor 13-cιs-retmoιc acid), more preferably retinoids other than retmoic acid These compounds are w ell known in the art and are commercially av ailable 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 Parish et al , 4,885,311, 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-retmoate [tocopherol ester of retinoic acid (trans- or as-)], adapalene {6-[3-(l-adamantyl)-4-methoxyphenyl]-2-naphthoιc acid} , and tazarotene (ethyl 6-[2-(4,4- dιmethylthιochroman-6-yl)-ethynyl]nιcotmate) Preferred retinoids are retinol, retinyl palmitate, retinyl acetate, retinyl propπonate, retinal and combinations thereof

The retinoid may be included as the substantially puie material, or as an extract obtained by suitable physical andor chemical isolation from natural (e g , plant) sources The retmoid is preferably substantially pure, more preferably essentially pure

The compositions of this invention may contain a safe and effective amount of the retmoid, such that the resultant composition is safe and effective for upregulating andor modulating the production of KGF or increasing the receptivity of keratinocytes to KGF The compositions preferably contam from or about 0 005% to or about 2%, more preferably 0 01% to or about 2%, retmoid 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 m 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-retmoate, adapalene, and tazarotene are most preferably used in an amount of from or about 0 01% to or about 2%o

Where the compositions of the present invention contam both a retmoid 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 agamst UV radiation which can cause increased scaling or texture changes in the stratum corneum and against other environmental agents which 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-carboxyhc acid (commercially available under the tradename Trolox^-), gallic acid and its alkyl esters, especially propyl gallate, uπc acid and its salts and alkyl esters, sorbic acid and its salts, amines (e g , N,N-dιethylhydroxylamιne, ammo-guamdine), sulfhydryl compounds (e g , glutathione), dihydroxy fumaπc acid and its salts, lycine pidolate, argmine pilolate, nordihydroguaiaretic acid, bioflavonoids, lysme, methiomne, pro ne. superoxide dismutase, silymaπn, 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 in topical compositions and applicable to the present invention is described in U S Patent No 4,847,071 , issued on July 1 1 , 1989 to Donald L Bissett, Rodney D Bush and Ranjit Chatterjee Chelators

The compositions of the present invention may also comprise a safe and effectiv e amount of a chelator or chelat g agent As used herein, "chelator" or "chelatmg 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 chelatmg agent is especially useful for providing protection against UV radiation which can contribute to excessive scalmg or skin texture changes and against other environmental agents which can cause skm damage

A safe and effective amount of a chelatmg agent may be added to the compositions of the subject invention, preferably from about 0 1% to about 10%o, more preferably from about 1% to about 5%, of the composition Exemplary chelators that are useful herein are disclosed in 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 m U S Patent Nos 5,686,082 and 5,686,367 Flavonoids suitable for use m 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, flavones selected from the group consisting of unsubstituted flavones, mono- substituted flavones, di-substituted flavones, and mixtures thereof, one or more isoflavones, coumaπns selected from the group consisting of unsubstituted coumaπns, mono-substituted coumaπns, 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 tπ-hydroxy chalcones (e.g., 2 ',3 ',4 '-trihydroxy chalcone, 4, 2 ',4 '-trihydroxy chalcone, 2, 2 ',4 '-trihydroxy chalcone, etc.), unsubstituted flavone, 7,2'-dιhydroxy flavone, 3',4'-dιhydroxy naphthoflavone, 4'-hydroxy flavone, 5,6-benzoflavone, and 7,8-benzoflavone, unsubsti ted isoflavone, daidzem (7,4'-dιhydroxy isoflavone), 5.7-dιhydroxy-4'-methoxy isoflavone, soy isoflavones (a mixture extracted from soy), unsubstituted coumarm, 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 coumarms, unsubstimted flavanone, methoxy flavanones, unsubstituted chalcone, 2',4-dιhydroxy chalcone, and mixtures thereof. Most preferred are unsubstimted 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 derivatized (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, Wisconsm). Mixtures of the above flavonoid compounds may also be used. The herein described flavonoid compounds are preferably present in 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-Inflammatorv 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%, more preferably from about 0.5% to about 5%, of the composition. The anti-inflammatory agent enhances the skin appearance benefits of the present mvention, e.g., such agents contribute to a more uniform and acceptable skin tone or color The exact amount of anti-inflammatory agent to be used in the compositions will depend on the particular anti- inflammatory agent utilized since such agents vary widely in potency Steroidal anti-inflammatory agents, including but not limited to, corticosteroids such as hydrocortisone, hydroxyltπamcinolone, alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethasone dipropionates, clobetasol valerate, desomde, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichloπsone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetomde, fludrocortisone, flumethasone pivalate, fluosmolone acetonide, fluocmomde, flucortine butylesters, fluocortolone, fluprednidene (flupredny dene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylpredmsolone, tπamcmolone acetonide, cortisone, cortodoxone, flucetomde, fludrocortisone, difluorosone diacetate, fluradrenolone, fludrocortisone, diflurosone diacetate, fluradrenolone acetonide, medrysone, amcinafel, amcmafide, betamethasone and the balance of its esters, chloropredmsone, chlorprednisone acetate, clocortelone, clesc olone, dichloπsone, diflurprednate, flucloromde, flunisohde, fluoromethalone, fluperolone. fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate, mepredmsone, paramethasone, prednisolone, predmsone, beclomethasone dipropionate, tπamcinolone, and mixtures thereof may be used The preferred steroidal anti-inflammatory for use is hydrocortisone

A second class of anti-inflammatory agents which is useful in the compositions includes the nonsteroidal anti-inflammatory 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-inflammatory Agents, Chemistry and Pharmacology. 1, R. A. Scherrer, et al , Academic Press, New York (1974).

Specific non-steroidal anti-mflammatory 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 sa cylates, such as aspirin, disalcid, benorylate, tπlisate, safapryn, solpπn, diflumsal, and fendosal;

3) the acetic acid derivatives, such as diclofenac, fenclofenac, mdomethacm, su ndac, tolmetin, isoxepac, furofenac, tiopmac, zidometacin. acematacm, fentiazac, zomepirac, clmdanac, oxepmac, felbinac, and ketorolac,

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

5) the propiomc acid derivatives, such as ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indopropfen, pirprofen, carprofen, 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, aspirin, mefenamic acid, meclofenamic acid, piroxicam and felbinac 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 mvention Such agents may suitably be obtamed as an extract by suitable physical andor chemical isolation from natural sources (e g , plants, fungi, by-products of microorganisms) For example, candehlla wax, alpha bisabolol, aloe v era, Manjistha (extracted from plants in the genus Rubia. particularly Rubia Cordifoha). and Guggal (extracted from plants in the genus Commrphora. particularly Commiphora Mukul), kola extract, chamomile. and sea whip extract, may be used

Additional anti-inflammatory agents useful herein include compounds of the Licorice (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 samrated or unsaturated esteis of the acids, preferably CJQ - C24, more preferably C_j g - C24 Specific examples of the foregoing include oil soluble licorice extract, the glycyrrhizic and glycyrrhetic acids themselves, monoammomum glycyrrhizmate, monopotassium glycyrrhizmate, drpotassium glycyrrhizmate, 1-beta-glycyrrhetιc acid, stearyl glycyrrhetinate, and 3- stearyloxy-glycyrrhetimc acid, and disodium 3-succιnyloxy-beta-glycyrτhetιnate Stearyl glycyrrhetinate is preferred

Topical Anesthetics

The compositions of the present invention may also comprise a safe and effective amount of a topical anesthetic Examples of topical anesthetic drugs include benzocaine, docaine, bupivacame, chlorprocaine, dibucaine, etidocame, mepivacaine, tetracame, dyclonme, hexylcame, procame, cocame, ketamine, pramoxine, 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 comprise 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 l,3-dιhydroxy-2-propanone, is a white to off- white, crystalline powder This material can be represented by the chemical formula C3H5O3 and the following chemical structure

O

HOH₂C— C — CH₂OH The compound can exist as a mixture of monomers and dimers, with the dimers predominating in 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 m 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 comprise 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 skm lightening agents include those known in the art, including kojic acid, arbutin, 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 copending patent application Serial No 08/479,935, filed on June 7, 1995 the name of Hillebrand, corresponding to PCT Application No U S 95/07432, filed 6/12/95, and copending patent application Serial No 08/390 152, filed on February 24, 1995 in the names of Kalla L Kvalnes, Mitchell A DeLong, Barton J Bradbury, 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 inv ention may comprise 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%o, more preferably from about 0 01%) to about 5%, and most preferably from about 0 05%o to about 2% Examples of antimicrobial and antifungal actives include β-lactam drugs, quinolone drugs, ciprofloxacin, norfloxacin, tetracycline, erythromycin, amikacin, 2,4,4'-tπchloro-2'-hydroxy diphenyl ether, 3,4,4'-tπchlorobanιlιde, phenoxyethanol, phenoxy propanol, phenoxyisopropanol, doxycyclme, capreomycin, chlorhexidine, chlortetracycline, oxytetracyc ne, clindamycin, ethambutol, hexamidine lsethionate, metromdazole, pentamidine, gentamicin, kanamycm, Imeomycm, methacyclme. methenamme, minocyclme, neomycm, netilmicm, paromomycin, streptomycin, tobramycm, miconazole, tetracycline hydrochloride, erythromycin, zinc erythromycin, erythromycin estolate, erythromycin stearate, amikacin sulfate, doxycyclme hydrochloride, capreomycin sulfate, chlorhexidine gluconate, chlorhexidine hydrochloride, chlortetracycline hydrochloride, oxytetracychne hydrochloride, clindamycin hydrochloride, ethambutol hydrochloride, metromdazole hydrochloride, pentamidme hydrochloride, gentamicin sulfate, kanamycm sulfate, Imeomycm hydrochloride, methacyclme hydrochloride, methenamme hippurate, methenamme mandelate, minocyclme hydrochloride, neomycin sulfate, netilmicm sulfate, paromomycin sulfate, streptomycin sulfate, tobramycm sulfate, miconazole hydrochloride, amanfadine hydrochloride, amanfadine sulfate, octopirox, parachlorometa xylenol, nystatin, tolnaftate, zmc 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- retmoic acid, trans-retinoic acid, retinol, phytic acid, N-acetyl-L-cysteme, lipoic acid, azelaic acid, arachidomc acid, benzoylperoxide, tetracycline, ibuprofen, naproxen, hydrocortisone, acetommophen resorcmol, phenoxyethanol, phenoxypropanol, phenoxyisopropanol, 2,4,4'-tπchloro-2'-hydroxy diphenyl ether, 3,4,4'-tπchlorocarbamlιde, octopirox, hdocame hydrochloride, clorrimazole, miconazole, neocycm 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 activ es 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-aminobenzoic acid, its salts and its derivatives (ethyl, isobutyl, glyceryl esters, p-dimethylammobenzoic acid), anmranilates (l e , o-ammo- benzoates, methyl, menthyl, phenyl, benzyl, phenylethyl, linalyl, terpmv l. and cyclohexenyl esters), sahcylates (amyl, phenyl, octyl, benzyl, menthyl, glyceryl, and di-pro-pyleneglycol esters), cinnamic acid derivatives (menthyl and benzyl esters, a-phenyl cinnamonitπle, butyl cinnamoyl pyruvate), dihydroxycinnamic acid derivatives (umbelhferone, mefhylumbelliferone, methylaceto-umbelliferone), trihydroxy-cinnamic acid derivatives (esculetm, methylesculetm, daphnetin, and the glucosides, esculm and daphnin), hydrocarbons (dφhenylbutadiene, stilbene), dibenzalacetone and benzalacetophenone, naphtholsulfonates (sodium salts of 2-naphthol-3,6-dιsulfonιc and of 2-naphthol-6,8-dιsulfomc acids), di- hydroxynaphthoic acid and its salts, o- and p-hydroxybiphenyldisulfonates, coumarm 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), quinoline derivatives (8-hydroxyqumolme salts, 2-phenylquιnolιne), hydroxy- or methoxy-substituted benzophenones, uric and violuπc acids, tannic acid and its derivatives (e g , hexaethylether), (butyl carbotol) (6-propyl piperonyl) ether, hydroqumone, benzophenones (oxybenzene, suhsobenzone, dioxybenzone, benzoresorcmol, 2,2',4,4'-tetrahydroxybenzophenone, 2,2'-dιhydroxy-4,4'- dimethoxybenzophenone, octabenzone), 4-ιsopropyldιbenzoylmethane, butylmethoxydibenzoylmethane, etocrylene, octocrylene, [3-(4'-methylbenzyhdene bornan-2-one) and 4-ιsopropyl-dι-benzoylmethane Of these, 2-ethylhexyl-p-methoxycιnnamate (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- diphenylacrylate, 2-ethylhexyl-sahcylate, glyceryl-p-aminobenzoate, 3,3,5-tπ-methylcyclohexylsahcylate, methylanthramlate, p-dimethyl-ammobenzoic acid or aminobenzoate, 2-ethylhexyl-p-dιmethyl-amιno- benzoate, 2-phenylbenzιmιdazole-5-sulfomc acid, 2-(ρ-dιmethylammophenyl)-5-sulfonιcbenzoxazoιc acid, octocrylene and mixtures of these compounds, are preferred More preferred organic sunscreen actives useful m the compositions useful m the subject invention are 2-ethylhexyl-p-methoxycιnnamate butylmethoxydibenzoyl-methane, 2-hydroxy-4-methoxybenzo- phenone, 2-phenylbenzιmιdazole-5-sulfomc acid octyldimethyl-p-ammobenzoic acid, octocrylene and mixtures thereof Also particularly useful m 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 Sabatel & Spirnak on March 12, 1991 The sunscreenmg agents disclosed therein have, in a smgle molecule, two distinct chiomophore moieties which exhibit different ultra-violet radiation absorption spectra One of the chromophore moieties absorbs predominantly in the UVB radiation range and the other absorbs strongly in the UVA radiation range

Preferred members of this class of sunscreenmg agents are 4-N,N-(2-ethylhexyl)mefhyl- aminobenzoic acid ester of 2,4-dιhydroxybenzophenone, N,N-dι-(2-ethylhexyl)-4-amιnobenzoιc acid ester with 4-hydroxydιbenzoylrnethane, 4-N,N-(2-ethylhexyl)methyl-ammobenzoιc acid ester with 4- hydroxydibenzoylmethane, 4-N,N-(2-ethylhexyl)methyl-amιnobenzoιc acid ester of 2-hydroxy-4-(2- hydroxyethoxy)benzophenone, 4-N,N-(2-ethylhexyl)-methylamιnobenzoιc acid ester of 4-(2- hydroxyethoxy)dιbenzoylmethane, N,N-di-(2-ethylhexy.)-4-aminobenzoic acid ester of 2-hydroxy-4-(2- hydroxyethoxy)benzophenone, and N,N-dι-(2-efhylhexyl)-4-amιnobenzoιc acid ester of 4-(2- hydroxyethoxy)dιbenzoylmethane and mixtures thereof

Especially preferred sunscreen actives include 4,4'-butylmethoxydιbenzoylmethane, 2-ethylhexyl- p-methoxycinnamate, phenyl benzimidazole sulfomc 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 variety of these materials 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%o, and most preferably from about 0 5%> to about 7% by weight of the composition

These materials include, but are not limited to, urea, guamdine, 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 , melibiose) and starches, sugar and starch derivatives

(e g , alkoxylated glucose and fucose), hyaluromc acid, lactamide monoethanolamine, acetarmde monoethanolamine, and mixtures thereof Also useful herein are the propoxylated glycerols described in

U S Patent No 4,976,953, to Orr et al, issued December 11, 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 carboxyhc 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 l%o to about 5%>, more preferably from about 0 1% to about 3%o, 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) Carboxyhc Acid Polymers

These polymers are crosslinked compounds containing one or more monomers derived from acrylic acid, substituted acrylic acids, and salts and esters of these acrylic acids and the substimted acrylic acids, wherein the crosslinking agent contams two or more carbon-carbon double bonds and is derived from a polyhydπc alcohol Polymers useful in the present invention are more fully descπbed in U S Patent No 5,087,445, to Haffey et al, issued February 11, 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 m C77vf International Cosmetic Ingredient Dictionary, Fourth Edition, 1991, pp 12 and 80

Examples of commercially available carboxyhc acid polymers useful herein include the carbomers, which are homopolymers of acrylic acid crosslinked with allyl ethers of sucrose or pentaerytπtol The carbomers are available as the Carbopol® 900 series from B F Goodrich (e g ,

Carbopol® 954) In addition, other suitable carboxyhc acid polymeric agents include copolymers of Cjg- 30 alkyl acrylates with one or more monomers of acrylic acid, methacrylic acid, or one of their short cham

(i.e , C_j_4 alcohol) esters, wherein the crosslinking agent is an allyl ether of sucrose or pentaerytπtol

These copolymers are known as acrylates/C,_{0 30} alkyl acrylate crosspolymers and are commercially available as Carbopol® 1342, Carbopol® 1382, Pemulen TR-1, and Pemulen TR-2, from B F Goodrich In other words, examples of carboxyhc acid polymer thickeners useful herein are those selected from the group consistmg of carbomers, acrylates/C_]0-C₃₀ alkyl acrylate crosspolymers, and mixtures thereof b) Crosslinked Polvacrylate Polymers

The compositions of the present invention can optionally comprise crosslinked polyacrylate polymers useful as thickeners or gelling agents including both catiomc and noniomc polymers, with the cationics being generally preferred Examples of useful crosslinked noniomc polyacrylate polymers and crosslinked catiomc 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 noniomc polyacrylamide polymers including substimted branched or unbranched polymers Most preferred among these polyacrylamide polymers is the noniomc polymer given the CTFA designation polyacrylamide and isoparaffin and laureth-7, available under the Tradename Sepigel 305 from Seppic Corporation (Fairfield, NJ) Other polyacrylamide polymers useful herein include multi-block copolymers of acrylamides and substimted acrylamides with acrylic acids and substimted acrylic acids Commercially available examples of these multi-block copolymers include Hypan SR150H, SS500V, SS500W, SSSA100H, from Lipo Chemicals, Inc , (Patterson, NJ) d) Polvsacchaπdes A wide variety of polysacchaπdes are useful herein "Polysacchaπdes" refer to gelling agents which contain a backbone of repeating sugar (I e , carbohydrate) units Nonlimiting examples of polysacchaπde gelling agents mclude those selected from the group consisting of cellulose, carboxymethyl hydroxyethylcellulose, cellulose acetate propionate carboxylate, hydroxyethylcellulose, hydroxyethyl ethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, methyl hydroxyethylcellulose, microcrystalline 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 cham or branched chain alkyl group through an ether linkage Typically these polymers are ethers of C,₀-C₃₀ straight or branched chain alcohols with hydroxyalkylcelluloses Examples of alkyl groups useful herein include those selected from the group consistmg of stearyl, isostearyl, lauryl, myπstyl, cetyl, isocetyl, cocoyl (l e , alkyl groups derived from the alcohols of coconut oil), palmityl, oleyl, noleyl, nolenyl, πcinoleyl, 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 Corporation (Wilmington, DE)

Other useful polysacchaπdes 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™ CS11 from Michel Mercier Products Inc (Mountainside, NJ) e) Gums Other thickenmg and gelling agents useful herein include materials which are primarily derived from natural sources Nonlimiting examples of these gelling agent gums include materials selected from the group consisting of acacia, agar, algm, alginic acid, ammonium alginate, amylopectin, calcium algmate, calcium carrageenan, carnitme, carrageenan, dextrin, gelatm, gellan gum, guar gum. guar hydroxypropyltπmomum chloride, hectoπte, hyaluroimc acid, hydrated silica, hydroxypropyl chitosan, hydroxypropyl guar, karaya gum, kelp, locust bean gum, natto gum, potassium algmate, potassium carrageenan, propylene glycol algmate, 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 consistmg of carboxyhc acid polymers, crosslinked polyacrylate polymers, polyacrylamide polymers, and mixtures thereof, more preferably selected from the group consisting of carboxyhc acid polymers, polyacrylamide polymers, and mixtures thereof Composition Preparation

The compositions of the present invention are generally prepared by conventional methods such as are known in the art of making topical compositions Such methods typically involve mixmg 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 keratinocytes to keratinocyte growth factor These methods comprise the step of topically applying to the skin of a host a safe and effective amount of a composition comprising a) a safe and effective amount of forskolin, and b) a dermatologically-acceptable carrier for the forskolin The amount of the composition which is applied, the frequency of application and the period of use will vary widely depending upon the level of the forskolin and/or other components of a given composition and the level of upregulation or increased receptivity of the keratinocytes which 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 skin appearance andor feel benefit Quantities of the present compositions which are typically applied per application are, in mg

A particularly useful application amount is about 1 mg/cπr to about 2 mg/cm^ Upregulating andor modulating the production of KGF and increasmg the receptivity of the keratinocytes 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 skm or other keratm structure for some esthetic, prophylactic, therapeutic or other benefit (1 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, andor 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-occlusiv e 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, mcludmg, but not limited to, upregulating andor modulatmg the production of KGF, increasmg the receptivity of the keratinocytes to KGF, and the like Such information may also include instructions for use to obtain such benefits, e g , mcludmg 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 pnntmg on the container per se or indirectly via a label or the like affixed to the container), or presented in a different manner mcludmg, 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 accordmgly comprise words, pictures, and the like.

Examples

The following examples further describe and demonstrate embodiments withm the scope of the subject invention The examples are given solely for the purpose of illustration and are not to be construed as limitations of the subject invention, as many variations thereof are possible without departmg from the spiπt and scope of the invention

Example 1

A skin 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 the forskolm with a suitable mixer and heat while stirring to a temperamre of 70-75°C. At temperamre add the forskolm Separately, blend the C phase components and heat while stirring to a temperamre 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 mmutes 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 w ater as follows gradually add the remammg components with stirring and heat to 55°C

Form Phase B (oil phase) m a separate suitable vessel by adding and stirring together the components of Phase B Begm heating and strrπng to 50°C Add Phase A to Phase B slowly with stirπng and mill for 15 minutes

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

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

Claims

What is claimed is

1 A method of upregulating and or modulatmg the production of keratinocyte growth factor characterized m 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 effectiv e amount of forskolin, and b) a dermatologically-acceptable carrier for the forskolm

2 A method of increasing the receptiv lty of keratinocytes to keratinocyte 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 compπsmg a) a safe and effective amount of forskolm, and b) a dermatologically-acceptable carrier for the forskolm

3 The method of Claim 1 or 2 wherein said composition additionally compnses a safe and effective amount of a skm care active selected from the group consisting of desquamatory actives, anti-acne actives, v itamin B, compounds, retinoids, anti-oxidants, radical scavengers, chelators. anti- mflammatory agents, topical anesthetics, tanning actives, skm lightening agents, anti-cellu te agents, flavonoids, antimicrobial actives, antifungal actives, sunscreen actives, conditioning agents, structuring agents, thickening agents, and combinations thereof

The method of any one of the precedmg claims wherein the composition comprises from about 0 01% to about 50%, by weight of the composition, of the forskolm

The method of any one of the precedmg claims wherein the composition compπses from about 0 1% to about 20%, by weight of the composition, of the forskolin

The method of any one of the preceding claims w herein the composition comprises from about 1% to about 10%, by w eight of the composition, of the forskolin

The method of any one of the preceding claims wherein the composition comprises from about 2% to about 8%, by weight of the composition, of the forskolm

The method of any one of the preceding claims wherein the composition comprises from about 4% to about 6%. bv weight of the composition of the forskolm