FIELD OF THE INVENTION

The present invention relates to an anti-microbial agent comprising selective tetrahydroxybenzene derivatives as the anti-microbial active particularly effective against cosmetically relevant microorganisms, more particularly, dandruff/acne/body malodour/dental cavities causing organisms and specifically relates to cosmetic anti-microbial compositions comprising the same in effective amounts. Said anti-microbial active of the present invention may be present in combination with or without other skin or hair care benefiting agents in the said composition. More particularly, the present invention relates to cost-effective cosmetic or dermopharmaceutical compositions for external applications that is especially effective against Malassezia furfur wherein said anti-dandruff active ingredient or pure compounds are obtained either synthetically/ semi-synthetically or from renewable natural plant sources of Embelia ribes. The antimicrobial agent of the present invention is thus strongly efficacious in mitigating the dandruff causing organism Malassezia sp., and comprises tetrahydroxybenzene derivatives of formula 1 given below

Formula 1

Where R = alkyl or alkenyl or alkylaryl

Background and prior art

Dandruff is scaly condition of the scalp and proliferation of Pityrosporum ovale (P. ovale)/ Malassezia furfur (M. furfur) has been considered as quite an important causative factor (KJ. McGinley et. al., J. Invest. Derm., 1975, 64, 401). The genus Pityrosporum/Malassezia is a lipid dependent yeast, growing very well in media containing lipids. The most suitable fatty acid is oleic acid for its lipid requirement (G. Midgley et. al., Microbiology & Microbial infections-Medical Mycology, Topley & Wilsons, vol.4, 9th Ed., 1998). In chapter 19, G. A. Pierre has reviewed various modes of intervention such as inhibitors of epidermal proliferation, keratolytic agents, anti-mycotic agents described as efficacious approaches for mitigating dandruff (G. A. Pierre, The Science of Hair Care edited by Charles Zviak, Marcel Dekker, New York, 1986, pp. 501-511). A number of commercial compounds are known to be useful in mitigating the dandruff via., inhibiting M. furfur proliferation. These are Zinc pyrithione (ZPTO) (G. Imokama et. al., J. Soc. Cosmet. Chem., 1982, 33, 27), amphotericin B (M.J. Marcon et. al., Antimicrob. Agents Chemo., 1987, 33, 951), Ketoconazole (K.A. Hammer et. al., Antimicrob. Agents Chemo., 2000, 44, 467) and climbazlole (A. Schmidt & B. Ruehl-Hoerster, Arzneim. Forsch., 1966, 46, 442). These compounds are incorporated in compositions at very low levels. But all these compounds whose safety limits are restrictive and hence generally brought in contact with the scalp for a short period of time and washed away.

Acne is caused by the anaerobic bacterium species, Propionibacterium acnes (P. acnes). The most common form of acne is known as Acne vulgaris, meaning "common acne". It is common human skin disease, characterised by areas of skin with seborrhea (scaly red skin), comedones (blackheads and whiteheads), papules (pinheads), pustules (pimples), nodules (large papules) and possibly scarring (Adityan et al., Indian J Dermatol Venerol Leprol, 2009, 75, 323-26. Acne occurs most commonly during adolescence, and often continues into adulthood and its main effects are psychological, such as reduced self-esteem (Goodman, Aust Fam Physician, 2006,35, 503-4) and in very extreme cases, depression (Purvis et. al., J Paediatr Child Health, 2006, 42, 793-6). Various treatment are existing for treatment of acne including benzoyl peroxide, antibiotics, retinoids, antiseborrheic medications, anti-androgen medications, hormonal treatments, salicylic acid, alpha hydroxy acid, azelaic acid, nicotinamide, and keratolytic soaps (Sagransky et al., Expert Opin Pharmacother, 2009, 10, 2555-62).

Streptococcus mutans is a gram-positive organism that is the primary causative agent in the formation of dental cavities in humans. Conditions in the oral cavity are diverse and complex, frequently changing from one extreme to another. Thus, to survive in the oral cavity, S. mutans must tolerate rapidly harsh environmental fluctuations and exposure to various anti-microbial agents in order to survive (Biswas et al., Antimicrobial agents and chemotherapy 2011, 55, 1460-9). S. mutans has over time developed strategies to successfully colonize and maintain a dominant presence in the oral cavity. The oral biofilm is continuously challenged by changes in the environmental conditions. If the adherence of S. mutans to the surface of teeth or the physiological ability (acidogenity and aciduricity) of S. mutans in dental biofilms can be reduced or eliminated, the acidification potential of dental biofilms and later cavity formations can be decreased (Argimon, S et al., Journal of clinical microbiology, 2011,49, 984-92). A number of commercial compounds or products are known to be useful to control this bacteria. These are: bakuchiol had been reported from the plant A. sanguinolenta (Rao et al., J Pharm Res., 2012, 5, 174-176), turmeric fraction and curcumenoids (Pandit et. al., Food Chem, 2011,126, 1565-70), macelignan from nutment (Yanti et. al., Phytotherapy research, 2008, 22, 308-12) and a commercial herbal tea obtained from roasted barley (Stauder et al., Current Microbiology, 2010, 61, 417-21).
People are associated with herbal materials since ages. It is a common practice in India, people wash their scalp with some of the herbal materials to alleviate the dandruff (Wealth of India, CSIR New Delhi).

The recent trends showed consumers are demanding the cosmetic preparations with herbal materials, which are more safe and biodegradable and renewable resources. There is hence a need for compositions with materials effective in mitigating dandruff in a morefriendly manner without giving any side effects.

Balakrishnan et al., mentioned that Termenalia chebula and Terminalia bellirica were the best sources for controlling the dandruff causing organism (Int J. Pharm and biosci., 2012(4), 38-44).

As would be apparent from the above that though there are several anti-microbial actives/ compositions widely prevalent in the art and in use effective against fungus especially Malassezia furfur, their safety limits are found to be restricted to very low levels and are hence generally brought in contact with the scalp for a short period of time and washed away.

Therefore it is the need of the day to explore for suitable, safe and cost-effective anti-microbial actives that would overcome the limitations and disadvantages of the known compositions presently in use in having high safety limits being preferably sourced from natural renewable plant material and would still be superiorly active in mitigating microbes preferably dandruff caused by the fungus especially Malassezia furfur, that can also be incorporated at higher levels in the compositions, if desired, for greater activity and yet be safe to thus have a wider consumer acceptance.

Objects of the invention:

It is thus the primary object of the present invention to provide for an antimicrobial agent and cosmetic anti-microbial compositions comprising the same which on one hand would also be efficacious in mitigating the dandruff causing organism Malassezia furfur and on the other would also overcome the limitations and disadvantages observed in the existing compositions presently in use, with better consumers acceptance.

Another object of the present invention is to provide for an anti-microbial agent and compositions comprising the same that would be effective against microbes related to malodour, pimples and oral microbes and would also control the growth of dandruff causing organism Malassezia furfur.
Yet another object of the present invention is to provide for the said anti-microbial agent that would be safe and can be incorporated in higher amounts in cosmetic anti-microbial compositions, if needed, and can be left on the scalp for a considerable period of time before being washed away to be thus more
effective vis-a-vis existing compositions with safety limits restricted to very low levels that are thus generally brought in contact with the scalp for a shorter period of time and washed away.
Yet another object of the present invention is to provide for said anti-microbial agent as the anti-dandruff active that would also effectively control said growth of dandruff causing organism Malassezia furfur under low effective concentrations when present in combination with or without other skin/hair care benefiting agents to be a cost-effective composition for treating dandruff.

Yet nother object of the present invention is to provide for an anti-microbial agent and cosmetic anti-microbial compositions comprising the same which would have benefit attributes of being user friendly in terms of ease of application and required reduced frequency of application and would also effectively mitigate/ control other fungus types selected from Streptococus mutans, Propionibacterium acne and Corynebacteriurn xerosis.

Yet another object of the present invention is to provide for an anti-microbial agent and cosmetic anti-microbial compositions comprising the same obtained either synthetic / semisynthetically or from natural renewable plant sources.

Still another object of the present invention is to provide for a safe anti-microbial agent with high safe levels of incorporation in the cosmetic anti-microbial compositions in higher amounts that can be retained on the scalp for a considerable time before washing to thus be superiorly effective against the dandruff causing fungus Malassezia furfur.

Summary of the Invention:

Thus according to the basic aspect of the present invention there is provided anti-microbial agent comprising any one or more of 1,2,4,5-tetrahydroxy benzene derivatives of Formula 1 as the anti-microbial active of Formula 1 hereunder

Formula 1

Where R = alkyl or alkenyl or alkyl-aryl In accordance with a another preferred aspect of the present invention there is provided anti-microbial agent comprising 3-undecyl-l, 2, 4, 5-tetrahydroxybenzene (Embeliol) of Formula 2 hereunder

Formula 2 Importantly, in keeping with the requirement of anti-microbial agent favouring skin/ hair care by inhibiting the growth of fungi or bacteria it has been surprisingly found that the above said Formula 1 compounds comprising any one or more of 1,2,4,5-tetrahydroxy benzene derivatives and preferably 3-undecyl-l,2,4,5-tetrahydroxybenzene (Embeliol) of Formula 2 meet the much desired criteria of a superior skin/hair care active in being efficacious against cosmetically relevant microorganisms as malodour, pimple controlling active, as oral care active that is especially effective as an anti-dandruff active thereby inhibiting the growth of Malassezia furfur which is thus found to be simple, for controlling the microbes under low effective concentrations and safe in having less or no side effects when present in combination with or without other skin/hair care benefitting agents.

The anti-microbial agent of the present invention is also efficacious in controlling the growth or reducing the counts of bacteria selected from Streptococus mutans, Propionibacterium acne, Corynebacterium xerosis to thus be an effective body malodour, pimple controlling and oral care active.
Also sustained efforts were directed to isolate the said anti-microbial agent of Formula 1 and Formula 2 preferably efficacious against dandruff causing Malassezia furfur from natural renewable material such as plants and according to yet another aspect of the present invention there is provided safe antimicrobial agent for effective mitigation of the proliferation of microbes preferably proliferation of the dandruff causing yeast M. furfur, comprising Formula 1 or Formula 2 compounds obtained either synthetically / semisynthetically or from extracts/ concentrates of plant Embelia ribes.

The above finding of anti-dandruff activity of the active embeliol of Formula 1 and preferably Formula 2 is also in substantial deviation to the known characteristics/ properties of the said plant provided herebelow: The plant, Embelia ribes (Viranga in Hindi) is a climbing shrub. The leaves are glossy green on the upper surface and more silvery on the lower, with scattered, minute sunken glands. Its fruits are globose berries, upto 4 mm in diameter and the dried fruits are either red or brownish black. The berries have a faint spicy odour and a pungent and astringent taste. Traditionally, the powdered berries are used to remove intestine worms. Seeds are also used as an astringent, alterative and nervine tonic and for constipation, colic dispepsia, flatulence and piles. The leaves are used for mouth ulcers and sore throats. The dried root bark powdered has been used to control toothache (Major herbs of Ayurveda, Edited by E. M. Willamson, Churchill Livingstone, 2002).

Embelin, a major active, isolated from the fruits was significant anti-fertility activity (Bhargava SK, Fitoterapia, 1988, 59(3), 163). Embelin showed antibacterial activity at 800ug/ml against Staphylococus aureus, S. a/bus and S. citreus (Gopal et al., Bull Med Ethnobotany Res., 1986, 7, 78). The fruit extracts of E. ribes showed antibacterial effects and prevented adherence of viable cells of Streptocosus mutans to smooth surfaces with a 50% inhibitory concentration of 10-30ug/ml. It has showed anti-enzymatic activity against gulcosysltransferase and the active principle has been identified as embelin (Namba et al., Shoyakugaku Zasshi, 1985, 39, 146). From the seeds of E. ribes, three new compounds: embelinol, embeliaribyl ester and embeliol (1,2,4,5-tetrhydroxy 3-undecanyl benzne) along with embelin were reported (Haq et al., Pharamzie, 2005, 60, 69-71). Importantly in view of the aforesaid, the finding of the present invention that extracts/ concentrates of plant Embelia ribes in being a rich source of embelin and a lean source of active embeliol is found to mitigate/ control the growth of microbes preferably dandruff causing yeast M. furfur is indeed unexpected and surprising when the active embeliol in isolation is considered and in view of the well known several biological properties of

Embelia ribes sourcing embelin as the major active as discussed above.
According to another preferred aspect of the present invention there is provided an anti-microbial agent wherein said anti-microbial active comprises 1,2,4,5-tetrahydroxy benzene derivatives preferably embeliol of Formula 2 either synthesized and/or obtained from natural renewable plant sources preferably Embelia ribes.

Advantageously, said anti-microbial agent is efficacious in controlling the growth or reducing the counts of microbes selected from Streptococus mutans, Propionibacterium acne, Corynebacterium xerosis preferably Malassezia furfur to be thus effective as an body malodour, pimple controlling, oral care active preferably effective as anti-dandruff active.

According to another aspect of the present invention there is provided an antimicrobial composition for topical use comprising anyone or more of 1, 2, 4, 5-tetrahydroxy benzene derivatives as the anti-microbial active of Formula 1 hereunder


Formula 1

Where R=alkyl or alkenyl or alkylaryl
And a cosmetically acceptable vehicle with or without other skin/ hair care benefiting agents.

According to another preferred aspect of the present invention there is provided said anti-microbial composition for topical use wherein said anti-dandruff active preferably comprises 3-undecyl-l,2,4,5-tetrahydroxybenzene (embeliol) of Formula 2.

According to another preferred aspect of the present invention there is provided said anti-microbial composition for topical use wherein said anti-microbial active preferably anti-dandruff active comprises 1,2,4,5-tetrahydroxy benzene derivatives preferably embeliol of Formula 2 either synthesized and/or obtained from natural renewable plant sources preferably Embelia ribes.

According to another aspect of the present invention there is provided said antimicrobial composition for topical use comprising
0.0001 wt% to 20 wt. % of said anti-microbial active, preferably 0.001 wt% to 10 wt% of said anti-microbial active and more preferably 0.01 wt% to 5 wt% of said anti-microbial active as at least one ingredient.

According to another preferred aspect of the present invention there is provided said anti-microbial composition for topical use comprising a leave-on or a wash-off product adapted for topical delivery in the forms selected from shampoo, cream, emulsions, gels, lotions, oils, sticks, sprays, packs, powders, wraps, woven or nonwoven wipes, films or patches as a vehicle for topical application of the said anti-microbial composition.

According to yet another preferred aspect of the present invention there is provided said anti-microbial composition for topical use wherein said antimicrobial active preferably anti-dandruff active comprises selectively pure 1,2,4,5-tetrahydroxybenzene derivatives of Formula 1 or preferably embeliol of Formula 2, as pure compounds or as at least one ingredient in the semi-pure extract of the reaction mixture or plant extract.

Specific examples of specific 1,2,4,5-tetrahydroxybenzene derivatives of the formula 1 for use in the compositions of the invention is 3-undecyl-l,2,4,5-tetrahydroxybenzene which can be semi-synthesized from the major plant compound, embelin by conventional known methods. The compound emblein is known to the literature and has been isolated from the seeds of Embelia (Ghazi et al., Phytoterapy Research, 2000, 14, 510-516) and fruits of Ardisia colorata (sumino M. et al., Chem Pharm Bull (Toyko), 2002, 50, 1484-87) and is reported to possess anti-bacterial (Chitra M et al., Fitoterapai, 2003, 74, 401-403), anti-tumor, anti-inflammatory and analgesic properties (Chitra M, at, Chemotherapy, 1994, 40, 109-113).

Detailed Description of the Invention:

As discussed hereinbefore the present invention provides for anti-microbial agent comprising selective tetrahydroxybenzene derivatives as the antimicrobial active preferably as an effective anti-dandruff active and particularly provides to cosmetic anti-microbial compositions comprising the same in effective amounts present in combination with or without other skin or hair care benefiting agents. More particularly, the present invention relates to cost-effective cosmetic or dermopharmaceutical compositions for external applications that is especially

effective against Malassezia furfur wherein said anti-dandruff active ingredient or pure compounds are obtained either synthetically/ semi-synthetically or from renewable natural plant sources of Embelia ribes.

A wide variety of cosmetic preparations are suitable, in particular Hair care products like., shampoos, lotions, hair oils; skin care products like creams, ointments, pastes, lotions etc., for the use according to the invention of the said compounds. Examples of other preparations which are suitable according to the invention and which may be mentioned are the following hair care and hairdressing compositions: hair rinses, hair tonics, hair regenerating compositions, hair lotions, water wave lotions, hair sprays, hair creams, hair gels, hair oils, hair pomades, skin care creams. Accordingly, these are always preparations which are applied to the hair/skin and the scalp for a shorter or longer time depending on the actual purpose for which they are used. Addition of the compounds according to the invention then effects simultaneous dandruff treatment. However, it is also possible to produce preparations which are used primarily or exclusively for the purpose of eliminating/mitigating dandruff.

The cosmetic compositions can be prepared according to the invention are supplied as shampoos, these can be clear liquids, opaque liquids (with pearly luster effect), in cream form, gel-like or else in powder form or in tablet form, and as aerosols.

The ingredients essentially employed in such a composition are surfactants, emulsifiers, emollients, silicones, thickeners, antioxidants, sunscreen agents chelating agents, perfumes, opacifiers, colors, other antimicrobials agents, herbal extracts, / compounds, pH adjusting agents and water to qs. The detergent raw materials on which these shampoos are based can be anionic, cationic, nonionic and amphoteric in nature and also be present in combinations of these substances.

The composition may contain usually employed vehicle such as may be aqueous, anhydrous or an emulsion. Preferably, the compositions are aqueous or an emulsion, especially water-in-oil or oil-in-water emulsion, preferentially oil in water emulsion. Water when present will be in amounts which may range from 5 to 99%, preferably from 20 to 85%, optimally between 40 and 80% by weight.

According to a still further aspect of the invention the cosmetic/ dermopharma-ceutical composition may contain various other skin benefit agents such as plasticizers, elastomers, calamine, pigments, antioxidants, chelating agents, and perfumes, as well as organic/ inorganic sunscreens and including such sunscreens as UV diffusing/ protection agents, typical of which is finely divided Titanium oxide and Zinc oxide.

A still further aspect of the invention the cosmetic composition of the present invention may optionally contain other adjunct minor components /ingredients such as including coloring agents, opacifiers, antimicrobial agents, pH adjusting agents and perfumes. Amounts of these other adjunct minor components may range anywhere from 0.0001 % up to 20 % by weight of the composition.
The composition may further include suitable skin benefiting agents comprising anti-aging, wrinkle-reducing, skin whitening, anti-acne, and sebum controlling/ reducing agents. Examples of these include alpha-hydroxy acids and esters, beta-hydroxy acids and esters, polyhydroxy acids and esters, kojic acid and esters, ferulic acid and ferulate derivatives, vanillic acid and esters, dioic acids (such as sebacic and azeleic acids) and esters, retinol, retinal, retinyl esters, hydroquinone, t-butyl hydroquinone, mulberry extract, licorice extract, and glycosides of benzyl protocatechuate derivatives other than the derivatives discussed herein above.

Suitable cosmetic carriers are well known to one skilled in the art. The cosmetic bases may be any bases which are ordinarily used for skin benefit agents and are not thus critical. Specific preparations of the cosmetics to which the skin benefit agents of the invention is applicable include creams, ointments, emulsions, lotions, washes, masks, packs, oils, sprays / aerosols and wipes. Cream bases are, for example, beeswax, cetyl alcohol, stearic acid, glycerine, propylene glycol, propylene glycol monostearate, polyoxyethylene cetyl ether and the like. Lotion bases include, for example, oleyl alcohol, ethanol, propylene glycol, glycerine, lauryl ether, sorbitan monolaurate and the like.

The cosmetically acceptable vehicle may act as a diluent, dispersant or carrier for the skin beneficial ingredient of the composition of the invention, so as to facilitate their distribution when the composition is applied to the skin.

Besides water, relatively volatile solvents may also serve as carriers within compositions of the present invention. Most preferred are monohydric C1-C3 alkanols. These include ethyl alcohol, methyl alcohol and isopropyl alcohol. The amount of monohydric alkanol may ranges from 1 to 70 %, preferably from 10 to 50 %, and optimally between i5 to 40 % by weight.

Emollient material also serves as cosmetically acceptable carriers. These may be in the form of silicone oils and synthetic esters. The amount of the emollient material ranges anywhere from 0.1 to 50 %, preferably between 0.5 and 30 % by weight.

Examples of anionic detergent substances of this type which may be mentioned are: C10 -C2o -alkyl- and alkylenecarboxylates, alkyl ether carboxylates, fatty alcohol sulfates, fatty alcohol ether sulfates, alkylolamide sulfates and sulfonates, fatty acid alkylolamide polyglycol ether sulfates, alkanesulfonates and hydroxyalkanesulfonates, olefinsulfonates, acyl esters of isethionates, alpha-sulfo fatty acid esters, alkylbenzenesulfonates, alkylphenol glycol ether sulfonates, sulfosuccinates, sulfosuccinic monoesters and diesters, fatty alcohol ether phosphates, protein-fatty acid condensation products, alkyl monoglyceride sulfates and sulfonates, alkyl glyceride ether sulfonates, fatty acid methyltaurides, fatty acid sarcosinates, and sulforicinoleates. These compounds and their mixtures are used in the form of their salts which are soluble in water or dispersible in water, for example the sodium, potassium, magnesium, ammonium, mono-, di- and triethanolammonium and analogous alkylammonium salts.

Examples of suitable cationic surfactants are quaternary ammonium salts such as di (C10 -C24 -alkyl) dimethylammonium chloride or bromide, preferably di (C12-C18 -alkyl) -dimethylammonium chloride or bromide; Ci0-C24 alkyldimethyl-ethylammonium chloride or bromide; Ci0 - C24 alkyltrimethyl-ammonium chloride or bromide, preferably cetyltrimethylammonium chloride or bromide and Cio -C24 -alkyltrimethylammonium chloride or bromide and other commonly available materials.
Examples of suitable nonionic surfactants which can be used as detergent substances are: fatty alcohol ethoxylates (alkylpolyethylene glycols); alkylphenol polyethylene glycols; alkyl mercaptan polyethylene glycols; fattyamine ethoxylates (alkylaminopolyethylene glycols); fatty acid ethoxylates (acylpolyethylene glycols); polypropylene glycol ethoxylates; alkanol amides, fatty acid alkylolamides (fatty acid amide polyethylene glycols); sucrose esters; sorbitol esters and polyglycol ether.

For the purposes of the invention, the term amphoteric surfactant is understood to refer to the compounds chosen, alone or as a mixture, from alkyl amphocarboxyglycinates, alkyl amphocarboxypropionates, alkyl ampho-diacetates, alkyl amphodipropionates, alkyl amphoglycinates, alkyl ampho-propionates, alkyl iminopropionates, alkyl iminodipropionates, alkyl ampho-propylsulphonates, alkylbetaines, alkylamidopropylbetaines, alkylsultaines and alkylamidopropylhydroxysultaines.

Thickners: thickeners intended to give the shampoos a sufficient consistency and improved cosmetic qualities. Among the known thickeners, carbomers (acrylic acid homopolymers crosslinked with an allylic ether of pentaerythritol, of sucrose or of propylene), PEG esters, laurylpyrrolidone, acrylic copolymers and cationic polymers of natural or synthetic origin, including certain polyquaternium compounds give very satisfactory results in the application considered, in particular bearing in mind that viscosities of greater than 1000 mPa.s, preferably between 1000 mPa.s and 30,000 mPa.s, could be obtained with these specific products ("Carbopol from BF Goodrich, "Atlas G-1821" from ICI, "Surfadone 300" from ISP, "Acrysol" from Rohm & Haas, "Jaguar. 162" and "Rhodicare" from Rhone-Poulenc, "Ucare Polymer Jr. 400" from Amerchol, "Mackernium" from Jan Dekker/Maclntyre and "Gafquat N" from ISP).

These specific thickeners and mixtures there of (not restricted) make it possible to obtain acceptable viscosities when they are used at concentrations of between 0 and 5% by weight relative to the whole composition, preferably between 0.2 and 3% by weight.

The preparations according to the invention can additionally contain further additives (0.001 to 20% wt) customary in cosmetics, for example conditioners perfumes, colorants, also those which simultaneously dye or tint the hair, solvents, opacifying agents and pearly luster agents, for example esters of fatty acids with polyols, magnesium and zinc salts of fatty acids, dispersions based on copolymers, thickening agents such as alkanol amides, sodium, potassium and ammonium chloride, sodium sulfate, fatty acid alkylolamides, cellulose derivatives, natural rubbers, also plant extracts, protein derivatives such as gelatin, collagen hydrolysates, polypeptides with a natural or synthetic basis, egg yolk, lecithin, lanolin and lanolin derivatives, fats, oils, fatty alcohols, silicones, deodorizing agents, substances with antimicrobial activity, substances with antiseborrhoeic activity, substances with keratolytic and keratoplastic effect, such as, for example, sulfur, salicylic acid and enzymes.

For the preparation of the cosmetic preparations the active substance is dissolved under stirring at a temperature in the range between 20 and 90°C, preferably at room temperature, in the detergent substance used. Subsequently, the further additives are added.

In the event of alcohol containing cosmetic preparations the active substance is dissolved in the alcohol at a temperature in the range between 20 and 40°C, preferably at room temperature. Subsequently, the further additives are added. In the event of hair rinses and oil-in-water emulsions the active substance is dissolved in the fatty phase, which means together with the oil and the emulgator, at a temperature in the range between 70 and 90°C, preferably at 75° C. Subsequently, hot water is added and the emulsion is stirred and cooled. The shampoos are produced in a manner known per se by mixing the individual components and-where necessary further processing appropriate for the particular type of preparation. Some of this wide variety of possible formulations are described by way of example in the exemplary embodiments.

Examples of other hair care cosmetic preparations in which the l-hydroxy-2-pyridones can be used according to the invention and which may be mentioned are: hair rinses, hair tonics and hair regenerating compositions, which are rinsed off from the hair after a certain time or, depending on the formulation, can also remain on the hair. These products contain, inter alia, substances from the group of the above mentioned cationic surfactants which display a reviving and antistatic property on the hair.

The antidandruff preparations according to the invention can also be supplied in the form of aqueous and aqueous alcoholic hair lotions, water wave lotions (hair setting compositions), also those in gel form, and in aerosol form as hair spray, as well as in the form of hair care and hairdressing creams and gels. Ethanol and isopropanol are preferably used as alcohols.

It is furthermore possible to incorporate the compounds which can be used according to the invention in anhydrous oily preparations such as hair oil, hair pomade and hair brilliantine.
The antidandruff active substance is incorporated in the preparations according to the invention in amounts which are normally between about 0.01 and about 5%. Within this range, the concentrations of the specific preparations depend on the purpose for which they are used. Certain formulations such as, for example, concentrates which must be diluted before they are used may also have considerably higher concentrations.

If the preparations remain on the hair, such as, for example, hair lotions, hair setting compositions, creams, etc., lower concentrations will be used, for example of about 0.005 to about 1%, preferably 0.001 to 0.75%. They are expediently used in higher concentrations if the cosmetic preparations act, where appropriate after dilution, for only a short time on the hair and scalp, such as, for example, shampoos or hair rinses. In these cases, for example, concentrations of about 0.01 to about 5%, preferably about 0.01 to about 2%, may be expedient.

The following examples illustrate the present invention. The stated amounts are based on weight.
Example: la- Preparation of Embeliol, compound 2
Taken 1.47 g (0.005 mole) of embelin In 100 ml RB flask added 10 ml of chloroform, cooled the flask to below 10°C, added 0.19g (0.005mole) of sodium borohydride and stirred for 1 hr at room temp. The progress of the reaction was monitored by TLC. After usual work up, 1.3g of the product, embeliol of formula 2 was obtained as pale brown colored powder.

Example: lb-Spectral characterization of tetrahydroxy benzene derivative preferably embeliol of Formula 2 The compound embeliol of Formula 2 was submitted for dandruff studies and showed good anti-dandruff activity was observed (MIC= 7.89ug/ml).

The tetrahydroxybenzene derivative of the invention, embeliol of Formula 2, displays the following characteristics. On thin layer chromatography using a pre-coated silica gel plate (Merck 1.05554.0001), the isolated substance provides a spot with an Rf value of 0.53 in hexane: ethyl acetate 8:2. The UV(CHCI3) spectrum shows an absorbance value at 216, 283, 292, 327 nm, IR spectrum values are at 3392 (br), 1640, 1595, 1485, 1114,1070 and 833 cm"1 and other characteristic signals, Proton NMR values in CDCI3 (400 MHz). 0.88 (3H, t J=6.4

Hz), 1.26 (16H, br s), 1,50 (1H, m), 1.54 (1H, m), 2.4 (1H, m), 2.63 (1H, m), 7.60 (1H, s).

Taken the above mentioned ingredients from phase A into beaker, heated the mixture to 80°C to melt the CMEA and cooled to 50°C. Taken all the ingredients mentioned in Phase B and added phase A material into Phase B under stirring, and stirred well for 15 mins. Adjusted the pH with Ortho phosphoric acid (between 6.5-6.8), and stirred well. To the above mixture, phase D material was added and stirred well. Later, the shampoo base viscosity was boosted with phase E ingredient and stirred well. Finally, the balance quantity was adjusted with DM water. Viscosity of the shampoo base is about 8000 cps at 30°C (brook filed viscometer LV3 spindle at 12 rpm).

Method of manufacturing

1. Prepare phase C by dispersing carbomer in DM water for 30 mins by slowly sprinkling it.
2. Weight accurately all the ingredients of phase A & B, heat them separately to 75°C.

3. Add phase C to phase B, and stir for 10 min.
4. Add phase A to phase BC and stir for 30 min, cool to 45°C.
5. Add phase D at 60°C, to the Phase ABC and stir for 5 min.
6. Add Phase E at 55°c to Phase ABCD.
7. Add phase F to at 50°C to Phase ABCDE.
8. Add phases G and H to phase ABCDEF and stir for 5 min.

Method of manufacturing

1. Prepare phase A by dispersing Polygel in DM water for 30 min by slowly sprinkling it. Neutralize with Triethanol amine.

2. Weight accurately all the ingredients of phase B and add to phase A and stir well for 10 min.

3. Add phase C to Phase AB and stir well for 10 min.

Example 5: Estimation of Minimum Inhibitory concentration (MIC values)

The Minimum inhibitory concentration (MIC) value of dihydroembelin was determined against the yeast Malassezia furfur (Pityrospermum ovale) and for the bacterial cultures (S.mutans, P.acne and C.xerosis). MIC is the minimum amount of an antimicrobial that will inhibit visible growth of the organism after a suitable period of incubation. MIC was determined as per IMCCLS guidelines published by the National Committee for Clinical Laboratory Standards, Wayne, PA, USA. (Reference method for broth dilution for anti-fungal susceptibility testing of yeasts; Approved Standard M27A, NCCLS 1997, Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; Approved standard M7-A5, NCCLS 2000).

Preparation of stock solution

Stock solution of the test samples were prepared by dissolving the neat samples in solvent containing DMSO and mixed thoroughly. The neat sample so dissolved in the solvent was further diluted with appropriate volumes of media diluent in order to give a final concentration of 20,000ug/ml. All test solutions were prepared afresh prior to determination of MIC.
Preparation of Inoculum: Inocula were prepared by growing M. furfur on Sabouraud Dextrose broth (SDB) with 1% Tween -80 for 48 hrs, and for the bacterial cultures (S.mutans, P.acne and C.xerosis) inoculum were prepared by growing the colonies in Tryptone Soya Broth (TSB) for 24 hours and abosorbance were measured by spectrophotometrically (K. A. Hammer et al., Antimicrob. Arents Chemo., 2000, 44, 467-469).

Macro tube dilution method was used to determining the MIC value for M. furfur, C. xerosis and S. mutans and agar dilution method used for determining the MIC value of P. acne (In Bailey & Scoot's Diagnostic Microbiolgy, 9th Ed., 1996). Inoculum concentration were maintained at 4X103 CFU/ml for M.furfur and 1X105 CFU/ml for C. xerosis, P.acne and S. mutans.

Example: MIC (µg/ml) is the minimum inhibitory concentration expressed as µg/ml, when assayed via the macro tube dilution method and agar dilution method. The MIC values obtained for the base formulations and active compound incorporated formulations in the experimental compositions are shown in Table 1 and pure compound of Formula 2 and embelin are shown in Table 2.

It is thus clearly evident from Table 2 above that embeliol a minor and much lesser known active that can be obtained from the plant Embelia ribes that can be quantitatively obtained synthetically or semi-synthetically (semi-synthetically from embelin) is surprisingly found to be promising and advantageously efficacious in having many folds lower MIC values inhibiting Propionibacterium acne and Malassezia furfur vis-a-vis embelin when compared in isolation. Such selective and special efficacy of embeliol of Formula 2 as compared to embelin is thus clearly an unexpected and selective advantage not previously known to be flowing from any prior art knowledge on embelin even when considered in combination to the plant source from which it is derived.

It is thus possible by way of the present advancement to provide for an anti-microbial agent and anti-microbial compositions comprising the same that is efficacious against cosmetically relevant microorganisms and is selectively and surprisingly efficacious against dandruff causing Malassezia furfur and is thus an effective anti-dandruff active comprising tetrahydroxybenzene derivatives of Formula 1 and preferably Embeliol of Formula 2. Said cosmetic anti-microbial compositions comprises said active in effective amounts present that may be present in combination with or without other skin or hair care benefiting agents. Advantageously, the cosmetic or dermopharmaceutical compositions for external applications are cost-effective and is especially effective against cosmetically relevant microorganisms wherein said active ingredient or pure compounds are obtained either synthetically/ semi-synthetically or from renewable natural plant sources of Embelia ribes. More advantageously, the anti-microbial agent in remaining effective in the presence of wide variety of bases/ shampoo bases employed in the said composition involving it, thus possesses superior compatibility with the ingredients of the composition thus favouring the achievement of various forms of the composition facilitating wider consumer acceptance.

WE CLAIM:

1. An anti-microbial agent comprising anyone or more of 1, 2, 4, 5-tetrahydroxy benzene derivatives as the anti-microbial active of Formula 1 hereunder

Formula 1

Where R = alkyl or alkenyl or alkylaryl

2. An antimicrobial agent as claimed in claim 1 wherein said anti-microbial
active preferably comprises 3-undecyl-l, 2, 4, 5-tetrahydroxybenzene
(Embeliol) of Formula 2 hereunder

3. An anti-microbial agent as claimed in anyone of claims 1 or 2 wherein said
anti-microbial active comprises 1, 2, 4, 5-tetrahydroxy benzene derivatives
preferably embeliol of Formula 2 either synthesized and/or obtained from
natural renewable plant sources preferably Embelia ribes.

4. An anti-microbial agent as claimed in anyone of claims 1 or 2 efficacious in controlling the growth or reducing the counts of microbes selected from Streptococus mutans, Propionibacterium acne, Corynebacterium xerosis preferably Malassezia furfur to be thus effective as an oral care, pimple care body malodour control preferably effective as an anti-dandruff active.

5. An anti-microbial composition for topical use comprising anyone or more of 1,2,4,5-tetrahydroxy benzene derivatives as the anti-microbial active of Formula 1 hereunder

Formula 1

Where R=alkyl or alkenyl or alkyl aryl
and

a cosmetically acceptable vehicle with or without other skin/ hair care benefiting agents.

6. An anti-microbial composition for topical use as claimed in claim 5 wherein said antimicrobial active preferably comprises 3-undecyl-l,2,4,5-tetrahydroxybenzene (embeliol) of Formula 2.

7. An anti-microbial composition for topical use as claimed in anyone of claims 5 or 6 wherein said anti-microbial active preferably anti-dandruff active comprises 1,2,4,5-tetrahydroxy benzene derivatives preferably embeliol of Formula 2 either synthesized and/or obtained from natural renewable plant sources preferably Embelia ribes.

8. An anti-microbial composition for topical use as claimed in anyone of Claims 5
to 7 comprising 0.0001 wt% to 20 wt. % of said anti-microbial active active, preferably 0.001 wt% to 10 wt% of said anti-microbial active and more preferably 0.01 wt% to 5 wt% of said anti-microbial active as at least one ingredient.

9. An anti-microbial composition for topical use as claimed in anyone of claims 5 to 8 comprising a leave-on or a wash-off product adapted for topical delivery in the forms selected from shampoo, cream, emulsions, gels, lotions, oils, sticks, sprays, packs, powders, wraps, woven or nonwoven wipes, films or patches as a vehicle for topical application of the said antimicrobial composition.

10. An anti-microbial composition for topical use as claimed in anyone of Claims 5 to 9 wherein said anti-microbial active preferably anti-dandruff active comprises selectively pure 1,2,4,5-tetrahydroxybenzene derivatives of Formula 1 or preferably embeliol of Formula 2, as pure compounds or as at least one ingredient in the semi pure extract of the reaction mixture or plant extract.