Title of Invention	A LIPOLYTIC COMPOSITION FOR TOPICAL APPLICATION
Abstract	A lipolytic composition for topical application comprising (i) melatonin and (ii) one or more of a lipolytic agent selected from niacinamide, gingko biloba extract or xanthates which may be caffeine, theophyllin or theobromine and (iii) a cosmetically acceptable vehicle.

Full Text

FORM -2 THE PATENTS ACT, 1970 (39 of 1970) PROVISIONAL SPECIFICATION (See Section 10) COSMETIC COMPOSITION HINDUSTAN LEVER LIMITED, a company incorporated under the Indian Companies Act, 1913 and having its registered office at Hindustan Lever House, 165/166, Backbay Reclamation, Mumbai -400 020, Maharashtra, India The following specification describes the invention Technical field The invention relates to a lipolytic composition for topical application that provides sebum / oil control on the skin and particularly relates to providing anti-cellulite benefits. Background and Prior art Many people perceive oiliness of the skin as an undesirable condition. Additionally many people seek relief from a condition known as cellulite where there is deposition of fat near the surface of the skin. Although many medical and therapeutic solutions have been suggested for removal of cellulite, many people prefer a cosmetic solution to the perceived problem since cosmetic solutions are perceived to be milder, with fewer side effects while providing the desired benefits. Excess lipid or fat accumulation near the surface of the skin is a problem associated with increased fat deposits in adipocytes, as well as increased sebum secretion from sebocytes. Thus delivery of lipolytic agents through cosmetic compositions which can be topically applied may cause lipolysis thereby decreasing the amount of lipid present in these cells, thus providing the benefits of cellulite reduction. Cellulite is fat that is deposited in pockets just below the surface of the skin. It is a result of increase in volume of adipocytes (fat cells) within the skin. The histological studies of subcutanous tissues suggest that the fat lobules (groups of adipose cells sheathed in connective tissue) are larger, and less restricted lobules, leading to an outward pressing against the dermis causing the bumps characteristic of cellulite. Concurrent with adipose deposition, venous capillaries tend to form microaneurisms while adjacent vessels become dilated. As blood flow is reduced, the capillary walls become leaky and leading to an increase in the infiltration of water in the tissue. Together, these result in a bumpy skin surface and spongy texture. 2 Fat is stored in special fat cells called adipocytes located all over the body. There are anywhere from 25 billion to 275 billion adipocytes. The average individual has around 30-35 billion. The adipocyte is a metabblically active cell that plays a central role in the control of the energetic balance. For this purpose, it possesses all the enzymes necessary for synthesis (lipogenesis) and for triglyceride storage, mobilization and liberation as free fatty acids (lipolysis). When adipocytes release fat (lipolysis), the adipocyte gets smaller, and when they store fat, the adipocyte gets larger (lipogenesis). Reducing the quantity of subcutaneous fat by stimulating basal lipolysis can therefore reduce the manifestations of cellulite. Lipolysis corresponds to the hydrolysis of triglycerides in free fatty acids and in glycerol. This reaction is catalyzed by a key enzyme: HSL (Hormone-sensitive Lipase). The determining signal required to trigger lipolysis is cyclic AMP (cAMP). The intracellular concentration of cAMP depends on two opposed action systems: adenylate cyclase (AC) which activates it, and phosphodiesterase (PDE) which cleaves it into 5,-AMP. Therefore a substance which is capable of stimulating adenylate cyclase or inhibiting phosphodiesterase will raise the intracellular cAMP levels, which activates the HSL enzyme and stimulates the lipolysis of fats by the adipocyte. E.g. caffeine inhibits phosphodiesterase and thus encourages the synthesis of the cAMP which stimulates the lipolysis. There have been a few reports of lipolytic agents delivered through compositions for topical application. W09947112 (P & G, 1999) describes a method for treating and/or preventing cellulite by administering a safe and effective amount of a skin care composition to a mammal having or prone to forming cellulite, comprising: (a) a safe and effective amount of niacinamide, and (b) a dermatologically acceptable carrier for the niacimamide. This patent also claims a method wherein additional actives are used which is a phosphodiesterase inhibitor selected from the group consisting of theophylline, caffeine, theobromine, salts thereof and mixtures thereof. 3 WO 2002098436 (Indena, 2002) describes pharmaceutical and/or cosmetic compositions for the treatment of localized adiposities and cellulite which contain a combination of the following active principles: (a) complex of escin/beta-sitosterol with phospholipids, (b) complex of gingko biloba dimeric flavonoids with phospholipids, (c) complex of centella asiatica triterpenes with phospholipids, and optionally one or both of (d) ethyl ximeninate, (e) coleus forskolii standard extract. CN 1348758 (Shanghai Jiahua Union, 2002) describes a composition containing melatonin and beta-dextran in certain proportions to form a skin anti wrinkle composition, the said two substances possess synergistic action mutually to give greater effect than by single substance. It is claimed here that compared to cosmetics containing vitamin A, vitamin E and ginseng extract alone, the wrinkle elimination effect can raise 15-20 %. While the first two publications, above mentioned are directed to reducing fat on the skin the last publication which comprises melatonin is directed to anti-wrinkling. Thus although some composition are disclosed in the art for fat and cellulite, there exists a need for developing more effective compositions for topical application which will provide lipolytic benefits and combat the condition of oily skin and cellulite. It is thus an object of the invention to provide for more effective compositions for topical application which give benefit in oiliness reduction and works effectively as an anti-cellulite product. The present inventors have through extensive experimentation and research developed compositions comprising melatonin that has been identified to have highly effective lipolytic efficacy. The present inventors have also developed synergistic compositions comprising melatonin and other known lipolytic agents that can be applied on the skin for lipolytic benefit. 4 Summary of the invention Thus, according to one aspect of the invention there is provided a lipolytic composition for topical application comprising (i) a lipolytic agent which is melatonin and (ii) a cosmetically acceptable vehicle. According to a preferred aspect of the invention there is provided a lipolytic composition comprising (i) melatonin and (ii) one or more of a lipolytic agent selected from niacinamide, gingko biloba extract or xanthates which may be caffeine, theophyllin or theobromine and (iii) a cosmetically acceptable vehicle. It is particularly preferred that the composition comprises a rubefacient agent. Detailed description of the invention The invention provides for a lipolytic composition comprising melatonin along with a cosmetically acceptable vehicle and preferably comprising a known lipolytic agent. 5 Melatonin is an organic compound that has the molecular formula C13H16N2O2 and a molecular structure as shown in Formula - 1. It is also known by the synonyms Acetamide, N-[2-(5-methyoxy-1H-indol-3-yl)ethyl] and N-acetyl-5-methoxytryptamine. Melatonin is produced in the human body by the pineal gland and has been known to play ah important role in sleep and waking pattern in humans. It has also been identified to have the functionality of anti-aging/anti-oxidant and skin lightening in topical applications. It is preferred that melatonin is present at 0.005 to 10%, more preferably 0.01 to 1 % by weight of the composition. The lipolytic actives which are present in the composition of the invention are selected from niacinamide, gingko biloba extract or xanthates which may be caffeine, theophyllin or theobromine, The more desirable ones are one or more of niacinamide, gingko biloba and caffeine. The total amount of lipolytic actives including melatonin is preferably in the range of 0.01 to 10% by weight of the composition. Rubefacient agent The composition of the invention preferably comprises one or more rubefacient agent. Rubefacient agent is a compound that produces a warming sensation on the skin when applied on it. These compounds are believed to act by the action of vasodilation and so are also known as vasodilators. Preferred rubefacient agents are selected from one or more of methyl nicotinate, methyl or glycol salicylate or capsaicin. A highly preferred rubefacient agent is methyl nicotinate. Rubefacient agents are preferably present in an amount in the range of 0.01 to 5%, more preferably in an amount in the range of 0.01 to 1% by weight of the composition. The Cosmetically Acceptable Vehicle The composition according to the invention also comprises a cosmetically acceptable vehicle to act as a diluant, dispersant or carrier for other materials present in the composition, so as to facilitate their distribution when the composition is applied to the skin. 6 Vehicles other than water can include liquid or solid emollients, solvents, humectants, thickeners and powders. Examples of each of these types of vehicle, which can be used singly or as mixtures of one or more vehicles, are as follows: Emollients, such as stearyl alcohol, glyceryl monoricinoleate, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, eicosanyl alcohol, behenyl alcohol, cetyl palmitate, silicone oils such as dimethylpolysiloxane, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, cocoa butter, corn oil, cotton seed oil, olive oil, palm kernel oil, rape seed oil, safflower seed oil, evening primrose oil, soybean oil, sunflower seed oil, avocado oil, sesame seed oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum jelly, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate;; Propellants, such as propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide; Solvents, such as ethyl alcohol, isopropanol, acetone, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether; Powders, such as chalk, talc, fullers earth, kaolin, starch, gums, colloidal silica sodium polyacrylate, tetra alkyl and/or trialkyl aryl ammonium smectites, chemically modified magnesium aluminium silicate, organically modified montmorillonite clay, hydrated aluminium silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate. The cosmetically acceptable vehicle is preferably present from 10 to 99.9%, preferably from 50 to 99% by weight of the emulsion, and can, in the absence of other cosmetic adjuncts, form the balance of the composition. 7 Optional skin benefit agents: Skin lightening ingredients can be advantageously included in the composition to provide skin lightening effects. These may include vitamin B6, vitamin C, vitamin A or their precursors and mixtures. Especially preferred additional vitamin is vitamin B6. Other skin lightening actives known in the art can also be employed in the invention. Non limiting examples of skin lightening actives useful herein include aloe extract, ammonium lactate, azelaic acid, kojic acid, lactic acid, linoleic acid, magnesium ascorbyl phosphate, 5-octanoyl salicylic acid, 2,4 resorcinol derivatives, 3,5 resorcinol derivatives, salicylic acid, 3,4,5 trihydroxybenzyl derivatives, and mixtures thereof. The composition preferably comprises from about 0.1% to about 10%, more preferably from about 0.1% to about 5%, of a skin lightening ingredient. The composition of the invention preferably includes an effective amount of a sunscreen or sun-block agent. Organic and inorganic sunscreens/sun-blocks may be suitably employed in the composition. Suitable organic sunscreen agents include 2-ethylhexyl-p-methoxycinnamate, butylmethoxydibenzoylmethane, 2-hydroxy-4-methoxybenzophenone, octyldimethyl-p-aminobenzoic acid and mixtures thereof. A safe and effective amount of sunscreen may be used in the compositions useful in the subject invention. The composition preferably comprises from about 0.1% to about 10%, more preferably from about 0.1% to about 5%, of a sunscreen agent. Inorganic sun-blocks are also preferably used in the present invention. These include, for example, zinc oxide iron oxide, silica, such as fumed silica, and titanium dioxide. Ultrafine titanium dioxide in either of its two forms, namely water-dispersible titanium dioxide and oil- dispersible titanium dioxide is especially suitable for the invention. Water-dispersible titanium dioxide is ultra-fine titanium dioxide, the particles of which are non-coated or which are coated with a material to impart a hydrophilic surface property to the particles. Examples of such materials include aluminium oxide and aluminium silicate. Oil-dispersible titanium dioxide is ultrafine titanium dioxide, the particles of which exhibit a hydrophobic surface property, and which, for this purpose, can be coated with 7 metal soaps such as aluminium stearate, aluminium laurate or zinc stearate, or with organosilicone compounds. By "ultrafine titanium dioxide" is meant particles of titanium dioxide having an average particle size of less than 100 nm, preferably 70 nm or less, more preferably from 10 to 40 nm and most preferably from 15 to 25 nm. Ultrafine titanium dioxide is the preferred inorganic sun-block agent. The total amount of sun block that is preferably incorporated in the composition according to the invention is from 0.1 to 5% by weight of the composition. Optional cosmetic ingredients The compositions of the present invention can comprise a wide range of other optional components. The CTFA Cosmetic Ingredient Handbook, Second Edition, 1992, which is incorporated by reference herein in its entirety, describes a wide variety of non-limiting cosmetic and pharmaceutical ingredients commonly used in the skin care industry, which are suitable for use in the compositions of the present invention. Examples include: antioxidants, binders, biological additives, buffering agents, colorants, thickeners, polymers, astringents, fragrance, humectants, opacifying agents, conditioners, exfoliating agents, pH adjusters, preservatives, natural extracts, essential oils, skin sensates, skin soothing agents, and skin healing agents. The invention will now be illustrated with the following non-limiting examples. Examples A lipolytic assay was set up to study the lipolysis efficiency of various compositions and the assay is described below. Lipolysis assay On the first day, 96 well plates were set up which has cells in Dulbecco' Minimal Eagle Media (DMEM) along with 10% fetal calf serum with 4.5 g/l of glucose with a total amount of 100 [i\ per well. 9 On the fifth day, 100 µl per well of a differentiation media was added which has DMEM along with 10% fetal calf serum with 4.5 g/l glucose and 0.5 mM isobutyl methyl xanthine and 1 µM dexamethasone and 10 µg/l insulin. On the seventh day, 100 µ.l per well of differentiation media was added. On the eleventh day, 100 µ\ per well of a maintenance media was added which has DMEM, 10% fetal calf serum along with 4.5g/l glucose and 10 \x\fm\ of insulin. On the thirteenth day, 100 µ\ per well of the maintenance media was added. On the fifteenth day, 100 µl per well of DMEM along with 10% FCS with high glucose was added along with 5 µ\ per well of the active being tested. On the seventeenth day, the plates were washed twice with PBS. 50 \i\ per well of 4% formaldehyde in PBS was added for 20 minutes at room temperature and then washed twice with distilled water. 50 |al per well of diluted red O dye (three parts of 0.5% oil red O dye dissolved in isopropanol with two parts of distilled water) and allowed to stain for two hours at 37 °C. The samples were washed 3 to 4 times with distilled water. 50 ml per well of isopropanol was added and the dye was allowed to dissolve for 15 minutes at room temperature. The OD (optical density) of the samples were measured at 540 nm using a spectrophotometer. The data are represented as percentage of a control sample which is taken to have 100% activity. Examples 1 and 2 The lipolytic activity of melatonin at a few concentrations were determined using the above described assay and the data are summarized in Table 1. Table-1 Examples % melatonin % lipolytic activity Control - 100 Example -1 0.010 83.4 Example-2 0.025 60.2 The data in table indicates that melatonin is a highly effective lipolytic agent. 10 Examples 3 to 9 Lipolytic activity of several other known lipolytic agents alone and in combination with melatonin were determined by the above described assay and the lipolytic activities are summarized in Table-2 Table-2 Active Ex-3% Ex-4 Ex-5 Ex-6 Ex-7 Ex-8 Ex-9 wt% wt% wt% wt% wt% wt% wt% Melatonin 0.005 - - - 0.005 0.005 0.005 Niacinamide - 0.15 - - 0.15 - - Gingko biloba - - 0.04 - - 0.04 - Caffeine - - - 0.025 - - 0.025 Lipolytic activity, % 112.4 86.1 107.7 78.9 88.6 94.1 87.8 The data in table -2 indicates that combinations of other known lipolytic actives along with melatonin (Examples 7 to 9) provide for synergistic lipolytic activity as compared to the actives taken alone (Examples 3 to 6). Examples 10,11 Some experiments were conducted when melatonin was taken along with a rubefacient agent viz. methyl nicotinate. The data is summarized in table-3. Table-3 Active Ex-3% Ex-10 Ex-11 wt% wt% wt% Melatonin 0.005 - 0.005 Methyl nicotinate - 0.0375 0.0375 Lipolytic activity, % 112.4 90.7 99.4 The data in Table-3 indicates that a rubefacient agent like methyl nicotinate when taken along with melatonin provides for synergistic lipolytic activity (Example 11) as compared to the activity obtained when the actives were taken individually. 11 Example 12,13 An experiment was conducted with a mixture of known lipolytic actives and a rubefacient agent and the results obtained were compared to the activity obtained when melatonin was added to it. The data is summarized in table -4 Table-4 Active Ex-12 Ex-13 wt% wt% Melatonin - 0.005 Niacinamide 0.15 0.15 Gingko biloba 0.04 0.04 Caffeine 0.025 0.025 Methyl Nicotinate 0.0375 0.0375 Lipolytic activity, % 64.3 26.6 The data in table-4 indicates that melatonin when added to a lipolytic composition containing known actives, is capable of providing highly enhanced lipolytic activity (Example 13). The invention thus provides for a lipolytic composition comprising melatonin that provides highly effective lipolytic activity on topical application. Dated this 28th day of March 2005 12

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345-mum-2005-descripiton (provisional).pdf

345-MUM-2005-DESCRIPTION(COMPLETE)-(20-11-2008).pdf

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345-MUM-2005-FORM 1(20-11-2008).pdf

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