KR101094306B1 - A composition comprising thymoquinone compounds having skin whitening activity - Google Patents

Abstract

PURPOSE: A pharmaceutical composition containing thymoquinone compounds for treating skin pigmentary disorders and to suppress tyrosinase activity and melanogenesis. CONSTITUTION: A cosmetic composition for skin whitening contains 0.0001-50 wt% of thymoquinone compounds of structural formula 1, 2, or 3 as an active ingredient. The composition is manufactured in the form of a skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, massage cream, foundation, hand cream, pack, soap, cleansing foam, or body cleanser. A pharmaceutical composition for treating and preventing skin pigmentary disorder contains the thymoquinone compounds as an active ingredient. The pharmaceutical composition is manufactured in the form of a cream, patch, spray, ointment, liniment, paste, or cataplasma.

Description

A composition comprising thymoquinone compounds having skin whitening activity}

The present invention relates to a skin whitening composition containing a thymoquinone compound as an active ingredient, a pharmaceutical composition for treating and preventing skin pigmentation diseases, and more specifically, to a thymoquinone, ditaimoquinone, and thymohydroquinone compound. The present invention relates to a cosmetic composition for skin whitening, a skin pigmentation disease treatment and a preventive pharmaceutical composition containing as an active ingredient.

Pigmentation on the skin, such as blemishes and freckles, is due to an increase in melanin in the epidermis, and melanin is also an important factor in determining skin color. Melanin is made from organelles called melanosomes in the melanocytes present in the basal epidermal layer. That is, mitosis of melanocytes occurs by ultraviolet rays, and then melanocytes are activated. Activated melanocytes promote the synthesis of tyrosinase and promote melanin production, which is then transported out of the epidermis and released (VJ Hearing and M. Jimenez., Int. J. Biochem, 19 (20), p.1141, 1987 ., I. Koiso., Fragrance J. 6, p39, 1990).

Naturally produced melanin is a mixture of alkali poorly soluble black melanin (new melanin) and alkali soluble yellow or red melanin (feomelanin) (Y. Tomita., Fragrance J , 6, p20, 1990.) Generally melanin Polymers are often referred to as numelanin, Prota (G. Prota., J. Invest. Dermatol., 75, p122, 1980.) and Pavel (S. Pavel et al., Cancer Detection and Prevention , 6, p311). ., 1983.), as well as the 5,6-dihydroxy indole which has been thought of before, as well as 5,6-dihydroxy indole, 5,6-dihydroxy indole-2-carboic acid which is a separate melanin monomer, and various melanin It was found that it is produced from intermediate metabolites. The melanin production process in melanosomes is that tyrosine is oxidized by the enzyme tyrosinase to be dopa → dopaquinone → dopachrome → 5,6-dihydroxyindole → indole-5,6-quinone, followed by indole-5,6. It is known to produce melanin by the polymerization of -quinones. Among them, tyrosine-dopaquinone is involved in the enzyme tyrosinase, and since then, it is known that the contribution of automatic oxidation is large. It is well known that pigmentation caused by sunbathing, or blackening, is a result of increased melanin production by ultraviolet rays in sunlight.

Looking at the mechanism of action of melanin inhibition from melanin production in melanocytes, which is clearly identified to date, melanin production is inhibited by melanin production by melanocytes, a mechanism that inhibits melanin production as a result of cytotoxicity to melanocytes. It is largely divided into two mechanisms of suppressive action. Recently published findings reveal that melanin is produced not only by tyrosinase but also by tyrosinase related protein 1 (TRP-1) and tyrosinase-retained protein 2 (TRP-2, Dopachrome tautomerase). These are also important enzymes involved in the biosynthesis of melanin, so developing a substance that can inhibit these enzymes may be a way to prevent skin pigmentation (Marmol V. at al., FEBS Letter , 327, p. 307, 1993; Winder AJ at al., Pigment Cell Research , 7, p.305, 1994).

As tyrosinase activity inhibitors developed to date, chelate-forming substances for copper ions of tyrosinase active sites, reducing agents such as vitamin C or kojic acid for reducing quinones to phenols, and bisulfite preparations for modifying tyrosinase itself are known. . In addition, hydroquinone, retinol or hydrocortisol are known as substances that inhibit the tyrosinase activity and exhibit a whitening effect.

The thymoquinone of Structural Formula 1 has an antioxidant effect (Houghton, PJ; Zarka, R; De Las Heras, B; Hoult, JR (1995) Planta medica 61 (1): 336) and protects the liver, kidney and heart (Al-Shabanah, OA; Badary, OA; Nagi, MN; Al-Gharably, NM; Al-Rikabi, AC; Al-Bekairi, AM) (1998), Journal of experimental & clinical cancer research : CR 17 (2): 1938) anticancer activity (Badary, OA; Nagi, MN; Al-Shabanah, OA; Al-Sawaf, HA; Al-Sohaibani, MO; Al Bekairi, AM (1997) Canadian journal of physiology and pharmacology 75 (12): 135661), which can be obtained from Callitris quadrivalvis , Monarda fistulosa .

It is also known to be obtained through organic synthetic methods (Gustavo PR, Paula IV, Patricia GV, CV. C., Pietro T., Letters). in Organic Chemistry , 2008, 5, 332-335., Yoshinori A., Reiko M., Motoo T., Masakazu S., J. Org . Chem . 1988,53, 5453-5457., Derek b., Jean-pierre f., Martial t., Tetrahedron , vol 44, No 20, pp 6397-6406, 1988., Marciana PU, Ygor WV, Maria CD, Arlene GC , Ursula B., and Timothy JB, J. Braz . Chem . Soc . , Vol. 19, No. 8, 1484-1489, 2008).

Ditaimoquinone of formula 2 is also known to exhibit anticancer activity. In particular, it has been reported to have anticancer activity against multi-resistant cancers (David R. Worthen et al, Anticancer Research , vol. 17, 1997, pp. 1-6). It can also be obtained through natural products or synthesis.

The thymohydroquinone of Structural Formula 3, like thymoquinone, has anticancer activity and also exhibits antibacterial and antifungal action (Eman Halawani, Advances in Biological Research 3 (5-6): 148-152, 2009). Thymohydroquinone can also be obtained by reducing thymoquinone (M. El-Dakhakhny, Planta Med, 11, 465-470, 1963).

The present inventors seek to find a substance that is effective in the skin whitening effect, the treatment and prevention of skin pigmentation disorders, and the treatment and prevention of skin whitening and skin pigmentation disorders among various natural substances and compounds obtained through organic chemical synthesis. As a result of screening for an effective substance, it was found that a natural extract containing thymoquinone compounds derived from nature or a thymoquinone compound obtained through synthesis showed excellent skin whitening efficacy and thus completed the present invention.

An object of the present invention is to provide a cosmetic composition for skin whitening containing a thymoquinone compound as an active ingredient, or a pharmaceutical composition for treating and improving skin pigmentation diseases.

In addition, the present invention effectively inhibits the activity of tyrosinase, an enzyme that plays a key role in the melanin biosynthesis process, and inhibits the biosynthesis of melanin in B16 melanoma cells, thereby greatly improving the skin whitening effect, treatment, prevention and improvement of skin pigmentation disease. It is an object to provide an excellent cosmetic composition or pharmaceutical composition.

In order to achieve the above object, the present invention provides a composition for skin whitening, comprising a thymoquinone compound as an active ingredient.

The present invention also provides a pharmaceutical composition for the treatment and prevention of skin pigmentation disorders, which comprises a thymoquinone compound as an active ingredient.

In addition, the present invention is characterized in that the skin whitening composition is a cosmetic composition for skin whitening.

In addition, the present invention is that the skin pigmentation disease occurs locally on the skin due to the increase in the synthesis of melanin pigment, and occurs in the spots, freckles, black spots, birthmarks, pigmentation by drugs, pigmentation after inflammation, and dermatitis At least one disease selected from hyperpigmentation.

In addition, the present invention is characterized in that the thymoquinone compounds are thymoquinone of the following structural formula (1).

In addition, the present invention is characterized in that the thymoquiron compounds are ditaimoquinone of the formula (2).

In addition, the present invention is characterized in that the thymoquiron compounds are thymohydroquinone of the formula (3).

The method for obtaining the thymoquinone compound in the present invention is not particularly limited and may be obtained through synthesis or extracted from natural products. The method for obtaining a thymoquinone compound through synthesis is, for example, dissolving thymol in a chloroform solvent and then oxidizing with MCPBA (1.2 equivalents) for 3 hours while stirring at room temperature or reflux conditions. Thymoquinone and thymohydroquinone can be obtained by passing the filtrate obtained by filtering excess MCPBA through silica gel by chromatography.

In addition, the thymoquinone compound of the present invention and a composition comprising the same have an excellent effect of promoting skin whitening or treating and preventing skin pigmentation diseases through inhibition of tyrosinase activity and inhibition of melanin production. In addition, since the thymoquinone compound has little toxicity and side effects, the thymoquinone compound may be used safely in the cosmetic composition and the pharmaceutical composition of the present invention.

In addition, the present invention is characterized in that it comprises 0.0001 to 50% by weight relative to the total weight of the thymoquinone compound. If the content is not more than 0.0001% by weight, the whitening effect, treatment and prevention of skin pigmentation disease is insufficient, and if the content is more than 50% by weight, the effect of increasing the content compared to the content is insufficient.

In addition, the present invention is a cosmetic composition for skin whitening skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisturizing lotion, nutrition lotion, massage cream, nutrition cream, moisturizing cream, hand cream, foundation, essence, It is characterized in that the nutritional essence, pack, soap, cleansing foam, cleansing lotion, cleansing cream, body lotion or body cleanser formulation.

In addition, the present invention is characterized in that the pharmaceutical composition for the treatment and prevention of skin pigmentation diseases is a cream, gel, patch, spray, ointment, warning, lotion, linen, pasta or cataplasma formulation. .

As an aspect of the present invention, a cosmetic for skin whitening containing a thymoquinone compound as an active ingredient is described in detail as follows.

The thymoquinone compounds of the present invention can be used in a variety of cosmetics and face washes having a skin whitening effect. Examples of products to which the present composition can be added include cosmetics such as various creams, lotions, skins, and the like, cleansing agents, face washes, soaps, treatments, and essences.

The cosmetic of the present invention may further comprise a component selected from the group consisting of water-soluble vitamins, oil-soluble vitamins, polymer peptides, polymer polysaccharides, sphingolipids and seaweed extract.

The water-soluble vitamins may be any compound that can be incorporated into cosmetics, but preferably vitamin B1, vitamin B2, vitamin B6, pyridoxine, pyridoxine, vitamin B12, pantothenic acid, nicotinic acid, nicotinic acid amide, folic acid, vitamin C, vitamin H, and the like. Their salts (thiamine hydrochloride, sodium ascorbate salt, etc.) and derivatives (ascorbic acid-2-sodium phosphate salt, ascorbic acid-2-magnesium phosphate salt, etc.) may also be used in the water-soluble vitamins that can be used in the present invention. Included. The water-soluble vitamins can be obtained by conventional methods such as microbial transformation, purification from microorganism culture, enzyme or chemical synthesis.

The oil-soluble vitamin may be any compound that can be incorporated into cosmetics, but preferably vitamin A, carotene, vitamin D2, vitamin D3, vitamin E (d1-alpha tocopherol, d-alpha tocopherol, d-alpha tocopherol), and the like. And derivatives thereof (ascorbic palmitate, ascorbic stearate, ascorbic acid dipalmitate, dl-alpha tocopherol acetate, dl-alpha tocopherolvitamin E, DL-pantothenyl alcohol, D-pantothenyl alcohol, pantothenyl ethyl) Ethers, etc.) are also included in the oil-soluble vitamins used in the present invention. Oil-soluble vitamins can be obtained by conventional methods such as microbial transformation, purification of microorganism culture, enzyme or chemical synthesis.

The polymeric peptide may be any compound as long as it can be compounded in cosmetics, and examples thereof include collagen, hydrolyzed collagen, gelatin, elastin, hydrolyzed elastin, and keratin. Polymeric peptides can be purified and obtained by conventional methods such as purification from microbial cultures, enzymatic methods or chemical synthesis methods, or can be purified and used from natural products such as dermis and pig silk such as pigs and cattle.

The polymer polysaccharide may be any compound as long as it can be blended into cosmetics. Preferably, hydroxyethyl cellulose, xanthan gum, sodium hyaluronate, chondroitin sulfate or a salt thereof (sodium salt, etc.) may be mentioned. For example, chondroitin sulfate or its salt, etc. can be normally purified from a mammal or fish.

The sphingolipid may be any compound as long as it can be blended into cosmetics. Preferably, ceramide, phytosphingosine, sphingosaccharide lipid, etc. may be mentioned. Sphingo lipids can usually be purified from mammals, fish, shellfish, yeasts or plants by conventional methods or obtained by chemical synthesis.

The seaweed extract may be any compound as long as it can be blended into cosmetics. Preferably, the seaweed extract may include brown algae extract, red algae extract, green algae extract, and the like. Also, calginine, arginic acid, sodium arginate, Potassium arginate and the like are also included in the seaweed extract used in the present invention. Seaweed extract can be obtained by purification from seaweed by conventional methods.

In addition to the said essential component, the cosmetic composition of this invention can also mix | blend the other component normally mix | blended with a cosmetic composition as needed.

Other components that may be added include fats and oils, moisturizers, emollients, surfactants, organic and inorganic pigments, organic powders, ultraviolet absorbers, preservatives, fungicides, antioxidants, plant extracts, pH adjusters, alcohols, pigments, flavorings, Blood circulation accelerators, cooling agents, restriction agents, purified water and the like.

Examples of the fat or oil component include ester fats, hydrocarbon fats, silicone fats, fluorine fats, animal fats, and vegetable fats and oils.

As ester fats and oils, glyceryl tri2-ethylhexanoate, cetyl 2-ethylhexanoate, isopropyl myristate, butyl mystinate, isopropyl palmitate, ethyl stearate, octyl palmitate, isocetyl isostearate, and stearic acid Butyl, ethyl linoleate, isopropyl linoleate, ethyl oleate, isocetyl acid isocetyl, isostyl acid isostearyl, isostaryl palmitate, octylate acid octyldodecyl, isostearic acid isetyl, diethyl sebacate, adipine Acid isopropyl, isoalkyl neopentane, tri (capryl, capric acid) glyceryl, trimethyl ethyl trimethylol propane, triisostearic acid trimethylol propane, tetra 2-ethylhexanoic penta erythritol Cetyl caprylate, lauric acid decyl, hexyl laurate, decyl myristin, myristin acid myristyl, myritic acid cetyl, stearyl stearate, decyl oleate, rininooleic acid , Isostearyl laurate, isotridecyl myristin, isocetyl palmitate, octyl stearate, isocetyl stearate, isodecate oleate, octylate decyl oleate, octyl dodecyl linoleate, isopropyl isopropyl acid, 2 -Cetostearyl ethylhexanoate, stearyl 2-ethylhexanoate, hexyl isostearate, ethylene glycol dioctanoate, ethylene glycol dioleate, propylene glycol dicapric acid, propylene glycol dicacapate, capric acid Propylene glycol, dicapric acid neopentyl glycol, dioctanoate neopentyl glycol, tricaprylic acid glyceryl, triundecyl glyceryl, triisopalmitinate glyceryl, triisostearate glyceryl, neopentane dodecyl Isostearyl octanoate, octyl isononate, hexyl decyl neodecanoate, octyl dodecyl neodecanoate, isocetyl isostearate, isostearyl isostearate, Sothete octylate, polyglycerol oleate, polyglycerine isostearate, triisocetyl citrate, triisoalkyl citrate, triisoctyl citrate, lauryl lactate, myritic lactate, octyl lactate, octyl lactate, tricitric acid Ethyl, acetyl triethyl citrate, acetyl tributyl citrate, trioctyl citrate, diisostearyl malic acid, 2-ethylhexyl hydroxystearate, di2-ethylhexyl succinate, diisobutyl adipicate, diisopropyl sebacinate, Dioctyl sebacate, cholesteryl stearate, cholesteryl isostearate, cholesteryl hydroxystearate, cholesteryl oleate, dihydrocholesteryl oleate, physteryl isostearate, phytic oleate, 12-Steloylhydroxystearate isocetyl, 12-Steloylhydroxystearate stearyl, 12-stealo Esters such as monohydroxystearic acid isostearyl; and the like.

Hydrocarbon-based fats and oils, such as squalene, a liquid paraffin, alpha-olefin oligomer, isoparaffin, ceresin, paraffin, a liquid isoparaffin, polybutene, microcrystal wax, and a vaseline, etc. are mentioned as a hydrocarbon-type fats and oils.

Examples of the silicone-based oils and fats include polymethylsilicone, methylphenylsilicone, methylcyclopolysiloxane, octamethylpolysiloxane, decamethylpolysiloxane, dodecamethylcyclosiloxane, dimethylsiloxane, methylcetyloxysiloxane copolymer, dimethylsiloxane and methylsteoxysiloxane copolymer, and alkyl. Modified silicone oil, amino modified silicone oil and the like.

Examples of the fluorine-based oil include perfluoropolyether and the like.

Animal or vegetable oils include avocado oil, almond oil, olive oil, sesame oil, rice bran oil, soybean oil, soybean oil, corn oil, rapeseed oil, almond oil, palm kernel oil, palm oil, castor oil, sunflower oil, grape seed oil. , Cottonseed oil, Palm oil, Cucumber nut oil, Wheat germ oil, Rice germ oil, Shea butter, Walnut colostrum oil, Marker demia nut oil, Meadow home oil, Egg yolk oil, Uji, Horse oil, Mink oil, Orange rape oil, Jojoba oil And animal or plant fats and oils such as candeler wax, carnava wax, liquid lanolin and hardened castor oil.

Examples of the moisturizing agent include a water-soluble low molecular moisturizer, a fat-soluble molecular moisturizer, a water-soluble polymer, and a fat-soluble polymer.

Water-soluble low molecular humectants include serine, glutamine, sorbitol, mannitol, pyrrolidone-sodium carboxylate, glycerin, propylene glycol, 1,3-butylene glycol, ethylene glycol, polyethylene glycol B (polymerization degree n = 2 or more), polypropylene Glycol (polymerization degree n = 2 or more), polyglycerol B (polymerization degree n = 2 or more), lactic acid, lactic acid salt, etc. are mentioned.

Examples of the fat-soluble low molecular humectants include cholesterol and cholesterol esters.

Examples of the water-soluble polymer include carboxyvinyl polymer, polyasparaginate, tragacanth, xanthan gum, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, water soluble chitin, chitosan, and dextrin. Can be.

Examples of the fat-soluble polymers include polyvinylpyrrolidone-eicosene copolymers, polyvinylpyrrolidone-hexadecene copolymers, nitrocellulose, dextrin fatty acid esters, polymer silicones, and the like.

Examples of the emollient include long-chain acyl glutamic acid cholesteryl esters, hydroxy stearic acid cholesterol, 12-hydroxystearic acid, stearic acid, rosin acid, lanolin fatty acid cholesteryl esters, and the like.

As surfactant, nonionic surfactant, anionic surfactant, cationic surfactant, amphoteric surfactant, etc. are mentioned.

As the nonionic surfactant, self-emulsifying glycerin monostearate, propylene glycol fatty acid ester, glycerin fatty acid ester, polyglycerol fatty acid ester, sorbitan fatty acid ester, POE (polyoxyethylene) sorbitan fatty acid ester, POE sorbitan fatty acid ester, POE Glycerin fatty acid ester, POE alkyl ether, POE fatty acid ester, POE hardened castor oil, POE castor oil, POE / POP (polyoxyethylene / polyoxypropylene) copolymer, POE / POP alkyl ether, polyether modified silicone, lauric acid Alkanolamide, alkylamine oxide, hydrogenated soybean phospholipid, etc. are mentioned.

Anionic surfactants include fatty acid soaps, alpha-acyl sulfonates, alkyl sulfonates, alkyl allyl sulfonates, alkyl naphthalene sulfonates, alkyl sulfates, POE alkyl ether sulfates, alkylamide sulfates, alkyl phosphates, POE alkylphosphates, and alkylamides. Phosphates, alkyloylalkyltaurine salts, N-acylamino acid salts, POE alkyl ether carboxylate salts, alkyl sulfosuccinate salts, sodium alkyl sulfo acetates, acylated hydrolyzed collagen peptide salts, perfluoroalkyl phosphate esters, and the like. have.

As cationic surfactant, alkyl trimethylammonium chloride, stearyl trimethyl ammonium chloride, stearyl trimethyl ammonium chloride, cetostearyl trimethyl ammonium chloride, distearyl dimethyl ammonium chloride, stearyl dimethyl benzyl ammonium bromide, behenyl trimethyl ammonium chloride, chloride Benzalkonium, diethylaminoethyl stearate, dimethylaminopropyl stearate, lanolin derivatives, quaternary ammonium salts, and the like.

Examples of amphoteric surfactants include the carboxybetaine type, the amide betain type, the sulfobetain type, the hydroxysulfobetain type, the amide sulfobetain type, the phosphobetaine type, the aminocarboxylate type, the imidazoline derivative type, and the amideamine type. An amphoteric surfactant etc. are mentioned.

Examples of the organic and inorganic pigments include inorganic pigments such as silicic acid, silicic anhydride, magnesium silicate, talc, sericite, mica, kaolin, Bengala, clay, bentonite, titanium mica, titanium oxide, bismuth chloride, zirconium oxide, magnesium oxide, Inorganic pigments such as calcium sulfate, barium sulfate, magnesium sulfate, calcium carbonate, magnesium carbonate, iron oxide, chromium oxide, chromium oxide, chromium hydroxide, Polyamide, polyester, polypropylene, polystyrene, polyurethane, vinyl resin, urea resin, phenol resin, fluorine resin, silicon resin, acrylic resin, melamine resin, epoxy resin, polycarbonate resin, divinylbenzene, styrene copolymer, Organic pigments such as silk powder, cellulose, CI pigment yellow, CI pigment orange, and composite pigments of these inorganic pigments and organic pigments;

As organic powder, Metal soaps, such as a calcium stearate; Alkyl phosphate metal salts such as sodium cetylinate, zinc lauryl acid and calcium laurate; Acylamino acid polyvalent metal salts such as N-lauroyl-beta-alanine calcium, N-lauroyl-beta-alanine zinc, and N-lauroylglycine calcium; Amide sulfonic acid polyvalent metal salts, such as N-lauroyl-taurine calcium and N-palmitoyl-taurine calcium; N-epsilon-lauroyl-L-lysine, N-epsilon-palmitolyzine, N-alpha-paratoylol nitin, N-alpha-lauroyl arginine, N-alpha-cured fatty acid acyl arginine -Acyl basic amino acid; N-acyl polypeptides, such as N-lauroyl glycyl glycine; Alpha-amino fatty acids such as alpha-aminocaprylic acid and alpha-aminolauric acid; Polyethylene, polypropylene, nylon, polymethyl methacrylate, polystyrene, divinylbenzene-styrene copolymer, ethylene tetrafluoride and the like.

Examples of the ultraviolet absorber include paraaminobenzoic acid, ethyl paraaminobenzoate, amyl paraaminobenzoic acid, octyl paraaminobenzoate, ethylene glycol salicylate, phenyl salicylate, octyl salicylate, benzyl salicylate, butylphenyl salicylate, homomentyl salicylic acid and benzyl cinnamic acid. , Paramethoxy cinnamic acid-2-ethoxyethyl, paramethoxy cinnamic acid octyl, diparamethoxy cinnamic acid mono-2-ethylhexaneglyceryl, paramethoxy cinnamic acid isopropyl, diisopropyl diisopropyl cinnamic acid ester mixture, wuro Canonic acid, ethyl urokanoate, hydroxymethoxybenzophenone, hydroxymethoxybenzophenonesulfonic acid and salts thereof, dihydroxymethoxybenzophenone, dihydroxymethoxybenzophenone sodium sulfonate, dihydroxybenzophenone , Tetrahydroxybenzophenone, 4- tert -butyl-4'-methoxydibenzoylmethane, 2,4,6-trianilino- p- (carbo-2'-ethylhexyl-1'-oxy) -1 , 3,5-triazine, 2- (2-hi And the like can be mentioned hydroxy-5-methylphenyl) benzotriazole.

As fungicides, hinokithiol, trichloric acid, trichlorohydroxydiphenyl ether, chlorhexidine gluconate, phenoxyethanol, resorcin, isopropylmethylphenol, azulene, salicylic acid, ginxitlionone, benzalkonium chloride, photosensitive Sodium No. 301, sodium mononitroguicol, undecylenic acid, and the like.

Examples of the antioxidant include butylhydroxyanisole, propyl gallic acid, and erythorbic acid.

Examples of the pH adjuster include citric acid, sodium citrate, malic acid, sodium malate, fmaric acid, sodium pmarate, succinic acid, sodium succinate, sodium hydroxide, sodium dihydrogen phosphate, and the like.

Examples of the alcohol include higher alcohols such as cetyl alcohol.

In addition, the compounding component which may be added other than this is not limited to this, Moreover, Although all said components can be mix | blended within the range which does not impair the objective and effect of this invention, Preferably it is 0.01-5 weight% with respect to gross weight, More Preferably it is mix | blended in 0.01 to 3 weight%.

The cosmetic of the present invention may take the form of a solution, an emulsion, a viscous mixture or the like.

Ingredients included in the cosmetic composition of the present invention may include components commonly used in cosmetic compositions in addition to the compound as an active ingredient, for example, conventional auxiliary agents such as stabilizers, solubilizers, vitamins, pigments and flavorings. And carriers.

The cosmetic composition of the present invention may be prepared in any formulation commonly prepared in the art, and includes, for example, milky lotion, cream, lotion, pack, foundation, lotion, essence, hair cosmetic, and the like. Specifically, the cosmetic composition of the present invention skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisturizing lotion, nutrition lotion, massage cream, nutrition cream, moisturizing cream, hand cream, foundation, essence, nutrition essence, Formulations of packs, soaps, cleansing foams, cleansing lotions, cleansing creams, body lotions and body cleansers.

When the formulation of the present invention is a paste, cream or gel, animal fiber, plant fiber, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide may be used as the carrier component .

In the case where the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component. Especially, in the case of a spray, a mixture of chlorofluorohydrocarbons, propane / Propane or dimethyl ether.

In the case of the solution or emulsion of the present invention, a solvent, a solvent or an emulsifier is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, , 3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan fatty acid esters.

When the formulation of the present invention is a suspension, a carrier such as water, a liquid diluent such as ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, Cellulose, aluminum metahydroxide, bentonite, agar or tracant, etc. may be used.

When the formulation of the present invention is an interfacial active agent-containing cleansing, the carrier component may include aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyltaurate, sarcosinate, fatty acid amide Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, linolenic derivatives or ethoxylated glycerol fatty acid esters.

In addition, the pharmaceutical composition for the treatment and prevention of skin pigmentation diseases containing a thymoquinone compound as an active ingredient as another embodiment of the present invention will be described in detail.

The pharmaceutical compositions of the present invention may further comprise suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions.

The pharmaceutical compositions of the present invention may be used in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, and other external preparations and sterile injectable solutions, respectively, according to conventional methods, preferably creams, It can be used in the form of gels, patches, sprays, ointments, warnings, lotions, linings, pastas or cataplasmas.

Carriers, excipients and diluents that may be included in the pharmaceutical compositions of the present invention include lactose, dextrose, sucrose, oligosaccharides, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, Calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

In the case of formulation, it is preferable to use diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents and surfactants that are commonly used.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations may contain at least one excipient such as starch, calcium carbonate, sucrose, or the like. ) Or lactose, gelatin and the like are preferably mixed. In addition to simple excipients, lubricants such as magnesium styrate talc may also be used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included . Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

The pharmaceutical composition of the present invention is a skin external preparation formulation that can be applied to the skin as a pharmaceutical composition in the form of an external preparation for skin, such as cream, gel, patch, spray, ointment, warning, lotion, linen, pasta or cataplasma. It may be prepared and used, but is not limited thereto.

The preferred dosage of the pharmaceutical composition of the present invention depends on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, and may be appropriately selected by those skilled in the art. However, for the preferred effect, the composition of the present invention is preferably administered at 0.0001 to 100 mg / kg, preferably 0.001 to 10 mg / kg per day. Topical administration may be administered once a day or may be divided several times. The dose is not intended to limit the scope of the invention in any way.

According to the present invention, a cosmetic composition for skin whitening containing a thymoquinone compound as an active ingredient, or a pharmaceutical composition for treating and improving skin pigmentation diseases can be prepared.

In addition, the cosmetic and pharmaceutical compositions of the present invention effectively inhibit the activity of tyrosinase, an enzyme that is essential for melanin biosynthesis, and inhibit the biosynthesis of melanin in B16 melanoma cells, thereby treating and preventing skin whitening and skin pigmentation disorders. , The improvement effect is very excellent.

Hereinafter, the present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited to the following examples, and includes modifications of equivalent technical ideas.

Example  One : Thymoquinone  Produce

8.9 g of m-chloroperbenzoic acid (Sigma Aldrich, USA) was added to the chloroform solvent under stirring under reflux where 5 g of thymol (Sigma Aldrich, USA) was dissolved. Excess m-chloroperbenzoic acid was filtered off and the filtrate was concentrated under reduced pressure. The obtained concentrate was dissolved in the same amount of hexane and separated using ethyl acetate: n-hexane = 1: 8 (volume ratio) in a column tube filled with silica gel (Merck, USA) to obtain 2.19 g of thymoquinone.

Example  2 : Of thymohydroquinone (I)  Produce

8.9 g of m-chloroperbenzoic acid (Sigma Aldrich, USA) was added to the chloroform solvent under stirring under reflux where 5 g of thymol (Sigma Aldrich, USA) was dissolved. After filtering the excess m-chloroperbenzoic acid, the filtrate was concentrated under reduced pressure. The obtained concentrate was dissolved in the same amount of hexane and separated using ethyl acetate: n-hexane = 1: 8 (volume ratio) in a column tube filled with silica gel (Merck, USA) to obtain 1.40 g of thymohydroquinone (I). .

Example  3: Of thymohydroquinone (II)  Produce

1 g of thymoquinone (Tokyo Chemical Industry, Japan) was dissolved in 0.5 ml ethanol, and stirred for 1 hour. The reaction solution was stored in refrigeration and the resulting powder was filtered and washed with 10 ml of water and 10 ml of ethanol. 100 ml of 2% aqueous hydrochloric acid was added to the filtered powder, and extracted with 50 ml of ethyl acetate. The extracted ethyl acetate layer was concentrated to give 0.54 g of thymohydroquinone (II).

Example  4 : Dithymoquinone  Produce

5 g of thymoquinone (Tokyo Chemical Industry, Japan) was dissolved in 10 mL of ether and then thinly applied to Petri dishes. The thin film product obtained by spontaneous evaporation of ether was stored under daylight conditions for 5 days to proceed with photochemical reaction. The product obtained through photochemical reaction was dissolved in 5 mL of ethyl acetate, adsorbed onto a column column filled with 50 g of silica gel (Merck, USA), and then mixed with ethyl acetate: n-hexane = 1: 8 (volume ratio). A total of four fractions were obtained using the solution and 3.47 g of ditaimoquinone was obtained by recrystallization of the third fraction.

Experimental Example  One : Tyrosinase  Activity inhibitory effect

In this experimental example, the inhibitory effect of tyrosinase activity was measured on commercially available thymoquinone (Tokyo Chemical Industry, Japan) and the thymoquinone compounds of Examples 1 to 4 above.

Inhibitory activity of tyrosinase is generally measured by spectroscopic method, which was performed by Barney et al. (Vanni A. at al., Annali) . di Chimica , 80 (35), 1990).

Tyrosinase is an enzyme purified from potatoes and mushrooms. In this experiment, one extracted from mushrooms was used. 1.0 ml of 0.1 M potassium phosphate buffer (pH 6.8), 0.3 ml of 0.3 mg / ml L-tyrosine aqueous solution and 0.1 ml of 1250 unit / ml mushroom tyrosinase (Sigma Aldrich, USA) were mixed and sample solution was added to each concentration according to the concentration. 0.2 ml each was added and the enzyme was reacted at 37 ° C for 10 minutes. Then, the absorbance of the reaction solution was measured at 480 nm (JASCO V-550, Japan) and calculated according to Equation 1 below to obtain the degree of enzyme inhibitory activity of the sample. As a positive control group, 0.2 ml of arbutin (Bioland Co., Ltd.) of the same concentration was used as a control group, and a reaction solution without adding a sample was used as a control group.

The results are shown in Table 1 below.

sample At a concentration of 100 μg / ml
Mushroom tyrosinase inhibition rate (%) Thymoquinone 95.25 Example 1 95.04 Example 2 89.39 Example 3 87.52 Example 4 85.47 Arbutin 53.21

As shown in Table 1, it was found that all of the thymoquinone compounds of the present invention have a better tyrosinase inhibitory effect than arbutin, which is widely used as a whitening cosmetic raw material. Therefore, the thymoquinone compound of the present invention was found to be excellent in tyrosinase inhibitory effect.

Experimental Example  2: B16-F1 Melanoma  Cytotoxicity Measurements Using Cells

In this experimental example, the cell viability of B16-F1 melanoma cells (CRL-6323, ATCC) was measured using the thymoquinone compounds of Examples 1 to 4 as samples.

In this experiment, MTT experiments were performed to measure cytotoxicity, and specific experimental methods are as follows.

B16-F1 melanoma cells were inoculated into 6 well plates (Nunc) at a density of 1 × 10 ⁵ cells in DMEM (Dulbecco's modified eagle's medium, Gibco) with 10% FBS (Fetal bovine serum, Gibco) % CO _2, and incubated at 37 ℃. Then, after replacing with fresh DMEM containing 10% FBS, the samples were treated by concentration and incubated for 3 days. After 3 days, the medium was removed and treated with 2 ml of 0.25 mg / ml MTT ((3- [4,5-dimethylthiazole-2-yl] -2,5-diphenyltetrazolium bromide), Sigma) solution for 4 hours at 37 ° C. Reacted. Thereafter, 2 ml of DMSO (dimethylsulfoxide) was added to the cells from which the MTT solution was removed to dissolve MTT formazan and measured by absorbance at 570 nm. All experiments were repeated three times to obtain an average value by statistical treatment, the results are shown in Table 2.

sample Cell survival rate (%) Thymoquinone (50 μg / ml) 97.15 ± 0.42 (100 μg / ml) 96.88 ± 0.26 Example 1 (50 μg / ml) 97.06 ± 0.38 (100 μg / ml) 96.74 ± 0.59 Example 2 (50 μg / ml) 98.67 ± 0.51 (100 μg / ml) 97.12 ± 0.54 Example 3 (50 μg / ml) 98.45 ± 0.22 (100 μg / ml) 97.17 ± 0.63 Example 4 (50 μg / ml) 98.14 ± 0.28 (100 μg / ml) 97.56 ± 0.56

As shown in Table 2, Examples 1 to 4 of the present invention, the cell survival rate of commercially available thymoquinone was close to 100%, it was found that the thymoquinone compounds do not exhibit cytotoxicity.

Experimental Example  3: B16-F1 Melanoma  Measurement of Melanin Biosynthesis Inhibitory Effect Using Cells

In this experimental example, the melanin production inhibitory effect was measured for the commercially available thymoquinone (Tokyo Chemical Industry, Japan) and the thymoquinone compounds of Examples 1 to 4 above.

B16-F1 melanoma cells produce melanin, using (melanogenesis) inhibitory effect Fu CUDA etc. (Fukuda et al., J. Soc . Cosmetic Chem . , 42 (361), 1991). Well counts according to all concentrations were prepared in triplicate.

Specifically, B16-F1 melanoma cells were inoculated into 6 well plates at a density of 1 × 10 ⁵ cells in DMEM with 10% FBS and incubated at 5% CO ₂ , 37 ° C. for one day. Then, after replacing with fresh DMEM containing 10% FBS, the samples were treated by concentration and incubated for 3 days. After 3 days, the cells from which the medium was removed were washed with 2 ml of PBS (phosphate buffer, saline) and treated with 0.5 ml of 1N NaOH to collect cells into 1.5 ml tubes to obtain intracellular melanin. The collected cells were transferred to a 96 well plate and absorbance was measured at 450 nm to determine the amount of melanin per protein. Arbutin (Bioland Co., Ltd.) at a concentration of 100 ug / ml was used as a control, and a reaction solution without adding a sample was used as a control of the experimental group.

Table 3 shows the results of inhibiting melanin production of the thymoquinone compounds obtained therefrom.

Sample (50 μg / ml) Melanin production inhibitory effect (%) Thymoquinone 93.46 Example 1 93.15 Example 2 92.63 Example 3 92.81 Example 4 90.46 Arbutin (100 μg / ml) 30.68

As shown in Table 3, the thymoquinone compounds of the present invention showed a high melanin production inhibitory effect even in a small amount of 50 ㎍ / ml. Compared with arbutin, which is already known to have excellent whitening effect, it showed a much better effect than when 100 μg / ml of arbutin corresponding to twice the amount of the tamoquinone compound of this example was added.

clinical Experimental Example  One : Thymoquinone  Whitening clinical trial

In this experimental example, in order to see the whitening activity of thymoquinone for skin whitening in clinical practice, the lotion of the Examples of Formulation (Test Group) and Comparative Formulation (Control) of Table 4 was used for women aged 19 to 22 years with healthy skin. After the artificial pigmentation was induced, the double-blind and randomized human test methods were applied to the test formulation for 6 weeks, and the skin whitening effect was evaluated.

Raw material Example of Formulation Comparative Formulation Example   Example 1 0.5 - Cytostolol 1.70 1.70 Polyglyceryl 2-oleate 1.50 1.50 Setares-4 1.2 1.2 cholesterol 1.5 1.5 Dicetyl phosphate 0.4 0.4 Concentrated glycerin 5.0 5.0 Sunflower oil 10.0 10.0 Carboxy Vinyl Polymer 0.2 0.2 Xanthan Gum 0.3 0.3 antiseptic a very small amount a very small amount Spices a very small amount a very small amount Purified water Balance Balance

clinical Experimental Example  1-1: Visual evaluation

The skin whitening effect was evaluated before, at 1, 2, 4, and 6 weeks of use. Evaluation criteria were evaluated by two observers using a 1 to 7 point scale. Table 5 shows the results of visual evaluation by observer 1, and Table 6 shows the results of visual evaluation by observer 2. The test group and the control group were repeatedly evaluated for each time point, and the test results were tested for the difference between the groups and time points by applying the repeated measures ANOVA (p <0.05).

<Evaluation Criteria>

0: no pigmentation

1: no light pigmentation

2: light pigmentation

3: light or normal pigmentation

4: normal pigmentation

5: moderate or severe pigmentation

6: severe pigmentation

7: very severe pigmentation

week N Evaluation S.E.Mean S.D

Test group

Week 0 20 6.39 0.1247 0.4532 1 week 20 5.56 0.1461 0.7192 2 weeks 20 4.66 0.1383 0.7174 3 weeks 20 3.96 0.1866 0.7719 4 Weeks 20 3.36 0.2050 0.9738

Control

Week 0 20 6.13 0.1557 0.6633 1 week 20 5.72 0.2006 0.8804 2 weeks 20 4.97 0.1745 0.8446 3 weeks 20 4.32 0.1918 0.8883 4 Weeks 20 3.83 0.1785 0.8430

week N Evaluation S.E.Mean S.D

Test group

Week 0 20 6.39 0.1379 0.6699 1 week 20 6.14 0.1358 0.6701 2 weeks 20 5.13 0.1377 0.6604 3 weeks 20 4.35 0.1497 0.5997 4 Weeks 20 3.32 0.1725 0.7073

Control

Week 0 20 6.26 0.1408 0.6196 1 week 20 6.39 0.1384 0.6082 2 weeks 20 5.51 0.1529 0.6265 3 weeks 20 5.20 0.1346 0.6622 4 Weeks 20 4.23 0.1622 0.6408

According to Tables 5 and 6, the case in which the formulation with the thymoquinone compound of the present invention was used showed a significant improvement compared to the control group which was not used.

clinical Experimental Example  1-2: Color meter  Melanin index measurement

Using the color difference meter (MPA-580), the melanin index was measured before and after 1, 2, 4, and 6 weeks of the formulation of the test group and the control group. Table 7 shows the results of evaluating the melanin index at each time point.

week N Evaluation S.E.Mean S.D

Test group

Week 0 20 196.88 8.8021 41.8645 1 week 20 195.09 8.7791 37.1164 2 weeks 20 190.43 8.6017 38.1363 3 weeks 20 182.33 8.1086 34.9613 4 Weeks 20 168.33 7.6339 29.7517

Control

Week 0 20 205.51 8.6112 39.0867 1 week 20 199.70 8.4673 36.0897 2 weeks 20 197.67 7.5559 31.5624 3 weeks 20 192.55 7.6878 30.7360 4 Weeks 20 189.54 7.5539 31.6962

According to Table 7, the melanin index was decreased in the test group using the formulation with the thymoquinone compound of the present invention compared to the control group.

Formulation example  1: flexible lotion ( skin )

As described below, a flexible lotion (skin) containing a thymoquinone compound obtained in Example 1 was prepared according to a conventional method.

Raw material content Example 1 3.0 glycerin 3.0 Butylene Glycol 2.0 Propylene glycol 2.0 Polyoxyethylene (60) Cured Castor Oil 1.00 ethanol 10.0 Triethanolamine 0.1 antiseptic a very small amount Pigment a very small amount Spices a very small amount Purified water Balance

Formulation example  2: nutrient lotion (lotion)

As described below, a nutrient lotion (lotion) containing a thymoquinone compound obtained in Example 2 was prepared according to a conventional method.

Raw material content Example 2 1.0 Cytostolol 1.70 Polyglyceryl 2-oleate 1.50 Setares-4 1.2 cholesterol 1.5 Dicetyl phosphate 0.4 Concentrated glycerin 5.0 Sunflower oil 10.0 Carboxy Vinyl Polymer 0.2 Xanthan Gum 0.3 antiseptic a very small amount Spices a very small amount Purified water Balance

Formulation example  3: nutrition cream

As described below, a nourishing cream containing a thymoquinone compound in Example 3 was prepared according to a conventional method.

Raw material content  Example 3 1.0 Cytostolol 4.0 Polyglyceryl 2-oleate 3.0 Setares-4 2.0 cholesterol 3.0 Dicetyl phosphate 0.4 Concentrated glycerin 5.0 Sunflower oil 22.0 Carboxy Vinyl Polymer 0.5 Triethanolamine 0.5 antiseptic a very small amount Spices a very small amount Purified water Balance

Formulation example  4. Essence

As described below, an essence containing the thymoquinone compounds obtained in Example 4 was prepared according to a conventional method.

Raw material content Example 4 1.0 Cytostolol 1.70 Polyglyceryl 2-oleate 1.50 Setares-4 2.0 cholesterol 3.0 Dicetyl phosphate 0.4 Concentrated glycerin 5.0 Sunflower oil 22.0 Carboxy Vinyl Polymer 0.5 Triethanolamine 0.5 antiseptic a very small amount Spices a very small amount Purified water Balance

Formulation example  5: Foundation

As follows, the foundation containing the thymoquinone compound obtained in Example 1 was manufactured according to a conventional method.

Raw material content Example 1 1.0 Beeswax 2.0 Pyromethicone 2.0 Liquid paraffin 5.0 Squalane 5.0 Stearic acid 2.0 Lipophilic monostearic acid glycerin 3.0 Caprylic / capric triglyceride 4.0 glycerin 4.0 Propylene glycol 3.0 Butylene glycol 3.0 Triethanolamine 1.0 Aluminum Magnesium Silicate 0.5 Pigment 12 antiseptic a very small amount Spices a very small amount Purified water Balance

Formulation example  6: hydrophilic ointment

As follows, a hydrophilic ointment containing the thymoquinone compounds obtained in Example 2 was prepared according to a conventional method.

Raw material Content (% by weight)   Example 2 0.5   White vaseline 250   Stearyl alcohol 220   Ethyl (or methyl) p-oxybenzoate 0.25   Propylene glycol 120   Sodium lauryl sulfate 15   Propyl p-oxybenzoate 0.15

Claims (14)

A cosmetic composition for skin whitening, comprising a thymoquinone compound of Structural Formula 1 as an active ingredient.

A cosmetic composition for skin whitening, comprising the following thymoquinone compound of Structural Formula 2 as an active ingredient.

A cosmetic composition for skin whitening, comprising the thymoquinone compound of Structural Formula 3 as an active ingredient.

4. The method according to any one of claims 1 to 3,
Cosmetic composition for skin whitening, characterized in that it comprises 0.0001 to 50% by weight relative to the total weight of the composition of the thymoquinone compound.
4. The method according to any one of claims 1 to 3,
Skin whitening effect,
A cosmetic composition for skin whitening, characterized by suppressing the activity of tyrosinase or the production of melanin.
delete 4. The method according to any one of claims 1 to 3,
Skin Lotion, Skin Softener, Skin Toner, Astringent, Lotion, Milk Lotion, Moisture Lotion, Nutrition Lotion, Massage Cream, Nutrition Cream, Moisture Cream, Hand Cream, Foundation, Essence, Nutrition Essence, Pack, Soap, Cleansing Foam, Cleansing Lotion , Cleansing cream, body lotion or body cleanser, characterized in that the cosmetic composition for skin whitening.
A pharmaceutical composition for the treatment and prophylaxis of skin pigmentation disorders, which comprises the thymoquinone compound of Structural Formula 1 as an active ingredient.

A pharmaceutical composition for the treatment and prophylaxis of skin pigmentation disorders, comprising a thymoquinone compound of Structural Formula 2 as an active ingredient.

A pharmaceutical composition for the treatment and prophylaxis of skin pigmentation disorders, comprising a thymoquinone compound of Structural Formula 3 as an active ingredient.

The method according to any one of claims 8 to 10,
The skin pigmentation disease occurs locally on the skin due to an increased synthesis of melanin pigment and is selected from blemishes, freckles, black spots, birthmarks, pigmentation by drugs, pigmentation after inflammation, and hyperpigmentation occurring in dermatitis Pharmaceutical composition for the treatment and prevention of skin pigmentation disease, characterized in that at least one disease.
The method according to any one of claims 8 to 10,
Pharmaceutical composition for the treatment and prevention of skin pigmentation disease, characterized in that it comprises 0.0001 to 50% by weight of the thymoquinone compound relative to the total weight of the composition.
The method according to any one of claims 8 to 10,
The treatment and prevention effect of skin pigmentation disease,
Pharmaceutical composition for the treatment and prevention of skin pigmentation disease, characterized by inhibiting the activity of tyrosinase or the production of melanin
The method according to any one of claims 8 to 10,
A pharmaceutical composition for the treatment and prophylaxis of skin pigmentation disorders, which is a cream, gel, patch, spray, ointment, warning, lotion, linen, pasta or cataplasma formulation.