WO2000072818A1

WO2000072818A1 - Topical compositions providing improved treatment of skin or scalp fungal infections

Info

Publication number: WO2000072818A1
Application number: PCT/US2000/013847
Authority: WO
Inventors: Thean Yeow Yeoh
Original assignee: Procter and Gamble Co
Current assignee: Procter and Gamble Co
Priority date: 1999-05-27
Filing date: 2000-05-19
Publication date: 2000-12-07
Anticipated expiration: 2001-11-27
Also published as: AU5146600A

Abstract

Disclosed are topical compositions for the treatment of fungal infections on the skin or scalp which comprise an active component consisting of itraconazole and methods for treating fungal infections using these compositions.

Description

TOPICAL COMPOSITIONS PROVIDING IMPROVED TREATMENT OF SKIN OR SCALP FUNGAL INFECTIONS

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit under 35 USC 119(e) of the U.S. provisional application of Thean Y Yeoh having Seπal No. 60/136,271, filed May 27, 1999. FIELD OF THE INVENTION

The present invention relates to methods of treating fungal infections on the skm or scalp and compositions for treating such infections Of specific concern are methods for the treatment of dandruff and compositions which provide improved anti-dandruff activity In particular, the present invention relates to methods and compositions utilizing ltraconazole as the active anti- fungal ingredient.

BACKGROUND OF THE INVENTION Vaπous anti-dandruff compositions are commercially available or otherwise known in the shampoo art These compositions typically compπse particulate, crystalline antimicrobial agents dispersed and suspended throughout the composition. Antimicrobial agents used for this purpose include sulfur, selenium sulfide and heavy metal salts of pyridmethione. Duπng the shampooing process, these antimicrobial agents deposit on the scalp to provide anti-dandruff activity.

Many anti-dandruff shampoos, however, do not provide sufficient antimicrobial agent deposition duπng the shampooing process. Without such deposition, the antimicrobial agents simply πnse away duπng shampoomg and therefore provide little or no anti-dandruff activity. In addition, the detersive surfactants in these shampoo compositions which are designed to remove oil, grease, dirt, and particulate matter will also carry away particulate antimicrobial agents duπng πnsmg, thus further decreasing deposition and anti-dandruff activity. ltraconazole is known m the art as an anti-fungal treatment which is generally orally administered. U.S. Patent 4,267,179, issued to Heeres et al. on May 12, 1981 (herein incorporated by reference) disclosed the broad class of heterocychc deπvatives of (4- phenylpιperazιn-l-yl-aryloxymethyl-1 ,3-dιoxolan-2-yl)methyl-lH-l ,2,4-tπazoles as orally administered anti-fungal agents and the synthesis procedures for these compounds. ltraconazole is a member of this class and is known as an anti-fungal medication. Please see Borgers, M., Xhonneux, B. and Van Cutsem, J., Oral ltraconazole versus Topical Bifonazole Treatment in Expeπmental Dermatophytosis, Mycoses Vol 36, pp 105-115, 1993. The use of anti-fungal agents in anti-dandruff shampoos is also known in the art. See PCT Applications WO 96/29045, WO 97/29733, WO 98/46201, and WO 98/46207. However, while ltraconazole is recognized as an anti-fungal agent, it has never been a preferred anti- dandruff active. Ketoconazole, elubiol and climbazole are the preferred anti-fungal agents used in the art. Also, the art teaches the requirement that anti-fungal agents must be used m combination with other active ingredients to achieve desired effectiveness. WO 96/29045 combines anti-fungal agents with a cytotoxic agent such as coal tar, selenium sulfide or zinc pyπthione. WO 97/29733, WO 98/46201 and WO 98/46207 combine the anti-fungal agents with a pyπthione salt, a amphoteπc phosphohpid active, and a cationic active respectfully. It has now been found that anti-fungal activity can be dramatically increased in topical compositions by the use of only ltraconazole as the anti-fungal agent. It is therefore an object of the present invention to provide an anti-fungal topical composition with improved activity. The improved activity also allows for the reduction of the levels of anti-fungal agents in anti-fungal compositions.

SUMMARY OF THE INVENTION

The present invention is directed to topical compositions for the treatment of fungal infections on the skin or scalp which compπse an active component consisting of ltraconazole and methods for treating fungal infections using these compositions.

DETAILED DESCRIPTION OF THE INVENTION

The topical anti-dandruff compositions of the present invention can compπse, consist of, or consist essentially of the essential elements and limitations of the invention descπbed herein, as well any of the additional or optional ingredients, components, or limitations descπbed herein. All percentages, parts and ratios are based upon the total weight of the shampoo compositions of the present invention, unless otherwise specified. All such weights as they pertain to listed ingredients are based on the active level and, therefore, do not include earners or by-products that may be included in commercially available mateπals. ltraconazole The topical anti-dandruff compositions of the present invention compπse an active component consisting of ltraconazole. ltraconazole is the compound 3H-l,2,4-Tπazole-3-one,4- [4-[4-[4-[[2-(2,4-dιchlorophenyl)-2-(lH-l ,2,4-tπazole-l -ylmethyl)-l ,3-dιoxolan-4- yl]methoxy]phenyl]-l-pιperazmyl]phenyl]-2,4-dιhydro-2-(l-methylpropyl) which has the formula:

The topical anti-fungal compositions comprise itraconazole at a level ranging from about 0.01% to about 5.0%, preferably from about 0.1% to about 3.0%, and more preferably from about 0.2% to about 2.0%. Itraconazole has been found to be superior to other anti-fungal agents. Optional Components Detersive Surfactant

The topical anti-fungal compositions of the present invention may optionally comprise a detersive surfactant selected from the group consisting of anionic surfactants, amphoteric surfactants, zwitterionic surfactants, and combinations thereof. A detersive surfactant provides an anti-fungal shampoo composition with cleaning performance. Anionic surfactant

When the topical composition is a shampoo, the detersive surfactant preferably comprises an anionic surfactant. The detersive surfactant component of the shampoo compositions is preferably an anionic surfactant. Concentrations of anionic surfactant can range from about 7% to about 30%, preferably from about 10% to about 25%, more preferably from about 12% to about 22%, by weight of the shampoo compositions.

Anionic surfactants for use in the shampoo compositions include alkyl and alkyl ether sulfates. These materials have the respective formulae ROS0₃M and RO(C₂H₄0)_xS0₃M, wherein R is alkyl or alkenyl of from about 8 to about 30 carbon atoms, x is an integer from 1 to

10, and M is a hydrogen, alkali metal (e.g., lithium, sodium, potassium), alkali earth metal (e.g., beryllium, magnesium, calcium, strontium, barium) ammonium or substituted ammonium.

Preferably, R has from about 10 to about 18 carbon atoms in both the alkyl and alkyl ether sulfates. The alkyl ether sulfates are typically made as condensation products of ethylene oxide and monohydric alcohols having from about 8 to about 24 carbon atoms. The alcohols can be derived from fats, e.g., coconut oil or tallow, or can be synthetic. Lauryl alcohol and straight chain alcohols derived from coconut oil are preferred. Such alcohols are reacted with between about 0 and about 10, and especially about 3, molar proportions of ethylene oxide and the resulting mixture of molecular species having, for example, an average of 3 moles of ethylene oxide per mole of alcohol, is sulfated and neutralized. Specific examples of alkyl ether sulfates which may be used in the shampoo compositions of the present invention are sodium and ammonium salts of coconut alkyl tπethylene glycol ether sulfate, tallow alkyl tπethylene glycol ether sulfate, and tallow alkyl hexaoxyethylene sulfate Highly preferred alkyl ether sulfates are those compnsmg a combination of individual compounds, the combination having an average alkyl chain length of from about 10 to about 16 carbon atoms and an average degree of ethoxylation of from about 1 to about 4 moles of ethylene oxide.

Other suitable anionic surfactants are the water-soluble salts of organic, sulfuπc acid reaction products of the general formula [ R*-S0₃-M ] where R- is selected from the group consisting of a straight or branched chain, saturated aliphatic hydrocarbon radicals having from about 8 to about 24, preferably about 10 to about 18, carbon atoms; and M hydrogen, alkali metal (e.g., lithium, sodium, potassium), alkali earth metal (e g., beryllium, magnesium, calcium, strontium, baπum) ammonium or substituted ammonium Examples of such surfactants are the salts of an organic sulfuπc acid reaction product of a hydrocarbon of the methane senes, including iso-, neo-, and n-paraffms, having about 8 to about 24 carbon atoms, preferably about 12 to about 18 carbon atoms and a sulfonatmg agent, e.g., S0₃, H₂S0 , obtained according to known sulfonation methods, including bleaching and hydrolysis Preferred are alkali metal and ammonium sulfonated Cio is n-paraffms.

Still other suitable anionic surfactants are the reaction products of fatty acids esteπfied with isethionic acid and neutralized with sodium hydroxide where, for example, the fatty acids are deπved from coconut oil; sodium or potassium salts of fatty acid amides of methyl tauπde in which the fatty acids, for example, are deπved from coconut oil Other similar anionic surfactants are descπbed m U.S. Patent 2.486,921, U S Patent 2,486,922; and U.S. Patent 2,396,278, which descπptions are incorporated herein by reference. Other anionic surfactants suitable for use m anti-fungal shampoo compositions are the succinnates, examples of which include disodium N-octadecylsulfosuccmnate; disodium lauryl sulfosuccmate; diammonium lauryl sulfosuccmate; tetrasodium N-(l,2-dιcarboxyethyl)-N- octadecylsulfosuccinnate; diamyl ester of sodium sulfosuccmic acid; dihexyl ester of sodium sulfosuccmic acid; and dioctyl esters of sodium sulfosuccmic acid Other suitable anionic surfactants include olefin sulfonates having about 10 to about 24 carbon atoms. The term "olefin sulfonates" is used herein to mean compounds which can be produced by the sulfonation of alpha-olefins by means of uncomplexed sulfur tπoxide, followed by neutralization of the acid reaction mixture in conditions such that any sulfones which have been formed in the reaction are hydrolyzed to give the corresponding hydroxy-alkanesulfonates. The sulfur tπoxide can be liquid or gaseous, and is usually, but not necessaπly, diluted by inert diluents, for example by liquid S0₂, chlorinated hydrocarbons, etc , when used m the liquid form, or by air, nitrogen, gaseous S0₂, etc., when used in the gaseous form

The alpha-olefins from which the olefin sulfonates are deπved from mono-olefms having from about 12 to about 24 carbon atoms, preferably from about 14 to about 16 carbon atoms Straight chain olefms are preferred.

In addition to the true alkene sulfonates and a proportion of hydroxy-alkanesulfonates, the olefin sulfonates can contain minor amounts of other mateπals, such as alkene disulfonates depending upon the reaction conditions, proportion of reactants, the nature of the starting olefms and impurities in the olefin stock and side reactions during the sulfonation process. A specific alpha-olefm sulfonate mixture of the above type is descπbed more fully in the

U.S. Patent 3,332,880, which descπption is incorporated herein by reference.

Another class of anionic surfactants suitable for use in the shampoo compositions are the beta-alkyloxy alkane sulfonates. These compounds can be represented by the formula:

where R¹ is a straight chain alkyl group having from about 6 to about 20 carbon atoms, R² is a lower alkyl group having from about 1 (prefeπed) to about 3 carbon atoms, and M hydrogen, alkali metal (e.g., lithium, sodium, potassium), alkali earth metal (e.g., beryllium, magnesium, calcium, strontium, baπum) ammonium or substituted ammonium.

Many other anionic surfactants suitable for use in the shampoo compositions are descπbed m McCutcheon's, Emulsifiers and Detergents, 1989 Annual, published by M. C. Publishing Co., and in U.S. Patent 3,929,678, which descπptions are incorporated herein by reference.

Preferred anionic surfactants for use m the shampoo compositions include ammonium lauryl sulfate, ammonium laureth sulfate, tπethylamme lauryl sulfate, tπethylamme laureth sulfate, tnethanolamme lauryl sulfate, tnethanolamme laureth sulfate, monoethanolamme lauryl sulfate, monoethanolamme laureth sulfate, diethanolamme lauryl sulfate, diethanolam e laureth sulfate, lauπc monoglyceπde sodium sulfate, sodium lauryl sulfate, sodium laureth sulfate, potassium lauryl sulfate, potassium laureth sulfate, sodium lauryl sarcosmate, sodium lauroyl sarcosinate, lauryl sarcosme, cocoyl sarcos e, ammonium cocoyl sulfate, ammonium lauroyl sulfate, sodium cocoyl sulfate, sodium lauroyl sulfate, potassium cocoyl sulfate, potassium lauryl sulfate, monoethanolamme cocoyl sulfate, monoethanolamme lauryl sulfate, sodium tndecyl benzene sulfonate, sodium dodecyl benzene sulfonate and combinations thereof.

Amphotenc and zwittenonic surfactants The detersive surfactant component of the topical anti-dandruff compositions may comprise an amphoteπc and or zwitterionic surfactant Concentrations of such surfactants can range from about 0 5% to about 20%, preferably from about 1% to about 10%, by weight of the compositions. Amphoteπc surfactants for use in the compositions include the deπvatives of aliphatic secondary and tertiary amines in which the aliphatic radical is straight or branched and one of the aliphatic substituents contains from about 8 to about 18 carbon atoms and one contains an anionic water solubihzmg group, e.g., carboxy, sulfonate, sulfate, phosphate, or phosphonate.

Zwitterionic surfactants for use in the compositions include the deπvatives of aliphatic quaternary ammonium, phosphonium, and sulfonium compounds, in which the aliphatic radicals are straight or branched, and wherein one of the aliphatic substituents contains from about 8 to about 18 carbon atoms and one contains an anionic group, e g., carboxy, sulfonate, sulfate, phosphate, or phosphonate These compounds can be represented by the formula-

where R² contains an alkyl, alkenyl, or hydroxy alkyl radical of from about 8 to about 18 carbon atoms, from 0 to about 10 ethylene oxide moieties and from 0 to about 1 glyceryl moiety; Y is selected from the group consisting of nitrogen, phosphorus, and sulfur atoms; R³ is an alkyl or monohydroxyalkyl group containing about 1 to about 3 carbon atoms; X is 1 when Y is a sulfur atom, and 2 when Y is a nitrogen or phosphorus atom; R⁴ is an alkylene or hydroxyalkylene of from about 1 to about 4 carbon atoms and Z is a radical selected from the group consisting of carboxylate, sulfonate, sulfate, phosphonate, and phosphate groups.

Examples of amphoteπc and zwitteπonic surfactants also include sultames and amidosultaines. Sultaines and amidosultames can be used as foam enhancing surfactants that are mild to the eye m partial replacement of anionic surfactants Sultames, including amidosultaines, include for example, cocodimethylpropylsultame, stearyldimethylpropylsultame, lauryl-bιs-(2-hydroxyethyl) propylsultame and the like; and the amidosultaines such as cocoamidodimethylpropylsultame, stearylamidododimethylpropylsulta e, laurylamιdobιs-(2-hydroxyethyl) propylsultame, and the like. Preferred are amidohydroxysultaines such as the C₁₂-C_]8 hydrocarbyl amidopropyl hydroxysultaines, especially C-_.2-Cι₄ hydrocarbyl amido propyl hydroxysulta es, e.g., laurylamidopropyl hydroxysulta e and cocamidopropyl hydroxy sultaine. Other sultames are descnbed in U.S. Patent 3,950,417, which descriptions are incorporated herein by reference

Other suitable amphoteπc surfactants are the ammoalkanoates of the formula R-NH(CH₂)_πCOOM, the lmmodialkanoates of the formula R-N[(CH₂)_mCOOM]₂ and mixtures thereof; wherein n and m are integers from 1 to 4, R is C₈-C₂₂ alkyl or alkenyl, and M is hydrogen, alkali metal, alkaline earth metal, ammonium or alkanolammonium.

Examples of suitable ammoalkanoates include n-alkylammo-propionates and n-alkylimmodipropionates, specific examples of which include N-laurylbeta-ammo propiomc acid or salts thereof, and N-lauryl-beta-immo-dipropionic acid or salts thereof, and mixtures thereof.

Other suitable amphoteπc surfactants include those represented by the formula:

where R¹ is alkyl or alkenyl having from about 8 to about 22 carbon atoms, preferably from about 12 to about 16 carbon atoms; R² is hydrogen or CH₂C0₂M; R³ is CH₂CH₂OH or

CH₂CH₂OCH₂CH₂COOM; R⁴ is hydrogen, CH₂CH₂OH, or CH₂CH₂OCH₂CH₂COOM; Z is

C0₂M or CH₂C0₂M; n is the integer 2 or 3, preferably 2; M is a hydrogen, alkali metal (e.g., lithium, sodium, potassium), alkali earth metal (e.g., beryllium, magnesium, calcium, strontium, baπum) ammonium or substituted ammonium. This type of surfactant is sometimes classified as an lmidazolme-type amphotenc surfactant, although it does not necessarily have to be deπved, directly or indirectly, through an lrmdazolme intermediate.

Suitable matenals of this type are marketed under the trade name MIRANOL and are understood to compπse a complex mixture of species, and can exist in protonated and non-protonated species depending upon pH with respect to species that can have a hydrogen at R². All such vaπations and species are meant to be encompassed by the above formula.

Examples of surfactants of the above formula are monocarboxylates and dicarboxylates. Examples of these matenals include cocoamphocarboxypropionate, cocoamphocarboxypropionic acid, cocoamphocarboxyglycmate (alternately referred to as cocoamphodiacetate), and cocoamphoacetate.

Commercial amphotenc surfactants include those sold under the trade names

MIRANOL C2M CONC. N.P., MIRANOL C2M CONC. O.P., MIRANOL C2M SF,

MIRANOL CM SPECIAL (Miranol, Inc.); ALKATERIC 2CIB (Alkaπl Chemicals);

AMPHOTERGE W-2 (Lonza, Inc.); MONATERIC CDX-38, MONATERIC CSH-32 (Mona Industπes); REWOTERIC AM-2C (Rewo Chemical Group); and SCHERCOTERIC MS-2

(Scher Chemicals).

Betame surfactants (zwittenomc) suitable for use in the shampoo compositions are those represented by the formula:

where R¹ is COOM or CH(OH)CH2Sθ3M, R² is lower alkyl or hydroxyalkyl; R³ is lower alkyl or hydroxyalkyl, R⁴ is a member selected from the group consisting of hydrogen and lower alkyl; R⁵ is higher alkyl or alkenyl; Y is lower alkyl, preferably methyl; m is an integer from 2 to 7, preferably from 2 to 3; n is the integer 1 or 0; and M is a hydrogen, alkali metal, alkali earth metal, ammonium or substituted ammonium

As used m this context, the term "lower alkyl" or "hydroxyalkyl" means straight or branch chained, saturated, aliphatic hydrocarbon radicals and substituted hydrocarbon radicals having from one to about three carbon atoms such as, for example, methyl, ethyl, propyl, isopropyl, hydroxypropyl, hydroxyethyl, and the like. The term "higher alkyl or alkenyl" means straight or branch chained saturated (i.e., "higher alkyl") and unsaturated (i.e., "higher alkenyl") aliphatic hydrocarbon radicals having from about eight to about 20 carbon atoms such as, for example, lauryl, cetyl, stearyl, oleyl, and the like. It should be understood that the term "higher alkyl or alkenyl" includes mixtures of radicals which may contain one or more intermediate linkages such as ether or polyether linkages or non-functional substitutents such as hydroxyl or halogen radicals wherein the radical remains of hydrophobic character.

Examples of suitable surfactant betames of the above formula wherein n is zero include the alkylbetames such as cocodimethylcarboxymethylbetame, lauryldimethylcarboxymethylbetame, lauryl dimethyl-alpha-carboxyethylbetaine, cetyldimethylcarboxymethylbetaine, lauryl-bιs-(2-hydroxyethyl)carboxymethylbetame, stearyl-bιs-(2-hydroxypropyl)carboxymethylbetame, oleyldimethyl-gamma- carboxypropylbetame, lauryl-bιs-(2-hydroxypropyl)alpha-carboxyethylbetame, etc. Suitable sulfobetaines include cocodimethylsulfopropyl-betame, stearyldimethylsulfopropylbetame, and lauryl-bιs-(2-hydroxyethyl)sulfopropylbetame.

Suitable amido betames and amidosulfo betames for use in the shampoo compositions include the amidocarboxybetaines, such as cocoamidodimethylcarboxymethylbetaine, laurylamidodimethylcarboxymethylbetame, cetylamidodimethylcarboxymethylbetame, laurylamido-bis-(2-hydroxyethyl)-carboxymethylbetame, cocoamιdo-bιs-(2-hydroxyethyl)- carboxymethylbetame, etc. Amido sulfobetaines include cocoamidodimethylsulfopropylbetame, stearylamidodimethylsulfopropylbetame, and laurylamιdo-bιs-(2-hydroxyethyl)-sulfopropylbetame. Suspending or Thickening Agent The topical anti-fungal compositions of the present invention may comprise a suspending or thickening agent to help maintain dispersion of particulate anti-fungal agents throughout the composition. Any known suspending or thickening agent may be used in such a shampoo compositions, provided that it is physically and chemically compatible with the essential components of the shampoo composition descnbed herein, or does not otherwise unduly impair product stability, aesthetics or performance

Crystalline suspending agents are preferred for suspending the particulate antimicrobial agent the shampoo compositions. The selected suspending agent, at the selected concentration, should help maintain the suspension for at a period of at least one month, preferably at least three months, more preferably at least about twent -four months, at ambient temperatures. In general, effective concentrations of the crystalline suspending agent range from about 0.5% to about 10%, preferably from about 0.5% to about 5%, more preferably about 1% to about 4%, most preferably about 1% to about 3%, by weight of the shampoo composition.

In general, concentrations of the crystalline suspending agent should be minimized to achieve only the desired property.

Preferred crystalline suspending agents are acyl derivatives and amme oxides, especially acyl deπvatives, especially those which can be solubihzed in a premix solution and then be recrystallized upon cooling. These materials compπse long chain (e.g., C₈-C₂ preferably C_]4- C₂₂, more preferably C₁₆-C₂₂) aliphatic groups, i.e., long chain acyl derivative materials and long chain amme oxides, as well as mixtures of such materials. Included are ethylene glycol long chain esters, alkanol amides of long chain fatty acids, long chain esters of long chain fatty acids, glyceryl long chain esters, long chain esters of long chain alkanolamides, and long chain alkyl dimethyl amme oxides, and combinations thereof.

Crystalline suspending agents are descπbed, for example, in U.S. Patent 4,741,855, which descπption is incorporated herein by reference.

Suitable suspending agents for use in the shampoo compositions herein include ethylene glycol esters of fatty acids preferably having from about 14 to about 22 carbon atoms, more preferably 16-22 carbon atoms. More preferred are the ethylene glycol stearates, both mono and distearate, but particularly the distearate containing less than about 7% of the mono stearate. Other suspending agents include alkanol amides of fatty acids, preferably having from about 16 to about 22 carbon atoms, more preferably about 16 to 18 carbon atoms. Prefeπed alkanol amides are steanc monoethanolamide, steanc diethanolamide, steanc monoisopropanolamide and steaπc monoethanolamide stearate. Other long chain acyl denvatives include long chain esters of long chain fatty acids (e.g., stearyl stearate, cetyl palmitate); glyceryl esters (e.g., glyceryl distearate) and long chain esters of long chain alkanol amides (e.g., stearamide diethanolamide distearate, stearamide monoethanolamide stearate). Ethylene glycol esters of long chain carboxy c acids, long chain amme oxides, and alkanol amides of long chain carboxyhc acids, in addition to the preferred materials listed above, may be used as suspending agents

Suspending agents also include long chain amme oxides such as alkyl (C₁₆-C₂₂) dimethyl amme oxides, e.g , stearyl dimethyl amme oxide. Other long chain acyl derivatives that can be used include N,N-dιhydrocarbyl (C-₂-C₂₂, preferably C*₆-C₁₈) amido benzoic acid and soluble salts thereof (e.g., Na and K salts), particularly N,N-dι(Cι₆-C*₈, and hydrogenated tallow) amido benzoic acid species of this family, which are commercially available from Stepan Company (Northfield, Illinois, USA).

The crystalline suspending agent can be incorporated into the shampoo compositions herein by solubilizmg it into a solution containing water and the anionic sulfate surfactant at a temperature above the melting point of the suspending agent. The suspending agent is then recrystallized, typically by cooling the solution to a temperature sufficient to induce crystallization.

Other suitable suspending agents for use in the shampoo compositions that can be used include polymenc thickeners, such as carboxyvmyl polymers, examples of which are descnbed U.S. Patent 2,798,053, and U.S. Patent 4,686,254, which descπptions are incorporated herein by reference. Examples of suitable carboxyvmyl polymers include Carbopol® 934, -940, -941, -956, -980, -981, -1342, and -1382, all commercially available from B. F. Goodπch Company Other suitable suspending agents include those which impart a gel-like viscosity to the composition, such as water soluble or colloidally water soluble polymers like cellulose ethers (e.g., hydroxyethyl cellulose), guar gum, polyvmyl alcohol, polyvmyl pyπohdone, hydroxypropyl guar gum, starch and starch derivatives, and other thickeners, viscosity modifiers, gelling agents, xanthan gum and combinations thereof. Other suitable suspending agents are descnbed m U.S. Patent 4,788,006, which descnption is incorporated herein by reference. Cationic Guar Polymer

The topical anti-fungal compositions of the present invention may compπse a cationic guar polymer having a select charge density. The cationic guar polymer, in combination with the essential components of the compositions, provides improved deposition of the antimicrobial agent onto the scalp and other areas of the skin. Concentrations of the cationic deposition polymer range from about 0.01% to about 1.0%, preferably from about 0.01% to about 0.5%, more preferably from about 0.02% to about 0.25%, by weight of the shampoo compositions.

The cationic guar polymer for use m an anti-dandruff shampoo composition is further defined as having a cationic charge density of from about 0.01 meq/g to about 3 meq/g, preferably from about 0.1 meq/g to about 2 meq/g, more preferably from about 0.8 to about 1.8 meq/g, wherein at least about 50%, preferably about 100%, by weight of the cationic guar polymer forms coacervates with detersive surfactant in the shampoo compositions. The formed coacervates are in the form of hydrated, dispersed colloids that are insoluble in the shampoo compositions.

The cationic guar polymers for use in the shampoo compositions are catiomcally substituted galactomannan (guar) gum deπvatives. The molecular weight of such deπvatives ranges generally from about 2,000 to about 3,000,000. Guar gum for use in preparing these guar gum derivatives is typically obtained as a naturally occurπng material from the seeds of the guar plant. The guar molecule itself is a straight chain mannan branched at regular intervals with single membered galactose units on alternative mannose units. The mannose units are linked to each other by means of beta (1-4) glycosidic linkages. The galactose branching anses by way of an alpha (1-6) linkage. Cationic deπvatives of the guar gums are obtained by reaction between the hydroxyl groups of the polygalactomannan and reactive quaternary ammonium compounds. The degree of substitution of the cationic groups onto the guar structure must be sufficient to provide the requisite cationic charge density descπbed hereinbefore. Suitable quaternary ammonium compounds for use in forming the guar cationic polymers include

R1

R4— N— R2 _z-

I R3 wherein R¹, R² and R³ are methyl or ethyl groups and R⁴ is an epoxyalkyl group of the formula

H₂C- CH— R5—

\ / O or R⁴ is a halohydnn group of the formula

X-CH₂-CH-R5 —

OH where R⁵ is C]-C₃ alkylene and X is chlonne or bromine, and Z is an amon such as Cl", Br", I" or HS0₄".

Cationic guar polymers (cationic deπvatives of guar gum) formed from the reagents described hereinbefore are represented by the formula

wherein R is guar gum. Preferably, the cationic guar polymer is guar hydroxypropyltπmethylammonium chloπde, which can be more specifically represented by the formula R— 0-CH₂-CH-CH₂N⁺(CH₃)₃Cr OH specific examples of which include Jaguar® C-13-S (cationic charge density 0.8meq/g) and Jaguar C-17 (cationic charge density 1.6meq/g) commercially available from Rhone-Poulenc Surfactants and Specialties, Cranbury N.J. U.S A Other suitable cationic guar polymers include hydroxypropylated cationic guar deπvatives Water

The anti-fungal compositions of the present invention may be aqueous systems which compπse from about 40% to about 92%, preferably from about 50% to about 85%, more preferably from about 60% to about 80%, water by weight of the compositions The pH of the shampoo compositions ranges, in general, from about 2 to about 10, preferably from about 3 to about 9, more preferably from about 4 to about 8, most preferably from about 5.5 to about 7.5. For zwitterionic or amphoteπc surfactant systems, the pH should be adjusted according to the lsoelectnc point of the selected surfactant to maintain an anionic species on the selected surfactant pnor to forming a coacervate with the cationic guar polymer descnbed herein.

Solid Cosmetic Carrier

The anti-fungal compositions of the present invention may also be m the form of a solid powder for application to the sk . Such a powder may compπse a solid cosmetic earner. The solid cosmetic earner may be talc, which is a hydrated magnesium silicate, used in the form of particles generally less than 40 μm in size; micas, which are alummosilicates compositions, which exist in the form of scales which are 2 to 200 μm; modified or unmodified starch, in particular πce starch; silica; alumina; boron nitπde; kaolin, which is a hydrated aluminum silicate; zinc and titanium oxides; precipitated calcium carbonate; magnesium carbonate or hydrocarbonate; metallic soaps deπved from a carboxyhc organic acid having 8 to 22 carbon atoms, for example zmc, magnesium or lithium stearate, zmc laurate, magnesium myπstate and the like; synthetic polymer (or copolymer) powders chosen from polyethylene and its denvatives, for example polytetrafluoroethylene, polystyrene and the like; polyacrylates, polymethacrylates, polyesters or polyamides and the like, for example nylon powders; powders m the form of hollow microspheres made from thermoplastic synthetic material, whose hollow part contains a gas Other Optional Components

The shampoo compositions of the present invention may further compπse one or more optional components known for use in shampoo compositions, provided that the optional components are physically and chemically compatible with the essential components descπbed herein, or do not otherwise unduly impair product stability, aesthetics or performance. Concentrations of such optional components typically range from about 0.001% to about 10%) by weight of the shampoo compositions.

Optional components include preservatives, conditioning agents, styling polymers, organic solvents, pearlescent aids, foam boosters, nonionic surfactants, pH adjusting agents, perfumes, proteins, dyes, skin active agents, sunscreens, vitamins, and viscosity adjusting agents.

This list of optional components is not meant to be exclusive, and other optional components can be used.

METHOD OF USE The topical anti-fungal compositions of the present invention may be used in direct application to the sk or m a conventional manner for cleaning skm and hair and controlling fungal infection on the skm or scalp. Directly applied compositions, such as powders, are use by applying an effective amount of the composition, typically from about 1 g to about 20 g, to the skm, for example the feet. The cleansing compositions herein are useful for cleansing the hair and scalp, and other areas of the body such as underarm, feet, and grom areas. An effective amount of the composition, typically from about 1 g to about 20 g of the composition, for cleaning hair, skm or other area of the body, is applied to the hair, skm or other area that has preferably been wetted, generally with water, and then πnsed off. Application to the hair typically includes working the shampoo composition through the hair such that most or all of the hair is contacted with the shampoo composition.

EXAMPLES

Minimal Inhibitory Concentration Index Results

The Minimum Inhibitory Concentration index is indicative of anti-fungal efficacy. Generally, the higher the index value of the composition, the better its anti-fungal efficacy, due to increased inherent ability of the anti-dandruff agent to inhibit the growth of microorganisms. Pnnciple

Malassezia furfur is grown m a flask containing mDixon medium (see E. Gueho, et al. Antoime Leeuwenhoek (1996), no. 69, 337-55, which descπption is incorporated by reference herein). Dilutions of solubilized anti-microbial active are then added to test tubes containing molten mDixon agar. M. furfur inoculum is added to each tube of molten agar, the tube vortexed, and the contents poured into separate stenle pern dishes. After the plates are incubated, they are observed for visible M. furfur growth. The lowest tested dilution of anti-microbial active that yields no growth is defined as the Minimal Inhibitory Concentration (MIC). An MIC index value is calculated companng the MIC value for anti-microbial active to the MIC value for ZPT. The MIC index value is indicative of the potency of an anti-microbial active. Equipment/Reagents Microbe Malassezia furfur (ATCC 14521)

Erlenmeyer flask 250ml Agar medium 9.5ml mDixon agar per concentration per active to be tested Solvent water, dimethyl sulfonyl oxide ("DMSO"), others suitable for actives to be tested

Zmc pyπdmethione ZPT having an average particle size of about 2.5 μm, preserved in

Darvan™, available from Arch Olm

Test tubes 2 tubes per anti-microbial active per concentration per active to be tested, steπhzed, size = 18mm x 150mm

Petn dishes 2 dishes per anti-microbial active per concentration per active to be tested, stenhzed, size = 15mm x 100mm Experimental procedure

1) Grow Malassezia furfur in a 250 ml Erlenmeyer flask containing 100 ml mDixon medium at 320 rpm and 30°C until turbid.

2) Prepare selected dilutions, using a two-fold dilution series, of anti-microbial active in solvent, which allows the sample active to be solubilized pnor to addition to the final test agar. For each concentration of the ZPT samples, the solvent must be DMSO; for other samples, the solvent may be water or DMSO or others suitable solvent. 3) Add 0.25 ml dilutions of anti-microbial active to test tubes containing 9.5 ml molten mDixon agar (held at 45°C in a water bath)

4) Add 0.25 M furfur inoculum (adjusted to 5 x 10⁵ cfu/ml by direct count) to each test tube of molten agar.

5) Vortex each tube, and pour the contents into separate pern dishes. 6) After the agar has solidified, invert the plates and incubate them at 30° for 5 days. 7) Observe the plates for visible M. furfur growth.

Determining index value

Determine the MIC index value by comparing the MIC for each anti-microbial active relative to that for ZPT, by dividing the MIC value for ZPT by the MIC value for the tested antimicrobial active For example, if the MIC_Zpτ value is 1.Oμg/g, and the MIC_test value is 4.0μg/g, then the index for that test active is 1. Oμg/g / 4. Oμg/g, which is equal to index value of 0.25.

Various anti-fungal agents were tested for efficacy m an Agar Dilution Minimal Inhibitory Concentration (MIC) Test.

Anti -dandruff MIC Potency

Agent

Zmc Pynthione 0.25 1.0

Itraconazole 0.016 15.6

Bifonazole 4 0.06

Climbazole 4 0.06

Clotπmazole 8 0.03

Econazole 8 0.03

Ketoconazole 0.5 0.5

Miconazole 4 0.06

Sulconazole 8 0.03

Fluconazole 12.5 0.02

Terbmafine 0.25 1.0

Amorolfine 0.5 0.5

Octopirox 25 0.01

Selenium Sulfide 0.5 0.5

Topical Compositions

The compositions illustrated in Examples I and II illustrate specific embodiments of the topical anti-fungal compositions of the present invention, but are not intended to be limiting thereof. Other modifications can be undertaken by the skilled artisan without departing from the spiπt and scope of this invention. These exemplified embodiments of the shampoo and foot powder compositions of the present invention provide excellent anti-fungal efficacy.

All exemplified compositions can be prepared by conventional formulation and mixing techniques. Component amounts are listed as weight percents and exclude minor matenals such as diluents, filler, and so forth. The listed formulations, therefore, compπse the listed components and any minor materials associated with such components. Exam le I - Anti-dandruff Sham oo

In preparing the composition described in Example I about one-third of the ammonium laureth sulfate (added as 25 wt% solution) is added to a jacketed mix tank and heated to about 74°C with slow agitation to form a surfactant solution. Sodium sulfate is added to the tank and allowed to disperse. Ethylene glycol distearate (EGDS) is added to the mixing vessel and allowed to melt. After the EGDS is melted and dispersed (e.g., after about 5-20 minutes), polyquaternium- 10 and lauryl alcohol are added to the surfactant solution. The resulting mixture is passed through a heat exchanger where it is cooled to about 35°C and collected in a finishing tank. As a result of this cooling step, the EGDS crystallizes to form a crystalline network in the product. The remainder of the ammonium laureth sulfate and the ammonium lauryl sulfate and sodium lauryl sulfate to the finishing tank with agitation to ensure a homogeneous mixture. Once all components have been added, viscosity and pH modifiers may also be added to the mixture to adjust product viscosity and pH to the extent desired.

Exam le II - Anti-fun al Foot Powder

The foot powder composition of Example II is prepared by thoroughly mixing the ingredients in a mixing vessel. The powder may then be ground and/or sifted if necessary.

Claims

WHAT IS CLAIMED IS :

1. A topical composition for treating fungal infections on the skm or scalp compnsmg an active component consisting of ltraconazole.

2. A topical composition according to Claim 1 wherein the composition compnses from 0.01% to 5.0% mtraconazole

3. A topical composition according to either of the preceding claims which further compnses from 7% to 30% by weight of a detersive surfactant selected from the group consisting of anionic surfactants, amphotenc surfactants, zwittenomc surfactants, and combinations thereof.

4. A topical composition according to Claim 3 wherein the detersive surfactant is an anionic surfactant.

5. A topical composition according to any of the preceding claims which further compnses a solid cosmetic earner.

6. A topical composition according to Claim 5 wherein the solid cosmetic earner is talc.

7. A method for treating dandruff on the scalp compnsmg the application of a safe and effective amount of the topical composition of any of the preceding claims to the scalp of a person m need of such treatment.

8. A method for treating athlete's foot compnsmg the application of a safe and effective amount of the topical composition of any of the preceding claims to the feet of a person in need of such treatment.