FIELD OF THE INVENTION

The present invention relates to skincare agents and cosmetic skin lightening agents and particularly relates to selective stilbene based skincare agents and cosmetic skin lightening compositions containing the same in effective amounts present in combination with or without other skin benefiting agents in the said composition. More particularly, the present invention relates to a simple and cost effective cosmetic/ dermopharmaceutical compositions for external applications to facilitate lightening of skin colour by way of dendrite elongation inhibition comprising said skin care agents either obtained synthetically and/or sourced from appropriate renewable plant source including Crotalaria medicaginea Lam., as extracts or concentrates. Advantageously, the said extracts/ concentrates are either used singly or in combination with suitable cosmetically/ dermopharmaceutically acceptable vehicles in the said compositions.

BACKGROUND ART

An increase in skin pigmentation over the basal constitutive level is referred to as facultative pigmentation. A major stimulus of facultative pigmentation in humans is UVR. UVR induced skin pigmentation or tanning as it is commonly known, involves several process like increased proliferation, enhanced tyrosinase expression, increased dendricity and increased transfer of melanin to ease the transfer the melanin keratinocytes.

Skin lightening is an important contributor to skin care attribute of cosmetic preparation/compositions, especially among darker skinned people including Asian population. Such a need includes a lightening of basal skin tone. Also it is desired by persons having spots, freckles or lesions which are hyperpigmented and thus need to be diminished. In other situations subjects may desire to reduce their natural skin colour or the skin darkening caused by exposure to intense sun rays. The degree of pigmentation of the skin is thus a principal cause of concern for many people. The complexion of the skin is determined by the pigment melanin. Melanocytes are the pigment producing cells that provide photo protection to the skin by synthesizing and distributing the pigment melanin to keratinocytes. These melanocytes are located in the basal layer of keratinocytes. Melanocytes and keratinocytes are resident population of epidermis and the color of skin is only because of the melanin in keratinocytes which is transferred from melanocytes. Melanocytes are derived from neural crest cells, comprise of 1-2% of epidermal cell population and are solely responsible for the production and transfer of melanin to keratinocytes and pilosebaceous follicle. Melanin is synthesized and packed in cytoplasmic organelles of melanocytes, called melanosomes and are later transferred to keratinocytes through specialized structures in the melanocytes called dendrites. Since melanocytes are the minor population in the epidermis, the presence of the multiple dendrites facilitates transfer of melanosomes to keratinocytes that surround melanocytes. Movement of the melanosomes along melanocyte dendrites is also necessary for the transfer of melanin pigment from melanocytes to basal and suprabasal keratinocytes to maintain the normal skin color. Melanocyte dendrite formation is regulated by multiple signaling pathways stimulated by paracrine factors released by keratinocytes (Hara et. al., J. Invest. Dermatol., 2000, 114, 438-443).

The dendricity of melanocytes is regulated by various intrinsic and extrinsic factors. Addition of agents that increase the intracellular levels of cyclic adenosine monophosphate, dibutyryl cyclinc adenosine monophosphate or isobutylmethyl xanthine (IBMX), has strong effects on dendrite formation (Glynis et. al., J. Invest. Dermatol., 2007, 127, 668-675). Each melanocyte makes contact with around 30-40 keratinocytes and this constitutes the epidermal melanin unit. Mammalian melanocytes in the epidermal unit extend their dendrites towards keratinocytes in response to UV rays in addition to proliferation and melanin synthesis leading to tanned skin (Suzuki et al., In Vitro Cell Dev. Biol. Anim., 1993, 29, 419-426). Increased number of dendrites and increase in the length of the dendrites, higher levels of transfer of melanin to keratinocytes have been established. Thus skin colour can be determined/regulated by modulating the elongation of dendrites or dendrite numbers (Akihiro, Fragr J, 2005, 33, 30 and Tada et. al., Bio. Ind., 2005, 22, 12-17). Under normal conditions it is not the number of melanocytes in the skin that determines the degree of pigmentation but their levels of activity and the transfer of melanin in to the neighboring keratinocytes.

Phospholipase A2 secreted by kertinocytes is also known to mediate melanocyte dendricity. The effective transfer of the synthesized melanin by the melanocytes to the keratinocytes plays a very critical role in the skin colour than the extent of synthesis of melanin by the melanocytes. The most effective mode of transfer of the melanin to the keratinocytes is governed by the dendritic phenomena of the melanocytes. Abrogating the dendriticity of melanocytes is of great importance for controlling skin colour (Yuko et. al., Biochimica et Biophysica Acta, 2006, 1769, 487).

There are several dendrite inhibitors already reported in the literature. Benzoquinone group of chemicals that includes methyl ophiopogonanone B and centaureidin, benzopyranone, xanthanone derivatives were reported to inhibit dendrite formation in melanocytes and effectively affect the skin colour (Yuko et. al., Biochimica et Biophysica Acta, 2006, 1769, 487). Inhibiting the dendrite formation in melanocytes assures to be more effective than tyrosinase inhibition for the purpose of skin lightening/whitening cosmetics (Tada et. al., USP: 7, 141, 601, 2006).

US patent 7,141,601 and Korean patent 20050084088 A by Tada et al. are directed to a method of inhibiting the elongation of melanocytic dendrites through a skin preparation comprising of methylophiopogonanone B (2, 3-dihydro-3[(4-methoxyphenyl) methyl]-5, 7-dihydroxy-6, 8-dimethyl-4H-l-benzopyran-4-one) extracted from the tubers of Ophiopogon japonicus ker-Gawler.

JP 2004143073 A further illustrates a 1, 3-dioxolane derivative of methyl-ophiopogonanone B to possess the same property of inhibiting the elongation of melanocytic dendrites.

JP 2001335420 A is related to a skin lotion comprising the essence of rhizomes of Acorus calamus; JP 2001335421 A is directed to the essence of Sophora subprostata) JP 2003081748 A teaches a fruit essence of Forsythia suspensa Thunb. Vahl of Oleaceae; JP 2003081747 A illustrates a skin care preparation comprising the essence of Lonicera japonica Thunb preferably the essence of bulbs, leaves and stems; JP 2002053421 A is directed to a cosmetic skin care preparation comprising Maackiain derived form the rhizomes of Sophora subprostrata; JP 2002154919 A comprises of a skin care preparation comprising the essence of the fruit of Phaseolus radiatus L; JP 2003081807 A is related to a bleaching cosmetic comprising an essence of Calendula officinalis L. and preferably an essence of a flower bud, a leaf and a stem; JP 2003113027 (A) is directed to a bleaching cosmetics by incorporating the essence of preferably enlarged root of plant of genus Ophiopogon such as Ophiopogon japonicus ker-Gawler etc.; JP 2003252742 A discloses a skin preparation having high bleaching effect comprising yeast extract as the active ingredient; JP 2001335502 A is related to a skin care preparation comprising the essence of rhizomes of Nardostachys jatamansi; JP 2002020303 A illustrates a cosmetic skin care preparation comprising the essence of rhizome of Thalictrum minus var. hypoleucum; JP 2004250354 A is related to a cosmetic preparation comprising extract of a plant belonging to Achillea family; JP 2003081746 A is directed to a bleaching cosmetics comprising an essence of Uncaria gambhir ROXBURGH, preferably the essence of leaves and sprigs; JP 2002154920 A is directed to a cosmetic skin care preparation including the essence of a ripe dried seed, preferably a fruit of Prunus armeniaca L. var. ansu axim. of the family Rosaceae; JP 2001335485 A directed to a skin care preparation comprising of a berberine derivative; all of which have the dendrite inhibition property. However, some of these products are associated with simultaneous disadvantages associated with each of them. For example, Acorus calamus is considered to be cytotoxic as reported by Padmaja et al. in Fitoterapia. 2002, 73, 508-510.

Our co- pending, Indian patent application 2140/CHE/2009, teaches dendrite elongation characteristics of an aromatic ketone isolated from Artocarpus altilis in cell lines.

Similarly, another co-pending Indian patent application 2217/CHE/2009, discloses two amide compounds, piperin and isopiperlongumine with dendrite elongation inhibition characteristics.

Also, yet another co-pending Indian patent application 479/CHE/2010 illustrates the dendrite elongation inhibition activity of the selective betuligenol and its derivatives thereby efficacious as skin lightening agent.

EP 1570838 Al is mainly directed to dendrite elongation inhibitor for melanocytes comprising of centaureidin that was used directly or in the form of a physiologically acceptable salt in cosmetic skin preparations intended for alleviating dyschromatosis to which the amount of melanin produced contributes less resulting from the accelerated migration of melanin granules from melanocytic dendrites.

While inhibiting the elongation of dendrites that occurs when melanocytes allow melanin granules to migrate is a well known skin lightening mechanism not so many lightening agents utilizing such a mechanism are known in the art and it can thus be said that there is a strong need in the art for the development of new skin lightening agents utilizing such a mechanism.

Therefore, the existing state of the art clearly reveals the need for newer, effective and safe dendrite elongation inhibitors and more importantly the need for possible isolation of the said dendrite elongation inhibitors from renewable resource materials such as plants apart from the synthetics.

OBJECTS OF THE INVENTION

It is thus the basic object of the present invention to provide for a new skin care agent imparting effective protection against pigmentation of the skin with dendrite elongation inhibition characteristics that would be effective, safe and compatible to the skin.

Another object of the present invention is directed to skin care formulation including a dermopharmaceutical and/ or a cosmetic composition involving the said skin care agent in effective amounts whose functional benefit includes the dendrite elongation inhibitory property that would cater to variety of skin conditions in association with an acceptable vehicle with or without other skin care benefiting agents.

Yet another object of the present invention is to provide for a skin care agent for variety of skin care formulations and the like with anti-tanning property involving dendrite inhibitory mechanism that can be sourced either synthetically or simply and cost effectively from natural renewable resources such as plants.

A further object of the present invention is to provide for a process of formulation of the selective extract and/ or active ingredient obtained from plant sources having dendrite elongation inhibitory property wherein such selective actives would act as a skin benefiting agent/ active especially favouring the lightening of skin colour.

A still further object of the present invention is directed to the preparation/ formulation of the skin care composition comprising effective amounts of either said synthetically active compounds or the extracts and /or active part of plant concentrates isolated from the plant sources such that the product obtained by incorporating said active ingredients/ extracts have good skin compatibility.

SUMMARY OF THE INVENTION

Thus according to the basic aspect of the present invention there is provided a skin lightening agent comprising an effective dendrite elongation inhibiting active selected from anyone or more of stilbene derivatives of Formula 1

In accordance with a another aspect of the present invention there is provided a skin lightening agent comprising stilbene derivative tetramethoxy piceatannol of Formula 2 as an effective dendrite elongation inhibiting active as hereunder.

Tetramethoxy piceatannol (Formula 2)

Importantly, in keeping with the requirement for a skin care agent involving mechanism for inhibiting the elongation of dendrites it has surprisingly been found that the above said compound meet the much desired criteria of a superior skin lightening agent by way of said inhibition of elongation of dendrites which is found to be simple in effecting the lightening of the skin under low effective concentrations, economical and safe in having less or no side effects when present in combination with or without other skin benefiting agents .

Also, efforts were further directed to provide said selective compounds for Formula 1 and specifically Formula 2 revealing the characteristic property of inhibiting the elongation of dendrites thereby resulting in skin lightening sourced from plant species and according to yet another aspect of the invention there is provided a skin lightening agent wherein the said agent comprises said stilbene derivatives of Formula 1 or preferably tetramethoxy piceatannol of Formula 2 as extracts/ concentrates from appropriate plant sources such as Crotalaria medicaginea or as extracts / concentrate from any other natural source material containing anyone or more of the actives of Formula 1 or tetramethoxy piceatannol of Formula 2 as atleast one ingredient as the dendrite elongation inhibiting active .

Advantageously, the above extract / concentrate of the selective compound of Formula 1 and 2 sourced from Crotalaria medicaginea surprisingly in substantial deviation from its known characteristics / biological properties revealed the characteristics of inhibiting the elongation of dendrites in accordance with the present invention.

Importantly, this was in substantial deviation from the well known several biological properties of the extracts from leaves of the plant as on record such as; the ethanolic extract of the leaves and stems of Crotalaria medicaginea exhibited anti¬fungal activity (Garg et al., Journal of Natural Products, 1991, 54, 104). Two new compounds, crotamadine and crotamarine were isolated from the 50% ethanolic extract of leaves and stems showed antifungal activity at a concentration of 62.5 ng/ml against Trichophyton mentagrophytes (Bhakuni et al., Journal of Natural Products, 1984, 47, 585-589).

In the backdrop of the abovesaid, it is indeed apparent that the actives of Formula 1 and 2 sourced from the Crotalaria medicaginea were thus surprisingly and selectively efficacious in terms of the desired mechanism for inhibiting the elongation of dendrites that is additionally endowed with favourable sunscreen properties.

In yet another aspect of the present invention there is provided the said skin lightening agent wherein the said actives are selected from anyone or more of stilbene derivatives of Formula 1 or is preferably tetramethoxy piceatannol of Formula 2 either obtained synthetically and/or from plant extracts.

In another preferred aspect of the present invention there is provided the said skin lightening agent wherein the said agent is selected from one or more of stilbene derivatives of Formula 1 or preferably tetramethoxy piceatannol of Formula 2, as extracts/ concentrates from plant Crotalaria medicaginea Lam., or as extracts/ concentrate from the said plant containing tetramethoxy piceatannol of Formula 2 as atleast one ingredient in methanol or more preferably in ethyl acetate, or any plant material itself sourcing such said actives of Formula 1 or Formula 2.

In yet another preferred aspect of the present invention there is provided the said skin lightening agent wherein the said dendrite elongation inhibiting active comprises extracts from plant parts preferably selected from leaves of plants of Crotalaria medicaginea, including its variants and containing tetramethoxy piceatannol of Formula 2 as at least one of its secondary metabolites.

In another aspect of the present invention there is provided a sunscreen agent comprising UVA and UVB actives selected from anyone or more of stilbene derivatives of Formula 1 hereunder Wherein R1 = H, CH3 or Ac R2 = H, CH3 or Ac R3 = H, CH3 or Ac R4 = H, CH3 or Ac and more preferably tetramethoxy piceatannol of Formula 2 Tetramethoxy piceatannol (Formula 2) sourced from either extracts/ concentrates of the appropriate plant Crotalaria medicaginea Lam., or the plant material itself.

In accordance with another aspect of the present invention there is provided a cosmetic and / or dermopharmaceutical composition for topical use comprising an effective amount of skin lightening agent including said dendrite elongation inhibiting active; and cosmetically/ dermopharmaceutically acceptable vehicle with or without other skin benefiting agents.

In accordance with yet another preferred aspect of the present invention there is provided the said cosmetic and/or dermopharmaceutical composition for topical use comprising an effective amount of dendrite elongation inhibiting actives of Formula 1 or preferably Formula 2 obtained synthetically, and/or from extracts/ concentrates from the said plant and preferably from the said select plant part such as leaves and preferably as a methanol extract / concentrate, or the plant material itself and a cosmetically/ dermopharmaceutically acceptable vehicle with or without other skin care benefiting agents.

In accordance with yet another preferred aspect of the present invention there is provided the said cosmetic and/or dermopharmaceutical composition for topical use comprising

a) 0.001 wt % to 20 wt. % of said dendrite elongation inhibiting active, preferably
0.01 wt % to 10 wt % of the said dendrite elongation inhibiting active and more preferably 0.1 wt % to 5 wt % of said dendrite elongation inhibiting active and

b) a cosmetically acceptable vehicle with or without other skin benefiting agents.
According to yet another preferred aspect of the present invention there is provided a cosmetic and/or dermopharmaceutical composition for topical use comprising a leave-on or a wash-off product adapted for topical delivery in the form of creams, ointments, emulsions, gels, lotions, oils, sticks, sprays, soaps, packs, wraps, woven or nonwoven wipes, films or patches as a vehicle for topical application of the said dendrite elongation inhibiting composition.

Most advantageously, a cosmetic and / or dermopharmaceutical composition for topical use is provided wherein the said skin lightening agent comprising said dendrite elongation inhibiting active selectively comprises any one or more of (a) stilbene derivatives selected from anyone or more of compounds of Formula 1 or preferably tetramethoxy piceatannol of Formula 2; (b) an extract/ concentrate of an appropriate natural source material comprising said selected anyone or more of stilbene derivatives of Formula 1 or preferably tetramethoxy piceatannol of Formula 2; and (c) any natural source material comprising anyone or more of the said active stilbene derivatives of Formula 1 or preferably tetramethoxy piceatannol of Formula 2.

In another aspect of the present invention there is provided a cosmetic and/ or skincare composition for topical use comprising an effective amount of sunscreen agent including the said UVA and UVB actives sourced from appropriate plant Crotalaria medicaginea Lam; and cosmetically/ dermopharmaceutically acceptable vehicle with or without other skin benefiting agents.

DETAILED DESCRIPTION OF THE INVENTON

As discussed herein before, the present invention provides a selective dendrite elongation inhibiting active compound or mixture of compounds as extracts of renewable natural source material or wherein said active compounds are obtained via synthesis acting as skin lightening agent and in particular favours in providing effective protection against darkening/ tanning of the skin in a cosmetic/ dermopharmaceutical composition for topical use. The invention is further related to a process for producing the said selective combination of skin lightening promoting actives or pure compounds/ agents with or without other carriers/ skin benefiting additives involving its selective isolation from plants (Ex. Crotalaria medicaginea Lam) and also to processes for producing the said compositions and achieving skin lightening effect.

According to one aspect of the invention there is provided a cosmetic and/ or dermopharmaceutical composition for topical use comprising the skin lightening agent as the dendrite elongation inhibiting active comprising selectively at least one or more stilbene derivatives of Formula 1 sourced synthetically and/or naturally preferably stilbene derivative of Formula 2 as represented hereunder; as an extract/ concentrate of an appropriate natural isolate or obtained synthetically; or even a natural source material itself sourcing the said active compound tetramethoxy piceatannol of Formula 1 and/ or Formula 2.
Wherein
R1 = H, CH3 or Ac
R2 = H, CH3 or Ac
R3 = H, CH3 or Ac
R4 = H, CH3 or Ac

In accordance with an exemplary and non-limiting embodiment, the said active
compounds selected from one or more of stilbene derivatives of Formula 1 of the
present invention is selected from tetramethoxy piceatannol of Formula 2 as given
below.

Tetramethoxy piceatannol (Formula 2) According to a further aspect of the invention, the said cosmetic and / or dermopharmaceutical composition for topical use includes dendrite elongation inhibitory agent comprising extracts / concentrate from leaves of Crotalaria medicaginea, preferably methanol concentrate comprising tetramethoxy piceatannol of Formula 1 or preferably Formula 2 or at least one compound of Formula 1.

Advantageously, a sunscreen agent comprising UVA and UVB actives selected from anyone or more of stilbene derivatives of Formula 1 hereunder Wherein
R1 = H, CH3 or Ac
R2 = H, CH3 or Ac
R3 = H, CH3 or Ac
R4 = H, CH3 or Ac
sourced from either extracts/ concentrates of the appropriate plant Crotalaria
medicaginea Lam., or the plant material itself, and a cosmetic/ skincare composition
containing the same is also provided by way of the present invention.

In accordance with yet another aspect of the invention there is provided a process for the extraction and isolation of dendrite elongation inhibitory agent from an appropriate source Crotalaria medicaginea comprising the steps of:

a) subjecting the air-dried leaves of Crotalaria medicaginea in powder form, to extraction with an organic solvent such as methanol to provide for an extract;

b) removing the solvent from the extract under vacuum to provide for a concentrate;

c) subjecting the concentrate to vacuum liquid chromatography using chloroform, ethyl acetate and ethyl acetate : MeOH (8:2) as eluents;

d) evaluating the fractions for dendrite elongation inhibition property to identify the active fraction;

e) subjecting the active fraction to further chromatography using eluents such as
Hexane, hexane: chloroform (9:1, 8:2, 7:3), pooling the fractions and concentrating the resulting solution to dryness in vacuo to provide for more enriched concentrate;

f) subjecting the enriched concentrate to a further purification, to provide for said compounds of the invention.

Specific examples of the stilbene derivative of Formula 1 for inclusion in the compositions of the invention are either isolated from the plant, Crotalaria medicaginea or manufactured synthetically.

The ingredients essentially employed in such a composition are surfactants, emulsifiers emollients, silicones, thickeners, antioxidants, sunscreen agents, chelating agents, perfumes, opacifiers, colors, antimicrobial agents, herbal extracts /compounds, pH adjusting agents and water to qs.

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/ dermopharmaceutical 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 diluant, 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 Q-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 15 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.

Surfactants are also included in the cosmetic compositions of the present invention. For leave-on products, total concentration of the surfactant range from 0.1 to 40 %, preferably from 1 to 20 %, optimally from 1 to 15 % by weight of the composition. For wash-off products, such as cleansers and soap, total concentration of surfactant will range at about 1 to about 90 %. The surfactant may be selected from the group consisting of anionic, nonionic, cationic and amphoteric actives. The inventive cosmetic composition of the invention optionally contains a lathering surfactant. By a "lathering surfactant" it is meant a surfactant which, when combined with water and mechanically agitated, generates a foam or lather. Preferably, the lathering surfactant should be mild, meaning that it must provide sufficient cleansing or detergent benefits but not overly dry the skin, and yet meet the lathering criteria described above. The cosmetic compositions of the present invention may contain a lathering surfactant in a concentration of about 0.01 % to about 50 %.

Silicone oils may be divided into the volatile and non-volatile variety. The term "volatile" as used herein refers to those materials which have a measurable vapor pressure at ambient temperature. Volatile silicone oils are preferably chosen from cyclic or linear polydimethylsiloxanes containing from 3 to 9, preferably from 4 to 5, silicon atoms. Nonvolatile silicone oils useful as an emollient material include polyalkyl siloxanes, polyalkylaryl siloxanes and polyether siloxane copolymers. The essentially non-volatile polyalkyl siloxanes useful herein include, for example, polydimethyl siloxanes with viscosities of from about 1 to about 25 million centistokes at 25°C. Among the preferred non-volatile emollients useful in the present compositions are the polydimethyl siloxanes having viscosities from about 10 to about 2,00,000 centistokes at 25°C.

Among the ester emollients are: (1) Alkenyl or alkyl esters of fatty acids having 10 to 20 carbon atoms (2) Ether-esters such as fatty acid esters of ethoxylated fatty alcohols (3) Polyhydric alcohol esters (4) Wax esters (5) Sterol esters (6) Fatty acids having from 10 to 30 carbon atoms may also be included as cosmetically acceptable carriers for compositions of this invention.

Humectants of the polyhydric alcohol-type may also be employed as cosmetically acceptable carriers in the compositions of the present invention. The amount of humectant may range anywhere from 0.5 to 30%, preferably between 1 and 15% by weight of the composition.

Thickeners/ rheology modifiers may also be utilized as part of the cosmetically acceptable carrier of compositions according to the present invention. Amounts of the thickener may range from 0.0001 to 10 %, usually from 0.001 to 5 %, by weight.

Collectively the water, solvents, silicones, esters, fatty acids, humectants and/ or thickeners constitute the cosmetically acceptable carrier in amounts from 1 to 99.9 %, preferably from 80 to 99 % by weight.

An oil or oily material may be present, together with an emulsifier to provide either a water-in-oil emulsion or an oil-in-water emulsion, depending largely on the average hydrophilic-lipophilic balance (HLB) of the emulsifier employed.

In the cosmetic compositions of the invention, there may be added various other plasticizers, elastomers, calamine, pigments, antioxidants, chelating agents, and perfumes, as well as organic sunscreens and sunscreens such UV diffusing agents, typical of which is finely divided titanium oxide and zinc oxide.

The details of the invention, its objects and advantages are explained hereunder in greater detail in relation to non-limiting exemplary illustrations as per the following examples:
General Extraction Procedure:

The extraction procedure of the invention involves extracting the active from the selective natural renewable source such as plants, preferably Crotalaria medicaginea Lam., belonging to the Fabaceae family.

The extracts to be used according to the invention are obtained from the leaf of the plant belonging to the above said family, specifically from Crotalaria medicaginea Lam.

Extract/Concentrates

The leaf extract/ concentrates of the leaves of the plant Crotalaria medicaginea Lam., according to the present invention generally comprise, as active ingredient, classes of chemicals like stilbene based aromatics. The final product involves a composition that varies depending on the starting material and on the selective method of extraction.

The Solvent Extraction process:

The extract/ concentrates used according to the present invention as described above for the purpose of producing desired multifunctional skin care formulation are prepared by conventional methods of extraction of the leaf of the plant. Such suitable conventional extraction methods, may include maceration, remaceration, agitation maceration, digestion, fluidized-bed extraction, ultrasound extraction, countercurrent extraction, cryogenic extraction, percolation, repercolation, evacolation, diacolation and solid-liquid extraction under continuous reflux which is carried out in a Soxhlet extractor, each of which is known to the person skilled in the art and any of which can be used in principle, reference may be made by way of example to Hagers Handbuch der Pharmazeutischen Praxis (5th.Sup. edition, Vol. 2, pp. 1026 1030, Springer Verlag, Berlin-Heidelberg-New York 1991). Solvents:

Solvents used for carrying out the extractions are preferably organic solvents, water or mixtures of organic solvents and water, in particular low molecular weight alcohols, esters, ethers, ketones or halogen-containing hydrocarbons with greater or lesser water contents (distilled or un-distilled), preferably aqueous, alcoholic solutions with greater or lesser water contents. However, preference is particularly given to extraction with water, methanol, ethanol, propanol, butanol and isomers thereof, acetone, methyl ethyl ketone, propylene glycols, polyethylene glycols, ethyl acetate, chloroform, dichloromethane, trichloromethane, and mixtures thereof.

The extraction usually takes place at 20°C to 140°C, preferably at 30°C to 120°C, in particular at the boiling temperature of the solvents or solvent mixtures. In one embodiment, the extraction is carried out under an inert gas atmosphere to avoid oxidation of the ingredients of the extract. The extraction times are adjusted by any person skilled in the art depending on the variable parameters for the extraction process such as starting material, the extraction method, the extraction temperature, the ratio of solvent to raw material, etc. After the extraction, the resulting crude extracts can optionally be subjected to further customary steps, such as, for example, concentration, fractionation by partitioning between solvents, purification, including different types of chromatography, concentration and/ or decoloration. If desired, the extracts prepared in this way can, for example, be subjected to selective removal of individual undesired ingredients. The extraction can be carried out to any desired degree of extraction, but is usually carried out exhaustively.

Air-dried aerial parts of Crotalaria medicaginea Lam., were grounded preferably, grounded coarsely and subjected to an extraction with one or more organic solvents like lower alcohols, preferably methanol, or esters, preferably, ethyl acetate or halogenated hydrocarbons, preferably chloroform, to provide an extract.

The present invention encompasses the finding that the extraction conditions and also the yields of the end extracts can be chosen depending on the desired field of use, through deployment of appropriate precise screening techniques, including dendrite elongation inhibitory activity and other related screens.

The invention, its objects and advantages are explained hereunder in greater detail in relation to non-limiting exemplary illustrations as per the following examples:

EXAMPLES:

Example 1 - Extraction of the active from the leaves of Crotalaria
medicaainea Lam.

The air-dried aerial parts of Crotalaria medicaginea Lam., (1025g) were powdered, extracted with methanol through soxhlet apparatus for 8 hrs. The dilute extract was concentrated under reduced pressure to get 80.0g of crude methanol concentrate.

The crude methanol concentrate showed dendrite inhibition property. The crude methanol concentrate (30g) was adsorbed on the silica gel, performed vacuum liquid chromatography using chloroform, ethyl acetate and ethyl acetate: methanol (8:2) to get six fractions 2.193g (Fr.l), 2.548g (Fr.2), 5.535g (Fr.3), 3.785g (Fr.4), 2.364g (Fr.5), and 1.3g (Fr.6) respectively. All Six fractions were submitted for biological activities and it was found that Fr.l, Fr.4 and Fr. 6 showed good dendrite inhibition property, Fr.5 showed less activity where as Fr.2 and Fr.3 were found to be toxic.

Example 2 - Isolation of active compound from the active fraction of Crotalaria medicaainea Lam.

One of the active fraction (Fr.l) of Crotalaria med/caginea Lam. (2.01 g) was dissolved in chloroform and adsorbed on silica gel (100-200 mesh, 5 g). 40 g of silica gel (100-200 mesh) was packed in glass column by using hexane as solvent, followed by loading the adsorbed silica gel. The column was eluted with hexane (200ml), hexane: chloroform 9:1 (400 ml) and hexane: chloroform 8:2 (300 ml). The fractions were analyzed by thin layer chromatography and fractions showing similar TLC behaviour were combined to obtain three sub fractions. Sub-fraction 3 from hexane: chloroform (8:2) was concentrated to yield another residue (1.05g) which was further purified through repeated silica gel chromatography with hexane: ethyl acetate (9:1) to get an yellow colored semisolid, 0.12g which is the preferred compound tetramethoxy piceatannol of Formula 2 of the invention. The compound of said Formula 2 displays the following characteristics:

On thin layer chromatography using a pre-coated silica gel plate, the isolated compound of Formula 2 provides a spot with an Rf value of 0.28 in hexane: ethyl acetate 8:2;

The UV (MeOH) spectrum shows A.max absorbance value at 325 nm; The IR spectrum values are at 1593, 1514, 1285, 1155 cm"1 and other characteristic signals; Proton (XH) NMR values in CDCI3 are at: 5 3.84 (6H, s), 3.91(3H, s), 3.95 (3H, s) 6.39 (1H, br s), 6.84 (1H, d, 3=8.1 Hz), 6.91 (1H, d, J = 16.2 Hz), 7.04 (1H, d, J=16.5 Hz) 7.05 (1H, d, J=8.1Hz), 7.07 (1H, br s); Carbon (13C) NMR values in CDCI3 are at: 5 55.2, 55.2, 55.8, 55.9, 99.7, 104.3, 104.3, 108.9, 111.3, 119.9, 126.7, 128.9, 130.2, 139.5, 149.0, 149.1, 160.9, 160.9. M+=300. Example 3 - Biological Evaluation

This example demonstrates the method of determining the dendrite elongation inhibition activity of the specially preferred extract/ compound/ formulations of the invention through cell culture method by estimating the length of dendrites.

The melanocyte cells, B16F10 were used for the present study. The cells were cultured in DMEM in the presence of 5% carbon dioxide, 10% serum, Pencillin (100>g/ml), streptomycin (50ng/ml), Amphotericin B. (2.5ng/ml). 1 X 10s cells were seeded in 60 mm cell culture dish and were incubated with and without the test material for 24 hrs. After 24 hr incubation, the cells were examined under an inverted microscope and the dendrite length was measured (USP 7141601B, 2006)

Table 1

Comparison of the % inhibition of the dendrites

It is thus concluded from the results under Table 1 that the crude methanolic extract inhibits the elongation of the length of the dendrites by 80%. It is also noteworthy that the specific stilbene compound tetramethoxy piceatannol of Formula 2 inhibits the elongation of dendrites by 44% at 10 (.iQ/ml and by 57% at 25 |ng/ml and most significantly the skincare cream formulated by the alcoholic crude concentrate inhibits the elongation of the dendrites by 24%. With the increase in concentration of the active, there is a gradual rise in % inhibition of the length of the dendrites without any noted saturation on dendrite elongation inhibition properties with increasing concentration thus facilitating different compositions with different wt % of the actives from lower to higher levels to thereby also impart higher degrees of skin lightening/ care to the subjects needing greater skin lightening in addition to the subjects requiring normal skin lightening, and which said compositions are also free of other skin related complications due to the employment of such high amount of actives.

Example 4: Formulation of skin cream

1. Phase A ingredients were heated to 70-75°C on water bath wherein the mixture was melted.

2. Phase B ingredients were also heated to 75-80°C in a separate container.

3. Phase A was mixed with Phase B at high speed and the mixture was emulsified for 5 minutes.

4. The extract/ crude concentrate were dissolved or suspended in water and alcohol mixture.

5. Phase C was added to Phase AB at 45°C and thoroughly mixed to yield the
skincare cream.

Example 5: Formulation of lotion

Table 3

Process for manufacturing the above said formulation in the form of lotion:

1. Demineralized/ DM water from Phase A was taken and the carbomer was dispersed carefully without forming lumps and stirred for 30 minutes, finally the pH was adjusted to 4.5 by using TEA.

2. After mixing Phase A ingredients, Phase B was added to phase A and stirred well for five minutes.

3. Phase C ingredients were heated at 70-75°C and added to Phase AB and stirred well for 5 minutes.

4. Phase ABC was cooled to 60°C and this mixture was neutralized by using Phase D and the pH adjusted between 6.5-7.00 and stirred well.

5. Phase ABCD was cooled to 45°C, colors and perfume were added and stirred well for another 5 minutes to yield the lotion.

Thus the present invention provides for a desired skin care/lightening agent and cosmetic skin lightening compositions obtained thereof and, in particular, provides for selective stilbene based skin care/ lightening agents and cosmetic and/ or dermopharmaceutical compositions containing the same. Importantly, the present invention thus favours in obtaining a skin care agent wherein the actives of the above said Formula 1 and tetramethoxy piceatanol of Formula 2 are either preferably obtained from safe and renewable sources, such as Crotalaria medicaginea Lam., or obtained as pure compound (via., Synthesis or isolation from appropriate extract) that is used either singly or in combination with a cosmetically/ dermopharmaceutically acceptable vehicle with or without other skin care benefiting agents.

WE CLAIM:

1. A skin lightening agent comprising an effective dendrite elongation inhibiting active selected from one or more of stilbene derivatives of Formula 1 Wherein
R1 = H, CH3 or Ac R2 = H, CH3 or Ac R3 = H, CH3 or Ac R4 = H, CH3 or Ac

2. A skin lightening agent comprising stilbene derivative tetramethoxy piceatannol of Formula 2 as an effective dendrite elongation inhibiting active as hereunder Tetramethoxy piceatannol (Formula 2)

3. A skin lightening agent as claimed in anyone of Claims 1 or 2, wherein the said actives are selected from anyone or more of stilbene derivatives of Formula 1 or is preferably tetramethoxy piceatannol of Formula 2 obtained synthetically and/or from plant extracts.

4. A skin lightening agent as claimed in any one of the preceding claims wherein the said agent is selected from one or more of stilbene derivatives of Formula 1 or preferably tetramethoxy piceatannol of Formula 2, as extracts/ concentrates from plant Crotalaria medicaginea Lam, or as extracts/ concentrate from the said plant containing tetramethoxy piceatannol of Formula 2 as atleast one ingredient in methanol or more preferably in ethyl acetate, or any plant material itself sourcing such said actives of Formula 1 or Formula 2.

5. A skin lightening agent as claimed in anyone of Claims 1 to 4 wherein the said dendrite elongation inhibiting active comprises extracts from plant parts preferably selected from aerial parts of plants of Crotalaria medicaginea, including its variants and containing tetramethoxy piceatannol of Formula 2 as at least one of its secondary metabolites.

6. A sunscreen agent comprising UVA and UVB active selected from anyone or more of stilbene derivatives of Formula 1 hereunder Wherein R1 = H, CH3 or Ac R2 = H, CH3 or Ac R3 = H, CH3 or Ac R4 = H, CH3 or Ac and preferably tetramethoxy piceatannol of Formula 2 Tetramethoxy piceatannol (Formula 2) sourced from either extracts/ concentrates of the appropriate plant Crotalaria medicaginea Lam., or the plant material itself.

7. A cosmetic and / or dermopharmaceutical composition for topical use comprising an effective amount of skin lightening agent including the dendrite elongation inhibiting active as claimed in anyone of Claims 1 to 5; and cosmetically/ dermopharmaceutically acceptable vehicle with or without other skin benefiting agents.

8. A cosmetic and/or dermopharmaceutical composition for topical use as claimed in claim 7 comprising an effective amount of dendrite elongation inhibiting actives of Formula 1 or preferably Formula 2 obtained synthetically, and/or from extracts/ concentrates from the said plant and preferably from the said select plant part such as aerial parts and preferably as a methanol extract / concentrate, or the plant material itself, and a cosmetically/ dermopharmaceutically acceptable vehicle with or without other skin care benefiting agents.

9. A cosmetic and/or dermopharmaceutical composition for topical use as claimed in
Claims 7 and 8 comprising

a) 0.001 wt % to 20 wt. % of said dendrite elongation inhibiting active, preferably 0.01 wt % to 10 wt % of the said dendrite elongation inhibiting active and more preferably 0.1 wt % to 5 wt % of said dendrite elongation inhibiting active and

b) a cosmetically acceptable vehicle with or without other skin benefiting agents.

10. A cosmetic and/or dermopharmaceutical composition for topical use as claimed in anyone of claims 7 to 9 comprising a leave-on or a wash-off product adapted for topical delivery in the form of creams, ointments, emulsions, gels, lotions, oils, sticks, sprays, soaps, packs, wraps, woven or nonwoven wipes, films or patches as a vehicle for topical application of the said dendrite elongation inhibiting composition.

11. A cosmetic and/ or dermopharmaceutical composition for topical use as claimed in anyone of claims 7 to 10 wherein the said skin lightening agent comprising said dendrite elongation inhibiting active selectively comprises any one or more of (a) stilbene derivatives selected from anyone or more of compounds of Formula 1 or preferably tetramethoxy piceatannol of Formula 2; (b) an extract/ concentrate of an appropriate natural source material comprising said selected anyone or more of stilbene derivatives of Formula 1 or preferably tetramethoxy piceatannol of Formula 2; and (c) any natural source material comprising anyone or more of the said active stilbene derivatives of Formula 1 or preferably tetramethoxy piceatannol of Formula 2.

12. A cosmetic and/ or skincare composition for topical use comprising an effective amount of sunscreen agent including the UVA and UVB actives sourced from Crotalaria medicaginea as claimed in 6; and cosmetically/ dermopharmaceutically acceptable vehicle with or without other skin benefiting agents.

13. A skin lightening agent comprising anyone or more of stilbene derivatives of Formula 1 or preferably Formula 2 as dendrite elongation inhibiting active in effective amounts and a cosmetic and/ or dermopharmaceutical composition obtained thereof substantially as herein described and illustrated with reference to the accompanying examples.