WO2011069915A1 - Composition à usage externe et procédé de production associé - Google Patents

Composition à usage externe et procédé de production associé Download PDF

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Publication number
WO2011069915A1
WO2011069915A1 PCT/EP2010/068852 EP2010068852W WO2011069915A1 WO 2011069915 A1 WO2011069915 A1 WO 2011069915A1 EP 2010068852 W EP2010068852 W EP 2010068852W WO 2011069915 A1 WO2011069915 A1 WO 2011069915A1
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WIPO (PCT)
Prior art keywords
composition
tranexamate
salt
external use
acid
Prior art date
Application number
PCT/EP2010/068852
Other languages
English (en)
Inventor
Masayoshi Miyamoto
Tomomi Kuromiya
Daisuke Suzuki
Original Assignee
Chanel Parfums Beaute
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chanel Parfums Beaute filed Critical Chanel Parfums Beaute
Priority to CN2010800560643A priority Critical patent/CN102686206A/zh
Priority to US13/514,623 priority patent/US8647650B2/en
Priority to EP10790635.6A priority patent/EP2509559B1/fr
Publication of WO2011069915A1 publication Critical patent/WO2011069915A1/fr
Priority to US14/140,302 priority patent/US8758785B2/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/044—Suspensions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/0241—Containing particulates characterized by their shape and/or structure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/38—Separation; Purification; Stabilisation; Use of additives
    • C07C227/40—Separation; Purification
    • C07C227/42—Crystallisation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/41—Particular ingredients further characterized by their size
    • A61K2800/412—Microsized, i.e. having sizes between 0.1 and 100 microns
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/60—Particulates further characterized by their structure or composition
    • A61K2800/65—Characterized by the composition of the particulate/core
    • A61K2800/652—The particulate/core comprising organic material
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]

Definitions

  • the present invention relates to a composition for external use containing a physiologically acceptable salt of a tranexamate as an active ingredient, and a method for producing the same. It also relates to fine particles of this salt, and to a cosmetic composition comprising same.
  • Patent Document 1 discloses an anti-pigmentation agent for external use using a tranexamate as an active ingredient.
  • Patent Document 2 exemplifies tranexamic acid and derivatives thereof as a skin-whitening ingredient to be usable with Coenzyme Q10.
  • Japanese Patent Laid-Open No. 04-46144 discloses an anti-pigmentation agent for external use using a tranexamate as an active ingredient.
  • Patent Document 2 exemplifies tranexamic acid and derivatives thereof as a skin-whitening ingredient to be usable with Coenzyme Q10.
  • Patent Document 3 exemplifies cetyl tranexamate as an oil-soluble skin-whitening ingredient to be usable with an L-ascorbic acid tetra-branched fatty acid ester derivative
  • Patent Document 4 discloses an anti-stress external preparation for skin using a tranexamate as an active ingredient.
  • the same discloses a method to dissolve a tranexamate using a large amount of an oil component such as an olive oil.
  • an oil component such as an olive oil.
  • the formulation form is limited to a cream or a milky lotion due to the use of a large amount of an oil component.
  • the obtained external preparation is sticky and oily and the sense of use is unfavorable.
  • Patent Document 5 discloses an external preparation for skin using a tranexamate or a salt thereof as well as a silicone oil. The same teaches that by the combination of a tranexamate or a salt thereof and a silicone oil the solubility of the tranexamate or a salt thereof in the composition can be enhanced, and the activity of the tranexamate can last over an extended time period.
  • a silicone oil is known as an oil component giving less heavy sense of use, due to the necessity of the use of a large amount of the same to dissolve the tranexamate, the range of choice for the formulation forms of the external preparation for skin becomes narrow.
  • the present inventor has studied intensively for coping with the problems to succeed in stably retaining an active ingredient derived from a tranexamate in a composition by dispersing a salt of the tranexamate in the composition in the state of fine particles, instead of dissolving the tranexamate in the composition. Furthermore, the inventor has also discovered that the salt of the tranexamate can be dispersed more stably by combining the salt with a water- soluble polymer selected from nonionic polymers and cationic polymers in the composition, thereby completing the present invention .
  • the present invention provides a method for producing a composition for external use in which a salt of a tranexamate is dispersed stably and stabilized fine particles of a salt of a tranexamate obtained by the method, as described hereinbelow. Furthermore, the present invention provides a composition containing a salt of a tranexamate wherein the salt is dispersed in the state of fine particles and a cosmetic method for inhibiting hyperpigmentation of and/or whitening the skin, for reducing aging spots or pigmentation spots by topical application to the skin of this composition .
  • a first object of this invention is thus a method for producing a composition for external use, the method comprising the steps of:
  • a second object of this invention is a composition for external use obtained by the above method.
  • a third object of this invention is the cosmetic use of the above composition for external use, for inhibiting pigmentation of and/or whitening the skin or for reducing aging spots or pigmentation spots.
  • a fourth object of this invention is a cosmetic method for inhibiting pigmentation of and/or whitening the skin or for reducing aging spots or pigmentation spots, the method comprising the topical application, to the skin, of the above composition for external use.
  • This invention also pertains to fine particles of a physiologically acceptable salt of a tranexamate obtainable by a method comprising the steps of:
  • composition for external use of the present invention contains a physiologically acceptable salt of a tranexamate (hereinafter referred to also as "a tranexamate salt”) as an active ingredient, in which composition the salt is dispersed in the state of fine particles.
  • a tranexamate salt a physiologically acceptable salt of a tranexamate
  • the composition for external use of the present invention is composed of a tranexamate salt dispersed in the composition in the state of fine particles, crystal growth of the active ingredient due to environmental changes hardly occurs, and the active ingredient can remain dispersed in the composition stably for an extended time period.
  • the composition for external use of the present invention can express skin- whitening activity for a prolonged period.
  • a state of fine particles means herein that the particles are so minute that they disperse and remain suspended in a composition to make a white turbid appearance.
  • the average particle size of the particles is 0.01 ⁇ to 100 ⁇ , preferably 0.05 ⁇ to 50.0 ⁇ , and more preferably 0.10 ⁇ to 10.0 ⁇ .
  • step a) is described.
  • a physiologically acceptable salt of a tranexamate is dissolved in a solvent.
  • the tranexamate salt is dissolved in a solvent under stirring.
  • the temperature of the solvent is preferably from 50 to 120°C, more preferably from 70 to 100°C, and further preferably from 80 to 90°C.
  • tranexamate used in the physiologically acceptable salt of a tranexamate is represented by the following formula (1),
  • R represents a group chosen from: a CI to C22 linear saturated hydrocarbon group, a C2 to C22 linear unsaturated hydrocarbon group, or a C3 to C22 branched, saturated or unsaturated, hydrocarbon group, which may be substituted by at least one substituent selected from hydroxy and amino groups .
  • the hydrocarbon group may be aliphatic or aromatic or it may comprise both an aromatic and an aliphatic moieties.
  • the hydrocarbon group include: an alkyl group, an alkenyl group, an alkynyl group, an alkyldienyl group, an aryl group, an alkylaryl group, an arylalkyl group, a cycloalkyl group, a cycloalkenyl group, and a cycloalkylalkyl group.
  • an aliphatic hydrocarbon group, especially an alkyl group is preferable. Its carbon number is preferably 8 to 20, and especially preferably 12 to 18.
  • substituents on the hydrocarbon group there is no particular restriction of the number of substituents on the hydrocarbon group.
  • the substituents may be either hydroxy groups or amino groups, or both of hydroxy group (s) and amino group (s) .
  • tranexamate represented by Formula (1) examples include lauryl tranexamate, myristyl tranexamate, cetyl tranexamate and stearyl tranexamate. Among them, cetyl tranexamate is especially preferable.
  • a physiologically acceptable salt of the tranexamate to be used in the present invention, insofar as the object of the present invention is not impeded, preferable examples thereof include a mineral acid salt, such as a hydrochloride salt, a phosphoric acid salt, a sulfuric acid salt, a bromic acid salt, and a nitric acid salt; an organic acid salt, such as an oxalic acid salt, a lactic acid salt, and a citric acid salt; and a carbonic acid salt of a tranexamate.
  • a tranexamate salt to be used in the present invention should preferably be selected from the group consisting of a cetyl tranexamate hydrochloride salt, a cetyl tranexamate phosphoric acid salt, a cetyl tranexamate sulfuric acid salt, a cetyl tranexamate bromic acid salt, a cetyl tranexamate nitric acid salt, a cetyl tranexamate oxalic acid salt, a cetyl tranexamate lactic acid salt, a cetyl tranexamate citric acid salt, and a cetyl tranexamate carbonic acid salt.
  • a cetyl tranexamate hydrochloride salt is especially preferable.
  • the tranexamate salt may be used singly or in combination of two or more types.
  • the tranexamate salt to be used as the source material can be obtained usually by an esterification method according to a dehydration condensation reaction between tranexamic acid having a carboxylic group and a higher alcohol having a hydroxy group.
  • Tranexamic acid is a publicly known compound, which can be produced, for example, by a method disclosed in Japanese Patent Laid-Open No. 09-077726.
  • the crystals of the tranexamate salt obtained by the above-mentioned method have usually the particle size of about 0.1 mm to 10.0 mm, and have a difficulty in being dissolved or dispersed directly and stably in a solvent.
  • the tranexamate salt can be dispersed in the state of fine particles.
  • the solvent to be used examples thereof may include water; a lower alcohol (preferably, an alcohol having 1 to 5 carbon atoms), such as methanol, ethanol, propanol and isopropanol ; a polyhydric alcohol, such as 1,3-butylene glycol, propylene glycol, dipropylene glycol and glycerin; an ether, such as ethyl ether and propyl ether; an ester, such as ethyl acetate and butyl acetate; a ketone, such as acetone and ethyl methyl ketone; and a mixture thereof.
  • water or a mixture of water and a polar organic solvent is preferable, and especially water is preferable .
  • the concentration of a tranexamate salt after the tranexamate salt is dissolved in a solvent should be selected appropriately depending on the solubility of the tranexamate salt in the solvent to be used, and there is no particular restriction.
  • the concentration is, for example, preferably 0.1 to 20.0 % by weight, more preferably 0.5 to 10.0% by weight, and further preferably 1.0 to 5.0 % by weight based on the total weight of the composition (solution obtained by dissolving a tranexamate salt and optionally other water-soluble components in a solvent) .
  • step b) is described.
  • the salt is precipitated by adding at least one salting-out agent to the solution obtained in the step a) .
  • the salting-out agent insofar as a salt of a tranexamate in a solution can be precipitated.
  • the sole requirement is thus that the salting-out agent be more soluble than the tranexamate salt in the solvent.
  • examples thereof include a citrate, an edetate, a glycolate, a phosphate, a hydrochloride, a sulfate, an acetate, a tartrate, a bromate, an oxalate, a lactate, a carbonate and a chloride salt.
  • salting-out agents a citrate, an edetate, a glycolate, a sulfate, a phosphate and a chloride salt are preferable, because a desired salt can be efficiently precipitated with a small amount of the salting-out agent and the compatibility with other components are good.
  • More specific examples include sodium citrate as a citrate; sodium edetate as an edetate; sodium glycolate as a glycolate; ammonium sulfate, sodium sulfate and magnesium sulfate as a sulfate; potassium phosphate and sodium phosphate as a phosphate; and sodium chloride and magnesium chloride as a chloride salt.
  • these salting-out agents are more preferable sodium citrate, sodium edetate, sodium glycolate, sodium chloride, magnesium chloride and magnesium sulfate.
  • the salting-out agent may be used singly or in combination of two or more types.
  • the temperature when the salting-out agent is added to the solution obtained in the step a) is, for example, preferably 30 to 120°C, more preferably 40 to 100°C, and further preferably 60 to 90°C.
  • the salting-out agent should preferably be added under stirring the solution.
  • the amount of the salting-out agent is preferably 0.05 to 5.0% by weight, more preferably 0.1 to 2.0% by weight, and further preferably 0.2 to 1.0% by weight based on the total weight of the composition (the mixture of the tranexamate salt, the solvent and the salting-out agent) .
  • a salt is precipitated preferably while stirring the obtained mixed solution.
  • the temperature of the mixed solution is higher than room temperature, the temperature of the mixed solution is preferably cooled to room temperature (20 to 40°C) .
  • the solution may be cooled by using a temperature adjusting device or naturally cooled.
  • the salt precipitated in the step b) is dispersed in a composition for external use in the state of fine particles having an average particle size of 0.01 lm to 100 ⁇ .
  • an average particle size used in the present application refers to a value (median size) measured (calculated) by using a laser diffraction particle size analyzer (SALD-7000, SHIMADZU) .
  • the tranexamate salt may be isolated and collected from the composition obtained in step (c) and added to another composition for external use.
  • a method for isolating a tranexamate salt examples thereof include centrifugat ion, filtration, spray-drying and freeze-drying .
  • this invention also pertains to a composition for external use that can be obtained in accordance with the above-mentioned steps a) to c) .
  • the content of the tranexamate salt dispersed in the composition for external use of the present invention is not particular restriction on the content of the tranexamate salt dispersed in the composition for external use of the present invention, insofar as it gives an effective dose, and the content may be selected appropriately depending on the form of a formulation or a product.
  • it is preferably 0.01 to 20.0% by weight, more preferably 0.1 to 10.0% by weight, and further preferably 0.5 to 5.0% by weight based on the total weight of the composition .
  • the composition for external use according to the present invention should preferably further contain a water- soluble polymer selected from nonionic polymers and cationic polymers.
  • a water-soluble polymer selected from nonionic polymers and cationic polymers in the composition, aggregation of a tranexamate salt can be suppressed even after a long period of storage, maintaining the stable dispersion state.
  • the water-soluble polymer may be added after the precipitation of a tranexamate salt, or during the precipitation of the tranexamate salt.
  • a water-soluble polymer may be added in the step a) or b) , or in the step c) .
  • water-soluble polymer selected from nonionic polymers and cationic polymers to be used in the present invention examples include polysaccharides, which may be modified, such as dextrin, cellulose derivatives including methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose or hydroxypropyl methyl cellulose stearoyl ester ; glucomannan, xylan, mannan, and agar ; synthetic polymers such as PVA (polyvinyl alcohol), PVM (polyvinyl methyl ether) or PVP (polyvinyl pyrrolidone) ; and natural gums such as locust bean gum, guar gum, tara gum or tamarind gum.
  • polysaccharides which may be modified, such as dextrin, cellulose derivatives including methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropy
  • At least one selected from the group consisting of locust bean gum, guar gum, tara gum, hydroxyethyl cellulose, and hydroxypropyl methyl cellulose stearoyl ester is preferable.
  • the water-soluble polymer selected from nonionic polymers and cationic polymers may be used singly or in combination of two or more types.
  • the content of the water-soluble polymer in the composition for external use of the present invention is preferably 0.01 to 5.00% by weight, more preferably 0.05 to 2.00% by weight, and further preferably 0.1 to 1.00% by weight based on total weight of the composition for external use.
  • the pH of the composition for external use of the present invention generally ranges from 3.0 to 8.0 and preferably from 4.0 to 6.0 in view of adequate activity and improvement of safety.
  • an active ingredient derived from a tranexamate which is instable between a dissolved and non-dissolved states, can be contained in the composition for external use in a stable condition for an extended time period by being dispersed in a composition in the state of fine particles. Since the tranexamate salt in the state of fine particles can be dispersed also in an aqueous medium, and it is not necessary to use a large amount of an oil component to disperse the active ingredient, a composition for external use with a refreshing sense of use suppressing sticky or oily feeling can be obtained. Furthermore, in case an oil component is added to the composition for external use, the content thereof can be appropriately adjusted according to the purpose, so that the range of selection for the form of a formulation or a product of the composition for external use can be broadened.
  • components to be used commonly in cosmetics or drugs such as a powder component, a liquid oil, a solid fat, a wax, a hydrocarbon oil, a higher fatty acid, a higher alcohol (preferably an alcohol having 6 or more carbon atoms, and more preferably an alcohol having 10 or more carbon atoms), a synthetic ester oil, a silicone compound, a surfactant, a co-surfactant, a film forming agent, a gelling agent, a metal sequestering agent, a lower alcohol, a polyhydric alcohol or a derivative thereof, a monosaccharide, an oligosaccharide, an amino acid, a plant extract, an organic amine, a polymer emulsion, a cooling agent, a pH adjustor, a buffer, a perfume and water, may be appropriately added if needed to produce a desired formulation form according to a conventional method.
  • a powder component a liquid oil, a solid fat, a wax, a hydrocarbon oil, a higher fatty
  • Examples of a powder component include inorganic powders, such as talc, kaolin, mica, sericite, white mica, gold mica, a synthetic mica, red mica, black mica, vermiculite, magnesium carbonate, calcium carbonate, aluminum silicate, barium silicate, calcium silicate, magnesium silicate, strontium silicate, a metal tungstate, silica, zeolite, barium sulfate, calcined calcium sulfate (calcined gypsum) , calcium phosphate, fluorine apatite, hydroxyapatite, ceramic powder, metallic soap (e.g.
  • inorganic powders such as talc, kaolin, mica, sericite, white mica, gold mica, a synthetic mica, red mica, black mica, vermiculite, magnesium carbonate, calcium carbonate, aluminum silicate, barium silicate, calcium silicate, magnesium silicate, strontium silicate, a metal tungstate, silica, zeolite, barium
  • organic powders such as polyamide resin powder (nylon powder) , polyethylene powder, polymethyl methacrylate powder, polystyrene powder, styrene/acrylic acid copolymer resin powder, benzoguanamine resin powder, polytetrafluoroethylene powder and cellulose powder
  • metal powder pigments such as aluminum powder and copper powder
  • organic pigments such as a zirconium-, barium-, and aluminum-lakes
  • natural colors such as chlorophyll and ⁇ -carotene.
  • liquid oil examples include avocado oil, camellia oil, turtle oil, macadamia nut oil, corn oil, mink oil, olive oil, rapeseed oil, yolk oil, sesame oil, persic oil, wheat germ oil, camellia kissi oil, castor oil, linseed oil, safflower oil, cotton seed oil, perilla oil, soybean oil, peanut oil, tea seed oil, Torreya seed oil, rice bran oil, Chinese tung oil, Japanese tung oil, jojoba oil, germ oil, and triglycerin.
  • Examples of a solid fat include cacao butter, coconut oil, horse tallow, hardened coconut oil, palm oil, beef tallow, mutton tallow, hardened beef tallow, palm kernel oil, lard, cattle bone fat, Japan tallow kernel oil, hardened oil, neats-foot oil, Japan tallow, and hardened castor oil.
  • Examples of a wax include bees wax, candelilla wax, cotton wax, carnauba wax, bayberry wax, Chinese insect wax, spermaceti, montan wax, bran wax, lanolin, kapok wax, acetylated lanolin, liquid lanolin, sugar cane wax, lanolin fatty acid isopropyl ester, hexyl laurate, reduction lanolin, jojoba wax, hard lanolin, shellac wax, POE lanolin alcohol ether, POE lanolin alcohol acetate, POE cholesterol ether, lanolin fatty acid polyethylene glycol, and POE hydrogenated lanolin alcohol ether.
  • hydrocarbon oil examples include liquid paraffin, ozokerite, squalane, pristane, paraffin, ceresin, squalene, vaseline, microcrystalline wax, and hydrogenated polydecene.
  • Examples of a higher fatty acid include lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, undecylenic acid, tall oil acid, isostearic acid, linoleic acid, linolenic acid, eicosapentaenoic acid (EPA) , and docosahexaenoic acid (DHA) .
  • Examples of a higher alcohol include linear alcohols, such as lauryl alcohol, cetyl alcohol, stearyl alcohol, behenyl alcohol, myristyl alcohol, oleyl alcohol, and cetostearyl alcohol; branched alcohols, such as monostearyl glyceryl ether (batyl alcohol), 2-decyltetradecanol, lanolin alcohol, cholesterol, phytosterol, hexyldodecanol , isostearyl alcohol, and octyldodecanol .
  • linear alcohols such as lauryl alcohol, cetyl alcohol, stearyl alcohol, behenyl alcohol, myristyl alcohol, oleyl alcohol, and cetostearyl alcohol
  • branched alcohols such as monostearyl glyceryl ether (batyl alcohol), 2-decyltetradecanol, lanolin alcohol, cholesterol, phytosterol, hexyldodecanol , isosteary
  • Examples of a synthetic ester oil include tripropylene glycol dineopentanoate, isononyl isononanoate, isopropyl myristate, cetyl octanoate, octyldodecyl myristate, isopropyl palmitate, butyl stearate, hexyl laurate, myristyl myristate, decyl oleate, hexyldecyl dimethyloctanoate, cetyl lactate, myristyl lactate, acetylated lanolin, isocetyl stearate, isocetyl isostearate, cholesteryl 12-hydroxystearate, ethylene glycol di-2-ethylhexanoate, dipentaerythritol fatty acid ester, N-alkylglycol monoisostearate, neopentyl glycol dicaprylate, diisosteary
  • silicone oils examples include silicone oils, including linear polysiloxanes such as dimethylpolysiloxane, methylphenylpolysiloxane and diphenylpolysiloxane and cyclic polysiloxanes, such as octamethyl cyclotetrasiloxane, decamethyl cyclopentasiloxane and dodecamethyl cyclohexasiloxane ; silicone resins forming a 3D net structure; silicone elastomers; various modified polysiloxanes, such as amino-modified polysiloxane, polyether-modified polysiloxane, alkyl-modified polysiloxane and fluorine-modified polysiloxane.
  • linear polysiloxanes such as dimethylpolysiloxane, methylphenylpolysiloxane and diphenylpolysiloxane
  • cyclic polysiloxanes such as octa
  • silicone elastomers examples include non-emulsifying organopolysiloxane elastomers or emulsifying organosiloxane elastomers.
  • non-emulsifying organopolysiloxane elastomers examples include dimethicone/vinyl dimethicone crosspolymers, lauryl dimethicone/vinyl dimethicone crosspolymers, and the like.
  • the dimethicone/vinyl dimethicone crosspolymers include products commercially available from DOW CORNING under the trade name of, for example, DC 9040 and DC 9045; products commercially available from GENERAL ELECTRIC under the trade name of SFE 839 and the Velvasil series products; products commercially available from SHIN ETSU under the trade name of, for example, KSG-15, KSG-16, and KSG-18 ( [dimethicone/phenyl vinyl dimethicone crosspolymer] ) ; and Gransil (TM) series products from GRANT INDUSTRIES.
  • DOW CORNING under the trade name of, for example, DC 9040 and DC 9045
  • GENERAL ELECTRIC under the trade name of SFE 839 and the Velvasil series products
  • products commercially available from SHIN ETSU under the trade name of, for example, KSG-15, KSG-16, and KSG-18 ( [dimethicone/phenyl vinyl dimethicone crosspolymer] )
  • the lauryl dimethicone/vinyl dimethicone crosspolymers include products commercially available from SHIN ETSU under the trade name of, for example, KSG-31, KSG-32, KSG-41, KSG- 42, KSG-43, and KSG-44.
  • emulsifying organosiloxane elastomers examples include polyalkoxylated silicone elastomers, polyglycerolated silicone elastomers, or the like.
  • the polyalkoxylated silicone elastomers include products commercially available from DOW CORNING under the trade name of, for example, DC9010 and DC9011; products commercially available from SHIN ETSU under the trade name of, for example, KSG-20, KSG-21, KSG-30, KSG-31, KSG-32, KSG-33, KSG-210, KSG- 310 , KSG-320, KSG-330, KSG-340, and X-226146.
  • the polyglycerolated silicone elastomers include products commercially available from SHIN ETSU under the trade name of, for example, KSG-710, KSG-810, KSG-820, KSG- 830, KSG-840, KSG-31, KSG-32, KSG-41, KSG-42, KSG-43, and KSG-44.
  • a silicone resin-hydrolyzed protein can be also used.
  • a silicone resin-hydrolyzed protein examples include (hydrolyzed silk/PG-propyl methylsilanediol ) crosspolymer and ( trimethylsilyl hydrolyzed wheat protein/PG-propyl methylsilanediol ) crosspolymer .
  • a commercially available product may be used as a silicone resin-hydrolyzed protein. Examples of such a commercially available product include products of Seiwa Kasei Co., Ltd. under the trade names of PROTESIL FN, PROTESIL LH, and PROTESIL GLH .
  • Examples of a surfactant include a lipophilic nonionic surfactant and a hydrophilic nonionic surfactant.
  • a lipophilic nonionic surfactant examples include a sorbitan fatty acid ester, such as sorbitan monooleate, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, diglycerol sorbitan penta-2-ethylhexylate and diglycerol sorbitan tetra-2-ethylhexylate ; a glyceryl polyglyceryl fatty acid, such as glyceryl mono-cotton seed oil fatty acid, glyceryl monoerucate, glyceryl sesquioleate, glyceryl monostearate, glyceryl , '-oleate pyroglutamate, and glyceryl monostearate malate; a propylene glycol fatty acid ester such as monostearate propy
  • Examples of a nonionic surfactant oil include a POE- sorbitan fatty acid ester, such as POE-sorbitan monooleate, POE-sorbitan monostearate, POE-sorbitan monooleate and POE- sorbitan tetraoleate ; a POE sorbitol fatty acid ester, such as POE-sorbitol monolaurate, POE-sorbitol monooleate, POE- sorbitol pentaoleate, POE-sorbitol monostearate; a POE- glycerin fatty acid ester, such as POE-glycerin monooleate, POE-glycerin monostearate, POE-glycerin monoisostearate and POE-glycerin triisostearate ; a POE-fatty acid ester, such as POE-monooleate, POE-distearate, POE-monodioleate
  • a POE-POP-alkyl ether such as POE-POP-cetyl ether, POE-POP-2-decyltetradecyl ether, POE-POP-monobutyl ether, POE-POP-hydrogenated lanolin and POE-POP-glycerin ether.
  • co-surfactants examples include higher alcohols.
  • linear fatty alcohols such as lauryl alcohol, cetyl alcohol, stearyl alcohol, behenyl alcohol, myristyl alcohol, oleyl alcohol, cetostearyl alcohol, and the like, are preferable. Cetyl alcohol is further preferable.
  • Examples of a gelling agents include nonionic polymers, cationic polymers, as well as anionic polymers and amphoteric polymers with an anionic group, such as gum Arabic, carrageenan, karaya gum, Tragacanth gum, Pyrus cydonia seed (marmelo) , casein, gelatin, sodium pectate, sodium alginate, xanthan gum, pectin, fucoidan, galactomannan, curdlan, gellan gum, Fucogel ® (a fucose-rich polysaccharide) , collagen, sodium hyaluronate, Alcasealan ® (a polysaccharide produced by alcaligenes ) , propylene glycol alginate, and dialkyl dimethyl ammonium cellulose sulfate) .
  • anionic group such as gum Arabic, carrageenan, karaya gum, Tragacanth gum, Pyrus cydonia seed (marmelo) , casein, gelatin
  • Examples of a metal sequestering agent include 1- hydroxyethane-1 , 1-diphosphonic acid; 1-hydroxyethane-l , 1- diphosphonic acid tetrasodium salt; disodium edetate; trisodium edetate; tetrasodium edetate; sodium citrate; sodium polyphosphate; sodium metaphosphate ; gluconic acid; phosphoric acid; citric acid; ascorbic acid; succinic acid; edetic acid; and trisodium ethylenediamine hydroxyethyl triacetate .
  • Examples of a lower alcohol include ethanol, propanol, isopropanol, isobutyl alcohol, and t-butyl alcohol.
  • Examples of a polyhydric alcohol or a derivative thereof include a dihydric alcohol, such as ethylene glycol, propylene glycol, pentylene glycol, trimethylene glycol, 1,2- butylene glycol, 1,3-butylene glycol, tetramethylene glycol, 2 , 3-butyleneglycol , pentamethylene glycol, 2-butene-l , 4-diol , hexylene glycol and octylene glycol; a trihydric alcohol, such as glycerin and trimethylolpropane ; a tetrahydric alcohol such as pentaerythritol (e.g.
  • a pentahydric alcohol such as xylitol
  • a hexahydric alcohol such as sorbitol and mannitol
  • a polyhydric alcohol polymer such as diethylene glycol, dipropylene glycol, triethylene glycol, polypropylene glycol and tetraethylene glycol
  • a dihydric alcohol alkyl ether such as ethylene glycol monomethyl ether and ethylene glycol monoethyl ether
  • a dihydric alcohol alkyl ether such as diethylene glycol monomethyl ether, diethylene glycol monoethyl ether and diethylene glycol monobutyl ether
  • a dihydric alcohol ether ester such as ethylene glycol monomethyl ether acetate and ethylene glycol monoethyl ether acetate
  • a glyceryl monoalkyl ether such as chimyl alcohol, selachyl alcohol and batyl alcohol
  • Examples of a monosaccharide include a triose, such as D-glyceryl aldehyde and dihydroxyacetone; a tetrose, such as D-erythrose, D-erythrulose, D-threose and erythritol; a pentose, such as L-arabinose, D-xylose, L-lyxose, D-arabinose, D-ribose, D-ribulose, D-xylulose and L-xylulose; a hexose, such as D-glucose, D-talose, D-psicose, D-galactose, D- fructose, L-galactose, L-mannose and D-tagatose; a heptose, such as aldoheptose and heprose; an octose such as octurose; a deoxy sugar
  • Examples of an oligosaccharide include sucrose, lactose, maltose, trehalose, cellobiose, gentiobiose, umbilicin, raffinose, gentianose, maltotriose, melezitose, planteose, unbelliferose, stachyose, and verbascose.
  • Examples of an amino acid include a neutral amino acid, such as threonine and cysteine; and a basic amino acid such as hydroxylysine .
  • amino acid derivative such as sodium acyl sarcosinate (sodium lauroyl sarcosinate) , acyl glutamate, sodium acyl ⁇ -alanine, glutathione, and pyrrolidone carboxylic acid may be exemplified.
  • Examples of an organic amine include monoethanolamine, diethanolamine, triethanolamine, morpholine, triisopropanolamine, 2-amino-2-methyl-l , 3-propanediol, and 2- amino-2-methyl-l-propanol .
  • Examples of a polymer emulsion include an acrylic resin emulsion, a poly (ethyl acrylate) emulsion, an acrylic resin solution, a poly(alkyl acrylate) emulsion, a poly(vinyl acetate) emulsion, and a natural rubber latex.
  • composition for external use according to the present invention may further contain various active agents such as vitamins, antioxidants, moisturizing agents, blood flow promoters, antibacterial agents, cell (skin) activating agents, emollients, anti-aging agents, anti-pollution agents, keratolytic agents, astringents, anti-inflammatory agents, whitening agents, and sunscreens.
  • active agents such as vitamins, antioxidants, moisturizing agents, blood flow promoters, antibacterial agents, cell (skin) activating agents, emollients, anti-aging agents, anti-pollution agents, keratolytic agents, astringents, anti-inflammatory agents, whitening agents, and sunscreens.
  • Examples of a vitamin include vitamins A, Bi , B 2 , B 6 , C and E and derivatives thereof, pantothenic acid and derivatives thereof and biotin.
  • antioxidants include ascorbic acid and its derivatives such as ascorbyl palmitate, ascorbyl tetraisopalmitate, ascorbyl glucoside, magnesium ascorbyl phosphate, sodium ascorbyl phosphate and ascorbyl sorbate; tocopherol and its derivatives, such as tocopheryl acetate, tocopheryl sorbate, and other esters of tocopherol; dibutyl hydroxytoluene (BHT) and butylated hydroxyanisole (BHA) ; gallic acid ester; phosphoric acid; citric acid; maleic acid; malonic acid; succinic acid; fumaric acid; cephalin; a hexametaphosphate ; phytic acid; ethylenediaminetetraacetic acid; and plant extracts, for instance from
  • moisturizing agent examples include polyethylene glycol; propylene glycol; dipropylene glycol; glycerin; 1,3- butylene glycol; xylitol; sorbitol; maltitol; mucopolysaccharides, such as chondroitin sulfuric acid; hyaluronic acid; sodium hyaluronate, sodium acetylated hyaluronate, mucoitinsulfuric acid; caronic acid; atelo- collagen; cholesteryl-12-hydroxystearate; bile salt; a main component of NMF (natural moisturizing factor) , such as a pyrrolidone carboxylic acid salt, and a lactic acid salt; amino acids such as urea, cysteine and serine; short-chain soluble collagen; a diglycerin (EO) PO addition product; homo- and copolymers of 2- methacryloyloxyethylphosphorylcholine commercially available from NOF under the name of,
  • emollients examples include glyceryl polymethacrylate, methyl gluceth-20, and the like.
  • anti-aging agents examples include acyl amino acids (specifically, products commercially available from SEDERMA under the trade name of Maxilip, Matrixyl 3000 or Biopeptide CL, or product commercially available from SEPPIC under the trade name of Sepilift); Pisum sativum extracts; hydrolyzed soy proteins; methylsilanol mannuronate; hydrolyzed cucurbita pepo seedcake; Scenedesmus extract; and the like.
  • acyl amino acids specifically, products commercially available from SEDERMA under the trade name of Maxilip, Matrixyl 3000 or Biopeptide CL, or product commercially available from SEPPIC under the trade name of Sepilift
  • Pisum sativum extracts hydrolyzed soy proteins
  • methylsilanol mannuronate hydrolyzed cucurbita pepo seedcake
  • Scenedesmus extract and the like.
  • anti-pollution agents examples include Moringa pterygosperma seed extracts (specifically, product commercially available from LSN under the trade name of Purisoft); Shea butter extract (specifically, products commercially available from SILAB under the trade name of Detoxyl, a blend of ivy extract, phytic acid, sunflower seed extract (for example, product commercially available from SEDERMA under the trade name of OSMOPUR) , and the like.
  • keratolytic agents examples include CC-hydroxy acids (specifically, glycolic, lactic, citric, malic, mandelic or tartaric acid) and ⁇ -hydroxy acids (specifically, salicylic acid), and their esters (specifically, C12-13 alkyl lactate), plant extracts containing these hydroxy acids (specifically, Hibiscus sabdriffa extracts), and the like.
  • astringents examples include hamamelis extracts, and the like.
  • anti-inflammatory agents examples include bisabolol, allantoin, tranexamic acid, zinc oxide, sulfur oxide and its derivatives, chondroitin sulfate, glycyrrhizinic acid and its derivatives (for example, glycyrrhizinates ) .
  • the composition for external use according to the present invention may contain at least one whitening agent to block the synthesis of structural proteins such as the melanocyte-specific glycoprotein Pmell7 involved in the mechanism of melanogenesis (stage I) .
  • a whitening agent may include the ferulic acid-containing cytovector (water, glycol, lecithin, ferulic acid, hydroxyethylcellulose ) commercially available from BASF under the trade name Cytovector (TM) .
  • composition for external use according to the present invention may contain at least one peptide as described in the patent application WO2009/010356.
  • the composition for external use according to the present invention may include a whitening agent having an inhibition effect on melanin synthesis and/or an inhibition effect on nanophthalmia- related transcription factor (MITF) expression and/or an anti-tyrosinase activity and/or an inhibition effect on endothelin-1 synthesis.
  • a whitening agent may include Glycyrrhiza glabra extract commercially available from Maruzen Pharmaceuticals under the trade name Licorice extract (TM) .
  • the composition for external use according to the present invention may include whitening agents having an antioxidant effect as well, such as vitamin C compounds, which include ascorbate salts, ascorbyl esters of fatty acids or of sorbic acid, and other ascorbic acid derivatives.
  • vitamin C compounds which include ascorbate salts, ascorbyl esters of fatty acids or of sorbic acid, and other ascorbic acid derivatives.
  • specific examples include ascorbyl phosphates (magnesium ascorbyl phosphate, sodium ascorbyl phosphate, and the like) , saccharide esters of ascorbic acid (ascorbyl-2- glucoside, 2-O-CC-D-glucopyranosyl L-ascorbate, or ⁇ - ⁇ - ⁇ -D- galactopyranosyl L-ascorbate, and the like) .
  • Active agents of this type are commercially available from DKSH under the trade name of Ascorbyl glucoside (TM) .
  • the composition for external use according to the present invention may include other whitening agents.
  • the other whitening agents include pigmentation inhibiting agents such as plant extracts (Narcissus tazetta extracts), arbutin, kojic acid, ellagic acid, cysteine, 4-thioresorcin, resorcinol or rucinol or their derivatives, glycyrrhizinic acid, hydroquinone- ⁇ - glucoside, and the like.
  • composition for external use according to the present invention may also include organic and/or inorganic sunscreens.
  • organic sunscreens may include dibenzoylmethane derivatives such as butyl methoxydibenzoylmethane (product commercially available from HOFFMANN LA ROCHE under the trade name of Parsol 1789); cinnamic acid derivatives such as ethylhexyl methoxycinnamate (product commercially available from HOFFMANN LA ROCHE under the trade name of Parsol MCX) , salicylates, para-aminobenzoic acids; ⁇ - ⁇ ' -diphenylacrylate derivatives; benzophenone derivatives; benzylidenecamphor derivatives such as terephtalylidene dicamphor sulphonic acid; phenylbenzimidazole derivatives; triazine derivatives; phenylbenzotriazole derivatives; anthranilic derivatives, and the like, all of which may be coated or encapsulated.
  • dibenzoylmethane derivatives such as butyl me
  • examples of the inorganic sunscreens may include nanopigments formed from coated or uncoated metal oxides, such as, for example, titanium oxide, iron oxide, zinc oxide, zirconium oxide or cerium oxide nanopigments; which are all UV photoprotective agents well known per se.
  • composition for external use of the present invention is arbitrarily selectable, and any of a solution type, an emulsion type, a and a gel type can be adapted.
  • the tranexamate crystals may be isolated from this composition and introduced in another composition for external use, which can be a liquid or semi-liquid or solid composition of any type, including solutions, emulsions, gels, but also powders optionally including a water and/or oil phase therein.
  • compositions for external use is also arbitrarily selectable, and the composition is applicable to facial cosmetics, such as a facial cleanser, a face lotion, an essence liquid, a milky lotion, a cream and a pack; makeup cosmetics, such as a foundation, a lipstick and an eye shadow; body makeup products; hair care cosmetics; oral care toiletries; perfumeries; cleansers; and ointments.
  • facial cosmetics such as a facial cleanser, a face lotion, an essence liquid, a milky lotion, a cream and a pack
  • makeup cosmetics such as a foundation, a lipstick and an eye shadow
  • body makeup products such as a foundation, a lipstick and an eye shadow
  • body makeup products such as a foundation, a lipstick and an eye shadow
  • body makeup products such as a foundation, a lipstick and an eye shadow
  • body makeup products such as a foundation, a lipstick and an eye shadow
  • body makeup products such as a foundation, a lipstick and an eye shadow
  • body makeup products such as a foundation,
  • compositions for external use according to the compositions of Table 1 were prepared as follows.
  • the components 1 to 3 were dissolved under heated and stirring at 85 ⁇ 5°C, and the composition was kept at 85 ⁇ 5°C with stirring, to which the components B heated to 70 ⁇ 5°C were added gradually.
  • the resulting composition was cooled down to room temperature (25 ⁇ 5°C) under stirring, which pH was then adjusted to 5.0 ⁇ 0.5 by the component 5 or 6.
  • NIKKOL TXC (trade name) of Nikko Chemicals Co. Ltd. was used.
  • compositions according to Table 2 were used, compositions for external use were prepared identically to Examples 1 to 6. Table 2
  • NIKKOL TXC (trade name) of Nikko Chemicals Co. Ltd. was used.
  • cetyl tranexamate hydrochloride salts in the compositions for external use according to Examples 1 to 6 were obtained in the state of a uniform fine particle suspension with white turbid appearance.
  • crystals of cetyl tranexamate hydrochloride salts were present as precipitated aggregates.
  • compositions for external use having the compositions shown in Table 5 were prepared as follows.
  • compositions for external use according to Examples 7 to 16 were obtained in the state of a uniform fine particle dispersion with white turbid appearance Especially in case locust bean gum, guar gum, tara gum, hydroxyethyl cellulose, or hydroxypropyl methyl cellulose stearoyl ester was used as a water-soluble polymer, excellent stability was recognized even at a temperature as high as 45°C.
  • compositions for external use (a W/O-type essence liquid) according to the compositions of Table 7 were prepared as follows.
  • the water phase components 1 to 9 and the oil phase components 10 to 19 were dissolved respectively under heating and stirring at 85 ⁇ 5°C, and the oil phase components were added with stirring to the water phase components kept at 80
  • NIKKOL TXC (trade name) of Nikko Chemicals Co. Ltd. was used.
  • compositions according to Table 8 were used, compositions for external use were prepared identically to Examples 17 to 24. Table 8
  • NIKKOL TXC (trade name) of Nikko Chemicals Co. Ltd. was used.
  • the compositions for external use according to Examples 17 to 24 were obtained in the state of a uniform dispersion with white turbid appearance. Especially in case a combination of sodium citrate and another salting-out agent was used, improved stability was recognized. In contrast, in cases of Comparative Examples 4 to 7, separation or aggregation was recognized, and the uniform dispersion state could not be maintained. Especially, in case the component A was added at 1.0% by weight or more, layer or water separation occurred within a day of the preparation of a composition for external use, and a composition in a uniform dispersion state for external use could not be afforded.
  • compositions for external use were prepared as follows according to the compositions set forth in Table 10 (an O/W- type milky lotion) .
  • Sodium citrate (Component 11) was added to the water phase mixture 1 kept at 85 ⁇ 5°C with stirring (a water phase mixture 2) .
  • the water phase mixture 2 was in a transparent state by visual observation.
  • Weight loss on drying 1.0% or less (105°C, 2 hours)
  • composition Polianthes tuberosa polysaccharide 1%, ethanol and water
  • the obtained milky lotions were homogeneous immediately after the preparations.
  • the homogeneous conditions could be maintained over 2-month storage at 45°C with respect to all the obtained milky lotions.
  • compositions for external use were prepared as follows according to the compositions set forth in Table 11 (a W/O- type cream) .
  • NIKKOL TXC (trade name) of Nikko Chemicals Co. Ltd. used .
  • the obtained creams were homogeneous immediately after the preparations.
  • the homogeneous conditions could be maintained over 2-month storage at 45°C with respect to all the obtained creams.
  • composition for external use of the present invention enjoys suppressed sticky or oily feeling, and therefore is, as a composition for external use providing comfortable feel of use, favorably applicable to drugs, quasi drugs and cosmetics.
  • the composition for external use of the present invention can be utilized in various formulation and product forms.

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Abstract

La présente invention concerne un procédé de production d'une composition à usage externe contenant un sel physiologiquement acceptable d'un tranexamate comme principe actif, lequel est dispersé dans la composition à l'état de particules fines. De ce fait, un sel physiologiquement acceptable du tranexamate est dissous dans un solvant pour préparer une solution, à laquelle un agent relargant est ajouté pour précipiter le sel. Ledit sel est dispersé dans une composition à usage externe à l'état de particules fines de telle façon que le sel de tranexamate puisse être mélangé sans utiliser une grande quantité d'huile pour obtenir une composition à usage externe offrant une excellente sensation à l'utilisation et une grande stabilité.
PCT/EP2010/068852 2009-12-11 2010-12-03 Composition à usage externe et procédé de production associé WO2011069915A1 (fr)

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JP5613546B2 (ja) 2014-10-22
US20140105949A1 (en) 2014-04-17
US8647650B2 (en) 2014-02-11
KR20120114279A (ko) 2012-10-16
JP2011140487A (ja) 2011-07-21
US8758785B2 (en) 2014-06-24
CN102686206A (zh) 2012-09-19
EP2509559B1 (fr) 2016-06-22
US20120244204A1 (en) 2012-09-27

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