DESC:Field of the Invention

The present invention provides for skin care composition and/or cosmetic skin lightening composition comprising synergistic combinations of 4-Hydroxyphenyl propane/butane derivatives of Formula 1 showing unexpected and significantly special effect in melanin synthesis inhibition. More particularly, the present invention is directed to a cost-effective cosmetic or dermopharmaceutical skin lightening compositions comprising said synergistic combinations of 4-Hydroxyphenyl propane/butane derivatives of Formula 1 favouring melanin synthesis inhibition actives for whitening of the skin in association with a cosmetically acceptable vehicle with or without other skin benefiting agents for external applications. The synergistic combination has simultaneous dendrite elongation inhibition and tyrosinase inhibition properties.

Background and prior art
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.
Ultra violet rays (UVR) and other forms of irradiation cause tanning. The colour change (tanning) of the skin tissue has its origin in melanin synthesis and the stagnation of the melanin inside the pigmented cells under the influence of hormones and stimulation by ultraviolet exposure. Freckles, wrinkles and the like are formed by the stagnation and the fixation of melanin inside the surface layer of the skin at some places.
As regards melanin synthesis on the skin surface, tyrosinase, which is an oxidative enzyme synthesized in the pigmented cells, oxidizes and polymerizes tyrosine thus synthesizing melanin.
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 processes like increased proliferation, enhanced tyrosinase expression, increased dendricity and increased transfer of melanin to ease the transfer of melanin to keratinocytes.
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 colour 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 melanolcytes to basal and suprabasal keratinocytes to maintain the normal skin colour. 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).
With the increase of dendrites number 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). 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), all of which 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). Also, increased number of dendrites and increase in the length of dendrites, higher levels of transfer of melanin to keratinocytes is an established phenomenon while subjected to the UV rays. 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 is the important factor. However, melanin synthesis involves many other enzymes, co-factors and hormones. The colour of the skin is the complex mixture of eumelanin and pheomelanin produced during the conversion of amino acid tyrosine to melanin involving various intermediates, enzymes and other factors which is not fully understood.
There is extensive research into ways of inhibiting melanin synthesis or reducing dendrite length and its fixation process in order to create a cosmetic skin whitening agent.
Melanin synthesis
Rumex extract acts on melanogenesis by competitive inhibition of tyrosinase. The available data suggests that Rumex extract is able to bind onto the enzyme’s active site, thereby inhibiting the substrate reduction which normally leads to melanin production (Simonot et.al., Cosmetics & toiletries magazine, 2002, 117, 51-56).
WO 2010115472 (A2) teaches on the combination of an extract of at least one Rumex plant species and S-hexadecene-1,16-dicarboxylic acid to show synergistic effect on the inhibition of melanin synthesis.
The Japanese patent, 2003-073224 teaches that the melanin formation inhibitor was obtained by including a solvent extract from one or more species of plants selected from Croton eluteria, Elettaria caradamomum and Carum carvi as an active ingredient.
Philippe has mentioned in US patent 6,306,376, 2001 that arbutin monoesters can be used in cosmetic or dermatological composition as a tyrosinase inhibitor and /or as melanin synthesis inhibitor.
The extracts with hot water, or extracts with ethanol, hexane, etc. of stems, branches, leaves, etc. of Cistus ladaniferus L., Cistus creticus L., Cistus monoperiensis L., Cistus salvifolius, etc. showed a strong inhibitory activity on production of melanin, a cell-activating activity and an anti-bacterial activity and labdanolic acid derivatives: labd-7-en-15-oic acid, labd-8(17)-en-15-oic acid, and labd-8-en-15-oic acid were responsible for strong inhibitory activity on production of melanin, a cell-activating activity and an anti-bacterial activity (Tamai et al., USP. 6,313,214; 2001)
Another US Patent (Matsuda et al., USP 6,759,557, 2004) discloses a macrocyclic ketone or hydroxy or hydroxyketone to inhibit the production of melanin, thereby controlling the skin pigmentation turning the skin fairer.
There are several agents: vitamin C, cysteine, kojic acid, arbutin, glutathione, hydroquinone and other efficient compounds extracted from natural substances are known for inhibiting melanin synthesis by lowering the tyrosinase activity or by bleaching and lightening the colour of the synthesized melanin. However, the stability, safety and whitening effect of these compounds are not sufficient, and no satisfactory whitening agent has been achieved till date.
Dendrite inhibition:
Phospholipse A2 secreted by keratinocytes 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 is thought to be more effective in the related prior arts than tyrosinase inhibition for the purpose of skin lightening/ whitening cosmetics (Tada et. al., USP: 7, 141, 601, 2006).
US patent 7141601 and Korean patent 20050084088A 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-1-benzopyran-4-one) extracted from the tubers of Ophiopogon japonicus ker-Gawler.

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

JP 2001335420A is related to a skin lotion comprising the essence of rhizomes of Acorus calamus; JP 2001335421A is directed to the essence of Sophora subprostata; JP 2003081748A teaches a fruit essence of Forsythia suspensa Thunb. Vahl of Oleaceae; JP 2003081747A illustrates a skin care preparation comprising the essence of Lonicera japonica Thunb preferably the essence of bulbs, leaves and stems; JP 2002053421A is directed to a cosmetic skin care preparation comprising Maackiain derived from the rhizomes of Sophora subprostrata; JP 2002154919A comprises of a skin care preparation comprising the essence of the fruit of Phaseolus radiatus L.; JP 2003081807A 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 2003252742A discloses a skin preparation having high bleaching effect comprising yeast extract as the active ingredient; JP 2001335502A 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 2004250354A 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 2001335485A 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.

EP 1570838A1 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 less contributes resulting form the accelerated migration of melanin granules from melanocytic dendrites.

Several prior arts on plant materials are available in alternative systems of medicine like Ayurveda and ethno medicine or folklore recommending herbal remedies for skin whitening activity.
Further in our co-pending patent application no. 3045/CHE/2011 dt. 05.09.2011 there is disclosed dendrite elongation inhibitory effect of some trans-stilbene derivatives and specifically illustrates the dendrite elongation inhibitory effect of trans-tetramethoxy piceatannol that was either obtained synthetically and/or from plant extracts of Crotalaria medicaginea Lam.
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.

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 favouring all the mechanistic pathways of skin colour inhibiting the elongation of dendrites and/or inhibiting melanin synthesis thus favour enhanced skin lightening characteristics.
The degree of pigmentation of the skin is thus a principal cause of concern for many people. To meet such skin lightening needs different attempts have been made to develop compounds and products that reduce the pigment production in the melanocytes. Conversely, it is also true that inhibition of tyrosinase may likely lead to skin lightening via inhibition of melanogenesis. For a more complete description of how tyrosinase acts within melanosomes, and how tyrosine inhibitors contribute to decreased melanin formation one can refer to United States Patent No.6537527 (March 25, 2003), to the updated review on hypo pigmenting agents and their biological, chemical and clinical aspects (F. Solano et al., Pigment Cell Res (2006), 19, 550-571) and to the review on tyrosinase inhibitors from natural and synthetic sources (Y.-J. Kim and H. Uyama, Cell.Mol.Life Sci. (2005) 62, 1707 – 1723) as examples of the many literature documents on the subject of tyrosinase inhibition, tyrosinase inhibitors and their role in skin lightening.
There are several tyrosinase inhibitors already in use in market place including 1,4-dihydroquinone, arbutin, aloesin, kojic acid, glabridin. However, these products are having simultaneous disadvantages associated with each of them. For example, 1,4-dihydroquinone can be considered to be a potent melanocyte cytotoxic agent and is also reported to induce mutations. Kojic acid and arbutin are marginal tyrosinase inhibitors, also not very bio-available and they have marginal efficacy.
p-Coumaric acid, a constituent of Sasa quelpaertensis Nakai, inhibits cellular melanogenesis stimulated by a-melanocyte stimulating hormone was reported by An, S. M.; Lee, S. I.; Choi, S. W.; Moon, S.-W.; Boo, Y. C. British Journal of Dermatology (2008), 159(2), 292-299. They elaborate that, the compd. (p-coumaric acid) inhibited a-MSH-stimulated cellular melanogenesis more effectively than arbutin or other structurally similar compounds, including 3-(4-hydroxyphenyl) propionic acid, cinnamic acid and caffeic acid. It also attenuated a-MSH-dependent increase of tyrosinase protein. The antimelanogenic effect of p-coumaric acid was also verified in neonatal human melanocytes. Further tyrosinase and melanin inhibition properties of this compound was reported by Criton, Marc; Le Mellay-Hamon, Veronique. Biological & Pharmaceutical Bulletin (2011), 34(3), 420-425.
Caffeic acid and its derivatives were identified as skin-lightening cosmetic by Shimai, Yoshiyuki; Nakano, Eiji; Ozawa, Noritaka; Nishiura, Atsuko. Jpn. Kokai Tokkyo Koho (1990), JP 02255607A 19901016. They had reported that, caffeic acid at 12.5 ppm inhibited melanin formation where as no effect was reported for kojic acid. Formulation containing the same was also disclosed by them. Later on phenylpropanoid compounds as melanin inhibitors were reported by Park, Young Mi; Yoon, Mi Yun; Kim, Kyoung Won etal., Yakhak Hoechi (2003), 47(6), 398-403. Caffeic acid acting as peroxidase inhibitors was also reported. (Cariel, Leon; Jean, Daniel Fr. Demande (1988), FR 2613622A1 19881014)
Various caffeic acid derivatives having skin lightening cosmetic application were described in prior art , methyl ester (Kim, Gi Ok; Han, Jong Heon; Kim, Bong Seok etal., Repub. Korea (2008), KR 791282B1 20080104), phenethyl ester (Ha, Gi Tae; Lee, Ji Yeon; Jung, Han Sol etal, Repub. Korean Kongkae Taeho Kongbo (2014), KR 2014080072A 20140630), stearyl ester from Paeonia suffruticosa (Liang, Chia-Hua; Chou, Tzung-Han; Tseng, Ya-Ping etal., Biological & Pharmaceutical Bulletin (2012), 35(12), 2198-2203), peptide conjugates(Cho, In Shik; Goo, Hyung Seo; Chi, Gyeong Yup etal, U.S. Pat. Appl. Publ. (2014), US 20140056835A1 20140227), phenylalanyl/prolyl hydroxamic acid (Kwak, Seon-Yeong; Yang, Jin-Kyoung; Choi, Hye-Ryung etal., Bioorganic & Medicinal Chemistry Letters (2013), 23(4), 1136-1142. ), amides (Cho, In Sik; Ji, Gyeong Yeop; Ryu, Geun Seok etal., Repub. Korean Kongkae Taeho Kongbo (2012), KR 2012029126A 20120326), amino acidyl-hydroxamic acid (Kwak, Seon-Yeong; Lee, Song; Choi, Hye-Ryung etal., Bioorganic & Medicinal Chemistry Letters (2011), 21(18), 5155-5158), glycoside derivatives(Yokoyama, Koji; Matsugami, Michio; Koiso, Ichiro etal., Kokai Tokkyo Koho (1993), JP 05201846A 19930810) and cyclohexanol ester(diacetyl derivative)( Kim, Yeong Su; Jung, Jae Gyeong; etal., Repub. Korean Kongkae Taeho Kongbo (2014), KR 2014124987A 20141028)
In contrary to these observations there are literature information teaching us that caffeic acid and its analogs were useful for treatment of depigmented skin. Caffeic acid solution remarkably accelerated skin pigmentation in patients with leukoderma (Takahashi, Hidehiko; Hayashi, Masaaki; Hara, Shin; Iikura, Yuko. Jpn. Kokai Tokkyo Koho (1997), JP 09151130A 19970610). Caffeic acid acting as cofactor in the lipoxygenase-catalyzed oxidation of 5-S-cysteinyldopa and 5-S-cysteinyldopamine (Mosca L; Foppoli C; Coccia R; Rosei M A. Pigment cell research/ sponsored by the European Society for Pigment Cell Research and the International Pigment Cell Society (1996), 9(3), 117-25) enhances polyphenoloxidase activity (Holmes, Earle W.; Thompson, Kenneth D. PCT Int. Appl. (2009), WO 2009082735A1 20090702) and also enhances the peroxidase-dependent oxidation of DOPA (Takahama, Umeo. Phytochemistry (1997), 46(3), 427-432).
The recent trends in demands of the consumers for cosmetic preparations are directed to certain extent to demonstrated skin care effect by overcoming some deficiency, having improved performance as skin protection means and providing several properties simultaneously in the same product. In particular for the purposes of skin lightening it is found desirable to achieve skin lightening effects and also simultaneously serve as sunscreens to protect the skin from the deleterious effects of exposure to harmful radiations when exposed to intense sun rays. Customers concern for such cosmetic preparation also demand specific skin compatibilities and addition of natural products to derive the stated attributes.
Therefore, it would be clearly apparent from the above said state of the art that on one hand there has been a continuous need for new, effective and safe melanin synthesis inhibitory agent that would also be effective towards inhibition of dendrite elongation so as to favour enhanced skin whitening, as well. There exists a continuous need in the art to provide for skin care actives / formulations, which would be an effective skin lightening agent, is more efficacious and would overcome the limitations and disadvantages observed in the existing tyrosinase inhibitors presently in use. There also remains a need to explore processes to obtain said selective actives. More specifically, there is a need for actives advantageously having conjoint attributes such as melanin inhibition, dendrite inhibition, tyrosinase inhibition, sunscreen and anti-aging.
Objects of the invention:
It is thus the primary object of the present invention to provide for skin lightening combination which synergistically inhibits the synthesis of melanin and act as an effective skin lightening agent with enhanced skin lightening characteristics.

Another object of the present invention is to provide for skin care composition comprising said skin lightening combination lightening composition, which on one hand inhibit the synthesis of melanin, synergistically and on the other hand would also be effective in inhibiting dendrite elongation and tyrosinase inhibition to behave as an effective skin lightening agent with enhanced skin lightening characteristics, favouring an improved performance spectrum of skin care.

Another object of the present invention is to provide for said skin care composition involving said skin lightening combination comprising said synergistic skin lightening agents that would effectively control melanin synthesis under low effective concentrations when present in combination with or without other skin care benefiting agents to bring about better complexion thus in a cost effective manner.

Another object of the present invention is to provide for said skin care composition comprising said skin lightening combination involving said synergistic melanin synthesis inhibitors (skin lightening agents) in effective amounts in combination with cosmetically/ dermopharmaceutically acceptable vehicle/ carriers with or without other skin benefiting agents which would be efficacious, safe and compatible to the skin with better consumer acceptance.

Yet another object of the present invention is to provide skin lightening combination that would be safe and can be incorporated in higher amount in cosmetic skin lightening compositions, if needed, and can be left on the face for a considerable period of time before being washed away to be thus more effective than existing compositions, simultaneously overcome the limitations and disadvantages observed in the existing compositions presently in use, with better consumers acceptance.

Another objective of the present invention is to provide an improved cosmetic skin lightening composition, which on one hand would be efficacious and would overcome the limitations and disadvantages observed in the existing tyrosinase inhibitors presently in use, with better consumers acceptance and on the other hand advantageously have conjoint attributes such as sunscreen and anti-aging thereby catering to multiple purposes of consumers.

Yet another object of the present invention is to provide for synergistically acting skin lightening combination obtained either synthetically / semi-synthetically and a cosmetic skin lightening compositions comprising the same as a skin benefiting composition especially favouring the lightening of skin colour. That would cater to variety of skin conditions in association with or without other skin care benefiting agents. That would imparts effective protection against hyper pigmentation of the skin also with synergistic melanin inhibition, sunscreen properties, having dendrite elongation inhibition and tyrosinase inhibition characteristics that would be effective, safe and compatible to the skin.

Summary of invention:
Thus according to the basic aspect of the present invention there is provided skin care composition comprising skin lightening combination comprising at least two 4-Hydroxyphenyl propane/butane derivatives as Formula 1 actives

FORMULA-1

Wherein,
R1=R2=R3=R4=H OR R3= R4=CH
When Z=CH__OH, R5=CH3; Or When Z = Carbonyl(C=O), R5=OH or ONa or OR7 (R7=C1-C4 alkyl) and, R6= H OR OH;
for enhanced skin lightening activity involving anyone or more pathways including melanin synthesis inhibition, tyrosinase inhibition and dendrite length inhibition.
In accordance with another aspect of the present invention there is provided skin lightening combination acting synergistically to inhibit the synthesis of melanin comprising any two compounds (keeping Formula 3 compound as one of the essential ingredients) or including three of the 4-hydroxyphenyl propane/butane derivatives, betuligenol of Formula 2, caffeic acid of Formula 3 and p-coumaric acid of Formula 4 as an effective melanin synthesis inhibitor composition as hereunder.
FORMULA -2:
Betuligenol, 4-(4-hydroxyphenyl)-2-Hydroxybutane, C10H14O2

FORMULA -3:
Caffeic acid, (E)-3-(3, 4-dihydroxyphenyl)-2-propenoic acid,
3, 4-Dihydroxy cinnamic acid. C9H8O4

FORMULA -4:
p-Coumaric acid, (E)-3-(4-hydroxyphenyl)-2-propenoic acid,
4-Hydroxy cinnamic acid. C9H8O3

Said synergistic skin care composition comprising skin lightening combination is provided comprising of 4-hydroxyphenyl propane/butane derivative of caffeic acid [(E)-3-(3, 4-dihydroxyphenyl)-2-propenoic acid]/ 3, 4-dihydroxy cinnamic acid of Formula 3 in combination with: betuligenol, 4-(4-hydroxyphenyl)-2-hydroxybutane represented by Formula 2 hereunder in the ratio range of 3 : 7 to 7 : 3.

FORMULA -2
According to another preferred aspect of the present invention a synergistic skin care composition comprising skin lightening combination is provided wherein said caffeic acid of Formula 3 in amounts of 0.00075 - 0.00175 wt% and betuligenol of Formula 2 in amounts of 0.00175 - 0.00075 wt% favouring anyone or more melanin synthesis inhibition, tyrosinase inhibition, dendrite length inhibition.
Preferably, a synergistic skin care composition comprising skin lightening combination is provided comprising of 4-hydroxyphenyl propane/butane derivative of caffeic acid [(E)-3-(3, 4-dihydroxyphenyl)-2-propenoic acid]/ 3, 4-dihydroxy cinnamic acid of Formula 3 in combination with: p-coumaric acid, (E)-3-(4-hydroxyphenyl)-2-propenoic acid or 4-hydroxy cinnamic acid represented by Formula 4 hereunder in the ratio range of 1:9 to 9:1 preferably 4:6.

FORMULA -4
More preferably, in said synergistic skin care composition comprising skin lightening combination wherein said caffeic acid of Formula 3 is in amounts of 0.00025 - 0.00225 wt% and p-coumaric acid of Formula 4 is in amounts of 0.00025-0.00225 wt% favouring anyone or more melanin synthesis inhibition, tyrosinase inhibition, dendrite length inhibition.
According to another preferred aspect of the present invention there is provided said synergistic skin care composition comprising skin lightening combination comprising of 4-hydroxyphenyl propane/butane derivative of caffeic acid [(E)-3-(3, 4-dihydroxyphenyl)-2-propenoic acid]/ 3, 4-dihydroxy cinnamic acid of Formula 3 in combination with : betuligenol, 4-(4-hydroxyphenyl)-2-hydroxybutane of Formula 2 and p-coumaric acid, (E)-3-(4-hydroxyphenyl)-2-propenoic acid or 4-hydroxy cinnamic acid of Formula 4 in the ratio range of 7:1:2 to 3:1:6 respectively.
Preferably in said synergistic skin care composition comprising skin lightening combination said caffeic acid of Formula 3 is in amounts of 0.00025 - 0.00225 wt% said betuligenol of Formula 2 is in amounts of 0.00025–0.00175 wt% and said p-coumaric acid of Formula 4 is in amounts of 0.00025–0.00225 wt% favouring anyone or more melanin synthesis inhibition, tyrosinase inhibition, dendrite length inhibition.
Advantageously, said synergistic skin care composition comprising skin lightening combination possesses said melanin synthesis inhibition in the range of 24.32-63.50 % said tyrosinase inhibition in the range of 24.47-52.26 % said dendrite length inhibition in the range of 24.63-31.33 % when said at least two or more Formula 3, Formula 2 and Formula 4 actives are present in combined amounts of upto 0.00625 wt% corresponding to about 25 µg/ml.
More preferably a synergistic skin care composition as cosmetic and/or dermopharmaceutical composition for topical use is provided comprising said skin lightening combinations in amounts 0.001 wt % to 15 wt. %, preferably 0.001 wt % to 10 wt % and more preferably 0.001 wt % to 5 wt % in combination with a cosmetically acceptable vehicle with or without other skin benefiting agents.
Preferably said synergistic skin care composition comprising skin lightening combination is provided in various forms including aqueous and aqueous alcoholic skin lotions, gel form of said skin lotions, aerosol as body spray and in the form of skin care and skin dressing creams and gels.
According to another aspect of the present invention there is provided a process for the manufacture of synergistic skin care composition comprising said skin lightening combination comprising the steps of mixing desired amounts of at least two Formula 1 actives of 4-Hydroxyphenyl propane/butane derivatives including Formula-3 active as the essential ingredient or all of the three Formula 1 actives of 4-hydroxyphenyl propane/butane derivatives with the cosmetically acceptable vehicle and obtaining there from said skin care composition.
Thus the skin care composition of the present invention comprises skin lightening combination, which on one hand inhibit the synthesis of melanin synergistically and on the other would also be effective in inhibiting dendrite elongation, tyrosinase inhibition and having sunscreen activity to behave as an effective skin lightening agent with enhanced skin lightening characteristics, favouring an improved performance spectrum of skin care.
Importantly, in keeping with the requirement for a skin care composition involving mechanism for inhibiting the elongation of dendrites and inhibiting the enzyme tyrosinase it has surprisingly been found that the above said composition meets the much desired criteria of a superior skin lightening agent by way of melanin synthesis inhibition favoured by simultaneous inhibition of elongation of dendrites and the enzyme tyrosinase, which is found to be efficacious 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. The synergy holds even when present in combination with cosmetically acceptable vehicles with or without other skin benefiting agents.
Advantageously, the above said combination of the selective compounds of Formula 2, 3 and 4 sourced synthetically or semi synthetically surprisingly in substantial deviation from its known characteristics / properties revealed the characteristics of synergistically inhibiting melanin synthesis. The synergistic combination inhibits the elongation of dendrites and the enzyme tyrosinase in accordance with the present invention.
More importantly, this was in substantial deviation from the well known several properties of the compounds of Formula 2, Formula 3 and Formula 4.
In the backdrop of the above said, it is indeed apparent that the actives of Formula 2, Formula 3 and Formula 4, sourced synthetically or semi synthetically, were thus surprisingly and selectively efficacious in terms of the desired mechanism for inhibiting the synthesis of melanin, elongation of dendrites and tyrosinase enzyme that is additionally endowed with favorable sunscreen properties.
In accordance with yet another aspect of the present invention there is provided the said skin lightening composition comprising any two or more of 4-Hydroxyphenyl propane/butane derivatives of Formula 1 or is more preferably any two compounds (keeping Formula 3 compound as one of the essential ingredients) or all the three of compounds, betuligenol of Formula 2, caffeic acid of Formula 3 and p-coumaric acid of Formula 4 as an effective melanin synthesis inhibitor composition obtained synthetically and / or semi synthetically.

Said 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, face wash, oils, sticks, sprays, soaps, packs, wraps, woven or nonwoven wipes, powders, films or patches as a vehicle for topical application of the said synergistically acting melanin synthesis inhibition combination.
Detailed Description of the Invention
As discussed hereinbefore, the present invention provides for synergistic melanin synthesis inhibiting skin lightening combination comprising Betuligenol: Caffic acid: p-coumaric acid as the skin lightening active preferably as an effective skin lightening active and particularly provides for cosmetic skin lightening compositions comprising the same in effective amounts present in combination with or without other skin care benefiting agents. More particularly, the present invention relates to cost-effective cosmetic or dermopharmaceutical compositions for external applications that is especially effective towards melanin synthesis inhibition wherein said skin lightening active ingredient or pure compounds are obtained either synthetically/semi-synthetically. Table 1 below shows the results of melanin synthesis inhibition of each individual compounds as well as their combination proving the synergistic effect. The three compounds betuligenol, caffeic acid and p-coumaric acid were coded as ‘c’, ‘a’, ‘b’, respectively and the combination is coded as ‘cab’. The synergistic effect of the combinations given in the Table 1 can be explained as follows, In the S.No.1 of Table 1, melanin synthesis inhibition values of Compounds ‘C’, ‘A’ and ‘B’ at 2.5µg/ml, 17.5 µg/ml and 5 µg/ml respectively were given 8.46%, 13.06% and 5.67%, respectively, the empirical addition value of all the three is 27.19% @ 25 µg/ml, whereas a combination mixture prepared by mixing compounds ‘C’, ‘A’ and ‘B’ at 2.5µg/ml, 17.5 µg/ml and 5 µg/ml, respectively has produced melanin synthesis inhibition value of 48.84% @25 µg/ml. Synergistic effect of the other combinations can be understood similarly, based on results given in Table 1. Table 1 also provides tyrosinase inhibition property data of these combinations, the synergistic combinations have tyrosinase inhibition property as well. Example-2 (Table 2) provides a non limiting example of preparation of a cosmetic cream containing a synergistic combination. Table 3 provides dendrite inhibition property of these combinations, in accordance with the object of the present invention, the synergistic combinations have dendrite inhibition also. For the purpose of better understanding Table-3 also gives the values of melanin synthesis inhibition and tyrosinase inhibition.Table-3 also gives values of melanin synthesis inhibition, tyrosinase inhibition and dendrite length elongation inhibition of the cosmetic skin lightening composition prepared as per example-2.
Thus Tables 1, 2, 3, exemplifies the objects of the present invention.
A wide variety of cosmetic preparations are suitable, in particular skin care products like creams, ointments, pastes, lotions, face wash, body wash, wipes etc., for the use according to the invention of the said compounds. Accordingly, these are always preparations, which are applied to the skin 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 skin lighting. However, it is also possible to produce cosmetic or medicinal preparations, which are used primarily or exclusively for the purpose of eliminating/mitigating other skin pigmentation disorders incorporating these actives.
The cosmetic compositions can be clear liquids, opaque liquids (with pearly luster effect), in cream form, gel-like or else in powder form or in tablet form (taken orally) and as aerosols.
The ingredients typically employed in such a composition are surfactants, emulsifiers, emollients, silicones, thickeners, antioxidants, sunscreen agents chelating agents, perfumes, opacifiers, colours, other skin lightening agents, herbal extracts, / compounds, pH adjusting agents and water to qs. The detergent raw materials 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.

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 colouring agents, opacifiers, skin lightening 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 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 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 between 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 -C20 -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; C10-C24 alkyldimethyl- ethylammonium chloride or bromide; C10 - C24 alkyltrimethyl-ammonium chloride or bromide, preferably cetyltrimethylammonium chloride or bromide and C10 -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; fatty amine 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 a sufficient consistency and improved cosmetic qualities. Among the known thickeners, carbomers (acrylic acid homopolymers cross linked 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, "Jaguar162" and "Rhodicare" from Rhone-Poulenc, "Ucare Polymer Jr. 400" from Amerchol, "Mackernium" from Jan Dekker/MacIntyre 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.
For the preparation of the cosmetic preparations the active substance is dissolved under stirring at a temperature in the range between 20 and 90oC, 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 40oC, 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 90oC, preferably at 75o C. Subsequently, hot water is added and the emulsion is stirred and cooled.
The cosmetic skin lightening compositions 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 these wide varieties of possible formulations are described by way of example in the exemplary embodiments.
The skin lightening preparations according to the invention can also be supplied in the form of aqueous and aqueous alcoholic skin lotions also those in gel form, and in aerosol form as body spray, as well as in the form of skin care and skin dressing creams and gels. Ethanol and isopropanol are preferably used as alcohols.
The synergistic skin lightening active substance is incorporated in the preparations according to the invention in amounts which are normally between about 0.1 and about 15%. 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 skin, such as, for example, creams, lotions etc., lower concentrations will be used, for example of about 0.001 to about 15%, preferably 0.001 to 5%. They are expediently used in higher concentrations if the cosmetic preparations act, where appropriate after dilution, for only a short time on the skin for example face wash and body wash. In these cases, for example, concentrations of about 0.001 to about 15%, preferably about 0.001 to about 10%, may be expedient.
Following examples illustrate the present invention. The stated amounts are based on weight.

Examples
Example -1:
Table -1: Synergistic melanin synthesis inhibition activity and Tyrosinase inhibition activity of the combinations
Melanin synthesis inhibition Tyrosinase inhibition
S.No Betuligenol (C) Caffeic acid (A) p-Coumaric acid (B) C+A+B @25µg/ml CAB @25µg/ml CAB @25µg/ml
1 8.46 % @2.5µg/ml 13.06 % @17.5µg/ml 5.67 % @5µg/ml 27.19 % 48.84 % 36.44 % @25µg/ml
2 0 23.10 % @10µg/ml 7.18 % @15µg/ml 30.28 % 63.50 % 43.88 % @25µg/ml
3 8.46 % @2.5µg/ml 10.99 % @7.5µg/ml 7.18 % @15µg/ml 26.63 % 51.75 % 25.61 % @25µg/ml
4 2.91 % @17.5µg/ml 10.99 % @7.5µg/ml 0 13.90 % 41.24 % 24.47 % @25µg/ml
5 0 -28.43% @22.5µg/ml 46.3 % @2.5µg/ml 17.87 % 40.46 % 42.56 % @25µg/ml
6 0 -4.62% @ 2.5µg/ml -0.64 % @22.5µg/ml -5.26 % 24.32 % 52.26 % @25µg/ml

Example: 2
Table 2. Skincare Formulation
Phase
Parameter
Quantity in g/100 g
A Stearic acid 15.00
Cetyl alcohol 0.50
B Glycerin 1.00
Sterile DM water QS. to 100
C Potassium hydroxide 0.50
Sterile DM water 2.00

D Isopropyl myristate 1.50
Dimethicone (DC200/350 cst) 1.00
E EDTA disodium salt 0.05
Sterile DM water 1.00
F Methylparaben 0.25
Propylparaben 0.15
Phenoxyethanol 0.50
Propyleneglycol 1.00
G
Perfume 0.50
Butylated hydroxyl toluene 0.10
Ethyl alcohol 3.00
Combination of Formula 2,3,4 compounds in the ratio 1:7:2 2.00

1. Heat Phase A to 75 degrees C on water bath and melt the mixture under stirring.

2. After sterilsation of water, transfer the water in to the main mixture and disperse the glycerin.

3. Disperse Phase C material, add Phase C to Phase B under high speed stirring. Then add Phase A to Phase ‘BC’ and stir for 5 minutes.

4. Transfer the phase D, into Phase ABC at high speed and stir for 5 minutes.
5. Dissolve EDDA- DS from Phase E, add to Phase ABCD and stir for 3 minutes.
6. Add Phase F ingredients at 75 degree C and stir for 2 minutes. Cool the material to 45 degree C by ordinary cooling system.
7. Disperse/ Dissolve Phase G materials at 45 degree C, add to Phase ABCDEF and stir for 5 minutes.
The above clearly reveal the possible forms of the cosmetic /skin lightening formulation involving the 4-Hydroxyphenyl propane/butane derivatives of Formula 2, 3, 4 as an active ingredient/s in effective amounts.
Example: 3
Table-3 gives melanin synthesis inhibition % @ 25 and 50 µg/ml, mushroom tyrosinase inhibition% @ 25µg/ml and dendrite elongation inhibition% @ 25µg/ml properties of the selected combinations.
Thus it is clear that the A composition comprising 1) an effective amount of betuligenol, 2) an effective amount of caffeic acid and 3) an effective amount of p-coumaric acid combined at a synergistically effective melanin synthesis inhibition ratio, provides multiple benefits of melanin synthesis inhibition, mushroom tyrosinase inhibition and dendrite length inhibition.

TABLE-3: Cumulative activity
S.No Ratio (C:A:B) Melanin synthesis inhibition % CAB Mushroom tyrosinase inhibition % CAB @25µg/ml Dendrite length inhibition% CAB @25µg/ml
Betuligenol (C) Caffeic acid (A) p-Coumaric acid (B)
@ 25µg/ml @ 50µg/ml
1 1 7 2 48.84% 30.09 36.44 30.32
2 0 4 6 63.50% 6.69 43.88 26.16
3 1 3 6 51.75% 37.77 25.61 31.33
4 7 3 0 41.24% 65.25 24.47 26.54
5 0 9 1 40.46% 32.78 42.56 24.63
6 0 1 9 24.32% 19.89 52.26 25.95
7 Cosmetic composition obtained from Example-2 37.48% 40.86 34.84 23.33

It is thus possible by way of the present advancement to provide for skin lightening composition particularly synergistic melanin synthesis inhibiting skin lightening combination comprising at least two or more of Betuligenol : Caffic acid : p-coumaric acid in selective amounts as the skin lightening actives and particularly provides for cosmetic skin lightening compositions comprising the same in effective amounts in combination with or without other skin care benefiting agents. More particularly, the present invention relates to cost-effective cosmetic or dermopharmaceutical compositions for external applications that are especially effective towards melanin synthesis inhibition wherein said skin lightening actives are obtained either synthetically/semi-synthetically.
,CLAIMS:We Claim:
1. A synergistic skin care composition comprising skin lightening combination comprising at least two 4-Hydroxyphenyl propane/butane derivatives as Formula 1 actives

FORMULA-1

Wherein,
R1=R2=R3=R4=H OR R3= R4=CH
When Z=CH__OH, R5=CH3; Or When Z = Carbonyl(C=O), R5=OH or ONa or OR7 (R7=C1-C4 alkyl) and, R6= H OR OH;
for enhanced skin lightening activity involving anyone or more pathways including melanin synthesis inhibition, tyrosinase inhibition and dendrite length inhibition.
2. A synergistic skin care composition comprising skin lightening combination as claimed in claim 1 comprising of 4-hydroxyphenyl propane/butane derivative of caffeic acid [(E)-3-(3, 4-dihydroxyphenyl)-2-propenoic acid]/ 3, 4-dihydroxy cinnamic acid as the essential ingredient represented by Formula 3 hereunder.

FORMULA-3

3. A synergistic skin care composition comprising skin lightening combination as claimed in anyone of claims 1 or 2 comprising of 4-hydroxyphenyl propane/butane derivative of caffeic acid [(E)-3-(3, 4-dihydroxyphenyl)-2-propenoic acid]/ 3, 4-dihydroxy cinnamic acid of Formula 3 in combination with: betuligenol, 4-(4-hydroxyphenyl)-2-hydroxybutane represented by Formula 2 hereunder in the ratio range of 3 : 7 to 7 : 3.

FORMULA -2
4. A synergistic skin care composition comprising skin lightening combination as claimed in claim 3 wherein said caffeic acid of Formula 3 in amounts of 0.00075 - 0.00175 wt% and betuligenol of Formula 2 in amounts of 0.00175 - 0.00075 wt% favouring anyone or more melanin synthesis inhibition, tyrosinase inhibition, dendrite length inhibition.
5. A synergistic skin care composition comprising skin lightening combination as claimed in claim 1 comprising of 4-hydroxyphenyl propane/butane derivative of caffeic acid [(E)-3-(3, 4-dihydroxyphenyl)-2-propenoic acid]/ 3, 4-dihydroxy cinnamic acid of Formula 3 in combination with: p-coumaric acid, (E)-3-(4-hydroxyphenyl)-2-propenoic acid or 4-hydroxy cinnamic acid represented by Formula 4 hereunder in the ratio range of 1:9 to 9:1 preferably 4:6.

FORMULA -4
6. A synergistic skin care composition comprising skin lightening combination as claimed in claim 5 wherein said caffeic acid of Formula 3 is in amounts of 0.00025 - 0.00225 wt% and p-coumaric acid of Formula 4 is in amounts of 0.00025-0.00225 wt% favouring anyone or more melanin synthesis inhibition, tyrosinase inhibition, dendrite length inhibition.
7. A synergistic skin care composition comprising skin lightening combination as claimed in claim 1 comprising of 4-hydroxyphenyl propane/butane derivative of caffeic acid [(E)-3-(3, 4-dihydroxyphenyl)-2-propenoic acid]/ 3, 4-dihydroxy cinnamic acid of Formula 3 in combination with : betuligenol, 4-(4-hydroxyphenyl)-2-hydroxybutane of Formula 2 and p-coumaric acid, (E)-3-(4-hydroxyphenyl)-2-propenoic acid or 4-hydroxy cinnamic acid of Formula 4 in the ratio range of 7:1:2 to 3:1:6 respectively.
8. A synergistic skin care composition comprising skin lightening combination as claimed in claim 7 wherein said caffeic acid of Formula 3 is in amounts of 0.00025 - 0.00225 wt% said betuligenol of Formula 2 is in amounts of 0.00025–0.00175 wt% and said p-coumaric acid of Formula 4 is in amounts of 0.00025–0.00225 wt% favouring anyone or more melanin synthesis inhibition, tyrosinase inhibition, dendrite length inhibition.
9. A synergistic skin care composition comprising skin lightening combination as claimed in anyone of claims 1-8 having said melanin synthesis inhibition in the range of 24.32-63.50 % said tyrosinase inhibition in the range of 24.47-52.26 % said dendrite length inhibition in the range of 24.63-31.33 % when said at least two or more Formula 3, Formula 2 and Formula 4 actives are present in combined amounts of upto 0.00625 wt% corresponding to about 25 µg/ml.
10. A synergistic skin care composition as cosmetic and/or dermopharmaceutical composition for topical use comprising skin lightening combinations as claimed in anyone of claims 1-9 in amounts 0.001 wt % to 15 wt. %, preferably 0.001 wt % to 10 wt % and more preferably 0.001 wt % to 5 wt % in combination with a cosmetically acceptable vehicle with or without other skin benefiting agents.
11. A synergistic skin care composition comprising skin lightening combination as claimed in anyone of claims 1-10 in various forms including aqueous and aqueous alcoholic skin lotions, gel form of said skin lotions, aerosol as body spray and in the form of skin care and skin dressing creams and gels.
12. A process for the manufacture of synergistic skin care composition comprising skin lightening combination as claimed in anyone of claims 1-11 comprising the steps of mixing desired amounts of at least two Formula 1 actives of 4-Hydroxyphenyl propane/butane derivatives including Formula-3 active as the essential ingredient or all of the three Formula 1 actives of 4-hydroxyphenyl propane/butane derivatives with the cosmetically acceptable vehicle and obtaining there from said skin care composition.

Dated this the 1st day of April, 2016 Anjan Sen
Anjan Sen and associates
(Applicants Agent)